HK1189594A

HK1189594A - Alkoxy-substituted 2,3-dihydroimidazo[1,2-c]quinazolines

Info

Publication number: HK1189594A
Application number: HK14102743.0A
Authority: HK
Inventors: W．J．斯科特; M．默维斯; U.伯默; U.门宁; 刘宁姝
Original assignee: Bayer Intellectual Property Gmbh
Priority date: 2010-11-11
Filing date: 2011-11-08
Publication date: 2014-06-13

Description

Alkoxy-substituted 2, 3-dihydroimidazo [1,2-c ] quinazolines

Technical Field

The present invention relates to arylamino alcohol substituted 2, 3-dihydroimidazo [1,2-c ] quinolines (hereinafter "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

The concept of developing anti-cancer drugs targeting aberrantly active protein kinases has met with much success over the last decade. In addition to the role of protein kinases, lipid kinases also play an important role in generating the second messengers of critical regulation. The PI3K family of lipid kinases produces 3' -phosphoinositides that bind to and activate a variety of cellular targets, initiating a broad signal transduction cascade (Vanhaaesebroeck et al, 2001; Toker,2002; Pendaries et al, 2003; Downes et al, 2005). These cascades ultimately induce changes in a variety of cellular processes including cell proliferation, cell survival, differentiation, vesicle trafficking (vesicle trafficking), migration, and chemotaxis.

PI3K can be classified into three different categories based on differences in structure and substrate preference. Although members of the class II family of PI3K have been implicated in the regulation of tumor growth (Brown & Shepherd,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 is generally divided into two distinct subclasses based on differences in protein subunit composition. I th_API 3-like 3K consists of a catalytic p110 catalytic subunit (p110 α, β or δ) that heterodimerizes with a member of the p85 regulatory subunit family. In contrast, item I_BPI 3-like 3K catalytic subunit (p 110. gamma.) heterodimerization with a different p101 regulatory subunit (Vanhaaesebroeck)&Waterfield,1999; Funaki et al, 2000; Katso et al, 2001). The C-terminal region of these proteins contains a catalytic domain with a homology to the protein kinase. PI3K gamma structure and I_ASimilar to p110, but lacking 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 subtypes is in c (kinase pocket) of the kinase domain.

I th_AThe PI 3K-like subtypes are associated with activated Receptor Tyrosine Kinases (RTKs) (including PDGFR, EGFR, VEGFR, IGF1-R, c-KIT, CSF-R, and Met) or with tyrosine phosphorylation by their p85 regulatory subunits that produce stimulation of lipid kinase activityAdapter proteins (e.g., Grb2, Cbl, IRS-1 or Gab 1). Activation of lipid kinase activity of the p110 β and p110 γ subtypes has been demonstrated to occur in response to binding of activated forms of the ras oncogene (Kodaki et al, 1994). Indeed, the oncogenic activity of these subtypes may require binding to ras (Kang et al, 2006). In contrast, the p110 α and p110 δ subtypes exhibit oncogenic activity through constitutive activation of Akt, independent of ras binding.

Class I PI3K catalyzing PI (4,5) P₂[PIP₂]To PI (3,4,5) P₃[PIP₃]The transformation of (3). PIP produced by PI3K₃Affecting a number of signaling processes that regulate and coordinate the biological endpoints of cell proliferation, cell survival, differentiation, and cell migration. PIP (PIP)₃Binding via Plckstrin-homology (PH) domain-containing proteins, including phosphoinositide-dependent kinase, PDK1 and Akt proto-oncogene products, localizes these proteins in the active signaling region and also directly facilitates their activation (Klippel et al, 1997; Fleming et al, 2000; Itoh;)&Takenawa,2002; Lemmon, 2003). Co-localization (co-localization) of PDK1 with Akt promotes phosphorylation and activation of Akt. Akt at Ser⁴⁷³The carboxyl terminal phosphorylation of (A) promotes Thr³⁰⁸Phosphorylation in the Akt activation cycle (Chan)&Tsichlis,2001; Hodgkinson et al, 2002; Scheid et al, 2002; Hresko et al, 2003). Once activated, Akt phosphorylates and regulates a variety of regulatory kinases that directly influence pathways of cell cycle progression and cell survival.

Many of the effects of Akt activation are mediated through its negative regulation of pathways that affect cell survival and are often deregulated in cancer. Akt promotes tumor cell survival by modulating the composition of apoptotic and cell cycle mechanisms. Akt is one of several kinases that phosphorylate and inactivate pro-apoptotic BAD proteins (del Peso et al, 1997; Pasorino et al, 1999). Akt can also be induced by placing caspase 9 at Ser¹⁹⁶Up-phosphorylation to block cytochrome C-dependent caspase activation, thereby promoting cell survival (Cardone et al, 1998).

Akt influences genes at various levelsDue to transcription. MDM2E3 ubiquitin ligase at Ser¹⁶⁶And Ser¹⁸⁶Akt-mediated phosphorylation on MDM2 promotes nuclear import and formation and activation of the ubiquitin ligase complex. Nuclear MDM2 targets p53 tumor inhibitors for degradation (a process that can be blocked by LY 294002) (Yap et al, 2000; Ogawara et al, 2002). Down-regulation of p53 by MDM2 negatively affects p 53-regulated pro-apoptotic genes (e.g., Bax, Fas, PUMA, and DR5), cell cycle inhibitors p21^Cip1And PTEN tumor suppressor transcription (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) promotes their binding to 14-3-3 proteins and export from the nucleus to the cytosol. This functional inactivation of Forkhead activity also affects the transcription of pro-apoptotic and pro-angiogenic genes, including Fas ligand (cieshomska et al, 2003), Bim (pro-apoptotic Bcl-2 family members) (Dijkers et al, 2000), and angiopoietin-1 (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, leading to Cdk1 inhibition, cell cycle arrest and apoptosis (Dijkers et al, 2000). Akt Thr is also reported¹⁴⁵P21 on^Cip1And Thr¹⁵⁷P27 on^Kip1Phosphorylation, which promotes their association with the 14-3-3 protein, leading to nuclear transport and cytoplasmic retention, preventing their inhibition of nuclear Cdks (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 translocation of NF κ B, resulting in surviving genes such as IAP and Bcl-X_LExpression of (2).

The PI3K/Akt pathway also passes through JNK and p38 associated with apoptosis induction^MAPKMAP kinase is associated with apoptosis inhibition. Akt is hypothesized to regulate kinases (apoptosis signal regulating kinase 1(ASK1) by two JNK/p38 (Kim et al, 2001; Liao)&Hung,2003; Yuan et al, 2003) and Mixed lineage kinase (mixed linkage kinase)3(MLK3)Phosphorylation and inhibition of (Lopez-Ilasaca et al 1997; Barthwal et al 2003; Figueroa et al 2003)) inhibits JNK and p38^MAPKAnd (6) conducting signals. P38 was observed in tumors treated with cytotoxic agents^MAPKInduction of Activity, and those that induce cell death are required (in Olson&Halahan, reviewed in 2004). Thus, inhibitors of the PI3K pathway may promote the activity of co-administered cytotoxic drugs.

Other roles of PI3K/Akt signaling are related to the modulation of cell cycle progression by modulating glycogen synthase kinase 3(GSK3) activity. GSK3 activity is elevated in quiescent cells where it drives Ser²⁸⁶Cyclin D of (3)₁Phosphorylate, target proteins for ubiquitination and degradation (Diehl et al, 1998) and block entry into the S-phase. Akt is mediated through Ser⁹Inhibits GSK3 activity (Cross et al, 1995). This results in cyclin D promoting cell cycle progression₁The level is increased. Inhibition of GSK3 activity also affects cell proliferation through activation of the wnt/β -catenin signaling pathway (Abbosh)&Nephew,2005; Naito et al, 2005; Wilker et al, 2005; Segrelles et al, 2006). Akt-mediated phosphorylation of GSK3 leads to stabilization and nuclear localization of β -catenin, which in turn leads to increased expression of c-myc and cyclin D1 (target of β -catenin/Tcf pathway).

Although PI3K signaling is exploited by many signal transduction networks associated with oncogenes and tumor suppressors, PI3K and its activity are associated with direct cancer. Overexpression of the p110 α and p110 β subtypes has been observed in bladder and colon tumors as well as cell lines, and is often associated with increased PI3K activity (bnistant et al, 2000). Overexpression of p110 α has been reported in ovarian and cervical tumors and tumor cell lines as well as in squamous cell lung cancer. Overexpression of p110 α in cervical and ovarian tumor cell lines has been associated with increased PI3K activity (Shayesteh et al, 1999; Ma et al, 2000). Increased PI3K activity has been observed in colorectal cancer (Phillips et al, 1998), and increased expression has been observed in breast cancer (Gershtein et al, 1999).

In recent years, somatic mutations in the gene encoding p110 α (PIK3CA) have been identified in a variety of cancers. The data collected to date indicate mutations 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% of glioblastomas (Samuels et al, 2004; Hartmann et al, 2005; Gallia et al, 2006), 25% of gastric cancers (Samuels et al, 2004; Byun et al, 2003; Li et al, 2005), 36% of hepatocellular carcinomas (Lee et al, 2005), 4-12% of ovarian cancers (Levine et al, 2005; Wang et al, 2006), 4% of lung cancers (Samuels et al, 2004; Whyte & Holbeck, 2005), and up to 40% of endometrial cancers (Oda et al, 3 CA). PIK3CA mutations have been reported in oligodendrogliomas (oligodendromas), astrocytomas, medulloblastomas, and thyroid tumors (Broderick et al, 2004; Garcia-Rostan et al, 2005). Based on the high frequency of mutations observed, PIK3CA is one of the two most frequently mutated genes associated with cancer, while the other is K-ras. More than 80% of the PIK3CA mutations cluster in two regions of the protein, the helical domain (E545K) and the catalytic domain (H1047R). Biochemical analysis and protein expression studies have demonstrated that both of these mutations result in increased constitutive p110 α catalytic activity and are carcinogenic in nature (Bader et al, 2006; Kang et al, 2005; Samuels & Ericson, 2006). PIK3CA knock-out mouse embryonic fibroblasts have recently been reported to be deficient in signaling downstream of various growth factor receptors (IGF-1, insulin, PDGF, EGF) and to be resistant to transformation by various oncogenic RTKs (IGFR, wild-type EGFR and EGFR, i.e., somatic mutation of Her 2/Neu) (Zhao et al, 2006).

Functional studies of PI3K in vivo have shown that siRNA-mediated down-regulation of p110 β inhibits both Akt phosphorylation and HeLa cell tumor growth in nude mice (Czauderna et al, 2003). In similar experiments, siRNA-mediated down-regulation of p110 β has also been shown to inhibit growth of malignant glioma cells in vitro and in vivo (Pu et al, 2006). Inhibition of PI3K function by a dominant negative p85 regulatory subunit blocks mitogenesis and cell transformation (Huang et al, 1996; Rahimi et al, 1996). A number of somatic mutations in the genes encoding the p85 α and p85 β regulatory subunits of PI3K, which lead to increased lipid kinase activity, have also been identified in a variety of cancer cells (Janssen et al, 1998; Jimenez et al, 1998; Philp et al, 2001; Jucker et al, 2002; Shekar et al, 2005). Neutralizing PI3K antibodies also block mitogenesis and can induce apoptosis in vitro (Roche et al, 1994; Roche et al, 1998; Benistant et al, 2000). In vivo proof of principle (proof-of-principle) studies using PI3K inhibitors LY294002 and wortmannin have shown that PI3K signaling slows tumor growth in vivo (Powis et al, 1994; Schultz 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 tolerance to targeted (e.g., imatinib and trastuzumab) and cytotoxic chemotherapy approaches as well as 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). It has also been demonstrated that activation of PI3K results in the expression of multiple drug resistance protein-1 (MRP-1) in prostate cancer cells and subsequent induction of resistance to chemotherapy (Lee et al, 2004).

The importance of PI3K signaling in tumorigenesis is further underscored by the following findings: the PTEN tumor inhibitor PI (3) P phosphatase belongs to the most frequently inactivated gene of 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. Cells containing functionally inactivated PTEN with elevated PIP₃Horizontal, high levels of PI3K signaling activity (Haas-Kogan et al, 1998; Myers et al, 1998; Taylor et al, 2000), increased proliferative potential, and reduced sensitivity to pro-apoptotic stimuli (Stambolic et al, 1998). Reconstitution of functional PTEN inhibits PI3K signaling (Taylor et al, 2000), inhibits cell growth and re-sensitizes cells to pro-apoptotic stimuli (Myers et al, 1998; Zhao et al, 2004). Similarly, PTEN function in tumors lacking functional PTENCan repair and inhibit tumor growth in vivo (Stahl et al, 2003; Su et al, 2003; Tanaka)&Grossman,2003) and sensitising the cells to cytotoxic agents (Tanaka)&Grossman,2003)。

The signal input to class I PI3K is diverse and can be deduced by genetic analysis. Thus, activation of AKT can be impaired in p110 α -deficient Murine Embryonic Fibroblasts (MEFs) when stimulated by traditional Receptor Tyrosine Kinase (RTK) ligands (e.g., EGF, insulin, IGF-1, and PDGF) (Zhao et al, 2006). However, MEFs in which p110 β is cleaved off or replaced by the kinase death allele of p110 β typically respond 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 the majority of the PI3K signal in classical RTK signaling and is responsible for tumor growth, proliferation, survival, angiogenesis and metabolism, while p110 β mediates GPCR signaling from mitogens and chemokines and may thereby modulate tumor cell proliferation, metabolism, inflammation and invasion (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, in a mouse prostate tumor model driven by PTEN deficiency, resection of p110 α was demonstrated to have no effect on tumorigenesis (Jia et al, 2008). Furthermore, downstream activation of AKT, cell transformation and growth of PTEN-deficient cells, as well as tumor xenografts, were inhibited in PTEN-deficient human cancer cell lines of p110 β, but not 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 loss of PTEN. For example, impaired focus formation (focus formation) in PTEN-deficient PC3 cells depletes endogenous p110 β with the addition of kinase-dead p110 β but not its wild-type counterpart (Wee et al, 2008). These studies indicate that PTEN-deficient tumor cells are dependent on p110 β and its catalytic activity for signaling and growth.

Genetic variation of the tumor suppressor PTEN is commonly found in many cancers (Liu et al, 2009), such as endometrial cancer (43%), CRPC (35-79%), glioma (19%) and melanoma (18%). For endometrial cancer, co-existing PIK3CA and PTEN gene variations were identified (Yuan & Cantley, 2008). In addition to mutations, PIK3CA amplification and PTEN loss of function have been found to be caused by a variety of molecular mechanisms. For example, PIK3CA amplification and PTEN loss of function were found in 30-50% and 35-60% of gastric cancer patients, respectively, despite the reports that PIK3CA and PTEN mutation rates were each less than 7% (Byun et al, 2003; Oki et al, 2006; Li et al, 2005; Sanger database).

