Cycloalkyl substituted pyrimidinediamine compounds and their uses
View Patent ↗The present disclosure provides 2,4-pyrimidinediamine compounds having antiproliferative activity, compositions comprising the compounds and methods of using the compounds to inhibit cellular proliferation and to treat proliferate diseases such as tumorigenic cancers.
1. A compound according to structural formula (I):
or a salt or N-oxide thereof, wherein:
R 2 is a (C6-C20)aryl, 5-20 membered heteroaryl, (C7-C28) arylalkyl or 6-28 membered heteroarylalkyl group, each optionally substituted with one or more of the same or different R 8 groups;
R 4 is a saturated or unsaturated bridged C5-C16 cycloalkyl ring substituted with an R 7 group;
R 5 is selected from hydrogen, (C1-C8)alkyl optionally substituted with one or more of the same or different R 8 groups, and a substituent selected from the group consisting of —CN, —NC, —NO 2 , halo, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, (C1-C3) fluoroalkyl, (C1-C3) perfluoroalkyl, —CF 3 , (C1-C3) haloalkoxy, (C1-C3) perhaloalkoxy, (C1-C3) fluoroalkoxy, (C1-C3) perfluoroalkoxy, —OCF 3 , —C(O)R a , —C(O)OR a , —C(O)CF 3 , and —C(O)OCF 3 ; and
R 7 is —C(O)OR d or —C(O)NR d R d ,
wherein
each R 8 group is, independently of the others, selected from a water-solubilizing group, R a , R b , lower cycloalkyl optionally substituted with one or more of the same or different R a and/or R b groups, lower heterocycloalkyl optionally substituted with one or more of the same or different R a and/or R b groups, lower alkoxy optionally substituted with one or more of the same or different R b groups and —O—(CH 2 ) x —R b ,
the water solubilizing group is
morpholino, piperidinyl, (C1-C6) N-alkyl piperidinyl, N-methyl piperidinyl, piperazinyl, (C1-C6) N-alkylpiperazinyl, N-methylpiperazinyl, N-ethyl piperidinyl, N-ethyl piperazinyl, pyrrolidinyl, N-alkyl pyrrolidinyl, N-methylpyrrolidinyl, diazepinyl, N-ethyl pyrrolidinyl, N-alkyl azepinyl, N-methyl azepinyl, N-ethyl azepinyl, homopiperazinyl, N-methyl homopiperazinyl, N-ethyl homopiperazinyl, or imidazolyl, wherein Y is selected from CH and N, Z is selected from CH 2 , O, S, NH, N—(CH 2 ) y —R a , N—(CH 2 ) y C(O)R a , N—(CH 2 ) y —C(O)OR a , N—(CH 2 ) y —S(O) 2 R a , N—(CH 2 ) y —S(O) 2 OR a and N—(CH 2 ) y —C(O)NR c R c , with the proviso that Y and Z are not both simultaneously CH and CH 2 , respectively;
x is an integer ranging from 1 to 6;
y is an integer ranging from 0 to 6;
R a is selected from hydrogen, lower alkyl, lower cycloalkyl, (C6-C14) aryl, phenyl, naphthyl, (C7-C20) arylalkyl and benzyl;
each R b is, independently of the others, selected from ═O, —OR a , (C1-C3) haloalkyloxy, —OCF 3 , ═S, —SR a , ═NR a , ═NOR a , —NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R a , —S(O) 2 R a , —S(O) 2 OR a , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R a , —OS(O) 2 R a , —OS(O) 2 OR a , —OS(O) 2 NR c R c , —C(O)R a , —C(O)OR a , —C(O)NR c R c , —C(NH)NR c R c , —C(NH)NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R a , —OC(O)OR a , —OC(O)NR c R c , —OC(NH)NR c R c and —OC(NR a )NR c R c ;
each R c is, independently of the other, an R a or, alternatively, two R c that are bonded to the same nitrogen atom may be taken together with this nitrogen atom to form a 5-8 membered heterocycloalkyl group which may optionally include from 1 to 3 additional heteroatomic groups selected from O, S, N—(CH 2 ) y —R a , N—(CH 2 ) y —C(O)R a , N—(CH 2 ) y —C(O)OR a , N—(CH 2 ) y —S(O) 2 R a , N—(CH 2 ) y —S(O) 2 OR a and N—(CH 2 ) y —C(O)NR a R a , and which may optionally include one or more of the same or different R 8 and/or lower alkyl substituents; and
each R d is, independently of the others, selected from R a and R c and a chiral auxiliary group selected from the group consisting of,
where R 9 is selected from hydrogen and lower alkyl.
2. The compound of claim 1 , R 4 is
wherein the dotted lines represent a single bond or a double bond.
