BR112018006498B1 - COMPOUND, USE OF THE SAME AND PHARMACEUTICAL COMPOSITION - Google Patents

Abstract

COMPOUNDS OR SALT, TAUTOMER OR N-OXIDE THEREOF AND PHARMACEUTICAL COMPOSITION. The invention provides a compound that inhibits or modulates the activity of p70S6 kinase, the compounds being of formula (1): or a salt, tautomer or N-oxide thereof; where: one of Y and Z is R3 and the other is Ar2; Q1 is an optionally substituted C1-8 alkylene group; and wherein a carbon atom of the C1-8 alkylene group may be optionally replaced by a cyclopropane-1,1-diyl or cyclobutane-1,1-diyl group, provided that the total number of carbon atoms in an alkylene group that contains such substitution does not exceed 8; Q2 is a bond or an optionally substituted C1-8 alkylene group; R1 is selected from hydrogen, NRxRy and a Cy1 group; Rx and Ry are each selected from hydrogen, C1-4 hydrocarbyl, or C1-4 hydroxyhydrocarbyl; or NRxRy forms an optionally substituted 4- to 7-membered heterocyclic ring; Cy1 is a monocyclic non-aromatic heterocyclic or carbocyclic with 3 to 7 optionally substituted C-linked members; R2 and R4 are each selected from hydrogen, fluorine, chlorine, optionally substituted C1-2 alkyl and optionally substituted C1-2 alkoxy; R3 is selected from (...).

Description

[0001] This invention relates to compounds that inhibit or modulate the activity of p70S6 kinase, pharmaceutical compositions containing the compounds and therapeutic uses of the compounds.

Fundamentals of Invention

[0002] The enzyme p70S6 kinase (also known as p70S6K, p70S6K1, pS6K, S6K, S6K1), is a serine-threonine kinase and a member of the AGC family. It is a downstream effector of the phosphatidylinositol 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway and p70S6K undergoes phosphorylation and activation in response to growth factors such as IGF-I, EGF, TGF -[alpha] and HGF.

[0003] Activation of p70S6K, in turn, phosphorylates several proteins involved in protein translation, including ribosomal protein S6 (RPS6), eIF4B and eEF2K. The net result of this is to promote translation, causing an increase in protein synthesis in a cell. High levels of protein synthesis are necessary for cell proliferation. It has also been demonstrated that p70S6K has a necessary role in the mitotic cycle of a cell (Lane et al, Nature, 1993, 363(6425):170-2).

[0004] The p70S6K kinase has been shown to be constitutively activated in human tumor cells, causing tumor cell proliferation. Inhibition of the mTOR/p70S6K pathway has been shown to cause a reduction in tumor cell proliferation and an increase in tumor cell apoptosis (Pene ET AL. (2002) Oncogene 21, 6587 and Le ET AL. (2003) Oncogene 22, 484 ). Therefore, inhibition of p70S6K activity would present an interesting approach for cancer treatment.

[0005] The mTOR/p70S6K pathway has been shown to be activated in renal cell carcinoma and is inhibited by CCI-779 (Robb, V. UMX.; Karbowniczek, M.; Klein-Szanto, UMX. J.; Henske, E. P. J. UROL 2007, 177, 346-52). Furthermore, patients with glioblastoma multiforme whose tumors express high levels of phosphorylated p70S6K have demonstrated benefits from treatment with CCI-779 (Galanis et al. J. Clin. Oncol. 2005, 23, 5294-304).

[0006] Additionally, a significant linear association between time to disease progression and inhibition of p70S6K activity in peripheral blood mononuclear cells (PBMCs) was reported following administration of the mTOR inhibitor CCI-779 to patients with cell carcinoma. kidney disease by Peralba et al. [(2003) Clinical Cancer Research 9, 2887]. This indicates that p70S6K activity is a driver of the disease in this context, and that p70S6K activity can potentially be used as a clinical biomarker.

[0007] The RPS6KB1 gene, which encodes p70S6K, is located in chromosomal region 17q23 and this region is amplified in breast cancer (Cancer Res. (1999) 59: 1408-11 Localization of pS6K to Chromosomal Region 17q23 and Determination of Its Amplification in Breast Cancer). This causes overexpression of the p70S6K protein and a statistically significant association between amplification and poor prognosis was observed in patients with breast cancer (Detecting activation of ribosomal protein S6 kinase by complementary DNA and tissue microarray analysis. J. Natl. Cancer Inst. 2000; 92:1252-9).

[0008] Furthermore, Belletti et al. published that S6K1 mediates survival and recurrence of breast cancer after surgery (Mol Oncol. 2014 May; 8(3):766-80).

[0009] P70S6K has a role in migration and invasion of ovarian cancer (p70 S6 kinase in the control of actin cytoskeleton dynamics and directed migration of ovarian cancer cells, Oncogene (2011), 1-13). Additionally, p70S6K has been shown to play a role in promoting the invasion, migration, and metastasis of highly aggressive triple-negative breast cancer cells (Targeting p70S6K Prevented Lung Metastasis in a Breast Cancer Xenograft Model, Akar et al, Molecular Cancer Therapeutics (2010) , 9 (5), 1180 and Hung et al, S6K1 promotes invasiveness of breast cancer cells in a model of metastasis of triple-negative breast cancer, Am. J. Transl, Res. July 18, 2014;6(4): 361-76).

[0010] Additionally, lymphangioleiomyomatosis (LAM) is a disease characterized by hyperactivation of the PI3K/Akt/mTOR/p70S6K axis due to the inactivation of the repressor complex mutation, tuberous sclerosis complex (TSC). LAM cells are also metastatic, giving rise to lung metastasis.

[0011] LAM is a rare and destructive lung disease that almost exclusively affects women and is associated with metastasis of tuberin-free cells (Taveira-DaSilva et al. (2006). Cancer Control. 2006; 13:276-285). Metastatic lesions develop in distant organs including lungs, kidney and lymph nodes, representing a severe and defining burden of the disease.

[0012] LAM occurs sporadically or as a manifestation of tuberous sclerosis complex (TSC), an autosomal dominant inherited disorder (expert review at http://www.orpha.net). LAM and TSC disorders are characterized by silencing mutations in tumor suppressors TSC1 or TSC2, causing hyperactivation of mTOR and S6K1. This, in turn, causes the growth and proliferation of LAM cells (Holz et al. (2014), Cell Cycle 2014; 13:371 - 382). S6K1 is also known to promote metastasis in other cancers: breast (Akar et al. (2010), Mol Cancer Ther; 9(5)) and ovarian (Wong et al. (2011), Oncogene (2011) 30, 2420-2432). Due to the dependence of LAM cells on S6K1 and the likely role of S6K1 in metastatic processes, it is anticipated that an S6K1 inhibitor will have disease-modifying properties for LAM.

[0013] Sporadic LAM has a prevalence of approximately 1 in 125,000 births, while pulmonary LAM, arising from TSC, has a prevalence of approximately 1 in 15,000 births (internet data, rare disease database, http:// www.orpha.net). There are no approved treatments for LAM and consequently LAM is currently classified as an orphan disease.

[0014] Since p70S6K promotes translation, it is known that p70S6K plays a crucial role in the pathology of diseases that depend on excessive protein synthesis (e.g., Fragile X Syndrome, Genetic Removal of p70 S6 Kinase 1 Corrects Molecular, Synaptic, and Behavioral Phenotypes in Fragile X Syndrome Mice. Klann et al, Neuron, Volume 76, Issue 2, pp. Furthermore, p70S6K has a role in the pathology of cancers that involve the synthesis of oncogenic proteins such as c-Myc, e.g. pancreatic cancer (The mTORC1/S6K1 Pathway Regulates Glutamine Metabolism through the eIF4B Dependent Control of c-Myc Translation , Blenis et al, Current Biology, Volume 24, Issue 19, p2274-2280, October 6, 2014). To treat these conditions, it would be advantageous to use an orally bioavailable p70S6K inhibitor to correct excessive protein synthesis.

[0015] P70S6K has been linked to the pathology of several brain cancers. Such conditions include, but are not limited to: • Brain metastases from cancers elsewhere in the body, for example, brain metastases from breast cancer, such as Distant metastasis in triplenegative breast cancer. Neoplasma 2013 ; 60: 290-294). • Brain metastases from metastatic breast cancer (central nervous system or brain metastases typically occur in 10-16% of patients with metastatic breast cancer and are associated with a poor prognosis - see Breast Dis. 2006-2007; 26:13947. ). • Gliomas and glioblastomas (S6K1 Plays a Key Role in Glial Transformation, Cancer Research (2008), 68(16), 6516-6523).

[0016] Additionally, a p70S6K inhibitor may be particularly useful for treating the following cancers that are dependent on p70S6K signaling: • Bladder cancer • Breast cancer • Colorectal cancer (CRC) • Diffuse large B-cell lymphoma (DLBCL ) • Gallbladder cancer • Gliomas and Glioblastomas • Head and neck cancers • Hepatocellular carcinoma • Olfactory neuroblastoma in humans • Leukemias • Lymphomas • Nasopharyngeal carcinoma • Neuroendocrine cancer • Non-small cell lung cancer (NSCLC) • Non-small cell lung cancer small cell • Ovarian cancer • Pancreatic cancer • Pheochromocytoma • Renal cell carcinoma (RCC) • Squamous cell carcinoma • Metastases, e.g. bone metastases and lung metastases

[0017] P70S6K also plays a crucial role in the pathology of several neurodevelopmental diseases (many referenced in The Autistic Neuron: Troubled Translation?. Bear et al, Cell 135, October 31, 2008). These diseases are particularly caused by excessive protein synthesis that is driven by P70S6K. Such conditions include, but are not limited to: • Fragile X syndrome, a rare neurodevelopmental disorder caused by excessive levels of p70S6K activity • Autism spectrum disorders and autism • Fragile X-associated tremor and ataxia syndrome (FXTAS) • Angelman syndrome • Tuberous sclerosis • PETN hamartoma syndrome • MECP2 duplication syndrome • Neurofibromatosis • Alzheimer's disease (see (1) Oddo et al, Reducing Ribosomal Protein S6 Kinase 1 Expression Improves Spatial Memory and Synaptic Plasticity in a Mouse Model of Alzheimer's Disease, The Journal of Neuroscience, October 14, 2015, 35(41):14042-14056 and (2) Genetic reduction of mammalian target of rapamycin improves Alzheimer's disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature, Journal of Neuroscience (2014), 34(23), 79887998) • Down Syndrome (mTOR Hyperactivation in Down Syndrome Hippocampus Appears Early During Development, Journal of Neuropathology & Experimental Neurology (2014), 73(7), 671-683)

PETN hamartoma syndrome

[0018] PTEN hamartoma tumor syndrome (PHTS) encompasses four major clinically distinct syndromes associated with germline mutations in the tumor suppressor PTEN. These allelic disorders, Cowden syndrome, Bannayan-Ruvalcaba-Riley syndrome, Proteus syndrome, and Proteus-like syndrome, are associated with dysregulated cellular proliferation, causing the formation of hamartomas (benign and malignant tumors of the thyroid, breast, and endometrium) (Genetics in Medicine (2009) 11, 687-694). The absence of PTEN causes a decrease (downregulation) in the levels of phosphorylated Akt, which, in turn, allows the survival, growth and unrestrained proliferation of the cells in question. As S6K1 is a key effector of Akt, an S6K1 inhibitor may be useful for controlling cancer growth. The prevalence of PHTS is currently unknown.

Neurofibromatosis type 1

[0019] Neurofibromatosis type 1 is a condition characterized by changes in skin color (pigmentation) and the growth of tumors along the nerves in the skin, brain, and other parts of the body. The signs and symptoms of this condition vary greatly between affected people. Most adults with neurofibromatosis type 1 develop neurofibromas, which are noncancerous (benign) tumors that are typically located on or just beneath the skin. These tumors can also occur on nerves near the spine or next to nerves in other parts of the body. Some people with neurofibromatosis type 1 develop cancerous tumors that grow along their nerves. These tumors, which normally develop in adolescence or adulthood, are called malignant peripheral nerve sheath tumors. People with neurofibromatosis type 1 also have a higher risk of developing other cancers, including brain tumors and cancer of blood progenitor tissues (leukemia).

[0020] Neurofibromatosis type 1 occurs in 1 in every 3,000 to 4,000 people around the world and, currently, surgery is the main treatment option; It is classified as an orphan disease because there are no targeted therapies (http://ghr.nlm.nih.gov/condition/Neurofibromatose-type-1).

[0021] Mutations in the NF1 gene cause neurofibromatosis type 1. The NF1 gene provides instructions for manufacturing the protein neurofibromin. This protein is produced in many cells, including nerve cells and specialized cells that surround nerves (oligodendrocytes and Schwann cells). Neurofibromin acts as a tumor suppressor. Mutations in the NF1 gene lead to the production of a non-functional version of neurofibromin that does not regulate cell growth and division. As a result, tumors, such as neurofibromas, can form along nerves throughout the body. An S6K1 inhibitor can control the growth of cells that express the mutated NF1 gene, reducing the production of the protein neurofibromin and other proteins essential for tumor growth.

The role of P70S6 in neurological diseases

[0022] P70S6K also plays a crucial role in the pathology of several neurodevelopmental diseases (many referenced in The Autistic Neuron: Troubled Translation?. Bear et al, cell 135, October 31, 2008). Particularly, these diseases are caused by excessive protein synthesis promoted by P70S6K.

[0023] It is known that precise translation control (protein synthesis) is absolutely necessary for the neurological processes of the brain, such as long-term synaptic plasticity and the formation of long-term memory. Furthermore, alterations in translational control are a common pathophysiological feature of human neurological disorders, including developmental disorders, neuropsychiatric disorders, and neurodegenerative diseases. Furthermore, it is known that translational control mechanisms are susceptible to modification by small molecules that penetrate the brain (Klann and Santini, Dysregulated mTORC1-dependent translational control: from brain disorders to psychoactive drugs, Front. Behav. Neurosci., 8 November 2011, doi: 10.3389/fnbeh.2011.00076).

[0024] S6K1 is known as a master regulator of protein biosynthesis through its role in translation initiation, as well as in the phosphorylation and activation of several substrates that promote protein production (eIF4B, PDCD4, SKAR, eEF2K, RPS6 - for review, see Ma and Blenis, Nature Reviews Molecular Cell Biology 10, 307318 (May 2009), doi:10.1038/nrm2672).

[0025] The following disorders are typified by underlying abnormalities in the regulation of protein translation that are linked to the observed pathologies. An S6K1 inhibitor, which works by reducing excessive protein translation, may therefore have uses in the treatment of these disorders.

[0026] It is possible to classify certain disorders into subgroups: (1) neurodevelopmental disorders (2) neurodegenerative diseases. Within each subclass, disorders are linked by common themes:

1. Neurodevelopmental disorders

[0027] Neurodevelopmental disorders are defined as diseases caused by abnormal development of the brain during the first two decades of life. It is possible to define a subgroup of these disorders that are characterized by mutations in a single gene. A common molecular abnormality in several of these disorders is loss-of-function mutations and/or deletion of genes encoding proteins that normally repress the mTORC1 signaling pathway. These disorders are listed below.

Fragile X syndrome

[0028] Fragile X syndrome (FXS) is a genetic disorder that gives rise to a range of developmental problems, including learning disorders and cognitive deficits. Typically, this disorder affects males more severely than females due to the fact that the disorder is inherited through the X chromosome. Typically, affected individuals have delays in speech and language development by 2 years of age. Most men with FXS have mild to moderate intellectual disabilities, while about one-third of affected women have intellectual disabilities. Children with FXS may also have anxious and hyperactive behavior, such as restless or impulsive actions. They may have attention deficit disorder (ADD), which includes a reduced ability to maintain attention and difficulty focusing on specific tasks. About one-third of individuals with FXS have features of autism spectrum disorders that affect communication and social interaction. Seizures occur in about 15 percent of men and about 5 percent of women with FXS. Most men and about half of women with FXS have distinct physical characteristics that become more apparent with age. These features include a long, narrow face, large ears, prominent jaw and forehead, abnormally flexible fingers, flat feet, and, in males, large post-pubertal testicles (macro-orchidism). FXS occurs in approximately 1 in 4,000 men and 1 in 8,000 women.

[0029] Mutations in the Fmr1 gene cause FXS. The Fmr1 gene provides instructions for making a protein called fragile X metal retardation protein, or FMRP. This protein helps regulate the production of other proteins and plays a role in the development of synapses, which are specialized connections between nerve cells. Synapses are important for relaying nerve impulses.

[0030] Almost all cases of FXS are caused by a mutation in a segment of DNA known as the CGG triplet repeat in the Fmr1 gene. Typically, this segment of DNA is repeated in the range between 5 and 44 times (most commonly 29 or 30 times). In people with FXS, however, the CGG segment is repeated more than 200 times. The abnormally expanded CGG segment turns off (silences) the Fmr1 gene, which prevents the gene from producing FMRP.

[0031] FMRP is a protein translation repressor. In the case of FXS patients who suffer from loss or insufficiency of FMRP, there is no repression of translation, which causes excessive production of a range of proteins normally controlled by FMRP. Many of these proteins are expressed in neurons and control synaptic plasticity (memory formation, learning, ability to store information). The lack of control over the production of these proteins causes the neuropathological state observed in patients with FXS. Klann et al. published that S6K1 has a central role in the excessive translation of these proteins and that genetic deactivation of S6K1 results in the correction of phenotypes in the mouse model of FXS (Genetic Removal of p70 S6 Kinase 1 Corrects Molecular, Synaptic, and Behavioral Phenotypes in Fragile Mice Syndrome. Neuron 76, 325-337, 2012). It has been determined that S6K1 inhibitors described herein also have the ability to decrease protein synthesis in neurons, which causes correction of abnormal phenotypes in a mouse model of FXS.

[0032] Furthermore, Tassone et al. (Genes, Brain and Behavior (2012), doi: 10.1111/j.1601-183X.2012.00768.x) published that lymphocytes isolated from the blood of human FXS patients exhibited higher levels of phosphorylated (activated) p70S6K and also higher levels of phosphorylated RPS6, the direct substrate of S6K1. This confirms that p70S6K is more highly activated in human FXS patients and supports the idea of inhibiting p70S6K activity in order to correct the disease. Additionally, this represents a possible clinical biomarker to evaluate the pharmacodynamic effect of the p70S6K inhibitor in the clinic.

Fragile X-associated tremor and ataxia syndrome (FXTAS)

[0033] Fragile X-associated tremor and ataxia syndrome (FXTAS) is a rare neurodegenerative disorder characterized by progressive cerebellar tremor triggered in adults and gait ataxia. It is a genetic disorder linked to the ).

[0034] The prevalence is estimated at 1-9 in every 100,000 individuals. The age of onset of tremor and/or ataxia in men is around 60 years. Clinical presentation is variable, with dominant manifestations including: cerebellar tremor, progressive cerebellar gait ataxia, frontal executive dysfunction, cognitive decline, peripheral neuropathy, and autonomic dysfunction. Other signs include mild parkinsonism and psychiatric manifestations (depression, anxiety and agitation) with the possibility of progression to dementia. In general, female carriers have less severe manifestations than men, but they also have a higher risk of early menopause, chronic muscle pain and hypothyroidism. FXTAS is caused by the repetitive expansion of CGG trinucleotides (55-200 repeats) in the permutation range of the Fmr1 gene. There is no specific treatment for FXTAS that targets the underlying pathological mechanism; therefore, FXTAS is classified as an orphan disease. Often, expansion of the CGG trinucleotide repeat causes reduced levels of the protein FMRP, a repressor of protein translation. This causes excessive protein translation which can be reversed through the use of an S6K1 inhibitor.

Autism spectrum disorders and autism

[0035] Autism spectrum disorders (ASD) and autism are terms for a group of complex brain development disorders. The disorders are characterized by difficulties in social interactions, verbal and nonverbal communication, and repetitive behavior. In 2013, a publication titled the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) brought together all autistic disorders into one general diagnosis of ASD. Previously, they were recognized as distinct subtypes, including autistic disorders, childhood disintegrative disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger syndrome. The US Centers for Disease Control and Prevention (CDC) classifies 1 in 68 American children as being on the autism spectrum. Studies also show that autism is four to five times more common among boys than girls. An estimated 1 in 42 boys and 1 in 189 girls are diagnosed with autism in the United States. Overall, ASD affects more than 3 million individuals in the U.S. and tens of millions around the world (Autism Speaks website, http://www.autismspeaks.org/). Furthermore, government statistics on autism suggest that prevalence rates are increasing. Fragile X syndrome (FXS) is the most common inherited cause of intellectual disabilities and the most common known cause of autism around the world (Penagarikano et al. (2007). The pathophysiology of Fragile Hum. Genet. 8, 109-129). This causal link between FXS and autism indicates that an S6K1 inhibitor that exhibits efficacy in treating FXS may also be useful in treating autism and ASDs.

Angelman syndrome

[0036] Angelman syndrome (AS) is a genetic-neurological disorder that is normally diagnosed in children and is characterized by developmental delay, severe intellectual disabilities, absence of speech, exuberant behavior with happy demeanor, motor impairment and epilepsy. AS is caused by a deficiency in the expression of the UBE3A gene, which can be caused by various abnormalities of chromosome 15 (Dan, B., Angelman syndrome: Current understanding and research prospects. Epilepsia, 2009. 50(11): p. 2331-2339 ). Although not precisely known, the prevalence of AS among children and young adults is between 1/10,000 and 1/20,000, defining AS as a rare disease. Mutations in the E3 ubiquitin ligase UBE3A have been identified in AS, which suggests that ubiquitin-dependent protein turnover may be impaired in this disorder, possibly causing elevated synaptic protein levels (Jiang and Beaudet, 2004). Furthermore, it has been reported that inhibition of S6K1 can improve hippocampal synaptic plasticity and learning in a mouse model of Angelman syndrome (Cellular and Molecular Life Sciences, pp 1-12). An S6K1 kinase inhibitor would exert its effects by reducing translation of synaptic protein levels.

tuberous sclerosis complex

[0037] Tuberous sclerosis complex is a genetic disorder characterized by the growth of various non-cancerous (benign) tumors in many parts of the body. These tumors can occur in the skin, brain, kidneys and other organs, in some cases leading to severe health problems. Tuberous sclerosis complex also causes developmental problems, and the signs and symptoms of the disorders vary in each person.

[0038] Tuberous sclerosis complex often affects the brain, causing seizures, behavioral problems such as hyperactivity and aggression, and intellectual disability or learning problems. Some affected children have distinctive features of autism, a developmental disorder that affects communication and interaction, as described above. Benign brain tumors can also develop in people with tuberous sclerosis complex; These tumors can cause serious or fatal complications. Tuberous sclerosis complex affects about 1 in every 6,000 people (http://ghr.nlm.nih.gov/condition/tuberous-sclerosis-complex).

[0039] Mutations in the TSC1 or TSC2 genes can cause tuberous sclerosis complex. The TSC1 and TSC2 genes provide instructions for making the proteins hamartin and tuberin, respectively. These proteins are involved in the PI3K signaling network and act as tumor suppressors, inhibiting mTOR activation through Rheb-GTP. When TSC1 or TSC2 are mutated, this causes the loss of tumor repression function, causing hyperactivation of mTOR.

[0040] Above all, the mTORC1 inhibitor rapamycin has been shown to be effective in improving learning and memory deficits in TSC2 heterozygous knockout mice (Ehninger et al., 2008b), which suggests that unrestrained mTORC1 signaling is a central molecular mechanism involved in behavioral anomalies.

[0041] One of the functional effectors of mTOR is S6K1; therefore, inhibiting S6K1 function may have disease-ameliorating effects.

MECP2 duplication syndrome

[0042] MECP2 duplication syndrome is a genetic condition that is inherited in an X-linked pattern and occurs almost exclusively in men. It is characterized by moderate to severe intellectual disability. Most people with this condition also have weak muscle tone in childhood, feeding difficulties, poor or absent speech, and seizures that may not improve with treatment or muscle stiffness (spasticity). Individuals with MECP2 duplication syndrome have delayed development of motor functions, such as sitting and walking. Many individuals with MECP2 gene duplication syndrome have recurrent respiratory infections. These respiratory infections are a major cause of death in affected individuals, with nearly half succumbing by the age of 25. The prevalence of MECP2 duplication syndrome is unknown; approximately 120 affected individuals have been reported in the scientific literature. MECP2 duplication syndrome arises due to a duplication of the MECP2 gene that causes excessive production of the MeCP2 protein in the brain. MeCP2 is a regulator of expression of other genes. Although MeCP2 is essential for normal brain function, an excess can cause abnormal regulation of target genes (http://ghr.nlm.nih.gov/condition/mecp2-duplication-syndrome). An S6K1 inhibitor can reduce the production of the MeCP2 protein through global translation reduction and may have utility as a therapeutic intervention in this disease.

Down's syndrome

[0043] Down syndrome (DS), also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21 (Patterson, D (Jul 2009). "Molecular genetic analysis of Down syndrome.” Human Genetics 126 (1): 195-214). every 1000 babies born each year (Weijerman, ME; de Winter, JP (Dec. 2010). "Clinical practice. The care of children with Down syndrome". European journal of pediatrics 169 (12): 1445-52).

[0044] Recent publications have identified that mTOR hyperactivation has a role in DS in the early stages of development. In control hippocampi (without DS), phosphorylated S6 was only detected prenatally; they became undetectable 2 months postnatally. In contrast, for DS patients, phosphorylated S6 and phosphorylated S6 kinase were detected prenatally and persisted throughout postnatal development. This was linked to increased expression of phosphorylated S6 protein (RPS6), phosphorylated p70S6K, phosphorylated eukaryotic initiation factor 4E binding protein 1, and phosphorylated mTOR in the hippocampus of DS compared to controls (J Neuropathol Exp Neurol. 2014 Jul;73 (7):671-83). Furthermore, it has been suggested that mTOR inhibitors, such as rapamycin or other analogues, may be useful in the treatments of cognitive deficits associated with DS (CNS Neurol Disord Drug Targets. 2014 Feb;13(1):34-40). Since S6K1 controls the phosphorylation and activation of the S6 protein, an S6K1 inhibitor may be therapeutically useful in combating hyperactivated mTOR signaling in patients with DS.

2. Neurodegenerative diseases Alzheimer's disease

[0045] The clinical symptoms of Alzheimer's disease (AD) include a gradual memory loss and subsequent dementia and neuropathological deposition of senile plaques and neurofibrillary tangles. AD accounts for 60% to 70% of dementia cases (Burns, A; Lliffe, S (February 5, 2009). "Alzheimer's disease." BMJ (Clinical research ed.) 338: b158). It is a devastating and relatively widespread disease - in 2010, there were between 21 and 35 million people around the world with AD ("Survival in dementia and predictors of mortality: a review". International journal of geriatric psychiatry 28 (11): 1109-24).

[0046] At the molecular level, AD is associated with (1) the progressive accumulation of β-amyloid peptides (Aβ) in the form of extracellular amyloid plaques in the human brain and (2) hyperphosphorylation of tau protein. Recent publications have implicated the PI3K/mTOR signaling pathway in the pathogenesis of the disease. For example, genetic deactivation of the mTOR protein in Tg2576 mice, a widely used AD animal model, was found to suppress β-amyloid deposits and recover memory deficits in the animals (J. Neurosci. 2014 Jun 4;34(23) :7988-98). Furthermore, post-mortem brain tissue tests from human patients with AD highlighted that alterations in mTOR signaling and autophagy occur in early stages of AD, causing a significant increase in Aβ (1-42) levels and hyperactivation of the PI3K/ Akt/mTOR (J. Neurochem. Jan. 27, 2015). The expression level of S6K1, the downstream target of mTOR, had increased in these samples, which suggests that therapeutic intervention by an S6K1 inhibitor may be useful to control amyloid-β protein synthesis and to decrease mTOR signaling. . Furthermore, elevated levels of phosphorylated mTOR and S6K1 were also found in some of the affected areas of the AD brain, such as the cortex, of APP/PS1 double transgenic mice, a model of AD (Lafay-Chebassier et al., 2005). .

