Cyclic compounds having a 1 ,3 diamino-functionality for use in the treatment of HIV infection

Field of the invention:

The present invention concerns cyclic compounds having a 1 ,3 diamino-functionality, capable of reactivating HIV expression, for use in the treatment of HIV infection.

Background Art:

At the end of 201 1 , an estimated 34 million people were living with Human Immunodeficiency Virus (HIV) and approximately 1 .7 million people died of acquired immunodeficiency syndrome (AIDS).

HIV is an RNA-retrovirus replicating through a DNA intermediate that is integrated into the host cell's DNA. HIV infects and kills the cells of the immune system, including CD4+ T cells and macrophages, which are critical for mounting effective immune response against invading pathogens.

Once the viral DNA is integrated in the cell's chromosomes, HIV replicates directly into proteins or into RNA and infects new cells.

While significant progresses have been made in the treatment of the infection by HIV, in particular in the field of antiretroviral therapies, current treatments are not curative and must be taken by HIV-infected patients for the rest of their life in order to prevent progression of the infection to AIDS. Highly active antiretroviral therapies (HAART) have been developed in recent years. These HAART consist of drugs acting at different levels of the life cycle of HIV, inhibiting virus entry, reverse transcription, integration and/or maturation. These HAART are capable of eliminating the circulating viruses, with a viral load below the detection limits of modern assays (i.e. 50 copies of virion RNA / ml_ of plasma).

Yet, when the HAART is stopped, plasma viral load increases again. This rebound has been attributed to HIV reservoirs in which the pro-virus is present in a non-expressing state. The best understood reservoirs of HIV are CD4+ T cells: the cells exist in a resting state in which HIV-RNA and HIV-proteins are not expressed or expressed at very low level. As a consequence, these cells are not recognized by the immune system and form a reservoir of HIV, which, upon activation of these cells results in the proliferation of the virus and infection of other cells. One of the approaches for eradicating these HIV reservoir cells is called the "activation/elimination" approach. The aim of this approach is to induce expression of viral HIV proteins inside the latent cells. The cells may then be killed by the damaging effects of virus production (viral cytopathic effect), apoptosis, or may be recognized by the immune system or therapeutic agents directed towards viral proteins.

One approach that has been developed consists in the stimulation of T-cells with interleukin-2 (IL-2). This approach however led to a rebound of viral load when the HAART was stopped. IL-2 in conjunction with an anti-CD3 monoclonal antibody resulted in toxic side effects.

Clinical trials are currently on-going to establish the safety and efficacy of compounds used to date as anticancer drugs, such as vorinostat (Zolinza®,Merck), LBH589 (Panibinostal®, Novartis) and Romidepsin. The first results indicate that these molecules result in important adverse effects.

Drugs intended for treating alcohol dependency have also been investigated (Disulfirame, Esperal® Sanofi-Aventis), but these compounds, studied in clinical trial, show low capacity to induce HIV replication.

Other preclinical trials are also on-going with NF-KB activators such as prostatin and bryostatin analogs, but the in-vivo safety and efficacy of these compounds has not been established to date.

To date, none of these drug classes has obtained its market authorization and there is therefore a need for new drugs capable of inducing HIV expression in latently infected reservoir cells.

Cyclic compounds having a 1 ,3 diamino-functionality are known from prior art. The 3,5-diamino-piperidyl scaffold has been shown to possess antiviral activity. These compounds target a structured RNA of the Hepatitis C Virus (HCV) that is essential for the initiation of viral protein synthesis, and inhibit virus replication. These compounds have also been described as antibacterial and antifungal agents. 1 ,3 diamino-cyclopentanes have also been described as antibacterial agents.

These cyclic 3,5 diamino-piperidines and 1 ,3 diamino-cyclopentanes share the property of being inhibitors of viral, bacterial and/or fungal proliferation, thereby reducing the load of pathogenic agents. In a totally surprising and unexpected manner, the inventors of the present invention have discovered that cyclic compounds having a 1 ,3-diamino functionality act as promoters of HIV replication.

The unexpected potency of these compounds to induce the reactivation of HIV expression is particularly useful for the treatment of HIV infection, as it enables eradicating the reservoirs.

The present invention therefore concerns a compound of formula (I), a pharmaceutically acceptable salt, solvate or hydrate thereof, enantiomers, mixture of enantiomers, diastereoisomers and mixture of diasteroisomers thereof for use in the treatment of HIV infection of the following formula (I):

wherein:

n is 0 or 1 ,

X is CH or N,

Ri and R'i are H, or R^ and R ₂ and/or R and R' ₂ form together a (C ₃ -C ₈ )heterocyclyl,

R ₂ and R' ₂ are independently one from the other H, (d-C ₆ )alkyl, aryl, heteroaryl, (C ₃ -

C ₈ )heterocyclyl, (C ₃ -C ₈ )carbocyclyl, (Ci-C ₆ )alkyl-aryl, (Ci-C ₆ )alkyl-heteroaryl, C(0)-Q, or S0 ₂ -Z,

Q is H, (CrC ₆ )alkyl, aryl, heteroaryl, (C ₃ -C ₈ )carbocyclyl, (C ₃ -C ₈ )heterocyclyl, (CrC ₆ )alkyl-aryl, (Ci-C ₆ )alkyl-heteroaryl, (Ci-C ₆ )alkyl-(C ₃ -C ₈ )heterocyclyl, (C C ₆ )alkyl-(C ₃ -C ₈ )carbocyclyl, NR _a R _b or OR _c ,

R _a and R _b are independently one from the other H, (CrC ₆ )alkyl, aryl, heteroaryl, (C ₃ -C ₈ )heterocyclyl, (C ₃ -C ₈ )carbocyclyl, (CrC ₆ )alkyl-aryl, (CrC ₆ )alkyl-heteroaryl, or R _a and R _b form together a (C ₃ - C ₈ )heterocyclyl,

R _c is (CrC ₆ )alkyl, (C ₃ -C ₈ )heterocyclyl, (C ₃ -C ₈ )carbocyclyl, heteroaryl, (CrC ₆ )alkyl-aryl, or (CrC ₆ )alkyl-heteroaryl,

Z is (CrC ₆ )-alkyl, aryl, heteroaryl, NR _a R _b , or CF ₃ , R ₃ is H, (d-C ₆ )alkyl, (C ₃ -C ₈ )heterocyclyl, (C ₃ -C ₈ )carbocyclyl, aryl, heteroaryl, (C C ₆ )alkyl-aryl, (CrC ₆ )alkyl-heteroaryl, or (C ₁ -C ₆ )alkyl-heteroaryl-(C ₁ -C ₆ )alkyl-C(0)-aryl, R ₄ and R ₅ are independently one from the other H, (CrC ₆ )alkyl, (C ₃ -C ₈ )heterocyclyl, (C ₃ - C ₈ )carbocyclyl, aryl, heteroaryl, (CrC ₆ )alkyl-aryl, (CrC ₆ )alkyl-heteroaryl, C(0)-V, R ₄ and R ₅ form together a (C ₃ -C ₈ )heterocyclyl or a heteroaryl, or one of R ₄ or R ₅ is - CH(R ₇ )-CO-V,

V is H, (CrC ₆ )alkyl, aryl, heteroaryl, (C ₃ -C ₈ )carbocyclyl, (C ₃ -C ₈ )heterocyclyl, (CrC ₆ )alkyl-aryl, (CrC ₆ )alkyl-heteroaryl, (Ci-C ₆ )alkyl-(C ₃ -C ₈ )heterocyclyl, (C C ₆ )alkyl-(C ₃ -C ₈ )carbocyclyl, NR,R _g , ORi ₀ or CH(Rn)-NH-CORi ₂ ,

Rio is as defined for R _c ,

R ₇ is the side chain of an amino-acid,

Rii is (C1 -C6) alkylamine,

Ri ₂ is aryl,

R ₆ is H, (CrC ₆ )alkyl, (C ₃ -C ₈ )heterocyclyl, (C ₃ -C ₈ )carbocyclyl, (C ₉ -C ₁₀ )carbocyclyl, aryl, heteroaryl, (Ci-C ₆ )alkyl-aryl, (Ci-C ₆ )alkyl-heteroaryl, , NR _d R _e , OR ₉ , C(0)-V, S0 ₂ -W, or -CH(R ₇ )-CO-V,

R _d and R _e are independently one from the other H, (CrC ₆ )alkyl, (C ₃ - C ₈ )heterocyclyl, (C ₃ -C ₈ )carbocyclyl, aryl, heteroaryl, (CrC ₆ )alkyl-aryl, (C C ₆ )alkyl-heteroaryl, C(0)-(Ci-C ₆ )alkyl, C(0)-aryl, C(0)-heteroaryl, C(0)-(C ₃ - C ₈ )carbocyclyl C(0)-(C ₃ -C ₈ )heterocyclyl, C(0)-(Ci-C ₆ )alkyl-aryl, C(0)-(C C ₆ )alkyl-heteroaryl, C(0)-(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )heterocyclyl, C(0)-(Ci-C ₆ )alkyl- (C ₃ -C ₈ )carbocyclyl, or R _d and R _e form together a (C ₃ -C ₈ )heterocyclyl,

R _f is H, (CrC ₆ )alkyl, (C ₃ -C ₈ )heterocyclyl, (C ₃ -C ₈ )carbocyclyl, aryl, heteroaryl, (CrC ₆ )alkyl-aryl, (Ci-C ₆ )alkyl-heteroaryl, C(0)-(Ci-C ₆ )alkyl, C(0)-aryl, C(O)- heteroaryl, C(0)-(C ₃ -C ₈ )carbocyclyl C(0)-(C ₃ -C ₈ )heterocyclyl, C(0)-(C C ₆ )alkyl-aryl, C(0)-(Ci-C ₆ )alkyl-heteroaryl, C(0)-(Ci-C ₆ )alkyl-(C ₃ -

C ₈ )heterocyclyl, or C(0)-(Ci-C ₆ )alkyl-(C ₃ -C ₈ )carbocyclyl,

R _g is H, (CrC ₆ )alkyl, (C ₃ -C ₈ )heterocyclyl, (C ₃ -C ₈ )carbocyclyl, aryl, heteroaryl, (CrC ₆ )alkyl-aryl, (CrC ₆ )alkyl-heteroaryl, or R _f and R _g form together a (C ₃ - C ₈ )heterocyclyl,

R ₉ is H, (CrC ₆ )alkyl, (C ₃ -C ₈ )heterocyclyl, (C ₃ -C ₈ )carbocyclyl, aryl, heteroaryl, (Ci-C ₆ )alkyl-aryl, (Ci-C ₆ )alkyl-heteroaryl, C(0)-(Ci-C ₆ )alkyl, C(0)-aryl, C(O)- heteroaryl, C(0)-(C ₃ -C ₈ )carbocyclyl C(0)-(C ₃ -C ₈ )heterocyclyl, C(0)-(C C ₆ )alkyl-aryl, C(0)-(Ci-C ₆ )alkyl-heteroaryl, C(0)-(Ci-C ₆ )alkyl-(C ₃ -

C ₈ )heterocyclyl, or C(0)-(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )carbocyclyl,

W is as defined for Z,

V is as defined above. for all radicals R ₁ to R ₁₂ , Rr, R?, _a to R _g , Q, V, W and Z:

said (C ₃ -C ₈ )heterocyclyl can be substituted by one or more groups such as methyl, ethyl, isopropyl, hydroxy, methoxy, amino, fluoro, chloro, bromo and iodo,

said aryl may be substituted with one or more groups independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxyl, amino, nitro, cyano, trifluoro, carboxylic acid or carboxylic ester, and

said heteroaryl may be substituted with one or more groups independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxyl, amino, nitro, cyano, trifluoro, carboxylic acid or carboxylic ester,

Advantageously:

n is 0 or 1 ,

X is CH or N,

Ri and R are H, or and R ₂ and/or R and R' ₂ form together a (C ₃ -C ₈ )heterocyclyl,

R ₂ and R' ₂ are independently one from the other H, (d-C ₆ )alkyl, aryl, heteroaryl, (C ₃ - C ₈ )heterocyclyl, (C ₃ -C ₈ )carbocyclyl, (Ci-C ₆ )alkyl-aryl, (Ci-C ₆ )alkyl-heteroaryl, C(0)-Q, or S0 ₂ - Z,

Q is H, (CrC ₆ )alkyl, aryl, heteroaryl, (C ₃ -C ₈ )carbocyclyl, (C ₃ -C ₈ )heterocyclyl, (C C ₆ )alkyl-aryl, (Ci-C ₆ )alkyl-heteroaryl, (Ci-C ₆ )alkyl-(C ₃ -C ₈ )heterocyclyl, (Ci-C ₆ )alkyl-(C ₃ - C ₈ )carbocyclyl, NR _a R _b or OR _c ,

R _a and R _b are independently one from the other H, (CrC ₆ )alkyl, aryl, heteroaryl, (C ₃ -C ₈ )heterocyclyl, (C ₃ -C ₈ )carbocyclyl, (CrC ₆ )alkyl-aryl, (CrC ₆ )alkyl-heteroaryl, or R _a and R _b form together a (C ₃ - C ₈ )heterocyclyl,

R _c is (CrC ₆ )alkyl, (C ₃ -C ₈ )heterocyclyl, (C ₃ -C ₈ )carbocyclyl, aryl, heteroaryl, (CrC ₆ )alkyl-aryl, or (CrC ₆ )alkyl-heteroaryl, Z is (CrC ₆ )-alkyl, aryl, heteroaryl, NR _a R _b , or CF ₃ ,

R ₃ is H, (d-C ₆ )alkyl, (C ₃ -C ₈ )heterocyclyl, (C ₃ -C ₈ )carbocyclyl, aryl, heteroaryl, (CrC ₆ )alkyl- aryl, (Ci-C ₆ )alkyl-heteroaryl, or (C ₁ -C ₆ )alkyl-heteroaryl-(C ₁ -C ₆ )alkyl-C(0)-aryl,

R ₄ and R ₅ are independently one from the other H, (CrC ₆ )alkyl, (C ₃ -C ₈ )heterocyclyl, (C ₃ - C ₈ )carbocyclyl, aryl, heteroaryl, (CrC ₆ )alkyl-aryl, (CrC ₆ )alkyl-heteroaryl, C(0)-V, R ₄ and R ₅ form together a (C ₃ -C ₈ )heterocyclyl or a heteroaryl, or one of R ₄ or R ₅ is -CH(R ₇ )-CO-V,

V is H, (CrC ₆ )alkyl, aryl, heteroaryl, (C ₃ -C ₈ )carbocyclyl, (C ₃ -C ₈ )heterocyclyl, (C C ₆ )alkyl-aryl, (Ci-C ₆ )alkyl-heteroaryl, (Ci-C ₆ )alkyl-(C ₃ -C ₈ )heterocyclyl, (Ci-C ₆ )alkyl-(C ₃ - C ₈ )carbocyclyl, NR _f R _g or ORi ₀ ,

R ₇ is the side chain of an amino-acid,

R ₆ is H, (CrC ₆ )alkyl, (C ₃ -C ₈ )heterocyclyl, (C ₃ -C ₈ )carbocyclyl, aryl, heteroaryl, (CrC ₆ )alkyl- aryl, (Ci-C ₆ )alkyl-heteroaryl, NR _d R _e , OR ₉ , C(0)-V, S0 ₂ -W, or -CH(R ₇ )-CO-V,

R _d and R _e are independently one from the other H, (CrC ₆ )alkyl, (C ₃ - C ₈ )heterocyclyl, (C ₃ -C ₈ )carbocyclyl, aryl, heteroaryl, (CrC ₆ )alkyl-aryl, (C C ₆ )alkyl-heteroaryl, C(0)-(Ci-C ₆ )alkyl, C(0)-aryl, C(0)-heteroaryl, C(0)-(C ₃ - C ₈ )carbocyclyl C(0)-(C ₃ -C ₈ )heterocyclyl, C(0)-(Ci-C ₆ )alkyl-aryl, C(0)-(C C ₆ )alkyl-heteroaryl, C(0)-(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )heterocyclyl, C(0)-(Ci-C ₆ )alkyl- (C ₃ -C ₈ )carbocyclyl, or R _d and R _e form together a (C ₃ -C ₈ )heterocyclyl,

R _f is H, (CrC ₆ )alkyl, (C ₃ -C ₈ )heterocyclyl, (C ₃ -C ₈ )carbocyclyl, aryl, heteroaryl, (Ci-C ₆ )alkyl-aryl, (Ci-C ₆ )alkyl-heteroaryl, C(0)-(Ci-C ₆ )alkyl, C(0)-aryl, C(O)- heteroaryl, C(0)-(C ₃ -C ₈ )carbocyclyl C(0)-(C ₃ -C ₈ )heterocyclyl, C(0)-(C C ₆ )alkyl-aryl, C(0)-(Ci-C ₆ )alkyl-heteroaryl, C(0)-(Ci-C ₆ )alkyl-(C ₃ -

C ₈ )heterocyclyl, or C(0)-(Ci-C ₆ )alkyl-(C ₃ -C ₈ )carbocyclyl,

R _g is H, (CrC ₆ )alkyl, (C ₃ -C ₈ )heterocyclyl, (C ₃ -C ₈ )carbocyclyl, aryl, heteroaryl, (CrC ₆ )alkyl-aryl, (CrC ₆ )alkyl-heteroaryl, or R _f and R _g form together a (C ₃ - C ₈ )heterocyclyl,

R ₉ is H, (CrC ₆ )alkyl, (C ₃ -C ₈ )heterocyclyl, (C ₃ -C ₈ )carbocyclyl, aryl, heteroaryl, (CrC ₆ )alkyl-aryl, (Ci-C ₆ )alkyl-heteroaryl, C(0)-(Ci-C ₆ )alkyl, C(0)-aryl, C(O)- heteroaryl, C(0)-(C ₃ -C ₈ )carbocyclyl C(0)-(C ₃ -C ₈ )heterocyclyl, C(0)-(C C ₆ )alkyl-aryl, C(0)-(Ci-C ₆ )alkyl-heteroaryl, C(0)-(Ci-C ₆ )alkyl-(C ₃ -

C ₈ )heterocyclyl, or C(0)-(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )carbocyclyl, R ₁₀ is as defined for R _c , and

W is as defined for Z.

