阅读说明：本技术 吲哚胺2,3-双加氧酶的调节剂 (Modulators of indoleamine2, 3-dioxygenase ) 是由 M.A.德拉罗萨 H.邓 G.艾文达 W.M.卡兹米尔斯基 J.F.米勒 V.萨马诺 Y 于 2018-06-27 设计创作，主要内容包括：提供的是式I的IDO抑制剂化合物及其药学上可接受的盐、它们的药物组合物、它们的制备方法以及将它们用于预防和/或治疗疾病的方法。式I：<Image he="130" wi="122" file="100004_DEST_PATH_IMAGE002.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>。(Provided are IDO inhibitor compounds of formula I and pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, processes for their preparation, and methods of using them for the prevention and/or treatment of disease. Formula I: 。)

1. A compound of formula I

Or a pharmaceutically acceptable salt thereof, wherein:

each X is CH, or one X is N and the other 3X are CH;

Q¹is a bond (i.e., absent), -C (O) C-or-C (O) -;

Q²is a key (i.e., don't store)At) or-C (O) -;

R¹is absent, halogen, C_1-3Alkyl OH or C (O) OC_1-3An alkyl group;

R³is C_5-9Aryl or 5-9 membered heteroaryl, wherein aryl and heteroaryl comprise bicyclic rings and heteroaryl contains 1-3 heteroatoms selected from O, S and N, and wherein R³May be optionally substituted by a substituent selected from the group consisting of halogen, OH, C_1-3Alkyl, OC_1-3Alkyl radical, C_1-3Fluoroalkyl, CN and NH₂(ii) a And

R⁴is H, C_1-3Haloalkyl, phenyl or C_1-6An alkyl group.

2. A compound or salt according to claim 1, wherein each X is CH.

3. A compound or salt according to claim 1 or claim 2 wherein Q is¹Is C (O) O.

4. A compound or salt according to any one of claims 1-3, wherein Q²Is C (O).

5. A compound or salt according to any one of claims 1-4, wherein R¹Is Br, OCH₃Or is absent.

6. A compound or salt according to any one of claims 1-5, wherein R³Is indole, benzodiazole, phenyl, pyridyl, diazole or pyrimidine, and wherein R³May be optionally substituted by a substituent selected from the group consisting of halogen, OH, C_1-3Alkyl, OC_1-3Alkyl radical, C_1-3Fluoroalkyl, CN and NH₂。

7. A compound or salt according to claim 6, wherein R³Is indole or benzodiazole, and wherein R³May be optionally substituted by a substituent selected from the group consisting of halogen, OH, C_1-3Alkyl, OC_1-3Alkyl radical, C_1-3Fluoroalkyl, CN and NH₂。

8. A compound or salt according to claim 7, wherein R³Is an unsubstituted indazole.

9. A compound or salt according to any one of claims 1-8, wherein R⁴Is H, C_1-4Alkyl, CF₃Or a phenyl group.

10. A compound or salt according to claim 9, wherein R⁴Is C_1-4An alkyl group.

11. A compound or salt according to claim 1, wherein each X is CH; q¹Is C (O) O; q²Is C (O); r¹Is Br, OCH₃Or is absent; r³Is indole, benzodiazole, phenyl, pyridyl, diazole or pyrimidine, and wherein R³May be optionally substituted by a substituent selected from the group consisting of halogen, OH, C_1-3Alkyl, OC_1-3Alkyl radical, C_1-3Fluoroalkyl, CN and NH₂(ii) a And R is⁴Is H, C_1-4Alkyl, CF₃Or a phenyl group.

12. A pharmaceutical composition comprising a compound or salt according to any one of claims 1-11.

13. A method of treating a disease or condition that would benefit from inhibition of IDO1, the method comprising the step of administering a composition according to claim 12.

14. The method according to claim 13, wherein in the disease or condition, a biomarker of IDO activity is elevated.

15. The method according to claim 13, wherein the biomarker is plasma kynurenine or a plasma kynurenine/tryptophan ratio.

