WO2011005871A1

WO2011005871A1 - Substituted 8-[6-carbonylamine-3-pyridyl]xanthines as adenosine a2b antagonists

Info

Publication number: WO2011005871A1
Application number: PCT/US2010/041228
Authority: WO
Inventors: Guoquan Wang; Jayson M. Rieger; Robert D. Thompson
Original assignee: Pgxhealth, Llc
Priority date: 2009-07-07
Filing date: 2010-07-07
Publication date: 2011-01-13

Abstract

Provided herein are substituted 8- [6 -carbonylamino-3 -pyridyl] xanthines of formula (I) and pharmaceutical compositions that are selective antagonists of A2B adenosine receptors (ARs). and stereoisomers and pharmaceutically acceptable salts thereof;

Description

SUBSTITUTED 8-[6-CARBONYLAMINE-S-PYRIDYL]XANTHINES AS ADENOSINE A2B ANTAGONISTS

RELATED APPLICATIONS

This application claims priority to U S Provisional Application No 61/223,474, filed on July 07, 2009; the entire contents of which is incorporated herein by reference.

STATEMENT OF GOVERNMENT RIGHTS

[0001] This invention was made with the assistance of government support under

United States Grant No. 5 R44 AI048979-03 from the National Institutes of Health. The government may have certain rights to the invention.

BACKGROUND OF THE INVENTION

[0002] The alkylxanthine theophylline (below), a weak non-selective adenosine

antagonist (See Linden, J., et al, Cardiovascular Biology of Purines, eds. G. Burnstock, et al, 1998, pp 1-20), is useful therapeutically for the treatment of asthma. However, its use is associated with unpleasant side effects, such as insomnia and diuresis. In recent years, the use of theophylline as a bronchodilator, for relief of asthma, has been supplanted by drugs of other classes, e.g,, selective β₂-adrenergic agonists,

corticosteroids, and recently leukotriene antagonists. These compounds also have limitations Thus, the development of a theophylline-like drug with reduced side effects is still desirable.

[0003] It has been recognized that theophylline and its analogue caffeine block endogenous adenosine acting as a local modulator of adenosine receptors in the brain and other organs at therapeutically useful doses. Adenosine activates four subtypes of G protein-coupled adenosine receptors (ARs), A_\IA_2AI^_IBI^₃- Enprofylline (below) is another example of a xanthine that has been reported to block A_2B adenosine receptors and is used

to treat asthma. It has also been shown by LaNoue et al (U.S. Patent No. 6,060,481) that selective adenosine A_2B antagonists are useful for improving insulin sensitivity in a patient.

[0004] It has been reported that therapeutic concentrations of theophylline or enprofylline block human A_2B receptors, and it has been proposed that antagonists selective for this subtype may have potential use as antiasthmatic agents. (See

Feoktistov, L, et al, Pharmacol. Rev. 1997, 49, 381-402; and Robeva, A.S., et al., Drug Dev. Res . 1996, 39, 243-252). Enprofylline has a reported K₁ value of 7 μM and is somewhat selective in binding to human A_2B ARs. (See Robeva, A. S., et al., Drug Dev. Res . 1996, 39, 243-252 and Linden, J., et al, MoI. Pharmacol. 1999, 56, 705-713). A_2B ARs are expressed in some mast cells, such as the BR line of canine mastocytoma cells, which appear to be responsible for triggering acute Ca²⁺ mobilization and degranulation. (See Auchampach, J. A., et al., MoI. Pharmacol. 1997, 52, 846-860 and Forsyth, P., et al., Inflamm. Res. 1999, 48, 301-307). A_2B ARs also trigger Ca²⁺ mobilization, and participate in a delayed IL8 release from human HMC-I mast cells. Other functions associated with the A_2B AR are the control of cell growth and gene expression, (See Neary, J., et al., Trends Neurosci. 1996, 19, 13-18) endothelial-dependent vasodilation (See Martin, P.L., et al, J. Pharmacol. Exp. Ther. 1993, 265, 248-253), and fluid secretion from intestinal epithelia. (See Strohmeier, G.R., et al, J. Biol. Chem. 1995, 270, 2387-2394). Adenosine acting through A_2B ARs has also been reported to stimulate chloride permeability in cells expressing the cystic fibrosis transport regulator. (See Clancy, J.P., et al., Am. J. Physiol. 1999, 276, C361-C369.)

[0005] Baraldi et al in U.S. 7,205,402, as well as WO 2003/063800, describe A_2B receptor antagonists of the following formula:

wherein A can be a bond, X can be a heteroaromatic ring, and M is a carbonyl- substituted carbon-based linker. Baraldi et al. does not describe any substituted 8- [6- carbonylamino-3-pyridyl]xanthines.

[0006] KaUa et al. in U.S. 6,825,349, as well as U.S. 7,151,125 and WO

2003/042214, describe A_2B receptor antagonists of the following formula:

O R³

R2

wherein X can be a heteroarylene, Y can be an alkylene, and Z can be an aryl or heteroaryl ring. Kalla et al. does not describe any substituted 8-[6-carbonylamino-3- pyridyl] xanthines .

[0007] Wang et al. in U.S. 7,342,006 describe A_2B receptor antagonists of the following formula:

wherein X can be a pyridyl and Z can be an amino group. Wang et al. does not describe any substituted 8-[6-carbonylamino-3-pyridyl]xanthines.

[0008] In view of a variety of uses currently being clinically studied for A_2B receptor antagonists, a continuing need exists for compounds that are selective A_2B receptor antagonists.

SUMMARY OF THE INVENTION

[0009] Accordingly, in some embodiments, substituted 8-[6-carbonylamino-3- pyridyl] xanthines or stereoisomers or pharmaceutically acceptable salts that act as antagonists of A_2B adenosine receptors are provided herein.

[0010] In some embodiments, pharmaceutical compositions are also provided herein, which include any one of the compounds described herein and a

pharmaceutically acceptable excipient.

3 [0011] In other embodiments, therapeutic methods are provided herein for treating a pathological condition or symptom in a mammal, such as a human, wherein the activity, e.g., over- activity, of adenosine A_2B receptors is implicated in one or more symptoms of the pathology and antagonism (i.e., blocking) is desired to ameliorate such symptoms.

[0012] Also provided are compounds as described herein, for use in medical therapy.

[0013] In still other embodiments, provided herein is the use of the compounds as described herein for the manufacture of a medicament for the treatment of a pathological condition or symptom in a mammal, which is associated with deleterious A_2B receptor activation or activity.

[0014] These and other parts of the present teachings, which will become apparent during the following detailed description, have been achieved, at least in part, by the inventors' discovery that the presently claimed 8-[6-carbonylamino-3-pyridyl]xanthines, or stereoisomers or pharmaceutically acceptable salts thereof, are antagonists of A_2B adenosine receptors.

DETAILED DESCRIPTION OF THE INVENTION

[0015] The indefinite articles "a" and "an" mean "at least one" or "one or more" when used in this application, including the claims, unless specifically indicated otherwise.

[0016] Specific and preferred values listed for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.

/. Compounds

[0017] In some embodiments, the present teachings provide compounds which act as

A_2B receptor modulators, e.g., A_2B receptor antagonists, such as substituted 8-[6- carbonylamino-3-pyridyl]xanthines.

[0018] As used herein "A_2B antagonist" refers to an agent that antagonizes the

Adenosine A_2B receptor with a Ki of <lμM. An A_2B antagonist may also be cross reactive with other adenosine receptor subtypes (e.g., A₁, A_2A, and A₃). An A_2B antagonist may be selective for A_2B (e.g., at least 10, 50, or 100/1 over another adenosine receptor subtype). The A_2B antagonist may activate other receptors with a greater or lesser affinity than the A_2B receptor. [0019] In some embodiments, the present teachings provide compounds of formula I:

and stereoisomers and pharmaceutically acceptable salts thereof;

wherein:

R is selected from: H, C₁-_O alkyl, C₁-_O haloalkyl, C₃-₅ alkenyl, and C₃-₅ alkynyl;

R¹ and R² are independently selected from: H, C_1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C₁-_S alkoxy, C₃_io cycloalkyl, (C₃_io cycloalkyl)Ci_₈ alkyl-, C_4-1O heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, C_6-10 aryl, (C_6-10 aryl)C_1-8 alkyl-, C_5-10 heteroaryl, and (C_5-10 heteroaryl)C_1-8 alkyl-, wherein R¹ and R² are independently substituted with 0-2

R la.

R^la, at each occurrence, is independently selected from: F, Cl, Br, I, Cr₆ alkyl,

C_2-6 alkenyl, C_2-6 alkynyl, -(CH₂)_aOR^a, -(CH₂)_aNR^aR^a, -(CH₂)_aNHOH,

-(CH₂)_aNR^aNR^aR^a, -(CH₂)_aNO₂, -(CH₂)_aCN, -(CH₂)_aCO₂R^a, -(CH₂)_aC(O)R^a,

-(CH₂)_aOC(O)R^a, -(CH₂)_aCONR^aR^a, CF₃, and OCF₃;

R^a, at each occurrence, is independently selected from: H, Cr₆ alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, (C_3-10 cycloalkyl)Crs alkyl-, C_4-10 heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, C_6-10 aryl, (C_6-10 aryl)Crs alkyl-, C_5-10 heteroaryl, and (C_5-10 heteroaryl)Crs alkyl-, wherein alkyl is optionally interrupted with 1-2

heteroatoms selected from O, S(O)_P, and NR^b;

R^b is independently selected from: H, Cr₆ alkyl, and benzyl;

R⁴ and R⁵ are independently selected from: H, C_1-8 alkyl, -C_1-8 alkyl-(CO₂R⁶), -C_1-8 alkyl-(CONR⁷R⁸), C_3-8 alkenyl, C_3-8 alkynyl, C_3-10 cycloalkyl,

(C_3-10 cycloalkyl)Crs alkyl-, C_6-10 aryl, (C_6-10 aryl)Crs alkyl-, C_4-10 heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, C_5-10 heteroaryl, and (C_5-10 heteroaryl)Crs alkyl-, wherein R⁴ and R⁵ are independently substituted with 0-3 R^4a and provided that at most one of R⁴ and R⁵ is H;

R^4a, at each occurrence, is independently selected from: =0, halo, cyano, nitro, OR^a, SR^a, HO-Ci_-8 alkyl-, -NR^bR^c, R^bR^cN-Ci_₈ alkyl-, C_6-I0 aryl-O-, C_6-I0 aryl,

(C_6-I₀ aryl)Ci-8 alkyl-, Crs haloalkyl, -COR^a, -CO₂R^a, and -CONR^bR^c; alternatively, one of R⁴ and R⁵ is selected from: -((CH₂W YV(CH₂WX¹,

\ -COR⁶, -CO₂R⁶, -CONR⁷R⁸, and -S(O)₂NR⁷R⁸;

X¹, at each occurrence, is independently selected from: OR⁶, -COR⁶, -CO₂R⁶,

Y, at each occurrence, is independently selected from: O, S, SO, S(O)₂, and

NR^b

alternatively, NR i 4_π R5 forms a 4-10 membered heterocyclic ring, consisting of: the shown N atom, carbon atoms, and 0-4 heteroatoms selected from O, S(0)_p, and N, wherein the ring is substituted with 0-4 substituents independently selected from: halo, cyano, nitro, 0R^a, SR^a, C_6-10 aryl, C_6-10 aryl-O-, HO-Cr₈ alkyl-, R¹³R⁰N-Cr₈ alkyl-, C₁-S haloalkyl, -NR^bR^c, -COR^a, -CO₂R^a, and -CONR^bR^c;

R⁶, at each occurrence, is independently is selected from: H, C_1-8 alkyl, R^aO-Ci_₈ alkyl, R^bR^cN-Ci-₈ alkyl-, C₁-S haloalkyl, C_3-10 cycloalkyl, (C_3-10 cycloalkyl)Ci-₈ alkyl-, C_6-10 aryl, (C_6-10 aryl)C_1-8 alkyl-, C_4-10 heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, Cs_-1O heteroaryl, and (Cs_-10 heteroaryl)Crs alkyl-, wherein R⁶ is substituted with 0-3 R^6a groups;

R^6a, at each occurrence, is independently selected from: halo, cyano, nitro, - 0R^a, -SR^a, C_6-10 aryl, C_6-10 aryl-O-, HO-C₁-S alkyl-, R^bR^cN-Crs alkyl-, C₁-S haloalkyl, -NR^bR^c, -COR^a, -CO₂R^a, and -CONR^bR^c;

R⁷ and R⁸, at each occurrence, are independently selected from: H, C₁-_S alkyl, R^aO-C_1-8 alkyl, R^bR^cN-C_1-8 alkyl-, C₁-_S haloalkyl, C_3-10 cycloalkyl,

(C_3-10 cycloalkyl)Crs alkyl-, C_6-10 aryl, (C_6-10 aryl)C_1-8 alkyl-, C_4-10 heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, Cs_-10 heteroaryl, (Cs_-10 heteroaryl)Crs alkyl-, and ((CH₂W Y)₉-(CH₂)^₄-X¹, wherein R⁷ and R⁸ are independently substituted with 0-3 R⁹ groups;

R^7a and R^8a, at each occurrence, are independently selected from: H, C₁-_S alkyl, R^aO-C_1-8 alkyl, R^bR^cN-C_1-8 alkyl-, C₁-_S haloalkyl, C_3-10 cycloalkyl,

(C_3-10 cycloalkyl)Crs alkyl-, C_6-10 aryl, (C_6-10 aryl)C_1-8 alkyl-, C_4-10 heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, and Cs_-10 heteroaryl, (Cs_-10 heteroaryl)Crs alkyl-, wherein R^7a and R^8a are independently substituted with 0-3 R⁹ groups;

R⁹, at each occurrence, is independently selected from: halo, cyano, nitro, -0R^a, -SR^a, C_6-10 aryl, C_6-10 aryl-O-, HO-C₁-S alkyl-, R^bR^cN-Crs alkyl-, C₁-S haloalkyl, -NR^bR^c, -COR^a, -CO₂R^a, and -CONR^bR^c; R^c, at each occurrence, is independently selected from H, C₁-_O alkyl, and benzyl; alternatively, NR^bR^c forms a ring selected from pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, and thiomorpholinyl ring;

a, at each occurrence, is independently selected from of 0, 1, and 2;

p, at each occurrence, is independently selected from 0, 1, and 2; and, q, at each occurrence, is independently selected from 1, 2, 3, and 4;

provided that when one of R⁴ or R⁵ is (a) phenyl-(alkyl)o-i-,

(b) pyrid-2-yl-(alkyl)o-i-, or (c) pyrimid-2-yl-(alkyl)o-i-, the alkyl group of (a)-(c) being optionally interrupted with 0-1 CO₂, C(O)NR , 7 , or C(O)NR , then:

(i) the other of R⁴ or R⁵ is other than an unsubstituted alkyl, alkenyl, or alkynyl;

(ii) the phenyl of group (a) is at least substituted at the 2 or 6 position by R^4a;

(iii) the pyridyl of group (b) is at least substituted at the 3 position by R 4a. ; (iv) the alkyl group of (a), (b), or (c) is substituted with at least one R^4a; (v) R¹ is cycloalkyl or (C_3-1O cycloalkyl)Ci-8 alkyl-; or

(vi) a combination of (i)-(v).

