IP Library › Granted Patent US 8,324,229

Granted Patent B2

US 8,324,229 · App. 12/679,895 · Granted Dec 4, 2012

Alkylthio pyrimidines as CRTH2 antagonists

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Quick Facts

Patent No.: US 8,324,229
App. No.: 12/679,895
Granted: Dec 4, 2012
Kind: B2

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Abstract

Provided herein are alkylthio substituted pyrimidine compounds having CRTH2 (G-protein-coupled chemoattractant receptor, expressed on Th2 cells) antagonistic activity, useful for the treatment or prophylaxis of diseases associated with CRTH2 activity, including the treatment of allergic diseases, eosinophil-related diseases and basophil-related diseases.

Claims (135)

1. A compound having formula I:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein

W is a single bond, —(CH 2 ) m —, —O—, —S(O) n —, —NR 7 —, —C(O)—, —C(O)O—, —C(O)NR 7 —, —NR 7 C(O)NR 7 — or —NR 7 C(O)O—;

R 1 is —CO 2 R 9 , —C(O)NR 8a R 8b , nitrile or tetrazolyl;

R 2 is (a) hydrogen; (b) halogen; (c) (C 1 -C 6 )alkyl; (d) (C 1 -C 6 )alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C 1 -C 6 )alkylcarbamoyl, di((C 1 -C 6 )alkyl)carbamoyl, (C 3 -C 7 )cycloalkylcarbamoyl or (C 3 -C 7 )heterocyclylcarbamoyl; (e) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; (f) (C 3 -C 7 )cycloalkyl; (g) —NR 8a R 8b ; (h) —SR 3 ; or (i) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen;

each R 3 is independently (a) hydrogen; (b) (C 1 -C 6 )alkyl optionally substituted by mono-, di-, or tri-halogen; (c) (C 3 -C 7 )cycloalkyl or (d) —C(O)R 9 ;

R 4a and R 4b are each independently selected from hydrogen or (C 1 -C 6 )alkyl;

each R 5 is independently (a) hydrogen; (b) halogen; (c) cyano; (d) nitro; (e) hydroxy; (f) phenyl; (g) phenyloxy; (h) benzyl; (i) benzyloxy; (j) guanidino; (k) heterocyclyl; (l) —NR 8a R 8b ; (m) sulfamoyl; (n) (C 1 -C 6 )alkylsulfonyl; (o) (C 1 -C 6 )alkylaminosulfonyl; (p) di(C 1 -C 6 )alkylaminosulfonyl; (q) —C(O)R 9 ; (r) —C(O)OR 9 ; (s) —C(O)NR 8a R 8b ; (t) —OC(O)NR 8a R 8b ; (u) —NR 7 C(O)OR 9 ; (v) —NR 7 C(O)R 9 ; (w) (C 2 -C 6 )alkenyl; (x) (C 1 -C 6 )alkyl optionally substituted by mono-, di-, or tri-halogen; (y) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen; or (z) (C 1 -C 6 )alkylthio optionally substituted by mono-, di-, or tri-halogen;

R 6 is (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) (C 2 -C 6 )alkenyl; (d) (C 2 -C 6 )alkynyl; (e) (C 3 -C 7 )cycloalkyl; (f) (C 1 -C 6 )alkyl substituted by aryl or heteroaryl; (g) (C 2 -C 4 )alkenyl substituted by aryl or heteroaryl; (h) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; (i) (C 1 -C 6 )alkyl substituted by —C(O)R 6a ; (j) (C 1 -C 6 )alkoxy substituted by mono-, di-, or tri-halogen; (k) (C 1 -C 6 )alkylthio substituted by mono-, di-, or tri-halogen; (l) aryl; or (m) heteroaryl; wherein said aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) guanidino; (f) heterocyclyl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j) benzyloxy; (k) —NR 8a R 8b ; (l) —C(O)R 9 ; (m) —C(O)NR 8a R 8b ; (n) —OC(O)NR 8a R 8b ; (o) —C(O)OR 9 ; (p) —NR 7 C(O)OR 9 ; (q) —NR 7 C(O)R 9 ; (r) sulfamoyl; (s) (C 1 -C 6 )alkylsulfonyl; (t) (C 1 -C 6 )alkylaminosulfonyl; (u) di(C 1 -C 6 )alkylaminosulfonyl; (v) (C 1 -C 6 )alkyl optionally substituted by mono-, di-, or tri-halogen; (w) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen; and (x) (C 1 -C 6 )alkylthio optionally substituted by mono-, di-, or tri-halogen;

R 6a is (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) (C 2 -C 6 )alkenyl; (d) (C 2 -C 6 )alkynyl; (e) (C 3 -C 7 )cycloalkyl; (f) (C 1 -C 6 )alkyl substituted by aryl or heteroaryl; (g) (C 2 -C 4 )alkenyl substituted by aryl or heteroaryl; (h) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; (i) (C 1 -C 6 )alkoxy substituted by mono-, di-, or tri-halogen; (j) (C 1 -C 6 )alkylthio substituted by mono-, di-, or tri-halogen; (k) aryl; or (l) heteroaryl; wherein said aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) guanidino; (f) heterocyclyl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j) benzyloxy; (k) —NR 8a R 8b ; (l) —C(O)R 9 ; (m) —C(O)NR 8a R 8b ; (n) —OC(O)NR 8a R 8b ; (o) —C(O)OR 9 ; (p) —NR 7 C(O)OR 9 ; (q) —NR 7 C(O)R 9 ; (r) sulfamoyl; (s) (C 1 -C 6 )alkylsulfonyl; (t) (C 1 -C 6 )alkylaminosulfonyl; (u) di(C 1 -C 6 )alkylaminosulfonyl; (v) (C 1 -C 6 )alkyl optionally substituted by mono-, di-, or tri-halogen; (w) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen; and (x) (C 1 -C 6 )alkylthio optionally substituted by mono-, di-, or tri-halogen;

each R 7 is independently (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; (d) (C 1 -C 6 )alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C 1 -C 6 )alkylcarbamoyl, di((C 1 -C 6 )alkyl)carbamoyl, (C 3 -C 7 )cycloalkylcarbamoyl or (C 3 -C 7 )heterocyclylcarbamoyl; (e) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; or (f) (C 3 -C 7 )cycloalkyl;

in each instance, independently, R 8a and R 8b are selected from (i) or (ii) as follows:

(i) R 8a and R 8b are each independently selected from (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; (d) (C 1 -C 6 )alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C 1 -C 6 )alkylcarbamoyl, di((C 1 -C 6 )alkyl)carbamoyl, (C 3 -C 7 )cycloalkylcarbamoyl or (C 3 -C 7 )heterocyclylcarbamoyl; (e) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; or (f) (C 3 -C 7 )cycloalkyl; or

(ii) each R 8a and R 8b , together with the N to which they are bonded, independently may form a 3 to 8 membered saturated or unsaturated ring optionally containing one or more O or S atoms, or one or more additional N atoms, in the ring;

each R 9 is independently (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; or (d) (C 1 -C 6 )alkyl substituted by aryl, alkoxy or mono-, di-, or tri-halogen;

k is 0, 1 or 2;

each m is independently 1, 2, 3 or 4; and

n is 0, 1 or 2.

2. The compound of claim 1 , wherein R 1 is —CO 2 H.

3. The compound of claim 1 wherein R 2 is —SR 3 .

4. The compound of claim 1 wherein each R 3 is independently (C 1 -C 6 )alkyl.

5. The compound of claim 1 wherein R 4a and R 4b are each independently hydrogen, methyl or ethyl.

6. A compound having formula II:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein

W is a single bond, —(CH 2 ) m —, —O—, —S(O) n —, —C(O)—, —C(O)O—, —C(O)NR 7 —, —NR 7 C(O)NR 7 — or —NR 7 C(O)O—;

each R 3 is independently (C 1 -C 6 )alkyl;

R 4a and R 4b are each independently selected from hydrogen, methyl or ethyl;

R 6 is (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) (C 2 -C 6 )alkenyl; (d) (C 2 -C 6 )alkynyl; (e) (C 3 -C 7 )cycloalkyl; (f) (C 1 -C 6 )alkyl substituted by aryl or heteroaryl; (g) (C 2 -C 4 )alkenyl substituted by aryl or heteroaryl; (h) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; (i) (C 1 -C 6 )alkyl substituted by —C(O)R 6a ; (j) (C 1 -C 6 )alkoxy substituted by mono-, di-, or tri-halogen; (k) (C 1 -C 6 )alkylthio substituted by mono-, di-, or tri-halogen; (l) aryl; or (m) heteroaryl; wherein said aryl and heteroaryl are optionally substituted at with one or more substituents selected from the group consisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) guanidino; (f) heterocyclyl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j) benzyloxy; (k) —NR 8a R 8b ; (l) —C(O)R 9 ; (m) —C(O)NR 8a R 8b ; (n) —OC(O)NR 8a R 8b ; (o) —C(O)OR 9 ; (p) —NR 7 C(O)OR 9 ; (q) —NR 7 C(O)R 9 ; (r) sulfamoyl; (s) (C 1 -C 6 )alkylsulfonyl; (t) (C 1 -C 6 )alkylaminosulfonyl; (u) di(C 1 -C 6 )alkylaminosulfonyl; (v) (C 1 -C 6 )alkyl optionally substituted by mono-, di-, or tri-halogen; (w) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen; and (x) (C 1 -C 6 )alkylthio optionally substituted by mono-, di-, or tri-halogen;

in each instance, independently, R 8a and R 8b are selected from (i) or (ii) as follows:

each R 9 is independently (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; or (d) (C 1 -C 6 )alkyl substituted by aryl, alkoxy or mono-, di-, or tri-halogen;

each k is independently 0, 1 or 2;

each m is independently 1, 2, 3 or 4; and

n is 0, 1 or 2.

7. A compound having formula III:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein

X is a single bond, —O(CH 2 ) p — or —NR 9 (CH 2 ) p —;

each R 3 is independently (a) hydrogen; (b) (C 1 -C 6 )alkyl optionally substituted by mono-, di-, or tri-halogen; (c) (C 3 -C 7 )cycloalkyl or (d) —C(O)R 9 ;

R 4a and R 4b are each independently selected from hydrogen or (C 1 -C 6 )alkyl;

R 6 is (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) (C 2 -C 6 )alkenyl; (d) (C 2 -C 6 )alkynyl; (e) (C 3 -C 7 )cycloalkyl; (f) (C 1 -C 6 )alkyl substituted by aryl or heteroaryl; (g) (C 2 -C 4 )alkenyl substituted by aryl or heteroaryl; (h) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; (i) (C 1 -C 6 )alkyl substituted by —C(O)R 6a ; (j) (C 1 -C 6 )alkoxy substituted by mono-, di-, or tri-halogen; (k) (C 1 -C 6 )alkylthio substituted by mono-, di-, or tri-halogen; (l) aryl; or (m) heteroaryl; wherein said aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) guanidino; (f) heterocyclyl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j) benzyloxy; (k) —NR 8a R 8b ; (l) —C(O)R 9 ; (m) —C(O)NR 8a R 8b ; (n) —OC(O)NR 8a R 8b ; (o) —C(O)OR 9 ; (p) —NR 7 C(O)OR 9 ; (q) —NR 7 C(O)R 9 ; (r) sulfamoyl; (s) (C 1 -C 6 )alkylsulfonyl; (t) (C 1 -C 6 )alkylaminosulfonyl; (u) di(C 1 -C 6 )alkylaminosulfonyl; (v) (C 1 -C 6 )alkyl optionally substituted by mono-, di-, (w) C 1 -C 6 optionally substituted by mono-, di-, or tri-halogen; and (x) (C 1 -C 6 )alkylthio optionally substituted by mono-, di-, or tri-halogen;

each R 7 is independently hydrogen or (C 1 -C 6 )alkyl;

in each instance, independently, R 8a and R 8b are selected from (i) or (ii) as follows:

each R 9 is independently (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; or (d) (C 1 -C 6 )alkyl substituted by aryl, alkoxy or mono-, di-, or tri-halogen;

k is 0, 1 or 2; and

each p is independently 1, 2, 3, 4, 5 or 6.

8. The compound of claim 7 , wherein each R 3 is independently (C 1 -C 6 )alkyl.

9. The compound of claim 7 wherein R 4a and R 4b are each independently hydrogen.

10. The compound of claim 7 , wherein

R 2 is —S(C 1 -C 6 )alkyl; and

R 7 and R 9 are each independently hydrogen.