Advantageously, are in cis configuration.

Advantageously, R ₂ and R' ₂ are H, C(0)-Q, S0 ₂ -Z as defined above, or and R ₂ and

R'i and R' ₂ form together a (C ₃ -C ₈ )heterocyclyl. Advantageously, Q is H, (d-C ₆ )alkyl, such methyl, (CrC ₆ )alkyl-aryl, such as benzyl, or OR _c , where R _c is as defined above and advantageously (CrC ₆ )alkyl or (CrC ₆ )alkyl-aryl. Advantageously, Z is aryl or NR _a Rt

More advantageously, R ₂ and R' ₂ are H.

Advantageously, R ₃ is aryl or (Ci-C ₆ )alkyl-heteroaryl-(Ci-C ₆ )alkyl-C(0)-aryl, more advantageously (Ci-C ₆ )alkyl-heteroaryl-(Ci-C ₆ )alkyl-C(0)-aryl. Preferred (Ci-C ₆ )alkyl- heteroaryl-(CrC ₆ )alkyl-C(0)-aryl is CH ₂ -1 ,2,3-triazolyl-CH ₂ -C(0)-p-cyclophanyl.

Advantageously, R ₄ and R ₅ are independently one from the other H, (CrC ₆ )alkyl, (C ₃ - C ₈ )heterocyclyl, (C ₃ - C ₈ )carbocyclyl, aryl, heteroaryl, (CrC ₆ )alkyl-aryl, (CrC ₆ )alkyl-heteroaryl, C(0)-V, R ₄ and R ₅ form together a (C ₃ -C ₈ )heterocyclyl or a heteroaryl, or one of R ₄ or R ₅ is - CH(R ₇ )-CO-V,

Advantageously, R ₆ is C(0)-V, where V is as defined for formula (I), V being advantageously (CrC ₆ )alkyl-aryl or OR ₁₀ , Rio being advantageously (CrC ₆ )alkyl, preferably te/t-butyl or (CrC ₆ )alkyl-aryl, preferably benzyl.

The compounds of formula (I) can be prepared according to the methods described in

WO 2009/099897, US6316626, WO 2006/024784 and Journal of Organic Chemistry 2013, 78, 12236-12242 (doi: 10. 1021/jo401994y).

In a first advantageous embodiment, the compounds of formula (I) are 1 ,3- diaminocyclopentanes, wherein n = 0 and X is CH of formula (1-1 ):

wherein R _{1 ;} R' _{1 ;} R ₂ , R' ₂ and Y are as defined in formula (I).

Advantageously, Y is OR ₃ or NR ₄ R ₅ , preferably OR ₃ , as defined in formula (I).

Advantageously, are in cis configuration. Advantageously, R ₂ and R' ₂ are H, C(0)-Q, S0 ₂ -Z as defined above, or R^ and R ₂ and R'i and R' ₂ form together a (C ₃ -C ₈ )heterocyclyl. Advantageously, Q is H, (d-C ₆ )alkyl, such as methyl, (CrC ₆ )alkyl-aryl, such as benzyl, or OR _c , where R _c is as defined above, and is advantageously (CrC ₆ )alkyl or (CrC ₆ )alkyl-aryl. Advantageously, Z is aryl or NR _a R _b .

More advantageously, R ₂ and R' ₂ are H.

Advantageously, R ₃ is aryl or (Ci-C ₆ )alkyl-heteroaryl-(Ci-C ₆ )alkyl-C(0)-aryl, more advantageously (Ci-C ₆ )alkyl-heteroaryl-(Ci-C ₆ )alkyl-C(0)-aryl. Preferred (CrC ₆ )alkyl- heteroaryl-(CrC ₆ )alkyl-C(0)-aryl is -CH ₂ -1 ,2,3-triazolyl-CH ₂ -C(0)-p-cyclophanyl

Advantageously, R ₄ and R ₅ are independently one from the other H, (CrC ₆ )alkyl, (C ₃ - C ₈ )heterocyclyl, (C ₃ - C ₈ )carbocyclyl, aryl, heteroaryl, (CrC ₆ )alkyl-aryl, (CrC ₆ )alkyl-heteroaryl, C(0)-V, R ₄ and R ₅ form together a (C ₃ -C ₈ )heterocyclyl or a heteroaryl, or one of R ₄ or R ₅ is - CH(R ₇ )-CO-V,

In a second advantageous embodiment, the compounds of formula (I) are 3, 5- diaminopiperidines wherein n = 1 and X is N of formula (I-2):

wherein R _{1 ;} R' R ₂ , R' ₂ , X and Y are as defined for formula (I).

Advantageously, Y is R ₆ , as defined in formula (I).

Advantageously, are in cis configuration.

Advantageously, R ₂ and R' ₂ are H, C(0)-Q, S0 ₂ -Z as defined above, or R^ and R ₂ and R'i and R' ₂ form together a (C ₃ -C ₈ )heterocyclyl. Advantageously, Q is H, (CrC ₆ )alkyl, such as methyl, (CrC ₆ )alkyl-aryl, such as benzyl, or OR _c , where R _c is as defined above. Advantageously, Z is aryl or NR _a Rt

More advantageously, R ₂ and R' ₂ are H.

Advantageously, R ₆ is H, aryl, heteroaryl, (CrC ₆ )alkyl-aryl, (CrC ₆ )alkyl-heteroaryl, C(0)-V, or -CH(R ₇ )-CO-V, where V is as defined for formula (I), V being advantageously (C C ₆ )alkyl-aryl, CH(Rn)-NH-CORi ₂ , Rn being advantageously (Ci-C ₆ )alkylamine, preferably butylamine and R ₁₂ being an aryl, preferably a phenyl or OR ₁₀ , Rio being advantageously (C C ₆ )alkyl, preferably te/t-butyl or (CrC ₆ )alkyl-aryl, preferably benzyl. Advantageously, when present, the aryl in R ₆ is chosen from among methoxyphenyl, advantageously 3-methoxyphenyl or 4-methoxyphenyl, ethoxyphenyl, advantageously 4- ethoxyphenyl dimethoxyphenyl, advantageously, 3,4-dimethoxyphenyl, trimethoxyphenyl, advantageously 3,4,5-trimethoxyphenyl, 9,9'-Spirobi[9H-fluorene], p-cyclophanyl (hydroxy- phenyl)amide, advantageously 3-(hydroxyphenyl)-4-benzamide, ethylphenyl, advantageously 4-ethylphenyl and phenylethanol, advantageously 4-phenylethanol.

Advantageously, when present, the heteroaryl is a 3- or 5-indolyl, advantageously substituted with a methoxy group.

Advantageously, the compound of formula (I) is selected in the list consisting of:

In a third advantageous embodiment, the compounds of formula (I) are 3, 5- diaminopiperidines wherein n = 1 and X is N of formula (I-2):

wherein R _{1 ;} R' _{1 ;} R ₂ , R' ₂ , X and Y are as defined for formula (I).

Advantageously, Y is R ₆ , as defined in formula (I).

Advantageously, NRiR ₂ and NR R^ are in cis configuration.

Advantageously, at least one of R ₂ and R' ₂ is H, C(0)-Q or S0 ₂ -Z as defined in formula (I). Advantageously, Q is OR _c , R _c being (CrC ₆ )alkyl, advantageously te/t-butyl. Advantageously, Z is (CrC ₆ )alkyl.

More advantageously, R ₂ and R' ₂ are C(0)-Q, R ₂ is H and R' ₂ is S0 ₂ -Z or R ₂ is C(O)- Q and R' ₂ is H.

Advantageously, R ₆ is H, (CrC ₆ )alkyl-aryl, (CrC ₆ )alkyl-heteroaryl or S0 ₂ -W wherein W is a defined above.

Advantageously, when present, the aryl in R ₆ is chosen from among phenyl, methoxyphenyl, advantageously 3-methoxyphenyl, Ν,Ν-dimethylphenylamine and phenylpyrrolidine.

Advantageously, when present, the heteroaryl is a 1 -methyl-5-indolyl, advantageously substituted with a methoxy group.

Advantageously, the compound of formula (I) is selected in the list consisting of:

The compound of formula (I) can also be used in the form of a pro-drug. By pro-drug, it is meant in the sense of the present invention, a compound that is administered in an inactive or less active form and that is metabolized in vivo into its active form, for example under the action of enzymes or gastric juice. Pro-drugs are useful to improve the physicochemical properties of a molecule, such as solubility or pharmacokinetics (bioavailability for example). In particular, a pro-drug may be obtained by acylation or phosphorylation of an amine or a hydroxyl group.

The compounds of formula (I) can also be used in combination with one or more HIV- 1 inducers. HIV inducers are compounds capable of activating HlV-protein expression and include DNA methylation inhibitors, such as 5-azacytidine (azacitidine), 5-aza-2'- deoxycytidine (5-aza-CdR, decitabine), 1 -Darabinofuranosyl-5-azacytosine (fazarabine), dihydro-5-azacytidine (DHAC), 5-fluorodeoxycytidine (FdC), oligodeoxynucleotide, duplexes containing 2-H pyrimidinone, zebularine, antisense oligodeoxynucleotides (ODNs), MG98, (-)- epigallocatechin-3-gallate, hydralazine, procaine and procainamide; histone deacetylase inhibitors, such as TSA, SAHA, MS-275, aminosuberoyl hydroxamic acids, M- Carboxycinnamic acid bishydroxamate, LAQ-824, LBH-589, belinostat (PXD-101 ) , Panobinostat (LBH-589), a cinnamic hydroxamic acid analogue of M-carboxycinnamic acid bishydroxamate, IF2357, aryloxyalkanoic acid hydroxamides, depsipeptide, apicidin, cyclic hydroxamic acid-containing peptide group of molecules, FK-228, red FK, cyclic peptide mimic linked by an aliphatic chain to a hydroxamic acid, butyrate, phenylbutyrate, sodium butyrate, valproic acid, pivaloyloxymethyl butyrate, 5 NOX-275, and MGCD0103; or NF-kappa-B- inducers selected from the group comprising: PMA, prostratin, bryostatin and TNF-alpha.

Advantageously, at least one compound of formula (I) is used in combination with an HIV therapy, such as immunotherapy, antiretrovirals, vaccines, such as therapeutic vaccines, and Highly Active Antiretroviral therapies (HAART).

Vaccines are for example therapeutic vaccines, more particularly anti-HIV vaccines, capable of restoring cell-mediated and/or humoral immunity to HIV-infected patients. These vaccines may be combined with cytokines that increase the response to the vaccine and/or restore the immune system by stimulating the growth of certain cells, such as CD4 lymphocytes.

The present invention therefore also concerns at least a compound of formula (I) for use in the treatment of HIV infection in combination with an HIV therapy. HIV therapies are known in the art and include: Lamivudine, Emtricitabine, Abacavir, Zidovudine, Didanosine, Stavudine, Adefovir, Tenofovir, Efavirenz, Etravirine, Nevirapine, Rilpivirine, Amprenavir, Fosamprenavir, Tipranavir, Lopinavir, Ritonavir, Indinavir, Saquinavir, Darunavir, Atazanavir, Nelfinavir, Raltegravir, Eviltegravir, Dolutegravir, Enfuvirtide, Maraviroc, and combinations thereof.

Advantageously, at least one product of formula (I) is used with an HIV therapy chosen, for example, from among: Lamivudine, Emtricitabine, Abacavir, Zidovudine, Didanosine, Stavudine, Adefovir, Tenofovir, Efavirenz, Etravirine, Nevirapine, Rilpivirine, Amprenavir, Fosamprenavir, Tipranavir, Lopinavir, Ritonavir, Indinavir, Saquinavir, Darunavir, Atazanavir, Nelfinavir, Raltegravir, Eviltegravir, Dolutegravir, Enfuvirtide, Maraviroc.

The present invention also concerns a pharmaceutical composition, comprising at least one compound of formula (I) as defined above for use in the treatment of HIV infection, advantageously in combination with an HIV therapy.

The pharmaceutical compositions of the invention can be intended for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal or rectal administration. The active ingredient can be administered in unit forms for administration, mixed with conventional pharmaceutical carriers, to animals or to humans. The pharmaceutical compositions may be immediate, delayed or sustained release compositions, advantageously sustained release compositions.

When a solid composition is prepared in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle and other conventional excipients known to those skilled in the art.

The compounds of the invention can be used in a pharmaceutical composition at a dose ranging from 0.01 mg to 1000 mg a day, administered in only one dose once a day or in several doses along the day, for example twice a day. The daily administered dose is advantageously comprised between 5 mg and 500 mg, and more advantageously between 10 mg and 200 mg. However, it can be necessary to use doses out of these ranges, which could be noticed by the person skilled in the art.

The present invention further concerns the use of at least one compound of formula (I) for the preparation of a medicament intended for the treatment of HIV infection, said medicament being used advantageously in combination with an HIV therapy.

The present invention further concerns a method for treating HIV infection, comprising the administration to a person in need thereof of at least one compound of formula (I), advantageously in combination with an HIV therapy. The present invention also concerns a combination product comprising:

(i) at least one compound of formula (I) as defined above,

(ii) at least one antiretroviral of HIV,

for simultaneous, separate or sequential use as a medicament.

Advantageously, the combination product is intended for the treatment of HIV infection.

Advantageously, the at least one antiretroviral of HIV is chosen from among entry inhibitors (or fusion inhibitors) such as Maraviroc and Enfuvirtide; nucleoside reverse transcriptase inhibitors (NRTI) and nucleotide reverse transcriptase inhibitors (NtRTI) such as Lamivudine, Emtricitabine, Abacavir, Zidovudine, Didanosine, Stavudine, Adefovir, Tenofovir; non-Nucleoside reverse transcriptase inhibitors (NNRTI), such as , Efavirenz, Etravirine, Nevirapine, Rilpivirine, ; integrase inhibitors, such as Raltegravir,Elvitegravir and Dolutegravir; protease inhibitors, such as Amprenavir, Fosamprenavir, Tipranavir, Lopinavir, Ritonavir, Indinavir, Saquinavir, Darunavir, Atazanavir, Nelfinavir. Advantageously, the compound of formula (I) is a compound of formula (1-1 ) or a compound of formula (I-2). The combination product according to the invention may be administered in the form of a single pharmaceutical composition comprising at least one compound of formula (I) and at least one antiretroviral of HIV. The combination product according to the invention may also be administered in the form of a first pharmaceutical composition comprising the at least one compound of formula (I) and a second pharmaceutical composition comprising the at least one antiretroviral. In that case, the pharmaceutical compositions may be administered by the same or by different routes. For example, one pharmaceutical composition can be administered orally and the second one parenterally.

Definitions:

The term HIV, in the sense of the present invention, is intended to designate the three types of the human immunodeficiency virus HIVO, HIV 1 and HIV2 and their subtypes.

Within the groups, radicals or fragments defined in the description and the claims, the number of carbon atoms is specified inside the brackets. For example, (CrC ₆ )alkyl designates an alkyl group or radical having 1 to 6 carbon atoms.

For the groups comprising two or more subgroups, the attachment is indicated with

For example, "-(C ₁ -C ₆ )alkyl-aryl-(C ₁ -C ₆ )alkenyl" indicates a radical alkyl bound to a radical aryl itself bound to an alkenyl wherein the alkyl is bound to the rest of the molecule.

In the sense of the present invention, the expression "(Ci-C ₆ )alkyl" designates an acyclic, saturated, linear or branched hydrocarbon chain comprising 1 to 6 carbon atoms. Examples of (d-C ₆ )alkyl groups include methyl, ethyl, propyl, butyl, pentyl or hexyl. Unless explicitly stated, the definitions propyl, butyl, pentyl and hexyl include all possible isomers. For example, butyl comprises n-butyl, /so-butyl, sec-butyl and te/t-butyl.

In the sense of the present invention, the expression "(Ci-C ₆ )alkylamine" designates an amine group bound to the molecule via an "(Ci-C ₆ )alkyl" as defined above. Examples of (Ci-C ₆ ) alkylamine groups include methylamine, ethylamine, propylamine, butylamine, pentylamine or hexylamine.

In the sense of the present invention, the expression "(C ₃ -C ₈ )carbocyclyr' designates a saturated or partially saturated mono-, di- or tri-cyclic structure comprising from 3 to 8 carbon atoms. Examples of "(C ₃ -C ₈ )carbocycly include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Unless explicitly stated, the cycloalkyl can be substituted by one or more groups such as methyl, ethyl, isopropyl, hydroxy, methoxy, amino, fluoro, chloro, bromo and iodo.

In the sense of the present invention, the expression "(C ₉ -Cio)carbocyclyl" designates a saturated or partially saturated di- or tri-cyclic structure comprising from 9 to 10 carbon atoms.

In the sense of the present invention, the expression "(C ₃ -C ₈ )heterocyclyr' designates saturated heterocycles having 3, 4, 5, 6, 7 or 8 atoms in the ring where 1 , 2 or 3 heteroatoms chosen from among N, O and S replace the corresponding number of carbon atoms. Examples of "(C ₃ -C ₈ )heterocyclyr' include aziridinyl, oxyranyl, pyrrolidinyl, tetrahydrofuranyl, oxazolyl, piperidinyl, piperazinyl and morpholinyl. Unless explicitly stated, the cycloalkyl can be substituted by one or more groups such as methyl, ethyl, isopropyl, hydroxy, methoxy, amino, fluoro, chloro, bromo and iodo.

In the sense of the present invention, the expression "R _x and R _y form together a (C ₃ -

C ₈ )heterocyclyl" is intended to mean that N, R _x and R _y represent together an heterocycle. For example, R _x and R _y can be connected to form a C ₄ -alkyl chain, forming a pyrrolidinyl ring with the nitrogen atom they are connected to.

