(Aralkylamino substituted in alpha and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions containing them, and these compounds for use in the treatment of proliferative diseases

摘要

A compound of formula II: ** Formula ** or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or a variant isotopic thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein: X, Y, and Z are each independently N or CRx, with the proviso that at least two of X, Y, and Z are nitrogen atoms; where Rx is hydrogen or C1-6 alkyl; R1 and R2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C (O) R1a, - C (O) OR1a, - (O) NR1bR1c, -C (NR1a) NR1bR1c, -OR1a, - OC (O) R1a, -OC (O) OR1a, -OC (O) NR1bR1c, - OC ( = NR1a) NR1bR1c, -OS (O) R1a, -OS (O) 2R1a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, - NR1aC (O) OR1d, - NR1aC (O) NR1bR1c, -NR1aC ( = NR1d) NR1bR1c, -NR1aS (O) R1d, -NR1aS (O) 2R1d, - NR1aS (O) NR1bR1c, -NR1a (ONR1a) ) 2NR1bR1c, -SR1a, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c, oS (O) 2NR1bR1c; wherein each R1a, R1b, R1c, and R1d is independently (i) hydrogen; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R1b and R1c together with the N atom to which they are attached form the heterocyclyl; R3 and R4 are each independently hydrogen or C1-6 alkyl; or R3 and R4 join together to form a bond, C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, or C2-6 heteroalkenylene; R5a is hydrogen or C1-6 alkyl; R5b is C1-6 alkyl or -C (O) OR1a; R5c is - (CR5fR5g) n- (C6-14 aryl) or - (CR5fR5g) n-heteroaryl; R5f and R5g are each independently (a) hydrogen or halo; (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C (O) R1a, -C (O) OR1a, - C (O) NR1bR1c, -C (NR1a) NR1bR1c, -OR1a, -OC (O) R1a, - OC (O) OR1a, - OC (O) NR1bR1c, -OC ( = NR1a) NR1bR1c, - OS (O) R1a, -OS (O) 2R'a, -OS (O) NR1bR1c, -OS (O) 2NR1bR1c, -NR1bR1c, -NR1aC (O) R1d, -NR1aC (O) OR1d, - NR1aC (O) NR1bR1c, -NR1aC ( = NR1d) NR1bR1c, NR1aS (O) R1d, -NRlaS (O) 2Rld, -NR1aS (O) NR1bR1c, - NR1bR1c, - NR1bR1c, - NR1bR1c (O) 2NR1bR1c, -SR1a, -S (O) R1a, -S (O) 2R1a, -S (O) NR1bR1c; o-S (O) 2NR1bR1c; or (d) when an occurrence of R5f and an occurrence of R5g bind to the same carbon atom, R5f and R5g together with the carbon atom to which they are attached form a C3-10 cycloalkyl or heterocyclyl; R 6 is hydrogen, C 1-6 alkyl, -C 1-6 alkyl, -S (O) -C 1-6 alkyl, or -SO 2 -C 1-6 alkyl; and n is 0, 1, 2, 3, or 4; wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R1, R2, R3, R4, R6, Rx, R1a, R1b, R1c, R1d, R5a , R5b, R5c, R5f, and R5g is optionally substituted with one or more, in one embodiment, one, two, three or four, substituents Q, in which each substituent Q is independently selected from (a) oxo, cyano , halo, and nitro; (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is optionally substituted with one or more , in one embodiment, one, two, three or four, Qa substituents; and (c) -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (NRa) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, - OC (O) NRbRc, -OC ( = NRa) NRbRc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRb, Rc, - OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rd, NRaC (O) ORd, -NRaC (O) NRbRc, - NRaC ( = NRd,) NRbRc, -NRaS (O) Rd, NRaS (O) 2Rd, -RaS (O) NRbRc, -NRaS (O) 2NRbRc, -SRa, -S (O) Ra, -S (O) 2Ra, -S (O) NRbRc, and -S (O) 2NRbRc, in which each Ra, Rb, Rc, and Rd, it is independently (i) hydrogen; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more , in one embodiment, one, two, three or four, Qa substituents; or (iii) Rb, and Rc, together with the N atom to which they are attached form the heterocyclyl, which is also optionally substituted with one or more, in one embodiment, one, two, three or four, Qa substituents; wherein each Qa is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (NRe) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, - OC (O) NRfRg, -OC ( = NRe) NRfRg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O ) Rh, NReC (O) ORh, -NReC (O) NRfRg, -NReC ( = NRh) NRfRg, -NReS (O) Rh, -NReS (O) 2Rh, NReS (O) NRfRg, - NReS (O) 2NRfRg, -SRe, -S (O) Re, -S (O) 2Re, -S (O) NRfRg, and -S (O) 2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form the heterocyclyl; and wherein the compound is not 6- (2- (difluoromethyl) -1H-benzo [d] imidazol-1-yl) -N- (1- (4 - ((R) -3- (methoxymethyl) morpholino) phenyl) ethyl) -2-morpholinopyrimidin-4-amine.