Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

• This invention relates to new potent and selective compounds as modulators of serotonin receptor 1 B (5-HTR ) also known as 5-hydroxytryptamine receptor 1 B (5-HT ).
• the compounds are of potential utility in the treatment of diseases and conditions mediated by serotonin receptor type 1 B (5-HTR ), such as cancer, including blood cancer and solid tumors and respiratory diseases and hepatic disorders.
• the invention also relates to the use of such compounds as medicaments, to pharmaceutical compositions containing them, and to synthetic routes for their production.
• Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine that acts as a neurotransmitter in the central nervous system (CNS), local mediator in the gut and vasoactive agent in the blood. It is synthesized by a two-step pathway from the essential amino-acid tryptophan. Most of the serotonin of the body is located in the periphery (Sarrouilhe D. et al, Serotonin and Cancer: What Is the Link?, Current Molecular Medicine 2015, 15, 62-77).
• Serotonin has been linked to a variety of CNS functions such as brain development, circadian rhythm, thermoregulation, cognition, pain, appetite, sexual drive, fear, mood, violent behavior, motor function and neuroendocrine secretion. Moreover, serotonin is implicated in many CNS and psychiatric disorders: Parkinson’s disease, depression, hallucination, schizophrenia, bulimia, anxiety, addiction, chronic stress. Consequently, serotoninergic systems are targets for a large array of psychoactive compounds including antidepressants, antipsychotics and hallucinogens (Marin P. et al, 5-HT Receptor-Associated Protein Networks: New Targets for Drug Discovery in Psychiatric Disorders?, Current Drug Targets, 2012, 13, 28-52).
• 5-HT as a neurotransmitter within the central and peripheral nervous systems, and also as a local hormone in numerous other tissues, including the gastrointestinal tract, the cardiovascular system and immune cells.
• This multiplicity of function implicates 5-HT in a vast array of physiological and pathological processes.
• This plethora of roles has consequently encouraged the development of many compounds of therapeutic value, including various antidepressant, antipsychotic and antiemetic drugs (Barnes N. M. et al, Neuronal 5-HT Receptors and SERT, Tocris Scientific Review Series, https://www.tocris.com/literature/scientific-reviews/5-ht-receptors).
• 5-HT G-protein coupled receptor
• the 5-HTi receptor family consists of five separate gene products: 5-HTIA, 5-HTIB, 5-HTID, 5-HTIE, and 5-HTIF receptors. Each is encoded by a single, intron-less reading frame and they share considerable sequence homology. All of these receptors couple to Gi/o to inhibit adenylyl cyclase and reduce cAMP levels, but additional signal transduction mechanisms have also been described. Several of these receptors are well known as autoreceptors that regulate the excitability of serotonin neurons and the release of serotonin, but also they are expressed in nonserotonergic neurons, where they can have analogous effects on other neurotransmitters.
• 5-HT receptor In the case of 5-HT receptor, it is distributed broadly in the CNS in serotonergic and nonserotonergic neurons. This autoreceptor has been found to reduce serotonin synthesis and release and enhance reuptake via the serotonin transporter. Also, it inhibits the release of a range of different neurotransmitters, depending on the neuron types that express it.
• Systemic administration of 5-HT receptor agonists have several behavioral effects including increased locomotion, changes in brain reward mechanisms, and decreased aggression, whereas selective antagonists may have some procognitive potential. The expression of this receptor in diverse and potentially competing sets of neurons may impact its utility as a clinical target, although several 5-HT /D receptor agonists are effective as antimigraine treatments.
• 5-HT receptor knockout mice have been tested extensively and have a distinct phenotype characterized by increased aggression and, in most cases, predisposition for addiction-like behaviors (Barnes N. M. et al, Neuronal 5-HT Receptors and SERT, Tocris Scientific Review Series, https://www.tocris.com/literature/scientific-reviews/5-ht-receptors).
• 5-HT receptor in uterine leiomyomas (UL) which cause a variety of complaints, such as abnormal uterine bleeding and fertility problems.
• 5-HT receptor is involved in proliferation and survival of UL cells.
• the efficacy of 5-HT receptor antagonists needs to be tested in vivo in preclinical studies to better understand its role in tumor growth and potential therapeutic target for the development of medical therapies in the management of UL.
• Serotonin has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH) and has been recognized as a potent naturally occurring pulmonary vasoconstrictor and smooth muscle cell mitogen. Serotonin promotes pulmonary artery (PA) remodeling and proliferation of human PA smooth muscle cells (hPASMCs) via the 5-HT receptor and the serotonin transporter (SERT). Serotonin can induce cellular Src-related kinase-regulated Nox1 -induced ROS and Nrf- 2 dysregulation, contributing to increased post-translational oxidative modification of proteins and activation of redox-sensitive signaling pathways in hPASMCs, associated with mitogenic responses.