The term "aryl" designates an aromatic, monocyclic ring that may be fused with a second saturated, unsaturated or aromatic ring. The term aryl include, without restriction to the following examples, phenyl, indanyl, indenyl, naphtyl, anthracenyl, phenanthrenyl, tetrahydronaphtyl, dihydronaphtyl, 9,9'-Spirobi[9H-fluorene] and p-cyclophanyl. The preferred aryl are those comprising one six-membered aromatic ring. The aryl group may be substituted with one or more groups independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxyl, amino, nitro, cyano, trifluoro, carboxylic acid or carboxylic ester. Examples of substituted phenyl groups are 2-, 3- or 4-methoxyphenyl, 3, 5- or 3, 4- dimethoxyphenyl, 3, 4, 5-trimethoxyphenyl, 2-, 3- or 4-hydroxyphenyl, 4-acylamidophenyl or 4-acylamido-3-hydroxy-phenyl.

The term heteroaryl designates a mono- or polycyclic aryl as defined above where one or more carbon atoms have been replaced with one or more heteroatoms chosen from among N, O and S. Unless explicitly stated, the term "heteroaryl" includes all possible isomers. Examples of heteroaryl groups include furyl, thienyl, imidazolyl, pyridyl, pyrrolyl, N- alkyl pyrrolyl, pyrimidinyl, pyrazinyl, tetrazolyl, triazolyl and triazinyl. The heteroaryl group may be substituted with one or more groups independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxyl, amino, nitro, cyano, trifluoro, carboxylic acid or carboxylic ester. Preferred heteroaryls are those having 5 or 6 atoms in the ring, such as indolyl, pyrrolyl, pyridinyl, pyrrazolyl, triazolyl, furanyl or thienyl.

In the sense of the present invention, the term "halogen" designates a fluorine, chlorine, bromine or iodine atom.

The term "amino acid" as used in the present invention refers to natural a-amino acids (e.g. Alanine (Ala), Arginine (Arg), Asparagine (Asn), Aspartic acid (Asp), Cysteine (Cys), Glutamine (Gin), Glutamic acid (Glu), Glycine (Gly), Histidine (His), Isoleucine (lie), Leucine (Leu), Lysine (Lys), Methionine (Met), Phenylalanine (Phe), Proline (Pro), Serine (Ser), Threonine (Thr), Tryptophan (Trp), Tyrosine (Tyr) and Valine (Val)) in the D or L form, as well as non-natural amino acid. In the sense of the present invention, the definition "R ₇ is the side chain of an aminoacid" is to be understood in its common meaning. By way of illustration, R ₇ is a CH ₂ -phenyl group in phenylalanine.

For the purpose of the invention, the term "pharmaceutically acceptable" is intended to mean what is useful to the preparation of a pharmaceutical composition, and what is generally safe and non-toxic, for a pharmaceutical use.

The term « pharmaceutically acceptable salt, hydrate of solvate » is intended to mean, in the framework of the present invention, a salt of a compound which is pharmaceutically acceptable, as defined above, and which possesses the pharmacological activity of the corresponding compound. Such salts comprise:

(1 ) hydrates and solvates,

(2) acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid and the like; or formed with organic acids such as acetic, benzenesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxynaphtoic, 2-hydroxyethanesulfonic, lactic, maleic, malic, mandelic, methanesulfonic, muconic, 2-naphtalenesulfonic, propionic, succinic, dibenzoyl-L-tartaric, tartaric, p- toluenesulfonic, trimethylacetic, and trifluoroacetic acid and the like, and

(3) salts formed when an acid proton present in the compound is either replaced by a metal ion, such as an alkali metal ion, an alkaline-earth metal ion, or an aluminium ion; or coordinated with an organic or inorganic base. Acceptable organic bases comprise diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases comprise aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

Examples:

• Example 1 : Test of Efficacy and cytotoxicity on Hela and J-Lat cells

Protocol :

Hela-p4 cells

Hel_a-p4 cells are HeLa CD4 LTR-LacZ wherein LacZ expression is induced by the trans-activating protein Tat of HIV, making possible the precise quantification of HIV-1 infectivity from a single replication cycle. Hel_a-CD4 cells growing exponentially at a density of 1 x 104/mL were placed in 96-well plates and infected the following day with 1 ng of HIV p24 antigen in the presence of different concentrations of compounds. The titles for a single cycle of the viruses were determined 48 hours after infection by quantifying the beta- galactosidase activity in lysates P4 by colorimetric test (CPRG, Promega) based on the cleavage of chlorophenol red-beta-D-galactopyranoside (CPRG) by beta-galactosidase. A cell viability assay measuring the absorbance at 690 nm using the yellow tetrazolium reagent MTS [3- (4,5-dimethyl-2-thiazolyl) -2,5-diphenyl tetrazolium bromide] (Promega) was carried out.

J-Lat cells

The J-Lat were grown in RPMI 1640 medium (Gibco-BRL) supplemented with 10% fetal bovine serum, 50 U/ml of penicillin, 50 mg/ml of streptomycin at 37uC in a humidified 95% air/5% C02 atmosphere. The cells were plated at 5.105 cells in a 96 well-plate. TNFn was purchased from Immunosource. SAHA (suberoylanilide hydroxamic acid), prostratin (12- deoxyphorbol-13-acetate) and vorinostat were obtained from Sigma-Aldrich. The J-Lat cells were treated for 24 h with the different compounds alone. The cells were washed twice in PBS, re-suspended in PBS containing 4% paraformaldehyde and fixed for 30 min. Cells were next washed and re-suspended in PBS. The percentage of GFP-positive cells was measured with a LSRFortessa cytometer (Becton-Dickinson) using FACSDiva Version 6.1 .3 according to the manufacturer's instructions. Results:

For the helap4 cells experiments, the efficacy of the compounds is determined in comparison with control cells containing wild type NL4-3 virus alone (i.e. without any added compound) and is expressed as percentage of control. Then, the viral replication was increased for several compounds at the 50 and 100 μΜ concentrations with an absence of cytotoxic effects at the same concentrations (MTS test) (table 1 ).

The results for the J-Lat cells experiments are expressed as a percentage of the living fluorescent cells. In this model, some slight increase of viral production measured by fluorescence are quantified (table 1 ).

Table 1

AB-84 1 12 75 nd 62 60 nd 0.1 6.9

AB-86 80 66 nd 81 74 nd 0.1 2.6

AB-103 125 143 nd 83 84 nd 0.2 0.4

AB-109 F3 164 153 289 1 10 95 75 0.1 4.9 ECO01-029-C 126 109 nd 94 89 nd 0.1 15.8

ECO01-030-C 125 103 nd 84 82 nd 0.1 0

ECO01-031-C 88 108 nd 88 82 nd 0.1 4.8

ECO01-033-C 103 146 nd 97 94 nd 0.1 0.2 ECO01-035-C 169 147 nd 105 88 nd 1.5 2.8

ECO01-037-C 103 103 nd 97 106 nd 0.6 0.2

ECO01-039-C 164 168 nd 95 108 nd 0.1 0.1

ECO01-041-C 114 131 nd 98 84 nd 1.0 0.1 ECO01-042-C 146 104 nd 85 60 nd 0.2 0.4

ECO01-055-C 111 153 nd 94 94 nd 0.4 0.1

ECO01-056-C 94 122 nd 68 81 nd 0.1 0.2

ECO02-003-C 140 118 nd 105 60 nd 0.4 0.5 ECO02-005-C 127 195 nd 106 97 nd 0.5 0.1

ECO02-025-C 90 123 nd 1 12 82 nd 0.3 0.3

ECO02-026-C 30 31 nd 26 26 nd 65.0 nd

ECO02-027-C 75 52 nd 100 45 nd 8.7 2.3

ECO02-028-C 107 89 nd 100 83 nd 0.3 0.2

ECO02-029-C 29 30 nd 25 25 nd 2.4 nd ECO02-030-C 139 166 nd 109 107 nd 0.5 0.1

ECO02-031 -C 146 222 nd 116 110 nd 0.2 0.1

ECO02-007-C 87 98 nd 97 98 nd 0.6 nd

ECO02-051 -C 124 200 397 95 96 77 1.1 nd ECO02-056-C 100 79 nd 67 38 nd 1.6 nd

ECO02-058-C 110 159 194 105 88 87 1.4 nd

ECO02-059-C 198 177 nd 95 67 nd 0.5 nd

ECO02-060-C 178 221 217 69 54 43 0.6 nd

ECO03-001 -B 1 18 170 360 97 104 109 0.6 nd

ECO03-002-C 120 165 317 1 15 1 16 74 0.5 nd

ECO03-03-C 148 341 440 105 104 104 0.4 nd

• Example 2 : CD4+ T Cells culture - VIH Patients

Protocol:

CD4+T cells

For experiments using primary cells obtained from HIV-infected, anti retroviral -treated, aviremic patients, total CD4+ cells are isolated by a MACS® Whole Blood MicroBead Technology (Miltenyi). Briefly, T CD4+ cells from whole blood are magnetically labeled with MACS MicroBeads and specific antibodies. Cells are separated in a MACS Column placed in a MACS Separator. The flow-through fraction can be collected as the negative fraction depleted of the labeled cells. The column is removed from the separator and the retained cells are eluted as the enriched, positively selected cell fraction. The T CD4+ cells were then cultured with a T cell activation/expansion kit (Miltenyi). The cells are activated for up to 3 days with Anti-Biotin MACSiBead Particle conjugated to monoclonal anti-biotin antibodies (anti CD2-biotin, anti CD3-CD3 and anti CD28-biotin). Expansion is achieved by adding IL-2 and fresh medium for 4 days. Then, these T CD4+ cells are considered as positive culture. A negative control was the same proportion of cells cultured without stimuli like antibodies and IL-2. The T CD4+ cells were cultured with compounds alone or in combination with antibodies or IL-2. The HIV production in cell culture media was measured by real time PCR (Cobas AmpliPrep/Cobas Taqman HIV-1 test, V2.0, Roche). The results are expressed in table 2 as a ratio of the viral load of interest/viral load of negative control or as a ratio of the viral load of interest/viral load of positive control.

Results:

In the T CD4+ cell model, some compounds were efficient to increase the production of HIV from cells of HIV-infected, ART-treated, aviremic patients. Depending of the compounds, they were efficient alone, or in combination with antibodies or IL2.

Table 2

Compounds Number of Antobodies+IL2(Control Compound Antobodies + Compound Compound Antobodies + Compound activated +) Compound + IL2 Compound + IL2 patient

ratio of the viral load of interest/viral ratio of the viral load of interest/viral load of negative control load of positive control

AB77 2 496 0,3 258 1,5 0,0006 0,5202 0,0030

8,7 0,5 11,7 1 0,0575 1,3448 0,1149

AB116 4 2,4 1,3 2,3 0,9 0,5417 0,9583 0,3750

3,2 0,8 1,1 0,9 0,2500 0,3438 0,2813

35,1 3 5,5 27,9 0,0855 0,1567 0,7949

23 1,4 4,5 0,7 0,0609 0,1957 0,0304

AB120 3 6 12 13 10 2,0000 2,1667 1,6667

2 1 1 6 0,5000 0,5000 3,0000

3 3 5 3 1,0000 1,6667 1,0000

AB378 2 12,8 4,3 26,3 2,8 0,3359 2,0547 0,2188

3,1 1 2,5 1 0,3226 0,8065 0,3226

AB289-2 3 2,1 1 1 1 0,4762 0,4762 0,4762

12 0,5 0,5 0,5 0,0417 0,0417 0,0417

4,3 1 55 12,2 0,2326 12,7907 2,8372

AB289-1 3 2,2 0,2 0,2 0,6 0,0909 0,0909 0,2727

19,3 2,5 9,2 1,9 0,1295 0,4767 0,0984

2,4 5,1 3,9 2,3 2,1250 1,6250 0,9583

AB287fl 2 308 1 11,6 1 0,0032 0,0377 0,0032

69 0,6 1,9 0,5 0,0087 0,0275 0,0072 PDA25 2 17 1 6,8 1 0,0588 0,4000 0,0588

7 0,9 9,9 0,7 0,1286 1,4143 0,1000

ECOOl-025 3 79 1 248 13 0,0127 3,1392 0,1646

38 1 1 1 0,0263 0,0263 0,0263

134 1 2 1 0,0075 0,0149 0,0075

EcoOl-026 2 504 1 122 2 0,0020 0,2421 0,0040

5 0,5 1 0,5 0,1000 0,2000 0,1000

ECO02-005 2 9,4 3,8 5,3 1,9 0,4043 0,5638 0,2021

212 2,2 3 3,9 0,0104 0,0142 0,0184

ECO02-051 2 93 1 157 1 0,0108 1,6882 0,0108

4 1 1 0 0,2500 0,2500 0,0000

ECO02-062 2 6 1 3 1 0,1667 0,5000 0,1667

3 3 1 2 1,0000 0,3333 0,6667

Example 3 :

The following compounds were assessed:

326,17

Compound B (AB-109f3): Mol. Wt. : 326,39

Co

Mol. Wt. : 518,48 In an experiment, MT2 cells (human lymphocytic cell line) are infected with the Lai ^' virus to a multiplicity of infection of 0.3 and incubated with compounds A, B, C or D at four different concentrations.

After 3 days of culture, real-time PCR quantification of the viral RNA of the supernatant is performed (COBAS Ampliprep/COBAS TaqMan HIV-1 assay, version 2).

The results are expressed as percentage of control (virus without any added compound) in Table 3.

Table 3:

These results demonstrate that compounds A, B, C and D induce viral replication at an extremely high level in human lymphocytes.

All the above results show that the compounds of formula (I) according to the present invention are capable of increasing viral replication, are not cytotoxic, and are hence useful for eradicating HIV reservoirs.

• Example 4

Preparation of compounds:

Compounds were prepared according to the Journal of Organic Chemistry 2013, 78, 12236- 12242 ECO01-003-Cdi benzyl 3-(2,3-dihydro-1 W-inden-1-yl)-3,6,7-triazabicyclo[3.2.1]octane-6,7- dicarboxylate : 233 mg, 43%, colorless oil ;

1 H NMR (500 MHz, (CD ₃ ) ₂ SO, 70°C) δ 1 .86 (s, 2H), 1 .94-1 .97 (m,

2H), 2.30 (br s, 1 H), 2.51 (br s, 1 H), 2.70 (bs s, 1 H), 2.73-2.78 (m,

1 H), 2.82-2.85 (m, 1 H), 3.10 (br s, 1 H), 4.20 (br s, 1 H), 4.31 (br s,

1 H), 4.42 (br s, 1 H), 5.13-5.26 (m, 4H), 7.17-7.19 (m, 4H), 7.32- 73.8 (m, 10H) ; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO, 70 °C) δ 24.4, 30.3

(2C), 35.7, 53.6, 55.8, 56.4, 66.9 (2C), 67.8, 124.3 (2C), 125.1 ,

126.0, 127.3-128.4 (8C), 136.4 (2C), 142.2 (2C), 143.3 (2C), 156.9

(2C) ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for

C30H32N3O4, 498.2387, found 498.2381 .

ECO01-004-C dibenzyl 3-(2-methoxyphenethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7- dicarboxylate : 357 mg, 63%, pale yellow oil ;

1 H NMR (500 MHz, (CD ₃ ) ₂ SO, 70°C) δ 1 .86 (m, 2H), 2.25 (br

s, 2H), 2.50-2.61 (m, 4H), 3.16 (br s, 2H), 3.77 (s, 3H), 4.38

(br s, 2H), 5.14 (s, 4H), 6.86 (t, J = 7.3 Hz, 1 H), 6.92 (d, J =

8.1 Hz, 1 H), 7.10 (dd, J = 7.4 Hz, 1 .3 Hz, 1 H), 7.16 (td, J =

7.8, 0.85 Hz, 1 H), 7.31 -7.37 (m, 10H) ; ¹³ C NMR (125 MHz,

(CD ₃ ) ₂ SO, 70°C) δ 26.9, 35.7, 55.4, 56.0 (2C), 56.4, 66.0,

66.8 (2C), 1 10.9, 120.3, 127.0-128.3 (13C), 130.8, 136.5

(2C), 156.8 (2C), 157.2 ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd

for C30H34N3O5, 516.24930, found 516.2481 1 .

ECO0-005-C dibenzyl 3-(2,3-dihydro-1 H-inden-2-yl)-3,6,7-triazabicyclo[3.2.1]octane-6,7- dicarboxylate : 168 mg, 30%, orange solid ;

¹ H NMR (500 MHz, (CD ₃ ) ₂ SO, 70°C) δ 1 .83-1 .87 (m, 2H), 2.26

(br s, 2H), 2.60 (d, J = 7.7 Hz, 1 H), 2.61 (d, J = 7.7 Hz, 1 H),

2.88 (q, J = 7.4 Hz, 1 H), 2.90 (d, J = 7.4 Hz, 1 H), 3.04 (br s,

2H), 3.23 (m, 1 H), 4.38 (br s, 2H), 5.10-5.18 (m, 4H), 7.1 1 -7.14

(m, 4H), 7.34 (br s, 10H) ; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO, 70°C)

δ 35.7, 36.0 (2C), 49.9, 53.8, 55.9 (2C), 64.4, 66.7 (2C), 124.0

(2C), 126.2 (2C), 127.5-128.4 (10C), 136.4 (2C), 141 .3 (2C),

156.9 (2C) ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for

C ₃ oH3 ₂ N ₃ 0 ₄ , 498.23873, found 498.23785.

