Bicyclic heterocyclic compounds and their therapeutic uses

Abstract

Bicyclic heterocyclic compounds and their therapeutic uses. The present invention relates to novel bicyclic heterocyclic compounds, pharmaceutical compositions comprising the compounds and the use of the compounds in the treatment of diseases such as cancer.

Description

[0001] This application is a divisional application of the invention patent application with application number 201811129977.8, application date December 19, 2014, and invention name “Bicyclic Heterocyclic Compounds and Therapeutic Uses Thereof” (referred to as “Divisional Application I”). The aforementioned divisional application I is a divisional application of the invention patent application with international application number PCT / GB2014 / 053778, international application date December 19, 2014, and invention name “Bicyclic Heterocyclic Compounds and Therapeutic Uses Thereof” (referred to as “Original Application”). The national application number obtained by the original application when entering the Chinese national phase is 201480069940.4. Technical Field

[0002] The present invention relates to novel bicyclic heterocyclic compounds, to pharmaceutical compositions comprising said compounds and to the use of said compounds in treating diseases such as cancer. Background Art

[0003] IAP family

[0004] The inhibitor of apoptosis protein (IAP) family includes eight members, namely XIAP, cIAP1, cIAP2, NAIP, ILP2, ML-IAP, survivin and BRUCE (also known as apollon). Members of the IAP family have been shown to inhibit programmed cell death through their ability to directly inhibit members of the caspase family of apoptotic enzymes, although the precise role of all eight members has not been fully defined. A common structural feature of all IAP family members is a ~70 amino acid zinc-binding fold, also known as the baculovirus IAP repeat (BIR) domain, which is present in one to three copies.

[0005] Many interactions between IAPs and other proteins are mediated by surface grooves on the BIR domains. BIR domains can be classified by their peptide binding specificity. There are three types of BIR domains; type III domains (capable of binding to caspase (and caspase-like) peptides specific for proline at the third (P3) position (e.g., XIAP BIR3), type II domains (similar to type III domains, but lacking the proline requirement, e.g., XIAP BIR2), and type I domains (will not bind to caspases or similar peptides, e.g., XIAP BIR1) (Eckelman et al. Cell Death and Differentiation 2008; 15: 920-928). BIRs are small (~70 amino acids) Zn-coordinating domains, and a variety of proteins use their N-termini to interact with the BIR domain grooves. BIR antagonists prevent caspases from binding to BIRs and thus cause increased caspase activity, inducing autoubiquitination and proteasomal degradation of IAPs.

[0006] IAP is overexpressed in many cancers, including renal, melanoma, colon, lung, breast, ovarian, and prostate cancers (Tamm et al., Clin. Cancer Research 2000; 6(5): 1796-803), and has been implicated in tumor growth, pathogenesis, and resistance to chemotherapy and radiation therapy (Tamm 2000).

[0007] XIAP

[0008] XIAP is a 57 kDa protein with three BIR domains, the second and third BIR domains bind caspases and RING-type zinc fingers (E3 ligases). In addition to caspases, XIAP also binds to several proteins, including ligation substrates such as TAK1 and cofactor TAB1, MURR1 involved in copper homeostasis (Burstein et al., EMBO 2004; 23: 244-254), endogenous inhibitors such as the second mitochondrial-derived activator of caspases (SMAC), and those proteins whose functions are less clear, such as MAGE-D1, NRAGE (Jordan et al., J. Biol. Chem. 2001; 276: 39985-39989).

[0009] The BIR3 domain binds and inhibits caspase-9, the apical caspase in the mitochondrial pathway of caspase activation. A groove on the surface of the BIR3 domain interacts with the N-terminus of the small subunit of caspase-9, thereby locking caspase-9 in its inactive monomeric form with an incompetent catalytic site (Shiozaki et al., Mol. Cell 2003; 11: 519-527).

[0010] In addition to caspase binding, XIAP also inhibits apoptosis by other mechanisms. XIAP forms a complex with TAK1 kinase and its cofactor TAB1, which causes activation of JNK and MAPK signal transduction pathways, thereby causing activation of NF-κB (Sanna et al., Mol Cell Biol 2002; 22: 1754-1766). XIAP also activates NF-κB, which is carried out by promoting NF-κB translocation to the nucleus and degrading IκB (Hofer-Warbinek et al., J. Biol. Chem. 2000; 275: 22064-22068, Levkau et al., Circ. Res. 2001; 88: 282-290).

[0011] Cells transfected with XIAP are able to block programmed cell death in response to a variety of apoptotic stimuli (Duckett et al., EMBO 1996; 15: 2685-2694, Duckett et al., MCB 1998; 18: 608-615, Bratton, Lewis, Butterworth, Duckett, and Cohen, Cell Death and Differentiation 2002; 9: 881-892).

[0012] XIAP is ubiquitously expressed in all normal tissues, but it is pathologically elevated in many acute and chronic leukemias, prostate, lung, kidney and other forms of tumors (Byrd et al., 2002; Ferreira et al., 2001; Hofmann et al., 2002; Krajewska et al., 2003; Schimmer et al., 2003; Tamm et al., 2000). In a new type of acute myeloid leukemia (AML), XIAP expression correlated with myelomonocytic French-American-British (FAB) subtype M4 / M5 (P<0.05) and the expression of monocytic markers in AML blasts. In addition, XIAP was found to be overexpressed in normal monocytes but undetectable in granulocytes. In AML, XIAP was significantly lower in patients with favorable cytogenetics rather than intermediate or poor cytogenetics (n=74; P<0.05) (Tamm et al., Hematol. J. 2004; 5(6): 489-95).

[0013] Overexpression confers resistance to multi-agent therapy and is associated with poor clinical outcomes in diseases including AML, renal cancer, melanoma (Tamm et al., Clin. Cancer Research 2000; 6: 1796-1803), and lung cancer (Hofmann et al., J. Cancer Res. Clin. Oncology 2002; 128(10): 554-60).

[0014] XIAP is translated by a cap-independent mechanism of translation initiation, which is mediated by a unique internal ribosome entry site (IRES) sequence element located in its 5' untranslated region. This allows XIAP mRNA to be actively translated during conditions of cellular stress when most cellular protein synthesis is inhibited. Upregulation of XIAP translation in response to stress increases resistance to radiation-induced cell death (Holcik et al., Oncogene 2000; 19: 4174-4177).

[0015] XIAP inhibition has been achieved using several techniques including RNA silencing, gene knockout, peptide ligand mimetics, and small molecule antagonists. in vitroStudies have shown that as a monotherapy, XIAP promotes apoptosis and sensitizes many tumor types to chemotherapy, including bladder (Kunze et al., 2008; 28 (4B): 2259-63). XIAP knockout mice are born at the expected Mendelian frequency, they have no obvious physical or tissue defects and have a normal life span (Harlin et al., Mol. Cell Biol. 2001; 21 (10): 3604-3608). This indicates that the lack of XIAP activity is non-toxic in normal tissues and shows a therapeutic window for tumor cells. Additional studies have shown that XIAP is a key discriminator between apoptosis of type 1 cells and type 2 cells (including hepatocytes) and should therefore be used with caution in patients with underlying liver conditions (Jost et al., Nature, 2009, 460, 1035-1041). It should be noted that cIAP1 and cIAP2 levels are upregulated in XIAP knockout mice and can prevent pathology through compensatory mechanisms, which indicates that pan-inhibition may be required for functional knockout. Similarly, cIAP1 and cIAP2 knockout mice are also asymptomatic (Conze et al., Mol. Biol. Cell 2005; 25(8): 3348-56). Although the lack of any IAP does not produce an obvious phenotype in mice, the loss of cIAP1 and cIAP2 or XIAP leads to mid-embryo lethality (Moulin, EMBO J., 2012).

[0016] Endogenous IAP antagonists such as SMAC have been used to validate members of this family as targets for therapeutic agents. SMAC peptides chemosensitize tumor cells, and the combination with platinum and tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) in xenografts results in delayed tumor growth (Fulda et al., Nat. Med. 2002; 808-815; Yang et al., Cancer Res. 2003; 63: 831-837).

[0017] The natural product embellin was determined to bind to the surface groove of the BIR3 domain of XIAP with similar affinity to the native SMAC peptide. in vitro It induces apoptosis in cell lines and causes tumor growth delay in xenografts (Nikolovska-Coleska et al., J. Med. Chem. 2004; 47(10): 2430-2440; Chitra et al., Chemotherapy 1994; 40: 109-113).

[0018] XIAP antisense oligonucleotides have been developed as therapeutic agents for solid tumors and hematological malignancies. In vitroThese antisense oligonucleotides have been shown to knock down protein expression levels by 70%, induce apoptosis and sensitize cells to chemotherapy, and delay tumor growth in vivo. One of these agents, AEG351156, has been studied in clinical trials (Hu et al., Clin. Cancer Res. 2003; 9: 2826-2836; Cummings et al., Br. J. Cancer 2005; 92: 532-538).

[0019] Small molecule antagonists of XIAP under development include peptide mimetics and synthetic agents. Peptide mimetics target the BIR3 domain, mimicking the SMAC degradation of caspase-9 bound to XIAP, and have been shown to induce apoptosis in a variety of tumor cell lines as single agents and chemosensitizers and are further undergoing clinical studies (Oost et al., J. Med. Chem. 2004; 47: 4417-4426; Sun et al., Bioorg. Med. Chem. Lett. 2005; 15: 793-797).

[0020] Synthetic small molecule antagonists of the BIR3 and BIR2 domains also exhibit antitumor activity in several different models, including induction of apoptosis by annexin-V staining and IC50 <10 µM against more than one-third of the NCI60 cell line panel. XIAP antagonists also induce dose-dependent cell death of primary cultured leukemia cells in 5 out of 5 chronic lymphocytic leukemia cell lines and 4 out of 5 acute myeloid leukemia cell lines (Schimmer et al., Cancer Cell 2004; 5: 25-35; Berezovskaya et al., Cancer Res. 2005; 65(6): 2378-86).

[0021] High levels of XIAP protein in tumor cell lines are inversely correlated with sensitivity to some anticancer drugs, specifically cytarabine and other nucleosides (Tamm et al., Clin. Cancer Research 2000; 6: 1796-1803). in vivo In two preclinical models of TRAIL-induced antitumor activity (Vogler 2008). Gene expression and transfection studies have shown that increased expression of the apoptosis inhibitor gene XIAP plays an important role in anoikis resistance and in the survival of circulating human prostate cancer cells, thereby promoting metastasis. Small molecule antagonists were found to be anti-metastatic in these models (Berezovskaya et al., Cancer Res. 2005; 65(6): 2378-86).

[0022] XIAP has also been found to be involved in other pathways associated with cancer and other diseases and these may also benefit from XIAP targeting agents. The E3 ligase activity of the RING finger domain of XIAP is able to bind both TAB1 and upstream BMP receptor (type 1), suggesting that XIAP may signal in a TGF-β-mediated pathway (Yamaguchi et al., EMBO 1999; 179-187). Overexpression of focal adhesion kinase (FAK) has been shown to cause upregulation of XIAP expression (Sonoda et al., J. Biol. Chem. 2000; 275: 16309-16315). E3 ligases are attractive therapeutic targets and molecules targeting this activity in other proteins such as MDM2 are being developed (Vassilev et al., Science 2004; 303: 844-848). Direct or indirect inhibition of XIAP ligase activity may also be used to treat cancer and other diseases. Dysregulation of apoptotic signaling, which can result from inhibition of IAP function that controls programmed cell death, is also implicated in a wide range of diseases, including disorders associated with cell accumulation (e.g., cancer, autoimmunity, inflammation, and restenosis) or disorders in which excessive apoptosis leads to cell destruction (e.g., stroke, heart failure, neurodegeneration such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, AIDS, ischemia (stroke, myocardial infarction), and osteoporosis).

[0023] XIAP is an important regulator of apoptosis in experimental autoimmune encephalomyelitis and a potential pharmacological target for the treatment of autoimmune diseases such as multiple sclerosis (MS) (Moore et al., 2004; 203(1): 79-93). Antisense-mediated knockdown of XIAP reverses paralysis in an animal model of MS, suggesting that therapies targeting XIAP and possibly other IAPs may be useful for the treatment of MS (Hebb et al., Curr. Drug Disc. Tech. 2008; 5(1): 75-7).

[0024] cIAP1, cIAP-2, XIAP and survivin are overexpressed in malignant pleural mesothelioma and are responsible for the great resistance of cultured mesothelioma cells to cisplatin. Levels of circulating TNF-α in mesothelioma patients before surgery to reduce tumor volume are significantly higher than those after surgery. TNF-α increases mRNA and protein levels of IAP-1, IAP-2 and XIAP (Gordon et al., 2007). NF-κB upregulation plays an important survival role in mesothelioma in response to the inflammatory effects of exposure to asbestos fibers (Sartore-Bianchi et al., 2007). IAP antagonists have the potential to reverse the pro-survival effects of TNF-α.

[0025] Once cIAP1 & 2 are depleted, the cell lines upregulate TNF-α expression sufficiently to act in an autocrine manner and the ability to kill cells is thought to be important for IAP activity (Nature Reviews Cancer (2010), 10(8), 561-74, Gryd-Hansen, M). However, In vivo Certain tumor types are surrounded by a network of proinflammatory cytokines and therefore tumor cells that switch to cell killing by apoptosis upon cIAP1 / 2 depletion can be triggered to apoptosis by TNF-α (or other death receptor cytokine agonists) that has been produced by surrounding cells in the tumor microenvironment such as tumor-associated macrophages or even by the tumor cells themselves. Certain tumor types such as breast tumors, ovarian tumors, and melanomas exhibit this "inflammatory phenotype" that may be targeted by IAP antagonists.

[0026] cIAP1 and cIAP2

[0027] Cellular IAP (cIAP) 1 and 2 are closely related members of the IAP family with three BIR domains, a RING domain, and a caspase recruitment (CARD) domain. A functional nuclear export signal is present in the CARD domain of cIAP1, which appears to be important for cell differentiation (Plenchette et al., Blood 2004; 104: 2035-2043). The presence of this CARD domain is unique to cIAP1 and cIAP2 within the IAP protein family. These two genes are located in tandem in chromosome 11q22 and are thought to have arisen by gene duplication in view of their high similarity.

[0028] cIAP1 (like XIAP and survivin) is widely expressed in tumor cell lines and has been found to be expressed at high levels in colorectal cancer, as well as lung, ovarian, renal, CNS and breast cancers (Tamm et al., Clin. Cancer Res. 2000; 6: 1796-1803). cIAP2 expression is generally more restricted and is thought to be regulated, despite being constitutively ubiquitinated and degraded by cIAP1 (Conze et al., Mol. Biol. Cell 2005; 25(8): 3348-56; Mahoney et al., PNAS 2008; 105: 11778-11783). Immunohistochemistry and Western blot analysis identified cIAP1 and cIAP2 as possible oncogenes, as both are overexpressed in a variety of lung cancers with or without higher copy numbers (Dia et al., Human Mol. Genetics 2003; 12(7): 791-801). cIAP1 expression levels appear to play a preferential role in early adenocarcinomas (Hofmann et al., J. Cancer Res. Clin. Oncology 2002; 128(10): 554-60).

[0029] Increased levels of cIAP1 and cIAP2 and decreased levels of endogenous inhibitors are associated with chemoresistance, as has been seen for XIAP. Overexpression of cIAP has been found In vitro It is associated with resistance to DNA alkylating agents such as carboplatin, cisplatin, and topoisomerase inhibitor VP-16 (Tamm et al., Clin. Cancer Res. 2000; 6: 1796-1803). It was found that the levels of cIAP1 and survivin were higher in thyroid cancer after cisplatin and doxorubicin treatment. Cells resistant to chemotherapy such as paclitaxel showed reduced SMAC expression and released very little of this protein from the mitochondria. It was found that downregulation of cIAP1 and survivin increased the cytotoxicity of cisplatin and doxorubicin, while overexpression of SMAC increased the efficacy of paclitaxel. However, silencing of cIAP1 and survivin by RNA interference restored sensitivity to doxorubicin and cisplatin (Tirrò et al.; Cancer Res. 2006; 66(8):4263-72).

[0030] SMAC mimetics such as LBW242 were initially thought to target XIAP primarily. However, studies have shown that targeting cIAP1 for degradation via autoubiquitination in cells (Yang et al., J. Biol. Chem. 2004; 279(17): 16963-16970) and that cIAP1 may contribute to the resulting apoptotic effects. siRNA of cIAP1 and tumor necrosis factor (TNF)-α induction (or stimulation) were found to combine synergistically and render cell lines more sensitive (Gaither et al., Cancer Res. 2007; 67(24): 11493-11498).

[0031] cIAP1 and cIAP2 have been shown to be key regulators of the NF-κB signaling pathway, which is involved in a variety of biological processes, specifically innate and adaptive immunity, as well as proliferation and survival. Dysregulation of the NF-κB pathway has been associated with inflammation and cancer, including hepatitis and ulcerative colitis, gastritis, hepatocellular carcinoma, colorectal cancer, and gastric cancer, as well as angiogenesis and metastasis. (Shen et al., Apoptosis 2009; 14: 348-363).

[0032] Upon ligand binding, TNF receptor (TNF-R) recruits TNFR-associated death domain (TRADD) and receptor interacting protein (RIP) 1. TRAF2 and cIAP1 / cIAP2 are then recruited to form a large membrane complex. RIP1 is ubiquitinated and these polyubiquitin chains serve as docking sites for downstream kinases, leading to NF-κB pathway signaling (Ea et al., Mol. Cell 2006; 22: 245-257; Wu et al., Nat. Cell Biol. 2006; 8: 398-406). The extended roles are complex and yet to be fully defined, but cIAP1 and cIAP2 are identified as key components of TNF-α-mediated NF-κB signaling regulation as well as constitutive (ligand-independent / classical) NF-κB signaling (Varfolomeev et al., Cell 2007; 131(4): 669-81). cIAP1 and cIAP2 have been shown to bind the adaptor protein TRAF2, which plays a role in both the classical and alternative NF-κB pathways as well as the MAPK pathway signaling pathway (Rothe et al., Cell 2005; 83: 1243-1252). cIAP1 and cIAP2 directly target RIP1 for ubiquitination in vitro (Betrand et al., Mol. Cell 2008; 30: 689-700).

[0033] TNF-α regulates many cellular functions including apoptosis, inflammation, immune responses, and cell growth and differentiation (Trace et al., Annu. Rev. Med. 1994; 45: 491-503) and therapeutic IAP antagonists may be beneficial in conditions where these functions are affected.

[0034] TNF-α production is seen in many malignancies and is one of the key drivers of cancer-associated inflammation, which drives tumor development and / or progression. cIAPs protect cancer cells from the lethal effects of TNF-α.

[0035] NAIP

[0036] NAIP was the first IAP discovered (Roy et al., Cell 1995; 80: 167-178). Among IAPs, NAIP is unique in that it has nucleotide binding and oligomerization domains and leucine-rich repeats similar to those contained in proteins generally involved in innate immunity. There are indications that NAIP may also be overexpressed in some cancers, including breast and esophageal cancers (Nemoto et al., Exp. Mol. Pathol. 2004; 76(3): 253-9) and MS (Choi et al., J. Korean Med. 2007; 22 Suppl: S17-23; Hebb et al., Mult. Sclerosis 2008; 14(5): 577-94).

[0037] ML-IAP

[0038] Melanoma inhibitor of apoptosis protein (ML-IAP) contains a single BIR and RING finger motif. ML-IAP is a potent inhibitor of apoptosis induced by death receptors and chemotherapeutic agents, and may act as a direct inhibitor of downstream effector caspases (Vucic et al., Curr. Biol. 2000; 10(21): 1359-66). ML-IAP is also known as baculovirus IAP repeat-containing protein 7 (BIRC7), kidney inhibitor of apoptosis protein (KIAP), RING finger protein 50 (RNF50) and Livin. The BIR domain of ML-IAP has an evolutionarily conserved fold required for anti-apoptotic activity. It has been found that most melanoma cell lines express high levels of ML-IAP compared to primary melanocytes that express undetectable levels. These melanoma cells have significantly greater resistance to drug-induced apoptosis. Increased ML-IAP expression confers resistance to apoptotic stimuli in melanoma cells and thus potentially contributes to the pathogenesis of this malignancy.

[0039] ILP-2

[0040] ILP-2, also known as BIRC8, has a single BIR domain and a RING domain. ILP-2 is expressed only in normal cells of the testis and binds to caspase 9 (Richter et al., Mol. Cell. Biol. 2001; 21: 4292-301).

[0041] Survivin

[0042] Survivin, also known as BIRC5, inhibits caspase 3 and caspase 7, but its main function is regulation of mitotic processes rather than apoptosis. Survivin promotes the formation of microtubules in the mitotic spindle, thereby counteracting apoptosis during the cell cycle. Inhibition of apoptosis by survivin predicts poor outcomes in colorectal cancer (Kawasaki et al., Cancer Res. 1998; 58(22): 5071-5074) and stage III gastric cancer (Song et al., Japanese J. Clin. Oncol. 2009; 39(5): 290-296).

[0043] BRUCE

[0044] BRUCE (BIR-repeat-containing ubiquitin conjugating enzyme) is a peripheral membrane protein in the trans-Golgi network with a single BIR domain, most similar to survivin. BRUCE inhibits through three mechanisms: (i) SMAC binding, (ii) HtrA2 protease, and (iii) caspase-mediated cleavage. In addition, BRUCE acts as an E2 / E3 ubiquitin ligase through the ubiquitin conjugating (UBC) domain. Summary of the invention

[0045] The present invention provides compounds of formula (I). The present invention provides compounds useful in therapy, in particular in the treatment of cancer. The compounds of formula (I) may be antagonists of the IAP protein family (IAP), and in particular antagonists of XIAP and / or cIAP (such as cIAP1 and / or cIAP2), and may be used to treat IAP-mediated conditions.

[0046] According to a first aspect of the present invention, there is provided a compound of formula (I):

[0047]

[0048] (I)

[0049] or a tautomeric or stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof;

[0050] in

[0051] X is CR 4 , N or NR 3 ;

[0052] in

[0053] • When X is CR 4 When U represents nitrogen and R 6 represents oxo; or

[0054] • When X is N, then U represents carbon and R 6 represents hydroxymethyl or -CH(OR x )CH2OR z ;or

[0055] • When X is NR 3 When U represents carbon and R 6 represents oxygen generation;

[0056] A dotted bond (-------) represents a single bond or a double bond, wherein at least two of the dotted bonds represent a double bond;

[0057] R 1 and R 2 independently represents hydrogen or methyl;

[0058] R 3 represents hydrogen, methyl or –NH2;

[0059] R 4 represents hydrogen, methyl, hydroxymethyl, –NH2 or fluorine;

[0060] R 5 represents unsubstituted n-butyl or benzyl substituted by one or two fluorine radicals on the phenyl group; and

[0061] R x and R z independently represents hydrogen or methyl.

[0062] In another aspect of the present invention, compounds of formula (I), pharmaceutical compositions comprising compounds of formula (I), and methods for synthesizing compounds of formula (I) are provided for use in preventing or treating the diseases or conditions described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 : Example 39 1 H NMR. Samples were acquired in DMSO-D6 and calibrated to δ = 2.50 ppm of undeuterated DMSO solvent residual. An internal reference standard (TCNB) was included which appeared as a singlet at δ = 8.5 ppm.

[0064] Figure 2: XRPD of Example 39.

[0065] Figure 3 :DSC of Example 39.

[0066] Figure 4 : Example 40 1 H NMR. Samples were acquired in DMSO-D6 and calibrated to δ = 2.50 ppm of undeuterated DMSO solvent residual. An internal reference standard (TCNB) was included which appeared as a singlet at δ = 8.5 ppm.

[0067] Figure 5 : XRPD of Example 40.

[0068] Figure 6 :DSC of Example 40.

[0069] Figure 7 : Example 41 1 H NMR. Samples were acquired in DMSO-D6 and calibrated to 2.50 ppm of undeuterated DMSO solvent residual.

[0070] Figure 8 : XRPD of Example 41.

[0071] Fig. 9 :DSC of Example 41.

[0072] Fig.10 : Example 42 1 H NMR. Samples were acquired in DMSO-D6 and calibrated to 2.50 ppm of undeuterated DMSO solvent residual.

[0073] Fig.11 : XRPD of Example 42.

[0074] Fig.12 :DSC of Example 42.

[0075] Fig.13 : XRPD of the reaction mixture of the product of L-(+)-lactate Form B of Example 40 (diffraction pattern marked 1) compared with L-(+)-lactate Form C of Example 43 (diffraction pattern marked 4), t=0h (diffraction pattern marked 2), 4 days later (diffraction pattern marked 3).

[0076] Fig.14 : XRPD of Example 43 isostructural to Form B at t=0 h (diffraction pattern marked 1), progress of the reaction mixture (diffraction patterns marked 2-6), and interconversion completed after heating t=5 days to give Form C (diffraction pattern marked 7).

[0077] Fig.15 : Example 43 1 H NMR. Samples were acquired in DMSO-D6 and calibrated to δ = 2.50 ppm of undeuterated DMSO solvent residual. An internal reference standard (TCNB) was included which appeared as a singlet at δ = 8.5 ppm.

[0078] Fig.16 : XRPD of Example 43 (diffractogram labeled 1) overlaid with anhydrous L-(+)-lactic acid (diffractogram labeled 2).

[0079] Fig.17 : DSC of Example 43 (Thermogram labeled 1) overlaid with anhydrous L-(+)-lactic acid (Thermogram labeled 2). DETAILED DESCRIPTION

[0080] definition

[0081] Unless the context indicates otherwise, references to formula (I) in all parts of this document (including uses, methods and other aspects of the invention) include references to all other subformulae, subgroups, preferences, embodiments and examples as defined herein.

[0082] The term "IAP" means any IAP family member XIAP, cIAP (cIAP1 and / or cIAP2), NAIP, ILP2, ML-IAP, survivin and / or BRUCE, specifically XIAP, cIAP1, cIAP2, ML-IAP, more specifically XIAP, cIAP1 and / or cIAP2, most specifically XIAP and / or cIAP1. Specifically, it means the BIR domain of an IAP, specifically the BIR domain of XIAP, cIAP1 or cIAP2.

[0083] "One or more IAP family members" means any IAP family member, specifically XIAP, cIAP1 and / or cIAP2, more specifically XIAP and / or cIAP1.

[0084] "Potency" is a measure of drug activity expressed in terms of the amount required to produce an effect of a given intensity. Highly potent drugs elicit a greater response at low concentrations. Potency is proportional to affinity and efficacy. Affinity is the ability of a drug to bind to a receptor. Efficacy is the relationship between receptor occupancy and the ability to elicit a response at the molecular, cellular, tissue or system level.

[0085] The term "antagonist" refers to a receptor ligand or drug type that blocks or inhibits an agonist-mediated biological response. Antagonists have affinity for their associated receptors but do not have agonistic efficacy, and binding will destroy the interaction of any ligand (e.g., endogenous ligand or substrate, agonist or inverse agonist) at the receptor and inhibit the function of any ligand (e.g., endogenous ligand or substrate, agonist or inverse agonist) at the receptor. Antagonism can occur directly or indirectly and can be mediated by any mechanism and at any physiological level. An example of indirect antagonism may be indirect antagonism of cIAP due to ubiquitination of cIAP that causes its degradation. Therefore, the antagonism of a ligand can manifest itself in functionally different ways under different circumstances. Antagonists mediate their effects by binding to active sites or allosteric sites on receptors, or they can interact at unique binding sites that are not usually involved in biological regulation of receptor activity. Antagonist activity may be reversible or irreversible depending on the persistence of the antagonist-receptor complex, which in turn depends on the nature of the antagonist receptor binding.

[0086] The term "treatment" as used herein in the context of treating a condition, i.e., a state, disorder, or disease, generally relates to treatments and therapies in which some desired therapeutic effect is achieved (e.g., inhibiting the progression of a condition), whether human or animal (e.g., in veterinary applications), and includes reducing the rate of progression, stopping the rate of progression, ameliorating the condition, reducing or alleviating at least one symptom associated with or caused by the treated condition, and curing the condition. For example, treatment may reduce one or several symptoms of a condition or completely eradicate the condition.

[0087] The term "prevention" as used herein in the context of treating a condition, i.e., a state, disorder or disease (i.e., using a compound as a preventative measure) generally relates to prevention or prevention, whether in humans or animals (e.g., in veterinary applications), in which some desired preventative effect is achieved (e.g., in preventing a disease from occurring or preventing a disease). Prevention includes complete and total blocking of all symptoms of a disorder for an unlimited period of time, slowing down the onset of only one or several symptoms of a disease, or making a disease less likely to occur.

[0088] References to the prevention or treatment of a disease state or condition, such as cancer, include within their scope alleviating or reducing the incidence of cancer.

[0089] As used herein, the term "mediate" as used, for example, in conjunction with the IAPs described herein (and, for example, as applied to various physiological processes, diseases, states, conditions, therapies, treatments or interventions) is intended to operate restrictively, such that the various processes, diseases, states, conditions, treatments and interventions to which the term applies are those in which the protein plays a physiological role. Where the term applies to a disease, state or condition, the biological role played by the protein may be direct or indirect and may be necessary and / or sufficient for the manifestation of the disease, state or condition (or its etiology or progression). Thus, protein function (and specifically abnormal levels of function, such as overexpression or underexpression) is not necessarily the proximal cause of the disease, state or condition: rather, it is contemplated that mediated diseases, states or conditions include those with multifactorial etiologies and complex progressions in which the protein is only partially involved. Where the term applies to treatment, prevention or intervention, the role played by the protein may be direct or indirect and may be necessary and / or sufficient for the treatment, prevention or intervention results. Thus, disease states or conditions mediated by the protein include the development of resistance to any particular cancer drug or treatment.

[0090] The combinations of the present invention may produce therapeutically effective effects relative to the therapeutic effects of the individual compounds / agents when administered separately.

[0091] The term "effective" includes favorable effects, such as addition, synergy, reduction of side effects, reduction of toxicity, increase in time to disease progression, increase in survival time, sensitization or resensitization of one agent to another, or increase in response rate. Advantageously, effective effects can allow lower doses of each or any component to be administered to the patient, thereby reducing the toxicity of chemotherapy while producing and / or maintaining the same therapeutic effect. In the context of the present invention, a "synergistic" effect refers to a therapeutic effect produced by a combination that is greater than the sum of the therapeutic effects of each agent of the combination when provided alone. In the context of the present invention, an "additive" effect refers to a therapeutic effect produced by a combination that is greater than the therapeutic effect of any agent of the combination when provided alone. The term "response rate" used herein refers to the degree to which the tumor size is reduced at a given time point, such as 12 weeks, in the case of solid tumors. Therefore, for example, a 50% response rate means a 50% reduction in tumor size. "Clinical response" mentioned herein refers to a response rate of 50% or greater. "Partial response" is defined herein as a response rate of less than 50%.

[0092] As used herein, the term "combination" when applied to two or more compounds and / or agents is intended to define a substance in which the two or more agents are associated. The terms "combined" and "combination" should be interpreted accordingly in this context.

[0093] The association of two or more compounds / agents in a combination may be physical or non-physical. Examples of physically associated combination compounds / agents include:

[0094] • a combination (eg, a single formulation) comprising two or more compounds / agents mixed together (eg, within the same unit dose);

[0095] • Compositions comprising substances in which two or more compounds / agents are chemically / physicochemically linked (e.g. by cross-linking, molecular coagulation or binding to a common carrier moiety);

[0096] • compositions comprising materials in which two or more compounds / agents are chemically / physicochemically co-packaged (e.g., disposed on or within a lipid vesicle, particle (e.g., microparticle or nanoparticle), or emulsion droplet);

[0097] • A pharmaceutical kit, drug pack or patient pack in which two or more compounds / agents are co-packaged or co-supplied (eg, as part of a group of unit doses).

[0098] Examples of combination compounds / agents that are not physically associated include:

[0099] • a substance (e.g., a non-unitary preparation) that contains at least one of the two or more compounds / agents together with instructions for temporarily associating at least one of the compounds to form a physical association of the two or more compounds / agents;

[0100] • a substance (e.g., a non-unitary preparation) that contains at least one of the two or more compounds / agents together with instructions for use in a combination therapy containing the two or more compounds / agents;

[0101] • a substance comprising at least one of the two or more compounds / agents together with instructions for administration to a patient population to which another or other of the two or more compounds / agents has been (or is being) administered;

[0102] • A substance comprising at least one of two or more compounds / agents in an amount or form particularly suitable for use with another or other combination of the two or more compounds / agents.

