HK1180685B

HK1180685B - Aminoalcohol substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis

Info

Publication number: HK1180685B
Application number: HK13108062.1A
Authority: HK
Inventors: W.斯科特; 刘宁姝; M．默维斯; A．哈格巴尔特; U.门宁; U.伯默
Original assignee: Bayer Intellectual Property Gmbh
Priority date: 2010-11-11
Filing date: 2011-11-08
Publication date: 2017-06-09

Description

Aminoalcohol substituted 2, 3-dihydroimidazo [1,2-c ] quinazoline derivatives for the treatment of hyperproliferative disorders and diseases associated with angiogenesis

Technical Field

The present invention relates to arylamino alcohol substituted 2, 3-dihydroimidazo [1,2-c ] quinazolines (hereinafter referred to as "compounds of general formula (I)") as described and defined herein, to processes for preparing said compounds, to intermediates used in the preparation of said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.

Background

In the last decade, many successes have been achieved in developing anticancer drugs that target active aberrant protein kinases. In addition to the role of protein kinases, lipid kinases also play an important role in critically regulating the production of second messengers. The PI3K lipid kinase family produces 3' -phosphoinositides that bind to and activate a variety of cellular targets, triggering a broad signal transduction cascade (Vanhaaesebroeck et al, 2001; Toker,2002; Pendaries et al, 2003; Downes et al, 2005). These cascades ultimately cause changes in a variety of cellular processes, including cell proliferation, cell survival, differentiation, vesicle transport, metastasis, and chemotaxis.

PI3K can be divided into three different types, based on differences in both structure and substrate selectivity. Whereas members of the PI3K family class II are involved in regulating tumor growth (Brown & liver, 2001; Trater et al, 2006), most studies have focused on class I enzymes and their role in cancer (Stauffer et al, 2005; Stephens et al, 2005; Vivanco & Sawyers,2002; Workman,2004; Chen et al, 2005; Hennessy et al, 2005; Cully et al, 2006).

Class I PI3K has traditionally been divided into two distinct subclasses, based on differences in protein subunit composition. I is_API 3K-like class includes a catalytic p110 catalytic subunit (p110 α or) that forms a heterodimer with one of the p85 regulatory subunit family members_BThe PI 3K-like catalytic subunit (p 110. gamma.) and the different p101 regulatory subunits form heterodimers (by Vanhaaesebroeck)&Waterfield,1999; Funaki et al, 2000; reviewed in Katso et al, 2001). The C-terminal region of these proteins contains a catalytic domain that is distantly homologous to the protein kinase. PI3K gamma structure similar to I_AClass p110, but lack the N-terminal p85 binding site (Domin)&Waterfield, 1997). Although similar in overall structure, homology between catalytic p110 subunits is low to moderate. The highest homology between PI3K isoforms is the kinase pocket in the kinase domain.

I_API 3-like K isoforms are either bound by their p85 regulatory subunits to activated Receptor Tyrosine Kinases (RTKs) (including PDGFR, EGFR, VEGFR, IGF1-R, c-KIT, CSF-R and Met), or to tyrosine phosphorylated adaptor proteins (such as Grb2, Cbl, IRS-1 or Gab1) with the result that lipid kinase activity is stimulatedActivity of isoform lipid kinases (Kodaki et al, 1994). indeed, oncogenic activity of these isoforms may be dependent on binding to ras (Kang et al, 2006). in contrast, by virtue of constitutive activation of Akt, p110 α andisoforms exhibit oncogenic activity independent of binding to ras.

Class I PI3K catalysis by PI (4,5) P₂[PIP₂]To PI (3,4,5) P₃[PIP₃]The transformation of (3). PIP generated by means of PI3K₃A variety of signal transduction processes that affect the biological endpoints that regulate and coordinate cell proliferation, cell survival, differentiation, and cell metastasis. PIP (PIP)₃Binding to proteins containing the substrate homolog (PH) domain of platelet-leukocyte C kinase, including phosphoinositide-dependent kinase, PDK1 and Akt proto-oncogene products, localize these proteins to active signaling regions and also directly contribute to their activation (Klippel et al, 1997; Fleming et al, 2000; Itoh; (R); Klippel et al, 1997; Fleming et al, 2000; Itoh;)&Takenawa,2002; Lemmon, 2003). This co-localization of PDK1 and Akt promotes phosphorylation and activation of Akt. Akt carboxy terminal Ser⁴⁷³Phosphorylation of (A) promotes Thr in the Akt activation loop³⁰⁸Phosphorylation (Chan)&Tsichlis,2001; Hodgekinson et al, 2002; Scheid et al, 2002; Hresko et al, 2003). Once active, Akt phosphorylates and regulates a variety of regulatory kinase pathways that directly affect cell cycle progression and cell survival.

Many of the effects of Akt activation are mediated by its negative regulatory effects on pathways that affect cell survival and are often dysregulated in cancer. Akt promotes tumor cell survival by modulating components of the apoptotic and cell cycle mechanisms. Akt is one of several kinases that phosphorylate and inactivate pro-apoptotic BAD proteins (delPaso et al, 1997; Pasorino et al, 1999). Akt phosphorylates Ser of caspase 9¹⁹⁶Blocking cytochrome C-dependent caspase activation may also promote cell survival (Cardone et al, 1998).

Akt affects gene transcription at several levels. Akt-mediated MDM2E3 ubiquitin ligase Ser¹⁶⁶And Ser¹⁸⁶The phosphorylation of MDM2 contributes to the nuclear import of MDM2 and the formation and activation of the ubiquitin ligase complex. Nuclear MDM2 targets the p53 tumor suppressor gene for degradation, a process that can be blocked by LY294002 (Yap et al, 2000; Ogalawa et al, 2002). The negative regulation of p53 by MDM2 negatively affects the pro-apoptotic genes regulated by p53 (e.g., Bax, Fas, PUMA, and DR5), cell cycle inhibitors, p21^Cip1And transcription of PTEN tumor suppressor genes (Momand et al, 2000; Hupp et al, 2000; Mayo et al, 2002; Su et al, 2003). Similarly, Akt-mediated phosphorylation of the Forkhead transcription factors FKHR, FKHRL, and AFX (Kops et al, 1999; Tang et al, 1999) causes them to bind to 14-3-3 proteins and be exported by the nucleus to the cytosol (Brunet et al, 1999). This functional inactivation of Forkhead activity also affects the transcription of pro-apoptotic and pro-angiogenic genes, including Fas ligand (Ciechomska et al, 2003), pro-apoptotic Bcl-2 family member Bim (Dijkers et al, 2000), and angiopoietin (Ang-1) antagonist Ang-2(Daly et al, 2004). Forkhead transcription factor regulating cyclin-dependent kinase (Cdk) inhibitor p27^Kip1Expression of (2). Indeed it has been demonstrated that PI3K inhibitors induce p27^Kip1Expression causes Cdk1 inhibition, cell cycle arrest and apoptosis. Akt is also reported to phosphorylate p21^Cip1(at Thr)¹⁴⁵) And p27^Kip1(at Thr)¹⁵⁷) Promote their binding to the 14-3-3 protein, cause nuclear export and cytoplasmic retention, and prevent them from inhibiting nuclear Cdk (Zhou et al, 2001; Motti et al, 2004; Sekimoto et al, 2004). In addition to these effects, Akt phosphorylates IKK (Romashkova)&Makarov, 1999) leads to phosphorylation and degradation of I κ B and subsequent nuclear transfer of NF κ B, resulting in survival genes such as IAP and Bcl-X_LExpression of (2).

The PI3K/Akt pathway also passes through JNK and p38^MAPKMAP kinase (associated with induction of apoptosis) has been implicated in the inhibition of apoptosis. Akt is speculated to regulate the kinase, apoptosis signal regulating kinase 1(ASK1), by phosphorylating and inhibiting two JNK/p38 (Kim et al, 2001: Liao)&Hung,2003; Yuan et al, 2003) and Mixed lineage kinase 3(MLK3) (Lopez-Ilasaca et al, 1997; Barthwal et al, 2003; Figueroa et al, 2003) to inhibit JNK and p38^MAPKSignal transduction of (3). Induction of p38 was observed in tumors treated with cytotoxic agents^MAPKActivity, which is essential for those agents that induce cell death (by Olson)&Reviewed in halahan, 2004). Therefore, PI3K pathway inhibitors may promote the activity of co-administered cytotoxic drugs.

Another role of PI3K/Akt signaling involves the modulation of cell cycle progression by modulating the activity of glycogen synthase kinase 3(GSK 3). Increased activity of GSK3 in quiescent cells, where it phosphorylates cyclin D₁Ser of (2)²⁸⁶Proteins that target ubiquitination and degradation (Diehl et al, 1998) and prevent entry into S phase. Akt phosphorylates Ser⁹Inhibits GSK3 activity (Cross et al, 1995). This results in cyclin D₁Inhibition of GSK3 activity also affects cell proliferation via activation of wnt/β -catenin signaling pathway (Abbosh)&Nephew, 2005; Naito et al, 2005; Wilker et al, 2005; Kim et al, 2006; Segrelles et al, 2006.) Akt-mediated phosphorylation of GSK3 leads to stabilization and nuclear localization of β -catenin, which in turn leads to enhanced expression of c-myc and cyclin D1 (a target of the β -catenin/Tcf pathway).

Although PI3K signaling is utilized by many signaling networks associated with both oncogene and tumor suppression, PI3K and its activity are directly associated with cancer in bladder and colon tumors and cell lines, p110 α andoverexpression of both isoforms, and in general, overexpression is associated with enhanced PI3K activity (Benistant et al, 2000). It has been reported to be overexpressed in ovarian and cervical tumors, tumor cell lines, and lung squamous cell carcinomaOverexpression and enhancement of p110 α in cervical and ovarian tumor cell linesThe activity of PI3K was relevant (Shayesteh et al, 1999; Ma et al, 2000). Enhanced PI3K activity has been observed in colorectal cancer (Phillips et al, 1998) and enhanced expression has been observed in breast cancer (Gershtein et al, 1999).

In recent years, somatic mutations encoding the p110 α (PIK3CA) gene have been identified in many cancers. Data collected to date indicate that PIK3CA is mutated in approximately 32% of colorectal cancers (Samuels et al, 2004; Ikenoue et al, 2005), 18-40% of breast cancers (Bachman et al, 2004; Campbell et al, 2004; Levine et al, 2005; Saal et al, 2005; Wu et al, 2005), 27% glioblastoma (Samuels et al, 2004; Hartmann et al, 2005, Gallia et al, 2006), 25% of gastric cancers (Byun et al, 2003; Samuels et al, 2004; Li et al, 2005), 36% hepatocellular carcinomas (Lee et al, 2005), 4-12% ovarian cancers (Levine et al, 2005; Wang et al, 2005), 4% lung cancers (Samuels et al, 2004; Whlbeck, 2006), and up to 40% endometrial cancers (Oda et al, 2005). PIK3CA has been reported to be mutated in oligodendrogliomas, astrocytomas, medulloblastomas, and thyroid tumors (Broderick et al, 2004; Garcia-Rosan et al, 2005). Based on the high frequency of mutations observed, PIK3CA is one of the two most frequently mutated genes associated with cancer, the other being K-ras. More than 80% of PIK3CA mutations were concentrated in two regions of the protein, the helical (E545K) domain and the catalytic (H1047R) domain. Biochemical analysis and protein expression studies have shown that both mutations result in an increase in constitutive p110 α catalytic activity and are carcinogenic in nature (Bader et al, 2006; Kang et al, 2005; Samuels & Ericson, 2006). Recently, it has been reported that embryonic fibroblasts of PIK3CA knockout mice are not sufficient to signal downstream from various growth factor receptors (IGF-1, insulin, PDGF, EGF) and are resistant to transformation by multiple oncogenic RTKs (IGFR, wild-type EGFR and somatotrophic mutants EGFR, Her2/Neu) (Zhao et al, 2006).

Functional studies of PI3K in vivo have shown that siRNA-mediated down-regulation of p110 β inhibits Akt phosphorylation and growth of HeLa cell tumors in nude mice (Czauderna et al, 2003). In similar experiments, siRNA-mediated down-regulation of p110 β has also been shown to inhibit the growth of glial tumor cells in vivo and in vitro (Pu et al, 2006). Inhibition of PI3K function by the dominant negative regulatory p85 regulatory subunit can block cell division and cell transformation (Huang et al, 1996; Rahimi et al, 1996). It has also been established in many tumor cells that some somatic mutations occurring in the genes encoding the regulatory subunits p85 α and p85 β of PI3K result in enhanced lipid kinase activity (Janssen et al, 1998; Jimenez et al, 1998; Philp et al, 2001; Jucker et al, 2002; Shekar et al, 2005). Neutralizing PI3K antibodies in vitro also blocks cell division and can induce apoptosis (Roche et al, 1994: Roche et al, 1998; Benistant et al, 2000). In vivo proof-of-principle studies using the PI3K inhibitors LY294002 and wortmannin demonstrated that inhibition of PI3K signaling slowed tumor growth (Pows et al, 1994; Shultz et al, 1995; Semba et al, 2002; Ihle et al, 2004).

Overexpression of class I PI3K activity, or stimulation of their lipid kinase activity, has been associated with resistance to targeted therapies (such as imatinib and trastuzumab) and cytotoxic chemotherapy and radiation therapy (West et al, 2002; Gupta et al, 2003; Osaki et al, 2004; Nagata et al, 2004; Gottschalk et al, 2005; Kim et al, 2005). Activation of PI3K has been shown to lead to the expression of multidrug resistance-associated protein-1 (MRP-1) and subsequent induction of resistance to chemotherapy in prostate cancer cells (Lee et al, 2004).

The importance of PI3K signaling in tumorigenesis has been further highlighted by the finding that the PTEN tumor suppressor gene encodes PI (3) P phosphatase, one of the most commonly inactivated genes in human cancers (Li et al, 1997, Steck et al, 1997; Ali et al, 1999; Ishii et al, 1999). PTEN makes PI (3,4,5) P₃Dephosphorylation to PI (4,5) P₂Thereby antagonizing PI 3K-dependent signaling. In cells containing non-functionally active PTEN, PIP₃Increased levels, high levels of PI3K signaling activity (Haas-Kogan et al, 1998; Myers et al, 1998; Taylor et al, 2000), increased proliferative potential, and decreased sensitivity to pro-apoptotic stimuli (Stambolic et al, 1998). Restoration of PTEN function inhibits PI3K signaling (Taylor et al, 2000), inhibits cell growth and restores sensitivity of cells to pro-apoptotic stimuli (Myers et al, 1998; Zhao et al, 2004). Similarly, in tumors lacking functional PTEN, PTEN is functionalRestoration of inhibition of tumor growth in vivo (Stahl et al, 2003; Su et al, 2003; Tanaka)&Grossman,2003) and sensitises cells to cytotoxic agents (Tanaka)&Grossman,2003)。

The signal transduction input to class I PI3K is diverse and can be inferred by genetic analysis. Thus, activation of AKT is impaired when stimulated by typical Receptor Tyrosine Kinase (RTK) ligands (e.g. EGF, insulin, IGF-1 and PDGF) in p110 α -deficient Murine Embryonic Fibroblasts (MEFs) (Zhao et al, 2006). However, MEFs, in which p110 β is deleted or replaced by the kinase inactive allele of p110 β, respond normally to growth factor stimulation by RTKs (Jia et al, 2008). In contrast, p110 β catalytic activity is required for AKT activation in response to GPCR ligands (e.g., LPA). Thus, p110 α appears to carry most of the PI3K signal in classical RTK signaling and is responsible for tumor cell growth, proliferation, survival, angiogenesis and metabolism, whereas p110 β mediates GPCR signaling from mitogens and chemokines and thus regulates tumor cell proliferation, metabolism, inflammation and infiltration (Vogt et al, 2009; Jia et al, 2009).

Mutations in the gene encoding p110 β are rare in tumors, but amplification of PI3K β has been found in many tumors (Benistant et al 2000; Brugge et al 2007). Importantly, PTEN-deficiency driven mouse prostate tumor models show that removal of p110 α has no effect on tumorigenesis (Jia et al, 2008). Furthermore, downstream activation of AKT, cellular transformation, and growth of PTEN-deficient cells and tumor xenografts were inhibited in PTEN-deficient human cancer cell lines with p110 β but without p110 α (e.g., PC-3, U87MG, and BT549) (Wee et al, 2008). Genetic studies have shown that kinase activity of p110 β is essential in cell transformation resulting from PTEN deletion. For example, addition of back-kinase inactivated p110 β instead of its wild-type counterpart reduced colony formation (focussformation) of PTEN-deficient PC3 cells that had depleted endogenous p110 β (Wee et al, 2008). These studies demonstrated that PTEN-deficient tumor cells are dependent on p110 β and its catalytic activity for signal transduction and growth.

Genetic alterations of the tumor suppressor PTEN are common in many cancers (Liu et al, 2009), such as endometrial cancer (43%), CRPC (35-79%), glioma (19%) and melanoma (18%). In the case of endometrial cancer, a concomitant genetic alteration in PIK3CA and PTEN was identified (Yuan & Cantley, 2008). In addition to mutations, PIK3CA amplification and PTEN loss of function were also found by a variety of molecular mechanisms. For example, amplification of PIK3CA and loss of PTEN function were found in 30-50% and 35-60% of gastric cancer patients, respectively, but PIK3CA and PTEN mutations were reported to be less than 7% each (Byun et al, 2003; Oki et al, 2006; Li et al, 2005; Sanger Database).

While some tumor types rely solely on PI3K α signaling, other tumors rely on PI3K β signaling or a combination of both PI3K α and PI3K β signaling.

Thus, there remains a need for PI3K α/β inhibitors that are capable of inhibiting the balance of both PI3K α and β targets.

WO2008/070150(bayer schering pharmaakatiengesellschaft) relates to 2, 3-dihydroimidazo [1,2-c ] quinazoline compounds, pharmaceutical compositions comprising such compounds and the use of such compounds or compositions for the inhibition of phosphatidylinositol-3-kinase (PI3K) and the treatment of diseases associated with PI3K activity, in particular for the treatment of hyperproliferative and/or angiogenic disorders, as a sole agent or in combination with other active ingredients. The compounds showed higher activity on PI3K α than on PI3K β (lower IC 50).

However, the above background art does not describe the compounds of the general formula (I) according to the present invention, stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, as described and defined in the claims herein and hereinafter referred to as "compounds of the present invention". The above-mentioned background art also does not show the pharmacological activity as shown by the compounds of general formula (I) of the present invention.

It has now been found that said compounds of the invention, as described and defined herein and hereinafter referred to as "compounds of the invention", have surprisingly advantageous properties, which constitute the present inventionThe compounds of the invention show a surprisingly balanced activity against the phosphatidylinositol-3-kinase α -isoform and the β -isoform as demonstrated in the biological section herein, which is indicated by PI3K β IC₅₀/PI3KαIC₅₀The ratio of (A) to (B) indicates.

The compounds of the present invention, including salts thereof, metabolites thereof, solvates of the salts, hydrates thereof, and stereoisomeric forms thereof, have antiproliferative activity and are therefore useful in the prevention or treatment of hyperproliferative-associated conditions: in particular, the compounds of general formula (I) according to the invention are therefore useful for the treatment or prevention of diseases caused by or accompanied by uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response or an inappropriate cellular inflammatory response, in particular wherein the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by the PI3K pathway, such as haematological tumours, solid tumours and/or metastases thereof, such as leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, breast tumours including non-small cell lung tumours and small cell lung tumours, lung tumours including non-small cell lung tumours and small cell lung tumours, Gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, urological tumors including renal tumors, bladder tumors and prostate tumors, skin tumors and sarcomas, and/or metastases thereof.

Disclosure of Invention

One embodiment of the present invention comprises a compound having the general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a physiologically acceptable salt thereof, or a mixture of same:

wherein:

R¹is represented by- (CH)₂)_n-(CHR⁴)-(CH₂)_m-N(R⁵)(R⁵’)；

R²Represents a heteroaryl group having the structure:

said heteroaryl group being optionally substituted with 1,2 or 3R⁶The substitution of the group(s),

wherein:

represents the point of attachment of the heteroaryl group to the rest of the compound of formula (I),

x represents N or C-R⁶，

X' represents O, S, NH, N-R⁶N or C-R⁶，

With the proviso that when X and X' are both C-R⁶When it is, then a C-R⁶Is C-H;

R³is methyl;

R⁴is a hydroxyl group;

R⁵and R⁵' same or different, and each independently is a hydrogen atom, C₁-C₆Alkyl radical, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, or C₁-C₆-alkoxy-C₁-C₆-an alkyl group,

or

R⁵And R⁵' together with the nitrogen atom to which they are attached represent a 3-to 7-membered nitrogen-containing heterocyclic ring optionally containing at leastAn additional hetero atom selected from oxygen, nitrogen or sulfur and which may optionally be substituted by 1 or more R⁶' group substitution;

R⁶each occurrence may be the same or different and is independently a hydrogen atom, a halogen atom, C₁-C₆Alkyl radical, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆Alkyl, aryl-C₁-C₆Alkyl, heteroaryl-C₁-C₆-alkyl, 3-to 8-membered heterocycle, 3-to 8-membered heterocyclyl-C₁-C₆-alkyl, -C₁-C₆-alkyl-OR⁷、-C₁-C₆-alkyl-SR⁷、-C₁-C₆-alkyl-N (R)⁷)(R⁷’)、-C₁-C₆-alkyl-C (= O) R⁷、-CN、-C(=O)OR⁷、-C(=O)N(R⁷)(R⁷’)、-OR⁷、-SR⁷、-N(R⁷)(R⁷') or-NR⁷C(=O)R⁷Each of which may optionally be substituted by 1 or more R⁸Substituted by groups;

R⁶each occurrence may be the same or different, and is independently C₁-C₆Alkyl radical, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, or C₁-C₆-alkyl-OR⁷；

R⁷And R⁷' may be the same or different at each occurrence and is independently a hydrogen atom, C₁-C₆Alkyl radical, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆Alkyl radical, C₃-C₆Cycloalkenyl, aryl-C₁-C₆-alkyl, heteroaryl, 3-to 8-membered heterocycle, 3-to 8-membered heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-an alkyl group;

R⁸independently at each occurrence is a halogen atom, nitro, hydroxy, cyano, formyl, acetyl, amino, C₁-C₆Alkyl radical, C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆Alkyl radical, C₁-C₆Cycloalkenyl, aryl-C₁-C₆-alkyl, heteroaryl, 3-to 8-membered heterocycle, heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-an alkyl group;

n is the integer 1 and m is the integer 1;

with the following conditions:

when said R is⁵And R⁵' together with the nitrogen atom to which they are attached represents:

time of flight

Wherein denotes the point of attachment to the remainder of the structure of formula (I), then

-said R having the structure²Heteroaryl group:

is not:

wherein denotes the point of attachment to the rest of the structure of formula (I).

Definition of

The terms mentioned herein preferably have the following meanings:

the term "halogen atom" or "halogen/halo" is understood to mean a fluorine, chlorine, bromine or iodine atom.

The term "C₁-C₆Alkyl "is understood to preferably mean a straight-chain or branched, saturated monovalent hydrocarbon radical having 1,2, 3,4,5 or 6 carbon atoms, for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl or 1, 2-dimethylbutyl or isomers thereof. In particular, the radicals have 1,2 or 3 carbon atoms ("C)₁-C₃-alkyl "), methyl, ethyl, n-propyl or isopropyl.

The term "C₁-C₆Alkoxy is to be understood as preferably meaning a straight-chain or branched, saturated monovalent hydrocarbon radical of the formula-O-alkyl, where the term "alkyl" is as defined above, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentoxy, isopentoxy or n-hexoxy, or isomers thereof.

The term "C₁-C₆-alkoxy-C₁-C₆Alkyl is understood to preferably denote C wherein one or more hydrogen atoms are defined as above, in the same or different manner₁-C₆Alkoxy in place of the straight-chain or branched saturated monovalent alkyl radicals as defined above, such as, for example, methoxyalkyl, ethoxyalkyl, propoxyalkyl, isopropoxyalkyl, butoxyalkyl, isobutoxyalkyl, tert-butoxyalkyl, sec-butoxyalkyl, pentoxyAlkyl, isopentoxyalkyl, hexyloxyalkyl, wherein the term "C₁-C₆-alkyl "is as defined above, or isomers thereof.