3. The compound of claim 1 , wherein R 5 selected from nitro, cyano, halo, fluoro, bromo, trifluoromethyl and trifluoromethoxy.
4. The compound of claim 3 , wherein R 5 is fluoro.
5. The compound of claim 1 , wherein R 2 is substituted with at least one water-solubilizing group.
6. A compound according to structural formula (I):
or a salt or N-oxide thereof, wherein:
R 2 is a substituted phenyl of the formula:
where one of R 11 , R 12 or R 13 is a water-solubilizing group, and the other two of R 11 , R 12 and R 13 are each, independently of one another, selected from hydrogen, lower alkyl, (C1-C3) alkyl, methyl, halo, chloro, fluoro, hydroxy, (C1-C3) hydroxyalkyl, —O(CH 2 ) x —R b , —NR c R c , —C(O)NR c R c , —C(O)NHR a , and —C(O)NHCH 3 ;
R 4 is a saturated or unsaturated bridged C5-C16 cycloalkyl ring substituted with an R 7 group;
R 5 is selected from hydrogen, (C1-C8)alkyl optionally substituted with one or more of the same or different R 8 groups, and a substituent selected from the group consisting of —CN, —NC, —NO 2 , halo, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, (C1-C3) fluoroalkyl, (C1-C3) perfluoroalkyl, —CF 3 , (C1-C3) haloalkoxy, (C1-C3) perhaloalkoxy, (C1-C3) fluoroalkoxy, (C1-C3) perfluoroalkoxy, —OCF 3 , —C(O)R a , —C(O)OR a , —C(O)CF 3 , and —C(O)OCF 3 ; and
R 7 is —C(O)OR d or —C(O)NR d R d ,
wherein
each R 8 group is, independently of the others, selected from a water-solubilizing group, R a , R b , lower cycloalkyl optionally substituted with one or more of the same or different R a and/or R b groups, lower heterocycloalkyl optionally substituted with one or more of the same or different R a and/or R b groups, lower alkoxy optionally substituted with one or more of the same or different R b groups and —O—(CH 2 ) x —R b , the water solubilizing group is
morpholino, piperidinyl, (C1-C6) N-alkyl piperidinyl, N-methyl piperidinyl, piperazinyl, (C1-C6) N-alkylpiperazinyl, N-methylpiperazinyl, N-ethyl piperidinyl, N-ethyl piperazinyl, pyrrolidinyl, N-alkyl pyrrolidinyl, N-methylpyrrolidinyl, diazepinyl, N-ethyl pyrrolidinyl, N-alkyl azepinyl, N-methyl azepinyl, N-ethyl azepinyl, homopiperazinyl, N-methyl homopiperazinyl, N-ethyl homopiperazinyl, or imidazolyl, wherein Y is selected from CH and N, Z is selected from CH 2 , O, S, NH, N—(CH 2 ) y —R a , N—(CH 2 ) y —C(O)R a , N—(CH 2 ) y —C(O)OR a , N—(CH 2 ) y —S(O) 2 R a , N—(CH 2 ) y —S(O) 2 OR a and N—(CH 2 ) y —C(O)NR c R c ,
with the proviso that Y and Z are not both simultaneously CH and CH 2 , respectively;
x is an integer ranging from 1 to 6;
y is an integer ranging from 0 to 6;
R a is selected from hydrogen, lower alkyl, lower cycloalkyl, (C6-C14) aryl, phenyl, naphthyl, (C7-C20) arylalkyl and benzyl;
each R b is, independently of the others, selected from ═O, —OR a , (C1-C3) haloalkyloxy, —OCF 3 , ═S, —SR a , ═NR a , ═NOR a , —NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R a , —S(O) 2 R a , —S(O) 2 OR a , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R a , —OS(O) 2 R a , —OS(O) 2 OR a , —OS(O) 2 NR c R c , —C(O)R a , —C(O)OR a , —C(O)NR c R c , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R a , —OC(O)OR a , —OC(O)NR c R c , —OC(NH)NR c R c and —OC(NR a )NR c R c ;
each R c is, independently of the other, an R a or, alternatively, two R c that are bonded to the same nitrogen atom may be taken together with this nitrogen atom to form a 5-8 membered heterocycloalkyl group which may optionally include from 1 to 3 additional heteroatomic groups selected from O, S, N—(CH 2 ) y —R a , N—(CH 2 ) y —C(O)R a , N—(CH 2 ) y —C(O)OR a , N—(CH 2 ) y —S(O) 2 R a , N—(CH 2 ) y —S(O) 2 OR a and N—(CH 2 ) y —C(O)NR a R a ,
and which may optionally include one or more of the same or different R 8 and/or lower alkyl substituents; and
each R d is, independently of the others, selected from R a and R c and a chiral auxiliary group selected from the group consisting of,
where R 9 is selected from hydrogen and lower alkyl.
