TW201417816A - Combination of AKT-inhibitors - Google Patents

Abstract

The present invention relates to combinations of at least two compounds A and B, compound A being an inhibitor of AKT kinase, and compound B a pharmaceutically acceptable salt of radium-223. Another aspect of the present invention relates to the use of such combinations as described supra for the preparation of a medicament for the treatment or prophylaxis of a disease, particurlarly for the treatment of cancer.

Description

AKT inhibitor combination

The present invention relates to a combination of at least two compounds A and B, compound A is an AKT inhibitor, and compound B is a pharmaceutically acceptable salt of an alkaline earth radioactive seed radium-223.

Another aspect of the invention relates to the use of such combinations as previously described for the preparation of a medicament for the treatment or prevention of a disease, in particular for the treatment of cancer.

Further, the present invention relates to a kit comprising: - one or more compounds A as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; Compound B as defined above, or a solvate or hydrate thereof; and optionally, one or more pharmaceutical agents C; wherein either or both of these compounds A and B are optionally used The form of the pharmaceutical formulation is administered simultaneously, jointly, separately or sequentially.

Component A can be administered by the oral, intravenous, topical, topical, intraperitoneal or nasal route.

Component B is preferably administered by the intravenous route.

Cancer is the second most common cause of death in the United States, causing 450,000 deaths each year. While substantial progress has been made in identifying some of the possible environmental and genetic causes of cancer, there is a need for other therapeutic modalities that target cancer and related diseases. In detail, it needs to be used Treatment of diseases associated with growth/proliferation disorders.

Cancer is a complex disease that occurs after the selection process for cells with acquired functional capabilities such as enhanced viability/resistance to apoptosis and unlimited proliferative potential. Therefore, it is preferable to develop a drug for cancer therapy to solve different characteristics of a tumor that has been determined.

A pathway that has been shown to mediate important survival signals in mammalian cells includes receptor tyrosine kinases such as platelet-derived growth factor receptor (PDGF-R), human epidermal growth factor 1/2/3 receptor (EGFR, HER2). /3) or insulin-like growth factor 1 receptor (IGF-1R). These receptors activate the phospholipid inositol 3-kinase (PI3K)/AKT pathway upon activation by the ligands, respectively. The phospholipid spectinokinase 3-kinase (PI3K)/AKT protein kinase pathway is important for controlling cell growth, proliferation and survival, and driving tumor progression. Therefore, within the class of serine-threonine-specific signaling kinases, AKT (protein kinase B; PKB) and isozymes AKT1 (PKBα), AKT2 (PKB β) and AKT3 (PKB γ) are highly regarded. For therapeutic intervention. AKT is primarily activated in a PI3-kinase dependent manner and this activation is regulated by the tumor suppressor PTEN (phosphatase and tensin homolog), which is primarily used as a functional antagonist of PI3K. In addition, an alternative mechanism for AKT activation has been observed. Such alternative mechanisms include activation of AKT by integrin-linked kinase (ILK), Ca2+/calmodulin-dependent kinase kinase (CaMKK), and DNA-dependent protein kinase (DNA-PK).

The PI3K/AKT pathway regulates basic cellular functions (eg, transcription, translation, growth, and survival) and is associated with human diseases including diabetes and cancer. This pathway is often over-activated in a wide range of tumor entities such as, for example, breast and prostate cancers. Upregulation can be attributed to the over- or constitutive activation of receptor tyrosine kinases (eg, EGFR, HER2/3), which are upstream and involved in their direct activation or functioning of some components. Type or loss of function mutants, such as PTEN loss. This pathway is targeted by more frequent genomic alterations (including mutations, amplifications, and rearrangements) than any other pathway in human cancer, with the possible exception of p53 and retinoblastoma pathways. Changes in the PI3K/AKT path trigger biological events A cascade of reactions that promote tumor progression, survival, angiogenesis, and metastasis.

Activation of AKT kinase promotes increased nutrient absorption and converts cells into glucose-dependent metabolism, thereby redirecting lipid precursors and amino acids to the assimilation process that maintains cell growth and proliferation. These metabolic phenotypes with over-activated AKT lead to malignant diseases that show metabolic conversion to aerobic glycolysis (Warburg effect). In this regard, it is discussed that the PI3K/AKT pathway is important for survival despite adverse growth conditions such as glucose depletion or hypoxia.

Another aspect of the activated PI3K/AKT pathway is to protect cells from progressive cell death ("apoptosis") and is therefore considered a switch survival signal. The PI3K/AKT pathway (especially AKT itself) is the target of cancer therapy by acting as a regulator of anti-apoptotic signaling in tumor cells. Activated AKT phosphorylates and regulates several targets (eg, BAD, GSK3, or FKHRL1) that affect different signaling pathways such as cell survival, protein synthesis, or cell migration. This PI3K/AKT pathway also plays a major role in the resistance of tumor cells to conventional anticancer therapies. Blocking the PI3K/AKT pathway can thus simultaneously inhibit tumor cell proliferation (eg, via inhibition of metabolic effects) and is sensitive to pro-apoptotic agents. AKT inhibition selectively sensitizes tumor cells to apoptotic stimulators such as Trail, Camphhothecin, and Doxorubicin. Depending on the genetic background/molecular manipulation of the tumor, AKT inhibitors can also induce apoptotic cell death in monotherapy.

The resistance of many types of cancer to chemotherapy and targeted therapy represents a major obstacle to successful cancer treatment. Cancer cells can circumvent the effects of the most commonly used drugs, albeit with different chemical structures and intracellular targets. Many potential mechanisms for the failure of therapeutic drugs have been well studied. Activation of the PI3K-AKT pathway plays a key role in different cellular functions such as growth, migration, survival and differentiation. Data accumulated over the last decade have been identified and this pathway plays a key role in resistance to chemical, radiological, and targeted therapies. Aggregate data describing the constitutive or remaining pathway activation in cells has developed resistance to conventional chemotherapy and radiation as well as other targeted therapies, such as EGFR antagonism. For example, in a cranberry-resistant CML cell line The experiments in China have shown that PI3K and AKT have high activity levels; importantly, cranberry resistance can be overcome by reducing PI3K and AKT activity. Another experimental evidence was observed in two pancreatic cancer cell lines in which a decrease in the amount of phosphorylated AKT increased gemcitabine-induced apoptosis. Synergistic anti-tumor activity with cisplatin was also demonstrated in a xenograft model of lung cancer.

The PI3K/AKT pathway is associated with resistance to chemotherapy and targeted therapy. Inhibition of AKT can provide a promising strategy to overcome resistance to radiation and DNA targeted therapies. In the latest publication, Hemmings and colleagues show that nuclear AKT on both T308 and S473 is phosphorylated in response to IR or DNA damaging cranberries. Using selective kinase inhibitors, siRNA targeting, and PI3K-deficient cell lines, the authors demonstrated that DNA-PK and PDK1 are required for AKT to phosphorylate and activate in response to DNA damage. Using gene knockout mice, the authors also demonstrated that only AKT1 was involved in this newly identified pathway. These findings clearly indicate that nuclear AKT is located downstream of DNA-PK in the DNA damage response signaling cascade, which provides a pro-survival signal by affecting the transcriptional regulation of DNA damage response genes, such as p21.

In addition, the degree of radiosensitivity is related to the degree of AKT activity. On the one hand, radiosensitivity can be explained by the lack of AKT activity, as observed in AKT1-deficient mice, and hyperactivation is associated with resistance. In addition, a regulatory network has been documented in which DNA-PKc specifically activates AKT by Ser473 phosphorylation following induction of DNA double strand breaks after radiation therapy. Activated AKT1 regulates crosstalk of gene expression programs induced by p53-dependent DNA damage. This results in increased survival and inhibition of apoptosis upon irradiation. Thus, increased activation of AKT can mediate resistance to radiation therapy.

In summary, because AKT is a central node in signaling pathways critical for tumor formation, tumor growth/proliferation, and survival, and has been found in a wide range of human primary tumors and tumors that become resistant to chemical and radiation therapy. The prevalence of AKT activation has led to the development of promising strategies for overcoming cancer treatment resistance in the treatment of AKT inhibitors in single and combination therapies.

Thus, inhibitors of AKT are indicated to be useful as a single agent and in combination with other drugs (eg, DNA targeting agents and radiation therapy) to supplement the therapeutically valuable compounds.

Alpharadin (Xofigo) uses radium-223 decay alpha radiation to kill cancer cells. Avalatin targets bone tissue by virtue of its chemical similarity to calcium. It has a role in the range of 2-10 cells and causes less damage to surrounding healthy tissue compared to current radiation therapy based on beta or gamma radiation. A median overall survival time was confirmed to be significantly increased in phase III clinical trials and Xofigo was approved as a therapeutic agent for patients with castration-resistant prostate cancer (CRPC) with symptomatic bone metastases.

The different AKT inhibitors are disclosed in, for example, WO2004/096131, WO2005/100344, WO2006/000589, WO2006/027346, WO2006/036395, WO2006/065601, WO2006/091395, WO2006/135627, WO 2008/070016, WO 2009/021990, WO2009 /021990, WO2009/021992, WO2010088177, WO2010/091808, WO2010/091824, WO2010101734, WO2010104705, WO2010114780, WO2011033265, WO2011055115, WO 2012/007345, WO 2012/007416, WO2012/080237, WO 2012/013713, WO 2012/136776 in.

In the most recent disclosure, Y. Li et al. (Bioorg. Med. Chem. Lett. 2009, 19, 834-836 and references cited therein) detail the difficulties in finding the best AKT inhibitor. The potential use of AKT inhibitors in a variety of disease settings, such as cancer, makes it highly desirable to supply new modified AKT inhibitors to currently available AKT inhibitors.

Different compounds have been disclosed in the prior art as cited above, which demonstrate inhibition of AKT kinase.

The AKT inhibitors mentioned in the prior art have been disclosed for the treatment or prevention of different diseases, especially cancer:

These findings clearly indicate that nuclear AKT is located downstream of DNA-PK in the DNA damage response signaling cascade, which provides a pro-survival signal by affecting the transcriptional regulation of DNA damage response genes, such as p21.

However, the prior art does not disclose a combination of the invention comprising an AKT kinase inhibitor or a physiologically acceptable salt thereof and a pharmaceutically acceptable salt of an alkaline earth radioactive seed radium-223.

A preferred suitable pharmaceutically acceptable salt of radium-223 is dichloride (Ra ²²³ Cl ₂ ).

Radium dichloride-223 is a novel targeted alpha emitter that selectively binds to regions of increased bone turnover in bone metastases and emits very short (<100 μm) high-energy alpha particles (Bruland OS, Nilsson S., Fisher DR et al, High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter ²²³ Ra: adjuvant or alternative to conventional modalities?, Clin. Cancer Res. 2006; 12: 6250s-7s).

It is the first targeted alpha emitter to be evaluated in Phase 3 studies.

As a osteogenic calcium mimetic, radium-223 binds to newly formed bone matrix, especially in the microenvironment of osteoblast or scleral metastasis (Henriksen G., Breistol K., Bruland OS et al., Significant antitumor effect from Bone-seeking, alpha-particle-emitting (223) Ra demonstration in an experimental skeletal metastases model , Cancer Res. 2002; 62: 3120-3125; Henriksen G., Fisher DR, Roeske JC et al., Targeting of osseous sites with alpha -emitting 223Ra:comparison with the beta-emitter 89Sr in mice , J. Nucl. Med 2003; 44:252-59).

Α induced by high energy particle radiation mainly double-stranded DNA breaks, efficient and produce highly localized cytotoxicity in cancer cells containing the target region of metastatic (Lewington VJ, Bone-seeking radionuclides for therapy, J.Nucl.Med 2005; 46 (Supplement 1): 38S-47S; Liepe K., Alpharadin , a 223Ra-based alpha-particle-emitting pharmaceutical for the treatment of bone metastases in patients with cancer , Curr. Opin. Investig. Drugs 2009; 10:1346- 58; McDevitt MR, Sgouros G., Finn RD, et al , Radioimmunotherapy with alpha-emitting nuclides , Eur. J. Nucl. Med. 1998; 25: 1341-51.).

The short path length of alpha particles also means reduced toxicity to adjacent healthy tissues and especially bone marrow (Kerr C., (223) Ra targets skeletal metastases and spares normal tissue , Lancet Oncol. 2002 ; 3:453; Li Y. , Russell PJ, Allen BJ, Targeted alpha-therapy for control of micrometastatic prostate cancer , Expert Rev. Anticancer Ther. 2004; 4: 459-68).

Radium-223 has demonstrated a favorable safety profile in Phase 1 and Phase 2 studies of patients with bone metastases with minimal bone marrow toxicity (Nilsson S., Larsen RH, Fossa SD et al, First clinical experience with alpha-emitting radium- 223 in the treatment of skeletal metastases, Clin.Cancer Res.2005; 11: 4451-59; Nilsson S., Franzen L., Parker C. et al., Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study , Lancet Oncol. 2007; 8:587-94).

Phase 2 studies have demonstrated that radium-223 reduces pain, improves disease-related biological indicators (such as bone alkaline phosphatase [ALP] and prostate specific antigen [PSA]), and has demonstrated survival benefits in patients with CRPC and bone metastases (Parker C) Pascoe S., Chodacki A. et al., A randomized, double-blind, dose-finding, multicenter, phase 2 study of radium chloride (Ra-223) in patients with bone metastases and castration-resistant prostate cancer , Eur. Urol.2012; September 13th.pii:S0302-2838(12)01031-7.doi:10.1016/j.eururo.2012.09.008.[Pre-press electronic version]; Nilsson S.,Strang P.,Aksnes AK A randomized, dose-response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration- resistant prostate cancer , Eur. J. Cancer 2012; 48: 678-86.

ALSYMPCA (atorvastatin Latin symptoms in patients with prostate cancer, AL pharadin in SYM ptomatic P rostate CA ncer patients) test provides evidence of the targeting principle role in oncology of α emitters. In this trial, radium-223 significantly prolonged the overall survival of patients with CRPC (castration-refractory prostate cancer) and bone metastases compared with placebo, reducing the risk of death by 30.5%. The median survival time with radium-223 was 2.8 months longer than placebo. All major secondary efficacy endpoints were statistically significant and favorable treatments using radium-223, including the time endpoints clinically defined to the first bone-related event, which was significantly prolonged in patients receiving radium-223.

A significant percentage of cancer patients are affected by bone metastases. Up to 85% of patients with advanced lung, prostate, and breast cancer develop bone metastasis (Garret R. Semin. Oncol. 72, 3433-3435 (1993) Bone destruction in cancer; Nielsen, OS, Munro AJ, Tannock IF. JC lin Oneal 9,509-5 24 (1991), Bone metastases: Pathophysiology and management policy.). Established treatments (such as hormonal therapy, chemotherapy, and external radiation therapy) often cause temporary reactions, but eventually most patients with bone cancer experience recurrence (Kanis JA. Bone 17, 101s-105s (1995), Bone and cancer. Pathophysiology and Treatment of metastases.). Therefore, there is a strong need for new therapies that alleviate pain and slow the progression of the tumor.

²²³ Ra is used as an alpha-emitting radiopharmaceutical that targets calcified tissue (eg, bone surface and bone tumor lesions). It can be suitably used as a osteogenic radiopharmaceutical.

It can therefore be used for prophylactic cancer treatment by delivering a focused dose to the bone surface of a high probability patient with undetected micrometastasis on the bone surface. Another example of its potential use should be the treatment of painful bone sites.

The alkaline earth radionuclide radium-223 is suitable for targeting calcified tissue (e.g., bone) and a physiologically acceptable solution comprising ²²³ Ra.

The alkaline earth radioactive seed radium-223 is suitable for use as a cationic material and/or with a chelating agent or Another form of carrier molecule having affinity for calcified tissue is associated to use the nucleus. Thus, in combination with a chelating agent, the chelating agent can then be combined with a molecule having affinity for calcified tissue. The effect of a radioisotope produced by providing a cascade of alpha particles on the surface of the bone and/or in a calcified tumor is used to alleviate the pain caused by various diseases and/or to target the lowest possible number of bone diseases For prophylactic use, and/or for the therapeutic treatment of confirmed bone cancer. Diseases in which radioisotopes can be used include, but are not limited to, bone metastases of prostate cancer, breast cancer, kidney cancer, and lung cancer, as well as primary bone cancer and multiple myeloma.

Surprisingly, it has been observed that by administering an AKT inhibitor or a physiologically acceptable salt thereof and a suitable pharmaceutically acceptable salt of the alkaline earth radioactive seed radium-223, compared to the individual monotherapy, A statistically significant reduction in systemic tumor burden and a reduction in total osteolytic lesion area occurred. In addition, an increase in bone necrosis and fibrosis area was observed in combination therapy as compared to individual monotherapy.

Thus, according to a first aspect, the present invention provides a combination of at least two compounds A and B, Compound A is an inhibitor of AKT kinase or a physiologically acceptable salt thereof, and Compound B is an alkaline earth radioactive seed radium-223 Suitable pharmaceutically acceptable salts.