The term "C₂-C₆Alkenyl "is understood to preferably mean a straight-chain or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2,3, 4,5 or 6 carbon atoms, in particular 2 or 3 carbon atoms (" C)₂-C₃-alkenyl "), it being understood that in case the alkenyl group comprises more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl group is, for example, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, homoallyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -pent-3-enyl, (E) -pent-2-enyl, (Z) -pent-2-enyl, (E) -pent-1-enyl, (Z) -pent-1-enyl, hex-5-enyl, (E) -hex-4-enyl, m, (Z) -hex-4-enyl, (E) -hex-3-enyl, (Z) -hex-3-enyl, (E) -hex-2-enyl, (Z) -hex-2-enyl, (E) -hex-1-enyl, (Z) -hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E) -1-methylprop-1-enyl, (Z) -1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E) -2-methylbut-2-enyl, (Z) -2-methylbut-2-enyl, (E) -1-methylbut-2-enyl, (Z) -1-methylbut-2-enyl, (E) -3-methylbut-1-enyl, (Z) -3-methylbut-1-enyl, (E) -2-methylbut-1-enyl, (Z) -2-methylbut-1-enyl, (E) -1-methylbut-1-enyl, (Z) -1-methylbut-1-enyl, 1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl, 4-methylpent-3-enyl, (E) -3-methylpent-3-enyl, (Z) -3-methylpent-3-enyl, (E) -2-methylpent-3-enyl, (Z) -2-methylpent-3-enyl, (E) -1-methylpent-3-enyl, (Z) -1-methylpent-3-enyl, isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-3-enyl, methyl-pentenyl, methyl-3-enyl, methyl-pentenyl, ethyl-1-, (E) -4-methylpent-2-enyl, (Z) -4-methylpent-2-enyl, (E) -3-methylpent-2-enyl, (Z) -3-methylpent-2-enyl, (E) -2-methylpent-2-enyl, (Z) -2-Methylpent-2-enyl, (E) -1-methylpent-2-enyl, (Z) -1-methylpent-2-enyl, (E) -4-methylpent-1-enyl, (Z) -4-methylpent-1-enyl, (E) -3-methylpent-1-enyl, (Z) -3-methylpent-1-enyl, (E) -2-methylpent-1-enyl, (Z) -2-methylpent-1-enyl, (E) -1-methylpent-1-enyl, (Z) -1-methylpent-1-enyl, 3-ethylbut-3-enyl, methyl-but-2-enyl, methyl-pent-1-enyl, methyl-but-1-enyl, methyl-pent-1-enyl, methyl-but-1-enyl, methyl, 2-ethylbut-3-enyl, 1-ethylbut-3-enyl, (E) -3-ethylbut-2-enyl, (Z) -3-ethylbut-2-enyl, (E) -2-ethylbut-2-enyl, (Z) -2-ethylbut-2-enyl, (E) -1-ethylbut-2-enyl, (Z) -1-ethylbut-2-enyl, (E) -3-ethylbut-1-enyl, (Z) -3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E) -1-ethylbut-1-enyl, a salt thereof, a solvate thereof, a salt thereof, a hydrate thereof, (Z) -1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E) -2-propylprop-1-enyl, (Z) -2-propylprop-1-enyl, (E) -1-propylprop-1-enyl, (Z) -1-propylprop-1-enyl, (E) -2-isopropylprop-1-enyl, (Z) -2-isopropylprop-1-enyl, (E) -1-isopropylprop-1-enyl, and (Z) -2-isopropylprop-1-enyl, (Z) -1-isopropylprop-1-enyl, (E) -3, 3-dimethylprop-1-enyl, (Z) -3, 3-dimethylprop-1-enyl, 1- (1, 1-dimethylethyl) vinyl, but-1, 3-dienyl, penta-1, 4-dienyl, hex-1, 5-dienyl or methylhexadienyl. In particular, the group is vinyl or allyl.

The term "C₂-C₆Alkynyl is understood as preferably meaning a straight-chain or branched, monovalent hydrocarbon radical which comprises one or more triple bonds and comprises 2,3, 4,5 or 6 carbon atoms, in particular 2 or 3 carbon atoms ("C)₂-C₃-alkynyl "). Said C is₂-C₆Alkynyl is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, prop-2-ynyl, but-3-methylbut-1-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-4-ynylPent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2-dimethylbut-3-ynyl, 1-dimethylbut-2-ynyl or 3, 3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

The term "C₃-C₆Cycloalkyl "is understood to mean preferably a saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 3,4,5 or 6 carbon atoms. Said C is₃-C₆Cycloalkyl is, for example, a monocyclic hydrocarbon ring, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or a bicyclic hydrocarbon ring, such as a perhydropentalene or decaline ring. The cycloalkyl ring may optionally contain one or more double bonds, for example a cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl, wherein the bond between the ring and the rest of the molecule (whether saturated or unsaturated) may be at any carbon atom of the ring.

The term "alkylene" is understood to mean preferably an optionally substituted hydrocarbon chain (or "chain") having 1,2, 3,4,5 or 6 carbon atoms, i.e. -CH-which is optionally substituted₂- ("methylene" or "monobasic chain" or such as-C (Me))₂-）、-CH₂-CH₂- ("ethylene", "dimethylene" or "dibasic chain"), -CH₂-CH₂-CH₂- ("propylene", "trimethylene" or "triad"), -CH₂-CH₂-CH₂-CH₂- ("butylene", "tetramethylene" or "tetrabasic"), -CH₂-CH₂-CH₂-CH₂-CH₂- ("Pentylene", "pentamethylene" or "five-membered chain") or-CH₂-CH₂-CH₂-CH₂-CH₂-CH₂- ("hexamethylene", "hexamethylene" or "six-membered chain"). In particular, the alkylene chain has 1,2, 3,4 or 5 carbon atoms, more particularlyAnd having 1 or 2 carbon atoms.

The term "3-to 8-membered heterocycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 2,3, 4,5, 6 or 7 carbon atoms and one or more heteroatom-containing groups selected from: c (= O), O, S, S (= O), S (= O)₂、NR^aWherein R is^aRepresents a hydrogen atom, C₁-C₆-alkyl-, or halo-C₁-C₆-alkyl-; it is to be understood that the heterocycloalkyl group may be attached to the rest of the molecule through any of the carbon atoms or the optionally present nitrogen atom.

In particular, the 3-to 8-membered heterocycloalkyl group can comprise 2,3, 4,5, 6, or 7 carbon atoms and one or more of the above-mentioned heteroatom-containing groups ("3-to 8-membered heterocycloalkyl"), more particularly, the heterocycloalkyl group can comprise 4 or 5 carbon atoms and one or more of the above-mentioned heteroatom-containing groups ("5-to 7-membered heterocycloalkyl").

In particular, the heterocycloalkyl group may be, for example, but not limited to, a 4-membered ring such as azetidinyl, epoxypropyl (oxyethanyl), or a 5-membered ring such as tetrahydrofuranyl, dioxolyl (dioxolanyl), pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, or a 7-membered ring such as diazepanyl (diazepanyl) ring. Optionally, the heterocycloalkyl ring may be benzo-fused.

The heterocyclyl group may be bicyclic, such as, but not limited to, a 5, 5-membered ring, for example, a hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) ring, or a 5, 6-membered bicyclic ring, for example, a hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl ring or an 8-oxa-3-azabicyclo [3.2.1] oct-3-yl ring.

As mentioned above, the nitrogen atom containing ring may be partially unsaturated, i.e. it may contain one or more double bonds, such as, but not limited to, a 2, 5-dihydro-1H-pyrrolyl, 4H- [1, 3,4] thiadiazinyl, 4, 5-dihydrooxazolyl or 4H- [1,4] thiazinyl ring, or it may be benzo-fused, such as, but not limited to, a dihydroisoquinolinyl ring.

The term "aryl" is understood to mean preferably a monovalent, aromatic or partially aromatic, monocyclic, bicyclic or tricyclic hydrocarbon ring having 6,7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms ("C₆-C₁₄Aryl "), in particular a ring having 6 carbon atoms (" C)₆-aryl "), such as phenyl; or biphenyl, or is a ring having 9 carbon atoms ("C₉-aryl "), such as indanyl or indenyl, or a ring having 10 carbon atoms (" C₁₀Aryl), such as tetralinyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C₁₃Aryl radicals), such as the fluorenyl radical, or a ring having 14 carbon atoms ("C)₁₄Aryl "), for example anthracenyl. A specific example of an aryl group is one of the following possible structures:

wherein z represents O, S, NH or N (C)₁-C₆-alkyl) and indicates the point of attachment of the aryl group to the rest of the molecule.

The term "heteroaryl" is understood as preferably meaning a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5,6, 7,8, 9, 10, 11, 12, 13 or 14 ring atoms ("5-to 14-membered heteroaryl"), in particular 5 or 6 or 9 or 10 carbon atoms, and which comprises at least one heteroatom which may be identical or different (such as oxygen, nitrogen or sulfur), in addition which may be benzo-fused in each case.

In particular, the heteroaryl group has the following structure:

wherein:

represents the point of attachment of said heteroaryl to the rest of the compound of general formula (I) as defined above,

x represents N or C-R⁶，

X' represents O, S, NH, N-R⁶N or C-R⁶，

-R⁶Each occurrence may be the same or different and is independently a hydrogen atom, a halogen atom, C₁-C₆Alkyl radical, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆Alkyl, aryl-C₁-C₆Alkyl, heteroaryl-C₁-C₆-alkyl, 3-to 8-membered heterocycle, 3-to 8-membered heterocyclyl-C₁-C₆-alkyl, -C₁-C₆-alkyl-OR⁷、-C₁-C₆-alkyl-SR⁷、-C₁-C₆-alkyl-N (R)⁷)(R⁷’)、-C₁-C₆-alkyl-C (= O) R⁷、-CN、-C(=O)OR⁷、-C(=O)N(R⁷)(R⁷’)、-OR⁷、-SR⁷、-N(R⁷)(R⁷') or-NR⁷C(=O)R⁷Each of which may optionally be substituted by 1 or more R⁸Substituted by groups;

-R⁷and R⁷' may be the same or different at each occurrence and is independently a hydrogen atom, C₁-C₆Alkyl radical, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆Alkyl radical, C₃-C₆Cycloalkenyl, aryl-C₁-C₆-alkyl, heteroaryl, 3-to 8-membered heterocycle, 3-to 8-membered heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-an alkyl group;

-R⁸independently at each occurrence is a halogen atom, nitro, hydroxy, cyano, formyl, acetyl, amino, C₁-C₆Alkyl radical, C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆Alkyl radical, C₁-C₆Cycloalkenyl, aryl-C₁-C₆-alkyl, heteroaryl, 3-to 8-membered heterocycle, heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-an alkyl group.

More particularly, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and their benzo derivatives, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl or azanylAnd the like.

In general and unless otherwise indicated, the heteroaryl or heteroarylene includes all possible isomeric forms thereof, e.g., positional isomers thereof. Thus, for some illustrative, non-limiting examples, the term pyridyl or pyridinylene includes pyridin-2-yl, pyridinylene-2-yl, pyridin-3-yl, pyridinylene-3-yl, pyridin-4-yl and pyridinylene-4-yl; alternatively, the term thienyl or thienylene includes thien-2-yl, thien-3-yl, and thien-3-yl.

As used throughout this document, the term "C₁-C₆At C₁-C₆-alkyl "or" C₁-C₆-alkoxy "is understood in the context of its definition to mean an alkyl group having from 1 to 6 limited numbers of carbon atoms, i.e. 1,2, 3,4,5 or 6 carbon atoms. It is also understood that the term "C" refers to₁-C₆"is to be understood as meaning any subrange comprised therein, such as C₁-C₆、C₂-C₅、C₃-C₄、C₁-C₂、C₁-C₃、C₁-C₄、C₁-C₅、C₁-C₆(ii) a In particular C₁-C₂、C₁-C₃、C₁-C₄、C₁-C₅、C₁-C₆(ii) a More particularly C₁-C₄(ii) a In "C₁-C₆-haloalkyl "or" C₁-C₆-haloalkoxy "is even more particularly C₁-C₂。

Similarly, the term "C" as used herein₂-C₆", as used throughout this document, e.g., at" C₂-C₆-alkenyl "and" C₂-C₆-alkynyl "is understood in the context of its definition to mean alkenyl or alkynyl groups having a limited number of carbon atoms from 2 to 6, i.e. 2,3, 4,5 or 6 carbon atoms. It is also understood that the term "C" refers to₂-C₆"is to be understood as meaning any subrange comprised therein, such as C₂-C₆、C₃-C₅、C₃-C₄、C₂-C₃、C₂-C₄、C₂-C₅(ii) a In particular C₂-C₃。

In addition, the term "C" as used herein₃-C₆", as used throughout this document, e.g., at" C₃-C₆-cycloalkyl "is understood in the context of the definition of" cycloalkyl "to mean cycloalkyl having 3 to 6 limited numbers of carbon atoms, i.e. 3,4,5 or 6 carbon atoms. It is also understood that the term "C" refers to₃-C₆"is to be understood as meaning any subrange comprised therein, such as C₃-C₆、C₄-C₅、C₃-C₅、C₃-C₄、C₄-C₆、C₅-C₆(ii) a In particular C₃-C₆。

The term "substituted" means that one or more hydrogens of the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the current circumstances is not exceeded and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "optionally substituted" means optionally substituted with the indicated group, radical or moiety.

Substituents of a ring system refer to substituents attached to an aromatic or non-aromatic ring system, e.g., the substituents replace available hydrogens on the ring system.

The term "one or more times" as used herein, for example in the definition of a substituent of a compound of the general formula according to the invention, is to be understood as meaning "one, two, three, four or five times, in particular one, two, three or four times, more particularly one, two or three times, even more particularly one or two times".

When the plural form of the words compound, salt, polymorph, hydrate, solvate and the like are used herein, it is to be understood that reference to a compound, salt, polymorph, isomer, hydrate, solvate and the like in the singular is also intended.

"stable compound" or "stable structure" refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

The term "carbonyl" refers to an oxygen atom bonded to a carbon atom of a molecule through a double bond.

The compounds of the present invention may contain one or more asymmetric centers, depending on the location and nature of the various substituents desired. Asymmetric carbon atoms may exist in either the (R) -or (S) -configuration, resulting in racemic mixtures with one asymmetric center and diastereomeric mixtures with multiple asymmetric centers. In some cases, asymmetry may also exist due to hindered rotation about a particular bond, for example, the central bond connects two substituted aromatic rings of a particular compound. The ring substituents may also be present in cis or trans form. All such configurations (including enantiomers and diastereomers) are contemplated to be within the scope of the present invention. Preferred compounds are those that produce a more desirable biological activity. Isolated, pure or partially purified isomers and stereoisomers, or racemic or diastereomeric mixtures of the compounds of the invention are included within the scope of the invention. Purification and isolation of such materials can be accomplished by standard techniques known in the art.

Tautomers (sometimes referred to as proton-moving tautomers) are two or more compounds that are linked by the migration of a hydrogen atom with the conversion of one or more single bonds and one or more adjacent double bonds. The compounds of the invention may exist in one or more tautomeric forms. For example, a compound of formula I may exist in tautomeric form Ia, tautomeric form Ib or tautomeric form Ic, or may exist as a mixture of any of these forms. All such tautomeric forms are intended to be included within the scope of the present invention.

The invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts, co-precipitates, metabolites, hydrates, solvates and prodrugs of all the example compounds. The term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic or organic acid addition salts of the compounds of the present invention. See, for example, S.M.Berge et al, "pharmaceutical salts," J.pharm.Sci.1977,66, 1-19. Pharmaceutically acceptable salts include those obtained by reacting a main compound as a base with an inorganic acid or an organic acid to form a salt, such as salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, and citric acid. Pharmaceutically acceptable salts also include those salts formed from the principal compound as an acid and reacted with a suitable base, for example, sodium, potassium, calcium, magnesium, ammonium or chorine salts. Those skilled in the art will also recognize that acid addition salts of the claimed compounds can be prepared by reacting the compounds with the appropriate inorganic or organic acid by any of a variety of known methods. Alternatively, the alkali metal salts and alkaline earth metal salts of the acidic compounds of the present invention are prepared by reacting the compounds of the present invention with an appropriate base by various known methods.

Representative salts of the compounds of the present invention include conventional, non-toxic salts or quaternary ammonium salts formed, for example, from inorganic or organic acids or bases by methods well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate (camphorate), camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectate (pectinate), persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, sulfate, etc, Tartrate, thiocyanate, tosylate and undecanoate salts.

Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. In addition, basic nitrogen-containing groups may be quaternized with, for example, the following agents: lower alkyl halides, such as methyl, ethyl, propyl or butyl chloride, bromide and iodide, dialkyl sulfates, such as dimethyl, diethyl, dibutyl sulfate, or diamyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl bromide and phenethyl bromide and the like.

For the purposes of the present invention, solvates are solid complexes of a solvent and a compound of the invention. Exemplary solvates include, but are not limited to, complexes of the compounds of the present invention with ethanol or methanol. Hydrates are a particular form of solvate, wherein the solvent is water.

In a preferred embodiment, the invention comprises a compound of formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a physiologically acceptable salt thereof, or a mixture of same, wherein:

R¹is represented by- (CH)₂)_n-(CHR⁴)-(CH₂)_m-N(R⁵)(R⁵’)；

R²Represents a heteroaryl group having the structure:

wherein:

represents the point of attachment of the heteroaryl group to the rest of the structure of formula (I);

R³is methyl;

R⁴is a hydroxyl group;

or

R⁵And R⁵' together with the nitrogen atom to which they are attached represent a 3-to 7-membered nitrogen-containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may optionally be substituted by 1 or more R⁶' group substitution;

R⁶each occurrence may be the same or different and is independently a hydrogen atom, a halogen atom, C₁-C₆Alkyl radical, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆Alkyl, aryl-C₁-C₆Alkyl, heteroaryl-C₁-C₆-alkyl, 3-to 8-membered heterocycle, 3-to 8-membered heterocyclyl-C₁-C₆-alkyl, -C₁-C₆-alkyl-OR⁷、-C₁-C₆-alkyl-SR⁷、-C₁-C₆-alkyl-N (R)⁷)(R⁷’)、-C₁-C₆-alkyl-C (= O) R⁷、-CN、-C(=O)OR⁷、-C(=O)N(R⁷)(R⁷’)、-OR⁷、-SR⁷、-N(R⁷)(R⁷') or-NR⁷C(=O)R⁷It isEach of which may optionally be substituted by 1 or more R⁸Substituted by groups;

n is the integer 1 and m is the integer 1;

with the following conditions:

time of flight

-said R having the structure²Heteroaryl group:

is not:

In another preferred embodiment, the invention comprises a compound of formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a physiologically acceptable salt thereof, or a mixture of same, wherein

R¹Is represented by- (CH)₂)_n-(CHR⁴)-(CH₂)_m-N(R⁵)(R⁵’)；

R²Represents a heteroaryl group having the structure:

wherein:

R³is methyl;

R⁴is a hydroxyl group;

or

n is the integer 1 and m is the integer 1;

with the following conditions:

time of flight

-said R having the structure²Heteroaryl group:

is not:

In a further preferred embodiment, the invention comprises a compound of formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a physiologically acceptable salt thereof, or a mixture of same, wherein:

R¹is represented by- (CH)₂)_n-(CHR⁴)-(CH₂)_m-N(R⁵)(R⁵’)；

R²Represents a heteroaryl group having the structure:

wherein:

represents the point of attachment of said heteroaryl group to the rest of the structure of formula (I), and

z represents N or C-R⁶；

R³Is methyl;

R⁴is a hydroxyl group;

or

R⁶' Each occurrence can be the same or different, and is independently C₁-C₆Alkyl radical, C₃-C₆-cycloalkyl-C₁-C₆-alkyl, or C₁-C₆-alkyl-OR⁷；

n is the integer 1 and m is the integer 1.

R¹is represented by- (CH)₂)_n-(CHR⁴)-(CH₂)_m-N(R⁵)(R⁵’)；

R²Represents a heteroaryl group having the structure:

wherein:

z represents N or C-R⁶；

R³Is methyl;

R⁴is a hydroxyl group;

or

n is the integer 1 and m is the integer 1.

In a further embodiment of the above aspects, the present invention relates to compounds of formula (I), wherein

R¹Is represented by- (CH)₂)_n-(CHR⁴)-(CH₂)_m-N(R⁵)(R⁵’)。

R²Represents a heteroaryl group having the structure:

wherein:

x represents N or C-R⁶，

X' represents O, S, NH, N-R⁶N or C-R⁶，

With the proviso that when X and X' are both C-R⁶When it is, then a C-R⁶Is C-H.

In a further embodiment of the above aspects, the invention relates to compounds of formula (I), wherein R³Is methyl.

In a further embodiment of the above aspects, the invention relates to compounds of formula (I), wherein R⁴Is a hydroxyl group.

or

R⁵And R⁵' together with the nitrogen atom to which they are attached represent a 3-to 8-membered nitrogen-containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may optionally be substituted by 1 or more R⁶' group substitution.

R⁶Each occurrence may be the same or different and is independently a hydrogen atom, a halogen atom, C₁-C₆Alkyl radical, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆Alkyl, aryl-C₁-C₆Alkyl, heteroaryl-C₁-C₆-alkyl, 3-to 8-membered heterocycle, 3-to 8-membered heterocyclyl-C₁-C₆-alkyl, -C₁-C₆-alkyl-OR⁷、-C₁-C₆-alkyl-SR⁷、-C₁-C₆-alkyl-N (R)⁷)(R⁷’)、-C₁-C₆-alkyl-C (= O) R⁷、-CN、-C(=O)OR⁷、-C(=O)N(R⁷)(R⁷’)、-OR⁷、-SR⁷、-N(R⁷)(R⁷') or-NR⁷C(=O)R⁷Each of which may optionally be substituted by 1 or more R⁸And (4) substituting the group.

R⁶' Each occurrence can be the same or different, and is independently C₁-C₆Alkyl radical, C₃-C₆-cycloalkyl-C₁-C₆-alkyl or C₁-C₆-alkyl-OR⁷。

R⁷And R⁷' may be the same or different at each occurrence and is independently a hydrogen atom, C₁-C₆Alkyl radical, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆Alkyl radical, C₃-C₆Cycloalkenyl, aryl-C₁-C₆-alkyl, heteroaryl, 3-to 8-membered heterocycle, 3-to 8-membered heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-an alkyl group.

R⁸Independently at each occurrence is a halogen atom, nitro, hydroxy, cyano, formyl, acetyl, amino, C₁-C₆Alkyl radical, C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₆Alkyl radical, C₁-C₆Cycloalkenyl, aryl-C₁-C₆-alkyl, heteroaryl, 3-to 8-membered heterocycle, heterocyclyl-C₁-C₆-alkyl, or heteroaryl-C₁-C₆-an alkyl group.

n is the integer 1 and m is the integer 1;

with the following conditions:

time of flight

-said R having the structure²Heteroaryl group:

is not:

R²Represents a heteroaryl group having the structure:

wherein:

● represents the point of attachment of the heteroaryl group to the remainder of the structure of formula (I).

●

In a further embodiment of the above aspects, the invention relates to compounds of formula (I), wherein R

²Represents a heteroaryl group having the structure:

wherein:

z represents N or C-R⁶。

In an embodiment of the above aspect, the present invention relates to a compound of formula (I) of any of the above embodiments in the form of a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

It is to be understood that the present invention relates to any subcombination within the scope of any embodiment of the compounds of general formula (I) of the invention described hereinabove.

More specifically, the present invention includes compounds of formula (I) as disclosed in the examples section below.

According to another aspect, the present invention relates to a process for preparing a compound of the present invention, said process comprising the steps described herein.

According to another aspect, the present invention relates to the preparation of compounds of general formula (I) useful in the present invention, in particular to intermediate compounds useful in the processes described herein. Specifically, the invention includes compounds of the general formula (XI):

wherein R1 and R3 are as defined above for general formula (I).

According to a further aspect, the present invention relates to the use of the intermediate compounds of formula (XI) described above for the preparation of the compounds of formula (I) of the present invention described above.

When a chemical name does not correspond to a chemical structure shown, the chemical structure shown is controlling rather than the chemical name provided.

Experiment of

General preparation method

The particular method of preparing the compounds for use in this embodiment of the invention depends on the particular compound desired. Factors such as the choice of particular substituents play a role in the route taken for the preparation of particular compounds of the invention. Those factors are recognized by those skilled in the art.

The compounds of the present invention may be prepared by using known chemical reactions and procedures. However, the following general preparation methods are provided, as well as the more detailed specific examples provided below in the experimental section describing the examples, to assist the reader in synthesizing the compounds of the invention.

The compounds of the present invention can be prepared according to conventional chemical methods and/or methods disclosed below, from starting materials that are commercially available or can be prepared according to conventional, conventional chemical methods. General methods for preparing the compounds are provided below, and the preparation of representative compounds is detailed in the examples.

Synthetic transformations useful in the synthesis of the compounds of the present invention, as well as the synthesis of intermediates involved in the synthesis of the compounds of the present invention, are known or readily available to those skilled in the art. Synthetically transformed corpus can be found in edibles such as:

march, Advance organic chemistry, 4 th edition, John Wiley: New York (1992)

R.C.Larock.comprehensive organic transformations, 2 nd edition, Wiley-VCH: NewYork (1999)

Carey, R.J.Sundberg.Advance organic chemistry, 2 nd edition, plenum Press, New York (1984)

T.W.Greene, P.G.M.Wuts.Protective Groups Inganic Synthesis, 3 rd edition, John Wiley: New York (1999)

L.S.Hegedus.TransitionMetalsuch Synthesis of Complexorganic molecules, 2 nd edition, Universal sciences Books: MillValley, CA (1994)

L.A.Paquette,Ed.TheEncyclopediaofReagentsforOrganicSynthesis;JohnWiley:NewYork(1994)

A.R.Katritzky;O.Meth-Cohn;C.W.Rees,Eds.ComprehensiveOrganicFunctionalGroupTransformations;PergamonPress:Oxford,UK(1995)

G.Wilkinson;F.GA.Stone;E.W.Abel,Eds.ComprehensiveOrganometallicChemistry;PergamonPress:Oxford,UK(1982)

B.M.Trost;I.Fleming.ComprehensiveOrganicSynthesis;PergamonPress:Oxford,UK(1991)

A.R.Katritzky;C.W.ReesEds.ComprehensiveHeterocylicChemistry;PergamonPress:Oxford,UK(1984)

A.R.Katritzky;C.W.Rees;E.F.V.Scriven,Eds.ComprehensiveHeterocylicChemistryII；PergamonPress:Oxford,UK(1996)

C.Hansch;P.G.Sammes;J.B.Taylor,Eds.ComprehensiveMedicinalChemistry:PergamonPress:Oxford,UK(1990)。

In addition, a retrospective review of synthetic methodologies and related subject matter includes organic reactions, John Wiley: New York, organic Synthesis, John Wiley: New York, reagent for organic Synthesis, John Wiley: New York, the reagent for organic chemistry, drug Synthesis, John Wiley: New York, Annual report organic Synthesis, AcademicPrecission: SangegoCA, and Methodendenderorganischen Chemie (Houben-Weyl), Thirieme: Stuttgart, Germany. Moreover, databases of synthetic transformations include chemical abstracts, which can be retrieved with CASOnLine or SciFinder, handbuchderorgansischen chemistry (beilstein), which can be retrieved with SpotFire, and REACCS.