ECO01-006-C dibenzyl 3-(4-methylphenethyl)-3,6,7- triazabicyclo[3.2.1]octane-6,7-dicarboxylate : 317 mg, 59%,

yellow oil ;

H NMR (500 MHz, (CD ₃ ) ₂ S0, 70°C) δ 1 .86 (br s, 2H), 2.26 (s, 5H),

2.52 (br s, 3H), 3.17 (br s, 3H), 4.39 (br s, 2H), 5.13 (br s, 4H), 7.02- 7.1 1 (m, 4H), 7.30-7.34 (m, 10H) ; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO,

70°C) δ 20.9, 32.1 , 35.6, 54.8 (2C), 55.9 (2C), 57.8, 66.8 (2C),

126.4-128.6 (13C), 130.8 (2C), 134.6, 136.5, 137.0, 156.7 (2C) ;

HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for C30H34N3O4, 500.25438,

found 500.25446. ECO01-008-C dibenzyl 3-(3-methylphenethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7- dicarboxylate : 230 mg, 42%, yellow oil ;

ECO01 -009-C dibenzyl 3-(1 ,2,3,4-tetrahydronaphthalen-1 -yl)-3,6,7- triazabicyclo[3.2.1]octane-6,7-dicarboxylate : 353 mg, 63%,

white solid ;

1H NMR (500 MHz, (CD ₃ ) ₂ SO, 70°C) δ 1.59-1.70 (m, 2H), 1.80-

1.87 (m, 4H), 2.32 (br s, 1 H), 2.61 -2.73 (m, 4H), 2.99 (br s, 1 H),

3.67 (br s, 1 H), 4.34 (br s, 1 H), 4.43 (br s, 1 H), 5.12-5.17 (m, 4H),

7.02-7.07 (m, 3H), 7.31 -7.36 (m, 10H), 7.52 (br s, 1 H) ; ¹³ C NMR

(125 MHz, (CD ₃ ) ₂ SO, 70°C) δ 21.1 , 22.1 , 29.1 , 35.7, 47.8, 53.6,

55.8, 56.7, 60.4, 66.9 (2C), 125.5, 126.1 , 126.4, 126.5, 127.4-

128.4 (1 1 C), 136.3, 136.9, 137.9, 156.7 (2C) ; HRMS (ESI-

Orbitrap) [M+H] ⁺ calcd for

C31 H34N3O4, 512.25438, found 512.25427.

ECO01-010-C dibenzyl 3-(2-(benzo[cfl[1 ,3]dioxol-5-yl)ethyl)-3,6,7- triazabicyclo[3.2.1]octane-6,7-dicarboxylate : 197 mg, 34%,

colorless paste ;

¹ H NMR (500 MHz, (CD ₃ ) ₂ SO, 70°C) δ 1.86 (br s, 2H), 2.24 (br

s, 2H), 2.50 (br s, 2H), 3.13 (s, 4H), 4.38 (br s, 2H), 5.12

4H), 5.93 (s, 2H), 6.60 (d, J = 3.1 Hz, 1 H), 6.72 (d, J = 1 .4 Hz,

1 H), 6.75 (d, J = 7.9 Hz, 1 H), 7.31 -7.34 (m, 10H) ; ¹³ C NMR

(125 MHz, (CD ₃ ) ₂ SO, 70°C) δ 32.2, 35.7, 55.0, 55.9 (2C), 57.9

(2C), 66.8 (2C), 100.5, 107.9, 108.8, 121.2, 127.4-127.7 (10

C), 128.2, 134.1 , 136.5, 145.3, 147.2, 156.6 (2C) ;

HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for C ₃ oH3 ₂ N ₃ 0 ₆ 530.22856, found 530.22937.

ECO01-011-C dibenzyl 3-(2,2-diphenylethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7- dicarboxylate : 216 mg, 35%, white solid ;

¹ H NMR (500 MHz, (CD ₃ ) ₂ SO, 70°C) δ 1.80 (s, 2H), 2.22 (br s,

2H), 3.02 (d, J = 7.15 Hz, 2H), 3.14 (br s, 2H), 4.17 (t, J = 4.2 Hz,

1 H), 4.32 (br s, 2H), 4.98 (br s, 4H), 7.13-7.30 (m, 20H) ; ¹³ C NMR

(125 MHz, (CD ₃ ) ₂ SO, 70°C) δ 35.6, 48.0, 54.7 (2C), 55.7 (2C),

61 .7, 66.7 (2C), 125.9 (2C), 127.3-128.2 (18C), 136.4 (2C), 144.1

(2C), 156.3 (2C) ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for

C35H36N3O4, 562.27003, found 562.26874. ECO01-012-C dibenzyl 3-(3-phenylpropyl)-3,6,7-triazabicyclo[3.2.1 ]octane-6,7- dicarboxylate : 285 mg, 52%, colorless oil ;

1 H NMR (500 MHz, (CD ₃ ) ₂ SO, 70°C) δ 1 .60 (m, 2H),1.85 (br m,

2H), 2.12 (br s, 2H), 2.32 (br s, 2H), 2.52 (t, J = 3.9 Hz, 2H), 3.07

(br s, 2H), 4.38 (br s, 2H), 5.13 (s, 4H), 7.17 (d, J = 6.9 Hz, 3H),

7.25 (t, J = 7.4 Hz, 2H), 7.29-7.36 (m, 10H) ; ¹³ C NMR (125 MHz,

(CD ₃ ) ₂ SO, 70°C) δ 27.9, 32.4 (2C), 35.8, 55.2 (2C), 55.9 (2C), 66.9

(2C), 125.5, 127.4-128.2 (14C), 136.4 (2C), 142.1 , 156.7 (2C) ;

HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for C30H34N3O4, 500.25438

found 500.25461 .

ECO01-015-C dibenzyl 3-(3-methoxyphenethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7- dicarboxylate : 318 mg, 57%, yellow paste ;

¹ H NMR (500 MHz, (CD ₃ ) ₂ SO, 70°C) δ 1 .86 (s, 2H), 2.23 (br s, 2H

2.56 (s, 4H), 3.15 (s, 2H), 3.74 (s, 3H), 4.38 (s, 2H), 5.13 (s, 4H

6.75 (s, 3H), 7.18 (t, J = 7.4 Hz, 1 H), 7.30-7.35 (m, 10H); ¹³ C NM

(125 MHz, (CD ₃ ) ₂ SO, 70°C) δ 32.7, 35.7, 54.9 (2C), 55.9 (2C), 57.

(2C), 66.8 (2C), 1 1 1 .5, 1 14.2, 120.7, 127.4-129.1 (1 1 C), 136.

(2C), 141 .8, 156.6 (2C), 159.4 ; HRMS (ESI-Orbitrap) [M+H] ⁺ cal

for C30H33N3O5, 516.24930 found 516.24731 .

ECO01-016-C dibenzyl 3-(2-methylphenethyl)-3,6,

triazabicyclo[3.2.1]octane-6,7-dicarboxylate : 251 mg, 46%,

white paste ;

¹ H NMR (500 MHz, (CD ₃ ) ₂ SO, 30°C) δ 1 .87 (br s, 2H), 2.1 1 (br

s, 2H), 2.21 (s, 3H), 2.40 (br s, 2H), 3.08 (br s, 2H), 3.44 (br s,

2H), 4.27 (br s, 1 H), 4.51 (br s, 1 H), 5.13 (s, 4H), 7.10 (s, 4H),

7.28-7.40 (m, 10H) ; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO, 30°C, two

rotamers) δ 18.8 (2C), 29.6, 30.0, 35.6, 36.0, 51 .8 (2C), 53.6

(2C), 55.5 (2C), 55.7 (2C), 56.4, 56.6, 66.3 (2C), 67.2 (2C),

125.8 (2C), 125.9 (2C), 126.9-129.9 (24C), 135.5 (2C), 136.2,

136.3, 136.7 (2C), 138.2 (2C), 155.2 (2C), 157.0, 157.6 ; HRMS

(ESI-Orbitrap) [M+H] ⁺ calcd for C30H34N3O4, 500.25438 found

500.25369.

ECO01-017-C dibenzyl 3-(3,4-dimethylphenethyl)-3,6,7- triazabicyclo[3.2.1]octane-6,7-dicarboxylate : 291 mg, 52%,

white paste ;

¹ H NMR (500 MHz, (CD ₃ ) ₂ SO, 30°C) δ 1 .86 (br s, 2H), 2.05 (br s,

1 H), 2.16 (br s, 6H), 2.33 (br s, 1 H), 2.42 (br s, 4H), 3.03 (br s,

1 H), 3.41 (br s, 1 H), 4.25 (br s, 1 H), 4.50 (br s, 1 H), 5.03-5.15 (m,

4H), 6.85 (d, J = 7.6 Hz, 1 H), 6.90 (s, 1 H), 7.00 (br s, 1 H), 7.27- 7.40 (br m, 10H) ; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO, 30°C, two

rotamers) δ 18.9 (2C), 19.3 (2C), 31 .9, 32.0, 35.6, 36.0, 51 .8 (2C),

53.7 (2C), 55.7 (2C), 56.5 (2C), 58.0 (2C), 66.2 (2C), 67.2 (2C),

125.7-129.6 (24C), 133.3 (2C), 135.8 (2C), 136.2 (2C), 136.3 (2C), 136.8 (2C), 137.3 (2C), 155.1 (2C), 156.9, 157.6 ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for C31 H36N3O4, 514.27003 found 514.26886. ECO01-018-C dibenzyl 3-(4-(methylsulfonyl)phenethyl)-3,6,7-triazabicyclo[3.2.1]oc tane 6,7-dicarboxylate : 349 mg, 57%, colorless paste ;

1 H NMR (500 MHz, (CD ₃ ) ₂ SO, 30°C) δ 1 .86 (br s, 2H),

2.06 (br d, J = 1 1 .5 Hz, 1 H), 2.35 (br d, J = 1 1 .5 Hz, 1 H),

2.51 (s, 1 H), 2.63 (br s, 3H), 3.07 (br d, J = 10.1 Hz, 2H),

3.16 (s, 3H), 4.26 (br s, 1 H), 4.51 (br s, 1 H), 5.12 (s, 4H),

7.33 (br s, 10H), 7.44 (d, J = 7.9 Hz, 2H), 7.82 (d, J ^■ ■ = 8.3

Hz, 2H) ; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO, 30°C,

rotamers) δ 31 .9, 32.0, 35.5, 35.9, 43.6 (2C), 51 .8 (2C),

53.8 (2C), 55.6 (2C), 56.5 (2C), 57.1 (2C), 66.2 (2C), 67.2

(2C), 126.9-129.5 (26C), 136.2 (2C), 136.3 (2C), 136.7 (2C), 138.4 (2C), 146.6 (2C), 155.1 (2C), 156.8, 157.7 ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for C30H34N3O6S, 564.21628 found 564.21625.

ECO01-019-C dibenzyl 3-(2-phenoxyphenethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7- dicarboxylate : 291 mg, 48%, yellow oil ;

1 H NMR (500 MHz, (CD ₃ ) ₂ SO, 60°C) δ 1 .81 (br s, 2H),

2.19 (br s, 2H), 2.57 (br s, 2H), 2.60 (br s, 2H), 3.00 (br

s, 2H), 4.33 (br s, 2H), 5.08 (br s, 4H), 6.85 (d, J = 8.0

Hz, 1 H), 6.90 (d, J = 8.0 Hz, 2H), 7.05-7.1 1 (m, 2H), 7.19

(t, J = 7.55 Hz, 2H), 7.20-7.28 (m, 12 H) ; ¹³ C NMR (125

MHz, (CD ₃ ) ₂ SO, 60°C) δ 26.7, 35.6, 51 .9, 55.0, 55.8

(2C), 56.4, 66.8 (2C), 1 17.3, 1 19.4 (2C), 122.6 (2C),

124.1 , 126.6-127.9 (10C), 128.2, 129.9, 130.8, 131 .5,

136.4 (2C), 153.9, 156.9 (2C), 157.5 ; HRMS (ESI-

Orbitrap) [M+H] ⁺ calcd for C35H36N3O5, 578.26495 found

578.26416.

ECO01-020-C dibenzyl 3-phenyl-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate

ECO01-021-C dibenzyl 3-(4-(trifluoromethyl)phenyl)-3,6,7-triazabicyclo[3.2.1 ]octane-6,7- dicarboxylate : 168 mg, 30 %, yellow oil ;

1 H NMR (500 MHz, (CD ₃ ) ₂ SO, 60°C) δ 2.03-2.06 (m, 1 H),

2.14-2.16 (m, 1 H), 3.03 (br s, 2H), 3.89 (br s, 2H), 4.66 (br

s, 2H), 5.15 (br m, 4H), 6.84 (br s, 2H), 7.17-7.32 (br m,

10H), 7.46 (d, J = 8.7 Hz, 2H) ; ¹³ C NMR (125 MHz,

(CD ₃ ) ₂ SO, 60°C) δ 33.5, 47.9, 50.3 (2C), 55.0, 67.0 (2C),

1 12.4 (2C), 1 17.3 (J = 32.0 Hz), 125.5 (J = 270.0 Hz), 126.0 (J = 3.6 Hz, 2C), 126.2-128.5 (10C), 136.2 (2C), 152.2, 156.0 (2C) ; HRMS (ESI- Orbitrap) [M+H] ⁺ calcd for C ₂₈ H ₂₇ F ₃ N ₃ 04, 526.1948 found 526.1937.

ECO01-032-C dibenzyl 3-(benzo[d][1 ,3]dioxol-5-yl)-3,6,7-triazabicyclo[3.2.1]octane-6,7- dicarboxylate : 254 mg, 47%, pale brown solid

H NMR (500 MHz, (CD ₃ ) ₂ SO, 60°C) δ 1 .98-2.05 (m, 2H),

2 !..83 (br s, 2H), 3.68 (br s, 2H), 4.57 (br s, 2H), 5.16 (br m,

4H), 5.90 (s, 2H), 6.16 (br s, 1 H), 6.43 (br s, 1 H), 6.73 (d, J

= 8.5 Hz, 1 H), 7.32 (br s, 10 H) ; ¹³ C NMR (125 MHz,

(CD ₃ ) ₂ SO, 60°C) δ 34.2, 49.1 , 51 .8, 55.4 (2C), 67.0 (2C),

97.1 , 100.4, 106.2, 108.2, 127.5-128.3 (1 1 C), 136.3,

139.9, 145.7, 148.0, 156.4 (2C) ; HRMS (ESI-Orbitrap)

[M+H] ⁺ calcd for C ₂₈ H ₂₇ N ₃ 0 ₆ , 502.1973 found 502.1991 .

ECO01-044-C dibenzyl 3-(3-methoxyphenyl)-3,6,7- triazabicyclo[3.2.1]octane-6,7-dicarboxylate : 312 mg,

59%, orange oil ;

¹ H NMR (500 MHz, (CD ₃ ) ₂ SO, 60°C) δ 2.02-2.09 (m, 2H),

2.90 (br s, 2H), 3.72 (s, 3H), 3.81 (br s, 2H), 4.62 (br s, 2H),

5.17 (br s, 4H), 6.30-6.38 (m, 3H), 7.10 (t, J = 8.1 Hz, 1 H),

7.32 (br s, 10H) ; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO, 60°C) δ

33.9, 48.0, 50.7, 54.7, 55.2 (2C), 67.0 (2C), 99.7, 103.5,

106.2, 127.5-128.3 (1 1 C), 129.6, 136.2, 151 .1 , 156.2 (2C),

160.4 ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for C ₂₈ H ₃₀ N ₃ O ₅ ,

488.2180 found 488.2184.

ECO01-046-C dibenzyl 3-(2-methoxyphenyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7- dicarboxylate : 335 mg, 63%, brown oil ;

¹ H NMR (500 MHz, (CD ₃ ) ₂ SO, 57°C) δ 1 .98-2.04 (m, 2H),

2.92 (br s, 2H), 3.56-3.69 (m, 2H), 3.70 (s, 3H), 4.51 (br s,

2H), 5.17 (br s, 4H), 6.86-6.92 (m, 3H), 6.98 (t, J = 8.6 Hz,

1 H), 7.29-7.32 (m, 10H) ; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO,

57°C) δ 35.3, 50.6, 52.9, 55.8 (3C), 66.9 (2C), 1 12.9, 120.4,

121 .0, 123.0, 127.2-128.2 (10C), 136.4 (2C), 139.9, 153.0,

156.4 (2C) ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for

C ₂₈ H ₃₀ N ₃ O ₅ , 488.2180 found 488.2189. ECO01-048-C dibenzyl 3-(naphthalen-2-ylmethyl)-3,6,7-triazabicyclo[3.2.1]octane-6 ,7- dicarboxylate : 430 mg, 76%, white solid ;

1 H NMR (500 MHz, (CD ₃ ) ₂ SO, 57°C) δ 1 .86 (br s, 2H), 2.23

(br s, 2H), 3.01 (br s, 2H), 3.92 (br s, 2H), 4.32 (br s, 2H),

5.01 (s, 4H), 7.27-7.50 (br m, 14H), 7.81 (d, J = 8.4 Hz,

1 H), 7.88 (d, J = 8.9 Hz, 1 H), 8.14 (br s, 1 H) ; ¹³ C NMR

(125 MHz, (CD ₃ ) ₂ SO, 57°C) δ 35.8, 50.6, 52.8 (2C), 55.6

(2C), 58.6, 66.7 (2C), 124.8, 125.5, 125.9, 127.2-128.2

(14C), 131 .5, 133.4, 133.7, 136.1 , 156.3 (2C) ; HRMS (ESI- Orbitrap) [M+H] ⁺ calcd for C32H32N3O4, 522.2387 found

522.2397.

ECO01-049-C dibenzyl 3-(3-(phenylcarbamoyl)phenyl)- 3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate : 368

mg, 59%, white solid ;

¹ H NMR (500 MHz, (CD ₃ ) ₂ SO, 57°C) δ 2.05-2.13 (m, 2H),

2.99 (br s, 2H), 3.96-4.30 (br s, 2H), 4.66 (br s, 2H), 5.17

(br s, 4H), 6.94-7.36 (br m, 17H), 7.78 (d, J = 7.9 Hz 2H),

10.04 (s, 1 H, NH) ^{■ 13} C NMR (125 MHz, (CD ₃ ) ₂ SO, 57°C)

δ 33.9, 48.1 , 50.4, 55.1 (2C), 67.1 (2C), 1 12.2, 1 16.2,

1 17.0, 120.3 (2C), 123.6, 127.6-128.9 (14C), 135.8, 136.2,

139.2, 149.7, 156.1 (2C), 165.9 ; HRMS (ESI-Orbitrap)

[M+H] ⁺ calcd for C34H33N4O5, 577.2445 found 577.2462.