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

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

WO2008/070150(Bayer Schering Pharma Aktiengesellschaft) relates to 2, 3-dihydroimidazo [1,2-c [, 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, particularly for the treatment of hyperproliferative and/or angiogenic disorders, as a single agent or in combination with other active ingredients. The compounds show increased activity (lower IC) on PI3K α compared to PI3K β₅₀)。

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

It has now been found that said present invention, as described and defined herein and hereinafter referred to as "compounds of the inventionThe inventive compounds have surprising and advantageous properties, which form the basis of the present invention, said properties being: as shown in the biological section herein, the compounds of the present invention exhibit a surprising balanced activity against inhibition of the α -and β -isoforms of phosphatidylinositol-3-kinase, which can be expressed as PI3K β IC₅₀/PI3KαIC₅₀The ratio of (a) to (b).

The compounds of the invention (including salts, metabolites, solvates of salts, hydrates and stereoisomeric forms thereof) exhibit antiproliferative activity and are therefore useful in the prevention or treatment of conditions associated with hyperproliferation: in particular, the compounds of general formula (I) of the present 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 leukaemia 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 cancer, lung, 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

According to a first aspect, the invention comprises a compound of 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-(CR⁴(R^4’))-(CH₂)_m-N(R⁵)(R^5’)；

R²Represents an optionally substituted by 1,2 or 3R⁶A group-substituted heteroaryl having the structure:

wherein:

represents the point of attachment of the heteroaryl group to the rest of the structure 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 1R⁸Radical substituted C₁-C₆-an alkyl group;

R⁴is a hydroxyl group;

R^4’is a hydrogen atom or C₁-C₆-an alkyl group;

R⁵is a hydrogen atom, C₁-C₆Alkyl radical, C₃-C₆-cycloalkyl-C₁-C₆Alkyl, aryl-C₁-C₆-alkyl or C₁-C₆-alkoxy-C₁-C₆-alkyl, wherein said aryl-C₁-C₆-alkyl radicals andin the same or different manner by R⁶One or more substitutions;

R^5’is aryl-C₁-C₆-alkyl, wherein said aryl-C₁-C₆Alkyl is substituted in the same or different manner by R⁶One or more substitutions;

or

R⁵And R^5’Together with the nitrogen atom to which they are bound represent a 3-to 8-membered nitrogen-containing heterocyclic ring, said 3-to 8-membered nitrogen-containing heterocyclic ring optionally containing at least one further heteroatom selected from oxygen, nitrogen or sulfur, and may optionally be substituted by 1 or more R^6’Substituted by groups;

R⁶may be the same or different at each occurrence and is independently a hydrogen atom, a halogen atom, or each may optionally be substituted with 1 or more R⁸Radical substituted 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)(R^7’)、-C₁-C₆-alkyl-C (= O) R⁷、-CN、-C(=O)OR⁷、-C(=O)N(R⁷)(R^7’)、-OR⁷、-SR⁷、-N(R⁷)(R^7’) or-NR⁷C(=O)R⁷；

R⁷And R^7’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-a cycloalkyl group,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 for 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.

Definition of

The terms mentioned herein preferably have the following meanings:

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

The term "C₁-C₆Alkyl is understood as preferably meaning 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-dimethylbutylOr 1, 2-dimethylbutyl or isomers thereof. In particular, the radicals have 1,2 or 3 carbon atoms ("C)₁-C₃-alkyl "), such as methyl, ethyl, n-propyl or isopropyl.

The term "halo-C₁-C₆Alkyl is understood to mean preferably a straight-chain or branched, saturated monovalent hydrocarbon radical, where the term "C" is₁-C₆Alkyl "is as defined above and wherein one or more hydrogen atoms are replaced by halogen atoms in the same or different manner, i.e. independently of each other. In particular, the halogen atom is F. Said halo-C₁-C₆Alkyl is, for example, -CF₃、-CHF₂、-CH₂F、-CF₂CF₃or-CH₂CF₃。

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 defined as 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 "halo-C₁-C₆Alkoxy is understood as preferably meaning a straight-chain or branched, saturated, monovalent C radical as defined above in which one or more hydrogen atoms are replaced by halogen atoms in the same or different manner₁-C₆-alkoxy groups. In particular, the halogen atom is F. Said halo-C₁-C₆Alkoxy is, for example, -OCF₃、-OCHF₂、-OCH₂F、-OCF₂CF₃or-OCH₂CF₃。

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 substituted straight or branched chain saturated monovalent as defined aboveAlkyl or their isomers, e.g. methoxyalkyl, ethoxyalkyl, propoxyalkyl, isopropoxyalkyl, butoxyalkyl, isobutoxyalkyl, tert-butoxyalkyl, sec-butoxyalkyl, pentoxyalkyl, isopentoxyalkyl, hexyloxyalkyl, where the term "C₁-C₆-alkyl "is as defined above.

The term "halo-C₁-C₆-alkoxy-C₁-C₆Alkyl is understood to preferably mean a straight-chain or branched, saturated, monovalent-C radical as defined above in which one or more hydrogen atoms are replaced by halogen atoms in the same or different manner₁-C₆-alkoxy-C₁-C₆-an alkyl group. In particular, the halogen atom is F. Said halo-C₁-C₆-alkoxy-C₁-C₆Alkyl is, for example, -CH₂CH₂OCF₃、-CH₂CH₂OCHF₂、-CH₂CH₂OCH₂F、-CH₂CH₂OCF₂CF₃or-CH₂CH₂OCH₂CF₃。

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, methyl-but-2-enyl, methyl-but-1-enyl, methyl-but-2-enyl, methyl-1, (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, (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, methyl-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, 2-ethylbut-3-enyl, 1-ethylbut-3-enyl, methyl-1-pentenyl, ethyl-3-enyl, ethyl-2-pentenyl, ethyl-1-, (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, (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, (Z) -1-isopropylprop-1-enyl, (E) -3, 3-dimethylprop-1-enyl, and (Z) -1-isopropylprop-1-enyl), (Z) -3, 3-dimethylprop-1-enyl, 1- (1, 1-dimethylethyl) vinyl, but-1, 3-dienyl, penta-nyl-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 contains one or more triple bonds and contains 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-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, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-1-ynyl, 3-methylpent-1-, 1, 1-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 on 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. an optionally substituted-CH₂- ("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 particularly 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 or C₁-C₆-alkyl-or halo-C₁-C₆-alkyl-; the heterocycloalkyl group may be attached to the rest of the molecule through either carbon atom or through the nitrogen atom, if present.

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, but not limited thereto, the heterocycloalkyl group may be a four-membered ring, such as azetidinyl, glycidylalkyl (oxyethanyl); or five-membered rings, such as tetrahydrofuranyl, dioxolyl (dioxolanyl), pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a six-membered ring, for example tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl (dithianyl), thiomorpholinyl, piperazinyl or trithianyl; or a seven-membered ring, such as a diazepanyl (diazepanyl) ring. Optionally, the heterocycloalkyl ring may be benzo-fused.

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

The term "aryl" is to be understood as preferably meaning 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 ("C)₆-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 (" C)₁₀-aryl "), such as tetralinyl, dihydronaphthyl or naphthyl, or is a ring having 13 carbon atoms (" C₁₃Aryl radicals ") such as the fluorenyl radical, or a ring having 14 carbon atoms (" C)₁₄Aryl) such as 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 represents the point of attachment of said 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 which has 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 (the heteroatom being, for example, oxygen, nitrogen or sulfur), which in addition in each case may be benzo-fused.

In particular, the heteroaryl group has the following structure:

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 general formula (I) as defined above,

x represents N or C-R⁶，

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

-R⁶May be the same or different at each occurrence and is independently a hydrogen atom, a halogen atom, or each may optionally be substituted with 1 or more R⁸Radical substituted 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 heteroCyclic, 3-to 8-membered heterocyclyl-C₁-C₆-alkyl, -C₁-C₆-alkyl-OR⁷、-C₁-C₆-alkyl-SR⁷、-C₁-C₆-alkyl-N (R)⁷)(R^7’)、-C₁-C₆-alkyl-C (= O) R⁷、-CN、-C(=O)OR⁷、-C(=O)N(R⁷)(R^7’)、-OR⁷、-SR⁷、-N(R⁷)(R^7’) or-NR⁷C(=O)R⁷；

-R⁷And R^7’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 for 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 (thia-4H-pyrazoyl), and the like, and benzo derivatives thereof, such as benzofuryl, 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 oxepinyl (oxapinyl) and 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, for example at "C₁-C₆-alkyl group "," C₁-C₆-haloalkyl "," C₁-C₆-alkoxy "or" C₁-C₆The term "C" as used in the context of the definition of-haloalkoxy₁-C₆"is understood to mean an alkyl group having a limited number of carbon atoms from 1 to 6, 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-C₆In the case of a haloalkoxy group, more particularly C₁-C₂。

Similarly, as used herein (as used throughout this document, e.g., at "C)₂-C₆-alkenyl "and" C₂-C₆-alkynyl ", as used in the context of its definition) the term" C₂-C₆"is understood to mean alkenyl or alkynyl groups having a limited number of carbon atoms of 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, as used herein (as used throughout this document, e.g., at "C)₃-C₆Used in the context of the definition of-cycloalkyl) — the term "C₃-C₆"is understood to mean cycloalkyl having a limited number of carbon atoms of from 3 to 6, 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 at the present time 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 a specified group, radical or moiety.

Ring system substituents represent substituents attached to an aromatic or non-aromatic ring system, e.g. replacing an available hydrogen on the ring system.

The term "one or more times" as used herein (e.g. in the definition of a substituent of a compound of general formula (la) of 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 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 a racemic mixture in the case of one asymmetric center and a diastereomeric mixture in the case of multiple asymmetric centers. In some cases, asymmetry may also exist due to hindered rotation about a particular bond (e.g., the central bond linking two substituted aromatic rings of a given compound).

The ring substituents may also be present in cis or trans form. All such configurations (including enantiomers and diastereomers) are intended to be included 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.

Optical isomers may be obtained by resolution of the racemic mixture according to conventional methods, for example by formation of diastereomeric salts using an optically active acid or base, or by formation of covalent diastereomers. Examples of suitable acids are tartaric acid, diacetyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Mixtures of diastereomers may be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, e.g., by chromatography or fractional crystallization. The optically active base or acid is then released from the separated diastereomeric salt. Another different method of separating optical isomers involves the use of chiral chromatography (e.g., a chiral HPLC column) with or without conventional derivatization, which is optimally selected to maximize separation of the enantiomers. Suitable chiral HPLC columns are produced by Diacel, such as chiralel OD and chiralel OJ, all of which are routinely selected. Enzymatic separation may also be used with or without derivatization. Likewise, the optically active compounds of the present invention can be obtained by chiral synthesis using optically active starting materials.

To distinguish the different types of isomers from each other, reference is made to IUPAC RulesSection E (Pure Appl Chem45,11-30,1976).

The present invention includes all possible stereoisomers of the compounds of the invention, either as single stereoisomers or as any mixture of said isomers in any proportion. The separation of single stereoisomers, such as single enantiomers or single diastereomers, of the compounds of the invention may be achieved by any suitable prior art method, such as chromatography, particularly, for example, chiral chromatography.

Tautomers, sometimes referred to as proton-moving tautomers, are two or more compounds that are related by the migration of a hydrogen atom accompanied by the conversion of one or more single bonds and one or more adjacent double bonds. The compounds of the present 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. It is intended that all such tautomeric forms are included within the scope of the invention.

Furthermore, any compound of the invention comprising a pyrazole moiety as heteroaryl may, for example, exist in the form of a 1H tautomer or a 2H tautomer or even in the form of a mixture of any amount of the two tautomers, or any compound of the invention comprising a triazole moiety as heteroaryl may, for example, exist in the form of a 1H tautomer, a 2H tautomer or a 4H tautomer or even in the form of a mixture of any amount of the 1H, 2H and 4H tautomers, i.e.:

the present invention includes all possible tautomers of the compounds of the invention, either as single tautomers or as any mixtures of said tautomers, in any ratio.

In addition, the compounds of the present invention may exist in the form of N-oxides, which are defined as compounds of the present invention in which at least one nitrogen is oxidized. The present invention includes all such possible N-oxides.

The invention also relates to useful forms of the compounds disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, especially pharmaceutically acceptable salts and co-precipitates.

The compounds of the invention may be present in the form of hydrates or solvates, wherein the compounds of the invention comprise as structural element of the crystal lattice of the compound a polar solvent, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions. In the case of stoichiometric solvates, such as hydrates, there may be semi- (hemi-) solvates or hydrates, (semi- (hemi-) solvates or hydrates, mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates, respectively. The present invention includes all such hydrates or solvates.

Furthermore, the compounds of the invention may be present in free form, e.g. as a free base or as a free acid or as a zwitterion, or may be present as a salt. The salt may be any salt, which may be an organic or inorganic addition salt, in particular any pharmaceutically acceptable organic or inorganic addition salt commonly used in pharmacy.

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.

Suitable pharmaceutically acceptable salts of the compounds of the invention may be, for example, acid addition salts of the compounds of the invention which carry a nitrogen atom in the chain or ring and which are sufficiently basic, for example with the following inorganic acids: such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid (disufuric acid), phosphoric acid or nitric acid, or acid addition salts with organic acids such as: such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, Mandelic acid, ascorbic acid, glucoheptylic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid (hemisulfuric acid), or thiocyanic acid.

In addition, another suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an ammonium salt, or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with: n-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1, 6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, tris (hydroxymethyl) aminomethane, aminopropanediol, sovak base, 1-amino-2, 3, 4-butanetriol. In addition, the basic nitrogen-containing groups may be quaternized with the following agents: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromide, and the like.

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.

The present invention includes all possible salts of the compounds of the invention, which may be single salts or any mixture of said salts in any proportion.

