US 12,516,046 B2 · 2-oxo-oxazolidine-5-carboxamides as NAV1.8 inhibitors

Abstract

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are inhibitors of Nav1.8 channel activity and may be useful in the treatment, prevention, management, amelioration, control and suppression of diseases mediated by Nav1.8 channel activity. The compounds of the present invention may be useful in the treatment, prevention or management of pain disorders, cough disorders, acute itch disorders, and chronic itch disorders.

A compound of structural Formula I:

or a pharmaceutically acceptable salt thereof, wherein
one of A and B is selected from:
1) aryl, and
2) heteroaryl,
wherein aryl and heteroaryl are unsubstituted or substituted with one to five substituents selected from Ra,
and the other of A and B is selected from:
1) aryl
2) heteroaryl,
3) C1-6alkyl-aryl,
4) —C3-8cycloalkyl-aryl,
5) —C2-8cycloheteroalkyl-aryl,
6) —C1-6alkyl-heteroaryl,
7) —C3-8cycloalkyl-heteroaryl,
8) —C2-8cycloheteroalkyl-heteroaryl,
9) —C1-6alkyl-O-aryl,
10) —C1-6alkyl-O-heteroaryl,
11) C3-12cycloalkyl,
12) C2-12cycloheteroalkyl,
13) —C1-6alkyl-C3-12cycloalkyl,
14) —C1-6alkyl-C2-12cycloheteroalkyl,
15) —C1-6alkyl-O—C3-12cycloalkyl,
16) —C1-6alkyl-O—C2-12cycloheteroalkyl,
17) —C0-6alkyl-aryl fused to a C4-6cycloalkyl or C4-6cycloheteroalkyl containing 1-3 heteroatoms independently selected from O, S and N(Rh)2,
18) —C0-6alkyl-aryl fused to a C4-6cycloalkenyl or C4-6cycloheteroalkenyl containing 1-3 heteroatoms independently selected from O, S and N(Rh)2,
19) —C0-6alkyl-heteroaryl fused to C4-6cycloalkyl or C4-6cycloheteroalkyl containing 1-3 heteroatoms independently selected from O, S and N(Rh)2, and
20) —C0-6alkyl-heteroaryl fused to C4-6cycloalkenyl or C4-6cycloheteroalkenyl containing 1-3 heteroatoms independently selected from O, S and N(Rh)2,
wherein alkyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, aryl and heteroaryl are unsubstituted or substituted with one to five substituents selected from Rb;
R1 is selected from the group consisting of:
1) hydrogen,
2) —C1-6alkyl,
3) —C3-6alkenyl,
4) —C3-6alkynyl,
5) —C3-10cycloalkyl,
6) —C2-10cycloheteroalkyl,
7) —C1-6alkyl-O—C1-6alkyl-,
8) —(CH2)S(O)Rj,
9) —(CH2)SC(O)NReRj,
10) —(CH2)nNReC(O)Rj,
11) —(CH2)nNReC(O)ORj,
12) —(CH2)nNReC(O)N(Re)2,
13) —(CH2)nNReC(O)NReRj,
14) —(CH2)nNReS(O)mRj,
15) —(CH2)nNReS(O)mN(Re)2,
16) —(CH2)nNReS(O)mNReRj, and
17) —(CH2)nNReRj,
wherein each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from Rc;
R2 is selected from the group consisting of:
1) hydrogen,
2) —C1-6alkyl,
3) —C2-6alkenyl,
4) —C2-6alkynyl,
5) —C3-10cycloalkyl,
6) —C2-10cycloheteroalkyl,
7) —C1-6alkyl-O—C1-6alkyl-,
8) —(CH2)SC(O)Rij
9) —(CH2)SC(O)NReRj,
