Triazine compounds as PI3 kinase and MTOR inhibitors

A pharmaceutically acceptable salt of a compound of the Formula I:

• wherein:
• R1 is
• wherein:
• 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 0, NH and S;
• the dashed line - - - - - represents an optional second bond;
• R2 is optionally substituted C6-C14aryl-NH—COR3, optionally substituted C1-C9heteroaryl-NH—COR3, —CH═CH—C6-C10aryl-NH—COR3 or —CH═CH—C1-C9heteroaryl-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-C10aryl, C1-C6haloalkyl, optionally substituted C1-C9heteroaryl, C1-C6hydroxylalkyl-, C3-C10saturated 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;
• l) 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-C6heteroaryl, 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, 0, 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-C6alkyl, optionally substituted C3-C6alkenyl, and optionally substituted C3-C6alkynyl, 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 0, 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) 0, 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-C6acyl-, 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-C6cycloalkyl 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-C6perfluoroalkyl-;
• and n) C(O)Rc wherein Rc is:
• i) H, ii) C1-C6alkyl, or iii) C3-C6cycloalkyl,
• wherein said pharmaceutically acceptable salt is selected from the group consisting of:
• acetate, aluminum, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzathine (N,N′-dibenzylethylenediamine), benzenesulfonate, benzoate, bicarbonate, bismuth, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate (camphorsulfonate), carbonate, chloride, choline, citrate, clavulariate, diethanolamine, dihydrochloride, diphosphate, edetate, edisylate (camphorsulfonate), esylate (ethanesulfonate), ethylenediamine, fumarate, gluceptate (glucoheptonate), gluconate, glucuronate, glutamate, hexafluorophosphate, hexylresorcinate, hydrabamine (N,N′-bis(dehydroabietyl)ethylenediamine), hydrobromide, hydrochloride, hydroxynaphthoate, 1-hydroxy-2-naphthoate, 3-hydroxy-2-naphthoate, iodide, isothionate (2-hydroxyethanesulfonate), lactate, lactobionate, laurate, lauryl sulfate, lithium, magnesium, malate, maleate, mandelate, meglumine (1-deoxy-1-(methylamino)-D-glucitol), mesylate, methyl bromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoate (4,4′-methylenebis-3-hydroxy-2-naphthoate, or embonate), pantothenate, phosphate, picrate, polygalacturonate, potassium, propionate, p-toluenesulfonate, salicylate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate (8-chloro-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione), triethiodide, tromethamine (2-amino-2-(hydroxymethyl)-1,3-propanediol), valerate, and zinc salts.