Oxazolidinones as TarO inhibitors

BACKGROUND OF THE INVENTION

Bacterial antibiotic resistance has become one of the most serious threats to modern health care. Cohen, Science 1992, 257: 1051-1055 discloses that infections caused by resistant bacteria frequently result in longer hospital stays, higher mortality and increased cost of treatment. Neu, Science 1992, 257: 1064-1073 discloses that the need for new antibiotics will continue to escalate because bacteria have a remarkable ability to develop resistance to new agents rendering them quickly ineffective. There have been various efforts to elucidate the mechanisms responsible for bacterial resistance, Coulton et al., Progress in Medicinal Chemistry 1994, 31: 297-349 teaches that the widespread use of penicillins and cephalosporins has resulted in the emergence of β-lactamases, a family of bacterial enzymes that catalyze the hydrolysis of the β-lactam ring common to numerous presently used antibiotics. More recently, Dudley, Pharmacotherapy 1995, 15: 9S-14S has disclosed that resistance mediated by β-lactamases is a critical aspect at the core of the development of bacterial antibiotic resistance.

Methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) have dramatically erroded the efficacy of β-lactam antibiotics. MRSA is emerging as a major cause of bloodstream infections in healthy individuals. In the 2013 Center for Disease Control and Prevention (CDC) Threat Level Report MRSA was designated as the second leading cause of mortality by drug-resistant bacterial pathogen in the US.

The most common mechanism of bacterial resistance to β-lactams involves inactivation by β-lactamases, and a successful strategy to overcome inactivation by combining a β-lactam and a β-lacatmase inhibitor has been used clinically for Gram negative infections (Walsh, C. T. (2003) Antibiotics: Actions, Origins, Resistance, ASM Press, Washington, D.C.). However, Gram positive MRSA strains develop resistance through a different mechanism: the acquisition of a β-lactam resistant peptidoglycan transpeptidase (TP) PBP2A (Beck, W. D., et al., J. Bacteriol. 165, 373-378 (1986); Hartman, B. J., and Tomasz, A. J. Bacteriol. 158, 513-516 (1984)).

The cell wall is the target of many widely used antibiotics, including β-lactams and glycopeptides. Wall teichoic acid (WTA) is an anionic glycophosphate polymer found as a major and integral component of most Gram-positive cell walls (Weidenmaier, C. and Peschel, A., Nature, April 2008, Vol. 6, 278-287; Swoboda, J. G. et al, ACS Chem. Biol. 4, 875-83 (2009); Lee, S. H. et al. Chemistry & Biology 18, 1379-89 (2011)). Although non-essential for S. aureus and B. subtilis at least under laboratory conditions, WTA has been shown to play a critical role in enabling Gram positive bacteria to adhere to an infected host cells (Weidenmaier, C. and Peschel, A., Nature, April 2008, Vol. 6, 278-287); In addition, WTA plays key roles in cell growth, division, peptidoglycan synthesis and β-lactam resistance in methicillin resistant Staphylococcus aureus (MRSA) (Sewell, E. W. C., and Brown, E.d., J. Antibiotics (2014) 67, 43-51; Pasquina, L. W., et al., Current Opinion in Microbiology 2013, 16: 531-537).

S. aureus has been known to evade host innate and adaptive immune defense system even though antibodies generated against S. aureus antigens are present in humans (Foster, Timothy J. Nature Review Microbiology 2005, 3, 948-958). Recently, WTA, as part of the S. aureus cell wall, was implicated in preventing epitope recognition and osponization by antibodies in the host (Spiegel, David A. et al. ACS Chemical Biology, Oct. 26, 2015 Just Accepted Manuscript). Therefore, WTA inhibitors can potentially sensitize pathogens to clearance by the host adaptive immune system. This approach can also be potentially useful for patients who have been previously administered S. aureus vaccine for the prevention of MRSA infections.

A recent study has shown that blocking the expression of wall teichoic acids (WTA) by inhibiting TarO, the first enzyme in the wall techoic acid biosyntheis in S. aureus, sensitizes methicillin-resistant S. aureus (MRSA) strains to β-lactams, even though β-lactam resistant transpeptidase is expressed (Campbell, J. Et al., ACS Chemical Biology, Vol. 6, No. 1, pp. 106-116, 2011). The study further showed that WTA expression is required for methicillin resistance to MRSA, and that preventing WTA biosynthesis by blocking TarO sensitizes MRSA strains to β-lactams due to the combined inactivation of the native penicillin binding proteins (PBP) and TarO. Further, the study showed that treatment of a TarO mutant of MW2, a MRSA strain exhibiting moderate reistance to β-lactams, showed an 8-fold increase in sensitivity to β-lactam antibiotics, including methicillin, imipenem, ceftazidime and cephradine, relative to the parent strain.

Finally, it has been suggested that Ticlopidine, an antiplatelet drug, may show low level activity against TarO and is only synergistic with the β-lactam antibiotic, cefuroxime, and restores the efficacy of cefuroxime in a community acquired MRSA strain USA300 (Sewell, E. W. C., and Brown, E. D., J. Antibiotics (2014) 67, 43-51). Based on these findings, the combination of a TarO inhibitor with a β-lactam antibiotic may be useful for treating MRSA infections, particularly in β-lactam resistant MRSA and MRSE strains.

Due to the decrease in efficacy of β-lactam antibiotics, such as dicloxacillin, cefuroxime and cefepime in treating dangerous bacterial pathogens, there is a need for the development of antibiotic combination agents to preserve the efficacy of β-lactams. The compounds of the present invention are novel TarO inhibitors which may be effective, alone or in combination with a β-lactam antibiotic, in preventing and treating bacterial infections. The compounds of the present invention, alone or in combination with a β-lactam antibiotic, may also be effective in enhancing bacterial clearance by the immune system.

Wall teichoic acids and their relevance to antibiotic resistance are disclosed in: Sewell, Edward W. C., and Brown, E. D., Journal of Antibiotics (2014), 67(1), 43-51; Pasquina, Lincoln W.; et al., Current Opinion in Microbiology (2013), 16(5), 531-537; Brown, E. D., et al., ACS Chemical Biology (2013), 8(1), 226-233; Gilmore, M. S., et al., Antimicrobial Agents and Chemotherapy (2011), 55(2), 767-774; and Swoboda, Jonathan G.; et al., ChemBioChem (2010), 11(1), 35-45.