[0020] In some embodiments, the present teachings provide compounds of formula I:

and stereoisomers and pharmaceutically acceptable salts thereof;

wherein:

R¹ is C₃_₈ cycloalkyl substituted with 0-2 R^la;

R is selected from: H, C_1-8 alkyl, C₃_g alkenyl, C₃_g alkynyl, C₁-_S alkoxy, C₃_g cycloalkyl, (C_3-8 cycloalkyl)Ci-8 alkyl-, C_4-1O heterocyclyl, (C_4-1O heterocyclyl)Ci-8 alkyl- , C₆-Io aryl, (C_6-10 aryl)C_1-8 alkyl-, Cs_-10 heteroaryl, and (Cs_-10 heteroaryl)Ci-₈ alkyl-, and is substituted with 0-2 R^la;

R^la, at each occurrence, is independently selected from: F, Cl, Br, I, Cr₆ alkyl, C₂-6 alkenyl, C₂-₆ alkynyl, -(CH₂)_aOR^a, -(CH₂)_aNR^aR^a, -(CH₂)_aNHOH, -(CH₂)_aNR^aNR^aR^a, -(CH₂)_aNO₂, -(CH₂)_aCN, -(CH₂)_aCO₂R^a, -(CH₂)_aC(O)R^a,

-(CH₂)_aOC(O)R^a, -(CH₂)_aCONR^aR^a, CF₃, and OCF₃;

R^a, at each occurrence, is independently selected from: H, C₁-O alkyl, C₂_6 alkenyl, C₂-6 alkynyl, C_3-1O cycloalkyl, (C_3-1O cycloalkyl)Ci-8 alkyl-, C_4-1O heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, C_6-10 aryl, (C_6-10 8TyI)Cr₈ alkyl-, C_5-10 heteroaryl, and (C₅__lo heteroaτyl)Cr₈ alkyl-, wherein alkyl is optionally interrupted with 1-2

heteroatoms selected from O, S(O)_P, and NR^b;

R^b is independently selected from: H, C₁-_O alkyl, and benzyl;

R⁴ and R⁵ are independently selected from: H, C_1-8 alkyl, -Ci_-8 alkyl-(CO₂R⁶), -C₁-_S alkyl-(CONR⁷R⁸), C₃_₈ alkenyl, C₃_₈ alkynyl, C₃__lo cycloalkyl,

(C_3-10 cycloalkyl)Crs alkyl-, C_6-10 aryl, (C_6-10 aryl)Crs alkyl-, C_4-10 heterocyclyl, (C_4-10 heterocyclyl)Ci-₈ alkyl-, C_5-10 heteroaryl, and (C_5-10 heteroaryl)Crs alkyl-, wherein R⁴ and R⁵ are independently substituted with 0-3 R^4a and provided that at most one of R⁴ and R⁵ is H;

R^4a, at each occurrence, is independently selected from: =0, halo, cyano, nitro, OR^a, SR^a, HO-C₁-S alkyl-, -NR^bR^c, R^bR^cN-Ci-₈ alkyl-, C_6-Io aryl-O-, C_6-Io aryl,

(C_6-IO aryl)Ci-8 alkyl-, C₁-S haloalkyl, -COR^a, -CO₂R^a, and -CONR^bR^c;

alternatively, one of R⁴ and R⁵ is selected from: -((CH₂W Y)₉-(CH₂)^-X¹, -NR⁷R⁸, -COR⁶, -CO₂R⁶, -CONR⁷R⁸, and -S(O)₂NR⁷R⁸;

X¹, at each occurrence, is independently selected from: OR⁶, -COR⁶, -CO₂R⁶, and -NR^7aR^8a;

Y, at each occurrence, is independently selected from: O, S, SO, S(O)₂, and

NR^S

alternatively, NR i 4_π R5 forms a 4-10 membered heterocyclic ring, consisting of: the shown N atom, carbon atoms, and 0-4 heteroatoms selected from O, S(0)_p, and N, wherein the ring is substituted with 0-4 substituents independently selected from: halo, cyano, nitro, 0R^a, SR^a, C_6-10 aryl, C_6-10 aryl-O-, HO-C₁-S alkyl-, R^bR^cN-Crs alkyl-, C₁-S haloalkyl, -NR^bR^c, -COR^a, -CO₂R^a, and -CONR^bR^c;

R⁶, at each occurrence, is independently is selected from: H, C_1-8 alkyl, R^aO-C_1-8 alkyl, R^bR^cN-C_1-8 alkyl-, C₁-S haloalkyl, C_3-10 cycloalkyl, (C_3-10 cycloalkyl)Crs alkyl-, C_6-10 aryl, (C_6-10 aryl)C_1-8 alkyl-, C_4-10 heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, C_5-10 heteroaryl, and (C_5-10 heteroaryl)Crs alkyl-, wherein R⁶ is substituted with 0-3 R^6a groups; R^6a, at each occurrence, is independently selected from: halo, cyano, nitro, - OR^a, -SR^a, C₆-I₀ aryl, C_6-Io aryl-O-, HO-Cr₈ alkyl-, R¹³R⁰N-Cr₈ alkyl-, C₁-S haloalkyl, -NR^bR^c, -COR^a, -CO₂R^a, and -CONR^bR^c;

R⁷ and R⁸, at each occurrence, are independently selected from: H, C₁-_S alkyl, RO-Ci-8 alkyl, R^bR^cN-Ci_₈ alkyl-, C₁-S haloalkyl, C_3-10 cycloalkyl,

(C_3-10 cycloalkyl)Crs alkyl-, C_6-10 aryl, (C_6-10 aryl)C_1-8 alkyl-, C_4-10 heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, Cs_-10 heteroaryl, (Cs_-10 heteroaryl)Crs alkyl-, and

((CH₂)₂-₄- Y)₉-(CH₂)^₄-X¹, wherein R⁷ and R⁸ are independently substituted with 0-3 R⁹ groups;

R^7a and R^8a, at each occurrence, are independently selected from: H, C₁-_S alkyl, R^aO-C_1-8 alkyl, R^bR^cN-C_1-8 alkyl-, C₁-S haloalkyl, C_3-10 cycloalkyl,

R⁹, at each occurrence, is independently selected from: halo, cyano, nitro, -OR^a, -SR^a, C_6-10 aryl, C_6-10 aryl-O-, HO-C₁-S alkyl-, R^bR^cN-Crs alkyl-, C₁-S haloalkyl, -NR^bR^c, -COR^a, -CO₂R^a, and -CONR^bR^c;

R^c, at each occurrence, is independently selected from H, Cr₆ alkyl, and benzyl; alternatively, NR^bR^c forms a ring selected from pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, and thiomorpholinyl ring;

a, at each occurrence, is independently selected from of 0, 1, and 2;

p, at each occurrence, is independently selected from 0, 1, and 2; and, q, at each occurrence, is independently selected from 1, 2, 3, and 4.

[0021] In some embodiments, the present teachings provide compounds of formula I:

and stereoisomers and pharmaceutically acceptable salts thereof;

wherein:

R is selected from: H, C_1-6 alkyl, C_1-6 haloalkyl, C_3-5 alkenyl, and C_3-5 alkynyl;

R¹ is selected from: H, C_1-8 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, C_1-8 alkoxy, C_3-8 cycloalkyl, (C_3-8 cycloalkyl)C_1-8 alkyl-, C_4-10 heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl- , C_6-1O aryl, (C_6-1O aryl)Ci_₈ alkyl-, Cs_-1O heteroaryl, and (Cs_-1O heteroaryl)C_1-8 alkyl-, and is substituted with 0-2 R^la;

R² is C_3-8 cycloalkyl substituted with 0-2 R^la;

R^la, at each occurrence, is independently selected from: F, Cl, Br, I, C₁-_O alkyl, C_2-6 alkenyl, C_2-6 alkynyl, -(CH₂)_aOR^a, -(CH₂)_aNR^aR^a, -(CH₂)_aNHOH,

-(CH₂)_aOC(O)R^a, -(CH₂)_aCONR^aR^a, CF₃, and OCF₃;

R^a, at each occurrence, is independently selected from: H, C₁-O alkyl, C₂_6 alkenyl, C₂_6 alkynyl, C_3-1O cycloalkyl, (C_3-1O cycloalkyl)Cr8 alkyl-, C_4-1O heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, C_6-10 aryl, (C_6-10 aryl)Cr₈ alkyl-, C_5-10 heteroaryl, and (Cs_-1O heteroaryl)Ci-8 alkyl-, wherein alkyl is optionally interrupted with 1-2

heteroatoms selected from O, S(O)_P, and NR^b;

R^b is independently selected from: H, Cr₆ alkyl, and benzyl;

R⁴ and R⁵ are independently selected from: H, C_1-S alkyl, -C_1-S alkyl-(CO₂R⁶), -C_1-8 alkyl-(CONR⁷R⁸), C_3-8 alkenyl, C_3-8 alkynyl, C_3-10 cycloalkyl,

(C_3-10 cycloalkyl)Ci-₈ alkyl-, C_6-10 aryl, (C_6-10 aryl)Crs alkyl-, C_4-10 heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, C_5-10 heteroaryl, and (C_5-10 heteroaryl)Crs alkyl-, wherein R⁴ and R⁵ are independently substituted with 0-3 R^4a and provided that at most one of R⁴ and R⁵ is H;

R^4a, at each occurrence, is independently selected from: =0, halo, cyano, nitro, OR^a, SR^a, HO-Ci_-8 alkyl-, -NR^bR^c, R^bR^cN-Ci_-8 alkyl-, C_6-I0 aryl-O-, C_6-I0 aryl,

(C₆-_I0 aryl)Ci-₈ alkyl-, d-₈ haloalkyl, -COR^a, -CO₂R^a, and -CONR^bR^c;

alternatively, one of R⁴ and R⁵ is selected from: -((CH₂)₂-₄- Y)_q-(CH₂)_2-4-X¹, -NR⁷R⁸, -COR⁶, -CO₂R⁶, -CONR⁷R⁸, and -S(O)₂NR⁷R⁸;

_R7a_R8a.

and -NR^7aR^8a;

Y, at each occurrence, is independently selected from: O, S, SO, S(O)₂, and

NR^b

alternatively, NR⁴R forms a 4-10 membered heterocyclic ring, consisting of: the shown N atom, carbon atoms, and 0-4 heteroatoms selected from O, S(O)_P, and N, wherein the ring is substituted with 0-4 substituents independently selected from: halo, cyano, nitro, OR^a, SR^a, C_6-10 aryl, C_6-10 aryl-O-, HO-Cr₈ alkyl-, R^bR^cN-Crs alkyl-, C₁-S haloalkyl, -NR^bR^c, -COR^a, -CO₂R^a, and -CONR^bR^c; R⁶, at each occurrence, is independently is selected from: H, C₁-_S alkyl, R^aO-Ci_₈ alkyl, R¹³R⁰N-C_1-8 alkyl-, Cr₈ haloalkyl, C_3-10 cycloalkyl, (C_3-10 cycloalkyl)Ci-₈ alkyl-, C₆-I₀ aryl, (C₆-I₀ aryl)C_1-8 alkyl-, C₄-I₀ heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, Cs_-1O heteroaryl, and (Cs_-10 heteroaryl)Ci-₈ alkyl-, wherein R⁶ is substituted with 0-3 R^6a groups;

R^6a, at each occurrence, is independently selected from: halo, cyano, nitro, - OR^a, -SR^a, C₆-I₀ aryl, C₆-I₀ aryl-O-, HO-Cr₈ alkyl-, R^bR^cN-Crs alkyl-, C₁-S haloalkyl, -NR^bR^c, -COR^a, -CO₂R^a, and -CONR^bR^c;

R⁷ and R⁸, at each occurrence, are independently selected from: H, C₁-_S alkyl, R^aO-Ci-₈ alkyl, R^bR^cN-Ci-₈ alkyl-, C₁-_S haloalkyl, C₃._lo cycloalkyl,

(C_3-1O cycloalkyl)Cr8 alkyl-, C_6-10 aryl, (C_6-1O aryl)C_1-8 alkyl-, C_4-10 heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, Cs_-10 heteroaryl, (Cs_-10 heteroaryl)Crs alkyl-, and

((CH₂)₂-₄- Y)_q-(CH₂)_2-4-X¹, wherein R⁷ and R⁸ are independently substituted with 0-3 R⁹ groups;

(C_3-10 cycloalkyl)Cr8 alkyl-, C_6-10 aryl, (C_6-10 aryl)C_1-8 alkyl-, C_4-10 heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, and Cs_-10 heteroaryl, (Cs_-10 heteroaryl)Crs alkyl-, wherein R^7a and R^8a are independently substituted with 0-3 R⁹ groups;

R⁹, at each occurrence, is independently selected from: halo, cyano, nitro, -OR^a, -SR^a, C_6-10 aryl, C_6-10 aryl-O-, HO-Cr₈ alkyl-, R^bR^cN-d-₈ alkyl-, Cr₈ haloalkyl, -NR^bR^c, -COR^a, -CO₂R^a, and -CONR^bR^c;

a, at each occurrence, is independently selected from of 0, 1, and 2;

[0022] The term "substituted" means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =0), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.