• PA pulmonary artery
• hPASMCs human PA smooth muscle cells
• SERT serotonin transporter
• Serotonin can induce cellular Src-related kinase-regulated Nox1 -induced ROS and Nrf- 2 dysregulation, contributing to increased post-translational oxidative modification of proteins and
• 5-HT receptors contribute to experimental pulmonary hypertension by inducing lung ROS production. This results suggest that 5-HT receptor-dependent cellular Src-related kinase-Nox1 -pathways contribute to vascular remodeling in PAH. (Hood, K Y. et al, Serotonin Signaling Through the 5-HT1B Receptor and NADPH Oxidase 1 in Pulmonary Arterial Hypertension, Arterioscler Thromb Vase Biol. 2017;37:1361-1370).
• Serum serotonin level was found to be suitable for prognosis evaluation of urothelial carcinoma in the urinary bladder, adenocarcinoma of the prostate and renal cell carcinoma.
• serotonin receptors 1 B and 2B are expressed in patients with hepatocellular cancer. Both receptors were associated with an increased proliferation index, and receptor 1 B correlated with the size of the tumor. Serotonin antagonists of receptors 1B and 2B consistently decreased viability and proliferation in Huh7 and HepG2 cell lines. (Soil C. et al, Expression of Serotonin Receptors in Human Hepatocellular Cancer, Clin Cancer Res; 18(21) November 1, 2012).
• 5-HTR selective antagonist decreased serotonin-mediated cell steatosis in HepG2 cells. Also, it was demonstrated that serotonin positively modulates cell proliferation/survival and cell steatosis in liver cancer cells by inducing autophagy and activating Notch signaling. (Niture S. et al, Serotonin induced hepatic steatosis is associated with modulation of autophagy and notch signaling pathway, Cell Communication and Signaling (2016) 16:78).
• 5-HT has been involved in autocrine loops of growth factors contributing to cell proliferation in aggressive tumors, but several studies have shown that serotonin can also exert an antineoplastic effect via inhibition of angiogenesis.
• An in silico screening was performed to search for small molecules that induce terminal differentiation and apomorphine, an HTR1/2 antagonist, was identified.
• BM bone marrow
• 5-HT2A receptor subtypes have been identified in both the central nervous system (CNS) and the periphery.
• CNS central nervous system
• 5-HT2A receptors have been found in many parts of the CNS including the cerebral cortex, basal ganglia, hippocampus, thalamus, cerebellum, and hypothalamus.
• 5-HT2A receptors are located in platelets, vascular smooth muscle, and uterine smooth muscle.
• 5-HT2A receptor has been implicated in various processes such as vascular smooth muscle contraction, extravascular smooth muscle contraction (including uterine contraction) and platelet aggregation (Nagatomo T et al, Functions of 5-HT2A receptor and its antagonists in the cardiovascular system, Pharmacology & Therapeutics 104 (2004) 59 - 81).
• Patent application WO 2018/130685 A1 discloses a combination therapy for treating cancer, particularly acute myeloid leukemia (AML), comprising an antineoplastic agent and a type 1 serotonin receptor (HTR1/5-HTi) modulator, e.g. a HTR1 antagonist, specifically is described apomorphine, methiothepin and SB-224289 (SB9) as serotonin receptor antagonists. All of them cross readily the blood brain barrier, acting to on central nervous system (CNS), and in the case of apomorphine and methiothepin are non- selective 5-HT receptor modulators.
• AML acute myeloid leukemia
• HTR1/5-HTi modulator e.g. a HTR1 antagonist
• SB9 serotonin receptor antagonists
• Patent application WO 95/15954 A1 discloses biphenylylamides compounds as 5-HTID antagonists to be used in the treatment of various CNS, endocrine and gastrointestinal disorders.
• 5-HTi receptor in particular 5-HT receptor
• diseases are selected from cancer, including blood cancer and solid tumors, and respiratory diseases.
• CNS In order to minimize side effects on CNS is desirable to develop new compounds with low penetration of the brain barrier and good selectivity over another 5-HT receptors, in particular good selectivity over the 5-HT2A receptor.
• the problem to be solved by the present invention is to provide novel, more selective and safe 5-HT receptor modulators with improve polarity and less brain penetration compared to the prior art compounds.
