HK1183302B

HK1183302B - Bicyclic azaheterocyclic carboxamides as inhibitors of the kinase p70s6k

Info

Publication number: HK1183302B
Application number: HK13110693.4A
Authority: HK
Inventors: Bayard R. Huck; Constantin Neagu; Reinaldo C. Jones; Lizbeth Celeste Deselm; Yufang Xiao; Srinivasa R. Karra; Ruoxi Lan; Igor Mochalkin; Amanda E. Sutton; Thomas E. Richardson
Original assignee: Merck Patent Gmbh
Priority date: 2010-07-29
Filing date: 2011-07-01
Publication date: 2017-05-05

Description

Bicyclic azaheterocyclic carboxamides as kinase P70S6K inhibitors

Technical Field

The present invention relates to a series of bicyclic azaheterocyclic carboxamide compounds useful in the treatment of hyperproliferative diseases (hyperproliferative diseases) such as cancer in mammals. The invention also includes the use of these compounds in the treatment of hyperproliferative diseases in mammals, particularly humans, and pharmaceutical compositions containing these compounds.

Brief description of the related art

Protein kinases constitute a large family of structurally related enzymes responsible for controlling various signal transduction processes in cells (Hardie, g. and Hanks, S. (1995) the protein kinase domains book.i and II, academic press, san diego, CA). Kinases can be classified into families according to the substrates they phosphorylate (e.g., protein tyrosine, protein serine/threonine, lipids, etc.). Sequence motifs that correspond generally to each of these kinase families have been identified (e.g., Hanks, S.K., Hunter, T., FASEBJ.,9:576-596(1995); Knighton et al, Science,253:407-414(1991); Hiles et al, Cell,70:419-429(1992); Kunz et al, Cell,73:585-596(1993); Garcia-Bustos et al, EMBOJ.,13:2352-2361 (1994)).

Protein kinases may be characterized by their regulatory mechanisms. These mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, and protein-polynucleotide interactions. A single protein kinase may be regulated by more than one mechanism.

Kinases regulate many different cellular processes, including but not limited to, proliferation, differentiation, apoptosis, motility (motility), transcription, translation and other signaling processes, by adding phosphate groups to target proteins. These phosphorylation events perform molecular on/off functions that can modulate or regulate the biological function of the target protein. Phosphorylation of target proteins occurs in response to various extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stress, etc. Appropriate protein kinases function in signaling pathways to activate or inactivate (directly or indirectly) e.g. metabolic enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels or pumps or transcription factors. Uncontrolled signaling due to defective control of protein phosphorylation has been implicated in a variety of diseases including, for example, inflammation, cancer, allergy/asthma, immune system diseases and conditions, central nervous system diseases and conditions, and angiogenesis.

Protein kinase 70S6K, 70kDa ribosomal protein kinase p70S6K (also known as SK6, p70/p85S6 kinase, p70/p85 ribosomal S6 kinase and pp70S6K), is a member of the protein kinase AGC subfamily. p70S6K is a serine-threonine kinase, a component of the phosphatidylinositol 3 kinase (PI3K)/AKT pathway. Downstream of PI3K is p70S6K, whose activation occurs in response to phosphorylation at multiple sites by various mitogens, hormones, and growth factors. p70S6K activity is also controlled by the mTOR-containing complex (TORC1) because rapamycin acts to inhibit p70S6K activity. p70S6K is regulated by PI3K downstream targets AKT and PKC ζ. Akt directly phosphorylates TSC2 and inactivates it, thereby activating mTOR. Furthermore, studies of mutant alleles of p70S6K inhibited by wortmannin but not rapamycin suggest that the PI3K pathway may exhibit an effect on p70S6K independent of the regulation of mTOR activity.

The enzyme p70S6K regulates protein synthesis through phosphorylation of S6 ribosomal proteins. S6 phosphorylation is associated with increased translation of mRNA encoding components of the translation apparatus, including ribosomal proteins and translation elongation factors, whose increased expression is required for cell growth and proliferation. These mrnas contain at their 5 'transcription start (called 5' TOP) a stretch of oligopyrimidine sequences which has been shown to be essential for their regulation at the translation level.

In addition to being involved in translation, p70S6K activation has also been implicated in cell cycle control, neuronal cell differentiation, regulation of cell motility and cellular responses important in tumor metastasis, immune responses and tissue repair. The p70S6K antibody disrupted the mitogenic response driving rat fibroblasts into S phase, indicating that p70S6K function is essential for progression from G1 to S phase in the cell cycle. Furthermore, inhibition of cell cycle proliferation by rapamycin at the cell cycle G1 to S phase has been identified as a consequence of inhibition of the production of the hyperphosphorylated, activated form of p70S 6K.

The role of p70S6K in tumor cell proliferation and protection from apoptosis is supported based on its involvement in growth factor receptor signaling, overexpression and activation in tumor tissues. For example, Northern and Western analyses showed that amplification of the PS6K gene was accompanied by a corresponding increase in the expression of each of mRNA and protein (cancer Res. (1999)59:1408-11-localization of PS6KtoChromosomal region17q23and determination of localization of ItsAmplification in Breast cancer (localization of PS6K to chromosome region17q23and determination of its amplification in breast cancer)).

Chromosome 17q23 was amplified in up to 20% of primary breast tumors, 87% of breast tumors containing a BRCA2 mutation and 50% of tumors containing a BRCA1 mutation as well as other cancer types such as pancreatic cancer, bladder cancer and neuroblastoma (see m.barlund, o.monni, j.kononen, r.cornelison, j.torhorst, g.sauter, o.p.kallioniemi and kallioniemia, cancer res, 2000,60: 5340-. 17q23 amplification has been shown to involve the PAT1, RAD51C, PS6K and SIGMA1B genes in breast cancer (cancer Res. (2000):60, pp.5371-5375).

The p70S6K gene has been identified as a target for amplification and overexpression of this region, and a statistically significant correlation between amplification and poor prognosis has been observed.

Clinical inhibition of p70S6K activation was observed in renal cancer patients treated with CCI-779 (rapamycin ester), an inhibitor of the upstream kinase mTOR. A significant linear correlation between disease progression and inhibition of p70S6K activity was reported.

In response to energy stress, tumor suppressor LKB1 activates AMPK, which phosphorylates TSC1/2 complex and renders it capable of inactivating mTOR/p70S6K channels. The LKB1 mutation results in boyle-jeghersdyrome (PJS), where patients with PJS are 15 times more likely to have cancer than the general population. In addition, the lung adenocarcinoma of 1/3 contained an inactivating LKB1 mutation.

p70S6K has been implicated in a variety of metabolic diseases and disorders. It has been reported that p70S6K deficiency enhances insulin sensitivity while preventing age and diet-induced obesity. The role of P70S6K in metabolic diseases and disorders such as obesity, diabetes, metabolic syndrome, insulin resistance, hyperglycemia, hyperaminoemia and hyperlipidemia is supported based on findings.

Compounds described as suitable for inhibition of p70S6K are disclosed in WO03/064397, WO04/092154, WO05/054237, WO05/056014, WO05/033086, WO05/117909, WO05/039506, WO06/120573, WO06/136821, WO06/071819, WO06/131835, WO08/140947 and PCT/US 10/000313.

Detailed Description

The object of the present invention is to provide novel p70S6K inhibitors useful for the treatment of hyperproliferative diseases, in particular diseases associated with a high activity of the above mentioned protein kinases, such as cancer, in mammals, which have superior pharmacological properties with respect to their activity and their solubility, metabolic clearance and bioavailability characteristics.

Accordingly, the present invention provides novel bicyclic azaheterocyclic carboxamide compounds and pharmaceutically acceptable salts, solvates, or prodrugs thereof, which are kinase inhibitors and are useful in the treatment of the above-mentioned diseases.

The compounds are defined by formula (I):

(I)，

and pharmaceutically acceptable salts, solvates of salts or prodrugs thereof,

wherein:

x is N or C-R³，

Y is NH, O or absent,

R¹is L¹-R⁴-L²-R⁵Or L¹-R⁴，

R²Is A, Hal, OH, OA, SH, CN, NH₂、NO₂、NHA、NH-L¹-Ar、NHCOA、NHCO-L¹-Ar、NHSO₂A、NHSO₂-L¹-Ar、NHCONHA、NHCONH-L¹-Ar、L¹-Ar、O-L¹-Ar、L¹-R⁴，

L¹Is a single bond, a methylene group or a methyl-substituted methylene group, wherein the methyl group of the methylene group or the methyl-substituted methylene group can be unsubstituted or substituted by Hal, OH, CN, NH₂、NH(LA)、N(LA)₂、NO₂、COOH、N₃Mono-or di-substituted with vinyl or ethynyl, and/or by R⁴Monosubstituted, and in which one or two CH₂The radicals being substituted by O or S atoms or by-NH-, -N (LA) -, -CONH-, -N (LA) COO-, -SO₂-or-NHCO-group replacement,

R³is H, A, Hal, OH, COOH, SH, NH₂、NO₂Or the CN group is selected from the group consisting of,

R⁴、R⁵each independently of the others, Ar which may be mono-or disubstituted by Hal or LA or a cyclic A,

L²is-NHCO-, -NHCOO-, -NHCONH-, -NHCONA-, -NHCOA-, -O-, -S-, -NH-, -NHSO-₂-、-SO₂NH-, -CONH-, -CONHCONH-, -NHCONHCO-or-A-,

ar is a monocyclic or bicyclic aromatic homocyclic or heterocyclic ring having 0, 1,2,3 or 4N, O and/or S atoms and 5, 6, 7, 8, 9 or 10 framework atoms, which may be unsubstituted or, independently of one another, Hal, A, OH, SH, OA, NH₂、NHA、NA₂、NO₂、CN、OCN、SCN、COOH、COOA、CONH₂、CONHA、CONA₂、NHCOA、NHCONHA、NHCONH₂、NHSO₂A、CHO、COA、SO₂NH₂、SO₂A and/or SO₂Hal is mono-, di-or tri-substituted,

and wherein the ring N atoms may be substituted with O atoms to form an N-oxide group,

and wherein in the case of bicyclic aromatic rings, one of the two rings may be partially saturated,

a is unbranched or branched, linear or cyclic alkyl having 1,2,3, 4,5, 6, 7 or 8C atoms, in which one or two CH' s₂The radicals may be substituted by O or S atoms and/or by-NH-, -CO-, -NHCOO-, -NHCONH-, -N (LA) -, -CONH-, -NHCO-or-CH = CH-groups, and wherein 1 to 3H atoms may be replaced by Hal, and wherein one or two CH groups₃The radicals being substituted by OH, SH, NH₂、NH(LA)、N(LA)₂、NHCOOH、NHCONH₂Or a substitution of the CN group,

LA is an unbranched or branched linear alkyl radical having 1,2,3 or 4C atoms, in which 1,2 or 3H atoms may be replaced by Hal,

hal is F, Cl, Br or I.

In general, all residues occurring more than once may be the same or different, i.e., independent of each other. In this context, residues and parameters have the meaning indicated for formula (I) unless explicitly indicated otherwise.

