therapeutic compounds useful for the prophylactic or therapeutic treatment of an HIV infection and t

专利摘要:
The present invention relates to a compound of the formula (Ia), (Ib), (IIa) and (IIb): (Ia), (Ib), (IIa), (IIb) which are useful in the treatment of an infection Retroviridae virus infection including an infection caused by the HIV virus.
公开号:BR112018071678B1
申请号:R112018071678-2
申请日:2017-08-17
公开日:2021-01-26
发明作者:Michael Graupe；Steven J. Henry；John O. Link；Charles William Rowe；Roland D. Saito；Scott D. Schroeder；Dimitrios Stefanidis；Winston C. Tse；Jennifer R. Zhang
申请人:Gilead Sciences, Inc.；
IPC主号:

专利说明:

CROSS REFERENCE TO RELATED REQUESTS
[0001] This claim claims priority benefit for US Provisional Order No. Serial 62 / 377,312, filed on August 19, 2016 and for US Provisional Order No. Serial 62 / 457,555, filed on February 10, 2017, the descriptions of which are incorporated by reference in their entirety. FIELD
[0002] The present description relates to new compounds for use in the treatment of a viral infection by Retroviridae including an infection caused by the HIV virus. The present description also relates to intermediates for its preparation and to pharmaceutical compositions containing said new compound. BACKGROUND
[0003] Positive single-stranded RNA viruses comprising the Retroviridae family include those from the subfamily Orthoretrovirinae and the genera Alpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Epsilontretrovirus, Lentivirus, and Spumavirus that cause many human and animal diseases. Among lentiviruses, HIV-1 infection in humans leads to depletion of helper T cells and immune dysfunction, producing immunodeficiency and vulnerability to opportunistic infections. Treatment of HIV-1 infections with highly active antiretroviral therapies (HAART) has been shown to be effective in reducing viral load and significantly delaying disease progression (Hammer, S.M., et al .; JAMA 2008, 300: 555-570). However, these treatments can lead to the emergence of strains of HIV resistant to current therapies (Taiwo, B., International Journal of Infectious Diseases 2009, 13: 552-559; Smith, RJ, et al., Science 2010, 327 : 697701). Therefore, there is an urgent need to discover new antiretroviral agents that are active against emerging drug-resistant HIV variants.
[0004] US Patent Publication No. 2014 / 0296266A1, published on October 2, 2014, describes compounds useful for the treatment of a viral infection by Retroviridae including an infection caused by the HIV virus. US Patent Publication 2014/0296266 A1 refers, among other things, to compounds of Formula I:
where: A is a 6-membered monocyclic heteroaryl with one or two nitrogen atoms, where the 6-membered monocyclic heteroaryl is replaced with a Z1 group in the position shown, a Z2 group, and optionally substituted with one or more (for example, 1 or 2) Z3 groups; R1 is 6-12 membered aryl, 5-12 membered heteroaryl or 3-12 membered heterocycle, where any 6-12 membered aryl, 5-12 membered heteroaryl or 3-12 membered heterocycle is optionally substituted with one or more (for example, 1, 2, 3, 4 or 5) Z4 groups; R2 is phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl or (C3-Co) carbocycle, wherein any phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl or R2 (C3-C7) carbocycle is optionally substituted with one or more (for example, 1,2, 3, 4 or 5) Z5 groups; each R3a and R3b is independently selected from H, halogen, (Ci-C /) alkyl and (Ci-C3) haloalkyl, or R3a is selected from H, (Ci-C3) alkyl and (Ci-C3) haloalkyl and R3b is selected from -OH and -CN; Z1 is selected from 6-12 membered aryl, 5-14 membered heteroaryl and 3-14 membered heterocycle, where any 6-12 membered aryl, 5-14 membered heteroaryl and 3- 3- membered heterocycle 14 members of Z1 is optionally substituted with one or more (for example, 1,2, 3, 4 or 5) Z1a or Z1b; each Z1a is independently selected from (C3-Co) carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, -CN, -ORn1, -OC (O) Rp1 , -OC (O) NRq1Rr1, -SRn1, -S (O) Rp1, -S (O) 2OH, -S (O) 2Rp1, -S (O) 2NRq1Rr1, - NRq1Rr1, -NRn1CORp1, -NRn1CO2Rp1, -NRn1CON1 , -NRn1S (O) 2Rp1, -NRn1S (O) 2ORp1, -NRn1S (O) 2NRq1Rr1, NO2, -C (O) Rn1, -C (O) ORn1, - C (O) NRq1Rr1 and -S (O) 2NRn1CORp1, in which any (C3-C7) carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl and 3-12 membered heterocycle of Z1a is optionally substituted with one or more (for example, 1,2, 3 , 4 or 5) groups Z1c or Z1d; each Z1b is independently selected from (C1-C8) alkyl, (C2-Ci) alkenyl and (C2-Ci) alkynyl, where any (C1-C8) alkyl, (C2-Ci) alkenyl and (C2-Ci) ) Z1b alkynyl is optionally substituted with one or more (for example, 1, 2, 3, 4 or 5) Z1c groups; each Z1c is independently selected from (C3-C7) carbocycle, phenyl, 5-6 membered monocyclic heteroaryl, 3-7 membered heterocycle, halogen, -CN, -ORn2, -OC (O) Rp2, -OC ( O) NRq2Rr2, - SRn2, -S (O) Rp2, -S (O) 2OH, -S (O) 2Rp2, -S (O) 2NRq2Rr2, -NRq2Rr2, -NRn2 CORp2, -NRn2CO2Rp2, -NRn2CONRq2R2, -NRn2C2R-2R2, 2 (O) 2Rp2, -NRn2S (O) 2 ORp2, -NRn2S (O2NRq2Rr2, NO2, -C (O) Rn2, -C (O) ORn2, -C (O) NRq2Rr2, halophenyl, halo-heteroaryl 5-6 members, 3-7 membered halo-heterocycle and (C1-Cs) heteroalkyl; each Z1d is independently selected from (C1-Cs) alkyl, (C2-Cs) alkenyl, (C2-Cs) alkynyl and (Ci- Cs) haloalkyl; each Rn1 is independently selected from H, (C1-Cs) alkyl, (C2-Cs) alkenyl, (C2-Cs) alkynyl, (C3-Co) carbocycle, 3-7 membered heterocycle , 5-6 membered monocyclic heteroaryl and phenyl, where any (C3-C7) carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic heteroaryl and Rn1 phenyl is optionally substituted with one or more (for example o, 1, 2, 3, 4 or 5) groups Z1c or Z1d, and in which any (C1-Cs) alkyl, (C2-Cs) alkenyl and (C2-Cs) alkynyl of Rn1 is optionally substituted with one or more (for example, 1,2, 3, 4 or 5) Z1c groups; each Rp1 is independently selected from (C1-Cs) alkyl, (C2-Cs) alkenyl, (C2-Cs) alkynyl, (C3-Co) carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic heteroaryl and phenyl, in which any (C3-C7) carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic heteroaryl and Rp1 phenyl is optionally substituted with one or more (for example, 1, 2, 3, 4 or 5) Z1c or Z1d groups, and where any (C1-Cs) alkyl, (C2-Cs) alkenyl and (C2-Cs) alkynyl of Rp1 is optionally substituted with one or more (for example, 1,2, 3, 4 or 5) Z1c groups; Rq1 and Rr1 are each independently selected from H, (C1-Cs) alkyl, (C2-Cs) alkenyl, (C2-Cs) alkynyl, (C3-C7) carbocycle, 3-7 membered heterocycle, monocyclic heteroaryl 5-6 membered and phenyl, where any (C3-C7) carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic heteroaryl and Rq1 or Rr1 phenyl is optionally substituted with one or more (for example, 1 , 2, 3, 4 or 5) groups Z1c or Z1d, and in which any (C1-Cs) alkyl, (C2-Cs) alkenyl and (C2-Cs) alkynyl of Rq1 or Rr1 is optionally substituted with one or more ( for example, 1, 2, 3, 4 or 5) groups Z1c, or Rq1 and Rr1 together with the nitrogen to which they are attached form a 5, 6 or 7 membered heterocycle, in which the 5, 6 heterocycle or 7 members is optionally substituted with one or more (for example, 1, 2, 3, 4 or 5) groups Z1c or Z1d; each Rn2 is independently selected from H, (C1-Cs) alkyl, (C2-Cs) alkenyl, (C2-Cs) alkynyl, (C / -C7) carbocycle, 3-7 membered heterocycle, monocyclic heteroaryl 5-6 membered, phenyl, halophenyl, 5-6 membered monocyclic haloheteroaryl, 3-7 membered haloheterocycle, (C1-Cs) haloalkyl and (C1-Cs) heteroalkyl; each Rp2 is independently selected from (C1-Cs) alkyl, (C2-Cs) alkenyl, (C2-Cs) alkynyl, (C3-Co) carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic heteroaryl , phenyl, halophenyl, 5-6 membered monocyclic haloheteroaryl, 3-7 membered haloheterocycle, (C1-Cs) haloalkyl and (C1-Cs) heteroalkyl; Rq2 and Rr2 are each independently selected from H, (C1-Cs) alkyl, (C2-Cs) alkenyl, (C2-Cs) alkynyl, (C3-C7) carbocycle, 3-7 membered heterocycle, monocyclic heteroaryl 5-6 membered phenyl, halophenyl, 5-6 membered monocyclic haloheteroaryl, 3-7 membered haloheterocycle, (C1-Cs) haloalkyl and (C1-C8) heteroalkyl, or Rq2 and Rr2 together with nitrogen to which they are attached form a 5-, 6- or 7-membered heterocycle; Z2 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) Rn3 and -C (O) NRq3Rr3, in which any 6-12 membered aryl, 5-12 membered C-linked heteroaryl and 3-12 membered C-linked heterocycle of Z2 is optionally substituted with one or more (for example, 1, 2, 3, 4 or 5) groups Z2b or Z2c, and where any (C2-C8) alkenyl and (C2-C8) alkynyl of Z2 is optionally substituted with one or more (for example, 1,2, 3, 4, or 5) Z2c groups; each Z2a is independently selected from (C3-C ) carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, -CN, -ORn4, -OC (O) Rp4, -OC (O) NRq4Rr4, -SRn4, -S (O) Rp4, -S (O) 2OH, -S (O) 2Rp4, -S (O) 2NRq4Rr4, - NRq4Rr4, -NRn4CORp4, -NRn4CO2Rp4, - NRn4CONRq4Rr4, -NRn4S (O) 2Rp4, -NRn4S (O) 2ORp4, -NRn4S (O) 2NRq4Rr4, NO2, -C (O) Rn4, -C (O) ORn4 and - C (O) NRq4Rr4, where any ( C3-C ) Carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl and 3-12 membered heterocycle of Z2a is optionally substituted with one or more (for example, 1, 2, 3, 4 or 5) Z2b or Z2c groups; each Z2b is independently selected from (C1-C4) alkyl, (C1-C4) heteroalkyl and (C1-C4) haloalkyl; each Z2c is independently selected from halogen, -CN, -ORn4, -OC (O) Rp4, -OC (O) NRq4Rr4, -SRn4, -S (O) Rp4, -S (O) 2OH, - S (O) 2RP4, -S (O) 2NRq4Rr4, -NRq4Rr4, -NRn4CORp4, -NRn4 CO2 Rp4, -NRn4CONRq4Rr4, -NRn4S (O) 2Rp4, -NRn4S (O) 2ORp4, -NrN4 (ON2N4) , -C (O) Rn4, -C (O) ORn4 and -C (O) NRq4Rr4; each Rn3 is independently selected from H, (C1-C4) alkyl, (C2-C4) alkenyl, (C3-C ) carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryl and 6- 12-membered, where any (C3-C ) Carbocycle, 3-12-membered heterocycle, 5-12-membered heteroaryl and 6-12-membered Rn3 aryl is optionally substituted with one or more (for example, 1 , 2, 3, 4 or 5) groups Z2b or Z2c, and in which any (C1-C4) alkyl, (C2-C4) alkenyl and (C2-C4) alkynyl of Rn3 is optionally substituted with one or more (for example , 1,2, 3, 4 or 5) Z2a groups; Rq3 and Rr3 are each independently selected from H, (C1-C4) alkyl, (C2-C4) alkenyl, (C3-C ) Carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryl and 6-12 member aryl, where any (C3-C7) carbocycle, 3-12 member heterocycle, 5-12 member heteroaryl and 6-12 member aryl of Rq3 or Rr3 is optionally substituted with one or more ( for example, 1, 2, 3, 4 or 5) groups Z2b or Z2c, and where any (C1-C4) alkyl and (C.-C4) alkenyl of Rq3 or Rr3 is optionally substituted with one or more (for example , 1, 2, 3, 4 or 5) groups Z2a, or Rq3 and Rr3 together with the nitrogen to which they are attached form a heterocycle or heteroaryl, where the heterocycle or heteroaryl is optionally substituted with one or more (for example, 1, 2, 3, 4 or 5) groups Z2b or Z2c; each Rn4 is independently selected from H, (C1-C4) alkyl, (C2-Cs) alkenyl, (C2-Cs) alkynyl, (C1-C4) haloalkyl and (C1-C4) heteroalkyl; each Rp4 is independently selected from (C1-Cs) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C4) haloalkyl and (C1-C4) heteroalkyl; Rq4 and Rr4 are each independently selected from H, (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C4) haloalkyl and (C1-C4) heteroalkyl; each Z3 is independently selected from halogen, (C1-C4) alkyl, -OH, -CN, (C1-C4) heteroalkyl and (C1-C4) haloalkyl; each Z4 is independently selected from (C1-Cs) alkyl, (C2-Cs) alkenyl, (C2-Cs) alkynyl, (C3-Co) carbocycle, halogen, -CN, -ORn5, -OC (O ) RP5, -OC (O) NRq5Rr5, -SRn5, -S (O) RP5, -S (O) 2OH, -S (O) 2Rp5, -S (O) 2NRq5Rr5, -NRq5Rr5, -NRn5CORp5, -NRn5CO2 Rp5 , -NRn5CONRq5Rr5, -NRn5S (O) 2Rp5, -NRn5S (O) 2ORp5, -NRn5S (O) 2 NRq5Rr5, NO2, -C (O) Rn5, -C (O) ORn5 and -C (O) NRq5Rr5, in that any (C3-C7) carbocycle, of Z4 is optionally substituted with one or more (for example, 1, 2, 3, 4 or 5) groups Z4a or Z4b, and where any (C-Cs) alkyl, (C2 -C8) alkenyl and (C.-CiGalquinyl of Z4 is optionally substituted with one or more (for example, 1, 2, 3, 4 or 5) groups Z4a H each Z4a is independently selected from halogen, -CN , -ORn6, -OC (O) Rp6, -OC (O) NRq6Rr6, -SRn6, -S (O) Rp6, - S (O) 2OH, -S (O) 2Rp6, -S (O) 2NRq6Rr6, - NRq6Rr6, -NRn6CORp6, - NRn6CO2Rp6, -NRn6CONRq6Rr6, -NRn6S (O) 2Rp6, -NRn6S (O) 2ORp6, - NRn6S (O) 2NRq6Rr6, NO2, -C (O) Rn6, -C (O) Rn6, -C (O) Rn6 (O) NRq6Rr6; each Z4b is independently selected from (C1-C4) alkyl, (C2-C4) alkenyl (C2-C4) alkynyl and (C1-C4) haloalkyl; each Rn5 is independently selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkynyl and (C2-C4) alkynyl; each Rp5 is independently selected from (C1-C4) Zalkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkynyl and (C2-C4) alkynyl; Rq5 and Rr5 are each independently selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkenyl and (C2-C4) alkynyl; each Rn6 is independently selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkynyl and (C2-C4) alkynyl; each Rp6 is independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkynyl and (C2-C4) alkynyl; Rq— and Rr- are each independently selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkenyl and (C2-C4) alkynyl; each Z5 is independently selected from (Ci-Ce) alkyl, halogen, -CN and -ORn0, where any (Ci-Cs) alkyl of Z5 is optionally substituted with one or more (for example, 1,2, 3 , 4 or 5) halogen; and each Rn7 is independently selected from H, (Ci-C /) alkyl, (Ci-C /) haloalkyl and (C3-Co) carbocycle; or a pharmaceutically acceptable salt thereof.
[0005] US Patent Publication No. 2014 / 0303164A1, published on October 9, 2014, describes compounds useful for the treatment of a viral infection by Retroviridae including an infection caused by the HIV virus. US Patent Publication 2014/0303164 A1 refers, among other things, to compounds of Formula IIId:
where A1 is CH, C-Z3 or nitrogen; A2 is CH or nitrogen; R1 is 6-12 membered aryl, 5-12 membered heteroaryl, or 3-12 membered heterocycle, where any 6-12 membered aryl, 5-12 membered heteroaryl, or R12 3-12 membered heterocycle it is optionally substituted with 1, 2, 3, 4 or 5 groups Z4, where the groups Z4 are the same or different; each R3a and R3b is independently H or (C1-C3) alkyl; Z1 is 6-12 membered aryl, 5-14 membered heteroaryl, or 3-14 membered heterocycle, where any 6-12 membered aryl, 5-14 membered heteroaryl, or Z1 3-14 membered heterocycle it is optionally substituted with 1, 2, 3, 4 or 5 Z1a or Z1b, where the groups Z1a and Z1b are the same or different; each Z1a is independently (C3-Co) carbocycle, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, -CN, -ORn1, -OC (O) Rp1, -OC (O) NRq1Rr1, - SRn1, -S (O) Rp1, -S (O) 2OH, -S (O) 2 Rp1, -S (O) .NRq1Rr1, -NRq1Rr1, -NRn1CORp1, -NRn1CO.Rp1, -NRn1CON Rq1Rr1, -NRn1 (-NRn1CON O) .Rp1, -NRn1S (O) .ORp1, -NRn1S (O) .NRq1Rr1, -C (O) Rn1, -C (O) ORn1, -C (O) NRq1Rr1 and -S (O) .NRn1CORp1, wherein any (C3-C ) carbocycle, 5-12 membered heteroaryl and 3-12 membered heterocycle of Z1a is optionally substituted with 1, 2, 3, 4 or 5 groups Z1c or Z1d, where groups Z1c and Z1d are the same or different; each Z1b is independently (C1-Cs) alkyl optionally substituted with 1, 2, 3, 4 or 5 halogen, which are the same or different; each Z1c is independently halogen, -CN, -OH, -NH2, - C (O) NRq2Rr2, or (C1-C8) heteroalkyl; each Z1d is independently (C1-C1) alkyl or (C1-C8) haloalkyl; each Rn1 is independently H, (C1-Ci) alkyl, (C3-C7) carbocycle, 3-0 membered heterocycle, or 5-6 membered monocyclic heteroaryl, where any (C3-Co) carbocycle, 3- membered heterocycle 7-member, or 5-6 membered monocyclic heteroaryl of Rn1 is optionally substituted with 1, 2, 3, 4 or 5 groups Z1c or Z1d, where the groups Z1c and Z1d are the same or different, and where any (C1 -Ci) Rn1 alkyl is optionally substituted with 1, 2, 3, 4 or 5 groups Z1c, where the groups Z1c are the same or different; each Rp1 is independently (C1-Ci) alkyl, (C3-Co) carbocycle, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, where any (C3-C7) carbocycle, 3- membered heterocycle 7 members, or 5-6 membered monocyclic heteroaryl of Rp1 is optionally substituted with 1, 2, 3, 4 or 5 Z1c or Z1d groups, where the Z1c and Z1d groups are the same or different, and any (Ci -Cs) alkyl of Rp1 is optionally substituted with 1, 2, 3, 4 or 5 groups Z1c, where the groups Z1c are the same or different; each Rq1 and Rr1 is independently H, (C1-Cs) alkyl, (C3-C ) carbocycle, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, where any (C3-Co) carbocycle, heterocycle 3-7 membered, or 5-6 membered monocyclic heteroaryl of Rq1 or Rr1 is optionally substituted with 1, 2, 3, 4 or 5 groups Z1c or Z1d, where the groups Z1c and Z1d are the same or different, and where any (C1-Cs) alkyl of Rq1 or Rr1 is optionally substituted with 1, 2, 3, 4 or 5 groups Z1c, where the groups Z1c are the same or different, or Rq1 and Rr1 together with the nitrogen to which they are linked to form a 5, 6 or 7 membered heterocycle, where the 5, 6 or 7 membered heterocycle is optionally substituted with 1, 2, 3, 4 or 5 groups Z1c or Z1d, where the groups Z1c and Z1d are the same or different; each Rq2 and Rr2 is independently H, (C1-Cs) alkyl, (C3-C7) Zcarbocycle, or Rq2 and Rr2 together with the nitrogen to which they are attached form a 5, 6, or 7 membered heterocycle; Z2 is (C2-Cs) alkenyl, (C2-Cs) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, -C (O) Rn3, or -C (O) NRq3Rr3, where any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle of Z2 is optionally substituted with 1, 2, 3, 4 or 5 groups Z2b or Z2c, where the groups Z2b and Z2c are the same or different, and where any (C2-Cs) alkenyl or (C2-Cs) alkynyl of Z2 is optionally substituted with 1, 2, 3, 4, or 5 Z2c groups, where the Z2c groups are the same or different; each Rn3 is independently H or (C1-C4) alkyl; each Rq3 and Rr3 is independently H or (C1-C4) alkyl; each Z2b is independently oxo, (C1-C4) alkyl, (C1-C4) heteroalkyl or (C1-C4) haloalkyl; each Z2c is independently oxo, halogen, -CN, -ORn4, -OC (O) Rp4, -OC (O) NRq4Rr4, -SRn4, -S (O) Rp4, -S (O) 2OH, -S (O) 2Rp4, - S (O) 2NRq4Rr4, -NRq4Rr4, -NRn4CORp4, -NRn4CO.Rp4, -NRn4CONRq4Rr4, - NRn4S (O) 2Rp4, -NRn4S (O) 2ORp4, -NRn44 (O) 2N O) Rn4, - C (O) ORn4, or -C (O) NRq4Rr4; each Rn4 is independently H, (C1-C4) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl; each Rp4 is independently (C1-Cs) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl; each Rq4 and Rr4 is independently H, (C1-C4) alkyl, (C1- C4) haloalkyl, or (C1-C4) heteroalkyl; each Z3 is independently (C1-C4) heteroalkyl; each Z4 is independently oxo, (C1-Cs) alkyl, (C3-C7) carbocycle, halogen, -CN, -ORn5, -NRq5Rr5, -NRn5CORp5, -NRn5CO2 RP5, -C (O) Rn5, -C (O) ORn5, or -C (O) NRq5Rr5, where any (C3-C7) carbocycle or (C1-Cs) alkyl of Z4 is optionally substituted with 1, 2, 3, 4 or 5 groups Z4a, where the groups Z4a are the same or different; each Z4a is independently halogen, -CN, or -ORn6; each Rn5, Rp5, Rq5, Rr5, and Rn6 is independently H or (C1-C4) alkyl; each Z5 is independently halogen, which can be the same or different; and n is 0, 1,2 or 3; or a pharmaceutically acceptable salt thereof.
[0006] Despite the above descriptions, there is a need for compounds that are potent and stable and exhibit improved pharmacokinetic and / or pharmacodynamic profiles for the treatment of a viral infection by Retroviridae including an infection caused by the HIV virus.
[0007] Also of interest in the field of HIV therapies and treatments is extending the pharmacokinetic property of the regimens provided to patients. While current HIV treatment regimens have progressed enough that patients no longer need to take multiple pills several times a day, patients still need to take one pill every day for the foreseeable period of their lives. Thus, it would be beneficial to have HIV therapies that require patients to take medication less than once a day (for example, once every two days, once a week, once every two weeks, once a month and so on). onwards).
[0008] New compounds are presented here that exhibit improved potency, improved metabolic stability and improved pharmacokinetic and / or pharmacodynamic profiles. SUMMARY
[0009] In some embodiments, the present description relates to a compound of formula (Ia):
(Ia) or a pharmaceutically acceptable salt thereof.
