KIF18A inhibitors

Patent metadata

Field	Value
Publication number	US-12459932-B2
Application number	US-201917416411-A
Country	US
Kind code	B2
Filing date	Dec 20, 2019
Priority date	Dec 20, 2018
Publication date	Nov 4, 2025
Grant date	Nov 4, 2025

Abstract

Compounds of formula (I): (I), as defined herein, and synthetic intermediates thereof, which are capable of modulating KIF18A protein thereby influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of KIF18A.

First claim

We claim:

1. A compound of formula I:

or any pharmaceutically-acceptable salt thereof, wherein:
X 1 is N or —CR 6 ;
R 1 is a group —Z—R 12 wherein Z is —C 0-4 alk-, —NR 11 —, —NR 11 SO 2 —C 0-4 alk-, —SO 2 NR 11 —C 0-4 alk-, —NR 11 SO 2 NR 11 —, —NR 11 SO 2 NR 11 —C(═O)—O—, —C 0-4 alk-S(═O)(═NH)—, C 0-4 alk-NR 11 —S(═O)(═NH), —C 0-4 alk-S—, —C 0-4 alk-S(═O)—, —C 0-4 alk-SO 2 —, C 0-4 alk-O—, —P—, —P(═O), —P(═O) 2 , —(C═O)—, —(C═O)NR 11 —, —C═N(OH)—, or —NR 11 (C═O); or
the group —Z—R 12 is —N═S(═O)—(R 12 ) 2 , wherein the two R 12 pair 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;
R 2 is halo or a group —Y—R 13 , wherein Y is —C 0-4 alk-, —N(C 0-1 alk)-C 0-4 alk-, —O—C 0-4 alk-, —S—, —S═O, —S(═O) 2 —, —SO 2 N(C 0-1 alk)-C 0-4 alk-, —N(C 0-1 alk)-SO 2 —C 0-4 alk-, —C 0-4 alk-S(═O)(═NH)—, —(C═O)—, —C 0-4 alk-(C═O)—O—; or
the group —Y—R 13 is —N═S(═O)—(R 13 ) 2 , wherein the two R 13 pair 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;
R 3 is H, methyl, or ethyl;
R 4 is H, halo, CN, C 1-4 alk, or C 1-4 haloalk;
R 5 is H, halo, C 1-8 alk, or C 1-4 haloalk;
R 6 is H, halo, CN, C 1-5 alk, C 1-4 haloalk, or R 6a ;
R 7 is H, halo, C 1-5 alk, or C 1-4 haloalk;
R 8 is H, halo, C 1-5 alk, or C 1-4 haloalk;
R 9 is H, halo, C 1-8 alk, or C 1-4 haloalk;
R x is selected from the group consisting of