• the present invention refers to new compounds of formula (I): wherein:
• G represents a group selected from: a) -C(O)NH, b) -NHC(O),
• - X 1 , X 2 , X 3 and X 4 represent a N atom or C-R 5 group
• R 1 and R 2 are independently selected from the group consisting of: a) hydrogen atom, b) linear or branched Ci-Ce alkyl optionally substituted by 1 , 2 or 3 substituents selected from -N(R 6 )R 7 and -OR 6 , halogen atom and C3-C6 cycloalkyl, c) Cs-Ce cycloalkyl, or R 1 and R 2 form together with the nitrogen atom to which they are attached a four to six-membered heterocyclic group, comprising additionally a second heteroatom selected from N and O;
• R 3 represents a group selected from: a) cyano group, and b) halogen atom
• R 4 represents a group selected from: a) halogen atom, b) C3-C4 cycloalkyl group, c) C1-C3 alkoxy group, d) C1-C3 haloalkyl group, e) cyano group,
• R 5 represents a group selected from: a) hydrogen atom, b) C1-C3 alkyl, c) halogen atom,
• R 6 and R 7 represent independently a group selected from: a) C1-C3 alkyl, b) hydrogen atom, with the proviso that at least one of the X 1 , X 2 , X 3 and X 4 represent a N atom, and pharmaceutically acceptable salts thereof.
• the present invention refers to processes for the preparation of the compounds defined in the first aspect.
• the present invention refers to pharmaceutical compositions comprising an effective amount of a compound defined in the first aspect.
• the present invention refers to a combination product comprising a compound as defined in the first aspect and another therapeutic agent selected from agents for treating cancer, respiratory diseases and hepatic disorders.
• Cancer is selected from blood cancer such as acute myeloid leukemia (AML), and solid tumors, respiratory diseases may be, among others, pulmonary arterial hypertension, and hepatic disorders may be, among others nonalcoholic steatohepatitis.
• AML acute myeloid leukemia
• hepatic disorders may be, among others nonalcoholic steatohepatitis.
• the present invention relates to the use of the compounds of the first aspect for the manufacture of a medicament, in particular for treating diseases that can be ameliorated by antagonism of serotonin receptor type 1 (HTR1), in particular by antagonism of 5-HTR ; wherein the disease or pathological condition susceptible of improvement by antagonism of serotonin receptor 5-HTR may be selected from cancer, respiratory diseases and hepatic disorders.
• Cancer is selected from blood cancer such as acute myeloid leukemia (AML), and solid tumors, respiratory diseases may be, among others, pulmonary arterial hypertension, and hepatic disorders may be, among others nonalcoholic steatohepatitis.
• AML acute myeloid leukemia
• hepatic disorders may be, among others nonalcoholic steatohepatitis.
• the present invention relates to methods for the treatment of diseases that can be ameliorated by antagonism of serotonin receptor 5-HTR , by administration of the compounds defined in the first aspect or the pharmaceutical compositions of the third aspect or the combination product of the fourth aspect to a subject in need of said treatment.
• the present invention relates to a compound as defined in the first aspect, a pharmaceutical composition as defined in the third aspect or a combination product as defined in the fourth aspect for use as a medicament.
• the present invention relates to a compound as defined in the first aspect, a pharmaceutical composition as defined in the third aspect or a combination product as defined in the fourth aspect for use in the treatment of a disease or pathological condition selected from the group consisting of cancer, respiratory diseases and hepatic disorders.
• Cancer is selected from blood cancer such as acute myeloid leukemia (AML), and solid tumors, respiratory diseases may be, among others, pulmonary arterial hypertension, and hepatic disorders may be, among others nonalcoholic steatohepatitis.
• AML acute myeloid leukemia
• hepatic disorders may be, among others nonalcoholic steatohepatitis.
• Figure 1 illustrates the flow cytometry histograms representing selectivity of several compounds against leukemic cells.
• the compounds of the invention are useful in the treatment or prevention of diseases known to be susceptible to amelioration by treating with modulators/antagonists of serotonin receptor type 1 (HTR1), in particular modulators/antagonists of the 5-HTR receptor.
• diseases are, for example, cancer, respiratory diseases and hepatic disorders.
• Cancer is selected from blood cancer such as acute myeloid leukemia (AML), and solid tumors, respiratory diseases may be, among others, pulmonary arterial hypertension, and hepatic disorders may be, among others nonalcoholic steatohepatitis.
• the derivatives of the present invention and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and I or salts thereof may be used in a method of treatment of pathological conditions or disease of human body which comprises administering to a subject in need of said treatment, an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
• halogen atom is used to designate an atom selected from the group consisting of chlorine, fluorine, bromine or iodine atom, preferably bromine, fluorine or chlorine atom.
• alkyl is used to designate linear or branched hydrocarbon radicals (C n H2n+i). Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methyl-butyl, 2-methyl-butyl, isopentyl, 1 -ethylpropyl, 1 ,1- di methyl propyl, 1 ,2-dimethylpropyl, n-hexyl, 1-ethylbutyl, 2-ethylbutyl, 1 ,1 -di methyl butyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl, 2, 3-di methyl butyl, 2- methylpentyl and 3-methyl pentyl.