16. The method according to claim 13, wherein the disease or condition is a chronic viral infection; chronic bacterial infections; cancer; sepsis or neurological conditions.

17. The method according to claim 13, wherein the chronic viral infections are those involving HIV, HBV or HCV; the chronic bacterial infection is tuberculosis or artificial joint infection; and the neurological disorder is major depressive disorder, huntington's disease, or parkinson's disease.

18. The method according to claim 17, wherein the disease or condition is inflammation associated with HIV infection; chronic viral infections involving hepatitis b virus or hepatitis c virus; cancer; or sepsis.

19. A compound or salt according to any one of claims 1-11 for use in the treatment of a disease or condition that would benefit from inhibition of IDO 1.

20. Use of a compound or salt according to any one of claims 1-11 in the manufacture of a medicament for the treatment of a disease or condition that would benefit from the inhibition of IDO 1.

Technical Field

Compounds, methods and pharmaceutical compositions for the prevention and/or treatment of HIV are disclosed; comprising preventing the progression of AIDS and systemic immunosuppression by administering a therapeutically effective amount of certain indoleamine2, 3-dioxygenase compounds. Also disclosed are methods of making such compounds and methods of using the compounds and pharmaceutical compositions thereof.

Background

Indoleamine-2, 3-dioxygenase 1(IDO1) is a heme-containing enzyme that catalyzes the indole epoxidation of tryptophan to produce N-formyl kynurenine, which is rapidly and constitutively converted to kynurenine (Kyn) and a range of downstream metabolites. IDO1 is the rate-limiting step of the kynurenine pathway of tryptophan metabolism, and expression of IDO1 is inducible in the case of inflammation. Stimuli that induce IDO1 include viral or bacterial products, or inflammatory cytokines associated with infection, tumor, or sterile tissue injury. Kyn and several downstream metabolites have immunosuppressive effects: kyn has antiproliferative and proapoptotic effects on T-cells and NK-cells (Munn, Shafizadeh et al 1999, Frumento, Rotondo et al 2002), while metabolites such as 3-hydroxyanthranilic acid (3-HAA) or the 3-HAA oxidative dimerization product vermillic acid (CA) inhibit phagocytic function (Sekkai, Guittet al 1997) and induce differentiation of immunosuppressive regulatory T-cells (Treg) while inhibiting differentiation of gut protective IL-17-or IL-22 producing CD4+ T-cells (Th17 and Th22) (Favre, Mold et al 2010). Among other mechanisms, IDO1 induction may be important in limiting immunopathology during active immune responses, promoting resolution of immune responses (resolution), and promoting fetal tolerance. However, in chronic situations such as cancer or chronic viral or bacterial infections, IDO1 activity prevents clearance of tumors or pathogens, and if the activity is systemic, IDO1 activity may lead to systemic immune dysfunction (Boasso and Shearer 2008, Li, Huang et al 2012). In addition to these immunomodulatory effects, metabolites of IDO1 (e.g., Kyn and quinolinic acid) are also known to be neurotoxic and found to be elevated in several neurologically impaired conditions and depression. Therefore, IDO1 is a therapeutic target to inhibit a variety of indications, for example to promote tumor clearance, to successfully clear refractory viral or bacterial infections, to reduce systemic immune dysfunction (manifested as persistent inflammation during HIV infection or immunosuppression during sepsis), and to prevent or reverse neurological conditions.

IDO1 and persistent inflammation in HIV infection:

Despite the success of antiretroviral therapy (ART) in inhibiting HIV replication and reducing the appearance of AIDS-related conditions, HIV-infected patients receiving ART have a higher incidence of non-AIDS morbidity and mortality than their uninfected counterparts. These non-AIDS conditions include cancer, cardiovascular disease, osteoporosis, liver disease, kidney disease, frailty, and neurocognitive dysfunction (Deeks 2011). Several studies have shown that non-AIDS morbidity/mortality is associated with persistent inflammation, which remains elevated in HIV-infected patients receiving ART compared to the corresponding population (Deeks 2011). It is therefore hypothesized that despite virologic suppression of ART, persistent inflammation and immune dysfunction are one cause of these non-AIDS-defining events (NADEs).