WTA inhibitors are disclosed in Brown, E. D. et al., Bioorganic & Medicinal Chemistry Letters (2014), 24(3), 905-910; Liang, Lianzhu; et al., Chemistry & Biology (Oxford, United Kingdom) (2013), 20(2), 272-284; Walker, S. et al., Bioorganic & Medicinal Chemistry Letters (2010), 20(5), 1767-1770; and WO2013148269.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds of structural formula I:

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and pharmaceutically acceptable salts thereof. The compounds of structural formula I, and embodiments thereof, are inhibitors of TarO and may be useful in the prevention, treatment, and suppression of diseases, disorders and conditions mediated by inhibition of TarO, such as bacterial infections. The compounds of the present invention, and pharmaceutically acceptable salts thereof, are also useful in combination with β-lactam antibiotics, such as imipenem and dicloxacillin, for the treatment of bacterial infections, particularly antibiotic resistant bacterial infections such as methicillin-resistant Staphylococcus aureus (MRSA) infections.

The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. The present invention also relates to methods for the treatment, control or prevention of disorders, diseases, and conditions that may be responsive to inhibition of TarO in a subject in need thereof by administering the compounds of the present invention, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions of the present invention. The present invention also relates to the use of compounds of the present invention, or pharmaceutically acceptable salts thereof, for manufacture of a medicament useful in treating diseases, disorders and conditions that may be responsive to the inhibition of TarO. The present invention is also concerned with treatment of these diseases, disorders and conditions by administering the compounds of the present invention, or pharmaceutically acceptable salts thereof, in combination with a therapeutically effective amount of another agent that may be useful to treat the disease, disorder and condition. The invention is further concerned with processes for preparing the compounds of the present invention, or pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is concerned with novel compounds of structural Formula I:

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or a pharmaceutically acceptable salt thereof; wherein

A is selected from the group consisting of:

- (1) aryl,
- (2) heteroaryl,
- (3) —O-aryl, and
- (4) —O-heteroaryl,
  
  wherein aryl and heteroaryl are unsubstituted or substituted with 1-5 substituents selected from R^a;
  
  B is selected from the group consisting of:
- (1) aryl, and
- (2) heteroaryl,
  
  wherein aryl and heteroaryl are unsubstituted or substituted with 1-4 substituents selected from R^b;
  
  X is selected from the group consisting of:
- (1) NR⁷,
- (2) —CR⁸R⁹, and
- (3) —O—;
  
  Y is selected from the group consisting of:
- (1) NR³,
- (2) —CR¹⁰R¹¹, and
- (3) —C(R¹²)═C(R¹³)—;
  
  R¹is selected from the group consisting of:
- (1) hydrogen,
- (2) halogen,
- (3) —C_1-6alkyl, and
- (4) —(CH₂)_p—OH,
  
  wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl;
  
  R²is selected from the group consisting of:
- (1) hydrogen,
- (2) halogen,
- (3) —C_1-6alkyl, and
- (4) —(CH₂)_p—OH,
  
  wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl, or R¹and R²together with the carbon atom they are attached to form a C_3-6cycloalkyl ring, wherein the cycloalkyl ring is unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl;
  
  R³is selected from the group consisting of:
- (1) hydrogen,
- (2) OH, and
- (3) —C_1-6alkyl,
  
  wherein alkyl is unsubstituted or substituted with one to five substituents selected from —C_1-6alkyl;
  
  each R⁴is independently selected from the group consisting of:
- (1) hydrogen,
- (2) halogen,
- (3) —C_1-6alkyl, and
- (4) —(CH₂)_p—OH,
  
  wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl;
  
  each R⁵is independently selected from the group consisting of:
- (1) hydrogen,
- (2) halogen,
- (3) —C_1-6alkyl, and
- (4) —(CH₂)_p—OH,
  
  wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl;
  
  R⁶is selected from the group consisting of:
- (1) hydrogen,
- (2) halogen,
- (3) —C_1-6alkyl,
- (4) —C_2-6alkenyl, and
- (5) —(CH₂)_p—OH,
  
  wherein CH₂, alkyl and alkenyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl;
  
  R⁷is selected from the group consisting of:
- (1) hydrogen,
- (2) halogen,
- (3) —C_1-6alkyl,
- (4) —C_2-6alkenyl, and
- (5) —(CH₂)_p—OH,
  
  wherein CH₂, alkyl and alkenyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl;
  
  R⁸is selected from the group consisting of:
- (1) hydrogen,
- (2) halogen,
- (3) —C_1-6alkyl, and
- (4) —(CH₂)_p—OH,
  
  wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl;
  
  R⁹is selected from the group consisting of:
- (1) hydrogen,
- (2) halogen,
- (3) —C_1-6alkyl, and
- (4) —(CH₂)_p—OH,
  
  wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl;
  
  R¹⁰is selected from the group consisting of:
- (1) hydrogen,
- (2) halogen,
- (3) —C_1-6alkyl, and
- (4) —(CH₂)_p—OH,
  
  wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl;
  
  R¹¹is selected from the group consisting of:
- (1) hydrogen,
- (2) halogen,
- (3) —C_1-6alkyl, and
- (4) —(CH₂)_p—OH,
  
  wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl;
  
  R¹²is selected from the group consisting of:
- (1) hydrogen,
- (2) halogen,
- (3) —C_1-6alkyl, and
- (4) —(CH₂)_p—OH,
  
  wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl;
  