[00010] In some embodiments, the present description refers to a compound of formula (Ib):
or a pharmaceutically acceptable salt thereof.
[00011] In some embodiments, the present description refers to a compound of formula (Ha):
or a pharmaceutically acceptable salt thereof.
[00012] In some embodiments, the present description relates to a compound of formula (llb):
or a pharmaceutically acceptable salt thereof.
[00013] In one embodiment, the present description relates to the use of a compound of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, in the treatment of a disease in an individual in need thereof.
[00014] In one embodiment, the present description refers to the use of a compound of formula (la), (lb), (lla) and / or (llb), or a pharmaceutically acceptable salt thereof, in the treatment of a disease in an individual in need of it.
[00015] In certain embodiments, the present description relates to a pharmaceutical composition comprising a compound of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition is an injectable form. In certain embodiments, the pharmaceutical composition is suitable for oral administration.
[00016] In some embodiments, the present description relates to a pharmaceutical composition comprising a compound of formula (la), (lb), (1a) and / or (llb), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient product. In certain embodiments, the pharmaceutical composition is a parenteral form (for example, injectable). In certain embodiments, the pharmaceutical composition is suitable for oral administration.
[00017] In certain embodiments, the present description relates to an article of manufacture comprising a unit dosage of a compound of formula (la) or (lb), or a pharmaceutically acceptable salt thereof.
[00018] In some embodiments, the present description relates to an article of manufacture comprising a unit dosage of a compound of formula (la), (lb), (lla) and / or (llb), or a pharmaceutically acceptable salt the same.
[00019] In certain embodiments, the present description relates to a method for treating or preventing an HIV infection in an individual in need thereof, comprising administering to the individual a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof.
[00020] In some embodiments, the present description relates to a method for treating or preventing an HIV infection in an individual in need thereof, comprising administering to the individual a compound of formula (Ia), (Ib), ( IIa), and / or (IIb), or a pharmaceutically acceptable salt thereof.
[00021] In certain embodiments, the present description relates to a method for preventing HIV infection in an individual, comprising administering to the individual a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof. In certain modalities, the individual is at risk of contracting the HIV virus, such as an individual who has one or more risk factors known to be associated with contracting the HIV virus.
[00022] In certain embodiments, the present description relates to a method for preventing an HIV infection in an individual, comprising administering to the individual a compound of formula (Ia), (Ib), (IIa), and / or ( IIb), or a pharmaceutically acceptable salt thereof. In certain modalities, the individual is at risk of contracting the HIV virus, such as an individual who has one or more risk factors known to be associated with contracting the HIV virus.
[00023] In certain embodiments, the present description relates to a method for treating or preventing an HIV infection in an individual in need thereof, comprising administering to the individual a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents.
[00024] In certain embodiments, the present description relates to a method for treating or preventing an HIV infection in an individual in need thereof, comprising administering to the individual a compound of formula (Ia), (Ib), ( IIa), and / or (IIb), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents.
[00025] In certain embodiments, the present description relates to a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof for use in medical therapy.
[00026] In certain embodiments, the present description relates to a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof for use in medical therapy.
[00027] In certain embodiments, the present description relates to a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of an HIV infection in an individual.
[00028] In certain embodiments, the present description refers to a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, for use in the treatment or preventing an HIV infection in an individual.
[00029] In certain embodiments, the present description refers to the use of a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament to treat or prevent an infection HIV in an individual.
[00030] In certain embodiments, the present description refers 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 medicine to treat or prevent an HIV infection in an individual.
[00031] In another embodiment, the present description relates to intermediates useful for the synthesis of the compound of formula (la) or (lb).
[00032] In another embodiment, the present description relates to intermediates useful for the synthesis of the compound of formula (la), (lb), (lla) and / or (llb).
[00033] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (la), (lb), (lla) and / or (llb) is the sodium salt.
[00034] The additional modalities of the present description are described here. BRIEF DESCRIPTION OF THE DRAWINGS
[00035] Figure 1 shows 1H NMR of (400 MHz, methanol-d ") from N- ((S) -1- (3- (4-chloro-3- (methylsulfonamido) -1- (2,2, 2-trifluoroethyl) -1 H-indazol-7-yl) -6- (3-methyl-3- (methylsulfonyl) but-1-in-1-yl) pyridin-2-yl) -2- (3,5 - difluorophenyl) ethyl) -2 - ((3bS, 4aR) -5,5-difluoro-3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1 H-cyclopropa [3,4] cyclopenta [ 1,2-c] pyrazol-1-yl) acetamide.
[00036] Figure 2 shows 1H NMR of (400 MHz, methanol-d ") of N- ((S) -1- (3- (4-chloro-3- (cyclopropanesulfonamido) -1- (2,2- difluoroethyl) -1 H- indazol-7-yl) -6- (3-methyl-3- (methylsulfonyl) but-1-in-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl ) ethyl) -2 - ((3bS, 4aR) -5,5-difluoro-3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1 H-cyclopropa [3,4] cyclopenta [1, 2-c] pyrazol-1-yl) acetamide.
[00037] Figure 3 shows the plasma concentration (nM) of Compound 38 after a single subcutaneous (SC) dose in rats.
[00038] Figure 4 shows a graph of plasma concentration over time of 200 mg / mL of Formula lb in 2% poloxamer 188 in saline when dosed by subcutaneous routine in dogs at 6 mg / kg.
[00039] Figure 5 shows a graph of plasma concentration over time of 100 mg / mL of Formula lb in 2% poloxamer 188 in saline when dosed by subcutaneous routine in dogs at 6 mg / kg.
[00040] Figure 6 shows a graph of plasma concentration over time of 200 mg / mL of Formula Ib, sodium salt in 2% poloxamer 188 in saline when dosed by subcutaneous routine in dogs at 6 mg / kg.
[00041] Figure 7 shows a graph of plasma concentration over time of 100 mg / mL of Formula Ib, as free acid in PWN, when dosed by subcutaneous routine in dogs at 6 mg / kg.
[00042] Figure 8 shows a graph of plasma concentration over time of 200 mg / mL of Formula Ib, in the form of free acid in NMP, when dosed by subcutaneous routine in dogs at 6 mg / kg.
[00043] Figure 9 shows a graph of plasma concentration over time of 200 mg / mL of Formula Ib, sodium salt in PWN, when dosed by subcutaneous routine in subjects at 6 mg / kg.
[00044] Figure 10 shows a graph of plasma concentration over time of 200 mg / mL of Formula Ib in 10% ethanol, 12% water and 78% PEG 200 when dosed subcutaneously in subjects at 6 mg / kg .
[00045] Figure 11 shows a graph of plasma concentration over time of 200 mg / mL of Formula Ib, salt in situ, in 10% ethanol, 12% water and 77% PEG 200 when subcutaneously in individuals at 6 mg / kg.
[00046] Figure 12 shows a graph of the plasma concentration over time of 200 mg / mL of Formula Ib in 10% ethanol, 13% water and 77% glycofurol, with 1.2 mol-eq. NaOH to form Na salt in situ when dosed in individuals at 6 mg / kg.
[00047] Figure 13 shows a graph of plasma concentration over time of a fixed 7.5 mg oral dose of Formula Ib in 10% ethanol, 20% vitamin E TPGS and 70% MIGLYOL 812 in dogs. DETAILED DESCRIPTION
[00048] The description below is made with the understanding that the present description should be considered as an example of the claimed matter, and is not intended to limit the claims attached to the specific modalities illustrated. Titles used throughout this description are provided for convenience and should not be construed to limit claims in any way. The modalities illustrated in any title can be combined with modalities illustrated under any other title.
[00049] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as that normally understood by someone skilled in the art.
[00050] When trade names are used here, it is intended to independently include the trade name product and the active pharmaceutical ingredient (s) of the trade name product.
[00051] When used herein and in the appended claims, the singular forms "one" and "one" and "a / o" include plural references, unless the context clearly indicates otherwise. Thus, for example, the reference to "the compound" includes a plurality of such compounds and the reference to "the test" includes reference to one or more tests, and so on.
[00052] When used herein, the term "Cmax" refers to the maximum observed plasma / serum concentration of the drug.
[00053] "Pharmaceutically acceptable" refers to compounds, salts, compositions, dosage forms and other materials that are useful in the preparation of a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
[00054] "Pharmaceutically acceptable excipient" includes, without limitation, any adjuvant, vehicle, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the United States Food and Drug Administration as being acceptable for use in humans or pets.
[00055] "Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and that has (or can be converted into 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, glycoheptonic acid, glyconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid , 2-naphthalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid and the like, and salts formed when an acidic proton in the parent compound is replaced by an ion metal, for example, an alkali metal ion (for example, a sodium or potassium), an alkaline earth ion (for example, calcium or magnesium) or an aluminum ion; or coordinated with an organic base such as diethanolamine, triethanolamine, $ - methylglycamine and the like. Also included in this definition are the ammonium and substituted or quaternized ammonium salts. Representative non-limiting lists of pharmaceutically acceptable salts can be found in SM Berge etal., J. Pharma Sci., 66 (1), 119 (1977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), p. 732, Table 38-5, both of which are incorporated herein by reference.
[00056] "Individual" and "individuals" refer to humans, domestic animals (eg dogs and cats), farm animals (eg cattle, horses, sheep, goats and pigs), laboratory animals (eg mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs and monkeys) and the like.
[00057] When used here, "treatment" or "treating" is an approach to obtain beneficial or desired results. For the purposes of the present description, beneficial or desired results include, but are not limited to, alleviating a symptom and / or decreasing the extent of a symptom and / or preventing an aggravation of a symptom associated with a disease or condition. In one embodiment, "treatment" or "treating" includes one or more of the following: a) inhibiting the disease or condition (for example, decreasing one or more symptoms resulting from the disease or condition, and / or decreasing the extent of the disease or condition); b) reducing or stopping the development of one or more symptoms associated with the disease or condition (for example, stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and / or c) relieving the disease or condition, for example, causing the regression of clinical symptoms, improving the state of the disease, delaying the progress of the disease, increasing the quality of life and / or prolonging survival.
[00058] When used here, "to postpone" the development of a disease or condition means to delay, prevent, reduce, delay, stabilize and / or postpone the development of the disease or condition. This postponement can be of varying length of time, depending on the history of the disease and / or the individual to be treated. As is evident to someone skilled in the art, a sufficient or significant postponement may, in effect, encompass prevention, insofar as the individual does not develop the disease or condition. For example, a method that "postpones" the development of AIDS is a method that reduces the likelihood of developing the disease over a period of time and / or reduces the extent of the disease over a period of time, when compared to not using it. of the method. These comparisons can be based on clinical studies, using a statistically significant number of individuals. For example, the development of AIDS can be detected using known methods, such as confirming the individual's HIV + status and assessing the individual's T cell count or other indication of AIDS development, such as extreme fatigue, weight loss, diarrhea persistent fever, high fever, swollen lymph nodes in the neck, armpits or groin, or the presence of an opportunistic condition known to be associated with AIDS (for example, a condition that is generally not present in individuals with a functioning immune system, however, occurs in AIDS patients). Development may also refer to the progress of the disease, which may initially be undetectable and includes occurrence, recurrence and onset.
[00059] When used herein, "prevention" or "prevent" refers to a regimen that protects against the onset of the disease or disorder in such a way that the clinical symptoms of the disease do not develop. Thus, "prevention" refers to the administration of a therapy (for example, administration of a therapeutic substance) to an individual before signs of the disease are detectable in the individual (for example, administration of a therapeutic substance to an individual in the absence of detectable infectious agent (eg, virus) in the individual). The individual may be an individual at risk of developing the disease or disorder, such as an individual who has one or more risk factors known to be associated with the development or onset of the disease or disorder. Thus, the term "preventing HIV infection" refers to the administration to an individual who does not have a detectable HIV infection, an anti-HIV therapeutic substance. It is understood that the individual for preventive anti-HIV therapy may be an individual at risk of contracting the HIV virus. In addition, it is understood that prevention may not result in complete protection against the onset of the disease or disorder. In some cases, prevention includes reducing the risk of developing the disease or disorder. The risk reduction may not result in the complete elimination of the risk of developing the disease or disorder.
[00060] When used here, an individual "at risk" is an individual who is at risk of developing a condition to be treated. An "at risk" individual may or may not have a detectable disease or condition, and may or may not have exhibited a detectable disease prior to treatment of the methods described herein. "At risk" denotes 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 having one or more of these risk factors is more likely to develop the disease or condition than an individual without these risk factors. For example, individuals at risk for AIDS are those who have HIV.
[00061] When used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount that is effective to induce the desired biological or medical response, including the amount of a compound that, when administered to an individual to treat a disease, it is sufficient to effect such treatment for the disease or an amount that is effective to protect against the contraction or onset of a disease. The effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the individual to be treated. The effective amount can include a range of quantities. As is understood in the art, an effective amount may be in one or more doses, that is, a single dose or multiple doses may be necessary to achieve the desired treatment result. 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 given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result can be or It is reached. Adequate doses of any co-administered compounds can optionally be reduced due to the combined action (for example, additive or synergistic effects) of the compounds.
[00062] "Enantiomers" are a pair of stereoisomers that are reflected images that cannot be superimposed on each other. A 1: 1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture of enantiomers in a ratio other than 1: 1 is a "scalemic" mixture.
[00063] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, however, which are not images reflected among themselves.
[00064] The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry in each chiral carbon can be specified by R or S. The resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (right or left). that they rotate the flat polarized light on the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and / or impeded rotation around a connection axis and can thus give rise to enantiomers, diastereomers and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) - or (S) -. The present description is intended to include all such possible isomers, including racemic mixtures, scalemic mixtures, diastereomeric mixtures, optically pure forms and intermediate mixtures. The optically active (R) - and (S) - isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
[00065] Except as expressly defined otherwise, this description includes all the tautomers of the compounds detailed herein, even if only one tautomer is expressly represented (for example, both tautomeric forms are intended and described by presenting a tautomeric form where a pair of two tautomers may exist). For example, if reference is made to a compound containing an amide (for example, by structure or chemical name), it is understood that the corresponding tautomer of imidic acid is included by this description and described the same as if the amide were expressly recited alone or together with imidic acid. Where more than two tautomers can exist, the present description includes all such tautomers, even if only a single tautomeric form is represented by the name and / or chemical structure.
[00066] The present description also provides prodrugs of the compound of Formula (la) or (lb). A "prodrug" is defined in the pharmaceutical field as a biologically inactive derivative of a drug that upon administration to the human body is converted to the biologically active source drug according to some chemical or enzymatic pathway.
[00067] Additionally, in some embodiments, the present description also provides prodrugs of the compound of Formula (la), (lb), (lla) and / or (llb).
[00068] It is understood by someone skilled in the art that this description also includes any compound described here (for example, a compound of Formula (la) or (lb)) that can be enriched in any or all of the atoms above the isotopic ratios of naturally occurring with one or more isotopes, such as, but not limited to, deuterium (2H or D).
[00069] Described are also compounds in which 1 to n hydrogen atoms attached to a carbon atom can be replaced by a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds can increase resistance to metabolism, and thus can be useful for increasing the half-life of 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 by means well known in the art, for example, using starting materials in which one or more hydrogen atoms have been replaced by deuterium.
[00070] Examples of isotopes that can be incorporated into the compounds described also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O , 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I and 125I, respectively. Substitution with positron-emitting isotopes, such as 11C, 18F, 15O and 13N, may be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupation. The isotopically labeled compounds of Formula (Ia) or (Ib), can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as shown below using an appropriate isotopically labeled reagent instead of the non-reactive reagent. previously used.
[00071] Additionally, in some embodiments, the isotopically labeled compounds of Formula (la), (Ib), (Ila) and / or (lib), can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples, as described below, using an appropriate isotopically labeled reagent instead of the unlabeled reagent previously employed.
[00072] The compounds described herein may have chiral centers and / or geometric isomeric centers (E and Z isomers), and it should be understood that all such optical, enantiomeric, diastereoisomeric and geometric isomers are covered. When the compounds are represented in their chiral form, it is understood that the modality covers, however, it is not limited to the specific diastereoisomerically or enantiomerically enriched form. Where chirality is not specified, however, it is present, it is understood that the modality is directed to the specific diastereoisomerically or enantiomerically enriched form; or a racemic or scalemic mixture of such (such) compound (s). When used here, "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1: 1.
[00073] Also provided are hydrates, solvates, tautomeric forms, polymorphs and pharmaceutically acceptable prodrugs of the compounds described herein.
[00074] In a preferred embodiment, the present description relates to the use of the compound of formula (la) or (Ib) in the treatment of a viral infection by Retroviridae including an infection caused by the HIV virus comprising the administration of a therapeutic amount peutically effective to an individual in need of it.
[00075] In a preferred embodiment, the present description relates to the use of the compound of formula (la), (Ib), (IIa) and / or (IIb) in the treatment of a viral infection by Retroviridae including an infection caused by HIV virus comprising administering a therapeutically effective amount to an individual in need thereof.
[00076] It is a desirable objective to discover a compound or a pharmaceutically acceptable salt thereof having a low EC50. The EC50 value refers to the concentration of a compound in an assay that reaches 50% of the maximum effectiveness. A compound with a lower EC50 achieves similar effectiveness with a lower concentration of compound compared to a compound with a higher EC50. Thus, a lower EC50 is generally preferred for drug development.
[00077] It is a desirable objective to discover a compound or a pharmaceutically acceptable salt thereof that has good physical and / or chemical stability. An increase in the overall stability of a compound can provide an increase in the circulation time in the body. With less degradation, a stable compound can be administered in smaller doses and still maintain effectiveness. Likewise, with less degradation, there is less concern about the by-products of the degradation of a compound.
[00078] It is a desirable objective to discover a compound or a pharmaceutically acceptable salt that has improved pharmacokinetic and / or pharmacodynamic profiles and long half-life. It is advantageous for a drug to have a moderate or low clearance and a long half-life, as this can lead to good bioavailability and high exposure in systemic exposure. Reducing the clearance and increasing the half-life of a compound could reduce the daily dose required for efficacy and, therefore, provide a better efficacy and safety profile. In this way, improved pharmacokinetic and / or pharmacodynamic profiles and long half-life can provide better patient compliance.
[00079] It is a desirable objective to discover a compound or a pharmaceutically acceptable salt of the same that has a good pharmacokinetic profile from a slow release injectable formulation. It is advantageous for a drug to have a low EC50 and pharmacokinetics and long action, as this can lead to low frequency of administration. Reducing the frequency of administration can provide better patient compliance. Reducing the frequency of administration may be desirable for patients with difficult or limited access to healthcare.
[00080] Advantageously, a compound of formula (la) and (Ib) has been found here which provides advantages over structurally close compounds (hereinafter referred to as compounds A and B) described in US Patent Publications Nos. 2014 / 0296266A1 and 2014 / 0303164A1:

[00081] Therefore, this description includes, however, is not limited to the supply of a compound of formula (la)
(la) or a pharmaceutically acceptable salt thereof and methods of using the compound of formula (la) for the treatment of a viral infection by Retroviridae including an infection caused by the HlV virus.
[00082] Therefore, this description includes, however, is not limited to the supply of a compound of formula (lb)
(lb) or a pharmaceutically acceptable salt thereof and methods of using the compound of formula (lb) for the treatment of a viral infection by Retroviridae including an infection caused by the HlV virus.
[00083] Likewise a compound of formula (1la) and (11b) is described herein, which provides advantages compared to Compounds A and B (shown above).
[00084] Therefore, the present description includes, however, is not limited to the supply of a compound of formula (lla)
(Ha) or a pharmaceutically acceptable salt thereof and methods of using the compound of formula (1a) for the treatment of a viral infection by Retroviridae including an infection caused by the HlV virus.
[00085] Therefore, the present description includes, however, it is not limited to the supply of a compound of formula (llb).
(llb) or a pharmaceutically acceptable salt thereof and methods of using the compound of formula (llb) for the treatment of a viral infection by Retroviridae including an infection caused by the HlV virus.
[00086] In some embodiments, the compounds described herein (for example, a compound of formula (la), (lb), (lla), and / or (llb), or pharmaceutically acceptable salt thereof) are used to prevent a HlV infection in an individual. In some embodiments, the compounds described herein are used to prevent HIV infection in an individual at risk of infection. In some embodiments, the compounds described herein are used for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1.
[00087] The compounds described herein (for example, a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharmaceutically acceptable salt thereof) are believed to be active against major HIV-1 mutants selected by clinical Protease Inhibitors (IPs), nucleoside reverse transcriptase inhibitors (NRTIs), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) and Integrase inhibitors (INSTIs). Combination Therapy
[00088] In certain embodiments, a method for treating or preventing an HIV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound described herein (for example, a compound of formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of 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. In one embodiment, a method for treating an HIV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound described herein (for example, a compound of Formula ( Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of 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.
[00089] In some embodiments, a method for treating or preventing an HIV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound described here (for example, a compound of formula (la), (lb), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of 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.In one embodiment, a method for treating an HIV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound described herein (for example, a compound of formula (Ia), (Ib), (IIa), and / or (IIb)), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g. example, one, two, three or four; or one or two or one to three, or one to four) additional therapeutic agents.
[00090] In one embodiment, pharmaceutical compositions comprising a compound described herein (for example, a compound of Formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, in combination with one or more (for example, a , two, three or four or one or two, or one to three, or one to four) additional therapeutic agents and a pharmaceutically acceptable excipient are provided.
[00091] In some embodiments, pharmaceutical compositions comprising a compound described herein (for example, a compound of Formula (Ia), (Ib), (IIa), and / or (IIb)), or a pharmaceutically acceptable salt of the even, 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 are provided.
[00092] In certain embodiments, the present description provides a method for the treatment of an HlV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein (for example, a compound of Formula (la ) or (lb)) or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents that are suitable for the treatment of an HlV infection.
[00093] In certain embodiments, the present description provides a method for the treatment of an HlV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein (for example, a compound of Formula (la ), (lb) (lla) and / or (llb)), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents that are suitable for the treatment of an infection by HlV.
[00094] In certain embodiments, the present description provides a method for the treatment of an HlV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein (for example, a compound of Formula (la ), (lb), (lla) and / or (llb)) or a pharmaceutically acceptable salt thereof.
[00095] In certain embodiments, a compound described herein (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound described herein (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with an additional therapeutic agent. In certain embodiments, a compound described herein (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound described herein (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In other embodiments, a compound described herein (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and / or they can be selected from different classes of therapeutic agents.
[00096] In some embodiments, a compound described herein (for example, a compound of Formula (la), (lb), (lla), and / or (llb)), or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound described herein (for example, a compound of Formula (la), (lb), (lla) and / or (llb)), or a pharmaceutically acceptable salt thereof, is combined with an additional therapeutic agent . In certain embodiments, a compound described herein (for example, a compound of Formula (la), (lb), (lla) and / or (llb)), or a pharmaceutically acceptable salt thereof, is combined with two agents additional therapeutic options. In other embodiments, a compound described herein (for example, a compound of Formula (la), (lb), (lla), and / or (llb)), or a pharmaceutically acceptable salt thereof, is combined with three therapeutic agents additional. In other embodiments, a compound described herein (for example, a compound of Formula (la), (lb), (lla) and / or (llb)), or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents . The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and / or they can be selected from different classes of therapeutic agents. Administration of HIV Combination Therapy
[00097] In certain embodiments, a compound described herein (for example, a compound of formula (la) or (Ib)), or a pharmaceutically acceptable salt thereof, is administered with one or more additional therapeutic agents. Co-administration of a compound described herein (for example, a compound of Formula (la) or (Ib)), or a pharmaceutically acceptable salt thereof, with one or more additional therapeutic agents, generally refers to the simultaneous or sequential administration of a compound described herein (for example, a compound of Formula (la) or (Ib)) and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound described herein (for example, a compound of Formula (la) or ( lb)), or a pharmaceutically acceptable salt thereof, and the one or more additional therapeutic agents are both present in the individual's body. When administered sequentially, the combination can be administered in two or more administrations.