HIV infects and kills CD4+ T cells, with particular preference for cells such as those CD4+ T cells that reside in lymphoid tissues at the mucosal surface (Mattapallil, Douek et al 2005). The loss of these cells, combined with the inflammatory response to infection, results in interference of the host relationship with all pathogens, including HIV itself, but extending to preexisting or acquired viral infections, fungal infections, and resident bacteria in skin and mucosal surfaces. Such dysfunctional hosts: pathogen relationships cause host overreaction to often minor problems and allow pathogen outgrowth in the microflora. Thus, the dysfunctional host: pathogen interactions lead to increased inflammation and thus to more severe dysfunction, leading to the vicious circle. Since inflammation is thought to lead to non-AIDS morbidity/mortality, the altered host is controlled: the mechanism of pathogen interaction is the therapeutic target.

The expression and activity of IDO1 was increased in untreated and treated models of HIV infection as well as in primate SIV infection (Boasso, Vaccari et al 2007, Favre, Lederer et al 2009, Byakwaga, Boum et al 2014, Hunt, Sinclair et al 2014, Tenorio, Zheng et al 2014). As shown by the ratio of plasma levels of enzyme substrate and product (Kyn/Tryp or K: T ratio), IDO1 activity is associated with other inflammatory markers and is one of the strongest predictors of non-AIDS morbidity/mortality (Byakwaga, Boum et al 2014, Hunt, Sinclair et al 2014, Tenorio, Zheng et al 2014). Furthermore, features consistent with the expected impact of increased IDO1 activity on the immune system are major features of HIV and SIV-induced immune dysfunction, such as a reduction in T cell proliferative responses to antigens and an imbalance of Treg: Th17 in the systemic and intestinal compartments (Favre, Lederer et al 2009, Favre, Mold et al 2010). Therefore, we and others hypothesize that IDO1 plays a role in the malignant cycle that drives immune dysfunction and inflammation associated with non-AIDS morbidity/mortality. Therefore, we propose that inhibition of IDO1 will reduce inflammation and reduce the risk of NADE in HIV infected persons with ART inhibition.

Persistent inflammation other than IDO1 and HIV

As mentioned above, inflammation associated with chronic HIV infection for treatment may be a driver of a variety of end organ diseases [ Deeks 2011 ]. However, these end organ diseases are not unique to HIV infection and are in fact common aging diseases that occur earlier in HIV-infected people. In the uninfected general population, inflammation of unknown etiology is a major contributor to morbidity and mortality [ Pinti, 2016 #88 ]. Indeed, many inflammatory markers are shared, such as IL-6 and CRP. If, as hypothesized above, IDO1 causes persistent inflammation in HIV-infected people by inducing immune dysfunction in the GI tract or systemic tissues, IDO1 may also cause inflammation and thus end-organ disease in a broader population. Examples of such end organ diseases associated with inflammation are cardiovascular diseases, metabolic syndrome, liver diseases (NAFLD, NASH), kidney diseases, osteoporosis and neurocognitive disorders. Indeed, the IDO1 pathway is linked in the literature to Liver disease (Vivoli abstract of italian nosoc. for the Study of the Liver Conference 2015), diabetes [ Baban,2010 #89], chronic kidney disease [ schefeld, 2009 #90], cardiovascular disease [ manggee, 2014 #92; manggee, 2014 #91], and mortality for all causes [ perovaara, 2006 #93] and therefore inhibition of IDO1 can be used to reduce inflammation in the general population to reduce the occurrence of specific end organ diseases associated with inflammation and aging.