  R¹³is selected from the group consisting of:
- (1) hydrogen,
- (2) halogen,
- (3) —C_1-6alkyl, and
- (4) —(CH₂)_p—OH,
  
  wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl;
  
  each R^ais independently selected from the group consisting of:
- (1) halogen,
- (2) —C_1-6alkyl,
- (3) —OC_1-6alkyl,
- (4) —OC_2-6alkenyl,
- (5) —OH,
- (6) oxo,
- (7) —CN,
- (8) —NO₂,
- (9) —NR^cR^d,
- (10) —CH₂NR^cR^d,
- (11) —SO₂C_1-6alkyl,
- (12) —C_3-6cycloalkyl,
- (13) —C_2-6cycloheteroalkyl,
- (14) aryl, and
- (15) heteroaryl,
  
  wherein —CH₂, alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1-4 substituents selected from: halogen, —C_1-6alkyl, —OC_1-6alkyl, and —CO₂C_1-6alkyl;
  
  each R^bis independently selected from the group consisting of:
- (1) halogen,
- (2) —C_1-6alkyl,
- (3) —C_2-6alkenyl,
- (4) —OC_1-6alkyl,
- (5) —OC_2-6alkenyl,
- (6) —OH,
- (7) oxo,
- (8) —CN,
- (9) —NO₂,
- (10) —NR^cR^d,
- (11) —SO₂C_1-6alkyl,
- (12) —C_3-6cycloalkyl,
- (13) —C_2-6cycloheteroalkyl,
- (14) aryl, and
- (15) heteroaryl,
  
  wherein alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1-4 substituents selected from: halogen, —C_1-6alkyl, —OC_1-6alkyl, and —CO₂C_1-6alkyl;
  
  each R^cis independently selected from the group consisting of:
- (1) hydrogen,
- (2) C_1-6alkyl,
- (3) C_2-6alkenyl,
- (4) C_1-6alkyl-OH,
- (5) C_3-6cycloalkyl,
- (6) C(O)C_1-6alkyl, and
- (7) SO₂C_1-6alkyl,
  
  wherein alkyl, alkenyl and cycloalkyl are unsubstituted or substituted with one to three substituents selected from halogen, —C_1-6alkyl, —OC_1-6alkyl, and —CO₂C_1-6alkyl;
  
  each R^dis independently selected from the group consisting of:
- (1) hydrogen,
- (2) C_1-6alkyl,
- (3) C_2-6alkenyl,
- (4) C_1-6alkyl-OH,
- (5) C_3-6cycloalkyl,
- (6) C(O)C_1-6alkyl, and
- (7) SO₂C_1-6alkyl,
  
  wherein alkyl, alkenyl and cycloalkyl are unsubstituted or substituted with one to three substituents selected from halogen, —C_1-6alkyl, —OC_1-6alkyl, and —CO₂C_1-6alkyl, or R^cand R^dtogether with the nitrogen atom they are attached to form a C_4-8cycloheteroalkyl ring, wherein the C_4-8cycloheteroalkyl ring is unsubstituted or substituted with 1-4 substituents selected from halogen, oxo, —C_1-6alkyl, —OC_1-6alkyl, and —CO₂C_1-6alkyl;
  
  m is 0 or 1;
  
  n is 0, 1, 2 or 3; and
  
  p is 0, 1, 2, 3, 4, 5 or 6.

The invention has numerous embodiments, which are summarized below. The invention includes the compounds as shown, and also includes individual diastereoisomers, enantiomers, and epimers of the compounds, and mixtures of diastereoisomers and/or enantiomers thereof including racemic mixtures.

In one embodiment of the present invention, A is selected from the group consisting of: aryl, heteroaryl, —O-aryl, and —O-heteroaryl, wherein aryl and heteroaryl are unsubstituted or substituted with 1-5 substituents selected from R^a.

In another embodiment of the present invention, A is selected from the group consisting of: aryl, heteroaryl, and —O-aryl, wherein aryl and heteroaryl are unsubstituted or substituted with 1-5 substituents selected from R^a. In another embodiment of the present invention, A is selected from the group consisting of: phenyl, naphthalene, tetrahydronaphthalene, isoquinoline, pyrazolo[1,5-a]pyridine, naphthyridine, quinoxaline, dihydrobenzodioxin, indole, indazole, thieno[3,2-c]pyridine, furo[2,3-c]pyridine, thiazole, quinoline, pyridine, pyrazole, quinazoline, dihydroisoindole, dihydrocyclopentan[b]pyridine, imidazo[2,1-b][1,3]thiazole, dihydropyrido[3,2-b][1,4]oxazine, benzothiophene, —O-phenyl, —O-naphthalene, isoindoline-1-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, and benzo[d]oxazol-2(3H)-one, wherein A is unsubstituted or substituted with 1-5 substituents selected from R^a.

In another embodiment of the present invention, A is selected from the group consisting of: phenyl, naphthalene, tetrahydronaphthalene, isoquinoline, pyrazolo[1,5-a]pyridine, naphthyridine, quinoxaline, dihydrobenzodioxin, indole, indazole, thieno[3,2-c]pyridine, furo[2,3-c]pyridine, thiazole, quinoline, pyridine, pyrazole, quinazoline, dihydroisoindole, dihydrocyclopentan[b]pyridine, imidazo[2,1-b][1,3]thiazole, dihydropyrido[3,2-b][1,4]oxazine, benzothiophene, —O-phenyl, and —O-naphthalene, wherein A is unsubstituted or substituted with 1-5 substituents selected from R^a.

In another embodiment of the present invention, A is selected from the group consisting of: aryl, and heteroaryl, wherein aryl and heteroaryl are unsubstituted or substituted with 1-5 substituents selected from R^a. In another embodiment of the present invention, A is selected from the group consisting of: phenyl, naphthalene, tetrahydronaphthalene, isoquinoline, pyrazolopyridine, naphthyridine, quinoxaline, dihydrobenzodioxin, indole, indazole, thieno[3,2-c]pyridine, furopyridine, thiazole, quinoline, pyridine, pyrazole, quinazoline, dihydroisoindole, dihydrocyclopentan[b]pyridine, imidazothiazole, dihydropyrido oxazine, and benzothiophene, wherein A is unsubstituted or substituted with 1-5 substituents selected from R^a. In another embodiment of the present invention, A is selected from the group consisting of: phenyl, naphthalene, tetrahydronaphthalene, isoquinoline, pyrazolo[1,5-a]pyridine, naphthyridine, quinoxaline, dihydrobenzodioxin, indole, indazole, thieno[3,2-c]pyridine, furo[2,3-c]pyridine, thiazole, quinoline, pyridine, pyrazole, quinazoline, dihydroisoindole, dihydrocyclopentan[b]-pyridine, imidazo[2,1-b][1,3]thiazole, dihydropyrido[3,2-b][1,4]oxazine, and benzothiophene, wherein A is unsubstituted or substituted with 1-5 substituents selected from R^a. In another embodiment of the present invention, A is selected from the group consisting of: phenyl, naphthalene, isoquinoline, pyrazolo[1,5-a]pyridine, naphthyridine, quinazoline, and benzothiophene, wherein A is unsubstituted or substituted with 1-5 substituents selected from R^a.

