ES2981834T3 - Antibacterial quinolines - Google Patents

Abstract

This disclosure relates to 6-substituted quinoline-2-piperidine derivatives for use in the treatment and/or prevention of tuberculosis. (Automatic translation with Google Translate, no legal value)

Description

DESCRIPTION

Antibacterial quinolines

Technical field

The present disclosure relates to novel 6-substituted quinoline-2-piperidine derivatives according to the general formula I, II, III and IV, or to pharmaceutically acceptable acid or base addition salts, a hydrate, a solvate, an N-oxide, stereochemically isomeric forms, in particular a diastereomer, an enantiomer or atropisomers, or mixtures thereof, a polymorph or an ester thereof. The present disclosure also relates to a pharmaceutical composition comprising a compound or prodrug thereof of formula I, II, III and IV, to the combination of that compound with at least one drug for tuberculosis and to its use in the treatment and/or prevention of tuberculosis.

Background

Mycobacterium tuberculosis (MTB) has been one of the major human pathogens since the beginning of human existence. As the human race began to develop, MTB became more easily transmitted and became one of the leading causes of death at the beginning of the twentieth century (Coma et al. Nat. Genet. 2013, 45, 1176-1182). The prognosis for patients with tuberculosis (TB) improved dramatically with the discovery and use of anti-TB drugs.

Tuberculosis (TB) is an airborne disease caused by Mycobacterium tuberculosis and seven closely related mycobacterial species, namely Mycobacterium bovis, Mycobacterium africanum, Mycobacterium microti, Mycobacterium caprae, Mycobacterium pinnipedii, Mycobacterium canetti, and Mycobacterium mungi, which together comprise the Mycobacterium tuberculosis complex. Most cases of TB are caused by Koch bacilli (MTB).

Mycobacterium tuberculosis is carried in atmospheric particles (droplet nuclei) 1-5 µm in diameter. Infectious droplet nuclei are generated by persons with pulmonary or laryngeal TB disease. Transmission occurs when an individual inhales droplet nuclei containing MTB, and the droplet nuclei traverse the oronasal passages, upper airways, and bronchi to reach the alveoli. These Koch bacilli are phagocytosed by alveolar macrophages; most of these bacilli are destroyed or inhibited. A small number may multiply intracellularly and are released after macrophage destruction. These Koch bacilli may spread through the lymphatic system or bloodstream to distant organs, frequently the regional lymph nodes, lung (apex), kidneys, brain, and bones. This dissemination process stimulates the immune system to generate a systemic response.

Individuals with latent tuberculosis infection (LTBI) carry the bacteria but do not show symptoms of TB disease and do not transmit the infection to others. LTBI begins when extracellular bacilli are ingested by macrophages and presented to other white blood cells. This triggers the immune response in which the white blood cells destroy or encapsulate most of the bacilli, leading to the formation of a granuloma. At this point, LTBI has been established. Latent tuberculosis infection (LTBI) can be detected by the tuberculin skin test or an interferon-gamma release assay. Within weeks of infection, the immune system can usually stop the multiplication of Koch bacilli, preventing further progression. In some people, Koch bacilli overcome the immune system and multiply, resulting in the progression of LTBI to TB disease. The progression of LTBI to TB disease can occur at any time from the initial infection to many years later. Without treatment, approximately 5% of individuals who have been infected with MTB will develop the disease within the first 1 to 2 years after infection, and another 5% will develop the disease at some point later in life. Therefore, without treatment, approximately 10% of individuals with normal immune systems who are infected with MTB will develop TB disease at some point in their lives.

Tuberculous disease can occur at pulmonary (more than 60%) and extrapulmonary sites. Patients with pulmonary TB typically present with cough and an abnormal chest x-ray and may be infectious. Although most cases of TB are pulmonary, TB can occur at almost any anatomic site or as disseminated disease. Extrapulmonary TB disease occurs at sites other than the lungs, including the larynx, lymph nodes, pleura, brain, kidneys, or bones and joints.

Individuals with extrapulmonary TB disease are usually not infectious unless they also have pulmonary disease. Individuals with extrapulmonary TB disease are also usually not infectious unless the extrapulmonary disease is located in the oral cavity or larynx, or the extrapulmonary disease includes an abscess or open lesion in which the concentration of organisms is high, especially if drainage from the abscess or lesion is extensive or if the drainage fluid is aerosolized. Individuals with TB pleural effusions may have underlying pulmonary TB that is masked on chest radiographs because the effusion fluid compresses the lung.

Miliary TB occurs when Koch bacilli enter the bloodstream and spread to all parts of the body, where they grow and cause disease at multiple sites. This condition is rare but serious. It is most common in infants and children younger than 5 years, and in severely immunosuppressed people. Miliary TB may be found in a single organ, including the brain, in multiple organs, or throughout the body. The condition is characterized by large numbers of TB bacilli, which can easily go unnoticed, and is fatal if left untreated. Up to 25% of patients with miliary TB may have a meningeal infection.

When TB occurs in the tissue surrounding the brain or spinal cord, it is called tuberculous meningitis. Tuberculous meningitis is often seen at the base of the brain on imaging studies. Symptoms include headache, decreased level of consciousness, and neck stiffness. The duration of illness before diagnosis is variable and is related in part to the presence or absence of other sites of involvement. In many cases, patients with meningitis have chest x-ray abnormalities consistent with previous or current TB, and they often have miliary TB.

Demographics of individuals at highest risk for progression from LTBI to TB include: individuals infected with human immunodeficiency virus (HIV); children; individuals recently infected with MTB (< 2 years); history of untreated or inadequately treated TB disease, including fibrotic changes on chest x-ray consistent with prior TB disease; individuals on immunosuppressive therapy (e.g., tumor necrosis factor-alpha antagonists, systemic corticosteroids [> 15 mg prednisone daily]; individuals on immunosuppressive therapy following organ transplant; silicosis; diabetes mellitus; chronic renal failure; leukemia; head, neck, or lung cancer; gastrectomy or jejunoileal bypass; low body mass index (BMI); smokers; drug and/or alcohol abusers; medically underserved and low-income populations.

Drug-resistant TB is caused by TB organisms that are resistant to drugs normally used to treat the disease. Drug-resistant TB is transmitted in the same way as drug-susceptible TB and is no more infectious than drug-susceptible TB. However, delayed recognition of drug resistance or prolonged periods of infectiousness may facilitate increased transmission and further development of drug resistance.

Multidrug-resistant TB (MDR-TB) is caused by organisms that are resistant to the most effective anti-TB drugs, namely isoniazid and rifampin. These drugs are considered first-line agents.

Extensively drug-resistant TB (XDR-TB) is a relatively rare type of drug-resistant TB. XDR-TB is resistant to isoniazid and rifampin, as well as any fluoroquinolone and at least one of the three injectable second-line drugs, namely amikacin, kanamycin, or capreomycin. Because XDR-TB is resistant to both first- and second-line drugs, patients are left with treatment options that are more toxic, more expensive, and much less effective.

The main goals of TB disease treatment are to cure the individual patient, to minimise the risk of death and disability, and to reduce the transmission of TB to others. To ensure these goals are achieved, TB disease must be treated for at least 6 months, and in some cases even longer. Most bacteria are killed during the first 8 weeks of treatment. However, there are persistent organisms that require longer treatment. If treatment is not continued long enough, surviving bacteria can cause the patient to become ill and infected again, potentially with drug-resistant strains of TB. There are a number of daily and intermittent therapy options, but the goal of TB disease treatment should be to provide the safest and most effective therapy in the shortest possible time. With appropriate treatment, almost all patients will recover and be cured. Regimens for TB disease treatment should contain multiple drugs to which the bacteria are susceptible. The usual regimen for starting TB disease treatment is four-drug therapy. Treatment with a single drug may lead to the development of a bacterial population resistant to that drug. Similarly, the addition of a single drug to a failing anti-TB regimen may result in additional resistance. When two or more drugs that have been shown to be susceptible in vitro are given together, each helps prevent the emergence of Koch bacilli resistant to the other drugs.

There are several TB drugs approved for the treatment of TB disease in the United States and Europe. These drugs are classified as first-line drugs, e.g. isoniazid, rifampin, pyrazinamide, ethambutol, rifabutin, rifapentine; or second-line drugs, e.g. streptomycin, cycloserine, capreomycin, 4-aminosalicylic acid, levofloxacin, moxifloxacin, gatifloxacin, amikacin, kanamycin, ethionamide. Isoniazid, rifampin, pyrazinamide, and ethambutol form the core of the initial TB treatment regimen. Two new drugs have recently been approved for the treatment of MDR-TB: bedaquiline and delamanid.

Rifabutin, approved to prevent Mycobacterium avium complex disease in patients with HIV infection but not approved for TB disease, is useful for treating TB disease in patients who are simultaneously taking drugs that interact with rifampin (e.g., certain antiretroviral drugs).

Amikacin and kanamycin are nearly identical aminoglycoside drugs used in the treatment of patients with TB disease caused by drug-resistant organisms. Rifabutin and rifapentine may also be considered first-line drugs in certain circumstances. Streptomycin was once considered a first-line drug and is still used in some cases in the initial treatment regimen. However, the increasing prevalence of streptomycin resistance in many parts of the world has diminished its general usefulness. The other drugs are reserved for special situations, such as drug intolerance or resistance.

There are four basic treatment regimens recommended for treating individuals with TB disease caused by Koch bacilli who are known or suspected to be susceptible to isoniazid, rifampin, pyrazinamide, and ethambutol. Each treatment regimen consists of a 2-month initial treatment phase followed by either a 4- or 7-month continuation phase. The 4-month continuation phase is used for the majority of patients. Although these regimens are broadly applicable, there are modifications that should be made in specific circumstances.

The initial phase of treatment is crucial to prevent the emergence of drug resistance and to determine the outcome of the regimen. Four drugs, isoniazid, rifampin, pyrazinamide, and ethambutol, should be included in the initial treatment regimen until the results of drug susceptibility testing are available. Each of the drugs in the initial regimen plays an important role. Isoniazid and rifampin allow for short-course regimens with high cure rates. Pyrazinamide has potent sterilizing activity that allows further shortening of the regimen from 9 to 6 months. Ethambutol helps prevent the emergence of rifampin resistance when primary resistance to isoniazid exists. If drug susceptibility testing results are known and the organisms are fully susceptible, then ethambutol need not be included. For children, ethambutol is not generally recommended except when the risk of drug resistance is high or for children with “adult-type” TB disease (upper lobe infiltration, cavity formation).

The continuation phase of treatment is administered for either 4 or 7 months. The 4-month continuation phase should be used in patients with uncomplicated, noncavitary, drug-susceptible TB if sputum conversion is documented within the first 2 months. The 7-month continuation phase is recommended for patients with cavitary or extensive pulmonary TB disease caused by drug-susceptible organisms who have a positive sputum culture at the time of completing 2 months of treatment; and patients whose initial phase of treatment did not include pyrazinamide or patients who are being treated with isoniazid and rifabutin once weekly and whose sputum culture at the time of completing the initial phase (i.e., after 2 months) is positive.

In individuals infected with human immunodeficiency virus (HIV), extrapulmonary TB disease is often accompanied by pulmonary TB. The approach to treating patients co-infected with HIV and TB is complex, and the clinical and public health consequences associated with treatment failure and other adverse outcomes are serious. HIV-infected patients commonly take multiple medications, some of which interact with anti-TB drugs.

The above treatment regimens are effective for people living with HIV, with two exceptions due to the increased risk of developing acquired drug resistance: once-weekly administration of isoniazid and rifabutin in the continuation phase should not be used in any HIV-infected patient; and patients with CD4+ lymphocyte counts <100 should be treated with daily or three-times-weekly therapy in both the initial and continuation phases. Every effort should be made to use a rifamycin-based regimen throughout the course of therapy in co-infected patients. The key role of rifamycins in successful TB treatment requires that drug-drug interactions between rifamycins and antiretroviral drugs be appropriately managed, rather than using TB treatment regimens that do not include a rifamycin or stopping antiretroviral treatment until anti-TB therapy is completed.

Of particular concern is the interaction of rifamycins with antiretroviral agents and other anti-infective drugs. Rifampin can be used for the treatment of TB with certain combinations of antiretroviral agents. Rifabutin, which has fewer drug interactions due to its lower induction of the cytochrome P450 system, can also be used instead of rifampin and appears to be equally effective. Therefore, patients with HIV-related TB disease should be treated with a regimen that includes a rifamycin for the entire course of TB disease treatment, unless the isolate is resistant to rifamycins or the patient has a serious side effect that is clearly due to rifamycins.

The minimum duration of treatment for HIV-infected adults should be considered to be six months, including for patients with culture-negative TB disease. If there is evidence of a slow or suboptimal response (e.g., cultures remain positive after 2 months of therapy), the continuation phase should be extended to 7 months (a total of 9 months of treatment).

Drug-resistant TB disease can develop by two different mechanisms, primary and secondary drug resistance. Primary resistance occurs in people who are initially exposed to and infected with resistant organisms. Secondary resistance, or acquired resistance, develops during TB therapy, either because the patient was treated with an inappropriate regimen or because the prescribed regimen was not taken properly, or for other reasons such as drug malabsorption or drug interactions leading to low serum levels.

Drug resistance is suspected in a patient with newly diagnosed TB disease based on previous treatment, contact with a known case of drug resistance, or time spent in a region where drug resistance is common. Drug resistance can only be demonstrated by drug susceptibility testing. Patients with strains of M. tuberculosis that are resistant to both isoniazid and rifampin (multidrug-resistant) are at high risk of treatment failure, relapse, newly acquired resistance, or death.

Current first-line TB therapy for drug-susceptible TB infection is highly effective in clearing the bacilli, provided there is full patient compliance. Importantly, despite an effective treatment regimen, TB still caused an estimated 10.4 million infections and 1.7 million deaths in 2017. TB is one of the top 10 causes of death worldwide. Approximately one-quarter of the world's population has latent TB. People infected with TB bacteria have a 5-15% lifetime risk of developing TB disease. However, patients with compromised immune systems, such as individuals living with HIV, malnutrition or diabetes, or smokers, are at much higher risk of becoming ill (WHO, WHO Global Tuberculosis Report 2017, 2017).

Current first-line treatment consists of a 2-month “intensive” period of a four-drug regimen containing rifampin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) followed by a longer “continuation” phase of RIF and INH to eradicate any remaining bacilli that have entered a dormant, slowly replicating phase (Hoagland DTet al., Adv Drug Deliv Rev. 1 July 2016, 102, 55-72).

The greatest concern of this epidemic is the emergence of resistant bacteria, multidrug-resistant TB (MDR-TB) remains a public health crisis and a threat to health security. WHO estimates that there were 600,000 new cases with resistance to rifampicin, the most effective first-line drug, of which 490,000 had MDR-TB (Hoagland DTet al., Adv Drug Deliv Rev.1 July 2016, 102, 55-72).

Quinolines are known in the art and have been used for tuberculosis. For example, EP1527050B1 teaches the use of diarylquinoline in the treatment of mycobacterial diseases, in particular it discloses the first-in-class ATP synthase inhibitor, bedaquiline.

US2016113919A1 describes the use of the stereoisomer of chloroquine for the treatment of tuberculosis-related diseases. Chloroquine belongs to the 4-aminoquinoline class. 2-aminoquinoline compounds are known in the art and have been used before in the pharmaceutical industry, albeit for different purposes.

US7868022B2 describes 2-aminoquinoline compounds useful as beta-secretase (BACE) inhibitors for the treatment of Alzheimer's disease (AD) and related diseases.

WO2012025237A9 describes 2-aminoquinoline compounds as KCNQ2/3 modulators for pain prophylaxis.

US7989628B2 discloses 2-aminoquinoline derivatives as 5-HT5A receptor antagonists useful in the treatment of a number of CNS and N<s>P<p>disorders.

WO2009001060A3 and Tantry, S. J. et al. (Med. Chem. Commun. 2016, 7, 1022-1032) disclose 2,4-diaminoquinolines as antituberculosis agents. In particular, both describe examples of 4-amino-2-piperidine-quinoline, in which the aryl rings of piperidine and quinoline are unsubstituted.

WO2017001661A1 relates to compounds for the treatment of tuberculosis, wherein the compounds have a 2-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)quinoline.

There is an urgent need for new and innovative treatment strategies to fight tuberculosis. Considerable progress has been made in TB drug discovery in recent years. Several drug candidates are in various stages of clinical development; drugs such as diarylquinolone (TMC207 or bedaquiline) received accelerated approval from the FDA for the treatment of MDR-TB; and delamanid was approved by the European Medicines Agency (EMA) of the European Union. Both drugs have been conditionally approved due to their adverse effects. The US Food and Drug Administration (FDA) has approved bedaquiline for MDR-TB and delamanid as a compassionate care option for XDR-TB and TDR-TB infections, and the EMA approved both agents for MDR-TB. These are the two new drug therapies approved after 40 years. The lack of viable alternatives in late-stage clinical development is indicative of the state of drug discovery in this field, and innovation is desperately needed to drive new projects.

These facts are disclosed in order to illustrate the technical problem addressed by this disclosure.

Overview

The present disclosure relates to the use of 6-aryl or heteroaryl substituted 1-(quinolin-2-yl)piperidine-4-carboxylic acid compounds which can surprisingly be used to treat and/or prevent tuberculosis. None of the prior art documents disclose the use of such compounds for the treatment of tuberculosis. In fact, the prior art documents disclosing 6-aryl or heteroaryl substituted 1-(quinolin-2-yl)piperidine-4-carboxylic acid core compounds all relate to different uses, and do not teach or suggest that these compounds can be used in the treatment of tuberculosis. The scope of the present invention is defined in the appended claims.

In one embodiment, the compounds disclosed in the present disclosure are used in the treatment of diseases caused by Mycobacterium tuberculosis (MTB), such as pulmonary, extrapulmonary or disseminated tuberculosis (TB).

One aspect of the present disclosure relates to a compound of general formula I or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide, stereoisomer, diastereomer, enantiomer, atropisomer, or polymorph thereof:

Formula I

in which

R<1>, R<2>, X, Y, Z, W are selected independently of each other;

R<1> is selected from H or C<1>-C<6> alkyl;

R<2> is selected from H or C<1>-C<6> alkyl;

X is selected from N, O, S, or CR<3>, and R<3> is selected from H, halogen, C<1>-C<6>alkoxy, or C<1>-C<6>haloalkyl; Y is selected from N or CR<4>, and R<4> is selected from H, C<1>-C<6>haloalkoxy, OH, C<1>-C<6>alkoxy, C<1>-Ca haloalkyl, halogen, or C<1>-C<6>alkyl;

Z is selected from N or CR<5>, and R<5> is selected from H, halogen, C<1>-Ca alkoxy, C<1>-Ca haloalkyl, C<1>-Ca haloalkoxy, OH, NO<2>, or C<1>-Ca alkyl;

W is selected from N or CRa, and Ra is selected from H, C<1>-Ca alkoxy, C<1>-Ca haloalkyl, halogen, or C<1>-Ca haloalkoxy;

m and n are independently selected from 0 or 1;

halogen is F or Cl;

provided that the group connected to the quinoline moiety at Ca is a substituted aryl ring, one of substituted or unsubstituted heteroaryl or fused heteroaroaryl selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, furan-2-yl, benzothiophenyl, indolyl or phenyl,

and the piperidine ring that is connected to the quinoline moiety at C<2> has its C<3> or C<4> substituted with a carboxylate group.

to

In the context of this disclosure, the numbering of quinoline is carried out according to IUPAC standards (formula V).

Formula V

In one embodiment, the compound is represented by the compound of formula I, wherein:

Formula I

R<1>is selected from H, CH<2>CH<3>or CH<3>;

R<2>is selected from H or CH<3>;

X is selected from N, O, S or CR<3>, and R<3> is selected from H, Cl, F, CF<3>or OCH<3>;

Y is selected from N or CR<4>, and R<4>is selected from H, F, Cl, CH<3>, OH, CF<3>, OCF<3>, OCH(CH<3>)< 2>u OCH<3>; Z is selected from N or CR<5>, and R<5>is H, OH, F, OCF<3>, OCH<3>, NO<2>, CF<3>or CH<3>;

W is selected from N or CR6, and R6 is H, F, Cl, CF<3>, OCH<3>or OCF<3>;

m and n are independently selected from 0 or 1;

provided that the group connected to the quinoline moiety at C6 is a substituted aryl, a substituted or unsubstituted heteroaryl or fused heteroaroaryl ring selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, furan-2-yl, benzothiophenyl, indolyl or phenyl.

In one embodiment, the compound is represented by the compound of formula II, wherein:

R<1>is selected from H or CH<2>CH<3>;

R<3>is selected from H, Cl, F, CF<3>or OCH<3>;

R<4>is selected from H, OH, Cl, F, OCF<3>, CH<3>, CF<3>, OCH(CH<3>)<2>or OCH<3>;

R<5>is selected from H, OH, F, OCF<3>, CF<3>, CH<3>, OCH<3>or NO<2>;

R6 is selected from H, Cl, F, CF<3>u OCF<3>u OCH<3>;

provided that the group connected to the quinoline moiety at C6 is a substituted aryl ring, a substituted or unsubstituted heteroaryl or fused heteroaroaryl ring selected from indolyl or phenyl.

In one embodiment, for the compound of formula II, R<3>is H, Cl, F or CF<3>.

In one embodiment, for the compound of formula II, R<4>is H, Cl, F, OCF<3>, OCH(CH<3>)<2>or OCH<3>.

In one embodiment, for the compound of formula II, R<5>is H, Cl, F, OH, OCF<3>or CF<3>.

In one embodiment, for the compound of formula II, R6 is H, Cl, CF<3>or OCH<3>.

In one embodiment, the compound is represented by the compound of formula III, wherein:

Formula III

R<1>is selected from H, CH<2>CH<3>or CH<3>;

R<2> is selected from H and CH<3>;

X is selected from N or CR<3>, and R<3>is H;

And is selected from N or CR<4>, and R<4> is selected from H, CH<3>, F, <3>, or OCH<3>;

Z is selected from N or CR<5>, and R<5> is selected from H or CH<3>;

W is selected from N or CR6, and R6 is selected from H or F;

m is selected from 0 or 1;

provided that the group connected to the quinoline moiety at C6 is a substituted aryl ring, a substituted or unsubstituted heteroaryl or fused heteroaroaryl ring selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl or pyrimidin-5-yl.

In one embodiment, for the compound of formula I when X and Z are both N, R<5>is OCH<3>.

In one embodiment, for the compound of formula I Y, Z or W is N.

In one embodiment, for the compound of formula I Y is N.

In one embodiment, for the compound of formula I when Z is N, R<4>is OCH<3>,

In one embodiment, for the compound of formula I when Z is N, R<4>is CH<3>.

In one embodiment, for the compound of formula I W is N.

In one embodiment, the compound is represented by the compound of formula IV, wherein:

Formula IV

X is O or S;

Ri is selected from H or CH<2>CH<3>;

provided that the group connected to the quinoline moiety at C6 is a substituted or unsubstituted aryl, heteroaryl or fused heteroaroaryl ring selected from furan-2-yl or benzothiophenyl.

In one embodiment, for compounds of formula II, III and IV, R<1>is H or CH<2>CH<3>.

In one embodiment, for compounds of formula I, II, III and IV, the salt is a hydrochloride.