[00098] In some embodiments, a compound described herein (for example, a compound of formula (la), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is administered with a or more additional therapeutic agents. Co-administration of a compound described herein (for example, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, with one or more additional therapeutic agents, generally refers to the simultaneous or sequential administration of a compound described herein (for example, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) and one or more additional therapeutic agents, such that the therapeutically effective amounts of the compound described herein (for example, a compound of Formula (la), (lb), (1a) and / or (llb)), or a pharmaceutically acceptable salt thereof, and the one or more Additional therapeutic agents are both present in the individual's body. When administered sequentially, the combination can be administered in two or more administrations.
[00099] Co-administration includes administration of unit doses of the compounds described herein (for example, a compound of Formula (la) or (lb)), or pharmaceutically acceptable salts thereof, before or after administration of unit doses of one or more more additional therapeutic agents. For example, the compound described herein (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, can be administered within seconds, minutes or hours after the administration of one or more additional therapeutic agents. In some embodiments, a unit dose of a compound described herein (for example, a compound of formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is administered first, followed in seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound described herein (for example, a compound of Formula (la) or (lb)) in seconds or minutes . In other embodiments, a unit dose of a compound described herein (for example, a compound of Formula (la) or (lb)) is administered first, followed, after a period of hours (for example, 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In still other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (for example, 1-12 hours), by administration of a unit dose of a compound described herein (for example , A compound of Formula (la) or (Ib)).
[000100] In some embodiments, coadministration includes the administration of unit dosages of the compounds described herein (for example, a compound of Formula (la), (Ib), (IIa) and / or (IIb)), or pharmaceutically acceptable salts before or after the administration of unit doses of one or more additional therapeutic agents. For example, the compound described herein (for example, a compound of Formula (Ia), (Ib), (IIa), and / or (IIb)), or a pharmaceutically acceptable salt thereof, can be administered in seconds , minutes or hours of administration of one or more additional therapeutic agents. In some embodiments, a unit dose of a compound described herein (for example, a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is administered first , followed in seconds or minutes by administering a unit dose of one or more additional therapeutic agents. Alternatively, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound described herein (for example, a compound of Formula (Ia), (Ib), (IIa), and / or (IIb)) in seconds or minutes. In other embodiments, a unit dose of a compound described herein (for example, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) is administered first, followed, after a period of hours ( for example, 1-12 hours), by administering a unit dose of one or more additional therapeutic agents. In still other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (for example, 1-12 hours), by administration of a unit dose of a compound described herein (for example , a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)).
[000101] For the avoidance of doubt, the co-administration of a compound described herein (for example, a compound of Formula (la), (lb), (lla), and / or (llb)), or a pharmaceutically acceptable salt thereof, with one or more additional therapeutic agents, may refer to co-administration with one or more of the therapeutic agents described herein, for example, those agents listed in paragraphs [0111] to [0162],
[000102] In certain embodiments, a compound described herein (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with one or more additional therapeutic agents in a dosage form unit for simultaneous administration to an individual. In certain embodiments, such a unit dosage form can be administered by any routine appropriate to the condition being treated. Suitable routines include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. In certain embodiments, the described compounds can be dosed parenterally. In certain embodiments, the unit dosage form can be routinely dosed intravenously, subcutaneously or intramuscularly. In certain embodiments, the unit dosage form is orally bioavailable and can be dosed orally. In certain embodiments, the unit dosage form can be a solid dosage form for oral administration.
[000103] In some embodiments, a compound described herein (for example, a compound of Formula (la), (lb), (lla) and / or (llb)), or a pharmaceutically acceptable salt thereof, is combined with a or more additional therapeutic agents in a unit dosage form for simultaneous administration to an individual. In certain embodiments, such a unit dosage form can be administered by any routine appropriate to the condition being treated. Suitable routines include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. In certain embodiments, the described compounds can be dosed parenterally. In certain embodiments, the unit dosage form can be routinely dosed intravenously, subcutaneously or intramuscularly. In certain embodiments, the unit dosage form is orally bioavailable and can be dosed orally. In certain embodiments, the unit dosage form can be a solid dosage form for oral administration.
[000104] The compound described herein (for example, a compound of Formula (la) or (lb), or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents, may be administered by any routine appropriate to the condition to be treated. Suitable routines include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. In certain embodiments, the described compounds can be dosed parenterally. In certain embodiments, the compounds described can be dosed intravenously, subcutaneously or intramuscularly. In certain embodiments, the compounds described are bioavailable orally and can be dosed orally.
[000105] The compound described herein (for example, a compound of Formula (la), (lb), (lla) and / or (llb), or a pharmaceutically acceptable salt thereof, in combination with one or more therapeutic agents can be administered by any routine appropriate to the condition being treated. Suitable routines include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intra-tecal and epidural) and the like. In certain embodiments, the described compounds can be dosed parenterally. In certain embodiments, the described compounds can be dosed routinely intravenously, subcutaneously or intramuscularly. In certain embodiments, the compounds described are orally bioavailable and can be dosed orally.
[000106] In certain embodiments, a compound of Formula (la) or (lb), or a pharmaceutically acceptable salt thereof, is formulated as a tablet, which may optionally contain one or more other compounds useful for the treatment of HlV. In certain embodiments, the tablet may contain one or more other compounds useful for the treatment of HlV, such as HlV protease inhibitors, non-nucleoside or non-nucleotide reverse transcriptase inhibitors, nucleoside inhibitors or reverse transcriptase HlV nucleotide , HlV integrase inhibitors, non-catalytic HlV (or allosteric) site integrase inhibitors, pharmacokinetic enhancers and combinations thereof.
[000107] In certain embodiments, a compound of Formula (la), (lb), (lla) and / or (llb), or a pharmaceutically acceptable salt thereof, is formulated as a tablet, which may optionally contain one or more other compounds useful for the treatment of HlV. In certain embodiments, the tablet may contain one or more other compounds useful for the treatment of HlV, such as HlV protease inhibitors, non-nucleoside or non-nucleotide reverse transcriptase inhibitors, nucleoside inhibitors or reverse transcriptase HlV nucleotide , HlV integrase inhibitors, non-catalytic HlV (or allosteric) site integrase inhibitors, pharmacokinetic enhancers and combinations thereof.
[000108] In certain embodiments, a compound of Formula (la), (lb), (lla) and / or (llb), or a pharmaceutically acceptable salt thereof, is formulated as a solution formulation, which may optionally contain a or more other compounds useful for the treatment of HlV. In certain embodiments, the tablet may contain one or more other compounds useful for the treatment of HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or reverse transcriptase nucleotide inhibitors , HIV integrase inhibitors, non-catalytic HIV (or allosteric) site integrase inhibitors, pharmacokinetic enhancers and combinations thereof.
[000109] In certain embodiments, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, is formulated as a suspension, which may optionally contain one or more other compounds useful for the treatment of HIV. In certain embodiments, the tablet may contain one or more other compounds useful for the treatment of HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or reverse transcriptase nucleotide inhibitors , HIV integrase inhibitors, non-catalytic HIV (or allosteric) site integrase inhibitors, pharmacokinetic enhancers and combinations thereof.
[000110] In certain embodiments, such tablets are suitable for dosing once a day. HIV Combination Therapy
[000111] In the above embodiments, the additional therapeutic agent may be an anti-HIV agent selected from the group consisting of combination drugs for HIV treatment, other drugs for HIV treatment, HIV protease inhibitors, non-HIV inhibitors HIV nucleoside or non-nucleotide reverse transcriptase, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, non-catalytic HIV site (or allosteric) integrase inhibitors, HIV entry inhibitors, maturation inhibitors HIV, latency reversal agents, compounds that target HIV capsid, immunobased therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, matrix protein inhibitors HIV p17, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, antagonists of complement C5a receptor, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine modulators kinase, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 junction inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, junction factor modulators, protein modulators containing COMM domain , HIV ribonuclease H inhibitors, retrocycline modulators, CDK-9 inhibitors, dendritic ICAM-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement H Factor modulators , ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, PC9 convertase propotein stimulators, ATP-dependent RNA helicase DDX3X inhibitors, i reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines and combinations thereof.
[000112] In some embodiments, the additional therapeutic agent is selected from the group consisting of combined HIV drugs, other drugs for the treatment of HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors , non-catalytic HIV site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immunobased therapies, PI3K inhibitors, HlV antibodies and bispecific antibodies, and "antibody-like" therapeutic proteins and combinations thereof. HlV Combination Drugs
[000113] Examples of combination drugs include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate and entricitabine); COM-PLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate and entricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate and entricitabine); TRUVADA® (tenofovir disoproxyl fumarate and entricitabine; TDF + FTC); DESCOVY® (tenofovir alafehamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, entricitabine and rilpivirine); GENVOYA® (tenofovir alafenamide, entricitabine, cobicistat and elvitegravir); darunavir, tenifovir hemifumarate alafehamide, entricitabine and cobicistat; efavirenz, lamivudine and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine, tenifovir alafenamide hemifuramate and emtricitabine; tinnofovir hemifumarate alafenamide, entricitabine and rilpivirine; tenofovir hemifumarate alafenamide, emtricitabine, cobicistat and elvitegravir; COMBIVIR® (zidovudine and lamivudine; AZT + 3TC); EPZICOM® (LIVEXA®; abacavir and lamivudine sulfate; ABC + 3TC); KALETRA® (ALUVIA®; lopinaver and ritonavir); TRIUMEQ® (dolutegravir, abacavir and lamivudine); TRI-ZIVIR® (abacavir, zidovudine and lamivudine sulfate; ABC + AZT + 3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; south-fact of atazanavir and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; cabotegravir and rilpivirine; cabotegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate and lamivudine; lamivudine, nevirapine and zidovudine; raltegravir and lamivudine; doravirin, lamivudine and tenofovir disoproxil fumarate; doravirin, lamivudine and tenofovir disoproxil; dolutegravir + lamivudine; lamivudine + abacavir + zidovudine; lamivudine + abacavir; lamivudine + tenofovir disoproxyl fumarate; lamivudine + zidovudine + nevirapine; lopinavir + ritonavir; lopinavir + ritonavir + abacavir + lamivudine; lopinavir + ritonavir + zidovudine + lamivudine; tenofovir + lamivudine; and tenofovir disoproxil fumarate + entricitabine + rilpivirine hydrochloride; lopinavir, ritonavir, zidovudine and lamivudine; Vacc-4x and romidepsin; and APH-0812. Other HIV Drugs
[000114] Examples of other drugs for the treatment of HIV include acemanan, alisporivir, BanLec, deferiprone, Gamimune, meethencephalin, naltrexone, Prolastine, REP 9, RPI-MN, VSSP, viral H1, SB-728-T, acid 1,5-Dicafeoilquin, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, 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-2 05, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuno and VIR-576. HIV Protease Inhibitors
[000115] HIV protease inhibitors include amprenavir, atazaavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir, saquinavir, saquinavir, saquinavir, saquinavir, saquinavir, saquinavir, saquinavir 17, TMB-657 (PPL-100), T-169, BL-008 and TMC-310911. HIV Reverse Transcriptase Inhibitors
[000116] Examples of HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinam, nevirapine, rilpivirine, AIC-292, KM-023 and VM-023 1500. Other examples of non-nucleoside reverse transcriptase inhibitors are described in U.S. Patent Publication No. US2016 / 0250215.
[000117] Examples of HIV reverse transcriptase nucleoside or nucleotide include adefovir, adefovir dipivoxil, azvudine, entrricibin, tenofovir, tenofovir alafenamide, tenofovir alafehamide fumarate, tenofovir alafenamoxide tenofovir haze, tenofovir disofoviroxide, tenofovir disovirate, tenofovir disovirate tenofovir disoproxil hemifumarate, VIDEX® and VIDEX EC® (didanosine, ddl), abacavir, abavavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tevexil, CMX-157, dapivirina, dapivirina, davivina rin, OCR-5753, tenofovir disoproxil orotate, fozivudine, toxoxin, lamivudine, phosphazidine, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148 and KP-1461.
[000118] In some embodiments, examples of HIV nucleoside or nucleotide reverse transcriptase inhibitors include adefovir, adefovir dipivoxil, azvudine, entricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofnofoxin, tenofonofoxin, tenofonofoxin, tenofonofen tenofovir fumarate disoproxyx, tenofovir disoproxyl hemifumarate, VIDEX® and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulphate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, 157xevine, fosexvine, CMV , doravirin, etravirine, OCR-5753, tenofovir disoproxy orotate, fozivudine, toxoxide, lamivudine, phosphatide, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148, KP-1461 and 4'-ethinyl-2-fluoro-2 '-deoxyadenosine (EFdA). HIV Integrase Inhibitors
[000119] Examples of HIV integrase inhibitors include elvitegra-vir, curcumin, curcumin derivatives, chicory acid, chicory acid derivatives, 3,5-Dicafoylquinic acid derivatives, 3,5-Dicafoylquinic acid derivatives, Aurintricarboxylic acid derivatives aurintricarboxylic acid, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tirfostin, tirfostin derivatives, quercetin, quercetin derivatives, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, quinolin dicheto derivatives -4-1, integrase inhibitor- LEDGF, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC- 48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC - 699174, stylbenedisulfonic acid, T-169 and cabotegravir.
[000120] Examples of non-catalytic HIV, or allosteric, sites of allosteric integrase (NCINI) include CX-05045, CX-05168 and CX14442. HIV Entry Inhibitors
[000121] Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 binding inhibitors, gp120 inhibitors and CXCR4 inhibitors.
[000122] Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or bispecific CCR5, B- antibodies 07, MB-66, C25P polypeptide, TD-0680 and vMIP (Haimipu).
[000123] Examples of gp41 inhibitors include albuvirtide, enfuviride, BMS-986197, enfuvirtide biobetter, biosimilar enfuvirtide, HIV-1 (P26-Bapc) fusion inhibitors, ITV-1 trimer, ITV-2, ITV- 2 3, ITV-4, PIE-12 and sifuvirtide.
[000124] Examples of CD4 binding inhibitors include ibalizumab and EACH analogs.
[000125] Examples of gp120 inhibitors include Radha-108 (re- ceptol) 3B3-PE38, BanLec, bentonite-based nanomedicine, fostensavir tromethamine, IQP-0831 and BMS-663068.
[000126] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide and vMIP (Haimipu). HIV Maturation Inhibitors
[000127] Examples of HIV maturation inhibitors include: BMS-955176 and GSK-2838232. Latency Reversal Agents
[000128] Examples of latency reversal agents include histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as velcade, protein kinase C (PKC) activators, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (suberanylhydroxamic or suberoyl acid, anilide and hydroxamic acid), IL-15, JQ1, disulfram, amphotericin B and ubiquitin inhibitors such as largazole and GSK-343 analogs.
[000129] Examples of HDAC inhibitors include romidepsin, volinostat and panobinostat.
[000130] Examples of PKC activators include indolactam, protease, ingenol B and DAG-lactones. Capsid Inhibitors
[000131] Examples of capsid inhibitors include capsid polymerization inhibitors or capsid disrupting compounds, HIV p7 nucleocapsid (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, AVI-621 series , AVI-101, AVI-201, AVI-301 and AVI-CAN1-15. Immunobased Therapies
[000132] Examples of immunobased therapies include modulators of toll-like receptors such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13; modulators of programmed cell death protein 1 (Pd-1); programmed death ligand 1 (Pd-L1) modulators; IL-15 agonists; DermaVir; interleukin-7; platenyl (hydroxychloroquine); proleucine (aldesleukin, IL-2); alpha interferon; interferon alfa-2b; alpha-n3 interferon; pegylated alpha interferon; gamma interferon; hydroxyurea; mycophenolate mofetil (MPA) and its derivative of mycophenolate mofetyl ester (MMF); ribavirin; rintatolimod, polymeric polyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15 / Fc fusion protein, normferon, peginterferon alfa-2a, peginterferon alfa-2b, recombinant interleukin-15, RPI-MN, GS-9620 and IR-103. Phosphatidylinositol 3-kinase (PI3K) inhibitors
[000133] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, nephrinib, panulisib, perifosine, pictilisib, pilaralisib, pu- quitinib mesylate, rigosertibe, rigosertibe, rigosertibe, rigosertibe, rigosertibe, rigosertibe, rigosertibe, rigosertibe, sonigosibe , taselisibe, AMG- 319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, PT-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB- 040093 , LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL -765 and ZSTK-474. HIV Antibodies, Bispecific Antibodies and Therapeutic Proteins "similar to the Antibody"
[000134] Examples of HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bnABs (widely neutralizing HIV-1 antibodies), BMS-936559, TMB-360 and those targeting HIV gp120 or gp41, Antibody Recruitment Molecules targeting HIV, monoclonal anti-CD63 antibodies, antibodies to anti-GB C virus, anti-GP120 / CD4, bispecific CCR5 antibodies, single-domain anti-nef antibodies, anti-Rev antibody, anti-CD18 antibodies derived from camelids, anti-ICAM-1 antibodies derived from camelid, DCVax-001, antibodies directed to gp140, therapeutic antibodies to HIV based on gp41, recombinant human mAbs (PGT-121), iba-lizumab, Immuglo, MB-66.
[000135] Examples of those who target HIV in such a way include bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5 + C2G12 + C4E10, 3-BNC -117, PGT145, PGT121, MDX010 (ipilimuma-be), VRC01 , A32, 7B2, 10E8, VRC-07-523, VRC-HIVMAB080-00-AB, MGD-014 and VRC07. Pharmacokinetic Enhancers
[000136] Examples of pharmacokinetic enhancers include cobicistat and ritonavir. Additional Therapeutic Agents
[000137] Examples of additional therapeutic agents include the compounds described in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (Gilead Sciences), 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
[000138] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521) / AIDSVAX B / E (gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA- 48, DCVax-001 (CDX-2401) , Vacc-4x, Vacc-C5, VAC-3S, recombinant multiclade DNA adenovirus-5 (rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35- GRIN, NA- cGM3 / VSSP ISA- 51, vaccines with poly-ICLC adjuvant, TatImmune, GTU-multiHIV (FIT-06), gp40 [delta] V2.TV1 + MF-59, rVSVIN HIV-1 gag vaccine, vaccine SeV-Gag, AT-20, DNK-4, AD35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP , G0VX-B11, G0VX-B21, TVI-HIV -1, Ad-4 (Ad4-env Clade C + Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVax-Tat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.M0S1.HIV-Env, Ad26.Mod.HIV vaccine, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001 and virus-like particle vaccines such as pseudovirion vaccine, CombiVICHvac, fusion vaccine LFn-p24 B / C, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, HIV anti-TAT vaccine, conjugated polypeptide vaccine, dendritic cell vaccines, DNA-based vaccine in gag, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), MHC / I class II epitope hybrid peptide vaccines i-key, ITV-2, ITV-3, ITV- 4, LIP0-5, Env multiclade vaccine, MVA vaccine, Pennvax-GP, ppt71 deficient HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine , RNActive HIV vaccine, SCB-703, Tat 0yi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp 120, Vacc-4x + romidepsin, variant gp120 polypeptide vaccine, rAd5 gag-pol env A / B / C vaccine. HIV Combination Therapy
[000139] In a particular embodiment, a compound described herein (for example, a compound of Formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more agents additional therapies selected from ATRIPLA® (efavirenz, tenofovir disoproxil fumarate and entricitabine); C0MPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate and entricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate and entricitabine); TRUVADA® (tenofovir disoproxyl fumarate and entricitabine; TDF + FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, entricitabine and rilpivirine); GENVOYA® (tenofovir alafenamide, entricitabine, cobicistat and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxyl fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir and lamivudine); dolutegravir, abacavir sulfate and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT + 3TC); EPZICOM® (LI-VEXA®; abacavir and lamivudine sulfate; ABC + 3TC); TRIZIVIR® (abacavir, zidovudine and lamivudine sulfate; ABC + AZT + 3TC); rilpinionine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir and ritonavir sulfate; darunavir; lamivudine; prolastin; fosamprenavir; calcium efavirenz from fosamprenavir; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil smoke; efavirenz, lamivudine and tinnofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine and zidovudine; abacavir; and abacavir sulfate.
[000140] In some embodiments, a compound described herein (for example, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with a , two, three, four or more additional therapeutic agents selected from among ATRIPLA (efavirenz, tenofovir disoproxil fumarate and entricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate and entricitabine); TRUVADA® (tenofovir disoproxyl fumarate and entricitabine; TDF + FTC); DESCO-VY® (tenofovir alafenamide and entricitabine); ODEFSEY® (tenofovir alafenamide, entricitabine and rilpivirine); GENVOYA® (tenofovir alafenamide, entricitabine, cobicistat and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxyl fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir and lamivudine); dolute-gravir, abacavir sulfate and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT + 3TC); EP-ZICOM® (LIVEXA®; abacavir and lamivudine sulfate; ABC + 3TC); TRIZIVIR® (abacavir, zidovudine and lamivudine sulfate; ABC + AZT + 3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir and ritonavir sulfate; darunavir; lamivudine; prolastin; fosamprenavir; calcium efavirenz from fosamprenavir; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine and zidovudine; abacavir; abacavir sulfate; 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA); and Bictegravir, or a pharmaceutically acceptable salt thereof.
[000141] It will be appreciated by someone skilled in the art that the additional therapeutic agents listed above can be included in more than one of the classes listed above. The particular classes are not intended to limit the functionality of the compounds listed in those classes.
[000142] In a specific embodiment, a compound described herein (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with one or two HlV nucleoside or nucleotide inhibitors reverse transcriptase. In a specific embodiment, a compound described herein (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with a nucleoside inhibitor or HlV nucleotide of reverse transcriptase and a non-nucleoside HlV reverse transcriptase inhibitor. In another specific embodiment, a compound described herein (for example, a compound of Formula (la) or (lb)) or a pharmaceutically acceptable salt thereof, combined with a reverse transcriptase HlV nucleoside or nucleotide inhibitor and an inhibitor compound of HlV protease. In a further embodiment, a compound described herein (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with a nucleoside inhibitor or HlV nucleotide of reverse transcriptase, a non-nucleoside HlV reverse transcriptase inhibitor and a pharmacokinetic enhancer. In certain embodiments, a compound described herein (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with at least one HlV nucleoside reverse transcriptase inhibitor, an integrase inhibitor and a pharmacokinetic enhancer. In another embodiment, a compound described herein (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with two HIV nucleoside or reverse transcriptase nucleotide inhibitors.
[000143] In some embodiments, a compound described herein (for example, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with a or two HIV nucleoside or nucleotide reverse transcriptase inhibitors. In a specific embodiment, a compound described herein (for example, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with an inhibitor of HIV nucleoside or reverse transcriptase nucleotide and a non-nucleoside HIV reverse transcriptase inhibitor. In another specific embodiment, a compound described herein (for example, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, combined with an inhibitor of a reverse transcriptase HIV nucleoside or nucleotide and an HIV protease inhibitor compound. In a further embodiment, a compound described herein (for example, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with an inhibitor of HIV nucleoside or nucleotide reverse transcriptase, an HIV non-nucleoside reverse transcriptase inhibitor and a pharmacokinetic enhancer. In certain embodiments, a compound described herein (for example, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with at least one inhibitor of HIV nucleoside reverse transcriptase, an integrase inhibitor and a pharmacokinetic enhancer. In another embodiment, a compound described herein (for example, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with two nucleoside inhibitors. or HIV reverse transcriptase nucleotide.
[000144] In a particular embodiment, a compound described herein (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with abacavir sulfate, tenofovir, tenofovir disoproxyl, fumarate tenofovir disoproxil, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide fumarate or tenofovir alafenamide hemifumarate.
[000145] In some embodiments, a compound described herein (for example, a compound of Formula (la), (lb), (lla) and / or (llb)), or a pharmaceutically acceptable salt thereof, is combined with sulfate of abacavir, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alamenamide hemifumarate, bictegravir (or 4-pharmaceutically), or an acceptable pharmaceutically ethinyl-2-fluoro-2'-deoxyadenosine (EFdA).
[000146] In some embodiments, a compound described herein (for example, a compound of Formula (la), (lb), (lla) and / or (llb)), or a pharmaceutically acceptable salt thereof, is combined with a HlV integrase inhibitor.