[0023] "Alkyl" includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C₁-_O alkyl, for example, includes C₁, C₂, C₃, C₄, C₅, and Ce alkyl groups. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.

[0024] "Alkenyl" includes the specified number of hydrocarbon atoms in either straight or branched configuration with one or more unsaturated carbon-carbon bonds that may occur in any stable point along the chain, such as ethenyl and propenyl. C₂_₆ alkenyl includes C₂, C₃, C₄, C₅, and Ce alkenyl groups.

[0025] "Alkynyl" includes the specified number of hydrocarbon atoms in either straight or branched configuration with one or more triple carbon-carbon bonds that may occur in any stable point along the chain, such as ethynyl and propynyl. C₂_₆ Alkynyl includes C₂, C₃, C₄, C₅, and Ce alkynyl groups.

[0026] "Cycloalkyl" includes the specified number of hydrocarbon atoms in a saturated ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. C₃_g cycloalkyl includes C₃, C₄, C₅, C₆, C₇, and Cg cycloalkyl groups.

Cycloalkyl also include bicycloalkyl and tricycloalkyl, both of which include fused and bridged rings (e.g., norbornane and adamantane).

[0027] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0028] "Aryl" refers to any stable 6, 7, 8, 9, 10, 11, 12, or 13 membered monocyclic, bicyclic, or tricyclic ring, wherein at least one ring, if more than one is present, is aromatic. Examples of aryl include fluorenyl, phenyl, naphthyl, indanyl, and

tetrahydronaphthyl .

[0029] "Heteroaryl" refers to any stable 5, 6, 7, 8, 9, 10, 11, or 12 membered, (unless the number of members is otherwise recited), monocyclic, bicyclic, or tricyclic heterocyclic ring that is aromatic, and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S. If the heteroaryl is defined by the number of carbons atoms, then 1, 2, 3, or 4 of the listed carbon atoms are replaced by a heteroatom. If the heteroaryl group is bicyclic or tricyclic, then at least one of the two or three rings must contain a heteroatom, though both or all three may each contain one or more heteroatoms. If the heteroaryl group is bicyclic or tricyclic, then only one of the rings must be aromatic. The N group may be N, NH, or N-substituent, depending on the chosen ring and if substituents are recited. The nitrogen and sulfur heteroatoms may optionally be oxidized (e.g., S, S(O), S(O)₂, and N-O). The heteroaryl ring may be attached to its pendant group at any nitrogen or carbon atom that results in a stable structure. The heteroaryl rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.

[0030] Examples of heteroaryl include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3Η- indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, 6H-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0031] "Ηeterocyclyl" refers to any stable 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered, (unless the number of members is otherwise recited), monocyclic, bicyclic, or tricyclic heterocyclic ring that is saturated or partially unsaturated, and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S. If the heterocyclyl is defined by the number of carbons atoms, then from 1, 2, 3, or 4 of the listed carbon atoms are replaced by a heteroatom. If the heterocyclyl is bicyclic or tricyclic, then at least one of the two or three rings must contain a

heteroatom, though both or all three may each contain one or more heteroatoms. The N group may be N, NH, or N-substituent, depending on the chosen ring and if substituents are recited. The nitrogen and sulfur heteroatoms optionally may be oxidized (e.g., S, S(O), S(O)₂, and N-O). The heterocyclyl may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclyls described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.

[0032] Examples of heterocyclyls include, but are not limited to,

decahydroquinolinyl, imidazolidinyl, imidazolinyl, indolinyl, isatinoyl,

methylenedioxyphenyl, morpholinyl, octahydroisoquinolinyl, oxazolidinyl, oxindolyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, l-aza-bicyclo[2.2.2]octane, 2,5-diaza-bicyclo[2.2.2]octane, and 2,5-diaza-bicyclo[2.2.1]heptane. Also included are fused ring and spiro compounds containing, for example, the above heterocyclyls.

[0033] In some embodiments, R⁴ is selected from:

-Ci-8 alkyl-(CO₂R⁶), -Ci_-8 alkyl-(CONR⁷R⁸), C₃-₈ cycloalkyl,

(C3-8 cycloalkyl)Ci-8 alkyl-, C_4-1O heterocyclyl, and (C_4-1O heterocyclyl)Ci_8 alkyl-, and is substituted with 0-2 R^4a;

alternatively, R⁴ is selected from:

2-R^4a-phenyl substituted with 0-1 R^4a,

(2-R^4a-phenyl)Ci-8 alkyl- substituted with 0-1 R^4a,

3-R^4a-pyrid-2-yl substituted with 0-1 R^4a,

(3-R^4a-pyrid-2-yl)C₁_₈ alkyl- substituted with 0-1 R^4a,

pyrid-3-yl substituted with 0-2 R^4a, (pyrid-3-yl)C_1-8 alkyl- substituted with 0-2 R^4a, pyrid-4-yl substituted with 0-2 R^4a, (pyrid-4-yl)C_1-8 alkyl- substituted with 0-2 R^4a, and pyrimid-2-yl substituted with 0-2 R^4a, and (pyrimid-2-yl)Ci_8 alkyl- substituted with 0-2

R 4a

R⁵ is selected from: H, C_1-8 alkyl, -C_1-8 alkyl-(CO₂R⁶), -C_1-8 alkyl-(CONR⁷R⁸),

C₃-₈ alkenyl, C₃-₈ alkynyl, C₃-₈ cycloalkyl, (C₃-₈ cycloalky^Crs alkyl-, C_6-10 aryl, (C₆-Io aryl)Ci-₈ alkyl-, C_4-10 heterocyclyl, (C_4-10 heterocyclyl)Ci-₈ alkyl-, C5-10 heteroaryl, and (Cs_-1O heteroaryl)Ci-₈ alkyl-, and is substituted with 0-3 R^4a; and,

alternatively, NR⁴R forms a 5-6 membered heterocyclic ring, consisting of: the shown N atom, carbon atoms, and 0-3 heteroatoms selected from O, S(O)_P, and N, wherein the ring is substituted with 0-3 substituents independently selected from: halo, cyano, nitro, OR^a, SR^a, C_6-10 aryl, C_6-10 aryl-O-, HO-Cr₈ alkyl-, R^bR^cN-Ci-₈ alkyl-, Cr₈ haloalkyl, -NR^bR^c, -COR^a, -CO₂R^a, and -CONR^bR^c;

provided that when R⁴ is pyrimid-2-yl substituted with 0-2 R^4a, or (pyrimid-2- yl)Ci-8 alkyl- substituted with 0-2 R^4a; and the alkyl group optionally interrupted with 0- 1 CO₂, C(O)NR⁷, or C(O)NR⁸, then:

(i) R is other than an unsubstituted alkyl, alkenyl, or alkynyl;

(iv) the alkyl group (pyrimid-2-yl)C₁_8 alkyl- is substituted with at least one

R 4a

(v) R¹ is cycloalkyl or (C_3-10 cycloalkyl)Ci_g alkyl-; or

(vi) a combination of (i), (iv) and (v).

[0034] In some embodiments, R⁴ is selected from:

-Ci_-4 alkyl-(CO₂R⁶), -Ci_-4 alkyl-(CONR⁷R⁸), C_3-6 cycloalkyl,

(C₃-6 cycloalkyl)Ci-₄ alkyl-, C_5-6 heterocyclyl, and (C_5-6 heterocyclyl)Ci_₄ alkyl-, and is substituted with 0-2 R^4a;

alternatively, R⁴ is selected from:

2-R^4a-phenyl substituted with 0-1 R^4a,

(2-R^4a-phenyl)Ci-₄ alkyl- substituted with 0-1 R^4a,

3-R^4a-pyrid-2-yl substituted with 0-1 R^4a,

(3-R^4a-pyrid-2-yl)Ci_-4 alkyl- substituted with 0-1 R^4a,

pyrid-3-yl substituted with 0-2 R^4a,

(pyrid-3-yl)Ci_₄ alkyl- substituted with 0-2 R^4a,

pyrid-4-yl substituted with 0-2 R^4a, and

(pyrid-4-yl)Ci_-4 alkyl- substituted with 0-2 R^4a,

R⁵ is selected from: H, Ci_-4 alkyl, C_3-6 cycloalkyl, and

(C₃-₆ cycloalkyl)Ci-₄ alkyl-; and,

alternatively, NR⁴R⁵ forms a 5-6 membered heterocyclic ring, consisting of: the shown N atom, carbon atoms, and 0-2 heteroatoms selected from O, S(O)_P, and N, wherein the ring is substituted with 0-3 substituents independently selected from: halo, cyano, nitro, OR^a, SR^a, phenyl, phenyl-O-, HO-Cr₄ alkyl-, R^bR^cN-d-₄ alkyl-, C_r4 haloalkyl, -NR^bR^c, -COR^a, -CO₂R^a, and -CONR^bR^c; [0035] In some embodiments, R⁴ is selected from:

-Ci_-4 alkyl-(CO₂R⁶), -C_1-4 alkyl-(CONR⁷R⁸), C₃.₆ cycloalkyl,

(C₃-₆ cycloalkyl)Ci-₄ alkyl-, C₅-₆ heterocyclyl, and (Cs_-6 heterocyclyl)Ci_₄ alkyl-, and is substituted with 0-2 R^4a;

alternatively, R⁴ is selected from:

2-R^4a-phenyl substituted with 0-1 R^4a,

(2-R^4a-phenyl)Cr₄ alkyl- substituted with 0-1 R^4a,

3-R^4a-pyrid-2-yl substituted with 0-1 R^4a,

(3-R^4a-pyrid-2-yl)C₁.₄ alkyl- substituted with 0-1 R^4a,

pyrid-3-yl substituted with 0-2 R^4a,

(pyrid-3-yl)Ci_₄ alkyl- substituted with 0-2 R^4a,

pyrid-4-yl substituted with 0-2 R^4a, and

(pyrid-4-yl)C₁_₄ alkyl- substituted with 0-2 R^4a,

R⁵ is selected from: H and C_1-4 alkyl; and,

alternatively, NR⁴R⁵ forms a 5-6 membered heterocyclic ring selected from: pyrrolidyl, piperidyl, piperazinyl, morpholinyl, and thiomorpholinyl, wherein the ring is substituted with 0-2 substituents independently selected from: halo, cyano, nitro, OR^a, SR^a, phenyl, phenyl-O-, HO-Cr₄ alkyl-, R^bR^cN-C_r4 alkyl-, C_r2 haloalkyl, -NR^bR^c, -COR^a, -CO₂R^a, and -CONR^bR^c.

[0036] In some embodiments, R⁴ is selected from: C₁-S alkyl-, C_6-8 aryl,

(C_6-8 aryl)Ci-₈ alkyl-, Cs_₇ heteroaryl, (Cs_₇ heteroaryl)Ci-₈ alkyl- and -CHR_xR₅,, wherein R⁴ is substituted with 0-2 R^4a;

Rx is selected from: hydrogen, C₁-S alkyl-, C_6-8 aryl, (C_6-8 OTyI)C₁ -₈ alkyl-, C5-7 heteroaryl, (Cs_-7 heteroaryl)Ci-8 alkyl-, C5-7 heterocyclyl,

(C5-7 heterocyclyl)Ci-8 alkyl-;

Ry is selected from -CO₂R^a, and -CONR^bR^d;

(C₆-Io aryl)Ci-₈ alkyl-, Cr₈ haloalkyl, -COR^a, -CO₂R^a, and -CONR^bR^c;

R^a, at each occurrence, is independently selected from: H, C₁-_O alkyl, C₂_₆ alkenyl, C₂_6 alkynyl, C_3-1O cycloalkyl, (C_3-1O cycloalkyl)Cr8 alkyl-, C_4-1O heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, C_6-1O aryl, (C_6-10 aryl)Cr₈ alkyl-, C_5-1O heteroaryl, and (Cs_-1O heteroaryl)Cr₈ alkyl-; R^b and R^c, at each occurrence, are independently selected from: H, C₁-_O alkyl, and benzyl, or NR^bR^c forms a ring selected from pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, and thiomorpholinyl ring; and

R^d is selected from - (CH₂CH₂O) I_-4H and -(CH₂CH₂O)I_-4(Ci-S alkyl);

[0037] In some embodiments, R⁴ is selected from:

C₄_io heterocyclyl substituted with 0-2 R^4a,

(C₄-I₀ heterocyclyl)Ci-₈ alkyl- substituted with 0-2 R^4a,

Ci-₈ alkyl substituted with 1-2 R^4a,

pyridyl substituted with -COO(d_₆ alkyl) or -CO(NH₂),

(C₆-Io aryl)Ci-₈ alkyl- substituted on alkyl with -COO(Ci-₆ alkyl), -CONH₂, -CONH(CH2CH2θ)!-₄H or -CONH(CH₂CH₂O)₁-₄(C₁-₈ alkyl); and

aryl substituted with -COO(Ci_₆ alkyl), pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, or thiomorpholinyl; R^4a, at each occurrence, is independently selected from: =0, halo, cyano, nitro, OR^a, SR^a, HO-C_W alkyl-, -NR^bR^c, R^bR^cN-Ci-₈ alkyl-, C_6-I₀ aryl-O-, Cr₈ haloalkyl, -COR^a, -CO₂R^a, and -CONR^bR^c;

R^a, at each occurrence, is independently selected from: H, Ci -6 alkyl, C_2-6 alkenyl, C₂-6 alkynyl, C_3-1O cycloalkyl, (C_3-1O cycloalkyl)Ci-₈ alkyl-, C_4-1O heterocyclyl, (C₄-I₀ heterocyclyl)Ci_₈ alkyl-, C_6-10 aryl, (C_6-10 aryl)Ci-₈ alkyl-, C_5-10 heteroaryl, and (C₅_io heteroaryl)Ci-₈ alkyl-;

R^b and R^c, at each occurrence, are independently selected from: H, Cr₆ alkyl, and benzyl, or NR^bR^c forms a ring selected from pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, and thiomorpholinyl ring.

