2,4- or 4,6-diaminopyrimidine compounds as IDH2 mutants inhibitors for the treatment of cancer
Provided are compounds of formula (I), wherein: ring A and ring B are each independently an optionally substituted 5-6 membered monocyclic aryl or heteroaryl; one of X, Y and W is CH and the two others are N; and Z is H or —C(R1)(R2)(R3). The compounds are inhibitors of isocitrate dehydronenase 2 (IDH2) mutants useful for treating cancer.
1. A compound having Formula I or a pharmaceutically acceptable salt or hydrate thereof, wherein:
ring A is an optionally substituted 6-membered monocyclic heteroaryl;
ring B is an optionally substituted 6-membered monocyclic heteroaryl;
W and X are N and Y is CH;
Z is C(R 1 )(R 2 )(R 3 );
R 1 and R 3 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —O—C 1 -C 4 alkyl, and CN, wherein any alkyl portion of R 1 is optionally substituted with —OH, NH 2 , NH(C 1 -C 4 alkyl), or N(C 1 -C 4 alkyl) 2 ;
R 2 is selected from: —(C 1 -C 6 alkyl), —(C 2 -C 6 alkenyl or alkynyl), —(C 1 -C 6 alkylene)-N(R 6 )—(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-N(R 6 )—(C 0 -C 6 alkylene)-Q, —(C 0 -C 6 alkylene)-N(R 6 )(R 6 ), alkylene)-N(R 6 )—S(O) 1-2 -(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-N(R 6 )—S(O) 1-2 -(C 0 -C 6 alkyl)-Q, —(C 1 -C 6 alkylene)-S(O) 1-2 —N(R 6 )(R 6 ), —(C 1 -C 4 alkylene)-S(O) 1-2 —N(R 6 )—(C 1 -C 6 alkylene)-Q, —C(O)N(R 6 )—(C 1 -C 6 alkylene)-C(O)—(C 0 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —C(O)N(R 6 )—(C 1 -C 6 alkylene)-C(O)—(C 0 -C 6 alkylene)-O—(C 0 -C 6 alkylene)-Q, —(C 1 -C 6 alkylene)-O—C(O)—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-O—C(O)—(C 0 -C 6 alkyl)-Q, —(C 0 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-Q, —(C 0 -C 6 alkylene)-C(O)—(C 0 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —(C 0 -C 6 alkylene)-C(O)—(C 0 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-Q, —(C 1 -C 6 alkylene)-O—C(O)—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-O—C(O)—(C 0 -C 6 alkylene)-Q, —(C 0 -C 6 alkylene)-C(O)N(R 6 )—(C 1 -C 6 alkyl), —(C 0 -C 6 alkylene)-C(O)N(R 6 )—(C 0 -C 6 alkylene)-Q, —(C 1 -C 6 alkylene)-N(R 6 )C(O)—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-N(R 6 )C(O)—(C 0 -C 6 alkylene)-Q, —(C 0 -C 6 alkylene)-S(O) 0-2 -(C 1 -C 6 alkyl), —(C 0 -C 6 alkylene)-S(O) 0-2 -(C 0 -C 6 alkylene)-Q, —(C 1 -C 6 alkylene)-N(R 6 )—C(O)—N(R 6 )—(C 1 -C 6 alkyl), —(C 0 -C 6 alkylene)-Q, —(C 0 -C 6 alkylene)-C(O)—(C 1 -C 6 alkyl), and —(C 0 -C 6 alkylene)-C(O)—(C 0 -C 6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R 2 is optionally substituted with one or more —OH, —O(C 1 -C 4 alkyl) or halo;
any terminal methyl moiety present in R 2 is optionally replaced with —CH 2 OH, CF 3 , —CH 2 F, —CH 2 Cl, C(O)CH 3 , C(O)CF 3 , CN, or CO 2 H;
each R 6 is independently selected from hydrogen and C 1 -C 6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; or
R 1 and R 3 are optionally taken together with the carbon atom to which they are attached to form C(═O), or
R 1 and R 2 are optionally taken together to form substituted carbocyclyl or an optionally substituted heterocyclyl.