IDO1 and oncology

IDO expression can be detected in a variety of human cancers (e.g., melanoma, pancreatic, ovarian, AML, CRC, prostate, and endometrial), and is associated with poor prognosis (Munn 2011). A variety of immunosuppressive effects can be attributed to IDO effects, including induction of Treg differentiation and over-activation, suppression of Teff immune responses and reduced DC function, all of which impair immune recognition and promote tumor growth (Munn 2011). IDO expression in human brain tumors is associated with decreased survival. Vertically grown and transgenic glioma mouse models demonstrated a correlation between reduced IDO expression and reduced Treg infiltration and increased long-term survival (Wainwright, balyasanikova et al 2012). In human melanoma, a high proportion of tumors (33 of 36) showed elevated IDO, suggesting an important role in establishing an immunosuppressive Tumor Microenvironment (TME) characterized by MDSCs expanding, activating and recruiting in a Treg-dependent manner (Holmgaard, zanarin et al 2015). In addition, immune cells expressing the host IDO have been identified in draining lymph nodes and tumors themselves (Mellor and Munn 2004). Therefore, both tumor and host derived IDO are thought to contribute to the immunosuppressive state of TME.

Inhibition of IDO is one of the first small molecule drug strategies proposed to reconstitute the immunogenic response against cancer (Mellor and Munn 2004). The D-enantiomer of 1-methyltryptophan (D-1MT or indoximod) was the first IDO inhibitor to enter clinical trials. Although this compound clearly inhibits the activity of IDO, it is a very weak inhibitor of isolated enzymes and the mechanism of action of this compound in vivo is still being elucidated. Researchers at Incyte optimized hit compounds obtained by the screening process as potent and selective inhibitors with sufficient oral exposure to demonstrate delay of tumor growth in a mouse melanoma model (Yue, Douty et al 2009). Further development of this series led to INCB204360, which has a high degree of selectivity for inhibition of IDO-1 over IDO-2 and TDO in cell lines transiently transfected with human or mouse enzymes (Liu, Shin et al 2010). Similar efficacy (IC50 s-3-20 nM) was observed for cell lines endogenously expressing IDO1 and primary human tumors. When at DC and initial CD4⁺CD25^-When tested in co-cultures of T cells, INCB204360 blocked these T cells to CD4⁺FoxP3⁺And (5) transformation of Tregs. Finally, when tested in a syngeneic model of immunocompetent mice (PAN02 pancreatic cells), the oral administration of INCB204360 provided significant dose-dependent inhibition of tumor growth, but had no effect on the same tumor implanted in immunodeficient mice. Other studies by the same investigator showed a correlation between inhibition of IDO1 and inhibition of systemic kynurenine levels and tumor growth in another syngeneic tumor model in immunocompetent mice. Based on these preclinical studies, INCB24360 entered a clinical trial for the treatment of metastatic melanoma (Beatty, O' Dwyer et al 2013).

In view of the importance of tryptophan catabolism in maintaining immunosuppression, it was not surprising that the second tryptophan metabolizing enzyme TDO2 has also been detected to be overexpressed by various solid tumors (e.g. bladder and liver cancer, melanoma). One survey of 104 human cell lines revealed that 20/104 had TDO expression, 17/104 had both IDO1 and 16/104 expression (Pilotte, Larrieu et al 2012). Similar to the inhibition of IDO1, selective inhibition of TDO2 may be effective in reversing the immune resistance of tumors overexpressing TDO2 (Pilotte, Larrieu et al 2012). These results support TDO2 inhibition and/or dual TDO2/IDO1 inhibition as viable therapeutic strategies to improve immune function.