[0038] In some embodiments, R⁴ is selected from:

C₄-io heterocyclyl,

(C₄-Io heterocyclyl)Ci_₈ alkyl-,

Ci-8 alkyl substituted with -COO(C_1-6 alkyl), -CO(NH₂), pyridyl substituted with -COO(C_1-6 alkyl) or -CO(NH₂),

(C_6-10 aryl)Ci-₈ alkyl- substituted on alkyl with -COO(C_1-6 alkyl), -CONH₂, -CONH(CH₂CH₂O)_1-4H or -CONH(CH₂CH₂O)_1-4(Cr₈ alkyl); and

aryl substituted with -COO(C_1-6 alkyl), pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, or thiomorpholinyl.

[0039] In some embodiments, R⁴ is selected from: C_4-1O heterocyclyl and

(C_4-1Q

alkyl-. In some embodiments, R⁴ is selected from:

wherein R^4a is H or halo. In some embodiments, R⁴ is C_1-8 alkyl substituted with - COO(C_1-6 alkyl), -CO(NH₂). In some embodiments, R⁴ is pyridyl substituted with - COO(C_1-6 alkyl) or -CO(NH₂). In some embodiments, R⁴ is (C_6-10 aryl)Ci-₈ alkyl- substituted on alkyl with -COO(C_1-6 alkyl), -CONH₂, -CONH(CH₂CH₂O)_1-4H or - CONH(CH₂CH₂O)_1-4(C₁-_S alkyl). In some embodiments, R⁴ is aryl substituted with - COO(C_1-6 alkyl), pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, or thiomorpholinyl .

[0040] In some embodiments, R is selected from: H, C_1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl. In some embodiments, NR⁴R⁵ forms a 5-7 membered heterocyclic ring, consisting of: the shown N atom, carbon atoms, and 0-2 heteroatoms selected from O, S(0)_p, and N, wherein the ring is substituted with 0-2 substituents independently selected from: halo, cyano, nitro, -OH, -O(C_1-8alkyl), -COOH and -CO₂(C_1-8alkyl).

[0041] In some embodiments, R is selected from: H, C_1-6 alkyl, C_1-6 haloalkyl, C_3-5 alkenyl, and C_3-5 alkynyl. In some embodiments, R is selected from: H, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, and i-butyl. In some embodiments, R is hydrogen.

[0042] In some embodiments, R¹ is selected from: C_1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl and (C_3-8 cycloalkyl)Ci-8 alkyl-. In some embodiments, R² is selected from: C₁-_S alkyl, C₃_g alkenyl, C₃_g alkynyl, C₃_s cycloalkyl and (C₃_g

alkyl-. In some embodiments, R¹ and R² are independently selected from: H, Cr₄ alkyl, C₃-₄ alkenyl, C₃-₄ alkynyl, C3-6 cycloalkyl, (C₃-₆ cycloalkyl)Ci-₄ alkyl-, phenyl, (phenyl)Cr₄ alkyl-, and (Cr₄ alkoxyphenyl)Ci-₄ alkyl-. In some embodiments, R¹ and R² are independently selected from: H, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, i-butyl, cyclopropyl, cyclopropylmethyl, phenyl, phenethyl, benzyl, and (methoxyphenyl)ethyl. In some embodiments, R¹ is selected from n-propyl and cyclopropyl; and, R² is n-propyl.

[0043] In some embodiments, R^4a, at each occurrence, is independently selected from: =0, F, Cl, cyano, OH, OC_1-4 alkyl, HO-C_1-4 alkyl-, -NR^bR^c, R^bR^cN-C_1-4 alkyl-, phenoxy, phenyl, (phenyl)Ci-₄ alkyl-, Cr₂ haloalkyl, -COR^a, -CO₂R^a, and -CONR^bR^c.

[0044] In some embodiments, R^4a, at each occurrence, is independently selected from: =0, F, Cl, cyano, OH, OCH₃, CH₂OH, NH₂, CH₂NH₂, phenoxy, phenyl, benzyl,

CF₃, -COCH₃, -CO₂H, -CO₂CH₃, and -CONH₂.

[0045] In some embodiments, R⁶, at each occurrence, is independently is selected from: H, C_1-4 alkyl, R^aO-Ci-₄ alkyl, R^bR^cN-C_1-4 alkyl-, Cr₂ haloalkyl, C_3-6 cycloalkyl,

(C3-6 cycloalkyl)Cr₄ alkyl-, C_6-10 aryl, (C_6-10 aryl)C_1-4 alkyl-, C_5-6 heterocyclyl,

(C5_6 heterocyclyl)C_1-4 alkyl-, C_5-6 heteroaryl, and (C_5-6 heteroaryl)Cr₄ alkyl-, wherein

R⁶ is substituted with 0-2 R^6a groups; and,

[0046] R^6a, at each occurrence, is independently selected from: halo, cyano, nitro, -

OR^a, -SR^a, phenyl, phenyl-O-, HO-Cr₄ alkyl-, R^bR^cN-C_r4 alkyl-, Cr₂ haloalkyl,

-NR^bR^c, -COR^a, -CO₂R^a, and -CONR^bR^c.

[0047] In some embodiments, R⁶, at each occurrence, is independently is selected from: H, methyl, ethyl, CF₃, cyclopropyl, cyclopropylmethyl, phenyl, and benzyl, wherein R⁶ is substituted with 0-2 R^6a groups; and,

R^6a, at each occurrence, is independently selected from: Cl, F, cyano, OH, OCH₃, phenyl, phenyl-O-, and CF₃.

[0048] In some embodiments, R⁷ and R⁸, at each occurrence, are independently selected from: H, Cr₄ alkyl, R^aO-C_1-4 alkyl, R^bR^cN-C_1-4 alkyl-, Cr₂ haloalkyl, C_3-6 cycloalkyl, (C₃-₆ cycloalky^C^ alkyl-, C_6-10 aryl, (C_6-10 aryl)C_1-4 alkyl-,

C₅_₆ heterocyclyl, (C_5-6 heterocyclyl)Ci_₄ alkyl-, C_5-6 heteroaryl,

(C_5-6 heteroaryl)Ci-₄ alkyl-, and ((CH₂W YV(CH₂)^₄-X¹, wherein R⁷ and R⁸ are independently substituted with 0-2 R⁹ groups; and,

R⁹, at each occurrence, is independently selected from: F, Cl, -CN, -OH, OC_1-4 alkyl, phenyl, phenoxy, HO-C_r4 alkyl-, CF₃, -NR^bR^c, -COR^a, -CO₂R^a, and -CONR^bR^c;

[0049] In some embodiments, R⁷, at each occurrence, is independently selected from: H, C_r4 alkyl, R^aO-C_1-4 alkyl, and ((CH₂)₂O)_q-(CH₂)₂-OH; and,

R⁸, at each occurrence, is independently selected from: H and Cr₄ alkyl.

[0050] In some embodiments, R^a, at each occurrence, is independently selected from: H, methyl, ethyl, n-propyl, cyclopropyl, cyclopropylmethyl, phenyl, and benzyl; and,

R^b is independently selected from: H, methyl, ethyl, n-propyl, and benzyl.

[0051] In some embodiments, X¹, at each occurrence, is independently OR⁶; and,

Y, at each occurrence, is independently O.

[0052] In some embodiments, the present teachings provide compounds of formula I:

and stereoisomers and pharmaceutically acceptable salts thereof;

wherein:

R is selected from: H, C_1-6 alkyl, C_1-6 haloalkyl, C₃_₅ alkenyl, and C₃_₅ alkynyl;

R¹ is selected from: C_1-8 alkyl, C₃_8 alkenyl, C₃_8 alkynyl, C₃_8 cycloalkyl and (C_3-8 cycloalkyl)Ci-₈ alkyl-;

R is selected from: C_1-8 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, C_3-8 cycloalkyl and (C_3-8 cycloalkyl)Ci-₈ alkyl-;

R⁴ is selected from:

C_4-10 heterocyclyl substituted with 0-2 R ₄a

(C_4-10 heterocyclyl)C_1-8 alkyl- substituted with 0-2 R ₄a

C_1-8 alkyl substituted with 1-2 R^4a,

pyridyl substituted with -COO(C_1-6 alkyl) or -CO(NH₂),

aryl substituted with -COO(C_1-6 alkyl), pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, or thiomorpholinyl;

R^4a, at each occurrence, is independently selected from: =0, halo, cyano, nitro, 0R^a, SR^a, HO-Ci_-8 alkyl-, -NR^bR^c, R^bR^cN-Ci_₈ alkyl-, C_6-I₀ aryl-O-, C_r8 haloalkyl, -C0R^a, -C0₂R^a, and -C0NR^bR^c;

R^a, at each occurrence, is independently selected from: H, Cr₆ alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-Io cycloalkyl, (C₃_io cycloalkyl)Ci-8 alkyl-, C₄_io heterocyclyl, (C_4-I0 heterocyclyl)Ci_₈ alkyl-, C_6-I0 aryl, (C_6-I0 aryl)Cr₈ alkyl-, C_5-I0 heteroaryl, and (C₅-I₀ heteroaryl)Ci-8 alkyl-;

R^b and R^c, at each occurrence, are independently selected from: H, Cr₆ alkyl, and benzyl, or NR^bR^c forms a ring selected from pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, and thiomorpholinyl ring; and

R⁵ is selected from: H, Ci_-8 alkyl, C_3-8 alkenyl, C_3-8 alkynyl;

or NR⁴R⁵ forms a 5-7 membered heterocyclic ring, consisting of: the shown N atom, carbon atoms, and 0-2 heteroatoms selected from O, S(0)_p, and N, wherein the ring is substituted with 0-2 substituents independently selected from: halo, cyano, nitro, -OH, -O(Ci.₈alkyl), -COOH and -CO₂(d_-8alkyl).

[0053] In some embodiments, at least one of R¹ or R² is a C_3-8 cycloalkyl or a (C_3-8 cycloalkyl)Ci_₈ alkyl-.

[0054] In another embodiment, the C(O)NR⁴R group of formula I is selected from:

[0055] In some embodiments, the compounds provided herein do not include the compounds of U.S. Publication No. 20030207879.

] In some embodiments, provided herein are compounds selected from:

4G 4H

5A 5B

and stereoisomers and pharmaceutically acceptable salts thereof.

[0057] The present teachings are intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0058] In some embodiments, the compounds provided herein are stable. As used herein "stable" means that the compound is suitable for pharmaceutical use.

[0059] The present invention covers stable compound and thus avoids, unless otherwise specified, the following bond types: heteroatom-halogen, N-S, O-S, O-O, and S-S.

[0060] The imidazole ring of the compounds described herein may exist in tautomeric forms or as tautomers, and thus are also included within the scope of the present teachings. The tautomeric isomers are represented as the structures (Ia) and (Ib):

(Ia) (Ib)

wherein R, R¹, R², X, and Z are as defined herein. By naming or referring to one compound, for example, its corresponding tautomer is also intended.

[0061] In other embodiments, provided herein are pharmaceutical composition comprising: a therapeutically effective amount of any one of the compounds described hereinand a pharmaceutically acceptable excipient.

[0062] The compounds described herein are generally named according to the IUPAC or

CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g., "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h" for hour or hours and "rt" for room temperature).

[0063] Examples of the molecular weight of compounds described herein can include (a) less than about 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 grams per mole; (b) less than about 950 grams per mole; (c) less than about 850 grams per mole, and, (d) less than about 750 grams per mole.

[0064] The compounds described herein may have a chiral center and may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. The present teachings are intended to encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein; it being known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optic ally- active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine therapeutic activity using the standard tests described herein or using other similar tests which are known in the art.

//. Methods

[0065] Applicants have discovered that the substituted 8-[6-carbonylamino-3- pyridyl] xanthines shown herein can be useful for the treatment of diseases or conditions associated with deleterious A_2B receptor activation or activity.

[0066] Accordingly, in some embodiments, provided herein are methods for treating a pathological condition or symptom in a mammal, wherein the activity, e.g., overactivity, of adenosine A_2B receptors is implicated in one or more symptoms of the pathology and antagonism (i.e., blocking) of its action is desired. The methods include administering to a mammal in need thereof a therapeutically effective amount of any one of the compounds described herein.

[0067] In some embodiments, providede herein are methods of treating a disease or condition. The methods include administering a therapeutically effective amount of at least one of the compounds described herein to a mammal in need thereof. The disease or condition can be, for example, asthma, allergies, allergic diseases {e.g., allergic rhinitis and sinusitis), autoimmune diseases {e.g., lupus), diarrheal diseases, insulin resistance, diabetes {e.g., Type I and Type II), prevention of mast cell degranulation associated with ischemia/reperfusion injuries, heart attack, inhibition of angiogenesis in neoplastic tissues, and inhibition of angiogenesis in diabetic retinopathy or hyperbaric oxygen-induced retinopathy.

[0068] In some embodiments, provided herein are compounds as described hereinfor use in medical therapy.

[0069] In some embodiments, provided herein are compounds as described hereinfor the manufacture of a medicament useful for the treatment of a disease in a mammal.

[0070] It is to be understood that any embodiment or feature of the present teachings may be combined with any other aspect or feature of the present teachings.