[0047] Additionally, Oddo et al. (Reducing Ribosomal Protein S6 Kinase 1 Expression Improves Spatial Memory and Synaptic Plasticity in a Mouse Model of Alzheimer's Disease, The Journal of Neuroscience, October 14, 2015, 35(41):14042-14056) published data supporting the following conclusions: (1) S6K1 activity is increased in the brains of AD patients, (2) in a mouse model of AD, S6K1 activity in the brain is also greater than control, (3) the genetic reduction of S6K1 in the model of AD mice (through haploinsufficiency) (1) enhanced synaptic plasticity and spatial memory deficit, and (2) reduced accumulation of amyloid-B (AB) and phospho-tau/total tau levels, the key neuropathological markers of AD . This validation lends credence to the hypothesis that manipulating S6K1 activity through a small molecule S6K1 inhibitor could be a valid therapeutic approach in AD.

Huntington's disease

[0048] Huntington's disease is a progressive and inherited brain disorder that causes uncontrolled movements, emotional problems and loss of thinking ability (cognition); There are two forms of the disease: (1) adult-onset Huntington's disease, the most common form of this disorder, which typically manifests in a person's third or fourth decade, and (2) juvenile Huntington's disease, which is less common and It begins in childhood or adolescence. In both forms, the disease is progressive, with affected individuals typically only living for 10 to 15 years after signs and symptoms manifest. Huntington's disease affects approximately 3 to 7 people per 100,000 people of European ancestry.

[0049] Huntington's disease is caused by mutations in the HTT gene, which causes the production of an abnormally long version of the huntingtin protein (Htt). The elongated protein is cut into smaller, toxic fragments that interconnect and accumulate in neurons, impairing the normal functioning of these cells. Dysfunction and eventual death of neurons in certain areas of the brain underlies the signs and symptoms of Huntington's disease. Recent publications show that mutant Htt contributes to the pathogenesis of Huntington's disease by enhancing mTORC1 activity (Sci. Signal., October 28, 2014, Vol. 7, Issue 349, p. ra103).

[0050] One of the functional effectors of mTOR signaling is S6K1; therefore, inhibiting S6K1 function may have disease-ameliorating effects. Additionally, inhibiting S6K1 may limit huntingtin protein production by decreasing global protein translation.

Parkinson's disease

[0051] Parkinson's disease (PD) is a progressive neurodegenerative condition that results from the death of dopamine-containing cells in the substantia nigra. People with PD typically present with symptoms and signs associated with parkinsonism, namely bradykinesia, rigidity, and resting tremor. PD is a common, chronic and progressive neurological condition that affects an estimated 100-180 people per 100,000 people (between 6 and 11 people per 6000 of the general UK population) and has an annual incidence of 4-20 every 100,000. There is an increasing prevalence with age and a higher incidence of PD in men (https://www.nice.org.uk/guidance/cg035/chapter/introduction).

[0052] Although PD has traditionally been considered a non-genetic condition, it is known that at least 5% of people have forms of the disease that occur because of a mutation in one of several specific genes. Mutations in specific genes have been conclusively shown to cause PD. These genes encode alpha-synuclein (SNCA), parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2 or dardarine), putative PTEN-induced kinase 1 (PINK1), DJ-1, and ATP13A2 (Lesage S, Brice A ; Brice (April 2009). "Parkinson's disease: from monogenic forms to genetic susceptibility factors".

[0053] Recent studies that address the mechanism of neurodegeneration in PD demonstrate the involvement of the mTORC1 signaling pathway in the survival mechanism of dopaminergic neurons. In vivo and in vitro studies show that degeneration induced by treatment with PD toxins, such as 6-OHDA and MPTP, causes an increase (upregulation) in the levels of RTP801, a protein encoded by a stress response gene RTP801, the which, in turn, reduces mTOR kinase activity. It has been proposed that the molecular mechanism linking high levels of RTP801 to mTORC1 inhibition and neurodegeneration involves TSC2 and Akt (Deyoung et al., 2008; Malagelada et al., 2008). Genetic manipulations that interfere with TSC2 or increase the expression of a constitutively active form of Akt protected against PD toxins and prevented the increase in RTP801 (Malagelada et al., 2008). However, rapamycin has been reported as a neuroprotective agent both in cell culture and in an MPTP mouse model (mouse model of PD). It has been proposed that rapamycin may enhance Akt activity through inhibition of mTORC1-dependent S6K1 activation and subsequent reduction of phospho-IRS-1, which is a scaffold protein involved in PI3K and Akt activation. (Shah et al., 2004). Therefore, it may also be the case that an inhibitor of S6K1 (a major effector of mTOR) will uncouple the same negative feedback loop to IRS-1, causing activation of Akt and greater survival of neurons from PD patients. Therefore, an S6K1 inhibitor may exhibit therapeutic effects when dosed to a patient with PD.

[0054] For the treatment of all the diseases described above, it would be advantageous to use an orally bioavailable P70S6K inhibitor with properties that allow penetration of the brain in sufficient concentration to achieve efficacy.

[0055] Therefore, it would be beneficial to develop compounds that have the ability to inhibit p70S6 kinase.

The Invention

[0056] The present invention provides a new class of arylalkylamino-substituted quinazolines as p70S6 kinase inhibitors.

[0057] In a first embodiment (Modality 1.0) of the invention, a compound with formula (1) is provided: or a salt, tautomer or N-oxide thereof; on what:

[0058] one of Y and Z is R3 and the other is Ar2;

[0059] Q1 is a C1-8 alkylene group optionally substituted by one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that, when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached; wherein a carbon atom of the C1-8 alkylene group may be optionally replaced by a cyclopropane-1,1-diyl or cyclobutane-1,1-diyl group as long as the total number of carbon atoms in an alkylene group containing such replacement does not exceed 8;

[0060] Q2 is a bond or a C1-8 alkylene group optionally substituted by one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached;

[0061] R1 is selected from hydrogen, NRxRy and a Cy1 group;

[0062] Rx and Ry are the same or different and each is selected from hydrogen, C1-4 hydrocarbyl or C1-4 hydroxyhydrocarbyl; or NRxRy forms a 4 to 7 membered heterocyclic ring that contains a total of 1 or 2 ring member heteroatoms, of which one is N and the other is selected from N, O and S and oxidized forms thereof, the ring heterocyclic being optionally substituted with one or two substituents selected from C1-4 hydrocarbyl, oxo, amino, C1-4 monohydrocarbylamino, C1-4 dihydrocarbylamino, fluorine and hydroxy, provided that there are at least two carbon atoms carbon in sequence between the amino, monohydrocarbylamino C1-4, dihydrocarbylamino C1-4 and hydroxy substituents, when present, and the nitrogen atom of the NRxRy group;

[0063] Cy1 is a non-aromatic monocyclic heterocyclic or carbocyclic group with 3 to 7 members bonded to C that contains 0, 1 or 2 ring member heteroatoms selected from N, O and S and oxidized forms of S, in which the carbocyclic and heterocyclic groups are optionally substituted with one or two substituents selected from C1-3 hydrocarbyl, fluorine, oxo and hydroxy;

[0064] R2 and R4 are the same or different and each is selected from hydrogen, fluorine, chlorine, C1-2 alkyl and C1-2 alkoxy, wherein each C1-2 alkyl and C1-2 alkoxy is optionally substituted with two or more fluorine atoms;

[0065] R3 is selected from hydrogen, fluorine, chlorine, C1-2 alkyl and C1-2 alkoxy, wherein each C1-2 alkyl and C1-2 alkoxy is optionally substituted with two or more fluorine atoms;

[0066] Ar1 is a monocyclic 5- or 6-membered heteroaryl or aryl ring containing 0, 1 or 2 ring member heteroatoms selected from O, N and S, the aryl or heteroaryl being optionally substituted with 1, 2 or 3 substituents R5 which are the same or different and are selected from halogen, cyano and a Ra-Rb group; a 3 4 43 3 43

[0067] R is a bond, O, CO, X C(X ), C(X )X , X C(X )X , S, SO, SO2, NRc, SO2NRc or NRcSO2;

[0068] Rb is: • hydrogen; • a carbocyclic or heterocyclic group containing 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidized forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more R6 substituents; and • an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyan; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups containing 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidized forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more R6 substituents; wherein one or two, but not all, of the carbon atoms of the acyclic C1-8 hydrocarbon group may be optionally replaced c 3 4 43 3 43 by O, S, SO, SO2, NR, X C(X), C(X )X or X C(X )X ;

[0069] R6 is selected from the substituents R5, except that R6 does not consist of or contain a carbocyclic or heterocyclic group;

[0070] X3 is O, S or NRc; It is

[0071] X4 is =O, =S or =NRc; It is

[0072] Rc is hydrogen or C1-4 hydrocarbyl;

[0073] Ar2 is a bicyclic 8 to 11 membered heteroaryl group containing 1, 2, 3 or 4 ring member heteroatoms selected from O, N and S and optionally being substituted with 1, 2 or 3 R7 substituents selected from from oxo, fluorine; chlorine; bromine; C1-4 hydrocarbyl optionally substituted with one or more fluorine atoms; C1-4 hydrocarbyloxy optionally substituted with one or more fluorine atoms; hydroxy; cyan; N(Rc)2; Rc-C(O)-; Rc-C(O)N(Rc)-; (Rc)2NC(O)-; Rc-SO2NRc-; Rc-NHC(O)NH-; (Rc)2NSO2-; and five- and six-membered monocyclic groups containing from 0 to 3 ring member heteroatoms selected from O, N and S, the five- and six-membered monocyclic groups being unsubstituted or substituted with one or more R8 substituents selected from of C1-4 hydrocarbyl, C1-4 hydrocarbyloxy, cyano, hydroxy, oxo, halogen, amino, C1-4 monohydrocarbylamino and C1-4 dihydrocarbylamino and wherein the hydrocarbyl moieties, when present, are optionally substituted with fluorine, C1-2 alkoxy, hydroxy, amino, mono-di-C1-2 alkylamino or di-C1-4 alkylamino;

[0074] and wherein, in each substituent consisting of or containing a hydrocarbyl group, the hydrocarbyl group is selected from alkyl, alkenyl, alkynyl and cycloalkyl groups and combinations thereof.

[0075] In another embodiment (Modality 1.1) of the invention, a compound with formula (1) is provided: or a salt, tautomer or N-oxide thereof; on what:

[0076] one of Y and Z is R3 and the other is Ar2;

[0077] Q1 is a C1-8 alkylene group optionally substituted by one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that, when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached;

[0078] Q2 is a bond or a C1-8 alkylene group optionally substituted with one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that, when a hydroxy substituent is present, there are at least two atoms of carbon between the hydroxy substituent and the nitrogen atom to which Q2 is attached;

[0079] R1 is selected from hydrogen, NRxRy and a Cy1 group;

[0080] Rx and Ry are the same or different and each is selected from hydrogen, C1-4 hydrocarbyl or C1-4 hydroxyhydrocarbyl; or NRxRy forms a 4 to 7 membered heterocyclic ring that contains a total of 1 or 2 ring member heteroatoms, of which one is N and the other is selected from N, O and S and oxidized forms thereof, the ring heterocyclic being optionally substituted with one or two substituents selected from C1-4 hydrocarbyl, oxo, amino, C1-4 monohydrocarbylamino, C1-4 dihydrocarbylamino, fluorine and hydroxy, provided that there are at least two carbon atoms carbon in sequence between the amino, monohydrocarbylamino C1-4, dihydrocarbylamino C1-4 and hydroxy substituents, when present, and the nitrogen atom of the NRxRy group;

[0081] Cy1 is a monocyclic non-aromatic heterocyclic or carbocyclic group with 3 to 7 members bonded to C that contains 0, 1 or 2 ring member heteroatoms selected from N, O and S and oxidized forms of S, in which the carbocyclic and heterocyclic groups are optionally substituted with one or two substituents selected from C1-3 hydrocarbyl, fluorine, oxo and hydroxy;

[0082] R2 and R4 are the same or different and each is selected from hydrogen, fluorine, chlorine, C1-2 alkyl and C1-2 alkoxy, wherein each C1-2 alkyl and C1-2 alkoxy is optionally substituted with two or more fluorine atoms;

[0083] R3 is selected from hydrogen, fluorine, chlorine, C1-2 alkyl and C1-2 alkoxy, wherein each C1-2 alkyl and C1-2 alkoxy is optionally substituted with two or more fluorine atoms;

[0084] Ar1 is a monocyclic 5- or 6-membered heteroaryl or aryl ring containing 0, 1 or 2 ring member heteroatoms selected from O, N and S, the aryl or heteroaryl being optionally substituted with 1, 2 or 3 substituents R5 which are the same or different and are selected from halogen, cyano and a Ra-Rb group; a 3 4 43 3 43

[0085] R is a bond, O, CO, X C(X ), C(X )X , X C(X )X , S, SO, SO2, NRc, SO2NRc or NRcSO2;

[0086] Rb is: • hydrogen; • a carbocyclic or heterocyclic group containing 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidized forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more R6 substituents; and • an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyan; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups containing 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidized forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more R6 substituents; wherein one or two, but not all, of the carbon atoms of the acyclic C1-8 hydrocarbon group may be optionally substituted with O, S, SO, SO2, NR, X C(X), C(X )X or X C(X )X ;

[0087] R6 is selected from the substituents R5, except that R6 does not consist of or contain a carbocyclic or heterocyclic group;

[0088] X3 is O, S or NRc; It is

[0089] X4 is =O, =S or =NRc; It is

[0090] Rc is hydrogen or C1-4 hydrocarbyl;

[0091] Ar2 is a bicyclic 8 to 11 membered heteroaryl group containing 1, 2, 3 or 4 ring member heteroatoms selected from O, N and S and optionally substituted with 1, 2 or 3 R7 substituents selected from from oxo, fluorine; chlorine; bromine; C1-4 hydrocarbyl optionally substituted with one or more fluorine atoms; C1-4 hydrocarbyloxy optionally substituted with one or more fluorine atoms; hydroxy; cyan; N(Rc)2; Rc-C(O)-; Rc-C(O)N(Rc)-; (Rc)2NC(O)-; Rc- SO2NRc-; Rc-NHC(O)NH-; (Rc)2NSO2-; and five- and six-membered monocyclic groups containing from 0 to 3 ring member heteroatoms selected from O, N and S, the five- and six-membered monocyclic groups being unsubstituted or substituted with one or more R8 substituents selected from of C1-4 hydrocarbyl, C14 hydrocarbyloxy, cyano, hydroxy, oxo, halogen, amino, C1-4 monohydrocarbylamino and C1-4 dihydrocarbylamino and wherein the hydrocarbyl moiety, when present, is optionally substituted with fluorine, C1 alkoxy -2, hydroxy, amino, mono-dia-C1-2 alkylamino or di-C1-4 alkylamino;

[0092] and wherein, in each substituent consisting of or containing a hydrocarbyl group, the hydrocarbyl group is selected from alkyl, alkenyl, alkynyl and cycloalkyl groups and combinations thereof.

[0093] Particular and preferred compounds of formula (1) are as defined in Embodiments 1.2 to 1.92 below.

[0094] 1.2 A compound, according to Embodiment 1.0 or 1.1, in which Y is Ar2 and Z is R3.

[0095] 1.3 A compound, according to Embodiment 1.0 or 1.1, in which Y is R3 and Z is Ar2.

[0096] 1.4 A compound, according to Modality 1.0 or 1.1, which contains formula (2): or a salt, tautomer or N-oxide thereof; wherein R1, R2, R3, R4, Ar1, Ar2, Q1 and Q2 are all as defined in Embodiment 1.0 or 1.1.

[0097] 1.4A A compound, according to Embodiment 1.0, wherein Q1 is a C1-6 alkylene group optionally substituted by one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached; and wherein a carbon atom of the C1-6 alkylene group may be optionally replaced by a cyclopropane-1,1-diyl or cyclobutane-1,1-diyl group, provided that the total number of carbon atoms in an alkylene group that contains such replacement does not exceed 6.

[0098] 1.4B A compound, according to Embodiment 1.4A, wherein Q1 is a C1-5 alkylene group optionally substituted by one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that when a substituent hydroxy is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached; wherein a carbon atom of the C1-5 alkylene group may be optionally replaced by a cyclopropane-1,1-diyl or cyclobutane-1,1-diyl group, provided that the total number of carbon atoms in an alkylene group containing such replacement does not exceed 5.

[0099] 1.4C A compound, according to Embodiment 1.4B, wherein Q1 is a C1-4 alkylene group optionally substituted by one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that when a substituent hydroxy is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached; wherein a carbon atom of the C1-4 alkylene group may be optionally replaced by a cyclopropane-1,1-diyl or cyclobutane-1,1-diyl group, provided that the total number of carbon atoms in an alkylene group containing such replacement does not exceed 4.

[00100] 1.4D A compound, according to Embodiment 1.4C, in which Q1 is cyclopropane-1,1-diyl.

[00101] 1.4E A compound, according to Embodiment 1.4C, in which Q1 is cyclobutane-1,1-diyl.

[00102] 1.5 A compound, according to any one of Embodiments 1.0 to 1.4, wherein Q1 is C1-6 alkylene optionally substituted by one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that, when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached.

[00103] 1.6 A compound according to Embodiment 1.5, wherein Q1 is C1-4 alkylene optionally substituted by one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that, when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached.

[00104] 1.7 A compound, according to Embodiment 1.6, in which the C1-4 alkylene is optionally substituted by a hydroxy substituent, provided that there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to the which Q2 is on.

[00105] 1.8 A compound, according to any of Embodiments 1.0 to 1.4, wherein Q1 is a group of the formula -(CRfRg)p- wherein p is 1 to 8, each Rf is independently selected from hydrogen and methyl and each Rg is independently selected from hydrogen, C1-4 alkyl and hydroxyl-C1-4 alkyl, provided that no more than one Rg is greater than methyl and provided that the total number of carbon atoms in -(CRfRg )p- does not exceed 8.

[00106] 1.9 A compound, according to Embodiment 1.8, in which the total number of carbon atoms in -(CRfRg)p- is in the range of 1 to 6.

[00107] 1.10 A compound, according to Embodiment 1.9, in which the total number of carbon atoms in -(CRfRg)p- is in the range of 1 to 4.

[00108] 1.11 A compound, according to any of Embodiments 1.8 to 1.10, where p is 1 or 2.

[00109] 1.12 A compound, according to Embodiment 1.11, where p is 1.

[00110] 1.13 A compound, according to any one of Embodiments 1.8 to 1.12, in which Rf is hydrogen and Rg is selected from hydrogen, methyl, ethyl, isopropyl and hydroxymethyl.

[00111] 1.13A A compound, according to any one of Embodiments 1.8 to 1.12, in which Rf is hydrogen and Rg is selected from hydrogen, methyl, ethyl, isopropyl, hydroxymethyl and hydroxyethyl.

[00112] 1.14 A compound, according to Embodiment 1.13, in which Q1 is selected from CH2, CH(CH3) and CH(CH2OH).

[00113] 1.14A A compound, according to Embodiment 1.13A, in which Q1 is selected from CH2, CH(CH3), CH(CH2OH) and CH(CH2CH2OH).

[00114] 1.15 A compound, according to Embodiment 1.13, in which Q1 is CH(CH3).

[00115] 1.16 A compound, according to any of Embodiments 1.0 to 1.4, in which the fraction -N(Q2-R1)-Q1-Ar1 has the formula: wherein R9 is hydrogen or a C1-4 alkyl optionally substituted with hydroxyl.

[00116] 1.17 A compound, according to any of Embodiments 1.0 to 1.4, in which the fraction -(Q2-R1)N-Q1-Ar1 has the formula: wherein R9 is hydrogen or a C1-4 alkyl optionally substituted with hydroxyl.

[00117] 1.18 A compound, according to Embodiment 1.16 or 1.17, in which R9 is hydrogen, methyl, ethyl, isopropyl or hydroxymethyl.

[00118] 1.18A A compound, according to Embodiment 1.16 or 1.17, in which R9 is hydrogen, methyl, ethyl, isopropyl, hydroxymethyl or hydroxyethyl.

[00119] 1.19 A compound, according to Embodiment 1.18, in which R9 is hydrogen, methyl or hydroxymethyl.

[00120] 1.19A A compound, according to Embodiment 1.18A, in which R9 is hydrogen, methyl, hydroxymethyl or hydroxyethyl.

[00121] 1.20 A compound, according to Embodiment 1.18, in which R9 is hydrogen.

[00122] 1.21 A compound, according to Embodiment 1.18, in which R9 is methyl.

[00123] 1.22 A compound, according to Embodiment 1.18, in which R9 is hydroxymethyl.

[00124] 1.22A A compound, according to Embodiment 1.18, in which R9 is hydroxyethyl.

[00125] 1.23 A compound, according to any one of Embodiments 1.0 to 1.22, in which Q2 is a bond or C1-6 alkylene.

[00126] 1.24 A compound, according to Embodiment 1.23, in which Q2 is a bond or C1-3 alkylene.

[00127] 1.25 A compound, according to Embodiment 1.24, in which Q2 is selected from a bond, CH2, CH2CH2 and CH2CH2CH2.

[00128] 1.26 A compound, according to Embodiment 1.25, in which Q2 is a bond, CH2, or CH2CH2.

[00129] 1.27 A compound, according to Embodiment 1.26, in which Q2 is a bond.

[00130] 1.28 A compound, according to Embodiment 1.26, in which Q2 is CH2.

[00131] 1.29 A compound, according to any one of Embodiments 1.0 to 1.28, in which R1 is selected from hydrogen and a Cy1 group.

[00132] 1.30 A compound, according to Embodiment 1.29, in which R1 is hydrogen.

[00133] 1.31 A compound, according to Embodiment 1.29, in which R1 is a Cy1 group.

[00134] 1.32 A compound, according to any of Embodiments 1.0 to 1.29 and 1.31, in which Cy1 is selected from C3-7 cycloalkyl and non-aromatic heterocyclic groups with 4 to 7 members linked to C that contain 1 or 2 ring member heteroatoms selected from N, O and S, wherein the cycloalkyl and heterocyclic groups are optionally substituted with one or two substituents selected from C1-3 hydrocarbyl, fluorine, oxo and hydroxy.

[00135] 1.33 A compound, according to Embodiment 1.32, in which Cy1 is selected from C3-6 cycloalkyl and non-aromatic heterocyclic groups with 4 to 6 members linked to C that contain 1 or 2 selected ring member heteroatoms from O and S, wherein the cycloalkyl and heterocyclic groups are optionally substituted with one or two substituents selected from C1-3 hydrocarbyl, fluorine, oxo and hydroxy.

[00136] 1.34 A compound, according to Embodiment 1.33, in which Cy1 is selected from C3-6 cycloalkyl and saturated non-aromatic heterocyclic groups with 4 to 6 C-linked members that contain 1 member heteroatom in the ring selected from from O and S, wherein the cycloalkyl and heterocyclic groups are optionally substituted with one or two substituents selected from saturated C1-3 hydrocarbyl, fluorine, oxo and hydroxy.

[00137] 1.35 A compound, according to Embodiment 1.33, in which Cy1 is selected from C3-6 cycloalkyl and saturated non-aromatic heterocyclic groups with 4 to 6 members linked to C that contain 1 member heteroatom of the selected ring from O, wherein the cycloalkyl and heterocyclic groups are optionally substituted with one or two substituents selected from C1-3 alkyl, fluorine, oxo and hydroxy.

[00138] 1.36 A compound, according to Embodiment 1.33, in which Cy1 is selected from C3-6 cycloalkyl and saturated non-aromatic heterocyclic groups with 4 to 6 members linked to C that contain 1 member heteroatom of the selected ring from O, wherein the cycloalkyl and heterocyclic groups are unsubstituted or substituted with one or two substituents selected from methyl, fluorine, oxo and hydroxy.

[00139] 1.37 A compound, according to Embodiment 1.33, in which Cy1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyran and tetrahydrofuran.

[00140] 1.38 A compound, according to Embodiment 1.33, in which Cy1 is tetrahydropyran.

[00141] 1.39 A compound, according to Embodiment 1.32, in which Cy1 is selected from non-aromatic heterocyclic groups with 4 to 7 members linked to C that contain a first ring member that is nitrogen and optionally a second member of the ring selected from N, O and S, in which the heterocyclic groups are optionally substituted with one or two substituents selected from C1-3 hydrocarbyl, fluorine, oxo and hydroxy.

[00142] 1.40 A compound, according to Embodiment 1.39, in which Cy1 is selected from saturated heterocyclic groups with 4 to 7 members linked to C that contain a first ring member that is nitrogen and optionally a second ring member selected from N, O and S, wherein the heterocyclic groups are optionally substituted with one or two substituents selected from saturated C1-3 hydrocarbyl, fluorine, oxo and hydroxy.

[00143] 1.41 A compound, according to Embodiment 1.40, in which Cy1 is selected from saturated heterocyclic groups with 4 to 7 members linked to C that contain a first ring member that is nitrogen and optionally a second ring member selected from N, O and S, wherein the heterocyclic groups are optionally substituted with one or two substituents selected from C1-3 alkyl, cyclopropyl, fluorine and hydroxy.

[00144] 1.42 A compound, according to Embodiment 1.41, in which Cy1 is selected from carbon-linked azetidine, pyrrolidine, piperidine, piperazine, morpholine, homomorpholine and thiomorpholine, each being optionally substituted with one or two selected substituents from C1-3 alkyl, cyclopropyl, fluorine and hydroxy.

[00145] 1.43 A compound, according to Embodiment 1.41, in which Cy1 is carbon-linked morpholine.

[00146] 1.44 A compound, according to any one of Embodiments 1.0 to 1.28, wherein R1 is NRxRy.

[00147] 1.45 A compound, according to any of Embodiments 1.0 to 1.28 and 1.44, in which Rx and Ry are the same or different and each is selected from hydrogen, C1-4 hydrocarbyl or C1-hydroxyhydrocarbyl 4.

[00148] 1.46 A compound, according to Embodiment 1.45, in which Rx and Ry are the same or different and each is selected from hydrogen, saturated C1-4 hydrocarbyl or saturated C1-4 hydroxyhydrocarbyl.

[00149] 1.47 A compound, according to Embodiment 1.46, in which Rx and Ry are the same or different and each is selected from hydrogen, C1-4 alkyl, cyclopropyl, methylcyclopropyl, cyclopropylmethyl, and C2-4 hydroxyalkyl .

[00150] 1.48 A compound, according to Embodiment 1.47, in which Rx and Ry are the same or different and each is selected from hydrogen and C1-4 alkyl.

[00151] 1.49 A compound, according to Embodiment 1.48, in which Rx and Ry are the same or different and each is selected from hydrogen and C1-3 alkyl.

[00152] 1.50 A compound, according to Embodiment 1.49, in which NRxRy is selected from amino, methylamino and dimethylamino.

[00153] 1.51 A compound, according to Embodiment 1.49, in which NRxRy is dimethylamino.

[00154] 1.52 A compound, according to any of Embodiments 1.0 to 1.28 and 1.44, in which NRxRy forms a 4 to 7 membered heterocyclic ring that contains a total of 1 or 2 ring member heteroatoms of which one is N and the other is selected from N, O and S and oxidized forms thereof, the heterocyclic ring being optionally substituted with one or two substituents selected from C1-4 hydrocarbyl, oxo, amino, C1-4 monohydrocarbylamino, di - C1-4 hydrocarbylamino, fluorine and hydroxy, as long as there are at least two carbon atoms in sequence between the amino, mono-hydrocarbylamino C1-4, dihydrocarbylamino C1-4 and hydroxy substituents, when present, and the atom of nitrogen from the NRxRy group.

[00155] 1.53 A compound, according to Embodiment 1.52, in which NRxRy forms a 4 to 7 membered non-aromatic heterocyclic ring that contains a total of 1 or 2 ring member heteroatoms, of which one is N and the other is selected from N, O and S, the heterocyclic ring being optionally substituted with one or two substituents selected from C1-4 hydrocarbyl, oxo, amino, saturated C1-4 monohydrocarbylamino, saturated C1-4 dihydrocarbylamino, fluorine and hydroxy, as long as there are at least two carbon atoms in sequence between the amino, saturated C1-4 monohydrocarbylamino, saturated C1-4 dihydrocarbylamino and hydroxy substituents, when present, and the nitrogen atom of the group NRxRy.

[00156] 1.54 A compound, according to Embodiment 1.53, in which NRxRy forms a saturated 4 to 7 membered heterocyclic ring that contains a total of 1 or 2 ring member heteroatoms, of which one is N and the other is selected from N, O and S, the heterocyclic ring being optionally substituted with one or two substituents selected from C1-4 alkyl, fluorine, oxo, amino, mono-C14 alkylamino, dia-C1-4 alkylamino and hydroxy.