[000147] In a particular embodiment, a compound described herein (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxyl, fumarate tenofovir disoproxil, tenofovir alafenamide, tenofovir alafenamide fumarate or tenofovir alafehamide hemifumarate.
[000148] In some embodiments, a compound described here (for example, a compound of formula (la), (lb), (lla) and / or (llb)), or a pharmaceutically acceptable salt thereof, combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafehamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, bictegravir (or a pharmaceutically acceptable salt thereof), or 4'-ethinyl-2-fluoro-2'-deoxiadin ).
[000149] In a particular embodiment, a compound described herein (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group which consists 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 entricudabine and lamiv.
[000150] In some embodiments, a compound described herein (for example, a compound of Formula (la), (lb), (lla) and / or (llb)), or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil smoke, tenofovir alafenamide, tinnofovir alafenamide fumarate and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.
[000151] In a particular embodiment, a compound described herein (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide and tenifovir alafenamide hemifumarate and a second additional therapeutic agent, the second additional therapeutic agent being entricitabine. In a particular embodiment, a compound of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of tenofovir alafenamide fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine. In a particular embodiment, a compound of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of tenofovir disoproxyl fumarate, tenofovir disoproxil and hemifumarate tenofovir disoproxil, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine. In some embodiments, the compound of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, and the first and second additional therapeutic agents, as described above, are administered simultaneously. Optionally, the compound of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, and the first and second additional therapeutic agents as described above are combined in a unit dosage form for simultaneous administration to an individual. In other embodiments, the compound of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, and the first and second additional therapeutic agents, as described above, are administered sequentially.
[000152] In some embodiments, a compound described herein (for example, a compound of Formula (la), (lb), (lla) and / or (llb)), or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxyxyl fumarate, tenofovir alafenamide and tenifovir alafenamide hemifumarate, and a second additional therapeutic agent, where the second additional therapeutic agent is entricitabine. In a particular embodiment, a compound of the formula (la), (lb), (lla) and / or (llb), or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of tenofovir alafenamide fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine. In a particular embodiment, a compound of formula (la), (Ib), (lla) and / or (llb), or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of in tenofovir disoproxil fumarate, tenofovir disoproxil and tenofovir disoproxil hemifumarate and a second additional therapeutic agent, the second additional therapeutic agent being entricitabine. In some embodiments, the compound of formula (la), (lb), (lla) and / or (llb), or a pharmaceutically acceptable salt thereof, and the first and second additional therapeutic agents, as described above , are administered simultaneously. Optionally, the compound of formula (la), (lb), (lla) and / or (llb), or a pharmaceutically acceptable salt thereof, and the first and second additional therapeutic agents as described above are combined in a dosage form unit for simultaneous administration to an individual. In other embodiments, the compound of formula (la), (lb), (11a) and / or (11b), or a pharmaceutically acceptable salt thereof, and the first and second additional therapeutic agents as described above are administered sequentially.
[000153] In some embodiments, a compound described herein (for example, a compound of Formula (la), (lb), (lla) and / or (llb)), or a pharmaceutically acceptable salt thereof, is combined with bicte - gravir or a pharmaceutically acceptable salt thereof.
[000154] A compound as described herein (for example, any compound of formula (la) or (lb)) can be combined with one or more additional therapeutic agents in any dosage amount of the compound of formula (la) or (lb) (for example, from 1 mg to 1000 mg of compound).
[000155] In some embodiments, a compound as described herein (for example, any compound of Formula (la), (lb), (lla), and / or (llb), or a pharmaceutically acceptable salt thereof can be combined with one or more therapeutic agents in any dosage amount of the compound of Formula (la), (lb), (1la) and / or (11b) (for example, from 1 mg to 1000 mg of compound).
[000156] In certain embodiments, a compound described here (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with 5-30 mg tenofovir alafenamide fumarate, hemifumarate tenofovir alafenamide or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, a compound described herein (for example, a compound of Formula (la) or (lb)), 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 alofenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound described here (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alamphenamide and 200 mg of emtricitabine. In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemi-fumarate or tenofovir alafenamide and 200 mg of entricitabine. A compound as described herein (for example, a compound of Formula (la) or (lb)) can be combined with the agents provided herein in any dosage amount of the compound (for example, from 1 mg to 1000 mg of compound) of the same if each combination of dosages were specifically and individually listed.
[000157] In some embodiments, a compound described herein (for example, a compound of Formula (la), (lb), (lla) and / or (llb)), or a pharmaceutically acceptable salt thereof, is combined with 5 -30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound described herein (for example, a compound of Formula (la), (lb), (lla) and / or (llb)), or a pharmaceutically acceptable salt thereof, is combined with 5- 10, 5- 15, 5-20, 525, 25-30, 20-30, 15-30 or 10-30 mg tenofovir fumarate alafehamide, tenofovir alafenamide hemifumarate or tenofovir alafenaamide and 200 mg of entricitabine . In certain embodiments, a compound described herein (for example, a compound of Formula (la), (lb), (lla) and / or (llb)), or a pharmaceutically acceptable salt thereof, is combined with 10 mg of fumarate tenofovir alafenamide, tenofovir alafenamide hemifumarate or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafehamide hemifumarate or tenofovir alafenamide and 200 mg entricitabine. A compound as described herein (for example, a compound of Formula (la), (lb), (1a) and / or (llb)) can be combined with the agents provided herein in any dosage amount of the compound (for example, 1 mg to 1000 mg of compound) as if each combination of dosages was specific and individually listed.
[000158] In certain embodiments, a compound described herein (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with 200-400 mg of tobacco smoke. tenofovir disoproxil, tenofovir disoproxil hemifumarate or tenofovir disoproxil, and 200 mg of entricitabine. In certain embodiments, a compound described herein (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with 200-250, 200-300, 200-350, 250 -350, 250 -400, 350400, 300-400 or 250-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil and 200 mg of entricitabine. In certain embodiments, a compound described herein (for example, a compound of Formula (la) or (lb)), or a pharmaceutically acceptable salt thereof, is combined with 300 mg tenofovir disoproxyl, hemifumarate tenofovir disoproxil or tenofovir disoproxil and 200 mg of entricitabine. A compound as described herein (for example, a compound of Formula (la) or (lb)) can be combined with the agents provided herein in any dosage amount of the compound (for example, from 1 mg to 1000 mg of compound) of the same as if each dosage combination was specifically and individually listed.
[000159] In some embodiments, a compound described herein (for example, a compound of Formula (la), (lb), (lla) and / or (llb)), or a pharmaceutically acceptable salt thereof, is combined with 200400 mg of tenofovir disoproxil fumarate, tenofovir hemifumarate disoproxil or tenofovir disoproxil and 200 mg of entricitabine. In certain embodiments, a compound described herein (for example, a compound of Formula (la), (lb), (lla), and / or (llb)), or a pharmaceutically acceptable salt thereof, is combined with 200 -250, 200- 300, 200-350, 250-350, 250-400, 350-400, 300-400 or 250-400 mg of tenofovir disoproxyl fu- marate, tenofovir disoproxyl hemifumarate or tenofovir disoproxil and 200 mg of emtricitabine. In certain embodiments, a compound described herein (for example, a compound of Formula (la), (lb), (lla) and / or (llb)), or a pharmaceutically acceptable salt thereof, is combined with 300 mg tenofovir disoproxylate fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil and 200 mg of entricitabine. A compound as described herein (for example, a compound of Formula (la), (lb), (1a) and / or (llb)) can be combined with the agents provided herein in any dosage amount of the compound (for example, example, from 1 mg to 1000 mg of compound) in the same way as if each combination of dosages was specific and individually listed.
[000160] In some embodiments, a compound described herein (for example, a compound of Formula (la), (lb), (lla) and / or (llb)), or its pharmaceutically acceptable salt, is combined with 20-80 mg bict-gravir or its pharmaceutically acceptable salt. A compound as described herein (for example, a compound of Formula (la), (lb), (1a) and / or (llb), or its pharmaceutically acceptable salt) can be combined with the agents provided herein in any dosage amount of the compound (for example, from 1 mg to 1000 mg of compound) as if each combination of dosages were specific and individually listed.
[000161] In one embodiment, kits comprising a compound described herein (for example, a compound of formula (la) or (lb)), or its pharmaceutically acceptable salt, in combination with one or more (for example, one, two, three, one or two, or one to three) additional therapeutic agents are provided.
[000162] In some embodiments, kits comprising a compound described herein (for example, a compound of Formula (la), (lb), (lla), and / or (llb)), or its pharmaceutically acceptable salt, in combination with one or more (for example, one, two, three, one or two or one to three) additional therapeutic agents are provided. Pharmaceutical Compositions
[000163] The pharmaceutical compositions described herein comprise a compound described herein (for example, a compound of formula (la) or (lb)), or its pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable excipients and optionally other agents therapeutic. The pharmaceutical compositions containing the active ingredient can be in any form suitable for the intended method of administration.
[000164] In some embodiments, pharmaceutical compositions described here comprise a compound described here (for example, a compound of formula (la), (lb), (lla), and / or (llb)), or a pharmaceutically acceptable salt of the even, together with one or more pharmaceutically acceptable excipients and optionally other therapeutic agents. The pharmaceutical compositions containing the active ingredient can be in any form suitable for the intended method of administration.
[000165] Pharmaceutical compositions comprising the compound described herein (for example, a compound of Formula (la) or (lb)), or its pharmaceutically acceptable salt, can be prepared with conventional vehicles (for example, inactive ingredient or excipient material) ) that can be selected according to common practice. The tablets can contain excipients including glidants, fillers, binders and the like. Aqueous compositions can be prepared in sterile form and, when intended for administration by administration other than oral, can generally be isotonic. All compositions can optionally contain excipients such as those presented in Rowe et al, Handbook of Pharmaceutical Excipients, 5th edition, American Pharmacists Association, 1986. Excipients can include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as hydroxylalkyl dextrin - lulose, hydroxyalkylmethylcellulose, stearic acid and the like.
[000166] In some embodiments, pharmaceutical compositions comprising the compound described here (for example, a compound of formula (la), (lb), (lla), and / or (llb)), or a pharmaceutically acceptable salt, can be prepared with conventional vehicles (for example, inactive ingredient or excipient material) that can be selected according to ordinary practice. The tablets can contain excipients including glidants, fillers, binders and the like. Aqueous compositions can be prepared in sterile form and, when intended for administration by administration other than oral, can generally be isotonic. All compositions can optionally contain excipients such as those presented in Rowe et al, Handbook of Pharmaceutical Excipients, 5th edition, American Pharmacists Association, 1986. For example, excipients can include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
[000167] Although it is possible to administer the active ingredient alone, it may be preferable to present the active ingredient as pharmaceutical compositions. The compositions, for both veterinary and human use, comprise at least the compound of formula (la) or (lb), together with one or more acceptable carriers and optionally other therapeutic ingredients. In one embodiment, the pharmaceutical composition comprises a compound of formula (la) or (lb), or its pharmaceutically acceptable salt, a pharmaceutically acceptable excipient and a therapeutically effective amount of 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, as defined hereinabove. In one embodiment, the pharmaceutical composition comprises a compound of formula (la) or (lb), or its pharmaceutically acceptable salt, a pharmaceutically acceptable excipient and another therapeutic ingredient The vehicle (s) is (are) "acceptable" in the sense that it is compatible with the other ingredients of the composition and is physiologically harmless ) to your receiver.
[000168] In some embodiments, although it is possible to administer the active ingredient alone, it may be preferable to present the active ingredient as pharmaceutical compositions. The compositions, both for veterinary and human use, comprise at least the compound of Formula (la), (lb), (lla) and / or (llb), together with one or more acceptable carriers and optionally other therapeutic ingredients. In some embodiments, the pharmaceutical composition comprises a compound of Formula (la), (lb), (1a) and / or (llb), or its pharmaceutically acceptable salt, a pharmaceutically acceptable excipient and a therapeutically effective amount of 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 as defined above. In some embodiments, the pharmaceutical composition comprises a compound of Formula (la), (lb), (1a) and / or (llb), or its pharmaceutically acceptable salt, a pharmaceutically acceptable excipient and another therapeutic ingredient. The vehicle (s) is (are) "acceptable" in the sense of being (s) compatible with the other ingredients of the composition and physiologically harmless (s) for its recipient.
[000169] The compositions include those suitable for various routes of administration. The compositions can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the pharmacy art. Such methods include the step of associating the active ingredient (for example, a compound of formula (la) or (lb) or its pharmaceutical salt) with one or more inactive ingredients (for example, a carrier, pharmaceutical excipient, etc.). ). The compositions can be prepared by uniformly and intimately associating the active ingredient with liquid vehicles or finely divided solid vehicles or both, and then, if necessary, shaping the product. Techniques and formulations are generally found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.
[000170] In some embodiments, the compositions include those suitable for various routes of administration. The compositions can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the pharmacy art. Such methods include the step of associating the active ingredient (for example, a compound of Formula (la), (lb), (lla) and / or (llb), or its pharmaceutical salt) with one or more inactive ingredients. (for example, a vehicle, pharmaceutical excipient, etc.). The compositions can be prepared by uniformly and intimately associating the active ingredient with liquid vehicles or finely divided solid vehicles or both, and then, if necessary, shaping the product. Techniques and formulations are generally found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.
[000171] The compositions described herein that are suitable for oral administration can be presented as discrete units (a unit dosage form) including, but not limited to, capsules, cachets or tablets, each containing a predetermined amount of the active ingredient.
[000172] When used for oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and these compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a nice preparation. Tablets containing the active ingredient in admixture with a non-toxic pharmaceutically acceptable excipient that are suitable for the manufacture of tablets are acceptable. These excipients can be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated by known techniques, including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thus provide a prolonged action over a longer period. For example, a time-delaying material such as glyceryl monostearate or glyceryl distearate can be used alone or with a wax.
[000173] In some embodiments, oral dosage forms (for example, tablets) are described here, which can be prepared using hot melt extrusion or spray drying dispersion (SDD) technologies.
[000174] In some embodiments, hard capsules filled with powder, beads or granules are described herein 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 excipients can be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.
[000175] In some embodiments, hard or soft capsules filled with liquid or semi-solid mixtures containing the active ingredient in admixture with a non-toxic pharmaceutically acceptable excipient which are suitable for the manufacture of hard or soft capsules are described here. These excipients can be, for example, solubilizing oils such as corn oil, sesame oil or corn oil; medium chain triglycerides and related esters, such as derived palm kernel oil or coconut oil; selfemulsifying lipid systems (SEDDS or SMEDDS), such as caprylic triglyceride or propylene glycol monocaprilat; viscosity modifiers, such as cetyl alcohol, sterile alcohol, glycerol stearate; and solubilizing and surfactant agents, such as polyethylene glycol, propylene glycol, glycerin, ethanol, polyethoxylated castor oil, poloxamers or polysorbates.
[000176] The pharmaceutical compositions of the present description can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known technique using the suitable dispersing or wetting agents and suspending agents that have been mentioned herein. The sterile injectable preparation can also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils can conventionally be used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, can also be used in the preparation of injectables.
[000177] In some embodiments, the sterile injectable preparation described herein can also be a sterile injectable solution or suspension prepared from a lyophilized powder reconstituted in a parenterally acceptable non-toxic diluent or solvent, such as a 1.3-liter solution. -butane-diol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils can conventionally be used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can also be used in the preparation of injectables.
[000178] Formulations suitable for parenteral administration include sterile aqueous and non-aqueous injection solutions that may contain antioxidants, buffers, bacteriostats and solutes that make the formulation isotonic with the intended recipient's blood; and sterile aqueous and non-aqueous suspensions which may include suspending agents and thickening agents. In certain embodiments, the suspension is a micro-suspension. In certain embodiments, the suspension is a nanosuspension.
[000179] In some embodiments, formulations suitable for parenteral administration (for example, intramuscular (IM) and subcutaneous (SC) administration) will include one or more excipients. Excipients must be compatible with the other ingredients of the formulation and physiologically harmless to their recipient. Examples of suitable excipients are well known to the person skilled in the art of parenteral formulation and can be found, for example, in Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey & Quinn), 6th edition 2009.
[000180] Examples of solubilization of excipients in a parenteral formulation (for example, a SC or IM 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 (for example, a SC or IM formulation) is described which comprises a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or its pharmaceutical salt, and a poloxamer, in particular 338 poloxamer. In some embodiments, the amount of poloxamer (e.g., poloxamer 388) in a parenteral administration described herein is less than about 5%, such as less than about 3%, about 2% ,% or about 0.5%.
[000181] Examples of solubilization of excipients in a parenteral formulation (for example, a SC or IM 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 (for example, a SC or IM formulation) is described which comprises a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or its pharmaceutical salt, and a poloxamer.
[000182] In certain embodiments, excipients include N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide, polyethylene glycol and / or tetraglycol / glycofurol.
[000183] In general, poloxamers are synthetic nonionic triblock of linear copolymers having a central hydrophobic polyoxypropylene chain adjacent to two hydrophilic polypropylene oxides, in certain cases in a 4: 2: 4 weight ratio. Consequently, in certain embodiments, the compositions described herein include a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or its pharmaceutical salt, and a block copolymer consisting of a polyoxypropylene segment and two segments of hydrophilic polypropylene oxide. In certain embodiments, the ratio of the polyoxypropylene segment to the two hydrophilic polypropylene oxide segments is 4: 2: 4 (hydrophilic polypropylene oxide: polyoxypropylene: hydrophilic polypropylene oxide). Poloxamers are generally understood to have the following structure:
where a and e are whole numbers (for example, a is 2-130 and b is 15-67). For example, poloxamer 188 is understood to vary in molecular weight from about 7680 to about 9510 Daltons (where a is about 80 and b and about 27). International Journal of PharmTech Research, Vol. 1, No.2, pp. 299-303, April-June 2009. In some cases, poloxamer 188 has an average molecular weight of about 8400 Daltons. Similarly, poloxamer 338 has a molecular weight in the range of about 12700 to about 17400 Da (where a is about 141 and b and about 44).
[000184] Examples of excipients in a parenteral formulation (for example, a SC or IM formulation) may also include polyethylene glycol. In general, polyethylene glycol (PEG) is a polyether having a general formula H- (O-CH2-CH2) n-OH. In certain embodiments, the PEG can be "capped" by an alkyl group. In these embodiments, the buffered PEG has the formula alkyl- (O-CH2-CH2) nO-alkyl (e.g., CH3- (O-CH2-CH2) n-OCH3. The pharmaceutical compositions of the present description may include PEG with a weight average molecular weight of approximately 100 to approximately 1000. In some embodiments, the average molecular weight of PEG in the pharmaceutical composition is approximately 100 to approximately 800. In some modalities, the average molecular weight of PEG in the pharmaceutical composition is approximately 200 to approximately 600. In some embodiments, the average molecular weight of PEG within the pharmaceutical composition is approximately 400. In some embodiments, the average molecular weight of PEG within the pharmaceutical composition is approximately 300. In some embodiments, the molecular weight average PEG within the pharmaceutical composition is approximately 200. In some embodiments of the pharmaceutical composition, the different molecular weight of PEG can be combined to obtain a property or prop desired properties (eg viscosity). Specific examples of PEG include but are not limited to PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600 and so on. PEG 100, for example, refers to a polyethylene glycol with an average molecular weight of about 100.
[000185] In some embodiments, the parenteral formulation (for example, a SC or IM formulation) described herein is an aqueous suspension. In some embodiments, the parenteral formulation (for example, an SC or IM formulation) described herein is an aqueous suspension comprising a compound of Formula (Ia), (Ib), (IIa), and / or (IIb), or its pharmaceutical salt and saline solution. In some embodiments, the parenteral formulation (for example, an SC or IM formulation) described herein is an aqueous suspension comprising a compound of Formula (Ia), (Ib), (IIa), and / or (IIb), or its pharmaceutically acceptable salt, saline and a poloxamer (such as poloxamer 338, 188 or 207).
[000186] In some embodiments, the parenteral formulation (for example, a SC or IM formulation) described herein is an aqueous suspension. In some embodiments, the parenteral formulation (for example, an SC or IM formulation) described herein is an aqueous suspension comprising a compound of Formula (Ia), (Ib), (IIa), and / or (IIb), or its pharmaceutical salt and saline solution. In some embodiments, the parenteral formulation (for example, an SC or IM formulation) described herein is an aqueous suspension comprising a compound of Formula (Ia), (Ib), (IIa), and / or (IIb), or its pharmaceutically acceptable salt, saline and a suspending agent. In some embodiments, the parenteral formulation (for example, an SC or IM formulation) described herein is an aqueous suspension comprising a compound of Formula (Ia), (Ib), (IIa), and / or (IIb), or its pharmaceutically acceptable salt, saline and poloxamer (such as poloxamer 338, 188 or 207).
[000187] In some embodiments, a suspension is provided comprising a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or its pharmaceutical salt, in a poloxamer and in a saline solution. In some embodiments, the concentration of poloxamer in saline is from about 0.1 to about 20%. In some embodiments, the concentration of poloxamer in saline is about 0.1 to about 10%. In some embodiments, the concentration of poloxamer in saline is about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7 %, 0.8%, 0.9%, 1%, 2,%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or about 10%. In certain embodiments, the concentration of poloxamer in saline is about 2%. In certain embodiments, the poloxamer is poloxamer 188. In certain embodiments, the compound is a compound of Formula (Ib) or its pharmaceutically acceptable salt. In certain embodiments, the compound is a compound of Formula (Ib). In certain embodiments, the compound is a sodium salt of the compound of Formula (Ib).
[000188] In some embodiments, a suspension is provided comprising a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or its pharmaceutical salt, in a poloxamer and mannitol. In some modalities, the concentration of poloxamer in mannitol is about 0.1 to about 20%. In some embodiments, the concentration of poloxamer in mannitol is from about 0.1 to about 10%. In some embodiments, the concentration of poloxamer in mannitol is about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0 , 8%, 0.9%, 1%, 2,%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or about 10%. In certain embodiments, the concentration of poloxamer in mannitol is about 2%. In certain embodiments, the poloxamer is poloxamer 188. In certain embodiments, the compound is a compound of Formula (lb) or its pharmaceutically acceptable salt. In certain embodiments, the compound is a compound of Formula (lb). In certain embodiments, the compound is a sodium salt of the compound of Formula (lb).
[000189] In certain embodiments, the composition is described as a solid dosage form, including a solid injectable dosage form, such as a solid deposit form.
[000190] In certain embodiments, the active ingredient (for example, a compound of formula lb) is present as a free acid. In certain embodiments, the active ingredient (for example, a compound of Formula 1b) is present as a sodium salt.
[000191] In certain embodiments, the pharmaceutical composition described herein is a parenteral formulation. In certain embodiments, the formulation is administered subcutaneously to an individual who needs it. In certain embodiments, the formulation is administered intramuscularly to an individual in need.
[000192] In certain embodiments, the parenteral formulation comprises N-methyl-2-pyrrolidone. In certain embodiments, the parenteral formulation essentially consists of N-methyl-2-pyrrolidone. In certain embodiments, the parenteral formulation comprises dimethyl sulfoxide.
[000193] In certain embodiments, the parenteral formulation comprises a compound of Formula (la), (lb), (lla), and / or (llb), or its pharmaceutical salt and water. In certain embodiments, the parenteral formulation comprises a compound of Formula (lb) or its pharmaceutical salt and water. In certain embodiments, the parenteral formulation further comprises an alcohol. In certain embodiments, alcohol is ethanol. In certain embodiments, the parenteral formulation further comprises polyethylene glycol. In certain embodiments, polyethylene glycol has an average molecular weight of about 200 g / mol. (polyethylene glycol 200). In certain embodiments, the parenteral formulation further comprises an inorganic base. In certain embodiments, the inorganic base is sodium hydroxide. In certain embodiments, the inorganic base is sodium ethoxide. In certain embodiments, the formulation comprises from about 0.1 molar equivalent to about 1.5 molar equivalents of the inorganic base (for example, NaOH or NaOEt). In certain embodiments, the formulation comprises from about 0.5 molar equivalent to about 1.5 molar equivalents of the inorganic base (for example, NaOH or NaOEt). In certain embodiments, the formulation comprises from about 1.0 molar equivalent to about 1.2 molar equivalents of the inorganic base (for example, NaOH or NaOEt). In certain embodiments, the formulation comprises about 1.2 molars of inorganic base (for example, NaOH or NaOEt).
