US 12,344,595 B2
2-amino-n-phenyl-nicotinamides as NAV1.8 inhibitors
Michael J. Breslin, Drexel Hill, PA (US); Christopher James Bungard, Lansdale, PA (US); Harry R. Chobanian, Westfield, NJ (US); Kristen L. G. Jones, Oreland, PA (US); Mark E. Layton, Harleysville, PA (US); Jian Liu, Edison, NJ (US); James J. Perkins, Churchville, PA (US); Jeffrey William Schubert, North Wales, PA (US); Shawn J. Stachel, Perkasie, PA (US); Linda M. Suen-Lai, Philadelphia, PA (US); and Zhe Wu, Blue Bell, PA (US)
Assigned to Merck Sharp & Dohme LLC, Rahway, NJ (US)
Appl. No. 17/289,152
Filed by Merck Sharp & Dohme LLC, Rahway, NJ (US)
PCT Filed Oct. 28, 2019, PCT No. PCT/US2019/058251
§ 371(c)(1), (2) Date Apr. 27, 2021,
PCT Pub. No. WO2020/092187, PCT Pub. Date May 7, 2020.
Claims priority of provisional application 62/754,852, filed on Nov. 2, 2018.
Prior Publication US 2022/0119363 A1, Apr. 21, 2022
Int. Cl. C07D 401/04 (2006.01); C07D 213/82 (2006.01); C07D 401/14 (2006.01); C07D 403/04 (2006.01); C07D 405/14 (2006.01); C07D 409/14 (2006.01); C07D 413/04 (2006.01); C07D 417/04 (2006.01); C07D 417/14 (2006.01); C07D 451/02 (2006.01); C07D 487/08 (2006.01); C07D 487/18 (2006.01); C07D 491/048 (2006.01); C07D 491/107 (2006.01); C07D 498/04 (2006.01); C07D 498/08 (2006.01); C07D 513/04 (2006.01)
CPC C07D 401/04 (2013.01) [C07D 213/82 (2013.01); C07D 401/14 (2013.01); C07D 403/04 (2013.01); C07D 405/14 (2013.01); C07D 409/14 (2013.01); C07D 413/04 (2013.01); C07D 417/04 (2013.01); C07D 417/14 (2013.01); C07D 451/02 (2013.01); C07D 487/08 (2013.01); C07D 487/18 (2013.01); C07D 491/048 (2013.01); C07D 491/107 (2013.01); C07D 498/04 (2013.01); C07D 498/08 (2013.01); C07D 513/04 (2013.01)] 15 Claims
 
1. A compound of structural formula I:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein
A is phenyl or phenyl fused to a saturated or unsaturated 5- or 6-membered ring containing 0-3 heteroatoms independently selected from O, S and N(Rb)q, wherein each phenyl, 5-membered ring and 6-membered ring is unsubstituted;
B is selected from the group consisting of:
(1) pyridine;
(2) pyrimidine; and
(3) pyridazine;
wherein pyridine, pyrimidine and pyridazine is unsubstituted or substituted with one to three substituents selected from Rb:
R1 is selected from the group consisting of:
(1) —SO2NH2,
(2) —SO2NH-heteroaryl,
(3) —SO2C1-6alkyl,
(4) —SO2C3-6cycloalkyl,
(5) —SO2C3-6cycloheteroalkyl,
(6) —C(O)NH2, and
(7) —CN,
wherein each alkyl, cycloalkyl, cycloheteroalkyl and heteroaryl is unsubstituted or substituted with one to four substituents 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) pyrrolidine,
(2) azetidine,
(3) piperidine,
(4) piperazine,
(5) azepane,
(6) azocane,
(7) thiomorpholine,
(8) oxazepane,
(9) 1,4-oxazepane,
(10) isoindoline,
(11) 2-isoindoline,
(12) dihydroisoquinoline,
(13) octahydroisoindole,
(14) azabicyclo[2.2.1]heptane,
(15) azabicyclo[3.1.1]heptane,
(16) azabicyclo[4.1.0]heptane,
(17) azabicyclo[3.2.1]octane,
(18) diazabicyclo[3.2.1]octane,
(19) azabicyclo[3.2.0]heptane,
(20) oxa-azabicyclo[3.2.1]octane,
(21) azaspiro[2.5]octane,
(22) azaspiro[2.6]nonane,
(23) azaspiro[3.5]nonane,
(24) oxa-azaspiro[3.5}nonane,
(25) oxa-oazaspiro[4.5]decane,
(26) dihydrothieno[3,2-c]pyridine,
(27) dihydrothiazolo[4,5-c]pyridine,
(28) dihydrooxazolo[4,5-c]pyridine,
(29) dihydroimidazo[1,2-a]pyrazine,
(30) hexahydrofuro[3,2-b]pyrrole,
(31) hexahydrocyclopenta[c]pyrrole, and
(32) azatricyclo[4.3.1.13,8]undecane,
wherein R3 is unsubstituted or substituted with one to eight substituents 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) —CF2CF3,
(3) —CHF2,
(4) —OCHF2,
(5) —OCH2CF3,
(6) —OCF3,
(7) CN,
(8) halogen,
(9) —Si(C1-6alkyl)3,
(10) —C1-6alkyl-O—Rk,
(11) —C1-6alkyl,
(12) —C2-6alkenyl,
(13) —C2-6alkynyl,
(14) —C3-6cycloalkyl,
(15) —C2-6cycloheteroalkyl,
(16) aryl,
(17) heteroaryl,
(18) —C1-6alkyl-C3-6cycloalkyl,
(19) —C1-6alkyl-C2-6cycloheteroalkyl,
(20) —C1-6alkyl-aryl,
(21) —C1-6alkyl-heteroaryl,
(22) —C2-6alkenyl-C3-6cycloalkyl,
(23) —C2-6alkenyl-C2-6cycloheteroalkyl,
(24) —C2-6alkenyl-aryl,
(25) —C2-6alkenyl-heteroaryl,
(26) —C2-6alkynyl-C3-6cycloalkyl,
(27) —C2-6alkynyl cycloheteroalkyl,
(28) —C2-6alkynyl-aryl,
(29) —C2-6alkynyl-heteroaryl,
(30) NO2,
(31) —OH,
(32) —(CH2)p-OC1-6alkyl,
(33) —(CH2)p-OC2-6alkenyl,
(34) —(CH2)p-OC2-6alkynyl,
(35) —(CH2)p-OC3-6cycloalkyl,
(36) —(CH2)p-OC2-6hetetocycloalkyl,
(37) —(CH2)p-O-aryl,
(38) —(CH2)p-O-heteroaryl,
(39) —OC1-6alkyl-C3-6cycloalkyl,
(40) —OC1-6alkyl-C2-6heterocycloalkyl,
(41) —OC1-6alkyl-aryl,
(42) —OC1-6alkyl-heteroaryl,
(43) —S(O)mRk,
(44) —C1-6alkyl-S(O)mRk,
(45) —C(O)Rk,
(46) —N(Ri)2, and
(47) —NRiRk,
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) —OC2-6alkenyl,
(29) —OC2-6alkynyl,
(30) —OC3-6cycloalkyl,
(31) —OC2-6heterocycloalkyl,
(32) —O-aryl,
(33) —O-heteroaryl,
(34) —OC1-6alkyl-cycloalkyl,
(35) —OC1-6alkyl-cycloheteroalkyl,
(36) —OC1-6alkyl-aryl,
(37) —OC1-6alkyl-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,
(2) —C1-6alkyl, and
(3) C2-6alkenyl;
each Rf is selected from the group consisting of:
(1) halogen,
(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.