	US 12,435,058 B2
	KIF18A inhibitors
Nuria A. Tamayo, Newbury Park, CA (US); Matthew Richard Kaller, Ventura, CA (US); Thomas T. Nguyen, Newbury Park, CA (US); Nobuko Nishimura, West Hills, CA (US); Qiufen May Xue, Thousand Oaks, CA (US); and John Gordon Allen, Newbury Park, CA (US)
Assigned to AMGEN INC., Thousand Oaks, CA (US)
Appl. No. 17/632,333
Filed by AMGEN INC., Thousand Oaks, CA (US)
PCT Filed Aug. 3, 2020, PCT No. PCT/US2020/044798 § 371(c)(1), (2) Date Feb. 2, 2022, PCT Pub. No. WO2021/026099, PCT Pub. Date Feb. 11, 2021.
Claims priority of provisional application 62/882,265, filed on Aug. 2, 2019.
Prior Publication US 2024/0254100 A1, Aug. 1, 2024
Int. Cl. C07D 401/04 (2006.01); A61K 31/497 (2006.01); A61K 31/5377 (2006.01); A61K 31/541 (2006.01); C07D 241/20 (2006.01); C07D 417/14 (2006.01)

CPC C07D 401/04 (2013.01) [A61K 31/497 (2013.01); A61K 31/5377 (2013.01); A61K 31/541 (2013.01); C07D 241/20 (2013.01); C07D 417/14 (2013.01)]

21 Claims

1. A compound of formula I:

or a pharmaceutically-acceptable salt thereof, wherein:

L is —(C═O)—NR⁸— or —NR⁸—(C═O)—;

R¹is a group —Z—R⁹; wherein Z is absent, —NR¹¹—, —NR¹¹SO₂—C_1-4alk-, —NR¹¹SO₂NR¹¹, —NR¹¹SO₂NR¹¹—C(═O)—O—, —SO₂NR¹¹—C_0-4alk-, C_0-4alk-S(═O)(═NH)—, C_0-4alk-S(═O)(═N⁺(CH₃)₂)—, C_1-4alk-, C_0-4alk-S—, C_0-4alk-S(═O)—, C_0-4alk-SO₂—, —O—, —P—, —P(═O), —P(═O)₂, —(C═O)—, —(C═O)NR¹¹—, —C═N(OH)—, or —NR¹¹(C═O);

R²is a group —Y—R¹⁰, wherein Y is absent, NH—, —NHSO₂—, SO₂NH—, or SO₂—;

R³is H, halo, C_1-4alk, or C_1-4haloalk;

R⁴is H, halo, C_1-4alk, or C_1-4haloalk;

R⁵is H, halo, C_1-8alk, or C_1-4haloalk;

R⁶is H, halo, C_1-8alk, or C_1-4haloalk;

R⁷is H, halo, C_1-4alk, or C_1-4haloalk;

R⁸is H or C_1-4alk;

R⁹is H, R^9a, or R^9b;

R¹⁰is halo, R^10aor R^10b;

R^xis

R^9ais selected from the group consisting of a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atoms selected from O and S, which is substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, C_1-6alk, C_1-4haloalk, —OR^a, —OC_1-4haloalk, CN, —C(═O)R^b, —C(═O)OR^a, —C(═O)NR^aR^a, —C(═NR^a)NR^aR^a, —OC(═O)R^b, —OC(═O)NR^aR^a, —OC_2-6alkNR^aR^a, —OC_2-6alkOR^a, —SR^a, —S(═O)R^b, —S(═O)₂R^b, —S(═O)₂NR^aR^a, —NR^aR^a, —N(R^a)C(═O)R^b, —N(R^a)C(═O)OR^b, —N(R^a)C(═O) NR^aR^a, —N(R^a)C(═NR^a)NR^aR^a, —N(R^a)S(═O)₂R^b, —N(R^a)S(═O)₂NR^aR^a, —NR^aC_2-6alkNR^aR^a, —NR^aC_2-6alkOR^a, —C_{1 -6}alkNR^aR^a, —C_1-6alkOR^a, —C_1-6alkN(R^a)C(═O)R^b, —C_1-6alkOC(═O)R^b, —C_1-6alkC(═O)NR^aR^a, —C_1-6alkC(═O)OR^a, R¹¹, and oxo;

R^9bis selected from the group consisting of C_1-6alk substituted by 0, 1, 2, 3, 4, or 5 group(s) selected from F, Cl, Br, —CH₂F, —CHF₂, —CF₃, —C(═O)OR^a, —OR^a, —OC_1-4haloalk, CN, NH₂, NH(CH₃), or N(CH₃)₂;

R¹⁰is a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atoms selected from O and S, which is substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, methyl, ethyl, CF₃, CH₂OH, —OH, —OCH₃, —NH₂, —NH(CH₃), and oxo; or;

R¹⁰is C_1-6alk substituted by 0, 1, 2, 3, 4, or 5 group(s) selected from F, Cl, Br, —OH, or —CF₃;

R¹¹is H or C_1-8alk;

R^ais independently, at each instance, H or R^b; and

R^bis independently, at each instance, C_1-6alk, phenyl, or benzyl, wherein the C_1-6alk is being substituted by 0, 1, 2 or 3 substituents selected from halo, —OH, —OC_1-4alk, —NH₂, —NHC_1-4alk, —OC(═O)C_1-4alk, or —N(C_1-4alk)C_1-4alk; and the phenyl or benzyl is being substituted by 0, 1, 2 or 3 substituents selected from halo, C_1-4alk, C_1-3haloalk, —OH, —OC_1-4alk, —NH₂, —NHC_1-4alk, —OC(═O)C_1-4alk, or —N(C_1-4alk)C_1-4alk.