In one embodiment, the compound is selected from:

ethyl 1-(6-(4-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(4-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(4-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(2-methoxypyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(2-methoxypyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(4-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(3-fluoro-4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(3-fluoro-4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(6-methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(6-methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate hydrochloride;

ethyl 1-(6-(furan-2-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(furan-2-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride;

ethyl 1-(6-(2-chloro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(3-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(2-doro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(4-methoxy-2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate hydrochloride; ethyl 1-(6-(3-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(3-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(4-methoxy-2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(3-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(3-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(4-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-nitrophenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(4-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(6-fluoropyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(4-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(2-fluoropyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(6-fluoropyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride;

1-(6-(3-nitrophenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(2-methylpyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3,5-dimethoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(1H-indol-5-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(6-(trifluoromethyl)pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(pyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(1H-indol-5-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride;

1-(6-(3,5-dimethoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(4-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(pyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(6-methylpyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(2-fluoropyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride; 1-(6-(6-(trifluoromethyl)pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride; 1-(6-(2-methylpyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-3-carboxylate;

ethyl 1-(6-(pyridin-2-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(4-methyl-6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(4-methyl-6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-fluoro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-chloro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3,4-dimethoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(pyridin-2-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-3-carboxylic acid hydrochloride;

ethyl 1-(6-(4-chloro-3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-chlorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(4-chlorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(pyridin-4-yl)quinolin-2-yl)pyrrolidine-3-carboxylate;

ethyl 1-(6-(benzo[b]thiophen-2-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(2-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(4-fluoro-2-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(4-methoxy-3-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(4-chloro-3-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-chloro-4-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(2-methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(5-fluoropyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-fluoropyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride; or 1-(6-(6-methylpyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride. In one embodiment, the compound is selected from:

1-(6-(4-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(2-methoxypyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(3-fluoro-4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid; 1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(6-methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(2-chloro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate ethyl; 1-(6-(4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(4-methoxy-2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate hydrochloride;

ethyl 1-(6-(3-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(3-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(6-methylpyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(pyridin-2-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-fluoro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(4-chloro-3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate; either

Ethyl 1-(6-(4-fluoro-2-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate.

Another aspect of the present disclosure relates to a pharmaceutical composition comprising the compounds of the present disclosure and a pharmaceutically acceptable excipient. Preferably, a therapeutically effective amount of the compounds described in the present disclosures or a pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable excipient.

Another aspect of the present disclosure relates to a compound of general formula XII or to a pharmaceutically acceptable salt, hydrate, solvate, N-oxide, stereoisomer, diastereomer, enantiomer or atropisomer, polymorph or ester thereof:

Formula XII

in which

R<1> is selected from H or C<1>-C<6> alkyl;

R<2> is selected from H or C<1>-C<6> alkyl;

X se selecciona de N, O, S o CR<3>, y R<3>se selecciona de H, alcoxilo C<1>-C<6>o haloalquilo C<1>-C<6>;

And is selected from N or CR<4>, and R<4> is selected from H, C<1>-C<6> haloalkoxy, OH, C<1>-C<6> alkoxy, C<1>-Ca haloalkyl, halogen or C<1>-C<6> alkyl;

Z is selected from N or CR<5>, and R<5> is selected from H, halogen, C<1>-Ca alkoxy, C<1>-Ca haloalkoxy, OH, NO<2>, or C<1>-Ca alkyl;

W is selected from N or CRa, and Ra is selected from H, C<1>-Ca haloalkyl, halogen, or C<1>-Ca haloalkoxy; m and n are independently selected from 0 or 1;

in which the halogen is F or Cl;

provided that when n is 0, X is either O or S to form a furyl or thiophene, respectively; Y and Z together with the thiophene to which they are attached can form a benzothiophene; or

Y and Z together with the benzene ring to which they are attached can form an indole ring.

In one embodiment for best results, the compound is represented by the compound of formula XII, wherein:

R<1>is selected from H, CH<2>CH<3>or CH<3>;

R<2>is selected from H or CH<3>;

X is selected from N, O, S or CR<3>, and R<3> is selected from H or OCH<3>;

And is selected from N or CR<4>, and R<4> is selected from H, OH, OCF<3>, OCH(CH<3>)<2>, or OCH<3>;

Z is selected from N or CR<5>, and R<5>is H, F, OCF<3>, OCH<3>, NO<2>, or CH<3>;

W is selected from N or CR6, and R6 is H, Cl or CF<3>;

m and n are independently selected from 0 or 1;

provided that when n is 0, X is O or S to form a furyl or thiophene, respectively; and Y and Z together with the thiophene to which they are attached can form a benzothiophene; or

Y and Z together with the benzene ring to which they are attached can form an indole ring.

In one embodiment for best results, the compound is represented by the compound of formula XIII

R<1>is selected from H or CH<2>CH<3>;

R<3>is selected from H or OCH<3>;

R<4>is selected from H, OH, Cl, F, OCF<3>, CF<3>, OCH(CH<3>)<2>or OCH<3>;

R<5>is selected from H, OH, Cl, F, OCF<3>, CF<3>, OCH<3>or NO<2>;

R6 is selected from H, Cl, CF<3>or OCF<3>;

R<4>and R<5>together with the carbon to which they are attached can form an indole ring.

In one embodiment for best results, the compound is represented by the compound of formula XIV

Formula XIV

Ri is selected from H, CH<2>CH<3>or CH<3>;

R<2>is selected from H or CH<3>;

X is selected from N or CR<3>, and R<3> is selected from H or OCH<3>;

Y is selected from N or CR<4>, and R<4>is selected from H, CH<3>, F, OCF<3>, CF<3>, OCH(CH<3>)<2>or OCH <3>;

Z is selected from N or CR<5>, and R<5> is selected from H or CH<3>;

W is selected from N or CR6, and R6 is selected from H or F;

m is selected from 0 or 1.

In one embodiment for best results, the compound is represented by the compound of formula XV

Formula XV

X is O or S;

R<1>is selected from H or CH<2>CH<3>;

R<4>and R<5>together with the carbon to which they are attached can form a benzene ring.

In one embodiment for best results, the compound of general formula XVI or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide, stereoisomer, diastereomer, enantiomer or atropisomer, polymorph or ester thereof:

Formula XVI

in which

R<1>, R<2>, X, Y, Z, W are selected independently of each other;

R<1> is selected from H or C<1>-C<6> alkyl;

R<2> is selected from H or C<1>-C<6> alkyl;

X se selecciona de N, O, S o CR<3>, y R<3>se selecciona de H, alcoxilo C<1>-C<6>o haloalquilo C<1>-C<6>;

And is selected from N or CR<4>, and R<4> is selected from H, C<1>-C<6> haloalkoxy, OH, C<1>-C<6> alkoxy, C<1>-Ca haloalkyl, halogen or C<1>-C<6> alkyl;

Z is selected from N or CR<5>, and R<5> is selected from H, halogen, C<1>-C<6> alkoxy, C<1>-C<6> haloalkoxy, OH, NO<2>, or C<1>-C<6> alkyl;

W is selected from N or CR6, and R6 is selected from H, C<1>-C<6> haloalkyl, halogen, or C<1>-C<6> haloalkoxy; m and n are independently selected from 0 or 1;

in which the halogen is F or Cl;

provided that the group connected to the quinoline moiety at C6 is a substituted or unsubstituted aromatic, heteroaromatic or fused heteroaromatic ring selected from pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, furan-2-yl, benzothiophenyl, indolyl or phenyl.

In one embodiment for best results, the compound is represented by the compound of formula XVI R<1> is selected from H, CH<2>CH<3> or CH<3>;

R<2>is selected from H or CH<3>;

X is selected from N, O, S or CR<3>, and R<3> is selected from H or OCH<3>;

And is selected from N or CR<4>, and R<4> is selected from H, OH, OCF<3>, OCH(CH<3>)<2>, or OCH<3>;

Z is selected from N or CR<5>, and R<5>is H, F, OCF<3>, OCH<3>, NO<2>, or CH<3>;

W is selected from N or CR6, and R6 is H, Cl or CF<3>;

m and n are independently selected from 0 or 1;

provided that the group connected to the quinoline moiety at C6 is a substituted or unsubstituted aromatic, heteroaromatic or fused heteroaromatic ring selected from pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, furan-2-yl, benzothiophenyl, indolyl or phenyl.

In one embodiment for best results, the compound is represented by the compound of formula XVII

R<1>is selected from H or CH<2>CH<3>;

R<3>is selected from H or OCH<3>;

R<4>is selected from H, OH, Cl, F, OCF<3>, CF<3>, OCH(CH<3>)<2>or OCH<3>;

R<5>is selected from H, OH, Cl, F, OCF<3>, CF<3>, OCH<3>or NO<2>;

R6 is selected from H, Cl, CF<3>or OCF<3>;

provided that the group connected to the quinoline moiety at C6 is a substituted or unsubstituted aromatic, heteroaromatic or fused heteroaromatic ring selected from indolyl or phenyl.

In one embodiment for best results, the compound is represented by the compound of formula XVIII

Formula XVIII

Ri is selected from H, CH<2>CH<3>or CH<3>;

R<2>is selected from H or CH<3>;

X is selected from N or CR<3>, and R<3> is selected from H or OCH<3>;

Y is selected from N or CR<4>, and R<4>is selected from H, CH<3>, F, OCF<3>, CF<3>, OCH(CH<3>)<2>or OCH <3>;

Z is selected from N or CR<5>, and R<5> is selected from H or CH<3>;

W is selected from N or CR6, and R6 is selected from H or F;

m is selected from 0 or 1;

provided that the group connected to the quinoline moiety at C6 is a substituted or unsubstituted aromatic, heteroaromatic or fused heteroaromatic ring selected from pyridin-3-yl, pyridin-4-yl or pyrimidin-5-yl.

In one embodiment for best results, the compound is represented by the compound of formula XIX

X is either O or S;

R<1>is selected from H or CH<2>CH<3>;

provided that the group connected to the quinoline moiety at C6 is a substituted or unsubstituted aromatic, heteroaromatic or fused heteroaromatic ring selected from furan-2-yl or benzothiophenyl.

In one embodiment, for the compound of formula XVII: Y is N.

In one embodiment, for the compound of formula XVII: R<2>, R<3>, R6 are H; and R<1> is H or CH<2>CH<3>.

In one embodiment, for the compound of formula XVII: X is N and Z is CH.

In one embodiment, for the compound of formula XVII: R<4>is CH<3>or OCH<3>.

In one embodiment, for the compound of formula XVIII: R<4>is OCH<3>or OCF<3>.

In one embodiment, for the compound of formula XVIII: R<5>is OH, F or OCF<3>, preferably R<5>is OCF<3>.

In one embodiment, for the compound of formula XVIII: R6 is Cl or CF<3>, preferably R6 is CF<3>.

In one embodiment, for compounds of formula XVI or formula XVII or formula XVIII or formula XIX: the salt is hydrochloride.

In one embodiment, the compound is:

ethyl 1-(6-(4-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(4-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(4-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(2-methoxypyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(2-methoxypyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(4-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(3-fluoro-4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(3-fluoro-4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(6-methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(6-methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate hydrochloride;

ethyl 1-(6-(furan-2-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(furan-2-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride;

ethyl 1-(6-(2-chloro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(3-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(2-chloro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(4-methoxy-2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate hydrochloride; ethyl 1-(6-(3-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(3-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(4-methoxy-2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(3-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(3-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(4-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-nitrophenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(4-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(6-fluoropyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(4-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(2-fluoropyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(6-fluoropyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride; 1-(6-(3-nitrophenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(2-methylpyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3,5-dimethoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(1H-indol-5-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(6-(trifluoromethyl)pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(pyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(1H-indol-5-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride;

1-(6-(3,5-dimethoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(4-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(pyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(6-methylpyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(2-fluoropyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride; 1-(6-(6-(trifluoromethyl)pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride; 1-(6-(2-methylpyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-3-carboxylate;

ethyl 1-(6-(pyridin-2-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(4-methyl-6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(4-methyl-6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-fluoro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-chloro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3,4-dimethoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(pyridin-2-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-3-carboxylic acid hydrochloride;

ethyl 1-(6-(4-chloro-3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-chlorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(4-chlorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(pyridin-4-yl)quinolin-2-yl)pyrrolidine-3-carboxylate;

ethyl 1-(6-(benzo[b]thiophen-2-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(2-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(4-fluoro-2-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(4-methoxy-3-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(4-chloro-3-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-chloro-4-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(2-methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(5-fluoropyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-fluoropyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate;

methyl 1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(6-methylpyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride.

Another aspect of the present disclosure relates to the use of the compounds of the present disclosure in medicine or veterinary medicine. Preferably, the compound is used in the treatment or prevention of tuberculosis.

In one embodiment, the compound disclosed herein is used in combination with at least one anti-HIV agent. Preferably, the anti-HIV agent is selected from the following: HIV protease inhibitor (PI), HIV nucleoside reverse transcriptase inhibitor (NRTI), HIV non-nucleoside reverse transcriptase inhibitor (NNRTI), HIV integrase inhibitor

In one embodiment, the compound is combined with the other TB drug. Preferably, the TB drug is selected from the following: isoniazid, rifamycin and derivatives, pyrazinamide, ethambutol, cycloserine, ethionamide, streptomycin, amikacin, kanamycin, rifampin (rifampicin), aminoglycosides, capreomycin, p-aminosalicylic acid, fluoroquinolones such as levofloxacin, moxafloxacin or gatifloxacin, or mixtures thereof, and all other first and second line medications.

In one embodiment, the anti-HIV agent or TB drug combination is administered simultaneously, separately, or sequentially.

The present disclosure also relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

In one embodiment, said pharmaceutical composition may comprise (i) a therapeutically effective amount of a described compound or a pharmaceutically acceptable salt or solvate thereof; and (ii) a pharmaceutically acceptable excipient.

In one embodiment, the compounds of the disclosure have surprisingly been found to inhibit the growth of Mycobacterium tuberculosis. In particular, the compounds exhibit growth inhibition in vitro at a concentration of not more than 15.6 pM, in particular not more than 7.8 pM. The compounds have also been found to be non-cytotoxic to the HepG2 cell line, metabolically stable in human microsomes, stable in plasma and relatively permeable in the parallel artificial membrane of the gastrointestinal tract.

In the present disclosure, 'C<1>-C<6> alkyl' refers to a linear or branched saturated hydrocarbon group containing from one to six carbon atoms. Examples of 'C<1>-C<6> alkyl' include methyl, ethyl, isopropyl, n-propyl, tert-butyl, sec-butyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl. Preferably, the hydrocarbon is linear.

In the present disclosure, 'halogen' as used herein refers to a fluoro (F), chloro (Cl), bromo (Br), or iodo (I), unless otherwise specified.

In the present disclosure, 'C<1>-C<6>haloalkyl' as used herein refers to a C<1>-C<6>alkyl group as defined above substituted with one or more halogen atoms.

In the present disclosure, 'aryl' as used herein refers to a C<6>-C<12> monocyclic or bicyclic hydrocarbon ring in which at least one ring is aromatic. Examples of an 'aryl' group include phenyl, naphthalenyl, tetrahydronaphthalenyl and indane.

In the present disclosure, 'C<1>-C<6>alkoxy' as used herein refers to a group -O(C<1>-C<6>alkyl) wherein C<1>-C<6>alkyl is as defined above. Examples of such groups include methoxy, ethoxy, isopropoxy, butoxy, pentoxy and hexyloxy.

In the present disclosure, 'C<1>-C<6>haloalkoxy' as used herein refers to a group -O(C<1>-C<6>alkyl) as defined above substituted with one or more halogen atoms.

In the present disclosure, 'heteroaryl' as used herein refers to a 5-6 membered monocyclic aromatic ring or a fused 8-10 membered bicyclic aromatic ring, which may be partially saturated, monocyclic or bicyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur. Examples of monocyclic aromatic ring include furyl, furazanyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyranyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, thienyl, thiazolyl, triazolyl, tetrazolyl, triazinyl, tetrazinyl, and the like. Examples of such bicyclic aromatic rings include azaindolyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzofuranyl, cinnolinyl, furopyridyl, imidazopyridyl, indolyl, isoindolyl, isobenzofuranyl, indolizinyl, indazolyl, isoquinolinyl, naphthyridinyl, quinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl.

In the present disclosure, 'bicyclic ring' and 'fused' in the context of a bicyclic ring refers to two rings that are joined together through a bond between two atoms (e.g., naphthalene), through a sequence of atoms to form a bridge (e.g., quinuclidine, adamantyl), or together at a single atom to form a spiro compound (e.g., 1,4-dioxa-8-aza-spiro[4.5]decane).

In the present disclosure, 'substituted aryl' or 'substituted heteroaryl' used herein with reference to a group R means that a particular group R (e.g., Ra, Rb, Rc) may be substituted with one or more groups selected from Rx, halogen, OH, ORx, SH, SRx, OCORx, SCORx, COOH, NH<2>, NO<2>, CN, NHRx, NRxRy, CORx, CSRx, COORx, OPhRxRy, CONH<2>, CONHRx, CONxNy, CONHOH, CONHNH<2>, CONHORx, CH<2>CH<2>NRxRx, CH<2>CH<2>NRxRy, NHCONH<2>, NRxCORy, NHCORx, CONHPhRx, CONRxRx, CONHNH<2>, COHRx, NHCORx, NHSO<2>Rx, where Rx and Ry are independently selected from C<1>-C<6> alkyl, C<1>-C<6> alkoxy, C<1>-C<6> haloalkyl, C<1>.C<6> haloalkoxy, aryl, heteroaryl, C<3>-C<10> cycloalkyl, C<1>-C<6> alkyl-aryl and heterocyclyl, or Rx and Ry, together with the heteroatom to which they are attached, can form a heterocyclyl.

In the present disclosure, 'unsubstituted heteroaryl' as used herein refers to pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, furan-2-yl or indolyl.

In the present disclosure, 'pharmaceutically acceptable' such as pharmaceutically acceptable carrier, excipient, etc. means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.

In the present disclosure, 'pharmaceutically acceptable salts' of the compounds of the present disclosure include salts with organic bases, salts with inorganic bases, salts with organic acids and salts with basic or acidic amino acids, as well as quaternary ammonium salts. In some cases, in particular, salts with acids may be employed. Examples of such salts include hydrochloric salt and trifluoroacetate salt.

In one embodiment, the compounds of the present disclosure are crystallized or recrystallized from solvents such as organic solvents. In such cases, a solvate (e.g., hydrate) may be formed. When in solvated form, the additional solvent is alcohols such as isopropanol (Isop) or ethanol (EtOH).

In the present disclosure, the prodrug form of the pharmacologically active compounds disclosed herein are degraded in vivo to yield the compounds according to the present disclosure. Prodrugs are usually (but not always) of lower potency at the target receptor than the compounds to which they are degraded. Prodrugs are particularly useful when the desired compound has chemical or physical properties that make its administration difficult or inefficient. For example, the desired compound may be only poorly soluble, is poorly transported across mucosal epithelium, or may have an undesirably short plasma half-life. Further discussion of prodrugs can be found in Redasani, V.K.et al.'Prodrug Design', Elsevier, UK,2015.

In the present disclosure, prodrug forms of a pharmacologically active compound are compounds according to formula I, II, III and IV, the pharmaceutically acceptable acid or base addition salts, the stereochemically isomeric form, the tautomeric forms thereof and the N-oxide forms thereof, which have an acid group which is esterified or aminated; or an amino group which forms a carbamate or an amide. Included in the esterified acid groups are 'pharmaceutically acceptable esters'.

In the present disclosure, amidated groups include groups of the formula -CONRdRe, where Rd is H, C1-C6 alkyl and Re is OH, H, C<1>-C<6> alkyl.

In the present disclosure, the carbamate includes groups of formula -NRfCOORg, where Rf is H or C<1>-C<6>alkyl and Rg is C<1>-C<6>alkyl or C<1>-C<6>alkyl substituted with -OCO(C<1>-C<6>alkyl).

In the present disclosure, amine includes groups of formula -NRfRh, where Rf is as previously described and Rh is H or C<1>-C<6> alkyl.

In the present disclosure, 'pharmaceutically acceptable esters' of the compounds are compounds in which one or more carboxyl groups (e.g. -COOH) are modified by reaction with an alcohol substituent A-OH to give -COOA groups, where A is C<1>-C<6> alkyl.

In the present disclosure, the N-oxide forms of the compounds according to formula I, II, III and IV are intended to comprise those compounds in which one or more nitrogen atoms are oxidized to give the so-called N-oxide, particularly those N-oxides in which the nitrogen of the amine radical is oxidized.

The skilled artisan will appreciate that the compounds of the present disclosure include those that are chemically stable. That is, the compounds of the invention include those that are sufficiently robust to withstand isolation from the reaction mixture to a useful degree of purity.

General methods for the preparation of salts and esters are well known to the person skilled in the art. The pharmaceutical acceptability of the salts and esters will depend on a variety of factors, including details of formulation processing and specific in vivo criteria, and such details will be evaluated by the person skilled in the art in the light of the present disclosure.

If a chiral center or other form of isomeric center, such as geometrical isomers, is present in a compound of the present disclosure, all isomeric forms, including enantiomers and diastereomers, are intended to be encompassed herein. Compounds of the present disclosure containing a chiral center are used as a mixture of isomers in all proportions (e.g., racemic mixture), enantiomerically enriched mixture, or in pure form. Individual isomers, or enantiomers, are obtained by methods known in the art, such as optical resolution of products or intermediates (e.g., chiral chromatography (e.g., chiral HPLC) or supercritical fluid chromatography (SFC)). Where compounds of the disclosure can exist as alternative tautomeric forms (e.g., keto/enol, imine/enamine), the disclosure relates to the individual tautomers in isolation, and to a mixture of the tautomers in all proportions.

Other aspects of the present disclosure are the provision of compounds according to the present disclosure, or a pharmaceutical composition comprising such a compound, for use in the treatment and/or prevention of tuberculosis.

In one embodiment, the compounds of general formula I, II, III and IV are used in combination with other TB drugs such as isoniazid, rifampin, pyrazinamide, ethambutol, fluoroquinolones, aminoglycosides and all other first and second line drugs.

In one embodiment, the present disclosure describes the use of one of the disclosed compounds in combination with at least one TB drug, or of a pharmaceutical composition comprising that compound in combination with at least one TB drug, for use in the treatment or prevention of tuberculosis.

In one embodiment, the TB drug is selected from the following: isoniazid, rifamycin and derivatives, pyrazinamide, ethambutol, cycloserine, ethionamide, streptomycin, amikacin, kanamycin, rifampin (rifampicin), capreomycin, p-aminosalicylic acid, aminoglycosides, fluoroquinolones such as levofloxacin, moxifloxacin or gatifloxacin, and all other first and second line medications.

In one embodiment, the compounds of general formula I, II, III and IV, whether or not in combination with another pharmacologically active compound, are administered orally, nasally, rectally, bronchially (inhalation), topically (eye drops, buccal and sublingual), vaginally, parenterally (subcutaneous, intramuscular, intravenous and intradermal) or by an implanted reservoir, and are prepared by any method known in the art or in pharmacy.

In one embodiment, the composition is prepared by bringing the active ingredient defined above into association with a carrier. In general, formulations are prepared by uniformly and intimately bringing the active ingredient into association with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

In one embodiment, the present disclosure describes the use of a compound of general formula I, II, III and IV as defined above in the preparation of an antimycobacterial agent, particularly as an agent for the treatment or prevention of tuberculosis.

In one embodiment, the compounds of formula I, II, III and IV, or a pharmaceutically acceptable derivative thereof, are prepared from the compound of general formula VI. In particular, the compounds according to formula I, II, III and IV can be prepared by reacting the compound of formula VI with the compound of formula VII according to scheme 1 using a Suzuki coupling reaction in the presence of a palladium catalyst, a suitable base and a suitable solvent.

In one embodiment, the compound of formula VII is a boronic acid in which R<7> is H; or the compound of formula VII is a boronic ester in which R<7> is C<1>-C<6> alkyl or the carbons in the two R<7> are taken together to form a saturated ring such as -O(C(R<8>)<2>)pO-, where p is 2 or 3 and R8 is H or C<1>-C<6> alkyl, thereby forming, for example, a pinacolate-boronate ester.

In one embodiment, the palladium catalyst is a palladium transition metal catalyst selected from the following: palladium diacetate, bis(triphenylphosphine)palladium(II) dichloride, tetrakis(triphenylphosphine)palladium(0), dichlorobis(tri-o-tolylphosphine)palladium(II), [1,2-bis(diphenylphosphino)ethane]dichloropalladium(II), 1,4-bis(diphenylphosphino)butane-palladium(II) chloride, (1,3-bis(diphenylphosphino)propane)palladium(II) chloride or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), more preferably the palladium catalyst is tetrakis(triphenylphosphine)palladium(0).

In one embodiment, the palladium catalyst described herein can be prepared in situ from ligands and metal salts. This includes reacting, under an inert atmosphere, a Pd(II) species and a phosphine ligand, such as palladium acetate and triphenylphosphine. Additional ligands that can be used with the methods described herein include ligands chosen from the following: 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,2-bis(diphenylphosphino)ethane (dppe), 1,4-bis(diphenylphosphino)butane (dppb), or 1,3-bis(diphenylphosphino)propane (dppp). These in situ catalysts can be prepared by an initial reaction of the ligand and metal salt, followed by addition to the reaction mixture, or by separately adding a ligand and metal salt directly to the reaction mixture.