[0103] As used herein, the term "combination therapy" is intended to define a therapy including a combination (as defined above) of two or more compounds / agents. Therefore, "combination therapy", "combination" and "combination" used in the present application may refer to a compound / agent used as part of the same overall treatment regimen. Therefore, the respective dosage of two or more compounds / agents may be different: each may be administered simultaneously or at different times. It will therefore be understood that the compound / agent of the combination may be sequentially (e.g., before or after) or simultaneously administered, in the same pharmaceutical preparation (i.e., together) or in different pharmaceutical preparations (i.e., separately). In the same preparation, it is simultaneously as a single preparation, and in different pharmaceutical preparations, it is non-single at the same time. In combination therapy, the respective dosage of two or more compounds / agents may also be different in terms of route of administration.

[0104] As used herein, the term "drug kit" defines a set of one or more unit doses of a pharmaceutical composition together with a dosing device (e.g., a measuring device) and / or a delivery device (e.g., an inhaler or a syringe), optionally all contained in a common outer package. In a drug kit comprising a combination of two or more compounds / agents, each compound / agent can be a single or non-single preparation. The unit dose can be contained in a blister package. The drug kit can optionally further include instructions for use.

[0105] As used herein, the term "pharmaceutical package" defines a group of one or more unit doses of a pharmaceutical composition, optionally contained in a common outer package. In a pharmaceutical package comprising a combination of two or more compounds / agents, each compound / agent can be a single or non-single preparation. The unit dose can be contained in a blister package. The pharmaceutical package can optionally further include instructions for use.

[0106] As used herein, the term "n-butyl" refers to a linear alkyl group containing 4 carbon atoms.

[0107] As used herein, the term "oxo" refers to the group =0.

[0108] The dotted bond (-------) represents a single bond or double bond required to complete the valence of the atoms connected by the bond. It will be understood that in some cases, the bond has aromatic character. The dotted bond (-------) represents a single bond or double bond, so that the ring containing X and U contains at least two double bonds. DETAILED DESCRIPTION OF THE INVENTION

[0110] It will be appreciated from formula (I) that the compounds of the present invention may be represented as follows:

[0111]

[0112] Where Q represents any of the following A, B or C:

[0113]

[0114] In one embodiment Q represents A. In one embodiment Q represents B. In one embodiment Q represents C.

[0115] In one embodiment X represents CR 4 or N. In an alternative embodiment, X represents CR 4 or NR 3 In an alternative embodiment, X represents N or NR 3 In a further embodiment, X represents CR 4 In a further alternative embodiment, X represents N. In a still further alternative embodiment, X represents NR 3 .

[0116] In one embodiment, R 1 and R 2 one of which represents hydrogen, and the other represents methyl, or R 1 and R 2 In one embodiment, R 1 and R 2 One of represents hydrogen, and the other represents methyl. In a further embodiment, R 1 Represents methyl and R 2 In an alternative embodiment, R 1 Represents hydrogen and R 2 In a further alternative embodiment, R 1 and R 2 All represent hydrogen.

[0117] In one embodiment, R 3 In an alternative embodiment, R 3 represents hydrogen or -NH2. In a further alternative embodiment, R 3 represents methyl or -NH2. In a further embodiment, R 3 In a further alternative embodiment, R 3 In a further alternative embodiment, R 3 Stands for –NH2.

[0118] In one embodiment, R 4 represents hydrogen or methyl. In a further embodiment, R 4 In an alternative embodiment, R 4 Represents methyl.

[0119] In one embodiment, R5 represents unsubstituted n-butyl or benzyl substituted by one or two fluorine groups at the 2, 3 and / or 4 positions of the phenyl group. 5 In an alternative embodiment, R 5 represents a benzyl group substituted by one or two fluorine groups on the phenyl group. In a further embodiment, R 5 represents a benzyl group substituted by one or two fluorine groups at the 2, 3 and / or 4 positions of the phenyl group. In a further embodiment, R 5 represents a benzyl group substituted by a fluorine at the 2, 3 or 4 position of the phenyl group (i.e., R 5 represents 2-fluorobenzyl, 3-fluorobenzyl or 4-fluorobenzyl). In a further embodiment, R 5 represents a benzyl group substituted by a fluorine at the 4-position of the phenyl group (i.e., R 5 In a further embodiment, R 5 represents a benzyl group substituted by two fluorine groups at the 2,3, 3,4 or 2,4 positions of the phenyl group (i.e., R 5 represents 2,3-difluorobenzyl, 3,4-difluorobenzyl or 2,4-difluorobenzyl). In still further embodiments, R 5 It means a benzyl group substituted by two fluorine groups at the 2 and 4 positions of the phenyl group (i.e. R 5 represents 2,4-difluorobenzyl).

[0120] In a further embodiment, R 5 represents unsubstituted n-butyl, 4-fluorophenyl or 2,4-difluorophenyl. In still further embodiments, R 5 Represents 4-fluorophenyl.

[0121] In one embodiment R 6 represents hydroxymethyl or -CH(OR x )CH2OR z In one embodiment R 6 represents a hydroxymethyl group.

[0122] In one embodiment R 6 Indicates -CH(OR x )CH2OR z In one embodiment, R x and R z One of them represents hydrogen and the other represents methyl or R x and R z In a further embodiment, R x Represents methyl and R z In an alternative embodiment, R x Represents hydrogen and R zIn a further alternative embodiment, R x and R z In a further embodiment, R x represents hydrogen or methyl and R z In a further alternative embodiment, R x and R z All represent methyl.

[0123] In one embodiment, R 6 represents hydroxymethyl, -CH(OH)CH2OH, -CH(OMe)CH2OH or -CH(OH)CH2OMe. In a further embodiment, R 6 represents hydroxymethyl, -CH(OH)CH2OH or -CH(OMe)CH2OH. In still further embodiments, R 6 represents a hydroxymethyl group.

[0124] In one embodiment R 6 Represents oxo (ie, =O).

[0125] Sub

[0126] In one embodiment the compound of formula (I) is wherein:

[0127] X is CR 4 , N or NR 3 ;

[0128] in

[0129] • When X is CR 4 When U represents nitrogen and R 6 represents oxo; or

[0130] • When X is N, then U represents carbon and R 6 represents hydroxymethyl or -CH(OR x )CH2OR z ;or

[0131] • When X is NR 3 When U represents carbon and R 6 represents oxygen generation;

[0132] A dotted bond (-------) represents a single bond or a double bond, wherein at least two of the dotted bonds represent a double bond;

[0133] R 1 and R 2 One of them represents hydrogen and the other represents methyl or R 1 and R 2 All represent hydrogen;

[0134] R3 represents hydrogen, methyl or –NH2;

[0135] R 4 represents hydrogen or methyl;

[0136] R 5 represents unsubstituted n-butyl or benzyl substituted by one or two fluorine groups at the 2, 3 and / or 4 positions of the phenyl group; and

[0137] R x and R z One of them represents hydrogen and the other represents methyl or R x and R z All represent hydrogen.

[0138] In a further embodiment the compound of formula (I) is wherein:

[0139] X is CR 4 , N or NR 3 ;

[0140] in

[0141] • When X is CR 4 When U represents nitrogen and R 6 represents oxo; or

[0142] • When X is N, then U represents carbon and R 6 represents hydroxymethyl or -CH(OR x )CH2OR z ;or

[0143] • When X is NR 3 When U represents carbon and R 6 represents oxygen generation;

[0144] A dotted bond (-------) represents a single bond or a double bond, wherein at least two of the dotted bonds represent a double bond;

[0145] R 1 and R 2 One of them represents hydrogen and the other represents methyl or R 1 and R 2 All represent hydrogen;

[0146] R 3 represents hydrogen, methyl or –NH2;

[0147] R 4 represents hydrogen or methyl;

[0148] R 5 represents unsubstituted n-butyl, 4-fluorobenzyl or 2,4-fluorobenzyl;

[0149] Rx represents hydrogen or methyl; and

[0150] R z Represents hydrogen.

[0151] In one embodiment the compound of formula (I) is a compound of formula (la):

[0152]

[0153] (Ia)

[0154] or its tautomeric or stereochemically isomeric form, pharmaceutically acceptable salt or solvate; wherein R 1 , R 2 , R 4 and R 5 As defined in any embodiment.

[0155] In one embodiment of the compound of formula (Ia), R 1 and R 2 One of them represents hydrogen and the other represents methyl or R 1 and R 2 In a further embodiment of the compound of formula (Ia), R 1 Represents hydrogen and R 2 Represents methyl or R 1 and R 2 All represent hydrogen.

[0156] In further embodiments of the compounds of Formula (Ia), R 1 Represents methyl and R 2 In an alternative embodiment of the compound of formula (Ia), R 1 Represents hydrogen and R 2 Represents methyl.

[0157] In one embodiment of the compound of formula (Ia), R 4 represents hydrogen or methyl.

[0158] In one embodiment of the compound of formula (Ia), R 5 represents unsubstituted n-butyl or benzyl substituted by one or two fluorine groups at the 2, 3 and / or 4 positions of the phenyl group. In one embodiment of the compound of formula (Ia), R 5 In an alternative embodiment of the compound of formula (Ia), R 5 represents a benzyl group substituted by one or two fluorine groups on the phenyl group. In a further embodiment of the compound of formula (Ia), R 5represents a benzyl group substituted by one or two fluorine groups at the 2, 3 and / or 4 positions of the phenyl group. In a further embodiment of the compound of formula (Ia), R 5 represents a benzyl group substituted by a fluorine at the 4-position of the phenyl group (i.e., R 5 In a further embodiment of the compound of formula (Ia), R 5 It means a benzyl group substituted by two fluorine groups at the 2 and 4 positions of the phenyl group (i.e. R 5 represents 2,4-difluorobenzyl).

[0159] In one embodiment the compound of formula (I) is a compound of formula (Ib):

[0160]

[0161] (Ib)

[0162] or its tautomeric or stereochemically isomeric form, pharmaceutically acceptable salt or solvate; wherein R 1 , R 2 , R 5 , R 6 , R x and R z As defined in any embodiment. In one embodiment R 6 represents hydroxymethyl or -CH(OR x )CH2OR z .

[0163] In one embodiment of the compound of formula (Ib) R 1 Represents methyl and R 2 Represents hydrogen or R 1 and R 2 All represent hydrogen.

[0164] In further embodiments of the compounds of formula (Ib) R 1 and R 2 All represent hydrogen.

[0165] In one embodiment of the compound of formula (Ib) R 5 represents unsubstituted n-butyl or benzyl substituted by one or two fluorine groups at the 2, 3 and / or 4 positions of the phenyl group. In one embodiment of the compound of formula (Ib), R 5 In an alternative embodiment of the compound of formula (Ib) R 5 represents a benzyl group substituted by one or two fluorine groups on the phenyl group. In a further embodiment of the compound of formula (Ib) R 5represents a benzyl group substituted by one or two fluorine groups at the 2, 3 and / or 4 positions of the phenyl group. In a further embodiment of the compound of formula (Ib) R 5 represents a benzyl group substituted by a fluorine at the 2, 3 or 4 position of the phenyl group (i.e., R 5 represents 2-fluorobenzyl, 3-fluorobenzyl or 4-fluorobenzyl). In a further embodiment of the compound of formula (Ib), R 5 It means a benzyl group substituted by two fluorine groups at the 2 and 4 positions of the phenyl group (i.e. R 5 In still further embodiments of the compound of formula (Ib), R 5 represents a benzyl group substituted by a fluorine at the 4-position of the phenyl group (i.e., R 5 represents 4-fluorobenzyl).

[0166] In one embodiment of the compound of formula (Ib) R 6 It represents hydroxymethyl, -CH(OH)CH2OH, -CH(OMe)CH2OH or -CH(OH)CH2OMe.

[0167] In further embodiments of the compounds of formula (Ib) R 6 It represents hydroxymethyl, -CH(OH)CH2OH or -CH(OMe)CH2OH.

[0168] In still further embodiments of the compounds of Formula (Ib), R 6 represents a hydroxymethyl group.

[0169] In one embodiment the compound of formula (I) is a compound of formula (Ic):

[0170]

[0171] (Ic)

[0172] or its tautomeric or stereochemically isomeric form, pharmaceutically acceptable salt or solvate; wherein R 1 , R 2 , R 3 and R 5 As defined in any embodiment.

[0173] In one embodiment of the compound of formula (Ic), R 1 and R 2 One of them represents hydrogen and the other represents methyl or R 1 and R 2 In a further embodiment of the compound of formula (Ic), R 1 Represents methyl and R 2 Represents hydrogen or R 1 and R2 All represent hydrogen.

[0174] In one embodiment of the compound of formula (Ic), R 3 In an alternative embodiment of the compound of formula (Ic), R 3 represents hydrogen or -NH2. In a further alternative embodiment of the compound of formula (Ic), R 3 represents methyl or -NH2. In a further embodiment of the compound of formula (Ic), R 3 In a further alternative embodiment of the compound of formula (Ic) R 3 In still further alternative embodiments of the compounds of formula (Ic), R 3 Stands for –NH2.

[0175] In one embodiment of the compound of formula (Ic) R 5 represents unsubstituted n-butyl or benzyl substituted by one or two fluorine groups at the 2, 3 and / or 4 positions of the phenyl group. In one embodiment of the compound of formula (Ic), R 5 In an alternative embodiment of the compound of formula (Ic): R 5 represents a benzyl group substituted by one or two fluorine groups on the phenyl group. In a further embodiment of the compound of formula (Ic) R 5 represents a benzyl group substituted by one or two fluorine groups at the 2, 3 and / or 4 positions of the phenyl group. In a further embodiment of the compound of formula (Ic) R 5 represents a benzyl group substituted by a fluorine at the 2- or 4-position of the phenyl group (i.e., R 5 represents 2-fluorobenzyl or 4-fluorobenzyl). In a further embodiment of the compound of formula (Ic), R 5 represents a benzyl group substituted by a fluorine at the 4-position of the phenyl group (i.e., R 5 In a further embodiment of the compound of formula (Ic), R 5 It means a benzyl group substituted by two fluorine groups at the 2 and 4 positions of the phenyl group (i.e. R 5 represents 2,4-difluorobenzyl).

[0176] In one embodiment the compound of formula (I) is a compound of formula (Id):

[0177]

[0178] (Id)

[0179] or its tautomeric or stereochemically isomeric form, pharmaceutically acceptable salt or solvate; wherein R 5 As defined in any embodiment.

[0180] In one embodiment of the compound of formula (Id) R 5 represents unsubstituted n-butyl or benzyl substituted by one or two fluorine groups at the 2, 3 and / or 4 positions of the phenyl group. In one embodiment of the compound of formula (Id), R 5 In an alternative embodiment of the compound of formula (Id): R 5 represents a benzyl group substituted by one or two fluorine groups on the phenyl group. In a further embodiment of the compound of formula (Id) R 5 represents a benzyl group substituted by one or two fluorine groups at the 2, 3 and / or 4 positions of the phenyl group. In a further embodiment of the compound of formula (Id) R 5 represents a benzyl group substituted by a fluorine at the 2, 3 or 4 position of the phenyl group (i.e., R 5 represents 2-fluorobenzyl, 3-fluorobenzyl or 4-fluorobenzyl). In a further embodiment of the compound of formula (Id), R 5 It means a benzyl group substituted by two fluorine groups at the 2 and 4 positions of the phenyl group (i.e. R 5 represents 2,4-difluorobenzyl). In still further embodiments of the compound of formula (Id) R 5 represents a benzyl group substituted by a fluorine at the 4-position of the phenyl group (i.e., R 5 represents 4-fluorobenzyl).

[0181] In one embodiment, the compound of formula (I) is a compound of formula (I), (Ia), (Ib) or (Ic), wherein R 1 Represents methyl and R 2 Represents hydrogen.

[0182] In one embodiment, the compound of formula (I) is a compound of formula (I), (Ia), (Ib) or (Ic), wherein R 1 and R 2 All represent hydrogen.

[0183] In one embodiment, the compound of formula (I) is a compound of formula (I), (Ia), (Ib) or (Ic), wherein R 1 Represents hydrogen and R 2 Represents methyl.

[0184] In one embodiment, the compound of formula (I) is a compound of formula (I), (Ia), (Ib), (Ic) or (Id), wherein R 5 represents an unsubstituted n-butyl group.

[0185] In one embodiment, the compound of formula (I) is a compound of formula (I), (Ia), (Ib), (Ic) or (Id), wherein R5 It represents a benzyl group substituted by one or two fluorine groups at the 2, 3 and / or 4 position of the phenyl group.

[0186] In one embodiment, the compound of formula (I) is a compound of formula (I), (Ia), (Ib), (Ic) or (Id), wherein R 5 It represents a benzyl group substituted by one or two fluorine groups on the phenyl group.

[0187] In one embodiment, the compound of formula (I) is a compound of formula (I), (Ia), (Ib), (Ic) or (Id), wherein R 5 It represents a benzyl group substituted by two fluorine groups on the phenyl group, for example 2,3 disubstituted, 2,4 disubstituted, 2,5 disubstituted, 3,5 disubstituted, 2,6 disubstituted or 3,4 disubstituted.

[0188] In one embodiment, the compound of formula (I) is a compound of formula (I), (Ia), (Ib), (Ic) or (Id), wherein R 5 It represents a benzyl group substituted by one or two fluorine groups at the 2, 3 and / or 4 position of the phenyl group.

[0189] In one embodiment, the compound of formula (I) is a compound of formula (I), (Ia), (Ib), (Ic) or (Id), wherein R 5 represents a benzyl group substituted by a fluorine at the 2, 3 or 4 position of the phenyl group (i.e., R 5 represents 2-fluorobenzyl, 3-fluorobenzyl or 4-fluorobenzyl).

[0190] In one embodiment, the compound of formula (I) is a compound of formula (I), (Ia), (Ib), (Ic) or (Id), wherein R 5 represents a benzyl group substituted by two fluorine groups at the 2,3, 3,4 or 2,4 positions of the phenyl group (i.e., R 5 represents 2,3-difluorobenzyl, 3,4-difluorobenzyl or 2,4-difluorobenzyl).

[0191] In one embodiment, the compound of formula (I) is a compound of formula (I), (Ia), (Ib), (Ic) or (Id), wherein R 5 It means a benzyl group substituted by two fluorine groups at the 2 and 4 positions of the phenyl group (i.e. R 5 represents 2,4-difluorobenzyl).

[0192] In one embodiment, the compound of formula (I) is a compound of formula (I), (Ia), (Ib), (Ic) or (Id), wherein R 5 represents a 2,4-difluorobenzyl group or a 4-fluorobenzyl group.

[0193] In one embodiment, the invention provides a compound of formula (I) comprising the free base of a compound of Examples 1-37, or a tautomeric or stereochemically isomeric form, a pharmaceutically acceptable salt or solvate thereof.

[0194] In one embodiment the invention provides a compound of formula (I) which is the free base of a compound of Examples 1-37, or a tautomeric or stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

[0195] In one embodiment the invention provides compounds of formula (I) comprising compounds of Examples 1-37, or tautomeric or stereochemically isomeric forms or solvates thereof.

[0196] In a further embodiment the compound is selected from the free base of Examples 1-34 or a tautomeric or stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

[0197] In a further embodiment, the present invention provides a compound of formula (I) comprising a compound selected from the group consisting of:

[0198] 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one;

[0199] 6-[(4-Fluorophenyl)methyl]-3,3,4-trimethyl-1-{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]acetyl}-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one;

[0200] 6-[(2,4-difluorophenyl)methyl]-3,3-dimethyl-1-{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]acetyl}-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one;

[0201] 6-[(2,4-difluorophenyl)methyl]-3,3,4-trimethyl-1-{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]acetyl}-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one;

[0202] 1-[5-((R or S)-1,2-dihydroxyethyl)-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl]-2-[(2R,5R)-2-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-5-methylpiperazin-1-yl]ethan-1-one;

[0203] 6-[(2,4-difluorophenyl)methyl]-1-{2-[(2R,5R)-2-{[(2S,5R)-2,5-dimethylmorpholin-4-yl]methyl}-5-methylpiperazin-1-yl]acetyl}-3,3-dimethyl-1H,2H,3H,5H,6H-pyrrolo[2,3-c]pyridin-5-one;

[0204] 4-amino-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1-{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]acetyl}-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one;

[0205] 1-{6-[(4-fluorophenyl)methyl]-5-((R or S)-2-hydroxy-1-methoxyethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one;

[0206] 4-amino-6-butyl-1-{2-[(2R,5R)-2-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-5-methylpiperazin-1-yl]acetyl}-3,3-dimethyl-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one;

[0207] 6-[(2,4-difluorophenyl)methyl]-3,3,4-trimethyl-1-{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]acetyl}-1H,2H,3H,5H,6H-pyrrolo[2,3-c]pyridin-5-one;

[0208] 6-butyl-1-{2-[(2R,5R)-2-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-5-methylpiperazin-1-yl]acetyl}-3,3-dimethyl-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one; and

[0209] 6-butyl-1-{2-[(2R,5R)-2-{[(2S,5R)-2,5-dimethylmorpholin-4-yl]methyl}-5-methylpiperazin-1-yl]acetyl}-3,3-dimethyl-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one;

[0210] or a tautomeric or stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

[0211] In a further embodiment, the present invention provides a compound selected from the group consisting of:

[0212] 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one dihydrochloride (E2);

[0213] 6-[(4-Fluorophenyl)methyl]-3,3,4-trimethyl-1-{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]acetyl}-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (E6);

[0214] 6-[(2,4-difluorophenyl)methyl]-3,3-dimethyl-1-{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]acetyl}-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (E8);

[0215] 6-[(2,4-difluorophenyl)methyl]-3,3,4-trimethyl-1-{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]acetyl}-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (E19);

[0216] 1-[5-((R or S)-1,2-dihydroxyethyl)-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl]-2-[(2R,5R)-2-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-5-methylpiperazin-1-yl]ethan-1-one dihydrochloride (E21);

[0217] 6-[(2,4-difluorophenyl)methyl]-1-{2-[(2R,5R)-2-{[(2S,5R)-2,5-dimethylmorpholin-4-yl]methyl}-5-methylpiperazin-1-yl]acetyl}-3,3-dimethyl-1H,2H,3H,5H,6H-pyrrolo[2,3-c]pyridin-5-one dihydrochloride (E22);

[0218] 4-Amino-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1-{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]acetyl}-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (E24);

[0219] 1-{6-[(4-Fluorophenyl)methyl]-5-((R or S)-2-hydroxy-1-methoxyethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one trihydrochloride (E27);

[0220] 4-Amino-6-butyl-1-{2-[(2R,5R)-2-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-5-methylpiperazin-1-yl]acetyl}-3,3-dimethyl-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (E30);

[0221] 6-[(2,4-difluorophenyl)methyl]-3,3,4-trimethyl-1-{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]acetyl}-1H,2H,3H,5H,6H-pyrrolo[2,3-c]pyridin-5-one dihydrochloride (E31);

[0222] 6-Butyl-1-{2-[(2R,5R)-2-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-5-methylpiperazin-1-yl]acetyl}-3,3-dimethyl-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (E32) and

[0223] 6-Butyl-1-{2-[(2R,5R)-2-{[(2S,5R)-2,5-dimethylmorpholin-4-yl]methyl}-5-methylpiperazin-1-yl]acetyl}-3,3-dimethyl-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (E37)

[0224] or a tautomeric or stereochemically isomeric form or a solvate thereof.

[0225] In a further embodiment, the compound is selected from the free base of Examples 2, 6, 19, 21, 22, 24, 27, 30, 31 and 32, or a tautomeric or stereochemically isomeric form, a pharmaceutically acceptable salt or solvate thereof.

[0226] In still further embodiments, the present invention provides a compound of formula (I) comprising 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one or a tautomeric or stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

[0227] In still further embodiments, the present invention provides a compound of formula (I) comprising 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one hydrochloride or a tautomeric or stereochemically isomeric form or solvate thereof.

[0228] In still a further embodiment, the present invention provides 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one dihydrochloride (E2).

[0229] In still further embodiments, the present invention provides 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one lactate or a tautomeric or stereochemically isomeric form or solvate thereof.

[0230] In still further embodiments, the present invention provides 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate or a tautomeric or stereochemically isomeric form or solvate thereof.

[0231] In still further embodiments, the compound is selected from Examples 38-42.

[0232] In still further embodiments, the present invention provides 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate (Form A) (E39).

[0233] In still further embodiments, the present invention provides 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate (Form B) (E40).

[0234] In still further embodiments, the present invention provides 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate (Form C) (E43).

[0235] In still further embodiments, the present invention provides 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate or a tautomeric or stereochemically isomeric form or solvate thereof.

[0236] In still further embodiments, the present invention provides 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate (Form F) (E41).

[0237] In still further embodiments, the present invention provides 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one methanesulfonate or a tautomeric or stereochemically isomeric form or solvate thereof.

[0238] In still further embodiments, the present invention provides 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one methanesulfonate (Form B) (E42).

[0239] In a further embodiment, the selected compound is not Example 35 or a tautomeric or stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

[0240] In a further embodiment, the selected compound is not Example 2 or a tautomeric or stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

[0241] For the avoidance of doubt, it is to be understood that each general and specific preference, embodiment and example for one substituent may be combined with each general and specific preference, embodiment and example for one or more, and in particular all, other substituents defined herein, and that all such embodiments are included in the present application.

[0242] Salts, solvates, tautomers, isomers, N-oxides, esters, prodrugs and isotopes

[0243] Reference to compounds of formula (I) and subgroups thereof also includes their ionic forms, salts, solvates, isomers (including geometric isomers and stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms, such as discussed below; in particular, their salts or tautomers or isomers or N-oxides or solvates; and more in particular, their salts or tautomers or N-oxides or solvates, even more in particular, their salts or tautomers or solvates.

[0244] Salt

[0245] Many compounds of formula (I) can exist in salt form, for example acid addition salts or in some cases salts of organic and inorganic bases, such as carboxylates, sulfonates and phosphates. All such salts are within the scope of the present invention, and reference to compounds of formula (I) includes salt forms of the compounds.

[0246] The salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods, such as Pharmaceutical Salts: Properties, Selection, and Use , P. Heinrich Stahl (editor), Camille G. Wermuth (editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; usually a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is used.

[0247] Acid addition salts (monobasic or dibasic) can be formed with a wide variety of acids (both inorganic and organic). Examples of acid addition salts include monobasic or dibasic salts formed with an acid selected from the group consisting of acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, butyric acid, (+) camphoric acid, camphor-sulfonic acid, (+)-(1 S)-camphor-10-sulfonic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, mucic acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-ketoglutaric acid, glycolic acid, hippuric acid, hydrohalic acid (e.g., hydrobromic acid, hydrochloric acid, hydroiodic acid), isethionic acid, lactic acid (e.g., (+)-L-lactic acid, (±)-DL-lactic acid), lactobionic acid, Maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyruvic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid and valeric acid, as well as acylated amino acids and cation exchange resins.

[0248] A specific group of salts includes salts formed from acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid (methanesulfonic acid), ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propionic acid, butyric acid, malonic acid, glucuronic acid and lactobionic acid. A specific subgroup of salts includes salts formed from hydrochloric acid, lactic acid (e.g., (+)-L-lactic acid, (-)-D-lactic acid or (±)-DL-lactic acid), sulfuric acid and methanesulfonic acid (methanesulfonic acid). Another specific subgroup of salts includes salts formed from lactic acid (e.g., (+)-L-lactic acid, (-)-D-lactic acid or (±)-DL-lactic acid), sulfuric acid and methanesulfonic acid (methanesulfonic acid). Another subset of specific salts includes salts formed from lactic acid (e.g., (+)-L-lactic acid, (-)-D-lactic acid, or (±)-DL-lactic acid) and sulfuric acid. One specific salt is the hydrochloride salt. Another specific salt is the lactate salt (e.g., compounds of Examples 39, 40, and 43). Another specific salt is the sulfate salt (e.g., compound of Example 41). Another specific salt is the methanesulfonate salt (e.g., compound of Example 42). One specific salt is the lactate salt (e.g., compounds of Examples 39, 40, and 43, particularly the compound of Example 43), e.g., the L-(+)-lactate salt.

[0249] If the compound is anionic or has a functional group that can be anionic (e.g., -COOH can be -COO - ), then the salt may be formed with an organic or inorganic base that generates a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Li + 、Na + and K+ ; Alkaline earth metal cations, such as Ca 2+ and Mg 2+ ; and other cations, such as Al 3+ or Zn + Examples of suitable organic cations include, but are not limited to, ammonium ions (i.e., NH4 + ) and substituted ammonium ions (e.g., NH3R + NH2R2 + 、NHR3 + 、NR4 + ). Some examples of suitable substituted ammonium ions are those derived from methylamine, ethylamine, diethylamine, propylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and tromethamine, and amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4 + .

[0250] In case the compounds of formula (I) contain amine functional groups, these can form quaternary ammonium salts, for example by reaction with alkylating agents according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of formula (I).

[0251] The compounds of the invention may exist as mono-, di- or tri-salts, in particular mono- or di-salts, depending on the pKa of the acid forming the salt.

[0252] The salt forms of the compounds of the present invention are generally pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are described in Berge wait , 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., 66, pp. 1-19. However, non-pharmaceutically acceptable salts may also be prepared as intermediate forms, which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms, which may be used, for example, to purify or isolate the compounds of the invention, also form part of the present invention.

[0253] In one embodiment of the invention, a pharmaceutical composition is provided comprising a solution (e.g., an aqueous solution) comprising a compound of formula (I) and its subgroups and examples as described herein in salt form at a concentration greater than 10 mg / mL, typically greater than 15 mg / mL and especially greater than 20 mg / mL.

[0254] N-oxides

[0255] Compounds of formula (I) containing an amine functional group may also form N-oxides. References herein to compounds of formula (I) containing an amine functional group also include the N-oxide.

[0256] In case the compound contains several amine functional groups, one or more than one nitrogen atom may be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.

[0257] N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid), see, e.g. Advanced Organic Chemistry , Jerry March, 4th edition, Wiley Interscience, pp. More specifically, N-oxides can be obtained by LW Deady ( Syn. Comm 1977, 7, 509-514), wherein the amine compound is reacted with between -Chloroperbenzoic acid (MCPBA) reaction.

[0258] Geometric isomers and tautomers

[0259] Compounds of formula (I) can exist in a variety of different geometric isomeric and tautomeric forms and references to compounds of formula (I) include all such forms. For the avoidance of doubt, where a compound can exist in one of several geometric isomeric or tautomeric forms and only one form is specifically described or shown, all other forms are still encompassed by formula (I).

[0260] For example, in compounds of formula (I), when X represents NH and U represents carbon, the benzene ring of the compound may exist in tautomeric forms, as shown below. For simplicity, general formula (I) shows one form 1, but the formula should be considered to include two tautomeric forms (1 and 2).

[0261]

[0262] Other examples of tautomeric forms include, for example, the keto form, the enol form, and the enolated form, as in, for example, the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / imino alcohol, amidine / enediamine, nitroso / oxime, thione / enethiol, and nitro / acid nitro.

[0263]

[0264] Stereoisomers

[0265] Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms.

[0266] In common form, stereocenters are shown with "dashed lines" or "wedge lines", e.g.

[0267]

[0268] Where a compound is described as a mixture of two diastereomers / epimers, the configuration of a stereocenter is not specified and is represented by a straight line.

[0269] Unless otherwise mentioned or indicated, where compounds of formula (I) contain one or more chiral centers and can exist in the form of two or more optical isomers, reference to compounds of formula (I) includes all optical isomeric forms thereof (e.g., enantiomers, epimers and diastereomers), either as individual optical isomers or as mixtures (e.g., racemic mixtures) or two or more optical isomers, unless the context requires otherwise.

[0270] Optical isomers can be characterized and identified by their optical activity (i.e., as + and – isomers or d and l isomers) or they may be characterized by their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry , Jerry March, 4th edition, John Wiley & Sons, New York, 1992, pp. 109-114, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl ., 1966, 5, 385-415.

[0271] Optical isomers may be separated by a variety of techniques including chiral chromatography (chromatography on a chiral support), and such techniques are well known to those skilled in the art.

[0272] As an alternative to chiral chromatography, optical isomers can be separated by forming diastereomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid and (-)-camphorsulfonic acid, separating the diastereomers by preferential crystallization and then dissociating the salts to obtain the individual enantiomers of the free base.

[0273] Additional enantiomeric separations can be achieved by covalently attaching an enantiomerically pure chiral auxiliary to the compound and then performing diastereomeric separation using conventional methods such as chromatography. This is then followed by cleavage of the covalent attachment to produce the appropriate enantiomerically pure product.

[0274] In the case where the compound of formula (I) exists as two or more optical isomer forms, one enantiomer in a pair of enantiomers can show advantages that are superior to another enantiomer, for example, with respect to biological activity. Therefore, in some cases, it may be desirable to use only one of a pair of enantiomers or only one of a plurality of diastereomers as a therapeutic agent. Therefore, the present invention provides compositions comprising compounds of formula (I) with one or more chiral centers, wherein at least 55% (for example, at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of formula (I) exist as a single optical isomer (for example, enantiomer or diastereomer). In a general embodiment, 99% or more (for example, substantially all) of the total amount of the compound of formula (I) can exist as a single optical isomer (for example, enantiomer or diastereomer).