According to a second aspect, the invention encompasses a combination of at least two compounds A and B, Compound A is an inhibitor of AKT kinase, and Compound B is a suitable pharmaceutically acceptable salt of the alkaline earth radioactive seed radium-223.

According to a third aspect, the invention comprises at least two combinations of compounds A and B, compound A is an inhibitor of AKT kinase or a physiologically acceptable salt thereof, and compound B is suitable for alkaline earth radioactive seed radium-223 A pharmaceutically acceptable inorganic salt.

Combinations comprising at least two compounds A and B as described and defined herein are also referred to as "combinations of the invention."

Additionally, the present invention relates to: A kit comprising: - a combination of: Component A: one or more AKT kinase inhibitors or physiologically acceptable salts, solvates, hydrates or stereoisomers thereof; Component B: alkaline earth radioactivity a suitable pharmaceutically acceptable salt of nucleoside radium-223 or a solvate or hydrate thereof; and optionally, component C: one or more other pharmaceutical agents; wherein any of the combinations mentioned above Any one or both of these components A and B are optionally prepared for simultaneous, co-administrative, separate or sequential administration of the pharmaceutical formulation/composition. The components can be administered independently of one another by the oral, intravenous, topical, topical, intraperitoneal or nasal route.

According to another aspect, the invention encompasses a combination as described above for the treatment or prevention of a disease.

According to another aspect, the invention encompasses the use of such combinations as previously described for the preparation of a medicament for the treatment or prevention of a disease.

A. Definition of terms used in compound description

As used herein, the term "one or more" is understood, for example, in the definition of a substituent of the compound A of the present invention to mean "one time, two times, three times, four times or five times, especially once, twice, three times. Or four times, more especially once, twice or three times, or even more especially one or two times."

When a plural form of the word compound, salt, polymorph, hydrate, solvate or the like is used herein, it also includes a single compound, a salt, a polymorph, an isomer, a hydrate, a solvent. Compound or analogue thereof.

The compounds of the invention may contain one or more asymmetric centers, depending on the location and nature of the various substituents desired. Asymmetric carbon atoms can exist in either (R) or (S) configurations. In some cases, asymmetry may also be present by limited rotation around a specified bond (eg, a central bond connecting two substituted aromatic rings of a particular compound).

Substituents on the ring may also exist in cis or trans form. It is intended that all such configurations be included within the scope of the present invention.

B. Definition

"1-6C alkyl group" is a linear chain having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (1-4C alkyl group), more preferably 1 to 3 carbon atoms (1-3C alkyl group). Or branched alkyl. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and tert-butyl, pentyl, hexyl. Other alkyl components having a number of other carbon atoms as referred to herein should be defined as mentioned above, taking into account the different lengths of the chains. The definition of "alkyl" given above applies as long as "alkyl" is part of the component consisting of "alkyl" with another component.

The term "1-6C alkenyl" is understood to preferably mean one or more double bonds and have 2, 3, 4, 5 or 6 carbon atoms, especially 2 or 3 carbon atoms ("2-3Cene" The linear or branched chain monovalent hydrocarbon group of the group "), it is understood that in the case where the alkenyl group contains more than one double bond, the double bonds may be separated or conjugated to each other. The alkenyl group is, for example, a vinyl group, an allyl group, (E)-2-methylvinyl group, (Z)-2-methylvinyl group, homoallyl group, (E)-but-2-enyl group, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl , (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pentyl 1-enyl, hex-5-alkenyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)- Hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl , isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1- Alkenyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl , 3-methylbut-2-enyl, (E)- 2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbutyl -2-alkenyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1- Dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl, 3-methyl Pent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl, 4-methylpent-3-enyl, (E)-3-methylpentyl 3-alkenyl, (Z)-3-methylpent-3-enyl, (E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl , (E)-1-methylpent-3-enyl, (Z)-1-methylpent-3-enyl, (E)-4-methylpent-2-enyl, (Z)- 4-methylpent-2-enyl, (E)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl, (E)-2-methylpentyl -2-alkenyl, (Z)-2-methylpent-2-enyl, (E)-1-methylpent-2-enyl, (Z)-1-methylpent-2-enyl , (E)-4-methylpent-1-enyl, (Z)-4-methylpent-1-enyl, (E)-3-methylpent-1-enyl, (Z)- 3-methylpent-1-enyl, (E)-2-methylpent-1-enyl, (Z)-2-methyl Pent-1-enyl, (E)-1-methylpent-1-enyl, (Z)-1-methylpent-1-enyl, 3-ethylbut-3-enyl, 2- Ethylbut-3-enyl, 1-ethylbut-3-enyl, (E)-3-ethylbut-2-enyl, (Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl, (E)-1-ethylbut-2-enyl, (Z)-1 -ethylbut-2-enyl, (E)-3-ethylbut-1-enyl, (Z)-3-ethylbut-1-enyl, 2-ethylbut-1-enyl , (E)-1-ethylbut-1-enyl, (Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylpropan-2- Alkenyl, 2-isopropylpropan-2-enyl, 1-isopropylprop-2-enyl, (E)-2-propylprop-1-enyl, (Z)-2-propyl Prop-1-enyl, (E)-1-propylprop-1-enyl, (Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1- Alkenyl, (Z)-2-isopropylpropan-1-enyl, (E)-1-isopropylpropan-1-enyl, (Z)-1-isopropylpropan-1-enyl , (E)-3,3-dimethylprop-1-enyl, (Z)-3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl) Vinyl, butadiene-1,3-dienyl, pent-1,4-dienyl or hex-1,5-dienyl. This group is especially a vinyl or allyl group.

The term "2-6C alkynyl" is understood to preferably mean one or more referenced bonds and contain 2, 3, 4, 5 or 6 carbon atoms, especially 2 or 3 carbon atoms ("2-3C alkyne" A linear or branched chain monovalent hydrocarbon group of the group "). The C ₂ -C ₆ alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pentane- 1-alkynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4 - alkynyl, hex-5-alkynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbutyl- 2-Alkynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1 -methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpentan-2 - alkynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethyl-but-3-ynyl, 1 -ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1 - dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. The alkynyl group is especially ethynyl, prop-1-ynyl or prop-2-ynyl.

NR ^5b R ^6b or NR ^8b R ^9b represents "amino group" and "mono or di-l-C alkylamino group" which independently contains one or two of the above-mentioned 1-6C alkyl groups in addition to the nitrogen atom. . Examples are methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, methyl(ethyl)amine and diisopropylamino.

"Aryl" means a monocyclic or bicyclic aromatic carbocyclic group generally having 6 to 10 carbon atoms; for example, phenyl or naphthyl. Phenyl is preferred.

The term "-(1-6C alkyl)-aryl" denotes an aryl group, as defined above, appended to the remainder of the molecule via a straight or branched alkyl chain, preferably -(CH ₂ )-aryl or -(CH ₂ CH ₂ )-aryl. A benzyl group is especially preferred.

The term "aryloxy" or "-O-aryl" denotes the same aryl moiety as defined by the term aryl, wherein the ring is attached to the remainder of the molecule via an oxygen atom.

The term "-O-(1-6C alkyl)-aryl" denotes the same aryl moiety as defined by the term aryl, wherein the ring is attached to the remainder of the molecule via an -O-(1-6C alkyl) spacer. . In this context, the -O-(1-6C alkyl) spacer is preferably -O-(CH ₂ )- or -O-(CH ₂ CH ₂ )-. A benzyloxy group is especially preferred.

"Halogen" is in the sense of the present invention iodine, bromine, chlorine or fluorine. "Halogen" is preferably chlorine or fluorine in the sense of the present invention. If halogen is used as a leaving group during the synthesis, bromine or iodine is Preferably.

The "1-4C haloalkyl group" which may be defined by one or more substitutions with a halogen is a linear or branched alkyl group having 1 to 4 carbon atoms in which at least one hydrogen is substituted by a halogen atom. Examples are chloromethyl or 2-bromoethyl. For the partially or completely fluorinated C ₁ -C ₄ alkyl group, the following partially or completely fluorinated groups of, for example: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1- Difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, tetrafluoroethyl and pentafluoroethyl, of which fluoromethyl, difluoromethyl, trifluoromethyl, A fluoroethyl group, a 1,1-difluoroethyl group or a 1,1,1-trifluoroethyl group is preferred. Partially or fully fluorinated C ₁ -C ₄ alkyl is considered to be encompassed by the term 1-4C haloalkyl.

The "1-6C alkoxy group" means a group having a linear or branched alkyl group having 1 to 6 carbon atoms in addition to an oxygen atom. Examples which may be mentioned are hexyloxy, pentyloxy, butoxy, isobutoxy, second butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy a group, preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and for a shorter chain (such as a 1-4C alkoxy group), the above definition should be applied in relation to the number of 1 to 4 carbon atoms. .

The "3-7C cycloalkyl group" represents a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group, preferably a cyclopropyl group.

"3-7C cycloalkoxy" or "-O-(3-7C cycloalkyl)" represents cyclopropoxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy. Preferably, it is a cyclopropoxy group.

The term "heteroaryl" means a monocyclic 5- or 6-membered aromatic heterocycle including, but not limited to, a 5-membered heteroarylfuranyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl. , isothiazolyl, imidazolyl, pyrazolyl, triazolyl (1,2,4-triazolyl, 1,3,4-triazolyl or 1,2,3-triazolyl), thiadiazole (1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl or 1,2,4-thiadiazolyl) and oxadiazole Base (1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl or 1,2,4-oxadiazolyl), and 6 members Heteroarylpyridyl, pyrimidine a pyridyl group and a pyridazinyl group, preferably a 5- or 6-membered heteroaryl group is a furyl group, a thienyl group, a pyrrolyl group, a thiazolyl group, an oxazolyl group, a thiadiazolyl group, an oxadiazolyl group, a pyridyl group, Pyrimidinyl, pyrazinyl or pyridazinyl. More preferably 5 or 6 heteroaryl is furan-2-yl, thiophen-2-yl, pyrrol-2-yl, thiazolyl, oxazolyl, 1,3,4-thiadiazolyl, 1,3 , 4-oxadiazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl or pyridazin-3-yl. If a substituent is present, the substituents can be located at any position that is chemically suitable.

The term heteroaryl includes the same heteroaryl moiety as defined above, but as indicated at the end of the "extension", as indicated by the general practitioner, includes two open bonds instead of one, and if a ring atom The number is limited in the scope of the patent application, and it refers only to the heteroaryl group having the corresponding ring size mentioned above. If a substituent is present, the substituents can be located at any position that is chemically suitable.

The term "- (l-6C alkyl) - heteroaryl" refers to heteroaryl connected to the rest of the molecule via a straight or branched chain alkyl group as defined above of an aryl group, preferably - (CH ₂₎ - heteroaryl Aryl or -(CH ₂ CH ₂ )-heteroaryl, wherein -(CH ₂ )-heteroaryl is especially preferred.

The term "heteroaryloxy" or "-O-heteroaryl" denotes the same heteroaryl moiety as defined by the term heteroaryl, wherein the ring is attached to the remainder of the molecule via an oxygen atom.

The term "-O-(1-6C alkyl)-heteroaryl" denotes the same heteroaryl moiety as defined by the term heteroaryl, wherein the ring is attached via an -O-(1-6C alkyl) spacer to The rest of the molecule.

The term "-O-(1-6C alkyl) spacer" may be varied in the understanding of the present invention, and may have a linear or branched chain (where possible) having 1-6, 1-5. An alkyl chain of 1-4, 1-3, 1-2 or 1 carbon atom.

"3-7C heterocyclic group" or "heteromeric" which is itself or a part of a longer term such as "-(3-7C)heterocycloalkyl" or "-O-(3-7C)heterocycloalkyl""Cyclo" or "heterocyclic" means a monocyclic or polycyclic ring, preferably a monocyclic or bicyclic ring, more preferably a monocyclic non-aromatic heterocyclic group, containing 4 to 10, preferably 4 to 7 ring atoms and up to 3 And preferably up to two heteroatoms and/or hetero groups derived from a series consisting of N, O, S, SO, SO ₂ . Heterocyclyl can be saturated or partially unsaturated and, unless otherwise stated, may be substituted one or more times with the same or different substituents selected from the group consisting of 1-4C alkyl, 1-4C haloalkyl, 1 a -4C alkoxy group, a hydroxyl group, a fluorine group, wherein the 1-4C alkyl group may be further substituted with a hydroxyl group as the case may be. Particularly preferred heterocyclic groups are 4- to 7-membered monocyclic saturated heterocyclic groups having up to two heteroatoms from the series consisting of O, N and S. For example and preferably, the following are mentioned: oxetanyl, tetrahydrofuranyl, azetidinyl, 3-hydroxyazetidinyl, 3-fluoroazetidinyl, 3,3- Difluoroazetidinyl, pyrrolidinyl, 3-hydroxypyrrolidinyl, pyrrolinyl, piperidinyl, 3-hydroxypiperidinyl, 4-hydroxypiperidinyl, 3-fluoropiperidinyl, 3 , 3-difluoropiperidinyl, 4-fluoropiperidinyl, 4,4-difluoropiperidinyl, piperazinyl, N-methyl-piperazinyl, N-(2-hydroxyethyl)-peri Zinyl, morpholinyl, thiomorpholinyl, azepanyl, homopiperazinyl, N-methyl-homopiperazinyl.

The term "heterocyclooxy" or "-O-heterocyclyl" or "-O-(3-7 membered heterocycloalkyl)" denotes the same heterocyclic moiety as defined by the term heterocyclyl, wherein the ring The C atom is connected to the rest of the molecule via an oxygen atom. Preferably, the heterocyclic moiety is unsubstituted or may be optionally substituted on the ring nitrogen atom with a substituent selected from the group consisting of 1-4C alkyl, 1-4C haloalkyl, 1-4C alkoxy.

The term "-O-(1-6C alkyl)-heterocyclyl" or "-O-(1-6C alkyl)-(3-7 membered heterocycloalkyl)" denotes as defined in the term heterocyclyl. The same heterocyclic group wherein the ring is attached to the remainder of the molecule via an -O-(1-6C alkyl) spacer. In one aspect of the invention, the heterocyclic moiety containing one or more ring nitrogen atoms is preferably attached to the -O-(1-6C alkyl) spacer via a ring nitrogen atom.

The NH(CO)-(1-6C alkyl) or NH(CO)R ¹¹ group includes, for example, NH(CO)CH ₃ , NH(CO)C ₂ H ₅ , NH(CO)C ₃ H ₇ , NH( CO)CH(CH ₃ ) ₂ .

The NHS(O) ₂ R ¹¹ group includes, for example, NHS(O) ₂ CH ₃ , NHS(O) ₂ C ₂ H ₅ , NHS(O) ₂ C ₃ H ₇ , NHS(O) ₂ CH(CH ₃ ) ₂ .

The NH(CO)NHR ¹¹ group includes, for example, NHC(O)NHCH ₃ , NHC(O)NHC ₂ H ₅ .

The C(O)OR ^10b group includes, for example, C(O)OH, C(O)OCH ₃ , C(O)OC ₂ H ₅ , C(O)C ₃ H ₇ , C(O)CH(CH ₃ ) ₂ , C(O)OC ₄ H ₉ , C(O)OC ₅ H ₁₁ , C(O)OC ₆ H ₁₃ ; for C(O)O(1-6C alkyl), the alkyl moiety may be linear Or a branch chain.

Unless otherwise indicated, the optionally substituted ingredients as set forth herein may be substituted one or more times independently of one another at any possible position. When any variable occurs more than once in any component, each definition is independent.

Unless otherwise indicated, a heteroaryl or heterocyclyl group as referred to herein may be a substituent or parent molecule designated by any of its possible positions, such as at any substitutable ring carbon or ring nitrogen atom. Replacement of the group. Similarly, it will be appreciated that any heteroaryl or heterocyclic group is likely to be attached to the remainder of the molecule via any suitable atom, if chemically suitable. Unless otherwise stated, any heteroatom of the heteroaryl group having an unsaturated valence referred to herein is considered to have a hydrogen atom to saturate the valence. Unless otherwise stated, a ring containing a quaternary ammonium or imido ring nitrogen atom (-N=) may preferably be unreacted on such an amine or imido ring nitrogen atom. The substituent or parent molecular group mentioned is quaternized.

Preferred compounds are those which produce a more desirable biological activity. Isolated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the invention are also included within the scope of the invention. Purification and separation of such materials can be accomplished by standard techniques known in the art.

Optical isomers can be obtained by resolution of racemic mixtures according to conventional methods, for example by formation of diastereomeric salts or formation of covalent diastereomers by the use of optically active acids or bases. Examples of suitable acids are tartaric acid, dimercapto tartaric acid, xylylmercapto tartaric acid and camphorsulfonic acid. Mixtures of diastereomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, such as chromatography or fractional crystallization. The optically active base or acid is then released from the separated diastereomeric salt. Different methods for separating optical isomers involve combining or not incorporating conventional derivatives The palm chromatography (e.g., for a palmitic HPLC column) is optimally selected to maximize separation of the enantiomers. Suitable palm-shaped HPLC columns are manufactured by Diacel, such as, for example, Chiracel OD and Chiracel OJ, which can be selected conventionally. Enzymatic separation with or without derivatization can also be used. The optically active compounds of the invention can likewise be obtained by the use of optically active starting materials for palm synthesis.