ECO01-052-C dibenzyl 3-(3-

(phenylcarbamoyl)phenyl)-3,6,7- triazabicyclo[3.2.1]octane-6,7-dicarboxylate : 186 mg,

58 %, white solid ;

1 H NMR (500 MHz, (CD ₃ ) ₂ SO, 57°C) δ 1 .30 (t, J = 7.0

Hz, 3H), 1 .86 (br s, 2H), 2.20 (br s, 2H), 3.19 (s, 6H),

3.98 (q, J = 6.9 Hz, 2H), 4.36 (br s, 2H), 5.12 (s, 4H),

6.80 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H), 7.30- 7.35 (m, 10H) ; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO, 57°C) δ

14.6, 31 .6, 35.7, 54.8, 55.8 (2C), 56.4, 58.0, 62.9, 66.8

(2C), 1 14.4 (2C), 127.6-128.3 (10C), 129.5 (2C), 132.0

(2C), 136.5 (2C), 156.7 (2C) ; HRMS (ESI-Orbitrap)

[M+H] ⁺ calcd for C31 H36N3O5, 530.2649 found 530.2643.

ECO01-053-C dibenzyl 3-(4-(azepane-1- carbonyl)phenyl)-3,6,7-triazabicyclo[3.2.1]octane- 6,7-dicarboxylate : 301 mg, 56%, white solid ;

1 H NMR (500 MHz, (CD ₃ ) ₂ SO, 57°C) δ 1 .56 (br s, 4H),

1 .66 (br s, 4H), 2.04 (br s, 1 H), 2.10 (br s, 1 H), 2.96 (br

s, 1 H), 3.48 (br s, 5H), 3.74-4.33 (br m, 2H), 4.68 (br s,

2H), 5.17 (br s, 4H), 6.60 (br s, 1 H), 6.74 (br s, 1 H),

7.10-7.34 (br m, 12H) ; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO,

57°C) δ 26.6, 28.0, 32.3, 34.1 , 47.6, 50.4, 55.1 (2C),

60.2, 61 .3, 62.5, 66.9 (2C), 1 12.2, 1 12.9, 124.2, 126.3,

126.8-128.4 (1 1 C), 136.3 (2C), 150.1 , 156.4 (2C), 170.5

; HRMS (ESI-Orbitrap)[M+H] ⁺ calcd for C34H39N4O5, 583.2915 found 583.2913.

ECO01-054-C dibenzyl 3-(4-(p-tolyloxy)phenyl)-3,6,7- triazabicyclo[3.2.1]octane-6,7-dicarboxylate : 403 mg,

66%, white solid ;

¹ H NMR (500 MHz, (CD ₃ ) ₂ SO, 57°C) δ 2.05 (br s, 2H),

2.30 (br s, 3H), 2. 88 (br s, 2H), 3.77 (br s, 2H), 4.61 (br s,

2H), 5.20 (br s, 4H), 6.85 (br s, 6H), 7.10-7.34 (br m, 12H)

; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO, 57°C) δ 20.1 , 34.1 , 48.4,

48.9, 51 .2 (2C), 55.0 (2C), 1 14.9 (2C), 1 17.3 (2C), 120.0

(2C), 127.6-128.3 (1 1 C), 130.0, 131 .4, 136.3 (2C), 146.2,

148.5, 156.0 (3C) ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for

C34H34N3O5, 562.2493 found 564.2488.

ECO02-008-C dibenzyl 3-(4-bromophenyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7- dicarboxylate : 514 mg, 44%, white solid ; o o

1 H NMR (500 MHz, (CD ₃ ) ₂ SO, 60°C) δ 1 .99-2.10 (m, 2H ,

2.90 (br s, 2H), 3.78 (br s, 2H), 4.62 (br s, 2H), 5.15 (br

4H), 6.67 (br s, 2H), 7.30 (br s, 12H) ; ¹³ C NMR (125 MH

(CD ₃ ) ₂ SO, 60°C) δ 33.8, 48.6, 50.3, 55.2 (2C), 59.7 (2C

109.0, 1 15.2 (2C), 126.4-127.8 (10C), 128.3 (2C), 131 .

136.2, 148.9, 156.2 (2C) ; HRMS (ESI-Orbitrap) [M+H]

calcd for C ₂₇ H ₂₇ N ₃ 0 ₄ Br, 536.1 190 found 536.1 177.

ECO02-013-C dibenzyl 3-(4-bromophenyl)-3,6,7- triazabicyclo[3.2.1]octane-6,7-dicarboxylate : 334 mg,

63%, colorless oil ;

1 H NMR (500 MHz, (CD ₃ ) ₂ SO, 60°C) δ 1 .84 (br s, 2H),

2.21 (br s, 2H), 2.57 (br s, 4H), 3.09 (br s, 2H), 4.39 (br s,

2H), 5.14 (br s, 4H), 7.01 -7.36 (m, 15H) ; ¹³ C NMR (125

MHz, (CD ₃ ) ₂ SO, 60°C) δ 32.6, 35.7, 52.2, 54.9, 55.9

(2C), 57.8, 66.8 (2C), 125.5 (2C), 127.0-128.0 (7C),

128.2 (2C), 128.3 (2C), 128.4 (2C), 136.4, 140.3 (2C),

156.8 (2C) ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for

0 ₂ 9Η ₃₂ Ν ₃ θ4, 486.2387 found 486.2390.

ECO02-014-C dibenzyl 3-(4-hydroxyphenethyl)-3,6,7- o o

triazabicyclo[3.2.1]octane-6,7-dicarboxylate 161

mg, 29%, colorless oil ; N N

¹ H NMR (500 MHz, (CD ₃ ) ₂ SO, 60°C) δ 1 .83-1 .85 (br m,

2H), 2.20 (br s, 2H), 2.47-2.55 (br m, 4H), 3.07 (br s,

2H), 4.37 (br s, 2H), 5.14 (br s, 4H), 6.67 (d, J = 8.4 Hz,

2H), 6.94 (d, J = 8.4 Hz, 2H), 7.34 (br s, 10H), 8.95 (s,

1 H, OH) ; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO, 60°C) δ 31 .7,

35.7, 52.2, 53.6, 55.9 (2C), 58.2, 66.8 (2C), 1 15.1 (2C),

127.5-128.3 (1 1 C), 129.2 (2C), 130.3, 136.4, 155.3,

156.8 (2C) ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for

C ₂ 9H ₃₂ N ₃ 0 ₅ , 502.2336 found 502.2335. ECO02-019-C dibenzyl 3-(4-methoxyphenethyl)-3,6,7- triazabicyclo[3.2.1]octane-6,7-dicarboxylate : 435 mg,

76%, colorless oil ;

1 H NMR (500 MHz, (CD ₃ ) ₂ SO, 60°C) δ 1 .82-1 .90 (m, 2H), 2.12 (br s, 2H), 2.50 (s, 4H), 3.10 (br s, 2H), 3.72 (s, 3H), 4.37 (br s, 2H), 5.13 (s, 4H), 6.82 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 7.28-7.38 (m, 10H) ; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO, 60°C) δ 31 .6, 35.7, 52.5, 54.7, 55.0 (2C), 55.8, 66.8 (2C), 1 13.8 (2C), 126.6-128.3 (9C), 128.3 (2C), 129.3 (2C), 132.5, 136.4, 156.7 (2C), 157.9 ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for C30H34N3O5, 516.2493 found 516.2489.

ECO02-036-C dibenzyl 3-(3-hydroxyphenethyl)-3,6,7- triazabicyclo[3.2.1]octane-6,7-dicarboxylate : 229 mg,

37%, white solid ;

¹ H NMR (500 MHz, (CD ₃ ) ₂ SO, 60 °C, δ) 1 .86 (br s, 2H), 2.22 (br s, 2H), 2.51 (br s, 4H), 3.20 (br s, 2H), 4.37 (br s, 2H), 5.14 (br s, 4H), 6.58-6.60 (m, 3H), 7.04 (t, J= 7.9 Hz, 1 H), 7.35 (br s, 10H), 9.05 (br s, 1 H, OH) ; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO, 60 °C, δ) 32.6, 35.7, 52.2, 55.0, 55.8 (2C), 57.8, 66.8 (2C), 1 12.9, 1 15.4, 1 19.1 , 127.5-129.0 (1 1 C), 136.5 (2C), 141 .5, 157.0 (2C), 157.3 ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for C ₂ 9H ₃₂ N ₃ 0 ₅ , 502.2336 found 502.2352.

ECO02-020-C dibenzyl 3-(4-phenylbutyl)-3,6,7- triazabicyclo[3.2.1]octane-6,7-dicarboxylate : 473 mg,

85%, colorless oil ;

¹ H NMR (500 MHz, (CD ₃ ) ₂ SO, 60°C) δ 1 .33 (m 2H), 1 .54 (m, 2H), 1 .80-1 .84 (m, 2H), 2.20 (br s, 2H), 2.31 (br s, 2H), 2.51 -2.56 (m, 2H), 2.99 (br s, 2H), 4.35 (br s, 2H), 5.12 (br s, 4H), 5.71 (s, 4H), 7.14-7.27 (m, 15H) ; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO, 60°C) δ 25.7, 28.1 , 35.0, 35.8, 52.5, 54.7, 55.8 (3C), 66.8 (2C), 125.3 (2C), 125.5-128.2 (14C), 136.4, 142.4, 156.8 (2C) ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for C31 H35N3O4, 514.2700 found 514.2700.

ECO02-047-C dibenzyl 3-(3-fluorophenethyl)-3,6,7- triazabicyclo[3.2.1]octane-6,7-dicarboxylate 360 mg, 66%, colorless oil ;

¹ H NMR (500 MHz, (CD ₃ ) ₂ SO, 57°C) δ 1 .86 (br s, 2H), 2.22 (br s, 2H), 2.58 (br s, 4H), 3.08 (br s, 2H), 4.37 (br s, 2H), 5.12 (br s, 4H), 6.97-6.99 (m, 3H), 7.25-7.40 (m, 1 1 H) ; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO, 57°C) δ 32.1 , 35.7, 52.2, 54.1 , 55.8 (2C), 57.3, 66.8 (2C), 1 12.4 (J = 20.8 Hz), 1 15.1 ( J = 20.8 Hz), 124.5 (J = 2.7 Hz), 126.4- 129.9 (1 1 C), 136.5 (2C), 143.2 (J = 7.5 Hz), 156.7 (2C), 162.2 (J

Orbitrap) [M+H] ⁺ calcd for NaC F, 504.2293 found 504.2289.

492.2857 oun 492.2849.

ECO02-076-C dibenzyl 3-(4-benzamidophenyl)-3,6,7- triazabicyclo[3.2.1]octane-6,7-dicarboxylate : 436 mg, 69%,

pale yellow solid ;

¹ H NMR (500 MHz, (CD ₃ ) ₂ SO, 57°C) δ 2.01 -2.07 (m, 2H), 2.88

(br s, 2H), 3.81 (br s, 2H), 4.62 (br s, 2H), 4.90-5.19 (m, 4H),

6.75 (br s, 2H), 7.34 (br s, 10H), 7.52-7.62 (m, 5H), 7.98 (d, J =

7.0 Hz, 2H), 9.93 (s, 1 H) ; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO,

57°C) δ 34.1 , 48.5, 50.9, 55.3 (2C), 67.1 (2C), 1 13.5 (2C),

121 .8 (2C), 127.5-131 .1 (16C), 135.3, 136.3 (2C), 146.3, 156.2

(2C), 164.9 ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for

C34H33N4O5, 577.2445 found 577.2435.

Hydrogenolysis of bicyclic hydrazines using flow hydrogenation

ECO01-026-C

Hydrogenation on H-Cube ^® :

ECO01-015-C (100 mg, 0.194 mmol) was solubilised in MeOH (77 ml_), c = 0.0025 M. 3 Runs at 35°C, 30 Bars at 1 mL/min. After evaporation, purification Chromatography on silica gel (CH ₂ CI ₂ to CH ₂ CI ₂ /MeOH/NH ₄ OH 90/9/1 ) afforded ECO01 -026-C2 (13 mg, 27%), colorless paste. ECO01-026-C2 1-(3-methoxyphenethyl)piperidine-3,5-diamine : 13 mg, 27%, yellow paste ;

¹ H NMR (500 MHz, CD ₃ OD, 27 °C) δ 0.87 (q, J= 11.7 Hz, 1 H), 1.72 (t, J = 10.4 Hz, 2H), 2.00-2.04 (m, 1H), 2.53-2.57 (m, 2H), 2.67-2.70 (m, 2H), 2.79-2.82 (m, 2H), 2.92 (dd, J= 10.4 Hz, J= 3.8 Hz, 2H), 3.67 (s, 3H), 6.64-6.69 (m, 3H), 7.07 (t, J = 5.33 Hz, 1 H) ; ¹³ C NMR (125 MHz, CD ₃ OD, 27 °C) 534.1, 42.5, 48.1 (2C), 55.6, 61.1,61.3 (2C), 112.5, 115.5, 122.0, 130.4, 142.9, 161.3 ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for C ₁₄ H ₂ 4N ₃ 0, 250.1914 found 250.1910.

ECO01-025-C2 piperidine-3,5-diamine : 3 mg, yellow oil

¹ H NMR (500 MHz, CD ₃ OD, 27 °C) δ 1.15 (q, J= 12.0 Hz, 1H), 2.10-2.13

(m, 1H), 2.13 (t, J= 10.4 Hz, 2H), 2.82-2.87 (m, 2H), 2.98 (ddd, J= 12.3 Hz, J = 4.09 Hz, J = 1.57 Hz, 2H) ; ¹³ C NMR (125 MHz, CD ₃ OD, 27 °C) δ 39.8 (2C), 49.2, 51.7 (2C) ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for C ₅ H ₁₄ N ₃ , 116.1182 found 116.1183.

ECO01-028-C 1-(2-methylphenethyl)piperidine-3,5-diamine : 13 mg,

28%, white paste ;

1H NMR (500 MHz, CD ₃ OD, 27 °C) δ 0.99 (q, J= 11.5 Hz, 1H), 1.82 (t, J = 10.4 Hz, 2H), 2.17 (d, J= 10.8 Hz, 1H), 2.34 (s, 3H), 2.57-2.62 (m, 2H), 2.84-2.87 (m, 2H), 2.93-2.95 (m, 2H), 3.08-3.10 (m, 2H), 7.10-7.15 (m, 4H) ; ¹³ C NMR (125 MHz, CD ₃ OD, 27 °C) δ 19.3, 31.2, 42.8, 48.1 (2C), 59.9, 61.5 (2C), 127.2, 127.4, 130.3, 131.3, 137.0, 139.1 ; HRMS (ESI- Orbitrap) [M+H] ⁺ calcd for C ₁₄ H ₂₄ N ₃ , 234.1965 found 234.1961.

ECO01-030-C 1-(3-methylphenethyl)piperidine-3,5-diamine : 12 mg,

26%, colorless paste ;

1H NMR (500 MHz, CD ₃ OD, 27 °C) δ 1.14 (q, J= 10.9 Hz, 1H), 1.99 (t, J = 9.4 Hz, 2H), 2.11 (d, J= 12.3 Hz, 1H), 2.30 (s, 3H), 2.65-2.68 (m, 2H), 2.76-2.77 (m, 2H), 3.00-3.02 (m, 4H), 6.98-7.03 (m, 3H), 7.14 (t, J= 7.5 Hz, 1H) ; ¹³ C NMR (125 MHz, CD ₃ OD, 27 °C) δ 21.4, 33.9, 39.8, 47.9 (2C), 60.1 (2C), 61.1, 126.8, 127.9, 129.4, 130.4, 139.1, 141.2 ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for C ₁₄ H ₂₄ N ₃ , 234.1965 found 234.1957.

ECO01-031-C 1-(2-methoxyphenethyl)piperidine-3,5-diamine : 18 mg,

37%, white solid ;

1H NMR (500 MHz, CD ₃ OD, 27 °C) δ 1.27 (q, J= 11.0 Hz, 1H), 2.08 (t, J= 9.0 Hz, 2H), 2.17 (d, J= 11.8 Hz, 1H), 2.65 (t, J= 8.7 Hz, 2H), 2.82 (t, J= 8.8 Hz, 2H), 3.03 (d, J = 10.5 Hz, 2H), 3.10 (t, J= 9.6 Hz, 2H), 3.82 (s, 3H), 6.85 (t, J= 7.1 Hz, 1H), 6.91 (d, J= 8.1 Hz, 1H), 7.17 (d, J= 7.6 Hz, 1H), 7.12 (t, J= 7.3 Hz, 1H) ; ¹³ C NMR (125 MHz, CD ₃ OD, 27 °C) δ 28.5, 38.4, 47.8, 55.8, 59.1, 59.2 (3C), 111.5, 121.5, 128.7, 129.1, 131.2, 158.9. HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for C ₁₄ H ₂ 4N ₃ 0, 250.1914 found 250.1903.

ECO01-033-C 1-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-3,5-diamine :

27 mg, 54%, pale brown solid ;

¹ H NMR (500 MHz, CD ₃ OD, 27 °C) δ 1.05 (q, J= 11.2 Hz, 1H), 1.87- 1.89 (m, 2H), 2.12 (d, J= 11.4 Hz, 1H), 2.60-2.63 (m, 2H), 2.73-2.75 (m,

2H), 2.93-3.01 (m, 4H), 5.88 (s, 2H), 6.67-6.72 (m, 3H) ; ¹³ C NMR (125

MHz, CD ₃ OD, 27 °C) δ 24.2, 33.7, 41.2, 47.9, 60.7 (2C), 61.2, 102.0,

109.1, 110.0, 122.5, 135.0, 147.3, 149.0 ; HRMS (ESI-Orbitrap) [M+H] ⁺

calcd for C ₁₄ H ₂₂ N ₃ 0 ₂ , 264.1707 found 264.1695.

