Substituted diazepine sulfonamides as bombesin receptor subtype-3 modulators
View Patent ↗Certain novel substituted diazepine sulfonamides 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.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof; wherein
X is selected from the group consisting of:
(1) CR 3 , and
(2) N;
Y is selected from the group consisting of:
(1) CR 4 , and
(2) N;
R is selected from the group consisting of:
(1) hydrogen,
(2) —(CH 2 ) n C 2-6 alkenyl, and
(3) —COC 1-6 alkyl;
R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of:
(1) hydrogen,
(2) —(CH 2 ) n halogen,
(3) —C 1-8 alkyl,
(4) —(CH 2 ) n C 2-8 alkenyl,
(5) —(CH 2 ) n C 2-8 alkynyl,
(6) —(CH 2 ) n CN,
(7) —(CH 2 ) n CF 3 ,
(8) —(CH 2 ) n CHF 2 ,
(9) —(CH 2 ) n CH 2 F,
(10) —(CH 2 ) n OCF 3 ,
(11) —(CH 2 ) n OR b ,
(12) —(CH 2 ) n COR c ,
(13) —(CH 2 ) n CO 2 R d ,
(14) —(CH 2 ) n OC(O)R c ,
(15) —(CH 2 ) n N(R c ) 2 ,
(16) —(CH 2 ) n NO 2 ,
(17) —(CH 2 ) n CH═NR a ,
(18) —(CH 2 ) n CH═N—OR a ,
(19) —(CH 2 ) n C(O)N(R c ) 2 ,
(20) —(CH 2 ) n C(O)NR a N(R c ) 2 ,
(21) —(CH 2 ) n C(O) 1-2 (CH 2 ) n CO 2 R a ,
(22) —(CH 2 ) n C(O)NR a (CH 2 ) n CO 2 R a ,
(23) —(CH 2 ) n NR c C(O)R c ,
(24) —(CH 2 ) n NR a SO 0-2 C 1-6 alkyl,
(25) —(CH 2 ) n SO 0-2 N(R c ) 2 ,
(26) —(CH 2 ) n SO 0-2 C 1-8 alkyl,
(27) —(CH 2 ) n SO 0-2 C 3-8 cycloalkyl,
(28) —(CH 2 ) n SO 0-2 aryl,
(29) —(CH 2 ) n SO 0-2 heteroaryl,
(30) —(CH 2 ) n C 3-10 cycloalkyl,
(31) —(CH 2 ) n C 3-10 cycloalkenyl,
(32) —(CH 2 ) n C 2-12 heterocycloalkyl,
(33) —(CH 2 ) n C 2-12 heterocycloalkenyl,
(34) —(CH 2 ) n aryl,
(35) —(CH 2 ) n heteroaryl,
(36) —(CH 2 ) n O(CH 2 ) n heteroaryl,
(37) —C(O)C 3-10 cycloalkyl,
(38) —C(O)C 3-10 cycloalkenyl,
(39) —C(O)C 2-12 heterocycloalkyl,
(40) —C(O)C 2-12 heterocycloalkenyl,
(41) —C(O)aryl,
(42) —C(O)heteroaryl,
(43) —C(O)NR c C 3-10 cycloalkyl,
(44) —C(O)NR c C 3-10 cycloalkenyl,
(45) —C(O)NR c C 2-12 heterocycloalkyl,
(46) —C(O)NR c aryl, and
(47) —C(O)NR c heteroaryl,
wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, —CH, and (CH 2 ) n are unsubstituted or substituted with 1-5 substituents selected from Re, and wherein R 3 and R 4 or R 4 and R 5 together with the atoms to which they are attached may form a 3-6 membered aromatic or non-aromatic ring containing 0 to 3 heteroatoms independently selected from oxygen, sulfur, nitrogen, and NR a , wherein the 3-6 membered aromatic or non-aromatic ring is unsubstituted or substituted with 1 to 5 substituents selected from R e ;