• C n -C m alkyl is therefore to be
• C n -C m alkoxy is used to designate radicals which contain a linear or branched C n -C m alkyl group linked to an oxygen atom.
• Preferred alkoxy radicals include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy and tert-butoxy.
• C n -C m cycloalkyl is used to designate hydrocarbon cyclic groups (C n H2n-i) having n to m carbon atoms.
• Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• haloalkyl is used to designate alkyl groups wherein one or more of their hydrogen atoms have been replace by a halogen atom.
• Preferred haloalky radicals include chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl and trifluoromethyl.
• the term four to six-membered heterocyclyl is used to designate saturated rings having four to six-members comprising carbon and a second heteroatom selected from N and O as part of the ring.
• the heterocyclyl groups include, for example, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl.
• atoms, radicals, chains or cycles present in the general structures of the invention are "optionally substituted". This means that these atoms, radicals, chains or cycles can be either unsubstituted or substituted in any position by one or more, for example 1 , 2 or 3 substituents, whereby the hydrogen atoms bound to the unsubstituted atoms, radicals, chains or cycles are replaced by chemically acceptable atoms, radicals, chains or cycles. When two or more substituents are present, each substituent may be the same or different.
• the term pharmaceutically acceptable salt is used to designate salts with a pharmaceutically acceptable acid or base.
• Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid and organic acids, for example citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid.
• Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium), alkali earth metal (e.g. calcium or magnesium) hydroxides, and organic bases, for example alkyl amines, phenylalkyl amines and heterocyclic amines.
• X' n may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and ptoluenesulphonate.
• mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate
• organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and ptoluenesulphonate.
• X' n is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably, X' is chloride, bromide, trifluoroacetate or methanesulphonate.
• R 1 and R 2 are linear or branched C1-C3 alkyl. In a preferred embodiment R 1 and R 2 are methyl groups.
• G represents -C(O)NH- wherein the carbonyl group is linked to the cycle comprising X 3 and X 4 and the amine group is linked to the cycle comprising X 1 and X 2 .
• R 3 is cyano group.
• R 4 is selected from halogen atom and C3-C4 cycloalkyl group.
• R 4 is selected from chlorine atom, fluorine atom and cyclopropyl group.
• the core :
• the core is:
• the core According to one embodiment of the present invention the compounds of formula (I) have one of the following formula (la), (lb) and (Ic) wherein R 4 represents a group selected from halogen atom and cyclopropyl group.
• Individual compounds of the present invention include: N-(4-bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyclopropyl-4-(5-methyl-1 ,2,4- oxadiazol-3-yl)phenyl)nicotinamide N-(4-bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-fluoro-4-(5-methyl-1,2,4- oxadiazol-3-yl)phenyl)nicotinamide N-(4-bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-chloro-4-(5-methyl-1,2,4- oxadiazol-3-yl)phenyl)nicotinamide N-(4-bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(4-(5-methyl-1,2,4-oxadiazol-3-
• preferred compounds are selected from:
• compounds are selected from: N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyclopropyl-4-(5-methyl-
• said other therapeutic agents are selected from the group consisting of chemotherapeutics drugs selected from Vincristine, Daunorubicin, Cytarabine, 6- mercaptopurine, Methotrexate, Cyclophosphamide, Prednisone, Dexamethasone, Nelarabine and immunotherapeutic agent selected from the group consisting of antibodies anti-PD1 , antibodies anti-PDL1 and antibodies anti-CTLA4.
• chemotherapeutics drugs selected from Vincristine, Daunorubicin, Cytarabine, 6- mercaptopurine, Methotrexate, Cyclophosphamide, Prednisone, Dexamethasone, Nelarabine
• immunotherapeutic agent selected from the group consisting of antibodies anti-PD1 , antibodies anti-PDL1 and antibodies anti-CTLA4.
• the immunotherapeutic agent is selected from the group consisting of ipilimumab, tremelimumab, nivolumab, pembrolizumab, CT-011 , AMP-224, MPDL3280A, MEDI4736 and MDX-1105.
• the compounds of this invention can be prepared by using the procedures described below in the schemes and examples, or by methods known in the art.
• the starting materials and intermediates may be obtained from commercial sources, prepared from commercially available compounds, or prepared using well known synthetic methods. To facilitate the description of the procedures, concrete examples have been used, but they do not restrict in any means the scope of the present invention.
• Reagents and conditions a) DCM, 0°C, 3 h; b) CS2CO3, Dioxane, reflux, 16 h; c) Zn; NH4CI, EtOH, 80°C, 16 h.
• Scheme 1 illustrates one of the synthetic route leading to compounds of formula (VI), which are intermediates in the synthesis of compounds of formula (I).
• reaction with methanesulfonyl chloride results in formation of the 2-aminoethyl methanesulfonate (III), which is reacted with the heteroarylalcohol or phenol (IV) to form the ether of compounds (V).