The term "in vivo hydrolysable ester" as used herein is understood to mean an in vivo hydrolysable ester of a compound of the invention which comprises a carboxy or hydroxy group, for example a pharmaceutically acceptable ester which can be hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for the carboxyl group include, for example, alkyl esters, cycloalkyl esters and optionally substituted phenylalkyl esters, in particular benzyl esters, C₁-C₆Alkoxymethyl esters, e.g. methoxymethyl ester, C₁-C₆Alkanoyloxymethyl esters, e.g. pivaloyloxymethyl ester, phthalidyl ester, C₃-C₈cycloalkoxy-carbonyloxy-C₁-C₆Alkyl esters such as 1-cyclohexylcarbonyloxyethyl ester; 1, 3-dioxole-2-carbonylmethyl (1,3-dioxolen-2-onylmethyl ester), such as 5-methyl-1, 3-dioxole-2-carbonylmethyl ester; and C₁-C₆Alkoxycarbonyloxyethyl esters, such as 1-methoxycarbonyloxyethyl ester, and the esters may be formed on any of the carboxyl groups of the compounds of the invention.

In vivo hydrolysable esters of compounds of the invention which contain a hydroxy group include inorganic acid esters (e.g. phosphate esters), [ α ] acyloxyalkyl ethers and related compounds which are cleaved by in vivo hydrolysis of the ester to form the parent hydroxy group. Examples of [ α ] acyloxyalkyl ethers include acetoxymethyl ether (acetoxymethyloxy) and 2, 2-dimethylpropionyloxymethyl ether (2, 2-dimethylpropionyloxymethyloxy). The selection of groups which form in vivo hydrolysable esters with hydroxyl groups include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, alkoxycarbonyl groups (to form alkyl carbonates), dialkylcarbamoyl and N- (dialkylaminoethyl) -N-alkylcarbamoyl groups (to form carbamates), dialkylaminoacetyl and carboxyacetyl groups. The present invention includes all such esters.

Furthermore, the present invention includes all possible crystal forms or polymorphs of the compounds of the present invention, either as a single polymorph or as a mixture of more than one polymorph in any ratio.

According to a second aspect, the present invention comprises a compound of formula (I) as described above, 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)(R^5’)；

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);

R³is 1R⁸Radical substituted C₁-C₆-an alkyl group;

R⁴is a hydroxyl group;

R^4’is a hydrogen atom or C₁-C₆-an alkyl group;

R⁵and R^5’Identical or different and independently of one another are a hydrogen atom, or C₁-C₆Alkyl radical, C₃-C₆-cycloalkyl-C₁-C₆Alkyl, aryl-C₁-C₆-alkyl or C₁-C₆-alkoxy-C₁-C₆-alkyl radicals, wherein the radicals are substituted in the same or different manner by R⁶One or more substitutions;

or

R⁶each occurrence of (a) may be the same or different and is independently a hydrogen atom, a methyl group;

R⁷and R^7’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;

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

According to a third aspect, the present invention comprises a compound of formula (I) as described above, 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)(R^5’)；

R²Represents a heteroaryl group having the structure:

wherein:

R³is 1R⁸Radical substituted C₁-C₆-an alkyl group;

R⁴is a hydroxyl group;

R^4’is a hydrogen atom or C₁-C₆-an alkyl group;

R⁵and R^5’Together with the nitrogen atom to which they are bound represent a 3-to 8-membered nitrogen-containing heterocyclic ring, said 3-to 8-membered nitrogen-containing heterocyclic ring containing one oxygen atom and optionally substituted by 1 or more R^6’Substituted by groups;

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

According to a fourth aspect, the present invention comprises a compound of formula (I) as described above, 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)(R^5’)；

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

x represents N or C-R⁶；

R³Is 1R⁸Radical substituted C₁-C₆-an alkyl group;

R⁴is a hydroxyl group;

R^4’is a hydrogen atom or C₁-C₆-an alkyl group;

or

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

According to a fifth aspect, the present invention comprises a compound of formula (I) as described above, 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)(R^5’)；

R²Represents a heteroaryl group having the structure:

wherein:

x represents N or C-R⁶；

R³Is 1R⁸Radical substituted C₁-C₆-an alkyl group;

R⁴is a hydroxyl group;

R^4’represents a hydrogen atom or C₁-C₆-an alkyl group;

R⁵and R^5’Are connected with themThe combined nitrogen atoms together represent a 3-to 8-membered nitrogen-containing heterocyclic ring, said 3-to 8-membered nitrogen-containing heterocyclic ring containing one oxygen atom and optionally substituted by 1 or more R^6’Substituted by groups;

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

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

R¹Is represented by- (CH)₂)_n-(CR⁴(R^4’))-(CH₂)_m-N(R⁵)(R^5’)；

wherein:

x represents N or C-R⁶，

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

R³Is 1R⁸Radical substituted C₁-C₆-an alkyl group;

R⁴Is a hydroxyl group;

R^4’Is a hydrogen atom or C₁-C₆-an alkyl group;

R⁵Is a hydrogen atom, C₁-C₆Alkyl radical, C₃-C₆-cycloalkyl-C₁-C₆Alkyl, aryl-C₁-C₆-alkyl or C₁-C₆-alkoxy-C₁-C₆-alkyl, wherein said aryl-C₁-C₆Alkyl is substituted in the same or different manner by R⁶One or more substitutions;

or

n is an integer 1 and m is an integer 1;

R²Represents a heteroaryl group having the structure:

wherein:

or

R⁵And R^5’Together with the nitrogen atom to which they are bound represent a 3-to 8-membered nitrogen-containing heterocyclic ring, said 3-to 8-membered nitrogen-containing heterocyclic ring comprising one oxygen atom and optionally substituted by 1 or more R^6’Substituted by groups;

R²Represents a heteroaryl group having the structure:

wherein:

x represents N or C-R⁶；

R³Is 1R⁸Radical substituted C₁-C₆-an alkyl group;

it is to be understood that the present invention relates to any subcombination within the scope of any embodiment of the invention of a compound of formula (I) above.

In yet another aspect, the invention includes compounds of formula (I) disclosed in the examples section below.

According to another aspect, the invention includes a method of making a compound of the invention, said method comprising the steps as described herein.

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

wherein R is¹And R³As defined above for formula (I).

According to a further aspect, the present invention comprises the use of an intermediate compound of formula (XI) as described above for the preparation of a compound of the invention of formula (I) as described above.

Experimental part

General preparation method

The particular method used to prepare the compounds used in this embodiment of the invention depends on the particular compound desired. Such factors as the choice of a particular substituent play a role in the pathway followed in the preparation of a particular compound of the invention. Those factors are readily 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 synthetic methods are provided to assist the reader in synthesizing the compounds of the invention, and more detailed specific examples are provided in the experimental section below describing the examples.

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

Synthetic transformations which may be employed in the synthesis of the compounds of the present invention, as well as in the synthesis of intermediates involved in the synthesis of the compounds of the present invention, are known or available to those skilled in the art. A summary of synthetic transformations can be found in the following editorial tables, for example:

march, advanced Organic Chemistry, 4 th edition, John Wiley: New York (1992)

R.C.Larock.comprehensive Organic Transformations, 2 nd edition, Wiley-VCH: New York (1999)

Carey, R.J.Sundberg.advanced Organic Chemistry, 2 nd edition, plenum Press: New York (1984)

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

L.S.Hegedus.Transmission Metals in the Synthesis of Complex organic molecules, 2 nd edition; University Science Books: Mill Valley, CA (1994)

L.A.Paquette,Ed.The Encyclopedia of Reagents for Organic Synthesis;John Wiley:New York(1994)

A.R.Katritzky;O.Meth-Cohn;C.W.Rees,Eds.Comprehensive OrganicFunctional Group Transformations;Pergamon Press:Oxford,UK(1995)

G.Wilkinson;F.G A.Stone;E.W.Abel,Eds.ComprehensiveOrganometallic Chemistry;Pergamon Press:Oxford,UK(1982)

B.M.Trost;I.Fleming.Comprehensive Organic Synthesis;Pergamon Press:Oxford,UK(1991)

A.R.Katritzky;C.W.Rees Eds.Comprehensive Heterocylic Chemistry;Pergamon Press:Oxford,UK(1984)

A.R.Katritzky;C.W.Rees;E.F.V.Scriven,Eds.ComprehensiveHeterocylic Chemistry II;Pergamon Press:Oxford,UK(1996)

C.Hansch;P.G.Sammes;J.B.Taylor,Eds.Comprehensive MedicinalChemistry:Pergamon Press:Oxford,UK(1990)。

In addition, a periodic review of The synthetic methods and related subject matter includes Organic Reactions, John Wiley: New York, Organic Synthesis, John Wiley: New York, Reagents for Organic Synthesis, John Wiley: New York, The Total Synthesis of Natural products, John Wiley: New York, The Organic Chemistry of Drug Synthesis, John Wiley: New York, Annual Reports in Organic Synthesis, Academic Press: San Diego CA, and Methoden der Organic Chemistry (Houben-Weyl), Thieme: Stuttgart, Germany. In addition, databases of synthetic transformations include Chemical Abstracts, which can be retrieved using CAS OnLine or SciFinder, Handbuch der Organischen Chemie (Beilstein), which can be retrieved using SpotFire and REACCS.

In the following, "PG" refers to a suitable protecting group, as known to those skilled in the art, for example, from T.W.Greene, P.G.M.Wuts.protective Groups in Organic Synthesis,3rd ed., John Wiley: New York (1999).

In scheme 1, vanillyl acetate may be converted to intermediate (III) by nitration conditions such as pure fuming nitric acid or nitric acid in the presence of another strong acid such as sulfuric acid. Hydrolysis of the acetate ester in intermediate (III) can be expected in the presence of a base such as sodium hydroxide, lithium hydroxide or potassium hydroxide in a protic solvent such as methanol. Protection of Intermediate (IV) for the production of compounds of formula (V) can be achieved by standard methods (Greene, T.W.; Wuts, P.G.M.; Protective group in Organic Synthesis; Wiley & Sons: New York,1999) (PG = protecting group well known to those skilled in the art). The conversion of the compound of formula (V) to the compound of formula (VI) can be achieved with ammonia in the presence of iodine, an aprotic solvent such as THF or dioxane. Reduction of the nitro group in formula (VI) can be achieved 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) is optimally achieved with ethylenediamine and heating in the presence of a catalyst such as elemental sulfur. The cyclisation of the compound of formula (VIII) to the compound of formula (IX) is effected using cyanogen bromide in the presence of an amine base such as triethylamine, diisopropylethylamine or pyridine in a halogenated solvent such as DCM or dichloroethane. The removal of the protecting group of formula (IX) depends on the group chosen and can be achieved by standard methods (Greene, T.W.; Wuts, P.G.M.; Protective Groups in Organic Synthesis; Wiley & Sons: New York, 1999). Alkylation of the phenol of formula (X) can be achieved in a polar aprotic solvent such as DMF or DMSO using a base such as cesium carbonate, sodium hydride or potassium tert-butoxide, and introducing a side chain carrying a suitable leaving group such as a halogen or sulfonate group, to provide the compound of formula (XI). Finally, amides of formula (I) can be formed in polar aprotic solvents using activated esters such as acid chlorides and anhydrides, or using carboxylic acids and suitable coupling agents such as PYBOP, DCC or EDCI.

In scheme 2, the compound of formula (IV) prepared above can be converted to the structure of formula (XII) using ammonia in the presence of iodine in an aprotic solvent such as THF or dioxane. Alkylation of the phenol of formula (XII) can be achieved in a polar aprotic solvent such as DMF or DMSO using a base such as cesium carbonate, sodium hydride or potassium tert-butoxide and introducing a side chain carrying a suitable leaving group such as a halogen or sulfonate group. Reduction of the nitro group in formula (XIII) can be achieved 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) is optimally achieved with diethylamine and heating in the presence of a catalyst such as elemental sulfur. The cyclisation of the compound of formula (XV) to the compound of formula (XVI) is effected using cyanogen bromide in the presence of an amine base such as triethylamine, diisopropylethylamine or pyridine in a halogenated solvent such as DCM or dichloroethane. Finally, amides of formula (I) can be formed in polar aprotic solvents using activated esters such as acid chlorides and anhydrides, or using carboxylic acids and suitable coupling agents such as PYBOP, DCC or EDCI.

In scheme 3, the compound of formula (X) prepared above can be converted to the amide (XVI) using activated esters such as acid chlorides and anhydrides in polar aprotic solvents, or the amide (XVI) can be formed using a carboxylic acid and a suitable coupling agent such as PYBOP, DCC or EDCI. The above amide (XVI) can then be converted to a compound of formula (I) in a polar aprotic solvent such as DMF or DMSO using a base such as cesium carbonate, sodium hydride or potassium tert-butoxide, and introducing a side chain carrying a suitable leaving group such as a halogen or sulfonate group.

In scheme 4, a compound of formula (IX) prepared as described above can be converted to the amide (XVII) in a polar aprotic solvent using activated esters such as acid chlorides and anhydrides, or the amide (XVII) can be formed using a carboxylic acid and a suitable coupling agent such as PYBOP, DCC or EDCI. 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 in Organic Synthesis; Wiley & Sons: New York, 1999). Alkylation of the phenol of formula (XVI) can be achieved in a polar aprotic solvent such as DMF or DMSO using a base such as cesium carbonate, sodium hydride or potassium tert-butoxide, and introducing a side chain carrying a suitable leaving group such as a halogen or sulfonate group.