[0275] Compounds encompassing double bonds may have an E (hetero) or Z (homo) stereochemistry at the double bond. Substituents on a bivalent ring or (partially) saturated group may have Cis -or Trans As used herein, the terms cis and trans are according to Chemical Abstracts nomenclature (J. Org. Chem. 1970, 35 (9), 2849-2867) and refer to the position of substituents on a ring portion.

[0276] Of particular interest are those compounds of formula (I) that are stereochemically pure. When a compound of formula (I) is, for example, designated as R, this means that the compound is substantially free of S isomers. If a compound of formula (I) is, for example, designated as E, this means that the compound is substantially free of Z isomers. The terms cis, trans, R, S, E and Z are well known to those skilled in the art.

[0277] Isotope variation

[0278] The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the present invention, ie compounds of formula (I), wherein one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[0279] Examples of isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen, such as 2 H (D) and 3 H (T); Carbon, e.g. 11 C. 13 C and 14 C; chlorine, such as 36 Cl; fluorine, such as 18 F; iodine, such as 123 I. 125 I and131 I; Nitrogen, such as 13 N and 15 N; oxygen, such as 15 O. 17 O and 18 O; phosphorus, such as 32 P; and sulfur, such as 35 S.

[0280] Certain isotope-labeled compounds of formula (I), for example those incorporating radioactive isotopes, can be used in drug and / or substrate tissue distribution studies. Compounds of formula (I) can also have valuable diagnostic features because they can be used to detect or differentiate the complex formation between labeled compounds and other molecules, peptides, proteins, enzymes or receptors. Detection or differentiation methods can use compounds labeled with labeling agents such as radioisotopes, enzymes, fluorescent materials, luminescent materials (e.g., luminol, luminol derivatives, luciferin, luminescent proteins and luciferase). Radioisotope tritium Right now 3 H (T) and carbon-14 Right now 14 C is particularly useful for this purpose due to its ease of incorporation and ready detection format.

[0281] Using heavier isotopes such as deuterium Right now 2 Substitution by H (D) may provide increased body Inside Certain therapeutic advantages result from reduced half-life or reduced dosage requirements and may therefore be used in some circumstances.

[0282] Using positron-emitting isotopes such as 11 C. 18 F. 15 O and 13 Substitution by N can be used in positron emission tomography (PET) studies to examine target occupancy.

[0283] Isotopically-labelled compounds of formula (I) may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations by using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.

[0284] ester

[0285] Esters of compounds of formula (I) having carboxylic acid groups or hydroxyl groups, such as carboxylic acid esters, acyloxy esters and phosphate esters, are also encompassed by formula (I). Examples of esters are compounds containing the group -C(=O)OR, wherein R is an ester substituent, for example C 1-7 Alkyl, C3-12 Heterocyclic or C 5-12 Aryl, especially C 1-6 Specific examples of ester groups include, but are not limited to, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, and -C(=O)OPh. Examples of acyloxy (reverse ester) groups are represented by -OC(=O)R, where R is an acyloxy substituent, such as C 1-6 Alkyl, C 3-12 Heterocyclic or C 5-12 Aryl, especially C 1-6 Specific examples of acyloxy groups include, but are not limited to, -OC(=O)CH3 (acetoxy), -OC(=O)CH2CH3, -OC(=O)C(CH3)3, -OC(=O)Ph, and -OC(=O)CH2Ph. Examples of phosphates are those derived from phosphoric acid.

[0286] In one embodiment of the invention, formula (I) includes within its scope esters of compounds of formula (I) having carboxylic acid groups or hydroxyl groups. In another embodiment of the invention, formula (I) does not include within its scope esters of compounds of formula (I) having carboxylic acid groups or hydroxyl groups.

[0287] Solvates and crystalline forms

[0288] Formula (I) also encompasses any polymorphs and solvates such as hydrates, alcoholates, and the like of the compounds.

[0289] The compounds of the present invention can, for example, form solvates with water (i.e., hydrates) or common organic solvents. As used herein, the term "solvate" means the physical association of the compounds of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate will be able to separate, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid. The term "solvate" is intended to cover solution phases and separable solvates. Non-limiting examples of suitable solvates include combinations of the compounds of the present invention with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine, etc. When the compounds of the present invention are in solution, they can exert their biological effects.

[0290] Solvates are well known in pharmaceutical chemistry. They are important for methods for preparing substances (e.g., with respect to their purification, storage of substances (e.g., their stability), and ease of handling of substances) and are usually formed as part of the separation or purification stage of chemical synthesis. One skilled in the art can determine by standard and long-standing techniques whether a hydrate or other solvate has been formed by the separation or purification conditions used to prepare a given compound. Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g., single crystal X-ray crystallography or X-ray powder diffraction), and solid-state NMR (SS-NMR, also known as magic angle spinning NMR or MAS-NMR). Such techniques are almost part of the standard analytical toolbox of a skilled chemist, such as NMR, IR, HPLC, and MS.

[0291] Alternatively, the skilled artisan may intentionally form a solvate using crystallization conditions that include the amount of solvent required for the particular solvate. Thereafter, standard methods described above may be used to determine whether a solvate is formed.

[0292] In one embodiment the salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one has <10% solvate present (e.g., not exceeding any of the following amounts: 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.1, 0.05 or 0.01%), such as a hydrate, alcoholate, isopropyl acetate, methyl acetate or an alkane such as heptane.

[0293] In one embodiment the salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one is anhydrous. In a further embodiment, the anhydrous salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one contains no more than 5% (e.g., no more than any of the following amounts: 4, 3, 2, 1, 0.5, 0.1, 0.05 or 0.01%) by weight of water.

[0294] In one embodiment, the salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one comprises a single crystalline form and no more than 5% (e.g., no more than any one of the following amounts: 4, 3, 2, 1, 0.5, 0.1, 0.05 or 0.01%) by weight of other crystalline forms.

[0295] In one embodiment the salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one is crystalline.

[0296] In one embodiment the salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one is amorphous.

[0297] Furthermore, the compounds of the present invention may have one or more polymorphs or amorphous crystalline forms and are likewise intended to be included within the scope of the present invention.

[0298] Reference herein to "polymorphism" refers to the presence of more than one crystal structure of a compound of formula (I). The ability of a compound to crystallize in more than one crystal variation may have an effect on the properties of the compound, such as physicochemical properties, shelf life, solubility, formulation properties, toxicity, bioavailability, hygroscopicity, and handling properties. In addition, the therapeutic effects of a pharmaceutical compound may be achieved through the polymorphism of the pharmaceutical molecule.

[0299] In one embodiment, the compound of formula (I) comprises a polymorphic form of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one or a salt thereof.

[0300] In a further embodiment, the compound of formula (I) comprises a polymorphic form of a salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one.

[0301] In a further embodiment, the compound of formula (I) comprises the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate. The compound may be prepared as defined herein in Example 39.

[0302] In still further embodiments, 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is prepared by Figure 1 As shown in 1 The samples were characterized by H NMR spectroscopy.

[0303] The X-ray powder pattern of a compound is characterized by the diffraction angle (2θ) and plane spacing (d) parameters of the X-ray diffraction spectrum. These parameters are related by the Bragg equation nλ=2d Sin θ (where n=1; λ=wavelength of the cathode used; d=plane spacing; and θ=diffraction angle). In this article, due to the characteristics of the data, the plane spacing, diffraction angle and the entire pattern are important for identifying crystals in X-ray powder diffraction. Relative intensity should not be strictly interpreted because it can change according to the direction of crystal growth, particle size and measurement conditions. In addition, diffraction angles generally mean diffraction angles that conform to the range 2θ±0.2°. Peak means the main peak, and includes peaks that are not greater than the medium at diffraction angles other than those mentioned above.

[0304] In still further embodiments, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by an XRPD pattern having peaks at the following diffraction angles: 6.5 ± 0.5°, 7.1 ± 0.5°, 7.9 ± 0.5°, 9.3 ± 0.5°, 10.2 ± 0.5°, 11.0 ± 0.5°, 11.6 ± 0.5°, 13.3 ± 0.5°, 14.4 ± 0.5°, 15.0 ± 0.5°, 16.7 ± 0.5°,18.0 ± 0.5°, 18.4 ± 0.5°, 20.0 ± 0.5°, 21.0 ± 0.5°, 23.4 ± 0.5°, 25.2 ± 0.5° and 26.1 ± 0.5° (2θ, 1d.p).

[0305] In still further embodiments, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by an XRPD pattern having peaks at the following diffraction angles: 6.5 ± 0.2°, 7.1 ± 0.2°, 7.9 ± 0.2°, 9.3 ± 0.2°, 10.2 ± 0.2°, 11.0 ± 0.2°, 11.6 ± 0.2°, 13.3 ± 0.2°, 14.4 ± 0.2°, 15.0 ± 0.2°, 16.7 ± 0.2°,18.0 ± 0.2°, 18.4 ± 0.2°, 20.0 ± 0.2°, 21.0 ± 0.2°, 23.4 ± 0.2°, 25.2 ± 0.2° and 26.1 ± 0.2° (2θ, 1d.p).

[0306] In still further embodiments, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by an XRPD pattern having peaks at the following diffraction angles: 6.5 ± 0.1°, 7.1 ± 0.1°, 7.9 ± 0.1°, 9.3 ± 0.1°, 10.2 ± 0.1°, 11.0 ± 0.1°, 11.6 ± 0.1°, 13.3 ± 0.1°, 14.4 ± 0.1°, 15.0 ± 0.1°, 16.7 ± 0.1°,18.0 ± 0.1°, 18.4 ± 0.1°, 20.0 ± 0.1°, 21.0 ± 0.1°, 23.4 ± 0.1°, 25.2 ± 0.1° and 26.1 ± 0.1° (2θ, 1d.p).

[0307] In still further embodiments, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by an XRPD pattern having peaks at the following diffraction angles: 6.5°, 7.1°, 7.9°, 9.3°, 10.2°, 11.0°, 11.6°, 13.3°, 14.4°, 15.0°, 16.7°, 18.0°, 18.4°, 20.0°, 21.0°, 23.4°, 24.8°, 25.1°, 26.3°, 27.4°, 28.8°, 29.9°, 30.4°, 31.3°, 32.5°, 33.7°, 34.9°, 35. 25.2° and 26.1° (2θ, 1d.p).

[0308] In still further embodiments, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by being substantially as follows Figure 2 XRPD pattern shown.

[0309] In still further embodiments, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by Figure 2 The XRPD pattern shown has a peak at the same diffraction angle (2θ) and optionally wherein the peak has a peak with Figure 2 The peaks shown have the same relative intensities.

[0310] The skilled artisan will understand that references herein to "intensity" with respect to XRPD peaks refer to relative intensity, which has been normalized to take into account background noise and other such parameters.

[0311] In still further embodiments, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by having Figure 2 The XRPD pattern shows the main peaks of diffraction angle (2θ) and intensity.

[0312] In still further embodiments, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by interplanar spacing (d) values ​​of 13.59 ± 0.5Å, 12.44 ± 0.5Å, 11.19 ± 0.5Å, 9.50 ± 0.5Å, 8.67 ± 0.5Å, 8.04 ± 0.5Å,7.62 ± 0.5Å, 6.65 ± 0.5Å, 6.15 ± 0.5Å, 5.90 ± 0.5Å, 5.31 ± 0.5Å, 4.93 ±0.5Å, 4.82 ± 0.5Å, 4.44 ± 0.5Å, 4.23 ± 0.5Å, 3.80 ± 0.5Å, 3.53 ± 0.5Å and 3.41 ± 0.5Å (d, 2d.p.).

[0313] In still further embodiments, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by interplanar spacing (d) values ​​of 13.59 ± 0.2Å, 12.44 ± 0.2Å, 11.19 ± 0.2Å, 9.50 ± 0.2Å, 8.67 ± 0.2Å, 8.04 ± 0.2Å,7.62 ± 0.2Å, 6.65 ± 0.2Å, 6.15 ± 0.2Å, 5.90 ± 0.2Å, 5.31 ± 0.2Å, 4.93 ±0.2Å, 4.82 ± 0.2Å, 4.44 ± 0.2Å, 4.23 ± 0.2Å, 3.80 ± 0.2Å, 3.53 ± 0.2Å and 3.41 ± 0.2Å (d, 2d.p.).

[0314] In still further embodiments, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by interplanar spacing (d) values ​​of 13.59 ± 0.1Å, 12.44 ± 0.1Å, 11.19 ± 0.1Å, 9.50 ± 0.1Å, 8.67 ± 0.1Å, 8.04 ± 0.1Å,7.62 ± 0.1Å, 6.65 ± 0.1Å, 6.15 ± 0.1Å, 5.90 ± 0.1Å 0.1Å, 5.31 ± 0.1Å, 4.93 ±0.1Å, 4.82 ± 0.1Å, 4.44 ± 0.1Å, 4.23 ± 0.1Å, 3.80 ± 0.1Å, 3.53 ± 0.1Å and 3.41 ± 0.1Å (d,2d.p.).

[0315] In still further embodiments, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by interplanar spacing (d) values ​​of 13.59 Å, 12.44 Å, 11.19 Å, 9.50 Å, 8.67 Å, ​​8.04 Å, 7.62 Å, 6.65 Å, 6.15 Å, 5.90 Å, 5.31 Å, 4.93 Å, 4.82 Å, 4.44 Å, 4.23 Å, 3.80 Å, 3.53Å and 3.41Å (d, 2d.p.).

[0316] In a further embodiment, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by a DSC peak temperature of 78.69°C±0.5°C and / or 113.91°C±0.5°C (e.g. 78.69°C±0.2°C and / or 113.91°C±0.2°C, in particular 78.69°C±0.1°C and / or 113.91°C±0.1°C, more in particular 78.69°C and / or 113.91°C).

[0317] In still further embodiments, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by a DSC onset temperature of 72.3°C±0.5°C (endothermic peak, broad) and / or 102°C±0.5°C (endothermic peak, broad) (e.g. 72.3°C±0.2°C and / or 102°C±0.2°C, particularly 72.3°C±0.1°C and / or 102°C±0.1°C, more particularly 72.3°C and / or 102°C).

[0318] In still further embodiments, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by Figure 3 DSC thermogram shown.

[0319] In a further embodiment, the compound of formula (I) comprises the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate. This compound may be prepared as defined in Example 40 herein.

[0320] In still further embodiments, 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by Figure 4 shown 1 H NMR spectrum.

[0321] In still further embodiments, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by an XRPD pattern having peaks at the following diffraction angles: 6.6 ± 0.5°, 9.4 ± 0.5°, 11.0 ± 0.5°, 13.2 ± 0.5°, 14.3 ± 0.5°, 15.8 ± 0.5°, 17.4 ± 0.5°, 18.4 ± 0.5°, 19.1 ± 0.5°, 20.4 ± 0.5°, 21.2 ± 0.5°, 22.1 ± 0.5°, 23.8 ± 0.5°, 24.9 ± 0.5°, 25.0 ± 0.5°, 26.1 ± 0.5°, 27.8 ± 0.5°, 28.4 ± 0.5°, 29.9 ± 0.5°, 30.1 ± 0.5°, 31. 20.9 ± 0.5°, 21.8 ± 0.5°, 23.1 ± 0.5°, 24.9 ± 0.5°, 26.7 ± 0.5° and 27.8 ± 0.5° (2θ, 1d.p).

[0322] In still further embodiments, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by an XRPD pattern having peaks at the following diffraction angles: 6.6 ± 0.2°, 9.4 ± 0.2°, 11.0 ± 0.2°, 13.2 ± 0.2°, 14.3 ± 0.2°, 15.8 ± 0.2°, 17.4 ± 0.2°, 18.4 ± 0.2°, 19.1 ± 0.2°, 20.4 ± 0.2°, 21.3 ± 0.2°, 22.1 ± 0.2°, 23.8 ± 0.2°, 24.9 ± 0.2°, 25.0 ± 0.2°, 26.1 ± 0.2°, 27.8 ± 0.2°, 28.4 ± 0.2°, 29.9 ± 0.2°, 30.1 ± 0.2°, 31. 20.9 ± 0.2°, 21.8 ± 0.2°, 23.1 ± 0.2°, 24.9 ± 0.2°, 26.7 ± 0.2° and 27.8 ± 0.2° (2θ, 1d.p).

[0323] In still further embodiments, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by an XRPD pattern having peaks at the following diffraction angles: 6.6 ± 0.1°, 9.4 ± 0.1°, 11.0 ± 0.1°, 13.2 ± 0.1°, 14.3 ± 0.1°, 15.8 ± 0.1°, 17.4 ± 0.1°, 18.4 ± 0.1°, 19.1 ± 0.1°, 20.4 ± 0.1°, 21.3 ± 0.1°, 22.1 ± 0.1°, 23.8 ± 0.1°, 24.9 ± 0.1°, 25.0 ± 0.1°, 26.1 ± 0.1°, 27.8 ± 0.1°, 28.8 ± 0.1°, 29.9 ± 0.1°, 30.9 ± 0.1°, 31. 20.9 ± 0.1°, 21.8 ± 0.1°, 23.1 ± 0.1°, 24.9 ± 0.1°, 26.7 ± 0.1° and 27.8 ± 0.1° (2θ, 1d.p).

[0324] In still further embodiments, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by an XRPD pattern having peaks at the following diffraction angles: 6.6°, 9.4°, 11.0°, 13.2°, 14.3°, 15.8°, 17.4°, 18.4°, 19.1°, 20.9°, 21.8°, 23.1°, 24.9°, 26.7° and 27.8° (2θ, 1d.p).

[0325] In still further embodiments, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by being substantially as follows Figure 5 XRPD pattern shown.

[0326] In still further embodiments, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by Figure 5 The XRPD pattern shown has a peak at the same diffraction angle (2θ) and optionally wherein the peak has a peak with Figure 5 The peaks shown have the same relative intensities.

[0327] In still further embodiments, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by having Figure 5 The XRPD pattern shows the main peaks of diffraction angle (2θ) and intensity.

[0328] In still further embodiments, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by interplanar spacing (d) values ​​of 13.39 ± 0.5Å, 9.40 ± 0.5Å, 8.04 ± 0.5Å, 6.70 ± 0.5Å, 6.19 ± 0.5Å, 5.61 ± 0.5Å, 5.09 ± 0.5Å, 4.82 ± 0.5Å, 4.64 ± 0.5Å, 4.25 ± 0.5Å, 4.07 ± 0.5Å, 3.85 ±0.5Å, 3.57 ± 0.5Å, 3.34 ± 0.5Å and 3.21 ± 0.5Å (d,2d.p.).

[0329] In still further embodiments, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by interplanar spacing (d) values ​​of 13.39 ± 0.2Å, 9.40 ± 0.2Å, 8.04 ± 0.2Å, 6.70 ± 0.2Å, 6.19 ± 0.2Å, 5.61 ± 0.2Å, 5.09 ± 0.2Å, 4.82 ± 0.2Å, 4.64 ± 0.2Å, 4.25 ± 0.2Å, 4.07 ± 0.2Å, 3.85 ±0.2Å, 3.57 ± 0.2Å, 3.34 ± 0.2Å and 3.21 ± 0.2Å (d,2d.p.).

[0330] In still further embodiments, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by interplanar spacing (d) values ​​of 13.39 ± 0.1Å, 9.40 ± 0.1Å, 8.04 ± 0.1Å, 6.70 ± 0.1Å, 6.19 ± 0.1Å, 5.61 ± 0.1Å, 5.09 ± 0.1Å, 4.82 ± 0.1Å, 4.64 ± 0.1Å, 4.25 ± 0.1Å, 4.07 ± 0.1Å, 3.85 ±0.1Å, 3.57 ± 0.1Å, 3.34 ± 0.1Å and 3.21 ± 0.1Å (d,2d.p.).

[0331] In still further embodiments, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by interplanar spacing (d) values ​​of 13.39Å, 9.40Å, 8.04Å, 6.70Å, 6.19Å, 5.61Å, 5.09Å, 4.82Å, 4.64Å, 4.25Å, 4.07Å, 3.85Å,3.57Å, 3.34Å and 3.21Å (d, 2d.p.).

[0332] In a further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by a DSC peak temperature of 85.25°C±0.5°C and / or 106.72°C±0.5°C (e.g. 85.25°C±0.2°C and / or 106.72°C±0.2°C, in particular 85.25°C±0.1°C and / or 106.72°C±0.1°C, more in particular 85.25°C and / or 106.72°C).

[0333] In still further embodiments, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by a DSC onset temperature of 68°C±0.5°C (large endotherm, broad) and / or 102°C±0.5°C (very small endotherm, broad) (e.g. 68°C±0.2°C and / or 102°C±0.2°C, particularly 68°C±0.1°C and / or 102°C±0.1°C, more particularly 68°C and / or 102°C).

[0334] In still further embodiments, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by Figure 6 DSC thermogram shown.

[0335] In a further embodiment, the compound of formula (I) comprises the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate. The compound may be prepared as defined in Example 41 herein.

[0336] In still further embodiments, 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterized by Figure 7 shown 1 H NMR spectrum.

[0337] In still further embodiments, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterized by an XRPD pattern having peaks at the following diffraction angles: 8.5 ± 0.5°, 13.5 ± 0.5°, 13.9 ± 0.5°, 14.3 ± 0.5°, 16.2 ± 0.5°, 17.3 ± 0.5°, 20.1 ± 0.5°, 21.3 ± 0.5°, 23.3 ± 0.5°, 24.4 ± 0.5° and 27.9 ± 0.5° (2θ, 1d.p).

[0338] In still further embodiments, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterized by an XRPD pattern having peaks at the following diffraction angles: 8.5 ± 0.2°, 13.5 ± 0.2°, 13.9 ± 0.2°, 14.3 ± 0.2°, 16.2 ± 0.2°, 17.3 ± 0.2°, 20.1 ± 0.2°, 21.3 ± 0.2°, 23.3 ± 0.2°, 24.4 ± 0.2° and 27.9 ± 0.2° (2θ, 1d.p).

[0339] In still further embodiments, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterized by an XRPD pattern having peaks at the following diffraction angles: 8.5 ± 0.1°, 13.5 ± 0.1°, 13.9 ± 0.1°, 14.3 ± 0.1°, 16.2 ± 0.1°, 17.3 ± 0.1°, 20.1 ± 0.1°, 21.3 ± 0.1°, 23.3 ± 0.1°, 24.4 ± 0.1° and 27.9 ± 0.1° (2θ, 1d.p).

[0340] In still further embodiments, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterized by an XRPD pattern having peaks at the following diffraction angles: 8.5°, 13.5°, 13.9°, 14.3°, 16.2°, 17.3°, 20.1°, 21.3°, 23.3°, 24.4° and 27.9° (2θ, 1 d.p).

[0341] In still further embodiments, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterized by being substantially as follows Figure 8 XRPD pattern shown.

[0342] In still further embodiments, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterized by Figure 8 The XRPD pattern shown has a peak at the same diffraction angle (2θ) and optionally wherein the peak has a peak with Figure 8 The peaks shown have the same relative intensities.

[0343] In still further embodiments, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterized by having Figure 8 The XRPD pattern shows the main peaks of diffraction angle (2θ) and intensity.

[0344] In still further embodiments, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterized by interplanar spacing (d) values ​​of 10.40 ± 0.5Å, 6.56 ± 0.5Å, 6.37 ± 0.5Å, 6.19 ± 0.5Å, 5.47 ± 0.5Å, 5.12 ± 0.5Å, 4.42 ± 0.5Å, 4.17 ± 0.5Å, 3.82 ± 0.5Å, 3.65 ± 0.5Å and 3.20 ± 0.5Å (d, 2d.p.).

[0345] In still further embodiments, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterized by interplanar spacing (d) values ​​of 10.40 ± 0.2Å, 6.56 ± 0.2Å, 6.37 ± 0.2Å, 6.19 ± 0.2Å, 5.47 ± 0.2Å, 5.12 ± 0.2Å, 4.42 ± 0.2Å, 4.17 ± 0.2Å, 3.82 ± 0.2Å, 3.65 ± 0.2Å and 3.20 ± 0.2Å (d, 2d.p.).

[0346] In still further embodiments, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterized by interplanar spacing (d) values ​​of 10.40 ± 0.1Å, 6.56 ± 0.1Å, 6.37 ± 0.1Å, 6.19 ± 0.1Å, 5.47 ± 0.1Å, 5.12 ± 0.1Å, 4.42 ± 0.1Å, 4.17 ± 0.1Å, 3.82 ± 0.1Å, 3.65 ± 0.1Å and 3.20 ± 0.1Å (d, 2d.p.).

[0347] In still further embodiments, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterized by interplanar spacing (d) values ​​of 10.40Å, 6.56Å, 6.37Å, 6.19Å, 5.47Å, 5.12Å, 4.42Å, 4.17Å, 3.82Å, 3.65Å and 3.20Å (d, 2d.p.).

[0348] In a further embodiment, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterized by a DSC peak temperature of 80.31°C ± 0.5°C and / or 149.07°C ± 0.5°C (e.g. 80.31°C ± 0.2°C and / or 149.07°C ± 0.2°C, in particular 80.31°C ± 0.1°C and / or 149.07°C ± 0.1°C, more in particular 80.31°C and / or 149.07°C).

[0349] In still further embodiments, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterized by a DSC onset temperature of 51.2°C±0.5°C (endothermic peak, broad) and / or 136°C±0.5°C (endothermic peak, broad) (e.g. 51.2°C±0.2°C and / or 136°C±0.2°C, particularly 51.2°C±0.1°C and / or 136°C±0.1°C, more particularly 51.2°C and / or 136°C).

[0350] In still further embodiments, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterized by Fig. 9 DSC thermogram shown.

[0351] In a further embodiment, the compound of formula (I) comprises the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one mesylate. The compound may be prepared as defined in Example 42 herein.

[0352] In still further embodiments, the methanesulfonate salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one is characterized by Fig.10 shown 1 H NMR spectrum.

[0353] In still further embodiments, the Form B polymorph of the methanesulfonate salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one is characterized by an XRPD pattern having peaks at the following diffraction angles: 6.6 ± 0.5°, 8.0 ± 0.5°, 11.8 ± 0.5°, 13.2 ± 0.5°, 14.3 ± 0.5°, 15.0 ± 0.5°, 15.6 ± 0.5°, 17.1 ± 0.5°, 17.4 ± 0.5°, 17.7 ± 0.5°, 19.2 ± 0.5°,20.3 ± 0.5°, 21.2 ± 0.5°, 22.3 ± 0.5°, 23.0 ± 0.5°, 24.0 ± 0.5°, 25.8 ± 0.5°, 26.8 ± 0.5° and 28.9 ± 0.5° (2θ, 1d.p).

[0354] In still further embodiments, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one mesylate is characterized by an XRPD pattern having peaks at the following diffraction angles: 6.6 ± 0.2°, 8.0 ± 0.2°, 11.8 ± 0.2°, 13.2 ± 0.2°, 14.3 ± 0.2°, 15.0 ± 0.2°, 15.6 ± 0.2°, 17.1 ± 0.2°, 17.4 ± 0.2°, 17.7 ± 0.2°. 0.2°, 19.2 ± 0.2°,20.3 ± 0.2°, 21.2 ± 0.2°, 22.3 ± 0.2°, 23.0 ± 0.2°, 24.0 ± 0.2°, 25.8 ± 0.2°, 26.8 ± 0.2° and 28.9 ± 0.2° (2θ, 1d.p).

[0355] In still further embodiments, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one methanesulfonate is characterized by an XRPD pattern having peaks at the following diffraction angles: 6.6 ± 0.1°, 8.0 ± 0.1°, 11.8 ± 0.1°, 13.2 ± 0.1°, 14.3 ± 0.1°, 15.0 ± 0.1°, 15.6 ± 0.1°, 17.1 ± 0.1°, 17.4 ± 0.1°, 17.7 ± 0.1°. 0.1°, 19.2 ± 0.1°,20.3 ± 0.1°, 21.2 ± 0.1°, 22.3 ± 0.1°, 23.0 ± 0.1°, 24.0 ± 0.1°, 25.8 ± 0.1°, 26.8 ± 0.1° and 28.9 ± 0.1° (2θ, 1d.p).

[0356] In still further embodiments, the Form B polymorph of the methanesulfonate salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one is characterized by an XRPD pattern having peaks at the following diffraction angles: 6.6°, 8.0°, 11.8°, 13.2°, 14.3°, 15.0°, 15.6°, 17.1°, 17.4°, 17.7°, 19.2°, 20.3°, 21.2°, 22.3°, 23.0°, 24.0°, 25.8°, 26.8° and 28.9° (2θ, 1d.p).

[0357] In still further embodiments, the Form B polymorph of the methanesulfonate salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one is characterized by being substantially as follows Fig.11 XRPD pattern shown.

[0358] In still further embodiments, the Form B polymorph of the methanesulfonate salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one is characterized by Fig.11 The XRPD pattern shown has a peak at the same diffraction angle (2θ) and optionally wherein the peak has a peak with Fig.11 The peaks shown have the same relative intensities.

[0359] In still further embodiments, the Form B polymorph of the methanesulfonate salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one is characterized by having Fig.11 The XRPD pattern shows the main peaks of diffraction angle (2θ) and intensity.

[0360] In still further embodiments, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one mesylate is characterized by interplanar spacing (d) values ​​of 13.39 ± 0.5Å, 11.05 ± 0.5Å, 7.50 ± 0.5Å, 6.70 ± 0.5Å, 6.19 ± 0.5Å, 5.90 ± 0.5Å, 5.68 ± 0.5Å, 5.18 ± 0.5Å, 5.09 ± 0.5Å, 5.01 ± 0.5Å 0.5Å, 4.62 ± 0.5Å, 4.37 ±0.5Å, 4.19 ± 0.5Å, 3.98 ± 0.5Å, 3.86 ± 0.5Å, 3.71 ± 0.5Å, 3.45 ± 0.5Å, 3.32 ± 0.5Å and 3.09 ± 0.5Å (d, 2d.p.).

[0361] In still further embodiments, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one mesylate is characterized by interplanar spacing (d) values ​​of 13.39 ± 0.2Å, 11.05 ± 0.2Å, 7.50 ± 0.2Å, 6.70 ± 0.2Å, 6.19 ± 0.2Å, 5.90 ± 0.2Å, 5.68 ± 0.2Å, 5.18 ± 0.2Å, 5.09 ± 0.2Å, 5.01 ± 0.2Å, 4.62 ± 0.2Å, 4.37 ± 0.2Å, 4.19 ± 0.2Å, 3.98 ± 0.2Å, 3.86 ± 0.2Å, 3.71 ± 0.2Å, 3.45 ± 0.2Å, 3.32± 0.2Å and 3.09 ± 0.2Å (d,2d.p.).

[0362] In still further embodiments, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one mesylate is characterized by interplanar spacing (d) values ​​of 13.39 ± 0.1Å, 11.05 ± 0.1Å, 7.50 ± 0.1Å, 6.70 ± 0.1Å, 6.19 ± 0.1Å, 5.90 ± 0.1Å, 5.68 ± 0.1Å, 5.18 ± 0.1Å, 5.09 ± 0.1Å, 5.01 ± 0.1Å 0.1Å, 4.62 ± 0.1Å, 4.37 ±0.1Å, 4.19 ± 0.1Å, 3.98 ± 0.1Å, 3.86 ± 0.1Å, 3.71 ± 0.1Å, 3.45 ± 0.1Å, 3.32 ± 0.1Å and 3.09 ± 0.1Å (d, 2d.p.).

[0363] In still further embodiments, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one mesylate is characterized by interplanar spacing (d) values ​​of 13.39 Å, 11.05 Å, 7.50 Å, 6.70 Å, 6.19 Å, 5.90 Å, 5.68 Å, 5.18 Å, 5.09 Å, 5.01 Å, 4.62 Å, 4.37 Å,4.19 Å, 3.98 Å, 3.86 Å, 3.71 Å, 3.45 Å, 3.32Å and 3.09Å (d, 2d.p.).

[0364] In a further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one methanesulfonate is characterized by a DSC peak temperature of 98.63°C ± 0.5°C and / or 177.11°C ± 0.5°C (e.g. 98.63°C ± 0.2°C and / or 177.11°C ± 0.2°C, in particular 98.63°C ± 0.1°C and / or 177.11°C ± 0.1°C, more in particular 98.63°C and / or 177.11°C).

[0365] In a further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one methanesulfonate is characterized by a DSC onset temperature of 73.3°C±0.5°C (endothermic peak, broad) and / or 160.8°C±0.5°C (endothermic peak, broad) (e.g. 73.3°C±0.2°C and / or 160.8°C±0.2°C, particularly 73.3°C±0.1°C and / or 160.8°C±0.1°C, more particularly 73.3°C and / or 160.8°C).