[0071] The examples provided in this application are non-inclusive unless otherwise stated. They include but are not limited to the recited groups. [0072] As used herein, the terms "mammal" and "patient" include warm blooded mammals that are typically under medical care (e.g., humans and domesticated animals). Examples of mammals include (a) feline, canine, equine, and bovine and (b) human.

[0073] As used herein, "treating" or "treatment" of a mammal or subject includes the administration of a compound or composition to a mammal or subject with the purpose of preventing, curing, healing, alleviating, relieving, altering, remedying, ameliorating, improving, stabilizing or affecting a disease or disorder, or a symptom of a disease or disorder. Treatment includes: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease- state but has not yet been diagnosed as having it; (b) inhibiting the disease- state, e.g., arresting its development; and/or (c) relieving the disease-state, e.g., causing regression of the disease state until a desired endpoint is reached. Treating also includes the amelioration of a symptom of a disease (e.g., lessen the pain or discomfort), wherein such

amelioration may or may not be directly affecting the disease (e.g., cause, transmission, expression, etc.).

[0074] "Pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 1, 2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic,

hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic. [0001] The "salt" of the present compound is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid or phosphoric acid; salts with an organic acid such as acetic acid, fumalic acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid or sulfosalicylic acid; quaternary ammonium salts such as methyl bromide, methyl iodide; salts with a halogen ion such as a bromine ion, achlorine ion or an iodine ion; salts with an alkali metal such as lithium, sodium or potassium; salts with an alkaline earth metal such as calcium or magnesium; salts with a metal such as iron or zinc; salts with ammonia; salts with an organic amine such as

triethylenediamine, 2-aminoethanol, 2,2-iminobis(ethanol), l-deoxy-l-(methylamino)-2- D- sorbitol, 2-amino-2-(hydroxymethyl)-l,3-propanediol, procaine or

N,Nbis(phenylmethyl)-l,2-ethanediamine, and the like.

[0075] The pharmaceutically acceptable salts of the present teachings can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p 1445, the disclosure of which is hereby incorporated by reference.

[0076] "Therapeutically effective amount" includes an amount of a compound of the present invention that is effective when administered alone or in combination to an indication listed herein. "Therapeutically effective amount" also includes an amount of the combination of compounds claimed that is effective to treat the desired indication. The combination of compounds can be a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27-55, occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased effect, or some other beneficial effect of the combination compared with the individual components.

[0077] In one embodiment, the methods described herein include administration of an additional therapeutic agent. Administration can be simultaneously or in any order. The two or more agents can be administered as a single pharmaceutical composition or as separate compositions. The administration of the compound described herein can be prior to the other agent(s), within minutes thereof, or up to about hours (e.g., 24 or 48) after the administration of the other agent(s).

///. Formulaions and Dosages

[0078] The compounds described herein can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, e.g., orally or parenterally, by intravenous, intramuscular, topical, inhalation or subcutaneous routes. Exemplary pharmaceutical compositions are disclosed in "Remington: The Science and Practice of Pharmacy", A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.

[0079] Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable excipient such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained. [0080] The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.

[0081] The active compound may also be administered intravenously or

intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0082] The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, isotonic agents, for example, sugars, buffers or sodium chloride are included. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0083] Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation included vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

[0084] For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a

dermatologically acceptable carrier, which may be a solid or a liquid.

[0085] Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid

compositions can be applied from absorbent pads, used to impregnate bandages and other dressings or sprayed onto the affected area using pump-type or aerosol sprayers.

[0086] Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.

[0087] Examples of useful dermatological compositions which can be used to deliver the compounds of the present invention to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508). Useful dosages of the compounds of the present invention can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the

extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.

[0088] Generally, the concentration of the compound(s) of the present invention in a liquid composition, such as a lotion, will be from (a) about 0.1-25 wt% and (b) about 0.5-10 wt%. The concentration in a semi-solid or solid composition such as a gel or a powder will be (a) about 0.1-5 wt% and (b) about 0.5-2.5 wt%.

[0089] The amount of the compound or an active salt or derivative thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In general, however, a suitable dose will be in the range of from (a) about 1.0-100 mg/kg of body weight per day, (b) about 10-75 mg/kg of body weight per day, and (c) about 5-20 mg per kilogram body weight per day.

[0090] The compound can be conveniently administered in unit dosage form; e.g., tablets, caplets, etc., containing (a) about 4-400 mg, (b) about 10-200 mg, and (c) about 20-100 mg of active ingredient per unit dosage form.

[0091] Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from (a) about 0.02-20 μM, (b) about 0.1-10 μM, and (c) about 0.5-5 μM. These concentrations may be achieved, for example, by the intravenous injection of a 0.005-0.5% solution of the active ingredient, or orally administered as a bolus containing about 4-400 mg of the active ingredient.

[0092] The compounds described herein can also be administered by inhalation from an inhaler, insufflator, atomizer or pressurized pack or other means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as carbon dioxide or other suitable gas. In case of a pressurized aerosol, the dosage unit may be determined by providing a value to deliver a metered amount. The inhalers, insufflators, atomizers are fully described in pharmaceutical reference books such as Remington's Pharmaceutical Sciences Volumes 16 (1980) or 18 (1990) Mack Publishing Co.

[0093] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.

[0100] In one embodiment, the pharmaceutical composition further comprises an additional therapeutic agent.

[0094] All patents, patent applications, books and literature cited in the specification are hereby incorporated by reference in their entirety. In the case of any inconsistencies, the present disclosure, including any definitions herein, will prevail.

[0095] The present teachings have been described with reference to various specific embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

[0096] The present teachings are further illustrated by the following examples which should not be construed as limiting.

EXAMPLES

[0097] Pharmacology

[0098] The ability of compounds described herein to act as an A_2B receptor antagonists may be determined using pharmacological models which are well known to the art or using test procedures described below.

[0099] The rat A_2B receptor cDNA was subcloned into the expression plasmid pDoubleTrouble using techniques described in Robeva, A. et al., Biochem. Pharmacol.,

51, 545-555 (1996). The plasmid was amplified in competent JM 109 cells and plasmid

DNA isolated using Wizard Megaprep columns (Promega Corporation, Madison, WI).

A_2B adenosine receptors were introduced into HEK-293 cells by means of Lipofectin as described in Feigner, P. L. et al, Proc. Natl. Acad. ScL USA, 84, 7413-7417 (1987).

[00100] Cell culture

[00101] Transfected HEK cells were grown under 5% CO₂/95% O₂ humidified atmosphere at a temperature of 37 °C. Colonies were selected by growth of cells in 0.6 mg/mL G418. Transfected cells were maintained in DMEM supplemented with Hams

F12 nutrient mixture (1/1), 10% newborn calf serum, 2 mM glutamine and containing 50

IU/mL penicillin, 50 mg/mL streptomycin, and 0.2 mg/mL Geneticin (G418, Boehringer

Mannheim). Cells were cultured in 10 cm diameter round plates and subcultured when grown confluent (approximately after 72 hours). [00102] Radioligand binding studies

[00103] AtA_2B receptors: Confluent monolayers of HEK-A_2B cells were washed with PBS followed by ice cold Buffer A (10 niM HEPES, 10 mM EDTA, pH 7.4) with protease inhibitors (10 μg/mL benzamidine, 100 μM phenylmethanesulfonyl fluoride, and 2 μg/mL of each aprotinin, pepstatin and leupeptin). The cells were homogenized in a Polytron (Brinkmann) for 20 s, centrifuged at 30,000 x g, and the pellets washed twice with buffer HE (10 mM HEPES, 1 mM EDTA, pH 7.4 with protease inhibitors). The final pellet was resuspended in buffer HE, supplemented with 10% sucrose and frozen in aliquots at -80 °C. For binding assays membranes were thawed and diluted 5-10 fold with HE to a final protein concentration of approximately 1 mg/mL. To determine protein concentrations, membranes, and bovine serum albumin standards were dissolved in 0.2% NaOH/0.01% SDS and protein determined using fluorescamine fluorescence. Stowell, C. P. et al, Anal. Biochem., 85, 572-580 (1978).

[00104] Saturation binding assays for rat A_2B adenosine receptors were performed with [³H]ZM214,385 (17 Ci/mmol, Tocris Cookson, Bristol UK) (Ji, X. et al., Drug Design Discov., 16, 216-226 (1999)) or ¹²⁵I-ABOPX (2200 Ci/mmol). To prepare ¹²⁵I- ABOPX, 10 μL of 1 mM ABOPX in methanol/1 M NaOH (20:1) was added to 50 μL of 100 mM phosphate buffer, pH 7.3. One or 2 mCi of Na¹²⁵I was added, followed by 10 μL of 1 mg/mL chloramine-T in water. After incubation, 20 minutes at room

temperature, 50 μL of 10 mg/mL Na-metabisulfite in water was added to quench the reaction. The reaction mixture was applied to a Cl 8 HPLC column, eluting with a mixture of methanol and 5 mM phosphate, pH 6.0. After 5 min at 35% methanol, the methanol concentration was ramped to 100% over 15 min. Unreacted ABOPX eluted in 11-12 minutes; ¹²⁵I-ABOPX eluted at 18-19 min in a yield of 50-60% with respect to the initial ¹²⁵I.

[00105] In equilibrium binding assays the ratio of ¹²⁷IZ¹²⁵I-ABOPX was 10-20/1. Radioligand binding experiments were performed in triplicate with 20-25 μg membrane protein in a total volume of 0.1 mL HE buffer supplemented with 1 U/mL adenosine deaminase and 5 mM MgCl₂. The incubation time was 3 h at 21 °C. Nonspecific binding was measured in the presence of 100 μM NECA. Competition experiments were carried out using 0.6 nM ¹²⁵I-ABOPX. Membranes were filtered on Whatman GF/C filters using a Brandel cell harvester (Gaithersburg, MD) and washed 3 times over 15-20 seconds with ice cold buffer (10 mM Tris, 1 mM MgCl₂, pH 7.4). B_max and K_D values were calculated by Marquardt's nonlinear least squares interpolation for single a site binding models. Marquardt, D. M., J. Soc. Indust. Appl. Math., U, 431-441.21 (1963). K₁ values for different compounds were derived from IC₅₀ values as described. Linden, J., J. Cycl. Nucl. Res., 8, 163-172 (1982). Data from replicate experiments are tabulated as means ± SEM.

[00106] At other Adenosine Receptors: [³H]CPX. Brans, R. F. et ah, Naunvn- Schmiedeberg's Arch. Pharmacol, 335, 59-63 (1987). ¹²⁵I-ZM241385 and ¹²⁵I-ABA were utilized in radioligand binding assays to membranes derived from HEK-293 cells expressing recombinant rat A₁, A_2A and A₃ ARs, respectively. Binding of [³H]R-N⁶- phenylisopropyladenosine. Schwabe, U. et al., Naunvn-Schmiedeberg's Arch.

Pharmacol, 313, 179-187 (1980). ([³H]R-PIA, Amersham, Chicago, IL) to A₁ receptors from rat cerebral cortical membranes and of [³H]CGS 21680. Jarvis, M.F. et al., L

Pharmacol Exp. Therap., 251, 888-893 (1989). (Dupont NEN, Boston, MA) to A_2A receptors from rat striatal membranes was performed as described. Adenosine deaminase (3 units/mL) was present during the preparation of the brain membranes, in a pre-incubation of 30 min at 30 °C, and during the incubation with the radioligands. All non-radioactive compounds were initially dissolved in DMSO, and diluted with buffer to the final concentration, where the amount of DMSO never exceeded 2%. Incubations were terminated by rapid filtration over Whatman GF/B filters, using a Brandell cell harvester (Brandell, Gaithersburg, MD). The tubes were rinsed three times with 3 mL buffer each.

[00107] At least six different concentrations of competitor, spanning 3 orders of magnitude adjusted appropriately for the IC₅₀ of each compound, were used. IC₅₀ values, calculated with the nonlinear regression method implemented in (Graph-Pad Prism, San Diego, CA), were converted to apparent K₁ values as described. Linden, J., L Cycl Nucl Res., 8:163-172 (1982). Hill coefficients of the tested compounds were in the range of 0.8 to 1.1.

[00108] Functional assays

[00109] Multiple methods are available for determining functional activity at A2B receptors. Described here are two representative methods.

[00110] Representative method 1: HEK- A_2B cells from one confluent T75 flask were rinsed with Ca²⁺ and Mg²⁺ -free Dulbecco's phosphate buffered saline (PBS) and then incubated in Ca²⁺ and Mg²⁺-free HBSS with 0.05% trypsin and 0.53 mM EDTA until the cells detached. The cells were rinsed twice by centrifugation at 250 x g in PBS and resuspended in 10 niL of HBSS composed of 137 niM NaCl, 5 niM KCl, 0.9 niM MgSO₄, 1.4 niM CaCl₂, 3 niM NaHCO₃, 0.6 niM Na₂HPO₄, 0.4 niM KH₃PO₄, 5.6 niM glucose, and 10 rnM HEPES, pH 7.4 and the Ca²⁺-sensitive fluorescent dye indo-1-AM (5 μM) 37 °C for 60 min. The cells were rinsed once and resuspended in 25 rnL dye- free HBSS supplemented with 1 U/ml adenosine deaminase and held at room temperature. Adenosine receptor antagonists prepared as IOOX stocks in DMSO or vehicle was added and the cells and transferred to a 37 °C bath for 2 minutes. Then the cells (1 million in 2 ml) were transferred to a stirred cuvette maintained at 37 °C within an Aminco SLM 8000 spectrofluorometer (SML instruments, Urbana IL). The ratios of indo-1 fluorescence obtained at 400 and 485 nm (excitation, 332 nm) was recorded using a slit width of 4 nm. NECA was added after a 100 s equilibration period.