7. The compound of claim 6 , wherein R 11 and R 12 are each hydrogen and R 13 is —OCH 2 NHR a .
8. The compound of claim 6 , wherein R 11 is hydrogen; R 12 is selected from (C1-C3) N-alkyl piperazinyl and N-methyl piperazinyl; and R 13 is methyl.
9. The compound of claim 6 , wherein R 2 is 3-methyl-4-(1-methyl-piperazin-4-yl)phenyl.
10. A compound according to structural formula (I):
or a salt or N-oxide thereof, wherein:
R 2 is a substituted phenyl of the formula:
where
R 11 is hydrogen;
R 12 is a water-solubilizing group, and
R 13 is selected from methyl, halo, chloro, fluoro, (C1-C3) alkoxy, —CH 2 OR e and —C(O)NHR e , where R e is selected from hydrogen, methyl and (C1-C3) alkyl;
R 4 is a saturated or unsaturated bridged C5-C16 cycloalkyl ring substituted with an R 7 group;
R 5 is selected from hydrogen, (C1-C8)alkyl optionally substituted with one or more of the same or different R 8 groups, and a substituent selected from the group consisting of —CN, —NC, —NO 2 , halo, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, (C1-C3) fluoroalkyl, (C1-C3) perfluoroalkyl, —CF 3 , (C1-C3) haloalkoxy, (C1-C3) perhaloalkoxy, (C1-C3) fluoroalkoxy, (C1-C3) perfluoroalkoxy, —OCF 3 , —C(O)R a , —C(O)OR a , —C(O)CF 3 , and —C(O)OCF 3 ; and
R 7 is —C(O)OR d or —C(O)NR d R d ,
wherein
each R 8 group is, independently of the others, selected from a water-solubilizing group, R a , R b , lower cycloalkyl optionally substituted with one or more of the same or different R a and/or R b groups, lower heterocycloalkyl optionally substituted with one or more of the same or different R a and/or R b groups, lower alkoxy optionally substituted with one or more of the same or different R b groups and —O—(CH 2 ) x —R b ,
each water solubilizing group is independently
morpholino, piperidinyl, (C1-C6) N-alkyl piperidinyl, N-methyl piperidinyl, piperazinyl, (C1-C6) N-alkylpiperazinyl, N-methylpiperazinyl, N-ethyl piperidinyl, N-ethyl piperazinyl, pyrrolidinyl, N-alkyl pyrrolidinyl, N-methylpyrrolidinyl, diazepinyl, N-ethyl pyrrolidinyl, N-alkyl azepinyl, N-methyl azepinyl, N-ethyl azepinyl, homopiperazinyl, N-methyl homopiperazinyl, N-ethyl homopiperazinyl, or imidazolyl, wherein Y is selected from CH and N, Z is selected from CH 2 , O, S, NH, N—(CH 2 ) y —R a , N—(CH 2 ) y —C(O)R a , N—(CH 2 ) y —C(O)OR a , N—(CH 2 ) y —S(O) 2 R a , N—(CH 2 ) y —S(O) 2 OR a and N—(CH 2 ) y —C(O)NR c R c , with the proviso that Y and Z are not both simultaneously CH and CH 2 , respectively;
x is an integer ranging from 1 to 6;
y is an integer ranging from 0 to 6;
R a is selected from hydrogen, lower alkyl, lower cycloalkyl, (C6-C14) aryl, phenyl, naphthyl, (C7-C20) arylalkyl and benzyl;
each R b is, independently of the others, selected from —OR a , (C1-C3) haloalkyloxy, —OCF 3 , ═S, —SR a , ═NR a , ═NOR a , —NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R a , —S(O) 2 R a , —S(O) 2 OR a , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R a , —OS(O) 2 R a , —OS(O) 2 OR a , —OS(O) 2 NR c R c , —C(O)R a , —C(O)OR a , —C(O)NR c R c , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R c , —C(NOH)NR c R c , —OC(O)R a , —OC(O)OR a , —OC(O)NR c R c , —OC(NH)NR c R c and —OC(NR a )NR c R c ;
each R c is, independently of the other, an R a or, alternatively, two R c that are bonded to the same nitrogen atom may be taken together with this nitrogen atom to form a 5-8 membered heterocycloalkyl group which may optionally include from 1 to 3 additional heteroatomic groups selected from O, S, N—(CH 2 ) y —R a , N—(CH 2 ) y —C(O)R a , N—(CH 2 ) y —C(O)OR a , N—(CH 2 ) y —S(O) 2 R a , N—(CH 2 ), —S(O) 2 OR a and N—(CH 2 ) y —C(O)NR a R a , and which may optionally include one or more of the same or different R 8 and/or lower alkyl substituents; and
each R d is, independently of the others, selected from R a and R c and a chiral auxiliary group selected from the group consisting of,
where R 9 is selected from hydrogen and lower alkyl.