• hydrogenation for example with zinc powder and ammonium chloride affords the intermediates of formula (VI).
• Reagents and conditions d) N-halosuccinimide, AcOH, RT; e) Zn(CN)2, T ris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)s), 1 , 1 '-Ferrocenediyl- bis(diphenylphosphine) (dppf), DMF, 120°C, 12h; f) Potassium bis(trimethylsilyl) amide 1 M in THF, room temperature, 12 h.
• intermediate of formula (Vlb) are obtained applying similar reactions as those described in Scheme 2.
• 4-chloropyrimidin-2-amine is halogenated with N-halosuccinimide in DMF at room temperature to obtain intermediates of formula (Vila).
• R 3 is a cyano group
• the introduction of said group is catalysed by a palladium complex, to provide the intermediate (Vlllb), which is converted in the intermediate (Vlb) by the reaction with disubstituted amino ethanol in the presence of a base for example potassium bis(trimethylsilyl) amide in THF at room temperature, as described in Scheme 3.
• Reagents and conditions j) N-halosuccinimide, acetonitrile, RT; k) di-tert-butyl decarbonate, TEA, DMAP, THF, 40°C, 3h; I) Zn(CN) 2 , (Pd 2 (dba) 3 ), (dppf), DMF, 120°C, 12h; m) HO-CH 2 -CH 2 -NR 1 R 2 , NaH, DMF, 80°C, 6 h; n) Trifluoroacetic acid, DCM, RT.
• Reagents and conditions o) [1 , 1 -bis(diphenylphosphino)ferrocene] dichloropalladium(l I) (Pd(dppf)CI 2 DCM), KOAc, dioxane/H 2 O, 100°C, 8h; p) or q) Pd(dppf)CI 2 DCM, Cs 2 CO 3 , dioxane/H 2 O, 100°C, 12h.
• Phenyl or heteroaryl bromide precursor (XIV) can react with bis(pinacolato)diboron in the presence of palladium catalyst to yield the intermediate (XV). Applying Suzuki reactions these intermediates may be converted to acids of formula (XVIII) by the reaction with the bromide precursor (XVI).
• An alternative route is possible by the coupling reaction of the precursor (XVIII) with the boronic acids (XIX), under palladium catalysed conditions.
• the synthesis of the amides of formula (Id) is carried out by the reaction of the amines of formula (VI) with the correspondent carboxylic acids (XVII) in the presence a coupling agent, such as HATLI, and a base at room temperature, as described in scheme 6.
• a coupling agent such as HATLI
• carboxylic acids of formula (XVII) can be converted to the corresponding acid chlorides using standard procedures. Reacting the corresponding acid chlorides of precursor (XVII) with the amines precursor of formula (VI) in the presence of a base such as triethylamine, derivatives of formula (Id) are also obtained.
• Scheme 7a
• precursor (XX) 2-aminoethyl methane sulfonate (III) gives the precursor (XXI), which after hydrolysis produce acids of formula (XXII).
• the amine precursor (XXV) can be synthesized by the Suzuki-type coupling reaction of the boronic acids or boronate derivatives (XXIII) with the precursor (XXIV), using a palladium catalyst. It is also possible by changing the functionality of the intermediates in a similar reaction depending on whether the product is commercial or not in this way, as shown in the reaction of the precursor (XXVI) with the boronic acids or boronate derivatives (XXVII), under palladium catalysed conditions.
• the synthesis of the inverse amides of formula (le) is carried out by the reaction of the amine precursor of formula (XXV) with the correspondent carboxylic acids (XXII) in the presence of a coupling agent, such as HATLI, and a base, at room temperature.
• a coupling agent such as HATLI
• Halo Halogen atom
• HATLI N-[(Dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide
• DIPEA N,N-Diisopropylethylamine
• TFA Trifluoroacetic acid
• THF Tetrahydrofuran
• the raw radioactivity data is adjusted to a logistic regression of 4 parameters using GraphPad Prism software, from the specific junction the value of IC50 is obtained. From the IC50 the Ki is calculated according to the following formula:
• the raw radioactivity data is adjusted to a logistic regression of 4 parameters using GraphPad Prism software, from the specific junction the value of IC50 is obtained. From the IC50 the Ki is calculated according to the following formula:
• AML cell lines (HL-60 or MonoMac-1) per mL were cultured in completed RPMI medium, supplemented with 10% Fetal bovine serum (FBS). Compounds were added to the medium at the concentration indicated (0.1 , 1 and 10 pM), while controls were treated with equivalent concentration of vehicle (DMSO).