In one embodiment, the suitable base is an inorganic base. Suitable inorganic bases include, but are not limited to, cesium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium phosphate, or sodium acetate. In a preferred embodiment, the base is selected from the group consisting of potassium carbonate, sodium carbonate, and cesium carbonate. More preferably, the base is cesium carbonate.

In one embodiment, suitable solvents include, but are not limited to, dimethylformamide (DMF), dimethylacetamide (DMA), 1,2-dimethoxyethane (DME), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), dioxane, benzene, toluene, methanol (MeOH), EtOH, 1-butanol (1-BuOH), Isop, dichloromethane (DCM), or water, and mixtures thereof. In a preferred embodiment, the solvent is dioxane, alone or in a mixture with water. More preferably, the solvent is a mixture of dioxane and water.

In one embodiment, the temperature is preferably from 50°C to 100°C, for example the temperature is 80°C.

In one embodiment, the catalyst loading is from 2 to 15 mol%, more preferably is 5 mol%.

In one embodiment, the compound of formula VI is prepared by reacting the compound of formula VIII with the compound of formula IX, according to Scheme 2:

wherein L<1> is a leaving group by reaction with a compound of general formula IX, preferably L<1> is a leaving group, preferably L<1> is a halogen selected from Br, Cl or F, more preferably L<1> is Cl or Br; and

R<1>, R<2>and m are as defined for the compound of general formula I.

In one embodiment, the compound of formula VIII and the compound of formula IX are reacted together at elevated temperature in the absence of solvent (neat). The reaction may be carried out in a protic solvent such as ethanol or in the presence of an aprotic solvent such as toluene.

In one embodiment, the compounds of formula I are prepared by preferably reacting the compound of formula VIII and the compound of formula IX in the presence of a solvent such as 1-BuOH and an alkaline agent such as N,N-diisopropylethylamine (DIPEA) to obtain the compound of formula VI.

In one embodiment, the temperature is preferably from 80°C to 160°C, for example the temperature is 130°C.

The compounds of general formula VIII are known and commercially available or are prepared by methods known to those skilled in the art.

In one embodiment, for example, a compound of general formula VIII, where L<1> is Cl, is prepared from a compound of general formula X

Formula X

by reacting with trichlorophosphate, phosphorus pentachloride, oxalyl chloride or thionyl chloride with heating in a polar aprotic solvent such as dimethylformamide (DMF) or acetonitrile (MeCN).

In one embodiment, compounds of general formula X are known and commercially available or are prepared by methods known to those skilled in the art. For example, a compound of general formula X is prepared from a compound of general formula XI.

Formula XI

by reacting with dihydrogen peroxide under acidic conditions or 3-chloroperbenzoic acid in halogenated solvents at room temperature to give the respective N-oxide; followed by reaction with acetic anhydride under heating conditions to provide the compound of formula X.

Detailed description

The present disclosure relates to the use of 1-(quinolin-2-yl)piperidine-4-carboxylic acid compounds substituted with a 6-aryl or heteroaryl for treating and/or preventing tuberculosis.

In one embodiment, compounds of general formula I are prepared.

Example 1

The compounds may generally be prepared by a succession of steps. The procedures used for the synthesis of the compounds of the present disclosure are illustrated by a general scheme. The starting materials and reagents used to prepare the compounds of the present disclosure are available from commercial suppliers or may be prepared by methods known to those skilled in the art. The general schemes are merely illustrative of methods by which the compounds of this invention are synthesized, modifications to these schemes are suggested by those skilled in the art having made reference to this disclosure.

In one embodiment, when the process is carried out at room temperature, the temperature is preferably from 20°C to 25°C, more preferably 20°C.

In one embodiment, the compounds are characterized by melting point, high performance liquid chromatography-mass spectrometry (HPLC-MS) and nuclear magnetic resonance (NMR). HPLC-MS was performed on the Waters Alliance 2690 HPLC instrument with detection by a Waters 2996 DAD (diode array detector) and a Waters QDA mass spectrometer operating in electrospray (ES) ionization mode.

In one embodiment, MS data acquisition was performed with appropriate software. Compounds are described according to their reported molecular ion corresponding to [M+H] or [M+2H] (protonated molecules) and/or [M-H] (deprotonated molecule). For molecules with multiple isotropic patterns (Br, Cl...), the reported value is the one obtained for the smallest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used.

In one embodiment, the HPLC column used was a Sunfire C18, 5 µm column (250 x 4.6 mm). The mobile phase was acetonitrile (A) and water with 0.1% formic acid (B) (75% A/25% B). The run time was 10 min, the flow rate was 1 mL/min, and the temperature was 35°C.

In one embodiment, the melting point was recorded on a Buchi PF-M560 apparatus at readings at 20°C/min.

In one embodiment, H-NMR spectra were recorded on a Bruker instrument operating at 400 or 500 MHz using the solvent as an internal standard. Peak multiplicity abbreviations are s (singlet), d (doublet), t (triplet), m (multiplet), a (broad), dd (doublet of doublets), ddd (doublet of doublets of doublets), dtd (doublet of triplets of doublets), ddt (doublet of doublet of triplets), dt (doublet of triplets), td (triplet of doublets), q (quartet), tt (triplet of triplets), and hept (heptet). Coupling constants are reported in hertz (Hz). C-NMR spectra were recorded at 101 or 126 MHz.

In one embodiment, column chromatography was performed using flash chromatography on silica gel 60 (Merck), particle size 0.063-0.2 mm, as the stationary phase.

In one embodiment, purification of the compounds was achieved by recrystallization by dissolving the crude compound in the minimum volume of a hot solvent of choice, usually a protic solvent, then covering the vessel and allowing it to cool to room temperature and then to 0°C gradually until crystal formation was observed.

In one embodiment, isolation of the pure compound was achieved in column chromatography by collecting column fractions containing the pure compound, evaporating the solvent on the rotary evaporator and drying the residue under high vacuum at 40°C.

In one embodiment, the method for synthesizing intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) is as follows:

DIPEA (5 mL) was added to a suspension of 2-chloro-6-bromoquinoline (590 mg, 2.4 mmol) and ethyl isonipecotate (570 mg, 3.6 mmol) in 1-BuOH (12 mL) and the mixture was allowed to stir at 130 °C for 48 h. The solvent was evaporated and the resulting residue was purified by column chromatography (silica gel, DCM-DCM/2% MeOH) to afford the title intermediate 1 as a yellow solid (850 mg, 96%).

In one embodiment, the method for synthesizing compound 1 (ethyl 1-(6-(4-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (114 mg, 0.1 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (650 mg, 1.79 mmol), (4-(trifluoromethoxy)phenyl)boronic acid (405 mg, 1.97 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80 °C for 17 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate (EtOAc) 6:1) to give the title compound 1 as a colorless solid (417 mg, 52%).

HPLC-MS [M+H]+ 445.17; PF: 188-194°C; 1H-NMR (400 MHz, CDCla) 87.92 (d,J= 9.2 Hz, 1H), 7.76 (sa, 3H), 7.70 7.64 (m, 2H), 7.30 ( d,J= 8.3 Hz, 2H), 7.03 (d,J= 9.2 Hz, 1H), 4.49 (dt,J= 13.4, 4.0 Hz, 2H), 4, 17 (q,J= 7.1 Hz, 2H), 3.13 (ddd,J= 13.9, 11.5, 2.8 Hz, 2H), 2.60 (tt,J= 11.0, 3.9 Hz, 1H), 2.09-2.01 (m, 2H), 1.88-1.76 (m, 2H), 1.31-1.23 (m, 3H); 13C-NMR (101 MHz, CDCla) 8 174.71, 157.43, 148.35, 147.57, 139.76, 137.58, 133.52, 128.67, 128.26, 127.15, 125.18, 122.98, 121.82, 121.28, 110.29, 60.51, 44.80, 41.49, 27.94, 14.2.

In one embodiment, the method for synthesizing compound 2 (1-(6-(4-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

An aqueous solution of potassium hydroxide (5 mL, 5 N solution) was added to a solution of compound 1 (ethyl 1-(6-(4-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate) (340 mg, 0.766 mmol) in dioxane (5 mL). The mixture was allowed to stir at 60 °C for 4 hours. The dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution. The aqueous solution was extracted with EtOAc, the organic phase was dried over anhydrous Na<2>SO<4>, filtered and evaporated under high vacuum to give compound 2 as a colorless solid (164 mg, 51%).

HPLC-MS [M+H]+417.18; PF: 245-250°C; 1H-NMR(400 MHz, DMSO-de) 88.08 (d,J= 9.2 Hz, 1H), 8.03 (d,J= 2.2 Hz, 1H), 7.89-7.84 (m, 3H), 7.63 (d,J= 8.7 Hz, 1H), 7.46 (d,J= 8.2 Hz, 2H), 7.30 (d,J= 9.3 Hz , 1H), 4.45 (dt,J= 13.6, 3.9 Hz, 2H), 3.09 (ddd,J= 13.8, 11.5, 2.8 Hz, 3H), 1, 93 (dd,J= 13.8, 4.0 Hz, 2H), 1.62-1.52 (m, 2H); 13C-NMR (101 MHz, DMSO-de) 8176.45, 157.55, 147.95, 147.57, 139.74, 138.14, 132.33, 128.71, 128.59, 127.02 , 125.70, 123.13, 121.93, 111.17, 44.61, 30.88, 28.22.

In one embodiment, the method for synthesizing compound 3 (ethyl 1-(6-(4-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (95 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.65 mmol), (4-hydroxyphenyl)boronic acid (251 mg, 1.82 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for 8 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1) to afford compound 3 as an off-white solid (165 mg, 27%).

HPLC-MS [M+H]+ 377.27; PF: 187-189°C; 1H-MRI (400 MHz, CDCla) 87.91 (d,J= 9.1 Hz, 1H), 7.78-7.70 (m, 3H), 7.57-7.51 (m, 2H) , 7.01 (d,J= 9.1 Hz, 1H), 6.94-6.88 (m, 2H), 4.46 (dt,J= 13.5, 4.0 Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.12 (ddd,J= 13.8, 11.4, 2.9 Hz, 2H), 2.59 (tt,J= 11, 0, 4.0Hz, 1H), 2.09-2.00 (m, 2H), 1.88-1.76 (m, 2H), 1.31-1.23 (m, 3H); 13C-NMR (101 MHz, CDCla) 8 174.87, 166.00, 157.30, 155.12, 137.66, 134.79, 133.51, 128.85, 128.24, 126.76, 124.34, 123.12, 115.74, 110.27, 60.56, 44.99, 41.50, 27.94, 14.23.

In one embodiment, the method for synthesizing compound 9 (1-(6-(4-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

An aqueous solution of potassium hydroxide (3 mL, 5 N solution) was added to a solution of compound 3 (ethyl 1-(6-(4-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) (113.5 mg, 0.3 mmol) in dioxane (3 mL). The mixture was allowed to stir at 60 °C for 4 hours. The dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution. The aqueous solution was extracted with EtOAc, the organic phase was dried over anhydrous Na<2>SO<4>, then filtered and evaporated under high vacuum to give compound 9 as a yellow solid (61 mg, 57%).

HPLC-MS [M+H]+ 349.21; PF: 270-278°C; 1H-NMR(500 MHz, DMSO-de) 88.04 (d,J= 9.2 Hz, 1H), 7.88 (d,J= 2.2 Hz, 1H), 7.77 (dd,J = 8.7, 2.2 Hz, 1H), 7.56 (dd,J= 8.4, 1.8 Hz, 3H), 7.24 (d,J= 9.3 Hz, 1H), 6 .91-6.83 (m, 2H), 4.46-4.38 (m, 2H), 3.10-3.01 (m, 2H), 2.55 (td,J= 7.2, 3.6 Hz, 1H), 1.95-1.89 (m, 2H), 1.57 (ddd,J= 11.3, 4.2, 1.9Hz, 2H); 13CRMN (126 MHz, DMSO-de) 8176.39, 172.52, 157.25, 146.77, 137.96, 134.15, 131.15, 128.41, 128.00, 126.81, 124 .10, 123.27, 116.22, 110.97, 44.64, 41.03, 28.08, 21.55, 14.54.

In one embodiment, the method for synthesizing compound 4 (ethyl 1-(6-(2-methoxypyrimidin-5-yl)quinoMn-2-M)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (95 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.65 mmol), (2-methoxypyrimidin-5-yl)boronic acid (280 mg, 1.82 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for 6 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to afford compound 4 as a colorless solid (296 mg, 47%).

HPLC-MS [M+H]+ 393.25; PF: 154-155°C; 1H-NMR (400 MHz, CDCla) 88.79 (sa, 2H), 7.92 (d,J= 9.2 Hz, 1H), 7.77 (d,J= 8.6 Hz, 1H), 7.72-7.65 (m, 2H), 7.04 (d,J= 9.2 Hz, 1H), 4.49 (dt,J= 13.9, 4.1 Hz, 2H), 4 .16 (q,J= 7.1 Hz, 2H), 4.07 (s, 3H), 3.14 (ddd,J= 13.8, 11.4, 2.9 Hz, 2H), 2, 60 (tt,J= 11.0, 4.0 Hz, 1H), 2.05 (dt,J= 12.0, 3.8 Hz, 2H), 1.87 1.75 (m, 2H), 1.26 (d,J= 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCla) 8174.69, 164.83, 157.48, 157.17, 147.76, 137.45, 128.22, 128.00, 127.81, 127.66, 124 .70, 123.10, 110.50, 60.54, 55.04, 44.73, 41.46, 27.93, 14.24.

In one embodiment, the method for synthesizing compound 6 (1-(6-(2-methoxypyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

Aqueous potassium hydroxide solution (5 mL, 5 N solution) was added to a solution of compound 4 (ethyl 1-(6-(2-methoxypyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylate) (200 mg, 0.51 mmol) in dioxane (4 mL). The mixture was allowed to stir at 60 °C for 4 hours. Dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution. The aqueous solution was extracted with EtOAc, the organic phase was dried over anhydrous Na<2>SO<4>, then filtered and evaporated under high vacuum to give compound 6 as a pale yellow solid (76.5 mg, 42%).

HPLC-MS [M+H]+ 365.24; PF: 238-242°C; 1H-NMR (400 MHz, DMSO-de) 8 12.10 (sa, 1H), 9.01 (sa, 2H), 8.13-8.04 (m, 2H), 7.93-7.88 (m, 1H), 7.70-7.62 (m, 1H), 7.33 (d,J= 9.3 Hz, 1H), 4.46 (dt,J= 13.5, 3.8 Hz, 2H), 3.98 (s, 3H), 3.19-3.04 (m, 2H), 2.59 (ddt,J= 11.1, 7.1, 3.9 Hz, 1H) , 1.99-1.89 (m, 2H), 1.66-1.52 (m, 2H); 13C-NMR (126 MHz, DMSO-de) 8 176.12, 172.22, 164.89, 157.44, 138.11, 128.14, 127.81, 125.21, 123.22, 111, 33, 55.11, 44.65, 28.11, 21.42.

In one embodiment, the method for synthesizing compound 5 (ethyl 1-(6-(4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (95 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.65 mmol), (4-isopropoxyphenyl)boronic acid (281 mg, 1.83 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for 6 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to afford compound 5 as a colorless solid (330 mg, 48%).

HPLC-MS [M+H]+ 419.31; PF: 175-178°C; 1H-NMR (400 MHz, CDCl3) 87.90 (d,J= 9.1 Hz, 1H), 7.80-7.70 (m, 3H), 7.61-7.56 (m, 2H) , 7.03-6.95 (m, 3H), 4.65-4.55 (m, 1H), 4.47 (dt,J= 14.1, 4.2 Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.11 (ddd,J= 13.9, 11.6, 2.8 Hz, 2H), 2.59 (tt,J= 11.1, 4 .0 Hz, 1H), 2.09-2.01 (m, 2H), 1.88-1.76 (m, 2H), 1.37 (d,J= 6.0 Hz, 6H), 1.31-1.23 (m, 3H); 13C-NMR (101 MHz, CDCl3) 8174.79, 157.27, 157.23, 147.04, 137.53, 134.78, 133.30, 128.78, 128.02, 126.91, 124 .30, 123.13, 116.20, 110.15, 69.99, 60.50, 44.92, 41.54, 29.71, 27.95, 22.11, 14.24. In one embodiment, the method for synthesizing compound 7 (1-(6-(4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

An aqueous solution of potassium hydroxide (4 mL, 5 N solution) was added to a solution of compound 5 (ethyl 1-(6-(4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) (200 mg, 0.48 mmol) in dioxane (4 mL). The mixture was allowed to stir at 60 °C for 5 hours. The dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution. The aqueous solution was extracted with EtOAc, the organic phase was dried over anhydrous Na<2>SO<4>, then filtered and evaporated under high vacuum to give compound 7 as an off-white solid (127 mg, 68%).

HPLC-MS [M+H]+ 391.28; PF: 269-273°C; 1H-NMR(500 MHz, DMSO-de) 88.05 (d,J= 9.2 Hz, 1H), 7.92 (d,J= 2.2 Hz, 1H), 7.80 (dd,J = 8.8, 2.2 Hz, 1H), 7.67-7.63 (m, 2H), 7.59 (d,J= 8.7 Hz, 1H), 7.26 (d,J= 9.3 Hz, 1H), 7.02-6.98 (m, 2H), 4.70-4.60 (m, 1H), 4.43 (dt,J= 13.3, 3.8 Hz , 2H), 3.12-3.02 (m, 2H), 2.56 (ddt,J= 11.1, 7.1, 3.9 Hz, 1H), 1.92 (dd,J= 13.6, 3.8 Hz, 2H), 1.62-1.50 (m, 2H), 1.29 (d,J= 6 Hz, 6H); 13C-NMR (126 MHz, DMSO-de) 8176.37, 157.29, 146.93, 138.00, 133.74, 132.48, 128.43, 128.03, 126.87, 124.41 , 123.27, 116.48, 111.01, 69.65, 44.62, 41.03, 28.09, 22.33.

In one embodiment, the method for synthesizing compound 8 (ethyl 1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (95 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.65 mmol), (3-fluorophenyl)boronic acid (256 mg, 1.83 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for 8 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to afford compound 8 as a colorless solid (320 mg, 51%).

HPLC-MS [M+H]+ 379.23; PF: 121-123°C; 1H-NMR (500 MHz, CDCl3) 67.92 (d,J= 9.2 Hz, 1H), 7.79-7.76 (m, 3H), 7.47-7.36 (m, 3H) , 7.03 (dd,J= 9.1, 6.7 Hz, 2H), 4.49 (dd,J= 13.6, 4.0 Hz, 2H), 4.16 (q,J= 7 ,1 Hz, 2H), 3.18-3.09 (m, 2H), 2.60 (tt,J= 11.0, 3.9 Hz, 1H), 2.07-2.03 (m, 2H), 1.85-1.80 (m, 2H), 1.27 (t,J= 7.1 Hz, 3H); 13C-NMR (126 MHz, CDCla) 6174.71, 164.25, 162.30, 157.46, 137.64, 128.64, 127.13, 122.60, 113.89, 113.72, 113 .56, 110.28, 60.52, 44.81, 41.50, 27.95, 14.25.

In one embodiment, the method for synthesizing compound 11 (1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

Aqueous potassium hydroxide solution (4 mL, 5 N solution) was added to a solution of compound 8 (ethyl 1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate) (275.7 mg, 0.73 mmol) in dioxane (4 mL). The mixture was allowed to stir at 60 °C for 5 hours. Dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution. The aqueous solution was extracted with EtOAc, the organic phase was dried over anhydrous Na<2>SO<4>, then filtered and evaporated under high vacuum to give compound 11 as an off-white solid (62 mg, 24%).

HPLC-MS [M+H]+ 351.15; PF: 275-280°C; 1H 1H-NMR (400 MHz, DMSO-d6) 613.32 (sa, 1H), 8.40-7.91 (m, 4H), 7.66 7.61 (m, 2H), 7.60- 7.38 (m, 2H), 7.27-7.17 (m, 1H), 4.48 (dt,J= 14.0, 4.1 Hz, 2H), 3.58-3.45 ( m, 2H), 2.70-2.64 (m, 1H), 2.00 (dd,J= 12.7, 4.4 Hz, 2H), 1.72-1.66 (m, 2H) ; 13C-NMR (126 MHz, DMSO-d6) 6 175.93, 164.20, 162.27, 142.01, 131.45, 131.39, 126.12, 123.05, 122.23, 114, 59, 114.53, 113.76, 113.59, 46.08, 40.20, 28.04.

In one embodiment, the method for synthesizing compound 12 (ethyl 1-(6-(3-fluoro-4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (95 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (528 mg, 1.46 mmol), (3-fluoro-4-isopropoxyphenyl)boronic acid (318 mg, 1.6 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for 7 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to afford compound 12 as an off-white solid (417.3 mg, 52%).

HPLC-MS [M+H]+ 437.24; PF: 148-150°C; 1H-NMR (400 MHz, DMSO-c/6) 8 7.90 (d,J= 9.1 Hz, 1H), 7.76-7.70 (m, 3H), 7.41 (dd, J = 12.6, 2.3 Hz, 1H), 7.35 (ddd, J = 8.5, 2.3, 1.1 Hz, 1H), 7.10-6.98 (m, 2H), 4.59 (hept,J= 12.2, 6.0 Hz, 1H), 4.47 (dt,J= 13.4, 3.9 Hz, 2H), 4.16 (q,J= 7, 1 Hz, 2H), 3.12 (ddd,J= 13.8, 11.6, 2.8 Hz, 2H), 2.59 (tt,J= 11.0, 3.9 Hz, 1H), 2.08-2.02 (m, 2H), 1.87-1.77 (m, 2H), 1.40 ( d,J= 6.1 Hz, 6H), 1.27 (t,J= 7.1 Hz, 3H); 13C-NMR (101 MHz, DMSO-d6) 8169.99, 152.59, 150.42, 147.98, 142.56, 132.80, 129.94, 128.78, 123.73, 122.28 , 119.80, 118.27, 117.67, 113.31, 110.23, 105.49, 67.83, 55.76, 40.10, 36.75, 23.19, 17.38, 9 .49.

In one embodiment, the method for synthesizing compound 10 (1-(6-(3-fluoro-4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

An aqueous solution of potassium hydroxide (4 mL, 5 N solution) was added to a solution of compound 12 (ethyl 1-(6-(3-fluoro-4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) (256 mg, 0.59 mmol) in dioxane (4 mL). The mixture was allowed to stir at 60 °C for 5 hours. The dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution. The aqueous solution was extracted with EtOAc, the organic phase was dried over anhydrous Na<2>SO<4>, then filtered and evaporated under high vacuum to give compound 10 as a colorless solid (184 mg, 76%).

HPLC-MS [M+H]+ 409.28; PF: 262-266°C; 1H-NMR (400 MHz, DMSO-d6) 8 12.26 (sa, 1H), 8.06 (d,J= 9.2 Hz, 1H), 7.99 (d,J= 2.4 Hz, 1H), 7.87-7.80 (m, 1H), 7.66-7.56 (m, 2H), 7.55-7.45 (m, 1H), 7.32-7.20 ( m, 2H), 4.67 (m, 1H), 4.67 (hept,J= 6.0 Hz, 1H), 4.44 (dt,J= 13.3, 3.8 Hz, 2H), 3.08 (ddd,J= 13.7, 11.5, 2.7 Hz, 2H), 2.57 (tt,J= 11.0, 3.9 Hz, 1H), 1.93 (dd,J= 13.5, 3.7 Hz, 2H), 1.57 (dtd,J= 13.1, 11 ,2, 3.9 Hz, 2H), 1.31 (d,J= 6.0 Hz, 6H); 13C-NMR (101 MHz, DMSO-d6) 8176.31, 157.38, 154.60, 152.18, 147.21, 138.05, 133.61, 132.40, 128.32, 126.88 , 124.89, 123.16, 122.82, 117.89, 114.62, 114.43, 111.09, 71.82, 44.57, 40.97, 28.08, 22.30.

In one embodiment, the method for synthesizing compound 14 (ethyl 1-(6-(6-methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (95 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.65 mmol), (6-methoxypyridin-3-yl)boronic acid (280 mg, 1.81 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for 7 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to afford compound 14 as an off-white solid (116 mg, 18%).