[000194] In certain embodiments, the parenteral formulation consists essentially of a compound of Formula (lb) or a pharmaceutical salt thereof, water, ethanol and polyethylene glycol 200.
[000195] In certain embodiments, the parenteral formulation consists essentially of a compound of Formula (lb) or its pharmaceutical salt, water, ethanol, polyethylene glycol 200 (polyethylene glycol with an average molecular weight of 200 g / mol.) And NaOH. In certain embodiments, the parenteral formulation consists essentially of a compound of Formula (lb) or its pharmaceutical salt, water, ethanol, polyethylene glycol 200 and NaOEt. In certain embodiments, the formulation comprises from about 0.1 molar equivalent to about 1.5 molar equivalents of NaOH or NaOEt. In certain embodiments, the formulation comprises from about 0.5 molar equivalent to about 1.5 molar equivalents of NaOH or NaOEt. In certain embodiments, the formulation comprises from about 1.0 molar equivalent to about 1.2 molar equivalents of NaOH or NaOEt. In certain embodiments, the formulation comprises about 1.2 molar equivalents of NaOH or NaOEt.
[000196] In certain embodiments, the parenteral formulation is a solution formulation comprising a mixture of ethanol, water and polyethylene glycol. In certain embodiments, the parenteral formulation is a solution formulation comprising a mixture of ethanol, water and PEG 200. In certain embodiments, the solution formulation comprises about 5% - 20% ethanol, about 5% to 20% water and about 60% to 90% PEG 200. In certain embodiments, the solution formulation comprises about 10% -15% ethanol, about 10% to 15% water and about 70% to 80% PEG 200. In certain embodiments, the solution formulation comprises about 10% ethanol, about 12% water and about 78% PEG 200. In certain embodiments, the solution formulation further comprises an inorganic base. In certain embodiments, the solution formulation further comprises sodium hydroxide or sodium ethoxide. In certain embodiments, the formulation of the solution further comprises sodium hydroxide. In certain embodiments, the formulation comprises from about 0.1 molar equivalent to about 1.5 molar equivalents of the inorganic base (for example, NaOH or NaOEt). In certain embodiments, the formulation comprises from about 0.5 molar equivalent to about 1.5 molar equivalents of the inorganic base (for example, NaOH or NaOEt). In certain embodiments, the formulation comprises from about 1.0 molar equivalent to about 1.2 molar equivalents of the inorganic base (for example, NaOH or NaOEt). In certain embodiments, the formulation comprises about 1.2 molars of inorganic base (for example, NaOH or NaOEt).
[000197] In some embodiments, solution formulations containing 200 mg / mL of Formula lb with about 0.1 to about 1.5 equivalents of NaOH in about 10% ethanol, about 12% water, and about 77% PEG are provided.
[000198] In certain embodiments, an oral formulation of a compound of formula (la), (lb), (lla), and / or (llb), comprising at least one excipient is provided. Excipients can include ethanol, medium chain triglycerides (eg MlGLYOL 810, MlGLYOL 821, MlGLYOL 840, etc.), vitamin E TPGS, glycerin and / or pharmaceutically acceptable oils (eg sesame oil, castor oil, safflower oil, vegetable oil, soy oil and so on). The oral formulations described herein can include any combination of one or more suitable excipients. Excipients taken together may be present in> 65% by weight of the total oral formulation,> 70% by weight of the total oral formulation,> 80% by weight of the total oral formulation,> 90% by weight of the total oral formulation or> 95% by weight of the total oral formulation.
[000199] In some embodiments, an oral formulation of a compound of Formula (la), (lb), (lla) and / or (llb) is provided. In certain embodiments, the oral formulation comprises a compound of Formula (la), (lb), (lla) and / or (llb), about 5% to about 20% ethanol, about 10% to about 30 % Vitamin E TPGS and about 50% to about 85% MlGLYOL 812. In some embodiments, the oral formulation comprises a compound of Formula (la), (lb), (lla) and / or (llb), about 8% to about 15% ethanol, about 15% to about 25% Vitamin E TPGS and about 60% to about 77% MlGLYOL 812. In certain embodiments, the oral formulation comprises a compound of Formula (la ), (lb), (lla) and / or (llb), in about 10% ethanol, about 20% Vitamin E TPGS and about 70% MlGLYOL 812. In certain embodiments, the oral formulation is prepared in hard gelatin capsules.
[000200] The amount of active ingredient that can be combined with the inactive ingredients to produce a dosage form may vary depending on the intended treatment objective and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration to humans can contain approximately 1 to 1000 mg of active material formulated with an appropriate and convenient amount of carrier material (for example, inactive ingredient or excipient material). In certain embodiments, the carrier material ranges from about 5 to about 95% of the total compositions (weight: weight).
[000201] It should be understood that, in addition to the ingredients particularly mentioned above, the compositions of these modalities may include other agents conventional in the art, taking into account the type of composition in question, for example, those suitable for oral administration may include flavoring agents.
[000202] In certain embodiments, a composition comprising an active ingredient described here (for example, a compound of formula (la) or (lb), or its pharmaceutically acceptable salt) in a variation does not contain an agent that affects the rate at which the active ingredient is metabolized. Thus, it is understood that compositions comprising a compound of formula (la) or (lb) in certain embodiments do not comprise an agent that affects (for example, slowing down, preventing or slowing down) the metabolism of a compound of formula (la) or (lb) or any other active ingredient administered separately, sequentially or simultaneously with a compound of formula (la) or (lb). It is also understood that any of the modes, kits, articles of manufacture and the like described herein in certain embodiments do not comprise an agent that affects (for example, slowing down, preventing or slowing down) the metabolism of a compound of formula (la) or (lb) or any other active ingredient administered separately, sequentially or simultaneously with a compound of either formula (la) or (lb).
[000203] In some embodiments, a composition comprising an active ingredient described herein (for example, a compound of Formula (la), (lb), (lla), and / or (llb), or its pharmaceutically acceptable salt) in a The variation does not contain an agent that affects the rate at which the active ingredient is metabolized. Thus, it is understood that compositions comprising a compound of Formula (la), (lb), (lla) and / or (llb) in certain embodiments do not comprise an agent that affects (for example, slowing, preventing or delaying) the metabolism of a compound of Formula (la), (lb), (lla) and / or (llb) or any other active ingredient administered separately, sequentially or simultaneously with a compound of Formula (la), (lb), (lla) ) and / or (llb). It is also understood that any of the modes, kits, articles of manufacture and the like described herein in certain embodiments do not comprise an agent that affects (for example, slowing down, preventing or slowing down) the metabolism of a compound of Formula (la), (lb), (lla) and / or (llb) or any other active ingredient administered separately, sequentially or simultaneously with a compound of any Formula (la), (lb), (lla), and / or (llb) . Methods of Use
[000204] In certain embodiments, a method for treating or preventing an HlV infection in an individual (e.g., a human), comprising administering a compound of formula (la) or (lb), or its pharmaceutically acceptable salt, to the individual is described. In some embodiments, a method for treating or preventing an HlV infection in an individual (e.g., a human), comprising administering a compound of Formula (la), (lb), (lla), and / or (llb ), or its pharmaceutically acceptable salt, to the individual. In certain embodiments, a method for inhibiting H1V virus replication, treating AlDS or delaying the onset of AlDS in an individual (e.g., a human), comprising administering a compound of formula (la) or (lb), or its pharmaceutically acceptable salt, to the individual is described.
[000205] In some embodiments, a method for inhibiting HlV virus replication, treating AIDS or delaying the onset of AIDS in an individual (eg, a human), comprising administering a compound of Formula (la) , (lb), (lla), and / or (llb), or their pharmaceutically acceptable salt, to the individual. In certain embodiments, a method for preventing an HlV in an individual (comprising a human), comprising administering a compound of formula (la) or (lb), or its pharmaceutically acceptable salt, to the individual is described. In certain embodiments, the individual is at risk of contracting the HlV virus, such as an individual who has one or more risk factors known to be associated with the contraction of the HlV virus.
[000206] In some embodiments, a method for preventing an HlV infection in an individual (e.g., a human), including administering a therapeutically effective amount of a compound of Formula (la), (lb), ( lla) and / or (llb), or its pharmaceutically acceptable salt, to the individual is described. In certain modes, the individual is at risk of contracting the HlV virus, as is an individual who has one or more risk factors known to be associated with the contraction of the HlV virus.
[000207] In certain embodiments, a method for treating an HlV infection in an individual (e.g., a human) is described, comprising administering a compound of formula (la) or (lb), or its pharmaceutically acceptable salt to the individual. In some embodiments, a method for treating an HlV infection in an individual (e.g., a human), comprising administering a compound of Formula (la), (lb), (lla) and / or (llb), or its pharmaceutically acceptable salt, to the individual is described.
[000208] In certain embodiments, a method for treating an HlV infection in an individual (e.g., a human), comprising administering to the individual in need thereof a therapeutically effective amount of a compound of formula (la) or (lb) , or their pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three or four; or one or two; or one to three; or one to four) selected additional therapeutic agents of the group consisting of HlV protease inhibitor compounds, reverse transcriptase HlV non-nucleoside inhibitors, reverse transcriptase HlV non-nucleotide inhibitors, reverse transcriptase HlV nucleoside inhibitors, reverse transcriptase HlV nucleotide inhibitors, of HlV integrase, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and the other drugs for the treatment of HlV, and their combinations are described. In certain embodiments, a method of treating an HlV infection in an individual (e.g., a human), comprising administering to the individual in need thereof a therapeutically effective amount of a compound of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of 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 selected from the group consisting of combined HlV drugs, other drugs for the treatment of HlV, HlV protease inhibitors, non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HlV nucleoside or reverse transcriptase nucleotide inhibitors, HlV integrase inhibitors, non-catalytic HlV (or allosteric) integrase inhibitors, HlV entry inhibitors, HlV maturation inhibitors, latency reversal agents, compounds that target caps HIV ideo, immunity-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, modulators peptidyl-prolyl cis-trans isomerase A, protein disulfide isomerase inhibitors, C5a complement receptor antagonists, DNA methyl transferase inhibitor, Vif dimerization antagonists, HIV-1 viral infectious factor inhibitors, inhibitors of TAT protein, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 inhibitors (MLK-3), HIV-1 junction inhibitors, Rev protein inhibitors, integrin antagonists, inhibitors nucleotide protein, junction factor modulators, protein 1 modulators containing COMM domain, HIV ribonuclease H inhibitors, retrocycline modulators, CDK-9 inhibitors, non-integrin 1-capture inhibitors and dendritic ICAM-3, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement H Factor modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase stimulators PC9, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combinations thereof. described.
[000209] In some embodiments, a method for treating an HIV infection in an individual (for example, a human), comprising administering to the individual in need thereof a therapeutically effective amount of a compound of Formula (Ia), (Ib) , (IIa), and / or (IIb), or their pharmaceutically acceptable salt, in combination with a therapeutically effective amount of 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 selected from the group consisting of HIV protease inhibitor compounds, HIV non-nucleoside reverse transcriptase inhibitors, HIV non-nucleotide reverse transcriptase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmaco enhancers and other drugs for the treatment of HIV, and their combinations are described. In certain embodiments, a method of treating an HIV infection in an individual (for example, a human), comprising administering to the individual in need thereof a therapeutically effective amount of a compound of Formula (Ia), (Ib), (IIa ), and / or (IIb), or their pharmaceutically acceptable salt, in combination with a therapeutically effective amount of 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 selected from the group consisting of combined HIV drugs, other drugs for the treatment of HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase, nucleoside or HIV nucleotide inhibitors reverse transcriptase inhibitors, HIV integrase inhibitors, non-catalytic HIV (or allosteric) site integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, targeting compounds HIV capsid, immunological therapies, phosphatidylinositol 3 kinase (PI3K) s inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, modulators peptidyl prolyl cis-trans isomerase A, disulfide protein inhibitors, C5a complement receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, infectious factor inhibitors viral infection, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed strain kinase-3 inhibitors (MLK-3), HIV-1 junction inhibitors, Rev protein inhibitors , integrin antagonists, nucleoprotein inhibitors, junction factor modulators, protein modulators containing COMM domain, HIV ribonuclease H inhibitors, retrocycline modulators, CDK-9 inhibitors, inhibitors dendritic ICAM-3 capture non-integrin 1, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, kinase inhibitors cyclin-dependent, PC9 proprotein convertase stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or any combinations of these are described. In certain embodiments, a compound of formula (Ia) or (Ib), or its pharmaceutically acceptable salt for use in medical therapy for an HIV infection (for example, HIV-1 or HIV virus replication (for example HIV-1 ) or AIDS or delaying the onset of AIDS in an individual (for example, a human) is described.
[000210] In some embodiments, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or its pharmaceutically acceptable salt for use in medical therapy for an HIV infection (for example, HIV- 1 or the replication of HIV (eg, HIV-1) or AIDS or delaying the onset of AIDS in an individual (eg, a human)) is described.
[000211] In certain embodiments, a compound of formula (Ia) or (lb), or a pharmaceutical product its acceptable salt for use in the manufacture of a drug for the treatment of an HlV infection or in the replication of the HlV or AIDS virus or in delaying the onset of AIDS in an individual (for example, a human) is described.
[000212] One embodiment refers to a compound of formula (la) or (lb), or its pharmaceutically acceptable salt, for use in the prophylactic or therapeutic treatment of an HlV or AlDS infection or for use in therapeutic treatment or delaying the start of AlDS.
[000213] In some embodiments, a compound of Formula (la), (lb), (lla) and / or (llb), or its pharmaceutically acceptable salt, for use in the manufacture of a medicament to treat an HlV infection or replication of the HlV or AlDS virus or the delay in the onset of AlDS in an individual (eg, a human) is described. One embodiment refers to a compound of Formula (la), (lb), (lla) and / or (llb), or its pharmaceutically acceptable salt, for use in the prophylactic or therapeutic treatment of an HlV or AlDS infection or for use in therapeutic treatment or delaying the onset of AlDS.
[000214] In certain embodiments, the use of a compound of formula (la) or (lb), or its pharmaceutically acceptable salt, for the manufacture of a drug for an HlV infection in an individual (for example, a human) is described. In certain embodiments, a compound of any of the formula (la) or (lb), or its pharmaceutically acceptable salt, is described for use in the prophylactic or therapeutic treatment of an HlV infection.
[000215] In some embodiments, the use of a compound of Formula (la), (lb), (lla) and / or (llb), or its pharmaceutically acceptable salt, for the manufacture of a medicament for an infection by HlV in an individual (for example, a human) is described. In certain embodiments, a compound of any of Formulas (la), (Ib), (lla) and / or (llb), or its pharmaceutically acceptable salt, is described for use in the prophylactic or therapeutic treatment of an HIV infection .
[000216] In certain modalities, in the methods of use, the administration is to an individual (for example, a human) in need of treatment. In certain modalities, in the methods of use, the administration has as its object (for example, a human) who is at risk of developing AIDS. Included here is a compound of formula (la) or (lb), or its pharmaceutically acceptable salt, for use in therapy. In one embodiment, the compound of formula (la) or (lb), or its pharmaceutically acceptable salt, for use in a method of treating an HlV infection or HlV or AlDS virus replication or delaying the onset of AlDS in an individual (for example, a human).
[000217] In some embodiments, a compound of formula (la), (lb), (lla), and / or (llb), or its pharmaceutically acceptable salt, for use in therapy is described herein. In some embodiments, the compound of Formula (la), (lb), (lla), and / or (llb), or its pharmaceutically acceptable salt, is for use in a method of treating an HlV infection or in replication of the HlV or AlDS virus or delayed onset of AlDS in an individual (eg, a human). Also described herein is a compound of formula (la) or (lb), or its pharmaceutically acceptable salt, for use in a method of treating or preventing HlV infection in an individual in need thereof. In certain embodiments, a compound of formula (la) or (lb), or its pharmaceutically acceptable salt, is provided for use in a method of treating HlV infection in an individual in need thereof. In certain embodiments, the individual in need of this is a human who has been infected with HlV. In certain modalities, the individual in need of this is a human who has been infected with HIV but who has not developed AIDS. In certain modalities, the individual in need of it is at risk of developing AIDS. In certain modalities, the individual in need of this is a human who has been infected with HIV and has developed AIDS.
[000218] In some embodiments, a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or its pharmaceutically acceptable salt, for use in a treatment or prevention method is described herein. HIV infection in an individual who needs it. In certain embodiments, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or its pharmaceutically acceptable salt, for use in a method of treating HIV infection in an individual in need of the same is provided. In certain modalities, the individual in need of this is a human who has been infected with HIV. In certain modalities, the individual in need of this is a human who has been infected with HIV but who has not developed AIDS. In certain modalities, the individual in need of this is an individual at risk for the development of AIDS. In certain modalities, the individual in need of this is a human who has been infected with HIV and who has developed AIDS.
[000219] In one embodiment, a compound of formula (Ia) or (Ib), or its pharmaceutically acceptable salt, 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 are provided as described herein for use in a method of treating or preventing HIV infection in a needy individual. In one embodiment, said additional therapeutic agents are selected from the group consisting of combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) site integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, targeting compounds the HIV capsid, immunological therapies and phosphatidylinositol 3-kinase (PI3K) inhibitors, anti-HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists , peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, C5a complement receptor antagonists, inhibitor DNA methyltransferase, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, kinase inhibitors -3 mixed lineage (MLK-3), HIV-1 junction inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, junction factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease inhibitors H, retrocycline modulators, CDK-9 inhibitors, dendritic ICAM-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement H Factor modulators, ubiquitin ligase inhibitors , deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, PC9 stimulators of proprotein convertase, DDP3X inhibitors of ATP-dependent RNA helicase, inhibitors of the transc initiation complex reverse riptase, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combination of these. In one embodiment, said additional therapeutic agents are selected from the group consisting of HIV protease inhibitor compounds, HIV non-nucleoside reverse transcriptase inhibitors, HIV non-nucleotide reverse transcriptase inhibitors, HIV nucleoside reverse transcriptase inhibitors , HIV nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers and other drugs for the treatment of HIV and their combinations.
[000220] In some embodiments, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or its pharmaceutically acceptable salt, 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 as described herein for use in a method of treating or preventing HIV infection in an individual in need thereof is provided. additional therapeutic agents are selected from the group consisting of HIV combination drugs, other HIV treatment drugs, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide inhibitors reverse transcriptase inhibitors, HIV integrase inhibitors, non-catalytic HIV (or allosteric) site integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, targeting compounds the HIV capsid, immunological therapies and phosphatidylinositol 3-kinase (PI3K) inhibitors, anti-HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, modulators peptidyl-prolyl cis-trans isomerase A, protein disulfide isomerase inhibitors, C5a complement receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV- viral infectivity factor inhibitors 1, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed strain kinase-3 inhibitors (MLK-3), HIV-1 junction inhibitors, Rev protein inhibitors, antagonists integrin inhibitors, nucleoprotein inhibitors, junction factor modulators, protein modulators 1 containing COMM domain, HIV ribonuclease H inhibitors, retrocycline modulators, CDK-9 inhibitors, non-inhibitors dendritic ICAM-3 capture integrin 1, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cycline dependent kinaceous inhibitors , PC9 proprotein convertase stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combinations of these . In one embodiment, said additional therapeutic agents are selected from the group consisting of HIV protease inhibitor compounds, HIV non-nucleoside reverse transcriptase inhibitors, HIV non-nucleotide reverse transcriptase inhibitors, HIV nucleoside reverse transcriptase inhibitors , HIV nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers and other drugs for treating HIV and combinations thereof. In one embodiment, a compound of formula (Ia) or (Ib), or its pharmaceutically acceptable salt, in combination with a first additional therapeutic agent selected from the group consisting of tenofovir alafenamide fumarate, tenofovir alafenamide and teem hemifumarate nofovir alafenamide, and a second additional therapeutic agent, in which the second additional therapeutic agent is emtricitabine, is provided for use in a method of treating or preventing HIV infection in an individual who needs it. In a particular embodiment, a compound of formula (Ia) or (Ib), or its pharmaceutically acceptable salt, in combination with a first additional therapeutic agent selected from the group consisting of tenofovir disoproxyl fumarate, tenofovir disoproxyl and tenofovir hemifumarate disoproxyl, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine, is provided for use in a method of treating or preventing HIV infection in an individual in need thereof.
[000221] In some embodiments, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or its pharmaceutically acceptable salt, in combination with a first additional therapeutic agent selected from the group consisting of fumarate tenofovir alafenamide, tenofovir alafenamide and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is entricitabine, is provided for use in a method of treating or preventing HIV infection in an individual in need of it. In a particular embodiment, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or its pharmaceutically acceptable salt, in combination with a first additional therapeutic agent selected from the group consisting of tenofovir fumarate disoproxil, tenofovir disoproxy and tenofovir disoproxil hemifumarate, and a second additional therapeutic agent, where the second additional therapeutic agent is emtricitabine, is provided for use in a method of treatment or prevention of HIV infection in an individual who needs it .
[000222] In a particular embodiment, a compound of formula (Ia) or (Ib), or its pharmaceutically acceptable salt, is provided to prevent HIV infection when the individual is exposed to the virus and / or to prevent the virus from establishing a permanent infection and / or preventing the onset of disease symptoms and / or preventing the virus from reaching detectable levels in the blood, for example, for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Therefore, in certain embodiments, methods are provided to reduce the risk of acquiring HIV (for example, HIV-1 and / or HIV-2). For example, methods to reduce the risk of acquiring HIV (for example, HIV-1 and / or HIV-2) comprise the administration of a compound of formula (Ia) or (Ib), or its pharmaceutically acceptable salt. In certain embodiments, methods for reducing the risk of acquiring HIV (for example, HIV-1 and / or HIV-2) include administering a compound of formula (Ia) or (Ib), or its pharmaceutically acceptable salt, in combination with one or more additional therapeutic agents. In certain embodiments, methods for reducing the risk of acquiring HIV (for example, HIV-1 and / or HIV-2) comprise administering a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (Ia) or (Ib) , or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.
[000223] In some embodiments, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or its pharmaceutically acceptable salt, is provided to prevent HIV infection from assuming if the individual is exposed to the virus and / or prevent the virus from establishing a permanent infection and / or prevent the onset of symptoms of the disease and / or prevent the virus from reaching detectable levels in the blood, for example, for pre-exposure prophylaxis or post-prophylaxis exposure (PEP). Therefore, in certain embodiments, methods are provided to reduce the risk of acquiring HIV (for example, HIV-1 and / or HIV-2). For example, methods to reduce the risk of acquiring HIV (for example, HIV-1 and / or HIV-2) include administering a compound of Formula (Ia), (Ib), (IIa), and / or (IIb ), or its pharmaceutically acceptable salt. In certain embodiments, methods for reducing the risk of acquiring HIV (for example, HIV-1 and / or HIV-2) include administering a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or its pharmaceutically acceptable salt, in combination with one or more additional therapeutic agents. In certain embodiments, methods for reducing the risk of acquiring HIV (for example, HIV-1 and / or HIV-2) comprise administering a pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula (Ia), (Ib) , IIa), and / or (IIb), or their pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.
[000224] In certain embodiments, methods for reducing the risk of acquiring HIV (for example, HIV-1 and / or HIV-2) comprise the administration of a compound of formula (Ia) or (Ib), or its pharmaceutically acceptable salt, in combination with safer sex practices. In certain embodiments, methods for reducing the risk of acquiring HIV (for example, HIV-1 and / or HIV-2) include administering to an individual at risk of acquiring HIV. Examples of individuals at high risk of acquiring HIV include, without limitation, an individual who is at risk of sexual transmission of HIV.
