Diaminopyrimidines as P2X

1. A compound of formula (1):

or a pharmaceutically acceptable salt thereof,

wherein:

X is:

—CR 2 —;

—O—;

—S(O) n —;

or —NR c —

wherein

n is from 0 to 2 and

R c is hydrogen or alkyl;

D is an optional oxygen;

R 1 is:

ethyl;

isopropyl;

iodo;

ethynyl; or

cyclopropyl;

R 2 , R 4 and R 6 are hydrogen;

R 3 is:

hydrogen;

alkyl;

alkenyl;

amino;

halo;

amido;

haloalkyl;

alkoxy;

hydroxy;

haloalkoxy;

nitro; amino;

hydroxyalkyl;

alkoxyalkyl;

hydroxyalkoxy;

alkynylalkoxy;

alkylsulfonyl;

arylsulfonyl;

cyano;

aryl;

heteroaryl;

heterocyclyl;

heterocyclylalkoxy;

aryloxy;

heteroaryloxy;

aralkyloxy;

heteroaralkyloxy;

optionally substituted phenoxy;

—C=C—R u ;

—(CH 2 ) m -(Z) n -(CO)—R b ;

—(CH 2 ) m -(Z) n -SO 2 —(NR c ) n R b

wherein

m and n each independently is 0 or 1,

Z is O or NR c ,

R a is hydrogen; alkyl; aryl; aralkyl; heteroaryl; heteroaralkyl; hydroxyalkyl; alkoxyalkyl; alkylsulfonylalkyl; aminoalkyl; cyanoalkyl; alkylsilyl, cycloalkyl, cycloalkylalkyl; heterocycl; and heterocyclylalkyl;

R b is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl, and

each R c is independently hydrogen or alkyl;

or R 2 and R 3 together with the atoms to which they are attached may form a five or six-membered ring that optionally includes one or two heteroatoms selected from O, S and N;

R 5 is:

hydrogen;

alkyl;

aryl;

aralkyl;

heteroaryl;

heteroaralkyl;

hydroxyalkyl;

alkoxyalkyl;

alkylsulfonylalkyl;

aminoalkyl;

cyanoalkyl;

alkylsilyl,

cycloalkyl,

cycloalkylalkyl;

heterocycl; or

heterocyclylalkyl; and

R 7 and R 8 each independently is:

hydrogen;

alkyl;

aminoalkyl;

aminosulfonyl;

cycloalkyl;

cycloalkylalkyl;

haloalkyl;

haloalkoxy;

hydroxyalkyl;

alkoxyalkyl;

alkylsulfonyl;

alkylsulfonylalkyl;

aminocarbonyloxyalkyl;

hydroxycarbonylalkyl;

hydroxyalkyloxycarbonylalkyl;

aryl;

aralkyl;

arylsulfonyl;

heteroaryl;

heteroarylalkyl;

heteroarylsulfonyl;

heterocyclyl; or

heterocyclylalkyl.

2. The compound of claim 1 , wherein X is: —O—; or —CH 2 —.

3. The compound of claim 1 , wherein R 7 and R 8 are hydrogen.

4. The compound of claim 2 , wherein one of R 7 and R 8 is hydrogen and the other is hydrogen, alkyl, hydroxyalkyl or haloalkyl.

5. The compound of claim 3 , wherin R 3 is: hydrogen; halo; alkoxy; haloalkoxy; hydroxy; or alkylsulfonyl.

6. The compound of claim 5 , wherein R 1 is isopropyl.

7. The compound of claim 3 , wherein R 5 is: hydrogen; alkyl; optionally substituted phenyl; optionally substituted pyridinyl; optionally substituted thienyl; optionally substituted imidazolyl; hydroxyalkyl; alkoxyalkyl; aminoalkyl; cyanoalkyl; alkylsilyl or cycloalkyl.

8. The compound of claim 3 , wherein R 5 is hydrogen or alkyl.

9. The compound of claim 6 , wherein R 5 is hydrogen or methyl.

10. The compound of claim 3 , wherein R 5 is heteroaryl selected from pyridinyl, pyrimdinyl, thienyl, furanyl, imidazolyl, pyrazolyl and pyrrolyl.

11. The compound of claim 3 , wherein R 5 is: hydrogen; methyl; ethyl; propyl; phenyl; methoxymethyl; pyridin-2-yl; pyridin-3-yl; pyridin-4-yl; 2-hydroxyethyl; 3-hydroxypropyl; hydroxymenthyl; methylaminomethyl; 2-cyanoethyl; thien-3-yl; 1-methylimidazol-5-yl; trimethylsilyl; or cyclopropyl.