10) —(CH2)SNReC(O)Rj,
11) —(CH2)SNReC(O)ORj,
12) —(CH2)SNReC(O)N(Re)2,
13) —(CH2)SNReC(O)NReRj,
14) —(CH2)SNReS(O)mRj,
15) —(CH2)SNReS(O)mN(Re)2,
16) —(CH2)SNReS(O)mNReRj, and
17) —(CH2)SNReRj,
wherein each CH2, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from Rf, and
wherein R2 and R3 and the carbon atom they are connected to can form a —C3-5cycloalkyl ring, or wherein R2 and R4 and the carbon atoms they are connected to can form a —C3-5cycloalkyl ring;
R3 is selected from the group consisting of:
1) hydrogen,
2) —C1-6alkyl,
3) —C2-6alkenyl,
4) —C2-6alkynyl,
5) —C3-10cycloalkyl,
6) —C2-10cycloheteroalkyl,
7) —C1-6alkyl-O—C1-6alkyl-,
8) —(CH2)SC(O)Rj,
9) —(CH2)SC(O)NReRj,
10) —(CH2)SNReC(O)Rj,
11) —(CH2)SNReC(O)ORj,
12) —(CH2)SNReC(O)N(Re)2,
13) —(CH2)SNReC(O)NReRj,
14) —(CH2)SNReS(O)mRj,
15) —(CH2)SNReS(O)mN(Re)2,
16) —(CH2)SNReS(O)mNReRj, and
17) —(CH2)SNReRj,
wherein each CH2, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from Rg;
R4 is selected from the group consisting of:
1) hydrogen, and
2) —C1-6alkyl,
wherein each alkyl is unsubstituted or substituted with one to five substituents selected from halogen;
R5 is selected from the group consisting of:
1) hydrogen, and
2) C1-6alkyl;
R6 is selected from the group consisting of:
1) hydrogen,
2) —C1-6alkyl,
3) —C2-6alkenyl, and
4) —C2-6alkynyl,
wherein each alkyl, alkenyl and alkynyl is unsubstituted or substituted with one to five substituents selected from halogen;
each Ra is independently selected from the group consisting of:
1) —CF3,
2) —OCF3,
3) —CHF2,
4) —OCHF2,
5) —CH2CF3,
6) —OCH2CF3,
7) —CF2CH3;
8) CN,
9) oxo,
10) halogen,
11) —S(O)2C1-6alkyl,
12) —C1-6alkyl,
13) —C2-6alkenyl,
14) —C2-6alkynyl,
15) —C3-6cycloalkyl,
16) —C2-6cycloheteroalkyl,
17) aryl,
18) heteroaryl,
19) —C1-6alkyl-aryl,
20) —C1-6alkyl-heteroaryl,
21) —C1-6alkyl-C3-6cycloalkyl,
22) —C1-6alkyl-C2-6cycloheteroalkyl,
23) —C2-6alkenyl-C3-6cycloalkyl,
24) —C2-6alkenyl-C2-6cycloheteroalkyl,
21) —C2-6alkenyl-aryl,
22) —C2-6alkenyl-heteroaryl,
27) —C2-6alkynyl-C3-6cycloalkyl,
23) —C2-6alkynyl-C2-6cycloheteroalkyl,
24) —C2-6alkynyl-aryl,
25) —C2-6alkynyl-heteroaryl,
26) —OH,
27) —(CH2)p—OC1-6alkyl,
28) —(CH2)p—OC2-6alkenyl,
29) —(CH2)p—OC2-6alkynyl,
30) —(CH2)p—OC3-6cycloalkyl,
31) —(CH2)p—OC2-6heterocycloalkyl,
32) —(CH2)p—O-aryl,
33) —(CH2)p—O-heteroaryl,
34) —OC1-6alkyl-C3-6cycloalkyl,
40) —OC1-6alkyl-C2-6heterocycloalkyl,
41) —OC1-6alkyl-aryl,
42) —OC1-6alkyl-heteroaryl,
43) —S(O)mRj,
44) —C1-6alkyl-S(O)mRj,
45) —N(Rk)2, and
46) —NRkRL,
wherein each Ra is unsubstituted or substituted with one to six substituents selected from halogen, CF3, OH, —C1-6alkyl, and —OC1-6alkyl;
each Rb is independently selected from the group consisting of:
1) —CF3,
2) —OCF3,
3) —CHF2,
4) —OCHF2,
5) —CH2CF3,
6) —OCH2CF3,
7) —CF2CH3;
8) CN,
9) oxo,
10) halogen,
11) —S(O) 2C1-6alkyl,
12) —C1-6alkyl,
13) —C2-6alkenyl,
14) —C2-6alkynyl,
15) —O—C1-6alkyl,
16) —C3-6cycloalkyl,
17) —O—C3-6cycloalkyl,
18) —C2-6cycloheteroalkyl,
19) aryl,
20) heteroaryl,
21) —C1-6alkyl-aryl,
22) —C1-6alkyl-heteroaryl,
23) —C1-6alkyl-C3-6cycloalkyl,
24) —C1-6alkyl-C2-6cycloheteroalkyl,
21) —C2-6alkenyl-C3-6cycloalkyl,
22) —C2-6alkenyl-C2-6cycloheteroalkyl,
27) —C2-6alkenyl-aryl,
23) —C2-6alkenyl-heteroaryl,
24) —C2-6alkynyl-C3-6cycloalkyl,
25) —C2-6alkynyl-C2-6cycloheteroalkyl,
26) —C2-6alkynyl-aryl,
27) —C2-6alkynyl-heteroaryl, 33) —OH,
28) —(CH2)q—OC1-6alkyl,
29) —(CH2)q—OC2-6alkenyl,
30) —(CH2)q—OC2-6alkynyl,
31) —(CH2)q—OC3-6cycloalkyl,
32) —(CH2)q—OC2-6heterocycloalkyl,
33) —(CH2)q—O-aryl,
34) —(CH2)q—O-heteroaryl,
40) —OC1-6alkyl-C3-6cycloalkyl,
41) —OC1-6alkyl-C2-6heterocycloalkyl,
42) —OC1-6alkyl-aryl,
43) —OC1-6alkyl-heteroaryl,
44) —S(O)mRj,
45) —C1-6alkyl-S(O)mRj,
46) —C(O)Rd, and
47) —NRkRL,
wherein each Rb is unsubstituted or substituted with one to six substituents selected from halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, —C1-6alkyl, and —OC1-6alkyl;
Rc is selected from:
1) —C1-6alkyl,
2) OH,
3) halogen, and
4) —OC1-6alkyl,
wherein alkyl can be unsubstituted or substituted with one to three halogens;
Rd is selected from:
1) hydrogen,
2) C1-6alkyl,
3) C3-6cycloalkyl,
4) aryl, and
5) heteroaryl;
Re is selected from:
1) hydrogen, and
2) C1-6alkyl;
Rf is selected from:
1) —C1-6alkyl,
2) OH,
3) halogen, and
4) —OC1-6alkyl,
wherein alkyl can be unsubstituted or substituted with one to three halogens;
Rg is selected from:
1) —C1-6alkyl,
2) OH,
3) halogen, and
4) —OC1-6alkyl,
wherein alkyl can be unsubstituted or substituted with one to three halogens;
Rh is selected from:
1) hydrogen, and
2) C1-6alkyl;
Ri is selected from:
1) hydrogen,
2) C1-6alkyl,
3) C3-6cycloalkyl,
4) aryl, and
5) heteroaryl;
Rj is selected from:
1) hydrogen,
2) C1-6alkyl,
3) C3-6alkenyl,
4) C3-6alkynyl,
5) C3-6cycloalkyl,
6) C2-5cycloheteroalkyl,
7) aryl, and
8) heteroaryl;
Rk is selected from:
1) hydrogen, and
2) C1-6alkyl;
RL is selected from:
1) hydrogen,
2) C1-6alkyl,
3) C3-6cycloalkyl,
4) aryl, and
5) heteroaryl;
m is independently selected from 0 to 2;
n is independently selected from 2 to 6;
p is independently selected from 0 to 3;
q is independently selected from 0 to 3;
r is independently selected from 0 to 2;
and
s is independently selected from 0 to 6.

253 more elements

2-oxo-oxazolidine-5-carboxamides as NAV1.8 inhibitors

Life of this patent

2-oxo-oxazolidine-5-carboxamides as NAV1.8 inhibitors

Life of this patent

Abstract

Claims34