[000225] In some embodiments, methods for reducing the risk of acquiring HIV (for example, HIV-1 and / or HIV-2) include administering a compound of Formula (Ia), (Ib), (IIa) , and / or (IIb), or its pharmaceutically acceptable salt, in combination with safer sexual practices. In certain embodiments, methods for reducing the risk of acquiring HIV (for example, HIV-1 and / or HIV-2) include administering to an individual at risk of acquiring HIV. Examples of individuals at high risk of contracting HIV include, without limitation, an individual who is at risk of sexual transmission of HIV.
[000226] In certain modalities, the reduction in the risk of acquiring HIV is at least about 40%, 50%, 60%, 70%, 80%, 90% or 95%. In certain modalities, the risk of acquiring HIV is reduced by at least about 75%. In certain modalities, the reduction in the risk of acquiring HIV is about 80%, 85% or 90%.
[000227] In another embodiment, the use of a compound of formula (Ia) or (Ib), or its pharmaceutically acceptable salt, for the manufacture of a medicament for the treatment of an HIV infection in a human who has or is in risk of having the infection is described.
[000228] In some embodiments, the use of a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or its pharmaceutically acceptable salt, for the manufacture of a medicine for the treatment of an HIV infection in a human who has or is at risk of having the infection is described.
[000229] Also described herein is a compound of formula (Ia) or (Ib), or its pharmaceutically acceptable salt, for use in the therapeutic treatment or delaying the onset of AIDS.
[000230] In some embodiments, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or its pharmaceutically acceptable salt, for use in therapeutic treatment or delaying the onset of AIDS.
[000231] Also described herein is a compound of formula (Ia) or (Ib), or its pharmaceutically acceptable salt, for use in the prophylactic or therapeutic treatment of an HIV infection.
[000232] In some embodiments, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or its pharmaceutically acceptable salt, for use in the prophylactic or therapeutic treatment of an infection is described herein. HIV.
[000233] In certain embodiments, a compound of formula (Ia) or (Ib), or its pharmaceutically acceptable salt, can be used as a research tool (for example, to study HIV inhibition of reverse transcriptase in an individual or in vitro).
[000234] In some embodiments, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or its pharmaceutically acceptable salt, can be used as a research tool (for example, to study the inhibition of HIV reverse transcriptase in an individual or in vitro) Administration Routines
[000235] The compound of formula (Ia) or (Ib), or its pharmaceutically acceptable salt, (also referred to herein as the active ingredient) can be administered by any routine appropriate to the condition being treated. Suitable routines 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 appreciated that the preferred routine may vary with, for example, the condition of the recipient. In certain embodiments, the described compounds can be dosed parenterally. In certain embodiments, the compounds described can be dosed intravenously, subcutaneously or intramuscularly. In certain embodiments, the compounds described are bioavailable orally and can be dosed orally.
[000236] In some embodiments, the compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or its pharmaceutically acceptable salt, (also referred to herein as the active ingredient) can be administered by any routine appropriate for the condition being treated. Suitable routines 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 appreciated that the preferred routine may vary with, for example, the condition of the recipient. In certain embodiments, the described compounds can be dosed parenterally. In certain embodiments, the compounds described can be dosed intravenously, subcutaneously or intramuscularly. In certain embodiments, the compounds described are bioavailable orally and can be dosed orally.
[000237] In some embodiments, the compound of Formula (la), (lb), (lla) and / or (llb), or its pharmaceutically acceptable salt, can be administered with a syringe suitable for administration of the compound. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the se-ring is pre-filled with the compound of Formula (la), (lb), (lla) and / or (llb), or its pharmaceutically acceptable salt.
[000238] In some embodiments, the compound of the formula (la), (lb), (lla), and / or (llb), or its pharmaceutically acceptable salt, can be administered with an autoinjector comprising a syringe. In some embodiments, the syringe is disposable. In some modes, the syringe is reusable. In some embodiments, the syringe is pre-filled with the compound of Formula (la), (lb), (lla) and / or (llb), or its pharmaceutically acceptable salt. Dosing Regimen
[000239] The compound, such as a compound of formula (la) or (lb), or its pharmaceutically acceptable salt, can be administered to an individual according to an effective dosing regimen over a desired period of time or duration, such as like at least about a day, at least about a week, at least about a month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more. In a variation, the compound is administered on a daily or intermittent schedule. In one variation, the compound is administered on a monthly schedule. In one variation, the compound is administered every two months. In a variation, the compound is administered every three months. In a variation, the compound is administered every four months. In a variation, the compound is administered every five months. In a variation, the compound is administered every 6 months.
[000240] In some embodiments, the compound, such as a compound of Formula (la), (lb), (lla), and / or (llb), or its pharmaceutically acceptable salt, can be administered to an individual according to an effective dosing regimen for a desired period of time or duration, such as at least one day, at least about a week, at least about a month, at least about 2 months, at least about 3 months, at least less about 4 months less about 6 months, or at least about 12 months or more. In some modalities, the compound is administered on a daily or intermittent schedule. In some modalities, the compound is administered on a monthly schedule. In some embodiments, the compound is administered every two months. In some embodiments, the compound is administered every three months. In some embodiments, the compound is administered every four months. In some modalities, the compound is administered every five months. In some embodiments, the compound is administered every 6 months.
[000241] In some embodiments, the compound, such as a compound of Formula (la), (lb), (lla) and / or (llb), or its pharmaceutically acceptable salt, can be administered to an individual at least at least about a month, at least about 4 months, or at least about 6 months. In some embodiments, the compound (for example, a compound of Formula (la), (lb), (lla), and / or (llb), or its pharmaceutically acceptable salt), can be administered subcutaneously to an individual by the least about a month. In some embodiments, the compound (for example, a compound of Formula (la), (lb), (1a) and / or (llb), or its pharmaceutically acceptable salt), can be administered routinely subcutaneously or intramuscularly to a individual at least about 4 months, or at least about 6 months. In some modalities, the compound (for example, a compound of Formula (la), (lb), (lla) and / or (llb), or its pharmaceutically acceptable salt), can be administered subcutaneously to an individual at least about a month. In some embodiments, the compound (for example, a compound of Formula (la), (lb), (lla) and / or (llb), or its pharmaceutically acceptable salt), can be administered subcutaneously or intramuscularly to one individual at least every 3 months.
[000242] The dosage or dosing frequency of a compound of formula (la) or (lb), or its pharmaceutically acceptable salt, can be adjusted throughout the treatment, based on the judgment of the doctor who administers it.
[000243] In some embodiments, the dosage or dosing frequency of a compound of Formula (la), (lb), (lla) and / or (llb), or its pharmaceutically acceptable salt, can be adjusted over time. treatment, based on the judgment of the administering physician.
[000244] The compound can be administered to an individual (e.g., a human) in an effective amount. In certain embodiments, the compound is administered once a day. In some embodiments, the compound can be administered to an individual (e.g., a human) in a therapeutically effective amount. In some embodiments, the compound is administered once a day. In some modalities, the compound is administered monthly. In some embodiments, the compound is administered every three months. In some embodiments, the compound is administered every four months. In some embodiments, the compound is administered every six months.
[000245] A compound as described herein (for example, a compound of formula (la) or (lb)), or its pharmaceutically acceptable salt, can be administered in a dosage amount that is effective. For example, the dosage amount can be from 1 mg to 1000 mg of compound. In certain embodiments, the dosage amount is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 100, 105, 110, 120, 130, 140 or 150 mg of compound. In certain embodiments, the dosage amount is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg.
[000246] In some embodiments, a compound as described herein (for example, a compound of Formula (la), (lb), (lla), and / or (llb)), or its pharmaceutically acceptable salt, can be administered in a dosage amount that is effective. For example, the dosage amount can be from 1 mg to 1000 mg of compound. In certain embodiments, the dosage amount is about 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 100, 105, 110, 120, 130, 140 or 150 mg of compound . In certain embodiments, the dosage amount is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg.
[000247] In some embodiments, a compound of formula (la), (lb), (lla), and / or (llb)), or its pharmaceutically acceptable salt, is administered in a dose once a day. In some embodiments, a compound of Formula (la), (lb), (lla), and / or (llb)), or its pharmaceutically acceptable salt, is administered in a single daily dose of about 1 mg.
[000248] In some embodiments, a compound of formula (la), (lb), (lla), and / or (llb)), or its pharmaceutically acceptable salt, is administered monthly. In some embodiments, a compound of Formula (la), (lb), (lla), and / or (llb)), or its pharmaceutically acceptable salt, is administered monthly at a dose of about 100 mg.
[000249] In some embodiments, a compound of Formula (la), (lb), (lla) and / or (llb)), or its pharmaceutically acceptable salt, is administered every 6 months. In some embodiments, a compound of Formula (la), (lb), (lla) and / or (llb)), or its pharmaceutically acceptable salt, is administered every 6 months at a dose of about 600 mg. Kits and Articles of Manufacture
[000250] The present description relates to a kit comprising a compound of formula (la) or (lb), or its pharmaceutically acceptable salt. In one embodiment, the kit can comprise one or more additional therapeutic agents as described above. The kit may further comprise instructions for use, for example, for use in inhibiting an HlV reverse transcriptase, such as for use in the treatment of an HlV or AlDS infection or as a research tool. Instructions for use are generally written instructions, although instructions for supporting electronic storage (for example, magnetic floppy disk or optical disk) are also acceptable.
[000251] In some embodiments, the present description relates to a kit comprising a compound of formula (la), (lb), (lla), and / or (llb), or its pharmaceutically acceptable salt. In one embodiment, the kit can comprise one or more additional therapeutic agents as described above. The kit may further comprise instructions for use, for example, for use in inhibiting an HlV reverse transcriptase, such as for use in the treatment of an HlV or AlDS infection or as a research tool. Instructions for use are generally written instructions, although instructions for supporting electronic storage (for example, magnetic floppy disk or optical disk) are also acceptable.
[000252] The present description also relates to a pharmaceutical kit comprising one or more receptors comprising a compound of formula (la) or (lb), or its pharmaceutically acceptable salt. Optionally associated with this (these) container (s) may be a notice in the form prescribed by a government agency that regulates the manufacture, use or sale of pharmaceutical products, a notice that reflects the agency's approval for the manufacture, use or sale for admi - human administration. Each component (if there is more than one component) can be packed in separate containers or some components can be combined in a container where cross-reactivity and expiration date allow. The kits can be in unit dosage forms, bulk packages (for example, multiple dose packages) or subunit doses. The kits may also include multiple unit doses of the compounds and instructions for use and be packaged in sufficient quantities for storage and use in pharmacies (for example, hospital pharmacies and compound pharmacies).
[000253] In some embodiments, the present description also relates to a pharmaceutical kit comprising one or more containers comprising a compound of Formula (la), (lb), (lla) and / or (llb), or its pharmaceutically acceptable salt . Optionally associated with this (these) container (s) may be a notice in the form prescribed by a government agency that regulates the manufacture, use or sale of pharmaceutical products, a notice that reflects the agency's approval for the manufacture, use or sale for administration human. Each component (if there is more than one component) can be packed in separate containers or some components can be combined in a container where cross-reactivity and expiration date allow. The kits can be in unit dosage forms, bulk packages (for example, multiple dose packages) or subunit doses. The kits can also include multiple unit doses of the compounds and instructions for use and be packaged in sufficient quantities for storage and use in pharmacies (for example, hospital pharmacies and compound pharmacies).
[000254] Also described are articles of manufacture comprising a unit dosage of a compound of formula (la) or (lb), or its pharmaceutically acceptable salt, in a packaging suitable for use in the methods described herein. Suitable packaging is known in the art and includes, for example, flasks, containers, clamping them, bottles, flasks, flexible packaging and the like. An article of manufacture can also be sterilized and / or sealed. In some embodiments, articles of manufacture are described here comprising a unit dosage of a compound of Formula (la), (lb), (lla), and / or (llb), or its pharmaceutically acceptable salt, in a packaging suitable for use in the methods described here. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, flasks, flexible packaging and the like. An article of manufacture can also be sterilized and / or sealed. Nomenclature
[000255] The compound name of formula (la) and (lb) of the current description when generated using ChemBioDraw Ultra 11.
is N- (1- (3- (4-chloro-3- (methylsulfonamido) -1- (2,2,2-trifluoroethyl) -1 H-indazol-7-yl) -6- (3-methyl-3 - (methylsulfonyl) but-1-in-1-yl) pyridin-2-yl) -2- (3,5-difluoro-phenyl) ethyl) -2- (5,5-difluoro-3- (trifluoromethyl) - 3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetamide.
is N - ((S) -1- (3- (4-chloro-3- (methylsulfonamido) -1- (2,2,2-trifluoroethyl) -1 H- indazol-7-yl) -6- (3 -methyl-3- (methylsulfonyl) but-1-in-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) -2 - ((3bS, 4aR) -5,5- difluoro-3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1 H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetamide.
[000256] The name of the compound of formula (lla) and (llb) of the current description when generated using ChemBioDraw Ultra 14.
is N- (1- (3- (4-chloro-3- (cyclopropanesulfonamido) -1- (2,2-difluoroethyl) -1 H- indazol-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-1 H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetamide.
is N - ((S) -1- (3- (4-chloro-3- (cyclopropanesulfonamido) -1- (2,2-difluoroethyl) - 1H-indazol-7-yl) -6- (3-methyl- 3- (methylsulfonyl) but-1-in-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) -2 - ((3bS, 4aR) -3- (difluoromethyl) -5 , 5-difluoro-3b, 4, 4a, 5-tetrahydro-1 H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetamide. Synthesis of the Compound of Formula (la), (Ib), (lla) and (llb)
[000257] The present description is also directed to processes and intermediates useful for preparing the object compound or its pharmaceutically acceptable salts.
[000258] Unless otherwise indicated, the methods and techniques of the present description are generally performed according to conventional methods well known in the art and as described in various general and more specific references which are cited and discussed throughout the present specification. See, for example, Loudon, Organic Chemistry, 5th edition, New York: Oxford University Press, 2009; Smith, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th edition, Wiley-lnterscience, 2013.
[000259] In certain cases, the processes described herein involve a step of forming a salt of a compound of the present description.
[000260] In certain cases, intermediates useful in the preparation of a compound of formula (la) or (lb) of the present description are provided. For example, these intermediates include any one or a combination of Compounds 1 to 23 or its salt. In certain embodiments, intermediates are selected from Compounds 8a, 12, 14, 19, 20, 21,22, 23 and / or 23b, their combinations or salts thereof.
[000261] In some embodiments, intermediates useful in preparing a compound of formula (1a) or (llb) of the present description are provided. For example, these intermediates include any or a combination of Compounds 1, 10, 20 and 25-37 or their salt. In some embodiments, intermediates are selected from Compounds 20, 32, 34, 35, 36 and / or 37, combinations of these, or their salts.
[000262] The compounds as described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, chromatography supercritical fluid (SFC) and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reverse phases, as well as ionic resins. More typically, the described compounds are purified by chromatography on silica gel and / or alumina. See, for example, Introduction to Modern Liquid Chromatography, 2a-ed., Ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.
[000263] During any of the processes for the preparation of the object compounds, it may be necessary and / or desirable to protect sensitive or reactive groups in any of the object molecules. This can be achieved through conventional protecting groups, as described in standard works, such as TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 4th ed., Wiley, New York 2006. Protective groups can be removed at a convenient subsequent step using methods known in the art.
[000264] Exemplary chemical entities useful in the methods of the modalities will now be described by reference to illustrative synthetic schemes for their general preparation here and the specific examples that follow. Someone skilled in the art will recognize that the transformations shown in the diagrams below can be performed in any order that is compatible with the functionality of the particular pending groups. Each of the reactions described in the general schemes is preferably carried out at a temperature from about 0 ° C to the reflux temperature of the organic solvent used.
[000265] The compounds described here may exhibit atropisomerism resulting from steric impediment that affects the rate of axial rotation around a single bond. The resulting conformational isomers can each be observed as distinct entities through characterization techniques such as NMR and HPLC. The compounds described herein can exist as a mixture of atropomers. However, the detection of atropisomers depends on factors such as temperature, solvent, purification conditions and time scale of the spectroscopic technique. The room temperature interconversion rate has a half-life of minutes to hours, hours to days or days to years. The proportion of atropisomers in the balance may not be the unit. The characterization data presented here may not represent the equilibrium state depending on the conditions of isolation and characterization that may include, but are not limited to handling, solvents used and temperature.
[000266] Representative syntheses of the compounds of the present description are described in the schemes below, and in the following particular examples. The following examples are merely illustrative and are not intended to limit this description in any way. Preparation of 2 - ((3bS, 4aR) -5,5-difluoro-3- (trifluoromethyl) -3b, 4, 4a, 5-tetrahydro-1 H-cyclopropa [3,4] cyclopenta [1,2 -c] pyrazol-1-yl) acetic (8a) and 2 - ((3bR, 4aS) -5,5-difluoro-3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1 H -cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetic (8b): Example 1 Preparation of Compounds 8a and 8b
Synthesis of lithium 2,2,2-trifluoro-1- (3-oxobicyclo [3.1.0] hexan-2-ylidene) ethan-1-olate (2):
[000267] A reactor was loaded with bicycles [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 via an addition funnel at a rate to maintain the internal temperature at <1 ° C. After the addition was complete, hexanes (235 mL) were added in a constant stream through an addition funnel and stirred for 15 min. The resulting solids were collected by filtration, washed with hexanes (3 x 400 ml) and dried to provide the title compound. Synthesis of ethyl 2- (3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1 H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetate ( 3):
[000268] A reactor was charged with 2,2,2-trifluoro-1- (3-oxobicyclo [3.1.0] hexan-2-ylidene) ethan-1-lithium lithium (177.2 g, 0.89 mol ) and EtOH (ethanol) (779 ml). The temperature was raised and maintained at 0 ° C. HCl in dioxane (4.0 N, 443 mL) was added via an addition funnel followed by the addition of ethyl hydroxyacetate HCl salt (138.4 g, 0.90 mol). The reaction temperature was adjusted to 35 ° C. After 1 h, the reaction volume was reduced by ~ 40% by distillation under reduced pressure. Water (1.3 L) was added with vigorous stirring and the temperature was adjusted to 15 ° C. The resulting solids were collected by filtration, washed with water (3 x 500 ml), hexanes (3 x 400 ml) and dried to provide the title compound. MS (m / z) 275.1 [M + H] +. Synthesis of 2- (5-oxo-3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1 H-cyclopropane [3,4] cyclopenta [1,2-c] pyrazole-1- il) ethyl acetate (4):
[000269] A reactor was charged with 2- (3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1 H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole-1- il) ethyl 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 amount to be added). The reaction mixture was heated to 50 ° C and the remaining NaClO2 (163.0 g, 1.80 mol) was added in five portions over 2 h. After consumption of the starting material, the temperature was adjusted to 20 ° C and aqueous sodium bisulfite (40% w / w, 350 ml) was added via an addition funnel. Ethyl acetate (1.75 L) was added and the layers were separated. The aqueous layer was re-extracted with EtOAc (ethyl acetate) (500 ml). The organic layers were combined and washed with saturated aqueous NaHCO3 (500 ml) and 1: 1 water / brine (500 ml). The organic layer was concentrated under reduced pressure and coevaporated with IPAc (isopropyl acetate) (300 ml). The crude solid was crystallized from an IPAc / heptane mixture. The resulting solids were collected by filtration, washed with heptane and dried to provide 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) acid acetic (5):
