US 11,377,438 B2 · 2-amino-n-heteroaryl-nicotinamides 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
A is pyridine, wherein pyridine is unsubstituted or substituted with one to three substituents selected from Ra;
B is pyridine, wherein pyridine is unsubstituted or substituted with one to three substituents selected from Rb;
R1 is selected from the group consisting of:
(1) —SO3H,
(2) —SO2NH2,
(3) —SO2C1-6alkyl,
(4) —SO2NH—C1-6alkyl,
(5) —SO2C3-6cycloalkyl,
(6) —C(O)NH2,
(7) —CO2H,
(8) —CN,
(9) halogen,
(10) —OH,
(11) —OC1-6alkyl, and
(12) —C1-6alkyl,
wherein each alkyl, and cycloalkyl is unsubstituted or substituted with one substituent selected from Rd;
R2 is selected from the group consisting of:
(1) hydrogen, and
(2) —C1-6alkyl;
R3 is selected from the group consisting of:
(1) a monocyclic, bicyclic or spirocyclic C3-12cycloalkyl ring, and
(2) a monocyclic, bicyclic or spirocyclic C2-12cycloheteroalkyl ring,
wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N(Rm)r, O, and S, wherein each cycloalkyl ring and each cycloheteroalkyl ring may be fused to an aryl or heteroaryl, and wherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to eight substitutents selected from Rc;
each Ra is selected from the group consisting of:
(1) —C1-6alkyl,
(2) —OC1-6alkyl,
(3) halogen,
(4) —OH,
(5) oxo,
(6) —CN,
(7) —C3-6cycloalkyl, and
(8) —C2-5cycloheteroalkyl,
wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to six substituents selected from halogen, OH, NH2, NH(C1-6alkyl) and N(C1-6alkyl)2;
each Rb is independently selected from the group consisting of:
(1) —CF3,
(2) —CHF2,
(3) —OCHF2,
(4) —OCH2CF3,
(5) —OCF3,
(6) CN,
(7) F,
(8) Cl,
(9) Br,
(10) —CH3,
(11) —C(CH3)3,
(12) —OCH3,
(13) cyclopropyl,
(14) cyclobutyl,
(15) piperidine,
(16) —CH2-cyclopropyl,
(17) —C2alkynyl-cyclopropyl, and
(18) pyrazole,
wherein each Rb is unsubstituted or substituted with one to five substituents selected from Rf;
each Rc is independently selected from the group consisting of:
(1) —CF3,
(2) —CH2CF3,
(3) —CHF2,
(4) —OCHF2,
(5) —OCF3,
(6) CN,
(7) oxo,
(8) —OH,
(9) halogen,
(10) —C1-6alkyl,
(11) —C2-6alkenyl,
(12) —C2-6alkynyl,
(13) —C3-6cycloalkyl,
(14) —C2-6cycloheteroalkyl,
(15) —C1-6alkyl-C3-6cycloalkyl,
(16) —C1-6alkyl-C2-6cycloheteroalkyl,
(17) —C1-6alkyl-aryl,
(18) —C1-6alkyl-heteroaryl,
(19) —C1-6alkenyl-C3-6cycloalkyl,
(20) —C1-6alkenyl-aryl,
(21) —C1-6alkenyl heteroaryl,
(22) —C1-6alkenyl-C2-6cycloheteroalkyl,
(23) —C2-6alkynyl-C3-6cycloalkyl,
(24) —C2-6alkynyl-C2-6cycloheteroalkyl,
(25) —C2-6alkynyl-aryl,
(26) —C2-6alkynyl heteroaryl,
(27) —OC1-6alkyl,
(28) —OC2-6 alkenyl,
(29) —OC2-6 alkynyl,
(30) —OC3-6 cycloalkyl,
(31) —OC2-6 heterocycloalkyl,
(32) —O-aryl,
(33) —O-heteroaryl,
(34) —OC1-6alkyl-cycloalkyl,
(35) —OC1-6alkyl-cycloheteroalkyl,
(36) —OC1-6alkyl-aryl,
(37) —OC1-6 alkyl-heteroaryl,
(38) —S(O)mRL,
(39) —S(O)RL,
(40) —S—RL,
(41) —C1-6alkyl-S(O)mRL,
(42) —C(O)RL,
(43) —C(O)C1-6alkyl-RL,
(44) —OC(O)RL,