The invention therefore relates in particular to compounds of the formula (I) in which at least one of the residues has one of the preferred meanings indicated below.

Hal denotes fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.

"A" denotes, for example, methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore pentyl, 1-, 2-or 3-methylbutyl, 1,1-, 1, 2-or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3-or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2, 3-or 3, 3-dimethylbutyl, 1-or 2-ethylbutyl, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methylpropyl, 1,1, 2-or 1,2, 2-trimethylpropyl.

"A" further means as defined aboveWherein one or two CH₂The radicals can be substituted by O or S atoms and/or by NH, N (LA), CONH, NHCO or-CH = CH-groups, and/or furthermore 1 to 3H atoms can be substituted by F and/or Cl, for example trifluoromethyl, pentafluoromethyl, 1, 1-difluoromethyl, 1,1, 1-trifluoroethyl, methoxy, ethoxy, N-propoxy, isopropoxy, N-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

In other examples of "A", one or two CH₃The radicals being substituted by OH, SH, NH₂、N(LA)H、N(LA)₂Or CN replacement, for example, N, N' -dimethylaminoalkyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 3-aminomethylcyclobutyl or cyanoalkyl.

Cyclic a preferably represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

"LA" denotes unbranched or branched linear alkyl having 1,2,3 or 4C atoms, in which 1,2 or 3H atoms may be replaced by Hal, for example methyl, ethyl, trifluoromethyl, difluoromethyl, 1,1, 1-trifluoroethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

"Ar" represents, for example, unsubstituted phenyl, naphthyl or biphenyl, further preferably, for example, phenyl, naphthyl or biphenyl, each of which is mono-, di-or tri-substituted with: A. fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, benzyloxy, sulfonamido, methylsulfinamino, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl.

"Ar" further represents phenyl, o-, m-or p-tolyl, o-, m-or p-ethylphenyl, o-, m-or p-propylphenyl, o-, m-or p-isopropylphenyl, o-, m-or p-tert-butylphenyl, o-, m-or p-hydroxyphenyl, o-, m-or p-nitrophenyl, o-, m-or p-aminophenyl, o-, m-or p- (N-methylamino) phenyl, o-, m-or p- (N-methylaminocarbonyl) phenyl, o-, m-or p-methoxyphenyl, o-, m-or p-ethoxyphenyl, o-, m-or p- (N, N-dimethylamino) phenyl, o-, m-or p- (N, N-dimethylaminocarbonyl) phenyl, o-, m-or p- (N-ethylamino) phenyl, o-, m-or p- (N, N-diethylamino) phenyl, o-, m-or p-fluorophenyl, O-, m-or p-bromophenyl, o-, m-or p-chlorophenyl, o-, m-or p- (methylsulfonylamino) phenyl, o-, m-or p- (methylsulfonyl) phenyl, further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-dibromophenyl, 2, 4-or 2, 5-dinitrophenyl, 2, 5-or 3, 4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro, 3, 5-dibromophenyl, 2, 4-or 2, 5-dinitrophenyl, 2, 5-or 3, 4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro, 2-amino-3-chloro, 2-amino-4-chloro, 2-amino-5-chloro or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino-or 3-nitro-4-N, N-dimethylaminophenyl, 2, 3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4, 6-or 3,4, 5-trichlorophenyl, 2,4, 6-trimethoxyphenyl, 2-hydroxy-3, 5-dichlorophenyl, p-iodophenyl, 3, 6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2-amino-6-chlorophenyl, 2-nitro-4-bromophenyl, 2, 3-diamino-4-chlorophenyl, 2,3, 4-dichlorophenyl, 2,3, 5-dichlorophen, 2, 5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-4-acetylaminophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetylaminophenyl or 2, 5-dimethyl-4-chlorophenyl, (4-methoxyphenyl) methyl, (3-methoxyphenyl) methyl, (4-methoxyphenyl) ethyl, (3-methoxyphenyl) ethyl.

"Ar" also preferably represents 2-, 3-or 4-phenyl, 2-, 3-or 4-benzyl, 2-, 3-or 4-phenylethyl, 2-or 3-furyl, 2-or 3-thienyl, 1-, 2-or 3-pyrrolyl, 1-, 2-, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, 3-, 4-or 5-isoxazolyl, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolylA group, a 2-, 3-or 4-pyridyl group, a 2-, 3-or 4-pyridylmethyl group, a 2-, 3-or 4-pyridylethyl group, a 2-, 4-, 5-or 6-pyrimidinyl group, a 2-, 3-, 5-or 6-pyrazin-1-or 4-yl group, further preferably a1, 2, 3-triazol-1-, -4-or-5-yl group, a1, 2, 4-triazol-1-, -3-or 5-yl group, a 1-or 5-tetrazolyl group, a1, 2, 3-oxadiazol-4-or-5-yl group, a1, 2, 4-oxadiazol-3-or-5-yl group, a 2-, 3-or 4-pyridylmethyl group, a 2-, 3-or 4-pyridylethyl group, 1,3, 4-oxadiazol-2-yl, 1,3, 4-thiadiazol-2-or-5-yl, 1,2, 4-thiadiazol-3-or-5-yl, 1,2, 3-thiadiazol-4-or-5-yl, 3-or 4-pyridazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 2-, 3-, 4-or 5-isoindolyl, 2-, 6-, or 8-purinyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazolyl, pyrazolyl, pyrimidinyl, pyridazinyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzisoxazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 4-, 5-, 6-or 7-benzo-2, 1, 3-oxadiazolyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolinyl, 3-, 4-, 5-, 6-, 7-or 8-quinolyl, 2-, 4-, 5-, 6-, 7-or 8-quinazolinyl, optionally substituted quinolyl, substituted quinolyl, Quinoxalin-2-, 3-, 4-or 5-yl, 4-, 5-or 6-phthalazinyl, 2-, 3-, 5-, 6-, 7-or 8-2H-benzo-1, 4-oxazinyl, further preferably 1, 3-benzodioxol-2-, 4-or 5-yl, thien-2-or 3-yl, 1, 4-benzodioxan-6-yl, 2,1, 3-benzothiadiazol-4-or-5-yl or 2,1, 3-benzooxadiazol-5-yl, furan-2-or 3-yl, 2, 3-dihydrobenzofuran-2- 3-, 4-or 5-yl, each of which is unsubstituted or mono-, di-or trisubstituted, for example by: carbonyl oxygen, F, Cl, Br, methyl, ethyl, propyl, phenyl, benzyl, -CH₂-cyclohexyl, hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, nitro, cyano, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, acetylamino, ureido, methylsulfonylamino, formyl, acetyl, aminosulfonyl and/or methylsulfonyl.

In which R is¹Is L¹-R⁴-L²-R⁵In the case of (2), the residue R⁴Obviously has a bridging function and is connected with a joint L¹And L²Instead of depending onAny further substitution which may be present.

The term "substituted" preferably means substituted with the above-mentioned substituents, wherein a plurality of different degrees of substitution are possible, unless otherwise indicated.

All physiologically acceptable salts, derivatives, solvates of salts and stereoisomers of these compounds, including mixtures thereof in various ratios, are also in accordance with the invention.

The compounds of formula (I) may have one or more chiral centres. Thus, it may exist in a variety of enantiomeric forms, and may be in racemic or optically active form. The invention therefore also relates to the optically active forms (stereoisomers), enantiomers, racemates, diastereomers and solvates of these compounds.

Since the pharmaceutical activity of racemates or stereoisomers of the compounds of the present invention may vary, it may be desirable to use enantiomers. In these cases, the final product or even the intermediate can be isolated as enantiomeric compound by a person skilled in the art or even by chemical or physical means as used in the synthesis.

For racemic amines, diastereomers are formed from the mixture by reaction with an optically active resolving agent. Examples of synthetic resolving agents are optically active acids such as tartaric acid in the R and S form, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g. N-benzoylproline or N-benzenesulfonylproline), or camphorsulphonic acids of different optical activity. Likewise advantageous is the resolution of the chromatographic enantiomers with the aid of optically active resolving agents, such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derived methacrylate polymers fixed on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane/isopropanol/acetonitrile, for example in a ratio of 82:15: 3.

A clever approach for resolving racemates containing ester groups (e.g. acetyl esters) is the use of enzymes, in particular esterases.

In preferred groups of compounds of the formula (I), the variables and substituents have the following meanings:

x is N, and X is N,

y is NH, and the catalyst is a catalyst,

R¹is L¹-R⁴，

R²Is LA, Hal, OH, O (LA), SH, CN, NH₂、NO₂、NH(LA)、NHCO(LA)、NHSO₂(LA)、NHCONH(LA)，

L¹Is a methyl-substituted methylene group, wherein the methyl group of the methyl-substituted methylene group is replaced by NH₂Or NH (LA), N (LA)₂Or cyclic A which may be mono-or di-substituted by Hal or LA,

R⁴is a monocyclic aromatic homocyclic or heterocyclic ring having 0, 1 or 2N, O and/or S atoms and 5 or 6 framework atoms, which may be unsubstituted or, independently of one another, Hal, A, OH, SH, OA, NH₂、NHA、NA₂、NO₂、CN、OCN、SCN、COOH、COOA、CONH₂、CONHA、CONA₂、NHCOA、NHCONHA、NHCONH₂、NHSO₂A、CHO、COA、SO₂NH₂、SO₂A and/or SO₂Hal is mono-, di-or tri-substituted,

hal is F, Cl, Br or I.