[0366] In still further embodiments, the Form B polymorph of the methanesulfonate salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one is characterized by Fig.12 DSC thermogram shown.

[0367] In a further embodiment, the compound of formula (I) comprises the C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate. The compound may be prepared as defined in Example 43 herein.

[0368] In still further embodiments, 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by Fig.15 shown 1 H NMR spectrum.

[0369] In still further embodiments, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by an XRPD pattern having peaks at the following diffraction angles: 7.4 ± 0.5°, 7.9 ± 0.5°, 8.3 ± 0.5°, 8.7 ± 0.5°, 9.0 ± 0.5°, 10.4 ± 0.5°, 11.2 ± 0.5°, 11.6 ± 0.5°, 12.3 ± 0.5°, 13.1 ± 0.5°, 14.8 ± 0.5°, 15.0 ± 0.5°, 16.1 ± 0.5°, 17.0 ± 0.5°, 18.1 ± 0.5°, 19. 0.5°, 13.9 ± 0.5°,14.7 ± 0.5°, 15.8 ± 0.5°, 16.5 ± 0.5°, 17.1 ± 0.5°, 17.9 ± 0.5°, 18.4 ± 0.5°, 18.9 ± 0.5°, 19.6 ± 0.5°, 20.4 ± 0.5°, 21.0 ± 0.5°, 21.8 ± 0.5°,22.9 ± 0.5°, 23.3 ± 0.5°, 23.6 ± 0.5°, 24.0 ± 0.5°, 24.9 ± 0.5° and 26.4 ± 0.5° (2θ, 1d.p).

[0370] In still further embodiments, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by an XRPD pattern having peaks at the following diffraction angles: 7.4 ± 0.2°, 7.9 ± 0.2°, 8.3 ± 0.2°, 8.7 ± 0.2°, 9.0 ± 0.2°, 10.4 ± 0.2°, 11.2 ± 0.2°, 11.6 ± 0.2°, 12.3 ± 0.2°, 13.1 ± 0.2°, 14.8 ± 0.2°, 15.0 ± 0.2°, 16.1 ± 0.2°, 17.0 ± 0.2°, 18.8 ± 0.2°, 19.1 ± 0.2°, 20.3 ± 0.2°, 21.8 ± 0.2°, 22.4 ± 0.2°, 23.8 ± 0.2°, 24.9 ± 0.2°, 25.8 ± 0.2°, 26.8 ± 0.2°, 27.8 ± 0.2°, 28.8 ± 0.2°, 29.9 ± 0.2°, 30.9 ± 0.2°, 31. 0.2°, 13.9 ± 0.2°,14.7 ± 0.2°, 15.8 ± 0.2°, 16.5 ± 0.2°, 17.1 ± 0.2°, 17.9 ± 0.2°, 18.4 ± 0.2°, 18.9 ± 0.2°, 19.6 ± 0.2°, 20.4 ± 0.2°, 21.0 ± 0.2°, 21.8 ± 0.2°,22.9 ± 0.2°, 23.3 ± 0.2°, 23.6 ± 0.2°, 24.0 ± 0.2°, 24.9 ± 0.2° and 26.4 ± 0.2° (2θ, 1d.p).

[0371] In still further embodiments, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by an XRPD pattern having peaks at the following diffraction angles: 7.4 ± 0.1°, 7.9 ± 0.1°, 8.3 ± 0.1°, 8.7 ± 0.1°, 9.0 ± 0.1°, 10.4 ± 0.1°, 11.2 ± 0.1°, 11.6 ± 0.1°, 12.3 ± 0.1°, 13.1 ± 0.1°, 14.3 ± 0.1°, 15.4 ± 0.1°, 16.3 ± 0.1°, 17. 0.1°, 13.9 ± 0.1°, 14.7 ± 0.1°, 15.8 ± 0.1°, 16.5 ± 0.1°, 17.1 ± 0.1°, 17.9 ± 0.1°, 18.4 ± 0.1°, 18.9 ± 0.1°, 19.6 ± 0.1°, 20.4 ± 0.1°, 21.0 ± 0.1°, 21.8 ± 0.1°,22.9 ± 0.1°, 23.3 ± 0.1°, 23.6 ± 0.1°, 24.0 ± 0.1°, 24.9 ± 0.1° and 26.4 ± 0.1° (2θ, 1d.p).

[0372] In still further embodiments, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by an XRPD pattern having peaks at the following diffraction angles: 7.4°, 7.9°, 8.3°, 8.7°, 9.0°, 10.4°, 11.2°, 11.6°, 12.3°, 13.1°, 13.9°, 14.7°, 15.8°, 16.5°, 17.1°, 17.9°, 18.4°, 18.9°, 19.6°, 20.4°, 21.0°, 21.8°,22.9°, 23.3°, 23.6°, 24.0°, 24.9° and 26.4° (2θ, 1d.p).

[0373] In still further embodiments, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by being substantially as follows Fig.16 The XRPD pattern labeled 1 is shown.

[0374] In still further embodiments, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by Fig.16 The same diffraction angle (2θ) of the XRPD pattern shown as 1 has a peak and optionally wherein the peak has a Fig.16 The peak marked 1 is shown with the same relative intensity.

[0375] In still further embodiments, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by having Fig.16 The XRPD pattern labeled 1 shows the main peaks in diffraction angle (2θ) and intensity.

[0376] In still further embodiments, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized as having major peaks at 8.7±0.5°, 17.1±0.5°, 17.9±0.5° and 18.9±0.5° (2θ, 1 d.p) as measured by XRPD.

[0377] In still further embodiments, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized as having major peaks at 8.7±0.2°, 17.1±0.2°, 17.9±0.2° and 18.9±0.2° (2θ, 1 d.p) as measured by XRPD.

[0378] In still further embodiments, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized as having major peaks at 8.7±0.1°, 17.1±0.1°, 17.9±0.1° and 18.9±0.1° (2θ, 1 d.p) as measured by XRPD.

[0379] In still further embodiments, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized as having major peaks at 8.7°, 17.1°, 17.9° and 18.9° (2θ, 1 d.p) as measured by XRPD.

[0380] In still further embodiments, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by interplanar spacing (d) values ​​of 11.94 ± 0.5Å, 11.19 ± 0.5Å, 10.65 ± 0.5Å, 10.16 ± 0.5Å, 9.82 ± 0.5Å, 8.50 ± 0.5Å, 7.90 ± 0.5Å, 7.62 ± 0.5Å, 7.19 ± 0.5Å, 6.75 ± 0.5Å, 6.37 ± 0.5Å, 6.02± 0.5Å, 5.61 ± 0.5Å, 5.37 ± 0.5Å, 5.18 ± 0.5Å, 4.95 ± 0.5Å, 4.82 ± 0.5Å, 4.69 ± 0.5Å, 4.53 ± 0.5Å, 4.35 ± 0.5Å, 4.23 ± 0.5Å, 4.07 ± 0.5Å, 3.88± 0.5Å, 3.82 ± 0.5Å, 3.77 ± 0.5Å, 3.71 ± 0.5Å, 3.57 ± 0.5Å and 3.37 ± 0.5Å(d, 2d.p.).

[0381] In still further embodiments, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by interplanar spacing (d) values ​​of 11.94 ± 0.2Å, 11.19 ± 0.2Å, 10.65 ± 0.2Å, 10.16 ± 0.2Å, 9.82 ± 0.2Å, 8.50 ± 0.2Å, 7.90 ± 0.2Å, 7.62 ± 0.2Å, 7.19 ± 0.2Å, 6.75 ± 0.2Å, 6.37 ± 0.2Å, 6.02± 0.2Å, 5.61 ± 0.2Å, 5.37 ± 0.2Å, 5.18 ± 0.2Å, 4.95 ± 0.2Å, 4.82 ± 0.2Å, 4.69 ± 0.2Å, 4.53 ± 0.2Å, 4.35 ± 0.2Å, 4.23 ± 0.2Å, 4.07 ± 0.2Å, 3.88± 0.2Å, 3.82 ± 0.2Å, 3.77 ± 0.2Å, 3.71 ± 0.2Å, 3.57 ± 0.2Å and 3.37 ± 0.2Å(d, 2d.p.).

[0382] In still further embodiments, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by interplanar spacing (d) values ​​of 11.94 ± 0.1Å, 11.19 ± 0.1Å, 10.65 ± 0.1Å, 10.16 ± 0.1Å, 9.82 ± 0.1Å, 8.50 ± 0.1Å, 7.90 ± 0.1Å, 7.62 ± 0.1Å, 7.19 ± 0.1Å, 6.75 ± 0.1Å, 6.37 ± 0.1Å, 6.02± 0.1Å, 5.61 ± 0.1Å, 5.37 ± 0.1Å, 5.18 ± 0.1Å, 4.95 ± 0.1Å, 4.82 ± 0.1Å, 4.69 ± 0.1Å, 4.53 ± 0.1Å, 4.35 ± 0.1Å, 4.23 ± 0.1Å, 4.07 ± 0.1Å, 3.88± 0.1Å, 3.82 ± 0.1Å, 3.77 ± 0.1Å, 3.71 ± 0.1Å, 3.57 ± 0.1Å and 3.37 ± 0.1Å(d, 2d.p.).

[0383] In still further embodiments, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by interplanar spacing (d) values ​​of 11.94 Å, 11.19 Å, 10.65 Å, 10.16 Å, 9.82 Å, 8.50 Å, 7.90 Å, 7.62 Å, 7.19 Å, 6.75 Å, 6.37 Å, 6.02 Å, 5.61 Å, 5.37 Å, 5.18 Å, 4.95 Å, 4.82Å, 4.69Å, 4.53Å, 4.35Å, 4.23Å, 4.07Å, 3.88Å, 3.82Å, 3.77Å, 3.71Å, 3.57Å and 3.37Å (d, 2d.p.).

[0384] In a further embodiment, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by a DSC peak temperature of 174.37°C±0.5°C (e.g. 174.37°C±0.2°C, specifically 174.37°C±0.1°C, more specifically 174.37°C).

[0385] In still further embodiments, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by a DSC onset temperature of 171.6°C±0.5°C (endothermic peak, sharp) (e.g., 171.6°C±0.2°C, particularly 171.6°C±0.1°C, more particularly 171.6°C).

[0386] In still further embodiments, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterized by Fig.17 The DSC thermogram labeled 1 is shown.

[0387] In one embodiment, the lactic acid salt (e.g., L-(+)-lactate) of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one is crystalline and is characterized by one or more (in any combination) or all of the following parameters:

[0388] (a) Fig.15 shown 1 H NMR spectrum; and / or

[0389] (b) an XRPD pattern having peaks at the following diffraction angles: 7.4 ± 0.5°, 7.9 ± 0.5°, 8.3 ± 0.5°,8.7 ± 0.5°, 9.0 ± 0.5°, 10.4 ± 0.5°, 11.2 ± 0.5°, 11.6 ± 0.5°, 12.3 ± 0.5°, 13.1 ± 0.5°, 13.9 ± 0.5°, 14.7 ± 0.5°, 15.8 ± 0.5°, 16.5 ± 0.5°,17.1 ± 0.5°, 17.9 ± 0.5°, 18.4 ± 0.5°, 18.9 ± 0.5°, 19.6 ± 0.5°, 20.4 ± 0.5°, 21.2 ± 0.5°, 22.4 ± 0.5°, 23.8 ± 0.5°, 24.9 ± 0.5°, 25.1 ± 0.5°, 26.8 ± 0.5°, 27.9 ± 0.5°, 28. 21.0 ± 0.5°, 21.8 ± 0.5°, 22.9 ± 0.5°, 23.3 ± 0.5°, 23.6 ± 0.5°, 24.0 ± 0.5°, 24.9 ± 0.5° and 26.4 ± 0.5° (2θ, 1d.p); and / or

[0390] (c) Basically Fig.16 The XRPD pattern shown as 1; and / or

[0391] (d) Fig.16 The same diffraction angle (2θ) of the XRPD pattern shown as 1 has a peak and optionally wherein the peak has a Fig.16 The same relative intensity as the peak labeled 1 shown; and / or

[0392] (e) have Fig.16 The main peak of diffraction angle (2θ) and intensity shown in the XRPD pattern labeled 1; and / or

[0393] (f) having major peaks at 8.7 ± 0.5°, 17.1 ± 0.5°, 17.9 ± 0.5° and 18.9 ± 0.5° (2θ, 1 d.p) as measured by XRPD; and / or

[0394] (g) The interplanar spacing (d) values ​​are 11.94 ± 0.5 Å, 11.19 ± 0.5 Å, 10.65 ± 0.5 Å, 10.16 ± 0.5 Å, 9.82 ± 0.5 Å, 8.50 ± 0.5 Å, 7.90 ± 0.5 Å, 7.62 ± 0.5 Å,7.19 ± 0.5 Å, 6.75 ± 0.5 Å, 6.37 ± 0.5 Å, 6.02 ± 0.5 Å, 5.61 ± 0.5 Å, 5.37 ± 0.5 Å, 5.18 ± 0.5 Å, 4.95 ± 0.5 Å, 4.82 ± 0.5 Å, 4.69±0.5 Å,4.53 ± 0.5 Å, 4.35 ± 0.5 Å, 4.23 ± 0.5 Å, 4.07 ± 0.5 Å, 3.88 ± 0.5 Å, 3.82 ± 0.5 Å, 3.77 ± 0.5 Å, 3.71 ± 0.5 Å, 3.57 ± 0.5 Å and 3.37 ± 0.5 Å (d,2d.p.); and / or

[0395] (h) a DSC peak temperature of 174.37°C ± 0.5°C (e.g. 174.37°C ± 0.2°C, in particular 174.37°C ± 0.1°C, more in particular 174.37°C); and / or

[0396] (i) a DSC onset temperature of 171.6°C ± 0.5°C (endothermic peak, sharp) (e.g. 171.6°C ± 0.2°C, in particular 171.6°C ± 0.1°C, more in particular 171.6°C); and / or

[0397] (j) Fig.17 The DSC thermogram labeled 1 is shown.

[0398] In particular, the Type C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate offers advantages in terms of stability and crystallinity.

[0399] Compound

[0400] Formula (I) also includes within its scope complexes of the compounds (e.g., inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals). Inclusion complexes, clathrates and metal complexes can be formed by methods well known to the skilled artisan.

[0401] Prodrug

[0402] Formula (I) also encompasses any prodrugs of the compounds of formula (I). The term "prodrug" means, for example in vivo Any compound that is converted into a biologically active compound of formula (I).

[0403] For example, some prodrugs are esters of active compounds (e.g., physiologically acceptable metabolically unstable esters). During metabolism, the ester group (-C(=O)OR) is cleaved to produce the active drug. Such esters can be formed by esterifying any carboxylic acid group (-C(=O)OH) in the parent compound, where appropriate, with prior protection of any other reactive groups present in the parent compound, followed by deprotection when necessary.

[0404] Examples of such metabolically labile esters include those of the formula -C(=O)OR, wherein R is:

[0405] C 1-7 Alkyl (e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);

[0406] C 1-7 aminoalkyl (eg, aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and

[0407] Acyloxy-C 1-7 Alkyl (e.g., acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 1-(1-methoxy-1-methyl)ethyl-carbonyloxyethyl; 1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl; (4-tetrahydropyranyloxy)carbonyloxymethyl; 1-(4-tetrahydropyranyloxy)carbonyloxyethyl; (4-tetrahydropyranyl)carbonyloxymethyl; and 1-(4-tetrahydropyranyl)carbonyloxyethyl).

[0408] Moreover, some prodrugs are enzymatically activated to produce an active compound or a compound that produces an active compound when further subjected to a chemical reaction (e.g., as in antigen-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT), and ligand-directed enzyme prodrug therapy (LIDEPT), etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative. In one embodiment, Formula (I) does not include within its scope prodrugs of compounds of Formula (I).

[0409] Advantages of the compounds of the present invention

[0410] The compounds of formula (I) may have various advantages over prior art compounds.

[0411] The compounds of the present invention may have particular advantages in one or more of the following aspects:

[0412] (i) Superior selectivity for the IKr (hERG) cardiac ion channel;

[0413] (ii) superior metabolic stability;

[0414] (iii) lower tendency for P450 inhibition;

[0415] (iv) superior oral bioavailability; and / or

[0416] (v) superior in vivo effect.

[0417] Superior selectivity for the IKr (hERG) cardiac ion channel

[0418] In the late 1990s, several drugs approved by the US FDA had to be withdrawn from the US market when they were linked to deaths caused by poor cardiac function. It was subsequently discovered that a side effect of these drugs was the formation of arrhythmias caused by blocking the hERG channel in heart cells. The hERG channel is a member of the potassium ion channel family, the first member of which was discovered in the late 1980s in mutants. Drosophila melanogasterIdentified in Drosophila (see, Jan, LY and Jan, YN (1990). A Superfamily of Ion Channels. Nature, 345(6277):672). The biophysical characteristics of the hERG potassium channel are described in Sanguinetti, MC, Jiang, C., Curran, ME and Keating, MT (1995). A Mechanistic Link Between an Inherited and an Acquired Cardiac Arrhythmia: HERGencodes the Ikr potassium channel. Cell, 81:299-307; and Trudeau, MC, Warmke, JW, Ganetzky, B. and Robertson, GA (1995). HERG, a Human Inward Rectifier in the Voltage-Gated Potassium Channel Family. Science, 269:92-95. Therefore, the elimination of hERG blocking activity remains an important consideration in the development of any new drug.

[0419] It has been found that many compounds of formula (I) have reduced hERG activity and / or good separation between IAP activity and hERG activity (larger 'therapeutic window'). One method for measuring hERG activity is patch clamp electrophysiology. Alternative methods for measuring functional hERG activity include hERG binding assays that can use commercially available membranes isolated from cells stably expressing the hERG channel or commercially available cell lines expressing the hERG channel.

[0420] Many compounds of formula (I) have an improved cardiac safety index (CSI) [CSI = hERG IC50 / Cmax (unbound)] (Shultz et al., J. Med. Chem., 2011; Redfern et al., Cardiovasc. Res., 2003). This may be due to an increase in hERG IC50 or a decrease in Cmax required for efficacy (due to better IAP potency and / or PK).

[0421] Specific compounds of formula (I) have reduced hERG ion channel blocking activity. Specific compounds of formula (I) have an average IC against hERG 50 Values, which are compound IC values ​​in cell proliferation assays 50The specific compounds of formula (I) have an average IC value of more than 30 times, more than 40 times, or more than 50 times for hERG. 50 The average IC values ​​of some compounds of the present invention for hERG are greater than 10 μM, more specifically greater than 20 μM and more preferably greater than 30 μM. 50 values ​​greater than 40 μM, or exhibited an IC value representative of this at concentrations of 10, 30, or 300 μM. 50 Some compounds of the invention had an average CSI (30-fold) above the minimum recommended value.

[0422] As can be seen from the data in Table 1 herein, the compounds of Examples 1-34 all have lower hERG propensity than the compound Example 259 (and 262 and 263) of WO 2012 / 143726. Specifically, the compounds of Examples 1-2, 11 and 34 of the present invention show an IC of 0.050 for hERG. 50 ≥40 μM, while the compound of Example 259 (and 262 and 263) of WO 2012 / 143726 showed 42% hERG inhibition at 10 μM. Therefore, the excellent selectivity for hERG is an important advantage of the compounds of the present invention over the IAP antagonist compounds disclosed in the prior art, especially those disclosed in WO 2012 / 143726.

[0423] Superior metabolic stability

[0424] The compounds of formula (I) may have favorable ADMET characteristics, such as better metabolic stability (e.g., determined with mouse liver microsomes), better P450 characteristics and / or beneficial clearance (e.g., low clearance). These characteristics may confer the advantage of making more drugs available in the systemic circulation to reach the appropriate site of action for exerting their therapeutic effects. Increased concentrations of drugs exerting pharmacological effects in tumors may result in improved efficacy, which thereby allows a reduction in the dose administered. Therefore, the compounds of formula (I) should exhibit reduced dosage requirements and should be easier to formulate and administer. In addition, the compounds may have reduced P450 (e.g., 3A4) turnover.

[0425] Lower P450 inhibition tendency

[0426] Many compounds of formula (I) are advantageous because they have different susceptibilities to P450 enzymes. For example, certain compounds of formula (I) have an IC greater than 10 μM against each of the cytochrome P450 enzymes 1A2, 2C9, 2C19, 3A4, and 2D6 (particularly 3A4). 50 Furthermore, in particular, the compounds are not P450 inhibitors.

[0427] Superior oral bioavailability

[0428] The compounds of the invention may have a physiochemical profile suitable for oral exposure (oral exposure or AUC). Specifically, the compounds of formula (I) may exhibit improved oral bioavailability. Oral bioavailability may be defined as the ratio (F) of the plasma exposure of the compound when administered by the oral route to the plasma exposure of the compound when administered by the intravenous (iv) route, expressed as a percentage.

[0429] Compounds having an oral bioavailability (F value, F%) of greater than 30%, more particularly greater than 40%, are particularly advantageous because they can be administered orally instead of parenterally, or both.

[0430] superior in vivo effect

[0431] Due to the increased potency against XIAP and / or cIAP, the compounds of the present invention are effective in cancer cell lines and in vivo The model can have an increased in vivo effect.

[0432] Preparation method of compound of formula (I)

[0433] In this section, as in all other sections of this application, references to formula (I) also include all other subgroups and instances thereof as defined herein, unless the context indicates otherwise.

[0434] The compounds of formula (I) can be prepared according to synthetic methods well known to those skilled in the art.

[0435] According to another aspect of the present invention, there is provided a method for preparing a compound of formula (I) as defined above, the method comprising:

[0436] (a) (i) reacting a compound of formula (II) with a compound of formula (III) or an optionally protected derivative thereof:

[0437]

[0438] (II)

[0439] Where R 5 , R 6 , U and X are as defined above for the compound of formula (I), L 1 represents a suitable leaving group, such as a halogen atom (eg, chlorine), and P 1 represents hydrogen or a suitable protecting group, such as tert-butoxycarbonyl (tBoc),

[0440]

[0441] (III)

[0442] Where R 1 and R 2 is as defined above for compounds of formula (I); then suitable for removing P as required 1 a deprotection reaction of a protecting group and any other protecting groups; or

[0443] (ii) reacting a compound of formula (IV) with a compound of formula (V) or an optionally protected derivative thereof:

[0444]

[0445] (IV)

[0446] Where R 5 , R 6 , X and U are as defined above for the compound of formula (I), and L 2 represents a suitable leaving group, such as halogen (eg, chlorine),

[0447]

[0448] (V)

[0449] Where R 1 and R 2 is as defined above for the compound of formula (I) and P 2 represents hydrogen or a suitable protecting group such as tert-butyloxycarbonyl (tBoc); then suitable for removing P as required 2 Deprotection reaction of the protecting group and any other protecting groups; and / or

[0450] (b) deprotecting a protected derivative of a compound of formula (I); and / or

[0451] (c) interconverting a compound of formula (I) or a protected derivative thereof into another compound of formula (I) or a protected derivative thereof; and

[0452] (d) optionally forming a pharmaceutically acceptable salt of the compound of formula (I).

[0453] Method (a) (i) generally comprises reacting a compound of formula (II) with a compound of formula (III) in a suitable solvent such as acetonitrile, optionally in the presence of a suitable additive such as potassium iodide and a suitable base such as potassium carbonate. This method can be carried out at ambient temperature or at an elevated temperature, for example 70°C.

[0454] Process (a)(ii) generally comprises reacting a compound of formula (IV) with a compound of formula (V) in a suitable solvent such as acetonitrile, optionally in the presence of a suitable additive such as potassium iodide and a suitable base such as potassium carbonate.

[0455] Method (b) generally includes any suitable deprotection reaction, and its condition will depend on the property of blocking group.When blocking group represents tBoc, this deprotection reaction will generally include the suitable acid used in suitable solvent.For example, described acid can suitably include trifluoroacetic acid or hydrogen chloride and described solvent can suitably include dichloromethane ethyl acetate, 1,4-dioxane, methanol or water.Optionally, solvent mixture can be used, for example aqueous methanol or ethyl acetate / 1,4-dioxane.

[0456] It will be appreciated that when the protecting group represents tBoc, deprotection using a suitable acid as described above can produce a compound of formula (I) as a pharmaceutically acceptable salt which can be isolated directly. Alternatively, the compound of formula (I) can be isolated as a free base using methods well known in the art and then optionally converted into a pharmaceutically acceptable salt according to method (d).

[0457] Method (c) generally involves interconversion procedures known to those skilled in the art. For example, in a compound of formula (I), a first substituent may be converted to a second alternative substituent by methods known to those skilled in the art. Many well-known functional group interconversions are known to those skilled in the art for converting precursor compounds to compounds of formula I, as described in Advanced Organic Chemistry , Jerry March, 4th edition, John Wiley & Sons, 1992. For example, possible metal-catalyzed functionalizations such as the use of organotin reagents (Stille reactions), Grignard reagents and reactions with nitrogen nucleophiles are described in 'Palladium Reagents and Catalysts' [Jiro Tsuji, Wiley, ISBN 0-470-85032-9] and Handbook of OrganoPalladium Chemistry for Organic Synthesis [Volume 1, edited by Ei-ichi Negishi, Wiley, ISBN 0-471-31506-0].

[0458] Process (d) can be carried out by treating a compound of formula (I) in its free base form dissolved in a suitable solvent with a stoichiometric amount or an excess of a pharmaceutically acceptable organic or inorganic acid and isolating the resulting salt by methods well known in the art such as solvent evaporation or crystallization.

[0459] If appropriate, the reactions previously described in processes (a), (b) and (c) are followed or preceded by one or more reactions known to the person skilled in the art and carried out in a suitable order to obtain the above defined R 1 , R 2 , R 5 and R 6 The desired substitution is obtained to obtain other compounds of formula (I). Non-limiting examples of such reactions whose conditions are found in the literature include:

[0460] Protection of reactive functional groups;

[0461] Deprotection of reactive functional groups;

[0462] Halogenation;

[0463] Dehalogenation;

[0464] Dealkylation;

[0465] Alkylation and arylation of amines, anilines, alcohols, and phenols;

[0466] Mitsunobu reaction on hydroxyl groups;

[0467] Cycloaddition reactions to appropriate groups;

[0468] Reduction of nitro groups, esters, cyano groups, and aldehydes;

[0469] Transition metal-catalyzed coupling reactions;

[0470] Acylation reaction;

[0471] Sulfonylation / introduction of sulfonyl groups;

[0472] saponification / hydrolysis of ester groups;

[0473] Amidation or transesterification of ester groups;

[0474] Esterification or amidation of carboxylic acid groups;

[0475] Halogen exchange;

[0476] nucleophilic substitution with amines, thiols, or alcohols;

[0477] Reductive amination;

[0478] Oxime formation on carbonyl and hydroxylamine groups;

[0479] S-oxidation;

[0480] N-oxidation;

[0481] Salt-forming effect.

[0482] The compound of formula (II) can be prepared from the compound of formula (IV) according to the following Scheme 1:

[0483] Solution 1

[0484]

[0485] Among them, X, U, R 5 , R 6 , L 1 , L 2 and P 1 As defined above.

[0486] Step (i) of Scheme 1 generally comprises reacting compounds of formula (IV) and (VI) optionally in the presence of a suitable additive such as potassium iodide and a suitable base such as potassium carbonate in a suitable solvent such as acetonitrile.

[0487] When L 1 Where chlorine is represented, step (ii) of Scheme 1 typically comprises reacting a compound of formula (VII) with a reagent capable of converting the hydroxy group to a good leaving group, such as methanesulfonyl chloride, in the presence of a base such as triethylamine.

[0488] Where X represents N, U represents carbon and R 6 Compounds of formula (IV) representing a hydroxymethyl group can be prepared according to the following Scheme 2:

[0489] Solution 2

[0490]

[0491] Where L 3 , L 4 , L 5 and L 6 represents a suitable leaving group, such as a halogen atom (i.e., fluorine, bromine or chlorine) and R 5 and L 2 As defined above.

[0492] When L 3 and L 4 When both represent fluorine, step (i) of Scheme 2 generally comprises reacting a compound of formula (VIII) with a base such as sodium bis(trimethylsilyl)amide in the presence of tetrahydrofuran and isobutyronitrile in a suitable solvent such as toluene. An example of such a reaction is shown herein in Preparation 11.

[0493] Step (ii) of Scheme 2 comprises reaction with a suitable reducing agent and generally comprises reacting a compound of formula (IX) with a borane-tetrahydrofuran complex in the presence of a suitable solvent such as tetrahydrofuran. An example of such a reaction is shown herein in Preparation 12. Step (ii) of Scheme 2 may also generally comprise reacting a compound of formula (IX) with nickel (II) chloride hexahydrate followed by addition of sodium borohydride. An example of such a reaction is shown herein in Preparation 12, Alternative Procedure.

[0494] Step (iii) of Scheme 2 typically involves cyclization of a compound of formula (X) using a suitable base such as potassium carbonate and a suitable solvent such as NMP. An example of such a reaction is shown herein in Preparation 13.

[0495] Step (iv) of Scheme 2 generally comprises reacting a compound of formula (XI) with a compound of formula R 5 -M compound reaction, where R 5 As defined above and M represents a residue of an organometallic substance, such that R 5 -M represents a nucleophilic organometallic reagent such as an organic zinc halide. Step (iv) generally also includes the use of lithium bromide, a catalyst such as [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride in a suitable solvent system such as tetrahydrofuran and NMP. An example of such a reaction is shown in Preparation 15 herein.

[0496] Step (v) of Scheme 2 generally involves halogenation of a compound of formula (XII), for example using N -bromosuccinimide. An example of such a reaction is shown herein in Preparation 16.

[0497] Step (vi) of Scheme 2 comprises lithiation and reaction with a suitable electrophilic reagent for the introduction of a formyl group, and generally comprises reacting a compound of formula (XIII) with MeLi in THF, followed by the addition of tBuLi / hexane, followed by the addition of dimethylformamide. An example of such a reaction is shown herein in Preparation 17.

[0498] Step (vii) of Scheme 2 involves reduction of the formyl group with a suitable reducing agent and typically comprises reacting a compound of formula (XIV) with sodium borohydride / methanol. An example of such a reaction is shown herein in Preparation 17.

[0499] When L 2When halogen, such as chlorine, step (viii) of Scheme 2 generally comprises reacting a compound of formula (XV) with a haloacetyl halide, such as chloroacetyl chloride, in MeCN, followed by addition of potassium carbonate / methanol. An example of such a reaction is shown herein in Preparation 18. Alternatively, a compound of formula (XIII) may be converted to a compound of formula (XV) by following a sequence similar to that described in Preparations 25-29, inclusive.

[0500] It will be understood that R 6 Indicates CH(OR x )CH2OR z Compounds of formula (XV) can be prepared in a manner analogous to Scheme 2 above by shifting forward step (v) of Scheme 2. Examples of suitable reaction sequences are shown herein in Preparations 38-42.

[0501] Where X represents NR 3 , U represents carbon and R 6 Compounds that are =0 can be synthesized using functional group interconversion on the appropriate intermediates of Scheme 2 or protected derivatives thereof, for example as shown in Preparations 22-24, 30-35 and 50.

[0502] It will also be understood that where R 5 Compounds of formula (IV) representing unsubstituted n-butyl or substituted benzyl can be prepared in a manner similar to Scheme 2 above by varying the organometallic reagent used in step (iv) of Scheme 2. Examples of such reactions are shown herein in Preparations 15A, 15B and 15C.

[0503] Where X represents CR 4 , U represents nitrogen and R 6 Compounds representing the oxo group can be synthesized using a sequence similar to that described in Preparations 43-49 and 51-58.

[0504] The compound of formula (V) or its optionally protected derivative can be prepared according to the following Scheme 3:

[0505] Solution 3

[0506]

[0507] Where R 1 , R 2 and P 2 As defined above for compounds of formula (V), L 7 represents a suitable leaving group such as a halogen atom (eg chlorine) and P 3 represents a suitable protecting group such as benzyl.

[0508] When P 3Where benzyl is represented, step (i) of Scheme 3 typically comprises reacting a compound of formula (XVI) with benzaldehyde in the presence of a suitable reducing agent such as sodium triacetoxyborohydride and 1,2-dichloroethane. An example of such a reaction is shown herein in Preparation 5.

[0509] When L 7 When chlorine is represented, step (ii) of Scheme 3 typically comprises reacting a compound of formula (XVII) with methanesulfonyl chloride in the presence of triethylamine and dichloromethane. An example of such a reaction is shown herein in Preparation 6.