If an "embodiment" is referred to in the context of the present invention, it should be understood to include a plurality of possible combinations.

To limit the different types of isomers to each other, refer to IUPAC Guidelines Part E ( Pure Appl Chem 45, 11-30, 1976).

The invention also includes all suitable isotopic variations of the compounds of the invention. An isotopic variation of a compound of the invention is defined as a variant in which at least one atom is replaced by an atom having the same atomic number but an atomic weight different from the atomic weight normally or predominantly found in nature. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H(氘), ³ H(氚), ¹¹ C, respectively. , ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I. Certain isotopic variations of the compounds of the invention, for example, isotopic variations of one or more radioisotopes (such as ³ H or ¹⁴ C), are useful for drug and/or matrix distribution studies. Deuterated and carbon 14 (i.e., ¹⁴ C) isotopes are particularly preferred due to their ease of preparation and detectability. In addition, isotopic substitutions such as guanidine may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and thus may be preferred in some circumstances. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures known to those skilled in the art, such as by descriptive methods or by the use of suitable isotopic variations of suitable reagents as described in the Examples below.

The invention includes all possible stereoisomers of the compounds of the invention in the form of a single stereoisomer or in any mixture of such stereoisomers in any ratio. this Separation of a single stereoisomer (e.g., a single enantiomer or a single diastereomer) of a compound of the invention may be by any suitable prior art method (such as chromatography, especially for example, palm chromatography) )to realise.

The invention includes all possible tautomers of the compounds of the invention in the form of a single tautomeric form or in the form of any mixture of such tautomers in any ratio.

Furthermore, the invention includes all possible crystalline forms or polymorphs of the compounds of the invention in the form of a single polymorph or in the form of a mixture of more than one polymorph in any ratio.

Combined Compound A

Compound A can be selected, for example, from AKT kinase inhibitors specifically or generally disclosed in publications as mentioned above, which are incorporated herein by reference.

In one embodiment, Compound A is selected from the group of AKT inhibitors that are generally or specifically disclosed in WO2009021992A2 or International Patent Application No. WO2012136776, which is incorporated herein by reference.

In a preferred embodiment, Compound A, which is an AKT inhibitor, is selected from the group of compounds of Formula (IIb):

Wherein R ^1b represents hydrogen, hydroxy, halogen, cyano, -N(R ^5b )(R ^6b ), -C(O)N(R ^8b )(R ^9b ), -C(O)OR ^8b , -C( O) (C ₁ -C ₆ alkyl), -N(H)C(O)(C ₁ -C ₆ alkyl), -N(H)S(O) ₂ R ^11b , -N(H)C (O) N(H)R ^11b , -S(O) _n -C ₁ -C ₆ alkyl, -S(O) ₂ N(R ^5b )(R ^6b ) or a group selected from the group consisting of C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-, C ₃ -C ₇ cycloalkyl-, aryl-, heteroaryl-, -(C ₁ -C ₆ alkyl)-aryl, -(C ₁ -C ₆ alkyl)-heteroaryl, -O-(C ₃ -C ₇ cycloalkyl), -O-aryl, -O- (3 to 7 membered heterocycloalkyl), -O-heteroaryl, -O-(C ₁ -C ₆ alkyl)-heteroaryl, -O-(C ₁ -C ₆ alkyl)- (3 to 7 membered heterocycloalkyl), - O-(C ₁ -C ₆ alkyl)-aryl, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-; wherein the group is optionally the same or differently selected from the substituents below Substituted one or more times: hydroxy, halogen, C ₁ -C ₆ alkyl-, C ₁ -C ₄ haloalkyl-, C ₁ -C ₆ alkoxy-, -N(R ^8b )(R ^9b ), Cyano, -C(O)N(R ^8b )(R ^9b ), -C(O)O(R ^10b ), -N(H)C(O)R ^11b , -N(H)C(O) ^{N (H) (R 11)} , - N (H) S (O) 2 R 11b, C 3 -C 7 cycloalkyl, 3-7 heterocycloalkyl -, aryl -; R & lt ^2b represents hydrogen, hydroxy, halogen, cyano, -N(R ^5b )(R ^6b ), -C(O)N(R ^8b )(R ^9b ), -C(O)O(R ^8b ), -C (O) (C ₁ -C ₆ alkyl), -N(H)C(O)(C ₁ -C ₆ alkyl), -N(H)S(O) ₂ R ^11b , -N(H) C(O)N(H)(R ^11b ), -S(O) _n -(C ₁ -C ₆ alkyl), -S(O) ₂ N(R ^5b )(R ^6b ) or selected from the group consisting of Group: C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-, C ₃ -C ₇ cycloalkyl-, aryl-, heteroaryl-, -(C ₁ -C ₆ alkyl )-aryl, -(C ₁ -C ₆ alkyl)-heteroaryl, -O-(C ₃ -C ₇ cycloalkyl), -O-aryl, -O- (3 to 7 members) Cycloalkyl), -O-heteroaryl, -O-(C ₁ -C ₆ alkyl)-heteroaryl, -O-(C ₁ -C ₆ alkyl)-(3 to 7 membered heterocyclic ring) Alkyl), -O-(C ₁ -C ₆ alkyl)-aryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl; wherein the group is optionally the same substituent selected from Or substituted one or more times differently: hydroxy, halogen, C ₁ -C ₆ alkyl-, C ₁ -C ₄ haloalkyl-, C ₁ -C ₆ alkoxy-, -N(R ^8b )(R ^9b ), cyano, -C(O)N(R ^8b )(R ^9b ), -C(O)O(R ^10b ), -N(H)C(O)R ^11b , -N(H)C (O) N (H) ( R 11b), - N (H) S (O) 2 R 11b, 3 membered to. 7 membered heterocycloalkyl, aryl, -; R ^3b represents hydrogen, hydroxy Halogen, ^{cyano, -N (R 5b) (R} 6b), - C (O) N (R 8b) (R 9b), - C (O) O (R 8b), - C (O) (C 1 -C ₆ alkyl), -N(H)C(O)(C ₁ -C ₆ alkyl), -N(H)S(O) ₂ R ^11b , -N(H)C(O)N( H) (R ^11b ), -S(O) _n -(C ₁ -C ₆ alkyl), -S(O) ₂ N(R ^5b )(R ^6b ) or a group selected from C ₁ - C ₆ alkyl-, C ₁ -C ₆ alkoxy-, C ₃ -C ₇ cycloalkyl-, aryl-, heteroaryl-, -(C ₁ -C ₆ alkyl)-aryl, - (C ₁ -C ₆ alkyl)-heteroaryl, -O-(C ₃ -C ₇ cycloalkyl), -O-aryl, -O- (3 to 7 membered heterocycloalkyl), - O-heteroaryl, -O-(C ₁ -C ₆ alkyl)-heteroaryl, -O-(C ₁ -C ₆ alkyl)-(3 to 7 membered heterocycloalkyl), -O a -(C ₁ -C ₆ alkyl)-aryl group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group; wherein the group is optionally substituted or substituted differently by a substituent selected from the group consisting of Multiple times: hydroxy, halogen, C ₁ -C ₆ alkyl-, C ₁ -C ₄ haloalkyl-, C ₁ -C ₆ alkoxy-, -N(R ^8b )(R ^9b ), cyano, -C(O)N(R ^8b )(R ^9b ), -C(O)O(R ^10b ), -N(H)C(O)R ^11b , -N(H)C(O)N(H ^{) (R 11b), - N} (H) S (O) 2 R 11b, 3 membered to. 7 membered heterocycloalkyl -, aryl -; R ^4b represents optionally identical halogen atoms or Substituted with one, two or three of the phenyl group; R ^5b represents hydrogen or C ₁ -C ₆ alkyl group, R ^6b represents hydrogen or C ₁ -C ₆ alkyl, R ^8b represents hydrogen or optionally substituted by hydroxyl of C ₁ -C ₆ alkyl, R ^9b represents hydrogen or C ₁ -C ₆ alkyl, R ^10b represents hydrogen or C ₁ -C ₆ alkyl, R ^11b represents hydrogen or C ₁ -C ₆ alkyl, X, Y Represents CH ₂ ; n is 0, 1 or 2; or an N-oxide, a salt, a tautomer or a stereoisomer of the compound, or the N-oxide, tautomer or stereoisomer salt.

In other embodiments, Compound A is selected from the group of compounds of Formula (IIb) above, wherein R ^1b represents hydrogen, hydroxy, halo, -N(R ^5b )(R ^6b ), -C(O)N(R ^8b ) (R ^9b ), -C(O)OR ^8b , -N(H)C(O)(C ₁ -C ₆ alkyl) or selected from C ₁ -C ₆ alkyl-, C ₁ -C ₄ a group of alkoxy-, C ₃ -C ₇ cycloalkyl-, aryl-, heteroaryl-; wherein the group is optionally substituted one or more times by substituents selected from the group consisting of: halogen, C ₁ -C ₆ alkyl -, C ₁ -C ₆ alkoxy -, - C (O) O (R 10b), 3 . 7 membered heterocycloalkyl membered to -, aryl -.

In other embodiments, Compound A is selected from the group of compounds of Formula (IIb) above, wherein R ^1b represents hydrogen, hydroxy, amine, methoxy, ethoxy, butoxy, pyridin-3-yl, Pyridin-4-yl, pyrazol-3-yl, 1-methyl-pyrazol-3-yl, imidazol-2-yl, methyl, propyl, -O-(CH ₂ )-O-CH ₃ , -O-CH ₂ - phenyl, -O-CH ₂ - _{cyclopropyl, -C (O) OCH 3,} -C (O) -NHCH 3, -C (O) -NH 2, 4- fluoro - benzene Base, -(CH ₂ ) ₂ -C(O)OCH ₃ , cyclopropyl or -NH-C(O)CH ₃ .

In other embodiments, Compound A is selected from the group of compounds of Formula (IIb) above, wherein R ^2b represents hydrogen or C ₁ -C ₆ alkyl-.

In other embodiments, Compound A is selected from the group of compounds of Formula (IIb) above, wherein R ^2b represents hydrogen or methyl.

In other embodiments, Compound A is selected from the group of compounds of Formula (IIb) above, wherein R ^3b represents hydrogen, hydroxy, halo, -N(R ⁵ )(R ⁶ ), -C(O)N(R ^8b ) (R ^9b ), -C(O)O(R ^8b ), -C(O)(C ₁ -C ₆ alkyl), -N(H)S(O) ₂ R ^11b , -S(O _n -(C ₁ -C ₆ alkyl) or selected from C ₁ -C ₆ alkyl-, C ₁ -C ₆ alkoxy-, aryl-, C ₂ -C ₆ alkenyl, -N(H a group of C(O)(C ₁ -C ₆ alkyl), wherein the group is optionally substituted one or more times by a substituent selected from the group consisting of halogen, -C(O)O ( R ^10b ).

In other embodiments, Compound A is selected from the group of compounds of Formula (IIb) above, wherein R ^3b represents hydrogen, hydroxy, amine, methyl, ethyl, methoxy, ethoxy, -O-CH ₂ -C(O)OCH ₃ , -S-CH ₃ , -SO ₂ -CH ₃ , bromine, chlorine, trifluoromethyl, C(O)NH ₂ , COOH, C(O)OCH ₃ , C(O OCH ₂ CH ₃ , C(O)NH ₂ , C(O)NHCH ₃ , C(O)N(CH ₃ ) ₂ , C(O)NH(CH ₂ ) ₂ -OH, -CH=CH ₂ , 4-fluoro-phenyl, NHC(O)CH ₃ , NHC(O)CF ₃ , NH-SO ₂ -CH ₃ or C(O)CH ₃ .

In other embodiments, Compound A is selected from the group of compounds of Formula (IIb) above, wherein R ^4b represents phenyl.

In other embodiments, Compound A is selected from the group of compounds of Formula (IIb) above, wherein R ^5b represents hydrogen.

In other embodiments, A compound selected from the general formula (lib) group of compounds wherein R ^6b represents hydrogen.

In other embodiments, Compound A is selected from the group of compounds of Formula (IIb) above, wherein R ^8b represents hydrogen or, optionally, a C ₁ -C ₄ alkyl group substituted with a hydroxy group.

In other embodiments, Compound A is selected from the group of compounds of Formula (IIb) above, wherein R ^9b represents hydrogen or C ₁ -C ₄ alkyl.

In other embodiments, Compound A is selected from the group of compounds of Formula (IIb) above, wherein R ^10b represents C ₁ -C ₄ alkyl.

In other embodiments, Compound A is selected from the group of compounds of Formula (IIb) above, wherein R ^11b represents C ₁ -C ₄ alkyl.

In other embodiments, Compound A is selected from the group of compounds of Formula (IIb) above, wherein X represents CH ₂ and Y represents CH ₂ .

The compound of formula (IIb) as described and defined herein can be prepared according to the preparation methods contained in WO2012136776, which is incorporated herein by reference.

In other embodiments, Compound A is selected from Group A consisting of 2-methyl-6-phenyl-5-(4-{[4-(5-pyridin-2-yl-1,2,4) -Triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]-triazolo[1,5-a]pyrimidine; 2-cyclopropyl-6-benzene 5-(4-{[4-(5-pyridin-2-yl-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2 , 4]-triazolo[1,5-a]pyrimidine; 2-cyclobutyl-6-phenyl-5-(4-{[4-(5-pyridin-2-yl-1,2,4 -triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]-triazolo[1,5-a]pyrimidine; 2-isopropyl-6-benzene 5-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1 , 2,4]triazolo[1,5-a]pyrimidine; 2,7-dimethyl-6-phenyl-5-(4-{[4-(5-pyridin-2-yl-1H-) 1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[1,5-a]pyrimidine; 2-ethyl- 6-phenyl-5-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl ) [1,2,4]triazolo[1,5-a]pyrimidine; 2-methyl-6-phenyl-5-[4-({4-[5-(1,3-thiazol-2-yl)-1H-1,2,4-triazol-3-yl]piperidin Pyridin-1-yl}methyl)phenyl][1,2,4]triazolo[1,5-a]pyrimidine; 2-methyl-6-phenyl-5-(4-{[4- (5-pyrimidin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[1, 5-a]pyrimidine; 2-methyl-6-phenyl-5-(4-{[4-(3-pyridin-2-yl-1H-pyrazol-5-yl)piperidin-1-yl] Methyl}phenyl)[1,2,4]triazolo[1,5-a]pyrimidine; 2-methyl-6-phenyl-5-(4-{[4-(5-pyridine-4) -yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[1,5-a]pyrimidine; 2-Bromo-6-phenyl-5-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]- Benzyl)[1,2,4]triazolo[1,5-a]pyrimidine; 2-ethynyl-6-phenyl-5-(4-{[4-(5-pyridine-2- -1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[1,5-a]pyrimidine; -methyl-5-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) -6-(3-thienyl)[1,2,4]triazolo[1,5-a]pyrimidine; N,N-dimethyl-6-phenyl-5-(4-{[4- (5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[1, 5-a]pyrimidine 2-amine; 6-phenyl-5-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl] Methyl}phenyl)-2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidine; N,N,2-trimethyl-6-phenyl-5 -(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2, 4] Triazolo[1,5-a]pyrimidin-7-amine; N-methyl-6-phenyl-5-(4-{[4-(5-pyridin-2-yl-1H-1, 2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[1,5-a]pyrimidin-2-amine; 2-A Oxy-6-phenyl-5-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl }phenyl)[1,2,4]triazolo[1,5-a]pyrimidine; 6-phenyl-5-(4-{[4-(5-pyridin-2-yl-1H-1, 2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[1,5-a]pyrimidin-2-amine; 2-methyl-6-phenyl-5-[4-({4-[3-(1H-pyrrol-2-yl)-1H-1,2,4-triazol-5-yl]piperidine- 1-yl}methyl)phenyl][1,2,4]triazolo[1,5-a]pyrimidine; 2-methyl-5-[4-({4-[3-(6-A) Pyridin-2-yl)-1H-1,2,4-triazol-5-yl]piperidin-1-yl}methyl)phenyl]-6-phenyl[1,2,4]triazole And [1,5-a]pyrimidine; 5-[4-({4-[3-(2-furyl)-1H-1,2,4-triazol-5-yl]piperidin-1-yl }methyl)phenyl]-2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidine; 5-[4-({4-[3-(2 -furyl)-1H-1,2,4-triazol-5-yl]piperidin-1-yl}methyl)phenyl]-6-phenylpyrazolo[1,5-a]pyrimidine; 7-[4-({4-[3-(2-furyl)-1H-1,2,4-triazol-5-yl]piperidin-1-yl}methyl)phenyl]-6- Phenylimidazo[1,2-a]pyrimidine; 2-methyl-6-phenyl-5-(4-{[4-(3-phenyl-1H-1,2,4-triazole-5) -yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[1,5-a]pyrimidine; or a salt of the compound, especially a pharmaceutically acceptable salt, A tautomer or a stereoisomer, or a tautomer or a salt of the stereoisomer, especially a pharmaceutically acceptable salt.

In some embodiments, Compound A is selected from Group B consisting of 1-[4-(6-methyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl Cyclobutanamine 1-[4-(6-ethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 1-{4-[3-benzene -6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl]- 3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid ethyl ester 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2- b] pyridazine-6-formamide 1-[4-(6-methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 1 -[4-(6-Bromo-8-methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine 2-[4-(1- Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid 1-[4-(6,8-dimethyloxy-3-phenylimidazole And [1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl]-8-methoxy-3-phenylimidazole And [1,2-b]pyridazine-6-formamide 1-[4-(8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl Cyclobutanamine 2-[4-(1-aminocyclobutyl)phenyl]-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid methyl ester 1 -[4-(6-ethyl-8- Oxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine 1-{4-[6-methoxy-3-phenyl-8-(pyridine 3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1-{4-[6-methoxy-3-phenyl-8-(1H-pyridyl) Zin-4-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine hydrochloride 1-[4-(6,8-diethyl-3-phenylimidazole And [1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 1-[4-(6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl Phenyl]cyclobutylamine 1-[4-(8-methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 1-{4-[6-Chloro-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1 -{4-[3-Phenyl-8-(1H-pyrazol-3-yl)-6-vinylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1 -{4-[6-ethyl-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 2 -[4-(1-Aminocyclobutyl)phenyl]-8-ethoxy-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 1 -{4-[6-Chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl} Cyclobutanamine 1-{4-[6-chloro-8-(1H-imidazol-2-yl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl} Butylamine 1-[4-(3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl ]-8-methoxy-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 1-{4-[3-phenyl-8-(1H- Pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl]-8-( 2-methoxyethoxy)-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 1-{4-[8-(benzyloxy)-6-chloro- 3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1-[4-(6-chloro-8-ethoxy-3-phenylimidazo[1 ,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]indole Ethyl-8-carboxylate 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-8-ol 1-{4-[ 6-(4-fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 2-[4-(1-aminocyclobutyl) Phenyl]-3-phenylimidazo[1,2-b]pyridazine-6,8-dimethylguanamine 2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl Imidazo[1,2-b]pyridazine-6-amine 1-{4-[6-(methylthio)-3-phenylimidazo[1,2-b]pyridazin-2-yl] Phenyl}cyclobutylamine N-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b Pyridazine-6-yl}acetamidamine N-{2-[4-(1-1-{4-[6-(methylsulfonyl)-3-phenylimidazo[1,2-b] Pyridazin-2-yl]phenyl}cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid Methyl N-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-yl}-2,2,2- Trifluoroacetamide 1-[4-(6-bromo-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine 1-{4-[6,8 - bis(4-fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1-{2-[4-(1-amino ring) Butyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-yl}ethanone 1-{4-[8-(4-fluorophenyl)-3-phenylimidazole And [1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine N-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1 ,2-b]pyridazine-6-yl}methanesulfonamide 1-[4-(6-chloro-8-cyclopropyl-3-phenylimidazo[1,2-b]pyridazine-2- Phenyl]cyclobutylamine 1-[4-(3-phenyl-8-propylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4- (1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-8-amine N-{2-[4-(1-aminocyclobutyl)benzene 3-phenylimidazo[1,2-b]pyridazin-8-yl}acetamide 1-[4-(6-chloro-7,8-dimethyl-3-phenylimidazolium [1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl]-7,8-dimethyl-3-phenyl Methyl imidazo[1,2-b]pyridazine-6-carboxylate 2-[4-(1-aminocyclobutyl)phenyl]-7,8-dimethyl-3-phenylimidazo[ 1,2-b]pyridazine-6-formamide 1-[4-(6-methoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazine- 2-yl)phenyl]cyclobutylamine 1-{4-[7,8-dimethyl-6-(methylthio)-3-phenylimidazo[1,2-b]pyridazine-2 -yl]phenyl}cyclobutylamine 1-[4-(6-ethoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)benzene Cyclobutanamine 2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]indole Methyl azine-6-carboxylate 2-[4-(1-aminocyclobutyl)phenyl]-8-ethoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid Methyl 2-[4-(1-aminocyclobutyl)phenyl]-8-(1H-imidazol-2-yl)-3-phenylimidazo[1,2-b]pyridazine-6- Methyl Formate {1-[4-(8-Ethylamino-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamic acid tert-butyl Ester 2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6- Formamide 2-[4-(1-aminocyclobutyl)phenyl]-8-ethoxy-3- Imidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-aminocyclobutyl)phenyl]-8-(1H-imidazol-2-yl)-N- Methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-aminocyclobutyl)phenyl]-N-methyl-3-benzene Imidazo[1,2-b]pyridazine-8-formamide 2-[4-(1-aminocyclobutyl)phenyl]-8-(cyclopropylmethoxy)-N- 3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-aminocyclobutyl)phenyl]-N-methyl-3-phenyl 8-(1-H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-aminocyclobutyl)phenyl]-N- Ethyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-( 1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxylic acid 2-[4-(1-aminocyclobutyl)phenyl]-N-methyl-3-benzene Imidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-aminocyclobutyl)phenyl]-N,N-dimethyl-3-phenylimidazolium [1,2-b]pyridazine-6-carboxamide 2-[4-(1-aminocyclobutyl)phenyl]-N-(2-hydroxyethyl)-3-phenylimidazo[ 1,2-b]pyridazine-6-formamide 2-[4-(1-aminocyclobutyl)phenyl]-N-(2-hydroxyethyl)-3-phenyl-8-( 1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxamide 3-{2-[4-(1-amino ring) Butyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-8-yl}propionic acid methyl ester 1-{4-[6-methoxy-3-phenyl-8- (1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1-{4-[6-methoxy-8-(1-A -1H-pyrazol-5-yl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1-{4-[6-methoxy- 3-phenyl-8-(pyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1-[4-(6,8-diethoxy 3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 1-[4-(8-butoxy-6-ethoxy-3-phenylimidazole And [1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine 1-[4-(6-ethoxy-3-phenylimidazo[1,2-b]pyridazine-2 -yl)phenyl]cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-ol (2- Methyl [4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-yl}oxy)acetate 8-[4-(1- Aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6- a pyridin-3(2H)-one, or a salt of the compound, especially a pharmaceutically acceptable salt, tautomer or stereoisomer, or a tautomer or a salt of the stereoisomer, especially A pharmaceutically acceptable salt.

In some embodiments, Compound A is selected from Group C consisting of: 1-[4-(6-methyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine 1-[4-(6-ethyl-3- Phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine 1-{4-[3-phenyl-6-(trifluoromethyl)imidazo[1,2- b] pyridazin-2-yl]phenyl}cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6 -ethyl formate 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 1-[4-(6 -methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 1-[4-(6-bromo-8-methyloxy-3 -Phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[ 1,2-b]pyridazine-6-carboxylic acid 1-[4-(6,8-dimethyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl Cyclobutanamine 2-[4-(1-aminocyclobutyl)phenyl]-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 1 -[4-(8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4-(1-aminocyclobutyl) Phenyl]-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid methyl ester 1-[4-(6-ethyl-8-methoxy-3) -Phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine 1-{4-[6 -methoxy-3-phenyl-8-(pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine 1-{4-[6-A Oxy-3-phenyl-8-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine hydrochloride 1-[4- (6,8-Diethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 1-[4-(6-chloro-3-phenylimidazole And [1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine 1-[4-(8-methoxy-3-phenyl-6-vinylimidazo[1,2-b Pyridazin-2-yl)phenyl]cyclobutylamine 1-{4-[6-Chloro-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1 -{4-[3-Phenyl-8-(1H-pyrazol-3-yl)-6-vinylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1 -{4-[6-ethyl-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 2 -[4-(1-Aminocyclobutyl)phenyl]-8-ethoxy-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 1 -{4-[6-Chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl} Cyclobutanamine 1-{4-[6-chloro-8-(1H-imidazol-2-yl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutane Amine 1-[4-(3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl] 8-methoxy-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 1-{4-[3-phenyl-8-(1H-pyridyl) Zyrid-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl]-8-(2 -methoxyethoxy)-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 1-{4-[8-(benzyloxy)-6-chloro-3 -Phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1-[4-(6-chloro-8-ethoxy-3-phenylimidazo[1, 2-b] Pyridazin-2-yl)phenyl]cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-8-carboxylic acid Methyl 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-8-ol 1-{4-[6-(4- Fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl]-3 -Phenylimidazo[1,2-b]pyridazine-6,8-dimethylhydrazine Amine 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-amine 1-{4-[6-(methylsulfide 3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine N-{2-[4-(1-aminocyclobutyl)phenyl]- 3-phenylimidazo[1,2-b]pyridazin-6-yl}acetamide N-{2-[4-(1-1-{4-[6-(methylsulfonyl)-3) -Phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[ 1,2-b]pyridazine-6-carboxylic acid methyl ester N-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine -6-yl}-2,2,2-trifluoroacetamide 1-[4-(6-bromo-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl] Cyclobutanamine 1-{4-[6,8-bis(4-fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1- {2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-yl}ethanone 1-{4-[8-( 4-fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine N-{2-[4-(1-aminocyclobutyl) Phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-yl}methanesulfonamide 1-[4-(6-chloro-8-cyclopropyl-3-phenylimidazolium [1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 1-[4-(3-phenyl-8-propylimidazo[1,2-b]pyridazin-2-yl )benzene Cyclobutanamine 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-8-amine N-{2-[4- (1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-8-yl}acetamidine 1-[4-(6-chloro-7,8- Dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl]-7, 8-dimethyl-3-phenylimidazo[1,2-b]pyridazine- 6-methyl formate 2-[4-(1-aminocyclobutyl)phenyl]-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazine-6-A Indole 1-[4-(6-methoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 1- {4-[7,8-Dimethyl-6-(methylthio)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine 1-[ 4-(6-ethoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4-(1 -aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxylic acid methyl ester 2-[4- (1-Aminocyclobutyl)phenyl]-8-ethoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid methyl ester 2-[4-(1-amino group Cyclobutyl)phenyl]-8-(1H-imidazol-2-yl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid methyl ester {1-[4-(8- Ethylamino-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamic acid tert-butyl ester 2-[4-(1-amino ring) Butyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-amine Cyclobutyl)phenyl]-8-ethoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-aminocyclobutyl) Phenyl]-8-(1H-imidazol-2-yl)-N-methyl-3-phenylimidazole And [1,2-b]pyridazine-6-formamide 2-[4-(1-aminocyclobutyl)phenyl]-N-methyl-3-phenylimidazo[1,2- b] pyridazine-8-formamide 2-[4-(1-aminocyclobutyl)phenyl]-8-(cyclopropylmethoxy)-N-methyl-3-phenylimidazole And [1,2-b]pyridazine-6-formamide 2-[4-(1-aminocyclobutyl)phenyl]-N-methyl-3-phenyl-8-(1H-pyridyl Zyrid-3-yl)imidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-aminocyclobutyl)phenyl]-N-ethyl-3-phenyl Imidazo[1,2-b]pyridazine-6-formamide 2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazole-3- Imidazo[1,2-b]pyridazine-6-carboxylic acid 2-[4-(1-aminocyclobutyl)phenyl]-N-methyl-3-phenylimidazo[1,2 -b]pyridazine-6-formamide 2-[4-(1-aminocyclobutyl)phenyl]-N,N-dimethyl-3-phenylimidazo[1,2-b] Pyridazine-6-formamide 2-[4-(1-aminocyclobutyl)phenyl]-N-(2-hydroxyethyl)-3-phenylimidazo[1,2-b]indole Pyrazine-6-carbamimidamine 2-[4-(1-aminocyclobutyl)phenyl]-N-(2-hydroxyethyl)-3-phenyl-8-(1H-pyrazole-3- Imidazo[1,2-b]pyridazine-6-carboxamide 3-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2 -b]pyridazine-8-yl}methyl propionate 1-{4-[6-methoxy-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2- b] pyridazin-2-yl]phenyl}cyclobutylamine 1-{4-[6-methoxy-8-(1-methyl-1H-pyrazol-5-yl)-3-phenylimidazole And [1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1-{4-[6-methoxy-3-phenyl-8-(pyridin-4-yl)imidazole And [1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1-[4-(6,8-diethoxy-3-phenylimidazo[1,2-b]indole Pyrazin-2-yl)phenyl]cyclobutanamine 1-[4-(8-butoxy-6-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl) Phenyl]cyclobutylamine 1-[4-(6-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4-(1-aminocyclobutane) Phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-ol ({2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazole) And [1,2-b]pyridazin-6-yl}oxy)acetic acid methyl ester, or a salt of the compound, especially a pharmaceutically acceptable salt, tautomer or stereoisomer, or the mutual An isomer or a salt of such a stereoisomer, especially a pharmaceutically acceptable salt.

In other embodiments, the compound for inhibiting AKT kinase as component A in the combination of the invention is selected from the group consisting of: 2-[4-(1-aminocyclobutyl)phenyl] 3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 1-[4-(6-methyloxy-3-phenylimidazo[1,2-b]pyridazine 2-yl)phenyl]cyclobutylamine 1-[4-(6-bromo-8-methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl Cyclobutanamine 1-[4-(6,8-dimethyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4 -(1-aminocyclobutyl)phenyl]-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 1-{4-[6-A Oxy-3-phenyl-8-(pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1-{4-[6-methoxy 3-phenyl-8-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine hydrochloride 1-{4-[6 -Chloro-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 2-[4-(1- Aminocyclobutyl)phenyl]-8-ethoxy-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1- Aminocyclobutyl)phenyl]-8-methoxy-N-methyl-3-phenylimidazo[1,2-b] Pyridazine-6-formamide 2-[4-(1-aminocyclobutyl)phenyl]-8-(2-methoxyethoxy)-3-phenylimidazo[1,2- b] pyridazine-6-formamide 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6,8-dimethyl Indole 1-[4-(6-methoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2- Methyl [4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxylate 2-[4-(1-Aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-A Indole 2-[4-(1-aminocyclobutyl)phenyl]-8-ethoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 2-[ 4-(1-Aminocyclobutyl)phenyl]-8-(cyclopropylmethoxy)-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-A Indole 2-[4-(1-aminocyclobutyl)phenyl]-N-methyl-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b Pyridazine-6-formamide 1-{4-[6-methoxy-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine- 2-yl]phenyl}cyclobutylamine 1-[4-(6,8-diethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutane An amine, or a salt of the compound, especially a pharmaceutically acceptable salt, mutual An isomer or a stereoisomer, or a tautomer or a salt of the stereoisomer, especially a pharmaceutically acceptable salt.

In other embodiments, the compound for inhibiting AKT kinase in a combination of the invention is selected from the group consisting of: 2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 1-[4-(6-bromo-8 -methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl]- 8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-aminocyclobutyl)phenyl]-8-ethoxy -N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide N-{2-[4-(1-aminocyclobutyl)phenyl]-3- Phenylimidazo[1,2-b]pyridazin-8-yl}acetamide 2-[4-(1-aminocyclobutyl)phenyl]-7,8-dimethyl-3-benzene Imidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazole-3 -yl)imidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-aminocyclobutyl)phenyl]-8-ethoxy-3-phenylimidazolium [1,2-b]pyridazine-6-carbamide 2-[4-(1-aminocyclobutyl)phenyl]-8-(cyclopropylmethoxy)-N-methyl-3 -Phenylimidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-aminocyclobutyl)phenyl]-N-methyl-3-phenylimidazo[ 1,2-b]pyridazine-6-formamide or a salt of the compound, especially a pharmaceutically acceptable salt, tautomer or stereoisomer, or the tautomer or the Isomer salts, in particular pharmaceutically acceptable salts.

In other embodiments, the compound for inhibiting AKT kinase in a combination of the invention is selected from the group consisting of: 2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl Imidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-aminocyclobutyl)phenyl]-8-methoxy-3-phenylimidazo[1, 2-b]pyridazine-6- Formamide 2-[4-(1-aminocyclobutyl)phenyl]-8-ethoxy-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6- Formamide 2-[4-(1-aminocyclobutyl)phenyl]-8-(2-methoxyethoxy)-3-phenylimidazo[1,2-b]pyridazine- 6-Protonamine 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6,8-dimethylguanamine N-{ 2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-8-yl}acetamide 2-[4-(1-amine Cyclobutyl)phenyl]-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-aminocyclobutane) Phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-amino) Cyclobutyl)phenyl]-8-ethoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-aminocyclobutyl)benzene -8-(1H-imidazol-2-yl)-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-amine Cyclobutyl)phenyl]-N-methyl-3-phenylimidazo[1,2-b]pyridazine-8-carboxamide 2-[4-(1-aminocyclobutyl)benzene -8-(cyclopropylmethoxy)-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-amino) Cyclobutyl)phenyl]-N-methyl-3-phenyl-8-(1H-pyrazol-3-yl)imidazole [1,2-b]pyridazine-6-formamide 2-[4-(1-aminocyclobutyl)phenyl]-N-(2-hydroxyethyl)-3-phenylimidazo[ 1,2-b]pyridazine-6-formamide or a salt of the compound, especially a pharmaceutically acceptable salt, tautomer or stand Isomer, or the tautomer or a salt of the stereoisomer, especially a pharmaceutically acceptable salt.

In other embodiments, Compound A for use in inhibiting AKT kinase in a combination of the invention is 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2- b]-pyridazine-6-formamide, or a salt of the compound, especially a pharmaceutically acceptable salt, tautomer or stereoisomer, or the tautomer or the stereoisomer Salt, especially a pharmaceutically acceptable salt.

The prior art and the AKT inhibitors mentioned in the list have been disclosed for the treatment or prevention of different diseases, especially cancer.

The specific compound of the list as disclosed above is preferably a combination of Compound A, preferably the compound used in the experimental part.

One of the AKT inhibitors specifically disclosed in the Examples section of Example 5 of WO 2012/136776 (hereinafter referred to as Compound A1) is used herein to demonstrate the synergistic behavior of the combinations of the invention.

Further, the combination of the invention comprising the pharmaceutically acceptable salts of the compound A1 and radium-223 as mentioned above is a special aspect of the invention.

In another aspect, the combination of the invention comprises a compound A1, or a pharmaceutically acceptable salt thereof, as mentioned above, and a pharmaceutically acceptable salt of an alkaline earth radioactive seed radium-223.

In another aspect, the combination of the invention comprises a compound A1, or a pharmaceutically acceptable salt thereof, and a di-chloride salt of radium-223, as mentioned above.

It will be appreciated that the invention also relates to any combination of the above embodiments of Compound A.

Combined component B

Component B is a suitable pharmaceutically acceptable salt of the alkaline earth radioactive seed radium-223.

Suitable pharmaceutically acceptable salts of radium-223 may be, for example, acid addition salts with the following acids: inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, disulfuric acid, phosphoric acid Or nitric acid; or an organic acid such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzimidyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectin Ester acid, persulfate, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, aminesulfonic acid, trifluoromethanesulfonic acid, dodecyl sulfate, ethane Sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalene disulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, dibutyl Acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerol phosphate, aspartic acid, sulfohydrate Salicylic acid, hemisulfate or thiocyanate.

A preferred suitable pharmaceutically acceptable salt of radium-223 is dichloride (Ra ²²³ Cl ₂ ).

Methods for the preparation of physiologically acceptable solutions comprising radium-223 are disclosed, for example, in WO 2000/40275 (A2), WO 2011/134671 (A1) and WO 2011 (134672 (A1).

A physiologically acceptable solution comprising radium-223 is shown as a unique mechanism of action for targeting radiopharmaceuticals. It represents a new generation of alpha-emitting therapeutic drugs based on the natural osteogenic nuclear species radium-223.

It is preferred to use an aqueous solution of radium chloride-223 ( ²²³ RaCl ₂ ) for intravenous injection of sterile and bacterial endotoxin.

Preferably, the solution is isotonic and contains sodium citrate buffered physiological saline to achieve a physiological pH.

A preferred dosing regimen of radium chloride-223 injection is to give 50 kBq per kilogram of body weight at 4 week intervals and one course of 6 injections. A single dose of Radium-223 of up to 250 kBq per kilogram of body weight was assessed in Phase I clinical trials. The adverse reactions observed at this dose were diarrhea and reversible myelosuppression (including one (1/5) grade 3 neutropenia).

For example, an aqueous solution of radium dichloride-223 can be supplied to a single volume containing 6 ml of filling volume. The second dose is in a 10 ml vial. This product has a radioactivity concentration of radium-223 of 1,000 kBq/mL (0.03 mCi/mL), corresponding to radium at 0.53 ng/mL on the reference date. The active moiety is an alpha particle-emitting nuclear species radium 223 (having a half-life of 11.4 days) in the form of a second-order cation (223Ra2+). The fraction of energy emitted by radium-223 and its daughter nuclei in the form of alpha particles was 95.3%, the fraction of emission in the form of beta particles was 3.6%, and the fraction of emission in the form of gamma radiation was 1.1%. The combined energy from the complete decay of the emitted radiation from radium-223 and its daughter core is 28.2 MeV.

Radium-223 is to be administered intravenously by qualified personnel in the form of a slow bolus injection. The intravenous access line is used for the application of radium-223. This line must be rinsed with isotonic saline before and after radium-223 injection.

Radium-223 selectively targets areas of increased bone turnover, such as in bone metastases, and is concentrated by forming a complex with hydroxyapatite. The alpha emission provides about 93% of the total radiation absorbed dose. High linear energy alpha particle radiation induces double strand DNA breaks, producing potent and localized cytotoxic effects in target regions containing metastatic cancer cells. The short path length of the alpha particles (less than 100 microns) minimizes the effects on adjacent healthy tissue, such as bone marrow.

According to an embodiment, the invention relates to any combination of component A referred to herein and any component B mentioned herein, optionally with any of the components C mentioned herein.

In one embodiment, the combined compound A is the compound used in the experimental part and the compound B is radium chloride-223 (Ra ²²³ Cl ₂ ) as used in the experimental part.

In a particular embodiment, the invention relates to the combination of component A and component B, as appropriate, and component C, as mentioned in the Examples section herein.

Further, the present invention relates to a kit comprising: - a combination of: Component A: one or more AKT kinase inhibitors or physiologically acceptable salts, solvates, hydrates or stereoisomers thereof ; Component B: a suitable pharmaceutically acceptable salt of the alkaline earth radioactive seed radium-223 or a solvate or hydrate thereof; and optionally a component C: one or more other pharmaceutical agents; In any of the combinations, either or both of the components A and B are optionally prepared for simultaneous, co-administrative, separate or sequential administration of the pharmaceutical formulation.

The term "component C" as at least one pharmaceutical agent includes the active compound itself as well as a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, and the active compound or pharmaceutically acceptable thereof. Any combination or pharmaceutical formulation of a salt, solvate, hydrate or stereoisomer. A list of such readily available medications is provided further below.

The components can be administered independently of one another by the oral, intravenous, topical, topical, intraperitoneal or nasal route.

Component A is administered intravenously or intraperitoneally, preferably by oral administration.

Component B is preferably administered by the intravenous route.

Component C is administered as the case may be.

The term "pharmaceutically acceptable" is used synonymously with the term "physiologically acceptable".

The term "pharmaceutically or physiologically acceptable salt" of component A refers to a relatively non-toxic inorganic or organic acid addition salt of a compound of the invention. See, for example, SM Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19. The pharmaceutically acceptable salts include those obtained by reacting a main compound serving as a base with a mineral acid or an organic acid to form a salt, such as a hydrochloride, a sulfate, a phosphate, a methanesulfonate or a camphor Acid salts, oxalates, maleates, succinates and citrates. The pharmaceutically acceptable salts also include the salts of the main compounds which act as acids and which are formed by reaction with a suitable base, such as the sodium, potassium, calcium, magnesium, ammonium and chloride salts. Those skilled in the art will further appreciate that acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable mineral or organic acid by any of a variety of known methods. Alternatively, the alkali metal and alkaline earth metal salts of the acidic compounds of the present invention can be prepared by reacting a compound of the present invention with a suitable base by various known methods.

Representative salts of Compound A of the present invention include the conventional non-toxic salts and quaternary ammonium salts formed by, for example, inorganic or organic acids or bases by methods well known in the art. For example, such acid addition salts include acetates, adipates, alginate, ascorbate, aspartate, benzoate, besylate, hydrogen sulfate, butyrate, Citrate, camphorate, camphor sulfonate, cinnamate, cyclopentane propionate, digluconate, lauryl sulfate, ethane sulfonate, fumarate, Glucose heptanoate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate, itaconate, Lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinic acid salt, nitrate, oxalate, pamoate, pectate ester, Persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, sulfate, tartrate, thiocyanate, tosylate and Undecanoate.

The basic salt includes an alkali metal salt such as a potassium salt and a sodium salt, an alkaline earth metal salt such as a calcium salt and a magnesium salt, and an ammonium salt formed with an organic base such as dicyclohexylamine and N-methyl-D-glucosamine. salt. Alternatively, the basic nitrogen-containing group can be quaternized by a reagent such as a lower alkyl halide such as methyl, ethyl, propyl or butyl chloride, bromide and iodide; dioxane sulfate Esters such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate or diamyl sulfate; long chain halides such as decyl, lauryl, myristyl and octadecyl chloride, bromide and Iodide; aralkyl halides such as benzyl and phenethyl bromide and other aralkyl halides.

Solvates for the purposes of the present invention are solid complexes of solvents with the compounds of the invention. Exemplary solvates will include, but are not limited to, the compounds of the invention and ethanol or methanol Complex. Hydrates are a particular form of the solvent in which the solvent is water.

The components of the present invention can be formulated into a tablet with a combination of a conventional tablet base such as lactose, sucrose, and corn starch, with a binder such as acacia, corn starch or gelatin; A disintegrant which decomposes and dissolves after administration, such as potato starch, alginic acid, corn starch, guar gum, tragacanth, gum arabic; intends to improve the flowability of the tablet particles and prevent A lubricant that adheres to the tablet mold and the surface of the punch, such as talc, stearic acid or magnesium stearate, calcium stearate or zinc stearate; intended to enhance the aesthetic quality of the tablet and make it more A dye, colorant, and flavoring agent such as peppermint, wintergreen, or cherry flavoring that is acceptable to the patient. Excipients suitable for oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols such as ethanol, benzyl alcohol and polyvinyl alcohol with or without the addition of pharmaceutically acceptable surfactants, suspending agents or Emulsifier. Various other materials may be present in the form of a coating or otherwise alter the physical form of the dosage unit. For example, a lozenge, pill or capsule may be coated with shellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of aqueous suspensions. It provides a mixture of the active ingredient with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by the reagents mentioned above. Other excipients, such as the above-described sweeteners, flavoring agents, and coloring agents, may also be present.

The components of the invention may also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil (such as liquid paraffin) or a mixture of vegetable oils. Suitable emulsifiers can be (1) naturally occurring gums such as acacia and tragacanth; (2) naturally occurring phospholipids such as soy and lecithin; (3) esters derived from fatty acids and hexitol anhydrides or Partial esters, such as sorbitan monooleate; (4) condensation products of such partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The lotion may also contain sweeteners and flavoring agents.

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

Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. These formulations may also contain a demulcent and preservative (such as methylparaben and propylparaben) as well as flavoring and coloring agents.

The components of the present invention may also be preferably injectable in a parenteral form (i.e., subcutaneous, intravenous, intraocular, intrasynovial, intramuscular) of a physiologically acceptable diluent and a compound of the pharmaceutical carrier. Or intraperitoneally, the pharmaceutical carrier may be added with or without the addition of a pharmaceutically acceptable surfactant (such as a soap or detergent), a suspending agent (such as a gum, a carbomer, a methyl group). a sterile liquid or liquid mixture of cellulose, hydroxypropylmethylcellulose or carboxymethylcellulose) or an emulsifier and other pharmaceutical adjuvants such as water, physiological saline, aqueous dextrose and related sugar solutions; An alcohol such as ethanol, isopropanol or cetyl alcohol; a diol such as propylene glycol or polyethylene glycol; a glycerol ketal such as 2,2-dimethyl-1,1-dioxolane-4 - methanol; ethers such as poly(ethylene glycol) 400; oils, fatty acids, fatty acid esters, or fatty acid glycerides, or acetylated fatty acid glycerides.

The oils useful in the parenteral formulations of the present invention are illustrated by petroleum, animal, vegetable or synthetic oils such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, paraffin oil and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include alkali metal, ammonium and triethanolamine salts of fatty acids and suitable detergents include cationic detergents such as dimethyldialkylammonium halides, alkylpyridyl halides and alkylamine acetates; anionic Detergents such as alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates, and sulfosuccinates; nonionic detergents such as fatty amine oxides, fatty acids Alkanolamine and poly(oxyethylene-oxypropylene) or oxidation An ethylene or propylene oxide copolymer; and an amphoteric detergent such as an alkyl-β-aminopropionate and a 2-alkylimidazolinium quaternary ammonium salt; and a mixture.

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

The description of the surfactant used in the parenteral formulation is a class of polyethylene sorbitan fatty acid esters (such as sorbitan monooleate) and the hydrophobicity of ethylene oxide and condensation with propylene oxide and propylene glycol. High molecular weight adducts of the matrix.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous suspension. These suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate , polyvinylpyrrolidone, tragacanth and gum arabic; dispersing or wetting agents may be naturally occurring phospholipids, such as lecithin; condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate; ethylene oxide and a condensation product of a long chain aliphatic alcohol, such as heptahexylethylhexadecanol; a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyoxyethylene sorbitan monooleate; Or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, such as polyoxyethylene sorbitan monooleate.

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

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

Another formulation used in the methods of the invention uses a transdermal delivery device ("patch"). These transdermal patches can be used to continuously or discontinuously infuse a controlled amount of a compound of the invention. The construction and use of a transdermal patch for the delivery of a medicinal agent is well known in the art (see, for example, U.S. Patent No. 5,023,252, issued toJ.S. The patches can be configured for continuous, pulsed or on-demand delivery of a pharmaceutical agent.

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

It may be necessary or necessary to introduce a component of the invention into a patient via a mechanical delivery device. The construction and use of mechanical delivery devices for delivering pharmaceutical agents are well known in the art. Direct techniques for, for example, direct administration of drugs to the brain generally involve placing a drug delivery catheter into the ventricular system of a patient to bypass the blood-brain barrier. An implantable delivery system for delivering a medicament to a particular anatomical region of the body is described in U.S. Patent No. 5,011,472, issued Apr. 30, 1991.

The compositions of the present invention may also contain other conventional pharmaceutically acceptable compounding ingredients, often referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions into suitable dosage forms can be used. Such components and procedures include the components and procedures described in the following documents, each of which is incorporated herein by reference: Powell, MF et al., "Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311; Strickley, RG "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1" PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. et al., "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical Science & Technology 1997, 51(4), 166-171.

Common pharmaceutical ingredients that may be used to formulate compositions for the intended route of administration, as appropriate, include: acidulants (examples include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalizing agents (examples) Including, but not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine/trolamine; adsorbents (examples include (but are not limited to) Powdered cellulose and activated carbon); aerosol propellants (examples include, but are not limited to, carbon dioxide, CCl ₂ F ₂ , F ₂ ClC-CClF ₂ and CClF ₃ ); venting agents (examples include (but are not limited to) Nitrogen and argon; antifungal preservatives (examples include, but are not limited to, benzoic acid, butyl paraben, ethyl p-hydroxybenzoate, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzene Sodium formate); antibacterial preservatives (examples include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol , phenylmercuric nitrate and thimerosal (thimerosal); antioxidant Agents (examples include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxymethoxybenzene, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate , sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); bonding materials (examples include (but not limited to) block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, polyfluorenes Oxygen, polyoxyalkylene and styrene-butadiene copolymers; buffers (examples include, but are not limited to, potassium metaphosphate, dipotassium hydrogen phosphate, sodium acetate, anhydrous sodium citrate, and sodium citrate dihydrate) Carrier (examples include (but not limited to) gum arabic syrup, aromatic syrup, aromatic elixirs, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection And bacteriostatic water for injection); chelating agents (examples include (but not limited to) disodium edetate and ethylenediaminetetraacetic acid); colorants (examples include (but are not limited to) FD&C Red No. 3, FD&C Red 20 No., FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D & C Orange No.. 5, D & C Red No. 8, caramel and ferric oxide red); clarifying agents (examples include (but are not limited to) bentonite); emulsifying agents (examples include (but are not limited to) acacia, cetomacrogol (Cetomacrogol ), cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate; encapsulating agents (examples include (but not limited to) gelatin and Flavored cellulose acetate; flavoring agents (examples include (but not limited to) anise oil, cinnamon oil, cocoa beans, menthol, orange oil, peppermint oil and vanillin); humectants (examples include (but not Limited to) glycerol, propylene glycol, and sorbitol); research agents (examples include, but are not limited to, mineral oil and glycerin); oils (examples include, but are not limited to) peanut oil, mineral oil, olive oil, peanut oil, sesame oil, and vegetable oil Ointment base (examples include, but are not limited to, lanolin, hydrophilic ointment, polyethylene glycol ointment, paraffin oil, hydrophilic paraffin oil, white ointment, yellow ointment and rose water ointment); penetration enhancer (via) Paper delivery) (examples include (but are not limited to) monohydric or polyhydric alcohols, monovalent alcohols Polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl acyl derivatives, cephalin, terpenes, Amides, ethers, ketones and ureas); plastic Chemical agents (examples include, but are not limited to, diethyl phthalate and glycerin); solvents (examples include, but are not limited to) ethanol, corn oil, cottonseed oil, glycerin, isopropanol, mineral oil, oleic acid, Peanut oil, purified water, water for injection, sterile water for injection and water for aseptic perfusion); hardener (examples include (but not limited to) cetyl alcohol, cetyl alcohol wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and Yellow wax); suppository base (examples include, but are not limited to, cocoa butter and polyethylene glycol (mixture)); surfactants (examples include, but are not limited to, benzalkonium chloride, nonoxynol ether 10, xin benzene polyol 9, polysorbate 80, sodium lauryl sulfate and sorbitan monopalmitate); suspending agents (examples include (but are not limited to) agar, bentonite, carbomer, carboxymethyl cellulose Sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, a Cellulose, gum tragacanth and Wei Gemu (of Veegum)); sweetening agents (examples include (but are not limited to) aspartame (Aspartame), dextrose, glycerol, mannitol, propylene glycol, sodium saccharin, Sorbitol and sucrose); tablet anti-adhesives (examples include (but not limited to) magnesium stearate and talc); tablet adhesives (examples include (but are not limited to) gum arabic, alginic acid, carboxymethyl fiber Sodium, compressible sugar, ethyl cellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone and pregelatinized starch); tablets and capsule diluents (examples include (but not Limited to) calcium hydrogen phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (examples include But not limited to) liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate phthalate and shellac; ingots ; agents direct compression excipients (examples include (but are not limited to) calcium hydrogen phosphate); lozenges disintegrants (examples Including (but not limited to) alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, potassium poured Lake Lin (polacrillin potassium), crosslinked polyvinylpyrrolidone, sodium alginate, sodium starch glycolate and starch); Lozenge slips (examples include, but are not limited to, colloidal cerium oxide, corn starch, and talc); lozenge lubricants (examples include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, hard fatty acid and zinc stearate); tablets / capsules opacifying agents (examples include (but are not limited to) titanium dioxide); lozenges polishing agents (examples include (but are not limited to) carnauba waxes (carnuba wax) and white wax); growth Thickeners (examples include, but are not limited to, beeswax, cetyl alcohol, and paraffin); tonicity agents (examples include, but are not limited to, dextrose and sodium chloride); tackifiers (examples include (but are not limited to) alginic acid, bentonite, carbomer, sodium carboxymethylcellulose, methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth); and wetting agents (examples include (but are not limited to) extending seventeen Ethyloxyhexadecanol, lecithin, sorbitol monooleate, polyoxyethylene sorbitan monooleate and polyoxyethylene hard Fatty acid ester).

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

Sterile Intravenous Solution : A 5 mg/mL solution of the desired compound of the invention can be prepared using sterile injectable water and adjusted if necessary. This solution was diluted to 1-2 mg/mL with sterile 5% dextrose for administration and administered by intravenous infusion over about 60 minutes.

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

Intramuscular suspension : The following solutions or suspensions can be prepared for intramuscular injection: 50 mg/mL of the desired water-insoluble compound of the invention 5 mg/mL sodium carboxymethylcellulose 4 mg/mL TWEEN 80 9 mg/mL sodium chloride 9 mg/ mL benzyl alcohol

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

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

Tablets : A large number of tablets are prepared by conventional procedures such that the dosage unit is 100 mg active ingredient, 0.2 mg colloidal cerium oxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch, and 98.8 mg lactose. Appropriate aqueous and non-aqueous coatings can be applied to increase palatability, improve aesthetics and stability, or delay absorption.

Immediate release of lozenges/capsules: These dosage forms are solid oral dosage forms prepared by conventional and novel methods. These unit dosage forms can be administered orally in the absence of water for immediate dissolution and delivery of the drug. The active ingredient is incorporated into a liquid containing ingredients such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The pharmaceutical compound can be compressed with a viscoelastic and thermoelastic sugar and a polymeric or sudsing component to produce a porous matrix to be used for immediate release without the need for water.

Commercial utility Component A

According to the combination as mentioned above, the compounds of the formulae (IIa) and (IIb) and stereoisomers thereof are compounds or component A. The compounds according to this combination have valuable pharmaceutical properties making them commercially viable. In particular, it inhibits the PI3K/AKT pathway and exhibits cellular activity. It is expected to be commercially applicable to disease therapies (eg, diseases that rely on over-activated PI3K/AKT). Abnormal activation of the PI3K/AKT pathway is an essential step towards the initiation and maintenance of human tumors and thus its inhibition (eg, using AKT inhibitors) should be understood as an effective pathway for human tumor therapy. For a recent review, see Garcia-Echeverria et al. (Oncogene, 2008, 27, 551-5526).

Component B

Due to the mechanism discussed in the preamble, component B is particularly suitable for acting on neoplastic diseases, particularly those that develop bone metastases.

combination

The combination of the invention is thus useful for the treatment or prophylaxis of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses or inappropriate cellular inflammatory responses, or with uncontrolled cell growth and proliferation And/or diseases of survival, inappropriate cellular immune response or inappropriate cellular inflammatory response, particularly where uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response such as hematological tumors, solid tumors and/or Or metastasis, such as leukemia and myelodysplastic syndromes, malignant lymphoma, head and neck tumors (including brain tumors and brain metastases), chest tumors (including non-small cell and small cell lung tumors), gastrointestinal tumors, endocrine tumors, breasts and Other women Tumors, urological tumors (including kidney, bladder and prostate tumors), skin tumors and sarcomas and/or their metastases.

One embodiment relates to the use of a combination according to any one of claims 1 to 7 for the preparation of a medicament for the treatment or prevention of cancer, in particular breast cancer, prostate cancer, hepatocellular carcinoma, lung cancer (especially non-small cell lung cancer), Colorectal cancer, melanoma, pancreatic cancer, and/or its metastatic agents.

In one embodiment, the invention relates to a combination comprising a compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt of the compound B alkaline earth metal radioactive seed radium-223 for use in the treatment of cancer indications In particular, the type of cancer that forms bone metastases is known.

Such cancer types are, for example, breast cancer, prostate cancer, lung cancer, kidney cancer or thyroid cancer.

Another embodiment relates to the use of a combination of the invention for the preparation of a medicament for the treatment or prevention of breast cancer or prostate cancer and/or its metastasis, in particular wherein the metastasis is bone metastasis.

In one embodiment, the invention relates to a method of treating or preventing cancer in a subject, in particular hepatocellular carcinoma, lung cancer, in particular non-small cell lung cancer, colorectal cancer, melanoma, pancreatic cancer or breast cancer, comprising The individual is administered a therapeutically effective amount as in any one of claims 1 to 7.

In another embodiment, the present invention relates to a method of treating or preventing cancer in a subject (especially hepatocellular carcinoma, lung cancer, especially non-small cell lung cancer, colorectal cancer, melanoma, pancreatic cancer, prostate cancer or breast cancer), It comprises administering to the individual a therapeutically effective amount of a combination according to any one of claims 1 to 7.

In another embodiment, the invention relates to a method of treating or preventing cancer in a subject (especially hepatocellular carcinoma, lung cancer (especially non-small cell lung cancer), colorectal cancer, melanoma, pancreatic cancer, prostate cancer or breast cancer and/or a method thereof, comprising administering to the individual An effective amount is a combination of any one of claims 1 to 7.

A preferred use of the combination of the invention is in the treatment of breast and prostate cancer (especially castration-refractory prostate cancer (CRPC)) and bone metastasis.

A preferred embodiment is the use of a combination of the invention for the treatment of prostate cancer, particularly castration-refractory prostate cancer (CRPC) and bone metastases.

A preferred embodiment is the use of the combination of the invention for the treatment of breast cancer and bone metastases.

As used herein, the term "inappropriate" in the context of the present invention, particularly in the context of "inappropriate cellular immune response or inappropriate cellular inflammatory response", is understood to mean preferably that the response is below normal or above normal, and These diseases are pathologically related, causing or causing pathology of such diseases.

Combinations of the invention can be used to inhibit, block, reduce, reduce, etc. cell proliferation and/or cell division and/or to produce apoptosis.

The invention includes a method comprising administering to a mammal, including a human, in need thereof, an amount of a compound A of the invention effective to treat a condition, and a compound B of the invention effective to treat the condition, or a pharmaceutically acceptable compound thereof Salts, isomers, polymorphs, metabolites, hydrates, solvates or esters, and the like.

Hyperproliferative disorders include, but are not limited to, psoriasis, keloids, and other hyperplasias that affect the skin, benign prostatic hyperplasia (BPH), and malignant neoplasia. Examples of malignant neoplasia treatable with the compounds of the invention include solid tumors and hematological tumors. Solid tumors can be through the breast, bladder, bone, brain, central and peripheral nervous system, colon, anus, endocrine glands (such as thyroid and adrenal cortex), esophagus, endometrium, germ cells, head and neck, kidney, liver, lung Tumors of the larynx and hypopharyngeal, mesothelioma, ovary, pancreas, prostate, rectum, kidney, small intestine, soft tissue, testicular, stomach, skin, ureter, vagina and vulva. Malignant neoplasia includes genetic cancer, exemplified by retinoblastoma and Wilms tumor. In addition, malignant neoplasia includes the original in these organs A neoplastic tumor and a corresponding secondary tumor in a distal organ ("tumor metastasis"). Hematological tumors can be caused by invasive and inert forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic and acute myeloid leukemia (CML/AML), acute lymphoblastic leukemia (ALL) Hodgkins disease, multiple myeloma, and T-cell lymphoma are exemplified. Also included are myelodysplastic syndromes, plasmacytoma formation, paraneoplastic syndromes, and cancers of unknown primary sites, as well as AIDS-related malignancies.

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

Examples of respiratory cancer include, but are not limited to, small cell lung cancer and non-small cell lung cancer, as well as bronchial adenomas and pleural pulmonary blastomas.

Examples of brain cancer include, but are not limited to, brainstem and hypothalamic gliomas, cerebellum and cerebral astrocytoma, neuroblastoma, ependymoma, and neuroectoderm and pineal tumors.

Male reproductive organ tumors include, but are not limited to, prostate cancer and testicular cancer. Tumors of the female reproductive organs include, but are not limited to, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, and genital cancer, as well as uterine sarcoma.

Gastrointestinal tumors include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer.

Urinary tract tumors include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvic cancer, ureteral cancer, urethral cancer, and human papillary renal cancer.

Eye cancer includes, but is not limited to, intraocular melanoma and retinoblastoma.

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

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

Head and neck cancer includes, but is not limited to, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip and oral cancer, and squamous cell carcinoma. Lymphomas include, but are not limited to, AIDS-associated lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and central Lymphoma of the nervous system.

Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

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

Such conditions have been well characterized in humans and are also present in similar pathogens in other mammals and can be treated by administering the pharmaceutical compositions of the invention.

The term "treating" or "treatment" as used throughout the text is used routinely, for example to manage or care for an individual to achieve resistance, alleviation, reduction, amelioration, amelioration of a disease or condition (such as a cancer). The purpose of the disease.

Combinations of the invention may also be used to treat conditions and diseases associated with excessive and/or abnormal angiogenesis.

Improper angiogenesis and ectopic performance can be harmful to organisms. Many pathological conditions are associated with extra blood vessel growth. Such conditions include, for example, diabetic retinopathy, ischemic retinal - vein occlusion retinopathy of prematurity [Aiello, et al., New Engl.J.Med 1994, 331,1480; Peer et al Lab.Invest 1995, 72,638..] Age-related macular degeneration [AMD; see Lopez et al. Invest. Opththalmol. Vis. Sci. 1996 , 37, 855], neovascular glaucoma, psoriasis, posterior fibrous hyperplasia, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc. In addition, increased blood supply associated with cancerous and neoplastic tissues promotes growth, leading to rapid tumor expansion and metastasis. In addition, the growth of new blood vessels and lymphatic vessels in tumors provides escape pathways to rebel cells, thereby promoting metastasis and the resulting spread of cancer. Thus, a combination of the invention can be used to treat and/or prevent any of the aforementioned angiogenic conditions, for example by inhibiting and/or reducing angiogenesis; by inhibiting proliferation of other types of cells involved in endothelial cell proliferation or angiogenesis, Blocking, reducing, reducing, etc., as well as causing cell death or apoptosis in these cell types.

Dosage and administration Component A

Based on standard laboratory techniques known for assessing compounds useful in the treatment of hyperproliferative disorders and angiogenic disorders, by standard toxicity testing and by standard pharmacology for the treatment of conditions identified above for mammals The analysis, and the comparison of the results of such results with the results of known agents for treating such conditions, can readily determine the effective dosage of a compound of the invention for treating each of the intended indications. The amount of active ingredient administered to treat any of these conditions can vary greatly depending on, for example, the particular compound and dosage unit employed, the mode of administration, the time of treatment, the age and sex of the patient being treated, and Treat the nature and extent of the condition.

The total amount of active ingredient to be administered will generally range from about 0.001 mg to about 200 mg per kilogram of body weight per day and preferably from about 0.01 mg to about 20 mg per kilogram of body weight per day. The clinically applicable administration schedule of the compound ranges from once to three times a day to once every four weeks. In addition, a "drug holiday" in which a patient is not given a drug for a certain period of time may be beneficial to the overall balance between pharmacological effects and tolerance. A unit dose may contain from about 0.5 mg to about 1500 mg of the active ingredient and may be administered one or more times a day or less than once a day. The average daily dose for administration by injection (including intravenous, intramuscular, subcutaneous and parenteral injection) and by infusion techniques is preferably from 0.01 to 200 mg per kg of total body weight. The average daily rectal administration regimen is preferably from 0.01 to 200 mg per kg of total body weight. The average daily vaginal dosage regimen is preferably from 0.01 to 200 mg per kg of total body weight. The average daily topical dosage regimen is preferably from 0.1 to 200 mg and the number of daily administrations is between one and four times. The transdermal concentration is preferably a concentration required to maintain a daily dose of 0.01 to 200 mg/kg. Average daily inhalation The dosage regimen is preferably from 0.01 to 100 mg per kg of total weight.

Component B

The preferred dosing regimen for radium-223 injection is to give 50 kBq per kilogram of body weight at 4 week intervals and one course of 6 injections. A single dose of Radium-223 of up to 250 kBq per kilogram of body weight was assessed in Phase I clinical trials. The adverse reactions observed at this dose were diarrhea and reversible myelosuppression (including one (1/5) grade 3 neutropenia).

For example, an aqueous solution of radium dichloride-223 can be supplied in a single dose 10 ml vial containing 6 ml of fill volume. This product has a radioactivity concentration of radium-223 of 1,000 kBq/mL (0.03 mCi/mL), corresponding to radium at 0.53 ng/mL on the reference date.

Radium-223 is to be administered intravenously by qualified personnel in the form of a slow bolus injection. The intravenous access line is used for the application of radium-223. This line must be rinsed with isotonic saline before and after radium-223 injection.

Of course, the specific initial and continuous dosing regimen for each patient will be based on the nature and severity of the condition as determined by the attending physician, the activity of the particular compound employed, the age and general condition of the patient, the time of administration, the route of administration, and the excretion of the drug. The rate, the drug combination, and the like vary. The desired mode of treatment and the dosage of the compound of the invention or a pharmaceutically acceptable salt or ester or composition thereof can be determined by those skilled in the art using conventional therapeutic tests.

Combination of the invention

The combination of the present invention is particularly useful for the treatment and prevention (i.e., prevention) of tumor growth and metastasis, especially for solid tumors of all indications and stages, especially in the presence or absence of pre-treatment of tumor growth. The type of tumor to the bone.

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

The combination of component A and component B of the present invention may be used as the sole pharmaceutical agent, or in the case where the combination of components A, B and C does not cause unacceptable adverse effects, with one or more A combination of other pharmaceutical agents C is administered. For example, a combination of components A and B of the present invention may be combined with component C (i.e., one or more other pharmaceutical agents) such as known anti-angiogenic agents, anti-hyperproliferative agents. An anti-inflammatory agent, an analgesic, an immunomodulator, a diuretic, an antiarrhythmic agent, an anti-hypercholesterolemia agent, an anti-lipidemia agent, an anti-diabetic agent or an anti-viral agent, and the like, and mixtures and combinations thereof.