HPLC-MS [M+H]+ 392.30; PF: 141-144°C ; 1H-NMR (400 MHz, CDCl3) 88.46 (dd, J = 2.6, 0.7 Hz, 1H), 7.91 (d,J= 9.2 Hz, 1H), 7.87 (dd ,J= 8.6, 2.5 Hz, 1H), 7.79-7.67 (m, 3H), 7.03 (d,J= 9.2 Hz, 1H), 6.83 (d, J= 8.5 Hz, 1H), 4.48 (dt,J= 13.4, 3.9 Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.99 ( s, 3H), 3.13 (ddd,J= 13.8, 11.5, 2.9 Hz, 2H), 2.60 (tt,J= 11.1, 4.0Hz, 1H), 2.07-2.02 (m, 2H), 1.87-1.77 (dtd,J= 13.3, 11.2, 4 .0 Hz, 2H), 1.27 (t,J= 7.1 Hz, 3H); 13C-NMR(101 MHz, CDCla) 8 174.71, 163.36, 157.34, 147.33, 144.85, 137.48, 137.38, 131.67, 129.93, 128.40, 127.24, 124.53, 123.09, 110.77, 110.29, 60.51, 53.55, 44.84, 41.49, 27.94, 14.24.

In one embodiment, the method for synthesizing compound 13 (1-(6-(6-methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

An aqueous solution of potassium hydroxide (5 mL, 5 N solution) was added to a solution of compound 14 (ethyl 1-(6-(6-methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate) (340 mg, 0.766 mmol) in dioxane (5 mL). The mixture was allowed to stir at 60 °C for 4 hours. Dioxane was evaporated, and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution. The aqueous solution was extracted with EtOAc, the organic phase was dried over anhydrous Na<2>SO<4>, then filtered and evaporated under high vacuum to give compound 13 as a colorless solid (79 mg, 23%).

HPLC-MS [M+2H]+ 365.21; PF: 221-225°C; 1H-NMR (400 MHz, DMSO-d6) 8 11.99 (sa, 1H), 9.00 (m, 2H), 8.14 (m, 1H), 8.09-8.02 (m, 2H ), 7.92-7.85 (m, 1H), 7.64 (d,J= 8.7 Hz, 1H), 7.30 (d,J= 9.3 Hz, 1H), 4.45 (dt,J= 13.2, 3.8 Hz, 2H), 3.97 (s, 3H), 3.09 (ddd,J= 13.8, 11.5, 2.7 Hz, 2H), 2.56 (ddt,J= 11.0, 7.8, 3.9 Hz, 1H), 1.98-1.89 (m, 2H), 1.64 1.49 (m, 2H); 13C-NMR (101 MHz, DMSO-d6) 8 176.31, 167.90, 164.73, 157.52, 157.45, 147.58, 146.54, 137.98, 128.04, 127, 73, 127.50, 125.16, 123.19, 111.25, 55.15, 44.49, 40.96, 28.11.

In one embodiment, the method for synthesizing compound 15 (ethyl 1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate hydrochloride) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (92 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.65 mmol), pyridin-4-ylboronic acid (230 mg, 1.81 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80 °C for 7 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1-1:2). Product fractions were collected and the solvent was evaporated. The resulting residue was dissolved in AcOEt and a 2 N solution of hydrochloric acid in diethyl ether (3 eq) was added dropwise at 0 °C. The precipitate was filtered and dried under high vacuum to obtain the title compound 15 as a colorless solid (181 mg, 28%).

HPLC-MS [M+H]+ 362.24; PF: 249-263°C ; 1H-NMR (400 MHz, DMSO-d6) 6 9.06-8.99 (m, 2H), 8.77-8.68 (m, 2H), 8.54-8.48 (m, 2H) , 8.48-8.37 (m, 2H), 7.71 (d,J= 9.8 Hz, 1H), 4.72-4.54 (m, 2H), 4.10 (q,J = 7.1 Hz, 2H), 3.59 (ddd,J= 14.1, 11.3, 2.8 Hz, 2H), 2.85 (tt,J= 10.8, 4.3 Hz, 1H), 2.07-2.02 (m, 2H), 1.83-1.73 (m, 2H), 1.20 (t,J= 7.1 Hz, 3H); 13C-NMR (101 MHz, DMSO-d6) 6 173.93, 154.53, 152.20, 142.63, 142.41, 139.93, 131.36, 130.50, 128.98, 124, 13, 121.55, 120.05, 114.38, 60.64, 47.48, 39.55, 28.06, 14.55.

In one embodiment, the method for synthesizing compound 18 (1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride) is as follows:

Potassium hydroxide (140 mg, 2.5 mmol) was added to a solution of compound 15 (ethyl 1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate hydrochloride) (190 mg, 0.5 mmol) in a solution of MeOH/water (4:2) (3 mL). The mixture was allowed to stir at room temperature for 4.5 hours. The organic solvent was evaporated and the resulting aqueous mixture was acidified with hydrochloric acid (37%) to pH 1. The aqueous solution was extracted with a mixture of DCM/Isop (7:3), the organic phase was dried with anhydrous Na<2>SO<4>, then filtered and evaporated under high vacuum to give compound 18 as a yellow solid (140 mg, 75%).

HPLC-MS [M+H]+334.15; PF: 293-297°C; 1H-NMR (400 MHz, DMSO-d6) 69.05-8.96 (m, 2H), 8.68 (d,J= 2.1 Hz, 1H), 8.56 (d,J= 8, 8 Hz, 1H), 8.51-8.34 (m, 4H), 7.68 (d,J= 9.8 Hz, 1H), 4.64-4.56 (m, 2H), 3, 54 (ddd,J= 13.8, 11.0, 2.7 Hz, 2H), 2.75 (tt,J= 10.6, 4.2 Hz, 1H), 2.07-2.01 ( m, 2H), 1.82-1.68 (m, 2H); 13C-NMR (101 MHz, DMSO-d6) 6 175.64, 153.97, 153.40, 152.85, 143.08, 142.22, 131.01, 130.37, 128.82, 123, 83, 121.70, 114.01, 47.14, 39.66, 28.13.

In one embodiment, the method for synthesizing compound 16 (ethyl 1-(6-(furan-2-yl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (96 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.66 mmol), furan-2-ylboronic acid (204 mg, 1.83 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for <6> hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to afford compound 16 as a yellow solid (123 mg, 21%).

HPLC-MS [M+H]+ 351.17; PF: 202-204°C;<1>H-NMR (400 MHz, CDCl3)<6>9.03 (d,J=<8 , 8>Hz, 1H), 8.10 (d,J= 9.5 Hz, 1H), 7.98-7.91 (m, 1H), 7.88 (d,J= 1.9 Hz,1H), 7.49 (d,J= 1.7 Hz, 1H), 7.06 (d,J= 9.6 Hz, 1H), 6.74 (d,J= 3.3 Hz, 1H), 6.53-6.47 (m, 1H), 4.69-4.50 (sa, 2H), 4.15 (q,J= 7.1 Hz, 2H), 3.69 (m, 2H), 2.73 (tt,J= 9.5, 4.4 Hz, 1H), 2.21 2.16 (m, 2H), 2.03-1.93 (m, 2H), 1.25 (t,J= 7.1 Hz, 3H);<13>C-NMR (101 MHz, CDCl3)<6>173.42, 152.08, 9, 143.12, 142.91, 129.09, 128.44, 121.41, 121.10, 120.58, 112.07, 111.15, 106.59, 60.99, 47.99, 39.66, 27.87, 14.17.

In one embodiment, the method for synthesizing compound 17 (1-(6-(furan-2-yl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

An aqueous solution of potassium hydroxide (5 mL, 5 N solution) was added to a solution of compound 16 (ethyl 1-(6-(furan-2-yl)quinolin-2-yl)piperidine-4-carboxylate) (450 mg, 1.29 mmol) in dioxane (5 mL). The mixture was allowed to stir at 60 °C for 4 hours. The dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution. The aqueous solution was extracted with EtOAc, the organic phase was dried over anhydrous Na<2>SO<4>, then filtered and evaporated under high vacuum to give compound 17 as a yellow solid (324 mg, 78%).

HPLC-MS [M+H]+ 323.14; PF: 210-214°C ;<1>H-NMR (400 MHz, DMSO-d<6>)<6>12.38 (sa, 1H), 8.44-8.26 (m, 1H), 8.21 (m, 1H), 8.10-8.00 (m, 1H), 7.93-7.78 (m, 2H), 1-7.47 (m, 1H), 7.03 (d,J= 3.4 Hz, 1H), 6.69-6.62 (m, 1H), 4.41-4.35 (m, 2H), 3.38-3.25 (m, 2H), 2.72-2.64 (m, 1H), 2.05-1.97 (m, 2H), 1.76 -1.64 (m, 2H) 112.56, 111.55, 105.70, 44.86, 40.76, 28.05.

In one embodiment, the method for synthesizing compound 19 (ethyl 1-(6-(2-chloro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (96 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.66 mmol), (2-chloro-4-methoxyphenyl)boronic acid (431 mg, 1.83 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for <6> hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to afford compound 19 as a colorless solid (604 mg, <8.6>%).

HPLC-MS [M+H]+ 425.18; PF: 132-135°C;<1>H-NMR (400 MHz, CDCl3)<6>7.89 (d,J= 9.2 Hz, 1H), 7.75-7.68 (m, 1H), 7.65-7.57 (m, 2H), 7.33 (d,J= 8.5 Hz, 1H), 7.07-6.98 (m, 2 H), 6.92 -6 .85 (m, 1H), 4.48 (dt,J= 13.5, 3.9 Hz, 2H), 4.16 (q,J =7.1 Hz, 2H), 3.85 (s, 3H), 3.12 (ddd,J =13.9, 11.6, 2.9 Hz, 2H), 2.59 (tt,J= 11.1, 4.0 Hz, 1H), 2.09-2.00 (m, 2H), 1.89-1.74 (m, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-NMR (101 MHz, CDCl3)<6>174.74, 159.21, 157.48, 137.52, 133.16, 133.11, 132.83, 132.04, 131.39, 127.71, 126.03, 122.51, 115.10, 113.09, 110.05, 60.49, 55.60, 44.91, 41.54, 27.92, 14.24.

In one embodiment, the method for synthesizing compound 23 (1-(6-(2-chloro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

An aqueous solution of potassium hydroxide (5 mL, 5 N solution) was added to a solution of compound 19 (ethyl 1-(6-(2-chloro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) (278 mg, 0.65 mmol) in dioxane (5 mL). The mixture was allowed to stir at 60 °C for 5 hours. The dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution. The aqueous solution was extracted with EtOAc, the organic phase was dried over anhydrous Na<2>SO<4>, filtered and evaporated under high vacuum to give compound 23 as an off-white solid (204 mg, 79%).

HPLC-MS [M+H]+ 397.17; PF: 190-195°C;<1>H-NMR (400 MHz, CDCl3)<6>7.90 (d,J= 9.0 Hz, 1H), 7.77-7.69 (m, 1H), 7.65-7.58 (m, 2H), 7.33 (d,J= 8.5 Hz, 1H), 7.08-6.99 (m, 2 H), 6.93-6.82 (m, 1H), 4.47 (dt,J= 13.6, 4.0 Hz, 2H), 3.85 (s, 3H), 3.16 (ddd,J= 13.8, 11.3, 2.9 Hz, 2H), 2.65 (tt,J= 11.0, 4.0 Hz, 1H), 2.09-2.02 (m, 2H), 1.91-1.79 (m, 2H);<13>C-NMR (101 MHz, CDCl3)<6>180.47, 177.05, 159.23, 157.38, 146.91, 133.27, 132.77, 132.03, .51, 127.73, 125.86, 122.53, 115.11, 113.10, 110.11, 55.60, 44.90, 41.15, 27.66.

In one embodiment, the method for synthesizing compound 20 (ethyl 1-(6-(4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (96 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.66 mmol), (4-methoxyphenyl)boronic acid (280 mg, 1.83 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80 °C for 7 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to afford the title compound 20 as a colorless solid (269 mg, 41%).

HPLC-MS [M+H]+ 391.19; PF: 176-179°C;<1>H-NMR (400 MHz, CDCl3)<6>7.91 (d,J= 9.2 Hz, 1H), 7.81-7.70 (m, 3H), 7.65-7.57 (m, 2H), 7.05-6.96 (m, 3H), 4.47 (dt,J= 13.5, 3.9 Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.86 (s, 3H), 3.18-3.06 (m, 2H), 2.59 (tt,J= 11.1, 4.0 Hz, 1H), 2.10-1.99 (m, 2H), 1.90-1.75 (m, 2H), 1.27 (t,J = 7.1 Hz, 3H); 4.35, 123.11, 114.24, 110.14, 60.49, 55.37, 44.90, 41.53, 27.95, 14.24.

In one embodiment, the method for synthesizing compound 21 (1-(6-(4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

Aqueous potassium hydroxide solution (3 mL, 5 N solution) was added to a solution of compound 20 (ethyl 1-(6-(4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) (167 mg, 0.43 mmol) in dioxane (3 mL). The mixture was allowed to stir at 60°C for 5 hours. Dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution. The aqueous solution was extracted with EtOAc, the organic phase was dried over anhydrous Na<2>SO<4>, then filtered and evaporated under high vacuum to give compound <21>as a pale yellow solid (106 mg, <6 8>%).

HPLC-MS [M+H]+ 363.18; PF: not applicable (oil);<1>H-NMR (400 MHz, DMSO-d<6>)<6>12.23 (sa, 1H), 8.09 (d,J= 9.3 Hz, 1H), 7.95 (d,J= 2.1 Hz, 1H), 7.86-7.80 (m, 1H), 7.73-7.66 (m, 2H), 63 (d,J= 8.7 Hz, 1H) 7.29 (d,J= 9.3 Hz, 1H), 7.08-6.99 (m, 2H), 4.43 (dt,J= 13.3, 3.8 Hz, 2H), 3.80 (s, 3H), 3.16-3.05 (m, 2H), 2.57 (tt,J= 10.9, 3.9 Hz, 1H), 1.96 1.88 (m, 2H), 1.66-1.51 (m, 2H); 132.71, 128.69, 128.03, 124.53, 123.16, 114.92, 111.17, 55.67, 44.81,40.89, 28.07.

In one embodiment, the method for synthesizing compound 30 (ethyl 1-(6-(3-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (96 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.66 mmol), (3-methoxyphenyl)boronic acid (280 mg, 1.83 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for <6> hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1) to afford compound 30 as an off-white solid (313 mg, 48%).

HPLC-MS [M+H]+ 391.22; PF: 104-107°C;<1>H-NMR (400 MHz, CDCl3)<8>7.93 (d,J= 9.1 Hz, 1H), 7.88-7.66 (m, 3H), 7.42-7.33 (m, 1H), 7.27-7.20 (m, 2H), 7.02 (d,J= 9.2 Hz, 1 H), 6.96-6.81 (m, 1H), 4.48 (dt,J= 13.4, 3.9 Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.89 (s, 3H), 3.19-3.07 (m, 2H), 2.68-2.53 (m, 1H), 2.05 (dd,J= 13.5, 3.7 Hz, 2H), 1.90-1.75 (m, 2H), 1.27 (t,J= 7.2 Hz, 3H);<13>C-NMR (101 MHz, CDCl3)<8>174.74, 160.00, 157.37, 147.51, 142.48, .64, 134.84, 129.76, 128.96, 126.95, 125.13, 122.99, 119.57, 112.71, 112.38, 110.16, 60.50, 55.34, 51.78, 44.86, 41.52, 27.93.

In one embodiment, the method for synthesizing compound 22 (1-(6-(3-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

Aqueous potassium hydroxide solution (3 mL, 5 N solution) was added to a solution of compound 30 (ethyl 1-(6-(3-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) (163 mg, 0.42 mmol) in dioxane (3 mL). The mixture was allowed to stir at 60 °C for 5 hours. Dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution. The aqueous solution was extracted with EtOAc, the organic phase was dried over anhydrous Na<2>SO<4>, then filtered and evaporated under high vacuum to give compound <2 2>as an off-white solid (134 mg, <8 8>%).

HPLC-MS [M+H]+ 363.18; PF: 200-205°C;<1>H-NMR (400 MHz, DMSO-d<6>)<8>12.21 (sa, 1H), 8.12 (d,J= 9.1 Hz, 1H), 8.07-8.01 (m, 1H), 7.88 (d,J=<8 , 8>Hz, 1H), 7.72-7.61 (m , 1H), 7.43-7.34 (m, 1H), 7.36-7.25 (m, 3H), 6.97-6.89 (m, 1H), 4.44 (dt,J= 13.3, 3.8 Hz, 2H), 3.84 (s, 3H), 3.20-3.05 (m, 2H), 2.64-2.53 (m, 1H), 1.94 (dd,J= 13.6, 3.7 Hz, 2H), 1.66 1.51 (m, 2H);<13>C-MRI (126 MHz, DMSO-d<6>)<8>176.17, 160.34, 157.20, 145.40, 6, 138.60, 134.19, 130.43, 129.03, 125.50, 123.00, 119.34, 113.23, 112.49, 111.25, 55.65, 44.87, 40.84, 28.09.

In one embodiment, the method for synthesizing compound 24 (ethyl 1-(6-(4-methoxy-2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate hydrochloride) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (96 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.66 mmol), (4-methoxy-2-(trifluoromethyl)phenyl)boronic acid (402 mg, 1.83 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for 7 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to afford compound 24 as an off-white solid (245 mg, 30%).

HPLC-MS [M+H]+ 459.19; PF: 134-137°C;<1>H-NMR (400 MHz, CD<3>OD)<8>8.43 (d,J= 9.7 Hz, 1H), 7.99 (d,J=<8 , 6>Hz, 1H), 7.86-7.83 (m, 1H), 7.80-7.72 (m, 1H), 7.59 (d,J= 9.8 Hz, 1H), 7.43-7.32 (m, 2H), 7.32-7.23 (m, 1H), 4.42 (dt,J= 13.8, 4.2 Hz, 2H), 4.21 (q,J= 7.1 Hz, 2H), 3.94 (s, 3H), 3.66 (ddd,J= 14.0, 11.0, 3.1 Hz, 2H), 2.90 (tt,J= 10.3, 4.4 Hz, 1H), 2.29-2.18 (m, 2H), 2.04-1.89 (m, 2H), 1.30 (t,J= 7.1 Hz, 3H);<13>C-MRI (101 MHz, CD<3>OD)<8>17 3.84, 159.52, 151.72, 143.17, 137.33, 136.02, 134.05, 133.39, 131.04, 128.58, 125.29, 122.57, 120.64, 116.77, 116.58, 112.31, 111.78, 60.58, 54.86, 46.29, 39.39, 27.34, 13.09.

In one embodiment, the method for synthesizing compound 28 (1-(6-(4-methoxy-2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

An aqueous solution of potassium hydroxide (3 mL, 5 N solution) was added to a solution of compound 24 (ethyl 1-(6-(4-methoxy-2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate hydrochloride) (163 mg, 0.35 mmol) in dioxane (3 mL). The mixture was allowed to stir at 60 °C for 5 hours. The dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution. The aqueous solution was extracted with EtOAc, the organic phase was dried over anhydrous Na<2>SO<4>, then filtered and evaporated under high vacuum to give compound 28 as a pale yellow solid (72 mg, 48%).

HPLC-MS [M+H]+ 431.16; PF: 215-217°C;<1>H-NMR (400 MHz, DMSO-d<6>)<8>12.24 (sa, 1H), 8.15 (sa, 1H), 7.73-7.63 (m, 2H), 7.54-7.56 (m, 1H), 7.41 (d,J= 8.3 Hz, 2H), 7.25 (m, 2H), 4.45 (dt,J= 13.7, 3.9 Hz, 2H), 3.90 (s, 3H), 3.26-3.13 (m, 2H), 2.68-2.55 (m, 1H), 2.01-1.93 (m, 2H), 1.69-1.57 (m, 2H) 2, 112.09, 112.04, 56.16, 45.30, 40.65, 28.04.

In one embodiment, the method for synthesizing compound 25 (ethyl 1-(6-(3-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (103 mg, 0.09 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (650 mg, 1.79 mmol), (3-(trifluoromethoxy)phenyl)boronic acid (375 mg, 1.97 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for 7 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to afford compound 25 as a colorless solid (402 mg, 25%).

HPLC-MS [M+H]+ 445.18; PF: 128-129°C;<1>H-NMR (400 MHz, CDCl3)<8>7.92 (d,J= 9.2 Hz, 1H), 7.79-7.73 (m, 3H), 7.72-7.63 (m, 2H), 7.34-7.25 (m, 2H), 7.03 (d,J= 9.2 Hz, 1 H), 4.49 (dt,J= 13.5, 4.0 Hz, 2H), 4.17 (q,J= 7.1 Hz, 2H), 3.14 (ddd,J=13.8, 11.4, 2.8 Hz, 2H), 2.60 (tt,J=11.0, 4.0 Hz, 1H), 2.05 (dt,J=12.3, 3.8 Hz, 2H), 1.82 (dtd,J= 13.3, 11.2, 4.0 Hz, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-NMR (101 MHz, CDCl3)<8>174.70, 157.40, 148.36, 9.75, 137.60, 133.53, 128.69, 128.26, 127.13, 125.18, 122.97, 121.82, 121.28, 119.26, 110.30, 60.52, 44.82, 41.48, 27.94, 14,24.

In one embodiment, the method for synthesizing compound 29 (1-(6-(3-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

An aqueous solution of potassium hydroxide (5 mL, 5 N solution) was added to a solution of compound 25 (ethyl 1-(6-(3-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate) (208 mg, 0.47 mmol) in dioxane (5 mL). The mixture was allowed to stir at 60°C for 4 hours. The dioxane was evaporated, and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution at 0°C. The product precipitated, and compound 29 was isolated as a colorless solid (187 mg, 100%).

HPLC-MS [M+H]+ 417.16; PF: 261-264°C;<1>H-NMR (500 MHz, DMSO-c/<6>)<8>8.43 (d,J= 9.7 Hz, 1H), 8.34-8.30 (m, 1H), 8.26 (d,J=<8 , 6>Hz, 1H), 8.19-8.12 (m, 1H), 7.85 (d ,J= 7.9 Hz, 1H), 7.78 (s, 1H), 7.70-7.61 (m, 2H), 7.43 (d,J=<8 , 6>Hz, 1H), 4.51-4.44 (m, 2H), 3.59-3.49 (m, 2H), 2.74 (tt,J= 10.5, 2.9 Hz, 1H), 2.06 (m, 2H), 1.81-1.70 (m, 2H) , 126.27, 121.64, 120.61, 119.71, 119.58, 113.53, 46.88, 40.11, 27.98.

In one embodiment, the method for synthesizing compound 26 (ethyl 1-(6-(3-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (96 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.66 mmol), (3-hydroxyphenyl)boronic acid (252 mg, 1.83 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for <6> hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to afford compound 26 as an off-white solid (486 mg, 78%).

HPLC-MS [M+H]+ 377.25; PF: 153-155°C;<1>H-NMR (400 MHz, DMSO-d<6>)<6>9.51 (s, 1H), 8.10 (d,J= 9.2 Hz, 1H), 7.94 (d,J= 2.1 Hz. 1H), 7.82-7.75 (m, 1H), 7.62 (d,J= 8.7 Hz, 1H), 7.29-7.25 (m, 1H), 7.20-7.07 (m, 2H), 6.80-6.72 (m, 1H), 4.44 (dt,J= 13.2, 3.8 Hz, 2H), 4.08 (q,J= 7.1 Hz, 2H), 3.16-3.04 (m, 2H), 2.67 (ddt,J= 11.1, 7.1, 4.0 Hz, 1H), 1.98-1.88 (m, 2H), 1.66-1.51 (m, 2H), 1.19 (t,J= 7.1 Hz, 3H);<13>C-NMR(101 MHz, DMSO-c/<6>)<6>174.57, 8.89, 158.31, 141.74, 134.20, 130.38, 128.71, 125.22, 123.13, 117.74, 114.52, 113.75, 111.11, 106.63, 102.92, 60.39, 40.93, 27.97, 14.56.