11. A compound according to structural formula (I):
or a salt or N-oxide thereof, wherein:
R 2 is selected from
where
Y 1 is selected from O, S, NH, N—(CH 2 ) y —R a , N—(CH 2 ) y —C(O)R a , N—(CH 2 ) y —C(O)OR a , N—(CH 2 ) y —S(O) 2 R a , N—(CH 2 ) y —S(O) 2 OR a and N—(CH 2 ) y —C(O)NR c R c ,
Y 2 is selected from O, S and S(O) 2 , and
the bonds including the dotted line are single bonds or double bonds;
R 4 is a saturated or unsaturated bridged C5-C16 cycloalkyl ring substituted with an R 7 group;
R 5 is selected from hydrogen, (C1-C8)alkyl optionally substituted with one or more of the same or different R 8 groups, and a substituent selected from the group consisting of —CN, —NC, —NO 2 , halo, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, (C1-C3) fluoroalkyl, (C1-C3) perfluoroalkyl, —CF 3 , (C1-C3) haloalkoxy, (C1-C3) perhaloalkoxy, (C1-C3) fluoroalkoxy, (C1-C3) perfluoroalkoxy, —OCF 3 , —C(O)R a , —C(O)OR a , —C(O)CF 3 , and —C(O)OCF 3 ; and
R 7 is —C(O)OR d or —C(O)NR d R d ,
wherein
each R 8 group is, independently of the others, selected from a water-solubilizing group, R a , R b , lower cycloalkyl optionally substituted with one or more of the same or different R a and/or R b groups, lower heterocycloalkyl optionally substituted with one or more of the same or different R a and/or R b groups, lower alkoxy optionally substituted with one or more of the same or different R b groups and —O—(CH 2 ) x —R b , where, wherein the water solubilizing group is
morpholino, piperidinyl, (C1-C6) N-alkyl piperidinyl, N-methyl piperidinyl, piperazinyl, (C1-C6) N-alkylpiperazinyl, N-methylpiperazinyl, N-ethyl piperidinyl, N-ethyl piperazinyl, pyrrolidinyl, N-alkyl pyrrolidinyl, N-methylpyrrolidinyl, diazepinyl, N-ethyl pyrrolidinyl, N-alkyl azepinyl, N-methyl azepinyl, N-ethyl azepinyl, homopiperazinyl, N-methyl homopiperazinyl, N-ethyl homopiperazinyl, or imidazolyl, wherein Y is selected from CH and N, Z is selected from CH 2 , O, S, NH, N—(CH 2 ) y —R a , N—(CH 2 ), C(O)R a , N—(CH 2 ) y —C(O)OR a , N—(CH 2 ) y —S(O) 2 R a , N—(CH 2 ) y —S(O) 2 OR a and N—(CH 2 ) y —C(O)NR c R c , with the proviso that Y and Z are not both simultaneously CH and CH 2 , respectively;
x is an integer ranging from 1 to 6;
y is an integer ranging from 0 to 6;
R a is selected from hydrogen, lower alkyl, lower cycloalkyl, (C6-C14) aryl, phenyl, naphthyl, (C7-C20) arylalkyl and benzyl;
each R b is, independently of the others, selected from ═O, —OR a , (C1-C3) haloalkyloxy, —OCF 3 , ═S, —SR a , ═NR a , ═NOR a , —NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R a , —S(O) 2 R a , —S(O) 2 OR a , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R a , —OS(O) 2 R a , —OS(O) 2 OR a , —OS(O) 2 NR c R c , —C(O)R a , —C(O)OR a , —C(O)NR c R c , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R a , —OC(O)OR a , —OC(O)NR c R c , —OC(NH)NR c R c and —OC(NR a )NR c R c ;
each R c is, independently of the other, an R a or, alternatively, two R c that are bonded to the same nitrogen atom may be taken together with this nitrogen atom to form a 5-8 membered heterocycloalkyl group which may optionally include from 1 to 3 additional heteroatomic groups selected from O, S, N—(CH 2 ) y —R a , N—(CH 2 ) y —C(O)R a , N—(CH 2 ) y C(O)OR a , N—(CH 2 ) y —S(O) 2 R a , N—(CH 2 ) y —S(O) 2 OR a and N—(CH 2 ) y —C(O)N a R a , and which may optionally include one or more of the same or different R 8 and/or lower alkyl substituents; and
each R d is, independently of the others, selected from R a and R c and a chiral auxiliary group selected from the group consisting of,
where R 9 is selected from hydrogen and lower alkyl.
12. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, excipient and/or diluent.