Hereinafter, "PG" refers to a suitable protecting group, which may be known to those skilled in the art from, for example, T.W.Greene; P.G.M.Wuts.Protective group in organic Synthesis, 3 rd edition; John Wiley: New York (1999).

Reaction scheme 1

In scheme 1, vanillin acetate is converted to intermediate (III) by nitration conditions such as pure fuming nitric acid, or nitric acid and in the presence of another strong acid such as sulfuric acid. It is contemplated that the acetate of intermediate (III) is hydrolyzed in a protic solvent such as methanol in the presence of a base such as sodium hydroxide, lithium hydroxide, or potassium hydroxide. Protection of Intermediate (IV) to yield a compound of formula (V) (PG = protecting group, well known to those skilled in the art) can be achieved by standard methods (Greene, t.w.; Wuts, p.g.m.; protective group organic synthesis; Wiley & Sons: new york, 1999). The conversion of the compound of formula (V) to the compound of formula (VI) can be achieved using ammonia in the presence of iodine in an aprotic solvent such as THF or dioxane. The reduction of the nitro group in formula (VI) can be accomplished using iron in acetic acid or hydrogen in the presence of a suitable palladium, platinum or nickel catalyst. The conversion of the compound of formula (VII) to the imidazoline of formula (VIII) can best be achieved with ethylenediamine in the presence of a catalyst such as elemental sulphur under heating. The cyclisation of the compound of formula (VIII) to the compound of formula (IX) is effected using cyanogen bromide in a halogenated solvent such as DCM or dichloroethane in the presence of an amine base such as triethylamine, diisopropylethylamine or pyridine. The removal of the protecting group in formula (IX) depends on the group chosen and can be achieved by standard methods (Greene, T.W.; Wuts, P.G.M.; protective group organic Synthesis; Wiley & Sons: New York, 1999). Alkylation of the phenol in formula (X) can be achieved using a base such as cesium carbonate, sodium hydride or potassium tert-butoxide in a polar aprotic solvent such as DMF or DMSO, introducing a side chain bearing a suitable leaving group such as a halide or sulfonate group to provide a compound of formula (XI). Finally, the amide of formula (I) may be formed using an active ester such as an acid chloride and an anhydride, or may be formed using a carboxylic acid and a suitable coupling agent such as PYBOP, DCC or EDCI in a polar aprotic solvent.

Reaction scheme 2

In scheme 2, compounds of formula (IV) prepared as described above can be converted to structures of formula (XII) using ammonia in the presence of iodine in an aprotic solvent such as THF or dioxane. Alkylation of the phenols in formula (XII) with the introduction of side chains bearing suitable leaving groups such as halide or sulfonate groups can be achieved using a base such as cesium carbonate, sodium hydride or potassium tert-butoxide in a polar aprotic solvent such as DMF or DMSO. Reduction of the nitro group in formula (XIII) may be accomplished using iron in acetic acid or hydrogen in the presence of a suitable palladium, platinum or nickel catalyst. The conversion of the compound of formula (XIV) to the imidazoline of formula (XV) can best be achieved with ethylenediamine in the presence of a catalyst such as elemental sulphur under heating. The cyclisation of the compound of formula (XV) to the compound of formula (XVI) is effected using cyanogen bromide in a halogenated solvent such as DCM or dichloroethane in the presence of an amine base such as triethylamine, diisopropylethylamine or pyridine. Finally, the amide of formula (I) may be formed using an active ester such as an acid chloride and an anhydride, or may be formed using a carboxylic acid and a suitable coupling agent such as PYBOP, DCC or EDCI in a polar aprotic solvent.

Reaction scheme 3

In scheme 3, compounds of formula (X) prepared as described above can be converted to amides (XVI) using active esters such as acid chlorides and anhydrides, or using carboxylic acids and suitable coupling agents such as PYBOP, DCC or EDCI in polar aprotic solvents. Amide (XVI) can then be converted to a compound of formula (I) using a base such as cesium carbonate, sodium hydride or potassium tert-butoxide in a polar aprotic solvent such as DMF or DMSO, introducing a side chain bearing a suitable leaving group such as a halide or sulfonate group.

Reaction scheme 4

In scheme 4, compounds of formula (IX) prepared as described above can be converted to amides (XVII) using active esters such as acid chlorides and anhydrides, or carboxylic acids and suitable coupling agents such as PYBOP, DCC or EDCI in polar aprotic solvents. The removal of the protecting group in formula (XVII) depends on the group chosen and can be achieved by standard methods (Greene, T.W.; Wuts, P.G.M.; protective Groups organic Synthesis; Wiley & Sons: New York, 1999). Alkylation of the phenol in formula (XVI) can be achieved using a base such as cesium carbonate, sodium hydride or potassium tert-butoxide in a polar aprotic solvent such as DMF or DMSO, introducing a side chain bearing a suitable leaving group such as a halide or sulfonate group.

Reaction scheme 5

In scheme 5, chlorinating agents such as POCl are used in aprotic solvents₃Or COCl₂The compound of formula XVIII can be converted to the bischloride compound of formula XIX. The chloride thus obtained can be converted into imidazolines of formula XXI by reaction with an appropriate amount of ethanolamine or an appropriately protected substitute, followed by reaction with a suitable activator such as sulfonyl chloride, PPh₃Or halogenating agents, e.g. SOCl₂And (4) activating. Chloride XXI can be converted to amine XXII in a polar solvent such as DMF or DMSO using any nucleophilic amine source such as ammonia, phthalimide or a protected amine such as benzylamine. By using literature (Greene, T.W.; Wuts, P.G.M.; protective Groupsin organic Synthesis;Wiley&Sons: New York,1999) deprotect the methyl ester to form the phenol of formula X.

In order that the invention may be better understood, the following examples are set forth. These examples are for illustration only and should not be construed as limiting the scope of the invention in any way. Any publications mentioned herein are incorporated by reference in their entirety.

Abbreviations and acronyms

A comprehensive list of abbreviations used by those of ordinary skill in the art of organic chemistry is found in the ACSStyleGuide (3 rd edition) or in Guidelins for authors of journal of organic chemistry. The abbreviations contained in the list, as well as all abbreviations used by those of ordinary skill in the art of organic chemistry, are incorporated herein by reference. For the purposes of the present invention, the chemical elements are identified in accordance with the periodic Table Blesoft elements, CASversion, handbook of chemistry and Physics, 67 th edition, 1986-87.

More specifically, when the following abbreviations are used throughout the present disclosure, they have the following meanings:

acac acetylacetonate

Ac₂O acetic anhydride

AcO (or OAc) acetate

anh anhydrous

aq aqueous

Ar aryl radical

atm atmospheric pressure

9-BBN 9-borabicyclo [3.3.1] nonyl

BINAP2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl

Bn benzyl group

bp boiling point

brs wide singlet

Bz benzoyl

BOC tert-butyloxycarbonyl radical

n-BuOH n-butanol

t-BuOH tert-butanol

t-BuOK Potassium tert-butoxide

C degree centigrade

calcd theoretical value

CAN ammonium ceric nitrate

Cbz benzyloxycarbonyl

CDI carbonyl diimidazole

CD₃OD methanol-d₄

The diatomite filtering agent is added into the mixture of the diatomite and the water,Corp.

CI-MS chemical ionization mass spectrometry

¹³CNMR carbon-13 nuclear magnetic resonance

m-CPBA m-chloroperoxybenzoic acid

d double peak

dd double doublet

DABCO1, 4-diazabicyclo [2.2.2] octane

DBU1, 8-diazabicyclo [5.4.0] undec-7-ene

DCCN, N' -dicyclohexylcarbodiimide

DCM dichloromethane

DEAD azodicarboxylic acid diethyl ester

dec decomposition

DIA diisopropylamine

DIBAL diisobutyl aluminum hydride

DMAP4- (N, N-dimethylamino) pyridine

DME1, 2-dimethoxyethane

DMFN, N-dimethylformamide

DMSO dimethyl sulfoxide

EE type (entgegen) (configuration)

EDCl or 1- (3-dimethylaminopropyl) -3-ethylcarbon dioxide

EDCI HCl imine hydrochloride

ee enantiomeric excess

EI electron collision

ELSD evaporative light scattering detector

equiv equivalent of

ES-MS electrospray mass spectrometry

EtOAc ethyl acetate

EtOH ethanol (100%)

EtSH ethanethiol

Et₂O Ether

Et₃N-Triethylamine

Fmoc 9-fluorenylmethoxycarbonyl

GC gas chromatography

GC-MS gas chromatography-mass spectrometry

h hours

hex Hexane

¹HNMR proton NMR

HMPA hexamethylphosphoramide

HMPT hexamethylphosphoric triamide

HOBT hydroxybenzotriazole

HPLC high performance liquid chromatography

insoluble in instol

IPA isopropyl amine

iPrOH Isopropanol

In the IR infrared

J coupling constant (NMR spectrum)

L liter

LAH lithium aluminum hydride

LC liquid chromatography

LC-MS liquid chromatography-mass spectrometry

Lithium LDA diisopropylamide

MmolL^-1(molarity)

m multiplet

m meta position

MeCN acetonitrile

MeOH methanol

MHz megahertz

min is divided into minutes

Microliter of μ L

mL of

Micromolar at μ M

mol mole of

mp melting point

MS Mass Spectrometry

Ms methanesulfonyl

m/z mass to charge ratio

N equivalent of L^-1(Standard)

NBSN-Bromosuccinimide

nM nanomolar

NMM 4-methylmorpholine

NMR nuclear magnetic resonance

o ortho position

obsd measurement

p para position

p pages

pp page

PdCl₂dppf [1,1' -bis (diphenylphosphino) ferrocene]Dichloro (phenyl) methane

Chemical palladium (II)

Pd(OAc)₂Palladium acetate

PG protecting groups, as is known to those skilled in the art

Are known (e.g. from

Negative logarithm of pH hydrogen ion concentration

Ph phenyl

Negative logarithm of pK equilibrium constant

pK_aNegative logarithm of dissociation equilibrium constant

PPA polyphosphoric acid

PS-DIEA polystyrene linked diisopropylethylamine

PyBOP benzotriazol-1-yl-oxy-tri-pyrrolidinyl-

Phosphonium hexafluorophosphates

q quartet peak

rac is racemic

R right (configuration)

rel refers to a compound in which one is chiral

The center is not determined, the chiral center is at

Storage of one or more defined chiral centres

Under the circumstances

R_fRetention factor (TLC)

RT Retention time (HPLC)

rt Room temperature

s single peak

S left (configuration)

t triplet peak

TBDMS, TBP tert-butyldimethylsilyl

TBDPS, TPS tert-butyldiphenylsilyl

TEA Triethylamine

THF tetrahydrofuran

Tf trifluoromethanesulfonyl (trifyl)

TFA trifluoroacetic acid

TFFH F-N, N, N ', N' -tetramethylformamide hexafluorophosphorus hexafluoride

Acid salts

TLC thin layer chromatography

TMADN, N, N ', N' -Tetramethylethylenediamine

TMSCl trimethylchlorosilane

Ts p-toluenesulfonyl group

v/v volume to volume ratio

w/v weight to volume ratio

w/w weight to weight ratio

ZZ type (zusammen) (configuration)

Detailed description of the experiments

Analytical HPLC-MS conditions:

the HPLC-MS data provided in the detailed experimental description below refer to the following conditions:

the method comprises the following steps: after 1.6min, the mixture is mixed with 99% of 0.1% formic acid aqueous solution and 1% CH₃CN to 1%0.1% aqueous formic acid solution 99% CH₃CN; 1%0.1% aqueous formic acid solution 99% CH after 1.6min₃CN, held for 0.4 min.

The method 2 comprises the following steps: after 1.6min, the mixture is mixed with 99% of 0.2% ammonia water and 1% of CH₃CN to 1% of 0.1% ammonia water and 99% of CH₃CN; 1%0.1% ammonia water 99% CH for 1.6min₃CNover1.6min, hold for 0.4 min.

Unless otherwise indicated, analytical HPLC utilized method 2.

Preparative HPLC conditions:

unless otherwise indicated, "purification by preparative HPLC" in the detailed experimental description below refers to the following conditions:

and (3) analysis:

preparation:

chiral HPLC conditions:

the chiral HPLC data provided in the detailed experimental description below refer to the following conditions:

and (3) analysis:

the system comprises the following steps:	Dionex:Pump 680,ASI 100,Waters:UV-Detektor 2487
		column:	Chiralpak IC 5μm 150x4.6mm
solvent:	hexane/ethanol 80:20+0.1% diethylamine
		Flow rate:	1.0mL/min
temperature:	25°C
		solutions of	1.0mg/mL EtOH/MeOH 1:1
Sample introduction:	5.0μl
		and (3) detection:	UV 280nm

preparation:

preparation of MPLC:

preparative Medium Pressure Liquid Chromatography (MPLC) is carried out by standard silica gel "flash chromatography" techniques (e.g., Still et al, 1978) or by using a silica gel short column and equipment such as the Flashmaster or BiotageFlash systems.

Unless otherwise stated, use is made of a cell equipped with IsoluteFlashNH₂FlashMasterII chromatography on reverse phase column with mixed solvent gradient (100% CH) for MPLC purification₂Cl₂Gradient to 90% CH over 12 min 3min₂Cl₂10% MeOH, gradient to 80% CH over 20min₂Cl₂20% MeOH, gradient to 70% CH over 10min₂Cl₂30% MeOH, gradient to 50% CH over 15min₂Cl₂50% MeOH) was eluted at the recommended flow rate relative to the column volume (i.e., 5g column, 10mL/min;50g column, 30 mL/min). The eluate was monitored by UV detector at 254 nm.

Optical rotation measurement conditions:

the optical rotation was measured in DMSO at a wavelength of 589nm, at 20 ℃, at a concentration of 1.0000g/100mL, for an integration time of 10s, and at a film thickness of 100.00 mm.

The structure of the compounds of the invention is confirmed using one or more of the following methods.

NMR

NMR spectra were obtained for each compound, which was consistent with the structure shown.

At 300 or 400MHzConventional one-dimensional NMR spectroscopy was performed on a Mercury-plus spectrometer. Will sampleThe product is dissolved in a deuterated solvent. Recording chemical shifts on the ppm scale and referencing appropriate solvent signals, e.g.¹DMSO-d of H spectrum₆2.49ppm、CD₃CN1.93ppm、CD₃OD3.30ppm、CD₂Cl₂5.32ppm and CDCl37.26ppm.

The percent yields reported in the following examples are based on the starting ingredients used in the minimum molar amounts. Air and moisture sensitive liquids and solutions were transferred with a syringe or pipette and introduced into the reaction vessel through a rubber septum. Commercial grade reagents and solvents were used without further purification. The term "concentration under reduced pressure" means using a Buchi rotary evaporator at about 15 mmHg. All temperatures reported are uncorrected, in degrees Celsius (° C).

Thin Layer Chromatography (TLC) was performed on precoated glass-backed silica gel 60AF-254250 μm plates.

Using Biotage optionally equipped with a robot cellThe reaction using microwave irradiation is performed in a microwave oven. The reported reaction times using microwave heating are understood to be the reaction times determined after the indicated temperatures have been reached.

The percent yields reported in the following examples are based on the starting ingredients used in the minimum molar amounts. Air and moisture sensitive liquids and solutions were transferred with a syringe or pipette and introduced into the reaction vessel through a rubber septum. Commercial grade reagents and solvents were used without further purification. The term "vacuum concentration" refers to the use of a Buchi rotary evaporator at a minimum pressure of about 15 mmHg. All temperatures reported are uncorrected, in degrees Celsius (° C).

The name of the compound was generated using ACD/NameBatch, version 12.01. In some cases, commonly accepted names for commercially available reagents are used.

Synthesis of intermediates

Intermediate A

Preparation of 2-aminopyrimidine-5-carboxylic acids

Sodium (1Z) -2- (dimethoxymethyl) -3-methoxy-3-oxoprop-1-en-1-oate was prepared as described in Zhichkin (Zhichkin et al, 2002).

(1Z) -2- (dimethoxymethyl) -3-methoxy-3-oxoprop-1-en-1-ol-sodium (1.37g,7.8mmol) was diluted in DMF (12mL) and guanidine hydrochloride (640mg,6.7mmol) was added. The mixture was stirred at 100 ℃ for 1h, then cooled to rt and diluted with water. Methyl 2-aminopyrimidine-5-carboxylate precipitated as a pale yellow solid, which was isolated by vacuum filtration (510mg,50%):¹HNMR(DMSO-d₆):8.67(s,2H),7.56(brs,2H),3.79(s,3H)。

methyl 2-aminopyrimidine-5-carboxylate (300mg,2.0mmol) was diluted in methanol (5mL) containing a few drops of water. Lithium hydroxide (122mg,5.1mmol) was added and the reaction mixture was stirred at 60 ℃ overnight. The mixture was concentrated under reduced pressure, then diluted in water and adjusted to pH4 with 1 MHCl. 2-aminopyrimidine-5-carboxylic acid precipitated as a white solid which was isolated by vacuum filtration (244mg,90%):¹HNMR(DMSO-d₆):12.73(1H,brs),8.63(2H,s),7.44(2H,brs)。

intermediate B

Preparation of 4- (3-chloropropyl) morpholine hydrochloride

To a solution of 1-bromo-3-chloropropane (45g,0.29mol) in toluene (100mL) was added morpholine (38g,0.44 mol). The solution was stirred at 84 ℃ for 3h, during which a precipitate formed. After cooling to rt, the precipitate was separated by vacuum filtration and extracted with diethyl etherWashed and the solid discarded. The mother liquor was acidified with HCl (4M in dioxane, 72mL,0.29mol), which resulted in the precipitation of the desired product as the HCl salt. The solvent was removed under reduced pressure and the resulting solid was dried to give the title compound (53g, 90%):¹HNMR(DMSO-d₆):11.45(1H,brs),3.94-3.77(4H,m),3.74(2H,t),3.39(2H,m),3.15(2H,m),3.03(2H,m),2.21(2H,m)。

intermediate B

Preparation of 6-amino-2-methylnicotinic acid

A suspension of 6-amino-2-methylnicotinonitrile (6-amino-2-methylnicotinonitril) (1.0g,7.5mmol) in aqueous KOH (20%,12mL) was heated at reflux temperature for 3 days. After this time, it was cooled to room temperature, neutralized with concentrated HCl, filtered and dried to give the desired product, which was used without further purification (1.1g, 96%).

Intermediate C

4- [ (2-oxo-1, 3, 2-dioxathiolan-4-yl) methyl]Morpholine hydrochloride (4- [ (2-oxide-1, 3,2-dioxathiolan-4-yl)methyl]morpholinohydochloride) preparation

3-Morpholin-4-ylpropan-1, 2-diol (2.1g,9.07mmol) was dissolved in DCM (15mL) and cooled to 0 ℃. The cooled solution was treated with thionyl chloride (1.81mL,24.8mmol) and then heated at reflux temperature for 1 h. The reaction mixture was then concentrated under reduced pressure to give a solid (2.5g,97%):¹HNMR(DMSO-d₆):11.4(1H,brs),5.64-5.55(1H,m)4.82(1H,dd),4.50(1H,dd),4.02-3.71(4H,m),3.55-3.33(4H,m),3.26-3.06(2H,brs)。

intermediate D

8- (benzyloxy) -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Preparation of quinazolin-5-amines

Step 1: 4-formyl-2-methoxy-3-nitrophenyl acetate

Fuming nitric acid (2200mL) was cooled to 0 ℃ under nitrogen, whereupon vanillin acetate (528g,2.7mol) was added portionwise, maintaining the internal temperature below 0 ℃. After 2h, the resulting mixture was poured onto ice with stirring. The slurry was filtered, and the resulting solid was washed with water (3 × 100mL) and air dried. After 2 days, the solid was heated in DCM (3000mL) until complete dissolution. The solution was allowed to cool to room temperature while hexane (3000mL) was added dropwise. The solid was filtered, washed with hexanes (500mL) and air dried to give 4-formyl-2-methoxy-3-nitrophenyl acetate (269g,41%):¹HNMR,(DMSO-d₆):9.90(s,1H),7.94(d,1H),7.75(d,1H),3.87(s,3H),2.40(s,3H)。

step 2: preparation of 4-hydroxy-3-methoxy-2-nitrobenzaldehyde

A mixture of 438g (1.8mol) of 4-formyl-2-methoxy-3-nitrophenylacetate and potassium carbonate (506g,3.7mol) in MeOH (4000mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give a viscous oil. It was dissolved in water, acidified with HCl (2N) solution and extracted with EtOAc. The organic layer was washed with saturated sodium chloride solution, dried (magnesium sulfate) and filtered. The solvent was concentrated to 1/3 volumes under reduced pressure and the resulting solid was filtered and air dried to give 4-hydroxy-3-methoxy-2-nitrobenzaldehyde (317g,88%):¹HNMR(DMSO-d₆):9.69(1H,s),7.68(1H,d),7.19(1H,d),3.82(3H,s)。

and step 3: preparation of 4- (benzyloxy) -3-methoxy-2-nitrobenzaldehyde

4-hydroxy-3-methoxy-2-nitrobenzaldehyde (155g,786mmol) was dissolved in DMF (1500mL) and the stirred solution was treated with potassium carbonate (217g,1.57mol) followed by benzyl bromide (161g,0.94 mol). Stir 16h, then concentrate the reaction mixture under reduced pressure and split between water (2L) and EtOAc (2L). The organic layer was washed with saturated sodium chloride solution (3 × 2L), dried (anhydrous sodium sulfate) and concentrated under reduced pressure. With Et₂The resulting solid was triturated with O (1L) to give 4- (benzyloxy) -3-methoxy-2-nitrobenzaldehyde (220g,97%):¹HNMR(DMSO-d₆):9.77(1H,s),7.87(1H,d),7.58(1H,d),7.51(1H,m),7.49(1H,m),7.39(3H,m),5.36(2H,s),3.05(3H,s)。

and 4, step 4: preparation of 4- (benzyloxy) -3-methoxy-2-nitrobenzonitrile

Iodine (272g,1.1mmol) was added to a mixture of 4- (benzyloxy) -3-methoxy-2-nitrobenzaldehyde (220g,766mmol) and ammonium hydroxide (28% solution, 3L) dissolved in THF (5L). After 16h, the reaction mixture was treated with sodium sulfite (49g,383mmol) and concentrated under reduced pressure to give a thick syrup. The slurry was filtered, washed with water (250mL) and dried to give 4- (benzyloxy) -3-methoxy-2-nitrobenzonitrile as a solid (206g,95%):¹HNMR(DMSO-d₆):7.89(1H,d),7.59(1H,d),7.49(2H,m),7.40(3H,m),5.35(2H,s),3.91(3H,s)。

and 5: preparation of 2-amino-4- (benzyloxy) -3-methoxybenzonitrile

A degassed solution of 4- (benzyloxy) -3-methoxy-2-nitrobenzonitrile (185g,651mmol) in glacial acetic acid (3500mL) and water (10mL) was cooled to 5 ℃ and treated with iron powder (182g,3.25 mol). After 3 days, the reaction mixture was filtered through Celite (Celite), and the filtrate was concentrated under reduced pressure. The oil thus obtained is treated with a saturated sodium chloride solution, neutralized with sodium bicarbonate solution and extracted into CH₂Cl₂In (1). The resulting emulsion was filtered through celite, then the organic layer was separated, washed with saturated sodium chloride solution, dried (anhydrous sodium sulfate) and concentrated under reduced pressure to give 2-amino-4- (benzyloxy) -3-methoxybenzonitrile as a solid (145g,88%):¹HNMR(DMSO-d₆):7.32-7.44(5H,m),7.15(1H,d),6.47(1H,d),5.69(2H,s),5.15(2H,s),3.68(3H,s)。

step 6: preparation of 3- (benzyloxy) -6- (4, 5-dihydro-1H-imidazol-2-yl) -2-methoxyaniline

A mixture of 2-amino-4- (benzyloxy) -3-methoxybenzonitrile (144g,566mmol) and sulphur (55g,1.7mol) in ethylenediamine (800mL) was degassed for 30min and then heated to 100 ℃. After 16h, the reaction mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, diluted with saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The resulting solid was recrystallized from EtOAc and hexanes to give 3- (benzyloxy) -6- (4, 5-dihydro-1H-imidazol-2-yl) -2-methoxyaniline (145g,86%):¹HNMR(DMSO-d₆)):7.27-7.48(5H,m),7.14(1H,d),6.92(2H,m),6.64(1H,m),6.32(1H,d),5.11(2H,s),3.67(3H,s),3.33(2H,s)。

and 7: 8- (benzyloxy) -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Preparation of quinazolin-5-amines

A mixture of 3- (benzyloxy) -6- (4, 5-dihydro-1H-imidazol-2-yl) -2-methoxyaniline (100g,336mmol) and triethylamine (188mL) in DCM (3L) was cooled to 0 ℃ and treated with cyanogen bromide (78.4g,740 mmol). The reaction mixture was stirred and allowed to gradually warm to room temperature. After 16h, the reaction mixture was diluted with saturated sodium bicarbonate solution and CH₂Cl₂And (4) extracting. The organic layer was washed 3 times with saturated bicarbonate solution and then with brine several times. The organic layer was dried (sodium sulfate) and concentrated under reduced pressure to give a semi-solid (130g, contaminated with triethylamine salt):¹HNMR(DMSO-d₆):7.30-7.48(7H,m),5.31(2H,s),4.32(2H,m),4.13(2H,m),3.81(3H,s)。

intermediate E

5-amino-7-methoxy-2, 3-dihydroimidazo [1,2-c]Preparation of quinazolin-8-ol bis (trifluoroacetate)

3- (benzyloxy) -6- (4, 5-dihydro-1H-imidazol-2-yl) -2-methoxyaniline (30g,93mmol) was added portionwise over 1H to a round-bottomed flask with TFA (400mL) pre-cooled with an ice bath. The reaction mixture was heated to 60 ℃ and stirred at this temperature for 17h, at which time it was cooled to rt and the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in DCM and hexane and concentrated under reduced pressure. The material thus obtained was dissolved in MeOH/CH₂Cl₂The solution (250mL,1:1) was concentrated under reduced pressure. The resulting solid was dried under vacuum with gentle heating overnight to give 5-amino-7-methoxy-2, 3-dihydroimidazo [1,2-c]Quinazolin-8-ol bis (trifluoroacetate) (44.7g,>100%):¹HNMR(DMSO-d₆):7.61(1H,m),6.87(1H,m),4.15(2H,brt),4.00(2H,m),3.64(3H,s)。

intermediate F

7-methoxy-8- [ (2R) -oxiran-2-ylmethoxy]-2, 3-dihydroimidazo [1,2-c]Quinazoline-5- Preparation of amines

Step 1: preparation of (R) -glycidyl methanesulfonate

A solution of (S) - (-) -glycidol (8.6mL,130mmol) and triethylamine (36.2mL,260mmol,2.0 equiv.) in DMF (250mL) was cooled on an ice bath and methanesulfonyl chloride (10.1mL,130mmol,1.0 equiv.) was added dropwise. The mixture was stirred at room temperature for 1.5 hours to give a 0.47m solution of (r) -glycidyl methanesulfonate in DMF, which was used without further purification.