In one embodiment, the method for synthesizing compound 27 (1-(6-(3-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

An aqueous solution of potassium hydroxide (5 mL, 5 N solution) was added to a solution of compound 26 (ethyl 1-(6-(3-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) (281 mg, 0.75 mmol) in dioxane (5 mL). The mixture was allowed to stir at 60°C for 4 hours. The dioxane was evaporated and the aqueous mixture was acidified with acetic acid to give a suspension. The product was isolated by filtration, washed with water and dried under high vacuum at 40°C. Compound 27 was isolated as a pale yellow solid (250 mg, 96%).

HPLC-MS [M+H]+ 349.14; PF: 316-319°C;<1>H-NMR (400 MHz, DMSO-d<6>)<6>12.90 (sa, 1H), 9.70 (sa, 1H), 8.43 (d,J= 9.6 Hz, 1H), 8.30 (sa, 1H), 8.18-8.13 (m, 1H), 8.02 (d,J=< 8 , 8>Hz, 1H), 7.61 (d,J= 9.8 Hz, 1H), 7.32-7.28 (m, 1H), 7.19-7.11 (m, 2H), 6.83 (d,J= 8.0, 1H), 4.58-4.45 (m, 2H), 3.56-3.50 (m, 2H), 2.73 (tt,J= 10.7, 4.1 Hz, 1H), 2.07-2.01 (m, 2H), 1.79-1.70 (m, 2H);<13>C-MRI (126 MHz, DMSO-d<6>)<6>175.64, 158.51, 152.30, 140.39, 20, 131.21, 130.55, 125.95, 121.65, 117.87, 115.38, 114.01, 113.27, 47.11, 39.04, 28.05.

In one embodiment, the method for synthesizing compound 31 (ethyl 1-(6-(4-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.05 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (500 mg, 1.3 mmol), (4-(trifluoromethyl)phenyl)boronic acid (280 mg, 1.5 mmol) and cesium carbonate (2.5 mL, 3 M solution) in a mixture of dioxane (13 mL) and water (2.1 mL). The suspension was allowed to stir at 80°C for 2 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 8:1-2:1) to afford compound 31 as an off-white solid (380 mg, 70%).

HPLC-MS [M+H]+ 429.22; PF: 175-177°C;<1>H-NMR (400 MHz, CDCl3)<8>7.93 (d,J= 9.2 Hz, 1H), 7.84-7.73 (m, 5H), 7.72-7.68 (m, 2H), 7.04 (d,J= 9.2 Hz, 1H), 4.49 (dt,J= 13, 7, 3.9 Hz, 2H), 4.17 (q,J= 7.2 Hz, 2H), 3.20-3.08 (m, 2H), 2.61 (tt,J= 11.0, 4.0 Hz, 1H), 2.06 (dt,J= 13.4, 3.9 Hz, 2H), 1.82 (dtd,J= 13.3, 11.2, 4.0 Hz, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-NMR (101 MHz, CDCl3)<8>174.69, 157.51, 147.88, 144.46, 137.66, 133.30, 129.02, 128.70, 28.62, 127.24, 127.17, 125.69, 125.56, 122.96, 110.34, 60.53, 44.77, 41.47, 27.94, 14.24.

In one embodiment, the method for synthesizing compound 36 (1-(6-(4-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

An aqueous solution of potassium hydroxide (5 mL, 5 N solution) was added to a solution of compound 31 (ethyl 1-(6-(4-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate) (210 mg, 0.4 mmol) in dioxane (5 mL). The mixture was allowed to stir at 80 °C for 2 hours. Dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution. The aqueous solution was extracted with a mixture of DCM/Isop (7:3), the organic phase was dried over anhydrous Na<2>SO<4>, filtered and evaporated under high vacuum to give compound 36 as a colorless solid <( 10 0>mg, 60%).

HPLC-MS [M+H]+ 401.19; PF: 278-281°C;<1>H-NMR (400 MHz, DMSO-d<6>)<8>13.54 (sa, 1H), 8.55-8.39 (m, 2H), 8.36 8.31 (m, 1H), 8.21-8.12 (m, 1H), 8.01 (d,J= 8.2 Hz, 2H), 7.88 (d,J= 8.3 Hz, 2H), 7.66 (d,J= 9.7 Hz, 1H), 4.62-4.43 (m, 2H), 3.56-3.48 (m, 2H), 2.75 (tt,J= 10.6, 4.1 Hz, 1H), 2.05 (dd,J= 13.7, 3.9 Hz, 2H) 8.40, 127.93, 126.77, 126.36, 121.72, 113.52, 47.21, 39.60, 28.06.

In one embodiment, the method for synthesizing compound 32 (ethyl 1-(6-(3-nitrophenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.06 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (500 mg, 1.3 mmol), (3-nitrophenyl)boronic acid (230 mg, 1.4 mmol) and cesium carbonate (2.5 mL, 3 M solution) in a mixture of dioxane (13 mL) and water (2.1 mL). The suspension was allowed to stir at 80°C for 1 hour. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1) to afford compound 32 as a yellow solid (330 mg, 52%).

HPLC-MS [M+H]+ 406.25; PF: 134-137°C;<1>H-NMR (400 MHz, CDCl3)<8>8.56-8.50 (m, 1H), 8.21-8.14 (m, 1H), 8.02 7.96 (m, 1H), 7.95 (d,J= 9.2 Hz, 1H), 7.88-7.72 (m, 3H), 7.66-7.57 (m, 1H), 7.06 (d,J= 9.2 Hz, 1H), 4.50 (dt,J= 13.4, 3.9 Hz, 2H), 4.17 (q,J= 7.1 Hz, 2H), 3.16 (ddd,J= 13.9, 11.6, 2.9 Hz, 2H), 2.61 (tt,J= 11.0, 4.0 Hz, 1H), 2.06 (dd,J= 14.0, 3.3 Hz, 2H), 1.90-1.75 (m, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-MRI (101 MHz, CDCl3)<8>174.68, .57, 148.79, 148.02, 142.65, 137.68, 132.79, 132.15, 129.69, 128.32, 127.41, 125.58, 122.98, 121.68, 121.56, 110.48, 44.73, 41.45, 27.94, 14.24.

In one embodiment, the method for synthesizing compound 39 (1-(6-(3-nitrophenyl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

An aqueous solution of potassium hydroxide (3.8 mL, 5 N solution) was added to a solution of compound 32 (ethyl 1-(6-(3-nitrophenyl)quinolin-2-yl)piperidine-4-carboxylate) (150 mg, 0.3 mmol) in dioxane (3.8 mL). The mixture was allowed to stir at 60°C for 1 hour. Dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution. The aqueous solution was extracted with a mixture of DCM/Isop (7:3), the organic phase was dried over anhydrous Na<2>SO<4>, filtered and evaporated under high vacuum to give compound 39 as an off-white solid <(100 mg, <66%).

HPLC-MS [M+H]+ 378.2; PF: 282-286°C;<1>H-NMR (400 MHz, DMSO-c/<6>)<8>13.58 (sa, 1H), 8.59-8.53 (m, 1H), 8.53 8.31 (m, 3H), 8.30-8.24 (m, 2H), 8.24-8.18 (m, 1H), 7. 86-7.77 (m, 1H), 7.70-7.61 (m, 1H), 4.64-4.42 (m, 2H), 3.61-3.41 (m, 2H), 2.75 (tt,J= 10.2, 4.0 Hz, 1H), 2.05 (dd,J= 13.8, 4.0 Hz, 2H), 1.84-1.65 (m, 2H) 121.46, 114.15, 113.56, 47.12, 40.60, 28.07.

In one embodiment, the method for synthesizing compound 33 (ethyl 1-(6-(4-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.06 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (500 mg, 1.3 mmol), (4-fluorophenyl)boronic acid (200 mg, 1.5 mmol) and cesium carbonate (2.5 mL, 3 M solution) in a mixture of dioxane (13 mL) and water (2.1 mL). The suspension was allowed to stir at 80°C for 18 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1-1:1) to afford compound 33 as a colorless solid (190 mg, 40%).

HPLC-MS [M+H]+ 379.23; PF: 144-146°C;<1>H-NMR (400 MHz, CDCl3)<6>7.91 (d,J= 9.2 Hz, 1H), 7.80-7.71 (m, 3H), 7.67-7.56 (m, 2H), 7.19-7.08 (m, 2H), 7.02 (d,J= 9.2 Hz, 1 H), 4.48 (dt,J= 13.5, 3.9 Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.13 (ddd,J= 13.9, 11.6, 2.9 Hz, 2H), 2.60 (tt,J= 11.1, 4.0 Hz, 1H), 2.11-1.99 (m, 2H), 1.90-1.75 (m, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-NMR (101 MHz, CDCl3)<6>174.73, 163.47, 157.36, 147.33, 137.55, 137.08, 134.02, 1 28.77, 128.56, 128.48, 127.05, 124.91, 123.01, 115.72, 115.51, 110.25, 60.51, 44.84, 41.50, 27.94, 14.24.

In one embodiment, the method for synthesizing compound 47 (1-(6-(4-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

An aqueous solution of potassium hydroxide (11 mL, 5 N solution) was added to a solution of compound 33 (ethyl 1-(6-(4-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate) (350 mg, 0.9 mmol) in dioxane (11 mL). The mixture was allowed to stir at 80°C for <6> hours. The dioxane was evaporated, and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution to give a suspension at 0°C. The product was isolated by filtration, washed with water, and dried under high vacuum at 40°C. Compound 47 was isolated as a yellow solid (360 mg, 95%).

HPLC-MS [M+H]+ 351.20; PF: 304-308°C;<1>H-NMR (400 MHz, DMSO-d<6>)<6>13.67 (sa, 1H), 8.57-8.39 (m, 2H), 8.22 (sa, 1H), 8.09 (dd,J=<8 , 8>Hz, 1H), 7.88-7.77 (m, 2H), 7. 64 (d,J= 9.7 Hz, 1H), 7.41-7.30 (m, 2H), 4.66-4.51 (m, 2H), 3.60-3.51 (m, 2H), 2.75 (tt,J= 10.7, 4.2 Hz, 1H), 2.04 (dd,J= 13.8, 3.8 Hz, 2H), 1.83-1.68 (m, 2H) 116.30, 113.43, 47.21, 39.66, 28.06.

In one embodiment, the method for synthesizing compound 34 (ethyl 1-(6-(pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.06 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (500 mg, 1.3 mmol), pyridin-3-ylboronic acid (180 mg, 1.5 mmol) and cesium carbonate (2.5 mL, 3 M solution) in a mixture of dioxane (13 mL) and water (2.1 mL). The suspension was allowed to stir at 80°C for 1 hour. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 1:2) to afford compound 34 as an off-white solid (240 mg, 46%).

HPLC-MS [M+H]+ 362.25; PF: 106-109°C;<1>H-NMR (400 MHz, CDCla)<8>8.93 (dd,J= 2.4, 0.9 Hz, 1H), 8.57 (dd,J= 4.8, 1.6 Hz, 1H), 7.99-7.90 (m, 2H), 7.82-7.72 (m, 3H), 7.33 (m, 1H), 7.04 (d,J= 9.2 Hz, 1H), 4.49 (dt,J= 13.3, 3.6 Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.20-3.08 (m, 2H), 2.60 (tt,J= 11.0, 4.0 Hz, 1H), 2.11-2.00 (m, 2H), 1.89-1.78 (m, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-NMR(101 MHz, CDCl3)<8>174.68, 157.48, 148.25, 148.05, 147.79, .59, 136.44, 134.13, 131.42, 128.47, 127.40, 125.37, 123.54, 123.04, 110.36, 60.52, 44.76, 41.47, 27.94, 14.24.

In one embodiment, the method for synthesizing compound 49 (1-(6-(pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride) is as follows:

An aqueous solution of potassium hydroxide (6.3 mL, 5 N solution) was added to a solution of compound 34 (ethyl 1-(6-(pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate) (200 mg, 0.766 mmol) in dioxane (6.3 mL). The mixture was allowed to stir at 80°C for <6> hours. The dioxane was evaporated, and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution to give a suspension at 0°C. The product was isolated by filtration, washed with water, and dried under high vacuum at 40°C. Compound 49 was isolated as a yellow solid (160 mg, 96%).

HPLC-MS [M+H]+ 334.15; PF: 309-313°C;<1>H-NMR (400 MHz, DMSO-d<6>)<8>9.31 (sa, 1H), 8.93-8.81 (m, 2H), 8.63 (d,J=<8 , 8>Hz, 1H), 8.49 (sa, 1H), 8.42 (d,J= 9.8 Hz, 1H), 8.31-8.19 (m, 1H), 8.11-7.99 (m, 1H), 7.69 (d,J= 9.8 Hz, 1H), 4.65-4.55 (m, 2H), 3.57 (ddd,J= 14.0, 11.3, 2.8 Hz, 2H), 2.76 (tt,J= 10.5, 4.2 Hz, 1H), 2.05 (dd,J= 13.8, 3.8 Hz, 2H), 1.84-1.70 (m, 2H); 24, 131.18, 131.01, 127.47, 127.16, 121.56, 119.86, 114.04, 47.39, 40.38, 28.10.

In one embodiment, the method for synthesizing compound 35 (ethyl 1-(6-(6-fluoropyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.06 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (500 mg, 1.3 mmol), (6-fluoropyridin-3-yl)boronic acid (211 mg, 1.5 mmol) and cesium carbonate (2.5 mL, 3 M solution) in a mixture of dioxane (13 mL) and water (2.1 mL). The suspension was allowed to stir at 80°C for 3 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1) to afford compound 35 as an off-white solid (270 mg, 53%).

HPLC-MS [M+H]+ 380.24; PF: 108-110°C;<1>H-NMR (400 MHz, CDCl3)<8>8.49 (m, 1H), 8.09-7.99 (m, 1H), 7.92 (d,J= 9.2 Hz, 1H), 7.81-7.66 (m, 3H), 7.08-6.98 (m, 2H), 4.49 ( dt,J= 13.5, 3.9 Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.14 (ddd,J= 13.8, 11.5, 2.9 Hz, 2H), 2.61 (tt,J= 11.0, 4.0 Hz, 1H), 2.11-2.00 (m, 2H), 1.89-1.74 (m, 2H), 1.27 (t,J = 7.1 Hz, 3H); 130.28, 128.35, 127.42, 125.28, 123.01, 110.48, 109.61,60.55, 44.76, 41.45, 27.93, 14.23.

In one embodiment, the method for synthesizing compound 38 (1-(6-(6-fluoropyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride) is as follows:

An aqueous solution of potassium hydroxide (3.8 mL, 5 N solution) was added to a solution of compound 35 (ethyl 1-(6-(6-fluoropyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate) (150 mg, 0.3 mmol) in dioxane (3.8 mL). The mixture was allowed to stir at 80°C for 4 hours. The dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution to give a suspension at 0°C. The product was isolated by filtration, washed with water and dried under high vacuum at 40°C. Compound 38 was isolated as an off-white solid (116 mg, <100>%).

HPLC-MS [M+H]+ 352.16; PF: 271-274°C;<1>H-NMR (400 MHz, DMSO-d<6>)<8>13.68 (sa, 1H), 12.41 (sa, 1H),<8 , 6 6>(d,J= 2.6 Hz, 1H), 8.63-8.44 (m, 1H), 8.45-8.35 (m, 2H), 8.33-8.28 (m, 1H), 8.18-8.05 (m, 1H), 7.65 (d,J= 9.8 Hz, 1H), 7.42-7.31 (m, 1H), 4.78-4.47 (m, 2H), 3.60-3.49 (m, 2H), 2.75 (tt,J= 10.7, 4.3 Hz, 1H), 2.04 (dd,J= 13.8, 3.9 Hz, 2H), 1.84-1.69 (m, 2H); 83, 133.26, 132.62, 131.12, 126.49, 121.63, 113.65, 110.50, 110.12, 47.21, 39.45, 28.06.

In one embodiment, the method for synthesizing compound 37 (ethyl 1-(6-(2-fluoropyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.06 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (500 mg, 1.3 mmol), (2-fluoropyridin-4-yl)boronic acid (211 mg, 1.5 mmol) and cesium carbonate (2.5 mL, 3 M solution) in a mixture of dioxane (13 mL) and water (2.1 mL). The suspension was allowed to stir at 80°C for 4 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1) to afford compound 37 as an off-white solid (150 mg, 23%).

HPLC-MS [M+H]+ 380.23; PF: 120-121°C;<1>H-NMR (400 MHz, CDCl3)<8>8.25 (d, J = 5.3 Hz, 1H), 7.93 (d,J= 9.2 Hz, 2H), 7.88-7.85 (m, 1H), 7.81-7.74 (m, 2H), 7.48 (dt,J= 5.3 , 1.7 Hz, 1H), 7.20 (sa, 1H), 7.05 (d,J= 9.2 Hz, 1H), 4.50 (dt,J= 13.9, 4.0 Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.22-3.10 (m, 2H), 2.61 (tt,J= 11.0, 4.0 Hz, 1H), 2.05 (dq,J= 12.3, 3.6 Hz, 2H), 1.81 (dtd,J= 13.4, 11.2, 4.0 Hz, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-MRI (101 MHz, CDCl3)<8>174, 61, 165.84, 157.68, 153.73, 148.79, 147.96, 137.78, 130.25, 127.83, 127.48, 125.91, 122.79, 119.15, 110.48, 106.36, 44.63, 41.41, 27.94, 14.23.

In one embodiment, the method for synthesizing compound 51 (1-(6-(2-fluoropyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride) is as follows:

An aqueous solution of potassium hydroxide (15.7 mL, 5 N solution) was added to a solution of compound 37 (ethyl 1-(6-(2-fluoropyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate) (500 mg, 1.3 mmol) in dioxane (15.7 mL). The mixture was allowed to stir at 80°C for 5 hours. The dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution to give a suspension at 0°C. The product was isolated by filtration, washed with water and dried under high vacuum at 40°C. Compound 51 was isolated as an off-white solid (509 mg, <100>%).

HPLC-MS [M+H]+ 352.13; PF: 326-330°C;<1>H-NMR (400 MHz, DMSO-d<6>)<8>13.78 (sa, 1H), 12.39 (sa, 1H), 8.64-8.44 (m, 2H), 8.45-8.33 (m, 2H), 8.29-8.19 (m, 1H), 7.85-7, 78 (m, 1H), 7.70-7.59 (m, 2H), 4.69-4.47 (m, 2H), 3.59-3.51 (m, 2H), 2.75 (tt,J= 10.7, 4.3 Hz, 1H), 2.04 (dd,J= 13.8, 4.0 Hz, 2H), 1.83-1.68 (m, 2H) 113.77, 107.09, 106.70, 47.16, 39.76, 32.58, 28.08.

In one embodiment, the method for synthesizing compound 40 (ethyl 1-(6-(2-methylpyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.09 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (700 mg, 1.9 mmol), (2-methylpyridin-4-yl)boronic acid (290 mg, 2.1 mmol) and cesium carbonate (3.5 mL, 3 M solution) in a mixture of dioxane (18 mL) and water (3 mL). The suspension was allowed to stir at 80°C for 20 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 1:2) to afford compound 40 as a yellow solid (160 mg, 20%).

HPLC-MS [M+H]+ 376.35; PF: 134-135°C;<1>H-NMR (500 MHz, CDCl3)<8>8.58-8.50 (m, 1H), 7.93 (d,J= 9.1 Hz, 1H), 7.86 (d,J= 2.1 Hz, 1H), 7.81 (dd,J= 8.7, 2.1 Hz, 1H), 7.76 (d ,J= 8.7 Hz, 1H), 7.47 (s, 1H), 7.43-7.38 (m, 1H), 7.03 (d,J= 9.2 Hz, 1H), 4.49 (dt,J= 13.6, 3.9 Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.15 (ddd,J= <13>C-NMR (126 MHz, CDCl3) )<8>174.64, 158.62, 157.55, 149.25, 148.63, 148.39, 137.77, 131.66, 128.13, 127.29, 125.64, 122.88, 120.98, 118.65, 60.54, 44.72, 41.44, 27.95, 24.46, 14.24.

In one embodiment, the method for synthesizing compound 53 (1-(6-(2-methylpyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride) is as follows:

An aqueous solution of potassium hydroxide (8.4 mL, 5 N solution) was added to a solution of compound 40 (ethyl 1-(6-(2-methylpyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate) (270 mg, 0.7 mmol) in dioxane (8.4 mL). The mixture was allowed to stir at 80°C for 4 hours. The dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution to give a suspension at 0°C. The product was isolated by filtration, washed with water and dried under high vacuum at 40°C. Compound 53 was isolated as a yellow solid (280 mg, <100>%).

HPLC-MS [M+H]+ 348.16; PF: 340-345°C;<1>H-NMR (400 MHz, DMSO-d<6>)<8>12.41 (sa, 1H), 8.87-8.80 (m, 1H),<8>,<6 8> 8.62 (m, 1H), 8.59-8.31 (m, 4H), 8.32-8.25 (m, 1H), 7.65 (d,J= 9.7 Hz, 1H), 4.69-4.47 (m, 2H), 3.64-3.54 (m, 2H), 2.82 (s, 3H), 2.74 (tt,J= 10.3, 4.1 Hz, 1H), 2.03 (dd,J= 13.9, 3.9 Hz, 2H), 1.83-1.62 (m, 2H) 3.67, 46.68, 40.54, 28.12, 19.89.

In one embodiment, the method for synthesizing compound 41 (ethyl 1-(6-(3,5-dimethoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.09 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (700 mg, 1.9 mmol), (3,5-dimethoxyphenyl)boronic acid (380 mg, 2.1 mmol) and cesium carbonate (3.5 mL, 3 M solution) in a mixture of dioxane (18 mL) and water (3 mL). The suspension was allowed to stir at 80°C for 17 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to afford compound 41 as an off-white solid (520 mg, 63%).

HPLC-MS [M+H]+ 421.30; PF: 85-87°C;<1>H-NMR (500 MHz, CDCl3)<8>7.92 (d,J= 9.2 Hz, 1H), 7.81-7.71 (m, 3H), 7.02 (d,J= 9.2 Hz, 1H), 6.82 (d,J= 2.2 Hz, 2H), 6.54-6.43 (m, 1H), 4.48 (dt,J= 13.5, 4.1 Hz, 2H), 4.16 (q,J =7.1 Hz, 2H), 3.87 (s,<6>H), 3.21-3.08 (m, 2H), 2.60 (tt,J= 11.0, 4.0 Hz, 1H), 2.09-2.01 (m, 2H), 1.89-1.76 (m, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-NMR (126 MHz, CDCl3)<8>174.73, 171.56, 161.12, 157.36, 143.17, 137.70, 134.97, 99, 126.85, 125.16, 122.92, 110.20, 105.33, 99.07, 60.52, 55.46, 44.90, 41.49, 27.95, 14.25.

In one embodiment, the method for synthesizing compound 46 (1-(6-(3,5-dimethoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

An aqueous solution of potassium hydroxide (5 mL, 5 N solution) was added to a solution of compound 41 (ethyl 1-(6-(3,5-dimethoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) (200 mg, 0.4 mmol) in dioxane (5 mL). The mixture was allowed to stir at 80°C for 4 hours. The dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution to give a suspension at 0°C. The product was isolated by filtration, washed with water and dried under high vacuum at 40°C. Compound 46 was isolated as a colorless solid (170 mg, <100>%).

HPLC-MS [M+H]+ 393.25; PF: 248-251°C;<1>H-NMR (400 MHz, DMSO-d<6>)<8>12.49 (sa, 1H), 8.43 (d,J= 9.7 Hz, 1H), 8.33-8.24 (m, 2H), 8.16-8.09 (m, 1H), 7.64 (d,J= 9.8 Hz, 1 H), 6.92 (d,J= 2.2 Hz, 2H), 6.56 (t,J= 2.2 Hz, 1H), 4.53 4.45 (m, 2H), 3.84 (s,<6>H), 3.53-3.47 (m, 2H), 2.74 (tt,J= 10.5, 4.2 Hz, 1H), 2.10-2.00 (m, 2H), 1.83-1.69 (m, 2H);<13>C-NMR (126 MHz, DMSO-c/<6>)<8>175.65, 161.46, 151.90, 142.98, 141.05, 136.78, 132.49, , 126.25, 121.54, 113.31, 105.30, 100.16, 55.85, 47.19, 40.36, 28.07.