R 6 is independently selected from the group consisting of:
(1) C 1-8 alkyl,
(2) —(CH 2 ) n C 3-10 cycloalkyl,
(3) —(CH2) n C3-10cycloalkenyl,
(4) —(CH2) n C 2-12 heterocycloalkyl,
(5) —(CH2) n C 2-12 heterocycloalkenyl,
(6) —(CH 2 ) n aryl, and
(7) —(CH2) n heteroaryl,
wherein alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, and (CH 2 ) n are unsubstituted or substituted with 1 to 5 substituents selected from R f ;
each R a is independently 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 —(CH 2 ) n OH;
each R b is independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —(CH 2 ) n CF 3 ,
(4) —(CH 2 ) n OC 1-6 alkyl,
(5) —(CH2) n SO 2 CF 3 ,
(6) —(CH 2 ) n C 2-6 alkenyl,
(7) —(CH2) n C 3-8 cycloalkyl,
(8) —(CH 2 ) n C 2-8 heterocycloalkyl,
(9) —(CH2) n aryl, and
(10) —(CH 2 ) n heteroaryl,
wherein alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and —(CH 2 ) n are unsubstituted or substituted with 1-4 substituents selected from —OH, halogen, —CN, —CF 3 , —C 1-6 alkyl, and —CO 2 H;
each R c is independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —(CH 2 ) n CF 3 ,
(4) —(CH 2 ) n CO 2 R a ,
(5) —(CH 2 ) n SO 2 CF 3 ,
(6) —(CH 2 ) n C 3-8 cycloalkyl,
(7) —(CH 2 ) n C 2-8 heterocycloalkyl,
(8) —(CH 2 ) n aryl, and
(9) —(CH 2 ) n heteroaryl,
wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and —(CH 2 ) n are unsubstituted or substituted with 1-4 substituents selected from —OH, halogen, —CN, and C 1-6 alkyl;
each R d is independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —C 3-8 cycloalkyl,
wherein alkyl and cycloalkyl are unsubstituted or substituted with 1-3 substituents selected from halogen, —CN, —OH, —N(R a ) 2 , and aryl;
each R e is independently selected from the group consisting of:
(1) —(CH 2 ) n halogen,
(2) —C 1-6 alkyl,
(3) —(CH 2 ) n CF 3 ,
(4) —(CH 2 ) n CN,
(5) —(CH 2 ) n C 2-8 alkenyl,
(6) oxo,
(7) thio,
(8) —(CH 2 ) n OR a ,
(9) —(CH 2 ) n N(R a ) 2 ,
(10) —(CH 2 ) n N(R a )COR a ,
(11) —(CH 2 )CON(R a ) 2 ,
(12) —(CH 2 ) n COR a ,
(13) —(CH 2 ) n N(R a )CO 2 R a ,
(14) —(CH 2 ) n CO 2 R a ,
(15) —(CH 2 ) n OC(O)R a ,
(16) —(CH 2 ) n C 3-8 cycloalkyl,
(17) —(CH 2 ) n C 2-8 heterocycloalkyl,
(18) —(CH 2 ) n aryl,
(19) —(CH 2 ) n heteroaryl,
(20) —(CH 2 ) n O(CH 2 ) n aryl,