[00157] 1.55 A compound, according to Embodiment 1.54, in which NRxRy forms a saturated 4 to 7 membered heterocyclic ring that contains a total of 1 or 2 ring member heteroatoms, of which one is N and the other is selected from N, O and S, the heterocyclic ring being optionally substituted with one or two substituents selected from C1-3 alkyl, fluorine oxo, amino, mono-C12 alkylamino, dia-C1-2 alkylamino and hydroxy.

[00158] 1.56 A compound, according to Embodiment 1.55, in which NRxRy forms a saturated 4 to 7 membered heterocyclic ring that contains a total of 1 or 2 ring member heteroatoms of which one is N and the other is selected from from N, O and S, the heterocyclic ring being optionally substituted with one or two substituents selected from methyl, fluorine, oxo, amino, methylamino, dimethylamino and hydroxy.

[00159] 1.57 A compound, according to Embodiment 1.55, in which NRxRy forms a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, homomorpholine and thiomorpholine, each being optionally substituted with one or two selected substituents from C1-3 alkyl, fluorine and hydroxy.

[00160] 1.57 A compound, according to Embodiment 1.55, in which NRxRy forms a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, homomorpholine and thiomorpholine, each being optionally substituted with one or two selected substituents from C1-3 alkyl, fluorine and hydroxy.

[00161] 1.57A A compound, according to any one of Embodiments 1.0 to 1.28, in which R1 is selected from: • hydrogen; • a Cy1 group in which Cy1 is selected from 4- to 7-membered saturated heterocyclic groups that contain a first ring member that is nitrogen and optionally a second ring member selected from N, O and S, in which the heterocyclic groups are optionally substituted with one or two substituents selected from C1-3 alkyl, cyclopropyl, fluorine and hydroxyl; and • NRxRy, where Rx and Ry are the same or different and each is selected from hydrogen, C1-4 alkyl, cyclopropyl, methylcyclopropyl, cyclopropylmethyl, and C2-4 hydroxyalkyl.

[00162] 1.58 A compound, according to any of Embodiments 1.0 to 1.57A, in which R2 is selected from hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl and trifluoromethoxy.

[00163] 1.59 A compound, according to Embodiment 1.58, in which R2 is hydrogen.

[00164] 1.60 A compound, according to any one of Embodiments 1.0 to 1.59, in which R3 is selected from hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl and trifluoromethoxy.

[00165] 1.61 A compound, according to Embodiment 1.60, in which R3 is hydrogen.

[00166] 1.62 A compound, according to any one of Embodiments 1.0 to 1.61, in which R4 is selected from hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl and trifluoromethoxy.

[00167] 1.63 A compound, according to Embodiment 1.62, in which R4 is hydrogen.

[00168] 1.64 A compound, according to any one of Embodiments 1.0 to 1.63, wherein Ar1 is a monocyclic aryl or heteroaryl ring selected from phenyl, furyl, thienyl, pyridine and pyrimidinyl, each of these optionally substituted with 1, 2 or 3 R5 substituents that are the same or different and are as defined in Embodiment 1.1.

[00169] 1.65 A compound, according to Embodiment 1.64, wherein Ar1 is a monocyclic aryl or heteroaryl ring selected from phenyl, furyl, thienyl and pyridine, each of which is optionally substituted with 1, 2 or 3 R5 substituents that are the same or different and are as defined in Modality 1.1.

[00170] 1.66 A compound, according to Embodiment 1.65, wherein Ar1 is a phenyl ring optionally substituted with 1, 2 or 3 R5 substituents that are the same or different and are as defined in Embodiment 1.1.

[00171] 1.67 A compound, according to any of Embodiments 1.0 to 1.66, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents that are the same or different and are selected from fluorine, chlorine , bromine, cyano and a Ra-Rb group;

[00172] Ra is a bond, O, CO, NRcC(=O), C(=O)NRc, NRcC(=O)NRc, C(=O) O, OC(=O), S, SO, SO2 , NRc, SO2NRc or NRcSO2;

[00173] Rb is: • hydrogen; • a carbocyclic or heterocyclic group containing 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidized forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more R6 substituents; and • an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyan; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups containing 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidized forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more R6 substituents; wherein one or two, but not all, of the carbon atoms of the acyclic C1-8 hydrocarbon group may be optionally substituted with O, S, SO, SO2 or NRc;

[00174] R6 is selected from the substituents R5, except that R6 does not consist of or contain a carbocyclic or heterocyclic group; It is

[00175] Rc is hydrogen or C1-4 hydrocarbyl.

[00176] 1.68 A compound, according to Embodiment 1.67, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents that are the same or different and are selected from fluorine, chlorine, bromine, cyano and a Ra-Rb group;

[00177] Ra is a bond, O, CO, NRcC(=O), C(=O)NRc, NRcC(=O)NRc, C(=O) O, OC(=O), S, SO, SO2 , NRc, SO2NRc or NRcSO2;

[00178] Rb is: • hydrogen; • a non-aromatic carbocyclic or heterocyclic group containing 3 to 6 ring members, of which 0, 1 or 2 are heteroatom ring members selected from O, N, S and SO2, the non-aromatic carbocyclic or heterocyclic group being optionally substituted with one or more R6 substituents; and • an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyan; amino; mono- or di-C1-4 alkylamino; and non-aromatic carbocyclic and heterocyclic groups containing from 3 to 6 ring members, of which 0, 1 or 2 are heteroatom ring members selected from O, N, S and SO2, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R6; wherein one or two, but not all, of the carbon atoms of the acyclic C1-8 hydrocarbon group may be optionally replaced by O, S, SO, SO2 or NRc;

[00179] R6 is selected from the substituents R5, except that R6 does not consist of or contain a carbocyclic or heterocyclic group; It is

[00180] Rc is hydrogen or C1-4 hydrocarbyl.

[00181] 1.69 A compound, according to Embodiment 1.68, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents that are the same or different and are selected from fluorine, chlorine, bromine, cyano and a Ra-Rb group;

[00182] Ra is a bond, O, CO, NRcC(=O), C(=O)NRc, SO2, NRc, SO2NRc or NRcSO2;

[00183] Rb is: • hydrogen; • a non-aromatic carbocyclic or heterocyclic group containing 3 to 6 ring members, of which 0, 1 or 2 are heteroatom ring members selected from O, N and S, the non-aromatic carbocyclic or heterocyclic group being optionally substituted with one or more R6 substituents; and • a saturated acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; fluorine; cyan; amino; mono- or di-C1-2 alkylamino; and non-aromatic carbocyclic and heterocyclic groups containing 3 to 6 ring members, of which 0, 1 or 2 are heteroatom ring members selected from O, N and S and oxidized forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more R6 substituents; wherein one or two, but not all, of the carbon atoms of the acyclic C1-8 hydrocarbon group may be optionally replaced by O or NRc;

[00184] R6 is selected from the substituents R5, except that R6 does not consist of or contain a carbocyclic or heterocyclic group; It is

[00185] Rc is hydrogen, C1-4 alkyl, cyclopropyl or cyclopropylmethyl.

[00186] 1.70 A compound, according to any one of Embodiments 1.0 to 1.66, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents selected from a L1-Cy2 group; fluorine; chlorine; bromine; C1-3 alkyl; C1-3 alkoxy; trifluoromethyl; difluoromethyl; hydroxy; cyan; trifluoromethoxy; difluoromethoxy; amino; C1-3 mono-alkylamino; di-C1-3 alkylamino; C1-3 alkanoyl; C1-3 alkanoylamino; carbamoyl; mono-C1-3 alkyl carbamoyl; di-C1-3 alkyl carbamoyl; an O-(CH2)k-OR10 group; and an Om-(CH2)n-NR11R12 group; R10 is hydrogen or C1-3 alkyl; R11 is hydrogen or C1-3 alkyl; R12 is hydrogen or C1-3 alkyl; k is 2, 3 or 4; m is 0 or 1; and n is 1, 2, 3 or 4, provided that, when m is 1, then n is 2, 3 or 4; L1 is a bond or linking group selected from C1-4 alkylene, -(CH2)p-NH-(CH2)q-, -(CH2)p-N(CH3)-(CH2)q-, -(CH2) p-C(=O)-(CH2)q-, - (CH2)p-C(=O)NH -(CH2)q-, -(CH2)p-C(=O)N(CH3) -(CH2)q-, - (CH2)p-NHC(=O) - (CH2)q- and -(CH2)p-N(CH3)C(=O) -(CH2)q-; p and q are each independently 0, 1, 2, or 3, provided that the total of p and q does not exceed 4; and Cy2 is a non-aromatic carbocyclic heterocyclic ring with three to seven ring members, which contain 0, 1 or 2 ring member heteroatoms selected from O, N and S and optionally substituted by one, two or three substituents selected from from hydroxy, C1-4 hydrocarbyl, C1-4 hydrocarbyl-C(=O), oxo, amino, C1-4 monohydrocarbylamino, C1-4 dihydrocarbylamino and fluorine.

[00187] 1.70A A compound, according to any one of Embodiments 1.0 to 1.66, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents selected from a L1-Cy2 group; fluorine; chlorine; bromine; C1-3 alkyl; C1-3 alkoxy; trifluoromethyl; difluoromethyl; hydroxy; cyan; trifluoromethoxy; difluoromethoxy; amino; C1-3 mono-alkylamino; di-C1-3 alkylamino; C1-3 alkanoyl; C1-3 alkylsulfonylamino; C13 alkanoylamino; carbamoyl; mono-C1-3alkyl carbamoyl; di-C1-3alkyl carbamoyl; an O-(CH2)k-OR10 group; and an Om-(CH2)n-NR11R12 group; R10 is hydrogen or C1-3 alkyl; R11 is hydrogen or C1-3 alkyl; R12 is hydrogen or C1-3 alkyl; k is 2, 3 or 4; m is 0 or 1; and n is 1, 2, 3 or 4, provided that, when m is 1, then n is 2, 3 or 4; L1 is a bond or linking group selected from C1-4 alkylene, -(CH2)p-NH-(CH2)q-, -(CH2)p-N(CH3)-(CH2)q-, -(CH2) p- C(=O)-(CH2)q-, -(CH2)p-C(=O)NH -(CH2)q-, -(CH2)p-C(=O)N(CH3) -(CH2)q- , - (CH2)p-NHC(=O) -(CH2)q- and -(CH2)p-N(CH3)C(=O) -(CH2)q-; p and q are each independently 0, 1, 2, or 3, provided that the total of p and q does not exceed 4; and Cy2 is a non-aromatic carbocyclic heterocyclic ring with three to seven ring members containing 0, 1 or 2 ring member heteroatoms selected from O, N and S and optionally being substituted by one, two or three substituents selected from of hydroxy, C1-4 hydrocarbyl, C1-4 hydrocarbyl-C(=O), oxo, amino, C1-4 monohydrocarbylamino, C1-4 dihydrocarbylamino and fluorine.

[00188] 1.71 A compound, according to Embodiment 1.70, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents selected from a L1-Cy2 group; fluorine; chlorine; bromine; C1-3 alkyl; C1-3 alkoxy; trifluoromethyl; difluoromethyl; hydroxy; cyan; trifluoromethoxy; difluoromethoxy; amino; C1-3 mono-alkylamino; di-C1-3 alkylamino; C1-3 alkanoyl; C1-3 alkanoylamino; carbamoyl; mono-C1-3alkyl carbamoyl; di-C1-3 alkyl carbamoyl; an O-(CH2)k-OR10 group; and an Om-(CH2)n-NR11R12 group; R10 is hydrogen, methyl or ethyl; R11 is hydrogen, methyl or ethyl; R12 is hydrogen, methyl; or ethyl; k is 2 or 3; m is 0 or 1; and n is 1, 2 or 3, provided that, when m is 1, then n is 2 or 3; L1 is a bond or linking group selected from C1-4 alkylene, -(CH2)p-NH-(CH2)q-, -(CH2)p-N(CH3)-(CH2)q-, -(CH2) p-C(=O)-(CH2)q-, -(CH2)p-C(=O)NH -(CH2)q-, -(CH2)p-C(=O)N(CH3) -(CH2)q-, - (CH2)p-NHC(=O) -(CH2)q- and -(CH2)p- N(CH3)C(=O) -(CH2)q-; p and q are each independently 0, 1 or 2; and Cy2 is a non-aromatic carbocyclic ring with three to six ring members or a heterocyclic ring with five or six ring members that contains 1 or 2 ring member heteroatoms selected from O, N and S, the heterocyclic and carbocyclic rings , each optionally being substituted by one, two or three substituents selected from hydroxy, C1-4 alkyl, cyclopropyl, cyclopropylmethyl, C1-4 alkanoyl, cyclopropylcarbonyl, oxo and fluorine.

[00189] 1.71A A compound, according to Embodiment 1.70 A, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents selected from a L1-Cy2 group; fluorine; chlorine; bromine; C1-3 alkyl; C1-3 alkoxy; trifluoromethyl; difluoromethyl; hydroxy; cyan; trifluoromethoxy; difluoromethoxy; amino; C1-3 mono-alkylamino; di-C1-3 alkylamino; C1-3 alkanoyl; C1-3 alkylsulfonylamino; C1-3 alkanoylamino; carbamoyl; mono-C1-3 alkyl carbamoyl; di-C1-3 alkyl carbamoyl; an O-(CH2)k-OR10 group; and an Om-(CH2)n-NR11R12 group; R10 is hydrogen, methyl or ethyl; R11 is hydrogen, methyl or ethyl; R12 is hydrogen, methyl; or ethyl; k is 2 or 3; m is 0 or 1; and n is 1, 2 or 3, provided that, when m is 1, then n is 2 or 3; L1 is a bond or linking group selected from C1-4 alkylene, -(CH2)p-NH-(CH2)q-, -(CH2)p-N(CH3)-(CH2)q-, -(CH2) p-C(=O)- (CH2)q-, -(CH2)p-C(=O)NH -(CH2)q-, -(CH2)p-C(=O)N(CH3) -(CH2)q-, - (CH2)p- NHC(=O) -(CH2)q- and -(CH2)p-N(CH3)C(=O) -(CH2)q-; p and q are each independently 0, 1 or 2; and Cy2 is a non-aromatic carbocyclic ring with three to six ring members or a heterocyclic ring with five or six ring members that contains 1 or 2 ring member heteroatoms selected from O, N and S, the heterocyclic and carbocyclic rings each being optionally substituted by one, two or three substituents selected from hydroxy, C1-4 alkyl, cyclopropyl, cyclopropylmethyl, C1-4 alkanoyl, cyclopropylcarbonyl, oxo and fluorine.

[00190] 1.72 A compound, according to Embodiment 1.71, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents selected from a L1-Cy2 group; fluorine; chlorine; bromine; C1-3 alkyl; C1-3 alkoxy; trifluoromethyl; difluoromethyl; hydroxy; cyan; trifluoromethoxy; difluoromethoxy; amino; C1-2 mono-alkylamino; di-C1-2 alkylamino; C1-3 alkanoyl; C2-3 alkanoylamino; carbamoyl; mono-C1-3 alkyl carbamoyl; di-C1-3 alkyl carbamoyl; an O-(CH2)k-OR10 group; and an Om-(CH2)n-NR11R12 group; R10 is hydrogen, methyl or ethyl; R11 is hydrogen, methyl or ethyl; R12 is hydrogen, methyl; or ethyl; k is 2 or 3; m is 0 or 1; and n is 1, 2 or 3, provided that when m is 1, then n is 2 or 3; L1 is a bond or linking group selected from C1-4 alkylene, -(CH2)p-NH-(CH2)q-, -(CH2)p-N(CH3)-(CH2)q-, -(CH2) p-C(=O)-(CH2)q-, -(CH2)p-C(=O)NH -(CH2)q-, -(CH2)p-C(=O)N(CH3) -(CH2)q-, - (CH2)p-NHC(=O) -(CH2)q- and -(CH2)p- N(CH3)C(=O) -(CH2)q-; p and q are each independently 0 or 1; and Cy2 is a non-aromatic heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydrofuran, and tetrahydropyran, the heterocyclic ring being optionally substituted by one or two substituents selected from hydroxy, C1-4 alkyl , cyclopropyl, cyclopropylmethyl, C1-4 alkanoyl, cyclopropylcarbonyl, oxo and fluorine.

[00191] 1.72A A compound, according to Embodiment 1.71 A, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents selected from a L1-Cy2 group; fluorine; chlorine; bromine; C1-3 alkyl; C1-3 alkoxy; trifluoromethyl; difluoromethyl; hydroxy; cyan; trifluoromethoxy; difluoromethoxy; amino; C1-2 mono-alkylamino; di-C1-2alkylamino; C1-3 alkanoyl; C1-2 alkylsulfonylamino; C2-3 alkanoylamino; carbamoyl; mono-C1-3 alkyl carbamoyl; di-C1-3 alkyl carbamoyl; an O-(CH2)k-OR10 group; and an Om-(CH2)n-NR11R12 group; R10 is hydrogen, methyl or ethyl; R11 is hydrogen, methyl or ethyl; R12 is hydrogen, methyl; or ethyl; k is 2 or 3; m is 0 or 1; and n is 1, 2 or 3, provided that, when m is 1, then n is 2 or 3; L1 is a bond or linking group selected from C1-4 alkylene, -(CH2)p-NH-(CH2)q-, -(CH2)p-N(CH3)-(CH2)q-, -(CH2) p-C(=O)- (CH2)q-, -(CH2)p-C(=O)NH -(CH2)q-, -(CH2)p-C(=O)N(CH3) -(CH2)q-, - (CH2)p- NHC(=O) -(CH2)q- and -(CH2)p-N(CH3)C(=O) -(CH2)q-; p and q are each independently 0 or 1; and Cy2 is a non-aromatic heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydrofuran, and tetrahydropyran, the heterocyclic ring being optionally substituted by one or two substituents selected from hydroxy, C1-4 alkyl , cyclopropyl, cyclopropylmethyl, C1-4 alkanoyl, cyclopropylcarbonyl, oxo and fluorine.

[00192] 1.73 A compound, according to Embodiment 1.72, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents selected from a L1-Cy2 group; fluorine; chlorine; bromine; C1-2 alkyl; C1-2 alkoxy; trifluoromethyl; difluoromethyl; hydroxy; cyan; trifluoromethoxy; difluoromethoxy; amino; C1-2 mono-alkylamino; di-C1-2 alkylamino; acetyl; acetylamino; carbamoyl; mono-C1-2 alkyl carbamoyl; di-C1-2 alkyl carbamoyl; dimethylaminoethoxy; where L1 is selected from a bond, O, NH, N(CH3), NHC(=O), C(=O)NH, N(CH3)C(=O) and C(=O)N( CH3); and Cy2 is selected from piperidine, piperazine, morpholine and tetrahydropyran, the heterocyclic ring being optionally replaced by one or two substituents selected from hydroxy, methyl and oxo.

[00193] 1.73A A compound, according to Embodiment 1.72 A, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents selected from a L1-Cy2 group; fluorine; chlorine; bromine; C1-2 alkyl; C1-2 alkoxy; trifluoromethyl; difluoromethyl; hydroxy; cyan; trifluoromethoxy; difluoromethoxy; C1-2 alkylsulfonylamino; amino; C1-2 monoalkylamino; di-C1-2alkylamino; acetyl; acetylamino; carbamoyl; mono-C1-2 alkyl carbamoyl; di-C1-2 alkyl carbamoyl; dimethylaminoethoxy; where L1 is selected from a bond, O, NH, N(CH3), NHC(=O), C(=O)NH, N(CH3)C(=O) and C(=O)N( CH3); and Cy2 is selected from piperidine, piperazine, morpholine and tetrahydropyran, the heterocyclic ring being optionally replaced by one or two substituents selected from hydroxy, methyl and oxo.

[00194] 1.74 A compound, according to Embodiment 1.73, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents selected from fluorine, chlorine, bromine, methyl, hydroxy, methoxy, trifluoromethyl, difluoromethyl , cyano, trifluoromethoxy, difluoromethoxy, morpholinyl, piperazinyl, N-methylpiperazinyl and dimethylaminoethoxy.

[00195] 1.74A A compound, according to Embodiment 1.73 A, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents selected from fluorine, chlorine, bromine, methyl, hydroxy, methoxy, trifluoromethyl , difluoromethyl, cyano, trifluoromethoxy, difluoromethoxy, methylsulfonylamino, morpholinyl, piperazinyl, N-methylpiperazinyl and dimethylaminoethoxy.

[00196] 1.75 A compound, according to any of Embodiments 1.0 to 1.66, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents selected from L1-Cy2; fluorine, chlorine, methyl, hydroxy, methoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy and dimethylaminoethoxy; where L1 is selected from a bond, O, NH, NHC(=O), C(=O)NH and C(=O)N(CH3); and Cy2 is selected from piperidine, piperazine, morpholine and tetrahydropyran, the heterocyclic ring being optionally replaced by one or two substituents selected from methyl and oxo.

[00197] 1.75A A compound, according to any of Embodiments 1.0 to 1.66, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents selected from L1-Cy2; fluorine, chlorine, methyl, hydroxy, methoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, methylsulfonylamino and dimethylaminoethoxy; where L1 is selected from a bond, O, NH, NHC(=O), C(=O)NH and C(=O)N(CH3); and Cy2 is selected from piperidine, piperazine, morpholine and tetrahydropyran, the heterocyclic ring being optionally replaced by one or two substituents selected from methyl and oxo.

[00198] 1.76 A compound, according to Embodiment 1.75, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents selected from fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl, difluoromethyl, cyano , trifluoromethoxy and difluoromethoxy.

[00199] 1.76A A compound, according to Embodiment 1.75 A, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents selected from fluorine, chlorine, bromine, methyl, hydroxyl, methoxy, methylsulfonylamino , trifluoromethyl, difluoromethyl, cyano, trifluoromethoxy and difluoromethoxy.

[00200] 1.77 A compound, according to Embodiment 1.76, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents selected from fluorine, chlorine, methyl, methoxy, trifluoromethyl and trifluoromethoxy.

[00201] 1.77A A compound, according to Embodiment 1.76 A, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents selected from fluorine, chlorine, methyl, hydroxyl, methoxy, methylsulfonylamino, trifluoromethyl and trifluoromethoxy.

[00202] 1.78 A compound, according to Embodiment 1.77, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents selected from fluorine, chlorine, methyl and methoxy.

[00203] 1.78A A compound, according to Embodiment 1.77 A, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents selected from fluorine, chlorine, methylsulfonylamino, methyl and methoxy.

[00204] 1.79 A compound, according to Embodiment 1.78, in which Ar1 is unsubstituted or is substituted with 1, 2 or 3 R5 substituents selected from fluorine, chlorine and methoxy.

[00205] 1.80 A compound, according to any one of Embodiments 1.0 to 1.79, in which Ar1 is unsubstituted or is substituted with one or two R5 substituents.

[00206] 1.81 A compound, according to Embodiment 1.80, in which Ar1 is unsubstituted or is substituted with a substituent R5.

[00207] 1.82 A compound, according to Embodiment 1.81, in which Ar1 is not substituted.

[00208] 1.83 A compound, according to Embodiment 1.81, in which Ar1 is replaced with a substituent R5.

[00209] 1.84 A compound, according to Embodiment 1.80, in which Ar1 is a phenyl ring that is unsubstituted or is substituted with one or two R5 substituents, in which at least one R5 substituent is present in the meta or para position of the phenyl ring.

[00210] 1.85 A compound, according to Embodiment 1.84, in which Ar1 is a phenyl ring that is substituted with a substituent R5 that is present in the meta position of the phenyl ring.

[00211] 1.86 A compound, according to Embodiment 1.84, in which Ar1 is a phenyl ring that is substituted with a substituent R5 that is present in the para position of the phenyl ring.

[00212] 1.87 A compound, according to Embodiment 1.84, wherein Ar1 is a phenyl ring that is unsubstituted or is substituted with a substituent R5 selected from 3-chloro, 4-chloro, 3-fluoro, 4- fluoro, 3-methoxy, 4-methoxy, 3-methyl and 4-methyl.

[00213] 1.88 A compound, according to Embodiment 1.87, wherein Ar1 is a phenyl ring that is unsubstituted or is substituted with a substituent R5 selected from 3-chloro, 3-fluoro, 4-fluoro and 3- methoxy.

[00214] 1.89 A compound, according to Embodiment 1.84, in which Ar1 is a phenyl ring that is substituted with two R5 substituents.

[00215] 1. 90 A compound, according to Embodiment 1.89, wherein Ar1 is a phenyl ring that is substituted with two substituents R5, wherein one substituent is present in the para position of the phenyl ring and the other is present in the substituent meta of the phenyl ring.

[00216] 1.91 A compound, according to Embodiment 1.90, in which Ar1 is 3,4-difluorophenyl.

[00217] 1.91A A compound, according to Embodiment 1.82, in which Ar1 is unsubstituted phenyl.

[00218] 1.91B A compound, according to Embodiment 1.66, in which Ar1 is unsubstituted phenyl or substituted phenyl with one or two substituents selected from fluorine, chlorine, methoxy, methylsulfonylamino and hydroxyl.

[00219] 1.91C A compound, according to Embodiment 1.66, in which Ar1 is unsubstituted phenyl or substituted phenyl with one or two substituents selected from fluorine, chlorine, methoxy and methylsulfonylamino.

[00220] 1.91D A compound, according to Embodiment 1.66, in which Ar1 is selected from unsubstituted phenyl, 3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2 ,6-difluorophenyl, 3,4-difluorophenyl, 3-methoxyphenyl, 3-methylsulfonylaminophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl and 4-hydroxyphenyl.

[00221] 1.91E A compound, according to Embodiment 1.66, in which Ar1 is selected from unsubstituted phenyl, 3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2 ,6-difluorophenyl, 3,4-difluorophenyl, 3-methoxyphenyl, 3-methylsulfonylaminophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl and 4-hydroxyphenyl.

[00222] 1.92 A compound, according to any one of Embodiments 1.0 to 1.91, wherein Ar2 is selected from fused heteroaromatic rings 5.6 and fused heteroaromatic rings 6.6, each containing 1, 2, 3 or 4 ring member heteroatoms selected from N, O and S and optionally being substituted with 1, 2, or 3 R7 substituents as defined in Embodiment 1.1.

[00223] 1.93 A compound, according to Embodiment 1.92, in which the fused heteroaromatic rings 5.6 and the fused heteroaromatic rings 6.6 each contain 1, 2, 3 or 4 nitrogen ring member heteroatoms.

[00224] 1.94 A compound, according to Embodiment 1.92 or 1.93, in which Ar2 is selected from fused heteroaromatic rings 5.6, each being optionally substituted by 1, 2 or 3 R7 substituents as defined in Embodiment 1.1.

[00225] 1.95 A compound, according to Embodiment 1.94, in which Ar2 is selected from pyrimido-imidazole, pyrido-imidazole, pyrimido-pyrrole, pyrido-pyrrole, benzo-imidazole, benzo-pyrrole, pyrimido-pyrazol groups , pyrido-pyrazole and benzo-pyrazole, each optionally being substituted by 1, 2 or 3 R7 substituents as defined in Embodiment 1.1.

[00226] 1.95A A compound, according to Embodiment 1.95, in which Ar2 is selected from pyrimido-pyrrole, pyrido-pyrrole, pyrimido-pyrazole, pyrido-pyrazole and pyrimido-imidazole groups, each of which is substituted optionally by 1, 2 or 3 R7 substituents as defined in Embodiment 1.1.

[00227] 1.96 A compound, according to Embodiment 1.95, in which Ar2 is selected from pyrimido-pyrrole, pyrido-pyrrole, pyrimido-pyrazole and pyrido-pyrazole groups, each of these optionally substituted by 1, 2 or 3 substituents R7 as defined in Embodiment 1.1.

[00228] 1.97 A compound, according to Embodiment 1.96, in which Ar2 is a pyrimido-pyrazole group that is optionally substituted by 1, 2 or 3 substituents R7 as defined in Embodiment 1.1.

[00229] 1.98 A compound, as defined in any of Embodiments 1.0 to 1.97, in which Ar2 is unsubstituted or is substituted with one or two substituents R7 selected from oxo, fluorine; chlorine; bromine; C1-4 hydrocarbyl optionally substituted with one or more fluorine atoms; C1-4 hydrocarbyloxy optionally substituted with one or more fluorine atoms; hydroxy; cyan; and five- and six-membered monocyclic groups containing from 0 to 3 ring member heteroatoms selected from O, N and S, the five- and six-membered monocyclic groups being unsubstituted or substituted with one or more R8 substituents selected from of C1-4 hydrocarbyl, C14 hydrocarbyloxy, cyano, hydroxy, oxo, halogen, amino, C1-4 monohydrocarbylamino and C1-4 dihydrocarbylamino.

