Kif18a inhibitors

Patent metadata

Field	Value
Publication number	US-2020239441-A1
Application number	US-201916724119-A
Country	US
Kind code	A1
Filing date	Dec 20, 2019
Priority date	Dec 20, 2018
Publication date	Jul 30, 2020
Grant date	—

Abstract

Compounds of formula (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

1 . A compound of formula I:

or any pharmaceutically-acceptable salt thereof, wherein:
X 1 is N or —CR 6 ;
R 1 is —CN, or a group —Z—R 12 wherein Z is —C 0-4 alk-, —NR 11 —, —NR 11 SO 2 —, —SO 2 NR 11 —, —NR 11 —S(═O)(═NH), —S(═O)(═NH)—, —S—, —S(═O)—, —SO 2 —, C 0-4 alk-O—, —(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-, —C(═O)NR a R a (C 1-4 alk), —O—C 0-4 alk-, S, S═O, S(═O) 2 , —SO 2 NR 13 , or —S(═O)(═NH)—;
R 3 is H, C 1-4 alk, or C 1-4 haloalk;
R 4 is H, halo, R 4a or R 4b ;
R 5 is H, halo, C 1-8 alk, or C 1-4 haloalk;
R 6 is H, halo, C 1-8 alk, C 1-4 haloalk, —O—C 1-8 alk, or —O—R 6a ; wherein R 6a is 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 7 is H, halo, C 1-8 alk, or C 1-4 haloalk;
R 8 is H, halo, C 1-8 alk, C 1-4 haloalk, —OH, —O—R 8a , or —O—R 8b ;
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 X 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, R 11a , or R 11b ;
R 12 is H, R 12a , or R 12b ;
R 13 is R 13a or R 13b ;
R 4a , R 8a , R 10k , R 11a , 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 b , —C(═O)OR a , —C(═O)NR a R a , —C(═NR a )NR a R a , —OC (═O)R b , —OC(═O)NR a R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —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 b , —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 b , —C 1-6 alkOC(═O)R b , —C 1-6 alkC(═O)NR a R a , —C 1-6 alkC(═O)OR a , R 14 , and oxo;
R 4b , R 8b , R 10l , R 11b , 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, —OR a , —OC 1-4 haloalk, or CN;
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 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 1-6 alk, C 1-4 haloalk, —OR a , —OC 1-4 haloalk, CN, —C(═O)R b , —C(═O)OR a , —C(═O)NR a R a , —C(═NR a )NR a R a , —OC(═O)R b , —OC(═O)NR a R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —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 b , —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 b , —C 1-6 alkOC(═O)R b , —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 , or the pharmaceutically-acceptable salt thereof, wherein X 1 is N; having the formula (Ia):

3 . The compound of claim 1 , or the pharmaceutically-acceptable salt thereof, wherein X 1 is —CR 6 ; having the formula (Ib):

4 . The compound of claim 1 , or the pharmaceutically-acceptable salt thereof, wherein R 3 is H or methyl.

5 . The compound of any one of claims 1 to 4 , or the pharmaceutically-acceptable salt thereof, 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, 1, or 2 atoms selected from O and S.

6 . The compound of claim 1 , or the pharmaceutically-acceptable salt thereof, wherein each of R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i , and R j 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 IV ring.

7 . The compound of claim 1 , or the pharmaceutically-acceptable salt thereof, wherein the group

is selected from:

8 . The compound of claim 1 , or the pharmaceutically-acceptable salt thereof, wherein the group

9 . The compound of claim 1 , or the pharmaceutically-acceptable salt thereof, wherein R 1 is —CN, or a group —Z—R 12 , wherein Z is a bond, —NH—, —NHSO 2 —, —SO 2 NH—, —S(═O)(═NH)—, —S—, —S(═O)—, —SO 2 —, —(C═O)—, —(C═O)NH—, or —NH(C═O)—; and
R 12 is selected from:
(a) H;
(b) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl,

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 Mary Catherine
• Minatti Ana Elena
• Bourbeau Matthew Paul
• Jia Lei

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D401/12 Primary

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