A number of preclinical studies have shown that the use of IDO-1 inhibitors in combination with T cell checkpoint regulatory mabs against CTLA-4, PD-1 and GITR is of significant, even synergistic, value. In each case, improved efficacy of immune activity/function and related PD aspects were observed in these studies across various murine models (Balachandran, Cavnar et al 2011, Holmgaard, zaamarin et al 2013, m. Mautino 2014, Wainwright, Chang et al 2014). Incyte IDO1 inhibitor (INCB204360, epacadostat) has been clinically tested in combination with CTLA4 blocker (ipilimumab), but it is unclear whether an effective dose has been reached due to the dose-limiting adverse events seen with the combination. In contrast, data from a recently published ongoing trial combining Epacadostat with Merck's PD-1mAb (pembrolizumab) indicates improved tolerability of the combination, allowing for higher doses of IDO1 inhibitor. There are encouraging several clinical responses across multiple tumor types. However, it is not clear whether this combination improves the single agent activity of pembrolizumab (Gangadhar, Hamid et al 2015). Similarly, Roche/Genentech is working on NGL919/GDC-0919 in combination with two mAbs of PD-L1 (MPDL3280A, Atezo) and OX-40 after the phase 1a safety and PK/PD studies have recently been completed for patients with advanced tumors.

IDO1 and Chronic infections

IDO1 activity produces kynurenine pathway metabolites such as Kyn and 3-HAA, which at least impair T cell, NK cell and macrophage activity (Munn, Shafizadeh et al 1999, Frumento, Rotondo et al 2002) (Sekkai, Guittet al 1997, Favre, Mold et al 2010). Kyn levels or Kyn/Tryp ratios are elevated in the context of chronic HIV infection (Byakwaga, Boum et al 2014, Hunt, Sinclair et al 2014, Tenorio, Zheng et al 2014), HBV infection (Chen, Li et al 2009), HCV infection (Larrea, Riezu-Boj et al 2007, Asghar, Ashiq et al 2015) and TB infection (Suzuki, Suda et al 2012) and are associated with antigen-specific T cell dysfunction (Boasso, Herbeuval et al 2007, Boasso, hard et al 2008, Loughman and huntad 2012, Ito, Ando et al 2014, Lepiller, Soulier et al 2015). Thus, it is believed that in the case of these chronic infections, inhibition of IDO 1-mediated pathogen-specific T cell responses plays a role in the persistence of the infection, and inhibition of IDO1 may have benefits in promoting clearance and addressing the infection.

IDO1 and sepsis

Increased IDO1 expression and activity was observed during sepsis, and the degree of increase in Kyn or Kyn/Tryp corresponded to increased disease severity, including increased mortality (Tattevin, Monnier et al 2010, Darcy, Davis et al 2011). In animal models, blockade of IDO1 or IDO1 gene knockout can protect mice from death in lethal doses of LPS or cecal ligation/perforation models (Jung, Lee et al 2009, Hoshi, Osawa et al 2014). Sepsis is characterized by an immunosuppressive phase in severe cases (houtchkiss, Monneret et al 2013), which may indicate the role of IDO1 as a mediator of immune dysfunction, and pharmacological inhibition of IDO1 may provide clinical benefit for sepsis.

IDO1 and neurological disorders

Besides immunological situations, IDO1 activity has also been associated with disease in neurological situations (reviewed in lovelac enouropharmacogenogy 2016(Lovelace, Varney et al 2016)). Kynurenine pathway metabolites (e.g., 3-hydroxykynurenine and quinolinic acid) are neurotoxic, but are in equilibrium with the interconvertive neuroprotective metabolite kynurenic acid or picolinic acid. Neurodegenerative and psychiatric disorders in which kynurenine pathway metabolites have been implicated in disease include multiple sclerosis, motor neuron disorders such as amyotrophic lateral sclerosis, huntington's disease, parkinson's disease, alzheimer's disease, major depression, schizophrenia, anorexia (lovelacee, Varney et al 2016). Animal models of neurological diseases have shown some impact of weak IDO1 inhibitors (e.g., 1-methyltryptophan) on disease, suggesting that IDO1 inhibition may provide clinical benefit for the prevention or treatment of neurological and psychiatric disorders.