Each of R 10a , R 10b , R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i , and R 10j is H, halo, R 10k , or R 10l ;
or alternatively, each of R 10a and R 10b pair, R 10c and R 10d pair, R 10e and R 10f pair, R 10g and R 10h pair, or R 10i and R 10j pair, 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 1-6 alk, C 1-4 haloalk, —OR a , —OC 1-4 haloalk, CN, —NR a R a , or oxo;
R 11 is H or C 1-8 alk;
R 12 is H, R 12a , or R 12b ;
R 13 is R 13a or R 13b ;
R 6a , R 10k , R 12a , and R 13a is 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 1-6 alk, C 1-4 haloalk, —OR a , —OC 1-4 haloalk, CN, —C(═O)R, —C(═O)OR a , —C(═O)NR a R a , —C(═NR a )NR a R a , —OC(═O)R, —OC(═O)NR a R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , —S(═O)R, —S(═O) 2 R, —S(═O) 2 NR a R a , —NR a R a , —N(R a )C(═O)R, —N(R a )C(═O)OR, —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R, —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a , —NR a C 2-6 alkOR a , —C 1-6 alkNR a R a , —C 1-6 alkOR a , —C 1-6 alkN(R a )C(═O)R, —C 1-6 alkOC(═O)R, —C 1-6 alkC(═O)NR a R a , —C 1-6 alkC(═O)OR a , R 14 , and oxo;
R 10l , R 12b , and R 13b is independently, at each instance, selected from the group consisting of C 1-6 alk substituted by 0, 1, 2, 3, 4, or 5 group(s) selected from F, Cl, Br, —C(═O)OR a , —OR a , —C 1-2 haloalk, —OC 1-4 haloalk, CN, NH 2 , NH(CH 3 ), or N(CH 3 ) 2 ;
R 14 is 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 1-6 alk, C 1-4 haloalk, —OR a , —OC 1-4 haloalk, CN, —C(═O)R, —C(═O)OR a , —C(═O)NR a R a , —C(═NR a )NR a R a , —OC(═O)R, —OC(═O)NR a R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR, —S(═O)R, —S(═O) 2 R, —S(═O) 2 NR a R a , —NR a R a , —N(R a )C(═O)R, —N(R a )C(═O)OR, —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R, —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a , —NR a C 2-6 alkOR a , —C 1-6 alkNR a R a , —C 1-6 alkOR a , —C 1-6 alkN(R a )C(═O)R, —C 1-6 alkOC(═O)R, —C 1-6 alkC(═O)NR a R a , —C 1-6 alkC(═O)OR a , and oxo;
R a is independently, at each instance, H or R b ; and
R b is independently, at each instance, C 1-6 alk, phenyl, or benzyl, wherein the C 1-6 alk is being substituted by 0, 1, 2 or 3 substituents selected from halo, —OH, —OC 1-4 alk, —NH 2 , —NHC 1-4 alk, —OC(═O)C 1-4 alk, or —N(C 1-4 alk)C 1-4 alk; and the phenyl or benzyl is being substituted by 0, 1, 2 or 3 substituents selected from halo, C 1-4 alk, C 1-3 haloalk, —OH, —OC 1-4 alk, —NH 2 , —NHC 1-4 alk, —OC(═O)C 1-4 alk, or —N(C 1-4 alk)C 1-4 alk.

2. The compound of claim 1 wherein R x is

3. The compound according to claim 1 wherein X 1 is —CR 6 ; having the formula (Ia):

4. The compound according to claim 1 wherein X 1 is N; having the formula (Ib):

5. The compound according to claim 1 wherein R 3 is H or methyl.

6. The compound according to claim 1 wherein each of R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i , and R 10j is H, halo, C 1-6 alk, or C 1-4 haloalk; and each of R 10a and R 10b pair combine with the carbon atom attached to each of them form a saturated 3-, 4-, or 5-membered monocyclic ring spiro to the R x ring; wherein said ring contains 0, 1, 2 or 3 N atoms and 0 or 1 atoms selected from O and S.

7. The compound according to claim 1 wherein each of R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i , and R 10j is H, methyl, or ethyl; and each of R 10a and R 10b pair combine with the carbon atom attached to each of them form a cyclopropyl, cyclobutyl, or cyclopentyl ring spiro to the R ring.

8. The compound according to claim 1 wherein R is selected from:

9. The compound according to claim 1 wherein R x is

10. The compound according to claim 1 wherein Z is absent, NH—, —NHSO 2 —(CH 2 ) 0-4 —, —N(CH 3 )—SO 2 —(CH 2 ) 0-4 —, —NCH 3 SO 2 NH, —NHSO 2 NH—C(═O)—O—, —SO 2 NH—(CH 2 ) 0-4 —, —(CH 2 ) 0-2 —S(═O)(═NH)—, —(CH 2 ) 0-2 —S—, —(CH 2 ) 0-2 —S(═O)—, (CH 3 CH)—S(═O)—, —(CH 2 ) 0-2 —SO 2 —, —O—, —P(═O), —(C═O)—, or —NH(C═O).

11. The compound according to claim 1 wherein the group —Z—R 12 is —N═S(═O)—(R 12 ) 2 , wherein the two

Assignees

• Amgen Inc

Inventors

• Tamayo Nuria A
• Banerjee Abhisek
• Brown James Alexander
• Frohn Michael J
• Chen Jian Jeffrey
• Li Kexue
• Liu Qingyian
• Low Jonathan Dante
• Ma Vu
• Pettus Liping H
• Walton Cabrera Mary Catherine
• Minatti Ana
• Bourbeau Matthew Paul
• Jia Lei
• Nguyen Thomas T
• Nishimura Nobuko
• Xue Qiufen May
• Allen John Gordon

Classifications

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title