In one embodiment, the method for synthesizing compound 42 (ethyl 1-(6-(1H-indol-5-yl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.09 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)pipendine-4-carboxylate) (700 mg, 1.9 mmol), (1H-indol-5-yl)boronic acid (330 mg, 2.1 mmol) and cesium carbonate (3.5 mL, 3 M solution) in a mixture of dioxane (18 mL) and water (3 mL). The suspension was allowed to stir at 80°C for 17 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to afford compound 42 as a grey solid (470 mg, 57%).

HPLC-MS [M+H]+ 400.22; PF: 159-162°C;<1>H-NMR (400 MHz, CDCla)<8>8.27 (sa, 1H), 7.96-7.92 (m, 2H), 7.90 (dd,J= 8.7, 2.2 Hz, 1H), 7.84 (d,J= 2Hz, 1H), 7.78 (d,J= 8.7 Hz, 1 H), 7.58-7.50 (m, 1H), 7.50-7.42 (m, 1H), 7.25-7.23 (m, 1H), 7.02 (d,J= 9.2 Hz, 1H), 6.63-6.61 (m, 1H), 4.48 (dt,J= 13.7, 3.9 Hz, 2H), 4.17 (q,J= 7.1 Hz, 2H), 3.12 (ddd,J= 13.3, 11.5, 2.9 Hz, 2H), 2.59 (tt,J= 11.1, 4.0 Hz, 1H), 2.11-2.00 (m, 2H), 1.91-1.76 (m, 2H), 1.28 (t,J = 7.1 Hz, 3H) 124.83, 123.22, 121.87, 119.12, 111.28, 110.10, 102.98, 60.50, 44.98, 41.56, 27.97, 14.25.

In one embodiment, the method for synthesizing compound 45 (1-(6-(1H-indol-5-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride) is as follows:

An aqueous solution of potassium hydroxide (6.3 mL, 5 N solution) was added to a solution of compound 42 (ethyl 1-(6-(1H-indol-5-yl)quinolin-2-yl)piperidine-4-carboxylate) (200 mg, 0.5 mmol) in dioxane (6.3 mL). The mixture was allowed to stir at 60°C for 4 hours. The dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution to give a suspension at 0°C. The product was isolated by filtration, washed with water and dried under high vacuum at 40°C. Compound 45 was isolated as a yellow solid (185 mg, 80%).

HPLC-MS [M+H]+ 372.24; PF: 318-321°C;<1>H-NMR (400 MHz, DMSO-d<6>)<8>13.44 (sa, 1H), 12.47 (sa, 1H), 11.30 (s, 1H), 8.50-8.43 (m, 1H), 8.39 (d,J=<8 , 8>Hz, 1H), 8.22 ( d,J= 2.1 Hz, 1H), 8.18-8.10 (m, 1H), 7.94 (d,J= 1.5 Hz, 1H), 7.62 (d,J= 9.8 Hz, 1H), 7.57-7.47 (m, 2H), 7.46-7.37 (m, 1H), 6.55-6.49 (m, 1H), 4.56-4.47 (m, 2H), 3.58-3.48 (m, 2H), 2.75 (tt,J= 10.5, 4.2 Hz, 1H), 2.11-2.00 (m, 2H), 1.84-1.69 (m, 2H); 8>175.65, 151.56, 143.08, 138.90, 136.15, 131.53, 130.01, 128.77, 126.81, 125.48, 121.77, 120.68, 118.79, 113.04, 112.52, 102.04, 47.15, 40.36, 28.06.

In one embodiment, the method for synthesizing compound 43 (ethyl 1-(6-(6-(trifluoromethyl)pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.09 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (700 mg, 1.9 mmol), (<6>-(trifluoromethyl)pyridin-3-yl)boronic acid (400 mg, 2.1 mmol) and cesium carbonate (3.5 mL, 3 M solution) in a mixture of dioxane (18 mL) and water (3 mL). The suspension was allowed to stir at 80°C for 15 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to afford compound 43 as a colorless solid (230 mg, 26%).

HPLC-MS [M+H]+ 430.21; PF: 183-184°C;<1>H-NMR (400 MHz, CDCla)<8>9.02 (d,J= 2.2 Hz, 1H), 8.14 -8 .07 (m, 1H), 7.94 (d,J= 9.2 Hz, 1H), 7.85-7.72 (m, 4H), 7.06 (d,J= 9.2 Hz , 1H), 4.51 (dt,J= 13.5, 3.9 Hz, 2H), 4.17 (q,J= 7.1 Hz, 2H), 3.16 (ddd,J= 13.8, 11.4, 2.9 Hz, 2H), 2.62 (tt,J= 11.0, 4.0 Hz, 1H), 2.11-2.00 (m, 2H), 1.92-1.74 (m, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-NMR (101 MHz, CDCl3)<8>174.62, 157.61, 148.29, 146.41, 146.06, 137.64, 135.09, 129.72, 128.22, 127.69, 125.93, 123.13, 122.99, 120.43, 110.52, 60.55, 44.67, 41.43, 27.93, 14.23.

In one embodiment, the method for synthesizing compound 52 (1-(6-(6-(trifluoromethyl)pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride) is as follows:

An aqueous solution of potassium hydroxide (7.5 mL, 5 N solution) was added to a solution of compound 43 (ethyl 1-(6-(6-(trifluoromethyl)pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate) (250 mg, 0.5 mmol) in dioxane (7.5 mL). The mixture was allowed to stir at 80 °C for 24 h. After 24 h dioxane (7.5 mL) was added followed by an aqueous solution of potassium hydroxide (7.5 mL, 5 N solution) and the reaction mixture was allowed to stir at reflux for 24 h. The mixture was evaporated and the resulting residue was acidified with 37% hydrochloric acid solution. No precipitate formed and the aqueous solution was extracted with EtOAc, the organic phase was dried with anhydrous Na<2>SO<4>, filtered and evaporated under high vacuum to obtain compound 52 as an off-white solid (120 mg, 60%).

HPLC-MS [M+H]+ 402.15; PF: 303-307°C;<1>H-NMR (400 MHz, DMSO-d<6>)<8>13.78 (sa, 1H), 12.43 (sa, 1H), 9.21 (d,J= 2.2 Hz, 1H), 8.61-8.48 (m, 1H), 8.52-8.45 (m, 1H), -8.37 (m, 2H), 8.27-8.19 (m, 1H), 8.05 (d,J= 8.2 Hz, 1H), 7.67 (d,J= 9.7 Hz, 1H), 4.61-4.53 (m, 2H), 3.75-3.41 (m, 2H), 2.75 (tt,J= 10.5, 4.4 Hz, 1H), 2.10-2.01 (m, 2H), 1.84 1.69 (m, 2H);<13>C-NMR (126 MHz, DMSO-d<6>)<8>175.66, 152.40, 148.62, 145.61, 143.40, 142.70, 0, 136.45, 131.98, 131.15, 127.26, 123.31, 121.68, 121.42, 121.43, 113.69, 47.16, 39.64, 28.09.

In one embodiment, the method for synthesizing compound 44 (ethyl 1-(6-(pyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (92.4 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.6 mmol), pyrimidin-5-ylboronic acid (223 mg, 1.8 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (15 mL) and water (2.5 mL). The suspension was allowed to stir at 80°C for 17 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 1:2) to afford compound 44 as a colorless solid (360 mg, 60%).

HPLC-MS [M+H]+ 363.22; PF: 128-130°C;<1>H-NMR (400 MHz, CDCl3)<8>9.18 (s, 1H), 9.03 (s, 2H), 7.94 (d,J= 9.1 Hz, 1H), 7.83-7.77 (m, 2H), 7.77-7.70 (m, 1H), 7.05 (d,J= 9.2 Hz, 1H), 4.50 (dt,J= 13.8, 3.9 Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.21-3.09 (m, 2H), 2.61 (tt,J= 11.0, 4.0 Hz, 1H), 2.11-2.00 (m, 2H), 1.89-1.74 (m, 2H), 1.27 (t,J = 7.1 Hz, 3H); 27.61, 125.52, 123.06, 110.55, 60.54, 44.66, 41.42, 27.93, 14.23.

In one embodiment, the method for synthesizing compound 48 (1-(6-(pyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride) is as follows:

An aqueous solution of potassium hydroxide (6.3 mL, 5 N solution) was added to a solution of compound 44 (ethyl 1-(6-(pyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylate) (200 mg, 0.5 mmol) in dioxane (6.3 mL). The mixture was allowed to stir at 80°C for <6> hours. The dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution to give a suspension at 0°C. The product was isolated by filtration, washed with water and dried under high vacuum at 40°C. Compound 48 was isolated as a colorless solid <(200>mg, <100>%).

HPLC-MS [M+H]+ 335.20; PF: 306-310°C;<1>H-NMR (400 MHz, DMSO-d<6>)<8>13.94 (sa, 1H), 9.35-9.14 (m, 3H), 8.70 (d,J=<8 , 8>Hz, 1H), 8.51-8.39 (m, 2H), 8.29-8.21 (m, 1 H), 7.70 (d,J= 9.8 Hz, 1H), 4.61 (sa, 2H), 3.65-3.53 (m, 2H), 2.76 (tt,J= 10.6, 4.3 Hz, 1H), 2.05 (dd,J= 14.0, 3.9 Hz, 2H), 1.85-1.70 (m, 2H) 9, 113.99, 47.52, 39.54, 28.11.

In one embodiment, the method for synthesizing compound 50 (ethyl 1-(6-(6-methylpyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.13 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (1 g, 2.7 mmol), (6-methylpyridin-3-yl)boronic acid (410 mg, 3.0 mmol) and cesium carbonate (5 mL, 3 M solution) in a mixture of dioxane (26 mL) and water (4.2 mL). The suspension was allowed to stir at 80°C for 24 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1-1:1) to afford compound 50 as an orange solid (160 mg, 14%).

HPLC-MS [M+H]+ 376.24; PF: 214-218°C;<1>H-NMR (400 MHz, CDCl3)<8>8.86-8.78 (m, 1H), 7.93 (d,J= 9.2 Hz, 1H), 7.91-7.81 (m, 1H), 7.83-7.68 (m, 3H), 7.23 (d,J= 8.0 Hz, 1 H), 7.03 (d,J= 9.2 Hz, 1H), 4.48 (dt,J= 13.5, 3.9 Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.14 (ddd,J= 13.9, 11.5, 2.9 Hz, 2H), 2.70-2.48 (m, 4H), 2.05 (dd,J= 13.4, 3.9 Hz, 2H), 1.89 1.74 (m, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-NMR (126 MHz, CDCl3)<8>174.70, 157.40, 156.73, 147.60, , 137.57, 134.56, 133.51, 131.56, 128.45, 127.31, 125.01, 123.17, 123.06, 110.31, 60.52, 44.79, 41.48, 27.95, 24.10,

In one embodiment, the method for synthesizing compound 80 (1-(6-(6-methylpyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride) is as follows:

An aqueous solution of potassium hydroxide (4 mL, 5 N solution) was added to a solution of compound 50 (ethyl 1-(6-(6-methylpyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate) (130 mg, 0.3 mmol) in dioxane (4 mL). The mixture was allowed to stir at 80 °C for 2 hours. Dioxane was evaporated and the resulting aqueous mixture was acidified with 37% hydrochloric acid solution. No precipitate was formed and the aqueous solution was extracted with a mixture of DCM/Isop (7:3), the organic phase was dried with anhydrous Na<2>SO<4>, filtered and evaporated under high vacuum to give compound 80 as a yellow solid (112 mg, 100%). HPLC-MS [M+H]+348.15; PF: 281-284°C;<1>H-NMR (400 MHz, D<2>O)<8>9.15 (d,J= 2.2 Hz, 1H), 8.94 (dd,J= 8.5, 2.1 Hz, 1H), 8.57 (d,J= 9.8 Hz, 1H), 8.38 (d,J= 2.0 Hz, 1H), 8 .27 (dd,J=<8>,<8>, 2.0 Hz, 1H), 8.17 (t,J= 8.5 Hz, 2H), 7.64 (d,J= 9.8 Hz, 1H), 4.52 (dt,J= 14.1, 4.2 Hz, 2H), 3.78 (ddd,J= 14.0, 11.0, 3.0 Hz, 2H), 3.11 (tt,J= 10.3, 4.5 Hz, 1H), 3.03 (s, 3H), 2.41 (dt,J= 12.5, 4.0 Hz, 2H), 2.08 (qd,J= 10.8, 5.5 Hz, 2H); 152.08, 150.13, 145.41, 144.40, 143.31, 138.41, 137.08, 135.99, 131.30, 128.44, 127.30, 121.49, 118.76, 118.09, 113.16, 46.62, 39.45, 27.24, 18.88.

In one embodiment, the method for synthesizing compound 54 (ethyl 1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-3-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (207 mg, 0.18 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (1.3 g, 3.5 mmol), pyridin-4-ylboronic acid (480 mg, 3.9 mmol) and cesium carbonate (6.5 mL, 3 M solution) in a mixture of dioxane (33 mL) and water (5.5 mL). The suspension was allowed to stir at 80°C for <6> hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1) to afford compound 54 as a colorless solid (750 mg, 57%).

HPLC-MS [M+H]+ 362.22; PF: 84-87°C;<1>H-NMR (400 MHz, CDCl3)<8>8.72-8.64 (m, 2H), 7.95 (d,J= 9.2 Hz, 1H), 7.89 (d,J= 2.1 Hz, 1H), 7.84 (dd,J=<8>,<8>, 2.1 Hz, 1H), 7.80 ( d,J= 8.7 Hz, 1H), 7.64-7.59 (m, 2H), 7.10 (d,J= 9.2 Hz, 1H), 4.60 (ddd,J= 13.3, 3.6, 1.8 Hz, 1H), 4.32 (ddd,J= 13.2, 4.8, 3.2 Hz, 1H), 4.20 (q,J= 7.1 Hz, 2H), 3.40 (m, 1H), 3.28 (ddd,J= 13.5, 10.8, 3.0 Hz, 1H), 2.65 (tt,J= 9.9, 4.0 Hz, 1H), 2.21-2.09 (m, 1H), 1.94-1.78 (m, 2H), 1. 75-1.59 (m, 1H), 1.30 (t,J = 7.1 Hz, 3H); 127.40, 125.60, 122.88, 121.32, 110.46, 60.61, 47.36, 45.56, 41.30, 27.58, 24.20, 14.25.

In one embodiment, the method for synthesizing compound 62 (1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-3-carboxylic acid hydrochloride) is as follows:

An aqueous solution of potassium hydroxide (14 mL, 5 N solution) was added to a solution of compound 54 (ethyl 1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-3-carboxylate) (450 mg, 1.2 mmol) in dioxane (14 mL). The mixture was allowed to stir at 80°C for 4 hours. The mixture was evaporated and the resulting residue was acidified with 37% hydrochloric acid solution. The aqueous solution was extracted with a mixture of DCM/Isop (7:3), the organic phase was dried over anhydrous Na<2>SO<4>, filtered and evaporated under high vacuum to give a yellow residue. The residue was suspended in EtOAc and a solution of hydrochloric acid in diethyl ether (1.5 mL, 2 N) was added dropwise at 0 °C to give a suspension. The solid was removed by filtration and compound 62 was isolated as an orange solid (74 mg, 51%).

HPLC-MS [M+H]+ 334.19; PF: 245-250°C;<1>H-NMR (500 MHz, DMSO-c/<6>)<8>8.98 (d,J= 5.9 Hz, 2H), 8.69-8.66 (m, 1H), 8.48-8.33 (m, 5H), 7.72-7.62 (m, 1H), 4.51-4.37 (m, 1H), 4.37-4.38 (m, 1H), 3.43-3.45 (m, 1H), 2.90-2.81 (m, 1H), 2.79-2.71 (m, 1H), 2.09-2.00 (m, 1H), 1.89-1.77 (m, 2H), 1.76-1.62 (m, 1H) 2, 65.37, 52.17, 48.94, 26.96, 24.28, 15.63.

In one embodiment, the method for synthesizing compound 55 (ethyl 1-(6-(pyridin-2-yl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (250 mg, 0.69 mmol), pyridine-2-boronic acid, pinacol ester (290 mg, 1.39 mmol), copper bromide (100 mg, 0.69 mmol), cesium carbonate (950 mg, 2.9 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(N) (51 mg, 0.069 mmol) were placed in a flask. The flask was degassed with N<2> for 10 minutes. Dry DMF (25 mL) was added and the resulting mixture was degassed for a further 10 minutes before the reaction mixture was heated at 100 °C for 18 hours. Water was added and the aqueous solution was extracted with EtOAc, the organic phase was dried with anhydrous Na<2>SO<4>, filtered and evaporated under high vacuum. The resulting residue was purified by column chromatography (silica gel, petroleum ether/EtOAc<2>:<1>) to afford compound 55 as a colorless solid (167 mg, 46%).

HPLC-MS [M+H]+ 362.24; PF: 134-137°C;<1>H-NMR (500 MHz, CDCla)<8>8.73-8.68 (m, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.22-8.16 (m, 1H), 8.07-7.90 (m, 2H), 7.84-7.74 (m, 2H), 7 .26-7.19 (m, 1H), 7.02 (d,J= 9.2 Hz, 1H), 4.54-4.48 (m, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.33-3.10 (m, 2H), 2.62 (tt,J= 10.8, 4.0 Hz, 1H), 2.11-2.02 (m, 2H), 1.91-1.80 (m, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-NMR (126 MHz, DMSO-d<6>)<8>174.58, 157.60, 156.27, 149.94, 148.36, .56, 137.64, 132.51, 128.12, 126.62, 125.93, 122.90, 122.53, 120.25, 111.06, 60.41, 44.42, 40.94, 28.02, 14.57.

In one embodiment, the method for synthesizing compound 61 (1-(6-(pyridin-2-yl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

Potassium hydroxide (85 mg, 1.5 mmol) was added to a solution of compound 55 (ethyl 1-(6-(pyridin-2-yl)quinolin-2-yl)piperidine-4-carboxylate) (100 mg, 0.3 mmol) in a mixture of MeOH and water (2.2 mL). The mixture was allowed to stir at room temperature for 4 hours. MeOH was evaporated, and the resulting aqueous mixture was acidified with acetic acid. The aqueous solution was extracted with EtOAc, the organic phase was dried over anhydrous Na<2>SO<4>, filtered, and evaporated under high vacuum. Compound 61 was isolated as a yellow solid (53 mg, 48%).

HPLC-MS [M+H]+ 334.19; PF: 280-283°C;<1>H-NMR (400 MHz, DMSO-c/<6>)<8>8.70-8.63 (m, 1H), 8.44 (d,J= 2.1 Hz, 1H), 8.31-8.22 (m, 1H), 8.12 (d,J= 9.2 Hz, 1H), 8.07-7.99 (m, 1H), 7.93-7.84 (m, 1H), 7.62 (d,J=<8 , 8>Hz, 1H), 7.37 7.25 (m, 2H), 4.49-4.41 (m, 2H), 3.12-3.05 (m, 2H), 2.48-2.42 (m, 1H), 1.95-1.88 (m, 2H), 1.60-1.50 (m, 2H);<13>C-NMR (101 MHz, DMSO-d<6>)<8>176.84, 157.68, 156.31, 149.91, 148.49, 138.42, 137.61, 128.03, 126.61, 125.90, 122.82, 122.47, 120.21, 111.02, 44.71, 41.90, 28.54.

In one embodiment, the method for synthesizing compound 57 (ethyl 1-(4-methyl-6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (175 mg, 0.15 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (1.1 g, 3.03 mmol), pyridin-4-ylboronic acid (410 mg, 3.33 mmol) and cesium carbonate <( 6 >ml, 3 M solution) in a mixture of dioxane (20 ml) and water (4 ml). The suspension was allowed to stir at 80°C for 20 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1-2:1) to afford compound 57 as a colorless solid (600 mg, 53%).

HPLC-MS [M+H]+ 376.29; PF: 287-289°C;<1>H-NMR (400 MHz, DMSO-d<6>)<8>9.01-8.90 (m, 2H), 8.54-8.41 (m, 3H), 8.35 (dd,J=<8>,<8>, 2.1 Hz, 1H), 7.65-7.52 (m, 2H), 4.47 (m, 2H), 4.10 (q,J= 7.1 Hz, 2H), 2.88-2.72 (m, 5H), 2.55-2.49 (m, 1H), 2.05 (dd,J= 14.0, 4.1 Hz, 2H), 1.81-1.69 (m, 2H), 1.21 (t,J= 7.1, 3H) 112.91, 73.90, 60.63, 46.74, 34.61, 28.03, 19.61, 14.55.

In one embodiment, the method for synthesizing compound 56 (1-(4-methyl-6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid) is as follows:

Potassium hydroxide (300 mg, 5.33 mmol) was added to a solution of compound 57 (ethyl 1-(4-methyl-6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate) (400 mg, 1.07 mmol) in a mixture of MeOH and water (11 mL). The mixture was allowed to stir at room temperature for 4 hours. MeOH was evaporated, and the resulting aqueous mixture was acidified with acetic acid. The aqueous solution was extracted with EtOAc, the organic phase was dried over anhydrous Na<2>SO<4>, filtered, and evaporated under high vacuum. Compound 56 was isolated as a colorless solid (300 mg, 85%).

HPLC-MS [M+H]+ 348.23; PF: 340-342°C; 1H-NMR (500 MHz, DMSO-d<6>)<6>8.66-8.61 (m, 2H), 8.23-8.18 (m, 1H), 7.99-7.93 (m, 1H), 7.87-7.82 (m, 2H), 7.65 (d,J= 8.7 Hz, 1H), 7.21 (sa, 1H), 4.52-4, 43 (m, 2H), 3.15-3.07 (m, 2H), 2.66 (s, 3H), 2.62-2.55 (m, 1H), 1.96-1.89 ( m, 2H), 1.59-1.51 (m, 2H); 13C-NMR(126 MHz, DMSO-d<6>)<6>176.65, 157.53, 150.36, 148.50, 147.39, 146.09, 130.13, 127.95, 127 .64, 123.37, 122.73, 121.32, 111.13, 44.09, 40.26, 27.83, 19.29.

In one embodiment, the method for synthesizing compound 58 (ethyl 1-(6-(3-fluoro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (96 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.66 mmol), (3-fluoro-4-methoxyphenyl)boronic acid (310 mg, 1.83 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for 5 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 3:1) to afford compound 58 as a colorless solid (417.3 mg, 52%).

HPLC-MS [M+H]+ 409.27; PF: 150-152°C;<1>H-NMR (400 MHz, CDCla)<6>7.91 (d,J= 9.1 Hz, 1H), 7.79-7.69 (m, 3H),<7>,<4 4>-<7 , 3 4>(m, 2H), 7.08-6.97 (m, 2H), 4.47 (dt,J = 13.5, 3.9 Hz, 2H), 4.16 (q,J= 7.2 Hz, 2H), 3.94 (s, 3H), 3.13 (ddd,J= 13.8, 11.5, 2.9 Hz, 2H), 2.59 (tt,J= 11.0, 4.0 Hz, 1H), 2.11-1.99 (m, 2H), 1.89-1.74 (m, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-NMR (101 MHz, CDCla)<6>174.73, 157.28, 153.86, 151.43, 146.71, 137.59, 134.29, 3.52, 126.98, 124.55, 123.01, 122.48, 114.64, 113.72, 110.26, 60.52, 56.40, 44.87, 41.48, 27.94, 14.23.

In one embodiment, the method for synthesizing compound 59 (ethyl 1-(6-(3-chloro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (96 mg, 0.083 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.66 mmol), (3-chloro-4-methoxyphenyl)boronic acid (341 mg, 1.83 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for <6> hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 3:1) to afford compound 59 as a colorless solid (400 mg, 57%).

HPLC-MS [M+H]+ 425.24; PF: 145-147°C;<1>H-NMR (400 MHz, CDCl3)<8>7.91 (d,J= 9.1 Hz, 1H), 7.79-7.65 (m, 4H), 7.58-7.49 (m, 1H), 7.06-6.97 (m, 2H), 4.47 (dt,J= 13.5, 3.9 Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.95 (s, 3H), 3.13 (ddd,J= 13.8, 11.5, 2.9 Hz, 2H), 2.59 (tt,J= 11.0, 4.0 Hz, 1H), 2.11-1.99 (m, 2H), 1.89-1.74 (m, 2H), 1.27 (t,J = 7.1 Hz, 3H); 128.70, 127.00, 126.09, 124.56, 123.02, 122.81, 112.34, 110.27, 60.52, 56.28, 44.87, 41.48, 27.94, 14.23.