Therefore, IDO inhibitors that effectively balance the above properties are found as disease modifying therapies for chronic HIV infection that reduce the incidence of non-AIDS morbidity/mortality; and/or disease modifying therapies to prevent mortality from sepsis; and/or enhance immune response to HIV, HBV, HCV and other chronic viral infections, chronic bacterial infections, chronic fungal infections, and to tumors; and/or for the treatment of depression or other neurological/neuropsychiatric disorders would be an advance in the art.

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Summary of The Invention

Briefly, in one aspect, the present invention discloses compounds of formula I

Or a pharmaceutically acceptable salt thereof, wherein: or a pharmaceutically acceptable salt thereof, wherein:

each X is CH, or one X is N and the other 3X are CH;

Q¹is a bond (i.e., absent), -C (O) C-or-C (O) -;

Q²is a bond (i.e., absent) or-C (O) -;

R¹is absent,Halogen, C_1-3Alkyl OH or C (O) OC_1-3An alkyl group;

R³is C_5-9Aryl or 5-9 membered heteroaryl, wherein aryl and heteroaryl comprise bicyclic rings and heteroaryl contains 1-3 heteroatoms selected from O, S and N, and wherein R³May be optionally substituted by a substituent selected from the group consisting of halogen, OH, C_1-3Alkyl, OC_1-3Alkyl radical, C_1-3Fluoroalkyl, CN and NH₂(ii) a And

R⁴is H, C_1-3Haloalkyl, phenyl or C_1-6An alkyl group.

In another aspect, the invention discloses methods for treating a disease or condition that would benefit from inhibition of IDO.

In another aspect, the present invention discloses pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in therapy.

In another aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition that would benefit from the inhibition of IDO.

In another aspect, the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or condition that would benefit from the inhibition of IDO.

In another aspect, the present invention discloses a method for treating a viral infection in a patient mediated at least in part by a virus in the retrovirus family of viruses, the method comprising administering to the patient a composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the viral infection is mediated by the HIV virus.

In another aspect, a particular embodiment of the invention provides a method of treating a subject infected with HIV, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

In yet another aspect, a particular embodiment of the present invention provides a method of inhibiting the progression of HIV infection in a subject at risk of contracting HIV, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. Those and other embodiments are further described below.

Detailed description of representative embodiments

Preferably, each X is CH.

Preferably, Q¹Is C (O) O.

Preferably, Q²Is C (O).

Preferably, R¹Is Br, OCH₃Or is absent.

Preferably, R³Is indole, benzodiazole, phenyl, pyridyl, diazole or pyrimidine, and wherein R³May be optionally substituted by a substituent selected from the group consisting of halogen, OH, C_1-3Alkyl, OC_1-3Alkyl radical, C_1-3Fluoroalkyl, CN and NH₂. More preferably, R³Is indole or benzobisoxazole and may optionally be substituted by a substituent selected from halogen, OH, C_1-3Alkyl, OC_1-3Alkyl radical, C_1-3Fluoroalkyl, CN and NH₂. Most preferably, R³Is an unsubstituted indazole.

Preferably, R⁴Is H, C_1-4Alkyl, CF₃Or a phenyl group. More preferably, R⁴Is C_1-4An alkyl group.

Preferably with NH-Q²-R³Stereochemistry of the bonded carbon atoms is depicted as

。

Preferred pharmaceutical compositions include unit dosage forms. Preferred unit dosage forms include tablets.

In particular, it is contemplated that the compounds and compositions of the present invention will be useful in the prevention and/or treatment of HIV; including the prevention of AIDS and the progression of systemic immunosuppression. It is contemplated that in many instances, such prevention and/or treatment will involve treatment with a compound of the present invention in combination with at least one other drug recognized as useful for such prevention and/or treatment. For example, IDO inhibitors of the present invention may be used in conjunction with other immunotherapy approaches, such as immune checkpoints (PD1, CTLA4, ICOS, etc.), and possibly in conjunction with growth factor or cytokine therapy (IL21, IL-7, etc.).