(21) —(CH 2 ) n O(CH 2 ) n heteroaryl, and
(22) —(CH 2 ) n OP(O)(OH) 2 ,
wherein alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and (CH 2 ) n are unsubstituted or substituted with 1 to 5 substituents selected from —(CH 2 ) 0-2 OH, —F, —CF 3 , —CO 2 C 1-6 alkyl, oxo, and —C 1-6 alkyl unsubstituted or substituted with —OH;
each R f is independently selected from the group consisting of:
(1) —(CH 2 ) n halogen,
(2) —(CH 2 ) n O m C 1-8 alkyl,
(3) —(CH 2 ) n O m C 2-8 alkenyl,
(4) —(CH 2 ) n CN,
(5) —(CH 2 ) n CCl 3 ,
(6) —(CH 2 ) n OH,
(7) —(CH 2 ) n C(O)H,
(8) —(CH 2 ) n C(O)C 1-8 alkyl,
(9) —(CH 2 ) n CO 2 H,
(10) —(CH 2 ) n CO 2 C 1-8 alkyl,
(11) —(CH 2 ) n O m CF 3 ,
(12) —(CH 2 ) n O m ,CHF 2 ,
(13) —(CH 2 ) n O m ,CH 2 F,
(14) —(CH 2 ) n O m C 3-10 cycloalkyl,
(15) —(CH 2 ) n O m C 3-10 cycloalkenyl,
(16) —(CH 2 ) n O m C 2-12 heterocycloalkyl,
(17) —(CH 2 ) n O m C 2-12 heterocycloalkenyl,
(18) —(CH 2 ) n O m aryl,
(19) —(CH 2 ) n O m heteroaryl,
(20) —SO 0-2 C 1-8 alkyl,
(21) —SO 0-2 C 3-8 cycloalkyl,
(22) —(CH 2 ) n N(R c ) 2 ,
(23) —(CH 2 ) n C(O)N(R c ) 2 , and
(24) —(CH 2 ) n NR c C(O)R c ,
wherein alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, and —(CH 2 ) n are unsubstituted or substituted with 1 to 3 substituents selected from —OH, —CF 3 , halogen, —C 1-6 alkyl and —CN;
each n is independently 0, 1, 2, 3, 4, or 5;
each m is independently 0 or 1;
each p is independently 0, 1 or 2; and
each q is independently 0, 1 or 2.
2. The compound of claim 1 wherein R is hydrogen or —CH 2 CH═CH 2 ; or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 wherein R is hydrogen; or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 wherein R 5 is independently selected from the group consisting of: hydrogen, —(CH 2 ) n halogen, —(CH 2 ) n OR b , —(CH 2 ) n CN, —(CH 2 ) n CF 3 , —(CH 2 ) n CHF 2 , —(CH 2 ) n CH 2 F, —(CH 2 )CCl 3 , and —C 1-8 alkyl; or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 wherein R 1 and R 2 are each independently selected from the group consisting of: hydrogen, —(CH 2 ) n halogen, —(CH 2 ) n OR b , —(CH 2 ) n CN, —(CH 2 ) n CF 3 , —(CH 2 ) n CHF 2 , —(CH 2 ) n CH 2 F, —C 1-8 alkyl, —SC 1-8 alkyl, —SC 3-8 cycloalkyl, wherein alkyl, cycloalkyl, and (CH 2 ) n are unsubstituted or substituted with 1 to 5 substituents selected from —C 1-6 alkyl, halogen, and —OH; or a pharmaceutically acceptable salt thereof.
