Claims for Patent: 10,172,864

Summary for Patent: 10,172,864

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 D. Konteatis, Janeta Popovici-Muller, Jeremy M. Travins, Robert Zahler, Zhenwei Cai, Ding Zhou
Assignee:	PHARMARESOURCES (SHANGHAI) CO Ltd , Servier Pharmaceuticals LLC
Application Number:	US15/392,681
Patent Claims:	1. A compound having Formula (Ia) or a pharmaceutically acceptable salt 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)N2, —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(R 8)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 compound of claim 1 or a pharmaceutically acceptable salt thereof, 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 compound of claim 1 or a pharmaceutically acceptable salt thereof, 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 compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is pyridinyl optionally substituted with halo or —C1-C4 haloalkyl. 5. The compound or claim 1 or a pharmaceutically acceptable salt thereof, 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 compound of claim 1 having Formula (B) or pharmaceutically acceptable salt or hydrate thereof, 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)2and 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 compound of claim 6 or a pharmaceutically acceptable salt thereof, 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 compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein each Xa is C—R9a. 9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein each R9a is H. 10. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein R9 is selected from halo and —C1-C4 haloalkyl. 11. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein R9 is halo. 12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, 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 compound of claim 6 or a pharmaceutically acceptable salt thereof, 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). 14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R7 and R8 are both hydrogen. 15. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein R7 and R8 are both hydrogen. 16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 17. A compound or a pharmaceutically acceptable salt thereof having the structure: 18. A compound or a pharmaceutically acceptable salt thereof having the structure: 19. A compound or a pharmaceutically acceptable salt thereof having the structure: 20. A pharmaceutical composition comprising a compound of claim 1 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 21. A pharmaceutical composition comprising a compound of claim 6 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.