	US 12,441,705 B2
	KIF18A inhibitors
Nuria A Tamayo, Newbury Park, CA (US); Abhisek Banerjee, Karnataka (IN); Jian Jeffrey Chen, San Diego, CA (US); Kexue Li, Newbury, CA (US); Liping H. Pettus, Thousand Oaks, CA (US); Matthew Paul Bourbeau, Woodland Hills, CA (US); and Lei Jia, San Diego, CA (US)
Assigned to AMGEN INC., Thousand Oaks, CA (US)
Appl. No. 17/416,415
Filed by AMGEN INC., Thousand Oaks, CA (US)
PCT Filed Dec. 20, 2019, PCT No. PCT/US2019/068170 § 371(c)(1), (2) Date Jun. 18, 2021, PCT Pub. No. WO2020/132649, PCT Pub. Date Jun. 25, 2020.
Claims priority of provisional application 62/783,065, filed on Dec. 20, 2018.
Prior Publication US 2022/0056015 A1, Feb. 24, 2022
Int. Cl. C07D 401/14 (2006.01); C07D 405/14 (2006.01); C07D 413/14 (2006.01)

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

34 Claims

1. A compound of formula I:

or any pharmaceutically-acceptable salt thereof, wherein:

X¹is N or —CR⁶;

X²is N or CR⁷;

X³is N or CR⁸;

X⁴is N or CR⁹;

wherein 1, 2, or 3 of X¹, X², X³and X⁴are N;

when all of X², X³and X⁴are not N; then L is —(C═O)—NR³—;

when any of X², X³and X⁴is N; then L is —(C═O)—NR³— or —NR³—(C═O)—;

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 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

(a) a group —Y—R¹³, wherein Y is absent; and R¹³is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl,

wherein each said ring is substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, methyl, CF₃, —OH, —OCHF₂, CN, and oxo; or

(b) a group —Y—R¹³, wherein Y is NH, —O—, —O—(CH₂)—, —O—(CH₂)—(CH₂)—, or —O—(CH₂)—(CH₂)—(CH₂)—, and wherein R¹³is

or R¹³is C_1-6alk substituted by 0, 1, 2, 3, 4, or 5 group(s) selected from F, Cl, Br, methyl, CF₃, —OH, or CN; or

(c) a saturated 5- or 6-membered monocyclic ring wherein each said ring contains 0, 1, or 2 N atoms and 0 or 1 O atom, and wherein each said ring is substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, C_1-6alk, C_1-4haloalk, —OH, —OC_1-4haloalk, CN, R¹⁴, and oxo;

R³is H, C_1-4alk, or C_1-4haloalk;

R⁴is H, halo, R^4aor R^4b;

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

R⁶is H, halo, C_1-8alk, C_1-4haloalk, —O—C_1-8alk, or —O—R^6a; wherein R^6ais 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;

R⁷is H, halo, R^7aor R^7b;

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

R⁹is H, halo, R^9aor R^9b;

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;

R^4a, R^7a, R^8a, R^9a, R^10k, and R^12ais 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^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^7b, R^8b, R^9b, R^10l, and R^12bis 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, —OR^a, —OC_1-4haloalk, or CN;

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 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_1-6alkNR^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 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.