	US 12,459,932 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, San Diego, 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 Cabrera, Camarillo, CA (US); Ana Minatti, Los Angeles, CA (US); Matthew Paul Bourbeau, Woodland Hills, CA (US); Lei Jia, San Diego, 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. 17/416,411
Filed by AMGEN INC., Thousand Oaks, CA (US)
PCT Filed Dec. 20, 2019, PCT No. PCT/US2019/068172 § 371(c)(1), (2) Date Jun. 18, 2021, PCT Pub. No. WO2020/132651, PCT Pub. Date Jun. 25, 2020.
Claims priority of provisional application 62/783,069, filed on Dec. 20, 2018.
Prior Publication US 2022/0073504 A1, Mar. 10, 2022
Int. Cl. C07D 413/14 (2006.01); C07D 401/12 (2006.01); C07D 401/14 (2006.01); C07D 405/14 (2006.01)

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

34 Claims

1. A compound of formula I:

or any pharmaceutically-acceptable salt thereof, wherein:

X¹is N or —CR⁶;

R¹is a group —Z—R¹²wherein Z is —C_0-4alk-, —NR¹¹—, —NR¹¹SO₂—C_0-4alk-, —SO₂NR¹¹—C_0-4alk-, —NR¹¹SO₂NR¹¹—, —NR¹¹SO₂NR¹¹—C(═O)—O—, —C_0-4alk-S(═O)(═NH)—, C_0-4alk-NR¹¹—S(═O)(═NH), —C_0-4alk-S—, —C_0-4alk-S(═O)—, —C_0-4alk-SO₂—, C_0-4alk-O—, —P—, —P(═O), —P(═O)₂, —(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 can 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 O and S;

R²is halo or a group —Y—R¹³, wherein Y is —C_0-4alk-, —N(C_0-1alk)-C_0-4alk-, —O—C_0-4alk-, —S—, —S═O, —S(═O)₂—, —SO₂N(C_0-1alk)-C_0-4alk-, —N(C_0-1alk)-SO₂—C_0-4alk-, —C_0-4alk-S(═O)(═NH)—, —(C═O)—, —C_0-4alk-(C═O)—O—; or

the group —Y—R¹³is —N═S(═O)—(R¹³)₂, wherein the two R¹³pair can 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 O and S;

R³is H, methyl, or ethyl;

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

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

R⁶is H, halo, CN, C_1-5alk, C_1-4haloalk, or R^6a;

R⁷is H, halo, C_1-5alk, or C_1-4haloalk;

R⁸is H, halo, C_1-5alk, or C_1-4haloalk;

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 ring; 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 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 F, Cl, Br, C_1-6alk, C_1-4haloalk, —OR^a, —OC_1-4haloalk, CN, —NR^aR^a, or oxo;

R¹¹is H or C_1-8alk;

R¹²is H, R^12a, or R^12b;

R¹³is R^13aor R^13b;

R^6a, R^10k, R^12a, and R^13ais independently, at each instance, selected from the group consisting of 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 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, —C(═O)OR^a, —C(═O)NR^aR^a, —C(═NR^a)NR^aR^a, —OC(═O)R, —OC(═O)NR^aR^a, —OC_2-6alkNR^aR^a, —OC_2-6alkOR^a, —SR^a, —S(═O)R, —S(═O)₂R, —S(═O)₂NR^aR^a, —NR^aR^a, —N(R^a)C(═O)R, —N(R^a)C(═O)OR, —N(R^a)C(═O)NR^aR^a, —N(R^a)C(═NR^a)NR^aR^a, —N(R^a)S(═O)₂R, —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, —C_1-6alkOC(═O)R, —C_1-6alkC(═O)NR^aR^a, —C_1-6alkC(═O)OR^a, R¹⁴, and oxo;

R^10l, R^12b, and R^13bis independently, at each instance, 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, —C(═O)OR^a, —OR^a, —C_1-2haloalk, —OC_1-4haloalk, CN, NH₂, NH(CH₃), or N(CH₃)₂;

R¹⁴is independently, at each instance, selected from the group consisting of 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 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, —C(═O)OR^a, —C(═O)NR^aR^a, —C(═NR^a)NR^aR^a, —OC(═O)R, —OC(═O)NR^aR^a, —OC_2-6alkNR^aR^a, —OC_2-6alkOR^a, —SR, —S(═O)R, —S(═O)₂R, —S(═O)₂NR^aR^a, —NR^aR^a, —N(R^a)C(═O)R, —N(R^a)C(═O)OR, —N(R^a)C(═O)NR^aR^a, —N(R^a)C(═NR^a)NR^aR^a, —N(R^a)S(═O)₂R, —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, —C_1-6alkOC(═O)R, —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 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.