[00230] 1.99 A compound, as defined in Embodiment 1.98, in which Ar2 is unsubstituted or is substituted with one or two R7 substituents selected from oxo, fluorine; chlorine; bromine; C1-4 alkyl optionally substituted with one or more fluorine atoms; C1-4 alkoxy optionally substituted with one or more fluorine atoms; hydroxy; cyan; and five- and six-membered monocyclic groups selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrole, pyrazole, imidazole, thiophene, furan, oxazole and isoxazole, the five- and six-membered monocyclic groups each being unsubstituted or substituted with one or more R8 substituents selected from C1-4 alkyl, C1-4 alkoxy, cyano, hydroxy, fluorine, chlorine, amino, methylamino and dimethylamino.

[00231] 1.100 A compound, as defined in Embodiment 1.99, in which Ar2 is unsubstituted or is substituted with one or two R7 substituents selected from oxo, fluorine; chlorine; bromine; C1-4 alkyl optionally substituted with one or more fluorine atoms; C1-4 alkoxy optionally substituted with one or more fluorine atoms; hydroxy and cyano.

[00232] 1.101 A compound, as defined in Embodiment 1.100, in which Ar2 is unsubstituted or is substituted with one or two R7 substituents selected from oxo, methyl, difluoromethyl, trifluoromethyl, amino, hydroxy and cyano.

[00233] 1.102 A compound, as defined in any of Embodiments 1.0 to 1.101, in which Ar2 is unsubstituted or monosubstituted.

[00234] 1.103 A compound, as defined in Embodiment 1.102, in which Ar2 is unsubstituted or is monosubstituted with a substituent R7 selected from methyl and amino.

[00235] 1.103A A compound, as defined in Embodiment 1.103, in which Ar2 is unsubstituted or is monosubstituted with a substituent R7 selected from methyl and cyano.

[00236] 1.104 A compound, as defined in Embodiment 1.104, in which Ar2 is unsubstituted or is substituted with a substituent R7 that is methyl.

[00237] 1.105 A compound, as defined in Embodiment 1.105, in which Ar2 is not substituted.

[00238] 1.106 A compound, as defined in any of Embodiments 1.0 to 1.105, wherein Ar2 is: where * denotes the point of attachment to the quinazoline ring.

[00239] 1.107 A compound with formula (3): or a salt, tautomer or N-oxide thereof, wherein R1, R2, R3, R4, Q1, Q2 and Ar1 are as defined in any of Embodiments 1.0 to 1.106.

[00240] 1.108 A compound with formula (4): or a salt, tautomer or N-oxide thereof, wherein R1, R2, R3, R4, R5, Q1 and Q2 are as defined in any of Embodiments 1.0 to 1.106; ex is 0, 1 or 2.

[00241] 1.109 A compound, according to Embodiment 1.108, in which Q1 is CH2 or CH(CH3), Q2 is a bond or CH2 and R1 is hydrogen.

[00242] 1.110 A compound, according to Embodiment 1.109, or Embodiment 1.109, wherein x is 0 or 1.

[00243] 1.111 A compound selected from the title compounds of examples 1 to 43 contained in this document.

[00244] 1.112 A compound, according to any one of Embodiments 1.0 to 1.111, which is in the form of a salt.

[00245] 1.113 A compound, according to Embodiment 1.112, in which the salt is an acid addition salt.

[00246] 1.114 A compound, according to Embodiment 1.113, or Embodiment 1.113, wherein the salt is a pharmaceutically acceptable salt.

[00247] 1.115 A compound, according to any one of Embodiments 1.0 to 1.114, which is in the form of a solvate.

[00248] 1.116 A compound, according to Embodiment 1.115, in which the solvate is a hydrate.

Definitions

[00249] References to “heterocyclic” and “carbocyclic” groups, as used herein, shall, unless the context indicates otherwise, include both aromatic and non-aromatic ring systems. Therefore, for example, the term “carbocyclic and heterocyclic groups” includes, within its scope, aromatic, non-aromatic, unsaturated, partially saturated and fully saturated heterocyclic and carbocyclic ring systems.

[00250] Heterocyclic or carbocyclic groups can be heteroaryl or aryl groups. Aryl or heteroaryl groups may be monocyclic or bicyclic groups as defined herein. The term “aryl” as used herein refers to a carbocyclic group with an aromatic character and the term “heteroaryl” is used herein to indicate a heterocyclic group with an aromatic character. Where the context permits, the terms “aryl” and “heteroaryl” may encompass bicyclic ring systems in which both rings are aromatic or one ring is non-aromatic and the other is aromatic. In such bicyclic systems that contain an aromatic and a non-aromatic group, the group may be linked by the aromatic ring or the non-aromatic ring.

[00251] The term “C-linked” (e.g., as in “heterocyclic or carbocyclic or non-aromatic monocyclic 4- to 7-membered C-linked group”) refers to a group as defined herein in which the point of attachment is through a carbon atom.

[00252] In formula (1), Ar1 is a monocyclic 5- or 6-membered heteroaryl or aryl ring that contains 0, 1 or 2 ring member heteroatoms selected from O, N and S. Examples of such rings include but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine and phenyl groups.

[00253] The aryl or heteroaryl ring Ar1 can be replaced with a substituent that consists of or includes a carbocyclic or heterocyclic group with 3- to 7 members. The carbocyclic or heterocyclic group may be aryl or heteroaryl groups as defined above, or they may be non-aromatic groups.

[00254] The term “non-aromatic group” refers to unsaturated ring systems without aromatic character, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. The terms “unsaturated” and “partially saturated” refer to rings in which the ring structure(s) contains atoms that share more than one valence bond, e.g., the ring contains at least one bond multiple, for example, a C=C N=C bond. The term “saturated” refers to rings in which there are no multiple bonds between the ring atoms. Saturated carbocyclic groups include the cycloalkyl groups cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Partially saturated carbocyclic groups include cycloalkenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctyl groups. Non-aromatic heterocyclic groups include azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, thiomorpholine S-oxide and S,S- dioxide, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, di - hydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran, imidazoline, imidazolidinone, oxazoline, thiazoline, pyrazoline, pyrazolidine.

[00255] In formula (1), Ar2 is a bicyclic 8- to 11-membered heteroaryl group that contains 1, 2, 3 or 4 ring member heteroatoms selected from O, N and S. The bicyclic heteroaryl group can be, for example, a group selected from a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 heteroatoms in the ring; a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; and a cyclopentyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 heteroatoms in the ring.

[00256] Particular examples of bicyclic heteroaryl groups that contain a five-membered ring fused to another five-membered ring include, but are not limited to, imidazothiazole (e.g., imidazo[2,1-b]thiazole) and imidazoimidazole (e.g., example, imidazo[1,2- a]imidazole). Particular examples of bicyclic heteroaryl groups that contain a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzoisothiazole, isobenzofuran, indole, isoindole groups. , indolizine, indoline, isoindoline, purine (e.g. adenine, guanine), indazole, pyrazolopyrimidine (e.g. pyrazolo[1,5-a]pyrimidine), triazolopyrimidine (e.g. [1,2,4]triazolo[1, 5-a]pyrimidine), benzodioxol and pyrazolopyridine (e.g. pyrazolo[1,5-a]pyridine). Particular examples of bicyclic heteroaryl groups that contain two fused six-membered rings include, but are not limited to, quinoline, isoquinoline, chromane, thiochromane, chromene, isochromene, chromane, isochromane, benzodioxane, quinolizidine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline groups , quinazoline, cinoline, phthalazine, naphthyridine and pteridine.

[00257] The term “hydrocarbyl”, as used herein, refers to aliphatic, alicyclic and aromatic groups containing a completely carbonic main chain and consisting of carbon and hydrogen atoms, except where otherwise stated. Examples of hydrocarbyl groups include alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl and carbocyclic aralkyl groups, aralkenyl and aralkinyl. Such groups may be unsubstituted or, where stated, substituted by one or more substituents as defined herein. In some cases, as defined herein, one or more, but not all, of the carbon atoms of the hydrocarbyl group may be exchanged for another atom or group of atoms.

[00258] The term “alkylene” (e.g., as in a C1-4 straight chain or branched alkylene chain), as used herein, refers to an alkanediyl group, that is, a bivalent saturated acyclic straight chain or branched-chain hydrocarbon. Examples of straight-chain alkylene groups include methylene (CH2), ethylene (CH2CH2), and propylene ((CH2CH2CH2). Examples of branched-chain alkylene groups include CH(CH3), CH2CH(CH3)CH2, and CH2(CH3)CH2CH2.

Salts

[00259] The compounds of the invention, as defined in Embodiments 1.0 to 1.111, can be represented in the form of salts.

[00260] The salts referenced above (and also defined in embodiments 1.112, 1.113 and 1.114) are typically acid addition salts.

[00261] Salts can be synthesized from the precursor compound by conventional chemical methods such as the methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-0268, Hardcover, 388 pages, August 2002. In general, such salts can be prepared by reacting the free base form of the compound with the acid in water or an organic solvent, or in a mixture from both; In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.

[00262] Acid addition salts (as defined in Embodiment 1.113) can be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g., L-ascorbic), L-aspartic, benzenesulfonic, benzoic acid. , 4- acetamidobenzoic, butanoic, camphoric (+), camphorsulfonic, (+)-(1S)- camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfonic, ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, methanoic, fumaric, galactaric, gentisic, glycoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrobromic , hydrochloric, iodide, isethionic, (+)-L-lactic, (±)-DL-lactic, lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalene -2-sulfonic, naphthalene-1,5-disulfonic, 1-hydroxy-2-naphtoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-aminosalicylic , sebacic, stearic, succinic, sulfuric, tannic, (+)-L-tartaric, thiocyanic, p-toluenesulfonic, undecylenic and valeric, as well as acylated amino acids and cation exchange resins.

[00263] The salt forms of the compounds of the invention are typically pharmaceutically acceptable salts and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pages. 1-19. However, salts that are not pharmaceutically acceptable can also be prepared as intermediate forms that can then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms which may be useful, for example, in purifying or separating the compounds of the invention, also form part of the invention.

N-oxides

[00264] Many compounds of Modalities 1.0 to 1.116 can form N-oxides. Where a compound contains multiple amine functions, one or more nitrogen atoms may be oxidized to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.

[00265] N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4th edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in a solvent inert such as dichloromethane.

[00266] Additional examples of conditions for the formation of N-oxides are disclosed in our previous publication, WO2008/139152.

Geometric isomers and tautomers

[00267] The compounds of the invention can exist in several different geometric tautomeric and isomeric forms and references to the compounds of formula (1), as defined in Embodiments 1.0 to 1.116, include all of these forms. For the avoidance of doubt, where a compound can exist in one of several geometric tautomeric and isometric forms and only one is specifically described or shown, all others will nevertheless be encompassed by formula (1) or subgroups, subsets, preferences and examples thereof.

Optical isomers

[00268] Where compounds of the formula contain one or more chiral centers and can exist in the form of two or more optical isomers, references to the compounds will include all optical isometric forms thereof (e.g., enantiomers, epimers and diastereoisomers) as individual optical isomers or mixtures (e.g., racemic mixture) or two or more optical isomers, unless the context requires otherwise.

[00269] Optical isomers can be classified and identified through their optical activity (i.e., as + and - isomers, or d and l isomers) or they can be classified in terms of their absolute stereochemistry using the developed “R and S” nomenclature by Cahn, Ingold and Prelog, see Advanced Organic Chemistry, by, Jerry March, 4th edition, John Wiley & Sons, New York, 1992, pages 109-114, and also see Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415.

[00270] Optical isomers can be separated by various techniques including chiral chromatography (chromatography on a chiral support) and such techniques are known to those skilled in the art.

[00271] As an alternative to chiral chromatography, optical isomers can be separated by forming diastereoisomeric salts with chiral acids, such as (+)-tartaric acid, (-)-pyroglucuramic acid, (-)-di-toluoyl-L-tartaric acid , (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid, separating the diastereoisomers by preferential crystallization and then dissociating the salts to provide the individual enantiomer of the free base.

[00272] Where the compounds of the invention exist as two or more optical isomeric forms, one enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity. Therefore, in certain circumstances, it may be desirable to use, as a therapeutic agent, only one of a pair of enantiomers, or only one of a plurality of diastereoisomers. Thus, the invention provides compositions that contain a compound with one or more chiral centers, wherein at least 55% (e.g., at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of formula (1) is present as an individual optical isomer (e.g. enantiomer or diastereoisomer). In a general embodiment, 99% or more (e.g., substantially all) of the total amount of the compound of formula (1) may be present as an individual optical isomer (e.g., enantiomer or diastereoisomer).

Isotopes

[00273] The compounds of the invention, as defined in any of Embodiments 1.0 to 1.116, may contain one or more isotopic substitutions and a reference to a particular element includes, within its scope, all isotopes of the element. For example, a reference to hydrogen includes, within its scope, 1H, 2H (D), and 3H (T). Similarly, references to carbon and oxygen include, within their scope, respectively, 12C, 13C and 14C and 16O and 18O.

[00274] Isotopes can be radioactive or non-radioactive. In one embodiment of the invention, the compounds do not contain any radioactive isotopes. Such compounds are preferred for therapeutic use. In another embodiment, however, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context.

Solvates

[00275] Compounds of formula (1), as defined in any of Embodiments 1.0 to 1.116, can form solvates.

[00276] Preferred solvates are solvates formed by the incorporation, into the solid state structure (e.g., crystalline structure) of the compounds of the invention, of molecules of a non-toxic pharmaceutically accepted solvent (referred to below as solvation solvent). Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethyl sulfoxide. Solvates can be prepared from recrystallization of the compounds of the invention with a solvent or mixture of solvents that contains the solvation solvent. One can determine whether or not a solvate has been formed in any instance by subjecting crystals of the compound to analysis using standard and well-known techniques such as thermogravimetry (TGE), differential scanning calorimetry (DSC), and X-ray crystallography.

[00277] Solvates can be stoichiometric or non-stoichiometric solvates.

[00278] Particularly preferred solvates are hydrates, and examples of hydrates include semihydrates, monohydrates and dihydrates.

[00279] For a more detailed discussion of solvates and the methods used to make and classify them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

Prodrugs

[00280] The compounds of formula (1), as defined in any of Embodiments 1.0 to 1.116, can be presented in the form of a prodrug.

[00281] “Prodrugs” mean, for example, any compound that is converted in vivo into a biologically active compound of formula (1), as defined in any of Embodiments 1.0 to 1.116.

[00282] For example, some prodrugs are esters of the active compound (e.g., a metabolically labile and physiologically acceptable ester). During metabolization, the ester group (- C(=O)OR) is cleaved to produce the active drug. Such esters may be formed through esterification, for example, of any hydroxyl groups present in the precursor compound with, where appropriate, prior protection of any other reactive groups present in the precursor compound, followed by deprotection if necessary.

[00283] Some prodrugs are also enzymatically activated to produce the active compound or a compound that, after additional chemical reaction, produces the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or it may be an amino acid ester derivative.

Complexes and clathrates

[00284] Also encompassed by formula (1) or subgroups, subsets, preferences and examples thereof are complexes (for example, inclusion complexes or clathrates, with compounds such as cyclodextrins or complexes with metals) of compounds.

Biological activity

[00285] Compounds of formula (1), as defined in any of Embodiments 1.0 to 1.116, have activities as p70S6 kinase inhibitors. As such, they may be useful in preventing or treating disease states and conditions in which p70S6 kinase or mutant forms thereof play an active part.

[00286] For example, it is anticipated that compounds of Embodiments 1.0 to 1.116 will be useful in treating a range of proliferative disorders, such as cancers.

[00287] Thus, in additional embodiments (Modality 2.1 to 2.9), the invention provides:

[00288] 2.1 A compound of formula (1), as defined in any of Embodiments 1.0 to 1.116, for use in medicine or therapy.

[00289] 2.2 A compound of formula (1), as defined in any of Embodiments 1.0 to 1.116, for use in the prevention or treatment of disease states and conditions mediated by p70S6 kinase or mutant forms thereof.

[00290] 2.3 A compound of formula (1), as defined in any of Embodiments 1.0 to 1.116, for use in the prevention or treatment of disease states and conditions characterized by abnormal expression of p70S6 kinase (for example, overexpression or expression of a mutant form of p70S6 kinase).

[00291] 2.4 A compound of formula (1), as defined in any of Embodiments 1.0 to 1.116, for use as an anti-cancer agent.

[00292] 2.5 The use of a compound of formula (1), as defined in any of Embodiments 1.0 to 1.116, for the manufacture of a medicine for the treatment of cancer.

[00293] 2.6 A method of treating a cancer, wherein the method comprises administering to a subject in need a therapeutically effective amount of a compound of formula (1), as defined in any of Embodiments 1.0 to 1.116, optionally together to another anticancer agent or radiotherapy.

[00294] 2.7 A compound of formula (1), as defined in any one of Embodiments 1.0 to 1.116, for use in improving a therapeutic effect of radiotherapy or chemotherapy in the treatment of a proliferative disease, such as cancer.

[00295] 2.8 The use of a compound of formula (1), as defined in any of Embodiments 1.0 to 1.116, for the manufacture of a medicament to improve a therapeutic effect of radiotherapy or chemotherapy in the treatment of a proliferative disease, such like cancer.

[00296] 2.9 A method for the prophylaxis or treatment of a proliferative disease, such as cancer, wherein the method comprises administering to a patient, combined with radiotherapy or chemotherapy, a compound of formula (1), as defined in any of Modalities from 1.0 to 1.116.

[00297] Examples of proliferative disorders (e.g., cancers), as defined in Embodiments 2.4 to 2.9, include, but are not limited to, carcinomas, e.g., carcinomas of the bladder, breast, colon, kidney, epidermis, liver, lung, esophagus, gallbladder, ovaries, pancreas, stomach, cervix, thyroid, prostate, gastrointestinal system or skin, tumors of hematopoietic tissues, such as leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphomas, non- Hodgkin, hairy cell lymphoma, or Burkitt lymphoma; tumors of hematopoietic tissues of myeloid lineage, for example, acute and chronic myelogenous leukemia, myelodysplastic syndrome or promyelocytic leukemia; follicular thyroid cancer; tumors of mesenchymal origin, for example, fibrosarcoma or rhabdomyosarcoma; tumors of the central or peripheral nervous system, for example, astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosa; keratoacanthoma; follicular thyroid cancer; or Kaposi's sarcoma.

[00298] A particular subset of cancers against which the compounds of Embodiments 1.0 to 1.116 should prove particularly active are cancers that are characterized by overexpression of P70S6 or elevated expression of P70S6 or the presence of mutant forms of P70S6 or elevated levels of activated (phosphorylated) p70S6K.

[00299] The ability of the compounds of the invention to inhibit p70S6 kinase can be determined using the protocols established in the examples section below.

[00300] Additional particular examples of cancers against which the compounds of Embodiments 1.0 to 1.116 should prove particularly active are: • breast cancer (overexpression is linked to poor prognosis and metastasis (see Mol. Can. Ther, 2010, 9, 1180), triple negative breast cancer • Diffuse large B-cell lymphoma: (see Expert Opin Ther Targets. Sep 2009;13(9):1085-93) • Glioblastoma multiforme (associated with elevated levels of P70S6K ( see J Clin Oncol. Aug 10, 2005;23(23):5294-304)) • Colorectal cancer in humans (in which the mTOR and p70S6K pathways are highly active (see Ann. Surg. Oncol. Sep. 2009 ;16(9):2617-28. Epub Jun 11, 2009))

[00301] Another subset of cancers against which the compounds of Modalities 1.0 to 1.116 should prove particularly active include: • breast cancer • glioblastoma multiforme; • colon adenocarcinomas; • non-small cell lung cancer; • small cell lung cancer; • cisplatin-resistant small cell lung cancer; • ovarian cancer; • leukemia; • pancreatic cancer; • prostate cancer; • breast carcinoma; • renal cell carcinoma; • multiple myeloma; • Kaposi's sarcoma; • Hodgkin lymphomas; • lymphangioleiomyomatosis; and • non-Hodgkin lymphomas or sarcoma

[00302] An additional subset of cancers against which the compounds of Embodiments 1.0 to 1.116 should prove particularly active includes brain cancers such as: • brain metastases from triple negative breast cancer; and • gliomas and glioblastomas.

Triple negative breast cancer

[00303] Most breast cancers are hormonally positive breast cancers, in which the growth of cancer cells is stimulated by exposure to estrogen and/or progesterone. Patients suffering from such cancers are typically treated with therapeutic agents that prevent or reduce the formation of estrogen in the body or prevent estrogen from binding to the cell and stimulating growth. Examples of such therapeutic agents include selective estrogen receptor modulators (SERMs), such as tamoxifen and toremifene; aromatase inhibitors such as anastrozole, exemestane and letrozole; estrogen receptor expression downregulators (ERDs) such as fulvestrant; and luteinizing hormone-releasing hormonal agents (LHRHs), such as goserelin, leuprolide, and triptorelin. Progesterone stimulation in hormonally positive cancer cells is affected by estrogen receptor activity; therefore, if estrogen exposure is reduced, progesterone sensitivity is also often affected.

[00304] Approximately one-quarter of breast cancers are HER2-positive breast cancers that are characterized by overexpression of human epidermal growth factor receptor 2 (HER2). HER2 positive cancers are typically treated with therapeutic agents (e.g., Herceptin) that target the receptor to slow growth and replication.

[00305] However, there are some breast cancers that are not positive for estrogen or progesterone and do not overexpress HER2 to a level that would characterize them as HER2 positive. Such forms of breast cancer are typically called triple negative breast cancers. Patients with triple-negative breast cancer have fewer treatment options than patients with hormone-positive or HER2-positive disease and are therefore generally more difficult to treat than estrogen-positive, progesterone-positive, and HER2-positive cancers. Triple negative breast cancers are also recognized as more likely to spread (metastasize) to the brain. Patients with brain metastases are typically considered incurable with standard treatment approaches.

[00306] The compounds of formula (1), as defined herein in Embodiments 1.0 to 1.116, can be used in the treatment of triple negative breast cancer and in the treatment of brain metastases arising from triple negative breast cancer. The compounds can also be used to treat brain metastases from other forms of cancer.

[00307] Furthermore, the compounds of formula (1), as defined herein in Embodiments 1.0 to 1.116, can be used in the prevention or treatment of metastases in general, for example, in the prevention or treatment of metastases in the brain, lung , liver, pancreas, kidney, bladder and gallbladder.

[00308] Thus, in additional embodiments 2.10 to 2.18, the invention provides:

[00309] 2.10 A compound, as defined in any of Embodiments 1.0 to 1.116, for use in the treatment of triple negative breast cancers.

[00310] 2.11 A compound, as defined in any of Embodiments 1.0 to 1.116, for use in preventing or treating metastases, for example, metastases in the brain, bones, lung, liver, pancreas, kidney, bladder and gallbladder, for example, brain metastases from triple-negative breast cancers.

[00311] 2.12 A compound, as defined in any of Embodiments 1.0 to 1.116, for use in the treatment of brain metastases arising from non-brain cancers.

[00312] 2.13 The use of a compound, as defined in any of Embodiments 1.0 to 1.116, for the manufacture of a medicine for the treatment of triple negative breast cancers.

[00313] 2.14 The use of a compound, as defined in any of Embodiments 1.0 to 1.116, for the manufacture of a medicament for the prevention or treatment of metastases, for example, metastases in the brain, bones, lung, liver, pancreas , kidney, bladder and gallbladder, for example, brain metastases from triple negative breast cancers.

[00314] 2.15 The use of a compound, as defined in any of Embodiments 1.0 to 1.116, for the manufacture of a medicine for the treatment of brain metastases arising from non-brain cancers.

[00315] 2.16 A method of treating a triple negative breast cancer in a subject (e.g., a human subject) in need, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, as defined in any of Modalities from 1.0 to 1.116.

[00316] 2.17 A method of preventing or treating metastases, for example, metastases in the brain, bones, lung, liver, pancreas, kidney, bladder and gallbladder (for example, brain metastases from triple negative breast cancers), in a subject (e.g., a human subject) in need, wherein the method comprises administering to the subject a therapeutically effective amount of a compound as defined in any one of Embodiments 1.0 to 1.116.

[00317] 2.18 A method of treating brain metastases from non-brain cancers in a subject (e.g., a human subject) in need, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, as defined in any one of Modalities from 1.0 to 1.116.

Gliomas

[00318] It is anticipated that the compounds of formula (1), as defined herein in Embodiments 1.0 to 1.116, will be useful in the treatment of gliomas due to their potency as inhibitors of S6K1 (which is known due to its role in the transformation glial) and their abilities to reach the site of action, that is, the brain.

[00319] Glioma is a common type of primary brain tumor that has its origin in glial cells in the brain and accounts for about 30% of all central nervous system tumors and primary brain tumors, and about 80% of all brain tumors malignant. Commonly, gliomas derive from three different types of cells that are normally found in the brain, that is, astrocytes, oligodendrocytes and ependymal cells. The main types of gliomas include ependymomas (associated with ependymal cells), astrocytomas (associated with astrocytes), oligodendrogliomas (associated with oligodendrocytes), brainstem glioma (developing in the brain stem), optic nerve glioma (developing in or around the optic nerve) and mixed gliomas (which contain cells from different types of glia).

[00320] An ependymoma is a type of glioma that develops from ependymal cells, typically in the lining of the ventricles of the brain or spinal cord. In children, these are typically found near the cerebellum. Ependymomas are rare, accounting for only about 2-3% of primary brain tumors. However, they account for about 8-10% of brain tumors in children and occur more frequently in children younger than 10 years of age.

[00321] Astrocytomas arise from star-shaped glial cells (astrocytes) in the telencephalon. Astrocytomas do not normally spread outside the brain and spinal cord and do not normally affect other organs, but they are the most common glioma and can occur in most parts of the brain and occasionally the spinal cord. In general, two broad classes of astrocytomas are recognized, namely astrocytomas with narrow infiltration zones (mostly invasive tumors; e.g. pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma), which are often clearly delineated in diagnostic images; and astrocytomas with diffuse zones of infiltration (e.g., high-grade astrocytoma, anaplastic astrocytoma, glioblastoma). Glioblastoma multiforme is a malignant astrocytoma and the most common primary brain tumor among human adults.

[00322] An oligodendroglioma is a type of glioma that develops from oligodendrocytes, which are the supporting tissue cells of the brain and are normally found in the telencephalon. About 4% of primary brain tumors are oliogodendrogliomas and these are most common in young adults and middle-aged adults. Seizures are a very common symptom of these gliomas, as are headache, weakness or changes in behavior or drowsiness.

[00323] Brain stem gliomas, as the name suggests, are tumors found in the brain stem. Most brain stem tumors cannot be removed surgically because of their remote location and the delicate, complex functions that this area controls. Brainstem gliomas occur almost exclusively in children, typically school-age children.

[00324] A mixed glioma is a malignant glioma composed of more than one type of glial cell. This type of glioma can also be referred to as oligoastrocytoma. Mixed gliomas are frequently found in the telencephalon, but can develop metastases in other parts of the brain. Only about 1% of primary brain tumors are mixed gliomas and they are found more often in adult men.

[00325] An optic nerve glioma is a type of malignant glioma (brain tumor) found in the optic chiasm. Optic nerve gliomas often surround the optic nerves and are often found in people with neurofibromatosis. A person suffering from an optic nerve glioma typically suffers from vision loss and may also suffer from hormonal disorders, as tumors are often found at the base of the brain where the structures responsible for hormonal control are located. Optic nerve gliomas are typically difficult to treat because of sensitivity to the structures surrounding the brain.

[00326] In addition to being classified according to the type of glial cell from which they come or the region of the brain in which they develop, gliomas can also be classified according to their “grade”, which is a measure of potential tumor growth and aggressiveness.

[00327] Therefore, gliomas are most often referred to as "low grade" or "high grade" glioma, with the grade being determined by pathological evaluation of the tumor. Tumors can be further classified according to the World Health Organization (WHO) classification system, under which tumors are classified from I (least advanced disease - best prognosis) to IV (most advanced disease - worst prognosis).