Further preferred are compounds of the sub-formulae 1 to 19 of the formula (I), in which the residues not specified in more detail have the meanings indicated for the preferred radicals of the above-mentioned compounds and their pharmaceutically acceptable salts, solvates of salts or prodrugs, wherein

In sub-formula 1

R²In the form of LA, the content of LA,

in sub-formula 2

L¹Is a methyl-substituted methylene group, wherein the methyl group of the methyl-substituted methylene group is mono-substituted with methylamino, dimethylamino or azetidine,

in sub-formula 3

R⁴Is phenyl which is unsubstituted or monosubstituted by Hal,

in sub-formula 4

R²Is methyl, ethyl, isopropyl or trifluoromethyl,

in sub-formula 5

L1 is a methyl-substituted methylene group in which the methyl group of the methyl-substituted methylene group is monosubstituted by a methylamino group,

in sub-formula 6

L¹Is methyl-substituted methylene, wherein the methyl group of the methyl-substituted methylene is monosubstituted with azetidin-1-yl,

in sub-formula 7

R⁴Is an unsubstituted phenyl group, and is a substituted phenyl group,

in sub-formula 8

R⁴Is phenyl meta-or para-substituted by F or Cl,

in sub-formula 9

R²In the form of LA, the content of LA,

L¹is methyl-substituted methylene, wherein the methyl group of the methyl-substituted methylene is mono-substituted with methylamino or azetidine,

in sub-formula 10

R²In the form of LA, the content of LA,

R⁴is phenyl which is unsubstituted or monosubstituted by Hal,

in sub-formula 11

R⁴is phenyl which is unsubstituted or monosubstituted by Hal,

in subformula 12

R²In the form of LA, the content of LA,

R⁴is phenyl which is unsubstituted or monosubstituted by Hal,

in sub-formula 13

R²Is methyl, ethyl, isopropyl or trifluoromethyl,

R⁴is phenyl which is unsubstituted or monosubstituted by Hal,

in sub-formula 14

R²In the form of LA, the content of LA,

R⁴is phenyl meta-or para-substituted by F or Cl,

in sub-formula 15

R²Is methyl, ethyl, isopropyl or trifluoromethyl,

R⁴is phenyl meta-or para-substituted by F or Cl,

in subformula 16

R²Is methyl, ethyl, isopropyl or trifluoromethyl,

L¹is a methyl-substituted methylene group, wherein the methyl group of the methyl-substituted methylene group is mono-substituted with a methylamino group,

R⁴is phenyl meta-or para-substituted by F or Cl,

in sub-formula 17

R²Is methyl, ethyl, isopropyl or trifluoromethyl,

R⁴is phenyl meta-or para-substituted by F or Cl,

in sub-formula 18

R²Is methyl, ethyl, isopropyl or trifluoromethyl,

L¹is a methyl-substituted methylene group, wherein the methyl group of the methyl-substituted methylene group is mono-substituted by methylamino or azetidineThe substitution is carried out by the following steps,

R⁴is phenyl substituted by F or Cl in meta-position,

in sub-formula 19

R²Is methyl, ethyl, isopropyl or trifluoromethyl,

L¹is methyl-substituted methylene, wherein the methyl group of the methyl-substituted methylene is mono-substituted with methylamino or azetidin-1-yl,

R⁴is phenyl substituted by F or Cl in meta-position,

and the remaining residues have the meanings as indicated above for formula (I).

The compounds of the present invention may be in the form of prodrug compounds. By "prodrug compound" is meant a derivative that is converted to the biologically active compound of the invention under living physiological conditions, e.g., by oxidation, reduction, hydrolysis, and the like, each of which is carried out enzymatically or without the involvement of an enzyme. Examples of prodrugs are compounds wherein an amino group of a compound of the invention is acylated, alkylated or phosphorylated, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino, or wherein a hydroxyl group is acylated, alkylated, phosphorylated or converted to a boronate ester (borate), e.g., acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaroyloxy, alanyloxy, or wherein a carboxyl group is esterified or amidated, or wherein a sulfhydryl group forms a disulfide bond with a carrier molecule, e.g., a peptide, that selectively delivers the drug to the target and/or to the cytosol of the cell. These compounds can be produced from the compounds of the present invention according to well-known methods. Other examples of prodrugs are compounds wherein the carboxylate group (carboxylate) of the compounds of the invention is for example converted to alkyl-, aryl-, choline-, amino, acyloxymethyl, linolenoyl ester.

Metabolites of the compounds of the invention are also within the scope of the invention.

When a compound of the invention or a prodrug thereof can undergo tautomerism, e.g., keto-enol tautomerism, individual forms, e.g., keto or enol forms, are claimed either individually or collectively as mixtures in any ratio. The same applies to stereoisomers, such as enantiomers, cis/trans isomers, conformational isomers and the like.

If desired, the isomers may be separated by methods well known in the art, for example, by liquid chromatography. The same applies to the enantiomers, for example, by using a chiral stationary phase. Furthermore, enantiomers can be separated by converting them into diastereomers, i.e., coupling with an enantiomerically pure auxiliary compound, followed by separation of the resulting diastereomer and removal of the auxiliary residue. Alternatively, any enantiomer of a compound of the invention may be stereoselectively synthesized using optically pure starting materials.

The compounds of the invention may be in the form of pharmaceutically acceptable salts or solvates of such salts. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. In case the compounds of the invention comprise one or more acidic or basic groups, the invention also comprises the corresponding pharmaceutically or toxicologically acceptable salts thereof, in particular pharmaceutically usable salts thereof. The compounds of the invention which contain acidic groups can therefore be present in salt form and can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium, potassium, calcium, magnesium salts, or salts of ammonia or organic amines (e.g., ethylamine, ethanolamine, triethanolamine) or amino acids. The compounds of the invention comprising one or more basic groups, i.e. groups which can be protonated, can be present in the form of salts and can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrochloric, hydrobromic, phosphoric, sulfuric, nitric, methanesulfonic, p-toluenesulfonic, napadisylic, oxalic, acetic, tartaric, lactic, salicylic, benzoic, formic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, malic, sulfamic, phenylpropionic, gluconic, ascorbic, isonicotinic, citric, adipic and other acids known to those skilled in the art. If the compounds of the invention contain both acidic and basic groups in the molecule, the invention also includes internal salts or betaines (zwitterions) in addition to the salt forms mentioned. The corresponding salts can be obtained by customary methods known to the person skilled in the art, for example by contacting them with organic or inorganic acids or bases in solvents or dispersants, or by anion exchange or cation exchange with other salts. The invention also encompasses all salts of the compounds of the invention which, owing to their low physiological compatibility, are not directly suitable for use in medicaments, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

By "solvate" is meant a solvent addition form comprising a stoichiometric or non-stoichiometric amount of solvent. Many compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming solvates. For example, if the solvent is water, the solvate formed is a hydrate, if the solvent is an alcohol, the solvate formed is an alkoxide, and if the solvent is an ether, the solvate formed is an etherate. Specific examples of the solvate include a monohydrate or a dihydrate, a methoxide, an ethoxide, or a diethyl ether.

It is understood by the skilled person that solvates of the pharmaceutically active ingredient or a pharmaceutically acceptable salt thereof are used in pharmaceutical compositions in many cases and it is known how to obtain these solvates.

In addition, the present invention relates to a pharmaceutical composition comprising the compound of the present invention or a prodrug compound thereof or a pharmaceutically acceptable salt or solvate thereof as an active ingredient together with a pharmaceutically acceptable carrier.

"pharmaceutical composition" means one or more active ingredients, one or more inert ingredients that make up a carrier, and any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention include any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the invention may additionally comprise one or more other compounds as active ingredients, for example one or more further compounds of the invention or prodrug compounds or other p70S6K inhibitors.

The pharmaceutical compositions include those suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition to be treated and on the nature of the active ingredient. It may conveniently be presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

In one embodiment, the compounds and pharmaceutical compositions are used to treat cancer, such as brain cancer, lung cancer, colon cancer, epidermoid cancer, squamous cell cancer, bladder cancer, stomach cancer, pancreatic cancer, breast cancer, head cancer, neck cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, uterine cancer, rectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, melanoma, hematological malignancies such as acute myelogenous leukemia, multiple myeloma, chronic myelogenous leukemia, glioma, kaposi's sarcoma, or any other type of solid or liquid tumor (liquidumor). The cancer to be treated is preferably selected from breast cancer, colorectal cancer, lung cancer, prostate cancer or pancreatic cancer or glioblastoma.

The invention also relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of hyperproliferative diseases associated with high activity of p70S6K, as well as diseases modulated by the p70S6K cascade or conditions mediated by aberrant proliferation (e.g., cancer and inflammation) in a mammal.

The present invention also relates to compounds or pharmaceutical compositions for treating angiogenesis or angiogenesis-related diseases in a mammal comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutically acceptable carrier.

In one embodiment, the compound or pharmaceutical composition is for use in treating a disease selected from: tumor angiogenesis, chronic inflammatory diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, atherosclerosis), skin diseases (e.g., psoriasis, eczema, and scleroderma), diabetes, diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration.

The present invention also relates to compounds or pharmaceutical compositions for inhibiting abnormal cell growth in a mammal comprising an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with an amount of another anticancer therapeutic, wherein the amounts of the compound, salt, solvate or prodrug and the chemotherapeutic agent are co-effective in inhibiting abnormal cell growth. Many anti-cancer therapeutic agents are currently known in the art. In one embodiment, the anticancer therapeutic is a chemotherapeutic selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics (intercallatingntibes), growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens. In another embodiment, the anti-cancer therapeutic is an antibody selected from the group consisting of bevacizumab (bevacizumab), CD 40-specific antibody, chTNT-1/B, dessertumab (denosumab), zanolimumab (zanolimumab), IGF 1R-specific antibody, lintuzumab (lintuzumab), edrecolomab (edrecolomab), WXG250, rituximab (rituximab), tiximumab (ticilimumab), trastuzumab (trastuzumab), and tuximab (cetuximab). In yet another embodiment, the anti-cancer therapeutic is an inhibitor of another protein kinase, such as Akt, Axl, aurora A, aurora B, dyrk2, epha2, fgfr3, igf1r, IKK2, JNK3, Vegfr1, Vegfr2, Vegfr3 (also known as Flt-4), KDR, MEK, MET, Plk1, RSK1, Src, TrkA, Zap70, cKit, bRaf, EGFR, Jak2, PI3K, NPM-Alk, c-Abl, BTK, FAK, PDGFR, TAK1, LimK, Flt-3, PDK1, and Erk.

The invention further relates to a method for inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal comprising administering to the mammal an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with radiation therapy, wherein the amount of the compound, salt, solvate or prodrug is effective in inhibiting abnormal cell growth or treating the hyperproliferative disorder in the mammal in combination with radiation therapy. Techniques for administering radiation therapy are known in the art, and these techniques may be used in the combination therapies described herein. The administration of the compounds of the invention in such combination therapy may be determined as described herein. It is believed that the compounds of the present invention may render abnormal cells more susceptible to radiation therapy aimed at killing and/or inhibiting the growth of these cells.

Thus, the present invention further relates to a method for sensitizing abnormal cells in a mammal to radiation therapy comprising administering to the mammal an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, effective to sensitizing abnormal cells to radiation therapy. The amount of the compound, salt or solvate in the method can be determined according to the means described herein for determining an effective amount of such compound. The present invention also relates to a method for inhibiting abnormal cell growth in a mammal comprising an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, a prodrug thereof, or an isotopically labeled derivative thereof, and an amount of one or more substances selected from the group consisting of an anti-angiogenic agent, a signal transduction inhibitor, and an antiproliferative agent.

In practical use, the compounds of the present invention may be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the oral dosage form compositions, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like. In the case of oral liquid preparations, any conventional pharmaceutical media may be used, for example, suspensions, elixirs and solutions, or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. In the case of oral solid preparations, the composition may be in the form of, for example, powders, hard and soft capsules, and tablets, and solid oral preparations are preferred over liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, the tablets may be coated by aqueous or non-aqueous techniques. These compositions and preparations should contain at least 0.1% of active compound. The percentage of active compound in these compositions may of course vary and may conveniently be between about 2% to about 60% by weight of the unit. The amount of active compound in these therapeutically useful compositions is such that an effective dose will be obtained. The active compounds may also be administered intranasally as, for example, liquid drops or sprays.

Tablets, pills, capsules and the like may also contain binders (e.g., tragacanth, acacia, corn starch or gelatin), excipients (e.g., dicalcium phosphate), disintegrants (e.g., corn starch, potato starch, alginic acid), lubricants (e.g., magnesium stearate) and sweeteners (e.g., sucrose, lactose or saccharin). When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.

The compounds of the present invention may also be administered parenterally. Solutions or suspensions of these active compounds may be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and fluid to the extent that easy syringability is achieved. It must be stable under the conditions of manufacture and storage and must be protected from the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium including, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be employed to provide effective dosages of the compounds of the present invention to mammals, particularly humans. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be used. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. The compounds of the invention are preferably administered orally.

The effective dosage of the active ingredient employed may vary depending upon the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. The dosage can be readily determined by one skilled in the art.

When treating or preventing cancer, inflammation or other proliferative diseases where the compounds of the invention are indicated to be desirable, satisfactory results are generally obtained when the compounds of the invention are administered, preferably as a single daily dose, at a daily dosage of from about 0.01 mg to about 100 mg per kilogram of animal body weight. For most large mammals, the total daily dosage is from about 0.1 mg to about 1000 mg, preferably from about 0.2 mg to about 50 mg. For a 70kg adult, the total daily dose will generally be from about 0.2 mg to about 200 mg. The dosing regimen may be adjusted to provide the optimal therapeutic response.

The invention also relates to a kit (set) consisting of the following individual packages:

a) an effective amount of a compound of the present invention or a physiologically acceptable salt, solvate or prodrug thereof, and

b) an effective amount of an additional pharmaceutically active ingredient.

The kit comprises a suitable container, such as a cartridge, a separate bottle, a bag or an ampoule. The kit may for example comprise separate ampoules, each containing an effective amount of a compound of the invention and/or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and an effective amount of a further pharmaceutically active ingredient in dissolved or lyophilized form.

Experimental part

Some abbreviations that may appear in this application are as follows:

abbreviations

Name (R)
		ACN	Acetonitrile
ATP	Adenosine triphosphate
		b	Broad peak
d	Double peak
		DMSO	Dimethyl sulfoxide
DIEA	N, N-diisopropylethylamine
		DTT	Dithiothreitol
EDTA	Ethylenediaminetetraacetic acid
		equiv.	Equivalent weight
Et	Ethyl radical
		h	Hour(s)
HEPES	4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid
		HPLC	High pressure liquid chromatography
LC/MS	Liquid chromatography coupled with mass spectrometry
		m	Multiple peaks
M	Molecular ion
		m/z	Mass to charge ratio
Me	Methyl radical
		min	Minute (min)
MS	Mass spectrometry
		N	Standard (concentration unit)
NMO	4-methylmorpholine-N-oxide(s)
		NMR	Nuclear magnetic resonance
PG	Protecting group
		psi	Pounds per square inch
q	Quadruple line (or quadruple peak)
		Rf	Retention factor
RT	At room temperature
		Rt.	Retention time
s	Single peak
		Tert	Of tertiary type
TEA	Triethylamine
		TFA	Trifluoroacetic acid
THAB	Tetrahexylammonium bromide
		THF	Tetrahydrofuran (THF)
UV	Ultraviolet ray
		VIS	Is visible

The compounds of the present invention may be prepared according to the procedures of the following schemes and examples using appropriate materials and are further illustrated by the following specific examples.

Furthermore, additional compounds of the invention claimed herein can be readily prepared by using the procedures described herein, together with ordinary skill in the art. However, the compounds illustrated in the examples are not to be construed as constituting the only category contemplated by the present invention. These examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily appreciate that these compounds can be prepared using known variations of the conditions and methods of the following preparative procedures.

The compounds of the invention are typically isolated in the form of their pharmaceutically acceptable salts (e.g., as described above). The amine-free base corresponding to the isolated salt may be formed as follows: neutralized with a suitable base such as aqueous sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and the free amine-free base is extracted into an organic solvent and subsequently evaporated. The amine-free base isolated in this manner can be further converted to another pharmaceutically acceptable salt as follows: dissolution with an organic solvent, followed by addition with a suitable acid, followed by evaporation, precipitation or crystallization.

The invention will be illustrated, but not limited to, by reference to the following schemes and specific embodiments described in the examples. Variables have the same meaning as described above unless otherwise indicated in the protocol.

All starting materials were obtained from commercial suppliers and used without further purification unless otherwise indicated. Unless otherwise indicated, all temperatures are expressed in ° c and all reactions are carried out at room temperature. The compounds were purified by silica chromatography or preparative HPLC.

The present invention also relates to a process for the manufacture of compounds of formula (I) and subformulae 1-19 according to the schemes and working examples described below.

In particular, the invention relates to a process for the manufacture of a compound of formula (I) wherein X is N and Y is NH, all other substituents having the meaning as defined for formula (I) in claim 1, wherein a formate ester of formula (IV) is prepared

(IV)，

With compounds of the formula (III)

H-Y-R¹

(III)，

To give a compound of the formula (II)

(II)，

Which is finally converted into the carboxamide of the formula (I)

(I)。

General synthetic procedure

Scheme 1

Refluxing the substituted 2-aminoisophthalic acid with formic anhydride at 185 deg.C for 4 hours to provide formic acid1bWhich upon treatment with concentrated ammonium hydroxide provides oxoquinazolinecarboxylic acid1c. Esterification of methanol and sulfuric acid under reflux conditions to provide the methyl ester1dWhich is converted to methyl 4-chloro-quinazolinecarboxylate by treatment with phosphorus oxychloride and Hunigs base in the presence of a phase transfer catalyst1e。

Scheme 2

In the presence of 2N sodium hydroxide andttreatment of aminoalcohols with di-tert-butylbicarbonate in the presence of-butanol as solvent2aTo provide a Boc protected aminoalcohol2b. Cyclizing it with thionyl chloride to the sulfoxide intermediate followed by oxidation with sodium periodate in the presence of a ruthenium catalyst to provide the cyclic intermediate2c. Nucleophilic attack with secondary amines2cAnd deprotection with hydrochloric acid/methanol in situ Boc affords the desired amine2d。

Scheme 3

4-chloroquinazoline derivatives in the presence of Hunigs bases3aWith primary amines2dReacting to provide a 4-aminoquinazoline intermediate3b. Aminolysis of ester groups with 7N ammonia/methanol solution to provide formamide3c. Deprotection with cesium carbonate in the presence of thiophenol provides for when R4 is protecting a Nosyl group3d。

Analytical method

Analytical LC/MS was performed using the following three methods:

method A: at a flow rate of 400. mu.L/min, sample loop 5. mu.L, mobile phase: (A) 0.1% formic acid in water, mobile phase (B) 0.1% formic acid in methanol using DiscoveryC¹⁸5 μm, 3 × 30mm column; the retention time is given in minutes. Details of the method: (I) running on a Quaternary Pumpg1311A (Agilent) together with UV/VIS diode array detector G1315B (Agilent) and ESI + mode Finnigan LCQDuoMS detector, UV detection at 254nm and 280nm, linear gradient (II) of 15-95% (B) gradient over 3.2min was held at 95% (B) for 1.4min (III) and linear gradient (IV) decreasing from 95-15% (B) over 0.1min was held at 15% (B) for 2.3 min.

Method B：WatersSymmetryC¹⁸3.5 μm, 4.6 × 75mm column, flow rate 1mL/min, sample loop 10 μ L, mobile phase (A) water with 0.05% TFA, mobile phase (B) ACN with 0.05% TFA, retention time given in minutes. Details of the method: (I) UV detection at 254nm and 280nm was performed on a BinaryPumpG1312A (Agilent) and UV/VIS diode array detector G1315B (Agilent) and an ESI + mode AgilentG1956B (SL) MS detector, and a linear gradient (II) of 20-85% (B) gradient over 10min was maintained at 85% (B) for 1min (III) and a 20-85% (B) reduced linear gradient (IV) over 0.2min was maintained at 20% (B) for 3.8 min.

Method C: gradient: 4.2 min/flow rate: 2ml/min99:01-0:100 water +0.1% (Vol.) TFA; acetonitrile +0.1% (Vol.) TFA; 0.0-0.2 min: 99: 01; 0.2-3.8 min: 99:01 → 0: 100; 3.8-4.2 min: 0: 100; column: chromolithperformancer RP18e, length 100mm, diameter 3 mm; wavelength: 220 nm.

Analytical chiral HPLC

Analytical chiral HPLC was performed using a ChiralPakAD-H column (250X4.6mm) from Daicel chemical industries, Inc. The method used an injection volume of 5.0. mu.L, 100% methanol flow rate of 1mL/min25oC for 15min, UV detection at 254 and 280 nm.

Preparative HPLC

Preparation was carried out using a WatersaltanisdC 18OBDModel (III)HPLC. The column was used at a flow rate of 60mL/min on a WatersPrepLC4000 system equipped with a sample loop (10mL) and an ISCOA-6 UV/Vis detector. The mobile phases were taken from two solvent pools containing (a) water and (B) HPLC-grade acetonitrile. Typical preparationModel (III)The run used a linear gradient (e.g., 0-60% solvent B over 60 min).

Examples

The working examples presented below are intended to illustrate specific embodiments of the invention and are not intended to limit the scope of the specification or claims in any way.

Chemical synthesis

This section provides experimental details for a variety of example compounds of formula (I) and synthetic intermediates thereof.

Synthesis of intermediates

4-chloro-2-methyl-quinazoline-8-carboxylic acid methyl ester(1)

2-methyl-4-oxo-4H-3, 1-benzoxazine-8-carboxylic acid

2-Aminoisophthalic acid (50.0 g; 276.0mmol) and Ac₂O (250.0 ml; 5.00V) was mixed and heated to 140 deg.C (over 4 h). The reaction mixture was cooled to room temperature and distilled under high vacuum on a rotary evaporator. The residual AcOH was removed by azeotropic distillation with toluene. The residue was slurried with ether, filtered and the solid dried in vacuo to provide the desired intermediate (50.3g, 89% yield).

2-methyl-4-oxo-3, 4-dihydroquinazoline-8-carboxylic acid

2-methyl-4-oxo-4H-3, 1-benzoxazine-8-carboxylic acid (51.5 g; 251.26mmol) was dissolved in NH₄OH (360.0 ml; 6.98V; 28% solution). Ammonium acetate (77.5 g; 1,005mmol) was added and the reaction mixture was heated at 80 ℃ for 2 h. The reaction mixture was cooled to room temperature and diluted with MeOH (40mL), followed by heating at 80 ℃ for 72h in a pressure bottle. The reaction mixture was concentrated on a rotary evaporator, then cooled on ice and filtered. The solid was dried in vacuo to afford the desired product (33.5g, 65% yield).

Formic acid Esters2-methyl-4-oxo-3, 4-dihydroquinazoline-8-carboxylic acid methyl ester

2-methyl-4-oxo-3, 4-dihydroquinazoline-8-carboxylic acid (28.2 g; 138.11mmol) was dissolved in anhydrous MeOH (1000 mL). Sulfuric acid (29.4 ml; 552.44mmol) was added dropwise to the reaction mixture under argon. The reaction mixture was refluxed overnight, cooled to room temperature, and then concentrated. The solid was filtered and dried in vacuo to afford the desired intermediate as a sulfate.

By K₂CO₃(8.87g、64.18mmol)/H₂Sulfate (40.6g, 128.36mmol) was treated with O (100 mL). Upon dissolution, an off-white precipitate formed. Addition of additional H₂O (100mL), the pH was adjusted to 6-7. The off-white solid was filtered, washed with water (150mL) and dried in vacuo to afford the desired intermediate (17.90g, 64% yield). The aqueous layer was extracted with EtOAc (250mL) to provide an additional 1.10 g: (A-B)4% yield).

4-chloro-2-methyl-quinazoline-8-carboxylic acid methyl ester

Treatment of methyl 2-methyl-4-oxo-3, 4-dihydroquinazoline-8-carboxylate (2.00 g; 9.17 mmol; 1.00eq.) with benzyltriethylammonium chloride (4.18 g; 18.33 mmol)/anhydrous CH with DIEA₃CN (5mL) suspension, POCl was slowly added to the flask with stirring₃(7.3mL, 80.2 mmol). The contents were warmed to 90 ℃ over 30min, cooled to-50 ℃ and poured slowly into 2n naoh (80mL, 160mmol) and water (80mL) that had been cooled in an acetone/dry ice bath (ice formed in the flask). The precipitated crimson (off-red) solid was filtered and washed with 10% aqueous K₂CO₃(15mL) washed and dried in vacuo to provide1(1.35 g; 62% yield). LC-MS [236.8(M +1)]

4-chloro-2-ethylquinazoline-8-carboxylic acid methyl ester(2)

According to the examples1The general procedure of (a) was to prepare this compound using propionic anhydride. LC-MS [251.0(M +1)]

4-chloro-2-isopropylquinazoline-8-carboxylic acid methyl ester(3)

According to the examples1The general procedure of (a) was to prepare this compound using isobutyric anhydride. LC-MS [265.0(M +1)]

4-chloro-2-trifluoromethyl-quinazoline-8-carboxylic acid methyl ester(4)

According toExamples1The general procedure of (a) was used to prepare the compound using trifluoroacetic anhydride. LC-MS [291.0(M +1)]

N- [ (2S) -2-amino-2-phenylethyl group]-N-methyl-4-nitrobenzenesulfonamide(5)

[ (1S) -phenyl) -2-hydroxyethyl]Carbamic acid tert-butyl ester

S-aminoalcohol (1g), di-tert-butylbicarbonate and NaOH were suspended in tBuOH and stirred at 70 ℃ for 5 h. The reaction mixture was cooled to 50 ℃ and H was added₂In O (50mL), the mixture was stirred vigorously at RT for 1 h. The resulting white precipitate was filtered and washed with H₂Washed with O and dried in vacuo to afford the desired intermediate.

[ (1S) -phenyl) -2-hydroxyethyl]Carbamic acid tert-butyl ester

Adding SOCl₂Solution of/MeCN (12.0ml) in N₂Cooling to-40 ℃ under atm. Slowly add [ (1S) -phenyl) -2-hydroxyethyl dropwise through syringe]Carbamic acid tert-butyl ester/CH₃CN (12.0ml) solution. Pyridine was added dropwise, the reaction was allowed to stir for 30min, and then the dry ice/MeCN bath was removed.

The reaction mixture was stirred for 2h, then concentrated. The residue was dissolved with EtOAc and filtered through a plug of silica gel. The filtrate was concentrated and dried in vacuo. The resulting intermediate, trichloro-ruthenium hydrate (0.08g, 0.35mmol) and sodium metaperiodate (0.21ml;4.16mmol) was treated with CH₃CN (3mL) and H₂O (3mL) was dissolved and stirred at room temperature overnight. H for reactants₂Dilute O and extract with EtOAc (3 ×). The combined organic layers were washed with brine, over MgSO₄Dried, filtered and concentrated. The crude product was purified by Biotage eluting with 0-30% EtOAc/hexanes to provide the desired intermediate (600mg, 45% overall yield).

((1S) -2- { methyl [ (4-nitrophenyl) sulfonyl ] sulfonyl]Amino } -1-phenylethyl) carbamic acid tert-butyl ester

A mixture of (4S) -4-phenyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (1 g; 3.34mmol), N-methyl-4-nitrobenzenesulfonamide (722 mg; 3.34mmol) and Cs₂CO₃(0.40 ml; 5.01mmol) in CH₃CN (25ml), stirred overnight. The reaction mixture was filtered, washed with water (50ml) and dried in vacuo to afford the desired intermediate (1.12 g; 77%).

N- [ (2S) -2-amino-2-phenylethyl group]-N-methyl-4-nitrobenzenesulfonamide

4 MHCl/dioxane (6ml) was added to ((1S) -2- { methyl [ (4-nitrophenyl) sulfonyl group]Amino } -1-phenylethyl) carbamic acid tert-butyl ester (1.05g;2.41mmol) was stirred at 50 ℃ for 2 hours. The reaction mixture was evaporated in vacuo to afford a white solid (HCl salt)5(763 mg; 85% yield). LC-MS [336(M +1)]

N- [ (2S) -2-amino-2- (5-fluoro-2-methoxyphenyl) ethyl]-N-methyl-4-nitrobenzenesulfonamide(6)

According to the examples5The general procedure of (a) was used to prepare this compound using N-methyl-4-nitrobenzenesulfonamide and the corresponding amino alcohol. LC-MS [384(M +1)]

N- [ (2S) -2-amino-2- (3-chlorophenyl) ethyl]-N-methyl-4-nitrobenzenesulfonamide(7)

According to the examples5The general procedure of (a) was used to prepare this compound using N-methyl-4-nitrobenzenesulfonamide and the corresponding amino alcohol. LC-MS [407(M +1)]

N- [ (2S) -2-amino-2- (4-chlorophenyl) ethyl]-N-methyl-4-nitrobenzenesulfonamide(8)

According to the examples5The general procedure of (a) was used to prepare this compound using N-methyl-4-nitrobenzenesulfonamide and the corresponding amino alcohol. LC-MS [370(M +1)]

N- [ (2S) -2-amino-2- (4-fluorophenyl) ethyl]-N-methyl-4-nitrobenzenesulfonamide(9)

According to the examples5The general procedure of (a) was used to prepare this compound using N-methyl-4-nitrobenzenesulfonamide and the corresponding amino alcohol. LC-MS [354(M +1)]

N- [ (2S) -2-amino-2- (3-fluorophenyl) ethyl]-N-methyl-4-nitrobenzenesulfonamide(10)

(1S) -2-azetidin-1-yl-1- (3-fluorophenyl) ethylamine(11)

According to the examples5The general procedure of (a) uses azetidine and the corresponding amino alcohol to prepare the compound. LC-MS [195(M +1)]

(S) -2-azetidin-1-yl-1-phenyl-ethylamine(12)

According to the examples5The general procedure of (a) uses azetidine and the corresponding amino alcohol to prepare the compound. LC-MS [177(M +1)]

(S) -2-azetidin-1-yl-1- (4-chloro-phenyl) -ethylamine(13)

According to the examples5The general procedure of (a) uses azetidine and the corresponding amino alcohol to prepare the compound. LC-MS [211(M +1)]

(1S) -2-azetidin-1-yl-1- (4-fluorophenyl) ethylamine(14)

(S) -2-azetidin-1-yl-1- (3-chloro-phenyl) -ethylamine(15)

Example Compounds of formula (I)

4- { [ (1S) -1- (4-fluorophenyl) -2- (methylamino) ethyl]Amino } -2-methyl-quinazoline-8-carboxamide(16)

IC₅₀p70S6K[nM]:2.8

4- [ ((1S) -1- (4-fluorophenyl) -2- { methyl [ (4-nitrophenyl) sulfonyl ] sulfonyl]Amino } ethyl) -amino]-2-Methylquinazoline-8-carboxylic acid methyl ester

Will be provided with1(100mg；0.42mmol)、9(123 mg; 0.32mmol) and DIEA (0.23mL) were dissolved in CH₃CN (4ml), stirred at 70 ℃ for 72 h. The reaction mixture was concentrated to provide the desired crude intermediate.

4- [ ((1S) -1- (4-fluorophenyl) -2- { methyl [ (4-nitrophenyl) sulfonyl ] sulfonyl]Amino } ethyl) amino]-2-methylquinazoline-8-carboxamide

Crude methyl 4- [ ((1S) -1- (4-fluorophenyl) -2- { methyl [ (4-nitrophenyl) sulfonyl ] -amino } ethyl) amino ] -2-methyl quinazoline-8-carboxylate (177 mg; 0.32mmol) was treated with methanolic ammonia (10ml, 7M) and stirred at 70 ℃ overnight.

The reaction mixture was concentrated to provide a crude intermediate. (M + H)539.1

4- { [ (1S) -1- (4-fluorophenyl) -2- (methylamino) ethyl]Amino } -2-methyl-quinazoline-8-carboxamide

Crude 4- [ ((1S) -1- (4-fluorophenyl) -2- { methyl [ (4-nitrophenyl) sulfonyl ] sulfonyl]Amino } ethyl) -amino]-2-methyl-quinazoline-8-carboxamide (161 mg; 0.30mmol) and Cs₂CO₃(488 mg; 1.50mmol) was suspended in CH₃CN (7ml), and stirred at room temperature for 10 minutes. Benzenethiol (Benzenethiol,0.12 ml; 1.20mmol) was added via syringe and the solution was stirred vigorously at room temperature overnight. The reaction mixture was concentrated, dissolved in DMSO (3ml), and purified by reverse phase chromatography (Yamazen, basic buffer) to provide as the free base916?(46 mg; 43% yield). LC-MS [354(M +1)]

4- { [ (1S) -1- (3-fluorophenyl) -2- (methylamino) ethyl]Amino } -2-methyl-quinazoline-8-carboxamide(17)

IC₅₀p70S6K[nM]:139

According to the examples16General procedure of1And10the compound is prepared. LC-MS [354.2(M +1)]

4- { [ (1S) -1- (4-chlorophenyl) -2- (methylamino) ethyl]Amino } -2-isopropylquinazoline-8-carboxamide(18)

IC₅₀p70S6K[nM]:23

According to the examples16General procedure of3And8the compound is prepared. LC-MS [398.2(M +1)]

4- { [ (1S) -1- (4-chlorophenyl) -2- (methylamino) ethyl]Amino } -2-methyl-quinazoline-8-carboxamide(19)

IC₅₀p70S6K[nM]:0.83

According to the examples16General procedure of1And8the compound is prepared. LC-MS [370.2(M +1)]

2-Ethyl-4- { [ (1S) -1- (3-fluorophenyl) -2- (methylamino) ethyl]Amino quinazoline-8-carboxylic acidAmines as pesticides(20)

IC₅₀p70S6K[nM]:1.97

According to the examples16General procedure of2And10the compound is prepared. LC-MS [368.2(M +1)]

4- { [ (1S) -1- (3-chlorophenyl) -2- (methylamino) ethyl]Amino } -2-ethyl-quinazoline-8-carboxamide(21)

IC₅₀p70S6K[nM]:0.87

According to the examples16General procedure of2And7the compound is prepared. LC-MS [384.2(M +1)]

4- { [ (1S) -1- (3-chlorophenyl) -2- (methylamino) ethyl]Amino } -2-methyl-quinazoline-8-carboxamide(22)

IC₅₀p70S6K[nM]:0.98

According to the examples16General procedure of1And7the compound is prepared. LC-MS [370.1(M +1)]

2-Ethyl-4- { [ (1S) -2- (methylamino) -1-phenylethyl]Amino quinazoline-8-carboxamides(23)

IC₅₀p70S6K[nM]:11

According to the examples16General procedure of2And5the compound is prepared. LC-MS [350.2(M +1)]

4- { [ (1S) -1- (4-chlorophenyl) -2- (methylamino) ethyl]Amino } -2-ethyl-quinazoline-8-carboxamide(24)

IC₅₀p70S6K[nM]:1.4

According to the examples16General procedure of2And8the compound is prepared. LC-MS [384.2(M +1)]

2-Ethyl-4- { [ (1S) -1- (4-fluorophenyl) -2- (methylamino) ethyl]Amino quinazoline-8-carboxamides(25)

IC₅₀p70S6K[nM]:10

According to the examples16General procedure of2And9the compound is prepared. LC-MS [368.2(M +1)]

2-methyl-4- { [ (1S) -2- (methylamino) -1-phenylethyl]Amino quinazoline-8-carboxamides(26)

IC₅₀p70S6K[nM]:6.46

According to the examples16General procedure of1System for making5Preparing the compound. LC-MS [336(M +1)]

4- { [ (1S) -1- (3-fluorophenyl) -2-, (Methylamino) ethyl group]Amino } -2- (trifluoromethyl) -quinazoline-8-carboxylic acid amide(27)

IC₅₀p70S6K[nM]:4.3

According to the examples16General procedure of4And10the compound is prepared. LC-MS [408(M +1)]

4- [ (S) -3-azetidin-1-yl-2- (3-fluorophenyl) -propyl]-2-ethyl-quinazoline-8-carboxamide(28)

IC₅₀p70S6K[nM]:18.5

4- [ (S) -3-azetidin-1-yl-2- (3-fluorophenyl) -propyl]-2-Ethyl-quinazoline-8-carboxylic acid methyl ester

Will be provided with2(100mg；0.40mmol)、11(69 mg; 0.36 mmol; 0.90eq.) and TEA (0.28ml;1.99mmol) were dissolved in CH₃CN (6mL), stirred overnight. The reaction mixture was filtered and the filtrate was concentrated to provide the desired intermediate. LC-MS [409(M +1)].

4- [ (S) -3-azetidin-1-yl-2- (3-fluorophenyl) -propyl]-2-ethyl-quinazoline-8-carboxamide

Coupling 4- { [ (1S) -2-azetidin-1-yl-1- (3-fluorophenyl) ethyl]Amino } -2-ethylquinazoline-8-carboxylic acid methyl ester (70.00 mg; 0.17mmol) was suspended in methanolic ammonia (0.98 ml; 7.00M; 6.85mmol) and stirred for 24 h. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (MeOH: EtOAc =1:9) to afford28(15mg)。LC-MS[394(M+1)].¹HNMR(DMSO-d₆,ppm)1.21(3H),1.91(2H),2.50(2H),.74(3H),3.00(1H),3.13(2H),5.50(1H),7.22(1H),7.30(2H),7.44(2H),7.54(1H),7.78(1H),8.56(3H),10.69(1H).

4- [ (S) -3-azetidin-1-yl-2-phenyl-propyl]-2-methyl-quinazoline-8-carboxamide(29)

IC₅₀p70S6K[nM]:5.84

According to the examples28General procedure of1And12the compound is prepared. LC-MS [362(M +1)].¹HNMR(DMSO-d₆,ppm)1.90(2H),2.47(5H),2.74(1H),2.97(1H),3.16(2H),5.49(1H),7.22(1H),7.30(4H),7.44(2H),7.54(1H),7.78(1H),8.55(3H),10.69(1H).

4- [ (S) -3-azetidin-1-yl-2-phenyl-propyl]-2-ethyl-quinazoline-8-carboxamide(30)

IC₅₀p70S6K[nM]:33.6

According to the examples28General procedure of2And12the compound is prepared. LCMS [376(M +1)].¹HNMR(DMSO-d₆,ppm)1.21(3H),1.91(2H),2.50(2H),2.74(3H),3.00(1H),3.13(2H),5.50(1H),7.22(1H),7.30(3H),7.44(2H),7.54(1H),7.78(1H),8.56(3H),10.69(1H).

4- [ (S) -3-azetidin-1-yl-2- (4-chlorophenyl) -propyl]-2-methyl-quinazoline-8-carboxamide(31)

IC₅₀p70S6K[nM]:2.6

According to the examples28General procedure of1And13the compound is prepared. LC-MS [397(M +1)].¹HNMR(DMSO-d₆,ppm)1.90(2H),2.46(3H),2.50(2H),2.74(1H),2.97(1H),3.16(2H),5.45(1H),7.47(2H),7.52(1H),7.78(1H),8.56(3H),10.55(1H).

4- [ (S) -3-azetidin-1-yl-2- (4-chlorophenyl) -propyl]-2-ethyl-quinazoline-8-carboxamide(32)

IC₅₀p70S6K[nM]:5.5

According to the examples28General procedure of2And13the compound is prepared. LCMS [411(M +1)].¹HNMR(DMSO-d₆,ppm)1.21(3H),1.91(2H),2.5(1H),2.73(3H),2.98(1H),3.13(3H),5.43(1H),7.37(3H),7.47(2H),7.78(1H),8.56(3H),10.66(1H).

4- [ (S) -3-azetidin-1-yl-2- (4-fluorophenyl) -propyl]-2-methyl-quinazoline-8-carboxamide(33)

IC₅₀p70S6K[nM]:44

According to the examples28General procedure of1And14the compound is prepared. LCMS [380(M +1)].)].¹HNMR(DMSO-d₆,ppm)1.90(2H),2.47(5H),2.7461(1H),2.97(1H),3.16(2H),5.49(1H),7.47(2H),7.52(1H),7.78(1H),8.56(3H),10.55(1H).

4- [ (S) -3-azetidin-1-yl-2- (3-fluorophenyl) -propyl]-2-methyl-quinazoline-8-carboxamide(34)

IC₅₀p70S6K[nM]:7

According to the examples28General procedure of1And11the compound is prepared. LC-MS [380(M +1)].¹HNMR(DMSO-d₆,ppm)1.91(2H),2.4821(5H),2.75(1H),2.98(1H),3.16(2H),5.49(1H),7.47(2H),7.52(1H),7.78(1H),8.56(3H),10.55(1H).

4- [ (S) -3-azetidin-1-yl-2- (3-chlorophenyl) -propyl]-2-methyl-quinazoline-8-carboxamide(35)

IC₅₀p70S6K[nM]:1.3

According to the examples28General procedure of1And15the compound is prepared. LC-MS [396(M +1)].¹HNMR(DMSO-d₆,ppm)1.91(2H),2.48(5H),2.74(1H),2.98(1H),3.16(2H),5.49(1H),7.47(2H),7.52(1H),7.78(1H),8.56(3H),10.55(1H).

4- [ (S) -3-azetidin-1-yl-2- (4-fluorophenyl) -propyl]-2-ethyl-quinazoline-8-carboxamide(36)

IC₅₀p70S6K[nM]:30

According to the examples28General procedure of2And14the compound is prepared. LC-MS [394(M +1)].¹HNMR(DMSO-d₆,ppm)1.21(3H),1.99(2H),2.50(1H),2.73(3H),2.98(1H),3.13(3H),5.43(1H),7.37(3H),7.47(2H),7.78(1H),8.56(3H),10.66(1H).

4- [ (S) -3-azetidin-1-yl-2- (3-chlorophenyl) -propyl]-2-ethyl-quinazoline-8-carboxamide(37)

IC₅₀p70S6K[nM]:1.7

According to the examples28General procedure of2And15the compound is prepared. LC-MS [410(M +1)].¹HNMR(DMSO-d₆,ppm)1.23(3H),1.94(2H),2.50(1H),2.75(3H),2.98(1H),3.20(3H),5.43(1H),7.35(3H),7.44(2H),7.78(1H),8.53(3H),10.64(1H).

Synthesis of intermediates

N- [ (2S) -2-amino-2- (4-trifluoromethyl-phenyl) ethyl]-N-methyl-4-nitrobenzenesulfonamide(38)

According to the examples5The general procedure of (a) was used to prepare this compound using N-methyl-4-nitrobenzenesulfonamide and the corresponding amino alcohol. LC-MS [404(M +1)]

(S)-N ¹ ,N ¹ -dimethyl-3-phenylpropane-1, 2-diamine(39)

According to the examples5The general procedure of (a) was to prepare the compound using dimethylamine and the corresponding amino alcohol. LC-MS [179(M +1)]

(S) -2-azido-1-phenyl-ethylamine(40)

To [ (1S) -phenyl) -2-hydroxyethyl at 0 DEG C]To a solution of tert-butyl carbamate (237mg, 1.0mmol, 1.0eq.) and TEA (278. mu.l; 2.0 mmol; 2.0eq.)/DCM (5ml) was added 4-methylbenzenesulfonyl chloride (210mg, 1.1mmol, 1.1eq.) in portions. Will be provided withThe resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine. The organic layer was MgSO₄Dried and concentrated. The crude was purified by Biotage using 0-30% ethyl acetate/hexanes to afford (2S) -2- [ (tert-butoxycarbonyl) amino group as a white solid]-2-phenylethyl 4-methylbenzenesulfonate (93% yield).

A mixture of (2S) -2- [ (tert-butoxycarbonyl) amino ] -2-phenylethyl 4-methylbenzenesulfonate (350mg, 0.9mmol, 1.0eq.) and sodium azide (117mg, 1.8mmol, 2.0eq.)/N, N-dimethylformamide (5ml) was stirred at 65 ℃ overnight. The mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated, washed with brine, dried, and concentrated to afford tert-butyl [ (1S) -2-azido-1-phenylethyl ] carbamate (90% yield).

To [ (1S) -2-azido-1-phenylethyl group]To a solution of tert-butyl carbamate (210mg, 0.8mmol, 1.0eq.)/THF (2ml) was added 4.0M hydrogen chloride/dioxane (2.0ml, 8.0mmol, 10.0 eq.). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ether. The precipitate was filtered and washed with ether to give (S) -2-azido-1-phenyl-ethylamine as a white solid40(85% yield). LC-MS [163(M +1)]

(S) -N- (2-amino-2- (3-chloro-4- (trifluoromethoxy) phenyl) ethyl) -N-methyl-4-nitrobenzenesulfonamide(41)

According to the examples5The general procedure of (a) was used to prepare this compound using N-methyl-4-nitrobenzenesulfonamide and the corresponding amino alcohol. LC-MS [454(M +1)]

(S) -N- (2-amino-2- (2, 4-difluorophenyl) ethyl) -N-methyl-4-Nitrobenzenesulfonamides(42)

According to the examples5The general procedure of (a) was used to prepare this compound using N-methyl-4-nitrobenzenesulfonamide and the corresponding amino alcohol. LC-MS [372(M +1)]

(S) -N- (2-amino-2- (2, 6-difluorophenyl) ethyl) -N-methyl-4-nitrobenzenesulfonamide(43)

(S) -N- (2-amino-2- (2, 5-difluorophenyl) ethyl) -N-methyl-4-nitrobenzenesulfonamide(44)

(S) -N- (2-amino-2- (2,4, 5-trifluorophenyl) ethyl) -N-methyl-4-nitrobenzenesulfonamide(45)

According to the examples5The general procedure of (a) was used to prepare this compound using N-methyl-4-nitrobenzenesulfonamide and the corresponding amino alcohol. LC-MS [390(M +1)]

(S) -1- (4-fluoro-2-trifluoromethyl-phenyl) -N x2, N x 2-dimethyl-ethane-1, 2-diamine(46)

According to the examples5The general procedure of (a) was used to prepare this compound using N-methyl-4-nitrobenzenesulfonamide and the corresponding amino alcohol. LC-MS [422(M +1)]

Example Compounds of formula (I)

4- [ (S) -1- (5-fluoro-2-methoxy-phenyl) -2-methylamino-ethylamino]-2-methyl-quinazoline-8-carboxamide(47)

IC₅₀p70S6K[nM]:12

According to the examples16General procedure of1And6the compound is prepared. LC-MS [384(M +1)].

2-methyl-4- [ (S) -2-methylamino-1- (4-trifluoromethyl-phenyl) -ethylamino]-quinazoline-8-carboxamides(48)

IC₅₀p70S6K[nM]:1

According to the examples16General procedure of1And38the compound is prepared. LC-MS [404(M +1)].

4- ((S) -1-benzyl-2-dimethylamino-ethylamino) -2-methyl-quinazoline-8-carboxylic acid amide(49)

IC₅₀p70S6K[nM]:452

According to the examples16General procedure of1And39the compound is prepared. LC-MS [364(M +1)].

4- [ (1S) -1- [ 4-fluoro-2- (trifluoromethyl) phenyl]-2- (methylamino) ethyl]Amino-2-methyl quinazoline-8-carboxamide(50)

IC₅₀p70S6K[nM]:260

According to the examples16General procedure of1And46the compound is prepared. LC-MS [422(M +1)].

4- ((S) -2-amino-1-phenyl-ethylamino) -2-trifluoromethyl-quinazoline-8-carboxylic acid amide(51)

IC₅₀p70S6K[nM]:8

To chloride4(175mg, 0.60mmol) andN,N-to a solution of diisopropylethylamine (0.53mL, 3.0mmol) in tetrahydrofuran (8.0mL) was added an amine40(132mg, 0.66mmol), the reaction was heated to 65 ℃ for 16 h. The reaction was diluted with saturated sodium chloride and ethyl acetate was added. The biphasic mixture was extracted three times with ethyl acetate and the combined extracts were dried over sodium sulfate. Column chromatography of the resulting residue (dichloromethane-10% methanol/dichloromethane) yielded the product as a pale yellow foam, lcms (esi)417(M + H). This material was dissolved in isopropanol (5.0mL), ammonium hydroxide (10.0mL) was added slowly, and the reaction was stirred at room temperature for 16 hours. The total volume of the reaction was reduced in vacuo to. The biphasic solution was extracted three times with ethyl acetate and the combined organics were dried over sodium sulfate. The extract was concentrated to crude 4- ((S) -2-azido-1-phenyl-ethylamino) -2-trifluoro-lMethyl-quinazoline-8-carboxamide, whose main peak by LC/MS analysis showed the correct M/z, LCMS (ESI)402(M + H).

The crude azide was dissolved in ethanol (15mL) and a catalytic amount of 5% palladium on carbon was added. The heterogeneous solution was stirred under hydrogen atmosphere for 2 hours, then the suspension was filtered through a pad of celite and the filtrate was concentrated to a pale yellow membrane. The material was redissolved with tetrahydrofuran (5.0mL) and treated with 4N hydrochloric acid/dioxane (4.0mL) for 15 minutes. The reaction was then concentrated to dryness, and the resulting solid was triturated three times with diethyl ether to provide the title compound (HCl salt) (202mg) as a pale yellow powder at 57% relative to the preceding four steps. LC-MS [376(M +1)].1HNMR(400MHz,DMSO-d6).ppm3.19-3.38(m,1H)3.67-3.89(m,1H)5.76(br.s.,1H)7.31(d,J=7.42Hz,1H)7.38(t,J=7.52Hz,2H)7.55(d,J=7.32Hz,2H)7.84(t,J=7.86Hz,1H)7.89-8.06(m,1H)8.63(dd,J=7.52,1.37Hz,1H)9.01(d,J=8.40Hz,2H)9.48(br.s.,1H)9.90(s,1H)。

(S) -4- ((1- (3-chloro-4- (trifluoromethoxy) phenyl) -2- (methylamino) ethyl) amino) -2-methyl-quinazoline-8-carboxamide(52)

IC₅₀p70S6K[nM]:1

(S) -4- ((2- (4-amino-N-methylphenylsulfonamido) -1- (3-chloro-4- (trifluoromethoxy) phenyl) ethyl) amino) -2-methylquinazoline-8-carboxylic acid methyl ester

To a solution of methyl 2-methyl-4-oxo-3, 4-dihydroquinazoline-8-carboxylate (91.65 mg; 0.42 mmol; 1.20eq.)/NMP (3mL) was added 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (104.58 μ l; 0.70 mmol; 2.00 eq.). The solution was stirred at room temperature for 5min, followed by PyBOP (273.21 mg; 0.52 mmol; 1.50eq.) and stirring for 10min, followed by the addition of N- (2S) -2-amino-2- [ 3-chloro-4- (trifluoromethoxy) phenyl ]]Ethyl-N-methyl-4-nitrobenzenesulfonamide hydrochloride41(171.60 mg; 0.35 mmol; 1.00eq.) and N-ethyl-N-isopropylpropan-2-amine (60.96. mu.l; 0.35 mmol; 1.00eq.)/NMP (1 mL). The reaction mixture was stirred at room temperature overnight.

After 14hr the reaction was diluted with water and purified by preparative HPLC to give 110mg (41%) of (S) -4- ((2- (4-amino-N-methylphenylsulfonamido) -1- (3-chloro-4- (trifluoromethoxy) phenyl) ethyl) amino) -2-methylquinazoline-8-carboxylic acid methyl ester. LC-MS [655(M +1) ]

(S) -4- ((2- (4-amino-N-methylphenylsulfonamido) -1- (3-chloro-4- (trifluoromethoxy) phenyl) ethyl) amino) -2-methylquinazoline-8-carboxamide

To a reaction vial containing a magnetic stir bar was added methyl 4- [ ((1S) -1- [ 3-chloro-4- (trifluoromethoxy) phenyl ] -2-methyl [ (4-nitrophenyl) sulfonyl ] aminoethyl) amino ] -2-methyl quinazoline-8-carboxylate trifluoroacetate (trifluoroacetate) (268.82 mg; 0.35 mmol; 1.00eq.), DMSO (2mL), IPA (2mL) and concentrated NH4OH (2 mL). The vessel was sealed and the reaction was stirred at 70 ℃ overnight.

The reaction was gradually improved (workdup) (EA/water) and then concentrated to yield 80mg (36%) of crude intermediate. LC-MS [640(M +1) ]

(S) -4- ((1- (3-chloro-4- (trifluoromethoxy) phenyl) -2- (dimethylamino) ethyl) amino) -2-methyl-quinazoline-8-carboxamide

Crude preparation(S) -4- ((2- (4-amino-N-methylphenylsulfonamido) -1- (3-chloro-4- (trifluoromethoxy) phenyl) ethyl) amino) -2-methylquinazoline-8-carboxamide(80.00 mg; 0.13 mmol; 1.00eq.) was dissolved in acetonitrile (4.0 ml). Cesium carbonate (245mg, 6.0eq) was added and the suspension stirred for 10 minutes. Benzenethiol (51.18 μ l; 0.50 mmol; 4.00eq.) is added via syringe and the solution is stirred vigorously at room temperature overnight. Water (3mL) was added and the homogeneous reaction was purified directly by preparative HPLC to yield 28mg (41%) of compound52。LC-MS[454(M+1)]

(S) -4- ((1- (2, 5-difluorophenyl) -2- (methylamino) ethyl) amino) -2-methylquinazoline-8-carboxamide(53)

IC₅₀p70S6K[nM]:3

According to the examples52General procedure of1And44the compound is prepared. LC-MS [372(M +1)]

(S) -4- ((1- (2, 4-difluorophenyl) -2- (methylamino) ethyl) amino) -2-methylquinazoline-8-carboxamide(54)

IC₅₀p70S6K[nM]:7

According to the examples52General procedure of1And42the compound is prepared. LC-MS [372(M +1)]

(S) -4- ((1- (2, 6-difluorophenyl) -2- (methylamino) ethyl) amino) -2-methylquinazoline-8-carboxamide(55)

IC₅₀p70S6K[nM]:6

According to the examples52General procedure of1And43the compound is prepared. LC-MS [372(M +1)]

(S) -2-methyl-4- ((2- (methylamino) -1- (2,4, 5-trifluorophenyl) ethyl) amino) quinazoline-8-carboxamide(56)

IC₅₀p70S6K[nM]:1

According to the examples52General procedure of1And45the compound is prepared. LC-MS [390(M +1)]

Synthesis of intermediates

N- (2S) -amino-2- (2-chloro-3-fluorophenyl) ethyl) -N-methyl-4-nitrobenzene-sulfonamide(57)

According to the examples5The general procedure of (a) was used to prepare this compound using N-methyl-4-nitrobenzenesulfonamide and the corresponding amino alcohol. LC-MS [388.1(M +1)]

N- (2S) -amino-2- (3, 4-dichlorophenyl) ethyl) -N-methyl-4-nitrobenzenesulfonamide(58)

According to the examples5The general procedure of (a) was used to prepare this compound using N-methyl-4-nitrobenzenesulfonamide and the corresponding amino alcohol. LC-MS [404.1(M +1)]

Example Compounds of formula (I)

(S) -4- ((1- (2-chloro-3-fluorophenyl) -2- (methylamino) ethyl) amino) -2-methylquinazoline-8-carboxamide(59)

According to the examples16General procedure of1And57the compound is prepared. LC-MS [370.2(M +1)]

(S) -4- ((1- (2-chloro-3-fluorophenyl) -2- (methylamino) ethyl) amino) -2-ethylquinazoline-8-carboxamide(60)

IC₅₀p70S6K[nM]:9

According to the examples16General procedure of2And57the compound is prepared. LC-MS [402.4(M +1)]

(S) -4- ((1- (3, 4-dichlorophenyl) -2- (methylamino) ethyl) amino) -2-methylquinazoline-8-carboxamide(61)

IC₅₀p70S6K[nM]:330

According to the examples16General procedure of1And58the compound is prepared. LC-MS [404.4(M +1)]

Biological activity

P70S6KEnzyme assay

P70S6K inhibitor compounds were diluted and plated into 96-well plates. Then adding to the compound plate a reaction mixture comprising the following components to initiate the enzymatic reaction; P70S6K (3nM, T412E mutant, Millipore) and assay buffer (containing 100mM hepes (pH7.5), 5mM MgCl₂1mM DTT, 0.015% Brij and 1. mu.M 24. mu. MATP in the substrate peptide FITC-AHA-AKRRRLSSLRA-OH (derived from the S6 ribosomal protein sequence, FITC = fluorescein isothiocyanate, AHA = 6-aminocaproic acid)). The reaction was incubated at 25 ℃ for 90min, and then 10mM EDTA was added to stop the reaction. The ratio of substrate and product (phosphorylated) peptides was analyzed on a caliper life sciences labchip3000 using a pressure of-1.4 psi, upstream and downstream voltages of-3000 and-700, respectively. On the resulting chromatogram, the product peak is resolved before the substrate peak.