[00111] Cyclic AMP generation was performed in DMEM/HEPES buffer (DMEM containing 50 mM HEPES, pH 7.4, 37 °C). Each well of cells was washed twice with DMEM/HEPES buffer, and then 100 μL adenosine deaminase (final concentration 10 IU/mL) and 100 μL of solutions of rolipram and cilostamide (each at a final

concentration of 10 μM) were added, followed by 50 μL of the test compound

(appropriate concentration) or buffer. After 15 minutes, incubation at 37 °C was terminated by removing the medium and adding 200 μL of 0.1 M HCl. Acid extracts were stored at -20 °C until assay. The amounts of cyclic AMP were determined following a protocol which utilized a cAMP binding protein (PKA) [van der Wenden et al., 1995], with the following minor modifications. The assay buffer consisted of 150 mM K₂HPO₄/10 mM EDTA/ 0.2% BSA FV at pH 7.5. Samples (20 mL) were incubated for 90 minutes at 0 °C. Incubates were filtered over GF/C glass microfiber filters in a Brandel M-24 Cell Harvester. The filters were additionally rinsed with 4 times 2 mL 150 mM K₂HPO₄/10 mM EDTA (pH 7.5, 4 °C). Punched filters were counted in Packard Emulsifier Safe scintillation fluid after 2 hours of extraction.

[00112] Representative method 2: Functional activity at the A2B receptor was assayed using the ACTOne assay (Codex BioSolutions, Montgomery Village, MD). HEK cells transfected with a proprietary cyclic nucleotide-gated channel were plated at 70,000/well (96 well format) in 100 μl of growth media on poly-D-lysine-coated black- walled plates. The cells were allowed to attach and grow overnight at 37°C. The following day, 100 μl of IX Dye Solution II containing 2 U/ml adenosine deaminase (Roche Applied Science, Indianapolis, IN) and 50 μM phosphodiesterase inhibitor Ro20-1724 (Sigma- Aldrich, St Louis, MO) was added to each well and the plate was incubated for two hours at room temperature in the dark. A 25 μl volume of 10X- concentrated antagonist was added and the plate was incubated for 15 minutes at room temperature. A baseline reading was taken using a fluorescence plate reader (Excitation 53OnM; Emission 565nM). A 25 μl volume of 10X-concentrated NECA was added to each well and the plates were incubated for 30 minutes at room temperature in the dark. Following the terminal incubation, an endpoint reading was taken using a fluorescence plate reader (Excitation 53OnM; Emission 565nM).

[00113] Each antagonist was assayed at 3 concentrations (1OnM, 3OnM and 100 nM) and each concentration was tested in triplicate. A complete NECA log dose-response (1 nM - 100 μM) in the presence of vehicle was performed in triplicate. The EC50 for NECA in this assay was typically around 7OnM.

[00114] Endpoint fluorescence data were managed using Microsoft Excel software. Two readings were obtained prior to and 30 minutes after NECA stimulation. The ratios of the two readings (F30/F0) were plotted versus NECA concentration and a curve was fit with a four parameter logistic equation using PRISM 5™ (GraphPad Software, San Diego, CA). The best- fit values for the "bottom" and "top" of the NECA dose-response curve were used to normalize the raw data. The normalized data for all doses of each antagonist were globally fit using the modified Gaddam/Schild equation (Lazareno and Birdsall, 1999, British Journal of Pharmacology 109: 1110-1119) and a pA2 value was determined with the Schild slope set as a constant equal to 1.0, the antagonist concentration fixed as a data set constant within the column title, and the remaining parameters shared for all data sets.

[00115] Representative compounds of the present invention have been shown to be active in the above affinity testing. The averaged results from the ACTOne functional assays are shown in Table 1.

Table 1

Activity: <100 nM High Potency

101 to 1000 nM Medium Potency >1000 nM Low Potency [00116] Synthesis and Characterization

[00117] The following abbreviations may have been used herein:

[¹²⁵I]ABA [¹²⁵I]TV⁶ -(4-aminobenzyl)-adenosine

1²⁵I-ABOPX ¹²⁵I-3-(4-amino-3-iodobenzyl)-8-oxyacetate-l -propyl- xanthine

AR adenosine receptor

CGS 21680 2-[4-[(2-carboxyethyl)phenyl]ethyl-amino]-5N-iV- ethylcarbamoyl adenosine

CPX 8-cyclopentyl- 1 ,3-dipropylxanthine

DMEM Dulbecco modified eagle medium

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

EDTA ethylenediaminetetraacetate

HEK cells human embryonic kidney cells

K₁ equilibrium inhibition constant

NECA 5 '-(iV-ethylcarbamoyl)adenosine

R-PIA R-Λ^-phenylisopropyladenosine

TEA triethylamine

TLC Thin layer chromatography

ZM 241385 4-(2-[7-amino-2-{furyl}{ l,2,4}triazolo{2,3- a}{ 1,3,5 }triazin-5-ylaminoethyl)phenol

[00118] Proton nuclear magnetic resonance spectroscopy was performed on a Varian- 300 MHz spectrometer and spectra were taken in OMSO-dβ■ Unless noted, chemical shifts are expressed as ppm downfield from relative ppm from DMSO (2.5 ppm).

Electro-spray-ionization (ESI) mass spectrometry was performed with a

ThermoFinnigan LCQ mass spectrometer.

[00119] All xanthine derivatives were homogeneous as judged using TLC (Silica gel 60 F₂₅₄, 0.25 mm, aluminium backed, EM Science, Gibbstown, NJ) and HPLC

(Shimadzu) using Varian C18 5 micron analytical column (4.6 mm x 150 mm) in linear gradient solvent system, at a flow rate of 1 ml / min. The solvent system used was MeOH (0.1% formic acid): H₂O (0.1% formic acid). Peaks were detected by UV absorption at 300 nm and 254 nm. NMR and mass spectra were shown to be consistent with the assigned structure.

[00120] General procedures for the preparation of compounds described herein (Schemes 1 and 2):

SCHEME 1 H? ² " _reflux

3

SCHEME 2

4

[00121] General procedures for the preparation of pyridine-2-carboxylic acid compounds 3 (Scheme 1):

[00122] A mixture of l,3-dialkyl-5,6-diaminouracil (1) (20 mmol ), 6-cyanonicotinic acid (2.75g, 18.5 mmol), 4-Dimethylaminopyridine (DMAP) (400 mg) , l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (4.6 g) and dry DCM ( 50 ml) in a flask was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by silica gel column to provide compound 2.

[00123] 2 (4.0 g) in 1 N NaOH (24 ml) was stirred under reflux for two hours. The mixture was neutralized to pH=7 with 6 N HCl. The solid was filtered and washed with water (3x 10 ml) and dried under vacuum to give product 3. The product was used in the next step without further purification.

[00124] 3A: 5-(2,3,6,7-tetrahvdro-2,6-dioxo-l,3-dipropyl-lH-purin-8- yl)pyridine-2-carboxylic acid :

[00125] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=9.50 min.

[00126] MS: m/z 358 (M+H)⁺.

[00127] SB^-d-cvclopropyl^.S.βJ-tetrahvdro^.β-dioxo-S-propyl-lH-purin-δ- yl)pyridine-2-carboxylic acid:

[00128] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=8.50 min.

[00129] MS: m/z 356 (M+H)⁺. [00130] 3C: S-dJ-dicyclopropyl-l^^J-tetrahydro-l^-dioxo-lH-purin-S- yl)pyridine-2-carboxylic acid:

[00131] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=7.02 min.

[00132] MS: m/z 354 (M+H)⁺.

[00133] General procedures for the preparation of amide compounds 4:

[00134] A mixture of Compound 3 (0.2 mmol), the corresponding substituted amine (or its HCl salt) (1.2 mmol), DMAP (30 mg) , EDAC (100 mg), dry DCM (4mL) and dry DMF (4 mL) in a flask was stirred at room temperature overnight. The solvent was evaporated. The residue was treated with water (20 mL) and the resulting solid was collected and purified by silica gel column to give product 4.

4G 4H

[00135] 4A: 5-(2,3,6.7-tetrahvdro-2,6-dioxo-l,3-dipropyl-lH-purin-8-yl)-N-

(pyridin-3-yl)pyridine-2-carboxamide:

[00136] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=10.27 min.

[00137] MS: m/z 434 (M+H).

[00138] 4B: 5-(2,3,6.7-tetrahvdro-2,6-dioxo-l,3-dipropyl-lH-purin-8-yl)-N-

((pyridin-3-yl)methyl)pyridine-2-carboxamide :

[00139] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=8.84 min.

[00140] MS: m/z 448 (M+H). [00141] 4C: methyl 2-(5-(2,3,6,7-tetrahvdro-2,6-dioxo-l,3-dipropyl-lH-purin-8- yl)pyridine-2-carboxamido)acetate :

[00142] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=9.58 min.

[00143] ¹H NMR (DMSO, d₆): 0.94(m, 6H), 1.59-1.84(m, 4H), 3.70(s, 3H),

3.92(t, 2H, J=7.2 Hz), 4.08(t, 2H, J=7.2 HZ), 4.12(d, 2H, J=6.0 Hz), 8.21(dd, J₁₌8.4 Hz,

J₂=0.9 Hz), 8.67(dd, J₁₌8.4 Hz, J₂=2.4 Hz), 9.29(t, IH, J=6.0Hz), 9.39(dd, J₁₌2.4 Hz,

J₂=0.9 Hz).

[00144] MS: m/z 429 (M+H).

[00145] 4D: methyl 2-(5-(2,3,6,7-tetrahvdro-2,6-dioxo-l,3-dipropyl-lH-purin-8- yl)pyridine-2-carboxamido)benzoate:

[00146] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=14.26 min.

[00147] ¹H NMR (DMSO, d₆): 0.94(m, 6H), 1.59-1.83(m, 4H), 3.89(t, 2H, J=7.1

Hz), 4.01(s, 3H), 4.06(t, 2H, J=7.1 Hz), 7.27 (t, IH, J=7.2Hz), 7.72(1H, J=7.2Hz),

8.08(d, IH, J=8.1Hz), 8.30(d, IH, J=8.1Hz), 8.68(dd, J₁₌8.4 Hz, J₂=2.1 Hz), 8.65(d, lH, J=8.1 Hz), 9.39(s, IH).

[00148] MS: m/z 491 (M+H).

[00149] 4E: 5-(2,3,6,7-tetrahvdro-2,6-dioxo-l,3-dipropyl-lH-purin-8-yl)-N-(4- morpholinophenyl)pyridine-2-carboxamide:

[00150] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=12.14 min.

[00151] MS: m/z 518 (M+H).

[00152] 4F: 5-(2,3,6,7-tetrahvdro-2,6-dioxo-l,3-dipropyl-lH-purin-8-yl)-N-r(N'-

(ethoxy carbonyl))piperazin-N-yllpyridine-2-carboxamide:

[00153] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=10.25 min.

[00154] MS: m/z 498 (M+H). [00155] 4G: (S)-methyl 2-(5-(23,6,7-tetrahvdro-2,6-dioxo-l,3-dipropyl-lH- purin-8-yl)pyridine-2-carboxamido)-3-methylbutanoate:

[00156] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=9.58 min.

[00157] MS: m/z 471 (M+H).

[00158] 4H: lN-ethyl-5-(2,3,6,7-tetrahvdro-2,6-dioxo-l,3-dipropyl-lH-purin-8- yl)-N-((pyridin-4-yl)methyl)pyridine-2-carboxamide:

[00159] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time =8.23 min.

[00160] MS: m/z 476 (M+H).

[00161] 41: 5-(l-cvclopropyl-2,3,6,7-tetrahvdro-2,6-dioxo-3-propyl-lH-purin-8- yl)-N-ethyl-N-((pyridin-4-yl)methyl)pyridine-2-carboxamide:

[00162] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time =6.43 min.

[00163] ¹H NMR (DMSO, d₆): 0.76(m, 2H), 0.94(m, 3H), 1.00-1.20(m, 5H),

1.78(m, 2H), 2.68(m, IH), 3.39(m, 2H), 4.03(m, 2H), 4.71(s, IH), 4.78(s, IH), 7.37(dd,

2H, J₁₌12.9Hz, J₂=6.0 Hz), 7.83(dd, IH, J₁₌10.8Hz, J₂=8.1 Hz), 8.52-8.63(m, 3H),

9.27(dd, IH, J₁= 39.0Hz, J₂=1.5 Hz).

[00164] MS: m/z 474 (M+H).

[00165] 4J: 5-Q-cvclopropyl-23A7-tetrahvdro-2,6-dioxo-3-propyl-lH-purin-8- yl)-N-((pyridin-3-yl)methyl)pyridine-2-carboxamide:

[00166] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time =7.20 min.

[00167] MS: m/z 446 (M+H).

[00168] 4K: (R)-methyl 2-(5-(2,3,6,7-tetrahvdro-2,6-dioxo-l,3-dipropyl-lH- purin-8-yl)pyridine-2-carboxamido)-3-phenylpropanoate:

[00169] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time =11.96 min.

[00170] MS: m/z 519 (M+H). [00171] 4L: (R)-methyl 2-(5-q-cvclopropyl-2,3,6,7-tetrahvdro-2,6-dioxo-3- propyl-lH-purin-8-yl)pyridine-2-carboxamido)-3-phenylpropanoate:

[00172] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=11.28 min.

[00173] MS: m/z 517 (M+H).

[00174] 4M: N-fό-chloropyridin-S-vD-S-Q-cvclopropyl^ΛόJ-tetrahydro^.ό- dioxo-3-propyl-lH-purin-8-yl)pyridine-2-carboxamide:

[00175] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time =11.30 min.

[00176] MS: m/z 466 (M+H).

[00177] 4N: (R)-methyl 2-(5-q-cvclopropyl-2,3,6,7-tetrahvdro-2,6-dioxo-3- propyl-lH-purin-8-yl)pyridine-2-carboxamido)-2-phenylacetate:

[00178] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time =11.21min.

[00179] MS: m/z 503 (M+H).

[00180] 40: S-Q-cvclopropyl^ΛβJ-tetrahvdro^.β-dioxo-S-propyl-lH-purin-δ- yl)-N-(3-(2-oxopyrrolidin-l-yl)propyl)pyridine-2-carboxamide:

[00181] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time =9.1min.