ECO01-035-C 1-(3-phenylpropyl)piperidine-3,5-diamine : 22 mg, 48%,

brown paste ;

¹ H NMR (500 MHz, CD ₃ OD, 27 °C) δ 1.18 (q, J= 10.2 Hz, 1H), 1.82 (m,

2H), 1.86 (br s, 1H), 2.13 (d, J= 12.2 Hz, 2H), 2.44-2.49 (m, 2H), 2.66 (t, J

= 7.6 Hz, 2H), 2.92 (d, J = 10.4 Hz, 2H), 3.05-3.08 (m, 2H), 7.15-7.21 (m,

3H), 7.25-7.28 (m, 2H) ; ¹³ C NMR (125 MHz, CD ₃ OD, 27 °C) δ 22.5, 28.0,

33.0, 46.5 (2C), 56.9, 58.3 (2C), 125.4 (2C), 127.9 (2C), 141.8 (2C) ; HRMS

(ESI-Orbitrap) [M+H] ⁺ calcd for C ₁₄ H ₂₄ N ₃ , 234.1965 found 234.1969.

ECO01-037-C 1-phenylpiperidine-3,5-diamine : 17 mg, 40%, colorless

paste ;

¹ H NMR (500 MHz, CD ₃ OD, 27 °C) δ 1.34-1.39 (m, 1H), 2.29-2.32 (m,

1H), 2.68 (t, J = 10.8 Hz, 2H), 3.01-3.22 (m, 2H), 3.74-3.77 (m, 2H), 6.94

(t, J= 7.3 Hz, 1H), 7.08 (d, J= 8.5 Hz, 2H), 7.31-7.34 (m, 2H) ; ¹³ C NMR

(125 MHz, CD ₃ OD, 27 °C) δ 38.4, 46.5 (2C), 55.6 (2C), 116.9 (2C), 120.0,

128.7 (2C), 150.8 ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for CnH ₁₈ N ₃ ,

192.1495 found 192.1501.

ECO01-039-C 1-(4-(methylsulfonyl)phenethyl)piperidine-3,5-diamine :

14 mg, 26%, white paste ;

¹ H NMR (500 MHz, CD ₃ OD, 27 °C) δ 1.10 (q, J= 11.2 Hz, 1H), 1.94-1.99 (m, 2H), 2.16 (d, J = 12.2 Hz, 1H), 2.74-2.77 (m, 2H), 2.99 (t, J= 7.6 Hz, 4H), 3.04 (d, J

= 10.5 Hz, 2H), 3.14 (s, 3H), 7.55 (d, J= 8.2 Hz, 2H), 792 (d, J= 8.2

Hz, 2H) ; ¹³ C NMR (125 MHz, CD ₃ OD, 27 °C) δ 32.4, 39.9, 43.0, 46.6

(2C), 58.7, 59.3 (2C), 127.0 (2C), 129.4 (2C), 138.4, 146.9 ; HRMS

(ESI-Orbitrap) [M+H] ⁺ calcd for C ₁₄ H ₂₄ N ₃ 0 ₂ S, 298.1584 found

298.1573.

ECO01-042-C 1-(benzo[d][1,3]dioxol-5-yl)piperidine-3,5-diamine

10.6 mg, 22%, colorless oil ;

¹ H NMR (500 MHz, CD ₃ OD, 27 °C) δ 1.17 (q, J= 8.4 Hz, 1H), 2.20-2.23

(m, 1H), 2.48 (t, J= 7.1 Hz, 2H), 3.05-3.10 (m, 2H), 3.50-3.52 (m, 2H),

5.91 (s, 2H), 6.45-6.49 (m, 1H), 6.65-6.67 (m, 1H), 6.73-6.77 (m, 1 H) ; ¹³ C

NMR (125 MHz, CD ₃ OD, 27 °C) δ 31.7, 40.1, 46.7 (2C), 58.1, 100.5,

100.7, 107.5, 109.8, 142.0, 146.9, 148.2 ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for C ₁₂ H ₁₈ N ₃ 0 ₂ , 236.1394 found 236.1386.

ECO01-055-C 1-(3-methoxyphenyl)piperidine-3,5-diamine :

12 mg, 26%, white paste ;

¹ H NMR (500 MHz, CD ₃ OD, 27 °C) δ 1.19 (q, J= 11.3 Hz, 1H), 2.20-2.23

(m, 1H), 2.50 (t, J= 7.3 Hz, 2H), 3.02-3.07 (m, 2H), 3.69 (dd, J= 11.8, 5.3

Hz, 2H), 3.78 (s, 3H), 6.45 (dd, J= 8.0, 3.4 Hz, 1H), 6.53-6.55 (m, 1H),

6.60 (dd, J= 8.2, 3.5 Hz, 1H), 7.15 (t, J= 8.2 Hz, 1H) ; ¹³ C NMR (125

MHz, CD ₃ OD, 27 °C) δ 41.7, 47.9 (2C), 55.7, 57.6 (2C), 104.4, 106.2,

110.8, 130.9, 153.6, 162.1 ; HRMS (ESI-Orbitrap) [M+H]+ calcd for C ₁₂ H ₂ oN ₃ 0, 222.1601 found 222.1595.

ECO01-056-C 1-(4-methoxyphenyl)piperidine-3,5-diamine :

21 mg, 46%, brown solid ;

¹ H NMR (500 MHz, CD ₃ OD, 27 °C) δ 1.13 (q, J= 11.3 Hz, 1H), 2.17-2.21

(m, 1H), 2.39 (t, J= 10.7 Hz, 2H), 3.03-3.07 (m, 2H), 3.50 (dd, J = 11.0,

5.1 Hz, 2H), 3.76 (s, 3H), 6.84 (d, J= 9.1 Hz, 2H), 6.97 (d, J= 9.1 Hz, 2H);

1 ³ C NMR (125 MHz, CD ₃ OD, 27 °C) δ 42.2, 48.5 (2C), 56.2, 59.9 (20),

115.7 (2C), 120.8 (2C), 146.9, 156.1; HRMS (ESI-Orbitrap) [M+H]+ calcd

for C ₁₂ H ₂₀ N ₃ O, 222.1601 found 222.1592.

ECO02-007-C azepan-1-yl(4-(3,5-diaminopiperidin-1- yl)phenyl)methanone : 15 mg, 28%, colorless oil ;

1H NMR (500 MHz, CD ₃ OD, 27 °C) δ 1.17 (q, J= 11.7 Hz, 1H), 1.55 (td, J = 12.6, 7.5 Hz, 1 H), 1.65 (br s, 6H), 1.86 (br s, 2H), 2.23 (td, J = 12.5, 8.0 Hz, 1H), 2.50 (t, J= 7.5 Hz, 2H), 2.94-2.99 (m, 2H), 3.23-3.34 (m, 1H), 3.54 (br s, 2H), 3.60 (d, J= 5.3 Hz, 2H), 3.89 (dd, J= 12.1, 4.0 Hz, 2H), 7.04 (d, J= 8.8 Hz, 2H), 7.33 (d, J= 8.8 Hz, 2H) ; ¹³ C NMR (125 MHz, CD ₃ OD, 27 °C) δ 25.9, 26.8, 27.5, 29.0, 32.3, 41.6, 46.2, 46.3, 55.4, 62.2, 62.5, 114.8 (2C), 126.2, 127.8 (2C), 151.5, 172.6 ; HRMS (ESI-Orbitrap) [M+H]+ calcd for Ci ₈ H ₂ 9N ₄ 0, 317.2336 found 317.2324.

ECO03-002-C N-(4-(3,5-diaminopiperidin-1-yl)phenyl)benzamide :

9 mg, 17 % colorless oil ;

¹ H NMR (500 MHz, CD ₃ OD , 27 °C) δ 1 .09 (q, J = 1 1 .4 Hz, 1 H), 2.20- 2.23 (m, 1 H), 2.40 (t, J = 1 1 .0 Hz, 2H), 2.96-3.03 (m, 2H), 3.69-3.73 (m,

2H), 7.01 (d, J = 9.0 Hz, 2H), 7.51 (t, J = 7.5 Hz, 2H), 7.56-7.58 (m, 3H),

7.93 (d, J = 7.3 Hz, 2H) ; ¹³ C NMR (125 MHz, CD ₃ OD, 27 °C) δ 41 .5,

46.6 (2C), 56.9 (2C), 1 16.7 (2C), 122.3 (2C), 127.1 (2C), 128.2 (2C),

130.7, 131 .3, 134.9, 148.1 , 167.2 ; HRMS (ESI- Orbitrap) [M+H] ⁺ calcd

for Ci ₈ H ₂₃ N ₄ 0, 31 1 .1866 found 31 1 .1864.

Hydrogenolysis under batch conditions according to the Journal of Organic Chemistry 2013, 78, 12236-12242

Bn0 ₂ C _N ECO01-041-C 1-(2,3-dihydro-1 H-inden-2-yl)piperidine-3,5-diamine :

18 mg, 77%, beige solid ;

¹ H NMR (500 MHz, CD ₃ OD, 27 °C) δ 1.00 (q, J= 11.7 Hz, 1H), 1.82 (t, J = 10.7 Hz, 2H), 2.18-2.21 (m, 1H), 2.92-2.97 (m, 4H), 3.12-3.21 (m, 4H), 3.31 (quint, J= 7.9 Hz, 1H), 7.16-7.18 (m, 2H), 7.23-7.24 (m, 2H) ; ¹³ C NMR (125 MHz, CD ₃ OD, 27 °C) δ 37.8 (2C), 43.3, 48.0 (2C), 59.9 (2C), 67.7, 125.4 (2C), 127.7 (2C), 142.3 (2C) ; HRMS (ESI-Orbitrap) [M+H]+ calcd for C ₁₄ H ₂₂ N ₃ , 232.1808 found 232.1800.

AB-77 (3S,5/¾-1-(3,4-dimethoxyphenethyl)piperidine-3,5-diamine :

62 mg,

Hz, 1 H

2.60-2.

Hz, 2H

CDCI ₃ ,

132.8,

AB-81 (S)-methyl 2-((3S,5R)-3,5-diaminopiperidin-1-yl)-3-phenylpropanoate :

39 mg, 98%, colorless oil; ¹ H NMR (400 MHz, CDCI ₃ , δ) 0.85 (q, J= 11.4 Hz, 1H), 1.47 (br s, 4H), 1.89 (t, J = 10.3 Hz, 1H), 2.05 (t, J = 10.3 Hz, 1H), 2.12 (d, J= 11.4 Hz, 1H), 2.80-2.99 (m, 4H), 3.04-3.15 (m, 2H), 3.50 (dd, J= 7.9 Hz, J= 7.0 Hz, 1H), 3.64 (s, 3H), 7.15-7.35 (m, 5H); ¹³ C NMR (75 MHz, CDCI ₃ , δ) 35.6, 44.8, 47.7, 47.9, 51.1, 56.3, 61.2, 69.1, 126.4, 128.3, 129.1, 138.1, 171.7; HRMS (ESI-TOF)[M+H] ⁺ calcd for C ₁₅ H ₂₄ N ₃ 0 ₂ 278.1869, found 278.1864; [a] _D ²⁰ -19.0 (c 1.0, CH ₃ OH)

289.2021

AB-86 (3S,5/¾-1-(1H-indol-5-yl)piperidine-3,5-diamine: 22 mg, 79%, colorless oil; ¹ H NMR (300 MHz, CDCI ₃ , δ) 0.96 (q, J= 11.6 Hz, 1H), 1.39 (br s, 4H), 2.24 (d, J = 11.6 Hz, 1 H), 2.33 (dd, J= 11.1 Hz, J= 10.3

Hz, 2H), 3.12 (m, 2H), 3.60 (dd, J= 11.1 Hz, J= 4.4 Hz, 2H), 6.48 (br s, 1H), 6.97 (dd, J= 8.8 Hz, J= 2.4 Hz, 1H), 7.17 (t, J= 2.7 Hz, 1H), 7.19

(d, J= 2.4 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 8.34 (br s, 1H); ¹³ C NMR

(75 MHz, CDCI ₃ , δ) 44.7, 47.8, 61.3, 102.3, 108.5, 111.5, 116.4, 124.7, 128.3, 131.4, 145.6; HRMS (ESI-TOF)[M+H] ⁺ calcd for Ci ₃ H ₁₉ N ₄ 231.1610, found 231.1606 AB-103 (3S,3'R,3"S,5R,5'S,5"R)-1 '-(3,4-dimethoxyphenethyl)- [1,3':5',1"-terpiperidine]-3,3",5,5"-tetraamine: 44 mg,

quantitative, colorless oil; ¹ H NMR (500 MHz, CD ₃ OD, δ) 1.55- 1.70 (m, 3H), 2.12 (d, J= 10.9 Hz, 1H), 2.45-2.56 (m, 6H), 2.60- 2.69 (m, 2H), 2.95-3.11 (m, 6H), 3.15-3.26 (m, 4H), 3.30-3.37 (m,

6H), 3.82 (s, 3H), 3.86 (s, 3H), 6.84 (d, J= 8.5 Hz, 1H), 6.91 (d, J

= 8.5 Hz, 1H), 6.94 (s, 1H); ¹³ C NMR (125 MHz, CD ₃ OD, δ) 28.7,

32.3, 34.5, 48.0, 48.1, 52.8, 53.5, 55.2, 56.7, 60.0, 60.8, 113.5,

114.0, 122.2, 132.4, 149.4, 150.6; HRMS (ESI-TOF)[M+Na] ⁺

calcd for C ₂₅ H4 ₅ N ₇ 0 ₂ Na 498.3532, found 498.3526

AB-109 F3 (fi)-methyl 2-((3S,5R)-3,5-diaminopiperidin-1-yl)-3-phenylpropanoate: 13 mg,

52%, colorless oil; ¹ H NMR (400 MHz, CDCI ₃ , δ) 0.85 (q, J= 11.4 Hz,

1H), 1.47 (br s, 4H), 1.89 (t, J = 10.3 Hz, 1H), 2.05 (t, J = 10.3 Hz,

1H), 2.12 (d, J= 11.4 Hz, 1H), 2.80-2.99 (m, 4H), 3.04-3.15 (m, 2H),

3.50 (dd, J= 7.9 Hz, J= 7.0 Hz, 1H), 3.64 (s, 3H), 7.15-7.35 (m, 5H);

1 ³ C NMR (75 MHz, CDCI ₃ , δ) 35.6, 44.8, 47.7, 47.9, 51.1, 56.3, 61.2,

69.1, 126.4, 128.3, 129.1, 138.1, 171.7; HRMS (ESI-TOF)[M+H] ⁺

calcd for Ci ₅ H ₂₄ N ₃ 0 ₂ 278.1869, found 278.1864; [a] _D ²⁰ = + 21.1 (c =

1.0, MeOH

AB-120 N-(4-((3S,5fi)-3,5-diaminopiperidin-1-yl)-2- hydroxyphenyl)benzamide : 21 mg, 95%, orange oil; ¹ H NMR

(300 MHz, CD ₃ OD, δ) 1.45 (q, J= 11.0 Hz, 1 H), 2.26 (d, J= 11.0

Hz, 1H), 2.74 (dd, J= 11.9 Hz, J = 9.2 Hz, 2H), 3.22 (m, 2H),

3.66 (dd, J= 11.9 Hz, J= 2.9 Hz, 2H), 6.57 (dd, J= 8.8 Hz, J =

2.3 Hz, 1H), 6.62 (d, J= 2.3 Hz, 1H), 7.52-7.60 (m, 4H), 7.97 (d,

J= 8.0 Hz, 2H); ¹³ C NMR (75 MHz, CD ₃ OD, δ) 36.4, 46.3, 54.6,

105.1, 108.4, 118.8, 124.3, 127.2, 128.4, 131.6, 134.2, 149.5,

150.2, 167.3; HRMS (ESI-TOF)[M+H] ⁺ calcd for Ci ₈ H ₂₃ N ₄ 0 ₂

327.1821, found 327.1821

AB-378 (3S,5fi)-1-(4-methoxybenzyl)piperidine-3,5-diamine 40

mg, quantitative, colorless oil; ¹ H NMR (250 MHz, CD ₃ OD, δ) 0.84 (q,

J= 11.6 Hz, 1 H), 1.62 (t, J= 10.4 Hz, 2H), 2.09 (d, J= 11.6 Hz, 1 H),

2.75-2.87 (m, 2H), 2.94 (dd, J= 10.4 Hz, J= 4.4 Hz, 2H), 3.50 (s, 2H),

3.77 (s, 3H), 6.86 (d, J= 8.5 Hz, 2H), 7.23 (d, J= 8.5 Hz, 2H); ¹³ C

NMR (125 MHz, CD ₃ OD, δ) 43.3, 48.1, 55.8, 61.5, 63.0, 114.8, 130.4,

2 HCI 131.9, 160.6; HRMS (ESI-Orbitrap)[M+H] ⁺ calcd for C ₁₃ H ₂₂ N ₃ 0236.1762, found 236.1756

AB289-2 N-(6-amino-1-(3,5-diaminopiperidin-1-yl)-1-oxohexan-2- yl)-4- ethylbenzamide 1H NMR (500MHz, (CD3)2SO, 70 °C) δ =

1.27 (t, J= 7.6, 3H) ; 1.44-1.67 (m, 2H) ; 1.72-1.80 (m, 2H) ; 1.85- 1.96 (m, 3H) ; 2.62 (broad d, J= 10.8, 1H) ; 2.72 (q, J= 7.6, 2H) ;

2.70-2.78 (m, 1H) ; 2.97 (t, J= 7.3, 2H) ; 3.27-3.37 (m, 2H) ; 3.51- 3.69 (m, 1H) ; 4.45-4.61 (m, 1H) ; 4.84-4.91 (m, 1H) ; 4.91-5.04 (m,

1H) ; 7.33 (d, J= 8.0, 2H) ; 7.80 (d, J= 8.0, 2H) 13C NMR (125MHz,

(CD3)2SO, 70 °C) δ = 15.8, 24.0, 28.3, 29.8, 31.8, 34.3, 40.5, 45.2,

46.2, 47.0, 49.9, 51.5, 128.7 (2C), 129.1 (2C), 132.1, 150.3, 170.6,

173.6. HRMS (ES+) m/z [M+H]+ Calcd for C20H34N5O2

376.27125, Found 376.27057.

