US 8,575,159 B2 · Triazine compounds as PI3 kinase and mTOR inhibitors

Abstract

Compounds of formula I wherein: R1 is and R2, R4, and R6-9 are defined herein, and pharmaceutically acceptable salts and esters thereof. These compounds inhibit PI3 kinase and mTOR, and may be used to treat diseases mediated by PI3 kinase and mTOR, such as a variety of cancers. Methods for making and using the compounds of this invention are disclosed. Various compositions containing the compounds of this invention are also disclosed.

A compound of the Formula I:

wherein:
R1 is
R6, R7, R8, R9 are each independently selected from the group consisting of a hydrogen atom, and a C1-C6alkyl optionally substituted with C2-C6alkenyl, C4-C6alkadienyl, C2-C6alkynyl or C4-C6alkadiynyl;
or one of R6 and R7 or R8 and R9, together with the carbon atoms to which they are attached form an optionally substituted 5-8 membered saturated or unsaturated ring containing 0, 1 or 2 atoms independently selected from O, NH and S;
the dashed line ----- represents an optional second bond;
R2 is optionally substituted C6-C14aryl-NH—COR3;
R3 is OR5, NR5R5 or NHR5;
R5 is independently selected from the group consisting of C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, optionally substituted C6-C10 aryl, C1-C6haloalkyl, optionally substituted C1-C9heteroaryl, C1-C6hydroxylalkyl-, C3-C10 saturated or unsaturated mono or bicyclic C3-C10cycloalkyl optionally substituted with OH, NR11R11 or 3-7 membered C1-C6heterocyclyl, and 3-10 membered saturated or unsaturated mono or bicyclic C1-C9heterocyclyl, with the proviso that three-membered cycloalkyl and heterocyclyl rings are saturated;
or two R5 groups taken together with the nitrogen atom to which they are attached form a 3 to 8 membered ring system optionally substituted with C1-C6alkyl, which ring system is saturated or unsaturated and has, in addition to said nitrogen atom, 0 to 2 heteroatom ring members selected from O, S, S(O), S(O)2 and NR10;
R10 is selected from the group consisting of H, C1-C6alkyl, —SO2(C1-C6alkyl), —COO(C1-C6alkyl), —CONH(C1-C6alkyl), —CON(C1-C6alkyl)2, —CO(C1-C6alkyl), and —SO2NHR11;
R11 is selected from the group consisting of H, C1-C6alkyl optionally substituted with OH, NR11R11 or a 3-7 membered C1-C6heterocyclyl, —CO(C1-C6alkyl), optionally substituted C6-C10aryl, and optionally substituted C1-C9heteroaryl;
R4 is selected from the group consisting of:
a) C1-C6alkyl′ optionally substituted with:
i) 3-10 membered C1-C9heterocyclyl optionally substituted with C1-C6alkyl-, ii) H2N—, iii) (C1-C6alkyl)NH—, iv) (C1-C6alkyl)2N—, v) NH(CH2)aN(C1-C6alkyl)2 wherein a is 2, 3 or 4, and vi) CHO, b) C3-C6alkenyl, c) C3-C6alkynyl, d) —O—C1-C8alkyl optionally substituted with —O—C1-C8alkyl, e) —O—C3-C8alkenyl, f) —O—C3-C8alkynyl, g) saturated or unsaturated mono or bicyclic C3-C8cycloalkyl, and h) saturated or unsaturated mono or bicyclic —O—C3-C12cycloalkyl, all the above optionally substituted with OH, NR11R11 or a 3-7 membered C1-C6heterocyclyl optionally substituted with C1-C6alkyl-, provided that an OH or NR11R11 is not directly bonded to a carbon atom that is double- or triple-bonded to another carbon atom;
i) —CH═CH—C6-C10aryl;
j) —CH═CH—C1-C9heteroaryl;
k) optionally substituted C6-C10aryl;