[00182] MS: m/z 480 (M+H).

[00183] 4P: 5-(l-cvclopropyl-2,3,6,7-tetrahvdro-2,6-dioxo-3-propyl-lH-purin-8- yl)-N-(2-(pyridin-3-yl)ethyl)pyridine-2-carboxamide:

[00184] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time =6.69 min.

[00185] MS: m/z 460 (M+H).

[00186] 40: S-Q-cvclopropyl^ΛβJ-tetrahvdro^.β-dioxo-S-propyl-lH-purin-δ- yl)-N-(3-morpholinopropyl)pyridine-2-carboxamide: [00187] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time =4.99 min.

[00188] MS: m/z 482 (M+H).

[00189] 4R: S-Q-cyclopropyl^ΛόJ-tetrahvdro^.ό-dioxo-S-propyl-lH-purin-δ- yl)-N-(2-(pyridin-4-yl)ethyl)pyridine-2-carboxamide:

[00190] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time =6.00 min.

[00191] MS: m/z 460 (M+H).

[00192] 4S: (S)-methyl 2-(5-d-cvclopropyl-2,3,6,7-tetrahvdro-2,6-dioxo-3- propyl-lH-purin-8-yl)pyridine-2-carboxamido)-3-methylbutanoate:

[00193] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=11.17 min.

[00194] MS: m/z 469 (M+H).

[00195] 4T: TBS protected 5-(l-cvclopropyl-2,3,6,7-tetrahydro-2,6-dioxo-3- propyl-lH-purin-8-yl)-N-(4-(hvdroxymethyl)phenyl)pyridine-2-carboxamide:

[00196] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time =15.27 min.

[00197] MS: m/z 575 (M+H).

[00198] 4U: S-α-cvclopropyl^ΛβJ-tetrahvdro^.β-dioxo-S-propyl-lH-purin-δ- yl)-N-(4-(hydroxymethyl)phenyl)pyridine-2-carboxamide:

[00199] 4T (25 mg) was suspended in 1 M TBAF (2mL) and the mixture was stirred at room temperature for 3h. THF was evaporated and the residue was triturated with water (5mL). The solid was filtrated and washed with water (2x2mL) and purified by silica gel column 4U.

[00200] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time =10.30 min. [00201] MS: m/z 461 (M+H).

[00202] 4V: (S)-methyl 2-(5-(l-cvclopropyl-2,3,6,7-tetrahvdro-2,6-dioxo-3- propyl-lH-purin-8-yl)pyridine-2-carboxamido)-3-phenylpropanoate:

[00203] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time= 11.25 min.

[00204] MS: m/z 517 (M+H).

[00205] 4W: 6-(5-(l-cvclopropyl-2,3,6,7-tetrahvdro-2,6-dioxo-3-propyl-lH- purin-8-yl)pyridine-2-carboxamido)pyridine-3-carboxamide:

[00206] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=10.16 min.

[00207] MS: m/z 475 (M+H).

[00208] 4X: methyl 6-(5-(l-cvclopropyl-2,3,6,7-tetrahvdro-2,6-dioxo-3-propyl- lH-purin-8-yl)pyridine-2-carboxamido)pyridine-3-carboxylate:

[00209] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=12.41 min.

[00210] MS: m/z 490 (M+H).

[00211] 4Y: l,3-dicvclopropvl-8-((S)-6-( l-methoxv-l-oxo-3-phenylpropan-2- yloxycarbonyl)pyridin-3-yl)xanthine:

[00212] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=10.13 min.

[00213] MS: m/z 515 (M+H).

[00214] 4Z: methyl 6-(5-(l,3-dicvclopropyl-2,3,6,7-tetrahydro-2,6-dioxo-lH- purin-8-yl)pyridine-2-carboxamido)pyridine-3-carboxylate:

[00215] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=11.51 min.

[00216] MS: m/z 488 (M+H). [00217] General procedures for the preparation of compounds 5:

[00218] Selected compound 4 (compound 4 with a methyl ester group) (0.25 mmol) was suspended in IN LiOH (5 mL) and the mixture was stirred at room temperature until all of the solid disappeared (about 25 min). The mixture was neutralized with 1 N HCl and the solid was filtered, washed with cold water. The jelly- like solid was suspended in methanol and most of the methanol was evaporated. The solid was filtered and dried under vacuum to give product 5. The product was used in the next step without further purification.

5A ^5B

[00219] 5A: (R^-fS-α-cvclopropyl^^.βJ-tetrahvdro^.β-dioxo-S-propyl-lH- purin-8-yl)pyridine-2-carboxamido)-3-phenylpropanoic acid:

[00220] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=10.85 min.

[00221] MS: m/z 503 (M+H).

[00222] 5B: (S)-2-(5-(l-cvclopropyl-2,3,6,7-tetrahvdro-2,6-dioxo-3-propyl-lH- purin-8-yl)pyridine-2-carboxamido)-3-phenylpropanoic acid:

[00223] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=10.73 min.

[00224] MS: m/z 503 (M+H).

[00225] General procedures for the preparation of compounds 7:

[00226] 5 (0.1 mmol), N-hydroxysuccinimide (30 mg, 0.26 mmol) and EDAC (50 mg) were suspended in DMF (5 mL) and the mixture was stirred at room temperature for 24 hr. The corresponding substituted amine (1 mmol) was added and the mixture was stirred overnight. The solvent was removed and the residue was purified by silica gel column to give product 7.

[00227] 7A: N-C(R)- 1 -(2-methoxyethylcarbamoyl)-2-phenylethyl)-5-( 1- cyclopropyl-23,6J-tetrahydro-2,6-dioxo-3-propyl-lH-purin-8-yl)pyridine-2- carboxamide:

[00228] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=10.70 min.

[00229] MS: m/z 560 (M+H).

[00230] 7B: TBS protected N-((R)-l-(2-(2-hydroxyethoxy)ethylcarbamoyl)-2- phenylethyl)-5-(l-cyclopropyl-2,3,6J-tetrahydro-2,6-dioxo-3-propyl-lH-purin-8- yl)pyridine-2-carboxamide:

[00231] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time=13.31 min.

[00232] MS: m/z 704 (M+H).

[00233] 7C: N-((R)-l-(2-(2-hvdroxyethoxy)ethylcarbamoyl)-2-phenylethyl)-5-(l- cvclopropyl-23,6J-tetrahvdro-2,6-dioxo-3-propyl-lH-purin-8-yl)pyridine-2- carboxamide:

[00234] HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH

95%. Retention Time =10.30 min.

[00235] MS: m/z 590 (M+H). Equivalents:

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope of the following claims.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A compound of formula I:

or a stereoisomer or a pharmaceutically acceptable salt thereof;

wherein:

R is selected from: H, C_1-6 alkyl, C_1-6 haloalkyl, C_3-5 alkenyl, and C₃_₅ alkynyl;

R¹ and R² are independently selected from: H, C_1-8 alkyl, C₃_₈ alkenyl, C₃_₈ alkynyl, C_1-8 alkoxy, C_3-1O cycloalkyl, (C_3-10 cycloalkyl)Ci-8 alkyl-, C_4-10 heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, C_6-10 aryl, (C_6-10 aryl)C_1-8 alkyl-, C₅__lo heteroaryl, and (Cs_-10 heteroaryl)Ci_₈ alkyl-, wherein R¹ and R² are independently substituted with 0-2 R^la;

R^la, at each occurrence, is independently selected from: F, Cl, Br, I, Ci-₆ alkyl, C_2-6 alkenyl, C_2-6 alkynyl, -(CH₂)_aOR^a, -(CH₂)_aNR^aR^a, -(CH₂)_aNHOH, -(CH₂)_aNR^aNR^aR^a, -(CH₂)_aNO₂, -(CH₂)_aCN, -(CH₂)_aCO₂R^a, -(CH₂)_aC(O)R^a, -(CH₂)_aOC(O)R^a, -(CH₂)_aCONR^aR^a, CF₃, and OCF₃;

R^a, at each occurrence, is independently selected from: H, C₁-_O alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, (C_3-10 cycloalkyl)Ci-₈ alkyl-,

C_4-10 heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, C_6-10 aryl,

(C_6-10 OTyI)Cr₈ alkyl-, Cs_-10 heteroaryl, and (Cs_-10 heteroaryl)Cr₈ alkyl-, wherein alkyl is optionally interrupted with 1-2 heteroatoms selected from O, S(O)_P, and NR^b;

R^b is independently selected from: H, C₁-_O alkyl, and benzyl;

R⁴ and R⁵ are independently selected from: H, C_1-8 alkyl, -C_1-8 alkyl- (CO₂R⁶), -C_1-8 alkyl-(CONR⁷R⁸), C_3-8 alkenyl, C_3-8 alkynyl, C_3-10 cycloalkyl, (C_3-10 cycloalkyl)Crs alkyl-, C_6-10 aryl, (C_6-10 aryl)Crs alkyl-, C_4-10 heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, Cs_-10 heteroaryl, and (Cs_-10 heteroaryl)Crs alkyl-, wherein R⁴ and R⁵ are independently substituted with 0-3 R^4a and provided that at most one of R⁴ and R⁵ is H; R^4a, at each occurrence, is independently selected from: =0, halo, cyano, nitro, OR^a, SR^a, HO-C_1-8 alkyl-, -NR^bR^c, RVN-C_1-8 alkyl-, C_6-10 aryl-O-, C_6-10 aryl, (C_6-10 aryl)Ci-₈ alkyl-, C₁-S haloalkyl, -COR^a, -CO₂R^a, and -CONR^bR^c; alternatively, one of R⁴ and R⁵ is selected from: -((CH₂)₂-₄- Y)_q-(CH₂)_2-4-X¹, -NR⁷R⁸, -COR⁶, -CO₂R⁶, -CONR⁷R⁸, and -S(O)₂NR⁷R⁸;

X¹, at each occurrence, is independently selected from: OR⁶, -COR⁶, - CO₂R⁶, and -NR^7aR^8a;

Y, at each occurrence, is independently selected from: O, S, SO, S(O)₂, and

NR^S

alternatively, NR _>4_π R5 forms a 4-10 membered heterocyclic ring, consisting of: the shown N atom, carbon atoms, and 0-4 heteroatoms selected from O, S(0)_p, and N, wherein the ring is substituted with 0-4 substituents independently selected from: halo, cyano, nitro, 0R^a, SR^a, C_6-10 aryl, C_6-1O aryl-O-, HO-Cr₈ alkyl-, R^bR^cN-C_r8 alkyl-, C_r8 haloalkyl, -NR^bR^c, -COR^a, -CO₂R^a, and - CONR^bR^c;

R⁶, at each occurrence, is independently is selected from: H, C_1-8 alkyl, R^aO- C_1-8 alkyl, R^bR^cN-C_1-8 alkyl-, C₁-_S haloalkyl, C_3-10 cycloalkyl, (C_3-10

cycloalky^Crs alkyl-, C_6-10 aryl, (C_6-10 aryl)C_1-8 alkyl-, C_4-10 heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, Cs_-10 heteroaryl, and (Cs_-10 heteroaryl)Ci-₈ alkyl-, wherein R⁶ is substituted with 0-3 R^6a groups;

R^6a, at each occurrence, is independently selected from: halo, cyano, nitro, - 0R^a, -SR^a, C_6-10 aryl, C_6-10 aryl-O-, HO-C₁-, alkyl-, R^bR^cN-C_r8 alkyl-, C₁-, haloalkyl, -NR^bR^c, -COR^a, -CO₂R^a, and -CONR^bR^c;

R⁷ and R⁸, at each occurrence, are independently selected from: H, Cr₈ alkyl, R^aO-C_1-8 alkyl, R^bR^cN-C_1-8 alkyl-, Cr₈ haloalkyl, C_3-10 cycloalkyl, (C_3-10 cycloalkyl)Cr8 alkyl-, C_6-10 aryl, (C_6-10 aryl)C_1-8 alkyl-, C_4-10 heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, Cs_-10 heteroaryl, (Cs_-10 heteroaryl)Crs alkyl-, and ((CH₂)₂-₄- Y)₉-(CH₂)^₄-X¹, wherein R⁷ and R⁸ are independently substituted with 0-3 R⁹ groups;

R^7a and R^8a, at each occurrence, are independently selected from: H, C₁-_S alkyl, R^aO-C_1-8 alkyl, R^bR^cN-C_1-8 alkyl-, C₁-_S haloalkyl, C_3-10 cycloalkyl, (C_3-10 cycloalkyl)Cr8 alkyl-, C_6-10 aryl, (C_6-10 aryl)C_1-8 alkyl-, C_4-10 heterocyclyl, (C₄-Io heterocyclyl)Ci_8 alkyl-, and Cs_-1Q heteroaryl, (Cs_-1Q heteroaryl)Crs alkyl-, wherein R , 7a^a and R ^a are independently substituted with 0-3 R groups;

R⁹, at each occurrence, is independently selected from: halo, cyano, nitro, - OR^a, -SR^a, C₆-I₀ aryl, C_6-Io aryl-O-, HO-Cr₈ alkyl-, R^bR^cN-Crs alkyl-, Cr₈ haloalkyl, -NR^bR^c, -COR^a, -CO₂R^a, and -CONR^bR^c;

R^c, at each occurrence, is independently selected from H, C₁-_O alkyl, and benzyl;

alternatively, NR^bR^c forms a ring selected from pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, and thiomorpholinyl ring;

a, at each occurrence, is independently selected from of 0, 1, and 2; p, at each occurrence, is independently selected from 0, 1, and 2; and, q, at each occurrence, is independently selected from 1, 2, 3, and 4; provided that when one of R⁴ or R is (a) phenyl-(alkyl)₀-r,

(b) pyrid-2-yl-(alkyl)o-r, or (c) pyrimid-2-yl-(alkyl)₀-r, the alkyl group of (a)-(c) being optionally interrupted with 0-1 CO₂, C(O)NR⁷, or C(O)NR⁸, then:

(ii) the phenyl of group (a) is at least substituted at the 2 or 6 position by

R 4a.

(iii) the pyridyl of group (b) is at least substituted at the 3 position by R^4a; (iv) the alkyl group of (a), (b), or (c) is substituted with at least one R^4a; (v) R¹ is cycloalkyl or (C_3-1O cycloalkyl)Ci_₈ alkyl-; or

(vi) a combination of (i)-(v).

2. A compound of claim 1, wherein at least one of R¹ or R² is a C_3-8 cycloalkyl or a (C_3-8 cycloalkyl)C_1-8 alkyl-.

3. A compound of formula I:

or a stereoisomer or a pharmaceutically acceptable salt thereof;

wherein: R is selected from: H, C_1-6 alkyl, C_1-6 haloalkyl, C_3-5 alkenyl, and C₃_₅ alkynyl;

R¹ is C₃-₈ cycloalkyl substituted with 0-2 R^la;

R² is selected from: H, C_1-8 alkyl, C₃_8 alkenyl, C₃_8 alkynyl, C_1-8 alkoxy, C₃_8 cycloalkyl, (C₃_s cycloalkyl)Ci_₈ alkyl-, C_4-1O heterocyclyl,

(C_4-10 heterocyclyl)C_1-8 alkyl-, C_6-10 aryl, (C_6-10 aryl)C_1-8 alkyl-, C_5-10 heteroaryl, and (C_5-10 heteroaryl)Ci-8 alkyl-, wherein R¹ and R² are independently substituted with 0-2 R^la;

R^la, at each occurrence, is independently selected from: F, Cl, Br, I,

Ci-₆ alkyl, C_2-6 alkenyl, C_2-6 alkynyl, -(CH₂)_aOR^a, -(CH₂)_aNR^aR^a, -(CH₂)_aNHOH, -(CH₂)_aNR^aNR^aR^a, -(CH₂)_aNO₂, -(CH₂)_aCN, -(CH₂)_aCO₂R^a, -(CH₂)_aC(O)R^a, -(CH₂)_aOC(O)R^a, -(CH₂)_aCONR^aR^a, CF₃, and OCF₃;

R^a, at each occurrence, is independently selected from: H, Cr₆ alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, (C_3-10 cycloalkyl)Cr₈ alkyl-,

C_4-10 heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, C_6-10 aryl,

(C_6-10 aryl)Cr8 alkyl-, C_5-10 heteroaryl, and (C_5-10 heteroaryl)Ci-8 alkyl-, wherein alkyl is optionally interrupted with 1-2 heteroatoms selected from O, S(O)_P, and NR^b;

R^b is independently selected from: H, Cr₆ alkyl, and benzyl;

R⁴ and R⁵ are independently selected from: H, C_1-S alkyl, -C_1-8 alkyl- (CO₂R⁶), -Ci_-8 alkyl-(CONR⁷R⁸), C_3-8 alkenyl, C_3-8 alkynyl, C_3-I0 cycloalkyl, (C_3-10 cycloalkyl)Cr₈ alkyl-, C_6-I0 aryl, (C_6-10 aryl)Cr₈ alkyl-, C_4-10 heterocyclyl, (C_4-10 heterocyclyl)C_1-8 alkyl-, C_5-10 heteroaryl, and (C_5-10 heteroaryl)Ci-₈ alkyl-, wherein R⁴ and R⁵ are independently substituted with 0-3 R^4a and provided that at most one of R⁴ and R⁵ is H;

R^4a, at each occurrence, is independently selected from: =0, halo, cyano, nitro, OR^a, SR^a, HO-C_1-8 alkyl-, -NR^bR^c, R^bR^cN-C_1-8 alkyl-, C_6-10 aryl-O-, C_6-10 aryl, (C_6-10 aryl)Ci-₈ alkyl-, Cr₈ haloalkyl, -COR^a, -CO₂R^a, and -CONR^bR^c; alternatively, one of R⁴ and R⁵ is selected from: -((CH₂)₂-₄- Y)_q-(CH₂)_2-4-X¹, -NR⁷R⁸, -COR⁶, -CO₂R⁶, -CONR⁷R⁸, and -S(O)₂NR⁷R⁸;

X¹, at each occurrence, is independently selected from: OR⁶, -COR⁶, - CO₂R⁶, and -NR^7aR^8a; Y, at each occurrence, is independently selected from: O, S, SO, S(O)₂, and NR^b;

alternatively, NR⁴R⁵ forms a 4-10 membered heterocyclic ring, consisting of: the shown N atom, carbon atoms, and 0-4 heteroatoms selected from O, S(O)_P, and N, wherein the ring is substituted with 0-4 substituents independently selected from: halo, cyano, nitro, OR^a, SR^a, C_6-1O aryl, C_6-1O aryl-O-, HO-C₁-_S alkyl-, R^bR^cN-Crs alkyl-, Cr₈ haloalkyl, -NR^bR^c, -COR^a, -CO₂R^a, and - CONR^bR^c;

R⁶, at each occurrence, is independently is selected from: H, C_1-8 alkyl, R^aO- Ci_₈ alkyl, R^bR^cN-Ci_₈ alkyl-, C₁-_S haloalkyl, C₃__lo cycloalkyl, (C₃__lo

cycloalkyl)Ci-₈ alkyl-, C_6-10 aryl, (C_6-10 aryl)C_1-8 alkyl-, C_4-10 heterocyclyl, (C_4-10 heterocyclyl)Ci-₈ alkyl-, Cs_-10 heteroaryl, and (Cs_-10 heteroaryl)Ci-₈ alkyl-, wherein R⁶ is substituted with 0-3 R^6a groups;

R^6a, at each occurrence, is independently selected from: halo, cyano, nitro, - OR^a, -SR^a, C₆-Io aryl, C_6-Io aryl-O-, HO-Cr₈ alkyl-, R^bR^cN-Cr₈ alkyl-, Cr₈ haloalkyl, -NR^bR^c, -COR^a, -CO₂R^a, and -CONR^bR^c;

R⁷ and R⁸, at each occurrence, are independently selected from: H, C₁-_S alkyl, RO-Ci_-8 alkyl, R^bR^cN-d_₈ alkyl-, C₁-_S haloalkyl, C₃-_I0 cycloalkyl, (C₃-Io cycloalkyl)Ci-8 alkyl-, C_6-10 aryl, (C_6-10 aryl)C_1-8 alkyl-, C_4-10 heterocyclyl, (C4-10 heterocyclyl)Ci_₈ alkyl-, Cs_-10 heteroaryl, (Cs_-10 heteroaryl)Crs alkyl-, and ((CH₂)₂-₄- Y)_q-(CH₂)_2-4-X¹, wherein R⁷ and R⁸ are independently substituted with 0-3 R⁹ groups;

R^7a and R^8a, at each occurrence, are independently selected from: H, Cr₈ alkyl, RO-Ci_-8 alkyl, R^bR^cN-d-₈ alkyl-, C₁-S haloalkyl, C3-10 cycloalkyl, (C₃-Io cycloalkyl)Ci-8 alkyl-, C_6-10 aryl, (C_6-10 aryl)C_1-8 alkyl-, C₄-I₀ heterocyclyl, (C₄-Io heterocyclyl)Ci_₈ alkyl-, and Cs_io heteroaryl, (Cs_io heteroaryl)Crs alkyl-, wherein R^7a and R^8a are independently substituted with 0-3 R⁹ groups;

R⁹, at each occurrence, is independently selected from: halo, cyano, nitro, - OR^a, -SR^a, C₆-I₀ aryl, C_6-Io aryl-O-, HO-C₁-S alkyl-, R^bR^cN-Crs alkyl-, C₁-S haloalkyl, -NR^bR^c, -COR^a, -CO₂R^a, and -CONR^bR^c;

a, at each occurrence, is independently selected from of 0, 1, and 2; p, at each occurrence, is independently selected from 0, 1, and 2; and, q, at each occurrence, is independently selected from 1, 2, 3, and 4.

4. A compound of formula I:

or a stereoisomers or a pharmaceutically acceptable salt thereof;

wherein:

R¹ is selected from: C_1-8 alkyl, C₃_8 alkenyl, C₃_8 alkynyl, C₃_8 cycloalkyl and (C₃_8 cycloalkyl)Ci_8 alkyl-;

R² is selected from: C₁-_S alkyl, C_3-8 alkenyl, C_3-8 alkynyl, C_3-8 cycloalkyl and (C_3-8 cycloalkyl)Ci-8 alkyl-;

R⁴ is selected from:

4a

C_4-1Q heterocyclyl substituted with 0-2 R

4a

(C_4-10 heterocyclyl)C_1-8 alkyl- substituted with 0-2 R ,

C_1-8 alkyl substituted with 1-2 R^4a,

pyridyl substituted with -COO(C_1-6 alkyl) or -CO(NH₂),

(C_6-10 aryl)Cr₈ alkyl- substituted on alkyl with -COO(C_1-6 alkyl),

-CONH₂, -CONH(CH₂CH₂O)_1-4H or -CONH(CH₂CH₂O)_1-4(Cr₈ alkyl); and aryl substituted with -COO(C₁-_O alkyl), pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, or thiomorpholinyl;

R^4a, at each occurrence, is independently selected from: =0, halo, cyano, nitro, OR^a, SR^a, HO-C_1-8 alkyl-, -NR^bR^c, R^bR^cN-Ci-₈ alkyl-, C_6-Io aryl-O-, Cr₈ haloalkyl, -COR^a, -CO₂R^a, and -CONR^bR^c;

R^a, at each occurrence, is independently selected from: H, C₁-_O alkyl, C₂_₆ alkenyl, C₂_6 alkynyl, C_3-1O cycloalkyl, (C_3-1O cycloalkyl)Ci-8 alkyl-,

C_4-1O heterocyclyl, (C_4-1O heterocyclyl)Ci-8 alkyl-, C_6-1O aryl,

(C_6-1O OTyI)C₁ -8 alkyl-, Cs_-1O heteroaryl, and (Cs_-1O heteroaryl)Ci-₈ alkyl-;

R^b and R^c, at each occurrence, are independently selected from: H, C₁-_O alkyl, and benzyl, or NR^bR^c forms a ring selected from pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, and thiomorpholinyl ring; and

R⁵ is selected from: H, C_1-S alkyl, C_3-S alkenyl, C_3-8 alkynyl; or NR⁴R⁵ forms a 5-7 membered heterocyclic ring, consisting of: the shown N atom, carbon atoms, and 0-2 heteroatoms selected from O, S(O)_P, and N, wherein the ring is substituted with 0-2 substituents independently selected from: halo, cyano, nitro, -OH, -O(C_1-8alkyl), -COOH and -CO₂(C_1-8alkyl).

5. A compound of claim 4, wherein at least one of R¹ or R² is a C_3-8 cycloalkyl or a (C_3-8 cycloalkyl)C_1-8 alkyl-.

6. A compound of any one of the preceding claims, wherein R is hydrogen.

7. A compound of any one of the preceding claims, wherein R¹ is selected from C_1-8 alkyl, and (C_3-8 cycloalkyl)C_1-8 alkyl-.

8. A compound of any one of the preceding claims, wherein R is selected from C_1-8 alkyl, and (C_3-8 cycloalkyl)C_1-8 alkyl-.

9. A compound of any one of the preceding claims, wherein R¹ and R² are

independently selected from: H, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, i-butyl, cyclopropyl, cyclopropylmethyl, phenyl, phenethyl, benzyl, and (methoxyphenyl)ethyl.

10. A compound of any one of the preceding claims, wherein R¹ and R² are independently selected from: n-propyl and cyclopropyl.

11. A compound of any one of the preceding claims, wherein R^4a, at each

occurrence, is independently selected from: =0, F, Cl, cyano, OH, OCH₃, CH₂OH, NH₂, CH₂NH₂, phenoxy, phenyl, benzyl, CF₃, -COCH₃, -CO₂H, -CO₂CH₃, and -CONH₂.

12. A compound of any one of the preceding claims, wherein R⁴ is

(C₆-Io aryl)Ci-₈ alkyl- substituted on alkyl with -COO(C_1-6 alkyl), -CONH₂, - CONH(CH₂CH₂O)_1-4H or -CONH(CH₂CH₂O)_1-4(Cr₈ alkyl).

13. A compound of any one of the preceding claims, wherein R⁵ is hydrogen.

4. A compound selected from:

4G 4H

5A 5B

and stereoisomers and pharmaceutically acceptable salts thereof.

15. A pharmaceutical composition comprising: a therapeutically effective amount of a compound of any one of the preceding claims and a pharmaceutically acceptable excipient.

16. A therapeutic method for treating a pathological condition or symptom in a mammal, wherein the activity of adenosine A_2B receptors is implicated and antagonism of its action is desired comprising administering to the mammal an effective amount of a compound of any one of claims 1-14.

17. A method for treating asthma, allergies, allergic diseases or an autoimmune disease comprising administering an effective amount of a compound of any one of claims 1-14 to a mammal in need of such treatment.

18. A method for treating diarrheal diseases, insulin resistance, diabetes, cancer, ischemia/reprefusion injuries, diabetic retinopathy or hyperbaric oxygen-induced retinopathy, comprising administering an effective amount of a compound of any one of claims 1-14 or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment.

19. Use of a compound of any one of claims 1-14 for therapy.

20. Use of a compound of any one of claims 1-14 for the manufacture of a

medicament useful for the treatment of a disease in a mammal.

21. A compound of any one of claims 1-14 for use in treating pathological condition or symptom in a mammal, wherein the activity of adenosine A_2B receptors is implicated and antagonism of its action is desired.

22. A compound of any one of claims 1-14 for use in treating asthma, allergies, allergic diseases or an autoimmune disease.

3. A compound of any one of claims 1-14 for use in treating diarrheal diseases, insulin resistance, diabetes, cancer, ischemia/reprefusion injuries, diabetic retinopathy or hyperbaric oxygen-induced retinopathy.