Step 2: preparation of 7-methoxy-8- [ (2R) -oxiran-2-ylmethoxy ] -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-amine

To 5-amino-7-methoxy-2, 3-dihydroimidazo [1,2-c ]]A solution of quinazolin-8-ol bis (trifluoroacetate) (intermediate E,0.30g,0.65mmol) in DMF (8mL) was added cesium carbonate to give a white suspension. The suspension was stirred at room temperature for 1.5h, then (R) -glycidyl methanesulfonate (intermediate F, step 1,3.9ml of 0.34m solution in DMF, 1.30mmol,2.0 eq) was added and the resulting solution was stirred at 60 ℃ for 20 h. The resulting suspension was concentrated under reduced pressure and the residue was taken up in saturated sodium bicarbonate solution (30mL) and 4:1CH₂Cl₂The isopropanol solution (30mL) was separated. With 4:1CH₂Cl₂The aqueous phase was extracted with isopropanol solution (30 mL). The combined organic phases were dried (anhydrous sodium sulfate) and concentrated under reduced pressure. Using MPLC (IsoluteFlashNH)₂Reversed phase column, 100% CH₂Cl₂5min, gradient to 95% CH over 15min₂Cl₂5% MeOH, gradient to 90% CH over 15min₂Cl₂10% MeOH, 15min gradient to 80% CH₂Cl₂20% MeOH and a gradient to 75% CH over 15min₂Cl₂25% MeOH) to give 7-methoxy-8- [ (2R) -oxiran-2-ylmethoxy]-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-amine (0.080g,43%):¹HNMR(DMSO-d₆+1 drop TFA-d)2.71(dd, J =2.5,4.8Hz,1H),2.85, (t, J =4.6Hz,1H),3.34-3.40(brm,1H),3.75(s,3H),3.82(s,3H),4.30(dd, J =6.6,11.4Hz,1H),4.10(brt, J =9.7Hz,2H),4.31(brt, J =9.7Hz,2H),4.54(dd, J =2.3,11.6Hz,1H),7.26(d, J =9.4Hz,1H),7.84(d, J =9.1Hz, 1H).

Intermediate G

7-methoxy-8- (oxiran-2-ylmethoxy) -2, 3-dihydroimidazo [1,2-c]Preparation of quinazolin-5-amines Prepare for

Step 1: preparation of racemic glycidyl methanesulfonate

Racemic glycidyl methanesulfonate was synthesized in a similar manner to intermediate F, step 1, substituting (S) - (-) -glycidol with racemic glycidol. The solution of racemic glycidyl methanesulfonate in DMF was used for further conversion without further purification.

Step 2: preparation of 7-methoxy-8- (oxiran-2-ylmethoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-amine

In a similar manner to intermediate F, step 2, with racemic glycidyl groupsSynthesis of intermediate G (0.30G,24%) instead of (R) -glycidyl methanesulfonate by mesylate-HPLC retention time 0.62min;¹HNMR(DMSO-d₆+1 drop TFA-d)2.71(dd, J =2.5,4.8Hz,1H),2.85, (t, J =4.6Hz,1H),3.34-3.40(brm,1H),4.30(dd, J =6.6,11.4Hz,1H),4.10(brt, J =9.7Hz,2H),4.31(brt, J =9.7Hz,2H),4.54(dd, J =2.3,11.6Hz,1H),7.21(d, J =9.4Hz,1H),7.79(d, J =9.1Hz, 1H).

Intermediate H

7-methoxy-8- [ (2S) -oxiran-2-ylmethoxy]-2, 3-dihydroimidazo [1,2-c]Quinazoline-5- Preparation of amines

Step 1: preparation of (S) -glycidyl methanesulfonate

(S) -glycidyl methanesulfonate was synthesized in a similar manner to intermediate F, step 1, replacing S) - (-) -glycidol with (R) - (+) -glycidol. This is a solution of (S) -glycidyl methanesulfonate in DMF, which is used for further transformation without further purification.

Step 2: preparation of 7-methoxy-8- [ (2S) -oxiran-2-ylmethoxy ] -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-amine

Intermediate G (0.14G,15%) was synthesized in a similar manner to intermediate F, step 2, substituting (S) -glycidyl methanesulfonate for (R) -glycidyl methanesulfonate with an HPLC retention time of 0.62min;¹HNMR(DMSO-d₆+1 drop TFA-d)2.71(dd, J =2.5,4.8Hz,1H),2.85, (t, J =4.6Hz,1H),3.34-3.40(brm,1H),4.30(dd, J =6.6,11.4Hz,1H),4.10(brt, J =9.7Hz,2H),4.31(brt, J =9.7Hz,2H),4.54(dd, J =2.3,11.6Hz,1H),7.21(d, J =9.4Hz,1H),7.79(d, J =9.1Hz, 1H).

Intermediate I

N- [ 7-methoxy-8- (oxiran-2-ylmethoxy) -2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl] Preparation of nicotinamide

Step 1: preparation of N- [8- (benzyloxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide

To 8- (benzyloxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c ]]A suspension of quinazolin-5-amine (21g,65mmol) and nicotinic acid (12g,97.7mmol) in DMF (240mL) was added diisopropylethylamine (33.7g,260.4mmol) followed by PYBOP (51g,97.7 mmol). The resulting mixture was stirred at room temperature for 3 days with the aid of an overhead stirrer. The resulting precipitate was isolated by vacuum filtration, washed repeatedly with EtOAc and dried under vacuum with gentle heating to give N- [8- (benzyloxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c ] s]Quinazolin-5-yl]Nicotinamide (27.3g,98%):¹HNMR(DMSO-d₆+2 drops of TFA-d 9.32(1H, s),8.89(1H, brm),8.84(1H, d),7.89(1H, brm),7.82(1H, d),7.37(1H, d),7.27(1H, d),7.16(6H, M),5.18(2H, s),4.36(2H, t),4.04(2H, t),3.78(3H, s); Mass Spectrum M/z338((M +1)⁺,6%)。

Step 2: preparation of N- [ 8-hydroxy-7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide

Reacting N- [8- (benzyloxy) -7-methoxy-2, 3-dihydroimidazo [1, 2-)c]Quinazolin-5-yl]Nicotinamide (20g,45.1mmol) was added portionwise over 1h to a round bottom flask containing TFA (400mL) pre-cooled with an ice bath. The reaction mixture was heated to 60 ℃ and stirred at this temperature for 17h, at which time it was cooled to room temperature. The reaction mixture was then concentrated under reduced pressure. Dissolving the residue in CH₂Cl₂And hexane, and concentrated under reduced pressure. The material thus obtained was dissolved in MeOH and CH₂Cl₂(250mL,1:1) and concentrated under reduced pressure. The resulting solid was dried under vacuum with gentle heating overnight to give N- [ 8-hydroxy-7-methoxy-2, 3-dihydroimidazo [1,2-c ]]Quinazolin-5-yl]Nicotinamide (17.3g,66%):¹HNMR(DMSO-d₆+2 drops of TFA-d 13.41(1H, s),12.21(1H, brs),9.38(1H, s),8.78(1H, d),8.53(1H, d),7.85(1H, d),7.59(1H, M),7.17(1H, d),4.54(2H, M),4.21(2H, M),3.98(3H, s); Mass Spectrum M/z481((M +1)⁺)。

And step 3: preparation of N- [ 7-methoxy-8- (oxiran-2-ylmethoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide

A mixture of N- { 8-hydroxy-7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } pyridine-3-carboxamide (0.85g,1.50mmol) and cesium carbonate (2.93g,8.99mmol,6.0 equivalents) in DMF (12.5mL) was stirred at room temperature for 1h, then treated with racemic epichlorohydrin (0.29mL,3.75mmol,2.5 equivalents), and the resulting mixture stirred at room temperature for 16 h. The resulting mixture was used for further transformation as a 0.120M solution of N- [ 7-methoxy-8- (oxiran-2-ylmethoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide in DMF.

Intermediate J

N- { 7-methoxy-8- [ (2R) -oxiran-2-ylmethoxy]-2, 3-dihydroimidazo [1,2-c]Quinazoline- Preparation of 5-yl nicotinamide

Mixing N- { 8-hydroxy-7-methoxy-2, 3-diHydroimidazo [1,2-c ] s]A mixture of quinazolin-5-yl } pyridine-3-carboxamide (intermediate I, step 2 (used as the di-TFA salt), 1.50g,2.65mmol) and cesium carbonate (4.32g,13.3mmol,5.0 equiv.) in DMF (37mL) was stirred at room temperature for 1h, then treated with (R) -glycidyl methanesulfonate (intermediate F, step 1,21.2mL,0.25M in DMF, 5.31mmol,2.0 equiv.). The resulting mixture was stirred at 60 ℃ for 16h, then cooled to room temperature and concentrated under reduced pressure. The resulting mixture was dissolved in water (50mL) and 4:1CH₂Cl₂The isopropanol solution (50mL) was separated. The organic phase was washed with concentrated sodium bicarbonate solution, dried (anhydrous sodium sulfate), and concentrated under reduced pressure. The resulting material was triturated with EtOH and concentrated under reduced pressure to give N- { 7-methoxy-8- [ (2R) -oxiran-2-ylmethoxy]-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl } nicotinamide (0.72g,69%) HPLC retention 0.94min;¹HNMR(DMSO-d₆+1 drop TFA-d)2.75(dd, J =2.5,5.1Hz,1H),2.88(appt, J =4.7,1H),3-42-3.47(M,1H),4.01(s,3H),4.14(dd, J =6.6,11.6Hz,1H),4.20-4.29(M,3H),4.52-4.59(M,2H),4.68(dd, J =2.3,11.6Hz,1H),7.47(d, J =9.4Hz,1H),7.92(dd, J =5.6,7.8Hz,1H),8.03(d, J =9.1Hz,1H),8.90 (mass spectrum brd, J =7.8Hz,1H),8.97(dd, J =1.5,6, 1H), ((d, J = 1H), 1H =5.5, 1H) ((M, 1H) ((dd, J =5, 1H) (+ 1H))⁺,11%)。

Examples

Comparative example 1 (from WO2008/070150):

n- {8- [ 2-hydroxy-3- (morpholin-4-yl) propoxy group]-7-methoxy-2, 3-dihydroimidazo [1,2-c]Quinazoles Preparation of in-5-yl-pyridine-3-carboxamides

Cesium carbonate (3g,9.37mmol) was added to N- (8-hydroxy-7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) nicotinamide ditrifluoroacetate (1.0g,1.88mmol) in DMF (40mL) and stirred for 1.5h, then 4- [ (2-oxo-1, 3, 2-dioxathiolane is addedPentan-4-yl) methyl]Morpholine hydrochloride (intermediate C,0.39g,1.88 mmol). After 3h, the reaction mixture is taken up with a further equivalent of 4- [ (2-oxo-1, 3, 2-dioxathiolan-4-yl) methyl]Morpholine hydrochloride (intermediate C, step 2) was treated and stirred at 60 ℃ overnight. The reaction mixture was concentrated under reduced pressure, and the product was extracted with 20% isopropanol/80% chloroform solution and washed with saturated sodium bicarbonate solution. The organics were dried (magnesium sulfate) and concentrated under reduced pressure, and the resulting residue was triturated with EtOAc and dried. Then by HPLC (Gilson,5% MeOH/95% H)₂O to 50% MeOH/50% H₂Gradient of O, 0.1% NH₄OH) purification of the solid to yield N- {8- [ 2-hydroxy-3- (morpholin-4-yl) propoxy]-7-methoxy-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl } pyridine-3-carboxamide (160mg,18%): hplcmrsrt =0.19min;¹HNMR(DMSO-d₆+1 drop TFA-d)13.40-13.38(1H, brs),9.45(1H, d),8.90(1H, dd),8.72(1H, d),8.06(1H, d),7.77(1H, dd),7.51(1H, d)4.59(2H, t),4.49-4.41(1H, brs),4.33-4.22(4H, M),4.06(3H, s)4.05-3.92(2H, M),3.86-3.67(2H, M),3.51(2H, d),3.43-3.13(4H, M); Mass Spectrum M/z495((M +1)⁺)。

The following examples were prepared in a similar manner to comparative example 1:

example 21: 6-amino-N- {8- [ 2-hydroxy-3- (morpholin-4-yl) propoxy]-7-methoxy-2, 3-dihydroimidazole Azolo [1,2-c ] s]Quinazolin-5-yl } pyridine-3-carboxamides

Preparation of nicotinic acid in step 2 using 6-amino-3-pyridinecarboxylic acid instead of intermediate I yielded (94.0mg,31%) TLC (9:1 CH)₂Cl₂1% NH in MeOH/MeOH +₄OH)R_f0.35;¹HNMR(DMSO-d₆+1 drop TFA-d)3.14-3.44(m,4H),3.48-3.56(m,2H),3.68-3.87(m,2H),3.94-4.03(m,2H),4.05(s,3H),4.22-4.32(m,4H),4.42-4.50(m,1H),4.50-4.59(m,2H),7.07(d, J =9.4Hz,1H),7.51(d, J =9.2Hz,1H),8.06(d, J =9.2Hz,1H),8.49(dd, J =1.9,9.2Hz,1H),8.80(d, J =2.1Hz,1H), Mass Spectrum M/z496((M +1)⁺,10%)。

Example 2:

n- (8- { [ (2R) -2-hydroxy-3- (morpholin-4-yl) propyl]Oxy } -7-methoxy-2, 3-dihydroimidazo [1, 2-c]preparation of quinazolin-5-yl) pyridine-3-carboxamides

Step 1: preparation of (2R) -3- (4-morpholinyl) -1, 2-propanediol

A solution of (S) -glycidol (1.00mL,15.0mmol) and morpholine (1.96mL,22.5mmol,2.5 equiv.) in anhydrous ethanol was heated with microwaves at 1400 ℃ for 4min, cooled to room temperature and concentrated at 70 ℃ under 12mbar vacuum to give (2R) -3- (4-morpholinyl) -1, 2-propanediol (2.47g,102%):¹HNMR(CDCl₃)2.37(ddJ=4.0,12.4Hz,1H),2.40-2.48(m,2H),2.57(dd,J=9.6,12.4Hz,1H),2.62-2.71(m,2H),3.50(dd,J=4.2,11.4Hz,1H),3.65-3.79(m,5H),3.79-3.88(m,1H)。

step 2: 4- [ (4R) - (2-oxo-1, 3, 2-dioxa)Thiolane-4-yl) methyl]Preparation of morpholine hydrochloride

(2R) -3- (4-morpholinyl) -1, 2-propanediol (0.447g,2.77mmol) in CH₂Cl₂(7.5mL) was cooled to 0 ℃ and thionyl chloride (0.41mL,5.55mmol,2.0 equiv.) was added dropwise. The obtained solution is mixed inHeating at reflux temperature for 1 hour, cooling to room temperature and concentrating under reduced pressure to give 4- [ (4R) - (2-oxo-1, 3, 2-dioxathiolan-4-yl) methyl]Morpholine hydrochloride (0.70g, 104%). This material was used in the next step without further purification.

And step 3: preparation of N- (8- { [ (2R) -2-hydroxy-3- (morpholin-4-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) pyridine-3-carboxamide

To N- (8-hydroxy-7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) nicotinamide ditrifluoroacetate (intermediate I, step 2,0.750g,1.3mmol) solution in DMF (50mL) cesium carbonate (1.30g,3.9mmol,3.0 equiv) was added and the resulting slurry was stirred at room temperature for 1.5 hours, then cyclic sulfite (0.275g,1.3mmol,1.0 equiv) was added. The mixture was stirred at 60 ℃ for 12h, cooled to room temperature, treated with additional cesium carbonate (0.86g,2.6mmol,2.0 equiv) and cyclic sulfite (0.275g,1.3mmol,1.0 equiv), and stirred at 60 ℃ for an additional 12 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 4:1CH₂Cl₂In isopropanol solution (100mL), then washed with saturated sodium bicarbonate solution (50mL) and saturated sodium chloride solution (50mL), dried (anhydrous sodium sulfate), and concentrated under reduced pressure. The residue was purified by preparative HPLC (1.77g) to give N- (8- { [ (2R) -2-hydroxy-3- (morpholin-4-yl) propyl)]Oxy } -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) pyridine-3-carboxamide (0.52g,82%): TLC (9:1 CH)₂Cl₂1% NH in MeOH/MeOH +₄OH)R_f0.35, preparative HPLC (condition A) retention time 3.70min;¹HNMR(DMSO-d₆+1 drop TFA-D)3.10-3.40(M,4H),3.47(brd, J =11.9Hz,2H),3.63-3.84(M,2H),3.88-4.01(M,2H),4.03(s,3H),4.20-4.30(M,4H),4.42(brs,1H),4.57(appt, J =10.3Hz,2H),7.50(D, J =9.2Hz,1H),7.96(dd, J =5.0,7.5Hz,1H),8.04(D, J =9.2Hz,1H),8.94(brd, J = 7Hz,1H),8.99(D, J =5.2Hz,1H),9.50(D, J =1.1Hz, 481H) ((M/z + 1z) ((D, J = 1.1H))⁺,11%)。

The following examples were prepared in a similar manner to example 2:

example 27: 2-amino-N- [8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl]-2-hydroxypropane Oxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl]Pyrimidine-5-carboxamides

TLC (9:1 CH) was prepared (61.0mg,31%) using cis-2, 6-dimethylmorpholine instead of morpholine in step 1 and 2-amino-5-pyrimidinecarboxylic acid instead of nicotinic acid in step 2₂Cl₂MeOH + NH in MeOH₄OH)R_f0.35, HPLC retention time 0.81min;¹HNMR(DMSO-d₆+1 drops A-d)1.08-1.14M,6H, 2.72-2.83(M,2H),3.23-3.30(M,1H),3.43-3.55(M,2H),3.77-3.89(M,2H),3.89-3.97(M,2H),3.99(s,3H),4.15-4.26(M,4H),4.39-4.54(M,3H),7.43(d, J =9.0Hz,1H),7.99(d, J =8.9Hz,1H),8.99(s,2H), mass M/z525((M +1)⁺,4.1%)。

Example 3:

preparation of N- (8- { [ (2S) -2-hydroxy-3- (morpholin-4-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) pyridine-3-carboxamide

Step 1: preparation of (2S) -3- (4-morpholinyl) -1, 2-propanediol

A solution of (R) -glycidol (0.33mL,5.0mmol) and morpholine (0.65mL,7.5mmol,1.5 equiv.) in absolute ethanol was dilutedThe wave was heated at 1400 ℃ for 4min, cooled to room temperature and concentrated at 70 ℃ under 12mbar vacuum to give (2S) -3- (4-morpholinyl) -1, 2-propanediol (0.91g,113%):¹HNMR(CDCl3)2.37(dd,J=3.9,12.5Hz,1H),2.41-2.48(m,2H),2.57(dd,J=9.7,12.5Hz,1H),3.51(dd,J=4.3,11.4Hz,1H),3.66-3.79(m,5H),3.81-3.87(m,1H)。

step 2: 4- [ (4S) - (2-oxo-1, 3, 2-dioxa)Thiolane-4-yl) methyl]Preparation of morpholine hydrochloride

(2S) -3- (4-morpholinyl) -1, 2-propanediol (0.90g,5.6mmol) in CH₂Cl₂(7.5mL) was cooled to 0 ℃ and thionyl chloride (0.81mL,11.1mmol,2.0 equiv.) was added dropwise. The resulting solution was heated at reflux temperature for 1 hour, cooled to room temperature and concentrated under reduced pressure to give 4- [ (4S) - (2-oxo-1, 3, 2-dioxathiolan-4-yl) methyl]Morpholine hydrochloride (1.40g, 103%). This material was used in the next step without further purification.

And step 3: preparation of N- (8- { [ (2S) -2-hydroxy-3- (morpholin-4-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) pyridine-3-carboxamide

To N- (8-hydroxy-7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) nicotinamide ditrifluoroacetate (intermediate I, step 2,0.210g,0.37mmol) solution in DMF (12mL) was added Cs₂CO₃(0.61g,1.86mmol,5.0 equiv.) and the resulting slurry was stirred at room temperature for 1.5 hours, then cyclic sulfite (0.092g,0.45mmol,1.2 equiv.) was added. The mixture was stirred at 60 ℃ for 12h, cooled to room temperature, treated with additional cesium carbonate (0.86g,2.6mmol,2.0 equiv) and cyclic sulfite (0.076g,0.37mmol,1.0 equiv), and stirred at 60 ℃ for an additional 3.5 days. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 4:1CH₂Cl₂In isopropanol solution (50mL) and then with saturated NaHCO₃(25mL) and saturated NaClThe solution (25mL) was washed and dried (anhydrous Na)₂SO₄) And concentrated under reduced pressure. Trituration with MeOH afforded crystals, which were washed with water then MeOH and dried at 50 ℃ under reduced pressure. The resulting solid (0.077g) was purified by preparative HPLC to give N- (8- { [ (2S) -2-hydroxy-3- (morpholin-4-yl) propyl)]Oxy } -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) pyridine-3-carboxamide (0.52g,82%): TLC (9:1 CH)₂Cl₂1% NH in MeOH/MeOH +₄OH)R_f0.35, HPLC (condition A) retention time 4.29min;¹HNMR(DMSO-d₆+1 drop TFA-d)3.09-3.41(m,4H),3.48(brd, J =11.7Hz,2H),3.62-3.85(m,2H),3.88-4.01(m,2H),4.03(s,3H),4.20-4.31(m,4H),4.41(brs,1H),4.52-4.62(m,2H),7.50(d, J =9.4Hz,1H),7.95(dd, J =5.3,7.9Hz,1H),8.04(d, J =9.2Hz,1H),8.92(brd, J =8.1Hz,1H),8.98(dd, J =1.1,5.3Hz,1H),9.49(d, J =1.5Hz, 1H).