In another embodiment of the present invention, A is selected from the group consisting of: phenyl, naphthalene, isoquinoline, pyrazolopyridine, naphthyridine, quinazoline, and benzothiophene, wherein A is unsubstituted or substituted with 1-5 substituents selected from R^a. In another embodiment of the present invention, A is selected from the group consisting of: phenyl, naphthalene, isoquinoline, pyrazolo[1,5-a]pyridine, 1,6-naphthyridine, quinazoline, and benzothiophene wherein A is unsubstituted or substituted with 1-5 substituents selected from R^a.

In another embodiment of the present invention, A is selected from the group consisting of: isoquinoline, and naphthyridine, wherein A is unsubstituted or substituted with 1-5 substituents selected from R^a. In another embodiment of the present invention, A is selected from the group consisting of: isoquinoline and 1,6-naphthyridine, wherein A is unsubstituted or substituted with 1-5 substituents selected from R^a.

In another embodiment of the present invention, A is aryl, wherein aryl is unsubstituted or substituted with 1-5 substituents selected from R^a. In another embodiment of the present invention, A is selected from the group consisting of: phenyl, naphthalene, and tetralin, wherein phenyl, naphthalene and tetralin are unsubstituted or substituted with 1-5 substituents selected from R^a. In another embodiment of the present invention, A is selected from the group consisting of: phenyl, and naphthalene, wherein phenyl and naphthalene are unsubstituted or substituted with 1-5 substituents selected from R^a. In another embodiment of the present invention, A is phenyl, wherein phenyl is unsubstituted or substituted with 1-5 substituents selected from R^a. In another embodiment of the present invention, A is naphthalene, wherein naphthalene is unsubstituted or substituted with 1-5 substituents selected from R^a. In another embodiment of the present invention, A is tetralin, wherein tetralin is unsubstituted or substituted with 1-5 substituents selected from R^a.

In another embodiment of the present invention, A is heteroaryl, wherein heteroaryl is unsubstituted or substituted with 1-5 substituents selected from R^a.

In another embodiment of the present invention, A is selected from the group consisting of: isoquinoline, pyrazolo[1,5-a]pyridine, 1,6-naphthyridine, quinoxaline, 2,3-dihydro-1,4-benzodioxine or benzodioxane, indole, thieno[3,2-c]pyridine, furo[2,3-c]pyridine, thiazole, quinoline, pyridine, pyrazole, quinazoline, 2,3-dihydroisoindole, 6,7-dihydro-5H-cyclopentan[b]pyridine, imidazo[2,1-b][1,3]thiazole, 2,3-dihydropyrido[3,2-b][1,4]oxazine, benzothiophene, isoindoline-1-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, and benzo[d]oxazol-2(3H)-one, wherein A is unsubstituted or substituted with 1-5 substituents selected from R^a.

In another embodiment of the present invention, A is selected from the group consisting of: isoquinoline, pyrazolo[1,5-a]pyridine, 1,6-naphthyridine, quinoxaline, 2,3-dihydro-1,4-benzodioxine or benzodioxane, indole, thieno[3,2-c]pyridine, furo[2,3-c]pyridine, thiazole, quinoline, pyridine, pyrazole, quinazoline, 2,3-dihydroisoindole, 6,7-dihydro-5H-cyclopentan[b]pyridine, imidazo[2,1-b][1,3]thiazole, 2,3-dihydropyrido[3,2-b][1,4]oxazine, and benzothiophene, wherein A is unsubstituted or substituted with 1-5 substituents selected from R^a.

In another embodiment of the present invention, A is selected from the group consisting of: isoquinoline, pyrazolo[1,5-a]pyridine, 1,6-naphthyridine, quinazoline, and benzothiophene, wherein A is unsubstituted or substituted with 1-5 substituents selected from R^a. In another embodiment of the present invention, A is selected from the group consisting of: isoquinoline, and 1,6-naphthyridine, wherein A is unsubstituted or substituted with 1-5 substituents selected from R^a.

In another embodiment of the present invention, A is isoquinoline, wherein A is unsubstituted or substituted with 1-5 substituents selected from R^a. In another embodiment of the present invention, A is pyrazolo[1,5-a]pyridine, wherein A is unsubstituted or substituted with 1-5 substituents selected from R^a. In another embodiment of the present invention, A is 1,6-naphthyridine, wherein A is unsubstituted or substituted with 1-5 substituents selected from R^a. In another embodiment of the present invention, A is quinazoline, wherein A is unsubstituted or substituted with 1-5 substituents selected from R^a. In another embodiment of the present invention, A is benzothiophene, wherein A is unsubstituted or substituted with 1-5 substituents selected from R^a.

In another embodiment of the present invention, B is selected from the group consisting of: aryl, and heteroaryl, wherein aryl and heteroaryl are unsubstituted or substituted with 1-4 substituents selected from R^b.

In another embodiment of the present invention, B is selected from the group consisting of: phenyl, pyridine, and pyrimidine, wherein phenyl, pyridine and pyrimidine are unsubstituted or substituted with 1-4 substituents selected from R^b.

In another embodiment of the present invention, B is selected from the group consisting of: phenyl, and pyridine, wherein phenyl and pyridine are unsubstituted or substituted with 1-4 substituents selected from R^b. In another embodiment of the present invention, B is phenyl, wherein phenyl is unsubstituted or substituted with 1-4 substituents selected from R^b. In another embodiment of the present invention, B is pyridine, wherein pyridine is unsubstituted or substituted with 1-4 substituents selected from R^b.

In another embodiment of the present invention, X is selected from the group consisting of: NR⁷, —CR⁸R⁹, and —O—. In another embodiment of the present invention, X is selected from the group consisting of: NR⁷, and —CR⁸R⁹. In another embodiment of the present invention, X is selected from the group consisting of: NR⁷. In another embodiment of the present invention, X is selected from the group consisting of: —CR⁸R⁹.

