US 12,723,035 B2 · Cycloalkyl 3-oxopiperazine carboxamides and cycloheteroalkyl 3-oxopiperazine carboxamides as Nav1.8 inhibitors

Abstract

Novel compounds of 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 Formula I 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
A is selected from:
(1) phenyl,
(2) pyridine, and
(3) thiazole,
wherein phenyl, pyridine and thiazole are substituted with one to five substituents selected from Ra;
B is selected from:
(1) cyclobutane,
(2) cyclopentane,
(3) cyclohexane,
(4) bicyclo[3.2.1]octane,
(5) bicyclo[3.1.0]hexane,
(6) bicyclo[2.2.2]octane,
(7) spiro[2.5]octane,
(8) bicyclo[1.1.1]pentane,
(9) spiro[3.3]heptane,
(10) spiro[2.3]hexane,
(11) spiro[2.2]pentane,
(12) piperidine,
(13) tetrahydropyran, and
(14) chromane,
wherein cyclopentane, cyclohexane, bicyclo[3.2.1]octane, bicyclo[3.1.0]hexane, bicyclo[2.2.2]octane, spiro[2.5]octane, bicyclo[1.1.1]pentane, spiro[3.3]heptane, spiro[2.3]hexane, spiro[2.2]pentane, piperidine, tetrahydropyran, and chromane are unsubstituted or substituted with one to six substituents selected from Rb, and wherein cyclobutane is substituted with one to six substituents selected from Rb;
R1 is hydrogen;
R2 is selected from:
(1) hydrogen,
(2) deuterium,
(3) —C1-6alkyl,
(4) —C2-6alkenyl,
(5) —C2-6alkynyl,
(6) —C3-6cycloalkyl,
(7) —C2-6cycloheteroalkyl,
(8) —C1-6alkyl-O—C1-6alkyl,
(9) —(CH2)sC(O)Rj,
(10) —(CH2)sC(O)NReRj,
(11) —(CH2)sNReC(O)Rj,
(12) —(CH2)sNReC(O)ORj,
(13) —(CH2)sNReC(O)N(Re)2,
(14) —(CH2)sNReC(O)NReRj,
(15) —(CH2)sNReS(O)mRj,
(16) —(CH2)sNReS(O)mN(Re)2,
(17) —(CH2)sNReS(O)mNReRj, and
(18) —(CH2)SNReRj,
wherein each CH2, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from Rd,
wherein R2 and R3 and the carbon atoms they are connected to can form a —C3-5cycloalkyl ring, and wherein R2 and R4 and the carbon atoms they are connected to can form a —C3-5cycloalkyl ring;
R3 is selected from:
(1) hydrogen,
(2) deuterium,
(3) —C1-6alkyl,
(4) —C2-6alkenyl,
(5) —C2-6alkynyl,
(6) —C3-6cycloalkyl,
(7) —C2-6cycloheteroalkyl,
(8) —C1-6alkyl-O—C1-6alkyl,
(9) —(CH2)sC(O)Rj,
(10) —(CH2)sC(O)NReRj,
(11) —(CH2)sNReC(O)Rj,
(12) —(CH2)sNReC(O)ORj,
(13) —(CH2)sNReC(O)N(Re)2,
(14) —(CH2)sNReC(O)NReRj,
(15) —(CH2)sNReS(O)mRj,
(16) —(CH2)sNReS(O)mN(Re)2,
(17) —(CH2)sNReS(O)mNReRj, and
(18) —(CH2)SNReRj,
wherein each CH2, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from Rd;
R4 is selected from:
(1) hydrogen,
(2) deuterium,
(3) —C1-6alkyl,
(4) —C2-6alkenyl,
(5) —C2-6alkynyl,
(6) —C3-6cycloalkyl,
(7) —C2-6cycloheteroalkyl,
(8) —C1-6alkyl-O—C1-6alkyl,
(9) —(CH2)sC(O)Rj,
(10) —(CH2)sC(O)NReRj,
(11) —(CH2)sNReC(O)Rj,
(12) —(CH2)sNReC(O)ORj,
(13) —(CH2)sNReC(O)N(Re)2,
(14) —(CH2)sNReC(O)NReRj,
(15) —(CH2)sNReS(O)mRj,
(16) —(CH2)sNReS(O)mN(Re)2,
(17) —(CH2)sNReS(O)mNReRj, and
(18) —(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 R4 and R5 and the carbon atoms they are connected to can form a —C3-5cycloalkyl ring;
R5 is selected from:
(1) hydrogen,
(2) deuterium,
(3) —C1-6alkyl,
(4) —C2-6alkenyl,
(5) —C2-6alkynyl,
(6) —C3-6cycloalkyl,
(7) —C2-6cycloheteroalkyl,
(8) —C1-6alkyl-O—C1-6alkyl,
(9) —(CH2)sC(O)Rj,
(10) —(CH2)sC(O)NReRj,
(11) —(CH2)sNReC(O)Rj,
(12) —(CH2)sNReC(O)ORj,
(13) —(CH2)sNReC(O)N(Re)2,
(14) —(CH2)sNReC(O)NReRj,
(15) —(CH2)sNReS(O)mRj,
(16) —(CH2)sNReS(O)mN(Re)2,
(17) —(CH2)sNReS(O)mNReRj, and
(18) —(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 R5 and R7 and the carbon atoms they are attached to may form a 4-, 5- or 6-membered saturated ring;
R6 is selected from:
(1) hydrogen,
(2) deuterium,
(3) —C1-6alkyl,
(4) —C2-6alkenyl,
(5) —C2-6alkynyl,