Example 4

Preparation of N- [8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] -2-hydroxypropyl } oxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyridine-3-carboxamide

Step 1: preparation of N- [8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] -2-hydroxypropyl } oxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] amine

Reacting 7-methoxy-8- [ (2R) -oxiran-2-ylmethoxy]-2, 3-dihydroimidazo [1,2-c]A solution of quinazolin-5-amine (intermediate F,1.50g,5.20mmol) and cis-2, 6-dimethylmorpholine (6.4mL,52.0mmol,10 equiv.) in DMF (36mL) was microwaved in two portionsThe reactor was heated at 140 ℃ for 45 min. The resulting combined mixture was concentrated under reduced pressure and purified by MPLC to give N- [8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl]-2-hydroxypropyl } oxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl]Amine (2.02g,96%) preparative HPLC retention time 4.29min;¹HNMR(DMSO-d₆+1 drop TFA-d)1.10(d, J =7.3Hz,3H),1.14(d, J =7.3Hz,3H),2.69(t, J =11.6Hz,1H),2.76(t, J =11.6Hz,1H),3.23-3.32(M,2H),3.43-3.54(M,2H),3.80(s,3H),3.81-3.87(M,1H),3.88-3.97(M,1H),4.31(appdd, J =8.6,12.1Hz,2H),4.35-4.43(M,1H),7.22(J =9.4Hz,1H),7.81(d, J =9.1Hz,1H), mass spectrum M/z404((M +1)⁺,100%)。

Step 2: preparation of N- [8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] -2-hydroxypropyl } oxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyridine-3-carboxamide

Mixing N- [8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl)]-2-hydroxypropyl } oxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl]A mixture of amine (2.02g,5.01mmol) and nicotinic acid (0.80g,6.51mmol,1.3 equiv.) in DMF (139mL) was treated with PyBOP (3.39g,6.51mmol,1.3 equiv.) and then N, N-diisopropylethylamine (3.50mL,20.0mmol,4.0 equiv.) to slowly form a clear solution. The mixture was stirred at room temperature for 24 h. The resulting solid was filtered and washed with DMF, H₂O and MeOH, then dried at 60 ℃ under reduced pressure to give N- [8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl]-2-hydroxypropyl } oxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl]Pyridine-3-carboxamide (1.64g,64%): TLC (9:1 CH)₂Cl₂1% NH in MeOH/MeOH +₄OH)R_f0.40;¹HNMR(DMSO-d₆+1 drop TFA-d)1.15(d, J =9.5Hz,3H),1.16(d, J =9.5Hz,3H),2.76(t, J =11.2Hz,1H),2.83(t, J =11.4Hz,1H),3.26-3.38(M,2H),3.50-3.58(M,2H),3.86-3.93(M,1H),3.95-4.02(M,1H),4.08(s,3H),4.26-4.33(M,4H),4.50(brs,1H),4.61 (apt, J =10.7Hz,2H),7.54(d, J =9.1Hz,1H),7.96 (mass spectrum, J =5.7,7.6, 1H),8.09(d = 9.92, 1H), 7.54(d, J =9.1Hz,1H),7.96(dd, M = 5.7.6, 1H),8.09(d = 9.92, 1H), 7.4H =9.1Hz,1H), 507 Hz,1H, 4.4.4.4.4H, 3H, 1^-,100%),509((M+1)⁺,24%)。

The following examples were prepared in a similar manner to example 4:

example 13: n- {8- [ 2-hydroxy-3- (morpholin-4-yl) propoxy group]-7-methoxy-2, 3-dihydroimidazo [1, 2-c]quinazolin-5-yl } -2-methylpyridine-3-carboxamide

TLC (9:1 CH) was prepared (50.0mg,58%) using intermediate G instead of intermediate F in step 1 and 2-methyl-3-pyridinecarboxylic acid instead of nicotinic acid in step 2₂Cl₂1% NH in MeOH/MeOH +₄OH)R_f0.45, HPLC retention time 0.81min;¹HNMR(DMSO-d₆+1 drop TFA-d)3.00(s,3H),3.10-3.40(m,4H),3.48(brd, J =12.1Hz,2H),3.64-3.83(m,2H),3.89-4.02(m,2H),4.02(s,3H),4.18-4.28(m,4H),4.38-4.46(m,1H),4.46-4.55(m,2H),7.50(d, J =9.0Hz,1H),7.96(dd, J =6.2,7.5Hz,1H),8.05(d, J =9.0Hz,1H),8.91(d, J =5.5Hz,1H),9.06(brd, J =8.3Hz, 1H); mass spectrum M/z495((M +1)⁺,5.5%)。

Example 5

Preparation of N- (8- { [ (2R) -2-hydroxy-3- (8-oxa-3-azabicyclo [3.2.1] oct-3-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) pyridine-3-carboxamide

Step 1: preparation of N- (8- { [ (2R) -2-hydroxy-3- (8-oxa-3-azabicyclo [3.2.1] oct-3-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-ylamine

Reacting 7-methoxy-8- [ (2R) -oxiran-2-ylmethoxy]-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-amine (intermediate F,0.195g,0.68mmol) and 8-oxa-3-azabicyclo [3.2.1]A solution of octane hydrochloride (0.506g,3.38mmol,10 equiv.) in DMF (4.5mL) was heated in a microwave reactor at 140 ℃ for 45 min. The resulting mixture was concentrated under reduced pressure. The residue is treated with 4:1CH₂Cl₂Treatment with isopropanol solution (25mL), washing with saturated sodium bicarbonate solution (25mL), drying (anhydrous sodium sulfate), and concentration under reduced pressure. The resulting residue was purified using MPLC to give N- (8- { [ (2R) -2-hydroxy-3- (8-oxa-3-azabicyclo [3.2.1]]Oct-3-yl) propyl group]Oxy } -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-ylamine (0.74g,16%): HPLC retention time 0.70min, Mass Spectrometry M/z402((M +1)⁺,7%)。

Step 2: preparation of N- (8- { [ (2R) -2-hydroxy-3- (8-oxa-3-azabicyclo [3.2.1] oct-3-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) pyridine-3-carboxamide

Reacting N- (8- { [ (2R) -2-hydroxy-3- (8-oxa-3-azabicyclo [3.2.1]]Oct-3-yl) propyl group]Oxy } -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]A mixture of quinazolin-5-ylamine (70.0mg,0.17mmol) and nicotinic acid (26.0mg,0.22mmol,1.3 equiv.) in DMF (2.5mL) was treated with PyBOP (11.3mg,0.22mmol,1.3 equiv.) and then N, N-diisopropylethylamine (0.12mL,0.70mmol,4.0 equiv.) slowly forming a clear solution. The mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure. The residue was taken up in water (10mL) and 4:1CH₂Cl₂The isopropanol solution (10mL) was separated. The organic phase was washed with saturated sodium bicarbonate solution, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The resulting residue was purified using MPLC to give a partially purified material (36.6mg), which was further purified using preparative HPLC to give N- (8- { [ (2R) -2-hydroxy-3- (8-oxa-3-azabicyclo [ 3.2.1)]Oct-3-yl) propyl group]Oxy } -7-methoxy-2, 3-dihydroimidazoleAzolo [1,2-c ] s]Quinazolin-5-yl) pyridine-3-carboxamide (10.0mg,11%) was HPLC retention time 0.98min;¹HNMR(DMSO-d₆+1 drop TFA-d)1.85-2.00(M,3H),2.10-2.19(M,1H),3.24(appt, J =11.5Hz,2H),3.29-3.38(M,2H),3.44(d, J =11.9Hz,2H),4.02(s,3H),4.20-4.29(M,4H),4.41(brs,1H),4.49(brappt, J =8.1Hz,2H),4.57(t, J =9.7Hz,2H),7.49(d, J =9.4Hz,1H),8.00-8.06(M,1H),8.04(d, J =11.1Hz,1H),8.98-9.04(M,2H),9.52(d, J =1.8, M,1H) ((M, J = 507 z)⁺,3%)。

The following examples were prepared in a similar manner to example 5:

example 16: n- (8- { [ (2R) -3- (azetidin-1-yl) -2-hydroxypropyl]Oxy } -7-methoxy-2, a salt thereof, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) -2-methylpyridine-3-carboxamide

Replacement of 8-oxa-3-azabicyclo [3.2.1] in step 1 with aziridine]Octane hydrochloride and replacement of nicotinic acid in step 2 with 2-methyl-3-pyridinecarboxylic acid (78.0mg,41%):¹HNMR(DMSO-d₆+1 drop TFA-d)2.99(s,3H),3.19-3.29(M,1H),3.34-3.42(M,1H),4.01(s,3H),4.06-4.18(M,6H),4.18-4.27(M,4H),4.45-4.55(M,2H),7.49(d, J =9.2Hz,1H),7.96(dd, J =5.8,7.5Hz,1H),8.04(d, J =9.2Hz,1H),8.91(dd, J =1.5,5.7Hz,1H),9.07(brd, J =7.5Hz,1H), mass spectrum M/z465((M +1)⁺,3.6%)。

Example 17: n- [8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl]-2-hydroxypropyl } oxy Base) -7-methoxy-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl]-2-methylpyridine-3-carboxamide

Use of cis-2, 6-dimethylmorpholine instead of 8-oxa-3-azabicyclo [3.2.1] in step 1]Octane hydrochloride and replacement of nicotinic acid in step 2 with 2-methyl-3-pyridinecarboxylic acid (0.67g,51%) with HPLC retention time 1.00min;¹HNMR(DMSO-d₆+1 drop TFA-d)1.10(d, J =5.8Hz,3H),1.13(d, J =5.8Hz,3H),2.66-2.83(M,2H),2.99(s,3H),3.20-3.34(M,2H),3.49(appbrt, J =12.0,2H),3.81-3.98(M,2H),4.02(s,3H),4.18-4.29(M,4H),4.41-4.55(M,3H),7.50(d, J =9.2Hz,1H),7.94(dd, J =5.7,7.5Hz,1H),8.05(d, J =9.0Hz,1H),8.91(dd, J =1.5,7.2Hz,1H),9.04 (J = 25.6H) ((M, 1z) ((M, J = 9.521 Hz, 1H))^-,18%),523((M+1)⁺,3.8%)。

Example 28: 2-amino-N- (8- { [ (2R) -2-hydroxy-3- (8-oxa-3-azabicyclo [3.2.1] s]Octa-3- Yl) propyl group]Oxy } -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) pyrimidine-5-carboxamide dihydrochloride

Using 2-amino-5-pyrimidinecarboxylic acid instead of nicotinic acid in step 2. The title compound was isolated as the di-HCl salt (48.9mg,25%) with an HPLC retention time of 0.86min;¹HNMR(DMSO-d₆+1 drop TFA-d)1.85-2.00(M,2H),2.09-2.18(M,1H),3.17-3.48(M,5H),3.82-3.90(M,1H),3.98(s,3H),4.12-4.28(M,4H),4.35-4.43(M,1H),4.43-54(M,3H),7.42(d, J =9.4Hz,1H),7.98(d, J =9.0Hz,1H),9.00(s,2H), Mass Spectrum/z 524((M +1)⁺,0.2%)。

Example 34: n- [8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl]-2-hydroxypropyl } oxy Base) -7-methoxy-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl]-1, 3-thiazole-5-carboxamide

Use of cis-2, 6-dimethylmorpholine instead of 8-oxa-3-azabicyclo [3.2.1] in step 1]Octane hydrochloride and 1, 3-thiazole-5-carboxylic acid instead of nicotinic acid in step 2 (82.0mg,69%) with HPLC retention time 1.01min;¹HNMR(DMSO-d₆+1 drop TFA-d)1.10(d, J =6.0Hz,3H),1.13(d, J =6.0Hz,3H),2.66-2.82(M,2H),3.23-3.31(M,2H),3.49(appbrt, J =12.0,2H),3.79-3.97(M,2H),4.01(s,3H),4.16-4.27(M,4H),4.41-4.50(M,3H),7.46(d, J =9.0Hz,1H),8.01(d, J =9.0Hz,1H),8.61(s,1H),9.31(s,1H), mass spectrum M/z513((M-1)^-,0.4%),515((M+1)⁺,0.9%)。

Example 35: n- (8- { [ (2R) -3- (azetidin-1-yl) -2-hydroxypropyl]Oxy } -7-methoxy-2, a salt thereof, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) -1, 3-thiazole-5-carboxamides

Using azetidine instead of 8-oxa-3-azabicyclo [3.2.1] in step 1]Octane hydrochloride and 1, 3-thiazole-5-carboxylic acid instead of nicotinic acid in step 2 (5.0mg,2.4%):¹HNMR(DMSO-d₆+1 drop TFA-d)2.72-2.87(M,2H),3.18-3.28(M,2H),3.33-3.45(M,2H),4.00(s,3H),4.05-4.25(M,6H),4.40-4.50(M,3H),7.44(d, J =9.0Hz,1H),8.00(d, J =9.0Hz,1H),8.61(s,1H),9.31(s,1H), Mass Spectrum M/z457((M +1)⁺,1.0%)。

Example 6

N- {8- [ 2-hydroxy-3- (thiomorpholin-4-yl) propoxy group]-7-methoxy-2, 3-dihydroimidazo [1,2-c] Preparation of quinazolin-5-yl } pyridine-3-carboxamides

Mixing N- [ 7-methoxy-8- (oxiranyl-2-methoxy) -2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl]Nicotinamide (intermediate I,7.6mL of a 0.120M solution in DMF, 0.92mmol) and thiomorpholine (0.46mL,4.60mmol,5.0 equiv.) were heated in a microwave reactor at 140 ℃ for 30 min. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in 4:1CH₂Cl₂In isopropanol solution (50 mL). With saturated NaHCO₃The resulting solution was washed with a solution (25mL), dried (anhydrous sodium sulfate), and concentrated under reduced pressure. The resulting residue was purified using MPLC to give an impure product (128mg) which was further purified using preparative HPLC to give N- {8- [ 2-hydroxy-3- (thiomorpholin-4-yl) propoxy]-7-methoxy-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl } pyridine-3-carboxamide (34.0mg,7%) HPLC retention time 0.61min;¹HNMR(DMSO-d₆+1 drop TFA-d)2.75-3.05(M,3H),3.05-3.44(M,4H),4.02(s,3H),4.19-4.28(M,4H),4.43(brs,1H),4.55 (breppt, J =9.8Hz,2H),7.47(d, J =9.1Hz,1H),7.77(dd, J =5.3,7.8,1H),8.02(d, J =9.1Hz,1H),8.72(brd, J =7.8Hz,1H),8.89(dd, J =1.5,5.1Hz,1H),9.43(brs,1H), mass spectrum M/z507((M-1)^-,100%),509((M+1)⁺,24%)。

The following examples were prepared in a similar manner to example 6:

example 10: n- {8- [3- (dimethylamino) -2-hydroxypropoxy group]-7-methoxy-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl } pyridine-3-carboxamides

Prepared using dimethylamine instead of thiomorpholine in step 1 (0.14g,68%) with HPLC retention time 0.52min;¹HNMR(DMSO-d₆+1 drops of TFA-d)2.82(s,3H),2.86(s,3H),3.18-3.30(M,2H),4.03(s,3H),4.20-4.28(M,4H),4.31-4.38(M,1H),4.52-4.59(M,2H),7.48(d, J =9.4Hz,1H),7.76(dd, J =5.1,7.8Hz,1H),8.03(d; J =9.1Hz,1H),8.71(brd, J =7.8Hz,1H),8.88, (dd, J =1.5,5.1Hz,1H),9.44(d, J =1.5Hz,1H); Mass Spectrum M/z439((M +1)⁺,4.6%)。

Example 11: n- (8- { [ (2R) -3- (dimethylamino) -2-hydroxypropyl]Oxy } -7-methoxy-2, 3-di Hydroimidazo [1,2-c ] s]Quinazolin-5-yl) pyridine-3-carboxamides

Prepared using dimethylamine instead of thiomorpholine in step 1 and intermediate J instead of intermediate I (0.14g,68%) with HPLC retention time 0.91min;¹HNMR(DMSO-d₆+1 drop TFA-d)2.82(s,3H),2.86(s,3H),3.17-3.30(M,2H),4.03(s,3H),4.19-4.29(M,4H),4.31-4.38(M,1H),4.52-4.60(M,2H),7.48(d, J09.4Hz,1H),7.93(dd, J =5.1,7.8Hz,1H),8.04(d, J09.1Hz,1H),8.90(brd; J =8.1Hz,1H),8.97, (brd, J =5.1Hz,1H),9.49(brs,1H), Mass Spectrum M/z439((M +1)⁺,2.5%)。

Example 12: n- (8- { [ (2R) -3- (diprop-2-ylamino) -2-hydroxypropyl]Oxy } -7-methoxy-2, 3- Dihydroimidazo [1,2-c ] s]Quinazolin-5-yl) pyridine-3-carboxamides

Prepared using diisopropylamine instead of thiomorpholine in step 1 and intermediate J instead of intermediate I (22.0mg,16%) with HPLC retention time 1.29min;¹HNMR(DMSO-d₆+1 drop TFA-d)1.22-1.34(m,12H),3.14-3.21(m,1H),3.35(brd, J =14.3Hz,1H),3.63-3.78(m,2H),4.01(s, 3H)) 4.19-4.31(M,5H),4.52-4.61(M,2H),7.49(d, J =9.2Hz,1H),7.93(dd, J =5.7,8.1Hz,1H),8.06(d, J =9.0Hz,1H),8.90(brd, J =8.1Hz,1H),8.97(dd, J =1.5,5.3Hz,1H),9.49 (d, J =1.5Hz,1H); Mass Spectrum M/z495((M +1)⁺,11%)。

Example 20: n- (8- { [ (2R) -3- (diprop-2-ylamino) -2-hydroxypropyl]Oxy } -7-methoxy-2, 3- Dihydroimidazo [1,2-c ] s]Quinazolin-5-yl) -2-methylpyridine-3-carboxamide

Using diisopropylamine instead of thiomorpholine in step 1 and intermediate J instead of intermediate I, and 2-methyl-3-pyridinecarboxylic acid instead of nicotinic acid in step 2 gave (0.66g,70%): HPLC retention time 1.33min;¹HNMR(DMSO-d₆+1 drop TFA-d)1.23-1.33(M,12H),3.00(s,3H),3.16(dd, J =10.1,14.1Hz,1H),3.34(dm, J =14.1,1H),3.70(sept, J =6.8Hz,2H),4.00(s,3H),4.20-4.31(M,5H),4.47-4.54(M,2H),7.50(d, J =9.4Hz,1H),7.99(dd, J =5.8,7.8Hz,1H),8.06(d, J =9.1Hz,1H),8.93(dd, J =1.5,5.8Hz,1H),9.11(brd, J =7.1, 1H) ((M/z + 1M) ((M, 1H) ((M, z))⁺,2.7%)。

Example 29: 2-amino-N- (8- { [ (2R) -3- (dimethylamino) -2-hydroxypropyl]Oxy } -7-methoxy- 2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) pyrimidine-5-carboxamides

Using dimethylamine instead of thiomorpholine in step 1 and intermediate J instead of intermediate I, and 2-amino-5-pyrimidinecarboxylic acid instead of nicotinic acid in step 2 gave (65.0mg,39%) HPLC retention time 0.79min;¹HNMR(DMSO-d₆+1 drop TFA-d)2.82(s,3H),2.85(s,3H),3.15-3.27(M,2H),3.99(s,3H),4.15-4.25(M,4H),4.29-4.38(M,1H),4.44-4.54(M,2H),7.42(d, J =9.2Hz,1H),7.99(d, J =9.0Hz,1H),9.02(s,2H), Mass Spectrum M/z455((M +1)⁺,3.7%)。

Example 41: n- (8- { [ (2R) -3- (diprop-2-ylamino) -2-hydroxypropyl]Oxy } -7-methoxy-2, 3- Dihydroimidazo [1,2-c ] s]Quinazolin-5-yl) -1, 3-thiazole-5-carboxamides

Using diisopropylamine instead of thiomorpholine in step 1 and intermediate J instead of intermediate I, and 1, 3-thiazole-5-carboxylic acid instead of nicotinic acid in step 2 gave (0.48g,55%) HPLC retention time 1.03min;¹HNMR(DMSO-d₆+1 drop TFA-d)1.23-1.33(M,12H),3.16(dd, J =9.9,14.4Hz,1H),3.34(dm, J =14.2,1H),3.70(sept, J =6.6Hz,2H),4.00(s,3H),4.18-4.25(M,3H),4.27-4.29(M,2H),4.42-4.49(M,2H),7.50(d, J =9.4Hz,1H),8.02(d, J =9.4Hz,1H),8.61(s,1H),9.32(s,1H), mass M/z501((M +1)⁺,2.3%)。

Example 7

N- (8- { [ (2R) -3- (azetidin-1-yl) -2-hydroxypropyl]Oxy } -7-methoxy-2, 3-dihydroimidazole Azolo [1,2-c ] s]Preparation of quinazolin-5-yl) pyridine-3-carboxamides

Step 1: preparation of N- (8- { [ (2R) -3- (azetidin-1-yl) -2-hydroxypropyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) amine

Reacting 7-methoxy-8- [ (2R) -oxiran-2-ylmethoxy]-2, 3-dihydroimidazo [1,2-c]A solution of quinazolin-5-amine (intermediate F,0.35g,1.21mmol) and azetidine (0.82mL,12.1mmol,10 equivalents) in DMF (10mL) was heated in a microwave reactor at 140 ℃ for 45 min. The resulting mixture was concentrated under reduced pressure and purified using MPLC to give N- (8- { [ (2R) -3- (azetidin-1-yl) -2-hydroxypropyl]Oxy } -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) amine (0.48g,115%) HPLC retention time 0.67min, Mass Spectrometry M/z346((M +1)⁺,100%)。

Step 2: preparation of N- (8- { [ (2R) -3- (azetidin-1-yl) -2-hydroxypropyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) pyridine-3-carboxamide

To N- (8- { [ (2R) -3- (azetidin-1-yl) -2-hydroxypropyl]Oxy } -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) amine (0.128g,0.37mmol) and nicotinic acid (0.057g,0.46mmol,1.3 equiv.) in DMF (4mL) was slurried in PyBOP (241mg,0.46mmol,1.3 equiv.) followed by diisopropylethylamine (0.25mL,1.48mmol,4.0 equiv.). The resulting mixture was stirred at room temperature. The mixture became a clear solution after a few hours. The resulting solution was stirred at room temperature for 48h, then concentrated under reduced pressure. The residue was taken up in 25mL of water and 4:1CH₂Cl₂The isopropanol solution (25mL) was separated. The organic phase was washed with saturated sodium bicarbonate solution, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The resulting residue was purified using MPLC to give a partially purified material (82mg), which was further purified using preparative HPLC, followed by trituration with ether to give N- (8- { [ (2R) -3- (azetidin-1-yl) -2-hydroxypropyl]Oxy } -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) pyridine-3-carboxamide (0.050g,28%) HPLC retention time 0.91min;¹HNMR(DMSO-d₆+1 drop TFA-d)2.18-2.28(m,1H),2.37-2.45(m,1H),3.24(dd, J =9.8,12.8Hz,1H),3.38(dd, J =2.5,12.6Hz,1H),4.02(s,3H),4.06-4.18(M,5H),4.21(appt, J =4.9Hz,2H),4.23-4.29(M,2H),4.52-4.60(M,2H),7.48(d, J =9.4Hz,1H),7.88(dd, J =5.3,7.6Hz,1H),8.30(d, J =9.1Hz,1H),8.85(brd, J =8.1Hz,1H),8.95(dd, J =1.5,6.8Hz,1H),9.48(d, J =1.5Hz,1H), mass M/z451((M + 1))⁺,0.2%)。

Example 8

N- (8- { [ (2R) -2-hydroxy-3- (pyrrolidin-1-yl) propyl]Oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c]Preparation of quinazolin-5-yl) pyridine-3-carboxamides

Step 1: preparation of N- (8- { [ (2R) -2-hydroxy-3- (pyrrolidin-1-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) amine

Reacting 7-methoxy-8- [ (2R) -oxiran-2-ylmethoxy]-2, 3-dihydroimidazo [1,2-c]A solution of quinazolin-5-amine (intermediate F,1.00g,3.47mmol) and pyrrolidine (2.87mL,34.7mmol,10 equivalents) in DMF (18mL) was heated in a microwave reactor at 140 ℃ for 45 min. The resulting mixture was concentrated under reduced pressure. The residue was purified using MPLC (2.5g) to give N- (8- { [ (2R) -2-hydroxy-3- (pyrrolidin-1-yl) propyl]Oxy } -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) amine (0.97g,78%) HPLC retention time 0.71min;¹HNMR(DMSO-d₆+1 drop TFA-d)1.82-1.92(M,2H),1.94-2.03(M,2H),3.02-3.14(M,3H),3.27-3.33(M,2H),3.52-3.61(M,2H),3.80(s,3H),4.06-4.16(M,4H),4.23(brsextet, J =4.3Hz,1H),4.28-4.34(M,2H),7.22(d, J =9.4Hz,1H),7.81(d, J =9.1Hz,1H), mass spectrum M/z360((M +1)⁺,100%)。

Step 2: preparation of N- (8- { [ (2R) -2-hydroxy-3- (pyrrolidin-1-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) pyridine-3-carboxamide

To N- (8- { [ (2R) -2-hydroxy-3- (pyrrolidin-1-yl) propyl]Oxy } -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) amine (0.250g,0.70mmol) and nicotinic acid (0.107g,0.87mmol,1.3 equiv.) in DMF (10mL) was slurried in PyBOP (0.452g,0.87mmol,1.3 equiv.) followed by diisopropylethylamine (0.48mL,2.78mmol,4.0 equiv.). The resulting mixture was stirred at room temperature. The mixture became a clear solution after a few hours. The resulting solution was stirred at room temperature for 24h, then concentrated under reduced pressure. The residue was taken up in water (25mL) and 4:1CH₂Cl₂The isopropanol solution (50mL) was separated. The organic phase was washed with saturated sodium bicarbonate solution, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The resulting residue (0.588g) was purified using MPLC to give N- (8- { [ (2R) -2-hydroxy-3- (pyrrolidin-1-yl) propyl]Oxy } -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) pyridine-3-carboxamide (0.16g,50%) HPLC retention time 1.00min;¹HNMR(DMSO-d₆+1 drop TFA-d)1.83-1.93(M,2H),1.93-2.05(M,2H),3.04-3.15(M,2H),3.29-3.34(M,2H),3.53-3.62(M,2H),4.03(s,3H),4.20-4.32(M,5H),4.53-4.60(M,2H),7.48(d, J =9.1Hz),7.88(dd, J =5.6,8.1Hz,1H),8.03(d, J =9.1Hz,1H),8.84, (brd, J =8.1Hz,1H),8.94(dd, J =1.5,5.3Hz,1H),9.47(d, J =1.5Hz,1H) ((M/z + 1M) ((M, 1H))⁺,17%)。

The following examples were prepared in a similar manner to example 8:

example 18: n- (8- { [ (2R) -2-hydroxy-3- (pyrrolidin-1-yl) propyl]Oxy } -7-methoxy-2, 3-di Hydroimidazo [1,2-c ] s]Quinazolin-5-yl) -2-methylpyridine-3-carboxamide

Using 2-methyl-3-pyridinecarboxylic acidHPLC retention time 1.01min instead of nicotinic acid preparation in step 2 (0.13g, 40%);¹HNMR(DMSO-d₆+1 drop TFA-d)1.84-1.93(M,2H),1.95-2.05(M,2H),2.99(s,3H),3.06-3.15(M,2H),3.28-3.34(M,2H),3.53-3.62(M,2H),4.02(s,3H),4.19-4.33(M,5H),4.46-4.54(M,2H),7.50(d, J =9.1Hz,1H),7.95(appt, J =6.5Hz,1H),8.04(d, J =9.1Hz,1H),8.91(brd, J =4.6Hz,1H),9.06(brs,1H); Mass Spectrometry M/z479((M +1)⁺,2.3%)。