In another embodiment of the present invention, Y is selected from the group consisting of: NR³, —CR¹⁰R¹¹, and —C(R¹²)═C(R¹³)—. In another embodiment of the present invention, Y is selected from the group consisting of: NR³and —CR¹⁰R¹¹. In another embodiment of the present invention, Y is NR³. In another embodiment of the present invention, Y is —CR¹⁰R¹¹. In another embodiment of the present invention, Y is —C(R¹²)═C(R¹³)—.

In another embodiment of the present invention, R¹is selected from the group consisting of: hydrogen, halogen, —C_1-6alkyl, and —(CH₂)_p—OH, wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl.

In another embodiment of the present invention, R¹is selected from the group consisting of: hydrogen, —C_1-6alkyl, and —(CH₂)_p—OH, wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R¹is selected from the group consisting of: hydrogen, —C_1-6alkyl, and —(CH₂)_p—OH. In another embodiment of the present invention, R¹is selected from the group consisting of: hydrogen, —CH₃, —CH₂CH₃, —CH₂OH, and —(CH₂)₂OH, wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R¹is selected from the group consisting of: hydrogen, —CH₃, —CH₂CH₃, —CH₂OH, and —(CH₂)₂OH.

In another embodiment of the present invention, R¹is selected from the group consisting of: hydrogen, and —C_1-6alkyl, wherein alkyl is unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl.

In another embodiment of the present invention, R¹is selected from the group consisting of: hydrogen, —CH₃, and —CH₂CH₃. In another embodiment of the present invention, R¹is selected from the group consisting of: hydrogen, and —CH₃.

In another embodiment of the present invention, R²is selected from the group consisting of: hydrogen, halogen, —C_1-6alkyl, and —(CH₂)_p—OH, wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl, or R¹and R²together with the carbon atom they are attached to form a C_3-6cycloalkyl ring, wherein the cycloalkyl ring is unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl.

In another embodiment of the present invention, R²is selected from the group consisting of: hydrogen, —C_1-6alkyl, and —(CH₂)_p—OH, wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl, or R¹and R²together with the carbon atom they are attached to form a cyclopropyl ring, wherein the cyclopropyl ring is unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R²is selected from the group consisting of: hydrogen, —CH₃, —CH₂CH₃, —CH₂OH, and —(CH₂)₂OH, or R¹and R²together with the carbon atom they are attached to form a cyclopropyl ring, wherein the cyclopropyl ring is unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl.

In another embodiment of the present invention, R¹and R²are each independently selected from the group consisting of: hydrogen, —C_1-6alkyl, and —(CH₂)_p—OH, provided that one of R¹and R²is selected from —C_1-6alkyl and —(CH₂)_p—OH. In another embodiment of the present invention, R¹and R²are each independently selected from the group consisting of: hydrogen, —CH₃, —CH₂CH₃, —CH₂OH, and —(CH₂)₂OH, provided that one of R¹and R²is selected from —CH₃, —CH₂CH₃, —CH₂OH, and —(CH₂)₂OH. In another embodiment of the present invention, R¹and R²are each independently selected from the group consisting of: hydrogen, and —C_1-6alkyl, provided that one of R¹and R²is selected from —C_1-6alkyl.

In another embodiment of the present invention, R¹is hydrogen, and R²is —C_1-6alkyl. In another embodiment of the present invention, R¹is hydrogen, and R²is —CH₃. In another embodiment of the present invention, R¹is hydrogen and R²is hydrogen or —C_1-6alkyl. In another embodiment of the present invention, R¹is hydrogen and R²is hydrogen or —CH₃.

In another embodiment of the present invention, R²is hydrogen, and R¹is —C_1-6alkyl. In another embodiment of the present invention, R²is hydrogen, and R¹is —CH₃. In another embodiment of the present invention, R²is hydrogen and R¹is hydrogen or —C_1-6alkyl. In another embodiment of the present invention, R²is hydrogen and R¹is hydrogen or —CH₃.

In another embodiment of the present invention, R³is selected from the group consisting of: hydrogen, OH, and —C_1-6alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents selected from —C_1-6alkyl.

In another embodiment of the present invention, R³is selected from the group consisting of: hydrogen, and —C_1-6alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents selected from —C_1-6alkyl. In another embodiment of the present invention, R³is selected from the group consisting of: hydrogen, OH, and —C_1-6alkyl.

In another embodiment of the present invention, R³is selected from the group consisting of: hydrogen, and OH. In another embodiment of the present invention, R³is —C_1-6alkyl. In another embodiment of the present invention, R³is OH. In another embodiment of the present invention, R³is hydrogen.

In another embodiment of the present invention, each R⁴is independently selected from the group consisting of: hydrogen, halogen, —C_1-6alkyl, and —(CH₂)_p—OH, wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, each R⁴is independently selected from the group consisting of: hydrogen, —C_1-6alkyl, and —(CH₂)_p—OH, wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, each R⁴is independently selected from the group consisting of: hydrogen, halogen, and —C_1-6alkyl, wherein alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl.

In another embodiment of the present invention, each R⁴is independently selected from the group consisting of: hydrogen, halogen, and —C_1-6alkyl. In another embodiment of the present invention, each R⁴is independently selected from the group consisting of: hydrogen, and —C_1-6alkyl. In another embodiment of the present invention, each R⁴is —C_1-6alkyl. In another embodiment of the present invention, each R⁴is hydrogen.

In another embodiment of the present invention, each R⁵is independently selected from the group consisting of: hydrogen, halogen, —C_1-6alkyl, and —(CH₂)_p—OH, wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, each R⁵is independently selected from the group consisting of: hydrogen, —C_1-6alkyl, and —(CH₂)_p—OH, wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl.

In another embodiment of the present invention, each R⁵is independently selected from the group consisting of: hydrogen, halogen, and —C_1-6alkyl, wherein alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl.