12. The compound of claim 1 wherein said compound is of the formula (II):

wherein:

X is:

—CH 2 —; or

—O—;

R 1 is:

alkyl;

alkenyl;

alkynyl;

cycloalkyl;

cycloalkenyl; or

halo;

R 3 is:

hydrogen;

alkyl;

alkenyl;

amino;

halo;

amido;

haloalkyl;

alkoxy;

hydroxy;

haloalkoxy;

nitro; amino;

hydroxyalkyl;

alkoxyalkyl;

hydroxyalkoxy;

alkynylalkoxy;

alkylsulfonyl;

arylsulfonyl;

cyano;

aryl;

heteroaryl;

heterocyclyl;

heterocyclylalkoxy;

aryloxy;

heteroaryloxy;

aralkyloxy;

heteroaralkyloxy;

optionally substituted phenoxy;

—C≡C—R a ;

—(CH 2 ) m -(Z) n-(CO)—R b ;

—(CH 2 ) m -(Z) n -SO 2 —(NR c ) n —R b

wherein

m and n each independently is 0 or 1,

Z is O or NR c ,

R a is hydrogen; alkyl; aryl; aralkyl; heteroaryl; heteroaralkyl; hydroxyalkyl; alkoxyalkyl; alkylsulfonylalkyl; aminoalkyl; cyanoalkyl; alkylsilyl, cycloalkyl, cycloalkylalkyl; heterocycl; and heterocyclylalkyl;

R b is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl, and

each R c is independently hydrogrn or alkyl;

R 5 is:

hydrogen;

alkyl;

aryl;

aralkyl;

heteroaryl;

heteroaralkyl;

hydroxyalkyl;

alkoxyalkyl;

alkylsulfonylalkyl;

aminoalkyl;

cyanoalkyl;

alkylsilyl,

cycloalkyl,

cycloalkyalkyl;

heterocycl; or

heterocyclylalkyl; and

R 7 and R 8 each independently is:

hydrogen;

alkyl;

cycloalkyl;

cycloalkylalkyl;

haloalkyl;

hydroxyalky;

alkoxyalky;

alkylsulfonyl;

alkylsulfonylalkyl;

aminocarbonyloxyalkyl;

hydroxycarbonylalkyl;

hydroxyalkyloxycarbonylalkyl;

aryl;

aralkyl;

arylsulfonyl;

heteroaryl;

heteroarylalkyl;

heteroarylsulfonyl;

heterocyclyl; or

heterocyclylalkyl.

13. The compound of claim 1 , wherein said compound is of the formula (III):

wherein:

R 1 is:

ethyl;

isopropyl;

iodo;

ethynyl; or

cyclopropyl;

R 3 is:

hydrogen;

alkyl;

alkenyl;

halo;

haloalkyl;

alkoxy;

hydroxy;

haloalkoxy;

alkylsulfonyl;

cyano; or

—C—C—R a ;

wherein

R a is hydrogen; alkyl; aryl; aralkyl; heteroaryl; heteroaralkyl; hydroxyalkyl; alkoxyalkyl; alkylsulfonylalkyl; aminoalkyl; cyanoalkyl; alkylsilyl, cycloalkyl, cycloalkylalkyl; heterocycl; and heterocyclylalkyl;

R 5 is:

hydrogen;

alkyl;

aryl;

aralkyl;

heteroaryl;

heteroaralkyl;

hydroxyalkyl;

alkoxyalkyl;

alkylsulfonylalkyl;

aminoalkyl;

cyanoalkyl;

alkylsilyl;

cycloalkyl;

cycloalkylalkyl;

heterocycl; or

heterocyclylalkyl;

R 7 and R 8 each independently is:

hydrogen;

alkyl;

cycloalkyl;

cycloalklalkyl;

haloalkyl;

hydroxyalky; or

alkoxyalkyl.

14. The compound of claim 1 , wherein said compound is of the formula (IV):

wherein:

R 3 is:

hydrogen;

alkyl;

alkenyl;

halo;

haloalkyl;

alkoxy;

hydroxy;

haloalkoxy;

alkylsulfonyl;

cyano; or

—C≡C—R a ;

wherein

R a is hydrogen; alkyl; aryl; aralkyl; heteroaryl; heteroaralkyl; hydroxyalkyl; alkoxyalkyl; alkylsulfonylalkyl; aminoalkyl; cyanoalkyl; alkylsilyl, cycloalkyl, cycloalkylalkyl; heterocycl; and heterocyclylalkyl;

R 5 is:

hydrogen;

alkyl;

aryl;

aralkyl;

heteroaryl;

heteroaralkyl;

hydroxyalkyl;

alkoxyalkyl;

alkylsulfonylalkyl;

aminoalkyl;

cyanoalkyl;

alkylsilyl,

cycloalkyl,

cycloalkylalkyl;

heterocycl; or

heterocyclylalkyl; and

R 7 and R 8 each independently is:

hydrogen;

alkyl;

cycloalkyl;

cycloalkylalkyl;

haloalkyl;

hydroxyalky; or

alkoxyalkyl.

15. A compound of the formula (VII):

or a pharmaceutically acceptable salt thereof,

wherein:

X is:

—CH 2 —;

—O—;

—S(O) n —;

or —NR c —

wherein

n is from 0 to 2 and

R c is hydrogen or alkyl;

D is an optional oxygen;

R 2 R 4 and R 6 are hydrogen;

R 3 is:

alkoxy; or

hydroxy;

one of R 7 and R 8 is hydrogen and the other is:

hydrogen;.

alkyl;

hydroxyalkyl; or

haloalkyl;

R 9 is:

hydrogen; or

alkyl; and

R 10 is:

iodo;

alkylsulfonyl; or

—C≡C—R a wherein R a is hydrogen or alkyl.

16. A method for treating asthma, said method comprising administering to a subject in need thereof an effective amount of a compound of claim 1 .