Example 24: n- (8- { [ (2R) -2-hydroxy-3- (pyrrolidin-1-yl) propyl]Oxy } -7-methoxy-2, 3-di Hydroimidazo [1,2-c ] s]Quinazolin-5-yl) pyrimidine-5-carboxamides

Prepared using 5-pyrimidinecarboxylic acid instead of nicotinic acid in step 2 (77.4mg,54%):¹HNMR(DMSO-d₆+1 drop TFA-d)1.83-1.92(M,2H),1.96-2.04(M,2H),3.06-3.15(M,2H),3.29-3.32(M,2H),3.53-3.62(M,2H),4.03(s,3H),4.19-4.33(M,5H),4.54-4.60(M,2H),7.48(d, J =9.4Hz,1H),8.03(d, J =9.4Hz,1H),9.38(s,1H),9.47(s,2H), mass M/z464((M-1)^-,100%),466((M+1)⁺,7.2%)。

Example 36: n- (8- { [ (2R) -2-hydroxy-3- (pyrrolidin-1-yl) propyl]Oxy } -7-methoxy-2, 3-di Hydroimidazo [1,2-c ] s]Quinazolin-5-yl) -1, 3-thiazole-5-carboxamides

Prepared using 1, 3-thiazole-5-carboxylic acid instead of nicotinic acid in step 2 (0.11g,81%):¹HNMR(DMSO-d₆+1 drop of TFA-d)1.84-1.91(m,2H),1.96-2.03(m,2H),3.06-3.14(m,2H),3.29-3.33(m,2H),3.53-3.62(m,2H),4.01(s,3H) 4.18-4.25(M,4H),4.25-4.32(M,1H),4.42-4.48(M,2H),7.45(d, J =9.4Hz,1H),8.02(d, J =9.4Hz,1H),8.61(s,1H),9.31(s,2H); Mass Spectrum M/z469((M-1)^-,4.9%),471((M+1)⁺,1.8%)。

Example 38: n- (8- { [ (2R) -2-hydroxy-3- (pyrrolidin-1-yl) propyl]Oxy } -7-methoxy-2, 3-di Hydroimidazo [1,2-c ] s]Quinazolin-5-yl) -4-methyl-1, 3-thiazole-5-carboxamide

Prepared using 4-methyl-1, 3-thiazole-5-carboxylic acid instead of nicotinic acid in step 2 (0.078g,55%):¹HNMR(DMSO-d₆+1 drop TFA-d)1.85-1.94(M,2H),1.98-2.06(M,2H),2.78(s,3H),3.08-3.17(M,2H),3.30-3.37(M,2H),3.56-3.65(M,2H),4.04(s,3H),4.19-4.27(M,4H),4.28-4.34(M,1H),4.44-4.48(M,2H),7.46(d, J =9.3Hz,1H),8.02(d, J =9.3Hz,1H),9.15(s,2H), Mass Spectrum M/z483((M-1)^-,22%),485((M+1)⁺,0.9%)。

Example 40: n- (8- { [ (2R) -2-hydroxy-3- (pyrrolidin-1-yl) propyl]Oxy } -7-methoxy-2, 3-di Hydroimidazo [1,2-c ] s]Quinazolin-5-yl) -1, 3-oxazole-5-carboxylic acid amides

Using 1, 3-oxazole-5-carboxylic acid instead of nicotinic acid in step 2 produced (0.047g,37%):¹HNMR(DMSO-d₆+1 drop TFA-d)1.82-2.05(M,4H),3.04-3.15(M,2H),3.28-3.34(M,2H),3.52-3.63(M,2H),4.00(s,3H),4.16-4.32(M,5H),4.39-4.49(M,2H),7.45(d, J =9.2Hz,1H),8.00(d, J =9.0Hz,1H),8.02(s,1H),8.63(s,1H), Mass Spectrum M/z454((M-1)^-,0.07%),456((M+1)⁺,3.2%)。

Example 9

N- (8- { [ (2R) -2-hydroxy-3- (piperidin-1-yl) propyl]Oxy } -7-methoxy-2, 3-dihydroimidazo [1, 2-c]preparation of quinazolin-5-yl) pyridine-3-carboxamides

Step 1: preparation of N- (8- { [ (2R) -2-hydroxy-3- (piperidin-1-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) amine

To 5-amino-7-methoxy-2, 3-dihydroimidazo [1,2-c ]]To a slurry of quinazolin-8-ol bis (trifluoroacetate) (intermediate E,3.00g,6.52mmol) in DMF (72mL) was added cesium carbonate (10.62g,32.6mmol,10.0 equiv.) and the resulting slurry was stirred at room temperature for 1.5h, then (R) -glycidyl methanesulfonate (intermediate F, step 1,45mL,0.29M in DMF, 13.0mmol,2.0 equiv.) was added. The mixture was stirred at 60 ℃ for 12 hours, concentrated under reduced pressure to a volume of about 50mL and divided into 3 portions. Each portion was treated with 2.15mL piperidine (total 6.45mL,65.2mmol,10 equivalents) and heated in a microwave reactor at 140 ℃ for 45 min. The combined resulting mixture was concentrated under reduced pressure. The resulting solid (1.93g) was purified by MPLC to give N- (8- { [ (2R) -2-hydroxy-3- (piperidin-1-yl) propyl]Oxy } -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) amine (1.93g,79%):¹HNMR(DMSO-d₆+1 drop TFA-d)1.30-1.43(m,1H),1.56-1.70(m,2H),1.70-1.84(m,2H),2.88-3.04(m,2H),3.11-3.32(m,2H),3.42-3.52(m,2H),3.82(s,3H),4.09-4.17(m,4H),4.28-4.38(m,3H),7.24(d, J =9.4Hz,1H),7.83(d, J =9.1Hz, 1H).

Step 2: preparation of N- (8- { [ (2R) -2-hydroxy-3- (piperidin-1-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) pyridine-3-carboxamide

To N- (8- { [ (2R) -2-hydroxy-3- (piperidin-1-yl) propyl]Oxy } -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) amine (0.125g,0.34mmol) and nicotinic acid (0.052g,0.42mmol,1.3 equiv.) in DMF (3.6mL) was slurried in PyBOP (0.218g,0.42mmol,1.3 equiv.) followed by diisopropylethylamine (0.23mL,1.34mmol,4.0 equiv.). The resulting mixture was stirred at room temperature. The mixture became a clear solution after a few hours. The resulting solid was removed by filtration, washed successively with DMF, water then MeOH and dried under reduced pressure at 50 ℃ to give N- (8- { [ (2R) -2-hydroxy-3- (piperidin-1-yl) propyl]Oxy } -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) pyridine-3-carboxamide (0.11g,66%) HPLC retention time 1.00min;¹HNMR(DMSO-d₆+1 drop TFA-d)1.30.1.44M,1H, 1.58-1.71(M,2H),1.72-1.85(M,3H),2.89-3.56(M,2H),3.18(dd, J =10.1,13.1Hz,1H),3.25-3.31(M,1H),3.45-3.52(M,2H),4.03(s,3H),4.20-4.29(M,4H),4.38-4.49(M,1H),4.53-4.60(M,2H),7.48(d, J =9.4Hz,1H),7.85(dd, J =5.3,7.9Hz,1H),8.04(d, J =9.1Hz,1H),8.82(brd, J = 8.1H), 8.93 = 8.93(dd, 1H), 1.47H, 1H, 475.47 Hz,1H) ((d, 1H))⁺,0.4%)。

The following examples were prepared in a similar manner to example 9:

example 14: n- (8- { [ (2R) -2-hydroxy-3- (morpholin-4-yl) propyl]Oxy } -7-methoxy-2, 3-dihydro Imidazo [1,2-c ]]Quinazolin-5-yl) -2-methylpyridine-3-carboxamide

Replacement of piperidine in step 1 with morpholine and replacement of nicotinic acid in step 2 with 2-methyl-3-pyridinecarboxylic acid gave (12.1g,39%) an HPLC retention time of 0.91min;¹HNMR(DMSO-d₆+1 drop TFA-d)2.99(s,3H),3.09-3.40(m,4H),3.48(brd, J =12.1Hz,2H),3.63-3.83(m,2H),3.89-4.01(m,2H),4.02(s,3H),4.18-4.29(m,4H),4.38-4.46(m,1H),4.46-4.55(m,2H),7.50(d, J =9.0Hz,1H),7.96(dd, J =6.2,7.5Hz,1H),8.05(d, J =9.0Hz,1H),8.91(d, J =5.5Hz,1H),9.06(brd, J =8.3Hz, 1H); mass spectrum M/z493((M-1)^-,100%),495((M+1)⁺,4.6%)。

Example 15: n- (8- { [ (2S) -2-hydroxy-3- (morpholin-4-yl) propyl]Oxy } -7-methoxy-2, 3-dihydro Imidazo [1,2-c ]]Quinazolin-5-yl) -2-methylpyridine-3-carboxamide

TLC (9:1CH, 56%) was prepared using (S) -glycidyl methanesulfonate (intermediate H, step 1) in step 1 instead of (R) -glycidyl methanesulfonate (intermediate F, step 1) and morpholine instead of piperidine and 2-methyl-3-pyridinecarboxylic acid instead of nicotinic acid in step 2 (0.059g,56%)₂Cl₂/MeOH+1%NH₄OHinMeOH)R_f0.44, HPLC retention time 0.81min;¹HNMR(DMSO-d₆+1 drop TFA-d)2.99(s,3H),3.09-3.40(m,4H),3.48(brd, J =12.1Hz,2H),3.63-3.83(m,2H),3.89-4.01(m,2H),4.02(s,3H),4.18-4.29(m,4H),4.38-4.46(m,1H),4.46-4.55(m,2H),7.50(d, J =9.0Hz,1H),7.96(dd, J =6.2,7.5Hz,1H),8.05(d, J =9.0Hz,1H),8.91(d, J =5.5Hz,1H),9.06(brd, J =8.3Hz, 1H); mass spectrum M/z495((M +1)⁺,2.3%)。

Example 19: n- (8- { [ (2R) -2-hydroxy-3- (piperidin-1-yl) propyl]Oxy } -7-methoxy-2, 3-dihydro Imidazo [1,2-c ]]Quinazolin-5-yl) -2-methylpyridine-3-carboxamide

TLC (9:1 CH) was prepared (0.059g,56%) using 2-methyl-3-pyridinecarboxylic acid instead of nicotinic acid in step 2₂Cl₂/MeOH+1%NH₄OHinMeOH)R_f0.45;¹HNMR(DMSO-d₆+1 drop TFA-d)1.32-1.44(M,1H),1.61-1.71(M,2H),1.72-1.85(M,3H),2.90-3.05(M,2H),2.99(s,3H),3.17(dd, J =10.1,13.1Hz,1H),3.28(dd, J =2.5,13.1Hz,1H),3.44-3.52(M,2H),4.02(s,3H),4.20-4.28(M,4H),4.38-4.44(M,1H),4.46-4.54(M,2H),7.50(d, J =9.4Hz,1H),7.96(dd, mass spectrum, J =6.1,7.3, 1H),8.05, (d, 9.91, 1H), 1.50 (d, J =9.4Hz,1H), 7.06 (dd, J =6.1,7.3, 1H),8.05(d, 1H =9, 1H), 1H, 9.06, 1H) ((dd, 1H))⁺,4.0%)。

Example 22: 6-amino-N- (8- { [ (2S) -2-hydroxy-3- (morpholin-4-yl) propyl]Oxy } -7-methoxy- 2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) pyridine-3-carboxamides

Using (S) -glycidyl methanesulfonate (intermediate H, step 1) instead of (R) -glycidyl methanesulfonate (intermediate F, step 1) and 6-amino-3-pyridinecarboxylic acid instead of nicotinic acid in step 2 gave (37.0mg,35%) HPLC retention time 0.82min;¹HNMR(DMSO-d₆+1 drop TFA-d)3.13-3.40(M,4H),3.43-3.53(M,2H),3.64-3.83(M,2H),3.89-3.98(M,2H),4.01(s,3H),4.18-4.28(M,4H),4.37-4.45(M,1H),4.45-4.54(M,2H),7.03(d, J =9.4Hz,1H),7.46(d, J =9.4Hz,1H),8.02(d, J =9.0Hz,1H),8.45(dd, J =2.1,9.2HZ,1H),8.75(d, J =1.7Hz,1H), Mass Spectrum M/z495((M +1)⁺,8.7%)。

Example 23: 6-amino-N- (8- { [ (2R) -2-hydroxy-3- (morpholin-4-yl) propyl]Oxy } -7-methoxy- 2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) -2-methylpyridine-3-carboxamide

Replacement of piperidine in step 1 with morpholine and replacement of nicotinic acid in step 2 with 6-amino-2-methyl-3-pyridinecarboxylic acid gave (60.0mg,69%) an HPLC retention time of 0.83min;¹HNMR(DMSO-d₆+1 drop TFA-d)2.81(s,3H),3.11-3.39(m,4H),3.43-3.51(m,2H),3.63-3.82(m,2H),3.89-3.98(m,2H),4.00(s,3H),4.16-4.27(m,4H),4.38-4.50(m,3H),6.86(d, J =9.4Hz,1H),7.46(d, J =9.2Hz,1H),8.02(d, J =9.2Hz,1H),8.57(d, J =9.4Hz, 1H); mass spectrum M/z510((M +1)⁺,4.4%)。

Example 25: 2-amino-N- {8- [ 2-hydroxy-3- (morpholin-4-yl) propoxy]-7-methoxy-2, 3-dihydroimidazole Azolo [1,2-c ] s]Quinazolin-5-yl } pyrimidine-5-carboxamides

Using morpholine instead of piperidine and racemic glycidyl mesylate instead of (R) -glycidyl mesylate in step 1, and 2-amino-5-pyrimidinecarboxylic acid instead of nicotinic acid in step 2 gave (40.0mg,46%) HPLC retention time 0.81min;¹HNMR(DMSO-d₆+1 drop TFA-d)3.15-3.39(m,4H),3.44-3.52(m,2H),3.63-3.83(m,2H),3.89-3.99(m,2H),4.00(s,3H),4.15-4.26(m,4H),4.37-4.45(m,1H),4.45-4.54(m,2H),7.44(d, J =9.2Hz,1H),8.00(d, J =9.2Hz,1H),8.99(s, 2H); mass spectrum M/z497((M +1)⁺,11%)。

Example 26: 2-amino-N- (8- { [ (2S) -2-hydroxy-3- (morpholin-4-yl) propyl]Oxy } -7-methoxy- 2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) pyrimidine-5-carboxamides

Using (S) -glycidyl methanesulfonate (intermediate H, step 1) instead of (R) -glycidyl methanesulfonate (intermediate F, step 1) and morpholine instead of piperidine and 2-amino-5-pyrimidinecarboxylic acid instead of nicotinic acid in step 2 in step 1 gave (75.0mg,71%) an HPLC retention time of 0.81min;¹HNMR(DMSO-d₆+1 drop TFA-d)3.14-3.38(m,4H),3.44-3.52(m,2H),3.69(appt, J =12.0Hz,1H),3.77/appt, J =12.1Hz,1H),3.90-3.98(m,2H),4.00(s,3H),4.16-4.25(m,4H),4.38-4.44(m,1H),4.46-4.52(m,2H),7.43(d, J =9.1Hz,1H),7.99(d, J =9.1Hz,1H),8.97(s, 2H); mass spectrum M/z497((M +1)⁺,8.8%)。

Example 30: n- (8- { [ (2R) -2-hydroxy-3- (morpholin-4-yl) propyl]Oxy } -7-methoxy-2, 3-dihydro Imidazo [1,2-c ]]Quinazolin-5-yl) -3H-imidazo [4,5-b]Pyridine-6-carboxamides

Morpholine was used in place of piperidine in step 1, and 3H-imidazo [4,5-b ] was used]Pyridine-6-carboxylic acid was prepared (0.18g,60%) instead of nicotinic acid in step 2 with HPLC retention time 0.75min;¹HNMR(DMSO-d₆+1 drop TFA-d)3.15-3.39(m,4H),3.45-3.51(m,2H),3.65-3.82(m,2H),3.91-4.02(m,3H),4.04(s,3H),4.21-4.28(m,4H),4.39-4.46(m,1H),4.56-4.63(m,2H)6.86(d, J =9.4Hz,1H),7.47(d, J =9.4Hz,1H),8.03(d, J =9.1Hz,1H),8.89(brs,1H),9.22(s,1H),9.38(s, 1H); mass spectrum M/z521((M +1)⁺,2.7%)。

Example 31: n- {8- [ 2-hydroxy-3- (morpholin-4-yl) propoxy group]-7-methoxy-2, 3-dihydroimidazo [1, 2-c]quinazolin-5-yl } -1, 3-thiazole-5-carboxamides

TLC (9:1CH, 27%) was obtained using morpholine instead of piperidine and racemic glycidyl methanesulfonate instead of (R) -glycidyl methanesulfonate in step 1 and 1, 3-thiazole-5-carboxylic acid instead of nicotinic acid in step 2₂Cl₂/MeOH+1%NH₄OHinMeOH)R_f0.48, HPLC retention time 0.78min;¹HNMR(DMSO-d₆+1 drop TFA-d)3.17-3.42(m,4H),3.49-3.54(m,2H),3.74(appt, J =11.8Hz,1H),3.82(appt, J =11.6Hz,1H)3.95-4.05(m,2H),4.06(s,3H),4.23-4.31(m,4H),4.43-4.53(m,3H),7.50(d, J =9.1Hz,1H),8.05(d, J =9.1Hz,1H),8.65(s,1H),9.36(s, 1H); mass spectrum M/z487((M +1)⁺,6.6%)。

Example 32: n- (8- { [ (2R) -2-hydroxy-3- (morpholin-4-yl) propyl]Oxy } -7-methoxy-2, 3-dihydro Imidazo [1,2-c ]]Quinazolin-5-yl) -1, 3-thiazole-5-carboxamides

Replacement of piperidine in step 1 with morpholine and replacement of nicotinic acid in step 2 with 1, 3-thiazole-5-carboxylic acid gave (0.18g,60%) HPLC retention time 0.88min;¹HNMR(DMSO-d₆+1 drop TFA-d)3.17-3.42(m,4H),3.49-3.54(m,2H),3.74(appt, J =11.8Hz,1H),3.82(appt, J =11.6Hz,1H),3.95-4.05(m,2H),4.06(s,3H),4.23-4.31(m,4H),4.43-4.53(m,3H),7.50(d, J =9.1Hz,1H),8.05(d, J =9.1Hz,1H),8.65(s,1H),9.36(s, 1H); mass spectrum M/z487((M +1)⁺,6.8%)。

Example 33: n- (8- { [ (2S) -2-hydroxy-3- (morpholin-4-yl) propyl]Oxy } -7-methoxy-2, 3-dihydro Imidazo [1,2-c ]]Quinazolin-5-yl) -1,3-thiazole-5-carboxamides

TLC (9:1CH, 41%) was prepared using (S) -glycidyl methanesulfonate (intermediate H, step 1) in step 1 instead of (R) -glycidyl methanesulfonate (intermediate F, step 1) and morpholine instead of piperidine and 1, 3-thiazole-5-carboxylic acid instead of nicotinic acid in step 2 (42.0mg,41%)₂Cl₂/MeOH+1%NH₄OHinMeOH)R_f0.43, HPLC retention time 0.81min;¹HNMR(DMSO-d₆+1 drop TFA-d)3.11-3.0(m,4H),3.43-3.52(m,2H),3.69(appt, J =11.8Hz,1H),3.78(appt, J =11.6Hz,1H)3.88-4.00(m,2H),4.01(s,3H),4.16-4.27(m,4H),4.37-4.51(m,3H),7.45(d, J =9.1Hz,1H),8.01(d, J =9.1Hz,1H),8.60(s,1H),9.31(s, 1H); mass spectrum M/z487((M +1)⁺,4.6%)。

Example 37: n- (8- { [ (2R) -2-hydroxy-3- (piperidin-1-yl) propyl]Oxy } -7-methoxy-2, 3-dihydro Imidazo [1,2-c ]]Quinazolin-5-yl) -1, 3-thiazole-5-carboxamides

Prepared using 1, 3-thiazole-5-carboxylic acid instead of nicotinic acid in step 2 (0.18g,60%) with HPLC retention time 1.10min;¹HNMR(DMSO-d₆+1 drop TFA-d)1.30-1.45(m,1H),1.60-1.86(m,5H),2.87-3.06(m,2H),3.12-3.31(m,2H),3.43-3.54(m,2H),4.01(s,3H),4.16-4.27(m,4H),4.35-4.50(m,3H),7.45(d, J =9.2Hz,1H),8.00(d, J =9.2Hz,1H),8.61(s,1H),9.31(s, 1H); mass spectrum M/z485((M +1)⁺,4.1%)。

Example 39: 2-amino-N- (8- { [ (2R) -2-hydroxy-3- (morpholin-4-yl) propyl]Oxy } -7-methoxy- 2,3-Dihydroimidazo [1,2-c ] s]Quinazolin-5-yl) -4-methyl-1, 3-thiazole-5-carboxamide

Replacement of piperidine in step 1 with morpholine and replacement of nicotinic acid in step 2 with 2-amino-4-methyl-1, 3-thiazole-5-carboxylic acid gave (0.18g,60%) HPLC retention time 0.83min;¹HNMR(DMSO-d₆+1 drop TFA-d)2.57(s,3H),3.11-3.38(m,4H),3.44-3.51(m,2H),3.69(appt, J =11.9Hz,1H),3.77(appt, J =11.5Hz,1H),3.90-3.98(m,2H),3.99(s,3H),4.16-4.26(m,4H),4.32-4.44(m,3H),7.44(d, J =9.1Hz,1H),8.00(s, 1H); mass spectrum M/z516((M +1)⁺,3.0%)。

In addition, the compounds of formula (I) of the present invention may be converted to any of the salts described herein by any method known to those skilled in the art. Similarly, any salt of the compound of formula (I) of the present invention may be converted to the free compound by any method known to those skilled in the art.

Pharmaceutical compositions of the compounds of the invention

The invention also relates to pharmaceutical compositions comprising one or more compounds of the invention. These compositions can be used to achieve a desired pharmacological effect by administration to a patient in need thereof. For purposes of the present invention, a patient is a mammal, including a human, in need of treatment for a particular condition or disease. Accordingly, the present invention includes pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the present invention or a salt thereof. A pharmaceutically acceptable carrier is preferably one that is relatively non-toxic and non-injurious to a patient at concentrations consistent with effective activity of the active ingredient, such that any side effects caused by the carrier do not destroy the beneficial effects of the active ingredient. A pharmaceutically effective amount of a compound is preferably an amount that results in or affects the particular condition being treated. The compounds of the present invention may be administered together with a pharmaceutically acceptable carrier in any effective conventional dosage unit form including immediate release, sustained release and timed release formulations in the following manner: oral, parenteral, topical, nasal, ocular (ophthalmic), sublingual, rectal, vaginal administration and the like.

For oral administration, the compounds may be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges (lozenes), melt gels (melts), powders, solutions, suspensions or emulsions and may be prepared according to methods known in the art for the preparation of pharmaceutical compositions. The solid unit dosage form may be a capsule, which may be of the ordinary hard or soft capsule type, comprising, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of the present invention can be compressed into tablets with conventional tablet bases (e.g., lactose, sucrose, and corn starch) and in combination with: binders such as acacia, corn starch or gelatin, disintegrating agents such as potato starch, alginic acid, corn starch and guar gum, tragacanth, acacia for assisting disintegration and dissolution of the tablets after administration, lubricants such as talc, stearic acid or magnesium stearate, calcium stearate or zinc stearate for improving the flowability of the tablet granulation and preventing adhesion of the tablet materials to the surfaces of the tablet dies and punches, and dyes, colorants and flavouring agents such as peppermint, oil of wintergreen or cherry flavouring for improving the organoleptic properties of the tablets and making them more acceptable to the patient. Suitable excipients for oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols (e.g., ethanol, benzyl alcohol, and polyvinyl alcohol), with or without the addition of pharmaceutically acceptable surfactants, suspending agents, or emulsifying agents. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar or both.

Dispersible powders and granules are suitable for use in the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, such as those described above, may also be present.

The pharmaceutical composition of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, such as liquid paraffin, or a mixture of vegetable oils. Suitable emulsifying agents may be (1) natural gums, for example gum acacia and gum tragacanth, (2) natural phosphatides, for example soya bean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, (4) condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. The suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate; one or more colorants; one or more flavoring agents; and one or more sweetening agents, such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent and a preservative such as methyl and propyl parabens as well as flavoring and coloring agents.

The compounds of the invention may also be administered parenterally, i.e., subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly or intraperitoneally, as injectable doses of the compounds, preferably in a physiologically acceptable diluent with a pharmaceutical carrier, which may be a sterile liquid or a mixture of liquids, such as water, saline, aqueous dextrose and related sugar solutions, alcohols such as ethanol, isopropanol or cetyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2, 2-dimethyl-1, 1-dioxolane-4-methanol, ethers such as poly (ethylene glycol) 400, oils, fatty acids, fatty acid esters or glycerides or acetylated glycerides, with or without the addition of pharmaceutically acceptable surfactants such as soaps or detergents, suspending agents such as pectin, sodium lauryl sulfate, sodium, Carbomer, methylcellulose, hypromellose or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.