In another embodiment of the present invention, each R⁵is independently selected from the group consisting of: hydrogen, halogen, and —C_1-6alkyl. In another embodiment of the present invention, each R⁵is independently selected from the group consisting of: hydrogen, and —C_1-6alkyl. In another embodiment of the present invention, each R⁵is —C_1-6alkyl. In another embodiment of the present invention, each R⁵is hydrogen.

In another embodiment, R⁶is selected from the group consisting of: hydrogen, halogen, —C_1-6alkyl, —C_2-6alkenyl, and —(CH₂)_p—OH, wherein CH₂and alkyl and alkenyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R⁶is selected from the group consisting of: hydrogen, halogen, —C_1-6alkyl, and —C_2-6alkenyl, wherein alkyl and alkenyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R⁶is selected from the group consisting of: hydrogen, halogen, and —C_1-6alkyl, wherein alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl.

In another embodiment of the present invention, R⁶is selected from the group consisting of: hydrogen, halogen, and —C_1-6alkyl. In another embodiment of the present invention, R⁶is selected from the group consisting of: hydrogen, and —C_1-6alkyl. In another embodiment of the present invention, R⁶is —C_1-6alkyl. In another embodiment of the present invention, R⁶is hydrogen.

In another embodiment of the present invention, R⁷is selected from the group consisting of: hydrogen, halogen, —C_1-6alkyl, —C_2-6alkenyl, and —(CH₂)_p—OH, wherein CH₂, alkyl and alkenyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl.

In another embodiment of the present invention, R⁷is selected from the group consisting of: hydrogen, —C_1-6alkyl, and —C_2-6alkenyl, wherein alkyl and alkenyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R⁷is selected from the group consisting of: hydrogen, and —C_2-6alkenyl, wherein alkenyl is unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In a class of this embodiment of the present invention, R⁷is selected from the group consisting of: hydrogen and —CH₂CH═CH₂. In another embodiment of the present invention, R⁷is selected from the group consisting of: —C_2-6alkenyl. In a class of this embodiment of the present invention, R⁷is —CH₂CH═CH₂. In another embodiment of the present invention, R⁷is hydrogen.

In another embodiment of the present invention, R⁸is selected from the group consisting of: hydrogen, halogen, —C_1-6alkyl, and —(CH₂)_p—OH, wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R⁸is selected from the group consisting of: hydrogen, and —C_1-6alkyl, wherein alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R⁸is selected from the group consisting of: —C_1-6alkyl, wherein alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R⁸is selected from the group consisting of: —C_1-6alkyl. In another embodiment of the present invention, each R⁸is hydrogen.

In another embodiment of the present invention, R⁹is selected from the group consisting of: hydrogen, halogen, —C_1-6alkyl, and —(CH₂)_p—OH, wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R⁹is selected from the group consisting of: hydrogen, and —C_1-6alkyl, wherein alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R⁹is selected from the group consisting of: —C_1-6alkyl, wherein alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R⁹is selected from the group consisting of: —C_1-6alkyl. In another embodiment of the present invention, each R⁹is hydrogen.

In another embodiment of the present invention, R¹⁰is selected from the group consisting of: hydrogen, halogen, —C_1-6alkyl, and —(CH₂)_p—OH, wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R¹⁰is selected from the group consisting of: hydrogen, and —C_1-6alkyl, wherein alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R¹⁰is selected from the group consisting of: —C_1-6alkyl, wherein alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R¹⁰is selected from the group consisting of: —C_1-6alkyl. In another embodiment of the present invention, each R¹⁰is hydrogen.

In another embodiment of the present invention, R¹¹is selected from the group consisting of: hydrogen, halogen, —C_1-6alkyl, and —(CH₂)_p—OH, wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R¹¹is selected from the group consisting of: hydrogen, and —C_1-6alkyl, wherein alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R¹¹is selected from the group consisting of: —C_1-6alkyl, wherein alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R¹¹is selected from the group consisting of: —C_1-6alkyl. In another embodiment of the present invention, each R¹¹is hydrogen.

In another embodiment of the present invention, R¹²is selected from the group consisting of: hydrogen, halogen, —C_1-6alkyl, and —(CH₂)_p—OH, wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R¹²is selected from the group consisting of: hydrogen, and —C_1-6alkyl, wherein alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R¹²is selected from the group consisting of: —C_1-6alkyl, wherein alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R¹²is selected from the group consisting of: —C_1-6alkyl. In another embodiment of the present invention, each R¹²is hydrogen.

In another embodiment of the present invention, R¹³is selected from the group consisting of: hydrogen, halogen, —C_1-6alkyl, and —(CH₂)_p—OH, wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R¹³is selected from the group consisting of: hydrogen, and —C_1-6alkyl, wherein alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R¹³is selected from the group consisting of: —C_1-6alkyl, wherein alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C_1-6alkyl, and —OC_1-6alkyl. In another embodiment of the present invention, R¹³is selected from the group consisting of: —C_1-6alkyl. In another embodiment of the present invention, each R¹³is hydrogen.

In another embodiment of the present invention, each R^ais independently selected from the group consisting of: halogen, —C_1-6alkyl, —OC_1-6alkyl, —OC_2-6alkenyl, —OH, oxo, —CN, —NO₂, —NR^cR^d, —CH₂NR^cR^d, —SO₂C_1-6alkyl, —C_3-6cycloalkyl, —C_2-6cycloheteroalkyl, aryl, and heteroaryl, wherein —CH₂, alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1-4 substituents selected from: halogen, —C_1-6alkyl, —OC_1-6alkyl, and —CO₂C_1-6alkyl. In another embodiment of the present invention, each R^ais independently selected from the group consisting of: halogen, —C_1-6alkyl, —OC_1-6alkyl, —OC_2-6alkenyl, —OH, oxo, —CN, —NO₂, —NR^cR^d, —CH₂NR^cR^d, —SO₂C_1-6alkyl, —C_3-6cycloalkyl, —C_2-6cycloheteroalkyl, aryl, and heteroaryl, wherein CH₂, alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1-4 substituents selected from: halogen.