[000270] To a solution of 2- (5-oxo-3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1 H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole -1-yl) ethyl acetate (80.40 g, 278.95 mmol) in 2-MeTHF (2-methyltetrahydrofuran) (167 ml) 2 M aqueous sodium hydroxide (167 ml) was added. After 25 minutes of stirring at room temperature, the reaction mixture was diluted with 2-MeTHF and was slowly acidified by the dropwise addition of concentrated HCl. The organic layer was isolated, and the aqueous layer was extracted with an additional portion of 2-MeTHF. The combined organic layers were washed with saturated aqueous sodium chloride, then dried over sodium sulfate, filtered and concentrated. The resulting oil was taken up in ethyl acetate. Hexanes were added with vigorous stirring until the formation of solids was observed. The solid was isolated by filtration and dried to provide the title compound. MS (m / z) 259.00 [M-H] -. Synthesis of 2- (3- (trifluoromethyl) -4,4a-dihydrospiro [cyclopropa [3,4] cyclopenta [1,2-c] pyrazole-5,2 '- [1,3] dithiolane] -1 acid (3bH) -yl) acetic (6):
[000271] To a solution of 2- (5-oxo-3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1 H-cyclopropa acid [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetic acid (3.0 g, 11.5 mmol) in DCM (dichloromethane) (25 mL) was added 1,2-ethanedithiol (1.07 mL, 12.68 mmol) followed by trifluoride complex boron-acetic acid (4.0 mL, 28.8 mmol). The reaction mixture was stirred at room temperature overnight. To the reaction mixture, water (60 ml) and 2-MeTHF (60 ml) were added. 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 diluted with hexanes (12 ml) with vigorous stirring to provide a solid. The solid was isolated by filtration and dried to provide the title compound. MS (m / z) 337.12 [M + H] +. Synthesis of 2- (5,5-difluoro-3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1 H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole-1- il) acetic (7):
[000272] To a suspension of 1,3-dibromo-5,5-dimethylhydantoin (12.75 g, 44.6 mmol) in DCM (35 mL) was added pyridine hydrofluoride (5.0 mL) at 0 The suspension was stirred at 0 ° C for 10 minutes. To the suspension was added a solution of 2- (3- (trifluoromethyl) - 4,4a-dihydrospiro [cyclopropa [3,4] cyclopenta [1,2-c] pyrazole-5,2 '- [1,3 ] dithioloan] -1 (3bH) -yl) acetic (5.00 g, 14.9 mmol) dropwise. After the addition was complete, the reaction mixture was stirred at 0 ° C for an additional 15 minutes. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (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 over sodium sulfate, filtered and concentrated. The resulting solid was taken up in MTBE (16 ml) and filtered to remove any resulting solid. The solution was then extracted with 2N NaOH (16 ml). The aqueous layer was diluted with water (16 ml) with vigorous stirring and stirred at room temperature for 15 minutes. The resulting solid was removed by filtration. The aqueous layer was acidified by the slow dropwise addition of concentrated HCl to pH ~ 1 with vigorous stirring to provide a solid precipitate. The solid was isolated by filtration to provide 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-1 H-cyclopropa [3,4] cyclopenta [1,2 -c] pyrazol-1-yl) acetic acid (8a) and 2 - ((3bR, 4aS) -5,5-difluoro-3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1H- cyclopropa [3,4] cyclopenta $ 112- c] pyrazol-1-yl) acetic (8b):
[000273] 2- (5,5-Difluoro-3- (trifluoromethyl) -3b) acid, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole- 1-yl) acetic was separated into its constituent enantiomers, the title compounds, by chiral SFC under the following conditions: Instrument: Thar 350 preparative SFC; Column: ChiralPak IC-10u, 300 x 50 mm ID; Mobile phase: 35% isopropanol (0.1% NH3-H2O) and CO2; Flow rate: 200 mL / min; Column temperature: 38; UV detection: 220 nm; Sample preparation: The compound was dissolved in ~ 45 mg / mL isopropanol; Injection: 6.5 mL per injection. Analytical SFC [mobile phase: A for CO2 and B for isopropanol (0.05% DEA); Gradient: B 20%; THE; Flow rate: 2.35 ml / min; Column: Chiralpak IC-3, 150 x 4.6 mm, 3 µm; Wavelength: 254 nm] 8a: t = 3.39 min, 8b: t = 2.17 min. Compound 8a - 1H NMR (400 MHz, chloroform-d) 4.93 (s, 2H), 2.52 - 2.43 (m, 2H), 1.44 - 1.38 (m, 1H), 1, 15 (m, 1H). Example 2 Preparation of Compound 12
Synthesis of 7-bromo-4-chloro-1H-indazol-3-amine (10):
[000274] 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 room temperature, EtOH (20 mL) was added to allow stirring. The solids were isolated by filtration, washed with cold EtOH and dried to provide 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):
[000275] A reactor was charged with 7-bromo-4-chloro-1H-indazol-3-amine (397.2 g, 1.6 mol) and Cs2CO / (1052 g, 3.2 mol) and then diluted with DMF (dimethylformamide) (4000 ml). To this was added slowly 2,2,2-trifluoroethyl trifluoromethanesulfonate (463.2 g, 1.9 mol) by means of addition funnel. After the addition was complete, the reaction mixture was allowed to stir for 1 hour, at which point H2O (16 L) was slowly added. At the end of the addition, the mixture was allowed to stir for 12 hours at 15 ° C. The suspension was filtered, and the collected solids were suspended in DMF (800 mL). To this was added H2O (4800 ml), and the resulting solids were collected by filtration and dried to provide the title compound. MS (m / z) 330.1 [M + H] +. Synthesis of 4-chloro-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1- (2,2,2-trifluoroethyl) -1H-indazol-3- amine (12):
[000276] A reaction vessel was charged with 7-bromo-4-chloro-1- (2,2,2-trifluoroethyl) -1H-indazol-3-amine (15.00 g, 45.66 mmol), bis (pinacolate) diboro (17.39 g, 68.49 mmol), potassium propionate (15.36 g, 136.98 mmol), dioxane (90 mL) and DMF (dimethylformamide) (30 mL). Bis (triphenylphosphine) palladium (II) dichloride (0.64 g, 0.91 mmol) was added and the reaction solution was degassed by bubbling argon for 2 min. The reaction mixture was heated to 105 ° C for 4 h. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite and the silica gel washed with EtOAc. 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 room temperature and stirred for 15 h. The solids were collected by filtration and dried to produce the title compound. MS (m / z) 376.7 [M + H] + 1H NMR (400 MHz, DMSO- d—) δ 7.69 (d, 1H), 7.06 (d, 1H), 5.55 (s , 2H), 5.45 (q, 2H), 1.32 (s, 12H). Example 3 Preparation of Compound 14
Synthesis of 3-methyl-3- (methylsulfonyl) but-1 -ine (14):
[000277] 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) added 3-chloro-3-methylbut-1 -ine (15.00 g, 146.3 mmol, 16.4 mL) was added dropwise. The resulting reaction mixture was heated to 40 ° C and stirred for 16 h. The reaction mixture was cooled to room temperature and diluted with EtOAc. The solution was washed with water and brine. The organic layer was collected and dried over sodium sulfate, then filtered. The solution was concentrated in vacuo and purified by silica gel chromatography to provide the title compound. Mp: 114.8-115.5. 1H NMR (400 MHz, chloroform- d) δ 3.04 (s, 3H), 2.58 (s, 1H), 1.67 (s, 6H). Example 4 Preparation of Compound 19
Synthesis of (S) -N - ((3,6-dibromopyridin-2-yl) methylene) -2-methylpropane-2-sulfinamide (16):
[000278] 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). To the reaction mixture, Cs2CO3 (41.94 g, 0.316 mol) was added as a solid in one portion. The reaction mixture was stirred 2 h then cooled to 5 ° C. Water (1.3 L) was added to the reaction mixture. The resulting suspension was stirred for 1 h, the solids were isolated by filtration, washed with water (5 x 100 ml) and dried to provide the title compound. MS (m / z) 368.9 [M + H] +. Synthesis of (S) -N - ((S) -1- (3,6-dibromopyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) -2-methylpropane-2-sulfinamide (17):
[000279] A reaction vessel was charged with (S) -N - ((3,6-dibromo-pyridin-2-yl) methylene) -2-methylpropane-2-sulfinamide (65.5 g, 177.95 mmol ) followed by DMF (dimethylformamide) (260 ml). The mixture was stirred for 5 min until homogeneous, and the solution was cooled to 8 ° C. To the reaction mixture, (3,5-difluorobenzyl) zinc bromide (0.5 M in THF (tetrahydrofuran), 516.04 mL) was added dropwise over 90 minutes. The mixture was stirred for an additional 2.5 h. To the reaction mixture was added 5% AcOH (acetic acid) in water (640 ml) over 10 min followed by CPME (cyclopentyl methyl ether) (320 ml) in one portion. The mixture was stirred for 5 minutes, warmed to room temperature and the layers were separated. The organic layer was washed with 5% AcOH (320 ml), then treated with 0.5 M NaOH (330 ml) and washed with brine. The organic layer was collected, dried with Na.SO4 and filtered. To the reaction mixture, MeOH (methanol) (33 mL) was added. To the stirred mixture, 3M HCl in CPME (128 mL) was added dropwise over 15 min. After stirring for 1 h, 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 basified with 8M NaOH and extracted with CPME (375 ml). The organic layer was washed with brine, dried over Na.SO4 and filtered to provide 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):
[000280] 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 CPME to a volume of 700 ml, to which was added acetonitrile (350 ml). To the stirred mixture, concentrated HCl (37%, 16.4 mL) was added dropwise over 10 minutes at room temperature. The slurry was vigorously stirred for 4 h. The solids were filtered and washed with 2: 1 CPME (cyclopropyl methyl ether): ACN to provide the title compound. MS (m / z) 393.3 [M + H] +. Synthesis of tert-butyl (S) - (1- (3,6-dibromopyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) carbamate (19):
[000281] A reaction vessel was loaded with 2-MeTHF (190 ml), water (190 ml) and (S) -1- (3,6-dibromopyridin-2-yl) -2- (3,5-difluorophenyl ) ethan-1-amine (46.9 g, 0.11 mol) followed by addition in portions of NaHCO / (30.34 g, 0.36 mol). The reaction mixture was cooled to 5 ° C and di-tert-butyl dicarbonate (27.47 g, 0.13 mol) was added. The reaction mixture was stirred at 0 ° C for 2 h and at room 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 column chromatography on silica to provide the title compound. MS (m / z) 492.8 [M + H] +. 1H NMR (400 MHz, methanol-d4) δ 7.85 (d, 1H), 7.42 (d, 1H), 6.90-6.72 (m, 3H), 5.33 (dd, 1H) , 3.10 (dd, 1H), 2.92 (dd, 1H), 1.36 (s, 9H). Example 5 Preparation of Formula (lb) (Compound 24)

Synthesis of tert-butyl (S) - (1- (3-bromo-6- (3-methyl-3- (methylsulfonyl) but-1-in-1-yl) pyridin-2-yl) -2- (3 , 5-difluorophenyl) ethyl) carbamate (20)
[000282] A reactor was charged with tert-butyl (S) - (1- (3,6-dibromo-pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) carbamate (50.00 g, 101.8 mmol), 3-methyl-3-methylsulfonyl-but-1-yne (17.86 g, 122.2 mmol), DMF (dimethylformamide) (90 mL) and Et3N (trimethylamine) (42.5 mL, 305.4 mmol). The reaction mixture was heated to 50 ° C. Bis (triphenylphosphine) palladium (II) dichloride (2.14 g, 3.1 mmol) and copper (I) iodide (0.58 g, 3.1 mmol) were added. After 30 min, the reaction mixture was diluted with MeCN (acetonitrile) (200 ml) and then NH4Cl aq. (200 ml) was added dropwise. A suspension was formed and adjusted to room temperature. After 3 h, the solids were collected by filtration. The mass was washed with MeCN / water (1: 1, 75 ml) twice and MTBE (tert-butyl methyl ether) (75 ml). The solid was dried to provide the title compound. MS (m / z) 556 [M + H] +. 1H NMR (400 MHz, chloroform-d) δ 7.84 (d, J = 8.2 Hz, 1H), 7.29 - 7.15 (m, 1H), 6.70 - 6.55 (m, 2H), 5.79 (d, J = 9.0 Hz, 1H), 5.57 - 5.45 (m, 1H), 3.21 - 3.05 (m, 4H), 2.99 - 2 , 88 (m, 1H), 1.80 (s, 6H). 1.40 * (s, 7H), 1.30 * (s, 2H). * indicates the presence of atropisomers in the 4.6: 1 ratio. Synthesis of tert-butyl (S) - (1- (3- (3-amino-4-chloro-1- (2,2,2-trifluoroethyl) -1H- indazol-7-yl) -6- (3- methyl-3- (methylsulfonyl) but-1-in-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) carbamate (21):
[000283] tert-Butyl (S) - (1- (3-bromo-6- (3-methyl-3- (methylsulfonyl) but-1-in-1-yl) pyridin-2-yl) -2- ( 3,5-difluorophenyl) ethyl) carbamate (1000.0 mg, 1.79 mmol), 4-chloro-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1- (2,2, 2-trifluoroethyl) -1H-indazol-3-amine (808.5 mg, 2.15 mmol), [1,1-bis (diphenylphosphino) ferrocene] dichloropalladium (II) ( 65.6 mg, 0.09 mmol) and cesium carbonate (876.7 mg, 2.69 mmol) were loaded into a round bottom flask and placed under argon. Dioxane (10 ml) and water (2 ml) were added and the suspension was degassed with argon bubbling for 60 seconds. After degassing, the reaction flask was equipped with a reflux condenser and heated to 80 ° C overnight. The reaction mixture was cooled to room temperature and the aqueous layer was removed. The organic layer was concentrated in vacuo and the resulting residue was purified by column chromatography on silica gel to provide the title compound. MS (m / z) 726.1 [M + H] +. 1H NMR (400 MHz, chloroform-d) δ 7.69 - 7.55 (m), 7.55 - 7.42 (m), 7.16 - 7.06 (m), 7.07 - 6, 96 (m), 6.89 (d), 6.60 (tt), 6.44 (dd), 6.20 (d), 6.16 (d), 6.08 (s), 5.69 - 5.53 (m), 5.29 (s), 5.26 (d), 4.95 - 4.85 (m), 4.64 (q), 4.59 - 4.46 (m) , 4.36 - 4.19 (m), 3.94 - 3.76 (m), 3.64 - 3.54 (m), 3.18 (s), 3.17 (s), 3, 01 - 2.84 (m), 2.78 - 2.68 (m), 1.86 - 1.82 (m), 1.38 (s), 1.34 (s), 1.26 (s) ), 1.23 (s), 1.15 (s). Synthesis of tert-butyl (S) - (1- (3- (4-chloro-3- (N- (methylsulfonyl) methylsulfonamide) -1- (2,2,2-trifluoroethyl) -1H-indazole-7 -yl) -6- (3-methyl-3- (methylsulfonyl) but-1-in-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) carbamate (22):
[000284] 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-in-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 room temperature. Triethylamine (21.82 ml, 156.54 mmol) was added followed by 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 hour. The organic layer was separated, and the aqueous layer was extracted with methylene chloride once. The combined organic layers were washed with water and brine, dried over MgS04, filtered and concentrated to a small volume. Hexanes were added. The liquid suspension was decanted. The remaining solid was dried under reduced pressure to provide the title compound. MS (m / z): 882.69 [M + H] +. 1H NMR (400 MHz, methanol-d4) δ 7.87 (d), 7.83 (d), 7.76 (s), 7.74 (s), 7.69 (s) 7.67 (s ), 7.65 (s), 7.52 - 7.47 (m), 7.46 (s), 7.37 (d), 7.33 (d), 7.11 - 7.03 (m ), 4.79 - 4.55 (m), 4.51 (t), 4.36 (dt), 4.20 - 4.05 (m), 3.64 (s), 3.62 (s ), 3.60 (s), 3.59 (s), 3.23 (s), 3.04 (d), 3.01 (d), 2.95 - 2.83 (m), 1, 81 (s), 1.34 (s), 1.29 (s), 0.98 (s). Synthesis of (S) -N- (7- (2- (1-amino-2- (3,5-difluorophenyl) ethyl) -6- (3-methyl-3- (methylsulfonyl) but-1-in-1 -yl) pyridin-3-yl) -4-chloro-1- (2,2,2-trifluoroethyl) -1H- indazol-3-yl) -N- (methylsulfonyl) methanesulfonamide (23):
[000285] A (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-in-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) carbamate (39 g, 44 mmol) dissolved in methylene chloride (120 ml), trifluoroacetic acid (80 ml) was added. The reaction mixture was stirred at room temperature for 50 minutes. The reaction mixture was diluted with methylene chloride and slowly poured into ice-cold saturated aqueous NaHC03. The organic layer was separated, washed with water and brine, dried over MgSO4, filtered and concentrated to dryness to provide 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-trifluoro-ethyl) -1H-indazol-7-yl) -6- (3-methyl-3- (methylsulfonyl) but-1-in-1-yl) pyridin-2-yl) - 2- (3,5-difluorophenyl) ethyl) -2 - ((3bS, 4aR) -5, 5-difluoro-3- (trifluoromethyl) -3b, 4, 4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) ace-tamide (24) :
[000286] (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) -1H-indazol-3-yl) -N- (methylsulfonyl) methanesulfonamide (1757 mg, 2.25 mmol ), 2 - (((3bS, 4aR) -5,5-difluoro-3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2- c] pyrazol-1-yl) acetic (666 mg, 2.36 mmol) and HATU (1- [bis (dimethylamino) methylene] 3-oxide hexafluorophosphate] -1H-1,2,3-triazole [4,5 -b] pyridinium) (854 mg, 2.25 mmol) were loaded into a round bottom flask and dissolved in DMF (dimethylformamide) (10.0 ml). To the solution, N, N-diisopropylethylamine (0.80 ml, 4.49 mmol) was added at a fast dropwise rate. After the addition was complete, the reaction mixture was stirred at room temperature for 15 minutes to provide the non-isolated intermediate 23b (MS (m / z) 1046.65 [M + H] +). To the solution was added aq. 2N (5.0 mL). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was collected and washed with two portions of 5% lithium chloride solution followed by saline. The organic layer was isolated, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel to produce the title compound as an amorphous solid. MS (m / z) 968.24 [M + H] +. 1H NMR (400 MHz, methanol-d4) δ 7.87 - 7.57 (m), 7.33 - 7.09 (m), 6.80 - 6.70 (m), 6.54 (d) , 6.47 (d), 6.37 - 6.19 (m), 5.02 - 4.94 (m), 4.90 - 4.70 (m), 4.70 - 4.51 (m ), 3.94 (dq), 3.32-3.28 (m), 3.23 (d), 3.07 (dd, J = 13.1, 7.6 Hz), 2.93 (dd ), 2.68-2.35 (m), 1.81 (s), 1.41 (q), 1.12-1.00 (m). 19F NMR (377 MHz, methanol-d4) δ -63.65, -71.78 (t), -72.35 (t), -82.75 (dd), -105.70 (ddd), -111 , 73 - -113.10 (m). To more fully characterize 23b, this compound was isolated. 1H NMR (400 MHz, DMSO-d6) δ 9.20 (d), 8.99 (d), 7.96 (d), 7.83 (d), 7.80 (d), 7.76 ( d), 7.45 (d), 7.41 (d) 7.31 (d), 7.02 (tt), 6.92 (m), 6.91 (d), 6.48 (m) , 4.92 (m) 4.88 (d), 4.79 (d), 4.73 (d), 4.71 (m), 4.69 (m), 4.62 (m), 4 , 60 (m), 4.38 (dq), 4.12 (dq), 3.68 (s), 3.66 (s), 3.63 (s), 3.58 (s), 3, 26 (s), 3.12 (dd), 3.05 (dd), 2.97 (dd), 2.78 (dd), 2.59 (m), 2.53 (m), 1.75 (s), 1.39 (m), 0.98 (m). Preparation of 2 - ((3bS, 4aR) -3- (difluoromethyl) -5,5-difluoro-3b, 4, 4a, 5-tetrahydro-1 H-cyclopropa [3,4] cyclopenta [1,2 -c] pyrazol-1-yl) acetic (32) Example 6 Preparation of Compound 32
lithium -difluoro-1- (3-oxobicyclo [3.1.0] hexan-2-ylidene) ethan-1-olate (25):
[000287] The title compound was prepared according to the method presented for the synthesis of compound 2 using ethyl 2,2-difluoroacetate. 1H NMR (400 MHz, CDCb) δ 6.17 (t, J = 53.6 Hz, 1H), 2.78-2.73 (m, 1H), 2.44-2.39 (m, lH) , 2.25-2.24 (m, 1H), 1.70-1.69 (m, 1H), 1.22-1.14 (m, 1H), 0.31-0.27 (m, 1H). Synthesis of sodium 2- (3- (difluoromethyl) -3b, 4,4a, 5-tetrahydro-1 H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetate ( 26):
[000288] Me-THF (1.32 L) was added to the 4 L reactor followed by 2,2-difluoro-1- (3-oxobicyclo [3.1.0] hexan-2-ylidene) ethan-1-olate lithium (247 g, 1.32 mol). HCl (4 N in dioxane) (0.685 L, 2.74 moles) was added slowly to the mixture maintaining an internal temperature around 20 ° C. After the addition of ethyl hydrazinoacetate hydrochloride (212.05 g, 1.372 mol), the resulting mixture was stirred at 20 ° C for 4 hours. The reaction mixture was heated to 50 ° C overnight. 10 N aqueous NaOH (0.548 L, 5.48 mol) was added slowly to the reaction mixture, and the internal temperature was maintained at 20 ° C. After addition, 300 ml of MeTHF was added and the resulting suspension was stirred at 20 ° C for 3 hours. The suspension was drained and filtered. The filter mass was washed with hexane (1 L) and dried in a vacuum oven at 56 ° C to obtain 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-1 H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetate ( 27):
[000289] 2- (3- (difluoromethyl) -3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) ethyl acetate previous step was loaded into a 4 L reactor and followed by the addition of EtOH (3.5 L) and concentrated H2SO4 (152 mL, 2.74 mol). The resulting mixture was stirred under reflux for 2 hours. EtOH was reduced in vacuo to 150 ml. H2O (500 ml) was added slowly. The solids were collected and washed with H2O and NaHCO3 and followed by hexane (500 ml). The solid was dried in an oven at 45 ° C to obtain the title compound. MS (m / z) 257.1 [M + H] +. Synthesis of 2- (3- (difluoromethyl) -5-oxo-3b, 4,4a, 5-tetrahydro-1 H-cyclo-propa [3,4] cyclopenta [1,2-c] pyrazole-1- il) ethyl acetate (28):
[000290] The title compound was prepared according to the method presented for the synthesis of compound 4 using 2- (3- (difluoro-methyl) -3b, 4,4a, 5-tetrahydro-1 H-cyclopropa [3 , 4] cyclopenta [1,2] -c] pyrazol-1-yl) ethyl acetate. MS (m / z) 271.1 [M + H] +. Synthesis of 2- (3- (difluoromethyl) -4,4a-dihydrospiro [cyclopropa [3,4] cyclo-pent [1,2-c] pyrazole-5,2 '- [1,3] dithiolane] - 1 (3bH) -yl) acetate (29):
[000291] A 2- (3- (difluoromethyl) -5-oxo-3b, 4,4a, 5-tetrahydro-1 H-cyclopropane [3,4] -cyclopenta [1,2-c] pyrazole -1-yl) ethyl acetate (148.5 g, 0.55 mol) in DCM (2.0 L) ethane-1,2-dithiol (88.0 g, 0.94 mol) was added in one portion , followed by BF3 * 2AcOH (175.8 g, 0.94 mol). The reaction was stirred at room temperature for 12 h. The system was cooled to 0 ° C and deactivated with saturated aqueous NaHCO3 (1000 mL). The organic layer was separated, washed with brine (500 ml) and dried over Na2SO4. The solvents were removed in vacuo, and the residue was purified by column chromatography on silica gel to provide the title compound. MS (m / z): 347.1 [M + H] +. Synthesis of 2- (3- (difluoromethyl) -5,5-difluoro-3b, 4,4a, 5-tetrahydro-1 H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole-1- il) ethyl acetate (30):
[000292] A solution of DBDMH (99 g, 0.35 mol) in DCM (120 mL) was cooled to -8 ° C in a teflon flask. HF / Py (120 ml) was added dropwise over a period of 30 min. The reaction was stirred at -78 ° C for 30 min. A solution of 2- (3- (difluoromethyl) - 4,4a-dihydrospiro [cyclopropa [3,4] cyclopenta [1,2-c] pyrazole-5,2 '- [1,3] dithiolan] -1 (3bH) -yl) ethyl acetate (40 g, 0.12 mol) in DCM (80 ml) was added dropwise over a period of 15 min at -78 ° C. The resulting mixture was stirred for 30 min and then slowly heated to -30 ° C and stirred for 1.5 h. The reaction mixture was slowly poured into aq. (500 mL) and extracted with EA (500 mL x 3). The combined organic layer was washed with aq. 10% (500 ml), brine (500 ml) and dried over Na2SO4. The solvents were removed in vacuo to provide the crude product, which was further purified by column chromatography to provide the title compound. MS (m / z): 293.2 [M + H] +. Separation of 2 - ((3bS, 4aR) -3- (difluoromethyl) -5,5-difluoro-3b, 4,4a, 5-tetrahydro-1 H-cyclopropa [3,4] cyclopenta [1,2- c] pyrazol-1-yl) ethyl acetate (31a) and 2 - ((3bR, 4aS) -3- (difluoromethyl) -5,5-difluoro-3b, 4,4a, 5-tetrahydro-1H- cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) ethyl acetate (31b):
[000293] 2- (3- (Difluoromethyl) -5,5-difluoro-3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole- 1-yl) ethyl acetate was separated by its constituent enantiomers, the title compounds, by chiral HPLC under the following conditions: Column: ChiralPak AD; Mobile phase: Hex / 3C EtOH = 95/5; Room temperature; UV detection: 250 nm. Analytical HPLC [mobile phase: Hex / 3C EtOH = 95/5; Flow rate: 0.75 mL / min; Column: Chiralpak AD-H 150 x 4.6 mm, 5 µm; Wavelength: 220 nm 31a: t = 5.30 min, 31b: t = 7.00 min.