(45) —CO2RL,
(46) aryl, and
(47) heteroaryl,
wherein each Rc is unsubstituted or substituted with one to five substituents selected from Rg;
Rd is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) OH,
(4) oxo,
(5) —C1-6alkyl,
(6) —OC1-6alkyl,
(7) NH2,
(8) NH(C1-6alkyl), and
(9) N(C1-6alkyl)2;
each Re is independently selected from the group consisting of:
(1) hydrogen, and
(2) —C1-6alkyl;
each Rf is selected from the group consisting of:
(1) halogen, F
(2) —C1-6alkyl,
(3) —OH,
(4) —OC1-6alkyl,
(5) —OC3-6cycloalkyl,
(6) —OC2-6cycloheteroalkyl,
(7) CN,
(8) —NH2,
(9) —NH(C1-6alkyl),
(10) —NH(C3-6cycloalkyl),
(11) —NH(C2-6cycloheteroalkyl),
(12) —N(C1-6alkyl)2,
(13) —N(C3-6cycloalkyl)2, and
(14) —N(C2-6cycloheteroalkyl)2,
wherein each alkyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from:
—OH, halogen, cyano, and —S(O)2CH3;
each Rg is selected from the group consisting of:
(1) halogen,
(2) C1-6alkyl,
(3) —OH,
(4) —OC1-6alkyl,
(5) —S(O)m—C1-6alkyl,
(6) —CN,
(7) —CF3,
(8) —OCHF2, and
(9) —OCF3,
wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from:
—OH, halogen, cyano, and —S(O)2CH3;
each Rh is independently selected from the group consisting of:
(1) hydrogen, and
(2) —C1-6alkyl;
each Ri is independently selected from the group consisting of:
(1) hydrogen, and
(2) —C1-6alkyl;
each Rj is selected from the group consisting of:
(1) —C1-6alkyl,
(2) —C2-6alkenyl,
(3) —C3-6cycloalkyl,
(4) —C2-6cycloheteroalkyl,
(5) aryl, and
(6) heteroaryl,
wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents independently selected from:
—C1-6alkyl, —C3-6cycloalkyl, —OH, —OC1-6alkyl, —OC3-6cycloalkyl, halogen, cyano, and —S(O)2CH3;
each Rk is selected from the group consisting of:
(1) —C1-6alkyl,
(2) —C2-6alkenyl,
(3) —C3-6cycloalkyl,
(4) —C3-6cycloalkyl,
(5) —C2-6cycloheteroalkyl,
(6) aryl, and
(7) heteroaryl,
wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents independently selected from:
—C1-6alkyl, —C3-6cycloalkyl, —OH, —OC1-6alkyl, —OC3-6cycloalkyl, halogen, cyano, and —S(O)2CH3;
each RL is selected from the group consisting of:
(1) —C1-6alkyl,
(2) —C2-6alkenyl,
(3) —C3-6cycloalkyl,
(4) —C2-6cycloheteroalkyl,
(5) aryl, and
(6) heteroaryl,
wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents independently selected from:
—C1-6alkyl, —C3-6cycloalkyl, —OH, —OC1-6alkyl, —OC3-6cycloalkyl, halogen, cyano, and —S(O)2CH3;
each Rm is independently selected from the group consisting of:
(1) hydrogen, and
(2) —C1-6alkyl;
each n is independently 0, 1, 2, 3 or 4;
each m is independently 0, 1 or 2;
each p is independently 0, 1, 2, 3 or 4;
each q is independently 0 or 1;
and
each r is independently 0 or 1.

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2-amino-n-heteroaryl-nicotinamides as Nav1.8 inhibitors

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2-amino-n-heteroaryl-nicotinamides as Nav1.8 inhibitors

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Abstract

Claims22