6. The compound of claim 5 wherein R 2 is hydrogen or —(CH 2 ) n halogen, wherein (CH 2 ) n is unsubstituted or substituted with 1 to 5 substituents selected from —C 1-6 alkyl, halogen, and —OH; or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 wherein R 6 is selected from the group consisting of:
C 1-8 alkyl, —(CH 2 ) n aryl, and —(CH 2 ) n heteroaryl, wherein alkyl, aryl, heteroaryl, and (CH 2 ) n are unsubstituted or substituted with 1 to 5 substituents selected from R f ; or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 wherein R 3 and R 4 are each independently selected from the group consisting of: hydrogen, —(CH 2 ) n halogen, —C 1-8 alkyl, —(CH 2 ) n C 2-8 alkenyl, —(CH 2 ) n CN, —(CH 2 ) n CF 3 , —(CH 2 ) n CHF 2 , —(CH 2 ) n CH 2 F, —(CH 2 ) n OCF 3 , —(CH 2 ) n OR b , —(CH 2 ) n COR c , —(CH 2 ) n CO 2 R d , —(CH 2 ) n N(R c ) 2 , —(CH 2 ) n CH═NR a , —(CH 2 ) n CH═N—OR a , —(CH 2 ) n C(O)N(R c ) 2 , —(CH 2 ) n C(O)NR a N(R c ) 2 , —(CH 2 ) n C(O) 1-2 (CH 2 ) n CO 2 R a , —(CH 2 ) n C(O)NR a (CH 2 ) n CO 2 R a , —(CH 2 ) n NR c C(O)R c , —(CH 2 ) n SO 0-2 C 1-8 alkyl, —(CH 2 ) n C 3-10 cycloalkyl, —(CH 2 ) n C 2-12 heterocycloalkyl, —(CH 2 ) n C 2-12 heterocycloalkenyl, —(CH 2 ) n aryl, —(CH 2 ) n heteroaryl, —C(O)C 2-12 heterocycloalkyl, —C(O)heteroaryl, —C(O)NR c C 2-12 heterocycloalkyl, and —C(O)NR c heteroaryl, wherein alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, —CH, and (CH 2 ) n are unsubstituted or substituted with 1-5 substituents selected from R e , and wherein R 3 and R 4 or R 4 and R 5 together with the atoms to which they are attached may form a 3-6 membered aromatic or non-aromatic ring containing 0 to 3 heteroatoms independently selected from oxygen, sulfur, nitrogen, and NRa, wherein the 3-6 membered aromatic or non-aromatic ring is unsubstituted or substituted with 1 to 5 substituents selected from R e ; or a pharmaceutically acceptable salt thereof
9. The compound of claim 1 of formula I:
or a pharmaceutically acceptable salt thereof; wherein
X is selected from the group consisting of:
(1) CR 3 , and
(2) N;
Y is CR 4 ;
R, R 2 and R 5 are hydrogen;
R 1 is CF 3 ;
R 3 and R 4 are each independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-8 alkyl, and
(3) —(CH 2 ) n heteroaryl,
wherein alkyl, heteroaryl, and (CH 2 ) n are unsubstituted or substituted with 1-5 substituents selected from R e , and wherein R 3 and R 4 together with the atoms to which they are attached may form a 3-6 membered aromatic or non-aromatic ring containing 0 to 3 heteroatoms independently selected from oxygen, sulfur, nitrogen, and NR a , wherein the 3-6 membered aromatic or non-aromatic ring is unsubstituted or substituted with 1 to 5 substituents selected from R e ;
R 6 is phenyl, wherein phenyl is unsubstituted or substituted with 1 to 5 substituents selected from R f ;
each R a is independently 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 —(CH 2 ) n OH;
each R e is independently selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) —(CH 2 ) n OR a , and
(3) —(CH 2 ) n CO 2 R a ,
wherein alkyl and (CH 2 ) n are unsubstituted or substituted with —(CH 2 ) 0-2 OH, —F, —CF 3 , —CO 2 C 1-6 alkyl, —C 1-6 alkyl unsubstituted or substituted with —OH;
each R f is independently selected from the group consisting of:
(1) —C 1-8 alkyl,
(2) —(CH 2 ) n O m CF 3 , and
(3) —C 3 - 10 cycloalkyl,
wherein alkyl, cycloalkyl, and —(CH 2 ) n are unsubstituted or substituted with 1 to 3 substituents selected from —OH, —CF 3 , halogen, —C 1-6 alkyl and —CN;
each n is independently 0, 1, 2, 3, 4, or 5;
each m is independently 0 or 1;
each p is 0 or 1; and
each q is 0 or 1.
10. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof
11. The compound of claim 10 which is:
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 10 which is:
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 10 which is:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 10 which is:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 10 which is:
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 10 wherein the pharmaceutically acceptable salt is a hydrochloride salt.
18. A composition which comprises a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
19. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, for use in medicine.
20. A method of treating obesity comprising administering a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.