In another embodiment of the present invention, each R^ais independently selected from the group consisting of: halogen, —C_1-6alkyl, —OC_1-6alkyl, oxo, —NO₂, —NR^cR^d, —CH₂NR^cR^d, —SO₂C_1-6alkyl, —C_2-6cycloheteroalkyl, and heteroaryl, wherein —CH₂, alkyl, cycloheteroalkyl and heteroaryl are unsubstituted or substituted with 1-4 substituents selected from: halogen, —C_1-6alkyl, —OC_1-6alkyl, and —CO₂C_1-6alkyl. In another embodiment of the present invention, each R^ais independently selected from the group consisting of: halogen, —C_1-6alkyl, —OC_1-6alkyl, oxo, —NO₂, —NR^cR^d, —CH₂NR^cR^d, —SO₂C_1-6alkyl, —C_2-6cycloheteroalkyl, and heteroaryl, wherein —CH₂, alkyl, cycloheteroalkyl and heteroaryl are unsubstituted or substituted with 1-4 substituents selected from: halogen. In another embodiment of the present invention, each R^ais independently selected from the group consisting of: halogen, —C_1-6alkyl, —OC_1-6alkyl, oxo, —NO₂, —NR^cR^d, —CH₂NR^cR^d, —SO₂C_1-6alkyl, —C_2-6cycloheteroalkyl, and heteroaryl, wherein —CH₂, alkyl, cycloheteroalkyl, and heteroaryl are unsubstituted or substituted with 1-4 substituents selected from: F. In another embodiment of the present invention, each R^ais independently selected from the group consisting of: F, Br, Cl, —CH₃, —CF₃, —CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCHF₂, oxo, —NO₂, —N(CH₃)₂, —CH₂N(CH₃)₂, —SO₂CH₃, morpholine, and pyrrole.

In another embodiment of the present invention, each R^ais independently selected from the group consisting of: —C_1-6alkyl, —OC_1-6alkyl, oxo, and —NO₂, wherein alkyl is unsubstituted or substituted with 1-4 substituents selected from: halogen, —C_1-6alkyl, —OC_1-6alkyl, and —CO₂C_1-6alkyl. In another embodiment of the present invention, each R^ais independently selected from the group consisting of: —C_1-6alkyl, —OC_1-6alkyl, oxo, and —NO₂, wherein alkyl is unsubstituted or substituted with 1-4 substituents selected from halogen. In another embodiment of the present invention, each R^ais independently selected from the group consisting of: —C_1-6alkyl, —OC_1-6alkyl, oxo, and —NO₂, wherein alkyl is unsubstituted or substituted with 1-4 substituents selected from F. In another embodiment of the present invention, each R^ais independently selected from the group consisting of: —CH₃, —CF₃, —CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCHF₂, oxo, and —NO₂.

In another embodiment of the present invention, each R^ais independently selected from the group consisting of: —CF₃, —OCH₃, oxo, and —NO₂.

In another embodiment of the present invention, each R^bis independently selected from the group consisting of: halogen, —C_1-6alkyl, —C_2-6alkenyl, —OC_1-6alkyl, —OC_2-6alkenyl, —OH, oxo, —CN, —NO₂, —NR^cR^d, —SO₂C_1-6alkyl, —C_3-6cycloalkyl, —C_2-6cycloheteroalkyl, aryl, and heteroaryl, wherein alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1-4 substituents selected from: halogen, —C_1-6alkyl, —OC_1-6alkyl, and —CO₂C_1-6alkyl. In another embodiment of the present invention, each R^bis independently selected from the group consisting of: halogen, —C_1-6alkyl, —C_2-6alkenyl, —OC_1-6alkyl, —OC_2-6alkenyl, —OH, oxo, —CN, —NO₂, —NR^cR^d, —SO₂C_1-6alkyl, —C_3-6cycloalkyl, —C_2-6cycloheteroalkyl, aryl, and heteroaryl, wherein alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1-4 substituents selected from: halogen.

In another embodiment of the present invention, each R^bis independently selected from the group consisting of: halogen, —C_1-6alkyl, —OC_1-6alkyl, —OC_2-6alkenyl, —NR^cR^d, —C_3-6cycloalkyl, and —C_2-6cycloheteroalkyl, wherein alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl are unsubstituted or substituted with 1-4 substituents selected from: halogen, —C_1-6alkyl, —OC_1-6alkyl, and —CO₂C_1-6alkyl. In another embodiment of the present invention, each R^bis independently selected from the group consisting of: halogen, —C_1-6alkyl, —OC_1-6alkyl, —OC_2-6alkenyl, —NR^cR^d, —C_3-6cycloalkyl, and —C_2-6cycloheteroalkyl, wherein alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl are unsubstituted or substituted with 1-4 substituents selected from: F. In another embodiment of the present invention, each R^bis independently selected from the group consisting of: F, Br, Cl, —CH₃, —CF₃, —CHF₂, —C(CH₃)F₂, —OCH₃, —OCH₂CH₃, —OCF₃, —OCF₂CH₃, —OCH₂CH═CH₂, —N(CH₃)₂, cyclopropyl, and pyrrolidine.

In another embodiment of the present invention, each R^bis independently selected from the group consisting of: halogen, —C_1-6alkyl, —OC_1-6alkyl, and —OC_2-6alkenyl, wherein alkyl, and alkenyl are unsubstituted or substituted with 1-4 substituents selected from: halogen, —C_1-6alkyl, —OC_1-6alkyl, and —CO₂C_1-6alkyl. In another embodiment of the present invention, each R^bis independently selected from the group consisting of: halogen, —C_1-6alkyl, —OC_1-6alkyl, and —OC_2-6alkenyl, wherein alkyl, and alkenyl are unsubstituted or substituted with 1-4 substituents selected from: F. In another embodiment of the present invention, each R^bis independently selected from the group consisting of: F, Br, Cl, —CH₃, —CF₃, —CHF₂, —OCH₃, —OCH₂CH₃, —OCF₃, —OCF₂CH₃, and —OCH₂CH═CH₂. In another embodiment of the present invention, each R^bis independently selected from the group consisting of: F, Cl, —CF₃, —OCH₃, —OCH₂CH₃, —OCF₃, and —OCH₂CH═CH₂.