Exemplary oils useful in the parenteral formulations of the invention are those derived from petroleum, animal, vegetable or synthetic sources, such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium and triethanolamine salts, and suitable detergents include cationic detergents such as dimethyl dialkyl ammonium halides, alkyl pyridinium halides and alkylamine acetates; anionic detergents such as alkyl sulfonates, aryl sulfonates and olefin sulfonates, alkyl sulfates and alkyl sulfosuccinates, olefin sulfates and olefin sulfosuccinates, ether sulfates and ether sulfosuccinates and monoglyceride sulfates and monoglycerides sulfosuccinates; nonionic detergents such as fatty amine oxides, fatty acid alkanolamides, and poly (oxyethylene-oxypropylene), ethylene oxide copolymers or propylene oxide copolymers; and amphoteric detergents such as alkyl-beta-aminopropionates and 2-alkylimidazoline quats, and mixtures.

The parenteral compositions of the invention will generally contain from about 0.5 to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be advantageously employed. To minimize or eliminate irritation at the injection site, such compositions may comprise a nonionic surfactant having a hydrophilic-lipophilic balance (HLB) of preferably from about 12 to about 17. The amount of surfactant in such formulations is preferably from about 5 to about 15% by weight. The surfactant may be a single component having the above HLB, or a mixture of two or more components having the desired HLB.

Exemplary surfactants for parenteral formulations are polyethylene sorbitan fatty acid esters such as sorbitan monooleate, and the high molecular weight adducts of ethylene oxide with a hydrophobic base formed by the condensation of propylene oxide and propylene glycol.

The pharmaceutical composition may be in the form of a sterile aqueous suspension for injection. Such suspensions may be formulated according to known methods using: suitable dispersing or wetting agents and suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide, for example lecithin, condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile solution or suspension for injection in a non-toxic parenterally-acceptable diluent or solvent. Diluents and solvents which can be used are, for example, water, ringer's solution, isotonic sodium chloride solution and isotonic glucose solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. In this regard, any less irritating fixed oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compositions of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycols.

Another formulation used in the methods of the invention utilizes a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or discontinuous delivery of a controlled amount of a compound of the present invention. The construction and use of transdermal patches for delivering agents is well known in the art (see, e.g., U.S. patent No.5,023,252 to 1991, published on 6/11, which is incorporated herein by reference). Such patches may be configured for continuous, pulsed, or on-demand delivery of the agent.

Controlled release formulations for parenteral administration include liposomal microspheres, polymeric microspheres, and polymeric gel formulations known in the art.

It may be desirable or necessary to deliver the pharmaceutical composition to a patient by a mechanical delivery device. The construction and use of mechanical delivery devices for delivering pharmaceutical agents is well known in the art. Direct techniques such as administering drugs directly to the brain typically involve placing a drug delivery catheter into the ventricular system of the patient to bypass the blood brain barrier. Such implantable delivery systems for transporting agents to specific anatomical locations of the body are described in U.S. patent No.5,011,472, published 4-30 1991.

The compositions of the present invention also necessarily or optionally include other conventional pharmaceutically acceptable formulation ingredients, often referred to as carriers or diluents. Conventional procedures for preparing such compositions into suitable dosage forms may be used. Such ingredients and procedures include those described in the following references, all of which are incorporated herein by reference: powell, M.F. et al, "Competition of excipients for particulate formulations" PDAJournarouF pharmaceutical science & Technology1998,52(5), 238-.

Common pharmaceutical ingredients that may be used to formulate the composition for the intended route of administration include:

acidulants (examples include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);

alkalizing agents (examples include, but are not limited to, ammonia, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine (triethanolamine), triethanolamine (trolamine));

adsorbents (examples include, but are not limited to, powdered cellulose and activated carbon);

aerosol propellants (examples include, but are not limited to, carbon dioxide, CCl₂F₂、F₂ClC-CClF₂And CClF₃）；

Air displacement agents (airtightly displacing agents) (examples include, but are not limited to, nitrogen and argon);

antifungal preservatives (examples include, but are not limited to, benzoic acid, butyl paraben, ethyl paraben, methyl paraben, propyl paraben, sodium benzoate);

antibacterial preservatives (examples include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, and thimerosal);

antioxidants (examples include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, thioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite);

adhesive substances (examples include, but are not limited to, block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones, polysiloxanes, and styrene-butadiene copolymers);

buffering agents (examples include, but are not limited to, potassium metaphosphate, dipotassium hydrogen phosphate, sodium acetate, anhydrous sodium citrate, and sodium citrate dihydrate);

a carrier (examples include, but are not limited to, acacia syrup, flavoring elixir, cherry syrup, cocoa syrup, orange syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection, and bacteriostatic water for injection)

Chelating agents (examples include, but are not limited to, sodium edetate and edetic acid);

colorants (examples include, but are not limited to FD & CRedNo.3, FD & CRedNo.20, FD & CYelow No.6, FD & CBlueNO.2, D & CGreen No.5, D & CorangeNo.5, D & CRedNo.8, caramel, and red iron oxide).

Clarifying agents (examples include, but are not limited to, bentonite);

emulsifying agents (examples include, but are not limited to, acacia, cetomacrogol, cetyl alcohol, glycerol monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate);

encapsulating agents (examples include, but are not limited to, gelatin and cellulose acetate phthalate);

flavors (examples include, but are not limited to, anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil, and vanillin);

humectants (examples include, but are not limited to, glycerin, propylene glycol, and sorbitol);

abrasives (examples include, but are not limited to, mineral oil and glycerin);

oils (examples include, but are not limited to, peanut oil, mineral oil, olive oil, peanut oil, sesame oil, and vegetable oil);

ointment bases (examples include, but are not limited to, lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment);

penetration enhancers (transdermal delivery) (examples include, but are not limited to, mono-or polyhydric alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalins, terpenes, amides, ethers, ketones, and ureas);

plasticizers (examples include, but are not limited to, diethyl phthalate and glycerol);

solvents (examples include, but are not limited to, ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection, and sterile water for rinsing);

hardening agents (examples include, but are not limited to, cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax, and yellow wax);

suppository bases (examples include, but are not limited to, cocoa butter and polyethylene glycol (mixtures));

surfactants (examples include, but are not limited to, benzalkonium chloride, nonoxynol 10, octoxynol 9, polysorbate 80, sodium lauryl sulfate, and sorbitan monopalmitate);

suspending agents (examples include, but are not limited to, agar, bentonite, carbomer, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, kaolin, methylcellulose, tragacanth and magnesium aluminum silicate);

sweetening agents (examples include, but are not limited to, aspartame, dextrose, glycerin, mannitol, propylene glycol, saccharin sodium, sorbitol, and sucrose);

tablet antiadherents (examples include, but are not limited to, magnesium stearate and talc);

tablet binders (examples include, but are not limited to, acacia, alginic acid, sodium carboxymethylcellulose, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);

tablet and capsule diluents (examples include, but are not limited to, dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium phosphate, sorbitol, and starch);

tablet coatings (examples include, but are not limited to, liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, methyl cellulose, ethyl cellulose, cellulose acetate phthalate, and shellac);

tablet direct compression excipients (examples include, but are not limited to, dibasic calcium phosphate);

tablet disintegrating agents (examples include, but are not limited to, alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrilin potassium (polacrilin potassium), cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycolate, and starch);

tablet glidants (examples include, but are not limited to, colloidal silicon dioxide, corn starch, and talc);

tablet lubricants (examples include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, and zinc stearate);

tablet/capsule opacifiers (examples include but are not limited to titanium dioxide);

tablet polishes (examples include, but are not limited to, carnauba wax and white wax);

thickening agents (examples include, but are not limited to, beeswax, cetyl alcohol, and paraffin wax);

tonicity agents (examples include, but are not limited to, dextrose and sodium chloride);

viscosity enhancers (examples include, but are not limited to, alginic acid, bentonite, carbomer, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium alginate, and gum tragacanth); and

wetting agents (examples include, but are not limited to, heptadecaethyleneoxycetanol, lecithin, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

The pharmaceutical composition of the present invention can be exemplified as follows:

sterile IV solution: sterile water for injection can be used to prepare a 5mg/mL solution of the desired compound of the invention, with the pH adjusted as necessary. The solution was diluted with sterile 5% dextrose to 1-2mg/mL for administration, and administered as an IV infusion over about 60 min.

Lyophilized powder for IV administration: sterile formulations can be prepared with (i)100-1000mg of the desired compound of the invention in lyophilized powder form, (ii)32-327mg/mL sodium citrate, and (iii)300-3000mg dextran 40. The formulation is reconstituted with sterile saline for injection or 5% dextrose to a concentration of 10-20mg/mL, then further diluted with saline or 5% dextrose to 0.2-0.4mg/mL and administered as an IV bolus or IV infusion over 15-60 minutes.

Intramuscular injection suspension: the following solutions or suspensions can be prepared for intramuscular injection:

50mg/mL of the desired Water-insoluble Compound of the invention

5mg/mL sodium carboxymethylcellulose

4mg/mLTWEEN80

9mg/mL sodium chloride

9mg/mL benzyl alcohol

Hard capsule: a large number of unit capsules were prepared by filling standard two-piece hard capsules with 100mg of powdered active ingredient, 150mg of lactose, 50mg of cellulose and 6mg of magnesium stearate.

Soft capsule: a mixture of the active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by positive displacement pump into molten gelatin to form soft capsules containing 100mg of the active ingredient. The capsules were washed and dried. The active ingredient may be dissolved in a mixture of polyethylene glycol, glycerol and sorbitol to prepare a water-miscible drug mixture.

Tablet formulation: a number of tablets were prepared by conventional procedures such that the dosage unit contained 100mg of active ingredient, 0.2mg of colloidal silicon dioxide, 5mg of magnesium stearate, 275mg of microcrystalline cellulose, 11mg of starch and 98.8mg of lactose. Suitable aqueous and non-aqueous coatings may be employed to increase palatability, improve appearance and stability, or delay absorption.

Immediate release tablet/capsule: these are solid oral dosage forms prepared by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the drug. The active ingredient is mixed in a liquid containing ingredients such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze-drying and solid-state extraction techniques. The pharmaceutical compound can be tableted with a viscoelastic and thermoelastic sugar and a polymer or effervescent component to produce a porous matrix that is quick-releasing without the need for water.

Combination therapy

The compounds of the present invention may be administered as the sole agent or in combination with one or more other agents, wherein the combination does not cause unacceptable adverse effects. The invention also relates to such combinations. For example, the compounds of the present invention may be combined with known agents and the like that are resistant to hyperproliferative diseases or other indications, as well as mixtures and combinations thereof. Other indications include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, anti-metabolites, DNA-intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, or anti-hormones.

The additional agent can be aldesleukin, alendronic acid, alpha-interferon (Alfaferone), alitretinoin, allopurinol, sodium allopurinol for injection (Aloprim), palonosetron hydrochloride injection (Aloxi), altretamine, aminoglutethimide, amifostine, amsacrine, anastrozole, dolaset (Anzmet), alfa bepotastine injection (Aranesp), Arglabin, arsenic trioxide, exemestane, 5-azacytidine, azathioprine, BAY80-6946, BCG or TiceBCG, amastatin b (bestatin), betamethasone acetate, betamethasone sodium phosphate, salmetene, bleomycin sulfate, bromouridine, bortezomib, busulfan, calcitonin, alemtuzumab (Campath), capecitabine, platinum, bipetamine, Celuotubrine, Cetyline, mellomycin sulfate, mellomycin, melphalan, doxine, melphalan, doxine, clodronic acid (clodronic acid), cyclophosphamide, cytarabine, carbamazepine, dactinomycin, daunorubicin citrate liposome (DaunoXome), dexamethasone sodium phosphate, estradiol valerate, dinilukine fusion 2 toxin (denileukandiftitox), methylprednisolone, deslorelin, dexrazoxane, diethylstilbestrol, fluconazole, docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, leuprolide acetate (Eligard), labyrin injection (Elitek), epirubicin hydrochloride injection (elence), aprepirubicin capsule (Emenden), epirubicin, alfa etinalfa, alfa efavirus (epothilones), alfa (Epogen), etaplatin, levamisole, estradiol, estramustine, ethinylol, fosiposide, etoposide, etofazole, ethastin, sodium phosphate, etheptane, trofavudine (elyne), trofavudine, estramustine, ethisterone, ethodoxagliptin, etoposide, etofavudine, doxine, Filgrastim, finasteride, filgrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoromethyltestosterone, flutamide, formestane, fosetabine, fotemustine, fulvestrant, gamma-globulin (Gammagard), gemcitabine, gemumab, imatinib mesylate (Gleevec), carmustine (Gliadel), goserelin, granisetron hydrochloride, histrelin, topotecan (Hycamtin), hydrocortisone, erythroxylnonyl adenine (Pyrothro-hydroxyynonadenylenen), hydroxyurea, temozolomide, idarubicin, ifosfamide, alpha interferon, alpha 2 interferon, alpha-2A interferon, alpha-2B interferon, alpha-n 35 1 interferon, alpha-n 3 interferon, beta interferon, gamma-1 a interferon, interleukin, alpha-2A interferon, alpha-2A interferon, Interferon alpha-2 b (intron a), gefitinib tablet (Iressa), irinotecan, granisetron, lentinan sulfate (lentinan sulfate), letrozole, folinic acid, leuprorelin acetate, levamisole, calcium levofolinate (levofolinic acid calcium salt), levothyroxine sodium, Levoxyl, lomustine, lonidamine, dronabinol, dichloromethyldiethylamine (meclorethamine), mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogen tablet (Menest), 6-mercaptopurine, mesna, methotrexate, Metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, modenal, myocin, nedaplatin, filgrastim (neulata), interleukin 11 (neugexa), leuca, neritin, OCT, nsertine, mestranol C, oxerusin C, oxtretin, oxepitretin, nedaplatin (neufrataxine), nefavudine, leucite, oxtemerite C, oxtansine, oxtemerite C, oxtemeritine, oxtemet 631570, oxepitretin, oxtemet, Oxaliplatin, paclitaxel, prednisone sodium phosphate (Pediapred), pemetrexed, pegvises, pentostatin, streptolysin (pisibanil), pilocarpine hydrochloride, pirarubicin, plicamycin, porphycin sodium, prednimustine, prednisolone, prednisone, equine estrogens, procarbazine, recombinant human erythropoietin alpha, raltitrexed, RDEA119, recombinant human interferon beta 1a injection (Rebif), rhenium-186, etidronate (etidronate), rituximab, rospirocin (Roferon-A), romopeptide, pilocarpine hydrochloride (Salagen), octreotide, sargrastim, semustine, Sizopyrane, sobuzogen, prednisolone, fosinopenic acid, streptozocin dry cell therapy, strontium chloride 89, levothyroxine sodium, talosin, tamsulosin, sothiamine, testolactone, paclitaxel, taxol, temozoloside, paclitaxel, temozoloside, and flutemoside, Testosterone propionate, methyltestosterone, thioguanine, thiotepa, thyroid stimulating hormone, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, troosulfan, tretinoin, methotrexate (Trexall), trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, vilrizine, dexrazoxane, neat stastin ester (zinostatin stimalamer), ondansetron, ABI-007, Acolbifene, interferon gamma-1 b (mmActiune), Affinitak, aminopterin, azoxifene, Asoprisrinil, alitame, atrasentan, sorafenib (sorafenib), bevacizumab (Avastin), CCI-779, Lecitb-501, CDC, cyproteracil acetate, Cetut acetate, Cetallopril, CDC, Cetiramitocin, valacil acetate, valacitrexate, valbutin, valbutritin, valbutrituximab, and so, DN-101, doxorubicin-MTC, dSLIM, dutasteride, Edotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implants, holmium-166 DOTMP, ibandronic acid, gamma interferon, pegylated interferon alpha-2 b (intron-PEG), ixabepilone (ixabepilone), keyhole limpet hemocyanin (keyholeletepekacin), L-651582, lanreotide, lasofoxifene, Libra, Lonafarnib, miropoxifene, Minodronate (Minodronate), MS-209, MTP-PE liposomes, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, Obmersenmen, OndiCO-TCS, Osidemem, docetaxel, pamidronate disodium, PN-21, Western-21, lypocetine, Najaponicase, Spiroxisein, Spiroseine, Spirosequin, Opadrol, doxetamide, doxorazem-13, doxoramin-21, Levone, doxoramin-401, doxoramin, T-138067, erlotinib hydrochloride tablet (Tarceva), Taxoprexin, alpha-1 thymosin, thiazolufrine, tipifarnib (tipifarnib), tirapazamine, TLK-286, toremifene, TransMID-107R, valcephrade, vapreotide, vatalanib (vatalanib), verteporfin, vinflunine, Z-100, zoledronic acid, or combinations thereof.

In one embodiment of the invention, a compound of general formula (I) as defined herein may optionally be administered in combination with one or more of the following agents: 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amsacrine, anastrozole, Arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY80-6946, BAY1000394, BAY86-9766(RDEA119, belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, cabazitaxel, calcium folinate, levofolinate, capecitabine, carboplatin, carmofur, carmustine, cataxomab, cisplatin, simox-white, cetuximab, chlorambucil, clorabeprinosine, chlorambucil, closterine, chlorambucil, clorpe, chlorantranilide, chlorantranilic, chlorantranilide, alexan, clorfarabine, azalide, clofarabine, clorfamitocide, clofarabine, clorfamitrazine, bexaglitazone, bexapride, clofarabine, dacarbazine, dactinomycin, dactinosporine alpha, dasatinib, daunorubicin, decitabine, degarelix, dinil interleukin fusion 2 toxin, denomab, deslorelin, dibromospiro-ammonium chloride, docetaxel, doxifluridine, doxorubicin + estrone, eculizumab, ecolomab, eletrocumab, eltrombopag, endostatin, enocitabine, epirubicin, epithiandrol, alfa-eptine, betatepatin, eptaplatin, eletatin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolitan, famazole, filgrastim, fludarabine, flutamide, flutametamide, formestan, fotemustine, fulvestramustine, gallium nitrate, ganaxanidol, gefitinib, gemcitabine, glutethimide, histretinomycin, histrexate, histretinomycin, hispidil, gefitinib, hispidil, gefitinib, geusine, hispidil, geusine, ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferon alpha, interferon beta, interferon gamma, ipilimumab, irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide, lenetin, lentinan, letrozole, leuprolide, levamisole, lisuride, lobaplatin, lomustine, lonidamine, maxol, medroxyprogesterone, megestrol, melphalan, melindroxane, mercaptopurine, methotrexate, methoxsalen, aminolevulinic acid methyl ester, methyltestosterone, mifamutide, miltefosine, mitilfuxin, miboplatin, mitoguazone, dibromodulcitol, mitomycin, mitotane, mitoxantrone, nedaplatin, nelarabine, nilotinib, nimotuzumab, pimozide, oxepin, oxepirubicin, oxaliplatin, oxepirubicin, and the like, p53 gene therapy, paclitaxel, palifermin, palladium-103 seeds, pamidronic acid, pamitumumab, pazopanib, pemetrexed, PEG-betaepoetin (methoxy PEG-betapotein, pegylated filgrastim, pegylated interferon alpha-2 b, pemetrexed, pentazocine, pentostatin, pellomycin, perphosphoramide, streptolysin, pirarubicin, rixafor, priomycin, chitosan, pleestradiol polyphosphate, polysaccharose-k, porfimer sodium, pralatrexate, prednimustine, procarbazine, quinagolide, raloxifene, raltitrexed, ramustine, propyleneimine, regorafenib, risezidine, rituximab, romidepsin, romiplosin, sargramostim, sipuleucel-T, cilazalanoline, bisodium, glycidib, glycitenfurtine, streptogramin, streptozocin, tamoxifen, tasolomine, tesil, tegafur + gimeramidine + oteracil, temoporfin, temozolomide, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thioguanine, tositumomab, topotecan, toremifene, tositumomab, trabectedin, trastuzumab, troosulfan, tretinoformate, trospilin, trofosfamide, tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vindesine, vinflunine, vinorelbine, vorinostat, vorozole, yttrium-90 glass microspheres, seting, setastin, zoledronic acid, and zorubicin.

Optional anti-hyperproliferative agents that may be added to the compositions include, but are not limited to, compounds listed in the cancer chemotherapeutic regimen of the merck index 11 (1996) (incorporated by reference), such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, asparaginase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (doxorubicin), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, dichloromethyldiethylamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, thioguanine, topotecan, meclofen, meclofenoxate, dactinomycin, and other drugs, Vinblastine, vincristine, and vindesine.

Other anti-hyperproliferative agents suitable for use with the compositions of the present invention include, but are not limited to, those compounds recognized in Goodmanandd Gilman's the pharmacological bases of therapeutics (Nintendition), Molinoff et al, McGraw-Hill, pp.1225-1287, (1996) (incorporated herein by reference) for the treatment of neoplastic disease, such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2' -difluorodeoxycytidine, docetaxel, red hydroxynonyladenine, ethinylestradiol, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluorometholone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-acetyl-Palatine (PALA), phosphono-L (PAL), phosphono-L) and salts thereof, Plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine.

Other anti-hyperproliferative agents suitable for use with the compositions of the present invention include, but are not limited to, other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifene and topotecan.

The compounds of the invention may also be administered in combination with a protein therapeutic. Such protein therapeutics suitable for use in the treatment of cancer or other angiogenic disorders and suitable for use with the compositions of the invention include, but are not limited to, interferons (e.g., alpha, beta, or gamma interferons), hyperactive monoclonal antibodies, Tuebingen, TRP-1 protein vaccines, Colostrinin, anti-FAP antibodies, YH-16, gimumab, infliximab, cetuximab, trastuzumab, dinil interleukin fusion 2 toxin, rituximab, alpha 1 thymosin, bevacizumab, mecamylamine, omprex, natalizumab, rhMBL, MFE-CP1+ 2767-P, ABT-ErbB 2-specific immunotoxin, SGN-35, MT-103, linline, AS-1402, B43-genistein, L-19 series radioimmunotherapy agents, AC-9301, NY-ESO-1 vaccine, IMC-1C11, CT-322, rhCC10, r (m) CRP, MORAB-009, Avisuramine (aviscumine), MDX-1307, Her-2 vaccine, APC-8024, NGR-hTNF, rhH1.3, IGN-311, endostatin, Voloximab (volociximab), PRO-1762, lexatuzumab (lexatuzumab), SGN-40, pertuzumab (pertuzumab), EMD-273, L19-IL-2 fusion protein, PRX-321, CNTO-328, MDX-214, tegafur peptide (tigotide), CAT-3888, labebetuzumab (labetuzumab), radioisotope-crosslinked trastuzumab of emiting particles, EM-Acukbce-1421, interleukin (hypericin), HPV-7, HPV-3516, HPV-30625, and Abelizumab (Labetuzumab), and the like, Javelin-melanoma, NY-ESO-1 vaccine, EGF vaccine, CYT-004-MelQbG10, WT1 peptide, agovacizumab (oregomab), ofatumumab, zalutumumab (zalutumumab), betheumatin interleukin (cindrekinbestudox), WX-G250, Albuferon, aflibercept, denosumab (denosumab), vaccine, CTP-37, efungumab (efungusab), or 131I-chTNT-1/B. Monoclonal antibodies that may be used as protein therapeutics include, but are not limited to, molobuzumab-CD 3, abciximab, edrecolomab, daclizumab, gemtuzumab (gentuzumab), alemtuzumab, ibritumomab (ibritumomab), cetuximab, bevacizumab, efalizumab (efalizumab), adalimumab (adalimumab), omalizumab (omalizumab), moruzumab-CD 3, rituximab, daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.

The compounds of general formula (I) as defined herein may optionally be administered in combination with one or more of the following agents: ARRY-162, ARRY-300, ARRY-704, AS-703026, AZD-5363, AZD-8055, BEZ-235, BGT-226, BKM-120, BYL-719, CAL-101, CC-223, CH-5132799, deforolimus, E-6201, enzastaurin, GDC-0032, GDC-0068, GDC-0623, GDC-0941, GDC-0973, GDC-0980, GSK-2110183, GSK-2126458, GSK-2141795, MK-2206, novolimus, OSI-027, pirifocine, PF-04691502, PF-05212384, RO-866, rapamycin, RG-7167, RO-4987655, selumetinib-5126766, selumetinib, TAK-733, trametinib, cetrorol, PX-866-XL-147, wzox-XL, zs-765.

In general, the use of cytotoxic and/or cytostatic agents in combination with a compound or composition of the invention will serve the following functions:

(1) produces better efficacy in reducing tumor growth or even eliminating tumors than either agent administered alone,

(2) allowing for the administration of smaller amounts of the administered chemotherapeutic agent,

(3) providing a chemotherapeutic treatment that is well tolerated by patients and has fewer harmful pharmacological complications than observed with single agent chemotherapy and certain other combination therapies,

(4) allowing the treatment of a broader spectrum of different cancer types in mammals, particularly humans,

(5) providing a higher response rate in the treated patient,

(6) provides longer survival in the treated patient compared to standard chemotherapy treatment,

(7) provide longer tumor progression time, and/or

(8) At least as good efficacy and tolerability as the agents used alone are obtained as compared to known cases where other cancer agents produce antagonistic effects in combination.

Method for sensitizing cells to radiation

In a different embodiment of the invention, the compounds of the invention can be used to sensitize cells to radiation. That is, treatment of cells with a compound of the invention prior to radiation therapy of the cells makes the cells more susceptible to DNA damage and cell death than they would be if the cells were not subjected to any treatment with a compound of the invention. In one aspect, a cell is treated with at least one compound of the invention.

Accordingly, the present invention also provides a method of killing cells, wherein one or more compounds of the invention are administered to the cells along with conventional radiation therapy.

The invention also provides methods of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of the invention to cause or induce cell death prior to treating the cell. In one aspect, after treating the cells with one or more compounds of the invention, the cells are treated with at least one compound, at least one method, or a combination thereof to cause DNA damage for inhibiting the function of normal cells or killing the cells.