Component C can be one or more pharmaceutical agents, such as 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, allen Monoclonal (alemtuzumab), alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole ), arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY 1000394, belonotecan ), bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, Bortezomib, buserelin, busulfan, cabazitaxel, calcium folinate, calcium levofolinate, capecitabine (capecitabine), carboplatin, carmofur, carmustine Ine), catomoximab, celecoxib, celmoleukin, cetuximab, chlorambucil, chlormadinone ), chlormethine, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib, cristantaspase ), cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, Dasatinib, daunorubicin (daunorubicin), decitabine, degarelix, denileukin diftitox, denosumab, deslorelin, dibromospironium chloride Dibrospidium chloride), docetaxel, doxifluridine, cranberry, cranberry + estrone, eculizumab, edrecolomab, Elliptinium acetate, eltrombopag, endostatin, enocitabine, epirubicin, epitistatinol, ibbertine α (epoetin alfa), epoetin beta, eptaplatin, eribulin, erlotinib, estradiol, estramustine ), etoposide, everolimus, exemestane, fadrozole, filgrastim, fludarabine, fluorouracil Fluorouracil), flutamide, formestane, fotemustine, fulvestran t), gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glutoxim, gosere Goserelin, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seed, ibandronic acid, Ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, Interferon alfa, interferon beta, interferon gamma, ipilimumab, irinotecan, ixabepilone, blue Resin (lanreotide), lapatinib, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin , levamisole, lisuride, lobaplatin, lomustine (lomustine), lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan, mepitiostane, 巯嘌呤(mercaptopurine), methotrexate, methoxsalen, methyl aminolevulinate, methyltestosterone, mifamurtide, miltefosine (miltefosine), miribatin, mitobronitol, mitoguazone, mitolacol, mitomycin, mitotan, Mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide, nimotuzumab, nimustine (nimustine), nitracrine, ofatumumab, omeprazole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel (paclitaxel), palifermin, palladium-103, pamidronate (pa Midronic acid), panitumumab, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), polyethylene Pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin , perfosfamide, picibanil, pirarubicin, plerixafor, plicamycin, pigolusam, poly Polyestradiol phosphate, polysaccharide-K, porfimer sodium, pralatrexate, prednimustine, procarbazine, quetiapine (procarbazine) Quinagolide), radium chloride-223, raloxifene, raltitrexed, ranimustine, razoxane, refamatetinib, rego Regorafenib, risedronic acid, rituximab, romidyl ester peptide (romidepsin), romiposttim, sargramostim, sipuleucel-T, sizofiran, sobuzoxane, glycididazole Sodium glycididazole, sorafenib, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen (tamoxifen), tasonermin, teceleukin, tegafur, tegafur + gimeracil + oteracil, temoprofen ( Temoporfin), temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, Thymafasin, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trobe Trabectedin, trastuzumab, treosulfan, tretinoin, trostatin Ilostane), triptorelin, trofosfamide, tryptophan, ubenimex, valrubicin, vandetanib, Vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, volts Vorinostat, vorozole, strontium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, left Zorubicin or a combination thereof.

Alternatively, the component C may be one or more of the following other pharmaceutical agents: gemcitabine, paclitaxel, cisplatin, carboplatin, sodium butyrate, 5-FU, cranberry, tamoxifen, etoposide , trastuzumab, gefitinib, intron A, rapamycin, 17-AAG, U0126, insulin, insulin derivatives, PPAR ligands, sulfonylurea drugs, Alpha-glucosidase inhibitor, biguanide, PTP-1B inhibitor, DPP- IV inhibitor, 11-β-HSD inhibitor, GLP-1, GLP-1 derivative, GIP, GIP derivative, PACAP, PACAP derivative, secretin or secretin derivative.

The optional anti-hyperproliferative agents which may be added as component C to the combination of components A and B of the present invention include, but are not limited to, those listed in the Merck Index 11th Edition (1996) for cancer chemotherapy drug regimens. Compounds, which are incorporated herein by reference, for example, aspartame, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, L-aspartate Aminase, cyclophosphamide, cytarabine, dacarbazine, actinomycin, daunorubicin, cranberry (doxorubicin), epirubicin, etoposide, 5-fluorouracil, hexamethylene melamine , hydroxyurea, ifosfamide, irinotecan, formazan tetrahydrofolate, lomustine, nitrogen mustard, 6-anthracene, mesna, methaqualin, mitomycin C, mitre Sputum, prednisone, prednisone, procarbazine, raloxifene, streptozin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine and vindesine.

Other anti-hyperproliferative agents suitable for use as component C in combination with components A and B of the present invention include, but are not limited to, in Goodman and Gilman's The Pharmacological Basis of Therapeutics (ninth edition), edited by Molinoff et al. Their compounds for the treatment of neoplastic diseases are identified in the publication of McGraw-Hill, pp. 1225-1287 (1996), which is incorporated herein by reference, such as the amine Aspartate, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel , erythrohydroxynonyl adenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoromethylol Testosterone (fluoxymesterone), flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, Mitotant, Pacific Yew (At this time, component B itself is not paclitaxel), pentastatin, N-phosphonium-L-aspartate (PALA), pucamycin, semustine, Nipaside, testosterone propionate, thiotepa, trimethyl melamine, uridine and vinorelbine.

Other anti-hyperproliferative agents suitable for use as component C in combination with components A and B of the present invention include, but are not limited to, other anticancer agents, such as epothilone and its derivatives, irinotene Kang, raloxifene and topotecan.

In general, the combination of a cytotoxic agent and/or a cytostatic agent as component C with a combination of components A and B of the present invention will be used to: (1) be reduced in comparison to administration of either agent alone Producing better efficacy or even eliminating tumors and/or metastasis in tumor growth and/or metastasis, (2) administering a smaller amount of administered chemotherapeutic agent; (3) providing chemotherapeutic properties that are well tolerated in patients Treatment, whose harmful pharmacological complications are less harmful pharmacological complications than those observed with single agent chemotherapy and some other combination therapies; (4) treating a wide range of different cancer types in mammals, especially humans; 5) providing a higher response rate in the patient being treated; (6) providing a longer survival time than the standard chemotherapy treatment in the patient being treated; (8) providing a longer tumor progression time, and/or (9) The efficacy and tolerability results produced are at least as good as the efficacy and tolerability results of the agents used alone, as compared to the known cases in which other cancer agents are combined to produce antagonism.

Experimental part

The procedures and procedures described in the art as cited in the present application (see the preamble) disclose the general synthetic route for the AKT-compound (which is a preferred compound A of the combination of the invention) in its experimental part. The specific procedure, the synthesis of component B, is disclosed in WO2000/040275.

An example demonstrating the synergistic effect of the combination of compounds A and B of the present invention

Monotherapy and combinations of Compound A and Compound B were tested in a homologous animal model similar to that of human breast cancer bone metastatic disease. This model is useful for testing the effects of cancer drug candidates on the transfer of breast cancer cells to bone.

For this extension, 4T1-GFP fluorescent mouse breast cancer cells were inoculated into the left ventricle of 4-5 week old female Balb/c mice. Animals that develop osteolytic bone metastases can be visually visualized by GFP fluorescence and X-ray radiography within 1-2 weeks after inoculation.

On day 7 after tumor cell inoculation, animals were randomized according to the presence of radiography and tumor metastasis. A single dose of radium 223 or vehicle, a daily dose of an AKT inhibitor or a single dose of radium 223 and a daily continuous dose of an AKT inhibitor are administered to the animal. Animals were sacrificed earlier on day 13 after inoculation or when they died. Osteolytic lesions and systemic tumor burden were measured by x-ray and fluorescence imaging at the time of sacrifice. In addition, tissue samples of the left and right tibia and femur were collected for other histomorphometric analysis. Tissues were embedded in paraffin for histomorphometric analysis of bone and tumor areas.

in conclusion:

Pharmacological inhibition of AKT kinase unexpectedly sensitized 4T1 tumor cells to radium 223 treatment. Treatment of 4T1 breast tumor cells with a combination of radium 223 and AKT inhibitor produced greater than additive (synergistic) inhibition of tumor growth in vivo, while systemic tumor burden was significantly reduced. In addition, radium 223 + AKTi combination therapy can effectively reduce the total osteolytic area, and radium 223 or AKT inhibitor monotherapy has not achieved this goal. In addition, the area of necrosis and fibrosis in the bone portion is significantly increased with the combination treatment.

These results indicate that the combination of AKT kinase inhibitor and radium 223 tumor cell combination treatment has superior therapeutic efficacy compared to the treatment of each single agent.

In MCF7, a breast cancer cell line with ER+ and activated PIK3CA mutations, Compound B showed only slight inhibition of tumor cell proliferation, while Compound A showed potent anti-proliferative activity. The combination of Compound A and Compound B further enhances the anti-proliferative effect. Monotherapy of Compound A and Compound B failed to induce tumor cell death, while strong induction of apoptosis was demonstrated in the combination group.

In 4T1, a triple-negative metastatic breast cancer cell line, Compound B and Compound A showed only moderate inhibition of tumor cell proliferation at lower (250 nM) doses, while Compound B showed strong anti-proliferation at higher doses. effect. The combination of Compound A and Compound B showed a significant synergistic effect.

In PC3, a tumor suppressor gene PTEN loss-of-function AR-negative CRPC cell line, Compound B showed moderate inhibition of tumor cell proliferation, and better anti-proliferative activity was observed under Compound A. All combination groups showed synergistic effects compared to the corresponding monotherapy groups.

In LNCaP, a tumor suppressor gene PTEN loss-of-function AR-positive CRPC cell line, Compound B was effective at a high dose (1600 Bq/mL) and Compound A showed a strong anti-proliferative effect. The combination of Compound A and Compound B showed synergistic anti-proliferative effects at low doses (250 nM and 800 Bq/mL). Although due to the effective single of Compound A in the high dose combination group A synergistic antiproliferative effect was not demonstrated by one agent activity, but a strong synergistic effect was observed in the analysis of apoptosis of caspase 3/7 cells in the low dose and high dose groups.

In conclusion, the combination of Compound A and Compound B demonstrated direct and synergistic anti-tumor activity in all four breast and prostate tumor cell lines tested, as well as hormone receptor-positive MCF7 (ER+) breast cancer and LNCaP (AR+) prostate tumors. Synergistic induction of tumor cell death was observed in cell lines.

AKTi is an AKT inhibitor as disclosed in Example 5 of the experimental part of WO 2012/136776.

Figure 1: Whole body tumor burden based on fluorescence imaging at sacrifice (mm2, median ± IQR 25% ± min/max).

The systemic tumor burden was reduced by a combination of radium 223 + AKTi. Statistical analysis was performed using the Kruskal-Wallis test. Pairwise comparisons with the control group were performed using the Mann-Whitney U-test when statistical differences (p=<0.0015703) were observed. Marks: ^** = statistically significant difference, where p value < 0.01 and NS = non-significant.

Group: Control group (Ctrl; Group 1) received radium 223 vehicle (sodium citrate buffer), vein Once and PEG/Wfi 60:40 pH 4.0, daily oral; Radium 223 group received 300kBq/kg radium 223, intravenously and PEG/Wfi 60:40 pH 4.0, daily oral; AKTi group received 50mg /kg AKTi, daily oral and radium 223 medium, once intravenously; combination group received 300kBq/kg radium 223, once intravenously and 50mg/kg AKTi, daily oral.

Figure 2: Total osteolytic area at the time of sacrifice (mm2, median ± IQR 25% ± min/max).

Treatment with a combination of AKTi and radium 223 reduced the total osteolytic area.

Group: Control group (Ctrl; group 1) received radium 223 vehicle (sodium citrate buffer), once intravenously and PEG/Wfi 60:40 pH 4.0, daily oral; radium 223 group received 300kBq/kg radium 223, once intravenously and PEG/Wfi 60:40 pH 4.0, daily oral; AKTi group received 50mg/kg AKTi, daily oral and radium 223 agent, intravenous once; combination group received 300kBq/kg radium 223 Intravenous and 50mg/kg AKTi, daily oral.

Figure 3: Total necrotic area (mm2, median ± IQR25% ± min/max) in the entire bone section.

Statistical analysis was performed using the Kruskal-Wallis test. When a statistical difference (p = 1.8649e-05) was observed, a pairwise comparison with the control group was performed using the Mann-Whitney U test. Mark: ^*** = statistically significant difference, where p value < 0.001, ^** = p value < 0.01, ^* = p value < 0.05, and NS = non-significant.

Group: Control group (Ctrl; group 1) received radium 223 vehicle (sodium citrate buffer), once intravenously and PEG/Wfi 60:40 pH 4.0, daily oral; radium 223 group received 300kBq/kg radium 223, once intravenously and PEG/Wfi 60:40 pH 4.0, daily oral; AKTi group received 50mg/kg AKTi, daily oral and radium 223 agent, intravenous once; combination group received 300kBq/kg radium 223 Intravenous and 50mg/kg AKTi, daily oral.

Figure 4: Total fiber denaturation area (mm2, median ± IQR 25% ± min / max) in the entire bone portion.

An increase in total fibrosis area has been detected following treatment with a combination of AKTi and radium 223.

Statistical analysis was performed using the Kruskal-Wallis test. When a statistical difference (p = 2.1788e-08) was observed, a pairwise comparison with the control group was performed using the Mann-Whitney U test. Mark: ^*** = statistically significant difference, where p value < 0.001, ^** = p value < 0.01, ^* = p value < 0.05, and NS = non-significant.

Group: Control group (Ctrl; group 1) received radium 223 vehicle (sodium citrate buffer), once intravenously and PEG/Wfi 60:40 pH 4.0, daily oral; radium 223 group received 300kBq/kg radium 223, once intravenously and PEG/Wfi 60:40 pH 4.0, daily oral; AKTi group received 50mg/kg AKTi, daily oral and radium 223 agent, intravenous once; combination group received 300kBq/kg radium 223 Intravenous and 50mg/kg AKTi, daily oral.

Figure 5. Effect of Compound A and Compound B on proliferation of MCF-7 cells on day 1-5 and induction of apoptosis on day 2.

(A) Results are shown as absorbance (450 nm) (average + SEM) measured in the WST-1 proliferation assay. (B) Results are shown in the form of Caspase 3/7/WST-1 values (mean + SEM). The results of the control cranberry (C), the compound A group (D1 = 250 nM and D2 = 5000 nM), and the compound B group (aD1 = 1600 Bq/ml and aD2 = 800 Bq/ml) were compared with the reference group. Using the model comparison, the Compound A and Compound B groups were compared separately to the corresponding combination groups (D1+aD1, D1+aD2, D2+aD1, and D2+aD2). The p values for the different therapeutic agents are indicated in the legend. An asterisk ( ^* ) indicates a statistically significant inhibition with a p-value < 0.05 and three asterisks ( ^*** ) indicating a p-value < 0.001 and NS = non-significant.

Figure 6. Effect of Compound A and Compound B on proliferation of 4T1 breast tumor cells on days 1-5.

The results are shown as absorbance (450 nm) (average + SEM) measured in the WST-1 proliferation assay. The results of the control cranberry (C), the compound A group (D1 = 250 nM and D2 = 5000 nM), and the compound B group (aD1 = 1600 Bq/ml and aD2 = 800 Bq/ml) were compared with the reference group. Using the model comparison, the Compound A and Compound B groups were compared separately to the corresponding combination groups (D1+aD1, D1+aD2, D2+aD1, and D2+aD2). The p values for the different therapeutic agents are indicated in the legend. An asterisk ( ^* ) indicates a statistically significant inhibition with a p-value < 0.05 and three asterisks ( ^*** ) indicating a p-value < 0.001 and NS = non-significant.

Figure 7. Effect of Compound A and Compound B on PC3 prostate tumor cell proliferation on days 1-5.

The results are shown as absorbance (450 nm) (average + SEM) measured in the WST-1 proliferation assay. The results of the control cranberry (C), the compound A group (D1 = 250 nM and D2 = 5000 nM), and the compound B group (aD1 = 1600 Bq/ml and aD2 = 800 Bq/ml) were compared with the reference group. Using the model comparison, the Compound A and Compound B groups were compared separately to the corresponding combination groups (D1+aD1, D1+aD2, D2+aD1, and D2+aD2). The p values for the different therapeutic agents are indicated in the legend. An asterisk ( ^* ) indicates a statistically significant inhibition with a p-value < 0.05 and three asterisks ( ^*** ) indicating a p-value < 0.001 and NS = non-significant.

Figure 8. Effect of Compound A and Compound B on proliferation of LNCaP prostate tumor cells on day 1-5 and induction of apoptosis on day 2.

(A) Results are shown as absorbance (450 nm) (average + SEM) measured in the WST-1 proliferation assay. (B) Results are presented as caspase 3/7/WST-1 values (mean + SEM). The results of the control cranberry (C), the compound A group (D1 = 250 nM and D2 = 5000 nM), and the compound B group (aD1 = 1600 Bq/ml and aD2 = 800 Bq/ml) were compared with the reference group. Using the model comparison, the Compound A and Compound B groups were compared separately to the corresponding combination groups (D1+aD1, D1+aD2, D2+aD1, and D2+aD2). The p values for the different therapeutic agents are indicated in the legend. An asterisk ( ^* ) indicates a statistically significant inhibition with a p-value < 0.05 and three asterisks ( ^*** ) indicating a p-value < 0.001 and NS = non-significant.

Claims (13)

A combination of at least two compounds A and B comprising Compound A as an AKT kinase inhibitor and Compound B being a pharmaceutically acceptable salt of an alkaline earth radioactive seed radium-223. A combination of claim 1, wherein the pharmaceutically acceptable salt of the alkaline earth radioactive seed radium-223 is radium dichloride-223. A combination of claim 1 or 2 wherein the compound A is a compound of the formula (IIb): Wherein: R ^1b represents hydrogen, hydroxy, halogen, cyano, -N(R ^5b )(R ^6b ), -C(O)N(R ^8b )(R ^9b ), -C(O)OR ^8b , -C (O) (C ₁ -C ₆ alkyl), -N(H)C(O)(C ₁ -C ₆ alkyl), -N(H)S(O) ₂ R ^11b , -N(H) C(O)N(H)R ^11b , -S(O) _n -C ₁ -C ₆ alkyl, -S(O) ₂ N(R ^5b )(R ^6b ) or a group selected from the group consisting of C _1- C ₆ alkyl-, C ₁ -C ₆ alkoxy-, C ₃ -C ₇ cycloalkyl-, aryl-, heteroaryl-, -(C ₁ -C ₆ alkyl)-aryl , -(C ₁ -C ₆ alkyl)-heteroaryl, -O-(C ₃ -C ₇ cycloalkyl), -O-aryl, -O- (3 to 7 membered heterocycloalkyl) , -O-heteroaryl, -O-(C ₁ -C ₆ alkyl)-heteroaryl, -O-(C ₁ -C ₆ alkyl)- (3 to 7 membered heterocycloalkyl), -O-(C ₁ -C ₆ alkyl)-aryl, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-; wherein the group is optionally the same or different from the substituents selected below Substituted one or more times: hydroxy, halogen, C ₁ -C ₆ alkyl-, C ₁ -C ₄ haloalkyl-, C ₁ -C ₆ alkoxy-, -N(R ^8b )(R ^9b ) , cyano, -C(O)N(R ^8b )(R ^9b ), -C(O)O(R ^10b ), -N(H)C(O)R ^11b , -N(H)C(O N(H)(R ^11b ), -N(H)S(O) ₂ R ^11b , C ₃ -C ₇ cycloalkyl, 3 to 7 membered heterocycloalkyl-, aryl- ; R ^2b represents hydrogen, hydroxy, halogen, cyano, -N(R ^5b )(R ^6b ), -C(O)N(R ^8b )(R ^9b ), -C(O)O(R ^8b ), -C(O)(C ₁ -C ₆ alkyl), -N(H)C(O)(C ₁ -C ₆ alkyl), -N(H)S(O) ₂ R ^11b , -N( H) C(O)N(H)(R ^11b ), -S(O) _n -(C ₁ -C ₆ alkyl), -S(O) ₂ N(R ^5b )(R ^6b ) or selected from of the following groups: C ₁ -C ₆ alkyl -, C ₁ -C ₆ alkoxy -, C ₃ -C ₇ cycloalkyl -, aryl -, heteroaryl -, - (C ₁ -C ₆ Alkyl)-aryl, -(C ₁ -C ₆ alkyl)-heteroaryl, -O-(C ₃ -C ₇ cycloalkyl), -O-aryl, -O- (3 to 7) Heterocycloalkyl), -O-heteroaryl, -O-(C ₁ -C ₆ alkyl)-heteroaryl, -O-(C ₁ -C ₆ alkyl)- (3 to 7 members) Heterocycloalkyl), -O-(C ₁ -C ₆ alkyl)-aryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl; wherein the group is optionally substituted with Substituting one or more substituents identically or differently: hydroxy, halogen, C ₁ -C ₆ alkyl-, C ₁ -C ₄ haloalkyl-, C ₁ -C ₆ alkoxy-, -N(R ^8b ) (R ^9b ), cyano, -C(O)N(R ^8b )(R ^9b ), -C(O)O(R ^10b ), -N(H)C(O)R ^11b , -N(H C(O)N(H)(R ^11b ), -N(H)S(O) ₂ R ^11b , 3 to 7 membered heterocycloalkyl-, aryl-; R ^3b represents hydrogen, hydroxy Base, halogen, cyano, -N(R ⁵ )(R ⁶ ), -C(O)N(R ^8b )(R ^9b ), -C(O)O(R ^8b ), -C(O)( C ₁ -C ₆ alkyl), -N(H)C(O)(C ₁ -C ₆ alkyl), -N(H)S(O) ₂ R ^11b , -N(H)C(O) N(H)(R ^11b ), -S(O) _n -(C ₁ -C ₆ alkyl), -S(O) ₂ N(R ^5b )(R ^6b ) or a group selected from the group consisting of C ₁ -C ₆ alkyl -, C ₁ -C ₆ alkoxy -, C ₃ -C ₇ cycloalkyl -, aryl -, heteroaryl -, - (C ₁ -C ₆ alkyl) - aryl group , -(C ₁ -C ₆ alkyl)-heteroaryl, -O-(C ₃ -C ₇ cycloalkyl), -O-aryl, -O- (3 to 7 membered heterocycloalkyl) , -O-heteroaryl, -O-(C ₁ -C ₆ alkyl)-heteroaryl, -O-(C ₁ -C ₆ alkyl)- (3 to 7 membered heterocycloalkyl), -O-(C ₁ -C ₆ alkyl)-aryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl; wherein the group is optionally substituted identically or differently with a substituent selected from One or more times: hydroxy, halogen, C ₁ -C ₆ alkyl-, C ₁ -C ₄ haloalkyl-, C ₁ -C ₆ alkoxy-, -N(R ^8b )(R ^9b ), cyanide , -C(O)N(R ^8b )(R ^9b ), -C(O)O(R ^10b ), -N(H)C(O)R ^11b , -N(H)C(O)N (H) (R ^11b ), -N(H)S(O) ₂ R ^11b , 3 to 7 membered heterocycloalkyl-, aryl-; R ⁴ represents the same as the halogen atom or Substituting phenyl with one, two or three times differently; R ⁵ represents hydrogen or C ₁ -C ₆ alkyl, R ⁶ represents hydrogen or C ₁ -C ₆ alkyl, R ⁸ represents hydrogen or optionally substituted by hydroxy C ₁ -C ₆ alkyl, R ⁹ represents hydrogen or C ₁ -C ₆ alkyl, R ¹⁰ represents hydrogen or C ₁ -C ₆ alkyl, R ¹¹ represents hydrogen or C ₁ -C ₆ alkyl, X, Y Represents CH ₂ ; n is 0, 1 or 2; or an N-oxide, a salt, a tautomer or a stereoisomer of the compound, or the N-oxide, tautomer or stereoisomer salt. A combination of claim 3, wherein R ^1b represents hydrogen, hydroxy, amino, methoxy, ethoxy, butoxy, pyridin-3-yl, pyridin-4-yl, pyrazol-3-yl, 1 -methyl-pyrazol-3-yl, imidazol-2-yl, methyl, propyl, -O-(CH ₂ )-O-CH ₃ , -O-CH ₂ -phenyl, -O-CH ₂ - _{cyclopropyl, -C (O) OCH 3,} -C (O) -NHCH 3, -C (O) -NH 2, 4- fluoro - _{phenyl, - (CH 2) 2 -} C (O) OCH ₃ , cyclopropyl, -NH-C(O)CH ₃ ; R ^2b represents hydrogen or methyl; R ^3b represents hydrogen, hydroxy, amine, methyl, ethyl, methoxy, ethoxy, -O -CH ₂ -C(O)OCH ₃ , -S-CH ₃ , -SO ₂ -CH ₃ , bromine, chlorine, trifluoromethyl, -C(=O)NH ₂ , -C(=O)OH, -C(=O)OCH ₃ , -C(=O)OCH ₂ CH ₃ , -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)NH(CH ₂ ) ₂ -OH, -CH=CH ₂ , 4-fluoro-phenyl, -NHC(=O)CH ₃ , -NHC(=O)CF ₃ , -NH- SO ₂ -CH ₃ , -C(=O)CH ₃ ; R ^4b represents phenyl; X represents CH ₂ ; and Y represents CH ₂ ; or N-oxide, salt, tautomer or stereoisomeric of the compound A conformation, or a salt of the N-oxide, tautomer or stereoisomer. A combination of claim 1 or 2 wherein compound A is selected from the group consisting of: 1-[4-(6-methyl-3-phenylimidazo[1,2-b]pyridazines; 2-yl)phenyl]cyclobutylamine 1-[4-(6-ethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 1- {4-[3-Phenyl-6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 2-[4-(1-amino ring Butyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid ethyl ester 2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl Imidazo[1,2-b]pyridazine-6-carboxamide 1-[4-(6-methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl) Phenyl]cyclobutylamine 1-[4-(6-bromo-8-methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2 -[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid 1-[4-(6,8-Dimethyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)-phenyl]cyclobutylamine 2-[4-(1 -aminocyclobutyl)phenyl]-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 1-[4-(8-methoxy- 3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl]-8-methoxy- 3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid methyl ester 1-[4-(6-ethyl-8-methoxy-3-phenylimidazo[1,2-b Pyridazin-2-yl)phenyl]cyclobutylamine 1-{4-[6-methoxy-3-phenyl-8-(pyridin-3-yl)imidazo[1,2-b]indole Pyrazin-2-yl]phenyl}cyclobutylamine 1-{4-[6-methoxy-3-phenyl-8-(1H-pyrazol-4-yl)imidazo[1,2-b] Pyridazin-2-yl]phenyl}cyclobutylamine hydrochloride 1-[4-(6,8-diethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl) Phenyl]cyclobutylamine 1-[4-(6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine 1-[4-(8- Methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine 1-{4-[6-chloro-3-phenyl- 8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1-{4-[3-phenyl-8-(1H- Pyrazol-3-yl)-6-vinylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine 1-{4-[6- 3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 2-[4-(1-amine Cyclobutyl)phenyl]-8-ethoxy-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 1-{4-[6-chloro 8-(1-methyl-1H-pyrazol-5-yl)-3-phenylimidazo[1,2-b]pyridazine- 2-yl]phenyl}cyclobutylamine 1-{4-[6-chloro-8-(1H-imidazol-2-yl)-3-phenylimidazo[1,2-b]pyridazine-2- Benzyl]cyclobutanamine 1-[4-(3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4-(1-amino) Cyclobutyl)phenyl]-8-methoxy-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 1-{4-[3-phenyl 8-(1-H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 2-[4-(1-aminocyclobutyl)benzene 8-(2-methoxyethoxy)-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 1-{4-[8-(benzyloxy) - 6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1-[4-(6-chloro-8-ethoxy-3- Phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1 ,2-b]pyridazine-8-carboxylic acid methyl ester 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-8-ol 1-{4-[6-(4-fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 2-[4-(1- Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6,8-dimethylguanamine 2-[4-(1-aminocyclobutyl)phenyl ]-3-phenylimidazo[1,2-b]pyridazine-6-amine 1-{4-[6-(sulfanyl)-3- Phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine N-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazole And [1,2-b]pyridazine-6-yl}acetamide N-{2-[4-(1-1-{4-[6-(methylsulfonyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl} ring Butylamine 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid methyl ester N-{2-[4-( 1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-yl}-2,2,2-trifluoroacetamide 1-[4-( 6-bromo-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine 1-{4-[6,8-bis(4-fluorophenyl)-3 -Phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl Imidazo[1,2-b]pyridazin-6-yl}ethanone 1-{4-[8-(4-fluorophenyl)-3-phenylimidazo[1,2-b]pyridazine- 2-yl]phenyl}cyclobutylamine N-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-yl }Methanesulfonamide 1-[4-(6-chloro-8-cyclopropyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine 1-[ 4-(3-Phenyl-8-propylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl ]-3-phenylimidazo[1,2-b]pyridazin-8-amine N-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1 ,2-b]pyridazine-8-yl}acetamide 1-[4-(6-chloro-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazine-2 -yl)benzene Cyclobutanamine 2-[4-(1-aminocyclobutyl)phenyl]-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid Methyl 2-[4-(1-aminocyclobutyl)phenyl]-7,8-dimethyl-3-phenylimidazo[1,2-b]indole Pyrazin-6-carboxamide 1-[4-(6-methoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl] Cyclobutanamine 1-{4-[7,8-dimethyl-6-(methylthio)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl} ring Butylamine 1-[4-(6-ethoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2- Methyl [4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxylate 2-[4-(1-Aminocyclobutyl)phenyl]-8-ethoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid methyl ester 2-[4- (1-Aminocyclobutyl)phenyl]-8-(1H-imidazol-2-yl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid methyl ester {1-[ 3-(8-Acetylamino-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamic acid tert-butyl ester 2-[4-( 1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxamide 2-[4 -(1-aminocyclobutyl)phenyl]-8-ethoxy-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1- Aminocyclobutyl)phenyl]-8-(1H-imidazol-2-yl)-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 2- [4-(1-Aminocyclobutyl)phenyl]-N-methyl-3-phenylimidazolium [1,2-b]pyridazine-8-formamide 2-[4-(1-aminocyclobutyl)phenyl]-8-(cyclopropylmethoxy)-N-methyl-3 -Phenylimidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-aminocyclobutyl)phenyl]-N-methyl-3-phenyl-8- (1H-pyrazol-3-yl)mi Zizo[1,2-b]pyridazine-6-carbamimid-2-[4-(1-aminocyclobutyl)phenyl]-N-ethyl-3-phenyl-imidazo[1, 2-b]pyridazine-6-formamide 2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)-imidazole [1,2-b]pyridazine-6-carboxylic acid 2-[4-(1-aminocyclobutyl)phenyl]-N-methyl-3-phenylimidazo[1,2-b]indole Pyrazine-6-carbamimidamine 2-[4-(1-aminocyclobutyl)phenyl]-N,N-dimethyl-3-phenylimidazo[1,2-b]pyridazine-6 -Procarbamide 2-[4-(1-aminocyclobutyl)phenyl]-N-(2-hydroxyethyl)-3-phenylimidazo[1,2-b]pyridazine-6- Formamide 2-[4-(1-aminocyclobutyl)phenyl]-N-(2-hydroxyethyl)-3-phenyl-8-(1H-pyrazol-3-yl)imidazolium [1,2-b]pyridazine-6-carbamide 3-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]indole Methyl oxa-8-yl}propionate 1-{4-[6-methoxy-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine 2-yl]phenyl}cyclobutylamine 1-{4-[6-methoxy-8-(1-methyl-1H-pyrazol-5-yl)-3-phenylimidazo[1, 2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1-{4-[6-methoxy-3-phenyl-8-(pyridin-4-yl)imidazo[1,2- b] pyridazin-2-yl]phenyl}cyclobutylamine 1-[4-(6,8-diethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl Phenyl]cyclobutylamine 1-[4-(8-butoxy-6-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutane Amine 1-[4-(6-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-ol ({2-[4-(1-amino ring) Methyl butyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-6-yl}oxy)acetate, or a salt of the compound, especially a pharmaceutically acceptable salt, An isomer or a stereoisomer, or a tautomer or a salt of the stereoisomer, especially a pharmaceutically acceptable salt. A combination of claim 1 or 2 wherein compound A is selected from the group consisting of AKT inhibitors consisting of 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1] ,2-b]pyridazine-6-formamide 1-[4-(6-methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclo Butylamine 1-[4-(6-bromo-8-methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine 1-[4- (6,8-Dimethyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4-(1-aminocyclobutyl) Phenyl]-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 1-{4-[6-methoxy-3-phenyl-8 -(pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 1-{4-[6-methoxy-3-phenyl-8-( 1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine hydrochloride 1-{4-[6-chloro-3-phenyl-8 -(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutylamine 2-[4-(1-aminocyclobutyl)phenyl] 8-ethoxy-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-aminocyclobutyl)phenyl] -8-methoxy-N-methyl-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-Aminocyclobutyl)phenyl]-8-(2-methoxyethoxy)-3-phenylimidazo[1,2-b]pyridazine-6-A Indole 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6,8-dimethylamine 1-[4-( 6-methoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine 2-[4-(1-amino group Cyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxylic acid methyl ester 2-[4-(1- Aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxamide 2-[4-( 1-aminocyclobutyl)phenyl]-8-ethoxy-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxamide 2-[4-(1-amino group Cyclobutyl)phenyl]-8-(cyclopropylmethoxy)-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide 2-[4- (1-Aminocyclobutyl)phenyl]-N-methyl-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-A Indole 1-{4-[6-methoxy-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl} Cyclobutylamine 1-[4-(6,8-diethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutylamine, or a salt of the compound Especially pharmaceutically acceptable salts, tautomers or Salts stereoisomers, tautomers or the stereoisomers thereof or of the particular pharmaceutically acceptable salt thereof. A combination of claim 1 or 2, wherein the compound A as a compound which inhibits AKT kinase is 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b - pyridazine-6-formamide, or a salt of the compound, especially a pharmaceutically acceptable salt, tautomer Or a stereoisomer, or a tautomer or a salt of such a stereoisomer, especially a pharmaceutically acceptable salt. Use of a combination according to any one of claims 1 to 7 for the preparation of a medicament for the treatment or prevention of cancer, in particular breast cancer, prostate cancer, hepatocellular carcinoma, lung cancer, especially non-small cell lung cancer, colorectal cancer, Melanoma, pancreatic cancer, and/or its metastatic agents. A use according to the combination of claim 8 for the preparation of a medicament for the treatment or prevention of breast cancer or prostate cancer and/or its metastasis. The use of claim 9 or 10, wherein the transfer is a bone transfer. A method of treating or preventing cancer, particularly hepatocellular carcinoma, lung cancer, especially non-small cell lung cancer, colorectal cancer, melanoma, pancreatic cancer or breast cancer, comprising administering to the individual a therapeutically effective amount as claimed in claim 1 A combination of any one of seven. A kit comprising: one or more compounds A as defined in any one of claims 3 to 7; one or more compounds B as defined in claim 1 or 2; and optionally one or more Other pharmaceutical agents C; wherein either or both of these components A and B are in the form of a pharmaceutical formulation, ready for simultaneous, co-administrative, separate or sequential administration. A composition comprising a combination of claims 1 to 7 and a pharmaceutically acceptable ingredient.