A common practice in the treatment of HIV is to employ more than one effective agent. Thus, according to another embodiment of the invention, there is provided a method for the prevention or treatment of a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses, the method comprising administering to a mammal that has been diagnosed with or at risk of developing said viral infection a compound as defined in formula I, wherein the virus is an HIV virus, and further comprising administering a therapeutically effective amount of one or more agents active against the HIV virus, wherein the agent active against the HIV virus is selected from nucleotide reverse transcriptase inhibitors; a non-nucleotide reverse transcriptase inhibitor; a protease inhibitor; entry, attachment and fusion inhibitors; an integrase inhibitor; a maturation inhibitor; CXCR4 inhibitors; and CCR5 inhibitors. Examples of such other drugs are dolastavir, Bictegravir and caboteravir.

"pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counterions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium and tetraalkylammonium salts and, when the molecule contains a basic functional group, salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate and oxalate. Suitable Salts include P, Heinrich Stahl, Camile G, Wermuth (eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.

The invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by conversion of an existing acid or base group to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; bases or organic salts of acidic residues such as carboxylic acids; and so on. Pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains a basic or acidic group, by conventional chemical methods. In general, these salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two; generally, nonaqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or ACN are preferred.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

In one embodiment, the pharmaceutical formulation containing a compound of formula I or a salt thereof is a formulation suitable for oral or parenteral administration. In another embodiment, the formulation is a long acting parenteral formulation. In another embodiment, the formulation is a nanoparticle formulation.

The present invention relates to compounds, compositions and pharmaceutical compositions useful as novel therapies for immunosuppression. While not wishing to be bound by any particular theory, it is believed that the compounds of the present invention are capable of inhibiting the catalytic I-Trp pair using molecular or active oxygen inhibitionN-enzymes of the oxidative pyrrole ring cleavage reaction of formylkynurenine.

Thus, in another embodiment of the present invention, there is provided a method for the prevention and/or treatment of HIV; including the prevention of AIDS and the progression of systemic immunosuppression.

Examples

The compounds of the present invention can be prepared by one skilled in the art following the general synthetic schemes below.

The following examples are presented to more fully describe the manner in which the above-described invention may be made and used. It should be understood that these examples are in no way intended to limit the true scope of the invention, but are presented for illustrative purposes. In the examples and synthetic schemes below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

Meaning of abbreviations

DEG C

DCM dichloromethane

DEA diethylamine

DIEA N, N-diisopropylethylamine

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

ESI electrospray ionization

h or hr

HATU (1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium

3-oxide hexafluorophosphate salt)

HPLC high performance liquid chromatography

J coupling constant, Hz

LCMS liquid chromatography-mass spectrometry

M moles of

Mg of Mg

min for

mL of

mM millimolar

mmol millimole

Mu L or uL microliter

Micro-molar of mu M or uM

MS Mass Spectrometry

N equivalent of

NBS N-bromosuccinimide

NMR nuclear magnetic resonance

PE Petroleum Ether

parts per million ppm

RT Room temperature

Rf Retention factors

TEA Triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography.

Description of the apparatus

¹H NMR spectra were recorded on a Varian 400 spectrometer. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are in hertz (Hz). The splitting pattern describes the apparent multiplicities and is designated as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad).

Analytical low resolution Mass Spectra (MS) were recorded using a gradient elution method on a Waters ACQUITY UPLC with SQ detector using Waters BEH C18, 2.1 x 50mm, 1.7 μm. Solvent A0.1% Formic Acid (FA)/water. Solvent B is 0.1 percent of FA/acetonitrile; 30% B for 0.5 min, followed by 30-100% B over 2.5 min.