Triazine compounds as PI3 kinase and MTOR inhibitors

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

wherein:

R 1 is

wherein:

R 6 , R 7 , R 8 , R 9 are each independently selected from the group consisting of a hydrogen atom, and a C 1 -C 6 alkyl optionally substituted with C 2 -C 6 alkenyl, C 4 -C 6 alkadienyl, C 2 -C 6 alkynyl or C 4 -C 6 alkadiynyl;

or one of R 6 and R 7 or R 8 and R 9 , 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;

R 2 is optionally substituted C 6 -C 14 aryl-NH—COR 3 , optionally substituted C 1 -C 9 heteroaryl-NH—COR 3 , —CH═CH—C 6 -C 10 aryl-NH—COR 3 or —CH═CH—C 1 -C 9 heteroaryl-NH—COR 3 ;

R 3 is OR 5 , NR 5 R 5 or NHR 5 ;

R 5 is independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, optionally substituted C 6 -C 10 aryl, C 1 -C 6 haloalkyl, optionally substituted C 1 -C 9 heteroaryl, C 1 -C 6 hydroxylalkyl-, C 3 -C 10 saturated or unsaturated mono or bicyclic C 3 -C 10 cycloalkyl optionally substituted with OH, NR 11 R 11 or 3-7 membered C 1 -C 6 heterocyclyl, and 3-10 membered saturated or unsaturated mono or bicyclic C 1 -C 9 heterocyclyl, with the proviso that three-membered cycloalkyl and heterocyclyl rings are saturated;

or two R 5 groups taken together with the nitrogen atom to which they are attached form a 3 to 8 membered ring system optionally substituted with C 1 -C 6 alkyl, 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 NR 10 ;

R 10 is selected from the group consisting of H, C 1 -C 6 alkyl, —SO 2 (C 1 -C 6 alkyl), —COO(C 1 -C 6 alkyl), —CONH(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —CO(C 1 -C 6 alkyl), and —SO 2 NHR 11 ;

R 11 is selected from the group consisting of H, C 1 -C 6 alkyl optionally substituted with OH, NR 11 R 11 or a 3-7 membered C 1 -C 6 heterocyclyl, —CO(C 1 -C 6 alkyl), optionally substituted C 6 -C 10 aryl, and optionally substituted C 1 -C 9 heteroaryl;

R 4 is selected from the group consisting of: a) C 1 -C 6 alkyl optionally substituted with: i) 3-10 membered C 1 -C 9 heterocyclyl optionally substituted with C 1 -C 6 alkyl-, ii) H 2 N—, iii) (C 1 -C 6 alkyl)NH—, iv) (C 1 -C 6 alkyl) 2 N—, v) NH(CH 2 ) a N(C 1 -C 6 alkyl) 2 wherein a is 2, 3 or 4, and vi) CHO, b) C 3 -C 6 alkenyl, c) C 3 -C 6 alkynyl, d) —O—C 1 -C 8 alkyl optionally substituted with —O—C 1 -C 8 alkyl, e) —O—C 3 -C 8 alkenyl, f) —O—C 3 -C 8 alkynyl, g) saturated or unsaturated mono or bicyclic C 3 -C 8 cycloalkyl, and h) saturated or unsaturated mono or bicyclic —O—C 3 -C 12 cycloalkyl, all the above optionally substituted with OH, NR 11 R 11 or a 3-7 membered C 1 -C 6 heterocyclyl optionally substituted with C 1 -C 6 alkyl-, provided that an OH or NR 11 R 11 is not directly bonded to a carbon atom that is double- or triple-bonded to another carbon atom; i) —CH═CH—C 6 -C 10 aryl; j) —CH═CH—C 1 -C 9 heteroaryl; k) optionally substituted C 6 -C 10 aryl; l) optionally substituted 5-10 membered C 1 -C 9 heteroaryl attached to the triazine moiety via a carbon atom; m) 3-10 membered saturated or unsaturated monocyclic C 1 -C 9 heterocyclyl attached to the triazine moiety through a carbon or nitrogen atom and optionally substituted with from 1 to 3 substituents independently selected from: OH, NR 11 R 11 , C 1 -C 6 alkyl, (C 1 -C 6 alkyl)amido-, (C 1 -C 6 alkyl)C(O)—, (C 1 -C 6 alkoxy)carbonyl-, adamantyl, C 1 -C 6 hydroxylalkyl-, (C 1 -C 6 alkyl)amido-; or a 3-7 membered C 1 -C 6 heterocyclyl, 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—C 6 -C 10 aryl; o) optionally substituted —O—C 1 -C 9 heteroaryl; p) —O-(3-12 membered saturated or unsaturated mono or bicyclic)C 1 -C 9 heterocyclyl optionally substituted with (C 1 -C 6 alkoxy)carbonyl-, H 2 NS(O) 2 —, or C 1 -C 6 alkyl further optionally substituted with OH, NR 11 R 11 or a 3-7 membered C 1 -C 6 heterocyclyl, with the proviso that three membered heterocyclyl is saturated; q) —NHC 6 -C 10 aryl, r) —NHC 1 -C 6 heteroaryl, s) —NHNH 2 , t) —NHNHC 1 -C 6 alkyl, u) —NHN(C 1 -C 6 alkyl) 2 , v) —NHOH, w) —