[00328] Gliomas can also be classified according to their location above or below the tensor membrane, the tensor which separates the cerebral region of the telencephalon (above) from the cerebellum (below). Supratentorial gliomas (i.e., tumors located above the tendon in the telencephalon) are more commonly found in adults (70%), while infratentorial gliomas (tumors located below the tensor, in the cerebellum) are more commonly found in children (70%).

[00329] An additional class of gliomas consists of tumors found in the pons of the brain stem. The brain stem has three parts (pons, midbrain and medulla); The pons controls critical functions such as breathing, making surgery on pontine gliomas extremely dangerous.

[00330] Thus, in additional embodiments 2.19 to 2.34, the invention provides:

[00331] 2.19 A compound, as defined in any of Embodiments 1.0 to 1.116, for use in the treatment of gliomas and glioblastomas.

[00332] 2.20 A compound for use, according to Embodiment 2.19, wherein the glioma is an ependymoma.

[00333] 2.21 A compound for use, according to Embodiment 2.19, wherein the glioma is an astrocytoma.

[00334] 2.22 A compound for use, according to Embodiment 2.19, wherein the glioma is a glioblastoma.

[00335] 2.23 A compound for use, according to Embodiment 2.19, wherein the glioma is a glioblastoma multiforme.

[00336] 2.24 A compound for use, according to Embodiment 2.19, wherein the glioma is an oligodendroglioma.

[00337] 2.25 A compound for use, according to Embodiment 2.19, wherein the glioma is a brainstem glioma.

[00338] 2.26 A compound for use, according to Embodiment 2.19, wherein the glioma is an optic nerve glioma.

[00339] 2.27 A compound for use, according to Embodiment 2.19, wherein the glioma is a mixed glioma.

[00340] 2.28 A compound for use, according to Embodiment 2.19, wherein the glioma is a low grade glioma.

[00341] 2.29 A compound for use, according to Embodiment 2.19, wherein the glioma is a high-grade glioma.

[00342] 2.30 A compound for use, according to Embodiment 2.19, wherein the glioma is a supratentorial glioma.

[00343] 2.31 A compound for use, according to Embodiment 2.19, wherein the glioma is an infratentorial glioma.

[00344] 2.32 A compound for use, according to Embodiment 2.19, wherein the glioma is a pontine glioma.

[00345] 2.33 The use of a compound, as defined in any of Embodiments 1.0 to 1.116, for the manufacture of a medicament for the treatment of a glioma as defined in any of Embodiments 2.19 to 2.32.

[00346] 2.34 A method of treating a glioma, as defined in any one of Embodiments 2.19 to 2.32, in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, as defined in any one of the Modalities from 2.19 to 2.32.

Neurodevelopmental diseases and neurodegenerative diseases

[00347] As discussed above, P70S6K also has a crucial role in the pathology of several neurodevelopmental diseases and neurodegenerative disorders and diseases and it is anticipated that inhibition of P70S6K will provide a means of treating many of these diseases. Thus, in additional embodiments 2.35 to 2.48, the invention provides:

[00348] 2.35 A compound, as defined in any of Embodiments 1.0 to 1.116, for use in the treatment of a neurodevelopmental disorder.

[00349] 2.36 A compound for use, according to Embodiment 2.35, in which the neurodevelopmental disorder is fragile X syndrome.

[00350] 2.37 A compound for use, according to Embodiment 2.35, wherein the neurodevelopmental disorder is autism or an autism spectrum disorder.

[00351] 2.38 A compound for use, according to Embodiment 2.35, wherein the neurodevelopmental disorder is fragile X-associated tremor and ataxia syndrome (FXTAS).

[00352] 2.39 A compound for use, according to Embodiment 2.35, in which the neurodevelopmental disorder is Angelman syndrome.

[00353] 2.40 A compound for use, according to Embodiment 2.35, in which the neurodevelopmental disorder is tuberous sclerosis complex.

[00354] 2.41 A compound for use, according to Embodiment 2.35, wherein the neurodevelopmental disorder is MECP2 gene duplication syndrome.

[00355] 2.42 A compound for use, according to Embodiment 2.35, wherein the neurodevelopmental disorder is Down syndrome.

[00356] 2.43 A compound, as defined in any of Embodiments 1.0 to 1.116, for use in the treatment of a neurodegenerative disease.

[00357] 2.44 A compound for use, according to Embodiment 2.43, wherein the neurodegenerative disease is Alzheimer's disease.

[00358] 2.45 A compound for use, according to Embodiment 2.43, wherein the neurodegenerative disease is Huntington's disease.

[00359] 2.46 A compound for use, according to Embodiment 2.43, wherein the neurodegenerative disease is Parkinson's disease.

[00360] 2.47 The use of a compound of formula (1), as defined in any of Embodiments 1.0 to 1.116 for the manufacture of a medicament for the treatment of a brain disorder, for example, a brain disorder as defined in any one of the Modalities from 2.35 to 2.46.

[00361] 2.48 A method of treating a brain disorder (e.g., a brain disorder as defined in any of Embodiments 2.35 to 2.46) in a subject (e.g., a mammalian subject, such as a human), wherein method comprises administering to the subject a therapeutically effective amount of a compound of formula (1), (2), (3) or (4), as defined in any of Embodiments 1.0 to 1.116.

[00362] Fragile X syndrome typically first manifests in childhood. A speech delay is common and is often the first symptom that brings a child to medical attention (around two or three years of age). Thus, in additional embodiments, the invention provides:

[00363] 2.48A A compound, according to any one of Modalities 1.0 to 1.116, for use in the treatment of fragile X syndrome in a patient under 20 years of age, for example, under 15 years of age, or under 12 years of age, or under 10 years of age, preferably under 8 years of age and even more preferably under 5 years of age.

[00364] 2.48B A method for treating fragile X syndrome, wherein the method comprises administering to a patient in need, a compound, as defined in any of Modalities 1.0 to 1.116, wherein the patient is less 20 years of age, for example, less than 15 years of age, or less than 12 years of age, or less than 10 years of age, preferably less than 8 years of age and even more preferably less than 5 years of age.

[00365] 2.48C The use of a compound, as defined in any of Embodiments 1.0 to 1.116, for the manufacture of a medicine for the treatment or prophylaxis of fragile X syndrome in a patient under 20 years of age, by example, under 15 years of age, or under 12 years of age, or under 10 years of age, preferably under 8 years of age, and even more preferably under 5 years of age.

Other diseases and conditions in which S6K1 may be related

[00366] As discussed above, P70S6K inhibitors may also be useful in the treatment of PETN hamartoma syndrome, neurofibromatosis type 1 and lymphangioleiomyomatosis (LAM). Thus, in additional embodiments (Embodiments 2.49 to 2.52), the invention provides:

[00367] 2.49 A compound, as defined in any of Embodiments 1.0 to 1.116, for use in the treatment of a condition that is PETN hamartoma syndrome.

[00368] 2.50 A compound, as defined in any of Embodiments 1.0 to 1.116, for use in the treatment of a condition that is neurofibromatosis type 1.

[00369] 2.51 A compound, as defined in any of Embodiments 1.0 to 1.116, for use in the treatment of a condition that is lymphangioleiomyomatosis.

[00370] 2.52 The use of a compound, as defined in any of Modalities 1.0 to 1.116, for the manufacture of a medicine for the treatment of a condition as defined in any of Modalities 2.49 to 2.51.

[00371] 2.53 A method of treating a condition, as defined in any one of Embodiments 2.49 to 2.51, in a subject (for example, a mammalian subject such as a human), wherein the method comprises administering to the subject an amount therapeutically effective of a compound of formula (1), (2), (3) or (4), as defined in any of Embodiments 1.0 to 1.116.

Determination of biological properties

[00372] The ability of compounds of Embodiments 1.0 to 1.116 to inhibit cell proliferation can also be determined using the protocols defined in the examples section below.

[00373] An advantage of the compounds of Modalities 1.0 to 1.116 is that they are selective kinase inhibitors.

[00374] Preferred compounds of Embodiments 1.0 to 1.116 are those that have an IC50 against p70S6 kinase of less than 5 μM, or less than 1 μM and preferably less than 0.1 μM.

[00375] For example, compounds of Embodiments 1.0 to 1.116 are selective inhibitors of p70S6 kinase compared to activity against Akt2 kinase. Preferred compounds of Embodiments 1.0 to 1.116 are at least 5 times more active against p70S6 kinase than against Akt2 kinase and more preferred compounds of Embodiments 1.0 to 1.116 are at least 10 times or at least 20 times more active against p70S6 kinase than against Akt2 kinase. Particularly more preferred compounds of Embodiments 1.0 to 1.116 are at least 100 times more active against p70S6 kinase than against Akt2 kinase.

[00376] Furthermore, compounds of Embodiments 1.0 to 1.116 are selective inhibitors of p70S6 kinase compared to activity against Aurora kinase. Preferred compounds of Embodiments 1.0 to 1.116 are at least 5 times more active against p70S6 kinase than against Aurora kinase A and/or B and more preferred compounds of Embodiments 1.0 to 1.116 are at least 10 times more active. active against p70S6 kinase than against Aurora kinase A and/or B.

[00377] Compounds of Embodiments 1.0 to 1.116 with greater selectivity for p70S6 kinase than against Aurora kinase A and/or Aurora B and/or Akt kinase should exhibit improved side effect profiles in relation to side effects arising from inhibition of Aurora kinase and Akt kinase. For example, in the case of Aurora kinase inhibition, neutropenia is a well-known clinical side effect.

[00378] Thus, in additional embodiments (Modality 2.54 to 2.57), the invention provides:

[00379] 2.54 A compound, according to any one of Embodiments 1.0 to 1.116, with an IC50 against p70S6 kinase of less than 5 μM.

[00380] 2.55 A compound according to any one of Embodiments 1.0 to 1.116 with an IC50 against p70S6 kinase of 1 μM or less.

[00381] 2.56 A compound, according to any one of Embodiments 1.0 to 1.116, with an IC50 against p70S6 kinase of less than 0.1 μM.

[00382] 2.57 A compound, according to any of Embodiments 2.54 to 2.56, for use in a therapy, treatment, method or use according to any of Embodiments 2.1 to 2.52.

[00383] Many compounds defined in Embodiments 1.0 to 1.116 have good brain penetration and are therefore useful in the treatment of brain disorders in which inhibition of p70S6 kinase is therapeutically effective.

[00384] The brain penetration ability of compounds of Embodiments 1.0 to 1.116 can be determined using an in vivo mouse model cassette, which is an industry standard means of evaluating brain penetration of small molecules (see, e.g. , “In vitro permeability analysis, pharmacokinetic and brain distribution study in mice of imperatorin, isoimperatorin and cnidilin in Radix Angelicae Dahuricae”, Fitoterapia, Volume 85, March 2013, pages 144-153).

Methods for preparing the compounds of the invention

[00385] The invention also provides methods for preparing a compound of formula (1).

[00386] Thus, in another embodiment (Modality 3.1), the invention provides a method for preparing a compound, as defined in any of Embodiments 1.0 to 1.116, characterized by the fact that Y is R3 and Z is Ar2, in which the method comprises:

[00387] (a) the reaction of a compound of formula (8): or a protected form thereof, in which Hal is a halogen, such as bromine, with a boronic acid or a boronate reagent of the formula Ar2-Bou in which Bou is a boronate or boronic acid residue, in the presence of a boronic acid catalyst. palladium; and then optionally removing any protecting group present; or

[00388] (b) the reaction of a compound of formula (9): or a protected form thereof, with a compound of the formula LG-Q2-R1 in which LG is a leaving group, such as a halogen; and then optionally removing any protecting groups present.

[00389] In another embodiment (Modality 3.2), the invention provides a method for preparing a compound, as defined in any one of Embodiments 1.0 to 1.116 wherein Y is Ar2 and Z is R3, wherein the method comprises:

[00390] (a) the reaction of a compound of formula (10): or a protected form thereof, in which Hal is a halogen, such as bromine, with a boronic acid or boronate reagent of the formula Ar2-Bou in which Bou is a boronate or boronic acid residue, in the presence of a palladium catalyst ; and then optionally removing any protecting group present; or

[00391] (b) the reaction of a compound of formula (11): or a protected form thereof, with a compound of the formula LG-Q2-R1 in which LG is a leaving group, such as a halogen; and then optionally removing any protecting groups present.

[00392] Reaction (a) in Embodiments 3.1 and 3.2 above can be carried out under Suzuki coupling conditions in the presence of a palladium catalyst such as bis(tri-t-butylphosphine) palladium (0) and a base (e.g. , a carbonate, such as potassium carbonate or cesium carbonate). The reaction can be carried out in a polar solvent, such as dimethylformamide (DMF) or dioxane, and the reaction mixture is normally subjected to heating, for example, to a temperature above 100 ° C.

[00393] Reaction (b) in Embodiments 3.1 and 3.2 above is normally carried out at room temperature in a polar solvent, such as dimethyl sulfoxide or dimethylformamide in the presence of a non-nucleophilic base, such as an alkali metal hydride (e.g. sodium).

[00394] Illustrative reaction schemes for compounds of formula (1) are set out below. Scheme 1

[00395] In scheme 1, when R2, R3 and R4 are hydrogen, the raw material is 6-bromo-2-chloro-quinazoline (12), which is commercially available. 6-Bromo-2-chloro-quinazoline (12) reacts with the aryl- or heteroarylalkylamine H2N-Q1-Ar1 in a polar solvent, such as dimethyl sulfoxide, normally at room temperature or, optionally, with slight heating, to provide the compound intermediate (13). The compound (13) reacts with sodium hydride in dimethylformamide at a reduced temperature of about 0 °C and a compound of formula (14), wherein LG1 is a suitable leaving group (e.g. halogen, methanesulfonate or tosylate), is then added to the resulting reaction mixture. The reaction mixture can then be heated to a mild temperature of about 50 °C to provide the bromine intermediate (15).

[00396] Alternatively, the bromine intermediate (15) can be synthesized directly from the raw material 6-bromo-2-chloro-quinazoline (12) by reaction with amino NH(Q1Ar1)(Q2R1) in a polar solvent, such as dimethyl sulfoxide, normally at room temperature or, optionally, with slight heating.

[00397] The bromine intermediate (15) is then reacted with the heteroaryl boronate (16) in a polar solvent, such as dioxane, in the presence of bis(tri-tert-butylphosphine) palladium (0) and cesium or potassium carbonate and, optionally, in the presence of potassium iodide under Suzuki reaction conditions, to provide the compound of formula (1) or a protected derivative thereof. The heteroaryl group Ar2 may be present in the boronate compound (16) in a protected form. For example, when Ar2 contains an NH group, a protecting group such as a Boc (tert-butoxycarbonyl) group can be attached to the nitrogen atom, replacing the hydrogen atom. After the reaction between the boronate compound (16) and the intermediate (15), a deprotection step may be necessary in order to provide the compound of formula (1). In the case of a Boc protecting group, it can be removed by treatment with an acid, such as hydrochloric acid.

[00398] Boronates and boronic acids of the formula Ar2-Bou are widely available commercially or can be prepared, for example, as described in the review article by N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2457. Therefore, boronates can be prepared by reacting the corresponding bromine compounds with an alkyl lithium, such as butyl lithium, and then reacting with a borate ester. The resulting boronate ester derivative can, if desired, be hydrolyzed to provide the corresponding boronic acid.

[00399] The compounds of formula (1), where Q2 is a bond and R1 is a cyclic group Cy1, can be prepared by the sequence of reactions shown in Scheme 2. Scheme 2

[00400] In scheme 2, 6-bromo-2-chloro-quinazoline (12) reacts with the carbocyclyl or heterocyclyl amine Cy1-NH2 in a polar solvent, such as dimethyl sulfoxide, normally at room temperature or, optionally, with slight heating , to provide the intermediate compound (17) which is then treated with the compound (18), where LG1 is a suitable leaving group (e.g. halogen, methanesulfonate or tosylate), under standard alkylation conditions to provide the compound of bromine (19). The bromine compound (19) then reacts with the heteroaryl boronate (16) under the Suzuki reaction conditions described above to provide the compound of formula (20) which corresponds to a compound of formula (1) in which Q2 is a bond and R1 is a Cy1 cyclic group. Alternatively, the bromine compound (19) reacts with bis borane pinacol ester to provide the boronate (19a) which then reacts with an Ar2-Br heteroaryl bromide under Suzuki bond conditions to provide the compound (20).

[00401] In cases where it is not possible to isolate a suitable Ar2-Bou reagent for use in the Suzuki reaction, then the reactivity of the Suzuki reaction can be reversed as illustrated in Scheme 3 below. Scheme 3

[00402] In Scheme 3, bromide (15) is converted to a boronate ester through coupling with bispinacolate diborane in the presence of potassium acetate using a palladium catalyst, such as [1,1'-Bis(diphenylphosphine)ferrocene ]dichloropalladium(II), together with dichloromethane. A polar solvent, such as DMSO, is preferred and the reaction mixture is heated to 80 oC under an atmosphere of nitrogen or argon to allow the reaction to take place. The resulting boronate ester then reacts with a halogen-substituted aromatic or heteroaromatic group under the Suzuki reaction conditions already described herein.

[00403] Compounds of formula (1) in which Z is Ar2 and Y is R3 can be prepared as described in this document using the regioisomer 7-bromo-2-chloro-quinazoline as the starting material.

[00404] A compound of formula (1), or a protected derivative thereof, once formed, can be converted into another compound of formula (1) by methods known to those skilled in the art. Examples of synthetic procedures for converting one functional group into another functional group are defined in standard texts, such as Advanced Organic Chemistry, by Jerry March, 4th edition, 119, Wiley Interscience, New York; Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2); and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-47131192-8).

[00405] In many of the reactions described above, it may be necessary to protect one or more groups to prevent the reaction from taking place in an undesirable location of the molecule. Examples of protecting groups and methods of protection and deprotection functional groups can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd edition; John Wiley and Sons, 1999).

[00406] Compounds made by the foregoing methods can be isolated and purified with any of a variety of methods known to those skilled in the art and examples of such methods include recrystallization and chromatographic techniques, such as column chromatography (e.g., flash chromatography). and HPLC.

Pharmaceutical formulations

[00407] Although it is possible for the active compound to be administered individually, it is preferable to present it as a pharmaceutical composition (e.g., formulations).

[00408] Thus, in another embodiment (Modality 4.1) of the invention, a pharmaceutical composition is provided comprising at least one compound of formula (1), as defined in any one of Embodiments 1.0 to 1.116, together with a pharmaceutically acceptable excipient.

[00409] The pharmaceutically acceptable excipient may be, for example, a carrier (e.g., a solid, liquid or semi-solid carrier), a diluent or bulking agent, a granulating agent, coating agent, binding agent, disintegrating agent, lubricant, preservative, antioxidant, buffering agent, suspending agent, thickening agent, flavoring agent, sweetener, flavor masking agent or any other excipient conventionally used in pharmaceutical compositions. Examples of excipients for various types of pharmaceutical compositions are defined in more detail below.

[00410] The pharmaceutical compositions may be in any form suitable for oral, parenteral, topical, intranasal, ophthalmological, optical, rectal, intravaginal or transdermal administration. Where the compositions are desired for parenteral administration, they may be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery to a target organ or tissue through injection, infusion or other means of delivery. Delivery may be via bolus injection, short-term infusion or long-term infusion and may be via passive delivery or with the use of a suitable infusion pump.

[00411] Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostatics, co-solvents, organic solvent mixtures, cyclodextrin complexing agents, emulsifying agents (to form and stabilize emulsion formulations ), liposome components to form liposomes, gelable polymers to form polymer gels, lyophilization protectants and combinations of agents to, inter alia, stabilize the active ingredient in a soluble form and make the formulation isotonic with the blood of the intended recipient. Pharmaceutical formulations for parenteral administration may also be in the form of sterile aqueous and non-aqueous suspensions that may include suspending agents and thickening agents (R. G. Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21(2) 2004, pp. 201-230).

[00412] A pharmaceutical molecule that is ionizable can be solubilized to the desired concentration through pH adjustment if the pKa of the drug is sufficiently far from the pH value of the formulation. The acceptable range is pH 2-12 for intravenous and intramuscular administration, but for subcutaneous administration, the range is pH 2.79.0. The pH of the solution is controlled by the salt form of the drug, strong bases/acids such as hydrochloric acid or sodium hydroxide, or by buffer solutions that include, but are not limited to, buffer solutions formed from glycine, citrate, acetate , maleate, succinate, histidine, phosphate, tris(hydroxymethyl)-aminomethane (TRIS) or carbonate.

[00413] The combination of an aqueous solution and a water-soluble organic solvent/surfactant (i.e., a cosolvent) is often used in injectable formulations. Water-soluble organic solvents and surfactants used in injectable formulations include, but are not limited to, propylene glycol, ethanol, polyethylene glycol 300, polyethylene glycol 400, glycerol, dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP; Pharmasolve ), dimethyl sulfoxide (DMSO), Solutol HS 15, Cremophor EL, Cremophor RH 60 and polysorbate 80. Such formulations can usually, but not always, be diluted before injection.

[00414] Propylene glycol, PEG 300, ethanol, Cremophor EL, Cremophor RH 60 and polysorbate 80 are the completely organic water-miscible solvents and surfactants used in commercially available injectable formulations and can be used in combinations with each other. The resulting organic formulations are typically diluted at least 2-fold prior to bolus or infusion administration.

[00415] Alternatively, increased water solubility can be achieved through molecular complexation with cyclodextrins.

[00416] Formulations may be presented in single-dose multi-dose containers, e.g., ampoules and sealed vials, and may be stored in a freeze-drying (lyophilization) condition requiring only the addition of sterile liquid carrier, e.g., water for injections, immediately before use.

[00417] The pharmaceutical formulation can be prepared by lyophilizing a compound of Formula (1) or acid addition salt thereof. Freeze-drying refers to the process of freeze-drying a composition. Freeze drying and freeze drying are therefore used synonymously in this document. A common process is to solubilize the compound and the resulting formulation is clarified, sterile filtered and aseptically transferred to suitable containers for lyophilization (e.g. vials). In the case of vials, they are partially corked with lids for freeze-drying. The formulation can be refrigerated until freezing and subjected to freeze-drying under standard conditions and then hermetically capped forming a dry and stable lyophilic formulation. The compound will normally have a low residual water content, e.g. less than 5%, e.g. less than 1% by weight based on the weight of the lyophilisate.

[00418] The freeze-drying formulation may contain other excipients, for example, thickening agents, dispersing agents, buffers, antioxidants, preservatives and tonicity adjusters. Typical buffers include phosphate, acetate, citrate and glycine. Examples of antioxidants include ascorbic acid, sodium bisulfite, sodium metabisulfite, monothioglycerol, thiourea, butylated hydroxytoluene, butylated hydroxyl anisole, and ethylenediaminetetraacetic acid salts. Preservatives may include benzoic acid and its salts, sorbic acid and its salts, alkyl esters of parahydroxybenzoic acid, phenol, chlorobutanol, benzyl alcohol, thimerosal, benzalkonium chloride, and cetylpyridinium chloride. The buffers mentioned above, as well as dextrose and sodium chloride, can be used to adjust tonicity, if necessary.

[00419] Bulking agents are generally used in freeze-drying technology to facilitate the process and/or provide volume and/or mechanical integrity to the freeze-dried cake. Bulking agent means a particular solid diluent, freely soluble in water, which, when freeze-dried with the compound or salt thereof, provides a physically stable freeze-dried cake, an improved freeze-drying process, and rapid and complete reconstitution. The bulking agent can also be used to make the isotonic solution.

[00420] The water-soluble bulking agent can be any of the pharmaceutically acceptable inert solid materials used for lyophilization. Such bulking agents include, for example, sugars such as glucose, maltose, sucrose and lactose; polyalcohols, such as sorbitol or mannitol; amino acids, such as glycine; polymers such as polyvinylpyrrolidone; and polysaccharides such as dextran.

[00421] The weight ratio of the bulking agent to the weight of the active compound is normally within the range of about 1 to about 5, e.g., from about 1 to about 3, e.g., in the range of about from 1 to 2.

[00422] Alternatively, they may be supplied in a solution form that can be concentrated and sealed in a suitable vial. Sterilization of dosage forms may be through filtration or autoclaving of the vials and their contents at the appropriate stages of the formulation process. The formulation provided may require additional dilution or preparation prior to shipment, e.g., dilution in suitable sterile infusion packets.

[00423] Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.

[00424] In a preferred embodiment of the invention, the pharmaceutical composition is in a form suitable for intravenous administration, for example, by injection or infusion.

[00425] In another preferred embodiment, the pharmaceutical composition is in a form suitable for subcutaneous (s.c.) administration.

[00426] Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, coated tablets, pills, dragees, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, lozenges or patches and buccal patches.

[00427] Pharmaceutical compositions containing compounds of formula (I) can be formulated according to known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

[00428] Therefore, tablet compositions may contain a single dosage of the active compound together with an inert diluent or carrier, such as a sugar or polyalcohol, for example; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar-derived diluent, such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof, such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and starches, such as corn starch. Tablets may also contain such standard ingredients as granulating and binding agents such as polyvinylpyrrolidone, disintegrants (e.g. expandable cross-linked polymers such as cross-linked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens) , antioxidants (e.g., BHT), buffering agents (e.g., phosphate or citrate buffers), and effervescent agents such as citrate/bicarbonate mixtures. Such excipients are known and do not need to be discussed in detail herein.

[00429] Capsule formulations may be of the hard or soft gelatin variety and may contain the active component in solid, semisolid, or liquid form. Gelatin capsules may be formed from animal or synthetic gelatin or plant-derived equivalents thereof.

[00430] Solid dosage forms (e.g., tablets, capsules, etc.) may be coated or uncoated, but typically have a coating, e.g., a protective film coating (e.g., a wax or varnish) or a release control coating. The coating (e.g., a Eudragit™-type polymer) can be configured to release the active component at a desirable location within the gastrointestinal tract. Therefore, the coating can be selected to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively releasing the compound into the stomach or ileum or duodenum.

[00431] Instead of or in addition to a coating, the drug may be presented in a solid matrix comprising a release controlling agent, for example, a release delaying agent that may be adapted to release the compound selectively under conditions of variable acidity or alkalinity in the gastrointestinal tract. Alternatively, the release delay coating or matrix material may be in the form of an erodible polymer (e.g., a maleic anhydride polymer) that is eroded substantially continuously as the dosage form passes through the gastrointestinal tract. As a further alternative, the active compound can be formulated into a delivery system that provides osmotic control of compound release. Osmotic release formulations and other delayed or extended release formulations can be prepared according to methods known to those skilled in the art.

[00432] The compound of formula (1), as defined in any of Embodiments 1.0 to 1.116, or a prodrug thereof, can be formulated with a carrier and administered in the form of nanoparticles. Nanoparticles offer the possibility of direct penetration into the cell. Nanoparticle drug delivery systems are described in “Nanoparticle Technology for Drug Delivery,” edited by Ram B Gupta and Uday B. Kompella, Informa Healthcare, ISBN 9781574448573, published March 13, 2006. Nanoparticles for drug delivery are also described in J. Control. Release, 2003, 91 (1-2), 167-172, and in Sinha et al., Mol. Cancer Ther. August 1, (2006) 5, 1909.

[00433] Pharmaceutical formulations can be presented to a patient in “patient kits” containing an entire treatment program in a single package, typically a pack of tablets. Patient kits have an advantage over traditional prescriptions, in which a pharmacist divides a patient's supply of a drug from a bulk supply, in which the patient always has access to the leaflet contained in the patient kit, normally absent in patient prescriptions . The inclusion of a leaflet demonstrated improvements in patient compliance with the doctor's instructions.

[00434] Compositions for topical use include ointments, creams, sprays, plasters, gels, drops and inserts (for example, intraocular inserts). Such compositions may be formulated according to known methods.

[00435] Compositions for parenteral administration are typically presented as sterile aqueous or oily solutions or fine suspensions, or may be provided in finely divided sterile powder forms to be compounded extemporaneously with sterile water for injection.

[00436] Examples of formulations for rectal or intravaginal administration include pessaries and suppositories that can be, for example, formed from a waxy or moldable material containing the active compound.

[00437] Compositions for administration by inhalation may be in the form of inhalable powder compositions or liquid or powder sprays and may be administered in standard form using powder inhalation devices or aerosol dispensing devices. Such devices are known in the art. For administration via inhalation, powder formulations typically comprise the active compound together with an inert solid diluent, such as lactose.