[0510] Step (iii) of Scheme 3 generally comprises reacting compounds of formula (XVIII) and (XIX) in the presence of a base such as potassium carbonate, an additive such as potassium iodide in a suitable solvent such as acetonitrile. An example of such a reaction is shown herein in Preparation 7.

[0511] Step (iv) of Scheme 3 generally comprises a deprotection reaction. 3 Where benzyl is represented, step (iv) typically comprises hydrogenation of a compound of formula (XX) in the presence of a suitable catalyst such as palladium on carbon in a suitable solvent system such as ethanol or a mixture of acetic acid and ethanol. An example of such a reaction is shown herein in Preparation 8.

[0512] Alternatively, a compound of formula (I) may be prepared by reacting a compound of formula (XXI) or an optionally protected derivative thereof with a compound of formula (XXII), followed by suitable removal of the protecting group P 2 And any other protecting group deprotection reaction to synthesize:

[0513]

[0514] (XXI)

[0515] Where R 1 and R 2 As defined above for compounds of formula (I) and P 2 represents a suitable protecting group such as tert-butoxycarbonyl (tBoc),

[0516]

[0517] (XXII)

[0518] Among them, X, U, R 5 and R 6 As defined above.

[0519] An example of a suitable compound of formula (XXII) includes compounds of formula (XV) as defined hereinbefore.

[0520] The reaction generally comprises reacting a compound of formula (XXI) with a compound of formula (XXII), such as a compound of formula (XV), in a suitable solvent and at a suitable temperature, such as ambient temperature, in the presence of a suitable base and a reagent capable of activating the carboxylic acid group present in the compound of formula (XXI). Suitable solvents should be inert to the reagents used, such as dichloromethane. Examples of suitable bases are triethylamine and N,N - diisopropylethylamine (DIPEA). An example of a suitable activating agent is bromo-tris-pyrrolidino- Hexafluorophosphate (PyBrop), O -Benzotriazole- N,N,N',N' -Tetramethyl-urea -hexafluoro-phosphate (HBTU), 1,1'-carbonyldiimidazole, 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (EDC), and 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea The process can optionally be carried out in the presence of a catalytic or stoichiometric amount of a suitable co-activating agent such as 1-hydroxybenzotriazole (HOBt) or 1-hydroxyazabenzotriazole (HOAt).

[0521] Compounds of formula (XXI) or optionally protected derivatives thereof may be prepared from compounds of formula (V) as defined above or optionally protected derivatives thereof by methods well known in the art, for example by reaction with an ester of a monohaloacetic acid such as benzyl bromoacetate in the presence of a suitable base such as potassium carbonate in a suitable solvent such as acetonitrile; and subsequent ester hydrolysis (or optional hydrogenolysis in the case of a benzyl ester). Compounds of formula (I) may be prepared in a sequence analogous to that described in Preparations 1-5.

[0522] Compounds of formula (XXII) may be prepared by using a sequence analogous to that described in Scheme 2 or as described in the following preparations: 38-42; 22-24, 30-35 and 50; or 43-49 and 51-58.

[0523] It will be appreciated that certain compounds, for example those of Formula (I), (II), (III), (V), (VI), (VII), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI) and (XXII), may exist in different diastereomeric and / or enantiomeric forms and that their preparation may utilize enantiomerically pure synthetic precursors.

[0524] Alternatively, racemic precursors may be used and the diastereomeric mixtures produced in these processes may be separated by methods well known to those skilled in the art, such as achiral or chiral preparative chromatography or resolution using diastereomeric derivatives: for example, crystallization of salts formed with enantiomerically pure acids such as L-tartaric acid; or enantiomer separation of diastereomeric derivatives formed by covalently attaching enantiomerically pure chiral auxiliary to the compound and then separating using conventional methods such as chiral chromatography. The covalent bonds are then cleaved to produce the appropriate enantiomerically pure product.

[0525] The required intermediates are, for example, formula (III), (VI), (VIII), R 5 Compounds of (XVI) and (XIX) are commercially available, known in the literature, prepared by methods analogous to those described in the literature or by methods analogous to those described in the experimental procedures of the examples below. Other compounds can be prepared by methods well known in the art via the group R 1 , R 2 , R 5 and R 6 Prepared by functional group interconversion.

[0526] In a further embodiment, the present invention provides novel intermediates. In one embodiment, the present invention provides novel intermediates of formula (II) or (IV) or (V) or (VII) or (XX). In an alternative embodiment, the present invention provides novel intermediates of formula (XXI) or (XXII).

[0527] Protecting Group

[0528] In many of the reactions described above, it may be necessary to protect one or more groups to prevent the reaction from occurring at undesired locations on the molecule. Examples of protecting groups and methods for protecting and deprotecting functional groups can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd ed.; John Wiley and Sons, 1999).

[0529] Specifically, the group R 1 and R 2 They may be synthesized in protected form and the protecting groups may be removed to yield compounds of formula (I).

[0530] The hydroxy group can be protected, for example, as an ether (-OR) or an ester (-OC(=O)R), for example, as: tert-butyl ether; tetrahydropyranyl (THP) ether; benzyl ether, diphenylmethyl ether (diphenylmethyl ether) or triphenylmethyl ether (triphenylmethyl ether); trimethylsilyl ether or tert-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH3).

[0531] Aldehyde or keto groups can be protected, for example, as acetals (R-CH(OR)2) or ketals (R2C(OR)2), respectively, by treating the carbonyl group (>C=O) with, for example, a primary alcohol. The aldehyde or keto groups are readily regenerated by hydrolysis using a large excess of water in the presence of an acid.

[0532] The amino group can be protected, for example, as an amide (-NRCO-R) or a carbamate (-NRCO-OR), for example as: formamide (-NHCO-CH3); benzyl carbamate (-NHCO-OCH2C6H5, -NH-Cbz or NH-Z); as tert-butyl carbamate (-NHCO-OC(CH3)3, -NH-Boc); 2-diphenyl-2-propyl carbamate (-NHCO-OC(CH3)2C6H4C6 H5, -NH-Bpoc), as 9-fluorenylmethyl carbamate (-NH-Fmoc), as 6-nitroveratrol carbamate (-NH-Nvoc), as 2-trimethylsilylethyl carbamate (-NH-Teoc), as 2,2,2-trichloroethyl carbamate (-NH-Troc), as allyl carbamate (-NH-Alloc) or as 2(-phenylsulfonyl)ethyl carbamate (-NH-Psec).

[0533] For example, in the case of compounds of formula II containing an amino group, the amino group may be protected by a protecting group as defined above (a particular group is Uncle The protective group can be carried by the reaction sequence to obtain the compound of formula (I) in N-protected form, which can then be deprotected by standard methods (e.g., by acid treatment in the case of the Boc group) to obtain the compound of formula (I).

[0534] Other protecting groups for amines such as cyclic amines and heterocyclic NH groups include tosyl and mesyl, benzyl such as right -methoxybenzyl (PMB) and tetrahydropyranyl (THP).

[0535] The carboxylic acid group may be protected as an ester, for example as: C 1-7 Alkyl ester (e.g., methyl ester; tert-butyl ester); C 1-7 Alkyl halide (e.g., C 1-7 trihaloalkyl ester); triC 1-7 Alkylsilyl-C 1-7 Alkyl ester; or C 5-20 Aryl-C 1-7 Alkyl esters (e.g., benzyl esters; nitrobenzyl esters; right-methoxybenzyl ester. The thiol group can be protected, for example, as a thioether (-SR), for example as: benzyl thioether; acetylaminomethyl ether (-S-CH2NHC(=O)CH3).

[0536] Isolation and purification of the compounds of the present invention

[0537] The compounds of the present invention can be isolated and purified according to standard techniques well known to those skilled in the art and examples of such methods include chromatographic techniques such as column chromatography (e.g., flash chromatography) and HPLC. One technique particularly suitable for purifying compounds is preparative liquid chromatography using mass spectrometry as a means of detecting the purified compounds emerging from the chromatographic column.

[0538] Preparative LC-MS is a standard and effective method for purifying small organic molecules such as the compounds described herein. The methods of liquid chromatography (LC) and mass spectrometry (MS) can be varied to provide better separation of crude materials and improved detection of samples by MS. Optimization of preparative gradient LC methods will involve changing the column, volatile eluents and modifiers, and the gradient. Methods for optimizing preparative LC-MS methods and then using them to purify compounds are well known in the art. Such methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC / MS; J Comb Chem. ;2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquidchromatography / mass spectrometer platform for the preparative purificationand analytical analysis of compound libraries; J Comb Chem. ; 2003; 5(3); 322-9. An example of such a system for purifying compounds by preparative LC-MS is described below in the Examples section of this application (under the heading "Mass-directed purification LC-MS system").

[0539] The recrystallization process of the compound of formula (I) and its salt can be carried out by methods well known to the skilled person - see for example (P. Heinrich Stahl (editor), Camille G. Wermuth (editor), ISBN: 3-90639-026-8, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Chapter 8, publisher Wiley-VCH). The products obtained from organic reactions are rarely pure when directly isolated from the reaction mixture. If the compound (or its salt) is a solid, it can be purified and / or crystallized by recrystallization from a suitable solvent. A good recrystallization solvent should dissolve a moderate amount of the substance to be purified at high temperatures but only a small amount of the substance at low temperatures. It should dissolve impurities easily or not dissolve impurities at low temperatures. Finally, the solvent should be easy to remove from the purified product. This usually means that it has a relatively low boiling point and the skilled person will know the recrystallization solvent for a specific substance or, if there is no such information, test several solvents. In order to obtain a good yield of the purified substance, a minimum amount of hot solvent is used to dissolve all impure substances. In fact, more than 3%-5% of solvent is needed so that the solution is unsaturated. If the impure compound contains impurities that are insoluble in the solvent, it can be removed by filtering and then crystallizing the solution. In addition, if the impure compound contains trace colored substances that are not owned by the compound, it can be removed by adding a small amount of decolorizing agent such as activated carbon to the hot solution, filtering it and then crystallizing it. Crystallization usually occurs spontaneously when the solution is cooled. If it does not occur, crystallization can be induced by cooling the solution to room temperature or by adding a pure substance (seed) of a single crystal. Recrystallization and / or optimization of yield can also be carried out by using an antisolvent or a cosolvent. In this case, the compound is dissolved in a suitable solvent at high temperature, filtered and then another solvent in which the desired compound has low solubility is added to help crystallization. Then vacuum filtration is usually used to separate the crystals, washing and then drying, for example, in a furnace or by a desiccant.

[0540] Other examples of methods for purification include sublimation, which includes a heating step under vacuum, for example using a cold finger, and crystallization from the melt (Crystallization Technology Handbook, 2nd edition, ed. A. Mersmann, 2001).

[0541] Biological effects

[0542] The compounds of the present invention, subgroups thereof and examples thereof are antagonists of inhibitor of apoptosis proteins (IAPs), and they are useful for preventing or treating disease states or conditions described herein. In addition, the compounds of the present invention and subgroups thereof are useful for preventing or treating diseases or conditions mediated by IAPs. Reference to preventing or preventing or treating disease states or conditions such as cancer includes within its scope mitigating or reducing the incidence of cancer.

[0543] Thus, for example, it is envisaged that the compounds of the invention may be used to alleviate or reduce the incidence of cancer.

[0544] The compounds of the present invention may be used to treat the adult population. The compounds of the present invention may be used to treat the pediatric population.

[0545] More specifically, the compounds of formula (I) and subgroups thereof are antagonists of IAPs. For example, the compounds of the invention have affinity for XIAP, cIAP1 and / or cIAP2 and specifically for an IAP selected from XIAP and cIAP1.

[0546] Specific compounds are compounds having affinity for one or more IAPs selected from XIAP, cIAP1 and cIAP2. Specific compounds of the present invention are IC 50 Those compounds with values ​​less than 0.1 μM.

[0547] Antagonist compounds of formula (I) are capable of binding to IAPs and exhibit potency for IAPs. In one embodiment, antagonist compounds of formula (I) exhibit selectivity for one or more IAPs relative to other IAP family members, and may be capable of binding to XIAP and / or cIAP and / or exhibit affinity for XIAP and / or cIAP, preferentially over binding to other IAP family members and / or exhibit affinity for other IAP family members.

[0548] In addition, many compounds of the invention exhibit selectivity for XIAP over cIAP or vice versa, selectivity for cIAP (particularly cIAP1) over XIAP, and such compounds represent an embodiment of the invention. In particular, the compounds of the invention may have an affinity for one or more IAP family members, particularly XIAP, cIAP1 and / or cIAP2, that is at least 10 times greater than the affinity for other IAP family members. This can be determined using the methods described herein. In another embodiment, the compounds of the invention may have equivalent affinity for XIAP, cIAP1 and / or cIAP2, particularly equivalent affinity for XIAP and cIAP1 (i.e., less than a 10-fold difference in affinity).

[0549] Activity against XIAP and cIAP1 may be particularly advantageous. Antagonizing XIAP and cIAP1 with equivalent potency should be able to trigger apoptosis by activating caspase-8 and switching away from pro-survival NF-κB signaling to apoptosis; and effective antagonism of XIAP will ensure that apoptosis is achieved before any intrinsic resistance mechanisms are upregulated to block the process. There is a temporary upregulation of NF-κB signaling when cIAP1 is consumed by autoubiquitination and proteasomal degradation, which is the reason why TNF-α is expressed in sensitive cell lines - this is also the reason for the upregulation of anti-apoptotic factors such as cIAP2 and c-FLIP. Therefore, effective XIAP antagonism that enhances effector caspase activation and cell death is needed, rather than allowing cIAP2-mediated resistance to establish. It is generally believed that the toxicity generated when these compounds are administered in vivo is caused by temporary induction of NF-κB signaling and thus upregulation of pro-inflammatory cytokines, which is mediated only by cIAP1 / 2 antagonism. Therefore, dual potency should enable the therapeutic window to be achieved before dose-limiting toxicity is encountered.

[0550] IAP function in controlling programmed cell death is also implicated in a wide range of diseases, including disorders associated with cell accumulation (e.g., cancer, autoimmune disorders, inflammation, and restenosis), disorders in which excessive apoptosis leads to cell loss (e.g., stroke, heart failure, neurodegeneration such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, AIDS, ischemia (stroke, myocardial infarction), and osteoporosis or in the treatment of autoimmune diseases such as multiple sclerosis (MS).

[0551] Thus, it is also contemplated that the compounds of the invention may be used to treat other conditions such as inflammation (e.g., arthritis, including rheumatoid arthritis), hepatitis, ulcerative colitis, gastritis, autoimmunity, restenosis, stroke, heart failure, neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, myotonic dystrophy and amyotrophic lateral sclerosis, AIDS, ischemia such as traumatic brain injury, spinal cord injury, cerebral ischemia, cerebral ischemia / reperfusion (I / R) injury, acute and chronic CNS injury ischemia, stroke or myocardial infarction, degenerative diseases of the musculoskeletal system such as osteoporosis, autoimmune diseases such as multiple sclerosis (MS) and type I diabetes, and eye diseases caused by uncontrolled programmed cell death such as retinal degeneration. In one embodiment, the compounds of the invention are useful for treating viral infections such as herpes virus, pox virus, Epstein-Barr virus, Sindbis virus, adenovirus, HIV, HPV, hepatitis such as hepatitis B (HBV) or hepatitis C (HCV) and HCMV; or mycobacterial infections such as tuberculosis (TB).

[0552] Due to their affinity for IAPs, the compounds may be used to provide a means of controlling programmed cell death. It is therefore expected that the compounds may prove useful in treating or preventing proliferative disorders such as cancer. In addition, the compounds of the invention may be useful in treating diseases where there are conditions associated with cell accumulation or where excessive apoptosis leads to cell death.

[0553] Examples of cancers (and their benign counterparts) that may be treated (or inhibited) include, but are not limited to, tumors of epithelial origin (different types of adenomas and carcinomas, including adenocarcinomas, squamous cell carcinomas, transitional cell carcinomas, and other cancers), such as bladder and urinary tract, breast, gastrointestinal tract (including esophagus, stomach (gastric), small intestine, colon, rectum, and anus), liver (hepatocellular carcinoma), gallbladder and biliary system, exocrine pancreas, kidney, lung (e.g., adenocarcinoma, small cell lung cancer, non-small cell lung cancer, bronchioalveolar cell carcinoma, and mesothelioma), head and neck (e.g., cancers of the tongue, oral cavity, larynx, pharynx, nasopharynx, tonsils, salivary glands, nasal cavity, and paranasal sinuses), ovary, fallopian tube, peritoneum, vagina, vulva, penis, cervix, myometrium, uterus Cancers of the endometrium, thyroid (e.g., thyroid follicular cell carcinoma), adrenal glands, prostate, skin and appendages (e.g., melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, dysplastic nevus); hematological malignancies (i.e., leukemias, lymphomas) and premalignant hematological conditions and borderline malignant conditions, including hematological malignancies of the lymphoid lineage and related conditions (e.g., acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], B-cell lymphomas such as diffuse large B-cell lymphoma [DLBCL], follicular lymphoma, Burkitt's lymphoma, mantle cell lymphoma, T-cell lymphomas and leukemias, natural killer [NK] cell lymphomas, Hodgkin's lymphoma, hairy cell leukemia, monoclonal gammopathy of uncertain significance, plasmacytoma, multiple myeloma, and post-transplant lymphoproliferative disorder), and hematological malignancies and related conditions of the myeloid lineage (e.g., acute myeloid leukemia [AML], chronic myeloid leukemia [CML], chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome, myeloproliferative disorders such as polycythemia vera, essential thrombocythemia and primary myelofibrosis, myeloproliferative syndrome, myelodysplastic syndrome, and promyelocytic leukemia); tumors of mesenchymal origin, such as sarcomas of soft tissue, bone, or cartilage, such as osteosarcoma, fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, Leiomyosarcoma, liposarcoma, angiosarcoma, Kaposi's sarcoma, Ewing's sarcoma, synovial sarcoma, epithelioid sarcoma, gastrointestinal stromal tumors, benign and malignant histiocytomas, and dermatofibrosarcoma protuberans; tumors of the central or peripheral nervous system (e.g., astrocytomas, gliomas and glioblastomas, meningiomas, ependymomas, pineal tumors, and schwannomas); endocrine tumors (e.g., pituitary adenomas, adrenal tumors, islet cell tumors, parathyroid tumors, carcinoid tumors, and medullary carcinoma of the thyroid gland); tumors of the eye and adnexal organs (e.g., retinoblastoma); germ and trophoblastic tumors (e.g., teratomas, seminoma, dysgerminoma, hygromas, and choriocarcinoma);and pediatric and embryonal tumors (e.g., medulloblastoma, neuroblastoma, Wilms tumor, and primitive neuroectodermal tumor); or congenital or other syndromes that predispose the patient to malignancy (e.g., xeroderma pigmentosum).

[0554] The growth of cells is a tightly controlled function. Cancer is a condition of abnormal cell growth, which occurs when cells replicate (increase in number), grow uncontrollably (become larger) and / or experience a reduction in cell death caused by apoptosis (programmed cell death), necrosis or anoikis in an uncontrolled manner. In one embodiment, abnormal cell growth is selected from uncontrolled cell proliferation, excessive cell growth or programmed cell death reduction. Specifically, the condition or disease of abnormal cell growth is cancer. Therefore, in the pharmaceutical composition, use or method for treating a disease or condition including abnormal cell growth (i.e., uncontrolled and / or rapid cell growth) of the present invention, the disease or condition including abnormal cell growth in one embodiment is cancer.

[0555] In one embodiment, the hematological malignancy is a leukemia. In another embodiment, the hematological malignancy is a lymphoma.

[0556] In one embodiment, the disease to be treated is a leukemia, such as acute and chronic leukemias, acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). In one embodiment the leukemia is refractory DLBCL.

[0557] In one embodiment, the lymphoma is MALT lymphoma.In one embodiment, the leukemia is AML.

[0558] In one embodiment, the hematological malignancy is multiple myeloma.

[0559] Many diseases are characterized by persistent and unregulated angiogenesis. Chronic proliferative diseases are often accompanied by significant angiogenesis, which can contribute to or maintain an inflammatory and / or proliferative state, or lead to tissue destruction through aggressive proliferation of blood vessels. Tumor growth and metastasis have been found to be angiogenesis-dependent. The compounds of the present invention can therefore be used to prevent tumor angiogenesis and disrupt its initiation. Specifically, the compounds of the present invention can be used to treat metastasis and metastatic cancer.

[0560] Metastasis or metastatic disease is the spread of a disease from one organ or part to another non-adjacent organ or part. Cancers that can be treated by the compounds of the invention include primary tumors (i.e., cancer cells at the original location), locally invasive tumors (cancer cells that penetrate and infiltrate surrounding normal tissues in a local area), and metastatic (or secondary) tumors, i.e., tumors formed by malignant cells that have circulated to other sites and tissues in the body through the bloodstream (hematogenous spread) or through lymphatic vessels or through body cavities (coelomic metastasis).

[0561] Specific cancers include hepatocellular carcinoma, melanoma, esophageal cancer, renal cancer, colon cancer, colorectal cancer, lung cancer such as mesothelioma or lung adenocarcinoma, breast cancer, bladder cancer, gastrointestinal cancer, ovarian cancer, and prostate cancer.

[0562] Specific cancers include renal cancer, melanoma, colon cancer, lung cancer, breast cancer, ovarian cancer, and prostate cancer. In one embodiment, the cancer is selected from melanoma, colon cancer, breast cancer, and ovarian cancer. In one embodiment, the cancer is melanoma. In one embodiment, the cancer is inflammatory breast cancer.

[0563] In one embodiment, the cancer is lung cancer, such as mesothelioma, including malignant peritoneal mesothelioma or malignant pleural mesothelioma.

[0564] In one embodiment, the cancer is breast cancer, particularly triple negative (triple-ve) breast cancer.

[0565] In one embodiment, the cancer is colorectal cancer.

[0566] Another aspect of the invention includes compounds of the invention for use in preventing or treating cancer in a patient selected from a subgroup of a cancer having a high inflammatory component. Such cancers are also referred to as "inflammatory phenotypes" and include tumors with increased cytokine signaling (e.g., TNF). In one embodiment, the cancer is an inflammatory tumor, e.g., melanoma, colon cancer, breast cancer, and ovarian cancer, particularly melanoma.

[0567] In one embodiment, the melanoma is a ras mutant melanoma.

[0568] Certain cancers are resistant to treatment with specific drugs. This may be due to the type of tumor (most common epithelial malignancies have intrinsic chemoresistance) or resistance may arise spontaneously as the disease progresses or as a result of treatment. In this regard, reference to mesothelioma includes mesothelioma with resistance to topoisomerase poisons, alkylating agents, anti-tubulin agents, antifolates, platinum compounds, and radiotherapy, particularly mesothelioma with cisplatin resistance. Similarly, reference to multiple myeloma includes bortezomib-sensitive multiple myeloma or refractory multiple myeloma and reference to chronic myeloid leukemia includes imitanib-sensitive chronic myeloid leukemia and refractory chronic myeloid leukemia.

[0569] The cancer may be a cancer sensitive to an antagonist of any one or more IAPs selected from XIAP, cIAP1, cIAP2, NAIP, ILP2, ML-IAP, survivin and BRUCE, more particularly XIAP, cIAP1, cIAP2, ML-IAP, most particularly XIAP.

[0570] It is also envisaged that the compounds of the invention and in particular those with affinity for IAP are particularly useful for treating or preventing cancers of a type associated with or characterised by the presence of high levels of IAP or amplification of 11q22, such as the cancers mentioned in this context in the introductory part of the present application.

[0571] High levels of IAPs due to IAP overexpression are found in many cancers and are associated with a poor prognosis. In addition, cancers with 11q22 amplification may also be sensitive to IAP antagonists. High levels of IAPs and amplification of 11q22 can be determined by the techniques outlined herein. Whether a particular cancer is a cancer that is sensitive to IAP function can be determined by the methods listed in the section entitled "Diagnostic Methods".

[0572] Another aspect provides the use of a compound for the manufacture of a medicament for the treatment of a disease or condition as described herein, in particular cancer.

[0573] The compounds may also be used to treat tumor growth, pathogenesis, resistance to chemotherapy and radiation therapy by sensitizing cells to chemotherapy and may be used as antimetastatic agents.

[0574] All types of therapeutic anticancer interventions must increase the stress exerted on target tumor cells. In alleviating the toxic effects of such stress, IAPs are directly implicated in counteracting the effects of cancer drugs and treatment regimens. Therefore, antagonists of IAPs represent a class of chemotherapeutics with the potential to: (i) sensitize malignant cells to anticancer drugs and / or treatments; (ii) mitigate or reduce the incidence of resistance to anticancer drugs and / or treatments; (iii) reverse resistance to anticancer drugs and / or treatments; (iv) potentiate the activity of anticancer drugs and / or treatments; (v) delay or prevent the onset of resistance to anticancer drugs and / or treatments.

[0575] Due to their affinity for IAPs, the compounds can be used to provide a means of controlling programmed cell death. It is therefore also envisaged that the compounds of the invention can be used to treat other conditions, for example inflammatory disorders such as hepatitis, ulcerative colitis and gastritis; neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, Huntington's chorea, myotonic dystrophy and amyotrophic lateral sclerosis; AIDS, ischemia such as restenosis, traumatic brain injury, spinal cord injury, cerebral ischemia, cerebral ischemia / reperfusion (I / R) injury, acute and chronic CNS injury ischemia, stroke or myocardial infarction; degenerative diseases of the musculoskeletal system such as osteoporosis; autoimmune diseases such as multiple sclerosis (MS) and type I diabetes; and eye diseases such as retinal degeneration.

[0576] The affinity of the compounds of the invention as IAP antagonists can be measured using the bioassays and biophysical assays listed in the Examples herein and the affinity level exhibited by a given compound can be measured in terms of IC 50 The specific compound of the present invention is IC 50 Compounds having a value of less than 1 μM, more particularly less than 0.1 μM.

[0577] In one embodiment, the invention provides a compound for use in treating a disease or condition mediated by an IAP (e.g., XIAP and / or cIAP, e.g., cIAP1). In another embodiment, the invention provides a compound for use in treating a disease or condition that overexpresses an IAP (e.g., XIAP and / or cIAP, e.g., cIAP1).

[0578] In one embodiment, the invention provides a compound for use in treating a disease or condition mediated by IAP, wherein the compound is an IC 50Less than 50 μM of an IAP antagonist. In particular, the IAP is XIAP, cIAP1 and / or cIAP2. In another embodiment, the disease or condition mediated by IAPs is cancer characterized by overexpression of at least one IAP and / or amplification of 11q22.

[0579] In one embodiment, the invention provides a compound for use in treating a disease or condition mediated by an IAP, wherein the compound has an IC of less than 10 μM against at least one IAP in an assay for IAPs (e.g., displacement binding). 50 .

[0580] Another aspect provides the use of a compound for the manufacture of a medicament for treating a disease or condition mediated by an IAP, wherein the compound is a compound having an IC of less than 50 μM against at least one IAP in an assay (e.g., displacement binding). 50 IAP antagonists.

[0581] Diagnostic Methods

[0582] Prior to administering a compound of formula (I), a patient may be screened to determine whether the disease or condition the patient suffers from or may suffer from is one susceptible to treatment with a compound having affinity for IAP.The term "patient" includes both human and veterinary subjects.

[0583] For example, a biological sample obtained from a patient can be analyzed to determine whether the condition or disease, e.g., cancer, that the patient suffers from or may suffer from is a condition or disease characterized by a genetic abnormality or abnormal protein expression that results in upregulated IAP levels or that results in pathways that are sensitive to normal IAP function or that result in upregulated biochemical pathways downstream of IAP activation.

[0584] Examples of such abnormalities leading to IAP activation or sensitization are loss or inhibition of apoptotic pathways, upregulation of receptors or ligands, cytogenetic abnormalities, or the presence of mutant variants of receptors or ligands. Tumors with upregulation of IAPs, in particular overexpression of IAPs, may be particularly sensitive to IAP antagonists. For example, overexpression of XIAP and cIAP has been identified in a range of cancers as discussed in the Background section.

[0585] Amplification of chromosome 11q22 has been detected in cell lines and primary tumors of squamous cell carcinomas of the esophagus (Imoto et al., 2001) and cervix (Imoto et al., 2002) and in primary lung cancer / cell lines (Dai et al., 2003). Immunohistochemistry and Western blot analysis have identified cIAP1 and cIAP2 as possible oncogenes in this region, as both are overexpressed in cancers in which this rare amplification is increased.

[0586] The term up-regulated includes increased expression or over-expression, including gene amplification (i.e., multiple gene copies), cytogenetic abnormalities, and increased expression by transcription. Thus, patients may undergo diagnostic testing to detect markers characteristic of up-regulated IAP. The term diagnosis includes screening. The term marker includes genetic markers, including, for example, measuring DNA composition to identify the presence of IAP mutations or 11q22 amplification. The term marker also includes markers characteristic of up-regulated IAP (including protein levels, protein status, and mRNA levels of the above proteins).

[0587] Diagnostic tests and screening are typically performed on a biological sample (i.e., body tissue or fluid) selected from the group consisting of: tumor biopsy, blood (isolation and enrichment of exfoliated tumor cells), cerebrospinal fluid, plasma, serum, saliva, stool biopsy, sputum, chromosome analysis, pleural fluid, peritoneal fluid, buccal spear, skin biopsy, or urine.

[0588] Methods for identifying and analyzing cytogenetic abnormalities, genetic amplifications, mutations, and protein upregulation are known to those skilled in the art. Screening methods may include, but are not limited to, standard methods such as reverse transcriptase polymerase chain reaction (RT-PCR) or In situ Hybridization such as fluorescence In situ Hybridization (FISH).

[0589] In screening by RT-PCR, the level of mRNA in the tumor is assessed by creating a cDNA copy of the mRNA and then amplifying the cDNA by PCR. PCR amplification methods, selection of primers, and conditions for amplification are known to those skilled in the art. Nucleic acid manipulation and PCR are performed by standard methods, for example as described by Ausubel, FM wait Editor, (2004) Current Protocols in Molecular Biology, John Wiley&Sons Inc., or Innis, MA wait Editors, (1990) PCR Protocols: a guide to methods and applications, Academic Press, San Diego. Reactions and manipulations involving nucleic acid technology are also described in Sambrook wait, (2001), 3rd edition, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, commercially available kits for RT-PCR (e.g., Roche Molecular Biochemicals) can be used, or methods as listed below and incorporated herein by reference: U.S. Patents 4,666,828; 4,683,202; 4,801,531; 5,192,659, 5,272,057, 5,882,864 and 6,218,529, which are incorporated herein by reference.

[0590] For assessing mRNA expression In situ Examples of hybridization techniques include fluorescent In situ Hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152: 649).

[0591] generally, In situ Hybridization includes the following major steps: (1) fixation of the tissue to be analyzed; (2) pre-hybridization treatment of the sample to increase accessibility of the target nucleic acid and reduce nonspecific binding; (3) hybridization of a mixture of nucleic acids to nucleic acids in a biological structure or tissue; (4) washing after hybridization to remove nucleic acid fragments that did not bind during hybridization; and (5) detection of hybridized nucleic acid fragments. The probes used in these applications are typically labeled, for example, with radioactive isotopes or fluorescent reporter molecules. Specific probes are sufficiently long, for example from about 50, 100 or 200 nucleotides to about 1000 or more nucleotides, so as to be able to specifically hybridize to the target nucleic acid under stringent conditions. Standard methods for performing FISH are described in Ausubel, FM wait Editor, (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview, John MS Bartlett, in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd edition; ISBN: 1-59259-760-2; March 2004, pp. 077-088; Series: Methods in Molecular Medicine.

[0592] The method used for gene expression profiling was provided by DePrimo wait (2003), BMC Cancer ,3:3). In brief, the protocol is as follows: double-stranded cDNA is synthesized from total RNA using (dT)24 oligomers to prime first-strand cDNA synthesis, followed by random hexamer primers for second-strand cDNA synthesis. The double-stranded cDNA is used as a template to synthesize double-stranded cDNA using biotinylated ribonucleotides. in vitro cRNA was transcribed. cRNA was chemically fragmented according to the protocol described by Affymetrix (Santa Clara, CA, USA) and then hybridized overnight on human genome microarrays.

[0593] Alternatively, the protein product expressed from the mRNA can be determined by immunohistochemical analysis of tumor samples, solid phase immunoassay using microtiter plates, Western blotting, 2-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry, and other methods known in the art for detecting specific proteins. Detection methods may include the use of site-specific antibodies. The skilled artisan will recognize that all such well-known techniques for detecting upregulation of IAPs, detecting IAP variants or mutants, or detecting 11q22 amplification can be used in the context of the present invention.

[0594] Abnormal levels of proteins such as IAPs can be measured using standard protein assays such as those described herein. Elevated levels or overexpression can also be detected in tissue samples such as tumor tissue by measuring protein levels using assays such as those from Chemicon International. The protein of interest can be immunoprecipitated from sample lysates and its levels measured.

[0595] Alternative methods for measuring overexpression or increase of IAP (including its isoforms) include measuring microvessel density. This can be measured, for example, using the method described by Orre and Rogers (Int J Cancer (1999), 84 (2), 101-8). Assay methods also include the use of markers.

[0596] Therefore, all of these techniques can also be used to identify tumors that are particularly suitable for treatment with the compounds of the invention.

[0597] Thus, in another aspect the invention includes the use of a compound according to the invention for the manufacture of a medicament for treating or preventing a disease state or condition in a patient who has been screened and identified as suffering from or at risk of suffering from a disease or condition that may be susceptible to treatment with a compound having affinity for IAP (i.e., an IAP antagonist).

[0598] Further embodiments provide methods of treating a patient having or at risk of having a disease or condition described herein (eg, cancer) comprising administering an effective amount of a compound of Formula (I).

[0599] Another aspect of the invention includes compounds of the invention for use in preventing or treating cancer in a patient selected from a subpopulation having overexpressed one or more IAP family members (eg, cIAP and / or XIAP).

[0600] Another aspect of the invention includes a compound of the invention for use in preventing or treating cancer in a patient selected to have a cytogenetic abnormality resulting in overexpression of IAP, such as a patient selected to have 11q22 amplification.

[0601] MRI assays of vascular normalization (eg, using MRI gradient echo, spin echo, and contrast enhancement to measure blood volume, relative vessel size, and vascular permeability) in combination with circulating biomarkers can also be used to identify treatments with the compounds of the invention.

[0602] Accordingly, another aspect of the invention is a method for diagnosing and treating a disease state or condition mediated by IAP, the method comprising (i) screening a patient to determine whether the disease or condition that the patient suffers from or may suffer from is a disease or condition that may be susceptible to treatment with a compound having affinity for IAP; and (ii) where the patient is indicated to be susceptible to the disease or condition, thereafter administering to the patient a compound of formula (I) and subgroups or examples thereof as defined herein.

[0603] Pharmaceutical preparations

[0604] While it is possible to administer the active compound alone, it is preferable to present it as a pharmaceutical composition (eg, formulation). In one embodiment, this is a sterile pharmaceutical composition.

[0605] Accordingly, the present invention also provides pharmaceutical compositions as defined above and methods for preparing pharmaceutical compositions comprising (e.g., mixing) at least one compound of formula (I) (and subgroups thereof, as defined herein) together with one or more pharmaceutically acceptable excipients and optionally other therapeutic or prophylactic agents (as described herein).

[0606] Pharmaceutically acceptable excipients may be selected from, for example, carriers (e.g., solid, liquid or semisolid carriers), adjuvants, diluents, fillers or expanders, granulating agents, coating agents, release control agents, adhesives, disintegrants, lubricants, preservatives, antioxidants, buffers, suspending agents, thickeners, flavoring agents, sweeteners, taste masking agents, stabilizers or any other excipients conventionally used in pharmaceutical compositions. Examples of excipients used in various types of pharmaceutical compositions are described in more detail below.

[0607] The term "pharmaceutically acceptable" as used herein relates to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of subjects (e.g., humans) within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio. Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0608] Pharmaceutical compositions containing compounds of formula (I) can be formulated according to known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

[0609] The pharmaceutical composition may be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ocular, aural, rectal, vaginal or transdermal administration. When the compositions are intended for parenteral administration, they may be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery to a target organ or tissue by injection, infusion or other means of delivery. Delivery may be by bolus injection, short-term infusion or longer-term infusion, and may be by passive delivery or by utilizing an appropriate infusion pump or injection driver.

[0610] Pharmaceutical preparations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, co-solvents, surfactants, organic solvent mixtures, cyclodextrin complexing agents, emulsifiers (for forming and stabilizing emulsion preparations), liposome components for forming liposomes, gelable polymers for forming polymer gels, lyophilization protective agents, and especiallyA combination of agents used to stabilize the active ingredient in soluble form and to render the formulation isotonic with the blood of the intended recipient. Pharmaceutical formulations for parenteral administration may also take the form of aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents (RG Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol. 21(2) 2004, pp. 201-230).

[0611] The formulation can be presented in unit dose or multi-dose containers such as sealed ampoules, vials and prefilled syringes, and can be stored in freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, prior to use. In one embodiment, the formulation is provided in a bottle as an active pharmaceutical ingredient for subsequent reconstitution with a suitable diluent.

[0612] The pharmaceutical preparation may be prepared by lyophilizing the compound of formula (I) or a subgroup thereof. Lyophilization refers to the process of freeze-drying a composition. Therefore, freeze-drying and lyophilization are used as synonyms herein.

[0613] Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.

[0614] The pharmaceutical composition of the present invention for parenteral injection may also include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions before use.

[0615] Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as sunflower oil, safflower oil, corn oil or olive oil) and injectable organic esters such as ethyl oleate. For example, appropriate fluidity can be maintained by the use of thickening materials or coating materials such as lecithin, by maintaining the desired particle size in the case of dispersants, and by the use of surfactants.

[0616] The compositions of the present invention may also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. Prevention of microbial action may be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include tension modifiers, such as sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical forms may be caused by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0617] In a specific embodiment of the present invention, the pharmaceutical composition is in a form suitable for intravenous administration (e.g., by injection or infusion). For intravenous administration, the solution can be administered by itself or injected into an infusion bag (containing a pharmaceutically acceptable excipient, such as 0.9% saline or 5% glucose) before administration.

[0618] In another specific embodiment, the pharmaceutical composition is in a form suitable for subcutaneous (sc) administration.

[0619] Suitable pharmaceutical dosage forms for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.

[0620] Thus, tablet compositions may contain a unit dose of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, e.g., lactose, sucrose, sorbitol, or mannitol; and / or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or its derivatives such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and starch such as corn starch. Tablets may also contain such standard ingredients as binders and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g., swellable cross-linked polymers such as cross-linked carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers), and effervescent agents such as citrate / bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here.

[0621] Tablets may be designed to release the drug upon contact with gastric fluid (immediate release tablets) or to release the drug in a controlled manner over an extended period of time or in a specific area of ​​the gastrointestinal tract (controlled release tablets).

[0622] Capsule formulations may be of hard gelatin or soft gelatin type and may contain the active ingredient in solid, semisolid or liquid form. Gelatin capsules may be formed from animal gelatin or its equivalent of synthetic or vegetable origin.

[0623] Solid dosage forms (e.g., tablets, capsules, etc.) may be coated or uncoated. Coatings may be used as protective films (e.g., polymers, waxes, or varnishes) or as mechanisms for controlling drug release or for aesthetic or labeling purposes. Coatings (e.g., Eudragit™ type polymers) may be designed to release active ingredients at desired locations within the gastrointestinal tract. Thus, coatings may be selected to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively releasing the compound in the stomach or ileum, duodenum, jejunum, or colon.

[0624] In place of coating or in addition to coating, the drug can be presented with a solid matrix containing a controlled release agent such as a release delaying agent, which can be suitable for releasing the compound in a controlled manner in the gastrointestinal tract. Alternatively, the drug can be presented with a polymer coating such as a polymethacrylate polymer coating, which can be suitable for selectively releasing the compound under different acidity or alkalinity conditions in the gastrointestinal tract. Alternatively, the matrix material or the retardation release coating can be in the form of an erodible polymer (e.g., a maleic anhydride polymer), which is substantially continuously eroded when the dosage form passes through the gastrointestinal tract. In another alternative, the coating can be designed to disintegrate under the action of intestinal microorganisms. As another alternative, the active compound can be formulated in a delivery system that provides osmotic control of compound release. Osmotic release and other delayed release or sustained release formulations (e.g., formulations based on ion exchange resins) can be prepared according to methods well known to those skilled in the art.

[0625] Formula (I) compound can be prepared with carrier and used in nanoparticle form, and the surface area of ​​described nanoparticle increases and helps its absorption.In addition, nanoparticle provides the possibility of directly penetrating into cells.Nanoparticle drug delivery system is described in " Nanoparticle Technology for Drug Delivery " edited by Ram B Gupta and Uday B.Kompella, InformaHealthcare, ISBN 9781574448573, announced on March 13, 2006.Nanoparticle for drug delivery is also described in J.Control.Release, 2003, 91 (1-2), 167-172 and Sinha wait Mol. Cancer Ther. August 1 (2006) 5, 1909.

[0626] The pharmaceutical composition generally comprises about 1% (w / w) to about 95% (w / w) of active ingredient and 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient or a combination of excipients. In particular, the composition comprises about 20% (w / w) to about 90% (w / w) of active ingredient and 80% (w / w) to 10% of a pharmaceutically acceptable excipient or a combination of excipients. The pharmaceutical composition comprises about 1% to about 95%, in particular about 20% to about 90% of active ingredient. The pharmaceutical composition according to the present invention may be, for example, in unit dosage form, such as in the form of an ampoule, a vial, a suppository, a prefilled syringe, a dragee, a tablet or a capsule.

[0627] Pharmaceutically acceptable excipients can be selected according to the desired physical form of the formulation, and can be selected, for example, from diluents (e.g., solid diluents such as fillers or expanders; and liquid diluents such as solvents and co-solvents), disintegrants, buffers, lubricants, flow aids, release controlling agents (e.g., polymers or waxes that retard or delay release), binders, granulating agents, pigments, plasticizers, antioxidants, preservatives, flavoring agents, taste masking agents, tonicity adjusting agents, and coating agents.

[0628] Technicians will have professional knowledge to select the appropriate amount of the ingredients used in the preparation. For example, tablets and capsules usually contain 0-20% disintegrant, 0-5% lubricant, 0-5% flow aid and / or 0-99% (w / w) filler / or expander (depending on the drug dosage). They can also contain 0-10% (w / w) polymer binder, 0-5% (w / w) antioxidant, 0-5% (w / w) pigment. Sustained-release tablets can additionally contain 0-99% (w / w) polymers (depending on dosage) that control (e.g., delay) release. The film coating of the tablet or capsule usually contains 0-10% (w / w) polymer, 0-3% (w / w) pigment and / or 0-2% (w / w) plasticizer.

[0629] Parenteral formulations typically contain 0-20% (w / w) buffer, 0-50% (w / w) cosolvent and / or 0-99% (w / w) water for injection (WFI) (depending on the dose and whether lyophilized). Formulations for intramuscular sustained release may also contain 0-99% (w / w) oil.

[0630] Pharmaceutical compositions for oral administration can be obtained by mixing the active ingredient with a solid carrier, granulating the resulting mixture if necessary and processing the mixture into tablets, dragee cores or capsules after adding suitable excipients if necessary or necessary. They can also be incorporated into a polymer or waxy matrix that allows the active ingredient to diffuse or release in measured amounts.

[0631] The compounds of the present invention can also be formulated as solid dispersants. Solid dispersions are uniform, very fine dispersed phases of two or more solids. Solid solutions (molecular dispersion systems) are a type of solid dispersions that are well known for use in pharmaceutical technology (see (Chiou and Riegelman, J. Pharm. Sci., 60, 1281-1300 (1971)) and can be used to increase the dissolution rate of poorly water-soluble drugs and increase their bioavailability.

[0632] The present invention also provides solid dosage forms comprising the solid solution described above. Solid dosage forms include tablets, capsules, chewable tablets, and dispersible or effervescent tablets. Known excipients can be blended with the solid solution to obtain the desired dosage form. For example, a capsule can contain a solid solution blended with (a) a disintegrant and a lubricant or (b) a disintegrant, a lubricant, and a surfactant. In addition, the capsule can contain a swelling agent, such as lactose or microcrystalline cellulose. Tablets can contain a solid solution blended with at least one disintegrant, a lubricant, a surfactant, a swelling agent, and a glidant. Chewable tablets can contain a solid solution blended with a swelling agent, a lubricant, and if necessary, with additional sweeteners (such as artificial sweeteners) and suitable flavors. The solid solution can also be formed by spraying a solution of a drug and a suitable polymer onto the surface of an inert carrier such as sugar beads ('blank pellet core (non-pareils)'). These beads can then be loaded into capsules or pressed into tablets.

[0633] The drug formulation can be provided to the patient in the form of a "patient pack" containing the entire course of treatment in a single package, usually a blister pack. Patient packs have an advantage over traditional prescriptions, in which the pharmacist separates the patient's supply of medication from the bulk supply, because the patient always has access to the package insert contained in the patient pack and usually absent from the patient's prescription. The inclusion of a package insert has been shown to improve patient compliance with the physician's instructions.

[0634] Compositions for topical use and nasal delivery include ointments, creams, sprays, patches, gels, drops, and inserts (eg, intraocular inserts). Such compositions may be formulated according to known methods.

[0635] Examples of formulations for rectal or vaginal administration include pessaries and suppositories, which may be formed, for example, from shaped plastic or waxy materials containing the active compound. Solutions of the active compound may also be used for rectal administration.

[0636] Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays and may be administered using standard forms of powder inhaler devices or aerosol dispensing devices. Such devices are well known. For administration by inhalation, powder formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.

[0637] The compound of formula (I) will generally be presented in a unit dosage form and will therefore generally contain enough compound to provide the desired level of biological activity. For example, the formulation may contain 1 nanogram to 2 grams of active ingredient, for example 1 nanogram to 2 milligrams of active ingredient. Within these ranges, specific subranges of the compound are 0.1 milligram to 2 grams of active ingredient (more typically 10 milligrams to 1 gram, for example 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (e.g. 1 microgram to 10 milligrams, for example 0.1 milligram to 2 milligrams of active ingredient).

[0638] For oral compositions, unit dosage forms may contain 1 mg to 2 g, more usually 10 mg to 1 g, for example 50 mg to 1 g, for example 100 mg to 1 g, of active compound.

[0639] The active compound will be administered to a patient (eg, a human or animal patient) in need thereof in an amount sufficient to achieve the desired therapeutic effect.

[0640] Treatment

[0641] The compounds of formula (I) and subgroups as defined herein can be used to prevent or treat many disease states or conditions mediated by IAP. Therefore, according to another aspect of the present invention, there is provided a method of treating a disease state or condition (e.g., cancer) mediated by IAPs such as XIAP and / or cIAP, the method comprising administering a compound of formula (I) as defined herein to a subject in need thereof. According to another aspect of the present invention, there is provided a method of treating a disease state or condition (e.g., cancer) that overexpresses IAPs such as XIAP and / or cIAP, the method comprising administering a compound of formula (I) as described herein to a subject in need thereof. Examples of such disease states and conditions are listed above and specifically include cancer.

[0642] The compounds are typically administered to a subject in need of such administration, such as a human or animal patient, particularly a human.

[0643] The compounds are usually administered in therapeutically or prophylactically useful and generally non-toxic amounts. However, in certain circumstances (e.g., in the case of life-threatening diseases), the benefits of administering a compound of formula (I) may outweigh the disadvantages of any toxic effects or side effects, in which case it may be considered desirable to administer the compound in an amount relevant to the degree of toxicity.

[0644] The compounds may be administered chronically to maintain a beneficial therapeutic effect or may be administered only for short periods of time. Alternatively, they may be administered in a continuous manner or in a manner providing intermittent administration (eg, pulsatile manner).

[0645] The typical daily dosage of a compound of formula (I) may range from 100 pg to 100 mg per kg body weight, more typically from 5 ng to 25 mg per kg body weight, and more typically from 10 ng to 15 mg per kg body weight (e.g., 10 ng to 10 mg, and more typically from 1 μg / kg to 20 mg / kg, e.g., 1 μg / kg to 10 mg / kg), although higher or lower dosages may be used as needed. A compound of formula (I) may be administered on a daily basis or on a repeated basis, e.g., every 2 days, or every 3 days, or every 4 days, or every 5 days, or every 6 days, or every 7 days, or every 10 days, or every 14 days, or every 21 days, or every 28 days.

[0646] The compound of the present invention can be orally administered in many doses, such as 1 to 1500 mg, 2 to 800 mg or 5 to 500 mg, such as 2 to 200 mg or 10 to 1000 mg, and specific dosage examples include 10, 20, 50 and 80 mg. The compound can be administered once a day or more than once a day. The compound can be administered continuously (i.e., taken every day without interruption during the duration of the treatment regimen). Alternatively, the compound can be administered intermittently (i.e., for a given period of time such as one week continuously during the duration of the entire treatment regimen, then stopped for a period of time such as one week, and then continued for another period of time such as one week, etc.). Examples of treatment regimens involving intermittent administration include the following regimens, in which administration is performed for one week and stopped for one week; or performed for two weeks and stopped for one week; or performed for three weeks and stopped for one week; or performed for two weeks and stopped for two weeks; or performed for four weeks and stopped for two weeks; or performed for one week and stopped for three weeks - for one or more cycles, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more cycles.

[0647] In one particular dosing regimen, the patient is given a one hour infusion of a compound of formula (I) daily for up to ten days, specifically up to five days up to a week and the treatment is repeated at desired intervals, such as two to four weeks, specifically every three weeks.

[0648] More specifically, the patient may be given a one hour infusion of a compound of formula (I) daily for 5 days and the treatment repeated every three weeks.

[0649] In another specific dosing regimen, the patient is given an infusion over 30 minutes to 1 hour, followed by a maintenance infusion of a variable duration, such as 1 to 5 hours, for example 3 hours.

[0650] In another specific dosing regimen, a continuous infusion is administered to the patient over a period of 12 hours to 5 days, specifically a continuous infusion for 24 hours to 72 hours.

[0651] In another specific dosing regimen, the compound is administered orally to a patient once a week.

[0652] In another specific dosing regimen, the compound is administered orally to the patient once a day for 7-28 days, such as 7, 14 or 28 days.

[0653] In another specific dosing regimen, the compound is administered orally to the patient once a day for 1 day, 2 days, 3 days, 5 days or 1 week, followed by resting for as many days as necessary to complete a one or two week cycle.

[0654] In another specific dosing regimen, the compound is administered orally to the patient once a day for 2 weeks, followed by 2 weeks off.

[0655] In another specific dosing regimen, the compound is administered orally to the patient once a day for 2 weeks, followed by 1 week off.

[0656] In another specific dosing regimen, the compound is administered orally to the patient once a day for 1 week, followed by 1 week off.

[0657] Ultimately, however, the amount of compound administered and the type of composition used will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.

[0658] IAP antagonists have been found to be useful as single agents or in combination with other anticancer agents. For example, it may be advantageous to combine an antagonist that induces apoptosis with another agent that acts by a different mechanism to modulate cell growth, thereby treating two of the characteristic features of cancer development. Combination experiments may be performed, for example, as described in Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regulat 1984;22: 27–55.

[0659] The compounds as defined herein may be administered as a single therapeutic agent or they may be administered in combination therapy with one or more other compounds (or therapies) for the treatment of a particular disease state, such as a neoplastic disease such as cancer as defined above. For the treatment of the above conditions, the compounds of the invention may advantageously be used in combination with one or more other agents, more specifically other anticancer agents or adjuvants (supporting agents in therapy) in cancer therapy. Examples of other therapeutic agents or therapies that may be administered with the compounds of formula (I) (whether simultaneously or at different time intervals) include, but are not limited to:

[0660] •Topoisomerase I inhibitors;

[0661] •Antimetabolites;

[0662] •Tubulin targeting agents;

[0663] • DNA binding agents and topoisomerase II inhibitors;

[0664] •Alkylating agents;

[0665] • Monoclonal antibodies;

[0666] •Anti-hormonal agents;

[0667] •Signal transduction inhibitors;

[0668] •Proteasome inhibitors;

[0669] • DNA methyltransferase inhibitors;

[0670] •Cytokines and retinoids;

[0671] •Chromatin-targeted therapies;

[0672] • Radiation therapy; and

[0673] •Other therapeutic or prophylactic agents.

[0674] Specific examples of anticancer agents or adjuvants (or their salts) include, but are not limited to, any agent selected from the following groups (i) to (xlvi) and optionally group (xlvii):

[0675] (i) platinum compounds, such as cisplatin (optionally in combination with amifostine), carboplatin or oxaliplatin;

[0676] (ii) Taxane compounds, such as paclitaxel, paclitaxel protein-bound particles (Abraxane TM ), docetaxel, cabazitaxel, or larotaxel;

[0677] (iii) topoisomerase I inhibitors, such as camptothecin compounds, for example, camptothecin, irinotecan (CPT11), SN-38 or topotecan;

[0678] (iv) topoisomerase II inhibitors, such as antitumor epipodophyllotoxin or podophyllotoxin derivatives, such as etoposide or teniposide;

[0679] (v) vinca alkaloids, such as vinblastine, vincristine, liposomal vincristine (Onco-TCS), vinorelbine, vindesine, vinflunine or vinvesir;

[0680] (vi) nucleoside derivatives, for example 5-fluorouracil (5-FU, optionally in combination with folinic acid), gemcitabine, capecitabine, tegafur, UFT, S1, cladribine, cytarabine (Ara-C, cytosine arabinoside), fludarabine, clofarabine or nelarabine;

[0681] (vii) antimetabolites, such as clofarabine, aminopterin or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine, mercaptopurine, 6-mercaptopurine, or hydroxyurea (hydroxyurea);

[0682] (viii) alkylating agents such as nitrogen mustards or nitrosoureas, for example cyclophosphamide, chlorambucil, carmustine (BCNU), bendamustine, thiotepa, melphalan, thiosulfan, lomustine (CCNU), altretamine, busulfan, dacarbazine, estramustine, fotemustine, ifosfamide (optionally in combination with mesna), pipobroman, procarbazine, streptozocin, temozolomide, uracil, dichloromethyldiethylamine, methylcyclohexylchloroethylnitrourea or nimustine (ACNU);

[0683] (ix) anthracyclines, anthraquinones and related drugs, such as daunorubicin, doxorubicin (optionally in combination with dexrazoxane), liposomal formulations of doxorubicin (e.g., Caelyx™, Myocet™, Doxil™), idarubicin, mitoxantrone, epirubicin, amsacrine or valrubicin;

[0684] (x) an epothilone, such as ixabepilone, patupilone, BMS-310705, KOS-862 and ZK-EPO, epothilone A, epothilone B, deoxyepothilone B (also known as epothilone D or KOS-862), azaepothilone B (also known as BMS-247550), aulimalide, isolaulimalide or luetherobin;

[0685] (xi) DNA methyltransferase inhibitors, such as temozolomide, azacytidine or decitabine, or SGI-110;

[0686] (xii) antifolates, such as methotrexate, pemetrexed disodium, or raltitrexed;

[0687] (xiii) cytotoxic antibiotics, such as actinomycin D, bleomycin, mitomycin C, dactinomycin D, carminomycin, daunorubicin, levamisole, plicamycin or mithramycin;

[0688] (xiv) tubulin-binding agents, such as combrestatin, colchicine or nocodazole;

[0689] (xv) signal transduction inhibitors, such as kinase inhibitors (e.g., EGFR (epidermal growth factor receptor) inhibitors, VEGFR (vascular endothelial growth factor receptor) inhibitors, PDGFR (platelet-derived growth factor receptor) inhibitors, MTKI (multi-targeted kinase inhibitors), Raf inhibitors, mTOR inhibitors, such as imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, dovotinib, axitinib, nilotinib, vandetanib, vatalinib, pazopanib, sorafenib, sunitinib, temsirolimus, everolimus (RAD 001), vemurafenib (PLX4032 / RG7204), dabrafenib, encofenib or IκB kinase inhibitors such as SAR-113945, bardoxolone, BMS-066, BMS-345541, IMD-0354, IMD-2560 or IMD-1041, or MEK inhibitors such as Selumetinib (AZD6244) and Trametinib (GSK121120212);

[0690] (xvi) Aurora kinase inhibitors, such as AT9283, barasertib (AZD1152), TAK-901, MK0457 (VX680), cenisertib (R-763), danusertib (PHA-739358), alisertib (MLN-8237), or MP-470;

[0691] (xvii) CDK inhibitors, such as AT7519, roscovitine, seliciclib, avocidib (flavopiridol), dinaciclib (SCH-727965), 7-hydroxy-staurosporine (UCN-01), JNJ-7706621, BMS-387032 (also known as SNS-032), PHA533533, PD332991, ZK-304709 or AZD-5438;

[0692] (xviii) PKA / B inhibitors and PKB (akt) pathway inhibitors such as AKT inhibitors such as KRX-0401 (perifosin / NSC 639966), ipatasertib (GDC-0068; RG-7440), afuresertib (GSK-2110183; 2110183), MK-2206, MK-8156, AT13148, AZD-5363, triciribine phosphate (VQD-002; triciribine phosphate monohydrate (API-2; TCN-P; TCN-PM; VD-0002), RX-0201, NL-71-101, SR-13668, PX-316, AT13148, AZ-5363, Semaphore, SF1126 or Enzastaurin HCl (LY317615) or MTOR inhibitors such as rapamycin analogs such as RAD 001 (everolimus), CCI 779 (temsirolemus), AP23573 and ridaforolimus, sirolimus (originally known as rapamycin), AP23841 and AP23573, calmodulin inhibitors such as CBP-501 (forkhead translocation inhibitor), enzastaurinHCl (LY317615) or PI3K inhibitors such as dactolisib (BEZ235), buparlisib (BKM-120; NVP-BKM-120), BYL719, copanlisib (BAY-80-6946), ZSTK-474, CUDC-907, apitolisib (GDC-0980; RG-7422), pictilisib (pictrelisib, GDC-0941, RG-7321), GDC-0032, GDC-0068, GSK-2636771, idelalisib (formerly CAL-101, GS 1101, GS-1101), MLN1117 (INK1117), MLN0128 (INK128), IPI-145 (INK1197), LY-3023414, ipatasertib, afuresertib, MK-2206, MK-8156, LY-3023414, LY294002, SF1126 or PI-103 or sonolisib (PX-866);

[0693] (xix) Hsp90 inhibitors, such as AT13387, herbimycin, geldanamycin (GA), 17-allylamino-17-demethoxygeldanamycin (17-AAG) (e.g., NSC-330507, Kos-953, and CNF-1010), 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG) (e.g., NSC-707545 and Kos-1022), NVP-AUY922 (VER-52296), NVP-BEP800, CNF-2024 (BIIB-021, oral purine), ganetespib (STA-9090), SNX-5422 (SC-102112), or IPI-504;

[0694] (xx) monoclonal antibodies (unconjugated or conjugated to radioisotopes, toxins or other agents), antibody derivatives and related agents, such as anti-CD, anti-VEGFR, anti-HER2, anti-CTLA4, anti-PD-1 or anti-EGFR antibodies, for example, rituximab (CD20), ofatumumab (CD20), ibritumomab tiuxetan (CD20), GA101 (CD20), tositumomab (CD20), epratuzumab (CD22), lintuzumab (CD33), gemtuzumab ozogamicin (CD33), alemtuzumab (CD52), galiximab (CD80), trastuzumab (HER2 antibody), pertuzumab (HER2), trastuzumab-DM1 (HER2), ertuinomab (HER2 and CD3), cetuximab (EGFR), panitumumab (EGFR), necitumumab (EGFR), nimotuzumab (EGFR), bevacizumab (VEGF), catumaxumab (EpCAM and CD3), abavolumab (CA125), farletuzumab (folate receptor), elotuzumab (CS1), denosumab (RANK ligand), figitumumab (IGF1R), CP751,871 (IGF1R), mapatumumab (TRAIL receptor), metMAB (met), mitumomab (GD3 ganglioside), naptumomab estafenatox (5T4), sildenafil (IL6), or immunomodulators such as CTLA-4 blocking antibodies and / or antibodies to PD-1 and PD-L1 and / or PD-L2 such as ipilimumab (CTLA4), MK-3475 (pembrolizumab, formerly lambrolizumab, anti-PD-1), nivolumab (anti-PD-1), BMS-936559 (anti-PD-L1), MPDL320A, AMP-514, or MEDI4736 (anti-PD-L1), or tremelimumab (formerly ticilimumab, CP-675,206, anti-CTLA-4);

[0695] (xxi) estrogen receptor antagonists or selective estrogen receptor modulators (SERMs) or estrogen synthesis inhibitors, such as tamoxifen, fulvestrant, toremifene, droloxifene, faslodex or raloxifene;

[0696] (xxii) aromatase inhibitors and related agents, such as exemestane, anastrozole, letrozole, testolactone aminoglutethimide, mitotane, or vorozole;

[0697] (xxiii) antiandrogens (i.e., androgen receptor antagonists) and related agents, such as bicalutamide, nilutamide, flutamide, cyproterone acetate, or ketoconazole;

[0698] (xxiv) hormones and their analogues, such as medroxyprogesterone, diethylstilbestrol (also known as estrogen) or octreotide;

[0699] (xxv) steroids, for example, drostanolone propionate, megestrol acetate, nandrolone (decanoate, phenylpropionate), fluoxymesterone, or gossypol;

[0700] (xxvi) steroidal cytochrome P450 17α-hydroxylase-17,20-lyase inhibitors (CYP17), such as abiraterone;

[0701] (xxvii) gonadotropin-releasing hormone agonists or antagonists (GnRA), such as abarelix, goserelin acetate, histrelin acetate, leuprolide acetate, triptorelin, buserelin, or deserorelin;

[0702] (xxviii) glucocorticoids, such as prednisone, prednisolone, dexamethasone;

[0703] (xxix) Differentiating agents such as retinoids, rexinoids, vitamin D or retinoic acid and retinoic acid metabolism blockers (RAMBAs) such as isotretinoin, alitretinoin, bexarotene or tretinoin;

[0704] (xxx) Farnesyl transferase inhibitors, such as tipifarnib;

[0705] (xxxi) Chromatin-targeted therapies, such as histone deacetylase (HDAC) inhibitors, e.g., panobinostat, resminostat, abexinostat, vorinostat, romidepsin, belinostat, entinostat, quisinostat, pracinostat, tefinostat, mocetinostat, givinostat, CUDC-907, CUDC-101, ACY-1215, MGCD-290, EVP-0334, RG-2833, 4SC-202, romidepsin, AR-42 (Ohio State University), CG-200745, valproic acid, CKD-581, sodium butyrate, suberoylanilide hydroxyamic acid (SAHA), depsipeptide (FR 901228), dacilast (NVP-LAQ824), R306465 / JNJ-16241199, JNJ-26481585, trichostatin A, clindamycin (chlamydocin), A-173, JNJ-MGCD-0103, PXD-101, or apicidin;

[0706] (xxxii) proteasome inhibitors, such as bortezomib, carfilzomib, delanzomib (CEP-18770), ixazomib (MLN-9708), oprozomib (ONX-0912), or marizomib;

[0707] (xxxiii) photodynamic drugs, such as porfimer sodium or temoporphine;

[0708] (xxxiv) Marine bioderived anticancer agents, such as trabectidin;

[0709] (xxxv) radiolabeled drugs for use in radioimmunotherapy, for example those radiolabeled with isotopes that emit beta particles (e.g., iodine-131, yttrium-90) or isotopes that emit alpha particles (e.g., bismuth-213 or actinium-225), such as ibritumomab tiuxetan or tositumomab iodine;

[0710] (xxxvi) telomerase inhibitors, such as telomestatin;

[0711] (xxxvii) matrix metalloproteinase inhibitors, for example batimastat, marimastat, prinostat or metastat;

[0712] (xxxviii) recombinant interferons (such as interferon-γ and interferon α) and interleukins (such as interleukin 2), such as aldesleukin, denileukin, interferon α2a, interferon α2b or pegylated interferon α2b

[0713] (xxxix) selective immune response modifiers, such as thalidomide or lenalidomide;

[0714] (xl) Therapeutic vaccines, such as sipuleucel-T (Provenge) or OncoVex;

[0715] (xli) Cytokine activators, including Picibanil, Romotide, Sizoran, Virulizine, or Thymosin;

[0716] (xlii) Arsenic trioxide;

[0717] (xliii) G-protein coupled receptor (GPCR) inhibitors, such as atrasentan;

[0718] (xliv) Enzymes such as L-asparaginase, pegaspargase, rasburicase or pegamidase;

[0719] (xlv) DNA repair inhibitors, such as PARP inhibitors, for example olaparib, velaparib, iniparib, INO-1001, AG-014699 or ONO-2231;

[0720] (xlvi) death receptor agonists (e.g., TNF-related apoptosis-inducing ligand (TRAIL) receptor), such as mapatumumab (formerly HGS-ETR1), conatumumab (formerly AMG 655), PRO95780, lexatumumab, dulalemin, CS-1008, apoxitumumab, or recombinant TRAIL ligands such as recombinant human TRAIL / Apo2 ligand;

[0721] (xlvii) Prophylactic agents (adjuvants); that is, agents that reduce or alleviate some of the side effects associated with chemotherapeutic agents, e.g.

[0722] – Antiemetics;

[0723] - agents that prevent or reduce the duration of chemotherapeutic-associated neutropenia and prevent complications caused by decreased platelet, red blood cell or white blood cell levels, such as interleukin-11 (e.g., oprelvekin), erythropoietin (EPO) and its analogs (e.g., darbepoetin alfa), colony stimulating factor analogs such as granulocyte macrophage colony stimulating factor (GM-CSF) (e.g., sargramostim) and granulocyte colony stimulating factor (G-CSF) and its analogs (e.g., filgrastim, pegfilgrastim);

[0724] - agents that inhibit bone resorption, such as denosumab or bisphosphonates, such as zoledronate, zoledronate, pamidronate, and ibandronate;

[0725] – Agents that suppress inflammatory responses, such as dexamethasone, prednisone, and prednisolone;

[0726] - agents used to reduce blood levels of growth hormone and IGF-I (and other hormones) in patients with acromegaly or other rare hormone-producing tumors, such as synthetic forms of the hormone somatostatin, such as octreotide acetate;

[0727] – Antidotes for drugs that lower folate levels, such as folinic acid or folic acid;

[0728] – Agents used for pain, such as opiates, such as morphine, diacetylmorphine, and fentanyl;

[0729] – Nonsteroidal anti-inflammatory drugs (NSAIDs), such as COX-2 inhibitors, for example, celecoxib, etoricoxib, and lumiracoxib;

[0730] – Agents for mucositis, such as palifermin;

[0731] -Agents used to treat side effects including anorexia, cachexia, edema, or thromboembolic episodes, such as megestrol acetate.

[0732] In one embodiment, the anticancer agent is selected from recombinant interferons (e.g. interferon-γ and interferon α) and interleukins (e.g. interleukin 2), such as aldesleukin, denileukin 2, interferon α2a, interferon α2b or pegylated interferon α2b; interferon-α2 (500 µ / ml), in particular interferon-β; and signal transduction inhibitors such as kinase inhibitors (e.g. EGFR (epidermal growth factor receptor) inhibitors, VEGFR (vascular endothelial growth factor receptor) inhibitors, PDGFR (platelet-derived growth factor receptor) inhibitors, MTKI (multi-targeted kinase inhibitors), Raf inhibitors, mTOR inhibitors such as imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, dovotinib, axitinib, nilotinib, vandetanib, vatalinib, pazopanib, sorafenib, sunitinib, temsirolimus, everolimus (RAD 001), vemurafenib (PLX4032 / RG7204), dabrafenib, encofenib or an IκB kinase inhibitor such as SAR-113945, bardoxolone, BMS-066, BMS-345541, IMD-0354, IMD-2560 or IMD-1041, or a MEK inhibitor such as Selumetinib (AZD6244) and Trametinib (GSK121120212), in particular a Raf inhibitor (e.g. vemurafenib) or a MEK inhibitor (e.g. trametinib).

[0733] Each compound present in the combination of the present invention can be administered in a dosage regimen that varies individually and by different routes. Therefore, the posology of each of two or more agents can be different: each can be administered at the same time or at different times. Those skilled in the art can know the dosage regimen and combination therapy used by his or her common knowledge. For example, the compound of the present invention can be used in combination with one or more other agents administered according to its existing combination regimen. The example of a standard combination regimen is provided below.

[0734] The taxane compound is advantageously administered at a dose of 50 to 400 mg per square meter of body surface area (mg / m 2 ), such as 75 to 250 mg / m 2 The dosage of paclitaxel is about 175 to 250 mg / m 2 and for docetaxel, the dose is about 75 to 150 mg / m 2 .

[0735] In each treatment course, the camptothecin compound is advantageously administered in an amount of 0.1 to 400 mg per square meter of body surface area (mg / m2 ), such as 1 to 300 mg / m 2 The dosage of irinotecan is about 100 to 350 mg / m 2 and for topotecan the dose is about 1 to 2 mg / m 2 .

[0736] In each course of treatment, the antitumor podophyllotoxin derivative is advantageously administered at a dose of 30 to 300 mg per square meter of body surface area (mg / m 2 ), such as 50 to 250 mg / m 2 The dosage of etoposide is about 35 to 100 mg / m 2 and for teniposide doses of about 50 to 250 mg / m 2 .

[0737] In each course of treatment, the antitumor vinca alkaloid is advantageously administered at a dose of 2 to 30 mg per square meter of body surface area (mg / m 2 ) in doses, specifically for vinblastine, doses of about 3 to 12 mg / m 2 For vincristine, the dose is about 1 to 2 mg / m 2 And for vinorelbine, the dose is about 10 to 30 mg / m 2 .

[0738] In each course of treatment, the antineoplastic nucleoside derivative is advantageously administered at a dose of 200 to 2500 mg per square body surface area (mg / m 2 ), for example 700 to 1500 mg / m 2 The dosage of 5-FU is 200 to 500 mg / m 2 For gemcitabine, the dose is about 800 to 1200 mg / m 2 and for capecitabine doses of approximately 1000 to 2500 mg / m 2 .

[0739] In each course of treatment, an alkylating agent such as nitrogen mustard or a nitrosourea is advantageously administered at a dose of 100 to 500 mg per square meter of body surface area (mg / m 2 ), such as 120 to 200 mg / m 2 The dosage of cyclophosphamide is about 100 to 500 mg / m 2 , for chlorambucil the dose is about 0.1 to 0.2 mg / kg, for carmustine the dose is about 150 to 200 mg / m 2 , and for lomustine the dose is about 100 to 150 mg / m 2 .

[0740] In each course of treatment, the antineoplastic anthracycline derivative is advantageously administered at a dose of 10 to 75 mg per square meter of body surface area (mg / m 2 ), such as 15 to 60 mg / m 2 The dosage of doxorubicin is about 40 to 75 mg / m 2 For daunorubicin, the dose is approximately 25 to 45 mg / m 2 and for idarubicin, the dose is about 10 to 15 mg / m 2 .

[0741] Antiestrogens are advantageously administered at a dosage of about 1 to 100 mg per day according to specific agents and the patient's condition to be treated.Tamoxifen is advantageously administered orally twice a day at a dosage of 5 to 50 mg, particularly 10 to 20 mg, for a sufficient time for therapy to be continued to achieve and maintain a therapeutic effect.Toremifene is advantageously administered orally once a day at a dosage of about 60 mg, for a sufficient time for therapy to be continued to achieve and maintain a therapeutic effect.Anastrozole is advantageously administered orally once a day at a dosage of about 1 mg.Droloxifene is advantageously administered orally once a day at a dosage of about 20-100 mg.Raloxifene is advantageously administered orally once a day at a dosage of about 60 mg.Exemestane is advantageously administered orally once a day at a dosage of about 25 mg.

[0742] The antibody is advantageously administered at about 1 to 5 mg per square meter of body surface area (mg / m 2 ) or, if different, as known in the art. In each course of treatment, trastuzumab is advantageously administered at a dose of 1 to 5 mg per square meter of body surface area (mg / m 2 ), specifically 2 to 4 mg / m 2 dosage administration.

[0743] In the case where the compound of formula (I) is administered with a combination therapy with one, two, three, four or more other therapeutic agents (particularly one or two, more particularly one), the compound may be administered simultaneously or sequentially. In the latter case, two or more compounds will be administered in a time period and in an amount and manner sufficient to ensure that a favorable effect or synergistic effect is achieved. When administered sequentially, they may be administered at closely spaced intervals (e.g., a time period of 5-10 minutes) or at longer intervals (e.g., at intervals of 1, 2, 3, 4 or more hours or even at intervals of longer time periods when necessary), with the precise dosage regimen being commensurate with the properties of the therapeutic agent. These dosages may be administered, for example, once, twice or more per course of treatment, which may be repeated, for example, every 7 days, 14 days, 21 days or 28 days.

[0744] In one embodiment, a compound of formula (I) is provided for the preparation of a medicament for treatment, wherein the compound is used in combination with one, two, three or four other therapeutic agents. In another embodiment, a medicament for the treatment of cancer is provided, comprising a compound of formula (I), wherein the medicament is used in combination with one, two, three or four other therapeutic agents. The present invention also provides the use of a compound of formula (I) for the preparation of a medicament for improving or enhancing the response rate in a patient suffering from cancer, wherein the patient is being treated with one, two, three or four other therapeutic agents.

[0745] It will be appreciated that the specific method and order of administration and the corresponding dosages and regimens for each component of the combination will depend on the specific other agents and compounds of the invention being administered, their routes of administration, the specific tumor being treated, and the specific host being treated. The optimal method and order of administration, as well as the dosages and regimens can be readily determined by those skilled in the art using conventional methods and based on the information set forth herein.

[0746] The weight ratio of the compound according to the present invention and one or more other anticancer agents when given as a combination can be determined by those skilled in the art. The exact dosage and frequency of the ratio and administration depend on the specific compound according to the present invention and other anticancer agents used, the specific condition being treated, the severity of the condition being treated, the age, body weight, sex, diet, administration time and general physical condition of the specific patient, the mode of administration and other medicaments that the individual can take, as known to those skilled in the art. In addition, it is obvious that the effective daily amount can be reduced or increased according to the reaction of the subject being treated and / or according to the evaluation of the doctor who prescribes the compound of the present invention. The scope of the specific weight ratio of the compound of formula (I) of the present invention and another anticancer agent can be 1 / 10 to 10 / 1, more specifically 1 / 5 to 5 / 1, and even more specifically 1 / 3 to 3 / 1.

[0747] The compounds of the invention may also be administered in conjunction with non-chemotherapeutic treatments such as radiation therapy, photodynamic therapy, gene therapy; surgery and dietary control.

[0748] The compounds of the present invention also have therapeutic applications in sensitizing tumor cells to radiotherapy and chemotherapy. Thus, the compounds of the present invention can be used as "radiosensitizers" and / or "chemosensitizers", or can be administered in combination with another "radiosensitizer" and / or "chemosensitizer". In one embodiment, the compounds of the present invention are used as chemosensitizers.

[0749] The term "radiosensitizer" is defined as a molecule that is administered to a patient in a therapeutically effective amount to increase the sensitivity of cells to ionizing radiation and / or to facilitate the treatment of a disease that is treatable with ionizing radiation.

[0750] The term "chemosensitizer" is defined as a molecule that is administered to a patient in a therapeutically effective amount to increase the sensitivity of cells to chemotherapy and / or to promote the treatment of a disease that is treatable with chemotherapy.

[0751] In one embodiment, the compounds of the present invention are administered together with a "radiosensitizer" and / or a "chemosensitizer". In one embodiment, the compounds of the present invention are administered together with an "immunosensitizer".

[0752] The term "immune sensitizer" is defined as a molecule that is administered to a patient in a therapeutically effective amount to increase the sensitivity of cells to an IAP antagonist, such as by promoting or increasing an immune response, such as by triggering the release of TNF.

[0753] Many cancer treatment regimens currently employ radiosensitizers in conjunction with x-ray radiation. Examples of x-ray activated radiosensitizers include, but are not limited to, the following: metronidazole, misonidazole, demethyl misonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145, nimorazole, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR), bromodeoxythymidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives thereof.

[0754] Photodynamic therapy (PDT) of cancer uses visible light as a radiation activator of the sensitizer. Examples of photodynamic radiation sensitizers include, but are not limited to, hematoporphyrin derivatives, photoporphyrins, benzoporphyrin derivatives, tin protoporphyrins, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanines, and therapeutically effective analogs and derivatives thereof.

[0755] The radiosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including, but not limited to: compounds of the invention; compounds that promote the incorporation of the radiosensitizer into target cells; compounds that control the flow of therapeutic agents, nutrients, and / or oxygen to target cells; chemotherapeutic agents that act on tumors with or without additional radiation; or other therapeutically effective compounds for the treatment of cancer or other diseases.

[0756] Chemosensitizers may be administered in combination with a therapeutically effective amount of one or more other compounds, including, but not limited to, compounds of the invention; compounds that promote the incorporation of chemosensitizers into target cells; compounds that control the flow of therapeutic agents, nutrients, and / or oxygen to target cells; chemotherapeutic agents that act on tumors; or other therapeutically effective compounds for the treatment of cancer or other diseases. Calcium antagonists such as verapamil have been found to be useful in combination with anti-tumor agents to establish chemosensitivity in tumor cells that are resistant to received chemotherapeutic agents and to enhance the efficacy of such compounds in drug-sensitive malignancies.

[0757] Examples of immune sensitizers include, but are not limited to, the following: immunomodulators, such as monoclonal antibodies, such as immune checkpoint antibodies [e.g., CTLA-4 blocking antibodies and / or antibodies to PD-1 and PD-L1 and / or PD-L2 such as ipilimumab (CTLA4), MK-3475 (pembrolizumab, formerly lambrolizumab, anti-PD-1), nivolumab (anti-PD-1), BMS-936559 (anti-PD-L1), MPDL320A, AMP-514 or MEDI4736 (anti-PD-L1) or tremelimumab (formerly ticilimumab, CP-675,206, anti-CTLA-4); or signal transduction inhibitors; or cytokines (e.g., recombinant interferon); or oncolytic viruses; or immune adjuvants (e.g., BCG).

[0758] The immunosensitizer may be administered in combination with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds of the present invention; compounds that promote the incorporation of the immunosensitizer into target cells; compounds that control the flow of drugs, nutrients and / or oxygen into target cells; therapeutic agents that act on tumors or other therapeutically effective compounds for treating cancer or other diseases.

[0759] For use in combination therapy with another chemotherapeutic agent, the compound of formula (I) and one, two, three, four or more other therapeutic agents can be formulated together, for example, in a dosage form containing two, three, four or more therapeutic agents, i.e., in a unit pharmaceutical composition containing all agents. In an alternative embodiment, a single therapeutic agent can be formulated separately and optionally presented with its instructions for use in the form of a kit.

[0760] In one embodiment, a combination of a compound of formula (I) and one or more (e.g., 1 or 2) other therapeutic agents (e.g., an anticancer agent as described above) is provided. In a further embodiment, a combination of an IAP antagonist as described herein and a PI3K / AKT pathway inhibitor is provided, the pathway inhibitor being selected from the group consisting of apitolisib, buparlisib, Copanlisib, pictilisib, ZSTK-474, CUDC-907, GSK-2636771, LY-3023414, ipatasertib, afuresertib, MK-2206, MK-8156, Idelalisib, BEZ235 (dactolisib), BYL719, GDC-0980, GDC-0941, GDC-0032, and GDC-0068.

[0761] In another embodiment, provided is a combination of a compound of formula (I) and one or more (eg, 1 or 2) other therapeutic agents (eg, anti-tumor agents) for use in therapy, such as the prevention or treatment of cancer.

[0762] In one embodiment, a pharmaceutical composition comprises a compound of formula (I) together with a pharmaceutically acceptable carrier and optionally one or more therapeutic agents.

[0763] In another embodiment, the invention relates to the use of a combination according to the invention for the manufacture of a pharmaceutical composition for inhibiting the growth of tumor cells.

[0764] In another embodiment, the invention relates to a product containing a compound of formula (I) and one or more anticancer agents as a combined preparation for simultaneous, separate or sequential use in the treatment of a patient suffering from cancer. Example

[0765] The invention will now be illustrated by reference to specific embodiments described in the following examples, but is not limited to these embodiments. Compounds were named using an automated naming package such as AutoNom (MDL) or as named by chemical suppliers.

[0766] The following synthetic procedures are provided to illustrate the methods used; for a given preparation or step, the precursors used may not necessarily originate from a single batch synthesized according to the step in a given description. In the examples, the following abbreviations are used.

[0767]

[0768]

[0769] NMR data: unless indicated, recorded at 25 °C on a Bruker Avance I spectrometer operating at 400 MHz 1 H NMR spectra. Topspin 2.1 software was used to process and analyze the data. For NMR data, in the case where the number of assigned protons was less than the theoretical number of protons in the molecule, it was ensured that the signals that were significantly lost were masked by solvent and / or water peaks. In addition, in the case where spectra were obtained in proton NMR solvents, exchange of NH and / or OH protons with the solvent occurred and therefore such signals were not normally observed.

[0770] Analytical and Preparative LC-MS Systems

[0771] Analytical LC-MS System and Method Description

[0772] In the following examples, compounds were characterized by mass spectrometry using the system and operating conditions shown below. Where atoms with different isotopes are present and a single mass is quoted, the mass stated for the compound is the monoisotopic mass (i.e., 35 Cl; 79 Br, etc.).

[0773] Waters Platform LC-MS System:

[0774] HPLC system: Waters 2795

[0775] Mass spectrometer: Micromass Platform LC

[0776] PDA detector: Waters 2996 PDA

[0777] ● Platform MS conditions:

[0778] Capillary voltage: 3.6 kV (3.40 kV when ES negative)

[0779] Cone voltage: 30 V

[0780] Source temperature: 120℃

[0781] Scan range: 125-800 amu

[0782] Ionization mode: Electrospray positive or

[0783] Electrospray negative or

[0784] Electrospray positive & negative

[0785] Waters Fractionlynx LC-MS System:

[0786] HPLC system: 2767 Autosampler – 2525 Binary Gradient Pump

[0787] Mass spectrometer detector: Waters ZQ

[0788] PDA detector: Waters 2996 PDA

[0789] ● Fractionlynx MS conditions:

[0790] Capillary voltage: 3.5 kV (3.25 kV when ES is negative)

[0791] Cone voltage: 40 V (25 V when ES is negative)

[0792] Source temperature: 120℃

[0793] Scan range: 125-800 amu

[0794] Ionization mode: Electrospray positive or

[0795] Electrospray negative or

[0796] Electrospray positive & negative

[0797] Agilent 1200SL-6140 LC-MS System - RAPID:

[0798] HPLC system: Agilent 1200 Series SL

[0799] Mass spectrometer detector: Agilent 6140 single-phase quadrupole

[0800] Secondary detector: Agilent 1200 MWD SL

[0801] ● Agilent MS conditions:

[0802] Capillary voltage: 4000V when ES is positive (3500V when ES is negative)

[0803] Fragmentor / Buff: 100

[0804] Gain: 1

[0805] Drying gas flow: 7.0 L / min

[0806] Gas temperature: 345℃

[0807] Sprayer Pressure: 35 psig

[0808] Scan range: 125-800 amu

[0809] Ionization mode: Electrospray positive-negative switching

[0810] Preparative LC-MS System and Method Description

[0811] Preparative LC-MS is a standard and effective method for purifying small organic molecules such as the compounds described herein. The methods of liquid chromatography (LC) and mass spectrometry (MS) can be varied to provide better separation of crude materials and improved detection of samples by MS. Optimization of preparative gradient LC methods will involve changing the column, volatile eluents and modifiers, and the gradient. Methods for optimizing preparative LC-MS methods and then using them to purify compounds are well known in the art. Such methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC / MS; J Comb Chem. ;2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquidchromatography / mass spectrometer platform for the preparative purificationand analytical analysis of compound libraries; J Comb Chem. ;2003; 5(3); 322-9.

[0812] Several systems for purifying compounds by preparative LC-MS are described below, although those skilled in the art will appreciate that alternative systems and methods to the systems and methods described may be used. With the information provided herein, or by employing alternative chromatography systems, those skilled in the art may purify the compounds described herein by preparative LC-MS.

[0813] Waters Fractionlynx System:

[0814] Hardware:

[0815] 2767 Dual Loop Autosampler / Fraction Collector

[0816] 2525 Preparation Pump

[0817] CFO (Column Flow Organizer) for column selection

[0818] RMA (Waters Reagent Manager) as a make-up pump

[0819] Waters ZQ Mass Spectrometer

[0820] Waters 2996 Photodiode Array Detector

[0821] Waters ZQ Mass Spectrometer

[0822] ● Waters MS operating conditions:

[0823] Capillary voltage: 3.5 kV (3.2 kV when ES negative)

[0824] Cone voltage: 25 V

[0825] Source temperature: 120℃

[0826] Scan range: 125-800 amu

[0827] Ionization mode: Electrospray positive or

[0828] Electrospray negative

[0829] Agilent 1100 LC-MS Preparative System:

[0830] Hardware:

[0831] Autosampler: 1100 Series "prepALS"

[0832] Pumps: 1100 series "PrepPump" for preparative flow gradients and 1100 series "QuatPump" for pumping modifiers in preparative flow

[0833] UV Detector: 1100 Series "MWD" Multi-Wavelength Detector

[0834] MS detector: 1100 series "LC-MSD VL"

[0835] Fraction collector: 2 x "Prep-FC"

[0836] Make-up pump: "Waters RMA"

[0837] Agilent Active Splitter

[0838] ● Agilent MS operating conditions:

[0839] Capillary voltage: 4000 V (3500 V when ES is negative)

[0840] Crusher / Buff: 150 / 1

[0841] Drying gas flow: 12.0 L / min

[0842] Gas temperature: 350℃

[0843] Sprayer Pressure: 50 psig

[0844] Scan range: 125-800 amu

[0845] Ionization mode: Electrospray positive or

[0846] Electrospray negative

[0847] ●Column:

[0848] Many commercially available columns (achiral and chiral) can be used so that they can cover a wide range of selectivities to the greatest extent when combined with mobile phase, organic modifier and pH changes. All columns are used according to the operating conditions recommended by the manufacturer. If available, columns with 5 micron particle sizes are usually used. For example, columns from Waters (including but not limited to XBridge™ Prep OBD™ C18 and Phenyl, Atlantis® Prep T3 OBD™ and Sunfire™ Prep OBDC18 5 µm 19 x 100 mm), Phenomenex (including but not limited to Synergy MAX-RP and LUX™ Cellulose-2), Astec (Chirobiotic™ columns include but not limited to V, V2 and T2) and Diacel® (including but not limited to Chiralpak® AD-H) can be used for screening.

[0849] ●Eluent:

[0850] Choose the mobile phase eluent in conjunction with the column manufacturer's recommended stationary phase limitations to optimize the separation performance of the column.

[0851] ●Methods:

[0852] Achiral Preparative Chromatography

[0853] As indicated, the compound examples described have been purified by HPLC using a method developed following the recommendations as described in Snyder LR,, Dolan JW, High-Performance Gradient Elution The Practical Application of the Linear-Solvent-Strength Model, Wiley, Hoboken, 2007.

[0854] Chiral Preparative Chromatography

[0855] Preparative separations using chiral stationary phases (CSPs) are a natural technique for resolving enantiomeric mixtures. As such, they can be applied to the separation of enantiomers and achiral molecules. Methods for optimizing preparative chiral separations on CSPs and then using them to purify compounds are well known in the art. Such methods are described in Beesley TE, Scott R. PW; Chiral Chromatography; Wiley, Chichester, 1998.

[0856] The values ​​for salt stoichiometry or acid content in the compounds provided herein are those obtained experimentally and may vary depending on the analytical method used. Where a salt form is not indicated, the compound is obtained as the free base.

[0857] Preparation 1:( R )-2-((S)-2-Benzyloxycarbonylamino-3-hydroxy-propionyl-amino)-propionic acid methyl ester

[0858] Diisopropylethylamine (375 mL) was added dropwise to a cooled mixture of (R)-2-amino-propionic acid methyl ester hydrochloride (100 g, 0.716 mol), EDC (165 g, 0.86 mol), benzyloxycarbonyl-L-serine (171.4 g, 0.716 mol) and DCM (3.6 L). The resulting mixture was stirred at ambient temperature under nitrogen for 16 h. vacuum After removing the solvent at 40 °C in 4% CO 2 , the residue was diluted with saturated sodium carbonate (1 L), water (1 L) and extracted with EtOAc (2 L, 2 x 1 L). The combined organic phases were washed with 2 M hydrochloric acid (1 L), saturated brine solution (1 L), dried over magnesium sulfate and vacuum The reaction mixture was concentrated at 40°C to obtain the title compound (172 g) as a colorless solid. 1H NMR(Me-d3-OD): 7.44-7.28 (6H, m), 5.13 (2H, s), 4.46 (1H, d), 4.43 (1H, d), 4.25 (1H, t), 3.82-3.68 (5H, m), 1.39 (3H, d).

[0859] Preparation 2: (3S,6R)-3-hydroxymethyl-6-methyl-piperazine-2,5-dione

[0860] To (R)-2-((S)-2-benzyloxycarbonylamino-3-hydroxy-propionyl-amino)-propionic acid methyl ester (which can be prepared as described in Preparation 1) (172 g, 0.53 mol) was added 10% palladium on carbon (8.6 g), MeOH (530 mL) and cyclohexene (344 mL) under nitrogen. The mixture was heated to reflux for 17 h. MeOH (500 mL) was added and reflux was continued for 1 h. The hot reaction mixture was filtered through a pad of celite and the filter cake was washed with hot MeOH (2 x 500 mL). The combined filtrates were concentrated. The resulting solid was slurried in 2-butanone (400 mL) and gasoline (400 mL) was gradually added over 10 min. After stirring for 30 min, the solid was filtered and the filter cake was washed with 2:1 gasoline / 2-butanone (300 mL). The filter cake was dried in vacuo at 40 °C to give the title compound (68.3 g) as an off-white solid. 1 H NMR (DMSO-d6): 8.08 (1H, s), 7.90 (1H, s), 5.11 (1H,t), 3.92 (1H, q), 3.80-3.71(1H, m), 3.71-3.60 (1H, m), 3.58-3.47 (1H, m),1.24 (3H, d).

[0861] Preparation 3: ((2R,5R)-5-methyl-piperazin-2-yl)-methanol hydrochloride

[0862] Towards( 3S,6R)-3-hydroxymethyl-6-methyl-piperazine-2,5-dione (which can be prepared as described in Preparation 2) (34 g, 0.215 mol) was added a solution of borane / THF (1 M, 1.6 L, 1.6 mol) and the mixture was heated to 70°C for 18 h. The solution was cooled on ice and then MeOH (425 mL) was gradually added followed by 5 M hydrochloric acid (113 mL). The mixture was heated to 70°C for 2 h and then cooled to ambient temperature. The resulting solid was filtered, the filter cake was washed with THF (200 mL) and dried under vacuum at 40°C to give the title compound (39.3 g) as a colorless solid. 1 H NMR (DMSO-d6): 9.79 (3H, s), 5.59 (1H, s), 3.76-3.40 (5H, m), 3.19-2.94 (2H, m), 1.28 (3H, d).

[0863] Preparation 4: (2R,5R)-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester

[0864] To ((2R,5R)-5-methyl-piperazin-2-yl)-methanol hydrochloride (which can be prepared as described in Preparation 3) (20 g, 119 mmol) in MeOH (96 mL) was added triethylamine (48.7 mL, 357 mmol) at 0°C (ice bath). Tert-butyl dicarbonate (61 g, 280 mmol) in MeOH (145 mL) was added over 30 min. The reaction temperature was maintained at <10°C for 1 h, warmed to ambient temperature over 1 h and then heated to 50°C for 18 h. The reaction was concentrated and the residue was dissolved in ethanol (397 mL). A solution of NaOH (23.8 g, 595 mmol) in water (397 mL) was added and the reaction was heated to 100°C for 18 h and then cooled to ambient temperature. The mixture was neutralized with 1 M HCl (~300 mL) to pH 9 (using a pH meter), then extracted with chloroform (3 x 700 mL), dried over sodium sulfate, filtered and concentrated. The residue was redissolved in MeOH and concentrated, then dried in vacuo at 40 °C to give the title compound (21 g, 75%) as a colorless solid. 1H NMR (Me-d3-OD): 4.20-4.07 (1H, m), 3.79 (1H,dd), 3.71-3.58 (2H, m), 3.54 (1H, dd), 3.24 (1H, dd), 3.18-3.01 (1H, m), 3.01-2.89 (1H, m), 2.55 (1H, dd), 1.48 (9H, s), 1.25 (3H, s).

[0865] Preparation 5: (2R,5R)-4-Benzyl-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester

[0866] A mixture of (2R,5R)-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (which can be prepared as described in Preparation 4) (3.48 g, 15.1 mmol), benzaldehyde (1.76 g, 16.6 mmol), sodium triacetoxyborohydride (3.84 g, 18.1 mmol) and 1,2-dichloroethane (30 mL) was stirred at 20 °C for 18 h and then partitioned between saturated aqueous NaHCO3 (150 mL) and DCM (3 x 50 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2, 0 – 30% EtOAc / petrol) gave the title compound (4.588 g, 74%) as a colorless solid. MS: [M+H] + = 321.

[0867] Preparation 6: (2R,5R)-4-Benzyl-5-chloromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester

[0868] Methanesulfonyl chloride (570 µL, 7.35 mmol) was added to a solution of (2R,5R)-4-benzyl-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (which can be prepared as described in Preparation 5) (1.9 g, 6.12 mmol) in DCM (30 mL) containing TEA (2.6 mL, 18.4 mmol) at 0°C. The solution was stirred at room temperature for 18 h. The reaction was partitioned between aqueous NH4Cl and DCM. The organic phase was collected, dried over MgSO4, filtered and concentrated in vacuo. Chromatography (30% EtOAc / petrol) gave the title compound (1.6 g) as a white solid. MS: [M+H] + = 339.

[0869] Preparation 7: (2R,5S)-4-Benzyl-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester

[0870] K2CO3 (81.6 g, 591 mmol) and KI (73.6 g, 443 mmol) were added to a solution of (2R,5R)-4-benzyl-5-chloromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (which can be prepared as described in Preparation 6) (50 g, 147.9 mmol) in acetonitrile (400 mL) followed by (R)-3-methyl-morpholine hydrochloride (26.4 g, 192 mmol). The reaction was stirred at 70 °C for 18 h. The solids were then removed by filtration and the solvent was removed in vacuo. The crude material was purified by chromatography using a pad of silica (20% EtOAc / petrol) to give the title compound (41.3 g) as a white solid. MS: [M+H] + = 404.

[0871] Preparation 8: (2R,5S)-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester

[0872] Palladium on carbon (10%) (33 g) and acetic acid (220 mL) were added to a solution of (2R,5S)-4-benzyl-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (which can be prepared as described in Preparation 7) (41.3 g, 102 mmol) / EtOH (300 mL). The mixture was stirred at room temperature under H2 (1 atm) for 18 h. The reaction mixture was then filtered through a pad of celite to remove the catalyst, and the solvent was removed in vacuo. The crude material was partitioned between saturated aqueous NaHCO3 and DCM, and the product was extracted with DCM (3x). The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give the title compound (30.5 g) as a light yellow oil. 1 H NMR (400 MHz, CDCl3): 4.43-3.87 (1H, m), 3.78 (1H,d), 3.73-3.55 (3H, m), 3.32 (1H, dd), 3.22 (1H, dd), 3.16-2.93 (3H, m), 2.93-2.72 (1H, m), 2.55-2.35 (2H, m), 2.35-2.15 (2H, m), 1.89 (1H, dd), 1.45 (9H,s), 1.26 (3H, d), 0.96 (3H, d).

[0873] Alternative procedures:

[0874] To a tightly sealed 10 L flange flask equipped with a stirring bar was added (2R,5S)-4-benzyl-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (500 g, 1.24 mol, 1.0 eq) (which can be prepared as described in Preparation 7) and ethanol (stock solution, 5 L). The flask was placed under nitrogen and 10% Pd / C (Aldrich, 50 g, 0.124 mol, 0.1 eq) was added as a paste in ethanol. The flask was purged several times with a di-vac pump and placed under a hydrogen atmosphere using 4 balloons. The reactants were warmed to 30 °C overnight, and then NMR confirmed complete consumption of the starting material. The reaction mixture was cooled to room temperature and filtered through a pad of celite under nitrogen. The filtrate was evaporated to dryness to give the title product as a colorless oil.

[0875] 1 H NMR(MeOD): 1.00 (3H, d), 1.25 (3H, d), 1.48 (9H, s), 2.08-2.14(1H, m), 2.28-2.35 (1H, m), 2.42-2.48 (1H, m), 2.49-2.55 (1H, dd), 2.80-3.06 (4H, m), 3.22-3.28 (2H, m), 3.61-3.78 (4H, m), 4.12-4.16 (1H, m).

[0876] 13 C NMR(MeOD): 14.6, 15.7, 28.8, 40.8, 44.8, 48.3, 50.3, 53.2, 54.3,57.5, 68.5, 73.9, 81.1,157.0.

[0877] Preparation 9: (2R,5S)-4-Benzyl-5-((3R,5R)-3,5-dimethyl-morpholin-4-ylmethyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester

[0878] K2CO3 (2.7 g, 19.5 mmol) and KI (1.83 g, 11.05 mmol) were added to a solution of (2R,5R)-4-benzyl-5-chloromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (which can be prepared as described in Preparation 6) (2.2 g, 6.5 mmol) in acetonitrile (30 mL) followed by (3R,5R)-3,5-dimethyl-morpholine (0.80 g, 7.0 mmol). The reaction was stirred at 70 °C for 18 h. The solids were then removed by filtration and the solvent was removed in vacuo. The residue was partitioned between water and dichloromethane. The organic phase was dried, filtered and the solvent evaporated. The crude material was purified by chromatography on silica (0-40% EtOAc / petrol) to give the title compound (2.56 g, 94%) as a white solid. MS: [M+H] + = 418.

[0879] Preparation 10: (2R,5S)-5-((3R,5R)-3,5-dimethyl-morpholin-4-ylmethyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester

[0880] Palladium on carbon (10%) (1.6 g) and acetic acid (10 mL) were added to a solution of (2R,5S)-4-benzyl-5-((3R,5R)-3,5-dimethyl-morpholin-4-ylmethyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (which can be prepared as described in Preparation 9) (2.5 g, 6.0 mmol) in EtOH (70 mL). The mixture was stirred at room temperature for 3 h under H2 (1 atm). The reaction mixture was then filtered through a pad of celite to remove the catalyst, and the solvent was removed in vacuo. The crude material was partitioned between saturated aqueous NaHCO3 and DCM, and the product was extracted with DCM (3x). The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give the title compound (1.53 g, 78%) as a light yellow oil. 1 H NMR (400 MHz, CDCl3): 4.16 (1H, s), 3.79-3.59 (3H, m), 3.44-3.19 (3H, m), 3.08 (1H, dd), 2.99-2.69 (4H, m), 2.52 (1H,dd), 2.29 (1H, dd), 1.47 (9H, s), 1.27 (3H, d), 1.00 (6H, d).

[0881] The following compounds were prepared by procedures similar to those described in Preparations 9 and 10:

[0882] 10A: (2R,5S)-5-((2S,5R)-2,5-dimethyl-morpholin-4-ylmethyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 328.

[0883] Preparation 11: 2-(5-Chloro-3-fluoro-pyridin-2-yl)-2-methyl-propionitrile

[0884] A solution of sodium bis(trimethylsilyl)amide (610 mL, 40% in tetrahydrofuran, 1.326 moles) was added to an ice-cold solution of 5-chloro-2,3-difluoropyridine (198.2 g, 1.326 moles) and isobutyronitrile (238 mL, 2.65 moles) in toluene (2 L). The mixture was stirred at room temperature under nitrogen overnight, then saturated aqueous ammonium chloride solution (1 L) was added. The phases were separated, and the aqueous phase was extracted with ethyl acetate (2 x 1 L). The combined organic extracts were dried (MgSO4) and concentrated in vacuo at 40 °C to give the title compound (259.8 g, 95%). 1 H NMR (400 MHz, DMSO-d6): 8.57 (1H,dd), 8.24 (1H, dd), 1.74 (6H, broad).

[0885] Preparation 12: 2-(5-chloro-3-fluoropyridin-2-yl)-2-methylpropylamine

[0886] Borane-tetrahydrofuran complex (1 M, 1.37 L, 1.365 mol) was added to a cooled solution of 2-(5-chloro-3-fluoro-pyridin-2-yl)-2-methyl-propionitrile (which can be prepared as described in Preparation 11) (135.6 g, 0.683 mol) in tetrahydrofuran (670 mL). The mixture was stirred at room temperature overnight under nitrogen and then cooled in ice. The mixture was quenched by the addition of 5M hydrochloric acid (335 mL). The resulting mixture was basified with 40% aqueous potassium hydroxide solution (460 mL) and the phases were separated. The basic aqueous phase was extracted with ethyl acetate (2 x 670 mL) and the combined organic extracts were washed with brine (670 mL), dried (MgSO4) and concentrated in vacuo at 40°C to give the title compound (102.9 g, 74%). 1 H NMR (400 MHz, DMSO-d6): 8.44 (1H, t), 7.95 (1H, dd), 2.85 (2H, d), 1.29 (6H, d).

[0887] Preparation 12, Alternative Procedure: 2-(5-chloro-3-fluoropyridin-2-yl)-2-methylpropylamine

[0888] To a 10 L flannel flask was added 2-(5-chloro-3-fluoro-pyridin-2-yl)-2-methyl-propionitrile (which can be prepared as described in Preparation 11) (200 g, 1.00 mol), nickel(II) chloride hexahydrate (239.4 g, 1.00 mol), and ethanol (3.0 L). The resulting green solution was cooled to 0 °C under nitrogen using a dry ice / acetone bath. Sodium borohydride (114.3 g, 3.02 mol) was added portionwise at a rate such that the reaction temperature remained below 6 °C (addition time = 1¾ h) to give a black suspension. Once the addition was complete, the cooling bath was replaced with an ice / water bath and the reaction was then allowed to warm to room temperature overnight. The reaction mixture was cooled to 0–4 °C in an ice bath. 25% aqueous ammonia solution (2680 mL) was added from a dropping funnel such that the reaction temperature remained below 10 °C (addition time = 1 h). Once the addition is complete, stirring is continued at approximately 0°C for 30 min, then the mixture is filtered through diatomaceous earth, and the residue is washed with ethanol (2 × 750 mL). (CAUTION! Do not let the filter pad dry out. Total filtration time is approximately 2 h). The light yellow / brown filtrate is transferred to a large rotary evaporator and concentrated until all ethanol is removed. The resulting green oil is transferred to a 5 L separatory funnel and 25% aqueous ammonia solution is added until the oil turns yellow (200 mL). The oil is separated, and the aqueous phase is extracted with toluene (2 × 300 mL). The combined organic extracts are washed with 1:1 25% aqueous ammonia solution / brine (300 mL), dried over sodium sulfate, filtered and concentrated on a rotary evaporator (bath temperature reaches 70°C) to give the crude product as a yellow oil (161 g), data consistent with those obtained above. It is used in the next step without purification.

[0889] Preparation 13: 6-Chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0890] A mixture of 2-(5-chloro-3-fluoropyridin-2-yl)-2-methylpropylamine (which can be prepared as described in Preparation 12 and Preparation 12, Alternative Procedure) (33 g, 0.163 mole), potassium carbonate (122 g, 0.884 mole) and NMP (100 mL) was heated to 150°C for 4 hours. The cooled mixture was diluted with water (330 mL) and extracted with toluene (3 x 300 mL). The combined organic extracts were washed with brine (160 mL), dried (MgSO4) and concentrated in vacuo at 40°C to give the crude material (24.8 g). Chromatography on silica eluting with 5-30% ethyl acetate / petrol gave the title compound (21 g, 71%). 1HNMR (400 MHz, DMSO-d6): 7.61 (1H, d), 6.75 (1H, d), 6.06 (1H, bs), 3.31 (2H, s), 1.21 (6H, s).

[0891] Preparation 14: tert-Butyl 6-chloro-3,3-dimethyl-2,3-dihydropyrrolo[3,2-b]pyridine-1-carboxylate

[0892] Di-tert-butyl dicarbonate (3.7 g, 17.1 mmol) was added to a mixture of 6-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (which can be prepared as described in Preparation 13) (2.6 g, 14.2 mmol), tetrahydrofuran (26 mL) and 2M sodium hydroxide (11.4 mL, 22.8 mmol) and stirred for 2 days. The biphasic mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo at 40°C to give the crude material (6.02 g). Chromatography on silica eluting with 5 - 30% ethyl acetate / petrol gave the title compound (2.23 g, 55%); 1 H NMR (400 MHz, DMSO-d6): 8.11 (1H, d), 7.85 (1H, bs), 3.77(2H, s), 1.52 (9H, s), 1.28(6H, s).

[0893] Preparation 15: 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0894] A solution of 4-fluorobenzylzinc chloride (2 L of a 0.5 M solution in THF, 1 mol) was added to a degassed mixture of 6-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (which can be prepared as described in Preparation 13) (91.3 g, 0.5 mol), lithium bromide (130.3 g, 1.5 mol), and [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridinyl)palladium(II) dichloride (6.8 g, 0.01 mol) in THF (685 mL) and NMP (910 mL) at 20°C with an exotherm. The resulting dark mixture was stirred at room temperature under nitrogen for 18 h. The reaction was quenched with 2.5% aqueous citric acid (900 mL) and extracted with toluene (2 x 900 mL). The combined organic phases were washed with water (3 x 900 mL), brine (900 mL), dried over MgSO4, filtered and concentrated in vacuo. The resulting solid was slurried in gasoline (450 mL) and toluene (100 mL). After stirring for 30 min, the solid was filtered and the filter cake was washed with gasoline (2 x 90 mL). The filter cake was dried in vacuo at 40 °C to give the title compound (107.3 g) as a grey solid. 1 H NMR (DMSO-d6): 7.60 (1H, d),7.30-7.22 (2H, m), 7.15-7.06 (2H, m), 6.53 (1H, d),5.64 (1H, s), 3.78 (2H,s), 3.22 (2H, d), 1.19 (6H, s).

[0895] The following compounds were prepared in a similar manner as described in Preparation 15:

[0896] 15A: tert-Butyl 6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridine-1-carboxylate, MS: [M + H] + = 357.

[0897] 15B: 6-(3-Fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine, MS: [M +H] + = 257.

[0898] 15C: 6-Butyl-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine, MS: [M+H] + = 205.

[0899] 15D: 6-(2-Fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine, MS: [M +H] + = 257.

[0900] 15E: 6-(2,4-Difluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine.

[0901] Preparation 16: 5-bromo-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0902] A solution of 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (which can be prepared as described in Preparation 15) (88.5 g, 0.345 mol) in DMF (1.67 L) was cooled to -5°C. Solid was added portionwise under exotherm. N -bromosuccinimide (61.5 g, 0.345 mol). The mixture was stirred for 1 h and warmed to room temperature. Water (2.66 L) was added under exothermic conditions and the resulting mixture was stirred at room temperature for 18 h. The solid was filtered and the filter cake was washed with water (270 mL). The filter cake was dissolved in THF (1.5 L), dried over MgSO4, filtered and concentrated in vacuo to give the title compound (109.7 g) as a yellow solid. 1 H NMR (DMSO-d6): 7.29-7.20 (2H, m), 7.20-7.03 (2H, m), 6.64(1H, s), 5.88 (1H, s), 3.89 (2H, s), 3.26 (2H, d), 1.20 (6H, s).

[0903] The following compounds were prepared in a manner similar to Preparation 16:

[0904] 16A: 5-bromo-6-(3-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine, MS: [M + H] + = 335, 337.

[0905] 16B: 5-bromo-6-(2-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine, MS: [M + H] + = 335, 337.

[0906] 16C: 5-Bromo-6-butyl-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine, MS: [M+H] + =283, 285.

[0907] 16D: 5-bromo-6-(2,4-difluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine.

[0908] Preparation 17: [6-(4-Fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl]-methanol

[0909] To 5-bromo-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (which can be prepared as described in Preparation 16) (22.8 g, 68.2 mmol) / THF (300 mL) cooled to -78°C was added MeLi (1.6 M in Et2O; 51.1 mL, 91.8 mmol) over 15 minutes. Then tert-butyl lithium (1.7 M in hexane, 96 mL, 164 mmol) was added over 30 minutes. After 15 minutes, DMF (26 mL) was added and the mixture was stirred at -78°C for another 50 minutes. Saturated NH4Cl (450 mL) aqueous solution was added and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 150 mL). The combined organic portions were washed with brine (200 mL), dried (MgSO4) and evaporated to give 6-(4-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carbaldehyde as a yellow solid which was used without any further purification. MS: m / z = 285 (M+H + ) +. The product (~ 68 mmol) was suspended in MeOH (250 mL) and cooled in an ice bath. NaBH4 (3.4 g, 81.8 mmol) was added in portions over 5 minutes. The cooling was removed and the mixture was stirred for another 20 minutes. The mixture was cooled in an ice bath and then 10% aqueous KHSO4 was carefully added over 10 minutes (caution: effervescence). After stirring at room temperature for 5 minutes, the mixture was recooled using an ice bath. The mixture was basified by the addition of 50% aqueous NaOH (~ 18 mL) and then concentrated in vacuo to approximately 1 / 3 of the volume. The resulting aqueous mixture was extracted with CH2Cl2 (1 x 200 mL, 2 x 100 mL) and the combined CH2Cl2 layers were dried (MgSO4). The CH2Cl2 solution was concentrated in vacuo to approximately 30 mL and then diluted with toluene (70 mL) to initiate crystallization of the product. The product was collected by filtration to obtain a colorless crystalline solid (10.6 g). A second batch (2.1 g) was collected from the filtrate. The filtrate was concentrated and the remaining material was purified by SiO2 chromatography (eluting with 25-50% EtOAc / hexanes) to give a third crop of material (2.1 g); the title compound was obtained in a total yield of 14.8 g (76% over 2 steps). MS: [M + H] + = 287.

[0910] An alternative procedure involves subsequent recrystallization from isopropanol.

[0911] The following compounds were prepared in a manner similar to Preparation 17:

[0912] (6-Butyl-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)-methanol, MS: [M+H] + = 235.

[0913] Preparation 18: 2-Chloro-1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}ethan-1-one

[0914] To a cooled (~5°C) suspension of [6-(4-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl]-methanol (which can be prepared as described in Preparation 17) (11.8 g, 41.3 mmol) in MeCN (175 mL) was added chloroacetyl chloride (6.9 mL, 86.7 mmol). The cooling was removed and the mixture was stirred at room temperature for 30 minutes. The mixture was then evaporated in vacuo and dissolved in MeOH (200 mL). K2CO3 solution (12 g in 100 mL H2O) was added and the mixture was stirred at room temperature for 20 minutes, after which the mixture was concentrated in vacuo to approximately 1 / 4 volume. The aqueous mixture was extracted with CH2Cl2 (1 x 100 mL, 2 x 30 mL), and the combined CH2Cl2 layers were dried (MgSO4). Evaporation in vacuo gave the product as a colorless crystalline solid (12.1 g, ~100%), MS: [M + H] + = 363.

[0915] The following compounds were prepared by methods similar to or analogous to Preparation 18:

[0916] 18A: 1-(2-Chloroacetyl)-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one, MS: [M + H] + = 349.

[0917] 18B: 2-Chloro-1-{6-[(2-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}ethan-1-one, MS: [M + H] + = 363.

[0918] 18C: 1-(2-Chloroacetyl)-6-[(4-fluorophenyl)methyl]-3,3,4-trimethyl-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one, MS: [M + H] + = 363.

[0919] 18D: 1-(2-Chloroacetyl)-6-[(2,4-fluorophenyl)methyl]-3,3-dimethyl-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one, MS: [M + H] + = 367.

[0920] 18E: 1-(2-Chloroacetyl)-6-[(2-fluorophenyl)methyl]-3,3,4-trimethyl-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one, MS: [M + H] + = 363.

[0921] 18F: 2-Chloro-1-{6-[(2,4-difluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}ethan-1-one, MS: [M + H] + =381.

[0922] 18G: 2-Chloro-1-[5-(1,2-dihydroxyethyl)-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl]ethan-1-one, MS: [M + H] + = 393.

[0923] 18H: 2-Chloro-1-{6-[(3-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}ethan-1-one, MS: [M + H] + = 363.

[0924] 18I: 1-(2-Chloro-acetyl)-6-(4-fluoro-benzyl)-3,3-dimethyl-1,2,3,6-tetrahydro-pyrrolo[2,3-c]pyridin-5-one, MS: [M+H] + = 349.

[0925] 18J: 1-(2-Chloro-acetyl)-6-(2,4-difluoro-benzyl)-3,3-dimethyl-1,2,3,6-tetrahydro-pyrrolo[2,3-c]pyridin-5-one, MS: [M + H] + = 367.

[0926] 18K: 2-Chloro-1-[5-((R or S)-1,2-dihydroxyethyl)-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl]ethan-1-one from the slower eluting precursor. MS: [M+H] + = 393.

[0927] 18L: 1-(2-Chloroacetyl)-6-[(2,4-fluorophenyl)methyl]-3,3,4-trimethyl-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one, MS: [M+H] + = 381.

[0928] 18M: 2-Chloro-1-{6-[(4-fluorophenyl)methyl]-5-(R or S)-1-hydroxy-2-methoxyethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}ethan-1-one, from the faster eluting precursor, MS: [M+H] + =407.

[0929] 18N: 2-Chloro-1-{6-[(4-fluorophenyl)methyl]-5-(R or S)-1-methoxy-2-hydroxyethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}ethan-1-one, from the faster eluting precursor, MS: [M+H] + =407.

[0930] 18O: 2-Chloro-1-{6-[(4-fluorophenyl)methyl]-5-(R or S)-1-hydroxy-2-methoxyethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}ethan-1-one from the slower eluting precursor, MS: [M+H] + =407.

[0931] 18P: 2-Chloro-1-{6-[(4-fluorophenyl)methyl]-5-(R or S)-1-methoxy-2-hydroxyethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}ethan-1-one, from the slower eluting precursor, MS: [M+H] + =407.

[0932] 18Q: 1-(2-Chloro-acetyl)-6-(2,4-difluoro-benzyl)-3,3,4-trimethyl-1,2,3,6-tetrahydro-pyrrolo[2,3-c]pyridin-5-one, MS: [M + H] + = 381.

[0933] 18R: 6-Butyl-1-(2-chloro-acetyl)-3,3-dimethyl-1,2,3,4-tetrahydro-pyrrolo[3,2-b]pyridin-5-one, MS: [M + H] + = 297.

[0934] 18S: 1-[6-Butyl-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl]-2-chloroethan-1-one, MS: [M + H] + = 311.

[0935] 18T: 6-Butyl-1-(2-chloro-acetyl)-3,3-dimethyl-1,2,3,6-tetrahydro-pyrrolo[2,3-c]pyridin-5-one, MS: [M + H] + = 297.

[0936] Preparation 19: (2R,5S)-4-(2-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylic acid tert-butyl ester

[0937] (2R,5S)-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (which can be prepared as described in Preparation 8) (15.5 g, 46.4 mmol), KI (12.8 g, 77.4 mmol) and K2CO3 (21.4 g, 155 mmol) were stirred in MeCN (70 mL) and cooled in an ice bath. 2-Chloro-1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}ethan-1-one (which can be prepared as described in Preparation 18) (14.0 g, 38.7 mmol) was then added as a solution in MeCN (100 mL). The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to approximately 1 / 4 volume. The mixture was partitioned between EtOAc (150 mL) and H2O (150 mL), then the aqueous layer was extracted with additional EtOAc (1 x 75 mL). The combined EtOAc layers were washed with 10% aqueous KH2PO4 (4 x 100 mL) and then brine (70 mL). The organic layer was dried (MgSO4) and evaporated to give the product as a colorless solid (25.8 g, 98%), MS: [M + H] + = 640.

[0938] The following compounds were prepared in a manner similar to Preparation 19:

[0939] (2R,5S)-5-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-4-(2-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 654.

[0940] (2R,5S)-5-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-4-(2-{6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 640.

[0941] (2R,5S)-4-(2-{6-[(2-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 640.

[0942] (2R,5S)-4-(2-{6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 626.

[0943] (2R,5S)-4-(2-{6-[(4-fluorophenyl)methyl]-3,3,4-trimethyl-5-oxo-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 640.

[0944] (2R,5S)-4-(2-{6-[(2,4-difluorophenyl)methyl]-3,3-dimethyl-5-oxo-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-5-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 658.

[0945] (2R,5S)-4-(2-{6-[(2,4-difluorophenyl)methyl]-3,3-dimethyl-5-oxo-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 644.

[0946] (2R,5S)-4-(2-{6-[(2-fluorophenyl)methyl]-3,3,4-trimethyl-5-oxo-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 640.

[0947] (2R,5S)-tert-butyl 5-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-4-(2-{6-[(4-fluorophenyl)methyl]-3,3,4-trimethyl-5-oxo-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methylpiperazine-1-carboxylate, MS: [M + H] + = 654.

[0948] (2R,5S)-4-(2-{6-[(2,4-difluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylic acid tert-butyl ester, 1H NMR (400MHz, Me-d3-OD): 8.12 (1H, s), 7.27-7.16 (1H,m), 7.06-6.86 (2H, m), 4.76 (2H, s), 4.17 (1H, s), 4.10-4.07 (2H, m), 3.99(1H, d), 3.74-3.49 (5H, m), 3.30-3.22(2H, m), 2.97-2.77 (4H, m), 2.59-2.43(2H, m), 2.43-2.32 (1H, m), 2.32-2.21 (1H, m), 1.47 (9H, s), 1.43 (6H, s),1.22 (3H, d), 1.00 (3H, d).

[0949] (2R,5S)-4-{2-[5-(1,2-dihydroxyethyl)-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxoethyl}-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylic acid tert-butyl ester. MS: [M+H] + = 670; Chiral HPLC (heptane / ethanol, 80:20, 0.2 % DEA, chiral PAk-IC column), faster eluting diastereomer A, MS: [M + H] + = 670 and slower eluting diastereomer B, MS: [M + H] + = 670.

[0950] (2R,5S)-4-(2-{6-[(3-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 640.

[0951] (2R,5S)-5-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-4-(2-{6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-1H,2H,3H,5H,6H-pyrrolo[2,3-c]pyridin-1-yl}-2-oxoethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 640.

[0952] (2R,5S)-4-(2-{6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-1H,2H,3H,5H,6H-pyrrolo[2,3-c]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 626.

[0953] (2R,5S)-5-{[(2S,5R)-2,5-dimethylmorpholin-4-yl]methyl}-4-(2-{6-[(4-fluorophenyl)methyl]-3,3,4-trimethyl-5-oxo-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 654.

[0954] (2R,5S)-4-(2-{6-[(2,4-difluorophenyl)methyl]-3,3-dimethyl-5-oxo-1H,2H,3H,5H,6H-pyrrolo[2,3-c]pyridin-1-yl}-2-oxoethyl)-5-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 658.

[0955] (2R,5S)-4-{2-[5-((R or S)-1,2-dihydroxyethyl)-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxoethyl}-5-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester, MS: [M+H] + = 684.

[0956] (2R,5S)-4-(2-{6-[(2,4-difluorophenyl)methyl]-3,3-dimethyl-5-oxo-1H,2H,3H,5H,6H-pyrrolo[2,3-c]pyridin-1-yl}-2-oxoethyl)-5-{[(2S,5R)-2,5-dimethylmorpholin-4-yl]methyl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 658.

[0957] (2R,5S)-4-(2-{4-amino-6-[(2,4-difluorophenyl)methyl]-3,3-dimethyl-5-oxo-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 659.

[0958] (2R,5S)-4-(2-{4-amino-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 641.

[0959] (2R,5S)-4-(2-{6-[(2,4-difluorophenyl)methyl]-3,3,4-trimethyl-5-oxo-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-5-{[(2S,5R)-2,5-dimethylmorpholin-4-yl]methyl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 672.

[0960] (2R,5S)-tert-butyl 4-(2-{6-[(4-fluorophenyl)methyl]-5-((R or S)1-hydroxy-2-methoxyethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylate (from the faster eluting isomer), MS: [M+H] + = 684.

[0961] (2R,5S)-tert-butyl 4-(2-{6-[(4-fluorophenyl)methyl]-5-((R or S)1-hydroxy-2-methoxyethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylate (from the slower eluting isomer), MS: [M+H] + = 684.

[0962] (2R,5S)-tert-butyl 4-(2-{6-[(4-fluorophenyl)methyl]-5-((R or S)1-methoxy-2-hydroxyethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylate (from the faster eluting isomer), MS: [M+H] + = 684.

[0963] (2R,5S)-tert-butyl 4-(2-{6-[(4-fluorophenyl)methyl]-5-((R or S)1-methoxy-2-hydroxyethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylate (from the slower eluting isomer), MS: [M+H] + = 684.

[0964] (2R,5S)-4-(2-{4-amino-6-butyl-3,3-dimethyl-5-oxo-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-5-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 603.

[0965] (2R,5S)-4-(2-{6-[(2,4-difluorophenyl)methyl]-3,3,4-trimethyl-5-oxo-1H,2H,3H,5H,6H-pyrrolo[2,3-c]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 658.

[0966] (2R,5S)-4-(2-{6-butyl-3,3-dimethyl-5-oxo-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-5-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 588.

[0967] (2R,5S)-4-(2-{6-butyl-3,3,4-trimethyl-5-oxo-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-5-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 602.

[0968] (2R,5S)-4-{2-[6-butyl-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxoethyl}-5-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 602.

[0969] (2R,5S)-4-(2-{6-butyl-3,3-dimethyl-5-oxo-1H,2H,3H,5H,6H-pyrrolo[2,3-c]pyridin-1-yl}-2-oxoethyl)-5-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 588.

[0970] (2R,5S)-5-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-4-(2-{6-[(4-fluorophenyl)methyl]-5-((R or S)-2-hydroxy-1-methoxyethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester, MS: [M+H] + = 698.

[0971] (2R,5S)-4-(2-{6-butyl-3,3-dimethyl-5-oxo-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-5-{[(2S,5R)-2,5-dimethylmorpholin-4-yl]methyl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester, MS: [M + H] + = 588.

[0972] Preparation 20: (2R,5S)-4-{2-[6-(2,4-difluoro-benzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-5-((3R,5R)-3,5-dimethyl-morpholin-4-ylmethyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester

[0973] (2R,5S)-4-{2-[6-(2,4-difluoro-benzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-5-((3R,5R)-3,5-dimethyl-morpholin-4-ylmethyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (146 mg, 0.22 mmol) was dissolved in DMF (3 mL). Sodium hydride (60%, 11 mg, 0.27 mmol) was added and the reaction mixture was stirred for 30 minutes. Iodomethane (0.017 mL, 0.27 mmol) was added and the reaction was stirred at room temperature for 30 minutes and then partitioned between water (10 mL) and EtOAc (2 x 10 mL). The organic portion was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography eluting with 0-10% MeOH / EtOAc and then by preparative HPLC to give the title compound (17.6 mg). MS: [M+H] + = 672.

[0974] Preparation 21: (2R,5S)-4-{2-[6-(2,4-difluoro-benzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester

[0975] (2R,5S)-4-{2-[6-(2,4-difluoro-benzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (670 mg, 1.04 mmol) was dissolved in THF (20 mL). Lithium tert-butoxide (170 mg, 2.08 mmol) was added followed by iodomethane (0.16 mL, 2.60 mmol). The reaction was stirred at room temperature overnight and then partitioned between water (30 mL) and EtOAc (2 x 30 mL). The organic portion was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography eluting with 0-10% MeOH / DCM to give the title compound (350 mg). MS: [M+H] + = 658.

[0976] The following compounds were prepared in a similar manner to Preparation 21:

[0977] 21A: (2R,5S)-4-[2-(6-butyl-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-pyrrolo[3,2-b]pyridin-1-yl)-2-oxo-ethyl]-5-((3R,5R)-3,5-dimethyl-morpholin-4-ylmethyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester, MS: [M+H] + = 602.

[0978] Preparation 22: tert-Butyl 6-[(4-fluorophenyl)methyl]-3,3-dimethyl-4-oxy-1H,2H,3H-pyrrolo[3,2-b]pyridine-1-carboxylate

[0979] To a stirred solution of tert-butyl 6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridine-1-carboxylate (which can be prepared as described in Preparation 15A) (3.88 g, 10.9 mmol) in DCM (30 mL) was added 3-chloroperoxybenzoic acid (77%, 2.7 g, 12.0 mmol) portionwise over 0.1 h at ambient temperature. The mixture was stirred for 3 h and then partitioned between saturated aqueous NaHCO3 solution (150 mL) and DCM (3 x 30 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was crystallized from ether-petrol to give the title compound (2.62 g). 1H NMR (400MHz, Me-d3-OD): 7.74 (1H, s), 7.35-7.24 (2H, m), 7.13-7.02 (2H, m), 3.96 (2H, s), 3.79 (2H, s), 1.57 (6H, s), 1.53 (9H, s).

[0980] Preparation 23: tert-Butyl 6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridine-1-carboxylate

[0981] A mixture of tert-butyl 6-[(4-fluorophenyl)methyl]-3,3-dimethyl-4-oxy-1H,2H,3H-pyrrolo[3,2-b]pyridine-1-carboxylate (which can be prepared as described in Preparation 22) (0.6 g, 1.6 mmol) and acetic anhydride (4 mL) was heated at 105 °C for 2 h, then at 140 °C for 3 h, cooled, and the resulting solution was poured into ice water (~100 g). The resulting colorless solid was collected by filtration and then suspended in methanol (15 mL). Aqueous NaOH solution (1 M, 1.8 mL) was added and the mixture was stirred for 0.25 h. The solution was concentrated in vacuo to 12 mL, then diluted with water (20 mL) and the resulting solid was collected by filtration to give the title compound (0.6 g). MS: [M+H] + = 373.

[0982] The following compounds were prepared in a manner similar to that of Preparation 23:

[0983] 23A: 6-[(2-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester

[0984] Preparation 24: 6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridine

[0985] A mixture of tert-butyl 6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridine-1-carboxylate (which can be prepared as described in Preparation 23) (0.6 g, 1.6 mmol), methanol (20 mL) and 5 M aqueous HCl solution (20 mL) was heated at reflux for 16 h, cooled, and then treated with water. The resulting solid was collected by filtration to give the title compound (0.255 g). MS: [M+H] + = 273.

[0986] Preparation 25: 1-[5-Bromo-6-(3-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-ethanone

[0987] To a solution of 5-bromo-6-(3-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (which can be prepared as described in Preparation 16A) (4.5 g, 13.43 mmol) in toluene (50 mL) was added acetyl chloride (1.05 mL, 14.78 mmol) and the reaction mixture was stirred at room temperature overnight. Saturated NaHCO3 sol...

Claims

1. A protected derivative of a compound of formula (I), wherein formula (I) is in X is CR 4 , N or NR 3 ; in When X is CR 4 When U represents nitrogen and R 6 represents oxo; or When X is N, then U represents carbon and R 6 represents hydroxymethyl or -CH(OR x )CH2OR z ;or When X is NR 3 When U represents carbon and R 6 represents oxygen generation; A dotted bond, i.e. ------, represents a single bond or a double bond, wherein at least two of the dotted bonds represent a double bond; R 3 represents hydrogen, methyl or -NH2; R 4 represents hydrogen, methyl, hydroxymethyl, -NH2 or fluorine; R 5 represents an unsubstituted n-butyl group or a benzyl group substituted by one or two fluorine groups on the phenyl group; R x and R z independently represents hydrogen or methyl; R 1 and R 2 independently represents hydrogen or methyl; The protected derivative of the compound of formula (I) is: in, X, U, dotted key, i.e. ------, R 5 , R 6 , R 1 and R 2 is as defined above, and P 1 represents a protecting group selected from the following:

2. The protected derivative of claim 1, wherein X is N, U represents carbon and R 6 represents a hydroxymethyl group.

3. The protected derivative of claim 1 or claim 2, wherein P 1 represents a protecting group selected from the following:

4. The protected derivative of claim 1, wherein P 1 is a protecting group, which is a tert-butyloxycarbonyl group, i.e. tBoc:

5. The protected derivative of claim 1 or claim 2, which is a compound of the formula:

6. The protected derivative of claim 1, which is a compound selected from the group consisting of: tert-butyl (2R,5S)-5-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-4-(2-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methylpiperazine-1-carboxylate; tert-butyl (2R,5S)-4-(2-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylate; tert-Butyl (2R,5S)-4-(2-{6-[(2-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylate; tert-butyl (2R,5S)-4-(2-{6-[(2,4-difluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylate; tert-butyl (2R,5S)-4-(2-{6-[(3-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-oxoethyl)-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylate; and Tert-butyl (2R,5S)-4-{2-[6-butyl-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxoethyl}-5-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-2-methylpiperazine-1-carboxylate.

7. A compound of formula (XIII) or a compound of formula (XIV): Where R 5 represents an unsubstituted n-butyl group or a benzyl group substituted by one or two fluorine groups on the phenyl group; and L 6 represents fluorine, bromine or chlorine.

8. The compound of claim 7, wherein L 6 Represents bromine.

9. The compound of claim 7 or claim 8, wherein R 5 represents an unsubstituted n-butyl group or a benzyl group substituted by one or two fluorine groups at the 2, 3 and / or 4 position of the phenyl group.

10. The compound of claim 7, wherein the compound is a compound of formula (XIII): Where R 5 and L 6 As defined in claim 7.

11. The compound of claim 7 or claim 10, wherein the compound of formula (XIII) is:

12. Use of a compound of formula (XIII) or a compound of formula (XIV) in the preparation of a protected derivative of a compound of formula (I) as defined in claim 1: Where R 5 and L 6 As defined in claim 7.

13. Use of a compound according to any one of claims 7 to 11 or a reagent comprising a compound according to any one of claims 7 to 11 for the preparation of a protected derivative of a compound of formula (I) as defined in claim 1.

14. Use of a compound according to any one of claims 7 to 11 or a reagent comprising a compound according to any one of claims 7 to 11 in a process for preparing a protected derivative of a compound of formula (I) as defined in claim 1.

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