In scheme 5, chlorination can be utilized in aprotic solventsAgents such as POCl₃Or COCl₂The compound of formula XVIII is converted to the dichloro compound of formula XIX. Thus, it can be prepared by reaction with an appropriate amount of ethanolamine or an appropriately protected substituent, followed by reaction with an appropriate activating agent such as sulfonyl chloride, PPh₃Or halogenating agents, e.g. SOCl₂Thereby converting the chloride obtained into the imidazoline of formula XXI. Chloride XXI can be converted to amine XXII by using any source of nucleophilic amine such as ammonia, phthalimide, or protected amine such as benzylamine in a polar solvent such as DMF or DMSO. Formation of the phenol shown in formula X can be achieved by deprotecting the methyl ester using any of the conditions outlined in the literature (Greene, T.W.; Wuts, P.G.M.; Protective Groups in Organic Synthesis; Wiley's corporation; Wiley's et al)&Sons:New York,1999)。

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

Abbreviations and acronyms

A comprehensive list of abbreviations used by technicians in ordinary Organic Chemistry in The field is available in The Guide of The ACS Style Guide (third edition) or The author of Journal of Organic Chemistry. The list includes abbreviations and all abbreviations used by those of ordinary skill in the art are incorporated herein by reference. For the purposes of the present invention, chemical elements are identified according to the periodic Table of the elements, CAS edition, 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/water-containing

Ar aryl radical

atm atmosphere

9-BBN 9-borabicyclo [3.3.1] nonyl

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

Bn benzyl group

bp boiling point

br s wide singlet

Bz benzoyl

BOC tert-butoxycarbonyl

n-BuOH n-butanol

t-BuOH tert-butanol

t-BuOK Potassium tert-butoxide

C degree centigrade

calcd calculated

CAN ammonium ceric nitrate

Cbz benzyloxycarbonyl (carbobenzozyloxy)

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

¹³C NMR carbon-13 nuclear magnetic resonance

m-CPBA m-chloroperoxybenzoic acid

d double peak

dd doublet of doublets

DABCO 1, 4-diazabicyclo [2.2.2] octane

DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene

DCC N, N' -dicyclohexylcarbodiimide

DCM dichloromethane

DEAD azodicarboxylic acid diethyl ester

dec decomposition

DIA diisopropylamine

DIBAL diisobutyl aluminum hydride

DMAP 4- (N, N-dimethylamino) pyridine

DME 1, 2-dimethoxyethane

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

Model E E (entgegen) (configuration)

EDCl or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, or

EDCI HCl 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

ee enantiomeric excess

Electron bombardment by EI

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

¹H NMR proton nuclear magnetic resonance

HMPA hexamethylphosphoramide

HMPT hexamethylphosphoric triamide

HOBT hydroxybenzotriazole

HPLC high performance liquid chromatography

insoluble in instol

IPA isopropyl amine

iPrOH Isopropanol

Of IR infrared

J coupling constant (NMR spectroscopy)

L liter

LAH lithium aluminum hydride

LC liquid chromatography

LC-MS liquid chromatography-mass spectrometry

LDA lithium diisopropylamide

M mol L^-1(mole)

m multiplet

m is between

MeCN acetonitrile

MeOH methanol

MHz megahertz

min for

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(equivalent (normal))

NBS N-bromosuccinimide

nM nanomolar

NMM 4-methylmorpholine

NMR nuclear magnetic resonance

o is adjacent to

observed by obsd

p pairs

p pages

pp page

PdCl₂dppf [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (II)

Pd(OAc)₂Palladium acetate

Negative logarithm of pH hydrogen ion concentration

Ph phenyl

Negative logarithm of pK equilibrium constant

Negative logarithm of pKa association equilibrium constant

PPA polyphosphoric acid

PS-DIEA polystyrene-bound diisopropylethylamine

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

q quartet peak

rac is racemic

R right (configuration)

rel means a compound in which one chiral center is undefined, said chiral center being present in the presence of one or more other defined chiral centers

R_fRetardation 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 (triflyl)

TFA trifluoroacetic acid

TFFH Fluoro-N, N, N ', N' -tetramethylformamidine hexafluorophosphate (Fluoro-N, N, N ', N' -tetramethylformamidinium hexa-fluorophosphate)

TLC thin layer chromatography

TMAD N, N, N ', N' -Tetramethylethylenediamine

TMSCl trimethylchlorosilane

Ts p-toluenesulfonyl group

v/v volume/volume ratio

w/v weight/volume ratio

w/w weight/weight ratio

Z Z type (configuration)

Description of the specific experiments

Analytical HPLC-MS conditions:

the HPLC-MS-data given in the detailed experimental description that follows relate to the following conditions:

the method comprises the following steps: 99% of 0.1% aqueous formic acid solution 1% of CH₃CN to 1% of 0.1% formic acid aqueous solution 99% CH₃CN, within 1.6 minutes; 1%0.1% aqueous formic acid solution 99% CH₃CN, within 1.6 minutes; for 0.4 min.

The method 2 comprises the following steps: 99% of 0.2% ammonia water and 1% of CH₃CN to 1% of 0.1% ammonia water and 99% of CH₃CN, within 1.6 minutes; 1% of 0.1% ammonia water and 99% of CH₃CN, within 1.6 minutes; for 0.4 min.

Unless otherwise indicated, analytical HPLC utilized method 2.

Preparative HPLC conditions:

unless otherwise stated, "purification by preparative HPLC" in the following description of the specific experiments refers to the following conditions:

and (3) analysis:

preparation:

chiral HPLC conditions:

the chiral HPLC-data given in the following detailed experimental description relate to the following conditions:

and (3) analysis:

system for controlling a power supply	Dionex:Pump680,ASI100,Waters:UV-Detektor2487
		Column:	Chiralpak IC5μm150x4.6mm
solvent:	hexane/ethanol 80:20+0.1% diethylamine
		Flow rate:	1.0mL/min
temperature:	25°C
		solution:	1.0mg/mL EtOH/MeOH1:1
injecting:	5.0μl
		and (3) detection:	UV280nm

preparation:

preparation of MPLC:

preparative Medium Pressure Liquid Chromatography (MPLC) is performed by standard silica gel "Flash chromatography" techniques (e.g., Still et al, 1978) or by using a silica gel column and a device such as a Flashmaster or Biotage Flash system.

Unless otherwise indicated, use of a Flash NH equipped with Isolute₂Flash Master II chromatograph on reverse phase column with mixed solvent gradient (100% CH) at flow rate recommended for column size (i.e. 5g column, 10mL/min.;50g column, 30mL/min.)₂Cl₂Last 3min, 90% CH within 12 min₂Cl₂A gradient of 10% MeOH; 20min. 80% CH₂Cl₂A gradient of 20% MeOH; 10min. 70% CH₂Cl₂A gradient of 30% MeOH; and 50% CH within 15min₂Cl₂Gradient of 50% MeOH) was eluted, thereby MPLC purification was performed. The eluate was monitored with a UV detector at 254 nm.

Optical rotation measurement conditions:

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

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

NMR

NMR spectra were obtained for each compound, consistent with the structures shown.

At 300MHz or 400MHzConventional one-dimensional NMR spectroscopy was performed on a Mercury-plus spectrometer.The sample was dissolved in deuterated solvents. Chemical shifts are recorded in ppm measurements and compared to appropriate solvent signals, e.g. for¹H spectrum, DMSO-d₆2.49ppm, CD₃CN 1.93ppm, CD₃OD 3.30ppm, CD₂Cl₂5.32ppm, and CDCl₃It was 7.26 ppm.

The percent yields reported in the following examples are based on the starting component used in the lowest molar amount. Air and moisture sensitive liquids and solutions were transferred through syringes or cannulae and introduced into the reaction vessel through rubber septa. Commercial grade reagents and solvents were used without further purification. The term "concentration under reduced pressure" means that a Buchi rotary evaporator is used at about 15mm Hg. All temperatures are reported uncorrected in degrees celsius (° C).

Thin-film chromatography (TLC) was carried out on pre-coated glass chromatography silica gel 60A F-254250 μm plates.

Biotage optionally equipped with an automated unit (robotic unit) was usedThe microwave oven performs a reaction using microwave radiation. The reported reaction time with microwave heating is intended to be understood as a fixed reaction time after the reaction temperature in question has been reached.

The percent yields reported in the following examples are based on the starting component used in the lowest molar amount. Air and moisture sensitive liquids and solutions were transferred through syringes or cannulae and introduced into the reaction vessel through rubber septa. Commercial grade reagents and solvents were used without further purification. The term "vacuum concentration" means that a Buchi rotary evaporator is used at a minimum pressure of about 15mm Hg. All temperatures are reported uncorrected in degrees celsius (° C).

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

Intermediate synthesisBecome into

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).

Sodium (1Z) -2- (dimethoxymethyl) -3-methoxy-3-oxoprop-1-en-1-oate (1.37g,7.8mmol) was dissolved in DMF (12mL) and guanidine hydrochloride (640mg,6.7mmol) was added. The mixture was stirred at 100 ℃ for 1 hour, then cooled to room temperature 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)δ:8.67(s,2H),7.56(br s,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 1M HCl. 2-aminopyrimidine-5-carboxylic acid precipitated as a white solid, which was isolated by vacuum filtration (244mg,90%):¹H NMR(DMSO-d₆)δ:12.73(1H,br s),8.63(2H,s),7.44(2H,br s)。

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 3 hours, during which time a precipitate formed. Cool to room temperature, then separate the precipitate by vacuum filtration, wash with ether, and discard the solid. Acidification of the mother liquor with HCl (4M in dioxane, 72mL,0.29mol) resulted in precipitation of the desired product as HCl salt. The solvent was removed under reduced pressure and the resulting solid was dried to give the title compound (53g,90%):¹H NMR(DMSO-d₆)δ:11.45(1H,br s),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 (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 obtain the desired product (1.1g,96%) used without further purification.

Intermediate C

4- [ (2-oxo-1, 3, 2-dioxathiolan-4-yl) methyl]Preparation of morpholine hydrochloride

3-Morpholin-4-ylpropane-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 temperatureFor 1 hour. The reaction mixture was then concentrated under reduced pressure to obtain a solid (2.5g,97%):¹H NMR(DMSO-d₆)δ:11.4(1H,br s),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,br s)。

intermediate D

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

Step 1 preparation of 4-formyl-2-methoxy-3-nitrophenylacetate

Fuming nitric acid (2200mL) was cooled to 0 ℃ under nitrogen, during which time vanillyl acetate (528g,2.7mol) was added in portions, maintaining the internal temperature below 10 ℃. After 2 hours, the resulting mixture was poured onto ice with stirring. The slurry was filtered and the resulting solid was washed three times with water (3x100mL) 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 hexane (500mL) and air dried to give 4-formyl-2-methoxy-3-nitrophenyl acetate (269g,41%):¹H NMR,(DMSOδ: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

4-formyl-2-methoxy-3-nitrophenylethylA mixture of the acid ester (438g,1.8mol) 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 solution (2N) and extracted with EtOAc. The organic layer was washed with saturated sodium chloride solution, dried (magnesium sulfate) and filtered. The solution was concentrated under reduced pressure to a volume of 1/3 and the resulting solid was filtered and air dried to give 4-hydroxy-3-methoxy-2-nitrobenzaldehyde (317g,88%):¹H NMR(DMSO9.69(1H,s),7.68(1H,d),7.19(1H,d),3.82(3H,s)。

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). After stirring for 16 h, the reaction mixture was concentrated under reduced pressure and separated 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. The resulting solid was used for Et₂O (1L) was triturated to give 4- (benzyloxy) -3-methoxy-2-nitrobenzaldehyde (220g,97%):¹H NMR(DMSOδ: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)。

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

To a mixture of 4- (benzyloxy) -3-methoxy-2-nitrobenzaldehyde (220g,766mmol) and ammonium hydroxide (28% solution, 3L) dissolved in THF (5L) was added iodine (272g,1.1 mmol). After 16 hours, the reaction mixture was treated with sodium sulfite (49g,383mmol) and concentrated under reduced pressure to give a thick slurry. The slurry was filtered, washed with water (250mL) and dried to give 4- (benzyloxy) -3-methoxy-2-nitrobenzonitrile (206g,95%) as a solid:¹H NMR(DMSO7.89(1H,d),7.59(1H,d),7.49(2H,m),7.40(3H,m),5.35(2H,s),3.91(3H,s)。

step 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, 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, after which 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 (145g,88%) as a solid:¹H NMR(DMSOδ: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: 3- (benzyloxy group) Preparation of (E) -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 30 min and then heated to 100 ℃. After 16 hours, 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%):¹H NMR(DMSOδ: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 16 hours, the reaction mixture was diluted with saturated sodium bicarbonate solution and with CH₂Cl₂And (4) extracting. The organic layer was washed three times with saturated sodium 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 (1)30g, with triethylamine salt contamination):¹H NMR(DMSO7.30-7.48(7H,m),5.31(2H,s),4.32(2H,m),4.13(2H,m),3.81(3H,s)。

intermediate E

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

3- (benzyloxy) -6- (4, 5-dihydro-1H-imidazol-2-yl) -2-methoxyaniline (30g,93mmol) was added portionwise over 1 hour to a round-bottomed flask containing TFA (400mL) pre-cooled with an ice bath. The reaction mixture was heated to 60 ℃ and allowed to stir at this temperature for 17 hours, during which time it was cooled to room temperature 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 at low heat overnight to give 5-amino-7-methoxy-2, 3-dihydroimidazo [1,2-c]Quinazolin-8-ol bis (trifluoroacetate) (44.7g,>100%):¹H NMR(DMSO-d₆)δ:7.61(1H,m),6.87(1H,m),4.15(2H,br t),4.00(2H,m),3.64(3H,s)。

intermediate F

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

Step 1: preparation of (R) -glycidyl methanesulfonate

A solution of (S) - (-) -glycidol (8.6mL,130mmol) and triethylamine (36.2mL,260mmol,2.0equiv.) in DMF (250mL) was cooled on an ice bath and methanesulfonyl chloride (10.1mL,130mmol,1.0equiv.) was added dropwise. The mixture was stirred at room temperature for 1.5 hours to give 0.47M 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 ]]To a solution of quinazolin-8-ol bis (trifluoroacetate) (intermediate E, 0.30g,0.65mmol) in DMF (8mL) was added cesium carbonate, resulting in a white suspension. The suspension was stirred at room temperature for 1.5 hours, then (R) -glycidyl methanesulfonate (intermediate F, step 1, 3.9mL of 0.34M DMF solution, 1.30mmol, 2.0equiv.) was added and the resulting solution was stirred at 60 ℃ for 20 hours. The resulting suspension was concentrated under reduced pressure, and the residue was taken up in saturated sodium bicarbonate solution (30mL) and 4:1CH₂Cl₂Treated between isopropanol solutions (30mL) and separated. The aqueous phase is treated with 4:1CH₂Cl₂Extraction with isopropanol solution (30 mL). The combined organic phases were dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was washed with MPLC (Isolute FlashNH)₂A reversed phase column; 100% CH₂Cl₂Last for 5min, 95% CH within 15min₂Cl₂A gradient of 5% MeOH; 90% CH within 15min₂Cl₂A gradient of 10% MeOH; 15min, inner 80% CH₂Cl₂A gradient of 20% MeOH; and 75% CH within 15min₂Cl₂Gradient of 25% MeOH) to give 7-methoxy-8- [ (2R) -oxiran-2-ylmethoxy]-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-amine (0.080g,43%):¹H NMR(DMSO-d₆+1 drop TFA-d)(dd,J=2.5,4.8Hz,1H),2.85,(t,J=4.6Hz,1H),3.34-3.40(br m,1H),3.75(s,3H),3.82(s,3H),4.30(dd,J=6.6,11.4Hz,1H),4.10(br t,J=9.7Hz,2H),4.31(br t,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

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

Step 1: preparation of racemic glycidyl methanesulfonate

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

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

Intermediate G was synthesized in a similar manner to intermediate F, step 2, substituting racemic glycidyl methanesulfonate for (R) -glycidyl methanesulfonate (0.30G,24%) with HPLC retention time 0.62min.;¹H NMR(DMSO-d₆+1 drop TFA-d)(dd,J=2.5,4.8Hz,1H),2.85,(t,J=4.6Hz,1H),3.34-3.40(br m,1H),4.30(dd,J=6.6,11.4Hz,1H),4.10(br t,J=9.7Hz,2H),4.31(br t,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

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

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. It was used for further transformations without further purification as a DMF solution of (S) -glycidyl methanesulfonate.