In another embodiment of the present invention, each R^bis independently selected from the group consisting of: —C_1-6alkyl, and —OC_1-6alkyl, wherein alkyl is unsubstituted or substituted with 1-4 substituents selected from: halogen. In another embodiment of the present invention, each R^bis independently selected from the group consisting of: —C_1-6alkyl, and —OC_1-6alkyl, wherein alkyl is unsubstituted or substituted with 1-4 substituents selected from: F. In another embodiment of the present invention, each R^bis independently selected from the group consisting of: —CH₃, —CF₃, —CHF₂, —OCH₃, —OCH₂CH₃, —OCF₃, and —OCF₂CH₃. In another embodiment of the present invention, each R^bis independently selected from the group consisting of: —CF₃, —OCH₃, —OCH₂CH₃, and —OCF₃. In another embodiment of the present invention, each R^bis independently selected from the group consisting of: —CF₃, and —OCH₃.

In another embodiment of the present invention, each R^cis independently selected from the group consisting of: hydrogen, —C_1-6alkyl, —C_2-6alkenyl, —C_1-6alkyl-OH, —C_3-6cycloalkyl, —C(O)C_1-6alkyl, and SO₂C_1-6alkyl, wherein alkyl, alkenyl and cycloalkyl are unsubstituted or substituted with one to three substituents selected from halogen, —C_1-6alkyl, —OC_1-6alkyl, and —CO₂C_1-6alkyl. In another embodiment of the present invention, each R^cis independently selected from the group consisting of: hydrogen, —C_1-6alkyl, —C_2-6alkenyl, —C_1-6alkyl-OH, —C(O)C_1-6alkyl, and SO₂C_1-6alkyl, wherein alkyl and alkenyl are unsubstituted or substituted with one to three substituents selected from halogen.

In another embodiment of the present invention, each R^cis independently selected from the group consisting of: hydrogen, —C_1-6alkyl, —C_2-6alkenyl, —C_1-6alkyl-OH, —C(O)C_1-6alkyl, and SO₂C_1-6alkyl, wherein alkyl and alkenyl are unsubstituted or substituted with one to three F substituents.

In another embodiment of the present invention, each R^cis independently selected from the group consisting of: hydrogen and C_1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three F substituents. In another embodiment of the present invention, each R^cis independently selected from the group consisting of: hydrogen and C_1-6alkyl. In another embodiment of the present invention, each R^cis independently selected from the group consisting of: hydrogen and CH₃.

In another embodiment of the present invention, R^cis hydrogen.

In another embodiment of the present invention, each R^cis independently selected from the group consisting of C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three F substituents. In another embodiment of the present invention, each R^cis independently selected from the group consisting of C_1-6alkyl. In another embodiment of the present invention, R^cis CH₃.

In another embodiment of the present invention, each R^dis independently selected from the group consisting of: hydrogen, —C_1-6alkyl, —C_2-6alkenyl, —C_1-6alkyl-OH, —C_3-6cycloalkyl, —C(O)C_1-6alkyl, and SO₂C_1-6alkyl, wherein alkyl, alkenyl and cycloalkyl are unsubstituted or substituted with one to three substituents selected from halogen, —C_1-6alkyl, —OC_1-6alkyl, and —CO₂C_1-6alkyl, or R^cand R^dtogether with the nitrogen atom they are attached to form a C_4-8cycloheteroalkyl ring, wherein the C_4-8cycloheteroalkyl ring is unsubstituted or substituted with 1-4 substituents selected from halogen, —C_1-6alkyl, —OC_1-6alkyl, and —CO₂C_1-6alkyl. In another embodiment of the present invention, each R^dis independently selected from the group consisting of: hydrogen, —C_1-6alkyl, —C_2-6alkenyl, —C_1-6alkyl-OH, —C_3-6cycloalkyl, —C(O)C_1-6alkyl, and SO₂C_1-6alkyl, wherein alkyl, alkenyl and cycloalkyl are unsubstituted or substituted with one to three substituents selected from halogen, —C_1-6alkyl, —OC_1-6alkyl, and —CO₂C_1-6alkyl.

In another embodiment of the present invention, each R^dis independently selected from the group consisting of: hydrogen, —C_1-6alkyl, —C_2-6alkenyl, —C_1-6alkyl-OH, —C(O)C_1-6alkyl, and SO₂C_1-6alkyl, wherein alkyl and alkenyl are unsubstituted or substituted with one to three substituents selected from halogen.

In another embodiment of the present invention, each R^dis independently selected from the group consisting of: hydrogen and C_1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three F substituents. In another embodiment of the present invention, each R^dis independently selected from the group consisting of: hydrogen and C_1-6alkyl. In another embodiment of the present invention, each R^dis independently selected from the group consisting of: hydrogen and CH₃. In another embodiment of the present invention, R^dis hydrogen.

In another embodiment of the present invention, each R^dis independently selected from the group consisting of C_1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three F substituents. In another embodiment of the present invention, each R^dis independently selected from the group consisting of C_1-6alkyl. In another embodiment of the present invention, R^dis CH₃.

In another embodiment of the present invention, m is 0 or 1. In a class of this embodiment, m is 0. In another class of this embodiment, m is 1.

In another embodiment of the present invention, n is 0, 1, 2 or 3. In another class of this embodiment, n is 1, 2, or 3. In another class of this embodiment, n is 0, 1, or 2. In another class of this embodiment, n is 1 or 2. In another class of this embodiment, n is 0 or 1. In another class of this embodiment, n is 0 or 2. In another class of this embodiment, n is 0. In another class of this embodiment, n is 1. In another class of this embodiment, n is 2. In another class of this embodiment, n is 3.

In another embodiment of the present invention, p is 0, 1, 2, 3, 4, 5 or 6. In a class of this embodiment, p is 0, 1, 2, 3, or 4. In another class of this embodiment, p is 0, 1, 2, or 3. In another embodiment of the present invention, p is 1, 2, 3, 4, 5 or 6. In another class of this embodiment, p is 1, 2, 3, or 4. In another class of this embodiment, p is 1, 2, or 3. In another class of this embodiment, p is 0, 1 or 2. In another class of this embodiment, p is 0 or 1. In another class of this embodiment, p is 1 or 2. In another class of this embodiment, p is 0. In another class of this embodiment, p is 1. In another class of this embodiment, p is 2.

In another embodiment of the present invention, the invention relates to compounds of structural formula Ia: