IP Library › Granted Patent US 8,193,228

Granted Patent B2

US 8,193,228 · App. 12/311,487 · Granted Jun 5, 2012

Substituted imidazole as bombesin receptor subtype-3 modulators

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Quick Facts

Patent No.: US 8,193,228
App. No.: 12/311,487
Granted: Jun 5, 2012
Kind: B2

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Abstract

Certain novel substituted imidazoles are ligands of the human bombesin receptor and, in particular, are selective ligands of the human bombesin receptor subtype-3 (BRS-3). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the modulation of BRS-3, such as obesity, and diabetes.

Claims (299)

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof; wherein

A is aryl, wherein aryl is unsubstituted or substituted with 0 to 4 substituents selected from R 6 ;

B is a mono- or bicyclic ring selected from the group consisting of:

(1) —C 3-8 cycloalkyl,

(2) —C 3-8 cycloalkenyl,

(3) —C 2-8 heterocycloalkyl,

(4) —C 2-8 heterocycloalkenyl,

(5) -aryl, and

(6) -heteroaryl,

wherein cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl are unsubstituted or substituted with 0 to 4 substituents selected from R 7 ;

X is independently selected from the group consisting of:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —C 2-8 alkenyl,

(4) —C 2-8 alkynyl,

(5) —(CH 2 ) n C 3-7 cycloalkyl,

(6) —(CH 2 ) n C 2-7 heterocycloalkyl,

(7) —(CH 2 ) n aryl,

(8) —(CH 2 ) n heteroaryl,

(9) —CF 3 ,

(10) halogen,

(11) —OR 11 ,

(12) —OCF 3 ,

(13) —COR 9 ,

(14) —CO 2 R 11 ,

(15) —CON(R 9 ) 2 ,

(16) —N(R 11 ) 2 ,

(17) —N(R 9 )C(O)C 1-6 alkyl,

(18) —N(R 9 )CO 2 R 11 ,

(19) —N(R 9 )SO 2 C 1-6 alkyl,

(20) —N(R 9 )SO 2 N(R 9 ) 2 ,

(21) —SH,

(22) —S(O) 0-2 C 1-6 alkyl, and

(23) —SO 2 N(R 11 ) 2 ,

wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and —(CH 2 ) n are unsubstituted or substituted with one to five substituents selected from R 8 , and wherein X and R 4 together with the atoms to which they are attached may form a 3-6 membered cycloalkyl ring containing 0-3 heteroatoms independently selected from oxygen, sulfur, and NR 9 , and wherein the 3-6 membered cycloalkyl ring is unsubstituted or substituted with 1 to 4 substituents selected from R 8 , provided that at least one of X, Y, R 4 and R 5 is not hydrogen;

Y is independently selected from the group consisting of:

(1) halogen,

(2) —OR 11 ,

(3) —OCF 3 ,

(4) —COR 9 ,

(5) —CO 2 R 9 ,

(6) —CON(R 9 ) 2 ,

(7) —CN,

(8) —N(R 11 ) 2 ,

(9) —N(R 9 )C(O)C 1-6 alkyl,

(10) —N(R 9 )CO 2 R 11 ,

(11) —N(R 9 )SO 2 C 1-6 alkyl,

(12) —N(R 9 )SO 2 N(R 9 ) 2 ,

(13) —SH,

(14) —S(O) 0-2 C 1-6 alkyl, and

(15) —SO 0-2 N(R 11 ) 2 ,

wherein alkyl is unsubstituted or substituted with one to five substituents selected from R 8 , and wherein Y and R 6 or Y and R 5 together with the atoms to which they are attached may form a 3-6 membered cycloalkyl ring containing 0-3 heteroatoms independently selected from oxygen, sulfur, and NR 9 , and wherein the 3-6 membered cycloalkyl ring is unsubstituted or substituted with 1 to 4 substituents selected from R 8 ;

R 1 and R 2 are each independently selected from the group consisting of:

(1) hydrogen,

(2) —(CH 2 ) n halogen,

(3) —(CH 2 ) n OR 11 ,

(4) —(CH 2 ) n CN,

(5) —(CH 2 ) n CF 3 ,

(6) —(CH 2 ) n CHF 2 ,

(7) —(CH 2 ) n CH 2 F,

(8) —(CH 2 ) n CCl 3 ,

(9) —C 1-8 alkyl,

(10) —(CH 2 ) n C 2-8 alkenyl,

(11) —(CH 2 ) n C 2-8 alkynyl,

(12) —(CH 2 ) n C 3-10 cycloalkyl,

(13) —(CH 2 ) n C 3-10 cycloalkenyl,

(14) —(CH 2 ) n C 2-12 heterocycloalkyl,

(15) —SC 1-8 alkyl,

(16) —SC 3-8 cycloalkyl,

(17) —(CH 2 ) n aryl,

(18) —(CH 2 ) n heteroaryl,

(19) —(CH 2 ) n CO 2 R 9 , and

(20) —(CH 2 ) n COC 1-8 alkyl,

provided that R 1 and R 2 are not both hydrogen, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and (CH 2 ) n are unsubstituted or substituted with 1 to 5 substituents selected from R 10 , and wherein two R 10 substituents together with the atom to which they are attached may form a 3-6 membered cycloalkyl or cycloalkenyl ring containing 0 to 3 heteroatoms independently selected from oxygen, sulfur, and NR 9 , and wherein the 3-6 membered cycloalkyl or cycloalkenyl ring is unsubstituted or substituted with 1 to 4 substituents selected from R 10 ;

R 3 is selected from the group consisting of:

(1) hydrogen,

(2) —C 1-6 alkyl, and

(3) —COC 1-6 alkyl;

R 4 and R 5 are each independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C 1-6 alkyl,

(4) —(CH 2 ) n C 3-8 cycloalkyl,

(5) —(CH 2 ) n C 2-8 heterocycloalkyl,

(6) —C 1-6 alkoxy,

(7) —OH,

(8) —CH 2 F,

(9) —CHF 2 ,

(10) —CF 3 ,

(11) —CN,

(12) —SR 11 ,

(13) aryl, and

(14) heteroaryl,

wherein alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and (CH 2 ) n are unsubstituted or substituted with one to five substituents selected from R 8 ;

R 6 is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —(CH 2 ) n halogen,

(3) —(CH 2 ) n OR 11 ,

(4) —(CH 2 ) n CN,

(5) —(CH 2 ) n CF 3 ,

(6) —(CH 2 ) n CO 2 R 9 ,

(7) —(CH 2 ) n N(R 11 ) 2 ,

(8) —(CH 2 ) n NO 2 ,

(9) —(CH 2 ) n NR 9 COC 1-6 alkyl,

(10) —(CH 2 ) n NR 9 CO 2 C 1-6 alkyl,

(11) —(CH 2 ) n NR 9 SO 2 C 1-6 alkyl, and

(12) —(CH 2 ) n SO 0-2 C 1-6 alkyl,

wherein alkyl is substituted with 1 to 3 halogens;

R 7 is selected from the group consisting of:

(1) —(CH 2 ) n halogen,

(2) —C 1-6 alkyl,

(3) —C 2-6 alkenyl,

(4) —(CH 2 ) n C 3-8 cycloalkyl,

(5) —(CH 2 ) n heterocycloalkyl,

(6) oxo,

(7) —(CH 2 ) n OR 11 ,

(8) —(CH 2 ) n CN,

(9) —(CH 2 ) n COR 9 ,

(10) —(CH 2 ) n CO 2 R 11 ,

(11) —(CH 2 ) n CONR 9 N(R 9 ) 2 ,

(12) —(CH 2 ) n O(CH 2 ) n CO 2 R 9 ,

(13) —(CH 2 ) n NO 2 ,

(14) —(CH 2 ) n CON(R 9 ) 2 ,

(15) —(CH 2 ) n N(R 11 ) 2 ,

(16) —(CH 2 ) n NR 9 (CH 2 ) n CO 2 R 9 ,

(17) —(CH 2 ) n NR 9 COC 1-6 alkyl,

(18) —(CH 2 ) n SO 2 N(R 9 ) 2 ,

(19) —(CH 2 ) n NR 9 SO 2 C 1-6 alkyl,

(20) —(CH 2 ) n SO 0-2 R 11 ,

(21) —(CH 2 ) n OP(O) 2 OH,

(22) —CH═N—OH,

(23) —(CH 2 ) n aryl,

(24) —(CH 2 ) n heteroaryl, and

(25) —(CH 2 ) n O(CH 2 ) n heteroaryl,

wherein alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and —(CH 2 ) n are unsubstituted or substituted with 1 to 3 halogens;

R 8 is selected from the group consisting of:

(1) oxo,

(2) —OH,

(3) halogen,

(4) —CN,

(5) —CF 3 ,

(6) —CHF 2 ,

(7) —CH 2 F,

(8) —C 1-8 alkyl,

(9) —C 1-8 alkoxy,

(10) —COC 1-8 alkyl,

(11) —CO 2 C 1-8 alkyl, and

(12) —CO 2 H,

wherein each alkyl and alkoxy carbon is unsubstituted or substituted with 1 to 3 halogen substituents;

R 9 is selected from the group consisting of:

(1) hydrogen, and

(2) —C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen and —OH;

R 10 is independently selected from the group consisting of:

(1) halogen,

(2) —OH,

(3) oxo,

(4) —CN,

(5) —CCl 3 ,

(6) —CF 3 ,

(7) —CHF 2 ,

(8) —CH 2 F,

(9) —SO 2 C 1-6 alkyl,

(10) —COC 1-8 alkyl,

(11) —CO 2 C 1-8 alkyl,

(12) —CO 2 H

(13) —C 1-8 alkyl, and

(14) —C 1-8 alkoxy,

wherein alkyl and alkoxy are unsubstituted or substituted with 1 to 4 substituents selected from —C 1-6 alkyl and halogen, and wherein the —C 1-6 alkyl substituent is unsubstituted or substituted with 1 to 3 halogens;

R 11 is selected from the group consisting of:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —C 3-8 cycloalkyl,

(4) —C 2-7 heterocycloalkyl,

(5) —(CH 2 ) m phenyl, and

(6) —(CH 2 ) m heteroaryl,

wherein alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with 1 to 3 halogens or —OH, and wherein phenyl and heteroaryl are unsubstituted or substituted with 1 to 3 halogens;

each n is independently 0, 1, 2, 3 or 4; and

each m is independently 1, 2, 3 or 4.

2. The compound of claim 1 wherein A is phenyl, wherein A is unsubstituted or substituted with 0 to 4 substituents selected from R 6 ; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein B is a ring selected from the group consisting of: cyclopentyl, phenyl, pyridine, pyrazole, triazole, thiazole, isothiazole, thiadiazole, and (1,4,5,6)tetrahydro-7H-pyrazolo-{3,4-b}-pyridine-7yl, wherein B is unsubstituted or substituted with 0 to 4 substituents selected from R 7 ; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein R 2 is selected from the group consisting of: hydrogen, halogen, —(CH 2 ) n OH, —C 1-8 alkyl, —(CH 2 ) n C 2-8 alkenyl, —(CH 2 ) n C 3-8 cycloalkyl, —SC 1-8 cycloalkyl, and —(CH 2 ) n phenyl, wherein alkyl, alkenyl, cycloalkyl, phenyl, and (CH 2 ) n are unsubstituted or substituted with 1 to 4 substituents selected from R 10 ; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein R 2 and R 3 are hydrogen; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 wherein R 1 is selected from the group consisting of: —(CH 2 ) n OH, —(CH 2 ) n CN, —(CH 2 ) n CF 3 , —(CH 2 ) n CHF 2 , —(CH 2 ) n CH 2 F, —C 1-8 alkyl, —(CH 2 ) n C 2-8 alkenyl, and —(CH 2 ) n C 3-8 cycloalkyl, wherein alkyl, alkenyl, cycloalkyl, and (CH 2 ) n are unsubstituted or substituted with 1 to 4 substituents selected from R 10 ; or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 wherein X is selected from the group consisting of: hydrogen, halogen, and —OH, provided that at least one of X, Y, R 4 and R 5 is not hydrogen; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 7 wherein Y is selected from the group consisting of: halogen, —OH, —OC 1-6 alkyl, —CO 2 R 9 , —CON(R 9 ) 2 , —N(R 11 ) 2 , —N(R 9 )C(O)C 1-6 alkyl, —N(R 9 )CO 2 R 11 , and —N(R 9 )SO 2 C 1-6 alkyl, and —SC 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents selected from R 8 , and wherein Y and R 5 together with the atoms to which they are attached may form a 3-6 membered cycloalkyl ring containing 0-3 heteroatoms independently selected from oxygen, sulfur, and NR 9 , and wherein the 3-6 membered cycloalkyl ring is unsubstituted or substituted with 1 to 4 substituents selected from R 8 ; or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 of formula III:

or a pharmaceutically acceptable salt thereof; wherein

B is a mono- or bicyclic ring selected from the group consisting of:

(1) —C 3-8 cycloalkyl,

(2) -aryl, and

(3) -heteroaryl,

wherein cycloalkyl, aryl, heteroaryl are unsubstituted or substituted with 0 to 4 substituents selected from R 7 ;

X is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen, and

(3) —OH,

provided that at least one of X, Y, R 4 and R 5 is not hydrogen;

Y is independently selected from the group consisting of:

(1) halogen,

(2) —OH,

(3) —OC 1-6 alkyl,

(4) —N(R 11 ) 2 ,

(5) —N(R 9 )C(O)C 1-6 alkyl,

(6) —N(R 9 )CO 2 R 11 ,

(7) —N(R 9 )SO 2 C 1-6 alkyl,

(8) —SH, and

(9) —SC 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with one to five substituents selected from R 8 ;

R 1 is independently selected from the group consisting of:

(1) —(CH 2 ) n OH,

(2) —(CH 2 ) n CN,

(3) —(CH 2 ) n CF 3 ,

(4) —(CH 2 ) n CHF 2 ,

(5) —(CH 2 ) n CH 2 F,

(6) —C 1-8 alkyl,

(7) —(CH 2 ) n C 2-8 alkenyl, and

(8) —(CH 2 ) n C 3-8 cycloalkyl,

wherein alkyl, alkenyl, cycloalkyl, and (CH 2 ) n are unsubstituted or substituted with 1 to 4 substituents selected from R 10 ;

R 4 and R 5 are each independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C 1-6 alkyl,

(4) —(CH 2 ) n C 3-8 cycloalkyl,

(5) —OH,

(6) —CHF 2 , and

(7) —CF 3 ,

wherein alkyl, cycloalkyl, and (CH 2 ) n are unsubstituted or substituted with one to five substituents selected from R 8 ;

R 6 is selected from the group consisting of:

(1) —C 1-6 alkyl, and

(2) halogen;

R 7 is selected from the group consisting of:

(1) halogen,

(2) —C 1-6 alkyl,

(3) —COC 1-6 alkyl,

(4) —CO 2 R 9 ,

(5) —CON(R 9 ) 2 ,

(6) —NH 2 ,

(7) —NHCO 2 C 1-6 alkyl, and

(8) —SOC 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with 1 to 3 halogens;

R 8 is selected from the group consisting of:

(1) oxo,

(2) —OH,

(3) halogen,

(4) —CN,

(5) —CF 3 ,

(6) —CHF 2 ,

(7) —CH 2 F, and

(8) —C 1-8 alkyl,

wherein each alkyl carbon is unsubstituted or substituted with 1 to 3 halogen substituents;

R 9 is selected from the group consisting of:

(1) hydrogen, and

(2) —C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen and —OH;

R 10 is selected from the group consisting of:

(1) —OH,

(2) oxo, and

(3) —CF 3 ;

R 11 is selected from the group consisting of:

(1) hydrogen, and

(2) —C 1-6 alkyl,

wherein each alkyl carbon is unsubstituted or substituted with 1 to 3 halogens;

each n is independently 0, 1, 2, 3 or 4; and

each q is independently 0, 1, 2, 3 and 4.

10. The compound of claim 9 wherein:

B is heteroaryl, wherein heteroaryl is unsubstituted or substituted with 0 to 4 substituents selected from R 7 ;

X, R 4 , and R 6 are hydrogen;

Y is —OH;

R 1 is independently selected from the group consisting of:

(1) —C 1-8 alkyl, and

(2) —(CH 2 ) n C 3-8 cycloalkyl,

wherein alkyl, cycloalkyl, and (CH 2 ) n are unsubstituted or substituted with 1 to 4 substituents selected from R 10 ;

R 5 is each independently selected from the group consisting of:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —CHF 2 , and

(4) —CF 3 ,

wherein alkyl is unsubstituted or substituted with one to five substituents selected from R 8 ; and

R 7 is halogen;