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

Intermediate G was synthesized in a similar manner to intermediate F, step 2, substituting (S) -glycidyl methanesulfonate for (R) -glycidyl methanesulfonate (0.14G,15%) with HPLC retention time 0.62min.;¹H NMR(DMSO-d₆+1 drop TFA-d)(dd,J=2.5,4.8Hz,1H),2.85,(t,J=4.6Hz,1H),3.34-3.40(br m,1H),4.30(dd,J=6.6,11.4Hz,1H),4.10(br t,J=9.7Hz,2H),4.31(br t,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

Preparation of N- [ 7-methoxy-8- (oxiran-2-ylmethoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] 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 ]]To 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 ambient temperature with the aid of an overhead stirrer for 3 days. The resulting precipitate was isolated by vacuum filtration, washed repeatedly with EtOAc, and dried under vacuum with slight heating to give N- [8- (benzyloxy) -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl]Nicotinamide (27.3g,98%):¹H NMR(DMSO-d₆+2 drops of TFA-d) Δ 9.32(1H, s),8.89(1H, br M),8.84(1H, d),7.89(1H, br M),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

Within 1 hour, N- [8- (benzyloxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c ] is added]Quinazolin-5-yl]Nicotinamide (20g,45.1mmol) was added portionwise to a round bottom flask containing TFA (400mL) pre-cooled with an ice bath. The reaction mixture was heated to 60 ℃ and allowed to stir at this temperature for 17 hours, during which time it was cooled to room temperature. Then, the reaction mixture was concentrated under reduced pressure. Dissolving the residue in CH₂Cl₂And hexane, and concentrated under reduced pressure. The material thus obtained was dissolved in MeOH and CH₂Cl₂The solution (250mL,1:1) was concentrated under reduced pressure. The resulting solid was dried under vacuum at low heat overnight to give N- (8-hydroxy-7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) nicotinamide (17.3g,66%):¹H NMR(DMSO-d₆+2 drops of TFA-d) Δ 13.41(1H, s),12.21(1H, br s),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,6.0equiv.) in DMF (12.5mL) was stirred at room temperature for 1 hour, then treated with racemic epichlorohydrin (0.29mL,3.75mmol,2.5equiv.) and the resulting mixture stirred at room temperature for 16 hours. 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

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

Mixing N- {8-hydroxy-7-methoxy-2, 3-dihydroimidazo [1,2-c]A mixture of quinazolin-5-yl } pyridine-3-carboxamide (intermediate I, step 2 (used as bis-TFA salt), 1.50g,2.65mmol) and cesium carbonate (4.32g,13.3mmol,5.0equiv.) in DMF (37mL) was stirred at room temperature for 1 hour, then treated with (R) -glycidyl methanesulfonate (intermediate F, step 1, 21.2mL,0.25M solution in DMF, 5.31mmol,2.0 equiv.). The resulting mixture was stirred at 60 ℃ for 16 hours at room temperature, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (50mL) and 4:1CH₂Cl₂The mixture was separated from the isopropanol solution (50 mL). 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 dried under reduced pressure to give N- { 7-methoxy-8- [ (2R) -oxiran-2-ylmethoxy group]-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl } nicotinamide (0.72g,69%): HPLC retention time 0.94min.;¹H NMR(DMSO-d₆+1 drop TFA-d)(dd, J =2.5,5.1Hz,1H),2.88(app t, 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(br d, J =7.8Hz,1H),8.97(dd, J =1.5,5.6, 1H),9.49(d = 1H) ((M, 1Hz,1H) ((br d, J =7.8Hz, 1H); M1H)⁺,11%)。

Examples

Comparative example 1 (from WO 2008/070150):

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

To N- (8-hydroxy-7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) nicotinamide bistrifluoroacetate (1.0g,1.88mmol) suspension in DMF (40mL) was added cesium carbonate (3g,9.37mmol) and stirred for 1.5h, then 4- [ (2-oxo-1, 3, 2-dioxathiolan-4-yl) methyl]Morpholine hydrochloride (intermediate C,0.39g,1.88 mmol). After 3 hours, 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 a solution of 20% isopropanol/80% chloroform and washed with a saturated solution of sodium bicarbonate. The organics were dried (magnesium sulfate) and concentrated under reduced pressure, and the resulting residue was triturated with EtOAc and filtered. The solid was then passed through HPLC (Gilson,5% MeOH/95% H)₂O to 50% MeOH/50% H₂Gradient of O, 0.1% NH₄OH) to obtain N- {8- [ 2-hydroxy-3- (morpholin-4-yl) propoxy ] group]-7-methoxy-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl } pyridine-3-carboxamide (160mg,18%): HPLC MS RT =0.19 min;¹H NMR(DMSO-d₆+1 drop TFA-d) Δ 13.40-13.38(1H, br s),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, br s),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)⁺)。

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,2.5equiv.) in anhydrous ethanol was heated in a microwave at 1400 ℃ for 4 minutes, cooled to room temperature and concentrated at 70 ℃ under 12mbar vacuum to give (2R) -3- (4-morpholinyl) -1, 2-propanediol (2.47g,102%):¹H NMR(CDCl₃)(dd J=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: preparation of 4- [ (4R) - (2-oxo-1, 3, 2-dioxathiolan-4-yl) methyl ] 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,2.0equiv.) was added dropwise thereto. The resulting solution was heated at reflux temperature for 1 hour, cooled to room temperature and concentrated 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)]To a solution of quinazolin-5-yl) nicotinamide bis-TFA salt (intermediate I, step 2, 0.750g,1.3mmol) in DMF (50mL) was added cesium carbonate (1.30g,3.9mmol,3.0equiv.), and the resulting slurry was stirred at room temperature for 1.5 hours, then cyclic sulfite (0.275g,1.3mmol,1.0equiv) was added. The mixture was stirred at 60 ℃ for 12 hours, cooled to room temperature, treated with additional cesium carbonate (0.86g,2.6mmol,2.0equiv.) and cyclic sulfite (0.275g,1.3mmol,1.0equiv.), and stirred at 60 ℃ for an additional 12 hours. The resulting 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 (1.77g) was purified by preparative HPLC 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)₂Cl₂/MeOH+1%NH₄MeOH solution of OH) R_f0.35, preparative HPLC (condition A) retention time 3.70 min;¹H NMR(DMSO-d₆+1 drop TFA-d)(M,4H),3.47(br D, 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(br s,1H),4.57(app t, 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(br D, J =7.7Hz,1H),8.99(D, J =5.2Hz,1H),9.50(D, J =1.1Hz,1H mass spectrum) ((M + 1z 481)⁺,11%)。

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,1.5equiv.) in anhydrous ethanol was heated in a microwave at 1400 ℃ for 4 minutes, cooled to room temperature and concentrated under 12mBar vacuum at 70 ℃ to give (2S) -3- (4-morpholinyl) -1, 2-propanediol (0.91g,113%):¹H NMR(CDCl3)δ2.37(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: preparation of 4- [ (4S) - (2-oxo-1, 3, 2-dioxathiolan-4-yl) methyl ] 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,2.0equiv.) was added dropwise thereto. 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 bis-TFA salt (intermediate I, step 2, 0.210g,0.37mmol) in DMF (12mL) with addition of Cs₂CO₃(0.61g,1.86mmol,5.0equiv.) and the resulting slurry was stirred at room temperature for 1.5 hours before the addition of cyclic sulfite (0.092g,0.45mmol,1.2 equiv). Mixing the mixture inStirred at 60 ℃ for 12h, cooled to room temperature, treated with additional cesium carbonate (0.86g,2.6mmol,2.0equiv.) and cyclic sulfite (0.076g,0.37mmol,1.0equiv.), and stirred at 60 ℃ for an additional 3.5 days. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in 4:1CH₂Cl₂In isopropanol solution (50mL) and then with saturated NaHCO₃Washed (25mL) with saturated NaCl solution (25mL) and dried (anhydrous Na)₂SO₄) And concentrated under reduced pressure. Trituration with MeOH yielded 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)₂Cl₂/MeOH+1%NH₄MeOH solution of OH) R_f0.35, HPLC (condition A) retention time 4.29 min;¹H NMR(DMSO-d₆+1 drop TFA-d)(m,4H),3.48(br d,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(br s,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(br d,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,10equiv.) in DMF (36mL) was heated in two portions in a microwave reactor at 140 ℃ for 45 minutes. The resulting combined mixture was concentrated under reduced pressure and purified by MPLC to obtain 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 4.29 min;¹H NMR(DMSO-d₆+1 drop TFA-d)(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(app dd, 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) ((M + 1); 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,1.3equiv) in DMF (139mL) was treated with PyBOP (3.39g,6.51mmol,1.3equiv.) followed by N, N-diisopropylethylamine (3.50mL,20.0mmol,4.0equiv.) slowly forming a clear solution. The mixture was stirred at room temperature for 24 hours. The resulting solid was filtered and washed with DMF, H₂Washed with MeOH and then dried under reduced pressure at 60 ℃ 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)₂Cl₂/MeOH+1%NH₄MeOH solution of OH) R_f0.40;¹H NMR(DMSO-d₆+1 drop TFA-d)(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(br s,1H),4.61(app t, J =10.7Hz,2H),7.54(d, J =9.1Hz,1H),7.96(dd, J =5.7,7.6Hz,1H),8.09(d, J =9.1, 1H),8.92 (J = 9.92 Hz,1H), 7.7.7.6 Hz,1H, 507 Hz,1H, 507H, 1H, 507 Hz, 3.1H, 1H, 7.3.3.3.3.3H, 4.3.3H, 4.3H, 4.7.4.4 (M,4H), 4H, 4.09 (d^-,100%),509((M+1)⁺,24%)。

Example 5

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

In a microwave reactor, adding N- [ 7-methoxy-8- (ethylene oxide-2-methoxy) -2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl]A mixture of nicotinamide (intermediate I, 7.6mL of 0.120M DMF, 0.92mmol) and thiomorpholine (0.46mL,4.60mmol,5.0equiv.) was heated 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). The resulting solution was taken up in saturated NaHCO₃The solution (25mL) was washed and dried (anhydrous Na)₂SO₄) And concentrated under reduced pressure. The resulting residue was purified with MPLC to obtain an impure product (128mg), which was further purified by 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 0.61 min;¹H NMR(DMSO-d₆+1 drop TFA-d)(M,3H),3.05-3.44(M,4H),4.02(s,3H),4.19-4.28(M,4H),4.43(br s,1H),4.55(br app t, 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(br d, J =7.8Hz,1H),8.89(dd, J =1.5,5.1Hz,1H),9.43(br s,1H), mass spectrum M/z507((M-1)^-,100%),509((M+1)⁺,24%)。

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

Example 6

N- (8- { [ (2R) -3- (diprop-2-ylamino) -2-hydroxypropyl]Oxy } -7-methoxy-2, 3-dihydroimidazole Azolo [1,2-c ] s]Quinazolin-5-yl) pyridine-3-carboxamides

In step 1, preparation was performed with diisopropylamine instead of thiomorpholine and intermediate J instead of intermediate I (22.0mg,16%) with HPLC retention time 1.29 min;¹H NMR(DMSO-d₆+1 drop TFA-d)(M,12H),3.14-3.21(M,1H),3.35(br d, 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(br d, J =8.1Hz,1H),8.97(dd, J =1.5,5.3Hz,1H),9.49, (d, J =1.5Hz,1H) ((M + 1); Mass Spectrum M/z 495)⁺,11%)。

Example 7

Preparation of N- (8- { [ (2R) -3- (diprop-2-ylamino) -2-hydroxypropyl ] oxy } -7- [2- (4-fluorophenyl) ethoxy ] -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) pyridine-3-carboxamide

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

Reacting N- (8- { [ (2R) -3- (diprop-2-ylamino) -2-hydroxypropyl]Oxy } -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]A solution of quinazolin-5-yl) pyridine-3-carboxamide (example 12, 0.244g,0.49mmol) in N-methylpyrrolidone (7mL) was warmed to 100 ℃ and Na was added portionwise₂S (0.19g,2.5mmol,5.0 equiv.). When Na is completed₂On addition of S, the reaction mixture was heated at 160 ℃ for 10 minutes, cooled to room temperature and concentrated under reduced pressure (0.3 mbar). The residue was treated with water (20mL) and the mixture was made slightly acidic with 0.1n hcl solution, and the resulting mixture was stirred at room temperature for 6 hours. The resulting solid was washed with water and dried under reduced pressure to give N- (8- { [ (2R) -3- (diprop-2-ylamino) -2-hydroxypropyl]Oxy } -7-hydroxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) pyridine-3-carboxamide (0.16g,65%):¹H NMR(DMSO-d₆+1 drop TFA-d)(m,12H),3.25(dd, J =8.6,11.9Hz,1H),3.39(br d, J =13.1,1H),3.61-3.73(m,2H),4.17-4.30(m,5H),4.53-4.60(m,2H),7.40(d, J =9.1Hz,1H),7.85(d, J =8.8Hz,1H),7.99(dd, J =5.3,7.8Hz,1H),8.95-9.01(m,2H),9.50(d,1.8Hz, 1H); mass Spectrometry M/z481((M +1)⁺,5.8%)。

Step 2: preparation of N- (8- { [ (2R) -3- (diprop-2-ylamino) -2-hydroxypropyl ] oxy } -7- [2- (4-fluorophenyl) ethoxy ] -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) pyridine-3-carboxamide

To N- (8- { [ (2R) -3- (diprop-2-ylamino) -2-hydroxypropyl group]Oxy } -7-hydroxy-2, 3-dihydroimidazo [1, 2-c)]To a suspension of quinazolin-5-yl) pyridine-3-carboxamide (0.16g,0.33mmol) in DMF (6.6mL) was added cesium carbonate (0.54g,1.67mmol,5.0equiv.), followed by 2- (4-fluorophenyl) ethyl bromide (0.093mL,0.67mmol,2.0 equiv.). The resulting golden yellow mixture was stirred at 50 ℃ for 16 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was taken up in water (25mL) and 4:1CH₂Cl₂The mixture was separated from the isopropanol solution (50 mL). The organic phase was washed with saturated sodium bicarbonate solution, dried (anhydrous sodium sulfate), and concentrated under reduced pressure. The residue was purified by MPLC to give N- (8- { [ (2R) -3- (diprop-2-ylamino) -2-hydroxypropyl]Oxy } -7- [2- (4-fluorophenyl) ethoxy]-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl) pyridine-3-carboxamide (0.10g,51%):¹H NMR(DMSO-d₆+1 drop TFA-d)(m,12H),3.07-3.14(m,2H),3.25(br d, J =12.0Hz,1H),3.65(sept, J =6.2Hz,2H),4.16-4.31(m,5H),4.48(t, J =7.2Hz,2H),4.52-4.61(m,2H),7.06(t, J =8.9Hz,2H),7.33(dd, J =5.5,8.5Hz,2H),7.47(d, J =9.2Hz,1H),7.92(dd, J =5.7,8.3Hz,1H),8.04(d, J =9.0Hz,1H),8.88(br d, J =8.1Hz,1H),8.96 (J = 5.1H), 1H, 8.47 (1H, 1H), 1 dm (1H); mass spectrum M/z601((M-1)^-,100%)。

The following examples were prepared in a similar manner to example 7.