I) optionally substituted 5-10 membered C1-C9heteroaryl attached to the triazine moiety via a carbon atom;
m) 3-10 membered saturated or unsaturated monocyclic C1-C9heterocyclyl attached to the triazine moiety through a carbon or nitrogen atom and optionally substituted with from 1 to 3 substituents independently selected from:
OH, NR11R11, C1-C6alkyl, (C1-C6alkyl)amido-, (C1-C6alkyl)C(O)—, (C1-C6alkoxy)carbonyl-, adamantyl, C1-C6hydroxylalkyl-, (C1-C6alkyl)amido-;
or a 3-7 membered C1-C6heterocyclyl, with the proviso that 3 membered heterocyclyl is saturated and attached to the triazine moiety through a nitrogen atom, and 5 membered bicyclic heterocyclyl is saturated;
n) optionally substituted —O—C6-C10aryl;
o) optionally substituted —O—C1-C9heteroaryl;
p) —O-(3-12 membered saturated or unsaturated mono or bicyclic)C1-C9heterocyclyl optionally substituted with (C1-C6alkoxy)carbonyl-, H2NS(O)2—, or C1-C6alkyl further optionally substituted with OH, NR11R11 or a 3-7 membered C1-C6heterocyclyl, with the proviso that three membered heterocyclyl is saturated;
q) —NHC6-C10aryl, r) —NHC1-C9heteroaryl, s) —NHNH2, t) —NHNHC1-C6alkyl, u) —NHN(C1-C6alkyl)2, v) —NHOH, w) —COOH, x) —COO—C1- C6alkyl, y)
—CONR12R13, z) —NR12R13,
wherein Z is CH2, O, S(O)n or NR10 and n is 0, 1 or 2;
ee) halogen, ff) C6-C14aryl-S(O)2—NH—, gg) R11NHC(O)NH—O—, and hh) optionally substituted 5-membered monocyclic C1-C4heteroaryl attached to the triazine moiety via a nitrogen atom;
R12 and R13 are each independently selected from H, optionally mono or disubstituted C1-C8alkyl, optionally substituted C3-C8alkenyl, and optionally substituted C3-C8alkynyl, the optional substituents being selected from C1-C6alkoxy, OH, NR11R11, and 3-7 membered C1-C6heterocyclyl, provided that an OH or NR11R11 is not directly bonded to a carbon atom that is double- or triple-bonded to another carbon atom;
or R12 and R13 taken together with the nitrogen atom to which they are attached form a 3 to 8 membered monocyclic ring system optionally substituted with C1-C6alkyl, which ring system is saturated or unsaturated and has, in addition to said nitrogen atom, 0 to 2 heteroatom ring members selected from O, S(O)n and NR10;
or R12 and R13 taken together with the nitrogen atom to which they are attached form wherein a and b are each independently —CH2—, O, S, or NR10, and x is 1-3;
C1-C9heteroaryl refers to a 5-10 membered aromatic ring system having one or more rings and 1, 2, 3 or 4 ring members independently selected from O, NR10, and S(O)n;
C1-C9heterocyclyl refers to a 3-10 membered ring system having one or more rings and 1, 2, 3 or 4 ring members independently selected from O, NR10, and S(O)n;
and
optionally substituted aryl and heteroaryl groups are unsubstituted or are substituted with 1 or 2 moieties selected from the group consisting of:
a) C1-C6alkyl optionally substituted with OH, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, —NH(CH2)wN(C1-C6alkyl)2 wherein w is 2, 3 or 4, or 3-10 membered C1-C9heterocyclyl optionally substituted with from 1 to 3 independently selected C1-C6alkyl- substituents;
b) halogen;
c) hydroxy;
d) NH2;
e) NO2;
f) SO2NH2;
g) COOH;
h) COO(C1-C6alkyl);
i) NHCOO(C1-C6alkyl);
j) NH(C1-C6alkyl);
k) N(C1-C6alkyl)2;
l) C(O)NRaRb, wherein Ra is H or C1-C6alkyl, and Rb is H, C1-C6alkyl, (C6-C14aryl)alkyl-, or (C1-C9heteroaryl)alkyl-;