In one embodiment, the method for synthesizing compound 60 (ethyl 1-(6-(3,4-dimethoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (135 mg, 0.12 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (840 mg, 2.33 mmol), (3,4-dimethoxyphenyl)boronic acid (470 mg, 2.56 mmol) and cesium carbonate (4.2 mL, 3 M solution) in a mixture of dioxane (22 mL) and water (3.6 mL). The suspension was allowed to stir at 80°C for <6> hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1) to afford compound 60 as a colorless solid (500 mg, 51%).

HPLC-MS [M+H]+ 421.29; PF: 151-153°C;<1>H-NMR (400 MHz, CDCl3)<8>7.92 (d,J= 9.2 Hz, 1H), 7.81-7.67 (m, 3H), 7.24-7.15 (m, 2H), 7.02 (d, J = 9.2 Hz, 1H), 6.96 (m, 1H), 4. 47 (dt,J= 13.4, 3.9 Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.98 (s, 3H), 3.93 (s, 3H), 3.12 (ddd,J= 13.8, 11.4, 2.8 Hz, 2H), 2.59 (tt,J= 11.1, 4.0 Hz, 1H), 2.11-1.99 (m, 2H), 1.90-1.75 (m, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-NMR(101 MHz, CDCl3)<8>174.76, 157.27, 149.20, 148.39, 3, 134.90, 134.01, 128.86, 126.90, 124.49, 123.06, 119.29, 111.55, 110.35, 110.20, 60.51, 55.99, 44.90, 41.50, 27.95, 14,24.

In one embodiment, the method for synthesizing compound 63 (ethyl 1-(6-(4-chloro-3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

t

Tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.6 mmol), (4-chloro-3-fluorophenyl)boronic acid (300 mg, 1.7 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (15 mL) and water (2.6 mL). The suspension was allowed to stir at 80 °C for 17 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 6:1-4:1) to afford compound 63 as a colorless solid (510 mg, 75%).

HPLC-MS [M+H]+ 413.19; PF: 115-116°C;<1>H-NMR (500 MHz, CDCh)<6>7.90 (d,J= 9.1 Hz, 1H), 7.84-7.63 (m, 3H), 7.55-7.40 (m, 2H), 7.41-7.33 (m, 1H), 7.02 (d,J= 9.2 Hz, ), 4.49 (dt,J= 13.7, 4.0 Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.24-3.10 (m, 2H), 2.60 (tt,J= 11.0, 3.9 Hz, 1H), 2.05 (dd,J= 13.5, 3.7 Hz, 2H), 1.88-1.76 (m, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-MRI (126 MHz, CDCh)<6>174.66, 159.35, 157.38, 141.63, 137.68, 130.78, 128.36, 127.49, 1 25.16, 123.19, 122.89, 119.44, 119.30, 114.98, 114.81, 110.38, 60.54, 44.81,41.44, 27.95, 14.25.

In one embodiment, the method for synthesizing compound 64 (ethyl 1-(6-(3-chlorophenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.6 mmol), (3-chlorophenyl)boronic acid (284 mg, 1.8 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (15 mL) and water (3 mL). The suspension was allowed to stir at 80°C for 16 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 6:1) to afford compound 64 as an off-white solid (510 mg, 80%).

HPLC-MS [M+H]+ 395.21; PF: 117-120°C;<1>H-NMR (500 MHz, CDCh)<6>7.92 (d,J= 9.1 Hz, 1H), 7.80-7.73 (m, 3H), 7.66 (sa, 1H), 7.55 (d,J= 7.7, 1H), 7.38 (m, 1H), 7.30 (d,J= 7.9 Hz, 1H), 7.03 (d,J= 9.2 Hz, 1H), 4.49 (dt,J= 13.4, 4.0 Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.20-3.09 (m, 2H), 2.60 (tt,J= 11.1,4.0 Hz, 1H), 2.05 (dd,J= 13.3, 3.8 Hz, 2H), 1.88-1.76 (m, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-MRI (126 MHz, CDCh)<6>174.72, 157.46, 147.82, 142.82, 134.69, 133.43, 130.01, 128.62, 127.16, 127.10, 126.86, 125.27, 125.13, 122.98, 110.29, 60.53, 44.80, 41.50, 27.96,

In one embodiment, the method for synthesizing compound 65 (ethyl 1-(6-(4-chlorophenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.6 mmol), (4-chlorophenyl)boronic acid (284 mg, 1.8 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (15 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for 24 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1-2:1) to afford compound 65 as an off-white solid (390 mg, 60%).

HPLC-MS [M+H]+ 395.21; PF: 160-164°C;<1>H-NMR (500 MHz, CDCl3)<8>7.91 (d,J= 9.1 Hz, 1H), 7.81-7.69 (m, 3H), 7.59 (d,J= 8.1 Hz, 2H), 7.41 (d,J= 8.2 Hz, 2H), 7.02 (d,J= 9 ,1 Hz, 1H), 4.53-4.44 (m, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.22-3.04 (m, 2H), 2.60 (tt,J= 11.1, 4.0 Hz, 1H), 2.05 (dd,J= 13.5, 3.8 Hz, 2H), 1.88-1.76 (m, 2H), 1.27 (t,J = 7.1 Hz, 3H); 128.24, 127.80, 126.46, 125.01, 122.88, 110.32, 60.56, 44.96, 41.38, 27.96, 14.25.

In one embodiment, the method for synthesizing the compound <6 6>(ethyl 1-(6-(3-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.6 mmol), (43-(trifluoromethyl)phenyl)boronic acid (345 mg, 1.7 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for 24 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to afford compound <66> as an off-white solid (520 mg, 75%).

HPLC-MS [M+H]+ 429.22; PF: 135-136°C;<1>H-NMR (500 MHz, CDCl3)<8>7.97-7.90 (m, 2H), 7.87-7.74 (m, 4H), 7.62 7.53 (m, 2H), 7.04 (d,J= 9.1 Hz, 1H), 4.50 (dt,J= 13.6, 4.0 Hz, 2H), 4.17 (q,J= 7.1 Hz, 2H), 3.15 (t,J= 12.3 Hz, 2H), 2.61 (tt,J= 11.0, 4.0 Hz, 1H), 2.06 (dd,J= 13.4, 3.7 Hz, 2H), 1.89-1.77 (m, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-NMR (126 MHz, CDCl3)<8>199.02, 174.68, 157.41, 141.73, 137.69, 131.57, 131.31, 131.05, 130.24, 129.24, 1 28.64, 127.25, 125.40, 123.73, 123.53, 122.98, 110.36, 60.54, 44.83, 41.46, 27.96, 14.24.

In one embodiment, the method for synthesizing compound 67 (ethyl 1-(6-(pyridin-4-yl)quinolin-2-yl)pyrrolidine-3-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (127 mg, 0.11 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (800 mg, 2.3 mmol), pyridin-4-ylboronic acid (310 mg, 2.5 mmol) and cesium carbonate (4 mL, 3 M solution) in a mixture of dioxane (20 mL) and water (3.4 mL). The suspension was allowed to stir at 80°C for <6> hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 1:2). The product was recrystallized from Isop and compound 67 was isolated as a yellow solid (279 mg, 50%).

HPLC-MS [M+H]+ 348.20; PF: 145-147°C;<1>H-NMR (500 MHz, CDCla)<6>8.67-8.62 (m, 2H), 7.93 (d,J= 9.0 Hz, 1H), 7.90-7.79 (m, 3H), 7.61-7.56 (m, 2H), 6.78 (d,J= 8.9 Hz, ), 4.20 (q,J= 7.1 Hz, 2H), 4.03-3.64 (m, 4H), 3.30-3.20 (m, 1H), 2.39-2.31 (m, 2H), 1.29 (t,J= 7.1 Hz, 3H); 167.28, 150.15, 148.04, 137.81, 131.05, 128.26, 126.75, 125.93, 122.64, 121.31, 110.82, 61.07, 49.40, 46.58, 43.05, 14,23.

In one embodiment, the method for synthesizing compound <68>(ethyl 1-(6-(benzo[b]thiophen-2-yl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.6 mmol), benzo[6]thiophen-2-ylboronic acid (323 mg, 1.8 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (15 mL) and water (2.6 mL). The suspension was allowed to stir at 80 °C for 24 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 8:1) to give compound <68> as a light brown solid <( 100> mg, <12>%).

HPLC-MS [M+H]+ 417.20; PF: 199-201°C;<1>H-NMR (500 MHz, CDCta)<6>8.02-7.86 (m, 3H), 7.89-7.69 (m, 3H), 7.58 (s, 1H), 7.39-7.27 (m, 2H), 7.02 (d,J= 9.1 Hz, 1H), 4.49 (d t,J= 13.8, 4.0 Hz, 2H), 4.17 (q,J= 7.1 Hz, 2H), 3.21-3.09 (m, 2H), 2.60 (tt,J= 11.0, 4.0 Hz, 1H), 2.10-2.01 (m, 2H), 1.88-1.76 (m, 2H), 1.28 (t,J= 7.1 Hz, 3H);<13>C-MRI (126 MHz, CDCta)<6>174.66, 169.30, 144.30, 140.91, 140.07, 139.32, 137.62, 127.99, 127.97, 124.70, 4.52, 124.15, 123.40, 122.22, 118.95, 110.37, 60.55, 44.82, 41.43, 27.96, 14.25.

In one embodiment, the method for synthesizing compound 69 (ethyl 1-(6-(2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.6 mmol), (2-(trifluoromethyl)phenyl)boronic acid (345 mg, 1.8 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (15 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for 22 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 6:1) to afford compound 69 as a colorless solid (509 mg, 70%).

HPLC-MS [M+H]+ 429.15; PF: 168-170°C;<1>H-NMR (400 MHz, CDCl3)<6>8.58-8.30 (m, 2H), 7.96-7.85 (m, 2H), 7.82 7.75 (m, 1H), 7.75-7.60 (m, 3H), 7.49 (d,J= 7.6 Hz, 1H), 4.62-4.48 (m, 2H), 4.11 (q,J= 7.1 Hz, 2H), 3.59-3.48 (m, 2H), 2.84 (tt,J= 10.5, 6.1 Hz, 1H), 2.05 (dd,J= 14.1, 3.7 Hz, 2H), 1.85-1.71 (m, 2H), 1.20 (t,J = 7.1 Hz, 3H); , 131.42, 131.37, 130.69, 127.97, 125.53, 118.45, 51.79, 44.63, 32.72, 19.30.

In one embodiment, the method for synthesizing compound 70 (ethyl 1-(6-(2-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.6 mmol), (2-(trifluoromethoxy)phenyl)boronic acid (354 mg, 1.8 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (15 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for 21 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 6:1) to afford compound 70 as a colorless solid (564 mg, 75%).

HPLC-MS [M+H]+ 445.12; PF: 161-164°C;<1>H-NMR (400 MHz, CDCl3)<6>8.49-8.37 (m, 2H), 8.04 (d,J= 2.0 Hz, 1H), 7.90-7.83 (m, 1H), 7.68-7.48 (m, 5H), 4.60-4.51 (m, 2H), 4.10 (q,J= 7.1 Hz, 2H), 3.58-3.45 (m, 2H), 2.84 (ddt,J= 15.0, 10.6, 4.7 Hz, 1H), 2.05 (dd,J= 13.6, 3.9 Hz, 2H), 1.85-1.70 (m, 2H), 1.20 (t,J= 7.1 Hz, 3H); 13C-NMR(126 MHz, CDCl3)<6>173.44, 151.64, 146.13, 143.11, 137.78, 134.27, 133.37, 131.41, 129.48, 127.79, 127.41, 121.60, , 120.31, 111.09, 60.98, 47.85, 39.73, 27.90, 14.16.

In one embodiment, the method for synthesizing compound 71 (ethyl 1-(6-(4-fluoro-2-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

t

Tetrakis(triphenylphosphine)palladium(0) (96 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.66 mmol), (4-fluoro-2-methoxyphenyl)boronic acid (311 mg, 1.83 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80 °C for <6> hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1) to afford compound 71 as a colorless solid (442 mg, 65%).

HPLC-MS [M+H]+409.24; PF: 93-96°C;<1>H-NMR (400 MHz, CDCl3)<8>7.92 (d,J= 9.2 Hz, 1H), 7.78-7.67 (m, 3H), 7.40 7.31 (m, 1H), 7.03 (d,J= 9.2 Hz, 1H), 6.82-6.71 (m, 2H), 4.50 (dt,J= 13.4, 3.9 Hz, 2H), 4.19 (q,J= 7.1 Hz, 2H), 3.84 (s, 3H), 3.22-3.10 (m, 2H), 2.62 (tt,J= 11.0, 4.0 Hz, 1H), 2.07 (dd,J= 13.5, 3.8 Hz, 2H), 1.92-1.77 (m, 2H), 1.30 (t,J= 7.1 Hz, 3H);<13>C-NMR (101 MHz, CDCl3)<8>174.72, 164.17, 161.73, 157.65, 137.71, 131.51, , 126.44, 122.66, 109.94, 107.24, 107.03, 99.58, 99.33, 60.50, 55.80, 45.04, 41.48, 27.91, 14.24.

In one embodiment, the method for synthesizing compound 72 (ethyl 1-(6-(4-methoxy-3-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (96 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.66 mmol), (4-methoxy-3-(trifluoromethyl)phenyl)boronic acid (402 mg, 1.83 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for <6> hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1) to afford compound 72 as a colorless solid (749 mg, 98%).

HPLC-MS [M+H]+ 459.10; PF: 137-141°C;<1>H-NMR (400 MHz, CDCl3)<8>7.95 (d,J= 9.2 Hz, 1H), 7.86 (d,J=2.4 Hz, 2H), 7.80-7.72 (m, 3H), 7.09 (d,J=<8 , 6>Hz, 1H), 7.04 (d,J= 9.2 Hz, 1H), 4.49 (dt,J= 13.5, 4.0 Hz, 2H), 4.17 (q,J= 7.1 Hz, 2H), 3.96 (s, 3H), 3.25-3.10 (m, 2H), 2.62 (tt,J= 10.9, 4.0 Hz, 1H), 2.12-2.02 (m, 2H), 1.92-1.77 (m, 2H), 1.27 (t,J= 7.2 Hz, 3H);<13>C-NMR (101 MHz, CDCl3)<8>174.57, 156.67, 132.90, 132.14, 131.49, 128.44, 127.74, 125.65, 125.03, 124.66, 122.84, 122.32, 119.25, 118.94, 112.48, 110.39, 60.58, 56.13, 45.14, 41.27, 14.23. In one embodiment, the method for synthesizing compound 73 (ethyl 1-(6-(4-chloro-3-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (96 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.66 mmol), (4-chloro-3-methoxyphenyl)boronic acid (371 mg, 1.99 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for 5 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to afford compound 73 as a colorless solid (420 mg, 60%).

HPLC-MS [M+H]+ 425.18; PF: 146-148°C;<1>H-NMR (400 MHz, CDCl3)<8>8.28-7.94 (m, 2H), 7.85-7.68 (m, 2H), 7.47 7.40 (m, 1H), 7.21-7.13 (m, 2H), 7.08-7.01 (m, 1H), 5-4.45 (m, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.99 (s, 3H), 3.39-3.21 (m, 2H), 2.64 (tt,J= 10.7, 4.1 Hz, 1H), 2.19-2.02 (m, 2H), 1.96-1.76 (m, 2H), 1.27 (t,J = 7.1 Hz, 3H); 112.73, 110.83, 110.49, 108.10, 100.68, 60.67, 56.25, 45.41,41.06, 27.91, 14.24.

In one embodiment, the method for synthesizing compound 74 (ethyl 1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (96 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.66 mmol), (43-fluorophenyl)boronic acid (280 mg, 1.99 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for 7 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to afford compound 74 as an off-white solid (421 mg, 62%).

HPLC-MS [M+H]+ 379.24; PF: 120-123°C;<1>H-NMR (400 MHz, CDCl3)<8>7.94 (d,J= 9.2 Hz, 1H), 7.91-7.74 (m, 3H), 7.53-7.31 (m, 3H), 7.08-6.98 (m, 2H), 4.49 (dt,J= 13.5, 4.0 Hz, 2H), 4.17 (q,J= 7.1 Hz, 2H), 3.27-3.11 (m, 2H), 2.61 (tt,J= 10.9, 4.0 Hz, 1H), 2.07 (dd,J= 13.5, 3.8 Hz, 2H), 1.91-1.76 (m, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-NMR (126 MHz, CDCl3)<8>174.64, 164.25, 162.30, 157.03, 143.15, 138.01, 133.92, 130.29, 128.89, 125.24, , 122.60, 122.61, 113.73, 110.34, 60.57, 44.99, 41.38, 27.95, 14.26.

In one embodiment, the method for synthesizing compound 75 (ethyl 1-(6-(3-chloro-4-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (96 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.66 mmol), (3-doro-4-fluorophenN)boronic acid (345 mg, 1.99 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for <6> hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to afford compound 75 as a colorless solid (664 mg, 97%).

HPLC-MS [M+H]+ 413.16; PF: 143-146°C;<1>H-NMR (400 MHz, CDCl3)<8>7.93 (d,J= 9.2 Hz, 1H), 7.86 (m, 1H), 7.78 7.65 (m, 3H), 7.55-7.44 (m, 1H), 7.26-7.17 (m, 1H), 7.04 ( d,J= 9.2 Hz, 1H), 4.49 (dt,J= 13.5, 3.9 Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.25-3.14 (m, 2H), 2.62 (tt,J= 10.8, 4.0 Hz, 1H), 2.07 (dd,J= 13.5, 3.8 Hz, 2H), 1.91-1.76 (m, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-NMR (101 MHz, CDCl3)<8>174.55, 158.70, 156.23, 138.07, 129.05, 126.64, , 125.11, 122.74, 121.37, 117.17, 116.95, 116.74, 110.45, 60.59, 45.09, 41.26, 27.92, 14.23.

In one embodiment, the method for synthesizing compound 76 (ethyl 1-(6-(2-methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (96 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.66 mmol), (2-methoxypyridin-3-yl)boronic acid (305 mg, 1.99 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for <6> hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1) to afford compound 76 as an off-white solid (515 mg, 79%).

HPLC-MS [M+H]+ 392.26; PF: 105-107°C;<1>H-NMR (400 MHz, CDCl3)<8>8.22-8.12 (m, 1H), 7.90 (d,J= 9.1 Hz, 1H), 7.84-7.61 (m, 4H), 7.05-6.95 (m, 2H), 4.48 (dt,J= 13.6, 3.9 Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 4.00 (s, 3H), 3.13 (ddd,J= 13.9, 11.4, 2.8 Hz, 2H), 2.59 (tt,J= 11.0, 4.0 Hz, 1H), 2.04 (dd,J= 13.4, 3.8 Hz, 2H), 1.89-1.74 (m, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-NMR (101 MHz, CDCl3)<8>174.73, 161.01, 157.46, 147.41, 145.38, 138.51, 137.62, 0.78, 130.58, 127.46, 126.28, 124.54, 122.69, 117.14, 110.00, 60.50, 53.53, 44.89, 41.52, 27.92, 14.24.

In one embodiment, the method for synthesizing compound 77 (ethyl 1-(6-(5-fluoropyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

OEt

Tetrakis(triphenylphosphine)palladium(0) (96 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.66 mmol), (5-fluoropyridin-3-yl)boronic acid (280 mg, 1.99 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80 °C for <6> hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1) to afford compound 77 as an off-white solid (540 mg, <8.6>%).

HPLC-MS [M+H]+ 380.21; PF: 113-115°C;<1>H-NMR (400 MHz, CDCl3)<8>8.77-8.74 (m, 1H), 8.43 (d,J= 2.7 Hz, 1H), 7.93 (d,J= 9.2 Hz, 1H), 7.86-7.71 (m, 3H), 7.70-7.64 (m, 1 H), 7.05 (d,J= 9.2 Hz, 1H), 4.50 (dt,J= 13.9, 3.9 Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.15 (ddd,J= 13.8, 11.4, 2.9 Hz, 2H), 2.61 (tt,J= 11.0, 4.0 Hz, 1H), 2.11-2.00 (m, 2H), 1.88 1.77 (m, 2H), 1.27 (t,J= 7.1 Hz, 3H);<13>C-NMR (101 MHz, CDCl3)<8>174.65, 161.07, 158.52, 157.55, 4, 138.18, 137.64, 136.20, 129.84, 128.29, 127.52, 125.71, 122.96, 120.87, 110.49, 60.55, 44.72, 41.43, 27.93, 14.23.

In one embodiment, the method for synthesizing compound 78 (ethyl 1-(6-(3-fluoropyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (96 mg, 0.08 mmol) was added to a stirred suspension of intermediate 1 (ethyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (600 mg, 1.66 mmol), (3-fluoropyridin-4-yl)boronic acid (280 mg, 1.99 mmol) and cesium carbonate (3 mL, 3 M solution) in a mixture of dioxane (16 mL) and water (2.6 mL). The suspension was allowed to stir at 80°C for <6> hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1-1:2) to afford compound 78 as a yellow solid (100 mg, 16%).

HPLC-MS [M+H]+ 380.16; PF: 97-101°C;<1>H-NMR (400 MHz, CDCl3)<8>8.63-8.51 (m, 1H), 8.47 (d,J= 5.0 Hz, 1H), 8.08-7.85 (m, 3H), 7.83-7.75 (m, 1H), 7.49 (m, 1H), 7.05 (d ,J= 9.3 Hz, 1H), 4.57-4.47 (m, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.29-3.12 (m, 2H), 2.63 (tt,J= 10.8, 4.0 Hz, 1H), 2.07 (dd,J= 13.4, 3.9 Hz, 2H), 1.90-1.76 (m, 2H), 1.27 (t,J = 7.1 Hz, 3H); 132.10, 129.87, 128.02, 126.84, 124.01, 122.50, 110.41, 60.59, 44.95, 41.28, 27.93, 14.23.

In one embodiment, the method for synthesizing intermediate 2 compounds (methyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) is as follows:

DIPEA (5 mL) was added to a suspension of 2-chloro-6-bromoquinoline (1 g, 4.1 mmol) and methyl isonipecotate (650 mg, 4.5 mmol) in 1-BuOH (20 mL) and the mixture was allowed to stir at 130 °C for 24 h. The solvent was evaporated and the resulting residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1) to afford intermediate 2 as an off-white solid (572 mg, 98%).

In one embodiment, the method for synthesizing compound 79 (methyl 1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate) is as follows:

Tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.07 mmol) was added to a stirred suspension of intermediate 2 (methyl 1-(6-bromoquinolin-2-yl)piperidine-4-carboxylate) (480 mg, 1.39 mmol), pyridin-4-ylboronic acid (285 mg, 1.66 mmol) and cesium carbonate (2.4 mL, 3 M solution) in a mixture of dioxane (10 mL) and water (2 mL). The suspension was allowed to stir at 80°C for 5 hours. The solvent was evaporated under high vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1). The impure product was dissolved in hot Isopropyl alcohol, filtered while hot and the filtrate was allowed to cool to 0°C. Crystals of the product were collected by filtration. Product compound 79 was isolated as an off-white solid (204 mg, 42%). HPLC-MS [M+H]+ 348.13; PF: 153-155°C;<1>H-NMR (400 MHz, CDCla)<8>8.70-8.61 (m, 2H), 7.93 (d,J= 9.2 Hz, 1H), 7.87 (d,J= 2.1 Hz, 1H), 7.85-7.73 (m, 2H), 7.62-7.55 (m, 2H) ), 7.04 (d,J= 9.2 Hz, 1H), 4.50 (dt,J= 13.4, 3.9 Hz, 2H), 3.71 (s, 3H), 3.15 (ddd,J= 13.9, 11.5, 2.9 Hz, 2H), 2.63 (tt,J= 11.0, 4.0 Hz, 1H), 2.05 (dd,J= 13.5, 3.8 Hz, 2H), 1.89 1.80 (m, 2H);<13>C-NMR (101 MHz, CDCla)<8>175.05, 157.59, 150.22, 148.44, 148.03, 137.74, 131.49, .01, 127.40, 125.62, 122.91, 121.32, 110.36, 51.79, 44.69, 41.32, 27.92.