Example 8

N- [8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl]-2-hydroxypropyl } oxy) -7- [2- (4- Fluorophenyl) ethoxy]-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl } pyridine-3-Carboxamides

Using 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 (Synthesis example 4) instead of N- (8- { [ (2R) -3- (diprop-2-ylamino) -2-hydroxypropyl in step 1]Oxy } -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) pyridine-3-carboxamide (synthetic example 6) was prepared (55.5mg,5%) with HPLC retention time 1.24 min;¹H NMR(DMSO-d₆+1 drop TFA-d)(d, J =6.0,3H),1.12(d, J =6.0Hz,3H),2.60-2.77(m,2H)3.09(t, J =7.2Hz,2H),3.16-3.30(m,2H),3.36-3.49(m,2H),3.80-3.96(m,2H),4.20-4.30(m,4H),4.38-4.47(m,1H),4.47-4.60(m,2H),7.05(t, J =8.9Hz,2H),7.32(dd, J =5.7,8.5Hz,2H),7.48(d, J =9.2Hz,1H),7.93(dd, J =5.3,6.4, 1H),8.02(d, J = 9.2H), 1.89.8H = 9H, 1H), 1.89.9H (d, 1H), 1H = 8.47 (d, 1H), 1H); mass spectrum M/z617((M +1)⁺,5.5%)。

Example 9

N- {7- [2- (4-fluorophenyl) ethoxy]-8- [ 2-hydroxy-3- (morpholin-4-yl) propoxy]-2, 3-dihydroimidazole Azolo [1,2-c ] s]Quinazolin-5-yl } pyridine-3-carboxamides

Using 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 (Synthesis example 4) instead of N- (8- { [ (2R) -3- (diprop-2-ylamino) in step 1-2-hydroxypropyl radical]Oxy } -7-methoxy-2, 3-dihydroimidazo [1, 2-c)]Quinazolin-5-yl) pyridine-3-carboxamide (synthesis example 6) was prepared (0.14g,45%):¹H NMR(DMSO-d₆+1 drop TFA-d)(t, J =6.7Hz,2H),3.15-3.37(m,4H),3.39-3,47(m,2H),3.63-3.83(m,2H),3.88-4.02(m,3H),4.20-4.30(m,4H),4.35-4.44(m,1H),4.47-4.60(m,2H),7.05(t, J =8.9Hz,2H),7.32(dd, J =5.7,8.5Hz,2H),7.48(d, J =9.2Hz,1H),7.93(dd, J =5.5,7.2Hz,1H),8.03(d, J =9.0Hz,1H),8.88(br d, J =7.5Hz,1H),8.98(d =6.0H, 1H), 1H (s, 47.47 Hz); mass Spectrometry M/z589((M +1)⁺,3.0%)。

Example 10

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

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

To 5-amino-7-methoxy-2, 3-dihydroimidazo [1,2-c ]]To a suspension of quinazolin-8-ol bis (trifluoroacetate) (intermediate E, 5.00g,10.9mmol) and cesium carbonate (17.7g,54.3mmol,5.0equiv.) in DMF (152mL) was added 2- (chloromethyl) -2-methyloxirane (2.32g,21.7mmol,2.0equiv.), and the resulting mixture was stirred at 60 ℃ for 16 h. The resulting suspension was concentrated under reduced pressure and the residue was taken up in water (100mL) and 4:1CH₂Cl₂In isopropanol solution (250mL)And (4) separating. The organic phase was washed with saturated sodium bicarbonate solution, dried (anhydrous sodium sulfate), and concentrated under reduced pressure. The residue was purified by MPLC to give 7-methoxy-8- [ (2-methyloxiran-2-yl) methoxy]-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-amine (2.18g,66%):¹H NMR(DMSO-d₆+1 drop TFA-d) δ 1.37(s,3H),3.79(s,3H),4.03-4.14(m,4H),4.26-4.39(m,4H),7.19(d, J =9.2Hz,1H),7.79(d, J =9.0Hz, 1H). .

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

In a microwave reactor, adding 7-methoxy-8- [ (2-methyloxirane-2-yl) methoxy]-2, 3-dihydroimidazo [1,2-c]A mixture of quinazolin-5-amine (0.54g,1.79mmol) and cis-2, 6-dimethylmorpholine (2.06g,17.9mmol,10equiv.) in DMF (16.2mL) was heated at 140 ℃ for 45 minutes, cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 4:1CH₂Cl₂In isopropanol solution (50mL), washed with saturated sodium bicarbonate solution, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by MPLC to give rel-N- [8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl]-2-hydroxy-2-methylpropyl } oxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl]Amine:¹H NMR(DMSO-d₆+1 drop TFA-d)(d,J=6.2Hz,3H),1.10(d,J=6.2Hz,3H),1.37(s,3H),2.78(app q,J=11.5Hz,2H),3.29(app q,J=9.6Hz,2H),3.51(d,J=12.6,1H),3.65(d,J=12.2Hz,1H),3.80(s,3H),3.87-3.98(br m,2H),4.06-4.15(m,4H),4.28-4.36(m,2H),7.22(d,J=9.2Hz,1H),7.82(d,J=9.2Hz,1H)。

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

Subjecting rel-N- [8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl]-2-hydroxy-2-methylpropyl } oxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl]A mixture of amine (0.40g,0.96mmol) and nicotinic acid (0.15g,1.25mmol,1.30equiv) in DMF (27mL) was treated with PyBOP (0.65g,125mmol,1.30mmol) followed by diisopropylethylamine (0.67mL,3.83mmol,4.0 equiv.). The resulting mixture was stirred at room temperature for 24 hours, and then concentrated under reduced pressure. The residue was taken up in water (500mL) and 4:1CH₂Cl₂The mixture was separated from the isopropanol solution (50 mL). The organic phase was washed with saturated sodium bicarbonate solution, dried (anhydrous sodium sulfate), and concentrated under reduced pressure. The residue was purified by MPLC to give rel-N- [8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl]-2-hydroxy-2-methylpropyl } oxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl]Pyridine-3-carboxamide (0.225g,45%):¹H NMR(DMSO-d₆+1 drop TFA-d) δ 1.09(d, J =6.0Hz,3H)1.12(d, J =6.0Hz,3H),1.41(s,3H),2.80(app q, J =12.8Hz,2H),3.25-3.38(m,2H),3.58(app t, J =13.1,2H),3.89-4.00(m,2H),4.02(s,3H),4.17(s,2H),4.20-4.30(m,2H),4.52-4.61(m,2H),7.49(d, J =9.4Hz,1 ddh), 7.86 (J, J =5.3,7.9Hz,1H),8.05(d, J =9.2Hz,1H),8.82(br d, J =8.10, 1H =8, 1H), 1.47.47 (1.47, 1H), 1.47H, 1H); mass spectrum M/z521((M-1)^-,46%)。

Example 11

Preparation of rel-2-amino-N- {8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] -2-hydroxy-2-methylpropyl } oxy) -7- [2- (4-fluorophenyl) ethoxy ] -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } pyrimidine-5-carboxamide

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

To rel-N- [8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl]-2-hydroxy-2-methylpropyl } oxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl]To a mixture of amine (example 10, step 2, 0.290g,0.69mmol) and 2-amino-5-pyrimidinecarboxylic acid (0.125g,0.90mmol,1.3equiv.) in DMF (20mL) was added PyBOP (0.468g,0.90mmol,1.3equiv.), followed by diisopropylethylamine (0.48mL,2.77mmol,4.0equiv.), and the resulting mixture was stirred at room temperature for 24 h. The resulting precipitate was removed using a membrane filter, washed successively with DMF, water and methanol, and dried under reduced pressure at 60 ℃ to give rel-2-amino-N- {8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl]-2-hydroxy-2-methylpropyl } oxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl } pyrimidine-5-carboxamide (0.26g,68%) HPLC retention time 0.99 min;¹H NMR(DMSO-d₆+1 drop TFA-d)(d, J =5.8,3H),1.11(d, J =5.8Hz,3H),1.41(s,3H),2.74-2.86(m,2H)3.25-3.36(m,2H),3.52-3.63(m,2H),3.89-3.98(m,2H),3.99(s,3H),4.15(s,2H),4.17-4.23(m,2H),4.46-4.53(m,2H),7.43(d, J =9.4Hz,1H),8.00(d, J =9.1Hz,1H),8.99Hz (s, 2H); mass spectrum M/z617((M +1)⁺,37%)。

Step 2: preparation of rel-2-amino-N- {8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] -2-hydroxy-2-methylpropyl } oxy) -7-hydroxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } pyrimidine-5-carboxamide

rel-2-amino-N- {8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl]-2-hydroxy-2-methylpropyl } oxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c]A suspension of quinazolin-5-yl } pyrimidine-5-carboxamide (0.248g,0.46mmol) in N-methylpyrrolidinone (5mL) was warmed to 60 ℃ and portionwise Na₂S (0.180g,2.30mmol,5.0 equiv.). The resulting mixture was heated at 160 ℃ for 10 minutes, cooled to room temperature and concentrated under reduced pressure (0.3 mbar). The residue was treated with water (25mL), made acidic with 1N HCl solution, and saturated NaHCO was used₃The solution was adjusted to pH 7. The resulting mixture was stirred at room temperature for 30 minutes, and the resulting precipitate was removed with a membrane filter. The mother liquor is treated with 4:1CH₂Cl₂Isopropanol solution (3X 50 mL). The combined organic phases were dried (anhydrous Na)₂SO₄) And concentrated under reduced pressure. The residue containing N-methylpyrrolidone (0.55g) was used for the next step without further purification.

And step 3: preparation of rel-2-amino-N- {8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] -2-hydroxy-2-methylpropyl } oxy) -7- [2- (4-fluorophenyl) ethoxy ] -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } pyrimidine-5-carboxamide

To rel-2-amino-N- {8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl]-2-hydroxy-2-methylpropyl } oxy) -7-hydroxy-2, 3-dihydroimidazo [1,2-c]Suspension of quinazolin-5-yl } pyrimidine-5-carboxamide (0.55g) in DMF (7.5mL) with Cs₂CO₃(0.68g,2.10mmol) followed by 2- (4-fluorophenyl) ethyl bromide (0.12mL,0.839 mmol). The resulting suspension was stirred at room temperature for 20 hours and at 50 ℃ for 6 hours. To the resulting mixture was added additional 2- (4-fluorophenyl) ethyl bromide (0.10mL,0.700mmol) and the resulting mixture was stirred at 50 ℃ for 16 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in water (50mL) and 4:1CH₂Cl₂The mixture was separated from the isopropanol solution (50 mL). The organic phase was washed with saturated NaHCO₃The solution (50mL) was treated and dried (anhydrous Na)₂SO₄) And concentrated under reduced pressure. The residue was purified by HPLC to give rel-2-ammoniaYl-N- {8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl]-2-hydroxy-2-methylpropyl } oxy) -7- [2- (4-fluorophenyl) ethoxy]-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl } pyrimidine-5-carboxamide (0.046g, 1.5% based on 2 steps) HPLC retention time 1.21min.;¹H NMR(DMSO-d₆+1 drop TFA-d) δ 1.07(d, J =6.4Hz,3H),1.09(d, J =6.4Hz,3H),1.35(s,3H),2.63-2.78(m,2H),3.10(app t, J =6.9Hz,2H),3.22(br s,2H),3.42-3.54(m,2H),3.86-3.98(m,2H),4.30(s,2H),4.15-4.25(m,2H),4.42(app t, J =6.8Hz,2H),4.46-4.54(m,2H),7.06(t, J =8.9Hz,2H),7.33(dd, J =5.7,8.7Hz,2H),7.41(d, J =9.0, 1H = 7.99(d, 1H = 9.01 Hz), 1.9H, 9Hz, 2H); mass spectrum M/z645((M-1)^-,100%),647((M+1)⁺,12%)。

Example 12

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

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

Subjecting rel-N- [8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl]-2-hydroxy-2-methylpropyl } oxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl]A suspension of pyridine-3-carboxamide (example 10, step 3, 0.27g,0.51mmol) in N-methylpyrrolidone (5mL) was warmed to 100 ℃ and Na was added₂S (0.199g,2.55mmol,5.0 equiv.). The mixture obtained is at 1Heated at 60 ℃ for 10 minutes, cooled to room temperature and concentrated under reduced pressure (0.3 mbar). The residue was treated with water (25mL), made acidic with 1N HCl solution, and saturated NaHCO was used₃The solution was adjusted to pH 7. The resulting mixture was stirred at room temperature for 4 hours, then 4:1CH was used₂Cl₂Isopropanol solution (4X 50 mL). The combined organic phases were dried (anhydrous Na)₂SO₄) And concentrated under reduced pressure. The residue containing N-methylpyrrolidone (.20g) was used in the next step without further purification.