[00438] The compounds of Embodiments 1.0 to 1.116 will normally be presented in single dosage form and, as such, will normally contain sufficient compound to provide the desired level of biological activity. For example, a formulation may contain from 1 nanogram to 2 grams of active ingredient, for example, from 1 nanogram to 2 milligrams of active ingredient. Within this range, particular subranges of the compound are from 0.1 milligrams to 2 grams of the active ingredient (more typically 10 milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams ( e.g. from 1 microgram to 10 milligrams, e.g. from 0.1 milligram to 2 milligrams of active ingredient).

[00439] For oral compositions, a single dosage form may contain from 1 milligram to 2 grams, more typically from 10 milligrams to 1 gram, for example, from 50 milligrams to 1 gram, for example, from 100 milligrams to 1 gram of active compound.

[00440] The active compound will be administered to a patient in need (for example, a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.

Treatment methods

[00441] It is anticipated that the compounds of Embodiments 1.0 to 1.116 will be useful as individual chemotherapeutic agents or, more typically, in combination therapy with chemotherapeutic agents or radiotherapy in the prophylaxis or treatment of a range of disease states or proliferative conditions. Examples of such disease states and conditions are defined below.

[00442] Particular examples of chemotherapeutic agents that can be co-administered with the compounds of Embodiments 1.0 to 1.116 include: • Topoisomerase I inhibitors • Antimetabolites • Agents that target Tubulin • Topoisomerase II inhibitors and DNA binding agents • EGFR inhibitors (e.g. Gefitinib - see Biochemical Pharmacology 78 2009 460-468) • mTOR inhibitors (e.g. Everolimus) • PI3K pathway inhibitors (e.g. PI3K, PDK1) • Akt inhibitors • Alkylating agent ( e.g., temozolomide, cyclophosphamide) • Monoclonal antibodies (e.g., antibodies targeting CTLA-4, PD-1, PD-L1, CD52, or CD20) Antihormones Signal Transduction Inhibitors Proteasome Inhibitors • DNA Methyltransferases • Cytokines and retinoids • Hypoxia-activated DNA damaging agents (e.g. Tirapazamine) • Aromatase inhibitors • Anti Her2 antibodies, (see e.g. http://www.wipo.int/pctdb/en/wo.jsp?wo =2007056118), • Angiogenesis inhibitors • HDAC inhibitors • MEK inhibitors • B-Raf inhibitors • ERK inhibitors • Small molecule HER2 inhibitors (e.g. lapatinib) • Bcr-Abl tyrosine kinase inhibitors (e.g. , Imatinib) • CDK4/6 inhibitor, e.g. Ibrance • VEGFR inhibitors • IGFR-1 inhibitors • Hedgehog signaling pathway inhibitors

[00443] Additional examples of chemotherapeutic agents that can be co-administered with a compound as defined in any of Embodiments 1.0 to 1.116 include: • Torc 1 inhibitors • PI3K pathway inhibitors (e.g., PI3K, PDK1) • Inhibitors of EGFR (e.g. Gefitinib - see: Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines, Biochemical Pharmacology 78 2009 460-468) • Taxanes (e.g. paclitaxel, docetaxel, cabazitaxel) • Platinum agents (e.g. e.g., cisplatin, carboplatin, oxaliplatin) • Anthracyclines (e.g., Doxorubicin) • Bcl-2 family protein inhibitors, e.g., ABT263 (navitoclax), a Bcl-2/Bcl-extra large (Bcl-xL) inhibitor

[00444] A particular combination comprises a compound, according to any one of Modalities 1.0 to 1.116, together with an EGFR inhibitor, such as Gefitinib or Erlotinib, or with an mTOR inhibitor, such as Everolimus.

[00445] The compounds can also be administered in conjunction with radiotherapy.

[00446] The compounds can be administered over a long term to maintain beneficial therapeutic effects or can be administered only for a short term. Alternatively, they may be administered in a pulsatile or continuous manner.

[00447] The compounds of the invention will be administered in an effective amount, that is, an amount that is effective to provide the desired therapeutic effect. For example, the "effective amount" may be an amount of the compound that, when administered to a cancer victim, slows the growth of the tumor, alleviates the symptoms of the disease and/or increases longevity.

[00448] The amount of the P70S6 inhibitor compound of the invention administered to the subject will depend on the type and severity of the disease or condition and the subject's characteristics, such as general health, age, sex, body weight and drug tolerance. The skilled individual will be able to determine appropriate dosages depending on these and other factors.

[00449] The compounds are, in general, administered to a subject in need of such administration, for example, a human or animal patient, preferably a human.

[00450] A normal daily dose of the compound of any of Embodiments 1.0 to 1.116 may be in the range of 100 picograms to 100 milligrams per kilogram of body weight, more typically 5 nanograms to 25 milligrams per kilogram of body weight, and more typically 10 nanograms to 15 milligrams per kilogram of body weight (e.g., 10 nanograms to 10 milligrams, and more typically 1 microgram per kilogram to 20 milligrams per kilogram, e.g., 1 microgram to 10 milligrams per kilogram), although higher or lower doses can be administered when necessary. The compound can be administered daily or repeatedly every 2, or 3, or 4, or 5, or 6, or 7, or 10, or 14, or 21, or 28 days, for example.

[00451] In a particular dosing schedule, a patient will be given an infusion of a compound for one-hour periods daily for up to ten days, in particular up to five days, for a week, and the treatment will be repeated at a desired interval. , such as two to four weeks, in particular every three weeks.

[00452] More particularly, a patient may be given an infusion of a compound for one-hour periods daily for 5 days and the treatment may be repeated every three weeks.

[00453] In another particular dosing schedule, a patient is given an infusion for 30 minutes to 1 hour followed by maintenance infusions of varying duration, for example, from 1 to 5 hours, for example, 3 hours.

[00454] In a particular additional dosing schedule, a patient is given a continuous infusion over a period of 12 hours for 5 days, in particular, a continuous infusion from 24 hours to 72 hours.

[00455] Ultimately, however, the administered amount of the compound and the type of composition used will be proportional to the nature of the disease or physiological condition being treated and will be at the discretion of the physician.

Diagnostic methods

[00456] Prior to administration of a compound of any of Embodiments 1.0 to 1.116, a patient may be examined to determine whether a disease or condition of which the patient is or may be a victim would be susceptible to treatment with a compound with activity against the p70S6 kinase.

[00457] For example, a biological sample taken from a patient can be analyzed to determine whether a condition or disease, such as cancer, that the patient is or may be a victim of is characterized by a genetic anomaly or abnormal protein expression that causes a upregulation of p70S6 kinase or a sensitization of a pathway to normal p70S6 kinase activity or an overexpression of phosphorylated p70S6 kinase. The term upregulation includes elevated expression or overexpression, including gene amplification (i.e., multiple gene copies) and increased expression through a transcriptional effect, and hyperactivity and activation, including activation through mutations. Therefore, the patient may undergo a diagnostic test to detect a characteristic marker of p70S6 kinase upregulation. The term diagnostic includes testing. By marker, we include genetic markers including, for example, measuring DNA composition to identify p70S6 mutations. The term marker also includes markers that are characteristic of p70S6 upregulation, including enzyme activity, enzyme levels, enzyme status (e.g., phosphorylated or not), and mRNA levels of the aforementioned proteins.

[00458] Tumors with upregulation of p70S6 kinase may be particularly sensitive to p70S6 inhibitors. Tumors can be tested, preferentially, for p70S6 upregulation. Therefore, the patient may undergo a diagnostic test to detect a characteristic marker of p70S6 upregulation. Diagnostic tests are typically conducted on a biological sample selected from biopsy samples, blood samples (isolation and enrichment of missed tumor cells), stool biopsy, sputum, chromosome analysis, pleural fluid, peritoneal fluid.

[00459] Methods for identifying and analyzing mutations and protein upregulation are known to those skilled in the art. Testing methods may include, but are not limited to, standard methods such as reverse transcriptase polymerase chain reaction (RT-PCR) or in situ hybridization.

[00460] When testing via RT-PCR, the level of mRNA in the tumor is assessed by creating a cDNA copy of the mRNA followed by amplifying the cDNA via PCR. PCR amplification methods, selection of primers and conditions for amplification are known to one skilled in the art. Nucleic acid manipulations and PCR are performed by standard methods, as described, for example, in Ausubel, F.M. et al., editors. Current Protocols in Molecular Biology, 2004, John Wiley & Sons Inc., or Innis, M.A. et-al., editors. PCR Protocols: a guide to methods and applications, 1990, Academic Press, San Diego. Reactions and manipulations involving nucleic acid techniques are also described in Sambrook et al., 2001, 3rd edition, Molecular Cloning: a Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, a commercially available kit for RT-PCR (e.g., Roche Molecular Biochemicals) may be used, or the methodology as set forth in US patents 4,666,828; 4,683,202; 4,801,531; 5,192,659, 5,272,057, 5,882,864 and 6,218,529 and incorporated herein by reference.

[00461] An example of an in situ hybridization technique for evaluating mRNA expression would be fluorescence in situ hybridization (FISH) (see Angerer, 1987 Meth. Enzymol., 152: 649).

[00462] In general, in situ hybridization comprises the following main steps: (1) fixation of tissue to be analyzed; (2) prehybridization treatment of the sample to increase the accessibility of specific nucleic acid, and to reduce nonspecific binding; (3) hybridizing the nucleic acid mixture to the nucleic acid in the biological structure or tissue; (4) post-hybridization washing to remove unligated nucleic acid fragments upon hybridization, and (5) detection of the hybridized nucleic acid fragments. The probes used in such applications are typically identified, for example, with radioisotopes or fluorescent probes. Preferred probes are sufficiently long, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides, to permit specific hybridization to the specific nucleic acid(s). under restrictive conditions. Standard methods for performing FISH are described in Ausubel, F.M. et al., editors. Current Protocols in Molecular Biology, 2004, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview, by John M. S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd edition.; ISBN: 1-59259-760-2; March 2004, pages. 077-088; Series: Methods in Molecular Medicine.

[00463] Alternatively, protein products expressed from mRNAs can be examined by immunohistochemistry of tumor samples, solid phase immunoassay with microtiter plates, protein immunoblot, two-dimensional SDS-polycrylamide gel electrophoresis, ELISA , flow cytometry and other methods known in the art for detecting specific proteins. Detection methods would include the use of specific localization antibodies. One skilled in the art will recognize that all of these known techniques for detecting p70S6 kinase upregulation would be applicable in the present case.

[00464] Thus, in another embodiment of the invention (Modality 5.1), there is provided a method for diagnosing and treating a disease state or condition mediated by p70S6 kinase, which method comprises (i) examining a patient to determine whether a disease or condition from which the patient is or may be susceptible to treatment with a compound with activity against p70S6 kinase; and (ii) where it is indicated that the disease or condition to which the patient is then susceptible, then administering to the patient a compound, as defined in any of Embodiments 1.0 to 1.116.

[00465] In another modality (Modality 5.2), there is provided the use of a compound, as defined in any of Embodiments 1.0 to 1.116, for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition in a a patient who has been examined and determined to be suffering from, or at risk of suffering from, a disease or condition that would be susceptible to treatment with a compound with activity against p70S6.

[00466] In an additional modality (Modality 5.3), a compound, as defined in any of Modalities 1.0 to 1.116, is provided for use in the treatment or prophylaxis of a disease state or condition in a patient that has been examined and determined as a victim of, or at risk of being a victim of, a disease or condition that would be susceptible to treatment with a compound with activity against p70S6.

[00467] In another embodiment of the invention (Modality 5.4), there is provided a method for the diagnosis and treatment of a disease state or condition characterized by the upregulation of p70S6 kinase or the presence of a mutated form of p70S6, a method comprising (i) examining a patient to determine whether a disease or condition of which the patient is or may be a victim is one that would be susceptible to treatment with a compound with activity against p70S6 kinase; and (ii) where it is indicated that the disease or condition to which the patient is then susceptible, then administering to the patient a compound as defined in any of Embodiments 1.0 to 1.116.

[00468] In an additional modality (Modality 5.5), a method is provided for treating a disease state or condition characterized by the upregulation of p70S6 kinase or the presence of a mutated form of p70S6, a method comprising administering a therapeutically effective amount of a compound, as defined in any of Embodiments 1.0 to 1.116, to a patient who has been examined and determined to be the victim of, or at risk of becoming the victim of, a disease or condition that would be susceptible to treatment with a compound having active against p70S6.

[00469] In another modality (Modality 5.6), there is provided the use of a compound, as defined in any of Modalities 1.0 to 1.116, for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition as defined in any of Embodiments 2.1 to 2.43, in a patient who has been examined and determined to be the victim of, or at risk of being the victim of, a mentioned disease, condition or disorder that would be susceptible to treatment with a compound with activity against p70S6.

[00470] In an additional embodiment (Modality 5.7), a compound, as defined in any one of Embodiments 1.0 to 1.116, is provided for use in the treatment or prophylaxis of a brain disease or disorder in a patient that has been tested and determined to be victim of, or at risk of being victim of, a disease state or condition as defined in any of Embodiments 2.1 to 2.43, which would be susceptible to treatment with a compound with activity against p70S6.

[00471] Triple negative breast cancers are characterized in which the cancer does not express the genes for the estrogen receptor (ER), progesterone receptor (PR) or HER2. The presence of ER and PR can be determined using standard immunohistochemical staining methods (see, for example, Narod et al, Triple-Negative Breast Cancer: Clinical Features and Patterns of Recurrence, Clin Cancer Res, August 1, 2007 13; 4429). Alternatively, it is possible to evaluate the gene expression of these proteins using methods such as quantitative real-time PCR (QRT-PCR), with commercially available PCR assays (see Jozefczuk et al, Quantitative real-time PCR-based analysis of gene expression, Methods Enzymol. 2011;500:99-109).

[00472] Overexpression of the HER2 protein can be evaluated using the CB11 monoclonal antibody in representative paraffin sections of each tumor using the peroxidaseantiperoxidase technique for immunohistochemical evaluation. A tumor is defined as exhibiting HER2 positivity when strong, complete membrane staining is observed in at least 10% of tumor cells (Narod et al, Clin Cancer Res, Aug 1, 2007 13;4429).

[00473] Thus, in another embodiment of the invention (Modality 5.8), there is provided a method for diagnosing and treating a cancer, as defined in any one of Embodiments 2.10 to 2.18, wherein the method comprises (i) testing a patient to determine whether a cancer of which the patient is or may be a victim does not express estrogen receptor, progesterone receptor and/or HER2; and (ii) where it is indicated that the cancer to which the patient is then susceptible, then administering to the patient a compound as defined in any of Embodiments 1.0 to 1.116.

[00474] In another modality (Modality 5.9), there is provided the use of a compound, as defined in any one of Embodiments 1.0 to 1.116, for the manufacture of a medicament for the treatment or prophylaxis of a cancer, as defined in any one of Modalities 2.10 to 2.18, in a patient who has been tested and determined to be the victim of, or at risk of being the victim of, a cancer that does not express estrogen receptor, progesterone receptor and/or HER2.

[00475] In an additional embodiment (Modality 5.10), a compound is provided, as defined in any of Embodiments 1.0 to 1.116, for use in the treatment or prophylaxis of a cancer as defined in any of Embodiments 2.10 to 2.18, in a patient who has been tested and determined to be suffering from, or at risk of, a cancer that does not express the estrogen receptor, progesterone receptor and/or HER2.

[00476] Fragile X syndrome occurs as a result of a mutation of the fragile X mental retardation 1 (FMR1) gene. In individuals affected by FXS, the FMR1 gene contains more than 45, more commonly more than 55, and in some cases more than 200 repeats of the CGG codon compared to between 5 and 44 times, more typically between 29 and 30 times, in individuals affected by FXS. unaffected. This mutation results in a failure in the expression of the fragile X metal retardation protein FMRP, causing excessive production of a range of proteins normally controlled by FMRP. As FXS is a genetic disease, the diagnosis of FXS can be readily achieved by performing a genetic test on a blood or skin sample from the patient in question. Patients with FXS will not express FMR1 mRNA, or will have lower FMR1 mRNA levels than unaffected individuals. FMR1 mRNA levels can be quantified using real-time PCR, assays which are commercially available. Additionally, the size of the CGG repeat can be determined by isolating genomic DNA through reaming followed by PCR. See, for example, Kumari et al. (HUMAN MUTATION, Vol. 35, No. 12, 1485-1494, 2014) for laboratory methods to obtain these data. Therefore, biomarkers that allow identification of FXS in a patient include FMR1 mRNA levels and the presence of exaggerated CGG repeats from a patient's genomic DNA.

[00477] Thus, in another embodiment of the invention (Modality 5.11), there is provided a method for diagnosing and treating Fragile X Syndrome, wherein the method comprises (i) examining a patient for one or more biomarkers indicative of Fragile X Syndrome. X fragile; and (ii) where such a biomarker is detected, then administering to the patient a compound as defined in any of Embodiments 1.0 to 1.116.

[00478] In another modality (Modality 5.12), there is provided the use of a compound, as defined in any of Embodiments 1.0 to 1.116, for the manufacture of a medicament for the treatment or prophylaxis of fragile X syndrome in a patient who has been screened for and found to carry one or more biomarkers indicative of fragile X syndrome.

[00479] In an additional embodiment (Modality 5.13), a compound, as defined in any of Embodiments 1.0 to 1.116, is provided for use in the treatment or prophylaxis of fragile X syndrome in a patient who has been tested and found to have one or more biomarkers indicative of fragile X syndrome.

[00480] In another embodiment of the invention (Modality 5.14), there is provided a method for diagnosing and treating fragile X syndrome, which method comprises (i) testing a patient to determine whether he or she has FMR1 mRNA levels indicative of the syndrome of fragile X; and (ii) where it is indicated that he has such levels of FMR1 mRNA, then administering to the patient a compound as defined in any of Embodiments 1.0 to 1.116.

[00481] In another modality (Modality 5.15), there is provided the use of a compound, as defined in any of Embodiments 1.0 to 1.116, for the manufacture of a medicament for the treatment or prophylaxis of fragile X syndrome in a patient who was examined and determined to have FMR1 mRNA levels indicative of fragile X syndrome.

[00482] In an additional modality (Modality 5.16) a compound, as defined in any of Modalities 1.0 to 1.116, is provided for use in the treatment or prophylaxis of fragile X syndrome in a patient who has been tested and determined to have FMR1 mRNA levels indicative of fragile X syndrome.

Brief description of the figures

[00483] Figure 1 illustrates the results obtained from an in vivo model of triple negative breast cancer as described in Example 44 of this document and, in particular, shows the percentage of tumor-free mice versus the number of days after tumor implantation when treated with 100mg/kg of Example 1 or the vehicle.

[00484] Figure 2 shows tumor volume versus number of days after tumor implantation when treated with 100mg/kg of Example 1 or the vehicle, in the in vivo model of triple negative breast cancer as described in Example 44 of this document.

[00485] Figure 3 shows the weights of the livers of the subject mice in Example 44.

[00486] Figure 4 shows the tumor weights of the subject mice in Example 44.

EXAMPLES EXAMPLES 1 TO 43

[00487] The compounds of Examples 1 to 43 in Table 1

Analytical data

[00488] 1H NMR spectra were recorded on a Bruker 400 machine.

LCMS Methods:

[00489] LCMS analysis was performed using the following method(s): LCMS Method 1

[00490] Elution gradient:

LCMS Method 2

[00491] LC-MS was performed using a Waters Acquity H class device with the SingleQda mass detector using positive/negative electrospray ionization. The column used was as follows: Waters Acquity BEH C18 (50 X 2.1 mm) 1.7 micron. Column flow rate: 0.55 mL/ min. Solvent system used: mobile phase (A) 5 mm Ammonium Acetate + 0.1% Formic Acid (FA) in water and (B) 0.1% FA in Acetonitrile according to the following gradient: LCMS Method 3

[00492] Elution gradient: LCMS Method 4

[00493] Elution gradient:

[00494] LCMS Method 5

[00495] Elution gradient:

[00496] LCMS Method 6

[00497] Elution gradient:

Chiral HPLC methods:

[00498] Chiral HPLC analysis was performed using the following methods:

Chiral HPLC Method 1

[00499] Chiral HPLC was performed using the Waters Super-critical Fluid Chromatography (SFC) Investigator analytical HPLC device with PDA detector. Flow rate: 4.0 ml/ min. Injection volume: 10 uL. Analytical column used: Chiralpak IB (250*4.6mm) particle size 5 microns. Solvent system used: mobile phase (A) liquid carbon dioxide (B) 100% methanol according to the following gradient: Chiral HPLC Method 2

[00500] An isocratic elution was used:

Chiral HPLC Method 3

[00501] Chiral HPLC was performed using a Waters Super-critical Fluid Chromatography (SFC) Investigator analytical HPLC device with PDA detector. Flow rate: 4.0 ml/ min. Injection volume: 35 uL. Analytical column used: Chiralpak IB (250*4.6mm) particle size 5 micron. Solvent system used: mobile phase (A) liquid carbon dioxide (B) 100% methanol according to the following gradient:

Chiral HPLC Method 4

[00502] Chiral HPLC was performed using a Waters Supercritical Fluid Chromatography (SFC) Investigator analytical HPLC with PDA detector. Flow rate: 4.0 ml/ min. Injection volume: 20 uL. Analytical column used: Chiralpak IB (250*4.6mm) particle size 5 micron. Solvent system used: mobile phase (A) liquid carbon dioxide (B) isopropanol:acetonitrile 50:50 according to the following gradient: Chiral HPLC Method 5

[00503] An isocratic elution was used: Chiral HPLC Method 6

[00504] An isocratic elution was used: Chiral HPLC Method 7

[00505] An isocratic elution was used: Chiral HPLC Method 8

[00506] Elution gradient: Chiral HPLC Method 9

[00507] Elution gradient: Chiral HPLC Method 10

[00508] Elution gradient:

Chiral HPLC Method 11

[00509] The same method as chiral method 10 was used, except that ethanol was used as solvent B. Chiral HPLC method 12

[00510] An isocratic elution was used:

Preparative HLPC methods: Preparative HLPC Method 1

[00511] Purification was carried out using a Waters PHP-01 Preparative HLPC system using an X Bridge C18 column (250 mm long x 19 mm internal diameter) with a particle size of 5 microns and a flow rate of 15 mL/ min. Solvent system used: mobile phases (A) 0.1% ammonia in 100% water and (B) 100% acetonitrile using the following gradient:

Preparative HLPC Method 2

[00512] Purification was carried out using Waters PHP-01 Preparative HLPC system using an X Bridge C18 column (250 mm long x 30 mm internal diameter) with a particle size of 5 microns and a flow rate of 30 mL/min. Solvent system used: mobile phases (A) 0.1% ammonia in 100% water and (B) 100% acetonitrile using the following gradient: Preparative HLPC Method 3

[00513] Elution gradient: Preparative HLPC Method 4

[00514] Elution gradient: Preparative HLPC Method 5

[00515] Elution gradient:

Preparative HLPC Method 6

[00516] The same method was used as for Preparative HLPC Method 5, except that the following elution gradient was used:

Preparative HLPC Method 7

[00517] The same method was used as for Preparative HLPC Method 5 except that the following elution gradient was used:

Synthetic scheme A

[00518] Int A is commercially available and can also be synthesized using methods described in the literature (Jain, Rama et al, PCT International Application WO2009153313)

[00519] Where X = CH or N and where R = protecting group, such as THP

[00520] Compound 4 can be isolated as the free base or a salt form, for example, monohydrochloride salt, depending on the isolation method used. Synthetic scheme B

[00521] Where X = CH or N and where R = protecting group such as THP

[00522] Compound 5 can be isolated as the free base or a salt form, for example, monohydrochloride salt, depending on the isolation method used. Synthetic scheme C

[00523] Where X = CH or N and where R = protecting group such as THP

[00524] Compound 5 can be isolated as the free base or a salt form, for example, monohydrochloride salt, depending on the isolation method used. Synthesis of intermediates: Intermediate A: 6-Bromo-2-chloro-quinazoline

[00525] A suspension of 6-Bromo-quinazolin-2-ol (2 g, 8.89 mmol) in POCl3 (20 mL) was stirred at 110°C for 5h. After completion of the reaction, the reaction mixture was concentrated in vacuo and the residue was slowly poured onto ice, resulting in a solid precipitate. The solid was filtered, washed with water followed by hexanes and then dried in vacuo to provide the title product (1.5 g, 69%).

[00526] 6-Bromo-quinazolin-2-ol is commercially available and can also be synthesized using methods described in the literature (Jain, Rama et al, PCT Int. Appl., 2009153313) Intermediate B: 4-Chloro-1- (tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine Step 1: 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine

[00527] 1H-Pyrazole [3,4-d]pyrimidin-4-ol (5.0 g, 36.7 mmol) was dissolved in POCl3 (61.2 mL, 100.67 g, 657 mmol) at room temperature under nitrogen. N,N-diisopropylethylamine (10.2 mL, 58.5 mmol) was added to the reaction mixture and the resulting mixture was refluxed at 110 oC for 4 hrs. After 4hrs, POCl3 was distilled under vacuum at 40 oC to obtain a thick dark red gum. The thick gum was poured into ice water (25 mL) and extracted through DCM (25 mL x 3). The organic layer was concentrated to 25 mL. The product was used as raw for the next step. Step 2: 4-Chloro-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

[00528] 3,4-Dihydropyran (6 mL, 5.53 g, 65.8 mmol) was slowly added at room temperature to a solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine ( 2 g, 12.9 mmol) and D-10-camphorsulfonic acid (0.324 g, 1.39 mmol) in anhydrous ethyl acetate (20 mL). The reaction mixture was then allowed to stir at room temperature for 24h. After completion of the reaction, as judged by TLC, the reaction mixture was concentrated in vacuo and purified by flash column chromatography on silica gel eluting with 10% ethyl acetate in hexanes to give the title product (1, 92 g, 62%). Intermediate C: N'-Benzyl-N,N-dimethyl-ethane-1,2-diamine

[00529] N,N dimethyl ethylene diamine (0.83g, 9.42 mmol) and glacial acetic acid (1.13 g, 1.18 mmol) were added at room temperature, under nitrogen, to a stirred solution of Benzaldehyde (1.0g, 9.42 mmol) in methanol (20 mL). The mixture was stirred at room temperature for 2h. Sodium triacetoxyborohydride (5.99 g, 2.83 mmol) was added at 0 ° C to the reaction mixture and the reaction mixture was stirred for 18 h at room temperature under nitrogen. The reaction mixture was concentrated in vacuo. Then, to the crude, 20 ml of 1N HCl was added and the aqueous was extracted with ethyl acetate (20 ml). The aqueous layer was separated, basified to pH 8 with solid NaHCO3 and extracted with DCM (7 x 30 mL). The DCM layer was separated, dried over Na2SO4 and concentrated in vacuo to provide the title product (1.0 g, 60%). Intermediate D: Tert-butyl ester of (R)-3-aminomethyl-morpholine-4-carboxylic acid Step 1: (R)-3-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-morpholine-4-carboxylic acid tert-butyl ester

[00530] Phthalimide (1.21g, 8.22 mmol) and triphenylphosphine (5.43g, 20.70 mmol) were added at room temperature to a solution of (R)-4-Boc-3-hydroxymethylmorpholine (1 .5 g, 6.90 mmol) in THF (7.5 mL). A solution of Diisopropylazodicarboxylate (DIAD) (4.18g, 0.0207mol) in THF (7.5 mL) was added dropwise to the reaction mixture and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 50 mL). The organic layer was then washed with brine (1 x 30 ml) as well as water (1 x 30 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was further purified by silica gel column chromatography, eluting with 16% ethyl acetate in hexane to give an oil (4.3 g, >100%). Step 2: (R)-3-Aminomethyl-morpholine-4-carboxylic acid tert-butyl ester

[00531] Hydrazine hydrate (99% in water, 1.19g, 23.53 mmol) was added at room temperature to a solution of acid tert-butyl ester (R)-3-(1,3-Dioxo -1,3-dihydro-isoindol-2-ylmethyl)-morpholine-4-carboxylic acid (4.3g, 12.4 mmol) in ethanol (26 mL) and toluene (26 mL). The reaction mixture was refluxed for 30 min, concentrated in vacuo and the residue was poured into ice water and extracted with ethyl acetate (3 x 100mL). The organic layers were combined and washed with brine, separated and dried over sodium sulfate, then concentrated in vacuo to provide the crude product. The crude product was further purified by flash column chromatography on silica gel, eluting with 4% methanol in chloroform to give the title product (1.63 g, 61%). Intermediate E: (S)-3-Aminomethyl-morpholine-4-carboxylic acid tert-butyl ester

[00532] Intermediate E was prepared from (S)-4-Boc-3-hydroxymethylmorpholine using the same method as described for intermediate D. Intermediate F: 6-Chloro-9-(tetrahydro-pyran-2-yl )-9H-purine

[00533] Intermediate F is commercially available (CAS No.: 7306-68-5). Intermediate G: 4-Chloro-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4d]pyrimidine

[00534] D-10 camphorsulfonic acid (0.07 g, 0.301 mmol) and 3,4-dihydropyran (1.24 g, 14.7 mmol) were added sequentially, at room temperature, to a suspension of 4-chloro- 3-methyl-1H-pyrazolo[3,4-d]pyrimidine (0.5 g, 2.97 mmol) in ethyl acetate (21 mL). The reaction mixture was stirred for 24h at room temperature and was then concentrated in vacuo before purification by flash column chromatography on silica gel, eluting with 8% ethyl acetate in hexane to give the title product ( 0.59 g, 79%). Intermediate H: N-{3-[(6-Bromo-quinazoline-2-ylamino)-methyl]-phenyl}-methanesulfonamide

[00535] Step 1: (6-Bromo-quinazoline-2-yl)-(3-nitro-benzyl)-amino

[00536] 3-Nitrobenzylamine hydrochloride (0.56 g, 2.97 mmol) and DIPEA (1.28 g, 1.73 mL, 9.89 mmol) were added at room temperature to a stirred solution of 6 -bromo-2-chloro-quinazoline (0.6 g, 2.46 mmol) in DMSO (6 mL). The resulting mixture was heated at 80 oC for 12h. The reaction mixture was poured into ice water and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with brine (20 mL), then water (20 mL), separated, dried over anhydrous sodium sulfate and concentrated in vacuo to provide the crude product. The crude product was purified by flash column chromatography on silica gel, eluting with 18% ethyl acetate in hexane to give the title product (0.97 g, >100%).

