Claims for Patent: 11,844,758

Summary for Patent: 11,844,758

Title:	Therapeutically active compounds and their methods of use
Abstract:	Provided are compounds useful for treating cancer and methods of treating cancer comprising administering to a subject in need thereof a compound described herein.
Inventor(s):	Zenon Konteatis, Janeta Popovici-Muller, Jeremy Travins, Robert Zahler, Zhenwei Cai, Ding Zhou
Assignee:	PHARMARESOURCES (SHANGHAI) CO Ltd , Servier Pharmaceuticals LLC
Application Number:	US17/158,867
Patent Claims:	1. A method for treating a glioma characterized by the presence of an isocitrate dehydrogenase 1 (IDH1) mutation comprising administering to a patient in need thereof a therapeutically effective amount of a compound having Formula (Ia) or a pharmaceutically acceptable salt or hydrate thereof, wherein: ring A is selected from phenyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, and wherein ring A is optionally substituted with up to two substituents independently selected from halo, —C1-C4 alkyl, —C1-C4 haloalkyl, —C1-C4 hydroxyalkyl, —NH—S(O)2—(C1-C4 alkyl), —S(O)2NH(C1-C4 alkyl), —S(O)2—(C1-C4 alkyl), C1-C4 alkoxy, —NH(C1-C4 alkyl), —OH, —OCF3, —CN, —NH2, —C(O)NH2, —C(O)NH(C1-C4 alkyl), —C(O)—N(C1-C4 alkyl)2, and cyclopropyl optionally substituted with OH; R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, —O—C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with —OH, —NH2, —CN, —O—C1-C4 alkyl, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)2; R2 and R5 are each independently selected from —(C1-C6 alkyl); —(C2-C6 alkenyl) and —(C2-C6 alkynyl), wherein any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more —OH, —O(C1-C4 alkyl), —CO2H, or halo; any terminal methyl moiety present in R2 and R5 is optionally replaced with —CH2OH, CF3, —CH2F, —CH2Cl, C(O)CH3, C(O)CF3, CN, or CO2H; and R7 and R8 are each independently selected from hydrogen and C1-C6 alkyl; provided that (i) when A is an optionally substituted pyridyl, then (A) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHCH2CH2OH, and (B) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NH—CH2CH3; (ii) when A is an optionally substituted heteroaryl selected from pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, then N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, or NHCH2CH(CH3)2; (iii) when A is optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHisopropyl, NHCH2CH3, or N(CH2CH3)2; (iv) when A is an optionally substituted phenyl, then N(R7)C(R4)(R5)(R6) is not the same as N(R8)C(R1)(R2)(R3); (v) when A is substituted 1-pyrazolyl, then (A) N(R7)C(R4)(R5)(R6); and N(R8)C(R1)(R2)(R3) are not both NHC(CH3)3. 2. The method of claim 1, wherein ring A is a 6-member monocyclic heteroaryl selected from pyridinyl, pyrimidinyl and pyrazinyl and wherein ring A is optionally substituted with up to two substituents independently selected from halo, —C1-C4 alkyl, —C1-C4 haloalkyl, —C1-C4 hydroxyalkyl, —NH—S(O)2—(C1-C4 alkyl), —S(O)2NH(C1-C4 alkyl), —S(O)2—(C1-C4 alkyl), C1-C4 alkoxy, —NH(C1-C4 alkyl), —OH, —OCF3, —CN, —NH2, —C(O)NH2, —C(O)NH(C1-C4 alkyl), —C(O)—N(C1-C4 alkyl)2, and cyclopropyl optionally substituted with OH. 3. The method of claim 1, wherein ring A is pyridinyl optionally substituted with up to two substituents independently selected from halo, —C1-C4 alkyl, —C1-C4 haloalkyl, —C1-C4 hydroxyalkyl, —NH—S(O)2—(C1-C4 alkyl), —S(O)2NH(C1-C4 alkyl), —S(O)2—(C1-C4 alkyl), C1-C4 alkoxy, —NH(C1-C4 alkyl), —OH, —OCF3, —CN, —NH2, —C(O)NH2, —C(O)NH(C1-C4 alkyl), —C(O)—N(C1-C4 alkyl)2, and cyclopropyl optionally substituted with OH. 4. The method of claim 1, wherein ring A is pyridinyl optionally substituted with halo or —C1-C4 haloalkyl. 5. The method of claim 1, wherein ring A is phenyl or a 6-member monocyclic heteroaryl selected from pyridinyl, pyrimidinyl and pyrazinyl wherein said phenyl or 6-member monocyclic heteroaryl is optionally substituted with up to two substituents independently selected from halo, —C1-C4 alkyl, —C1-C4 haloalkyl, —C1-C4 hydroxyalkyl, —NH—S(O)2—(C1-C4 alkyl), —S(O)2NH(C1-C4 alkyl), —S(O)2—(C1-C4 alkyl), C1-C4 alkoxy, —NH(C1-C4 alkyl), —OH, —OCF3, —CN, —NH2, —C(O)NH2, —C(O)NH(C1-C4 alkyl), —C(O)—N(C1-C4 alkyl)2, and cyclopropyl optionally substituted with OH; R1 and R4 are each independently selected from C1-C4 alkyl and C1-C4 haloalkyl; R3 and R6 are both hydrogen; R2 and R5 are each —(C1-C6 alkyl); wherein: any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more —OH, —O(C1-C4 alkyl), —CO2H, or halo; any terminal methyl moiety present in R2 and R5 is optionally replaced with —CH2OH, CF3, —CH2F, —CH2Cl, C(O)CH3, C(O)CF3, CN, or CO2H; and R7 and R8 are each independently selected from hydrogen and C1-C6 alkyl. 