COOH, x) —COO—C 1 -C 6 alkyl, y) —CONR 12 R 13 , z) —NR 12 R 13 ,

wherein Z is CH 2 , 0, S(O) n or NR 10 and n is 0, 1 or 2;

ee) halogen, ff) C 6 -C 14 aryl-S(O) 2 —NH—, gg) R 11 NHC(O)NH—O—, and hh) optionally substituted 5-membered monocyclic C 1 -C 4 heteroaryl attached to the triazine moiety via a nitrogen atom;

R 12 and R 13 are each independently selected from H, optionally mono or disubstituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 alkenyl, and optionally substituted C 3 -C 6 alkynyl, the optional substituents being selected from C 1 -C 6 alkoxy, OH, NR 11 R 11 , and 3-7 membered C 1 -C 6 heterocyclyl, provided that an OH or NR 11 R 11 is not directly bonded to a carbon atom that is double- or triple-bonded to another carbon atom;

or R 12 and R 13 taken together with the nitrogen atom to which they are attached form a 3 to 8 membered monocyclic ring system optionally substituted with C 1 -C 6 alkyl, 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 NR 10 ;

or R 12 and R 13 taken together with the nitrogen atom to which they are attached form

wherein a and b are each independently —CH 2 —, O, S, or NR 10 , and x is 1-3;

C 1 -C 9 heteroaryl 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, NR 10 , and S(O) n ;