[00537] Step 2: (3-Amino-benzyl)-(6-bromo-quinazolin-2-yl)-amino

[00538] Glacial acetic acid (0.30 g, 5.0 mmol) and powdered iron (100 mesh) (0.30 g, 5.4 mmol) were added at room temperature to a stirred solution of (6 -Bromo-quinazolin-2-yl)-(3-nitro-benzyl)-amino (0.97 g, 2.70 mmol) in methanol (10 mL). The resulting mixture was heated at 60 oC for 4h. The reaction mixture was poured into ice water and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with brine (20 mL), then water (20 mL), separated, dried over anhydrous sodium sulfate and concentrated in vacuo to provide the crude product which was used directly in the next step.

[00539] Step 3: N-{3-[(6-bromo-quinazolin-2-ylamino)-methyl]-phenyl}-methanesulfonamide

[00540] 2,6-lutidine (0.30 g, 0.33 mL, 2.80 mmol) and methanesulfonyl chloride (0.29 g, 0.196 mL, 2.53 mmol) were added at 0 oC to a stirred solution of (3-Amino-benzyl)-(6-bromo-quinazolin-2-yl)-amino (0.85 g, 2.58 mmol) in DCM (13 mL). The resulting mixture was then stirred for 6h at room temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with brine (20 mL), then water (20 mL), separated, dried over anhydrous sodium sulfate and concentrated in vacuo to provide the crude product. The crude product was purified by flash column chromatography on silica gel, eluting with 40% ethyl acetate in hexane to give the title product (0.6 g, 57%). Intermediate I: N-{3-[(R)-1-(6-Bromo-quinazolin-2-ylamino)-ethyl]-phenyl}-methanesulfonamide

[00541] The title compound was prepared using the same method as described for intermediate H, with the exception that (R)-1-(3-nitrophenyl)ethylamine hydrochloride (0.70 g, 3.45 mmol) was used instead of 3-nitrobenzylamine hydrochloride in step 1. Final step yield: 0.7 g (57%).

[00542] Synthetic scheme A is illustrated with reference to Example 1 below. EXAMPLE 1 ((R )-1-Phenyl-ethyl)-[6-( 1 H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amino

[00543] Step 1: (6-Bromo-quinazolin-2-yl)-((R)-1-phenyl-ethyl)-amino

[00544] (R)-(+)-1-phenylethylamine (6.0 g, 49.51 mmol) and DIPEA (21.4 g, 28.84 mL, 166 mmol) were added to a solution of 6-Bromo -2- chloro-quinazoline (10 g, 41.07 mmol) in DMSO (100 mL). The resulting mixture was heated at 80 oC for 12h. The reaction mixture was poured into ice water resulting in a solid precipitate. The solid was collected in vacuo and washed with ice water (3 x 100 mL) to provide the title product which was used in the next step without purification (13.2 g, 98%).

[00545] Step 2: ((R)-1-Phenyl-ethyl)-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxoborolan-2-yl)-quinazolin-2- yl]-amino

[00546] Bis(pinacolato)diborane (17.4 g, 68.52 mmol) was added, followed by potassium acetate (11.8 g, 120.2 mmol), under nitrogen, at room temperature, to a stirred solution of (6-Bromo-quinazolin-2-yl)-((R)-1-phenyl-ethyl)-amine (13.2 g, 40.22 mol) in 1,4-dioxane (149 mL). Nitrogen gas was bubbled into the resulting mixture for 30 min. Palladium(II) dichloride dichloromethane complex 1,1-bis(diphenylphosphine)ferrocene (1.6 g, 1.96 mmol) was then added to the reaction mixture. The reaction mixture was then heated at 80 oC for 3h. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 200 mL). The organic layers were combined and washed with brine (100 mL), followed by water (100 mL), then separated and dried over anhydrous sodium sulfate. The organic layer was concentrated in vacuo, then purified by flash column chromatography on silica gel, eluting with 15% ethyl acetate in hexanes to give the title product which was used in the next step without further purification (19.9 g, >100%).

[00547] Step 3: ((R)-1-Phenyl-ethyl)-{6-[1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4- yl]-quinazolin-2-yl}-amine

[00548] Intermediate B (19.4 g, 81.28 mmol) was added followed by Cs2CO3 (88.3 g, 271.01 mmol), under nitrogen, at room temperature, to a solution of ((R)- 1-phenyl-ethyl)-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxoborolan-2-yl)-quinazolin-2-yl]-amine (19.9 g, 67 .89 mmol) in a THF:water mixture (267 mL, 4:1 ratio). Nitrogen gas was bubbled into the resulting mixture for 45 min, and tetrakis(triphenylphosphine)palladium (0) (7.84 g, 6.78 mmol) was then added to the reaction mixture. The reaction mixture was then heated at 80 oC for 4 h under nitrogen. The reaction mixture was poured into water and extracted with ethyl acetate (2 x 300 mL). The organic layers were combined and washed with water (100 mL), separated, then dried over anhydrous sodium sulfate. The organic layer was concentrated in vacuo, then purified by flash column chromatography on silica gel, eluting with 45% ethyl acetate in hexanes to give the title product (15 g, 49%).

[00549] Step 4: ((R)-1-Phenyl-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine

[00550] 4N HCl in 1,4-dioxane (41.5 mL) was added under nitrogen at room temperature to a stirred solution of ((R)-1-phenyl-ethyl)-{6-[1 -(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-quinazolin-2-yl}-amine (15.0 g, 33.2 mol) in a mixture of methanol (36 mL) and 1,4-dioxane (150 mL). The reaction mixture was further stirred for 3h at room temperature.

[00551] The reaction mixture was filtered in vacuo, and the filtered solid was washed with ethyl acetate (3 x 50 mL), then hexane (3 x 50 mL) to provide the HCl salt. The solid was added to water (100 mL) and the resulting mixture was basified to pH 8.3 using saturated aqueous NaHCO3 solution. The resulting suspension was stirred for 30 min at room temperature, then filtered in vacuo. The solid was resuspended in water in a Büchner funnel and the resulting slurry was stirred for 10 mins and then filtered in vacuo. The water slurry process was repeated seven more times. The resulting filtered solid was dried in vacuo to give the title product (9.0 g, 74%).

[00552] Optionally, it is possible to retain the title compound as the HCl salt omitting the final basification process. EXAMPLE 2 ((R )-1-(3-Chloro-phenyl)-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine

[00553] The title product was prepared from intermediate A (0.4 g, 1.64 mmol) using the same method as described by example 1 with the following exceptions: (a) (R)-1-(3 -chloro-phenyl)-ethylamine was used instead of (R)-1-phenyl-ethylamine in step 1, (b) in step 4, the following method was used: N-((R)-1-(3- chlorophenyl)ethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)quinazolin-2-amine (0.12 g , 0.247 mmol) was dissolved in methanol (1 mL) and 4N HCl in dioxane (3 mL) was added at room temperature. After stirring at room temperature for 4h, the solid precipitate thus formed was filtered and washed with ethyl acetate to provide the title product as the monohydrochloride salt (0.050 g, 46%). EXAMPLE 3 ((R )-1-(3-Fluoro-phenyl)-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amino

[00554] The title product was prepared from intermediate A (0.4 g, 1.64 mmol) using the same method as described by Example 1 with the following exceptions: (a) (R)-1-(3 -fluoro-phenyl)-ethylamine was used instead of (R)-1-phenyl-ethylamine in step 1, (b) in step 4, the method described by example 2 was used, resulting in the compound being isolated as the monohydrochloride salt (0.040 g, 68%). EXAMPLE 4 ((R )-1-(4-Fluoro-phenyl)-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazoline2-yl]-amine

[00555] The title product was prepared from intermediate A (0.35 g, 1.43 mmol) using the same method as described by example 1 with the following exceptions: (a) (R)-1-(4 -fluoro-phenyl)-ethylamine was used instead of (R)-1-phenyl-ethylamine in step 1, (b) in step 4, after concentration of the reaction mixture in vacuo, the crude product was purified through purification by preparative HLPC to provide the title product (0.020 g, 22%). EXAMPLE 5 ((S )-2-Hydroxy-1-phenyl-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine

[00556] The title product was prepared from intermediate A (0.4 g, 1.64 mmol) using the same method as described by Example 1 with the following exceptions: (a) (S)-2-phenylglycinol was used instead of (R)-1-phenyl-ethylamine in step 1, (b) in step 4, after concentration of the reaction mixture in vacuo, the crude product was purified by preparative HLPC purification to provide the free base . 4N HCl in dioxane (0.05 ml) was added to a solution of free base in ethyl acetate (1 ml) at 10°C, followed by stirring at room temperature for 30 min. After 30 min, the reaction mixture was concentrated in vacuo and triturated with ethyl acetate to provide the title product as the monohydrochloride salt (0.050 g, 37%). EXAMPLE 6 (4-Fluorobenzyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-methylamine

[00557] The title product was prepared from intermediate A (0.4 g, 1.64 mmol) using the same method as described by Example 1 with the following exceptions: (a) N-(4-fluorobenzyl)- N-methylamine was used instead of (R)-1-phenylethylamine in step 1, (b) in step 4, after concentration of the reaction mixture in vacuo, the product was triturated with methanol and ethyl acetate to give the title product as the monohydrochloride salt (0.080 g, 59%). EXAMPLE 7 Benzyl-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-methylamine

[00558] The title product was prepared from intermediate A (0.6 g, 2.46 mmol) using the same method as described by Example 1 with the following exceptions: (a) N-benzyl-N-methylamine was used instead of (R)-1-phenyl-ethylamine in step 1, (b) in step 4, the method of Example 6 was applied. The title product was isolated as the monohydrochloride salt (0.080 g, 60%). EXAMPLE 8 ((R )-1-Phenyl-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-methylamine

[00559] The title product was prepared from intermediate A and following scheme B and the method described below. Step 1: (6-Bromo-quinazolin-2-yl)-((R)-1-phenyl-ethyl)-amine

[00560] As described in step 1 of Example 1 Step 2: (6-Bromo-quinazolin-2-yl)-methyl-((R)-1-phenyl-ethyl)-amine

[00561] A solution of (6-Bromo-quinazoline-2-yl)-((R)-1-phenyl-ethyl)-amine (0.45 g, 1.37 mmol) in DMF (5 mL) was added , to a suspension of NaH (60% in mineral oil) (0.082 g, 2.05 mmol) in DMF (5 mL) at 0 °C under nitrogen. The reaction mixture was stirred at 0°C for 30 minutes. Mel (0.233 g, 1.64 mmol) was added and the reaction mixture was stirred at room temperature for 2h. The reaction mixture was then diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were separated, dried over anhydrous sodium sulfate, then concentrated in vacuo to provide the crude product. The crude product was purified by flash column chromatography on silica gel, eluting with 5 - 8% ethyl acetate in hexanes to give the title product (0.45 g, 96%). Step 3 Methyl-((R)-1-phenyl-ethyl)-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxoborolan-2-yl)-quinazolin-2-yl] -the mine

[00562] (6-Bromo-quinazolin-2-yl)-methyl-((R)-1-phenyl-ethyl)-amine (0.45 g, 1.31 mmol) was subjected to the conditions of step 2, Example 1, to provide the title product (0.25 g, 49%). Step 4: Methyl-((R)-1-phenyl-ethyl)-{6-[1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4- yl]-quinazolin-2-yl}-amine

[00563] Methyl-((R)-1-phenyl-ethyl)-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxoborolan-2-yl)-quinazolin-2-yl ]-amine (0.25 g, 0.64 mmol) was subjected to the conditions of step 3, Example 1 to provide the title product (0.1 g, 34%). Step 5: ((R)-1-Phenyl-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-methylamine

[00564] 4N HCl in dioxane (2 mL) was added at room temperature to a solution of Methyl-((R)-1-phenyl-ethyl)-{6-[1-(tetrahydro-pyran -2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-quinazolin-2-yl}-amine (0.1 g, 0.21 mmol) in methanol (3 mL) and the reaction mixture was stirred at room temperature for 5 h. During the reaction a solid was precipitated; the solid was therefore filtered in vacuo and washed with ethyl acetate, then dried in vacuo to give the title product (0.080 g, 91%).

[00565] The compound is isolated as the monohydrochloride salt. EXAMPLE 9 (4-Fluorobenzyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine

[00566] The title product was prepared from intermediate A (1.2 g, 4.96 mmol) using the same method as described by Example 1 with the following exceptions: (a) 4-fluorobenzylamine was used instead of (R)-1-phenylethylamine in step 1, (b) in step 4, after treatment with 4N HCl in dioxane (6.0 mL) and stirring for 3h, the reaction mixture was concentrated in vacuo, poured in water and the resulting reaction mixture was basified to pH 8 using sodium bicarbonate (aq) solution. The resulting suspension was filtered in vacuo to provide the title product. Final stage yield: 0.105 g (48%). EXAMPLE 10 (3-Fluorobenzyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine

[00567] The title product was prepared from intermediate A (1.0 g, 4.13 mmol) using the same method as described by Example 1 with the following exceptions: (a) 3-fluorobenzylamine was used instead of (R)-1-phenylethylamine in step 1, (b) in step 4, the isolation method described in example 9 was used but, additionally, the filtered product was suspended in ethyl acetate (5 mL) for 15 min at room temperature, followed by filtration in vacuo. Final stage yield: 0.112 g (34%). EXAMPLE 11 (3-Chlorobenzyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine

[00568] The title product was prepared from intermediate A (0.60 g, 2.48 mmol) using the same method as described by example 1 with the following exceptions: (a) 3-chlorobenzylamine was used instead of (R)-1-phenylethylamine in step 1, (b) in step 4, the isolation method described in example 9 was used but, in addition, the filtered product was further purified by preparative HLPC purification using the method of Preparative HLPC 1. Final step yield: 0.036 g (17%). EXAMPLE 12 ((R)-1-Phenyl-ethyl)-[7-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine

[00569] The title product was prepared using the same method as described by Example 1 with the following exceptions: (a) 7-bromo-quinazolin-2-ol (1.2 g, 4.96 mmol) was used instead of 6-bromo-quinazolin-2-ol in the synthesis of Int. A, (b) in step 4, the reaction time was 1h. The isolation method described in example 9 was used, but the filtered solid was additionally purified by flash column chromatography, eluting with methanol in 3% chloroform, followed by purification by preparative HLPC using preparative HLPC method 2 Final stage yield: 0.022 g (17%).

[00570] 7-Bromo-quinazoline-2-ol can be purchased from various commercial sources, as indicated by availability in Scifinder databases, or can be prepared via the route described in international patent application WO2007117607. EXAMPLE 13 ((R )-1-Phenyl-ethyl)-[6-(1H-pyrazolo[3,4-b]pyridin-4-yl)-quinazolin-2-yl]-amine

[00571] The title product was prepared from ((R)-1-Phenyl-ethyl)-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxoborolan-2-yl )-quinazolin-2-yl]-amino (0.3 g, 0.799 mmol) using the same method as described by Example 1 with the following exceptions: (a) in step 3, 4-chloro-1H-pyrazolo[3, 4- b]pyridin was used instead of intermediate B. Furthermore, in step 3, a solvent mixture of DMF:water was used (4:1, 5 mL) and heating was at 130 oC in a microscopic reactor. -waves. Step 4 was an HCl salt formation step: 4N HCl in dioxane (0.08 mL) was added at 10°C to a suspension of ((R)-1-Phenyl-ethyl)-[6- (1H-pyrazolo[3,4- b]pyridin-4-yl)-quinazolin-2-yl]-amine (0.080 g, 0.218 mmol) in ethyl acetate (0.8 mL) and the reaction mixture was stirred at the same temperature for 40 min. The reaction mixture was then concentrated in vacuo and triturated with ethyl acetate to provide the title product as the monohydrochloride salt (0.070 g, 80%)

[00572] 4-Chloro-1H-pyrazolo[3,4-b]pyridine can be purchased from several commercial sources. EXAMPLE 14 ((R )-1-Phenyl-ethyl)-[6-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-quinazoline-2-yl]-amino

[00573] The title product was prepared from ((R)-1-Phenyl-ethyl)-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxoborolan-2-yl )-quinazolin-2-yl]-amine (0.35 g, 0.933 mmol) using the same method as described by Example 1 with the following exceptions: (a) 4-chloro-7H-pyrrolo[2,3-d] pyrimidine was used in step 3 instead of intermediate B, (b) an HCl salt formation step was included, the method for which is described in example 13. The compound is isolated as the monohydrochloride salt (0.055 g, 83% ).

[00574] 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine can be purchased from several commercial sources. EXAMPLE 15 ((R)-1-Phenyl-ethyl)-[6-(1H-pyrrolo[2,3-b]pyridin-4-yl)-quinazolin-2-yl]-amine

[00575] The title product was prepared from ((R)-1-Phenyl-ethyl)-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxoborolan-2-yl )-quinazolin-2-yl]-amine (0.20 g, 0.533 mmol) using the same method as described by Example 1 with the following exceptions: (a) in step 3, 4-bromo-1H-pyrrolo[2, 3-b]pyridine was used instead of intermediate B, potassium carbonate was used instead of cesium carbonate, and dioxane:water (4:1) was used as solvent instead of THF:water, (b) one step HCl salt formation method was included, the method for which is described in Example 13. The compound is isolated as the monohydrochloride salt (0.070 g, 80%).

[00576] 4-Bromo-1H-pyrrolo[2,3-b]pyridine can be purchased from several commercial sources. EXAMPLE 16 N-Benzyl-N',N'-dimethyl-N-[6-(1H-pyrazolo[3,4-d]pyrimidine-4-yl)-quinazoline-2-yl]-ethane-1,2- diamine

[00577] The title compound can be prepared using Synthetic Scheme A, following the method of Example 1, using N'-Benzyl-N,N-dimethyl-ethane-1,2-diamine (intermediate C) in step 1. In step 4, the following method was followed:

[00578] Step 4

[00579] 4N HCl in 1,4-dioxane (0.25 mL, 1.0 mmol) was added under nitrogen at room temperature to a stirred solution of N-Benzyl-N',N'-dimethyl-N -{6-[1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-quinazolin-2-yl}-ethane-1,2-diamine (0.40 g, 0.79 mmol) in 1,4-dioxane (4 mL). The reaction mixture was further stirred for 4h at room temperature. An additional aliquot of 4N HCl in 1,4-dioxane (0.25 mL, 1.0 mol) was added and the reaction mixture was stirred for 3h at room temperature. The reaction mixture was then concentrated in vacuo to provide the crude product which was added to water. The resulting mixture was basified with saturated NaHCO3 solution (aq) at pH 8. The resulting mixture was extracted through ethyl acetate and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 2.5% methanol in chloroform to give a crude yellow solid which was further triturated using ethyl ether. The solid recovered from trituration (0.086 g, 0.189 mmol) was dissolved in 1,4-dioxane (0.8 mL) at room temperature and 4 M HCl in 1,4-dioxane (0.06 mL, 0.24 mmol). was added. The reaction mixture was stirred for 30 minutes at room temperature, after which the reaction mixture was concentrated in vacuo and triturated with ethyl ether (1 mL) to provide the title product as the monohydrochloride salt (0.067 g, overall yield of 19%). EXAMPLE 17 Benzyl-(R)-1-morpholin-3-ylmethyl-[6-( 1 H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine

[00580] The title compound was prepared according to synthetic Scheme C.

[00581] Step 1: ((R)-3-(((6-bromoquinazolin-2-yl)amino)methyl)tert-butyl morpholine-4-carboxylate)

[00582] Int D (1.5 g, 6.93 mmol) and DIPEA (3.0 g, 4.04 mL, 23.21 mmol) were added at room temperature to a stirred solution of Int A (1 .4 g, 5.75 mmol) in DMSO (14 mL). The resulting mixture was heated at 80 oC for 18h. The reaction mixture was poured into ice water and extracted with ethyl acetate (3 x 50 mL). The organic layer was then washed with brine (50 ml) as well as water (50 ml), separated, dried over anhydrous sodium sulfate and concentrated in vacuo to provide the crude product. The crude product was purified by flash column chromatography on silica gel, eluting with 25% ethyl acetate in hexane to give the title product (1.58 g, 65%).

[00583] Step 2: ((R)-3-((benzyl(6-bromoquinazolin-2-yl)amino)methyl) tert-butyl morpholine-4-carboxylate)

[00584] A solution of tert-butyl ((R)-3-(((6-bromoquinazolin-2-yl)amino)methyl)morpholine-4-carboxylate) (1.58 g, 3.73 mmol) was added ), in DMF (22 mL), at 0 oC, under nitrogen, to a suspension of sodium hydride (0.74 g, 18.5 mmol) in dry DMF (22 mL). The reaction mixture was stirred for 30 min at 0 oC and then brought to room temperature before benzyl bromide (1.92 g, 11.23 mmol) was added. The reaction mixture was stirred at 0 oC for 30 min. The reaction mixture was poured into ice water and extracted with ethyl acetate (3 x 50 mL). The organic layers were separated, combined and then washed with brine (50 ml), followed by water (50 ml), dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel, eluting with 10% ethyl acetate in hexane to give the title product (1.8 g, 94%).

[00585] Step 3: ((R)-3-((benzyl(6-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)quinazolin-2-yl)amino) tert-butyl methyl)morpholine-4-carboxylate)

[00586] ((R)-3-((benzyl(6-bromoquinazolin-2-yl)amino)methyl)morpholine-4-tert-butylcarboxylate) (1.8 g, 3.51 mmol) was subjected to the same conditions as described by Example 1, step 2, to provide the title product. Yield: 2.3 g (> 100%).

[00587] Step 4: ((3R)-3-((benzyl(6-(1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazolo[3,4-d]pyrimidin-4- il)quinazolin-2-yl)amino)methyl)morpholine-4-tert-butyl carboxylate)

[00588] ((R)-3-((benzyl(6-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)quinazolin-2-yl)amino)methyl)morpholine tert-Butyl-4-carboxylate) (2.30 g, 4.10 mmol) was subjected to the same conditions as described by Example 1, step 3, to provide the title product (1.2 g, 46%).

[00589] Step 5: ((R)-N-benzyl-N-(morpholin-3-ylmethyl)-6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)quinazolin-2-amine)

[00590] ((3R)-3-((benzyl(6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)quinazolin tert-butyl-2-yl)amino)methyl)morpholine-4-carboxylate) (1.2 g, 1.88 mmol) was subjected to the same conditions as described by Example 1, step 4, and purified as follows: after Upon completion of the reaction, the reaction mixture was filtered in vacuo and the resulting filtered solid was washed with ethyl acetate (3 x 50 mL) and hexane (3 x 50 mL). The solid was further triturated in acetone, then filtered in vacuo to provide the title product as a monohydrochloride salt (0.48 g, 52%). EXAMPLE 18 Benzyl-(S)-1-morpholin-3-ylmethyl-[6-( 1 H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine

[00591] The title compound was prepared from Int A (1.3 g, 5.34 mmol) via synthetic Scheme C above using the same method as in Example 17 with the following exceptions: (a) in step 1 , intermediate E, (S)-3-Aminomethyl-morpholine-4-carboxylic acid tert-butyl ester (prepared by a procedure analogous to intermediate D) was used instead of (R)-3 acid tert-butyl ester -Aminomethyl-morpholine-4-carboxylic acid, (b) in step 5, grinding in acetone was omitted. The compound is isolated as the monohydrochloride salt. Final stage yield: 0.63 g (67%). EXAMPLE 19

[00592] [(R)-1-(3,4-Difluoro-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl] -the mine

[00593] Step 1: ((R)-6-bromo-N-(1-(3,4-difluorophenyl)ethyl)quinazolin-2-amine)

[00594] (R)-1-(3,4-difluorophenyl)ethylamine (0.39 g, 2.48 mmol) and DIPEA (1.08 g, 1.46 mL, 8.4 mmol) were added at temperature ambient, to a stirred solution of intermediate A (0.5 g, 2.05 mol) in DMSO (5 mL). The resulting mixture was heated at 80 oC for 12h. The reaction mixture was poured into ice water, resulting in a precipitate. The solid was filtered in vacuo and washed with ice water to provide the title product (0.7 g, 94%).

[00595] Step 2: ((R)-N-(1-(3,4-difluorophenyl)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl )quinazolin-2-amine)

[00596] Bis(pinacolato)diborane (0.84 g, 3.31 mmol) was added, followed by potassium acetate (0.57 g, 5.80 mmol), under nitrogen, at room temperature, to a stirred solution of ((R)-6-bromo-N-(1-(3,4-difluorophenyl)ethyl)quinazolin-2-amine) (0.70 g, 1.92 mmol) in 1,4-dioxane (8 mL ). The resulting mixture was purged by bubbling with nitrogen for 30 minutes. To the reaction mixture, the complex 1,1-bis(diphenylphosphine)ferrocene palladium(II dichloride) dichloromethane (0.08 g, 0.098 mmol) was added. The reaction mixture was then heated at 80 oC for 2h. The reaction mixture was poured into water and extracted with ethyl acetate (2 x 40 mL). The combined organic layers were washed with brine (20 mL), then water (20 mL), separated and dried over anhydrous sodium sulfate before concentration in vacuo. The crude residue was purified by flash column chromatography on silica gel, eluting with 7% ethyl acetate in hexane to give the title product (0.94 g, >100%).

[00597] Step 3: (N-((R)-1-(3,4-difluorophenyl)ethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3 ,4-d]pyrimidin-4-yl)quinazolin-2-amine)

[00598] Intermediate B (0.65 g, 2.72 mmol) was added, followed by Cs2CO3 (2.97 g, 9.12 mmol), under nitrogen, at room temperature, to a stirred solution of ((R )-N-(1-(3,4-difluorophenyl)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborolane-2-yl)quinazolin-2-amine) (0 .94 g, 2.29 mmol) in a THF:water mixture (12.5 mL, 4:1). The mixture was purged by bubbling with nitrogen gas for 45 min, and Tetrakis(triphenylphosphine)palladium(0) (0.26g, 0.225 mmol) was added at room temperature to the resulting mixture. The reaction mixture was then heated at 80 oC for 3h. The resulting reaction mixture was poured into water and the product was extracted using ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (20 mL), then water (20 mL), separated and dried over anhydrous sodium sulfate, then concentrated in vacuo to provide the crude product. The crude was purified by flash column chromatography on silica gel, eluting with 45% ethyl acetate in hexane to give the title product (0.6 g, 54%).