2. A compound or a pharmaceutically acceptable salt or hydrate thereof having Structural Formula (Ia) wherein:
ring A′ is 6-membered monocyclic heteroaryl optionally substituted with one or two substituents independently selected from chloro, fluoro, —CF 3 , —CHF, —CH 3 , —CH 2 CH 3 , —CF 2 CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 ;
ring B′ is selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl and pyrimidin-6-yl, wherein ring B′ is optionally substituted with one to two substituents independently selected from halo; —CN; —OH; C 1 -C 4 alkyl optionally substituted with halo, CN, —OH, or cyclopropyl; —S(O) 2 —C 1 -C 4 alkyl; —S(O)—C 1 -C 4 alkyl; —S(O) 2 —NH—C 1 -C 4 alkyl; —S(O) 2 —N(C 1 -C 4 alkyl) 2 ; —S(O) 2 -azetidin-1-yl; —O—C 1 -C 4 alkyl; —CH 2 —O—CH 3 , morpholin-4-yl, cyclopropyl, —S(O) 2 —NH-cyclopropyl; —C(O)—O—CH 3 ;
W and X are N and Y is CH; and
is selected from C 1 -C 6 alkyl optionally substituted with halo or —OH; —(C 1 alkylene)-aryl, wherein the aryl is optionally substituted with —OH, —CH 2 OH, halo, —OCH 3 or methyl; —(C 0 -C 1 alkylene)-cycloalkyl, wherein the alkylene is optionally substituted with methyl and the cycloalkyl is optionally substituted with halo, —OCH 3 or methyl; saturated heterocyclyl optionally substituted with halo or methyl; —C(O)—C 1 -C 6 alkyl; —C(O)—O—C 1 -C 6 alkyl; —C(O)—(C 0 -C 1 alkylene)-cyclopropyl; and C(O)-benzyl.
3. The compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein R 1 is independently selected from hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 OH, CN, or R 1 and R 3 are taken together to form ═O.
4. The compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein R 1 and R 2 are taken together to form carbocyclyl or heterocyclyl, either of which is optionally substituted with up to 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, ═O, —OH, and —C(O)C 1 -C 4 alkyl.
5. The compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein R 2 is selected from: —(C 1 -C 4 alkyl) optionally substituted with fluoro or —OH; —(C 0 -C 4 alkylene)-O—(C 1 -C 4 alkyl)- and —(C 0 -C 2 alkylene)-Q, wherein Q is optionally substituted with up to 3 substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, ═O, —C(O)—C 1 -C 4 alkyl, —CN, and halo.
6. The compound of claim 5 or a pharmaceutically acceptable salt or hydrate thereof, wherein Q is selected from pyridinyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, phenyl, pyrazolyl, morpholinyl and oxetanyl, wherein Q is optionally substituted with up to 2 substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, ═O, fluoro, chloro, and bromo.
7. The compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein R 1 and R 2 are taken together to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo[2.2.1]heptanyl and azetidinyl, any of which is optionally substituted with up to 2 substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, —OH, —C(O)CH 3 , fluoro, and chloro.
8. The compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein ring A is selected pyridinyl, pyrimidinyl and pyrazinyl wherein ring A is optionally substituted with up to two substituents independently selected from halo, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —C 1 -C 4 hydroxyalkyl, —NH—S(O) 2 -(C 1 -C 4 alkyl), —S(O) 2 NH(C 1 -C 4 alkyl), —CN, —S(O) 2 -(C 1 -C 4 alkyl), C 1 -C 4 alkoxy, —NH(C 1 -C 4 alkyl), —OH, —CN, and —NH 2 .
9. The compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein ring B is selected from pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl, wherein ring B is optionally substituted with up to two substituents independently selected from halo, —C 1 -C 4 alkyl, —C 2 -C 4 alkynyl, —C 1 -C 4 haloalkyl, —C 1 -C 4 hydroxyalkyl, C 3 -C 6 cycloalkyl, —(C 0 -C 2 alkylene)-O—C 1 -C 4 alkyl, —O—(C 1 -C 4 alkylene)-C 3 -C 6 cycloalkyl, —NH—S(O) 2 -(C 1 -C 4 alkyl), —S(O) 2 NH(C 1 -C 4 alkyl), —S(O) 2 —NH—(C 3 -C 6 cycloalkyl), —S(O) 2 -(saturated heterocyclyl), —CN, —S(O) 2 -(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —OH, C(O)—O—(C 1 -C 4 alkyl), saturated heterocyclyl, and —NH 2 .
10. The compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein ring A is selected from 6-aminopyridin-2-yl, 6-chloropyridin-2-yl and 6-trifluoromethylpyridin-2-yl.