[000294] Compound 31a - 1H NMR (400 MHz, chloroform-d) δ 6.63 (t, J = 54.8 Hz, 1H), 4.83 (s, 2H) 4.24 (q, J = 7 , 2 Hz, 2H), 2.48-2.45 (m, 2H), 1.38-1.36 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1 , 13-1,12 (m, 1H) Synthesis of 2 - ((3bS, 4aR) -3- (difluoromethyl) -5,5-difluoro-3b, 4,4a, 5-tetrahydro-1H-cyclopropa [ 3.4] cyclopenta [1,2-c] pyrazol-1-yl) acetic acid (32):
[000295] To a solution of 2 - ((3bS, 4aR) -3- (difluoromethyl) -5,5-difluoro-3b, 4,4a, 5-tetrahydro-1 H-cyclopropa [3,4 ] cyclopenta [1,2-c] pyrazol -1- yl) ethyl acetate (26 g, 89.0 mmol) in THF (180 mL), MeOH (90 mL) and water (90 mL) was added LiOH (5 , 13 g, 213.5 mmol). The mixture was stirred for 4 h. The mixture was concentrated to remove most of the THF and MeOH, the aqueous was acidified by 1N HCl to adjust the pH to 2-3, then extracted with EA (600 ml x 2). The organic phase was separated and combined, dried over Na2SO4, filtered and concentrated in vacuo to provide the title compound. MS (m / z) 265.0 [M + H] +. Example 7 Preparation of Compound 34
Synthesis of 7-bromo-4-chloro-1- (2,2-difluoroethyl) -1H-indazol-3-amine (33):
[000296] To a 2000 mL round-bottom flask with 4 necks, 7-bromo-4-chloro-1H-indazol-3-amine (130 g, 527.40 mmol, 1.00 equiv), N , N-dimethylformamide (1300 mL), Cs2CO3 (260 g, 797.99 mmol, 1.50 equiv) with stirring for 20 min, followed by the addition of 1,1-difluoro-2-iodoethane (122 g, 635.59 mmol, 1.20 eq). The resulting mixture was stirred overnight at 65 ° C, then cooled to room temperature, quenched by the addition of 3 L of water / ice and extracted with 3 x 1.5 L of ethyl acetate. The combined organic layer was washed with 1 x 1.5 L of H2O, 1 x 1.5 L of brine, dried over anhydrous sodium sulfate, concentrated in vacuo and recrystallized from ethanol to produce the title compound. MS (m / z) 312.1 [M + H] + Synthesis of 4-chloro-1- (2,2-difluoroethyl) -7- (4,4,5,5-tetramethyl-1,3,2- dioxoborolano-2-yl) -1 H-indazol-3-amine (34):
[000297] 7-bromo-4-chloro-1- (2,2-difluoroethyl) -1H-indazole- were placed in a round-bottom flask with 4 necks of 3000 mL purged and maintained with an inert nitrogen atmosphere. 3-amine (80 g, 257.63 mmol, 1.00 equiv), 1,4-dioxane (800 mL), N, N-dimethylformamide (800 mL), KOAc (76 g, 774.40 mmol, 3, 00 equiv), 4,4,5,5-tetramethyl-2- (tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane (197 g, 775.78 mmol, 3, 00 equiv) and Pd (PPh3) 2Ch (8 g, 11.40 mmol, 0.04 equiv). The mixture was stirred for 4 h at 110 ° C, then cooled to room temperature, quenched by the addition of 5 L of water / ice and extracted with 2 x 2 L of ethyl acetate. The combined organic layer was washed with 1 x 1 L of HO, 1 x 1 L of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:10) to provide the title compound. MS (m / z): 358 [M + H] +. 1H- NMR: (DMSO-d6, 300 MHz, ppm): δ 7.63-7.66 (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 (llb) (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-in-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) carbamate (35):
[000298] tert-Butyl (S) - (1- (3-bromo-6- (3-methyl-3- (methylsulfonyl) but-1-in-1-yl) pyridin-2-yl) -2- ( 3,5-difluorophenyl) ethyl) carbamate (300 mg, 0.53 mmol), 4-chloro-1- (2,2-difluoroethyl) -7- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2 - yl) -1H-indazol-3-amine (250 mg, 0.7 mmol), [1,1-bis (diphenylphosphino) ferrocene] dichloropalladium (ll) (14 mg, 0.016 mmol) and potassium carbonate (186 mg, 1.35 mmol) were loaded into a microwave tube and placed under argon. 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® Initiator]) for 7 minutes. The reaction mixture was cooled to room temperature and partitioned between EtOAc and 0.1 N HCl. The aqueous layer was removed and the organic layer was concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel to provide the title compound. MS (m / z) 708.20 [M + H] +). 1H NMR (400 MHz, methanol-d4) δ 7.91 - 7.50 (m), 7.28 - 6.89 (m), 6.88 - 6.65 (m), 6.56 (dd) , 6.46 - 6.17 (m), 6.08 - 5.60 (m), 4.76 - 4.47 (m), 4.04 - 3.73 (m), 3.73 - 3 , 41 (m), 3.22 (s), 3.17 - 2.69 (m), 1.80 (s), 1.29 (d), 0.98 (d). Synthesis of tert-butyl (S) - (1- (3- (4-chloro-3- (cyclopropanesulfonamido) -1- (2,2-difluoroethyl) -1H-indazol-7-yl) -6- (3- methyl-3- (methylsulfonyl) but-1-in-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) carbamate (36):
[000299] tert-Butyl (S) - (1- (3- (3-amino-4-chloro-1- (2,2-difluoroethyl) -1H-in-dazol-7-yl) -6- (3 -methyl-3- (methylsulfonyl) but-1-in-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) carbamate (700 mg, 0.99 mmol) and 4 -dimethylaminopyridine (24 mg, 0.2 mmol) were dissolved in pyridine (2 mL) with stirring at room temperature. Cyclopropane-1-sulfonyl chloride (222, 2.2 mmol) was added. The reaction mixture was stirred at 70 ° C until the reaction was complete. Water was added and stirred for 1 hour, and the resulting precipitate was collected by vacuum filtration, then dissolved in methylene chloride, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica to produce the title compound. MS (m / z): 812.44 [M + H] +. 1H NMR (400 MHz, methanol-d4) δ 7.93 - 7.58 (m), 7.50 - 7.15 (m), 7.00 (dd), 6.82 - 6.51 ( m), 6.47 - 6.29 (m), 6.18 - 5.65 (m), 4.77 - 4.43 (m), 4.31 - 4.08 (m), 3.99 - 3.63 (m), 3.22 (s), 3.18 - 2.71 (m), 1.80 (s), 1.28 (s), 1.20 - 0.76 (m) . Synthesis of (S) -N- (7- (2- (1-amino-2- (3,5-difluorophenyl) ethyl) -6- (3-methyl-3- (methylsulfonyl) but-1-in-1 -yl) pyridin-3-yl) -4-chloro-1- (2,2-difluoroethyl) -1H-indazol -3-yl) cyclopropanesulfonamide (37):
[000300] To a solution of tert-butyl (S) - (1- (3- (4-chloro-3- (cyclopropamine-sulfonamido) -1- (2,2-difluoroethyl) -1 H-indazole-7- yl) -6- (3-methyl-3- (methylsulfonyl) but-1-in-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) carbamate (705 mg, 0.87 mmol) in dichloromethane (5 ml), trifluoroacetic acid (3 ml) was added. The reaction mixture was stirred for 1 hour and then slowly poured into a saturated sodium bicarbonate solution. It was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated to produce the title compound. MS (m / z): 712.34 [M + H] +. 1H NMR (400 MHz, methanol-d4) δ 7.93 - 7.58 (m), 7.50 - 7.15 (m), 7.00 (dd), 6.82 - 6.51 (m) , 6.47 - 6.29 (m), 6.18 - 5.65 (m), 4.77 - 4.43 (m), 4.31 - 4.08 (m), 3.99 - 3 , 63 (m), 3.22 (d), 3.18 - 2.71 (m), 1.80 (d), 1.28 (s), 1.20 - 0.76 (m). 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-in-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) -2 - ((3bS, 4aR) -5.5 -difluoro-3- (trifluoro-methyl) -3b, 4,4a, 5-tetrahydro-1 H-cyclopropa- [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetamide (38 ):
[000301] (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) -1 H-in-dazol-3-yl) cyclopropenesulfonamide (514 mg, 0.72 mmol), 2- ((3bS, 4aR) -3- (difluoromethyl) -5,5-difluoro-3b, 4,4a, 5-tetrahydro-1H-cycloprop [3,4] cyclopenta [1,2-c] pyrazole -1-yl) acetic (191 mg, 0.72 mmol), 1-hydroxybenzotriazole (49 mg, 0.36 mmol) and 1- (3-dimethyl-minopropyl) -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 room temperature for 30 minutes. Water was added and stirred for 1 hour. The resulting precipitate was collected by vacuum filtration and then dissolved in methylene chloride, dried over MgSO4, filtered and concentrated. The residue was purified by RP-HPLC to produce the title compound as a TFA salt. MS (m / z) 958.88 [M + H] +. 1H NMR (400 MHz, Methanol-d4) δ 7.90 - 7.56 (m), 7.30 - 7.07 (m), 6.91 - 6.54 (m), 6.54 - 6, 39 (m), 6.37 - 6.21 (m), 6.16 - 5.70 (m), 4.85 - 4.57 (m), 4.34 - 4.12 (m), 3 , 87 - 3.41 (m), 3.23 (s), 3.17 - 3.02 (m), 3.00 - 2.77 (m), 2.57 - 2.37 (m), 1.81 (s), 1.50 - 0.84 (m). Biological Examples Example A Test A: Antiviral assay in MT4 cells
[000302] For the antiviral assay, 0.4 μl of 189X test concentration of compound serially diluted 3 times in DMSO was added to 40 μL of cell growth medium (RPMI 1640, 10% FBS, Pekinicin-Streptomycin 1%, 1% L-Glutamine, 1% HEPES) in each well of the 384-well plate (10 concentrations) in quadruplicate.
[000303] 1 ml aliquots of MT4 cells were pre-infected for 3 hours at 37 ° C with 25 μL of cell growth medium (simulated infected) or a fresh 1: 250 dilution of an ABI raw material concentrated HIV-IIIb (0.004 moi). Infected and uninfected cells were diluted in cell growth medium and 35 μL (2000 cells) were added to each well of the assay plates.
[000304] The assay plates were then kept in a humidified incubator with 5% CO2 at 37 ° C. After 5 days of incubation, 25 μl of 2X concentrated CellTiter-GloTM reagent (catalog number G7573, Promega Biosciences, Inc., Madison, WI) was added to each well of the assay plate. Cell lysis was performed by incubation at room temperature for 10 minutes and then the chemiluminescence was read using an Envision plate reader (PerkinElmer). EC50 values were calculated as the concentration of the compound that caused a 50% decrease in the luminescence signal, a measure of HIV-1 replication. Example B Test B: Cytotoxicity assay
[000305] The cytotoxicity of the compound and the corresponding CC50 values were determined using the same protocol described in the antiviral assay (Test A), except that uninfected cells were used. The compound of the present description demonstrates antiviral activity (Test A) as represented in the table below in comparison with Compound A and Compound B.
Example C Test C. Pharmacokinetic analysis after intravenous administration to Spraque-Dawley rats and Beagle dogs and cynomolous monkeys Test and formulation
[000306] The administration of compound 24 and 38IV was formulated in 5% ethanol, 20% PG, 300% PEG at 45%, pH 2 at 30% (HCl 0.01 N) at 0.5 mg / ml. The intravenous infusion doses of Compound A and Compound B were formulated in a sterile solution of 5% ethanol, 45% PEG 400 and 50% water (pH 2.0) at 0.5 mg / mL. All IV formulations were in solution. Used Animals
[000307] Each rat IV dosing group consisted of 3 male SD rats. At dosage, animals generally weighed between 0.317 and 0.355 kg. The animals were fasted overnight before administration of the dose and up to 4 hours after dosing. Each IV dog dosing group consisted of 3 male naive beagle dogs. At dosage, the animals weighed ~ 10-12 kg. The animals were fasted overnight before administration of the dose and up to 2 hours after dosing.
[000308] Each dosing group of cynomolgus monkey (cino) consisted of 3 cino naive males. At dosage, the animals weighed ~ 3.2-4 kg. The animals were fasted overnight before administration of the dose and up to 2 hours after dosing. Dosage
[000309] For the IV 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 to administer a dose of 1 mg / kg to 2 ml / kg. Sample collection
[000310] Serial venous blood samples (approximately 0.4 mL each for the rat and 1.0 mL each for the dog) were collected at specified time points after dosing each animal. Blood samples were collected in Vacutainer ™ tubes (Becton-Disckinson Corp, New Jersey, USA) containing EDTA as an anticoagulant and were immediately placed in pending centrifugation on wet plasma ice. Centrifugation started within 1 hour of collection. All samples were placed in 96-well tubes and kept on dry ice before storage at approximately -70 ° C. Determination of the concentrations of the Compound of Formula (I) in plasma
[000311] An LC / MS / MS method was used to measure the concentration of test compounds in plasma. Calculations
[000312] Non-compartmental pharmacokinetic analysis was performed on plasma concentration-time data. A summary of the pharmacokinetic parameters is shown in the tables below.
Example D Test D. Metabolic Stability in Cultured Human Liver Hepatocytes
[000313] The radio-labeled test compounds, in which tritium was introduced into the structure instead of one or more hydrogens, were prepared according to methods known in the art.
[000314] The radio-labeled compounds were incubated in cryopreserved hepatocytes grouped at a substrate concentration of 0.25 μM and a radioactivity concentration of 10 uCi / mL. The final concentration of hepatocytes was 1 million cells / mL. The hepatocyte / compound reaction mixture was dissolved in InVi- trROGRO ™ KHB buffer (catalog Z99074, BioreclamationIVT, Inc., Baltimore, MD) at pH 7.4. The incubations were performed in duplicate. A cell-free control and a positive control were included in the incubations. Incubations were carried out with gentle shaking in an incubator at 37 ° C under a humid atmosphere of 95% air / 5% CO. (v / v). The aliquots (100 ml) were removed after 0, 1, 3 and 6 hours and added to 200 ml of extinction solution which comprised 0.1% (v / v) TFA in 5% water / 95% acetonitrile ( v / v). The samples were placed on a shaker for 10 min, followed by centrifugation at 3000 g for 30 min. The supernatant samples were analyzed on a Dionex HPLC / PerkinElmer Flow Scintillation Analyzer as described below. Liquid Chromatography - Radiochromatography
[000315] Quantification was performed by comparing radio-labeled metabolites and peaks of origin measured on a Radiomatic 625TR Flow Scintillation Analyzer coupled to a Dionex / Chromeleon chromatography system. The column was a Phenomenex Synergi fusion RP (150 x 4.6 mm, 4 mm) maintained at 32 degrees Celsius. Mobile phase A consisted of 0.1% (v / v) TFA in 99% water / 1% acetonitrile (v / v). Mobile phase B consisted of 0.1% (v / v) TFA in 5% water / 95% acetonitrile (v / v). The flow rate was 1 ml / min using a 100 ml sample injection volume. The gradient was as follows: Mobile phase B was linearly increased from 75% for 47 min, maintained at 75% for 3 min, changed to 2%, maintained at 2% for 10 min.
[000316] Metabolic stability was determined by measuring the change in relative abundance of metabolites and source over time and by calculating the rate of disappearance of the original compound. Stability data were used to calculate predicted human liver clearance values according to methods known in the art. The predicted human liver clearance values are shown in the table below.

[000317] The following can be deduced from the above comparative data:
[000318] compound 24 is more potent in an HIV antiviral assay compared to compounds A and B (about 9 and about 16 times more potent, respectively). Compound 24 has a longer terminal in vivo half-life in the rat compared to compounds A and B (about 14 and about 9 times longer, respectively). Compound 24 has a lower in vivo clearance in the rat compared to compounds A and B (about 10 and about 8.6 times less, respectively). Compound 24 has a longer terminal in vivo half-life in the dog compared to compounds A and B (about 5 and about 4 times longer, respectively). Compound 24 has a lower in vivo clearance in the dog compared to compounds A and B (about 3 and about 4 times less, respectively). Compound 24 is more stable in human hepatocytes with a predicted lower liver clearance compared to compounds A and B (about 9 and about 4 times more stable, respectively).
[000319] The data above demonstrate that compound 24, has improved antiviral potency and an improved pharmacokinetic profile (which is demonstrated by the longer half-life in rat and dog and lower predicted human clearance) compared to compounds A and B.
[000320] Additionally, compound 38 is more potent in an HIV antiviral assay compared to compounds A and B (about 4 and about 8 times more potent, respectively). Compound 38 has a longer terminal in vivo half-life in the rat compared to compounds A and B (about 9.5 and about 6.3 times longer, respectively). Compound 38 has a lower in vivo clearance in the rat compared to compounds A and B (about 6.3 and about 5.4 times less, respectively). Compound 38 has a similar in vivo clearance and terminal half-life in the dog compared to compounds A and B. Compound 38 is more stable in human hepatocytes with a predicted lower liver clearance compared to compounds A and B (about 4 , 5 and about 2 times more stable, respectively).
[000321] The above data demonstrates that compound 38, has improved antiviral potency and an improved pharmacokinetic profile (which is demonstrated by the longer half-life in rats and dogs and lower predicted human clearance) compared to compounds A and B.
[000322] The specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are pharmaceutical vehicles present, as well as the type of formulation and mode of administration used, and such expected variations or differences in results are contemplated in in accordance with the practice of this description.
[000323] The examples described herein describe the synthesis of compounds described herein, as well as the intermediates used to prepare the compounds. It should be understood that the individual steps described here can be combined. It should also be understood that separate batches of a compound can be combined and then carried on to the next synthetic step. Formulation Example
[000324] 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 injection (SC) to the rats and the pharmacokinetic profile (PK) was determined. As can be seen in Figure 3, Compound 38 maintains plasma concentrations well above paEC95 for> 10 weeks from a single SC injection. These data demonstrate that Compound 38 exhibits sustained release pharmacokinetics.
[000325] A suspension of a compound of formula 1b 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 profile (PK) was determined. Figure 4 shows a graph of the plasma concentration of the Formula 1b compound as a function of time. As the data shows in Figure 4, the Formula 1 compound has measurable plasma concentrations on day 70 demonstrating sustained release pharmacokinetics.
[000326] A suspension of a compound of Formula lb in 2% poloxamer 188 in saline (100 mg / ml) was prepared. The suspension was administered to dogs subcutaneously at a dose of 6 mg / kg and the pharmacokinetic profile (PK) was determined. Figure 5 shows a graph of the plasma concentration of the Formula 1b compound as a function of time. As the data shows in Figure 5, the Formula 1 compound has measurable plasma concentrations on day 70 demonstrating sustained release pharmacokinetics.
[000327] A suspension of the sodium salt of a compound of Formula lb 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 profile (PK) was determined. Figure 6 shows a graph of the plasma concentration of the Formula 1b compound as a function of time. As Figure 6 shows, the Formula 1 compound has measurable plasma concentrations on day 70, demonstrating sustained release pharmacokinetics.
[000328] A solution of a compound of formula lb in NMP (100 mg / ml) was prepared. The solution was administered to dogs subcutaneously at a dose of 6 mg / kg and the pharmacokinetic profile (PK) was determined. Figure 7 shows a graph of the plasma concentration of the Formula 1b compound as a function of time. As the data shows in Figure 7, the Formula 1 compound has measurable plasma concentrations on day 70 demonstrating sustained release pharmacokinetics.
[000329] A solution of a compound of Formula lb in NMP (200 mg / ml) was prepared. The solution was administered to dogs subcutaneously at a dose of 6 mg / kg and the pharmacokinetic profile (PK) was determined. Figure 8 shows a graph of the plasma concentration of the compound of formula lb as a function of time. As the data shows in Figure 8, the Formula 1 compound has measurable plasma concentrations on day 70 demonstrating sustained release pharmacokinetics.
[000330] A solution of the sodium salt of a compound of Formula lb in NMP (200 mg / ml) was prepared. The solution was administered to dogs subcutaneously at a dose of 6 mg / kg and the pharmacokinetic profile (PK) was determined. Figure 9 shows a graph of the plasma concentration of the Formula 1b compound as a function of time. As the data shows in Figure 9, the Formula 1 compound has measurable plasma concentrations on day 70 demonstrating sustained release pharmacokinetics.
[000331] A formulation of a solution of a compound of Formula lb in 10% ethanol, 12% water and 78% PEG 200 (200 mg / ml) was prepared. The solution was administered to dogs subcutaneously at a dose of 6 mg / kg and the pharmacokinetic profile (PK) was determined. Figure 10 shows a graph of the plasma concentration of the Formula 1b compound as a function of time. As the data shows in Figure 10, the Formula 1 compound has measurable plasma concentrations on day 28, demonstrating sustained release pharmacokinetics.
[000332] A solution formulation containing 200 mg / mL of Formula lb with 1.2 molar equivalent NaOH to form the sodium salt in situ in 10% ethanol, 12% water and 77% PEG is provided. Subjects were administered orally with this formulation at 6 mg / kg. A solution of the Formula 1 compound in 10% ethanol, 12% water and 7% PEG200 (200 mg / ml) with 1.2 molar equivalent NaOH was prepared to form the sodium salt in situ. The solution was administered to dogs subcutaneously at a dose of 6 mg / kg and the pharmacokinetic profile (PK) was determined. Figure 11 shows a graph of the plasma concentration of the Formula 1b compound as a function of time. As the data shows in Figure 11, the Formula 1 compound has measurable plasma concentrations on day 28 demonstrating sustained release pharmacokinetics.
[000333] A formulation of a solution of the compound of Formula lb in 10% ethanol, 13% water and 77% glycofurol (200 mg / ml) with 1.2 molar equivalent NaOH was prepared to form the sodium salt. doctor in situ. The solution was administered to dogs subcutaneously at a dose of 6 mg / kg and the pharmacokinetic profile (PK) was determined. Figure 12 shows a graph of the plasma concentration of the Formula 1b compound as a function of time. As the data shows in Figure 12, the Formula 1 compound has measurable plasma concentrations on day 28 demonstrating sustained release pharmacokinetics. Oral Formulation Example
[000334] An oral formulation containing a compound of Formula 1b in 10% ethanol, 20% Vitamin E TPGS and 70% MlGLYOL 812 was prepared in hard gelatin capsules. The dogs received a fixed 7.5 mg dose of the Formula 1b compound orally and the pharmacokinetic profile (PK) was determined. Figure 13 shows the change in plasma concentration over time for the Formula 1b compound.
[000335] All references, including publications, patents and patent documents are hereby incorporated by reference, as if they were individually incorporated by reference. The present description provides reference to various modalities and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the present description.

权利要求:
Claims (25)
[0001]
1. Compound, characterized by the fact that it presents Formula (la):
[0002]
2. Compound according to claim 1, characterized by the fact that it is a compound of Formula (lb)
[0003]
3. Pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of the compound, as defined in claim 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt.
[0004]
4. Compound, characterized by the fact that it presents the Formula (lla):
[0005]
5. Compound according to claim 4, characterized by the fact that it is a compound of Formula (llb)
[0006]
6. Pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of the compound, as defined in claim 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt.
[0007]
7. Pharmaceutical composition according to claim 3, characterized by the fact that the composition is suitable for oral administration.
[0008]
8. Pharmaceutical composition according to claim 7, characterized by the fact that the composition is a capsule.
[0009]
Pharmaceutical composition according to claim 8, characterized by the fact that the capsule is a hard capsule.
[0010]
Pharmaceutical composition according to claim 8, characterized in that the capsule is a soft capsule.
[0011]
Pharmaceutical composition according to claim 7, characterized in that the composition comprises a dosage amount of 1 mg to 1000 mg.
[0012]
Pharmaceutical composition according to claim 11, characterized in that the composition comprises a dosage amount of 10 mg to 50 mg.
[0013]
Pharmaceutical composition according to claim 11, characterized in that the composition comprises a dosage amount of 50 mg to 300 mg.
[0014]
Pharmaceutical composition according to claim 11, characterized in that the composition comprises a dosage amount of 300 mg to 1000 mg.
[0015]
15. The compound according to claim 2, characterized by the fact that the compound is an amorphous solid.
[0016]
16. Pharmaceutical composition, according to claim 6, characterized by the fact that the composition is suitable for oral administration.
[0017]
17. Pharmaceutical composition according to claim 16, characterized by the fact that the composition is a capsule.
[0018]
18. Pharmaceutical composition according to claim 17, characterized in that the capsule is a hard capsule.
[0019]
19. Pharmaceutical composition according to claim 17, characterized in that the capsule is a soft capsule.
[0020]
Pharmaceutical composition according to claim 16, characterized in that the composition comprises a dosage amount of 1 mg to 1000 mg.
[0021]
21. Pharmaceutical composition according to claim 20, characterized in that the composition comprises a dosage amount of 10 mg to 50 mg.
[0022]
22. Pharmaceutical composition according to claim 20, characterized in that the composition comprises a dosage amount of 50 mg to 300 mg.
[0023]
23. Pharmaceutical composition according to claim 20, characterized in that the composition comprises a dosage amount of 300 mg to 1000 mg.
[0024]
24. The compound according to claim 5, characterized by the fact that the compound is a pharmaceutically acceptable salt.
[0025]
25. The compound according to claim 24, characterized by the fact that the compound is a salt of trifluoroacetic acid.

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法律状态:
2020-03-24| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2020-05-05| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2020-12-08| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-01-26| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 17/08/2017, OBSERVADAS AS CONDICOES LEGAIS. |

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2021-02-02| B09W| Correction of the decision to grant [chapter 9.1.4 patent gazette]|Free format text: O PRESENTE PEDIDO TEVE UM PARECER DE DEFERIMENTO NOTIFICADO NA RPI NO 2605 DE 08-12-2020, TENDO SIDO CONSTATADO QUE ESTA NOTIFICACAO FOI EFETUADA COM INCORRECOES (ERRO NO NUMERO DE PAGINAS DO RELATORIO DESCRITIVO ? QUADRO 1), ASSIM RETIFICA-SE A REFERIDA PUBLICACAO. |

优先权:

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申请号 | 申请日 | 专利标题

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US201662377312P| true| 2016-08-19|2016-08-19|

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