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

To rel-N- [8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl]-2-hydroxy-2-methylpropyl } oxy) -7-hydroxy-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl]Suspension of pyridine-3-carboxamide (0.200g) in DMF (7.5mL) with addition of Cs₂CO₃(0.513g,1.57mmol,4.0equiv.) followed by the addition of 2- (4-fluorophenyl) ethyl bromide (0.11mL,0.787 mmol). The resulting suspension was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was taken up in water (50mL) and 4:1CH₂Cl₂The mixture was separated from the isopropanol solution (50 mL). The organic phase was washed with saturated NaHCO₃The solution (50mL) was treated and dried (anhydrous Na)₂SO₄) And concentrated under reduced pressure. The residue (0.26g) was purified by HPLC (Isolute Flash NH)₂A reversed phase column; 100% CH₂Cl₂Last 10min, 90% CH within 1min₂Cl₂A gradient of 10% MeOH; 10min, 80% CH in₂Cl₂A gradient of 20% MeOH; and 80% CH₂Cl₂20% MeOH for 10min.) to give a substance (0.10g), which was further purified by preparative HPLC to give rel-N- {8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl]-2-hydroxy-2-methylpropyl } oxy) -7- [2- (4-fluorophenyl) ethoxy]-2, 3-dihydroimidazo [1,2-c]Quinazolin-5-yl } pyridine-3-carboxamide (0.015g, 0.5% based on 2 steps) HPLC retention time 1.34min.;¹H NMR(DMSO-d₆+1 drop TFA-d)(d, J =6.6Hz,3H),1.10(d, J =6.6Hz,3H),1.37(s,3H),2.66-2.79(m,2H),3.11(app t, J =7.1Hz,2H),3.23(br s,2H),3.44-3.54(m,2H),3.89-3.97(m,2H),4.15(s,2H),4.22-4.28(m,2H),4.47(app t, J =6.8Hz,2H),4.53-4.60(m,2H),7.07(t, J =8.8Hz,2H),7.33(dd, J =5.6,8.6Hz,2H),7.47(d, J =9.1, 1H),7.90(dd =8, 1.8, 1H), 1.47 (d, 1H =9.1, 1H),7.90 (J =8, 8H), 1.8.04 (dd, 1.6, 8H), 1.47 (d, 1.95H); mass spectrum M/z631((M +1)⁺,0.8%)。

Furthermore, the compounds of formula (I) of the present invention may be converted into any of the salts described herein by any method known to those skilled in the art. Likewise, 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 (troche), lozenges (lozenge), melt gels (melt), 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 the 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, 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, in 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, carbomer, methylcellulose, hypromellose or carboxymethylcellulose, or emulsifying agents and other pharmaceutically acceptable adjuvants.

Exemplary oils useful in the parenteral formulations of the invention are those of petroleum, animal, vegetable or synthetic origin, 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 quaternary ammonium salts, and mixtures thereof.

The parenteral compositions of the invention will typically comprise 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. One such implantable delivery system for delivering agents to specific anatomical locations of the body is described in U.S. patent No.5,011,472 issued on 30/4 1991.

The compositions of the present invention may also contain, as necessary or desired, other conventional pharmaceutically acceptable formulation ingredients, which are commonly 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, "compatibility of Excipients for particulate Formulations" PDA Journal of 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 (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);

coloring agents (examples include, but are not limited to FD & C Red No.3, FD & C Red No.20, FD & CYelow No.6, FD & C Blue No.2, D & C Green No.5, D & C Orange No.5, D & C Red No.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 (arachis oil), mineral oil, olive oil, peanut oil (peanout oil), sesame oil, and vegetable oils);

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, mono-or polyvalent 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, polacrillin potassium, crospovidone, 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, glucose and sodium chloride);

viscosity increasing agents (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 (heptadecaethyleneoxycetanol), lecithin, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

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

sterile intravenous 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 to 1-2mg/mL with sterile 5% glucose for administration and administered as an intravenous infusion over about 60 min.

Lyophilized powder for intravenous administration: sterile preparations can be prepared from (i)100-1000mg of the desired compound of the invention in the form of a lyophilized powder, (ii)32-327mg/mL sodium citrate, and (iii)300-3000mg dextran 40. The formulation is reconstituted to a concentration of 10-20mg/mL with sterile saline for injection or 5% glucose, then further diluted to 0.2-0.4mg/mL with saline or 5% glucose and administered as an intravenous bolus or intravenous 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/mL TWEEN80

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, respectively.

Soft capsule: preparing a mixture of active ingredients in a digestible oil such as soybean oil, cottonseed oil or olive oil and mixingOver-displacement pumps 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 may be everolimus (afinitor), aldesleukin, alendronic acid, alpha-interferon (alfaferone), alitretinoin, allopurinol, sodium allopurinol for injection (alorim), palonosetron hydrochloride injection (aloxi), altretamine, aminoglutethimide, amifostine, amsacrine, anastrozole, dolasetron tablet (anzmet), alfa bepotein injection (aranesp), arglabin, arsenic trioxide, exemestane tablet, 5-azacytidine, azathioprine, BAY80-6946, BCG or tide, aprotinin (bestatin), betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, uridine bromide, bortezomib, busulfan, calcitonin, apsilate, amapatatin, peimedine, peyrone, betamethasone, bleomycin, carmustine, melphalan, beraprone, beraprost, BCG, berrubine, melphalan, sinne, melphalan, Cisplatin, cladribine, clodronic acid, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin citrate liposome (daunoxeme), dexamethasone sodium phosphate, estradiol valerate, dinilukin 2(denileukin diftox), methylprednisolone, deslorelin, dexrazoxane, diethylstilbestrol, fluconazole, docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, leuprolide acetate (eligard), labyrine injection (elitek), epirubicin hydrochloride injection (ellence), aprepirubicin capsule (endemic), epirubicin, alfa eptin (epoetin alfa), alfa (epogen), etaplatin, levamisole, estradiol (estradiol), estradiol, estramustine, amifostine, etidronic acid, etoposide, diethylcarbamazepine liposome, dexamectin, diethylcarbamazepine, dexamectin, doxine, dexamectin, doxin, etoposide, doxin, doxycycline, fadrozole, farston, filgrastim, finasteride, filgrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, fosetastine, fulvestrant, gamma-globulin (gammagard), gemcitabine, gemumab, imatinib mesylate (gleevec), carmustine wafer capsule (gliadel), goserelin, glatirnestron hydrochloride, histretron, topotecan (hycamtin), hydrocortisone, erythroxyladenine (eynyladenine), hydroxyurea, ibritumomab, idacin, ifosfamide, alpha interferon, alpha 2 interferon, alpha-2A interferon, alpha-2B interferon, alpha-1 interferon, alpha-3 interferon, gamma-351 a, gamma-interferon, Interleukin-2, interferon alpha (intron A), gefitinib tablet (iressa), irinotecan, granisetron, lentinan sulfate, letrozole, leucovorin, leuprolide acetate, levamisole, calcium levofolinate (levofolinic acid calcium salt), levothyroxine sodium (levothroid), levothyroxine sodium (levoxyl), lomustine, lonidamine, dronabinol, mechlorethamine, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogen tablet (menest), 6-mercaptopurine, mesna, methotrexate, metivox, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, trilostane (Modrenal), Myocoet, nedaplatin, filgrastim (neurin), recombinant interleukin 11 (nethea), glutethionine (netrux), milbexate, medetomidine (D), and mycophenolate, NSC-631570, OCT-43, octreotide, ondansetron hydrochloride, cefixime (orapirred), oxaliplatin, paclitaxel, prednisone sodium phosphate (pidiapred), pemetrexed, pyroxin, pentostatin, streptolysin (picibanil), pilocarpine hydrochloride, pirarubicin, plicamycin, porfimer sodium, poinimustine, prednisolone, prednisone, equine estrogens, procarbazine, recombinant human erythropoietin alpha, raltitrexed, RDEA119, recombinant human interferon beta 1a injection (rebif), rhenium-186 hydroxyethylphosphonate, rituximab, roscovalen (roferon-A), romopeptide, pilocarpine hydrochloride (salagen), octreotide, sargrastim, semustine, xifuran, sobutyrazol, prednisolone, phosphoethanine, dry cell therapy, strontium 89, sodium thyroxine chloride, levofloxacin, and paclitaxel, Tamsulosin, tasolinamine, testolactone, docetaxel injection (taxotere), teiaceinterleukin, temozolomide, teniposide, testosterone propionate, methyltestosterone, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, troosulfan, tretinoin, methotrexate (trexal), trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, viloliqin, dexrazoxane, netrostatinstimalamer, ondansetron, ABI-007, acolbine, interferon gamma-1 b (actammu), afitufin, aminopterin, acyclonifene, oxyptericin, apitansinoid, arbitracin, abenzapine, abenzol, trexab (779), tretinomycin, CDC-501, celecoxib, cetuximab, clinatropine, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin, eflornithine, isoxatecan, 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 (keyhol lipped hemoanin), L-651582, lanreotide, lasofoxifene, libra, farnesol protein transferase inhibitor (lonafinaranfamib), mirhexifen, minophosphonic acid (minodronate), MS-209, MTP-PE liposomes, MX-6, nararelin, nevira, novalubicin, norvonospherol, trexostat, TCidosoxel, paclitaxel, disodium-S, dimeglumine, dimeglume, dimerate, medrycan, melphalan, paclobulin, PN-401, QS-21, quazepam, R-1549, raloxifene, ranpirnase, 13-cis-retinoic acid, satraplatin, seocalcitol, T-138067, erlotinib hydrochloride tablets (tarceva), taxoprxin, alpha-1 thymosin, thiazolufrine, tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valcephradine, 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: 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinol, altretamine, aminoglutethimide, amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY80-6946, BAY1000394, BAY86-9766(RDEA119), belotecan (belotecan), bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, cabazitaxel (bazitaxel), calcium folinate, calcium levofolinate, capecitabine, carboplatin, carmofur, carmustine, rituximab (cisplatin), catapaucimaxob, celecoxib, western interleukin, bevacizumab, chlorambucil, chloracetic acid, loratadine, picloratadine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, dabecortine alpha, dasatinib (dasatinib), daunorubicin, decitabine, degarelix (degarelix), dinebin interleukin 2(denileukin diftox), deluzumab (denosumab), deslorelin, dibromospiro-ammonium chloride, docetaxel, deoxyfluorouracil, doxorubicin + estrone, eculizumab (ecumab), eculizumab, eletrinol, eletrinylammonium, itratepa (eltrombopag), endostatin, enocitabine, epirubicin, epitiazerol, epoetin alpha, epoetin beta, epta, eribulin (eribulin), erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fava, filgrastimethamine, fludarabine, flunomide, trospide, trospigotu, doxin, trospidrox, doxastin, doxin, doxastin, valtrexaprop-b, valtrexaprop-p, trospitrexaprop-b, trospile, trospitrexaprop-b, trospi, Gefitinib, gemcitabine, gemtuzumab, glutathione (glutoxim), goserelin, histamine dihydrochloride, histrelin, hydroxyurea, I-125 seeds, ibandronic acid, ibritumomab, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferon alpha, interferon beta, interferon gamma, ipimab, irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide, legetin, lentinan, letrozole, leuprolide, levamisole, lisuride, lobaplatin, lomustine, lonidamine, maxolone, medroxyprogesterone, megestrol, melphalan, meindrostan, mercaptopurine, methotrexate, methoxsalen, methylketovalerate, methyltestosterone, mivampitide, miltefosine, miriplatin, miiplatin (miiplatin), dibromomannitol, mitoxantrone, mitomycin, gliptin, medroxyprin, mitomycin, imipramiperin, mibemectin, imipramiperin, and mitomycin, Mitotane, mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide, nimotuzumab, nimustine, nitrazine (nitracrine), ofatumumab, omeprazole, opper leukin, oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, pamidronic acid, panitumumab, pazopanib, pemetrexed, PEG-epothilones beta (methoxy PEG-epothilones beta), polyethylene glycol filgrastim (pegfilgrastim), polyethylene glycol interferon alpha-2 b, pemetrexed, pentazocine, pentostatin, pellomycin, phosphoramide, piscibacilide, pirarubicin, plerixafot, plicamycin, poliglusam, estradiol polyphosphate, polysaccharide-K, porphin sodium, larprimisum, prednimustine, procarbazine, quinacrine, raloxifene, raloxifenesin, triptoresinone, triptoresinolide, triptorellose, picamide, pemetrexendine, pem, Ramomustine, propyleneimine, regorafenib, risedronic acid, rituximab, romidepsin, rolimiprole, sargrastim, sipuleucel-T, cilazasugar, sobuzole, sodium glycin, sorafenib, streptozotocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tasonamine, tesil interleukin, tegafur + gimeracil + oteracil, temoporfil, temozolomide, temsirolimus, teniposide, testosterone, tetrodotril, thalidomide, thiotepa, thymalfasin, thioguanine, taslizumab, topotecan, toremifene, tositumomab, trastuzumab, osufovan, tretinoin, triptorelin, urotropine, urotropinirostrin, suramin, tretinoin, valvacizumab, vinpocetine, valdecoxib, valrubicin, tretazarin, tretinomycin, trovafloxacin, valdecoxib, tretinomycin, trovampil, tremulin, valdecoxib, valrubicin, tremulin, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, flurazole, yttrium-90 glass beads, cilastatin ester, 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 edition (1996) (incorporated by reference), such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, asparaginase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, and, 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 Goodman and Gilman's The Pharmacological Basis of Therapeutics (9 th edition), edited by Molinoff et al, McGraw-Hill, pages 1225-1287 (1996) (incorporated by reference) for use in The treatment of neoplastic disease, such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2' -difluorodeoxycytidine, docetaxel, erythrononyl adenine, ethinylestradiol, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone hexanoate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, medecan, Paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), 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 2, rituximab, alpha 1 thymosin, bevacizumab, mecamylamine, omprex-bane, natalizumab, rhMBL, MFE-CP1+ mfzd-2767-P, ABT-828, ErbB 2-specific immunotoxin, SGN-35, mfn-103, linum (rinfabate), AS-1402, B43-genistein, L-19 series radioimmunotherapeutic, 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 (cindrekin bestudox), WX-G250, Albuferon, aflibercept, denosumab (denosumab), vaccine, CTP-37, efungumab (efungumab) or 131I-chTNT-1/B. Monoclonal antibodies useful as protein therapeutics include, but are not limited to, molobuzumab-CD 3, abciximab, edrecolomab, daclizumab, gemtuzumab (gentuzumab), alemtuzumab, ibritumomab tiuxetan (ibritumomab), cetuximab, bevacizumab, efalizumab (efalizumab), adalimumab (adalimumab), omalizumab, moelimumab-CD 3, rituximab, daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.

A compound of formula (I) as defined herein may optionally be administered in combination with one or more of the following: 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, Incarzatourette (enzastaurin), GDC-0032, GDC-0068, GDC-0623, GDC-0941, GDC-0973, GDC-0980, GSK-2110183, GSK-2126458, GSK-2141795, MK-2206, novolimus, OSI-027, piperacillin, PF-04691502, PF-05212384, PX-866, rapamycin, RG-7167, RO-8749655, RO-5126766, Semitertinib (selumetinib), TAK-300, metribuzoniprole, Quierrol-147, Zolmius-XL, Zolmimus-554 (Wzorni XL), ZSTK-474.

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 wider range 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 useful 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 in the cell. 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 initiation of irradiation or other induction that causes DNA damage to the 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 present invention effectively inhibit allo-MEK and are therefore useful in the treatment or prevention of diseases of, 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 allo-MEK, e.g. hematological tumors, solid tumors and/or metastases thereof, such as 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, kidney tumors, lung tumors, kidney tumors, lung tumors, 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.