In one embodiment, preferred compounds of general formula I are as follows:

1-(6-(4-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(2-methoxypyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(3-fluoro-4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(6-methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(2-chloro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(4-methoxy-2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate hydrochloride;

ethyl 1-(6-(3-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(3-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(6-methylpyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(pyridin-2-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-fluoro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(4-chloro-3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(4-fluoro-2-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate; either

a salt, hydrate, solvate, N-oxide, stereoisomer, stereoisomer, in particular diastereomer, enantiomer or atropisomers, or mixtures thereof, polymorph or pharmaceutically acceptable ester thereof.

Example 2

In one embodiment, the in vitro cytotoxicity assay was performed as follows. The in vitro cytotoxicity assay was performed on the HepG2 cell line using a tetrazolium reduction assay for assessment of cell viability (MTS reduction as described by Cory A. et al (Cancer Commun. 1991, 3 (7), 207-212)). The assay was performed in 96-well plates for 48 h at 37°C and 5% CO<2> in incubation medium (low glucose DMEM with Glutamax, 10% FBS, 1% Pen/Strep and DMSO). Cells were exposed to <8> different compound concentrations in successive dilutions (usually <2> base), plus a positive control (a compound at a concentration known to decrease cell viability by above 50%) and a negative control (incubation medium). Six replicate wells were tested for each condition. Compound stock solutions in DMSO were prepared at 20 mM where possible, filter sterilized, aliquoted and stored at -20°C. The maximum compound concentrations tested depended on their solubility in the incubation medium and the maximum percentage of DMSO allowable without loss of cell viability. At the end of the incubation period, tetrazolium reagent (Promega's CellTiter 96® aqueous solution) was added; cells were incubated for a further 3 hours to promote reduction of tetrazolium to formazan by viable cells. The amount of soluble formazan produced was assessed by reading the absorbance at 490 nm on a spectrophotometer plate reader. The average absorbance of the negative control wells corresponded to <100% cell viability; The absorbance obtained from each test condition was then transformed into a percentage of cell viability; these results were plotted against compound concentration and a non-linear regression fit was performed. Where possible, the IC<50> was calculated as the compound concentration that reduces cell viability by 50%.

Example 3

In one embodiment, Mycobacterium tuberculosis REMA susceptibility assay was performed as follows. The susceptibility of M. tuberculosis was accessed by exposing susceptible M. tuberculosis H37Rv, in particular M. tuberculosis strain ATCC 25618, to the different compounds and assessing their growth inhibition by the REMA method (resazurin microtiter assay) based on Palomino JC et al (Mycobacterium tuberculosis Antimicrob. Agents Chemother. 2002, 46, <8>, 2720-2722). The assay was performed in 96-well plates for <6> days at 37°C in Middlebrook 7H9 medium. Cells were exposed to <8> different compound concentrations in two-fold serial dilutions; The incubation medium was used as a negative control and <2>positive controls were accessed: rifampicin at a concentration known to inhibit growth and moxifloxacin at <8>different concentrations ranging from no growth inhibition to complete growth inhibition. Stock solutions of the compound in DMSO were prepared at a concentration at least 40-fold higher than the maximum concentration tested. At the end of the incubation period, resazurin was added and cells were incubated for another 2 days in order to promote the colour change of resazurin from blue to pink each time growth occurred. Colours were recorded and the lowest concentration at which no colour change was observed (the last blue well) was assumed to be the minimum inhibitory concentration (MIC) for that compound in M. tuberculosis.

Example 4

In one embodiment, the metabolic stability assay was carried out as follows. Metabolic stability was assessed by incubating test compounds in 96-well plates in 5 aliquots of 40 µl each (one for each time point) in liver microsome incubation medium. This medium contained MgCl (3.3 mM), NADPH-cofactor system (NADPH (3 mM), glucose-<6>-phosphate (5.3 mM), glucose-<6>-phosphate dehydrogenase (0.67 units/ml) and 0.42 mg of liver microsomal protein per ml in phosphate buffer (100 mM, pH 7.4). Control incubations were performed by replacing the NADPH-cofactor system with phosphate buffer. Test compounds (1 µM, final solvent concentration 1.6%) were incubated with the microsomes at 37°C and with orbital shaking at 100 rpm. Imipramine and propranolol were incubated in parallel as reference compounds. Each reaction was performed in duplicate. Five time points were analyzed for 60 minutes. Reactions were stopped by adding 12 volumes of 90% acetonitrile in water to the reaction mixture. Incubation aliquots were collected, followed by protein sedimentation by centrifugation. Supernatants were analyzed using a Shimadzu VP HPLC system with a reversed-phase HPLC column, coupled with the API 3000 tandem mass spectrometer (PE Sciex). The TurbolonSpray source was used in positive and negative ion modes. Data acquisition and analysis were performed with Analyst 1.5.2 software (PE Sciex). The elimination constant (kel), half-life (t-io) and intrinsic clearance (Clint) were determined on the plot of ln(AUC) versus time, using linear regression analysis for each test and reference compound.

Example 5

In one embodiment, the distribution coefficient determination (LogD) assay was carried out as follows. Test compounds were incubated in Eppendorf-type polypropylene microtubes in triplicate: a 5 µl aliquot of a 10 mM DMSO stock solution of each test compound was added into the mutually presaturated mixture containing 500 µl phosphate buffered saline (pH 7.4) and 500 µl octanol. The solution was allowed to mix on a rotator for 1 hour at 30 rpm. Phase separation was ensured by centrifugation. The octanol phase was diluted 100-fold with 40% acetonitrile in water for analysis, and the aqueous phase was analyzed without dilution. Mebendazole was used as a reference compound. All samples (both phases) were analyzed on a Shimadzu VP HPLC system with a reversed-phase column coupled to an API 3000 tandem mass spectrometer (PE Sciex). The TurbolonSpray ion source was used in positive ion mode. Data acquisition and analysis were performed using Analyst 1.5.2 software. The distribution coefficients of the analyzed compounds were calculated as the logarithm of the partition ratios (D) in both solvents according to the following equation.

D =<100 . So>

Sp

where:So- peak area of the compound in the octanol phase

Sp- peak area of the compound in the buffer saline phase

phosphate

Example<6>

In one embodiment, the pKa determination assay was performed as follows. The tendency of a compound to donate a proton is measured as its acid ionization constant (dissociation constant), or Ka. A more practical scale to represent acidity is the pKa, which is the negative logarithm of the Ka (pKa = -log Ka). The pKa determinations of the test compounds and 3 reference compounds were evaluated by potentiometric titration according to technical protocols for pKa measurement provided by Pion Inc. and Sirius Analytical Inc. Briefly, the pKas of the compounds were determined by the pH-metric method based on potentiometric acid-base titration at 25°C. The test and reference compounds were dissolved in an acidified MeOH-water (1:4) solution of 150 mM NaCl (pH 2) and slowly titrated with a MeOH-water (1:4) solution of 10 mM NaOH. The recorded pH of the solution as a function of the volume of NaOH used during the titration was used to construct the titration curve. The titration of the acidified NaCl solution in the absence of any compound was used to plot the blank. The buffering capacity at each point on the titration curve was calculated as the ratio of the (constant) NaOH flow rate to the rate of pH increase. The pKa value was determined from the resulting graph of buffering capacity versus pH as the maximum of the buffering capacity. The pH-metric method allows pKa measurements in a range between 2 and 12. Data acquisition and analysis were performed using SmartLoggerII1.0.14 software (Beckman Coulter). Data analysis was performed using GraphPad Prism 5.01 and Excel 2010 software.

Example 7

In one embodiment, the stability assay in human plasma (HP) was performed as follows. Test compounds (1 µM, 1% DMSO final concentration) were incubated in 5 aliquots of 70 µl each (one for each time point), in duplicate, at 37°C with orbital shaking at 100 rpm. Five time points were analyzed for 120 minutes. Two reference compounds were analyzed in parallel. Reactions were stopped by the addition of 420 µl of acetonitrile:water mixture (90:10) and subsequent sedimentation of plasma proteins was achieved by centrifugation. Supernatants were analyzed on a Shimadzu VP HPLC system with a reverse phase column, coupled to an API 3000 tandem mass spectrometer (PE Sciex). Both positive and negative ion modes of the TurboIonSpray ion source were used. Data acquisition and analysis were performed using Analyst 1.5.2 software (PE Sciex). The percentage of test compounds remaining in plasma after incubation and their half-lives (T<1>/<2>) were calculated.

Example 8

In one embodiment, the human plasma protein binding (PPB) assay was performed as follows. The assay was performed in a multi-use 96-well dialysis unit (HTD96b dialyzer). Each individual well unit consisted of 2 chambers separated by a vertically aligned dialysis membrane of predetermined pore size (MWCO 12-14 kDa). 120 µl of undiluted plasma with known spikes of compound (1 pM, final DMSO concentration 1%) was added to one chamber and the same volume of phosphate buffered saline pH 7.4 to the other chamber. The HTD96b dialyzer was covered with an adhesive sealing film and incubated at 37°C and orbital shaking at 100 rpm for 5 hours. Verapamil as a reference compound was also evaluated in parallel. For sample preparation, an aliquot of the contents of each chamber was mixed with the same volume of the blank matrix. In order to define nonspecific loss of the compound during this assay, a standard solution was created by mixing an aliquot of the plasma with known additions of the blank buffer without dialysis. The samples were diluted 10-fold with 100% acetonitrile with subsequent sedimentation of plasma proteins by centrifugation. The supernatants were analyzed with a Shimadzu VP HPLC system with a reversed-phase column, coupled to an API 3000 tandem mass spectrometer (PE Sciex). The positive and negative ion modes of the TurboIonSpray ion source were used. Data acquisition and analysis were performed with Analyst 1.5.2 software (PE Sciex).

The percentage of compound bound to plasma protein and its recovery were calculated using the following equations:

fPeak area in the >.

tampon_______________

Protein binding = 1 - -100%

Peak area in the

plasma

^"Peak area in buffer Peak area in eK

plasma

Recovery = -100%

Peak area in the standard solution

V .J

The percentage of compound bound to plasma protein and its recovery were calculated using the values obtained for each compound in the quantification of the 3 samples (in buffer, plasma and standard solution).

Example 9

In one embodiment, the PAMPA assay was performed. All steps of the PAMPA assay were performed according to the plON Inc. PAMPA Explorer™ manual. The main principle of the assay is the incubation of the compound in the aqueous buffered donor chamber, which is separated from the buffered acceptor chamber by a phospholipid or hydrocarbon membrane fixed on a filtration support. After the test, the concentrations in the corresponding donor and acceptor chambers are measured and the permeability is calculated. The GIT model was simulated using the GIT-0 phospholipid mixture. Verapamil and quinidine (high permeability) and ranitidine (low permeability) were used as reference compounds. All compounds were tested in quadruplicate. Prisma HT buffer (pH 7.4) containing 50 pM test compound (final DMSO concentration 0.5%) was added to the donor chamber. Acceptor sink buffer was added to each receiver chamber. Incubation was performed at room temperature for 4 h without shaking. After incubation, aliquots from both chambers were transferred to UV-Vis optical plates and absorbance in the range of 202-500 nm was recorded in 4 nm steps. Compounds with low UV-Vis signal were evaluated by LC-MS/MS (using a Shimadzu VP HPLC system with a reversed-phase HPLC column, coupled with the API 3000 tandem mass spectrometer (PE Sciex) and the TurboIonSpray ion source used in positive ion mode; data acquisition and analysis were performed with Analyst 1.5.2 software (PE Sciex)).

The apparent permeability coefficient was then calculated using the following formula.

l<,>

°gP<n>

app = l<,>

og10( , - 72xx<2 .303 x V D v , n [drug]ac,>

ÁArrfe:aa xr^ T ie mmJ po ' x logw(1 - 2 x [ /<,>rmaeo<]>d<)>

Vd- volume of transport buffer in donor well (0.3 ml);

Area - surface area of lipids on the insert (effective growth area of the insert - 0.3 cm2);Time - assay time, seconds;

[drug]ac- Final OD of test compound in acceptor well;

[drug]d- Initial OD of test compound in donor well.

The apparent permeability coefficient was calculated for each compound (logPapp).

In one embodiment, the compounds of the disclosure, for example when tested in the cytotoxicity assay described in Example 2, typically have an IC<50> value of not less than 50 pM.

In one embodiment, compounds of the disclosure, when tested in the susceptibility assay described in Example 3, may typically have an MIC of less than 15.6 pM. Compounds of the disclosure, when tested in the assay described in Example 3, may have an MIC between 3.91 pM and 15.6 pM. In one embodiment, compounds of the disclosure were tested in the assays described in Examples 2 and 3 as described above and the following results were obtained:

Table 1 - REMA and CI<50> results for the selected compounds

In Table 1, the REMA and cytotoxicity results are set out as follows:

REMA of MTB growth ( |j M)< 7.8<7.8-15.6 15.6-31.5 31.5-62.5>C M hM) > 100 50-100 20-50 < 20 Table 2 - REMA and CI<50> results for the selected compounds

In Table 2, the REMA and cytotoxicity results are set out as follows:

+

MTB growth REMA (j M)< 7.8<7.8-15.6 15.6-31.5 31.5-62.5>

IC50(jM) ><100>50-100 20-50 <<20>

In one embodiment, the compounds of the present disclosure have been shown to inhibit the growth of Mycobacterium tuberculosis in a standard REMA assay (Palomino JCet al, Mycobacterium tuberculosis Antimicrob. Agents Chemother. 2002, 46, <8>, 2720-2722) with a minimum inhibitory concentration (MIC) of no more than 15.6 µM. Surprisingly, the compounds of the present disclosure exhibited a MIC of no more than 15.6 µM. Even more surprisingly, the best performing embodiments of the present disclosure have a MIC of no more than 7.8 µM. The compounds of the disclosure have also been found to be non-cytotoxic to the HepG2 cell line, metabolically stable in human microsomes, stable in plasma, and relatively permeable in the parallel artificial membrane of the gastrointestinal tract. LogD and pKa have been described. The disclosed compounds are promising antimycobacterial agents.

In one embodiment, the compounds of the disclosure were tested in an assay set forth in Example 4 as described above and the following results were obtained.

Table 3 - Clmtyt-i results for the selected compounds

n.d. = not determined

In one embodiment, the compounds of the disclosure were tested in an assay set forth in example 5, <6>, 7, <8> and 9 as described above and the following results were obtained:

Table 4 - Additional biological data for selected compounds

n.d.-Not determined.

The term “comprising” whenever used herein is intended to indicate the presence of stated features, integers, steps, components, but does not exclude the presence or addition of one or more other features, integers, steps, components, or groups thereof.

Those of ordinary skill in the art will appreciate that, unless otherwise indicated herein, the particular sequence of steps described is illustrative only and may be varied without departing from the disclosure. Thus, unless otherwise stated, the steps described are not in order, meaning that, where possible, the steps may be performed in any convenient or desirable order.

Claims (1)

CLAIMS Compound of general formula I or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide, stereoisomer, diastereomer, enantiomer, atropisomer or polymorph thereof: Formula I wherein R<1>, R<2>, X, Y, Z, W are independently selected from each other; R<1>is selected from H or C<1>-C<6>alkyl; R<2>is selected from H or C<1>-C<6>alkyl; X is selected from N, O, S or CR<3>, and R<3>is selected from H, halogen, C<1>-C<6>alkoxy or C<1>-C<6>haloalkyl; Y is selected from N or CR<4>, and R<4> is selected from H, C<1>-C<6> haloalkoxy, OH, C<1>-C<6> alkoxy, C<1>-C<6> haloalkyl, halogen, or C<1>-C<6> alkyl; Z is selected from N or CR<5>, and R<5> is selected from H, halogen, C<1>-C<6> alkoxy, C<1>-C<6> haloalkyl, C<1>-C<6> haloalkyl; W is selected from N or CRa, and Ra is selected from H, C<1>-C<6> alkoxy, C<1>-C<6> haloalkyl, halogen, or C<1>-C<6> alkyl; m and n are independently selected from 0 or i; halogen is F or Cl; with the proviso that the group connected to the quinoline moiety at Ca is a substituted or unsubstituted substituted aryl, heteroaryl or fused heteroaroaryl ring selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, furan-2-yl, benzothiophenyl, indolyl or phenyl, and the piperidine ring which is connected to the quinoline moiety at C<2>has its C<3>or C<4>substituted with carboxylate group. Compound of formula I according to claim 1, wherein Ri is selected from H, CH<2>CH<3>or CH<3>; R<2>is selected from H or CH<3>; X is selected from N, O, S or CR<3>, and R<3>is selected from H, Cl, F, CF<3>or OCH<3>; Y is selected from N or CR<4>, and R<4> is selected from H, F, Cl, CH<3>, OH, CF<3>, OCF<3>, OCH(CH<3>)<2>, or OCH<3>; Z is selected from N or CR<5>, and R<5> is H, OH, F, OCF<3>, OCH<3>, NO<2>, CF<3>, or CH<3>; W is selected from N or CRa, and Ra is H, F, Cl, CF<3>, OCH<3>, or OCF<3>; m and n are independently selected from 0 or i; with the proviso that the group connected to the quinoline moiety at C6 is a substituted or unsubstituted substituted aryl, heteroaryl or fused heteroaroaryl ring selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, furan-2-yl, benzothiophenyl, indolyl or phenyl. Compound of Formula II according to claim 1 or 2, wherein R<1> is selected from H or CH<2>CH<3>; R<3> is selected from H, Cl, F, CF<3>, or OCH<3>; R<4> is selected from H, OH, Cl, F, OCF<3>, CH<3>, CF<3>, OCH(CH<3>)<2>, or OCH<3>; R<5> is selected from H, OH, F, OCF<3>, CF<3>, CH<3>, OCH<3>, or NO<2>; R6 is selected from H, Cl, F, CF<3>, or OCF<3>, or OCH<3>; with the proviso that the group connected to the quinoline moiety at C6 is a substituted or unsubstituted aryl, heteroaryl, or fused heteroaroaryl ring selected from indolyl or phenyl. Compound of Formula III according to claim 1 or 2, wherein Formula III R<1> is selected from H, CH<2>CH<3> or CH<3>; R<2> is selected from H and CH<3>; X is selected from N or CR<3>, and R<3> is H; Y is selected from N or CR<4>, and R<4> is selected from H, CH<3>, F, CF<3> or OCH<3>; Z is selected from N or CR<5>, and R<5> is selected from H or CH<3>; W is selected from N or CR6, and R6 is selected from H or F; m is selected from 0 or 1; with the proviso that the group connected to the quinoline moiety at C6 is a substituted or unsubstituted substituted aryl, heteroaryl or fused heteroaroaryl ring selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl or pyrimidin-5-yl. Compound of Formula IV according to claim 1 or 2, wherein Formula IV X is O or S; Ri is selected from H or CH<2>CH<3>; with the proviso that the group connected to the quinoline moiety at C<6> is a substituted or unsubstituted heteroaryl or fused heteroaroaryl ring selected from furan-<2>-yl or benzothiophenyl. <6>. Compound 7. Compound <8>. Compound 9. Compound <1 0>. Compound <1 1>. Compound <1 2>. Compound 13. Compound 14. Compound ethyl 1-(6-(4-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate; 1-(6-(4-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid; ethyl 1-(6-(4-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(2-methoxypyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate; 1-(6-(2-methoxypyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylic acid; 1-(6-(4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid; ethyl 1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate; 1-(6-(4-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid; 1-(6-(3-fluoro-4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid; 1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylic acid; ethyl 1-(6-(3-fluoro-4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate; 1-(6-(6-methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid; ethyl 1-(6-(6-methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate hydrochloride; ethyl 1-(6-(furan-2-yl)quinolin-2-yl)piperidine-4-carboxylate; 1-(6-(furan-2-yl)quinolin-2-yl)piperidine-4-carboxylic acid; 1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride; 1-(6-(2-chloro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate ethyl; 1-(6-(4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate ethyl; 1-(6-(4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid; 1-(6-(3-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid; 1-(6-(3-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid; -(6-(2-chloro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid; 1-(6-(4-methoxy-2-(trifluoromethyl)phenyl)quinolin-2-yl) hydrochloride ethyl piperidine-4-carboxylate; 1-(6-(3-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate, ethyl; 1-(6-(3-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylate, ethyl ; 1-(6-(3-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid; 1-(6-(4-methoxy-2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine- 4-carboxylic acid; 1-(6-(3-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid; 1-(6-(3-methoxyphenyl)quinolin-2-yl)piperidine-4- ethyl carboxylate; ethyl 1-(6-(4-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(3-nitrophenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(4-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(6-fluoropyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate; 1-(6-(4-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid; ethyl 1-(6-(2-fluoropyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate; 1-(6-(6-fluoropyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride; 1-(6-(3-nitrophenyl)quinolin-2-yl)piperidine-4-carboxylic acid; ethyl 1-(6-(2-methylpyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(3,5-dimethoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(1H-indol-5-yl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(6-(trifluoromethyl)pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(pyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylate; 1-(6-(1H-indol-5-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride; 1-(6-(3,5-dimethoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid; 1-(6-(4-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylic acid; 1-(6-(pyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylic acid; 1-(6-(pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid; 1-(6-(6-methylpyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate ethyl; 1-(6-(2-fluoropyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride; 1-(6-(6-(trifluoromethyl)pyridine-3- 1-(6-(2-methylpyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid; 1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid; -yl)quinolin-2-yl)piperidine-3-carboxylate ethyl; ethyl 1-(6-(pyridin-2-yl)quinolin-2-yl)piperidine-4-carboxylate; 1-(4-methyl-6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid; ethyl 1-(4-methyl-6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(3-fluoro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(3-chloro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(3,4-dimethoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate; 1-(6-(pyridin-2-yl)quinolin-2-yl)piperidine-4-carboxylic acid; 1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-3-carboxylic acid hydrochloride; ethyl 1-(6-(4-chloro-3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(3-chlorophenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(4-chlorophenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(3-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(pyridin-4-yl)quinolin-2-yl)pyrrolidine-3-carboxylate; ethyl 1-(6-(benzo[b]thiophen-2-yl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(2-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(4-fluoro-2-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(4-methoxy-3-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(4-chloro-3-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(3-chloro-4-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(2-methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(5-fluoropyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(3-fluoropyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate; methyl 1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate; or 1-(6-(6-methylpyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride. 15. Compound according to any of the preceding claims, wherein the compound is selected from: 1-(6-(6-methylpyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride. 1-(6-(4-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid; 1-(6-(2-methoxypyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylate ethyl ester; 1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate ethyl ester; 1-(6-(3-fluoro-4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid 4-carboxylic; 1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylic acid; ethyl 1-(6-(6-methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(2-chloro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate; 1-(6-(4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid; ethyl 1-(6-(4-methoxy-2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate hydrochloride; ethyl 1-(6-(3-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(3-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylate; 1-(6-(3-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid; ethyl 1-(6-(6-methylpyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(pyridin-2-yl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(3-fluoro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate; ethyl 1-(6-(4-chloro-3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate; 1-(6-(2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate ethyl; or 1-(6-(4-fluoro-2-methoxyphenyl)quinolin-2-yl)piperidine- 4-ethyl carboxylate. 16. Compound according to any of the preceding claims, for use in medicine or veterinary medicine. 17. Compound according to any of claims 1-15, for use in the treatment or prevention of tuberculosis. 18 . Compound for use according to any of the preceding claims 16-17, in combination with at least one anti-HIV agent, preferably wherein the anti-HIV agent is selected from an HIV protease inhibitor, a nucleoside inhibitor, HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase, and an HIV integrase inhibitor. 19. Compound for use according to any of the preceding claims 16-18, in combination with at least one additional drug for tuberculosis, preferably wherein the drug for tuberculosis is selected from the group of isoniazid, rifamycin and derivatives, pyrazinamide, ethambutol, cycloserine, ethionamide, streptomycin, amikacin, kanamycin, rifampin (rifampicin), aminoglycosides, capreomycin, p-aminosalicylic acid, fluoroquinolones such as levofloxacin, moxafloxacin or gatifloxacin, or mixtures thereof. 20. Compound for use according to any of 21. A pharmaceutical composition comprising a compound according to any of the preceding claims 1-15 and a pharmaceutically acceptable salt thereof. pharmaceutically acceptable excipient.