• Primary validation screenings were analyzed after 72 h of treatment, EC50 was determined upon 48 h treatments. Cells were stained with the live-dead discrimination dye 7-aminoactinomycin D (7-AAD) and Hoechst 33342 and acquired in a flow cytometer, with a volumetric counting. Live cells were discriminated based on a discrete FSC-SSC profile, 7-AAD negativity and dim positivity to Hoechst 33342. EC50 was calculated with the Prism GraphPad software.
• MNCs mononuclear cells
• Isolated MNCs were culture in IMDM medium supplemented with 3% heat-inactivated fetal bovine serum, 1x BIT (StemCell Technologies), 5 ng/mL human IL3, 2 mM NaPyr and 5 x 10-5 M p-mercaptoethanol.
• Cells were treated with vehicle control (DMSO), and 10 pM of a selected compound (example compound or reference compound), for 72 h at 37°C and 5% CO2. After treatment, cells were stained for the pan-hematopoietic marker CD45 and the live-death discriminator 7-AAD and acquired in a flow cytometry.
• Histograms show the intensity of CD45 staining (X axis) and SSC (Y axis) within the live cell gate. Blast gate (upper right) and lymphocyte gate (lower left) are indicated in each histogram. Selectivity against AM L blasts is represented by the reduction of the relative frequency of AM L blasts versus lymphocytes.
• peripheral blood-mononuclear blood cells per mL were cultured in completed RPMI medium, supplemented with 10% FBS. Compounds were added to the medium at 0.5/1/5/10/50 jiM, while controls were treated with equivalent concentration of vehicle (DMSO).
• DMSO vehicle
• EC50 was calculated with the Prism GraphPad software.
• Table 1 shows the binding of some compounds of the present invention in serotonin receptors.
• Table 1 SB41 SB-216641 (CAS No. 193611-67-5) N-[3-[3-(Dimethylamino)ethoxy]-4- methoxyphenyl]-2'-methyl-4'-(5-methyl-1 ,2,4-oxadiazol-3-yl)-[1 , 1 '-bi pheny I]- 4-carboxamide hydrochloride.
• SB9 SB-224289-HCI (CAS No. 180084-26-8) 1'-Methyl-5-[[2'-methyl-4'-(5- methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine hydrochloride.
• Table 2 shows the cytotoxic capacity of some compounds of the present invention on AML cell lines.
• SB41 SB-216641 (CAS No. 193611-67-5) N-[3-[3-(Dimethylamino)ethoxy]-4- methoxyphenyl]-2'-methyl-4'-(5-methyl-1 ,2,4-oxadiazol-3-yl)-[1 , 1 '-bi pheny I]- 4-carboxamide hydrochloride.
• SB9 SB-224289-HCI (CAS No.
• Table 3 shows the cytotoxic capacity of some compounds of the present invention on healthy cell lines.
• SB41 SB-216641 (CAS No. 193611-67-5) N-[3-[3-(Dimethylamino)ethoxy]-4- methoxyphenyl]-2'-methyl-4'-(5-methyl-1 ,2,4-oxadiazol-3-yl)-[1 , 1 '-bi pheny l] ⁇ 4-carboxamide hydrochloride.
• tPSA value N-[3-[3-(Dimethylamino)ethoxy]-4- methoxyphenyl]-2'-methyl-4'-(5-methyl-1 ,2,4-oxadiazol-3-yl)-[1 , 1 '-bi pheny l] ⁇ 4-carboxamide hydrochloride.
• Tabla 4 shows the stimated value of tPSA for some exemplified compounds.
• the compounds of the present invention are potent 5-HT receptor modulators with a good selectivity against the other serotonin recptor, and more specifically against the 5-HT2A receptor.
• the compounds of the present invention show an enhanced cytotoxic activity against AML cells, significant less cytotoxic against healthy cell lines and a lower potential of brain penetration, compared to reported 5-HT receptor modulators.
• the derivatives of the present invention are useful in the treatment or prevention of diseases known to be susceptible to improvement by treatment with a modulator of 5- HT serotonin receptor.
• diseases are, for example, cancer selected from blood cancer such as acute myeloid leukemia (AML), and solid tumors, and respiratory diseases such as pulmonary arterial hypertension.
• the derivatives of the invention and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and/or salts thereof may be used in a method of treatment of disorders of the human body which comprises administering to a subject requiring such treatment an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
• the present invention also provides pharmaceutical compositions which comprise, as an active ingredient, at least a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with other therapeutics agents, as have been mentioned above, and with a pharmaceutically acceptable excipient such as a carrier or diluent.
• the active ingredient may comprise 0.001 % to 99% by weight, preferably 0.01 % to 90% by weight of the composition depending upon the nature of the formulation and whether further dilution is to be made prior to application.
• the compositions are made up in a form suitable for oral, topical, nasal, rectal, percutaneous or injectable administration.
• compositions of this invention are well known per se and the actual excipients used depend inter alia on the intended method of administering the compositions.
• compositions of this invention are preferably adapted for injectable and oral (per os) administration.