m) —Y-Q, wherein Y is:
i) O, ii) NH, iii) N(C1-C6alkyl), iv) NHSO2, v) SO2NH, vi) NHCONH, vii) NHCON(C1-C6alkyl), viii) S(O)q, q is 0, 1 or 2, ix)-C(O)NH—, x) —NHC(O)— xi)-C(O)N(CH3)—, xii) C(O), or xiii) absent, and Q is selected from:
i) C6-C10aryl, optionally substituted with from 1 to 3 substituents independently selected from:
A) C1-C6alkoxy- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, 3) di(C1-C6alkyl)amino-, 4) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl-, or 5) hydroxyl, B) (C1-C6alkoxy)carbonyl-, C) (C1-C6alkoxy)C(O)NH—, D) C1-C6alkyl- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, E) (C1-C6alkyl)amino-, F) di(C1-C6alkyl)amino-, G) (C1-C6alkyl)amido- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, H) (C1-C6alkyl)carboxyamido-, I) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl- or C1-C6hydroxylalkyl-, J) heterocyclyl(C1-C6alkyl)- optionally substituted by C1-C6alkyl-, K) halogen, L) hydroxyl, M) C1-C6hydroxylalkyl-, N) perfluoro(C1-C6)alkyl-, O) H2N—, P) O2N—, Q) H2NSO2—, R)HO2C—, and S) NC—, ii) 5-10 membered C1-C9heteroaryl, optionally substituted with from 1 to 3 substituents independently selected from:
A) C1-C6alkoxy- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, 3) di(C1-C6alkyl)amino-, 4) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl-, or 5) hydroxyl, B) (C1-C6alkoxy)carbonyl-, C) (C1-C6alkoxy)C(O)NH—, D) C1-C6alkyl- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, E) (C1-C6alkyl)amino-, F) di(C1-C6alkyl)amino-, G) (C1-C6alkyl)amido- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, H) (C1-C6alkyl)carboxyamido-, I) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl- or C1-C6hydroxylalkyl-, J) heterocyclyl(C1-C6alkyl)- optionally substituted by C1-C6alkyl-, K) halogen, L) hydroxyl, M) C1-C6hydroxylalkyl-, N) perfluoro(C1-C6)alkyl-, O) H2N—, P)O2N—, Q) H2NSO2—, R)HO2C—, and S)NC—, iii) 3-10 membered C1-C9heterocyclyl, optionally substituted with from 1 to 3 substituents independently selected from:
A) C1-C6alkyl-, B) heterocyclyl(C1-C6alkyl)-, C) (C6-C14aryl)alkyl-, D) C1-C8acyl-, E) (C1-C6alkoxy)carbonyl-, F) (C1-C6alkyl)carboxyl-, G) halogen, H) C1-C6haloalkyl-, I) hydroxyl, J) C1-C6hydroxyalkyl-, K) H2N—, L) (C1-C6alkyl)amino-, M) di(C1-C6alkyl)amino-, N) HO2C—, O) (C1-C6alkoxy)carbonyl-, P) (C1-C6alkyl)carboxyl-, Q) (C1-C6alkyl)amido-, R)H2NC(O)—, S) (C1-C6alkyl)carboxyamido-, T) 5-10 membered C1-C9heteroaryl, U) C6-C14ary, V) C3-C8cycloalkyl W) 3-10 membered C1-C9heterocyclyl, X) NC—;
and Y) —NO2;
iv) C3-C10cycloalkyl, v) C1-C6alkyl, vi) C2-C6alkenyl, vii) C2-C6alkynyl, viii) C1-C6hydroxyalkyl-, ix) (CH2)vO(C1-C6alkyl), x) (CH2)vNH2, xi) (CH2)vNH(C1-C6alkyl), xii) (CH2)vN(C1-C6alkyl)2, xiii) O(CH2)vN(C1-C6alkyl)2, xiv) (CH2)vC6-C10aryl, xv) —CN, xvi) (CH2)v 5-10 membered C1-C9heteroaryl, xvii) (CH2)v 3-10 membered C1-C9heterocyclyl, optionally substituted by C1-C6alkyl-, wherein v is 1, 2, 3 or 4, and xviii) C1-C6 perfluoroalkyl-;
and n) C(O)Rc wherein Rc is:
i) H, ii) C1-C6alkyl, or iii) C3-C6cycloalkyl,
or a pharmaceutically acceptable salt thereof.

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Triazine compounds as PI3 kinase and mTOR inhibitors

Life of this patent

Triazine compounds as PI3 kinase and mTOR inhibitors

Life of this patent

Abstract

Claims21