In one embodiment, the cells are killed by treating the cells with at least one DNA damaging agent. That is, after treating a cell with one or more compounds of the invention sensitizes the cell to cell death, the cell is treated with at least one DNA-damaging agent to kill the cell. DNA damaging agents that may be used in the present invention include, but are not limited to, chemotherapeutic agents (e.g., cisplatin), ionizing radiation (X-ray, ultraviolet radiation), carcinogens, and mutagenic agents.

In another embodiment, the cells are killed by treating the cells with at least one method to cause or induce DNA damage. Such methods include, but are not limited to: activating a cellular signal transduction pathway (which causes DNA damage when the pathway is activated), inhibiting a cellular signal transduction pathway (which causes DNA damage when the pathway is inhibited), and inducing a biochemical change in a cell (wherein the change causes DNA damage). By way of non-limiting example, DNA repair pathways in a cell may be inhibited, thereby preventing repair of DNA damage and resulting in abnormal accumulation of DNA damage in a cell.

In one aspect of the invention, the compounds of the invention are administered prior to irradiation or other induction that causes DNA damage to cells. In another aspect of the invention, the compounds of the invention are administered concurrently with irradiation or other induction that causes DNA damage to cells. In yet another aspect of the invention, the compounds of the invention are administered immediately after the onset of irradiation or other induction that causes DNA damage to cells.

In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo.

As described above, it has surprisingly been found that the compounds of the invention effectively inhibit allogeneic MEK (allo-MEK) and are therefore useful in the treatment or prevention of diseases caused by, or accompanied by, uncontrolled cell growth, proliferation and/or survival, or an inappropriate cellular immune response or inappropriate cellular inflammatory response, in particular wherein the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by allogeneic MEK, for example haematological tumours, solid tumours and/or metastases thereof, such as leukaemia and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, diseases such as cancer, cancer of the brain and brain, Breast, gastrointestinal, endocrine, breast and other gynaecological tumours including non-small cell and small cell lung tumours, urological tumours including renal, bladder and prostate tumours, skin tumours and sarcomas, and/or metastases thereof.

Thus, according to another aspect, the present invention relates to a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described and defined herein, for use in the treatment or prevention of a disease, as described above.

Accordingly, another particular aspect of the present invention is the use of a compound of general formula (I) as described above for the preparation of a pharmaceutical composition for the treatment or prevention of a disease.

The diseases mentioned in the first two paragraphs are diseases caused by or accompanied by uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response or an inappropriate cellular inflammatory response, in particular wherein said uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by Mps-1, such as hematological tumors, solid tumors and/or metastases thereof, e.g. leukemia and myelodysplastic syndrome, malignant lymphomas, head and neck tumors including brain tumors and brain metastases, breast tumors including non-small cell lung tumors and small cell lung tumors, gastrointestinal tumors, inflammatory diseases, Endocrine tumors, breast tumors and other gynecological tumors, urological tumors including renal tumors, bladder tumors and prostate tumors, skin tumors and sarcomas, and/or metastases thereof.

In the context of the present invention, in particular in the context of an "inappropriate immune response or inappropriate cellular inflammatory response" as used herein, the term "inappropriate" is understood to preferably mean a response which is weaker or stronger than the normal response and which is associated with, causes or leads to the pathology of the disease.

Preferably, the use is for the treatment or prevention of a disease, wherein the disease is a hematological tumor, a solid tumor and/or metastases thereof.

Methods of treating hyperproliferative disorders

The present invention relates to methods of treating hyperproliferative disorders in mammals using the compounds of the present invention and compositions thereof. The compounds may be used to inhibit, block, reduce, etc., cell proliferation and/or cell division and/or induce apoptosis. The method comprises administering to a mammal, including a human, in need thereof an amount of a compound of the present invention, a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, and the like, effective to treat the condition. Hyperproliferative disorders include, but are not limited to, psoriasis, keloids and other hyperplasia affecting the skin, Benign Prostatic Hyperplasia (BPH), solid tumors such as breast cancer, respiratory tract cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and their distant metastases. Such conditions also include lymphomas, sarcomas and leukemias.

Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are not limited to, small cell lung cancer and non-small cell lung cancer as well as bronchial adenomas and pleural pneumococcal tumors.

Examples of brain cancers include, but are not limited to, brainstem and hypothalamic gliomas, cerebellum and brain astrocytomas, medulloblastomas, ependymomas, and neuroectodermal and pineal tumors.

Tumors of the male reproductive organs include, but are not limited to, prostate cancer and testicular cancer. Tumors of female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancers, as well as uterine sarcomas.

Tumors of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small intestine, and salivary gland cancers.

Urinary tract tumors include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureter cancer, urinary tract cancer, and human papillary renal cancer.

Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to, squamous cell carcinoma, kaposi's sarcoma, malignant melanoma, merkel cell skin cancer, and non-melanoma skin cancer.

Head and neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip cancer, oral cavity cancer, and squamous cell. Lymphomas include, but are not limited to, aids-related lymphoma, non-hodgkin's lymphoma, cutaneous T-cell lymphoma, burkitt's lymphoma, hodgkin's disease, and central nervous system lymphoma.

Sarcomas include, but are not limited to, soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas, lymphosarcomas, and rhabdomyosarcomas.

Leukemias include, but are not limited to, acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also exist in other mammals with similar etiologies, and can be treated by administering the pharmaceutical compositions of the present invention.

Reference throughout this document to the use of the term "treating" or "treatment" is conventional, e.g., for the purpose of counteracting, alleviating, reducing, alleviating, ameliorating the condition of a disease or disorder such as sarcoma, and the like.

Methods of treating kinase disorders

The invention also provides methods for treating disorders associated with abnormal mitogen extracellular kinase activity including, but not limited to, stroke, heart failure, hepatomegaly, cardiac enlargement, diabetes, alzheimer's disease, cystic fibrosis, symptoms of xenograft rejection, septic shock, or asthma.

An effective amount of a compound of the invention may be used to treat such disorders, including those diseases mentioned in the background section above (e.g., cancer). Moreover, such cancers and other diseases may be treated with the compounds of the present invention regardless of the mechanism of action and/or the relationship of the kinase to the condition.

The phrase "abnormal kinase activity" or "abnormal tyrosine kinase activity" includes abnormal expression or activity of the gene encoding the kinase or the polypeptide encoded thereby. Examples of such aberrant activity include, but are not limited to, overexpression of the gene or polypeptide; gene amplification; mutations that produce constitutively active or highly active kinase activity; gene mutation, deletion, substitution, addition, and the like.

The present invention also provides methods of inhibiting kinase activity, particularly mitogen extracellular kinase activity, comprising administering an effective amount of a compound of the present invention, including salts, polymorphs, metabolites, hydrates, solvates, prodrugs (e.g., esters) and diastereomeric forms thereof. Kinase activity may be inhibited in cells (e.g., in vitro) or in cells of a mammalian subject, particularly a human patient in need of treatment.

Methods of treating angiogenic disorders

The invention also provides methods of treating conditions and diseases associated with excessive and/or abnormal angiogenesis.

Inappropriate and abnormal expression of angiogenesis can be harmful to an organism. Many pathological states are associated with growth of unrelated (extra) blood vessels. These include, for example, diabetic retinopathy, ischemic retinal vein occlusion, and retinopathy of prematurity [ Aiello et al, new engl.j.med.1994,331, 1480; peer et al, lab. invest.1995,72,638], age-related macular degeneration [ AMD; see Lopez et al invest, opthalmols, vis, 1996,37,855], neovascular glaucoma, psoriasis, retrolental fibroplasia, angiofibroma, inflammation, Rheumatoid Arthritis (RA), restenosis, in-stent restenosis, restenosis following vascular grafts, and the like. In addition, the increased blood supply associated with cancerous and tumor tissue promotes growth, resulting in rapid tumor enlargement and metastasis. In addition, the growth of new blood and lymph vessels in tumors provides an exit route for cancerous cells (renegadecells), promoting metastasis and leading to the spread of cancer. Thus, the compounds of the present invention may be used to treat and/or prevent any of the aforementioned angiogenic disorders, e.g., by inhibiting and/or reducing angiogenesis; inhibit, block, reduce, etc., endothelial cell proliferation or other types associated with angiogenesis, and cause cell death or apoptosis of such cells.

Dosage and administration

Effective dosages of the compounds of the present invention for the treatment of each of the desired indications can be readily determined based on standard laboratory techniques known to evaluate compounds for the treatment of hyperproliferative and angiogenic disorders, by standard toxicity tests, as well as by standard pharmacological tests for determining treatment of the disorders described hereinabove in mammals, and by comparing these results with those of known drugs used to treat these disorders. The amount of active ingredient administered in the treatment of one of these conditions may vary widely depending on the following considerations: the particular compound and dosage unit employed, the mode of administration, the course of treatment, the age and sex of the patient to be treated, and the nature and extent of the condition being treated.

The total amount of active ingredient to be administered is generally from about 0.001mg/kg to about 200mg/kg body weight/day, and preferably from about 0.01mg/kg to about 20mg/kg body weight/day. A clinically useful dosing regimen will be one to three times daily dosing to once every four weeks. In addition, a "drug withdrawal period" (where no drug is administered to the patient for a certain period of time) may be advantageous for the overall balance between pharmacological efficacy and tolerability. A unit dose may contain from about 0.5mg to about 1500mg of the active ingredient and may be administered one or more times per day, or less than once per day. The average daily dose administered by injection, including intravenous, intramuscular, subcutaneous and parenteral injection, and using infusion techniques, may preferably be from 0.01 to 200mg/kg of total body weight. The average daily rectal dosage regimen is preferably from 0.01 to 200mg/kg of total body weight. The average daily vaginal dosage regimen is preferably 0.01-200mg/kg total body weight. The average daily topical dosage regimen is preferably 0.1-200mg administered one to four times daily. The transdermal concentration is preferably the concentration required to maintain a daily dose of 0.01-200 mg/kg. The average daily inhaled dose regimen is preferably from 0.01 to 100mg/kg of total body weight.

The specific starting and maintenance dosage regimen for each patient will, of course, vary depending upon the following factors: the nature and severity of the condition as determined by the clinician, the activity of the particular compound used, the age and general health of the patient, the time of administration, the route of administration, the rate of excretion of the drug, the drug combination, and the like. Thus, the desired therapeutic regimen and the amount of a compound of the invention, pharmaceutically acceptable salt, ester or composition thereof to be administered can be determined by one skilled in the art using routine therapeutic testing.

Preferably, the disease of the method is a hematological tumor, a solid tumor and/or metastases thereof.

The compounds of the invention are particularly useful for the treatment and prevention (i.e. prevention) of tumor growth and metastasis, in particular of solid tumors of all indications and stages, with or without prior treatment of said tumor growth.

Methods for determining specific pharmacological or pharmaceutical properties are well known to those skilled in the art.

The example assay experiments described herein are intended to illustrate the invention and the invention is not limited to the examples provided.

Biological evaluation

The utility of the compounds of the invention can be demonstrated by their in vitro activity, for example, in the in vitro tumor cell proliferation assay described below. The link between activity in vitro tumor cell proliferation experiments and antitumor activity in a clinical setting is well established in the art. For example, the therapeutic effects of paclitaxel (Silvestrini et al, 1993), Tepesso (Bissery et al, 1995) and topoisomerase inhibitors (Edelman & Gandara,1996) are demonstrated by utility in an in vitro tumor proliferation assay.

The activity of the compounds of the invention can be demonstrated by in vitro, ex vivo and in vivo assays well known in the art. For example, to demonstrate the activity of the compounds of the present invention, the following assay can be used.

Biological assay

The examples were tested one or more times in the chosen biological assay. When the test is more than one time, the data is reported as the mean or median, where:

● the mean (also called arithmetic mean) represents the sum of the values obtained divided by the number of trials, and

● the median represents the median of the sets of values in ascending or descending order. If the number of values of the data set is odd, the median value is the middle value. If the number of values of the data set is even, the median value is the arithmetic mean of the two values in the middle.

Examples were synthesized one or more times. When synthesized more than once, the data from the biological assay represents the mean or median value calculated using a data set obtained by testing one or more synthetic batches.

Determination of% inhibition and IC of Compounds in PI3K α kinase assay₅₀Value of

The PI3K α inhibitory activity of the compounds of the invention was quantified using the HTRF-based PI3K inhibition assay described below.

Chemical reagent and assay material

PI3-KinaseHTRFassay kit (#33-017) from Millipore was used as a reagent for quantification of the kinase reaction itself and the reaction products. Using the kit, by substituting energy fromDetection of phosphatidylinositol 3,4, 5-triphosphate (PIP) by biotinylated ligands of the mass transfer complex₃) The energy transfer complex is composed of europium-labeled anti-GST monoclonal antibody, GST-labeled PH domain, biotinylated PIP₃Recombinant full-length human p110 α labeled with N-terminal His 6-and unlabeled recombinant full-length human p85 α (Co-expressed by baculovirus-infected Sf21 insect cells and Using Ni²⁺NTA-agarose purified) was used as kinase (Millipore product # 14-602).

For the assay, 50nL of an 80-fold concentrated solution of the test compound in DMSO was pipetted into a black, small-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and PI3K α and phosphatidylinositol-4, 5-diphosphate (PIP) were added₂,13.8μM=>Final concentration in 4 μ L reaction volume =10 μ M) solution (3 μ L) in 1x reaction buffer (exact composition not disclosed by the vendor) and incubation of the mixture at 22 ℃ for 15min to allow pre-binding of test compound with enzyme before the kinase reaction starts the amount of PI3K α was chosen to bring the enzyme reaction in the linear range and this amount depends on the activity of the batches, typical assay concentrations are in the range of 90ng/mL>Tumor concentration in 4. mu.L assay volume 10. mu.M) solution in reaction buffer (1. mu.L) and the resulting mixture was incubated at 22 ℃ for 20 min.

Stop solution (containing biotinylated PIP used as tracer) by adding 1. mu.L₃) The reaction was stopped, then 1 μ L of detection mixture (containing europium-labeled anti-GST monoclonal antibody, GST-labeled PH domain and streptavidin-allophycocyanin) was added, and the resulting mixture was incubated at 22 ℃ for 3h to form detection reagents and PIP produced in the kinase reaction₃Or biotinylated PIP added with stop solution₃A complex of (a) and (b). The energy transfer complex (evaluation of europium-labeled anti-GST monoclonal antibody, GST-labeled PH domain, biotinylated PIP) was then assessed by measuring the resonance energy transfer from europium-labeled anti-GST monoclonal antibody to streptavidin-allophycocyanin₃And streptavidin-Allophycocyanin (APC). Thus, fluorescence emissions at 620nm and 665nm after excitation at 350nm were determined using a TR-FRET reader, such as, for example, Pherastar (BMGLABTechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of emission at 665nm and emission at 620nm was taken as biotinylated PIP bound to GST-labeled PH domain₃Measure of the amount of (a), PIP generated therewith₃The amount of (c) is inversely related. Data were normalized (enzyme reaction without inhibitor =0% inhibition; all other assay components in the absence of enzyme =100% inhibition). Typically, the values of the test compounds at each concentration are determined in duplicate on the same microtiter plate at 10 different concentrations in the range 25 μ M to 1.3nM (25 μ M,8.3 μ M,2.8 μ M,0.93 μ M,0.31 μ M,103nM,34nM,11nM,3.8nM and 1.3nM, the dilution series being prepared by 1:3 serial dilution at the level of the stock solution concentrated 80-fold before the determination), and the IC is calculated using the software itself according to a 4-parameter fit₅₀The value is obtained.

The compounds of the following examples showed an average IC of less than 10 nanomolar in a PI3K α biochemical assay showing₅₀1,5, 6,8, 9, 10, 12, 14, 17, 18, 19, 20, 21, 23,25, 27, 28, 29, 30, 32, 34, 35, 36, 37, 38, 39, 41 the compounds of the following examples show an average IC of 10-50 nanomolar in a PI3K α display biochemical assay₅₀2,3, 4, 7, 11, 16, 24 the following example compounds show an average IC of greater than 50 nanomolar in a PI3K α display biochemical assay₅₀: 40. table 1 provides the percent inhibition values obtained for the example compound at a concentration of 0.93 μ M:

determination of% inhibition and IC of Compounds in PI3K β kinase assay₅₀Value of

PI3K β inhibitory activity of the compounds of the invention was quantified using an HTRF-based PI3K inhibition assay as described below.

Chemical reagent and assay material

PI3-KinaseHTRFassay kit from Millipore (#33-017) was used as a reagent forQuantification of the kinase reaction itself and the reaction products. With this kit, phosphatidylinositol 3,4, 5-triphosphate (PIP) was detected by replacing the biotinylated ligand from the energy transfer complex₃) The energy transfer complex is composed of europium-labeled anti-GST monoclonal antibody, GST-labeled PH domain, biotinylated PIP₃Recombinant full-length human p110 β labeled with N-terminal His 6-and unlabeled recombinant full-length human p85 α (Co-expressed by baculovirus-infected Sf21 insect cells and Using Ni²⁺NTA-agarose purified) was used as kinase (Millipore product # 14-603).

For the assay, 50nL of an 80-fold concentrated solution of the test compound in DMSO was pipetted into a black, small-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and PI3K β and phosphatidylinositol-4, 5-diphosphate (PIP) were added₂,13.8μM=>Final concentration in 4 μ L reaction volume =10 μ M) solution (3 μ L) in 1x reaction buffer (exact composition not disclosed by the vendor) and incubation of the mixture at 22 ℃ for 15min to allow pre-binding of test compound with enzyme before the kinase reaction starts the amount of PI3K β was chosen to bring the enzyme reaction in the linear range and this amount depends on the activity of the batches, typical assay concentrations are in the range of 120ng/mL>Tumor concentration in 4. mu.l assay volume 10. mu.M) solution in reaction buffer (1. mu.L) and the resulting mixture was incubated at 22 ℃ for 20 min.

Stop solution (containing biotinylated PIP used as tracer) by adding 1. mu.L₃) The reaction was terminated. Then 1. mu.L of the assay mixture (containing europium-labeled anti-GST monoclonal antibody, GST-labeled PH domain and streptavidin-allophycocyanin) was added and the resulting mixture was incubated at 22 ℃ for 3h to form the detection reagent and PIP produced in the kinase reaction₃Or biotinylated PIP added with stop solution₃A complex of (a) and (b). The energy transfer complex (labeled with europium) was then evaluated by measuring the resonance energy transfer from the europium-labeled anti-GST monoclonal antibody to streptavidin-allophycocyaninanti-GST monoclonal antibodies, GST-tagged PH domains, biotinylated PIP₃And streptavidin-Allophycocyanin (APC). Thus, fluorescence emissions at 620nm and 665nm after excitation at 350nm were determined using a TR-FRET reader, such as, for example, Pherastar (BMGLABTechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of emission at 665nm and emission at 620nm was taken as biotinylated PIP bound to GST-labeled PH domain₃Measure of the amount of (a), PIP generated therewith₃The amount of (c) is inversely related. Data were normalized (enzyme reaction without inhibitor =0% inhibition, all other assay components in the absence of enzyme =100% inhibition). Typically, the values of the test compounds at each concentration are determined in duplicate on the same microtiter plate at 10 different concentrations in the range 25 μ M to 1.3nM (25 μ M,8.3 μ M,2.8 μ M,0.93 μ M,0.31 μ M,103nM,34nM,11nM,3.8nM and 1.3nM, the dilution series being prepared by 1:3 serial dilution at the level of the stock solution concentrated 80-fold before the determination), and the IC is calculated using the software itself according to a 4-parameter fit₅₀The value is obtained.

The compounds of the following examples showed an average IC of less than 10 nanomolar in a PI3K β biochemical assay showing₅₀25, 28, 29, 38 and 39 the compounds of the following examples show an average IC of 10-50 nanomolar in a PI3K β -display biochemical assay₅₀2,5, 8, 9, 10, 11, 12, 14, 16, 17, 18, 19, 20, 21, 23, 24, 27, 30, 32, 34, 35, 36, 37 and 41 the compounds of the following examples show an average IC of greater than 50 nanomolar in a PI3K β display biochemical assay₅₀: 1.3, 4, 6,7 and 40. Table 1 provides the percent inhibition values obtained for the example compound at a concentration of 0.93 μ M:

TABLE 1

It is believed that one skilled in the art can, using the preceding information and information available in the art, utilize the present invention to its fullest extent. Those skilled in the art will recognize that changes may be made in the structure, materials, compositions and methods disclosed in the present invention without departing from the spirit or scope of the invention, which is set forth herein, and that such changes are considered to be within the scope of the invention. The compounds described in the examples are intended to be representative of the invention, it being understood that the scope of the invention is not limited to the examples. The headings set forth above are intended to guide where certain information may be found in the present application, but are not to be construed as the only places in the invention where information on such subject matter may be found.

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All publications and patents cited above are incorporated herein by reference.

Claims

1. A compound selected from the following, or a salt thereof, or a mixture thereof:

n- (8- { [ (2R) -2-hydroxy-3- (morpholin-4-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) pyridine-3-carboxamide

N- (8- { [ (2R) -2-hydroxy-3- (8-oxa-3-azabicyclo [3.2.1] oct-3-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) pyridine-3-carboxamide

N- (8- { [ (2R) -3- (azetidin-1-yl) -2-hydroxypropyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) pyridine-3-carboxamide

N- (8- { [ (2R) -2-hydroxy-3- (pyrrolidin-1-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) pyridine-3-carboxamide

N- (8- { [ (2R) -2-hydroxy-3- (piperidin-1-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) pyridine-3-carboxamide

N- (8- { [ (2R) -3- (dimethylamino) -2-hydroxypropyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) pyridine-3-carboxamide

N- (8- { [ (2R) -2-hydroxy-3- (morpholin-4-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -2-methylpyridine-3-carboxamide

N- (8- { [ (2R) -3- (azetidin-1-yl) -2-hydroxypropyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -2-methylpyridine-3-carboxamide

N- (8- { [ (2R) -2-hydroxy-3- (pyrrolidin-1-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -2-methylpyridine-3-carboxamide

N- (8- { [ (2R) -2-hydroxy-3- (piperidin-1-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -2-methylpyridine-3-carboxamide

N- (8- { [ (2R) -3- (diprop-2-ylamino) -2-hydroxypropyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -2-methylpyridine-3-carboxamide

N- (8- { [ (2R) -2-hydroxy-3- (pyrrolidin-1-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) pyrimidine-5-carboxamide

N- (8- { [ (2R) -2-hydroxy-3- (pyrrolidin-1-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -1, 3-thiazole-5-carboxamide

N- (8- { [ (2R) -2-hydroxy-3- (piperidin-1-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -1, 3-thiazole-5-carboxamide

N- (8- { [ (2R) -2-hydroxy-3- (pyrrolidin-1-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -1, 3-oxazole-5-carboxamide.

2. The compound of claim 1, or a salt thereof, or a mixture thereof, wherein the salt is a physiologically acceptable salt.

3. The compound of claim 1, or a salt thereof, or a mixture thereof, which is: n- (8- { [ (2R) -2-hydroxy-3- (morpholin-4-yl) propyl ] oxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -2-methylpyridine-3-carboxamide.

4. A pharmaceutical composition comprising a compound of any one of claims 1-3, or a salt thereof, or a mixture thereof, and a pharmaceutically acceptable diluent or carrier.

5. The pharmaceutical composition of claim 4, wherein the salt is a pharmaceutically acceptable salt.

6. A pharmaceutical composition comprising:

-one or more compounds according to any one of claims 1 to 3, or a salt thereof, or a mixture thereof; and

-one or more agents selected from: a taxane; an epothilone; mitoxantrone; prednisolone; dexamethasone; estramustine; vinblastine; vincristine; doxorubicin; doxorubicin; idarubicin; daunorubicin; bleomycin; etoposide; cyclophosphamide; ifosfamide; procarbazine; melphalan; 5-fluorouracil; capecitabine; fludarabine; cytarabine; 2-chloro-2' -deoxyadenosine; thioguanine; an antiandrogen; bortezomib; cisplatin, carboplatin, eptaplatin, miriplatin, nedaplatin, oxaliplatin, and satraplatin; chlorambucil; methotrexate and rituximab.

7. The pharmaceutical composition of claim 6, wherein the salt is a pharmaceutically acceptable salt.

8. The pharmaceutical composition of claim 6 or 7, wherein the taxane is selected from the group consisting of docetaxel, paclitaxel, and paclitaxel.

9. The pharmaceutical composition of claim 6 or 7 wherein said epothilone is selected from the group consisting of ixabepilone, paclitaxel, and salgopirone.

10. The pharmaceutical composition of claim 6 or 7, wherein the antiandrogen is selected from flutamide, cyproterone acetate and bicalutamide.

11. The pharmaceutical composition of claim 6 or 7, wherein the one or more agents are selected from cisplatin and carboplatin.

12. Use of a compound of any one of claims 1-3, or a salt thereof, or a mixture thereof, for the manufacture of a medicament for preventing or treating a disease caused by uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, wherein the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is mediated by the phosphatidylinositol-3-kinase pathway.

13. The use of claim 12, wherein the salt is a pharmaceutically acceptable salt.

14. The use of claim 12, wherein the disease caused by uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response or an inappropriate cellular inflammatory response is a hematological tumor, a solid tumor and/or metastases thereof.

15. Use according to claim 14, wherein the hematological tumors, solid tumors and/or metastases thereof are selected from the group consisting of leukemias and myelodysplastic syndromes, malignant lymphomas, tumors of the head and neck, thoracic, gastrointestinal, endocrine, breast and other gynaecological, urological, skin and sarcoma and/or metastases thereof.

16. The use according to claim 15, wherein the head and neck tumor is selected from the group consisting of brain tumors and brain metastases.

17. The use of claim 15, wherein the breast tumor is selected from the group consisting of a non-small cell lung tumor and a small cell lung tumor.

18. The use of claim 15, wherein the urological tumour is selected from the group consisting of renal tumours, bladder tumours and prostate tumours.