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.

Thus, another particular aspect of the invention is the use of a compound of 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 to be understood as preferably meaning 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" 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 any 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 (renegade cells), 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 to which the method is directed is a hematological tumor, a solid tumor and/or metastases thereof.

The compounds of the invention are particularly useful in the treatment and prevention (i.e. prevention) of tumor growth and metastasis, particularly 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), taxotere (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 selected biological assays. When tested more than once, data is reported as mean or median values, where:

the mean, also called arithmetic mean, represents the total number of values obtained divided by the number of tests, and

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

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

Percent inhibition and IC of Compounds in PI3K alpha kinase assay₅₀Determination of value

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

Chemical and assay material

AsReagents for the kinase reaction itself and for quantification of the reaction product, PI 3-kinase HTRF assay kit from Millipore (#33-017) was used. Using this kit, the energy transfer complex (europium-labeled anti-GST monoclonal antibody, GST-labeled PH domain, biotinylated PIP) was replaced₃And streptavidin-Allophycocyanin (APC) for the detection of phosphatidylinositol 3,4, 5-triphosphate (PIP) produced in a kinase reaction₃). As kinase, used was Sf21 co-expressed by baculovirus-transfected insect cells and using Ni²⁺NTA-Sepharose purified N-terminal His 6-tagged recombinant full-length human p110 α and unlabeled recombinant full-length human p85 α complex (Millipore products # 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-bisphosphate (PIP) were added₂,13.8μM=>Final concentration in 4 μ L reaction volume =10 μ M) of 3 μ L solution in 1 × reaction buffer (exact composition not disclosed by the supplier) and the mixture was incubated at 22 ℃ for 15 minutes to pre-bind the test compound to the enzyme before starting the kinase reaction. The amount of PI3K alpha was chosen so that the kinase reaction was in the linear range and was dependent on the activity of the individual batches (lot), with a typical concentration determined being 90 ng/mL. Then, adenosine triphosphate (ATP,40 μ M = g) was added>Final concentration in 4 μ Ι assay volume of 10 μ Μ) in reaction buffer and the resulting mixture was incubated at 22 ℃ for a reaction time of 20min.

By adding 1. mu.L of stop solution (containing biotinylated PIP used as tracer)₃) To stop the reaction, 1 μ L of detection mixture (containing europium-labeled anti-GST mab, GST-labeled PH domain and streptavidin-allophycocyanin) was then added, and the resulting mixture was incubated at 22 ℃ for 3 hours, allowing the detection reagent to react with PIP produced in the kinase reaction₃Or with biotinylated PIP added with stop solution₃A complex is formed. Subsequently, by measuring the amount of europium-labeled anti-GST monoclonal antibodyEvaluation of the amount of europium-labeled anti-GST monoclonal antibody, GST-labeled PH domain, biotinylated PIP by resonance energy transfer of streptavidin-allophycocyanin₃And streptavidin-Allophycocyanin (APC). Thus, fluorescence emission at 620nm and 665nm after excitation at 350nm was measured using a TR-FRET reader such as Pherastar (BMGLABTtechnologists, Offenburg, Germany) or Viewlux (Perkin-Elmer). Emission ratios at 665nm and 622nm were collected as biotinylated PIP bound to GST-labeled PH domains₃Is measured with the PIP produced₃The amount of (c) is inversely related. Data were normalized (enzyme reaction without inhibitor =0% inhibition, all other assay components without enzyme =100% inhibition). Typically, test compounds are tested at 10 different concentrations on the same microtiter plate, two values are tested for each concentration, and IC is calculated by 4-parameter fitting using internal software₅₀Values, the concentration was 25. mu.M to 1.3nM (25. mu.M, 8.3. mu.M, 2.8. mu.M, 0.93. mu.M, 0.31. mu.M, 103nM, 34nM, 11nM, 3.8nM and 1.3nM, dilution series were prepared at 80-fold concentrate levels by a series of 1:3 dilutions prior to assay).

The following example compounds show the average IC in PI3K alpha Biochemical assays₅₀Less than 10 nanomoles: examples 1, 7, 10 and 11. The compounds of the following examples also show the average IC of the PI3K alpha biochemical assay₅₀10-50 nanomolar: examples 2,3, 8, 9 and 12. The percentage inhibition values obtained for the example compounds at a concentration of 0.93. mu.M are given in Table 1.

Percent inhibition and IC of compounds in PI3K beta kinase assay₅₀Determination of value

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

Chemical and assay material

As a reagent for the kinase reaction itself and for the quantification of the reaction product, PI 3-kinase HTRF measurement reagent from Millipore (#33-017) was usedAnd (5) a box. Using this kit, the energy transfer complex (europium-labeled anti-GST monoclonal antibody, GST-labeled PH domain, biotinylated PIP) was replaced₃And streptavidin-Allophycocyanin (APC) for the detection of phosphatidylinositol 3,4, 5-triphosphate (PIP) produced in a kinase reaction₃). As kinase, used was Sf21 co-expressed by baculovirus-transfected insect cells and using Ni²⁺NTA-Sepharose purified N-terminal His 6-complex of tagged recombinant full-length human p 110. beta. and untagged recombinant full-length human p 85. alpha. (Millipore products # 14-603).

For the assay, 50nL of an 80-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and PI3K β and phosphatidylinositol-4, 5-bisphosphate (PIP) were added₂,13.8μM=>Final concentration in 4 μ Ι reaction volume =10 μ M) of 3 μ Ι solution in 1x reaction buffer (exact composition not disclosed by the supplier) and the mixture was incubated at 22 ℃ for 15 minutes to pre-bind the test compound with the enzyme before starting the kinase reaction. The amount of PI3K β was chosen so that the kinase reaction was in the linear range and was dependent on the activity of the individual batches (lot), with a typical concentration determined of 120 ng/mL. Then, adenosine triphosphate (ATP,40 μ M = g) was added>Final concentration of 10 μ M in 4 μ L assay volume) in reaction buffer to start the kinase reaction and incubate the resulting mixture at 22 ℃ for a reaction time of 20min.

By adding 1. mu.L of stop solution (containing biotinylated PIP used as tracer)₃) The reaction was stopped. Then 1 μ L of the detection mixture (containing europium-labeled anti-GST mab, GST-labeled PH domain and streptavidin-allophycocyanin) was added and the resulting mixture was incubated at 22 ℃ for 3 hours, allowing the detection reagent to react with PIP produced in the kinase reaction₃Or with biotinylated PIP added with stop solution₃A complex is formed. Subsequently, europium-labeled anti-GST monoclonal antibody, GST-labeled PH domain, raw blue were evaluated by measuring resonance energy transfer from europium-labeled anti-GST monoclonal antibody to streptavidin-allophycocyaninPierised PIP₃And streptavidin-Allophycocyanin (APC). Thus, the fluorescence emission at 620nm and 665nm after excitation at 350nm is measured using a TR-FRET reader such as, for example, Pherastar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and 622nm was collected as biotinylated PIP bound to GST-labeled PH domain₃Is measured with the PIP produced₃The amount of (c) is inversely related. Data were normalized (enzyme reaction without inhibitor =0% inhibition, all other test components without enzyme =100% inhibition). Typically, test compounds are tested at 10 different concentrations on the same microtiter plate, two values are tested for each concentration, and IC is calculated by 4-parameter fitting using internal software₅₀Values, the concentration was 25. mu.M to 1.3nM (25. mu.M, 8.3. mu.M, 2.8. mu.M, 0.93. mu.M, 0.31. mu.M, 103nM, 34nM, 11nM, 3.8nM and 1.3nM, dilution series were prepared at 80-fold concentrate levels by a series of 1:3 dilutions prior to assay).

The following example compounds show the average IC in PI3K beta biochemical assays₅₀Less than 10 nanomoles: example 9. The compounds of the following examples also show the average IC of the PI3K beta biochemical test₅₀10-50 nanomolar: examples 2, 7,8, 11. The following compounds of the examples show the average IC in the PI3K beta biochemical test₅₀Greater than 50 nanomoles: examples 1,3, 10 and 12. The percentage inhibition values obtained for the example compounds at a concentration of 0.93. mu.M are given in Table 1.

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 of 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-(CR⁴(R^4’))-(CH₂)_m-N(R⁵)(R^5’)；

wherein:

x represents N or C-R⁶，

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

R³is 1R⁸Radical substituted C₁-C₆-an alkyl group;

R⁴is a hydroxyl group;

R^4’is a hydrogen atom or C₁-C₆-an alkyl group;

or

R⁵And R^5’Together with the nitrogen atom to which they are bound represent a 3-to 8-membered nitrogen-containing heterocyclic ring, said 3-to 8-membered nitrogen-containing heterocyclic ring optionally containing at least one further heteroatom selected from oxygen, nitrogen or sulfur, and may optionally be substituted by 1 or moreR is^6’Substituted by groups;

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

2. A compound according to claim 1, 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)(R^5’)；

R²Represents a heteroaryl group having the structure:

wherein:

R³is 1R⁸Radical substituted C₁-C₆-an alkyl group;

R⁴is a hydroxyl group;

R^4’is a hydrogen atom or C₁-C₆-an alkyl group;

or

R⁵And R^5’With nitrogen bound to themThe atoms together represent a 3-to 8-membered nitrogen-containing heterocyclic ring, said 3-to 8-membered nitrogen-containing heterocyclic ring optionally containing at least one other heteroatom selected from oxygen, nitrogen or sulfur, and may optionally be substituted by 1 or more R^6’Substituted by groups;

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

3. A compound according to claim 1 or 2, 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)(R^5’)；

R²Represents a heteroaryl group having the structure:

wherein:

R³is 1R⁸Radical substituted C₁-C₆-an alkyl group;

R⁴is a hydroxyl group;

R^4’is a hydrogen atom or C₁-C₆-an alkyl group;

R⁸independently for 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-RingAlkyl radical, 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.

4. A compound according to any one of claims 1,2 or 3, selected from:

n- (8- { [ (2R) -3- (diprop-2-ylamino) -2-hydroxypropyl ] oxy } -7- [2- (4-fluorophenyl) ethoxy ] -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) pyridine-3-carboxamide;

n- [8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] -2-hydroxypropyl } oxy) -7- [2- (4-fluorophenyl) ethoxy ] -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } pyridine-3-carboxamide;

n- {7- [2- (4-fluorophenyl) ethoxy ] -8- [ 2-hydroxy-3- (morpholin-4-yl) propoxy ] -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } pyridine-3-carboxamide;

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

rel-2-amino-N- {8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] -2-hydroxy-2-methylpropyl } oxy) -7- [2- (4-fluorophenyl) ethoxy ] -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } pyrimidine-5-carboxamide;

rel-N- {8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] -2-hydroxy-2-methylpropyl } oxy) -7- [2- (4-fluorophenyl) ethoxy ] -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } pyridine-3-carboxamide.

5. The compound of any one of claims 1,2, 3 or 4, selected from:

6. A compound according to claim 1, 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)(R^5’)；

R²Represents a heteroaryl group having the structure:

wherein:

x represents N or C-R⁶；

R³Is 1R⁸Radical substituted C₁-C₆-an alkyl group;

R⁴is a hydroxyl group;

R^4’is a hydrogen atom or C₁-C₆-an alkyl group;

or

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

7. A compound according to claim 1 or 6, 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)(R^5’)；

R²Represents a heteroaryl group having the structure:

wherein:

x represents N or C-R⁶；

R³Is 1R⁸Radical substituted C₁-C₆-an alkyl group;

R⁴is a hydroxyl group;

R^4’is a hydrogen atom or C₁-C₆-an alkyl group;

R⁷and R^7’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-C₆Alkyl, heteroarylA group, a 3-to 8-membered heterocycle, a 3-to 8-membered heterocyclyl-C₁-C₆-alkyl or heteroaryl-C₁-C₆-an alkyl group;

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

8. The compound of any one of claims 1,6 or 7, which is:

rel-2-amino-N- {8- ({ (2R) -3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] -2-hydroxy-2-methylpropyl } oxy) -7- [2- (4-fluorophenyl) ethoxy ] -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } pyrimidine-5-carboxamide.

9. A process for the preparation of a compound of general formula (I) according to any one of claims 1 to 8, comprising the steps of: reacting the intermediate compound of formula (XI) with a compound of formula (XIa) to obtain a compound of formula (I),

wherein R is¹And R³As defined in any one of claims 1 to 8 with respect to general formula (I);

R²COOH

(XIa)

wherein R is²As defined for the general formula (I) in any one of claims 1 to 8,

wherein R is¹、R²And R³As defined for general formula (I) in any one of claims 1 to 8.

10. A compound of general formula (I) according to any one of claims 1 to 8 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, for use in the treatment or prophylaxis of a disease.

11. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 8 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, and a pharmaceutically acceptable diluent or carrier.

12. A pharmaceutical combination comprising:

-one or more compounds of general formula (I) according to any one of claims 1 to 8 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;

and

-one or more agents selected from: a taxane, such as docetaxel, paclitaxel or taxol; epothilones such as ixabepilone, paclitaxel (Patupilone) or salgopilone (Sagopilone); mitoxantrone; prednisolone; dexamethasone; estramustine; vinblastine; vincristine; doxorubicin; doxorubicin; idarubicin; daunorubicin; bleomycin; etoposide; cyclophosphamide; ifosfamide; procarbazine; melphalan; 5-fluorouracil; capecitabine; fludarabine; cytarabine; Ara-C; 2-chloro-2' -deoxyadenosine; thioguanine; antiandrogens, such as flutamide, cyproterone acetate or bicalutamide; bortezomib; platinum derivatives, such as cisplatin or carboplatin; chlorambucil; methotrexate and rituximab.

13. Use of a compound of general formula (I) according to any one of claims 1 to 8 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, for the treatment or prophylaxis of a disease.

14. Use of a compound of general formula (I) according to any one of claims 1 to 8 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, for the preparation of a medicament for the treatment or prophylaxis of a disease.

15. The use of claim 10, 13 or 14, wherein the disease is a disease caused by uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response or an inappropriate cellular inflammatory response, particularly wherein the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by the PI3K pathway, more particularly wherein the disease caused by uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is a hematological tumor, a solid tumor and/or metastases thereof, such as leukemia and myelodysplastic syndrome, malignant lymphoma, 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, 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.

16. A compound of the general formula (XI):

wherein R is¹And R³As defined for general formula (I) in any one of claims 1 to 8.

17. Use of a compound of general formula (XI) according to claim 16 for the preparation of a compound of general formula (I) according to any one of claims 1 to 8.