11. The compound of claim 7 , wherein

R 6 is aryl or heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) —NR 8a R 8b ; (f) —C(O)R 9 ; (g) —C(O)NR 8a R 8b ; (h) —OC(O)NR 8a R 8b ; (i) —NR 7 C(O)OR 9 ; (j) —NR 7 C(O)R 9 ; (k) —C(O)OR 9 ; (l) guanidino; (m) heterocyclyl; (n) phenyl; (o) phenyloxy; (p) benzyl; (q) benzyloxy; (r) sulfamoyl; (s) (C 1 -C 6 )alkylsulfonyl; (t) (C 1 -C 6 )alkylaminosulfonyl; (u) di(C 1 -C 6 )alkylaminosulfonyl; (v) (C 1 -C 6 )alkyl optionally substituted by mono-, di-, or tri-halogen; (w) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen; and (x) (C 1 -C 6 )alkylthio optionally substituted by mono-, di-, or tri-halogen; and

R 7 and R 9 are each independently hydrogen or (C 1 -C 6 )alkyl.

12. A compound having formula IV:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein

X is a single bond, —O(CH 2 ) p — or —NR 9 (CH 2 ) p —;

each R 3 is independently (C 1 -C 6 )alkyl;

R 4a and R 4b are each independently selected from hydrogen or (C 1 -C 6 )alkyl;

each R 7 is independently hydrogen or (C 1 -C 6 )alkyl;

in each instance, independently, R 8a and R 8b are selected from (i) or (ii) as follows:

each R 9 is independently (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; or (d) (C 1 -C 6 )alkyl substituted by aryl, alkoxy or mono-, di-, or tri-halogen;

each R 10 is independently (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) —NR 8a R 8b ; (f) —C(O)R 9 ; (g) —C(O)NR 8a R 8b ; (h) —OC(O)NR 8a R 8b ; (i) —NR 7 C(O)OR 9 ; (j) —NR 7 C(O)R 9 ; (k) —C(O)OR 9 ; (l) guanidino; (m) heterocyclyl; (n) phenyl; (o) phenyloxy; (p) benzyl; (q) benzyloxy; (r) sulfamoyl; (s) (C 1 -C 6 )alkylsulfonyl; (t) (C 1 -C 6 )alkylaminosulfonyl; (u) di(C 1 -C 6 )alkylaminosulfonyl; (v) (C 1 -C 6 )alkyl optionally substituted by mono-, di-, or tri-halogen; (w) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen; and (x) (C 1 -C 6 )alkylthio optionally substituted by mono-, di-, or tri-halogen;

each k is independently 0, 1 or 2;

each p is independently 1, 2, 3, 4, 5 or 6; and

q is 0, 1, 2, 3, 4 or 5.

13. The compound of claim 7 , having formula V:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein

R 2 is hydrogen or halogen;

R 3 is (C 1 -C 6 )alkyl;

q is 0, 1, 2, 3, 4 or 5.

14. The compound of claim 12 having formula VI:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

15. The compound of claim 7 having formula VII:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

16. The compound of claim 12 , wherein

each R 10 is independently (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) —NH 2 ; (f) —NH(C 1 -C 6 )alkyl; (g) —N((C 1 -C 6 )alkyl) 2 ; (h) —C(O)(C 1 -C 6 )alkyl; (i) —CO 2 H; (j) —NHC(O)(C 1 -C 6 )alkyl; (k) —C(O)O(C 1 -C 6 )alkyl; (l) phenyl; (m) phenyloxy; (n) benzyl; (o) benzyloxy; (p) sulfamoyl; (q) (C 1 -C 6 )alkylsulfonyl; (r) (C 1 -C 6 )alkylaminosulfonyl; (s) di(C 1 -C 6 )alkylaminosulfonyl; (t) (C 1 -C 6 )alkyl optionally substituted by mono-, di-, or tri-halogen; (u) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen; or (v) (C 1 -C 6 )alkylthio optionally substituted by mono-, di-, or tri-halogen.

17. The compound of claim 12 having formula VIII:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein X is a single bond, —O— or —NH—.

18. The compound of claim 7 having formula IX:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein

R 2 is hydrogen or halogen; and

X is a single bond, —O— or —NH—.

19. The compound of claim 1 having the formula