• the compositions for oral administration may take the form of tablets, sustained release tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powder inhalation, or liquid preparations, such as mixtures, elixirs, syrups or suspensions, all containing the compound of the invention; such preparations may be made by methods well-known in the art.
• diluents which may be used in the preparation of the compositions, include those liquid and solid diluents, which are compatible with the active ingredient, together with colouring or flavouring agents, if desired.
• Tablets or capsules may conveniently contain between 2 and 500 mg of active ingredient or the equivalent amount of a salt thereof.
• the liquid composition adapted for oral use may be in the form of solutions or suspensions.
• the solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form syrup.
• the suspensions may comprise an insoluble active compound of the invention or a pharmaceutically acceptable salt thereof in association with water, together with a suspending agent or flavouring agent.
• compositions for parenteral injection may be prepared from soluble salts, which may or may not be freeze-dried and which may be dissolved in pyrogen free aqueous media or other appropriate parenteral injection fluid. Effective doses are normally in the range of 2-2000 mg of active ingredient per day. Daily dosage may be administered in one or more treatments, preferably from 1 to 4 treatments, per day.
• Reagents, solvents and starting products were acquired from commercial sources.
• concentration refers to the vacuum evaporation using a Buchi rotavapor.
• reaction products were purified by "flash" chromatography on silica gel (40-63 pm) with the indicated solvent system.
• the spectroscopic data were measured in a Varian Mercury 400 spectrometer.
• the melting points were measured in a Buchi 535 instrument.
• the HPLC-MS were performed on a Gilson instrument equipped with a Gilson 321 piston pump, a Gilson 864 vacuum degasser, a Gilson 189 injection module, a 1/1000 Gilson splitter, a Gilson 307 pump, a Gilson 170 detector, and a Thermoquest Fennigan aQa detector.
• the Intermediate 11 was synthetized using the procedure above, but using N- bromosuccinimide.
• the Intermediate 16 was synthetized using the procedure above, but using 5-bromo-6- fluoropyridin-2-amine.
• the Intermediate 18 was synthetized using the procedure above, but using 6-amino-2- fluoronicotinonitrile.
• Methyl 2-bromophenol-5-carboxylate 1000 mg, 4.33 mmol
• caesium carbonate 2115.2 mg, 6.49 mmol
• 2-(dimethylamino)ethyl methanesulfonate 1457.4 mg, 4.33 mmol
• the dioxane was remove under vacuum and saturated NaHCCh was added.
• the reaction mixture was filtered through celite and the filtrate was washed with NaHCCh saturated for two times. The organic layers were collected, dried with sodium sulphate and the solvent was removed under reduced pressure. The crude was purified by flash chromatography column (Hexane/ethyl acetate) to obtain the amine intermediate (279.5 mg, 57.6%).
• Example 18 N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4'-(5-methyl- 1 ,2,4-oxadiazol-3-yl)-2'-(trifluoromethyl)-[1 ,1 '-biphenyl]-4-carboxamide
• Example 32 2'-chloro-N-(5-cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4'-(5- methyl-1 , 2, 4-oxadiazol-3-yl)-[1 ,1 '-biphenyl] -4-carboxamide
• Example 33 N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2'- cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide
• 6 11.12 (s, 1 H), 8.64 (s, 1 H), 8.04 (d, 2H), 7.88 (dd, 1 H), 7.61 (m, 3H), 7.44 (d, 1 H), 4.51 (t, 2H), 2.68 (s, 3H), 2.66 (t, 2H), 2.21 (s, 6H), 1.91 (td, 1 H), 0.92 (m, 2H), 0.73 (m, 2H).
• Example 36 N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2'- cyclopropyl-4'-(5-methyl-1 ,2,4-oxadiazol-3-yl)-[1 ,1 '-biphenyl]-4-carboxamide
• Example 38 2'-chloro-N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-4'- (5-methyl-1 ,2,4-oxadiazol-3-yl)-[1 ,1 '-biphenyl]-4-carboxamide
• Example 40 N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-fluoro-4-(5- methyl-1 ,2,4-oxadiazol-3-yl)phenyl)nicotinamide
• Example 42 N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(4-(5-methyl- 1 ,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinamide
• Example 43 N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-methoxy-4- (5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide
• 6 11.25 (s, 1 H), 9.24 (d, 1 H), 8.40 (m, 2H), 8.09 (d, 2H), 8.03 (d, 1 H), 7.74 (d, 1 H), 7.71 (s, 1 H), 4.28 (t, 2H), 3.97 (s, 3H), 2.77 (t, 2H), 2.70 (s, 3H), 2.29 (s, 6H).