To assess the inhibitory potential of the compounds, IC50 values were determined, as shown in the chemical synthesis section above.

Claims

1. A compound of formula (I)

(I)，

And a pharmaceutically acceptable salt thereof,

wherein:

x is N, and X is N,

y is NH, and the catalyst is a catalyst,

R¹is L¹-R⁴，

R²In the form of LA, the content of LA,

L¹is a methyl-substituted methylene group, wherein the methyl group of the methyl-substituted methylene group is replaced by NH₂Or NH (LA), N (LA)₂Or a cyclic A which may be mono-or di-substituted by Hal or LA,

R⁴is phenyl which is unsubstituted or mono-, di-or trisubstituted independently of one another by Hal or linear A,

a is unbranched or branched, linear or cyclic alkyl having 1,2,3, 4,5, 6, 7 or 8C atoms, one CH of which₂The radicals being replaceable by O atoms and/or by-NH-groups and in which 1 to 3H atoms are replaceable by Hal,

hal is F, Cl, Br or I.

2. A compound according to claim 1, wherein residues not specified in more detail have the meaning indicated in claim 1, but wherein L is¹Is a methyl-substituted methylene group, wherein the methyl group of the methyl-substituted methylene group is mono-substituted with methylamino, dimethylamino, or azetidine.

3. A compound according to claim 1, wherein residues not specified in more detail have the meaning indicated in claim 1, but wherein R is⁴Is phenyl which is unsubstituted or monosubstituted by Hal.

4. A compound according to claim 1, wherein residues not specified in more detail have the meaning indicated in claim 1, but wherein R is²Is methyl, ethyl, isopropyl or trifluoromethyl.

5. A compound according to claim 1, wherein residues not specified in more detail have the meaning indicated in claim 1, but wherein L1 is methyl-substituted methylene, wherein the methyl group of the methyl-substituted methylene is mono-substituted with methylamino.

6. A compound according to claim 1, wherein residues not specified in more detail have the meaning indicated in claim 1, but wherein L is¹Is a methyl-substituted methylene group, wherein the methyl group of said methyl-substituted methylene group is mono-substituted with azetidin-1-yl.

7. A compound according to claim 1, wherein residues not specified in more detail have the meaning indicated in claim 1, but wherein R is⁴Is unsubstituted phenyl.

8. A compound according to claim 1, wherein residues not specified in more detail have the meaning indicated in claim 1, but wherein R is⁴Is phenyl meta or para substituted by F or Cl.

9. A compound according to claim 1, wherein residues not specified in more detail have the meaning indicated in claim 1, but wherein L is¹Is a methyl-substituted methylene group wherein the methyl group of the methyl-substituted methylene group is mono-substituted with methylamino or azetidine.

10. A compound according to claim 1, wherein residues not specified in more detail have the meaning indicated in claim 1, but wherein L is¹Is a methyl-substituted methylene group, wherein the methyl group of said methyl-substituted methylene group is mono-substituted with methylamino or azetidine,

R⁴is phenyl which is unsubstituted or monosubstituted by Hal.

11. The method ofCompounds according to claim 1, wherein residues which are not specified in more detail have the meaning indicated in claim 1, but wherein R is²Is methyl, ethyl, isopropyl or trifluoromethyl,

L¹is a methyl-substituted methylene group, wherein the methyl group of said methyl-substituted methylene group is mono-substituted with methylamino or azetidine,

R⁴is phenyl which is unsubstituted or monosubstituted by Hal.

12. A compound according to claim 1, wherein residues which are not specified in more detail have the meaning indicated in claim 1, but wherein

R⁴is phenyl meta or para substituted by F or Cl.

13. A compound according to claim 1, wherein residues not specified in more detail have the meaning indicated in claim 1, but wherein R is²Is methyl, ethyl, isopropyl or trifluoromethyl,

R⁴is phenyl meta or para substituted by F or Cl.

14. A compound according to claim 1, wherein residues not specified in more detail have the meaning indicated in claim 1, but wherein R is²Is methyl, ethyl, isopropyl or trifluoromethyl,

L¹is a methyl-substituted methylene group, wherein the methyl group of said methyl-substituted methylene group is mono-substituted with a methylamino group,

R⁴is benzene meta-or para-substituted by F or ClAnd (4) a base.

15. A compound according to claim 1, wherein residues not specified in more detail have the meaning indicated in claim 1, but wherein R is²Is methyl, ethyl, isopropyl or trifluoromethyl,

L¹is a methyl-substituted methylene group, wherein the methyl group of said methyl-substituted methylene group is mono-substituted with azetidin-1-yl,

R⁴is phenyl meta or para substituted by F or Cl.

16. A compound according to claim 1, wherein residues not specified in more detail have the meaning indicated in claim 1, but wherein R is²Is methyl, ethyl, isopropyl or trifluoromethyl,

R⁴is phenyl substituted by F or Cl meta.

17. A compound according to claim 1, wherein residues not specified in more detail have the meaning indicated in claim 1, but wherein R is²Is methyl, ethyl, isopropyl or trifluoromethyl,

L¹is a methyl-substituted methylene group, wherein the methyl group of said methyl-substituted methylene group is mono-substituted with methylamino or azetidin-1-yl,

R⁴is phenyl substituted by F or Cl meta.

18. A compound selected from:

4- { [ (1S) -1- (4-fluorophenyl) -2- (methylamino) ethyl ] amino } -2-methyl-quinazoline-8-carboxamide,

4- { [ (1S) -1- (3-fluorophenyl) -2- (methylamino) ethyl ] amino } -2-methyl-quinazoline-8-carboxamide,

4- { [ (1S) -1- (4-chlorophenyl) -2- (methylamino) ethyl ] amino } -2-isopropylquinazoline-8-carboxamide,

4- { [ (1S) -1- (4-chlorophenyl) -2- (methylamino) ethyl ] amino } -2-methyl-quinazoline-8-carboxamide,

2-ethyl-4- { [ (1S) -1- (3-fluorophenyl) -2- (methylamino) ethyl ] amino } quinazoline-8-carboxamide,

4- { [ (1S) -1- (3-chlorophenyl) -2- (methylamino) ethyl ] amino } -2-ethylquinazoline-8-carboxamide,

4- { [ (1S) -1- (3-chlorophenyl) -2- (methylamino) ethyl ] amino } -2-methyl-quinazoline-8-carboxamide,

2-ethyl-4- { [ (1S) -2- (methylamino) -1-phenethyl ] amino } quinazoline-8-carboxamide,

4- { [ (1S) -1- (4-chlorophenyl) -2- (methylamino) ethyl ] amino } -2-ethylquinazoline-8-carboxamide,

2-ethyl-4- { [ (1S) -1- (4-fluorophenyl) -2- (methylamino) ethyl ] amino } quinazoline-8-carboxamide,

2-methyl-4- { [ (1S) -2- (methylamino) -1-phenethyl ] amino } quinazoline-8-carboxamide,

4- { [ (1S) -1- (3-fluorophenyl) -2- (methylamino) ethyl ] amino } -2- (trifluoromethyl) -quinazoline-8-carboxamide,

4- [ (S) -2-azetidin-1-yl-1- (3-fluorophenyl) -ethylamino ] -2-ethyl-quinazoline-8-carboxamide,

4- [ (S) -2-azetidin-1-yl-1-phenyl-ethylamino ] -2-methyl-quinazoline-8-carboxamide,

4- [ (S) -2-azetidin-1-yl-1-phenyl-ethylamino ] -2-ethyl-quinazoline-8-carboxamide,

4- [ (S) -2-azetidin-1-yl-1- (4-chlorophenyl) -ethylamino ] -2-methyl-quinazoline-8-carboxamide,

4- [ (S) -2-azetidin-1-yl-1- (4-chlorophenyl) -ethylamino ] -2-ethyl-quinazoline-8-carboxamide,

4- [ (S) -2-azetidin-1-yl-1- (4-fluorophenyl) -ethylamino ] -2-methyl-quinazoline-8-carboxamide,

4- [ (S) -2-azetidin-1-yl-1- (3-fluorophenyl) -ethylamino ] -2-methyl-quinazoline-8-carboxamide,

4- [ (S) -2-azetidin-1-yl-1- (3-chlorophenyl) -ethylamino ] -2-methyl-quinazoline-8-carboxamide,

4- [ (S) -2-azetidin-1-yl-1- (4-fluorophenyl) -ethylamino ] -2-ethyl-quinazoline-8-carboxamide,

4- [ (S) -2-azetidin-1-yl-1- (3-chlorophenyl) -ethylamino ] -2-ethyl-quinazoline-8-carboxamide,

and pharmaceutically acceptable salts thereof.

19. A pharmaceutical composition comprising a compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, as an active ingredient, and a pharmaceutically acceptable carrier.

20. Use of a compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a hyperproliferative disease.

21. Use of a compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease, wherein the disease is selected from: cancer, inflammation or kidney disease, pain, benign skin hyperplasia, restenosis, prostate disease, angiogenesis or vasculogenesis-related disease, a skin disease selected from psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, and retinopathy of prematurity and age-related macular degeneration.

22. The use of claim 21, wherein the disease is selected from the group consisting of: tumor angiogenesis, hemangioma, glioma, melanoma, and kaposi's sarcoma.

23. The use of claim 21, wherein the disease is selected from breast cancer, colorectal cancer, lung cancer, prostate cancer, pancreatic cancer or glioblastoma.

24. The use of claim 21, wherein the disease is pancreatitis.

25. A kit consisting of the following individual packages:

a) an effective amount of a compound of one or more of claims 1-18, or a pharmaceutically acceptable salt thereof, and

b) an effective amount of an additional pharmaceutically active ingredient.

26. A process for the manufacture of a compound of formula (I),

wherein X is N and Y is NH and all other substituents have the meanings defined for formula (I) in claim 1, wherein the formic esters of the formula (IV)

(IV)，

With a compound of the formula (III),

H-Y-R¹

(III)，

to give a compound of the formula (II)

(II)，

Which is finally converted into the carboxamide of the formula (I)

(I)。