	US 12,054,476 B2
	KIF18A inhibitors
Nuria A. Tamayo, Newbury Park, CA (US); Abhisek Banerjee, Karnataka (IN); James Alexander Brown, Moorpark, CA (US); Michael J Frohn, Thousand Oaks, CA (US); Jian Jeffrey Chen, Camarillo, CA (US); Kexue Li, Newbury Park, CA (US); Qingyian Liu, Camarillo, CA (US); Jonathan Dante Low, Reseda, CA (US); Vu Ma, Oak Park, CA (US); Liping H. Pettus, Thousand Oaks, CA (US); Mary Catherine Walton, Pacifica, CA (US); Ana Elena Minatti, Los Angeles, CA (US); Matthew Paul Bourbeau, Woodland Hills, CA (US); and Lei Jia, Newbury Park, CA (US)
Assigned to AMGEN INC., Thousand Oaks, CA (US)
Filed by AMGEN INC., Thousand Oaks, CA (US)
Filed on Dec. 14, 2021, as Appl. No. 17/551,105.
Application 17/551,105 is a continuation of application No. 16/724,119, filed on Dec. 20, 2019, granted, now 11,236,069.
Claims priority of provisional application 62/783,061, filed on Dec. 20, 2018.
Prior Publication US 2022/0106293 A1, Apr. 7, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 401/14 (2006.01); C07D 401/12 (2006.01); C07D 405/14 (2006.01); C07D 413/14 (2006.01); C07D 419/14 (2006.01); C07D 491/107 (2006.01)

CPC C07D 401/14 (2013.01) [C07D 401/12 (2013.01); C07D 405/14 (2013.01); C07D 413/14 (2013.01); C07D 419/14 (2013.01); C07D 491/107 (2013.01)]

31 Claims

1. A compound of formula (I):

or any pharmaceutically-acceptable salt thereof, wherein:

X¹is N;

R¹is —CN, or a group —Z—R¹²wherein Z is —C_0-4alk-, —NR¹¹—, —NR¹¹SO₂—, —SO₂NR¹¹—, —NR¹¹—S(═O)(═NH), —S(═O)(═NH)—, —S—, —S(═O)—, —SO₂—, C_0-4alk-O—, —(C═O)—, —(C═O)NR¹¹—, —C═N(OH)—, or —NR¹¹(C═O); or

the group —Z—R¹²is —N═S(═O)—(R¹²)₂, wherein the two R¹²pair alternatively combine with the sulfur atom attached to each of them to form a saturated or partially-saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from the group consisting of O and S;

R²is halo or a group —Y—R¹³, wherein Y is —C_0-4alk-, —NH—(CH₂)_0-4—, —C(═O)NR^a(C_1-4alk), —O—C_0-4alk-, S, S═O, S(═O)₂, —SO₂NR¹³, or —S(═O)(═NH)—;

R³is H, C_1-4alk, or C_1-4haloalk;

R⁴is H, halo, R^4aor R^4a;

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

R⁷is H, halo, C_1-8alk, or C_1-4haloalk;

R⁸is H, halo, C_1-8alk, C_1-4haloalk, —OH, —O—R^8a, or —O—R^8b;

R⁹is H, halo, C_1-8alk, or C_1-4haloalk;

R^xis selected from the group consisting of

each of R^10a, R^10b, R^10c, R^10d, R^10e, R^10f, R^10g, R^10h, R¹⁰ⁱ, and R^10jis H, halo, R^10k, or R^10l;

or alternatively, each of R^10aand R^10bpair, R^10cand R^10dpair, R^10eand R^10fpair, R^10gand R^10hpair, or R¹⁰ⁱand R^10jpair, independently, can combine with the carbon atom attached to each of them to form a saturated or partially-saturated 3-, 4-, 5-, 6-membered monocyclic ring spiro to the R^xring; wherein said 3-, 4-, 5-, 6-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from the group consisting of O and S, and further wherein said 3-, 4-, 5-, 6-membered monocyclic ring is substituted by 0, 1, 2 or 3 group(s) selected from the group consisting of F, Cl, Br, C_1-6alk, C_1-4haloalk, —OR^a, —OC_1-4haloalk, CN, —NR^aR^a, and oxo;

R¹¹is H, R^11a, or R^11b;

R¹²is H, R^12a, or R^12b;

R¹³is R^13aor R^13b;

R^4a, R^8a, R^10k, R^11a, R^12a, and R^13ais independently, at each instance, a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from the group consisting of O and S, which is substituted by 0, 1, 2 or 3 group(s) selected from the group consisting of 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_1-6alkNR^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, R¹⁴, and oxo;

R^4b, R^8b, R^10l, R^11b, R^12b, and R^13bis independently, at each instance, C_1-6alk substituted by 0, 1, 2, 3, 4, or 5 group(s) selected from the group consisting of F, Cl, Br, —OR^a, —OC_1-4haloalk, and CN;

R¹⁴is independently, at each instance, a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atoms selected from the group consisting of O and S, which is substituted by 0, 1, 2 or 3 group(s) selected from the group consisting of 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_1-6alkNR^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, and oxo;

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 substituted by 0, 1, 2 or 3 substituents selected from the group consisting of halo, —OH, —OC_1-4alk, —NH₂, —NHC_1-4alk, —OC(═O)C_1-4alk, and —N(C_1-4alk)C_1-4alk; and the phenyl or benzyl is substituted by 0, 1, 2 or 3 substituents selected from the group consisting of halo, C_1-4alk, C_1-3haloalk, —OH, —OC_1-4alk, —NH₂, —NHC_1-4alk, —OC(═O)C_1-4alk, and —N(C_1-4alk)C_1-4alk.