(6) —C3-6cycloalkyl,
(7) —C2-6cycloheteroalkyl,
(8) —C1-6alkyl-O—C1-6alkyl,
(9) —(CH2)sC(O)Rj,
(10) —(CH2)sC(O)NReRj,
(11) —(CH2)sNReC(O)Rj,
(12) —(CH2)sNReC(O)ORj,
(13) —(CH2)sNReC(O)N(Re)2,
(14) —(CH2)sNReC(O)NReRj,
(15) —(CH2)sNReS(O)mRj,
(16) —(CH2)sNReS(O)mN(Re)2,
(17) —(CH2)sNReS(O)mNReRj, and
(18) —(CH2)SNReRj,
wherein each CH2, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from Rg, and
wherein R6 and R7 and the carbon atoms they are connected to can form a —C3-5cycloalkyl ring;
R7 is selected from:
(1) hydrogen,
(2) deuterium,
(3) —C1-6alkyl,
(4) —C2-6alkenyl,
(5) —C2-6alkynyl,
(6) —C3-6cycloalkyl,
(7) —C2-6cycloheteroalkyl,
(8) —C1-6alkyl-O—C1-6alkyl,
(9) —(CH2)sC(O)Rj,
(10) —(CH2)sC(O)NReRj,
(11) —(CH2)sNReC(O)Rj,
(12) —(CH2)sNReC(O)ORj,
(13) —(CH2)sNReC(O)N(Re)2,
(14) —(CH2)sNReC(O)NReRj,
(15) —(CH2)sNReS(O)mRj,
(16) —(CH2)sNReS(O)mN(Re)2,
(17) —(CH2)sNReS(O)mNReRj, and
(18) —(CH2)SNReRj,
wherein each CH2, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from Rg;
R8 is selected from:
(1) hydrogen,
(2) —C1-6alkyl,
(3) —C3-6cycloalkyl, and
(4) —C2-6cycloheteroalkyl,
wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from halogen;
R9 is selected from:
(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:
(1) CN,
(2) halogen,
(3) —S(O)2C1-6alkyl,
(4) —C1-6alkyl,
(5) —C2-6alkenyl,
(6) —C2-6alkynyl,
(7) —C3-6cycloalkyl,
(8) —C2-6cycloheteroalkyl,
(9) aryl,
(10) heteroaryl,
(11) —C1-6alkyl-aryl,
(12) —C1-6alkyl-heteroaryl,
(13) —C1-6alkyl-C3-6cycloalkyl,
(14) —C1-6alkyl-C2-6cycloheteroalkyl,
(15) —C2-6alkenyl-C3-6cycloalkyl,
(16) —C2-6alkenyl-C2-6cycloheteroalkyl,
(17) —C2-6alkenyl-aryl,
(18) —C2-6alkenyl-heteroaryl,
(19) —C2-6alkynyl-C3-6cycloalkyl,
(20) —C2-6alkynylC2-6cycloheteroalkyl,
(21) —C2-6alkynyl-aryl,
(22) —C2-6alkynyl-heteroaryl,
(23) —OH,
(24) —(CH2)p—O—C1-6alkyl,
(25) —(CH2)p—O—C2-6alkenyl,
(26) —(CH2)p—O—C2-6alkynyl,
(27) —(CH2)p—O—C3-6cycloalkyl,
(28) —(CH2)p—O—C2-6cycloheteroalkyl,
(29) —(CH2)p—O-aryl,
(30) —(CH2)p—O-heteroaryl,
(31) —OC1-6alkyl-C3-6cycloalkyl,
(32) —OC1-6alkyl-C2-6cycloheteroalkyl,
(33) —OC1-6alkyl-aryl,
(34) —OC1-6alkyl-heteroaryl,
(35) —S(O)rRh,
(36) —C1-6alkyl-S(O)rRh,
(37) —N(Rk)2,
(38) —C(O)RL, and
(39) —NRkRL,
wherein Ra is unsubstituted or substituted with one to six substituents selected from halogen, CF3, OH, C1-6alkyl, and —OC1-6alkyl, provided that CN, halogen and OH are unsubstituted;
each Rb is independently selected from the group consisting of:
(1) F,
(2) Cl,
(3) —CH3,
(4) —CF3,
(5) —CH2CF3,
(6) —CH(CH3)CF3,
(7) —CF2CH3,
(8) ═CH2,
(9) cyclopropyl,
(10) —OCH3,
(11) —OCF3,
(12) —OCHF2, and
(13) —OCH2CF3,
wherein cyclopropyl is unsubstituted or substituted with one to five substituents selected from F, Cl, CF3, OCF3, CN, CH2CF3, CF2CH3, —CH3, and O—CH3;
Rd is selected from:
(1) —C1-6alkyl,
(2) OH,
(3) halogen, and
(4) —OC1-6alkyl,
wherein alkyl is unsubstituted or substituted with one to three halogens;
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 is 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 is unsubstituted or substituted with one to three halogens;
Rh 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, 1 and 2;
p is independently selected from 0, 1, 2 and 3;
r is independently selected from 0, 1 and 2;
and
s is independently selected from 0, 1, 2, 3, 4, 5, and 6.

262 more elements

Cycloalkyl 3-oxopiperazine carboxamides and cycloheteroalkyl 3-oxopiperazine carboxamides as Nav1.8 inhibitors

Life of this patent

Cycloalkyl 3-oxopiperazine carboxamides and cycloheteroalkyl 3-oxopiperazine carboxamides as Nav1.8 inhibitors

Life of this patent

Abstract

Claims47