[00599] Step 4: ((R)-N-(1-(3,4-difluorophenyl)ethyl)-6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)quinazolin-2-amine )

[00600] 4N HCl in 1,4-dioxane (6 mL) was added under nitrogen at room temperature to a stirred solution of (N-((R)-1-(3,4-difluorophenyl)ethyl )-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)quinazolin-2-amine) (0.6 g, 1 .23 mmol) in a mixture of methanol (1.4 mL) and 1,4-dioxane (6 mL). The reaction mixture was further stirred for 1h at room temperature, at which point a precipitate was formed, which was filtered in vacuo and washed with ethyl acetate (3 x 30 mL) followed by hexane (3 x 30 mL). The solid was then added to water (10 mL) and the resulting mixture was basified to pH 8 using a saturated NaHCO3 solution, with stirring for 30 min. The reaction mixture was filtered in vacuo, washing with water, to provide the title product (0.27 g, 54%). EXAMPLE 20

[00601] ((R)-1-Phenyl-ethyl)-[6-(9H-purin-6-yl)-quinazolin-2-yl]-amine

[00602] The title product was prepared from intermediate A (10 g, 41.1 mmol) using the same method as described by example 19 with the following exceptions: (a) in step 1, (R)-1- phenyl ethylamine was used instead of (R)-1-(3,4-difluorophenyl)ethylamine (b) in step 3, intermediate F, 6-chloro-9-(tetrahydro-pyran-2-yl)- 9H-purine was used instead of intermediate B. Final step yield: 0.26 g (46%). EXAMPLE 21

[00603] Benzyl-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine

[00604] The title product was prepared from intermediate A (0.5 g, 2.05 mmol) using the same method as described by example 19, except that, in step 1, benzylamine was used instead of (R )-1-(3,4-difluorophenyl)ethylamine. Final stage yield: 0.2 g (40%). EXAMPLE 22

[00605] [6-(3-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]- ((R)-1-phenyl-ethyl)-amine

[00606] The title product was prepared from intermediate A (10 g, 41.1 mmol) using the same method as described by example 19 with the following exceptions: (a) in step 1, (R)-1- phenylethylamine was used instead of (R)-1-(3,4-difluorophenyl)ethylamine, (b) in step 3, the intermediate G, 4-chloro-3-methyl-1-(tetrahydro-pyran -2-yl)-1H- pyrazolo[3,4-d]pyrimidine, was used instead of intermediate B, (c) in step 4, preparative HLPC (using Preparative HLPC Method 3) was used as the final step to purify the title product. Final step yield: 0.12 g (24%). EXAMPLE 23

[00607] (3-Methoxy-benzyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine

[00608] The title product was prepared from intermediate A (0.5 g, 2.05 mmol) using the same method as described by example 19, except that in step 1, 3-methoxy benzylamine was used instead of (R)-1-(3,4-difluorophenyl)ethylamine. Final stage yield: 0.27 g (59%). EXAMPLE 24

[00609] 2-Fluoro-benzyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine

[00610] The title product was prepared from intermediate A (0.4 g, 1.64 mmol) using the same method as described by example 19, except that in step 1, 2-fluorobenzylamine was used instead of ( R)-1-(3,4-difluorophenyl)ethylamine. Final stage yield: 0.17 g (46%). EXAMPLE 25

[00611] (3,4-Difluoro-benzyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine

[00612] The title product was prepared from intermediate A (0.5 g, 2.05 mmol) using the same method as described by example 19, except that, in step 1, 3,4-difluorobenzylamine was used in instead of (R)-1-(3,4-difluorophenyl)ethylamine. Final stage yield: 0.34 g (78%). EXAMPLE 26

[00613] N-(3-{[6-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-methyl}-phenyl)-methanesulfonamide

[00614] Intermediate H (0.6 g, 1.47 mmol) was subjected to the conditions of steps 2-4 of Example 19, followed by purification via Preparative HLPC Method 4 to provide the title product (0.05 g, 11%). EXAMPLE 27

[00615] [(R)-1-(3-Methoxy-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine

[00616] The title product was prepared from intermediate A (0.6 g, 2.46 mmol) using the same method as described by example 19, except that in step 1, (R)-(+)-1 -(3-methoxyphenyl)ethylamine was used instead of (R)-1-(3,4-difluorophenyl)ethylamine. Final step yield: 0.4 g (59%). EXAMPLE 28

[00617] [(R)-1-(2-Fluoro-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine

[00618] The title product was prepared from intermediate A (0.5 g, 2.05 mmol) using the same method as described by example 19 with the following exceptions: (a) in step 1, (R)- 1-(2-fluorophenyl)ethylamine was used instead of (R)-1-(3,4-difluorophenyl)ethylamine, (b) in step 4, a final grinding with acetone was applied. Final step yield: 0.3 g (42%). EXAMPLE 29

[00619] ((S)-1-Phenyl-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidine-4-yl)-quinazoline-2-yl]-amino

[00620] The title product was prepared from intermediate A (2.5 g, 10.3 mmol) using the same method as described by example 19 with the following exceptions: (a) (S)-(-)-α- Methyl benzyl amino was used instead of (R)-1-(3,4-difluorophenyl)ethylamine in step 1, (b) in step 4, a final grinding with ethyl acetate was applied. Final stage yield: 0.56 g (47%). EXAMPLE 30

[00621] N-(3-{(R)-1-[6-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethyl}-phenyl)-methanesulfonamide

[00622] Intermediate I (1.0 g, 1.47 mmol) was subjected to the conditions of steps 2-4 of Example 19 to provide the title product. Final stage yield: 0.22 g (39%). EXAMPLE 31

[00623] (R)-3-Phenyl-3-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-propan-1-ol

[00624] The title product was prepared from intermediate A (0.5 g, 2.05 mmol) using the same method as described by example 19, with the exception that, in step 1, (R)-3 -Amino-3-phenyl-propan-1-ol was used instead of (R)-1-(3,4-difluorophenyl)ethylamine. Final stage yield: 0.14 g (38%). EXAMPLE 32

[00625] [(R)-1-(2,4-Difluoro-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl] -the mine

[00626] The title product was prepared from intermediate A (0.5 g, 2.05 mmol) using the same method as described by example 19 with the exception that (R)-1-(2, 4-Difluoro-phenyl)-ethylamine was used in step 1 instead of (R)-1-(3,4-difluorophenyl)ethylamine. Final stage yield: 0.205 g (56%). EXAMPLE 33

[00627] [(R)-1-(2,6-Difluoro-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl] -the mine

[00628] The title product was prepared from intermediate A (0.5 g, 2.05 mmol) using the same method as described by example 19 with the exception that (R)-1-(2, 6-difluorophenyl)ethanamine was used in step 1 instead of (R)-1-(3,4-difluorophenyl)ethylamine. Final stage yield: 0.235 g (47%). EXAMPLE 34

[00629] 4-[2-((R)-1-Phenyl-ethylamino)-quinazolin-6-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

[00630] The title product was prepared from intermediate A (1.0 g, 4.11 mmol) using the same method as described by example 19 with the following exceptions: (a) (R)-1-phenyl- ethylamine was used in step 1 instead of (R)-1-(3,4-difluorophenyl)ethylamine; (b) step 3 was performed as described above; and (c) step 4 was omitted. 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile is commercially available. Final stage yield: 0.142 g (19%).

[00631] Step 3: 4-[2-((R)-1-Phenyl-ethylamino)-quinazolin-6-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

[00632] To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (0.35 g, 1.96 mmol) and ((R)-1-Phenyl-ethyl) -[6-(4,4,5,5-tetramethyl-[1,3,2]dioxoborolan-2-yl)-quinazolin-2-yl]-amine (0.75 g, 2.00 mmol) in DMF (7 mL) an aqueous solution of 1M NaHCO3 (5.9 mL, 5.9 mmol) was added under a nitrogen atmosphere at room temperature. The reaction mixture was purged with nitrogen gas for 30 minutes and then dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.0997 mmol) was added at room temperature to the reaction mixture. The resulting reaction mixture was then heated at 80 °C for 18 h. The reaction mixture was poured into water and extracted with ethyl acetate (2 x 20mL). The organic layers were combined and washed with brine (20 ml), then separated, dried over anhydrous sodium sulfate and concentrated in vacuo to provide the crude title product. The crude was purified by flash column chromatography on silica gel, eluting with 60% ethyl acetate in hexane to provide the title product which was then further purified by preparative HLPC using method 5. EXAMPLE 35

[00633] 2-{(R)-1-[6-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethyl}-phenol

[00634] The title product was prepared from intermediate A (0.8 g, 3.29 mmol) using the same method as described by example 19 with the following exceptions: (1) 2-((R)-1 -Amino-ethyl)-phenol was used in step 1 instead of (R)-1-(3,4-difluorophenyl)ethylamine; and (2) in step 4, the reaction mixture was not immediately filtered, but was first basified to pH 8 using a saturated aqueous NaHCO3 solution. The aqueous phase was extracted with EtOAc (2 x 20 mL). The organic layers were combined and concentrated in vacuo to give the crude title product which was purified by flash column chromatography on silica gel, eluting with 4% methanol in chloroform to give the title product which was then purified. additionally through preparative HLPC using method 6. Final step yield: 0.032 g (12%). EXAMPLE 36

[00635] 3-{(R)-1-[6-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethyl}-phenol

[00636] The title product was prepared from intermediate A (0.8 g, 3.29 mmol) using the same method as described by example 19 with the exception that 3-((R)-1-amino- ethyl)-phenol was used in step 1 instead of (R)-1-(3,4-difluorophenyl)ethylamine. Final stage yield: 0.126 g (16%). EXAMPLE 37

[00637] 4-{(R)-1-[6-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethyl}-phenol

[00638] The title product was prepared from intermediate A (0.8 g, 3.29 mmol) using the same method as described by example 19 with the following exceptions: (1) 4-((R)-1 -Amino-ethyl)-phenol was used in step 1 instead of (R)-1-(3,4-difluorophenyl)ethylamine (2) in step 4, the reaction mixture was not immediately filtered, but was first basified to pH 8 using a saturated aqueous NaHCO3 solution, and was then filtered in vacuo. The isolated solid was then purified by preparative HLPC using method 6 to provide the title product. Final step yield: 0.1 g (20%). EXAMPLE 38

[00639] (S)-2-(2-Fluoro-phenyl)-2-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethanol

[00640] The title product was prepared from intermediate A (0.6 g, 2.46 mmol) using the same method as described by example 19 with the exception that (S)-2-Amino-2-( 2-fluoro-phenyl)-ethanol was used in step 1 instead of (R)-1-(3,4-difluorophenyl)ethylamine. EXAMPLE 39

[00641] (S)-2-(3-Fluoro-phenyl)-2-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethanol

[00642] The title product was prepared from intermediate A (0.8 g, 3.29 mmol) using the same method as described by example 19 with the exception that (S)-2-amino-2-( 3-fluoro-phenyl)-ethanol was used in step 1 instead of (R)-1-(3,4-difluorophenyl)ethylamine. EXAMPLE 40

[00643] (S)-2-(4-Fluoro-phenyl)-2-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethanol

[00644] The title product was prepared from intermediate A (0.8 g, 3.29 mmol) using the same method as described by example 19 with the exception that (S)-2-amino-2-( 4-fluoro-phenyl)-ethanol was used in step 1 instead of (R)-1-(3,4-difluorophenyl)ethylamine. EXAMPLE 41

[00645] (R)-3-(2-Fluoro-phenyl)-3-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-propan-1 -ol

[00646] The title product was prepared from intermediate A (0.8 g, 3.29 mmol) using the same method as described by example 19 with the exception that (R)-3-amino-3-( 2-fluoro-phenyl)-propan-1-ol was used in step 1 instead of (R)-1-(3,4-difluorophenyl)ethylamine. Final stage yield: 0.144 g (34%). EXAMPLE 42

[00647] (R)-3-(3-Fluoro-phenyl)-3-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-propan-1 -ol

[00648] The title product was prepared from intermediate A (0.8 g, 3.29 mmol) using the same method as described by example 19 with the exception that (R)-3-amino-3-( 3-fluoro-phenyl)-propan-1-ol was used in step 1 instead of (R)-1-(3,4-difluorophenyl)ethylamine. Final step yield: 0.1 g (24%). EXAMPLE 43

[00649] (R)-3-(4-Fluoro-phenyl)-3-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-propan-1 -ol

[00650] The title product was prepared from intermediate A (0.6 g, 2.46 mmol) using the same method as described by example 19 with the following exceptions: (1) (R)-3-amino- 3-(4-fluoro-phenyl)-propan-1-ol was used in step 1 instead of (R)-1-(3,4-difluorophenyl)ethylamine; and (2) in step 4 the reaction mixture was concentrated in vacuo, added to water and the resulting reaction mixture was basified to pH 8 using a saturated aqueous NaHCO3 solution. The mixture was stirred for 30min at room temperature and was then filtered in vacuo, washing with water (3 x 30 mL), followed by hexane (2 x 15 mL). The crude material was purified by preparative HLPC using method 7. Final step yield: 0.203 g (31%). N/A = not applicable

EXAMPLE 44 BIOLOGICAL ACTIVITY Determination of p70S6 inhibitory activity

[00651] The ability of the compounds of the invention to inhibit P70S6 kinase can be determined using the protocol below.

[00652] Buffer composition:

[00653] 20 mM MOPS, 1 mM EDTA, Brij-35, 5% Glycerol, 0.1% b-mercaptoethanol, 1 mg/mL BSA

[00654] Method:

[00655] Analysis of p70S6K kinase (h)

[00656] In a volume of 25 μL of the final reaction, p70S6K (h) (5 10 mU) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 100 μM KKRNRTLTV, Mg acetate at 10 mM and [Y-33P-ATP] (specific activity approx. 500 cpm/pmol, concentration as needed). The reaction is started by adding the MgATP mixture. After incubation for 40 minutes at room temperature, the reaction is stopped by adding 5 μL of a 3% phosphoric acid solution. 10 μL of the reaction mixture is then soaked in a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol before drying and scintillation counting.

Assessment of brain and plasma concentrations in an in vivo mouse model cassette

[00657] The compounds of this invention were evaluated in an in vivo mouse model cassette to determine brain and plasma concentrations after oral dosing. This is an industry standard and a recognized means of evaluating brain penetration of small molecules (for a recent literature article, see: in vitro permeability analysis, pharmacokinetic and brain distribution study in mice of imperatorin, isoimperatorin and cnidilin in Radix Angelicae Dahuricae , Phytotherapy, Volume 85, March 2013, pp. 144-153). It is also recognized that high brain concentrations (and high brain:plasma concentration ratios) cause greater brain exposure - this is clearly advantageous if the brain is the site of action.

[00658] Experimental method:

[00659] For a single cassette study, male CD-1 mice were used (n=3 per time point, three time points: 1.0 hr, 3.0 hr, and 8.0 hr).

[00660] 5 compounds were dosed orally per cassette (2.5 mg/kg dose level per compound, 0.25 mg/ml dose conc., 10.0 ml/kg dose volume).

[00661] Formulation used to solubilize compounds: DMSO 10% / 90% hypromellose-β-cyclodextrin (20% w/v aqueous)

[00662] Sampling was terminal and plasma and brain matrices were generated. To prepare plasma samples, proteins were precipitated using acetonitrile. To prepare brain samples, protein precipitation and homogenization with acetonitrile were performed. Samples were analyzed using HPLC-TDE MS using electrospray ionization.

[00663] Brain and plasma concentrations and brain-plasma ratios observed for the compounds tested are defined in the table below.

[00664] In summary, the compounds of the invention demonstrate a potent inhibition of p70S6K1. The tested compounds exhibit favorable brain and plasma concentrations in mice after oral dosing, with brain concentrations exceeding those in plasma, causing high brain:plasma ratios. In general, it is considered that a brain:plasma ratio > 0.5 is favorable for treating brain diseases.

Evaluation of the Efficacy of Compounds in Combating Tumor Initiation and Metastasis in an In Vivo Model of Triple Negative Breast Cancer (TNBC)

[00665] S6K1 is known to play a crucial role in the recurrence of TNBC cancers after surgery, mainly through the activity of S6K1 in promoting the survival of cancer cells in the host through the phosphorylation and activation of the antiapoptotic protein Bcl2 and Gli1 (Belletti 2014). Additionally, S6K1 promotes metastasis of TNBC cells (Akar 2010, Hung 2014).

[00666] To test the efficacy of an S6K1 inhibitor in an in vivo model of tumor initiation and metastasis, the following experiment was established:

[00667] A total of 22 female athymic nude mice (Hsd:Athymic Nude-Foxn1nu) were purchased from Harlan (UK) and acclimatized for 7 days before the start of the study. Animals were housed in individually ventilated cages (5 per cage) with individual mice identified through ear piercing. All animals had free access to a standard, commercially certified diet and sanitized water during the study. Housing was maintained under standard conditions: 20-24°C, 40-70% humidity, and a 12-h day/night cycle.

[00668] On day -1, animals were randomly assigned to treatment groups as indicated in the table below, and drug treatment began. On day 0, MDA-MB-231 cells (1x106 in matrigel) were implanted into the second layer of breast fat.

[00669] The dosage route was oral and the formulation was as follows: DMSO 10% / hypromellose-β-cyclodextrin 90% (20% w/v aqueous).

[00670] Treatment groups:

[00671] During the experiment, the following measured results were evaluated: 1. ) Tumor palpation times (latency) (2) tumor volume (3) tumor and organ weight as a measure of metastasis (4) visual appearance of metastatic nodules in the lungs.

[00672] Results:

[00673] Tumor palpation time

[00674] The compound of Example 1 delays the time of appearance (palpation) of the tumor and also decreases the incidence rate (see Figure 1) compared to the control.

[00675] Tumor volume

[00676] Example 1 induces a significant reduction in tumor volume (Figure 2) compared to the control.

[00677] Liver and tumor weights were measured on day 21. Treatment with the compound of Example 1 caused a reduction in liver weight compared to the vehicle treatment group, which may indicate a reduction in metastatic lesions for the vehicle treatment group. treatment (see Figure 3). Additionally, tumors from treated animals weighed significantly less (see Figure 4).

[00678] The Visual Appearance of Metastatic Nodules in the Lungs

[00679] At necropsy, the lungs of vehicle-treated and compound-treated animals were examined for the presence of metastatic nodules:

[00680] This shows that example 1 is effective in reducing the metastatic burden in the mouse lungs arising as spontaneous metastasis from a TNBC primary tumor.

[00681] Taken together, this indicates that Example 1, an S6K1 inhibitor, is effective in (a) preventing tumor initiation (b) limiting the growth of tumors that present and (c) preventing metastasis to the lung originating from the primary tumor.

Evaluation of compounds in audiogenic seizure assays, an in vivo model of Fragile X Syndrome (FXS)

[00682] Seizures occur in conjunction with FXS and autism in up to a quarter of children with these disorders (Berry-Kravis E (2002) Epilepsy in fragile X syndrome. Dev. Med. Child Neurol. 44(11):724-728) . Increased susceptibility to sound-induced seizures, called audiogenic seizures (AGS), is a robust and reliable phenotype in FXS (Fmr1 KO) mice that does not occur in WT mice. The audiogenic seizure assay (AGS) is a well-documented mouse model of FXS (Audiogenic seizures susceptibility in transgenic mice with phage X syndrome, Epilepsia. 2000 Jan;41(1):19-23). In such a model it is possible to dose compounds to observe the effects on the mouse's susceptibility to audiogenic seizures. The following AGS experiment was established to test the efficacy of compounds in this application:

[00683] The following experimental setup was used:

[00684] FXS mouse line used: FVB background

[00685] Vehicle used: DMSO 10% / hypromellose-β-cyclodextrin 90% (20% aqueous w/v)

[00686] Animals were evaluated in AGS after 7 consecutive days of dosing.

[00687] Method:

[00688] The experiment chamber consisted of a plastic cage with dimensions of 25 x 25 x 47 cm in which a bell (Electrical bell Heath Zenith, model 172C-A) was mounted on the ceiling of the cage.

[00689] The mice were taken out of their housing one by one and transferred to the experiment chamber and allowed to explore the new environment (basal noise ~65 dB) for a period of 30 seconds, after which the bell was rung (124 dB) for a period of 60 seconds.

[00690] The resulting motor responses were classified using a scale modified from one originally described by Jobe et al. (1973): no response (NR: pause or continued exploration), violent running (WR), convulsions (S) or respiratory arrest and/or death (RA). Motor response rate is defined as the percentage of animals per group that respond to the stimulus.

[00691] Results:

[00692] The data shows that both the incidence of audiogenic seizures and the severity of response were reduced by the administration of Example 1.

EXAMPLE 45 PHARMACEUTICAL FORMULATIONS (i) Tablet Formulation

[00693] A tablet composition containing a compound of formula (1), as defined in any one of Embodiments 1.0 to 1.116, can be prepared by mixing 50 mg of the compound with 197 mg of lactose (BP) as diluent and 3 mg magnesium stearate as a lubricant and compression to form a tablet in a known manner.

(ii) Capsule Formulation

[00694] A capsule formulation is prepared by mixing 100 mg of a compound of formula (1), as defined in any of Embodiments 1.0 to 1.116, with 100 mg of lactose and filling the resulting mixture into gelatin capsules standard opaque hard shells.

(iii) Injectable formulation I

[00695] A parenteral composition for administration by injection can be prepared by dissolving a compound of formula (1), as defined in any of Embodiments 1.0 to 1.116, in water containing 10% propylene glycol to provide a concentration of active compound 1.5% by weight. The solution is then sterilized through filtration, placed in an ampoule and sealed.

(iv) Injectable formulation II

[00696] A parenteral composition for injection is prepared by dissolving in water a compound of formula (1), as defined in any of Embodiments 1.0 to 1.116, (2 mg/ml) and mannitol (50 mg/ml), filtering the solution in a sterile manner and placing it in 1 ml sealable vials or ampoules.

(v) Injectable formulation III

[00697] A formulation for intravenous delivery by injection or infusion can be prepared by dissolving the compound of formula (1), as defined in any of Embodiments 1.0 to 1.116, (for example, in a salt form) in water at 20 mg/ml. The vial is then sealed and sterilized by autoclaving.

(vi) IV injectable formulation

[00698] A formulation for intravenous delivery by injection or infusion can be prepared by dissolving the compound of formula (1), as defined in any of Embodiments 1.0 to 1.116, (for example, in a salt form) in water containing a buffer (e.g. 0.2 M acetate pH 4.6) at 20mg/ml. The vial is then sealed and sterilized by autoclaving.

(vii) Subcutaneous injection formation

[00699] A composition for subcutaneous administration is prepared by mixing a compound of formula (1), as defined in any of Embodiments 1.0 to 1.116, with pharmaceutical grade corn oil to provide a concentration of 5 mg/ml . The composition is sterilized and placed in a suitable container.

(viii) Freeze-dried formulation

[00700] Aliquots of the formulated compound of formula (1), as defined in any of Embodiments 1.0 to 1.116, are placed in 50 ml vials and lyophilized. During lyophilization, the compositions are frozen using a one-step freezing protocol at (-45°C). The temperature is raised to -10°C for annealing, then reduced to freezing at -45°C, followed by primary drying at +25°C for approximately 3400 minutes, followed by secondary drying with a gradual increase in temperature to 50°C . The pressure during primary and secondary drying is set at 80 millitor.

Equivalents

[00701] The preceding examples are presented for the purpose of illustrating the invention and should not be interpreted as imposing any limitations on the scope of the invention. It will immediately be apparent that various modifications and alterations can be made to the specific embodiments of the invention described above and illustrated in the examples without departing from the principles underlying the invention. All such modifications and changes are intended to be incorporated by this order.

Claims (10)

1. Compound characterized by the fact that it has formula (1): or a salt thereof; where: one of Y and Z is R3 and the other is Ar2; Q1 is a C1-4 alkylene group optionally substituted by a hydroxy substituent, provided that, when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached; Q2 is a bond or a C1-6 alkylene group; R1 is selected from hydrogen, NRxRy and a Cy1 group; Rx and Ry are the same or different and each is selected from hydrogen and C1-3 hydrocarbyl; Cy1 is a C-linked monocyclic non-aromatic heterocyclic group selected from C-linked azetidine, pyrrolidine, piperidine, piperazine, morpholine, homomorpholine and thiomorpholine, and being optionally substituted with one or two substituents selected from C1-3 hydrocarbyl, fluorine and hydroxy; R2 and R4 are hydrogen; R3 is hydrogen; Ar1 is a phenyl group optionally substituted with 1 or 2 substituents R5, which are the same or different and are selected from fluorine, chlorine, methoxy, methylsulfonylamino and hydroxyl; Ar2 is a bicyclic heteroaryl group selected from pyrimido-pyrrole, pyrido-pyrrole, pyrimido-pyrazole, pyrido-pyrazole and pyrimido-imidazole and being optionally substituted with 1, 2 or 3 substituents R7 selected from oxo, methyl, difluoromethyl , trifluoromethyl, amino, hydroxy and cyano; and wherein, in each substituent consisting of or containing a hydrocarbyl group, the hydrocarbyl group is selected from alkyl, alkenyl, alkynyl and cycloalkyl groups and combinations thereof. 2. Compound according to claim 1, characterized by the fact that Y is Ar2 and Z is R3. 3. Compound according to claim 2, characterized by the fact that Q1 is selected from CH2, CH(CH3), CH(CH2OH) and CH(CH2CH2OH). 4. Compound according to any one of claims 1 to 3, characterized in that Q2 is a C1-3 bond or alkylene. 5. Compound according to any one of claims 1 to 4, characterized in that R1 is hydrogen. 6. Compound, according to claim 1, characterized by the fact that it is of formula (3): or a salt thereof, wherein R1, R2, R3, R4, Q1, Q2 and Ar1 are as defined in any one of claims 1 to 5. 7. Compound according to claim 1, characterized in that it is selected from the group consisting of: ((R)-1-Phenyl-ethyl)-[6-(1H-pyrazolo[3,4-d] pyrimidin-4-yl)-quinazolin-2-yl]-amine; ((R)-1-(3-Chloro-phenyl)-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine; ((R)-1-(3-Fluoro-phenyl)-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine; ((R)-1-(4-Fluoro-phenyl)-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazoline-2-yl]-amine; ((S)-2-Hydroxy-1-phenyl-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine; Benzyl-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-methylamine; (3-Fluorobenzyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine; ((R)-1-Phenyl-ethyl)-[6-(1H-pyrazolo[3,4-b]pyridin-4-yl)-quinazolin-2-yl]-amine; Benzyl-(S)-1-morpholin-3-ylmethyl-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine; [(R)-1-(3,4-Difluoro-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine; Benzyl-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine; (3,4-Difluoro-benzyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine; N-(3-{[6-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-methyl}-phenyl)-methanesulfonamide; [(R)-1-(3-Methoxy-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine; [(R)-1-(2-Fluoro-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine; N-(3-{(R)-1-[6-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethyl}-phenyl)-methanesulfonamide; (R)-3-Phenyl-3-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-propan-1-ol; [(R)-1-(2,4-Difluoro-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine; [(R)-1-(2,6-Difluoro-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine; 2-{(R)-1-[6-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethyl}-phenol; 3-{(R)-1-[6-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethyl}-phenol; 4-{(R)-1-[6-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethyl}-phenol; (S)-2-(2-Fluoro-phenyl)-2-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethanol; (S)-2-(3-Fluoro-phenyl)-2-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethanol; and (S)-2-(4-Fluoro-phenyl)-2-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethanol; and pharmaceutically acceptable salts thereof. 8. Compound according to claim 1, characterized by the fact that it is ((R)-1-Phenyl-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin -2-yl]-amine or a pharmaceutically acceptable salt thereof. 9. Pharmaceutical composition characterized by the fact that it comprises a compound as defined in any one of claims 1 to 8 and a pharmaceutically acceptable excipient. 10. Use of a compound, as defined in any one of claims 1 to 8, characterized by the fact that it is for the manufacture of a medicine for: • the treatment of triple negative breast cancers; • the prevention or treatment of metastases, for example, metastases in the brain, bones, lung, liver, pancreas, kidney, bladder and gallbladder, for example, brain metastases from triple negative breast cancers; • the treatment of gliomas and glioblastomas; • the treatment of a neurodevelopmental disorder (such as Fragile X Syndrome); or • the treatment of a neurodegenerative disease.