Synthesis of RA20

2-Bromo-1 -tricyclo[8.2.2.24,7]hexadeca-1 (13) ,4,6,10(14),11 ,15-hexaen-5-yl-ethanone (150 mg, 0.45 mmol) and NaN ₃ (31 mg, 0.47 mmol) were stirred at room temperature in H ₂ 0/acetone (1:2; 4.5 mL) for 3 h. (4-tert-Butoxycarbonylamino-2-prop-2-ynyloxy- cyclopentyl)-carbamic acid tert-butyl ester (135 mg, 0.38 mmol) in acetone (1.5 mL) was then added, followed by the addition of sodium ascorbate (1 M, 0.19 ml_) and CuS0 ₄ (1 M, 0.19 ml_). The resultant mixture was then stirred at room temperature until complete consumption of the alkyne and was monitored by TLC. After addition of water the product was extracted with EtOAc, dried over Na ₂ S0 ₄ and concentrated in vacuo. The crude product was purified flash chromatography on silica gel (cyclohexane: AcOEt 50:50) to give 203 mg (83 %) of the product.

¹ H NMR (400 MHz, CDCI ₃ ): 1.44 (19H, bs), 1.87 (1H, bs), 2.04 (1H, bs), 2.55 (1H, m), 2.85 (1H, m), 2.99-3.08 (2H, m), 3.12-3.25 (4H, m), 3.85 (1H, m), 3.93 (1H, s), 3.97 (1H, s), 4.08 (1H, bs), 4.77 (2H, m, H-6), 5.29 (1H, d, 17.6, H-9), 5.85 (1H, d, 17.6, H-9), 6.38 (1H, d, 7.8), 6.43 (1 H, d, 7.8), 6.51 (1 H, d, 7.8), 6.55 (1 H, d, 7.8), 6.59 (1 H, d, 7.8), 6.74 (1 H, d, 7.8), 7.02 (1H,s), 7.75(1 H,s, H-8).

¹³ C NMR (75 MHz, CDCI ₃ ): 28.5 (6)(CH ₃ ), 34.8 (CH ₂ ), 35.1 (2)(CH ₂ ), 35.9 (CH ₂ ), 37.2 (2)(CH ₂ ), 49.2 (CH), 55.8 (CH), 56.3 (CH ₂ ), 62.8 (CH ₂ ) 79.2 (2)(C), 83.5 (CH), 124.6 (CH), 131.2 (CH), 132.2 (CH), 132.9 (CH), 133.0 (CH), 133.1 (CH), 134.3 (C), 136.9 (CH), 137.8 (CH), 139.3 (C), 140.1 (C), 140.4 (C), 142.7 (C), 145.7 (C), 155.5 (2)(C), 192.1 (C).

MS (ES): 646 (MH ⁺ ), 688 (MNa ⁺ ).

A solution of the Boc-protected triazole derivative in AcOEt (173 mg, 0.26 mmol) was cooled in an ice-bath and HCI (g) was bubbled inside until the formation of a white precipitate (few minutes). The solution was then filtered and rinsed with AcOEt and DCM to obtain 130 mg (96 %) of RA 20 hydrochloride.

¹ H NMR (300 MHz, CD ₃ OD): 1.86 (1 H, m), 2.27 (2H, t, 7.6), 2.68 (1 H, dt), 2.92 (1 H, m), 3.04- 3.28 (6H, m), 3.65 (1H, m), 3.89 (2H, m), 4.35 (1H, m), 4.76 (1H, d, 12.2), 4.84 (1H, d, 12.2), 5.70 (1H, d, 17.8, H-9), 6.16 (1H, d, 17.8, H-9), 6.46 (1H, d, 7.8), 6.55-6.63 (3H, m), 6.79 (1H, d, 7.8), 6.86 (1 H, d, 7.8), 7.29 (1 H, s), 8.16 (1 H, s, H-8).

¹³ C NMR (75 MHz, CD ₃ OD): 32.7 (CH ₂ ), 34.0 (CH ₂ ), 34.2 (CH ₂ ), 34.5 (CH ₂ ), 34.6 (CH ₂ ), 35.5 (CH ₂ ), 47.4 (CH), 55.1 (CH), 58.1 (CH ₂ ), 61.5 (CH ₂ ), 80.4 (CH), 83.5 (CH), 128.5 (CH), 131.0 (CH), 132.1 (CH), 132.8 (CH), 133.2 (CH), 133.7 (CH), 133.9 (C), 136.8 (CH), 137.9 (CH), 139.6 (C), 139.8 (C), 140.8 (C), 142.6 (C), 191.5 (C).

MS (ES): 446(MH ⁺ ), 468 (MNa ⁺ ).

PDA25 1-(3,4-dimethoxybenzyl)piperidine-3,5-diamine ¹ H NMR

(500MHz, CD30D) δ= 1.55 (q, J= 11.9, 1H, H4) ; 2.13 (t, J= 11.0, 2H) ;

2.49 (d, J= 11.9, 1H) ; 3.21 (dd, J= 11.0, J=4.3, 2H) ; 3.45-3.47 (m, 2H) ;

3.68 (s, 2H) ; 3.77-3.85 (m, 6H) ; 6.88-6.95 (m, 3H) ¹³ C NMR (125MHz,

CD30D) δ = 32.4, 45.8 (2C) ; 53.9 (2C), 55.0, 55.1 ,61.0, 111.5, 112.6,

121.6, 128.8, 148.9, 149.3. HRMS (APCI+-Orbitrap)[M+H] ⁺ calcd for

C ₁₄ H ₂₄ N ₃ 0 ₂ 266.18685, Found 266.18570

AB542 1 -isopropylpiperidine-3,5-diamine ¹ H NMR (500MHz, CD30D) δ =

0.88 (q, J = 1 1 .6, 1 H) ; 1 .07 1 .08 (2s, 2 _X 3H) ; 1 .83 (t, J = 10.7, 2H) ; 2.07-2.16

(m, 1 H) ; 2.73-2.86 (m, 3H) ; 2.91 (dd, J = 10.7, J = 4.1 , 2H) ¹³ C NMR

(125MHz, CD30D) δ = 18.4 (2C), 43.3, 48.5 (2C), 55.8 (C7), 57.2 (2C)

Acylation of byclic hydrazines

dibenzyl

dibenzyl 3,6,7-triazabicyclo[3.2.1 ]octane-6,7-dicarboxylate (350 mg, 0.918 mmol) was solubilized in dry CH ₂ CI ₂ (5 mL) and in dry DMF (0.2 mL). methoxyphenylacetic acid (168 mg, 1 .01 mmol), triethylamine (0.87 ml, 6.43 mmol) and EDC (264 mg, 1 .38 mmol) were added. Mixture was stirred at RT under Ar overnight. The reaction was monitored by TLC until disappearance of the initial product. The solution was quenched with NaHC0 ₃ , extracted with CH ₂ CI ₂ . The organic layer was dried over MgS0 ₄ , filtered and evaporated. Flash chromatography (Cyclohexane to Cyclohexane/ Ethyl acetate 4/6) afforded ECO02-018-C (178 mg, 37%), colorless oil.

ECO02-018-C dibenzyl 3-(2-(3 methoxyphenyl)acetyl)-3,6,7- triazabicyclo[3.2.1]octane-6,7-dicarboxylate : 178 mg, 37%,

colorless oil ;

¹ H NMR (500 MHz, (CD ₃ ) ₂ SO, 60 °C) δ 1 .95-1 .97 (m, 1 H), 2.09

(d, J = 1 1 .6 Hz, 1 H), 2.86 (br s, 1 H), 3.20 (s, 1 H), 3.48 (br s,

1 H), 3.58 (br s, 1 H), 3.72 (s, 3H), 4.08 (br s, 1 H), 4.50 (br s 3H), 5.1 1 (s, 4H), 6.70 -6.73 (m, 2H), 6.79 (dd, J = 7.8, 3.3 Hz, 1 H), 7.18 (t, J = 7.8 Hz, 1 H), 7.35 (br s, 10H) ; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO, 60 °C) δ 35.0, 40.6, 46.5, 49.9, 55.5 (2C), 55.9, 68.2 (2C), 1 12.9, 1 15.8, 122.2, 128.4-130.1 (12C), 137.0, 137.7, 156.8 (2C), 160.2, 171 .6 ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for C ₃ oH32N ₃ 0 ₆ , 530.2286 found 530.2283.

ECO02-021-C dibenzyl 3-(2-(4-methoxyphenyl)acetyl)-3,6,7- triazabicyclo[3.2.1]octane-6,7-dicarboxylate : 167 mg, 34%,

colorless oil ;

1 H NMR (500 MHz, (CD ₃ ) ₂ SO, 60 °C) δ 1 .94-1 .98 (m, 1 H), 2.08 (d,

J = 1 1 .5 Hz, 1 H), 2.84 (br s, 1 H), 3.20-3.25 (m, 1 H), 3.44 (br s,

1 H), 3.53 (br s, 1 H), 3.72 (s, 3H), 4.06 (br s, 1 H), 4.50 (br s 3H),

5.1 1 (s, 4H), 6.84 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H),

7.35 (br s, 10H) ; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO, 60 °C) δ 34.0,

38.8, 45.7, 48.6, 54.5 (2C), 55.1 , 67.2 (2C), 1 13.7 (2C), 127.2- 128.3 (12C), 130.2, 136.1 (2C), 156.0 (2C), 158.0, 171 .0 ; HRMS

(ESI-Orbitrap) [M+H] ⁺ calcd for C ₃₀ H ₃₂ N ₃ O ₆ , 530.2286 found

530.2278.

ECO02-008-C (414 mg, 0.774 mmol), was solubilized in DMF (4 mL) and water (1 .2 mL). 4- methoxyphenylboronic acid (141 mg, 0.929 mmol), K ₂ C0 ₃ (374 mg, 2.71 mmol), and Pd(Ph ₃ ) ₄ (44.7 mg, 0.0387 mmol) were added under Ar. Mixture was stirred at 90°C, overnight under Ar. The reaction was monitored by TLC until disappearance of the initial product. The solution was quenched with NaHC0 ₃ , extracted with CH ₂ CI ₂ . The organic layer was dried over MgS0 ₄ , filtered and evaporated. Flash chromatography (Cyclohexane to Cyclohexane/ Ethyl acetate 7/3) afforded ECO02-023-C (273 mg, 48%), white solid. ECO02-023-C dibenzyl 3-(4'-methoxy-[1 ,1 '-biphenyl]-4- yl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate :

273 mg, 48%, white solid ;

¹ H NMR (500 MHz, (CD ₃ ) ₂ SO, 60 °C) δ 2.01 -2.05 (m, 1 H),

2.08-2.12 (m, 1 H), 2.91 (br s, 2H), 3.79 (s, 3H), 3.84 (br s,

2H), 4.63 (br s 2H), 5.1 1 -5.19 (s, 4H), 6.76-6.79 (m, 2H),

6.99 (d, J = 8.8 Hz, 2H), 7.32 (br s, 10H), 7.79 (d, J = 8.7

Hz, 2H), 7.51 (d, J = 7.9 Hz, 2H) ; ¹³ C NMR (125 MHz,

(CD ₃ ) ₂ SO, 60 °C) δ 34.0, 48.4, 50.5, 55.2 (3C), 67.0 (2C),

1 13.7, 1 14.4, 126.6-128.3 (16C), 129.6, 131 .4, 132.8,

136.2, 148.9, 156.2 (2C), 158.2 ; HRMS (ESI-Orbitrap)

[M+H] ⁺ calcd for C34H34N3O5, 564.2493 found 564.2480.

Acetylation of bicyclic hydrazine

ECO02-045-C dibenzyl 3-(3-acetoxyphenethyl)-3,6,7- triazabicyclo[3.2.1]octane-6,7-dicarboxylate : 105 mg,

quant., transparent oil ;

¹ H NMR (500 MHz, (CD ₃ ) ₂ SO, 60 °C, δ) 1 .60 (br s, 2H),

2.25 (br s, 5H), 2.57 (br s, 2H), 3.07 (br s, 2H), 3.20 (br s,

2H), 4.37 (br s, 2H), 5.13 (br s, 4H), 6.92 (br s, 2H), 7.04 (br

s, 1 H), 7.34 (br s, 1 1 H) ; ¹³ C NMR (125 MHz, (CD ₃ ) ₂ SO, 60

°C, δ) 20.8, 28.9, 35.7, 52.1 , 54.7, 55.8 (2C), 57.4, 66.8 (2C),

1 19.2, 121 .6, 125.8, 127.5-129.1 (1 1 C), 136.4 (2C), 141 .9,

150.6, 156.8 (2C), 168.9 ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd

for C31 H34N3O6, 544.2442 found 544.2440.

Reductive amination of protected diaminopiperidines

ECO02-056-C

ECO02-051 -C (65 mg, 0.206 mmol) was solubilized in MeOH (1 .5 ml_) and DCM (1 .5 ml_). Freshly distilled benzaldehyde (328 mg, 0.309 mmol) and MgS0 ₄ (tip of spatula) were added. Mixture was stirred 1 h under Ar at RT. NaBH(OAc) ₃ (131 mg, 0.618 mmol), was added and mixture was stirred 1 h. NaBH(OAc) ₃ (87 mg, 0.412 mmol) was added and mixture was stirred overnight under Ar at RT. The reaction was monitored by TLC (not completed reaction). The solution was quenched with water, extracted with CH ₂ CI ₂ . The organic layer was dried over MgS0 ₄ , filtered and evaporated. Flash chromatography (CH ₂ CI ₂ to CH ₂ CI ₂ /MeOH/NH ₄ OH 90/9/1 ) afforded ECO02-056-C (31 mg, 40%), white solid. ECO02-056-C di-tert-butyl (1-benzylpiperidine-3,5-diyl)dicarbamate :

31 mg, 44%, white solid ;

¹ H NMR (500 MHz, CD ₃ OD, 27 °C) δ 0.98 (q, J= 12.0 Hz, 1H), 1.30 (br s, 18H), 1.63 (br s, 2H), 1.91-1.96 (m, 1H), 2.82-2.86 (m, 2H), 3.45-3.49 (m, 4H), 7.10-7.17 (m, 1H), 7.21 (br s, 4H) ; ¹³ C NMR (125 MHz, CD ₃ OD, 27 °C, δ) 28.7 (6C), 38.2, 47.7 (2C), 58.9 (2C), 63.4, 80.0 (2C), 128.4, 129.4 (2C), 130.4 (2C), 138.8, 157.6 (2C) ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for C22H36N3O4, 406.2700 found 406.2706.

ECO02-058-C di-tert-butyl (1-(furan-2-ylmethyl)piperidine-3,5- diyl)dicarbamate : 41 mg, 51%, pale yellow solid ;

1H NMR (500 MHz, CD ₃ OD, 27 °C) δ 1.07 (q, J= 11.8 Hz, 1H), 1.43 (br s, 18H), 1.74-1.83 (m, 2H), 2.03 (br s, 1H), 2.93-2.99 (m, 2H), 3.56-3.66 (m, 4H), 6.27-6.30 (m, 1H), 6.36-6.39 (m, 1H), 7.46 (s, 1H) ; ¹³ C NMR (125 MHz, CD ₃ OD, 27 °C) δ 27.3 (6C), 36.4, 46.2 (2C), 53.4, 56.9 (2C), 78.6 (2C), 108.8, 109.8, 142.1, 151.0, 156.1 (2C); HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for C ₂₀ H ₃ 4N ₃ O ₅ , 396.2488 found 396.2493.

oun 489.3077.

ECO02-062-C di-tert-butyl 1-(4-(dimethylamino)benzyl)piperidine-3,5- diyl)dicarbamate : 26 mg, 28%, white solid ;

¹ H NMR (500 MHz, CDCI ₃ , 27 °C) δ 1.20-1.45 (m,

2.01 (br s, 3H), 2.70 (br s, 2H), 2.91 (s, 6H), 3.45

2H), 4.60 (br s, 2H, NH), 6.67 (d, J= 8.3 Hz, 2H), 7

; ¹³ C NMR (125 MHz, CDCI ₃ , 27 °C) δ 28.4 (6C),

(2C), 57.7 (2C), 61.8, 79.3 (2C), 112.5 (2C), 125.

155.0 (2C) ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for

found 449.3127. Deprotection of diaminopiperidines

ECO02-056-C (31 mg, 0.074 mmol) was solubilized in HCI 4M/Dioxane (1 mL). Mixture was stirred under Ar, 0.5h at RT. Evaporation of the solvents crude gives ECO02-063-C (28 mg, quant.), white solid._ECO02-064-C and ECO02-065-C were purified by preparative HPLC

using a C18 Hypersil column ( elution gradient H ₂ 0/MeCN 80/20 to 20/80).

ECO02-063-C 1 -benzylpiperidine-3,5-diamine trihydrochloride : 28 mg,

quant., white solid ;

¹ H NMR (500 MHz, CD ₃ OD , 27 °C) δ 2.02 (q, J = 12.1 Hz, 1 H), 2.66 (d, J

= 1 1 .7 Hz, 1 H), 3.26 (t, J = 1 1 .7 Hz, 2H), 3.67 (d, J = 4.6 Hz, 2H), 3.85-3.90

(m, 2H), 4.55 (s, 2H), 7.51 -7.52 (m, 3H), 7.68-7.69 (m, 2H) ; ¹³ C NMR (125

MHz, CD ₃ OD, 27 °C) δ 30.4, 43.4 (2C), 51 .0 (2C), 60.8, 128.9 (2C), 129.9

(2C), 131 .1 (2C) ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for Ci ₂ H ₂ oN ₃ ,

206.1652 found 206.1658.