C 1 -C 9 heterocyclyl 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, NR 10 , 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) C 1 -C 6 alkyl optionally substituted with OH, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , —NH(CH 2 ) w N(C 1 -C 6 alkyl) 2 wherein w is 2, 3 or 4, or 3-10 membered C 1 -C 9 heterocyclyl optionally substituted with from 1 to 3 independently selected C 1 -C 6 alkyl- substituents; b) halogen; c) hydroxy; d) NH 2 ; e) NO 2 ; f) SO 2 NH 2 ; g) COOH; h) COO(C 1 -C 6 alkyl); i) NHCOO(C 1 -C 6 alkyl); j) NH(C 1 -C 6 alkyl); k) N(C 1 -C 6 alkyl) 2 ; l) C(O)NR a R b , wherein R a is H or C 1 -C 6 alkyl, and R b is H, C 1 -C 6 alkyl, (C 6 -C 14 aryl)alkyl-, or (C 1 -C 9 heteroaryl)alkyl-; m) —Y-Q, wherein Y is: i) 0, ii) NH, iii) N(C 1 -C 6 alkyl), iv) NHSO 2 , v) SO 2 NH, vi) NHCONH, vii) NHCON(C 1 -C 6 alkyl), viii) S(O) q , q is 0, 1 or 2, ix) —C(O)NH—, x) —NHC(O)— xi) —C(O)N(CH 3 )—, xii) C(O), or xiii) absent, and Q is selected from: i) C 6 -C 10 aryl, optionally substituted with from 1 to 3 substituents independently selected from: A) C 1 -C 6 alkoxy-optionally substituted with 1) H 2 N—, 2) (C 1 -C 6 alkyl)amino-, 3) di(C 1 -C 6 alkyl)amino-, 4) C 1 -C 9 heterocyclyl- optionally substituted by C 1 -C 6 alkyl-, or 5) hydroxyl, B) (C 1 -C 6 alkoxy)carbonyl-, C) (C 1 -C 6 alkoxy)C(O)NH—, D) C 1 -C 6 alkyl- optionally substituted with 1) H 2 N—, 2) (C 1 -C 6 alkyl)amino-, or 3) di(C 1 -C 6 alkyl)amino-, E) (C 1 -C 6 alkyl)amino-, F) di(C 1 -C 6 alkyl)amino-, G) (C 1 -C 6 alkyl)amido- optionally substituted with 1) H 2 N—, 2) (C 1 -C 6 alkyl)amino-, or 3) di(C 1 -C 6 alkyl)amino-, H) (C 1 -C 6 alkyl)carboxyamido-, I) C 1 -C 9 heterocyclyl-optionally substituted by C 1 -C 6 alkyl- or C 1 -C 6 hydroxylalkyl-, J) heterocyclyl(C 1 -C 6 alkyl)- optionally substituted by C 1 -C 6 alkyl-, K) halogen, L) hydroxyl, M) C 1 -C 6 hydroxylalkyl-, N) perfluoro(C 1 -C 6 )alkyl-, O) H 2 N—, P) O 2 N—, Q) H 2 NSO 2 —, R) HO 2 C—, and S) NC—, ii) 5-10 membered C 1 -C 9 heteroaryl, optionally substituted with from 1 to 3 substituents independently selected from: A) C 1 -C 6 alkoxy- optionally substituted with 1) H 2 N—, 2) (C 1 -C 6 alkyl)amino-, 3) di(C 1 -C 6 alkyl)amino-, 4) C 1 -C 9 heterocyclyl- optionally substituted by C 1 -C 6 alkyl-, or 5) hydroxyl, B) (C 1 -C 6 alkoxy)carbonyl-, C) (C 1 -C 6 alkoxy)C(O)NH—, D) C 1 -C 6 alkyl- optionally substituted with 1) H 2 N—, 2) (C 1 -C 6 alkyl)amino-, or 3) di(C 1 -C 6 alkyl)amino-, E) (C 1 -C 6 alkyl)amino-, F) di(C 1 -C 6 alkyl)amino-, G) (C 1 -C 6 alkyl)amido- optionally substituted with 1) H 2 N—, 2) (C 1 -C 6 alkyl)amino-, or 3) di(C 1 -C 6 alkyl)amino-, H) (C 1 -C 6 alkyl)carboxyamido-, I) C 1 -C 9 heterocyclyl- optionally substituted by C 1 -C 6 alkyl- or C 1 -C 6 hydroxylalkyl-, J) heterocyclyl(C 1 -C 6 alkyl)- optionally substituted by C 1 -C 6 alkyl-, K) halogen, L) hydroxyl, M) C 1 -C 6 hydroxylalkyl-, N) perfluoro(C 1 -C 6 )alkyl-, O) H 2 N—, P) O 2 N—, Q) H 2 NSO 2 —, R) HO 2 C—, and S) NC—, iii) 3-10 membered C 1 -C 9 heterocyclyl, optionally substituted with from 1 to 3 substituents independently selected from: A) C 1 -C 6 alkyl-, B) heterocyclyl(C 1 -C 6 alkyl)-, C) (C 6 -C 14 aryl)alkyl-, D) C 1 -C 6 acyl-, E) (C 1 -C 6 alkoxy)carbonyl-, F) (C 1 -C 6 alkyl)carboxyl-, G) halogen, H) C 1 -C 6 haloalkyl-, I) hydroxyl, J) C 1 -C 6 hydroxyalkyl-, K) H 2 N—, L) (C 1 -C 6 alkyl)amino-, M) di(C 1 -C 6 alkyl)amino-, N) HO 2 C—, O) (C 1 -C 6 alkoxy)carbonyl-, P) (C 1 -C 6 alkyl)carboxyl-, Q) (C 1 -C 6 alkyl)amido-, R) H 2 NC(O)—, S) (C 1 -C 6 alkyl)carboxyamido-, T) 5-10 membered C 1 -C 9 heteroaryl, U) C 6 -C 14 ary, V) C 3 -C 6 cycloalkyl W) 3-10 membered C 1 -C 9 heterocyclyl, X)NC—; and Y) —NO 2 ; iv) C 3 -C 10 cycloalkyl, v) C 1 -C 6 alkyl, vi) C 2 -C 6 alkenyl, vii) C 2 -C 6 alkynyl, viii) C 1 -C 6 hydroxyalkyl-, ix) (CH 2 ) v O(C 1 -C 6 alkyl), x) (CH 2 ) v NH 2 , xi) (CH 2 ) v NH(C 1 -C 6 alkyl), xii) (CH 2 ) v N(C 1 -C 6 alkyl) 2 , xiii) O(CH 2 ) v N(C 1 -C 6 alkyl) 2 , xiv) (CH 2 ) v C 6 -C 10 aryl, xv) —CN, xvi) (CH 2 ) v 5-10 membered C 1 -C 9 heteroaryl, xvii) (CH 2 ) v 3-10 membered C 1 -C 9 heterocyclyl, optionally substituted by C 1 -C 6 alkyl-, wherein v is 1, 2, 3 or 4, and xviii) C 1 -C 6 perfluoroalkyl-; and n) C(O)R c wherein R c is: i) H, ii) C 1 -C 6 alkyl, or iii) C 3 -C 6 cycloalkyl,

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.

2. A pharmaceutically acceptable salt of: 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea:

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.