6. The method of claim 1, wherein the compound has formula (B), wherein: X is N; each Xa is independently N or C—R9a, provided that when one Xa is N, then the other two Xa are both C—R9a; R9 is selected from the group consisting of halo, —C1-C4 alkyl, —C1-C4 haloalkyl, —C1-C4 hydroxyalkyl, —NH—S(O)2—(C1-C4 alkyl), —S(O)2NH(C1-C4 alkyl), —S(O)2—(C1-C4 alkyl), C1-C4 alkoxy, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —OH, —OCF3, —CN, —NH2, —C(O)NH2, —C(O)NH(C1-C4 alkyl), —C(O)—N(C1-C4 alkyl)2, and cyclopropyl optionally substituted with OH; each R9a is independently selected from the group consisting of hydrogen, halo, —C1-C4 alkyl, —C1-C4 haloalkyl, —C1-C4 hydroxyalkyl, —NH—S(O)2—(C1-C4 alkyl), —S(O)2NH(C1-C4 alkyl), —CN, —S(O)2—(C1-C4 alkyl), C1-C4 alkoxy, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —OH, —OCF3, —CN, —NH2, —C(O)NH2, —C(O)NH(C1-C4 alkyl), —C(O)—N(C1-C4 alkyl)2, and cyclopropyl optionally substituted with OH; R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, —O—C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with —OH, —NH2, —CN, —O—C1-C4 alkyl, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)2; R2 and R5 are each independently selected from —(C1-C6 alkyl); —(C2-C6 alkenyl) and —(C2-C6 alkynyl), wherein any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more —OH, —O(C1-C4 alkyl), —CO2H, or halo; any terminal methyl moiety present in R2 and R5 is optionally replaced with —CH2OH, CF3, —CH2F, —CH2Cl, C(O)CH3, C(O)CF3, CN, or CO2H; and R7 and R8 are each independently selected from hydrogen and C1-C6 alkyl. 7. The method of claim 6, wherein: R1 and R4 are each independently selected from C1-C4 alkyl and C1-C4 haloalkyl; R3 and R6 are both hydrogen; and R2 and R5 are each —(C1-C6 alkyl); wherein any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more —OH, —O(C1-C4 alkyl), —CO2H, or halo; any terminal methyl moiety present in R2 and R5 is optionally replaced with —CH2OH, CF3, —CH2F, —CH2Cl, C(O)CH3, C(O)CF3, CN, or CO2H; and R7 and R8 are each independently selected from hydrogen and C1-C6 alkyl. 8. The method of claim 6, wherein each Xa is C—R9a. 9. The method of claim 8, wherein each R9a is H. 10. The method of claim 6, wherein R9 is selected from halo and —C1-C4 haloalkyl. 11. The method of claim 6, wherein R9 is halo. 12. The method of claim 6, wherein R1 and R4 are each independently selected from the group consisting of C1-C4 alkyl and C1-C4 haloalkyl, and R2 and R5 are each —(C1-C6 alkyl). 13. The method of claim 6, wherein R7 and R8 are both hydrogen. 14. The method of claim 1, wherein the compound is selected from: 3 4 13 14 17 18 32 35 70 73 74 76 86 100 101 103 104 114 130 136 141 142 156 180 196 271 335 339 344 345 346 363 386 404 15. The method of claim 1, wherein the IDH1 mutation is an IDH1 R132H or R132C mutation. 16. A method for treating a glioma characterized by the presence of an isocitrate dehydrogenase 1 (IDH1) mutation comprising administering to a patient in need thereof a therapeutically effective amount of a compound having Formula: or a pharmaceutically acceptable salt or hydrate thereof. 17. The method of claim 16, wherein the IDH1 mutation is an IDH1 R132H or R132C mutation. 18. The method of claim 16, wherein the method further comprises administering a second therapeutic agent useful in the treatment of cancer. 19. A method for treating a glioma characterized by the presence of an isocitrate dehydrogenase 1 (IDH1) mutation comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising or a pharmaceutically acceptable salt or hydrate thereof and one or more pharmaceutically acceptable excipients. 20. The method of claim 19, wherein the IDH1 mutation is an IDH1 R132H or R132C mutation.