• Example 48 N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(4-(5-methyl- 1 ,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinamide
• 6 11.65 (s, 1 H), 9.22 (d, 1 H), 8.69 (s, 1 H), 8.50 (dd, 1 H), 8.39 (m, 2H), 8.13 (s, 1 H), 7.83 (d, 1 H), 7.77 (d, 1 H), 4.34 (t, 2H), 2.75 (t, 2H), 2.73 (s, 3H), 2.26 (s, 6H).
• Example 51 N-(5-bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2- cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide
• Example 53 N-(5-bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-chloro-4- (5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide
• 6 11.03 (s, 1 H), 9.21 (d, 1 H), 8.44 (dd, 1 H), 8.14 (s, 1 H), 8.10 (d, 1 H), 8.04 (d, 1 H), 7.92 (d, 1 H), 7.85 (d, 1 H), 7.75 (d, 1 H), 4.46 (t, 2H), 2.71 (s, 3H), 2.66 (t, 2H), 2.24 (s, 6H).
• Example 54 N-(5-cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2- cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide
• Example 58 N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-fluoro-4- (5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide
• 6 11.38 (s, 1H), 9.19 (d, 1H), 8.65 (s, 1H), 8.40 (dd, 1H), 8.23 (t, 1H), 8.01 (ddd, 2H), 7.91 (dd, 1H), 4.47 (t, 2H), 2.70 (s, 3H), 2.66 (t, 2H), 2.20 (s, 6H).
• Example 60 N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2- cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide
• Example 62 6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-4-(2- (dimethylamino)ethoxy)pyrimidin-2-yl)nicotinamide
• Example 63 N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2-(2- cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxamide
• 5 11 .49 (s, 1 H), 9.43 (s, 2H), 8.43 (s, 1 H), 8.07 (s, 1 H), 7.92 (q, 2H), 7.67 (s, 1 H), 4.28 (t, 2H), 2.75 (t, 2H), 2.69 (s, 3H), 2.63 (td, 1 H), 2.28 (s, 6H), 0.98 - 0.88 (m, 2H), 0.66 (q, 2H).
• Example 64 N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2-(2- cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxamide
• 5 11 .78 (s, 1 H), 9.44 (s, 2H), 8.71 (s, 1 H), 8.13 (s, 1 H), 7.92 (q, 2H), 7.67 (s, 1 H), 4.35 (t, 2H), 2.75 (t, 2H), 2.69 (s, 3H), 2.63 (td, 1 H), 2.27 (s, 6H), 0.98 - 0.89 (m, 2H), 0.66 (q, 2H).
• Example 65 4-bromo-3-(2-(dimethylamino)ethoxy)-N-(6-(2-fluoro-4-(5-methyl- 1 ,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)benzamide
• Example 66 4-bromo-N-(6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl)pyridin-3-yl)-3-(2-(dimethylamino)ethoxy)benzamide
• Example 68 4-bromo-3-(2-(dimethylamino)ethoxy)-N-(6-(4-(5-methyl-1,2,4- oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)pyridin-3-yl)benzamide
• Example 69 4-bromo-3-(2-(dimethylamino)ethoxy)-N-(6-(2-methoxy-4-(5-methyl- 1 ,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)benzamide
• Example 70 4-bromo-N-(6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl)pyridin-3-yl)-3-(2-(dimethylamino)ethoxy)benzamide
• 6 10.75 (s, 1H), 9.12 (d, 1H), 8.45 (d, 1H), 8.42 (dd, 1H), 8.38 (dd, 1H), 8.13 (d, 1H), 8.03 (d, 1H), 7.86 (d, 1H), 7.70 (d, 1H), 7.63 (dd, 1H), 4.48 (t, 2H), 3.54 (t, 2H), 2.79 (s, 6H), 2.72 (s, 3H).
• Example 71 4-cyano-N-(6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl)pyridin-3-yl)-3-(2-(dimethylamino)ethoxy)benzamide
• Example 72 4-cyano-3-(2-(dimethylamino)ethoxy)-N-(6-(2-fluoro-4-(5-methyl-1,2,4- oxadiazol-3-yl)phenyl)pyridin-3-yl)benzamide
• Example 74 4-cyano-3-(2-(dimethylamino)ethoxy)-N-(6-(4-(5-methyl-1,2,4- oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)pyridin-3-yl)benzamide
• Example 76 4-cyano-N-(6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl)pyridin-3-yl)-3-(2-(dimethylamino)ethoxy)benzamide
• 5 10.89 (s, 1 H), 9.12 (d, 1 H), 8.45 (d, 1 H), 8.42 (dd, 1 H), 8.38 (dd, 1 H), 8.13 (d, 1 H), 8.03 (t, 2H), 7.79 (d, 1 H), 7.75 (dd, 1 H), 4.56 (t, 2H), 3.39 (t, 2H), 2.76 (s, 6H), 2.72 (s, 3H).

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