ECO02-064-C 1 -(3,5-dimethoxybenzyl)piperidine-3,5-diamine : 21 mg,

95%, white solid ;

¹ H NMR (500 MHz, CD ₃ OD , 27 °C) δ 1 .56 (q, J = 1 1 .8 Hz, 1 H), 2.1 1 (t, J =

10.9 Hz, 2H), 2.52 (d, J = 1 1 .6 Hz, 1 H), 3.18-3.22 (m, 2H), 3.40-3.45 (m,

2H), 3.65 (s, 2H), 3.78 (s, 6H), 6.40-6.43 (m, 1 H), 6.53-6.54 (m, 2H) ; ¹³ C

NMR (125 MHz, CD ₃ OD, 27 °C) δ 34.0, 47.5 (2C), 55.7 (2C), 55.8 (2C),

62.9, 1 10.4, 108.1 (2C), 140.5, 162.6 (2C) ; HRMS (ESI-Orbitrap) [M+H] ⁺

calcd for C14H24N3O2, 266.1863 found 266.1862.

ECO02-068-C 1 -(isoquinolin-5-ylmethyl)piperidine-3,5-diamine

trihydrochloride : 6 mg, 83%, yellow paste ;

¹ H NMR (500 MHz, CD ₃ OD , 27 °C) δ 1 .63 (q, J = 1 1 .8 Hz, 1 H), 2.34 CI (t, J = 10.5 Hz, 1 H), 2.52 (d, J = 1 1 .7 Hz, 2H), 3.26-3.29 (m, 2H), 3.44- 3.46 (m, 2H), 4.33 (s, 2H), 8.06 (t, J = 8.2, 7.2 Hz, 1 H), 8.28 (d, J = 7.1

Hz, 1 H), 8.52 (d, J = 8.3 Hz, 1 H), 8.66 (d, J = 6.7 Hz, 1 H), 8.90 (d, J =

6.6 Hz, 1 H), 9.84 (s, 1 H) C NMR (125 MHz, CD ₃ OD, 27 °C) δ 32.3,

45.8 (2C), 54.0 (2C), 58.0 123.1 , 128.3, 130.5, 130.6, 131 .0, 132.0,

HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for Ci ₅ H ₂ i N ₄ , 257.1765 found 257.17

ECO02-069-C 1-(4-(dimethylamino)benzyl)piperidine-3,5-diami

trihydrochloride : 20 mg, quant., beige solid ;

¹ H NMR (500 MHz, D ₂ 0, 27 °C) δ 1 .86 (q, J = 12.1 Hz, 1 H), 2.67-2.70 (

1 H), 2.92 (t, J = 1 1 .7 Hz, 2H), 3.36 (s, 6H), 3.63 (s, 6H), 3.65-3.69 (

2H), 3.72-3.77 (m, 2H), 4.39 (s, 2H), 7.76 (s, 4H) ; ¹³ C NMR (125 MH

D ₂ 0, 27 °C) δ 43.2 (2C), 43.7, 46.4 (2C), 60.3 (2C), 62.9, 120.5 (2

129.2 (2C), 132.9, 143.0 ; HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for Ci ₄ H ₂₅ 249.2078 found 249.2074.

ECO03-001-B 1-(phenylsulfonyl)piperidine-3,5-diamine : 43 mg,

quant., colorless oil ;

¹ H NMR (500 MHz, CD ₃ OD , 27 °C) δ 1.67 (q, J= 11.9 Hz, 1 H), 2.49 (t,

J = 11.3 Hz, 2H), 2.57 (d, J= 11.8 Hz), 3.52-3.55 (m, 2H), 4.15-4.19

(m, 2H), 7.67-7.71 (m, 2H), 7.76 (t, J= 7.4 Hz, 1H), 7.87 (d, J= 7.5 Hz,

2H) ; ¹³ C NMR (125 MHz, CD ₃ OD, 27 °C) δ 31.8, 45.6 (2C), 46.9 (2C),

127.2 (2C), 128.4 (2C), 133.5, 136.1 ; HRMS (ESI- Orbitrap) [M+H] ⁺ calcd for CnH ₁₈ N ₃ 0 ₂ S, 366.2023 found 366.2020.

ECO01-026-C2 (100 mg, 0.401 mmol) was solubilized in acetic anhydride (2.30 mL). Anhydrous pyridine (0.30 mL) and DMAP (2.4 mg, 0.020 mmol) were added. Mixture was stirred under Ar, 3h at RT. The reaction was monitored by TLC until disappearance of the initial product. In an ice bath, the solution was quenched with NaHC0 ₃ , extracted with Ethyl Acetate. The organic layer was dried over MgS0 ₄ , filtered and evaporated. Flash chromatography (CH ₂ CI ₂ to CH ₂ CI ₂ /MeOH/NH ₄ OH 90/9/1) afforded ECO02-072-C (26 mg, 19%), white solid. ECO02-072-C N,N'-(1-(3-methoxyphenethyl)piperidine-3,5- diyl)diacetamide : 26 mg, 19%, white solid ;

¹ H NMR (500 MHz, CD ₃ OD , 27 °C) δ 1.21 (q, J= 10.5 Hz, 1H), 1.86 (t, J= γ J 10.7 Hz, 2H), 1.94 (s, 6H), 2.11-2.13 (m, 1H), 2.66-2.69 (m, 2H), 2.77-2.80 O O (m, 2H), 3.11 (dd, J= 10.5, 4.0 Hz, 2H), 3.79 (s, 3H), 3.93-3.99 (m, 2H),

6.75 (dd, J = 8.1, 2.6 Hz, 1H), 6.79-6.80 (m, 2H), 7.18 (t, J= 8.1 Hz, 1H) ;

1 ³ C NMR (125 MHz, CD ₃ OD, 27 °C) δ 21.2 (2C), 32.8, 35.8, 45.2 (2C),

54.2, 57.0 (2C), 59.4, 111.2, 114.0, 120.7, 129.0, 141.5, 159.9, 171.3 (2C) ;

HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for C ₁₈ H ₂₈ N ₃ 0 ₃ , 334.2125 found

334.2125. Sulfonylation of diaminopiperidines

ECO02-072-C (100 mg, 0.401 mmol) was solubilized in anhydrous CH ₂ CI ₂ (1 ml_). Anhydrous pyridine (36 μΙ_, 0.441 mmol) was added. At 0°C, methane sulfonyl chloride (68 μΙ_, 0.882 mmol) was added. Mixture was stirred 10 min at 0°C and at RT for 7h under Ar. The reaction was monitored by TLC until disappearance of the initial product. Mixture was quenched with water and NaOH 3M, extracted with CH ₂ CI _2. The organic layer was washed with a saturated aqueous solution of NaCI, dried over MgS0 ₄ , filtered and evaporated. Flash chromatography (CH ₂ CI ₂ to CH ₂ CI ₂ /MeOH/NH ₄ OH 90/9/1) afforded mono-substitued compound ECO02-073-C (5.5 mg) as a yellow oil. The aqueous layer was adjusted at pH = 7 with HCI 3M and extracted with Ethyl Acetate. The organic layer was washed with NaCI sat, dried over over MgS0 ₄ , filtered and evaporated. Crude product was obtained to give ECO02-073-B2 (84 mg, 52%), white solid.

ECO02-073-C rac-c/s-N-(5-amino-1-(3-methoxyphenethyl)piperidin-

3-yl) methanesulfonamide : 5.5 mg, yellow oil ;

1H NMR (500 MHz, CD ₃ OD , 27°C) δ 1.11 (q, = 11.8 Hz, 1H), 1.78 (t,

J= 10.6 Hz, 1H), 1.90 (t, J= 10.7 Hz, 1H), 2.21-2.24 (m, 1H), 2.67-2.69

(m, 2H), 2.79-2.80 (m, 2H), 2.90-2.94 (m, 1H), 2.97 (s, 3H), 3.04-3.08

(m, 1 H), 3.15-3.19 (m, 1 H), 3.41 -3.46 (m, 1 H), 3.79 (s, 3H),

6.75-6.81 (m, 3H), 7.19 (t, J = 8.0 Hz, 1 H) ; ¹³ C NMR (125 MHz,

CD ₃ OD, 27 °C) δ 34.1, 41.4, 41.5, 48.1, 50.5, 55.6, 60.3, 60.8, 61.2,

112.6, 115.4, 122.1, 130.5, 142.9, 161.3 ; HRMS (ESI-Orbitrap) [M+H] ⁺

calcd for C ₁₅ H ₂₆ N ₃ 0 ₃ S, 328.1689 found 328.1688. ECO02-073-B2 N,N'-(1-(3-methoxyphenethyl)piperidine-3,5- diyl)dimethanesulfonamide : 84 mg, 52%, white solid ;

1H NMR (500 MHz, CD ₃ OD , 27 °C) δ 1.23 (q, J= 12.2 Hz, 1H), 1.90 (t,

J= 10.8 Hz, 2H), 2.31-2.33 (m, 1H), 2.69-2.72 (m, 2H), 2.79-2.82 (m,

2H), 2.99 (s, 6H), 3.14-3.18 (m, 2H), 3.43-3.48 (m, 2H), 3.79 (s, 3H),

6.75-6.77 (m, 1H), 6.80-6.82 (m, 2H), 7.19 (t, J=8.1 Hz, 1H) ; ¹³ C NMR

(125 MHz, CD ₃ OD, 27 °C) δ 32.8, 38.7, 40.0 (2C), 50.5 (2C), 54.2, 58.5

(2C), 59.1, 111.3, 114.0, 120.7, 129.0, 141.5, 160.0 ; HRMS (ESI- Orbitrap) [M+H] ⁺ calcd for Ci ₆ H ₂₈ N ₃ 0 ₅ S ₂ , 406.1465 found 406.1466. Carbamoylation of diaminopiperidines

ECO01-026-C2 (100 mg, 0.401 mmol) was solubilized in anhydrous pyridine (0.8 ml_). At 0°C, methyl chloroformate was added (94 μΙ_, 1 .2 mmol). Mixture was stirred 10 min at 0°C and at RT for 4h under Ar. The reaction was monitored by TLC until disappearance of the initial product. Mixture was quenched with water, extracted with CH ₂ CI _2. The organic layer with a saturated aqueous solution of NaCI, dried over MgS0 ₄ , filtered and evaporated. Flash chromatography (Cyclohexane to Ethyl Acetate) afforded ECO02-074-C (87 mg, 59 %), white solid.

ECO02-074-C dimethyl (1 -(3-methoxyphenethyl)piperidine-3,5- diyl)dicarbamate : 87 mg, 59%, white solid ;

¹ H NMR (500 MHz, CD ₃ OD , 27 °C) δ 1 .19 (q, J= 1 1 .8 Hz, 1 H), 1 .84

(t, J = 10.7 Hz, 2H), 2.12-2.14 (m, 1 H), 2.66-2.68 (m, 2H), 2.77-2.79

(m, 2H), 3.09-3.1 1 (m, 2H), 3.60-3.72 m, 8H), 3.79 (s, 3H), 6.75-6.77

(m, 1 H), 6.79-6.80 (m, 2H), 7.19 (t, J = 8.1 Hz, 1 H) ; ¹³ C NMR (125

MHz, CD ₃ OD, 27 °C) δ 34.2, 37.9, 48.2 (2C), 52.4 (2C), 55.6, 58.9

(2C), 60.9, 1 12.6, 1 15.4, 122.1 , 130.4, 142.9, 158.8, 161 .3 (2C) ;

HRMS (ESI-Orbitrap) [M+H] ⁺ calcd for Ci ₈ H ₂₈ N ₃ 0 ₅ , 366.2023 found

366.2020.

Monocarbamoylation of diaminopiperidines

ECO01-026-C2 (100 mg, 0.401 mmol), was solubilized in THF (4 ml_) and NaOH 1 M (4 ml_). Boc ₂ 0 (219 mg, 1 .00 mmol) was added. Mixture was stirred 2h under Ar at RT. The reaction was monitored by TLC until disappearance of the initial product. THF was evaporated. Mixture was extracted with Ethyl Acetate. The organic layer with a saturated aqueous solution of NaCI, dried over MgS0 ₄ , filtered and evaporated. Crude product was purified on Si0 ₂ (CH ₂ CI ₂ to CH ₂ CI ₂ /MeOH/NH ₄ OH 90/9/1 ) afforded ECO02-078-C (24 mg), colorless oil. ECO02-078-C tert-butyl 5-amino-1-(3-methoxyphenethyl)piperidin-3- yl)carbamate : 24 mg, byproduct, colorless oil ;

¹ H NMR (500 MHz, CD ₃ OD , 27 °C) δ 1 .07 (q, J = 1 1 .8 Hz, 1 H), 1 .46 (s, 9H),

1 .82 (td, J = 10.5, 4.8 Hz, 2H), 2.13-2.17 (m, 1 H), 2.66-2.69 (m, 2H), 2.78- 2.81 (m, 2H), 2.93-2.99 (m, 1 H), 3.05-3.1 1 (m, 2H), 3.62-.365 (m, 1 H), 3.79

(s, 3H), 6.75-6.80 (m, 3H), 7.19 (t, J = 8.1 Hz, 1 H) ; ¹³ C NMR (125 MHz,

CD ₃ OD, 27 °C) δ 28.8 (3C), 34.1 , 39.9, 47.6, 48.1 , 55.6, 58.9, 60.7, 60.9,

80.2, 1 12.6, 1 15.5, 122.1 , 130.4, 142.9, 157.7, 161 .3 ; HRMS (ESI-Orbitrap)

[M+H] ⁺ calcd for Ci ₉ H32N ₃ 0 ₃ , 350.2438 found 350.2439.

Sulfonylation of protected diaminopiperidines

ECO02-051 -C (79 mg, 0.251 mmol) was suspended in CH ₂ CI ₂ (5 ml_) and anhydrous pyridine (22 μΙ_, 0.276 mmol). At 0 °C, benzenesulfonylchloride (35 μΙ_, 0.276 mmol) was added. Mixture was stirred overnight under Ar at RT. At 0°C, benzenesulfonylchloride (35 μΙ_, 0.276 mmol) was added and mixture was stirred 6h under Ar at RT. Water and NaOH 2M were added. The aqueous layer extracted with Ethyl Acetate. The organic layer with a saturated aqueous solution of NaCI, dried over MgS0 ₄ , filtered and evaporated. Flash chromatography (Cyclohexane to Cyclohexane/Ethyl Acetate 5/5) afforded ECO02-081-C (60 mg, 52%), white solid.

ECO02-081-C di-tert-butyl (1 -(phenylsulfonyl)piperidine-3,5- diyl)dicarbamate : 60 mg, 52%, white solid ;

H NMR (500 MHz, CD ₃ OD , 27 °C) δ 1 .1 1 (q, J = 12.1 Hz, 1 H), 1 .46

(s, 18H), 1 .98-2.02 (m, 3H), 3.57 (br s, 2H), 3.80-3.90 (m, 2H), 7.62- 7.65 (m, 2H), 7.65-7.70 (m, 1 H), 7.83 (d, J = 7.3 Hz, 2H) ; ¹³ C NMR

(125 MHz, CD ₃ OD, 27 °C) δ 27.2 (6C), 35.8; 46.0 (2C), 49.5 (2C),

79.0 (2C), 127.2 (2C), 129.0 (2C), 132.8 , 136.8, 156.0 (2C)

Preparation of ECO03-03-C

ECO01-026-C2 (100 mg, 0.401 mmol) was solubilized in THF (4 ml_) and NaOH 1 M (4 ml_). Boc ₂ 0 (394 mg, 1 .80 mmol) was added. Mixture was stirred 2h under Ar at RT. The reaction was monitored by TLC until disappearance of the initial product. THF was evaporated. Mixture was extracted with Ethyl Acetate. The organic layer with a saturated aqueous solution of NaCI, dried over MgS0 ₄ , filtered and evaporated. Flash chromatography (Cyclohexane to Cyclohexane/ Ethyl Acetate 6/4) afforded ECO03-03-C (1 10 mg, 61 %).

ECO03-03-C di-tert-butyl (1-(3-methoxyphenethyl)piperidine- BocHN

3,5-diyl)dicarbamate : 1 10 mg, 61 %, white solid ;

1 H NMR (500 MHz, CD ₃ OD , 27 °C) δ 1 .14 (q, J = 1 1 .8 Hz, 1 H),

1 .45 (s, 18H), 1 .82 (t, J = 10.6 Hz, 2H), 2.03-2.1 1 (m, 1 H), 2.64- 2.67 (m, 2H), 2.77-2.81 (m, 2H), 3.04-3.09 (m, 2H), 3.62-3.65 (m,

2H), 3.79 (s, 3H), 6.73-6.77 (m, 1 H), 6.79-6.81 (m, 2H), 7.18 (t, J

= 8.1 Hz, 1 H) ; ⁱ³ C NMR (125 MHz, CD ₃ OD, 27 °C) δ 28.8 (6C),

34.2, 38.0, 47.7 (2C), 55.6, 59.0 (2C), 60.9, 80.1 (2C), 1 12.6,

1 15.4, 122.1 , 130.4, 143.0, 157.7, 161 .3 (2C) ; HRMS (ESI- Orbitrap) [M+H] ⁺ calcd for ^H^Os, 450.2962 found 450.2949.

Preparation of ECO02-045-C

ECO02-045-C dibenzyl 3-(3-acetoxyphenethyl)-3,6,7- triazabicyclo[3.2.1]octane-6,7-dicarboxylate : 105 mg,

quant., transparent oil ;

¹ H NMR (500 MHz, (CD ₃ ) ₂ SO, 60 °C, δ) 1 .60 (br s, 2H),

2.25 (br s, 5H), 2.57 (br s, 2H), 3.07 (br s, 2H), 3.20 (br s,

2H), 4.37 (br s, 2H), 5.13 (br s, 4H), 6.92 (br s, 2H), 7.04

(br s, 1 H), 7.34 (br s, 1 1 H) ; ¹³ C NMR (125 MHz,

(CD ₃ ) ₂ SO, 60 °C, δ) 20.8, 28.9, 35.7, 52.1 , 54.7, 55.8 (2C),

57.4, 66.8 (2C), 1 19.2, 121 .6, 125.8, 127.5-129.1 (1 1 C),

136.4 (2C), 141 .9, 150.6, 156.8 (2C), 168.9 ; HRMS (ESI- Orbitrap) [M+H] ⁺ calcd for C ₃ iH ₃₄ N ₃ 0 ₆ , 544.2442 found

544.2440.