11. The compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein ring B is selected from pyridin-2-yl, 4-chloropyridin-2-yl, 4-trifluoromethylpyridin-2-yl, 4-cyanopyridin-2-yl, 4-isopropylpyridin-2-yl, 6-chloropyridin-2-yl, 4-(1-cyanocyclopropyl)pyridin-2-yl, 4-difluoromethylpyridin-2-yl, 4-(1,1-difluoroethyl)pyridine-2-yl, 2-(morpholin-4-yl)pyridin-4-yl, 2-dimethylaminopyridin-4-yl, 5-chloropyridin-3-yl, 5-cyanopyridin-3-yl, 5-cyanopyridin-3-yl, 5-cyanopyridin-4-yl, 5-fluoropyridin-3-yl, 5-trifluoromethypyridin-3-yl, 6-chloropyridin-4-yl, 6-cyanopyridin-4-yl, 6-cyclopropylpyridin-4-yl, 6-ethoxypyridin-4-yl, 6-fluoropyridin-3-yl, 6-fluoropyridin-4-yl, 6-methylpyridin-4-yl, 6-trifluoromethylpyridin-4-yl, pyridin-4-yl, pyrimidin-4-yl and 6-(trifluoromethyl)pyrimidin-4-yl.
12. A compound or a pharmaceutically acceptable salt or hydrate thereof, having Structural Formula (Ia) wherein:
ring A′ is 6-membered monocyclic heteroaryl optionally substituted with one or two substituents independently selected from chloro, fluoro, —CF 3 , —CHF 2 , —CH 3 , —CH 2 CH 3 , —CF 2 CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 ;
ring B′ is selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl and pyrimidin-6-yl, wherein ring B′ is optionally substituted with one to two substituents independently selected from halo; —CN; —OH; C 1 -C 4 alkyl optionally substituted with halo, CN, —OH, or cyclopropyl; —S(O) 2 —C 1 -C 4 alkyl; —S(O)—C 1 -C 4 alkyl; —S(O) 2 —NH—C 1 -C 4 alkyl; —S(O) 2 —N(C 1 -C 4 alkyl) 2 ; —S(O) 2 -azetidin-1-yl; —O—C 1 -C 4 alkyl; —CH 2 —O—CH 3 , morpholin-4-yl, cyclopropyl, —S(O) 2 —NH-cyclopropyl; —C(O)—O—CH 3 ;
W and X are N and Y is CH; and
the moiety represented by
is selected from 2-hydroxycyclopentyl, 2-methylcyclopropyl, 3,3-difluorocyclobutyl, —(CH 2 ) 3 CH 3 , —CH(CH 3 )—C(CH 3 ) 3 , —CH(CH 3 )—CH 2 OCH 3 , —C(O)—C(CH 3 ) 3 , —C(O)—CH(CH 3 ) 2 , —C(O)—CH 2 (CH)(CH 3 ) 2 , —C(O)-cyclopropyl, —C(O)—OC(CH 3 ) 3 , —C(O)—OCH 2 CH(CH 3 ) 2 , —C(O)—OCH 2 CH 3 , —C(O)—OCH(CH 3 ) 2 , —CH(CH 3 )—CH(CH 3 ) 2 , —CH(CH 3 )—CH 2 CH 3 , —CH 2 C(CH 3 ) 2 —CH 2 OH, —CH 2 C(OH)(CH 3 ) 2 , CH 2 C(CH 3 ) 3 , —CH 2 CF 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 )—CH 2 CH 3 , —CH 2 CH 2 CH(CH 3 ) 2 , —CH 2 -cyclopropyl,
cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, isopropyl, oxetan-3-yl, bicyclo[12.2.1]heptanyl, tetrahydropyran-4-yl, and tetrahydropyran-3-yl.
13. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.
14. The pharmaceutical composition of claim 13 , further comprising a second therapeutic agent useful in the treatment of cancer.
15. A compound or a pharmaceutically acceptable salt or hydrate thereof selected from the group consisting of:
Cmpd
No
Structure
100
108
109
110
111
112
114
115
116
117
118
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120
121
122
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450
451
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471
472
473
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511
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531
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541
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547
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563
564
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566
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569
570
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573
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581
582
583
584
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591
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601
602
603
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609
610
611
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613
614
615
616
617
618
619
621
622
623
624
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626
627
628
629
630
631
632
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639
640
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646
647
648
649
650
651
652
653
654
655
657
658
660
662
663
664
665
667
669
670
671
672
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681
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719
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721
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723
724
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728
730
734
735
736
737
738
739