Nitrogen containing bicyclic compounds as modulators of multiple histamine receptor subtypes

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt or ester thereof. The compounds have activity against multiple histamine receptor subtypes, including for example histamine H1 and H4.

Description

[0001] P36919PCOO / WZO

[0002] NITROGEN CONTAINING BICYCLIC COMPOUNDS AND THEIR THERAPEUTIC USE

[0003] Field of the Invention

[0004] The present invention relates to nitrogen containing bicyclic compounds based on and / or related to the tetrahydroquinazoline scaffold, and their therapeutic use. More particularly, it relates to compounds, pharmaceutical compositions containing them, and their use for the modulation of multiple histamine receptors, including for example both the histamine H4 and Hi receptors and for the treatment of disease states, disorders and conditions mediated by modulation of those histamine receptors.

[0005] Background of the Invention

[0006] The histamine H4 receptor (H4R) is a recently identified receptor for histamine. It is part of the histamine receptor family that also consists of the histamine Hi receptor (H1R), histamine H2 receptor (H2R) and histamine H3 receptor (H3R). Modulation of H4 receptors controls the release of inflammatory mediators and inhibits leukocyte recruitment, thus providing the ability to prevent and / or treat ^-mediated diseases and conditions, including the deleterious effects of allergic responses such as inflammation. In some cases it may be beneficial to also simultaneously modulate the H1R or H3R in addition to the H4R and with which certain compounds described herein interact.

[0007] WO 2011 / 078143 discloses 4-substituted sulphonamide compounds. There are no aminomethylthienyl derivatives, and there is no mention about dual inhibition of H1R and H4R.

[0008] WO 2012 / 012264 describes several compounds with affinity for the H4R and their use in the treatment of ocular allergy. The compounds are used in combination with olopatadine and are likely to have high affinity for the H4R.

[0009] Smits et al J. Med. Chem. 2008 51 :7855-7865 describes a quinazoline that has affinity for both the H4R and H1R. No reference to ocular allergy has been made in this manuscript.

[0010] Deml et al Mol Pharmacol. 2009 Nov; 76(5) describes compounds with high H1R affinity but no significant affinity for the H4R has been observed for any of these compounds. These compounds were originally designed as H1R antagonists and were studied for their interaction with the H4R.

[0011] Gallois-Bernos et al. Journal of Receptor, Ligand and Channel Research 2012:5 9-20 discusses the compound alcaftadine, a marketed H1R antagonist for ocular allergy (registered for ocular itching only). It is claimed that this compound interacts with the H4R and despite its very low affinity, has an effect on immune cell chemotaxis that helps alleviate the symptoms of ocular allergy. Ko and co-workers report in J. Med. Chem. 2018 61 : 2949-2961 a new chemotype of potent H4R antagonists for the treatment of atopic dermatitis. Most notably, the tricyclic aromatic pyrido[2,3- e]tetrazolo[1 ,5- a]pyrazine-containing compounds show high H4R activity and oral bioavailability. The compounds are reported to be highly selective and show no activity on a panel of other drug targets, including H1R.

[0012] Werfel and co-workers show in Atopic Dermatitis and Inflammatory Skin Disease 2019 143: P1830-1837 that the H4R antagonists ZPL-3893787 (aka PF-3893787) improves inflammatory skin lesions in patients with atopic dermatitis, confirming that H4R as therapeutic option.

[0013] Mowbray and co-workers describe in Bioorganic & Medicinal Chemistry Letters 2011 21 : 6596-6602 the clinical development candidate PF-3893787 as a potent H4R antagonist with more than a hundred-fold selectivity over other histamine receptor subtypes.

[0014] Lazewska et al. in Molecules 2023: 28: 4199 describe triazine-containing H4R antagonists with moderate activity for H4R while having no significant affinity for H1R and H3R. The described compounds showed anti-inflammatory and analgesic effects and were also shown to be active in a pruritus model.

[0015] Summary of the Invention

[0016] The present invention relates to novel compounds, which act as dual antagonists of both the histamine Hi and H4 receptors. Some of the compounds exemplified herein additionally have some antagonist activity on the H2 and / or H3 receptors.

[0017] The present invention is a compound of formula (I): or a pharmaceutically acceptable salt or ester thereof; wherein:

[0018] Y is CRg or N;

[0019] Ri is

[0020]

[0021] Re, R7 and Rs are independently selected from H, C1-4 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-4 alkoxy, C1-4 alkylthio, (CH2)o-3C3-7cycloalkyl, aryl, C1-4 alkyl-aryl and heteroaryl; R9 is H, halogen or C1-C5 alkyl;

[0022] R2, and R3 are independently selected from H, CM alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-4 alkoxy, C1-4 alkylthio, (CH2)o-3C3-7cycloalkyl, aryl, C1-4 alkyl-aryl, CF3, cyano, heteroaryl, Ci- 04 alkyl-heteroaryl, Ci-C4 alkyl-heteroaryl or R2 and R3 taken together with the attached C- atoms form a 3-6 membered cycloalkyl ring; wherein Xa is O or S; wherein Za is CRc or N; wherein Zb is CRb or N; wherein Ra, Rb, Rc and Rd are each independently selected from H, halogen, C1-4 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-4 alkoxy, C1-4 alkylthio, (CH2)o-3C3-7cycloalkyl, aryl, heteroaryl, C1-4 alkyl-aryl, cyano, heteroaryl, C1-C4 alkyl-heteroaryl or Ra and Rb, or Rb and Rc taken together with the attached C atoms form a 5-7 membered cycloalkyl ring, a 5-6 membered aryl ring, a 5-6 membered heteroaryl ring or a 4 to 8 membered nonaromatic heterocyclic group, one or more substituents independently selected from C1- ealkyl, (CH2)O-3C3-7 cycloalkyl, alkoxyalkyl containing 2 to 8 carbon atoms, C1-C4 alkyl- heteroaryl, Ci-4alkylOCF3, (CH2)i-4aryl and C1-6 hydroxyalkyl, or Rc and R19 or Rd and R19 taken together are to form a 6 membered ring; is one of the structures shown below: wherein Rn, R12, 13, 14, R15, 16, R17 and R18 are independently selected from H, F, OH, C1-4 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-4 alkoxy, C1-4 alkylthio, (CH2)o-3C3-7cycloalkyl, O- C3-6 cycloalkyl, aryl, NH-Ci-Ce acyl, O-aryl, NH-aryl, S-aryl, O-C1-4 alkyl-aryl, C1-4 alkyl-aryl, CF3, O-CF3, S-CF3, hydroxy, O-C1-4 alkyl-N(CH3)2, heteroaryl, O-heteroaryl, NH-heteroaryl, S-heteroaryl, C1-C4 alkyl-heteroaryl, Ci-C4 alkyl-heteroaryl and NRmRn, wherein Rm and Rn are independently selected from H, C1-4 alkyl, aryl and phenethyl; wherein any alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic group can independently be optionally substituted with one or more substituents selected from halogen, C1-6 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-4 alkoxy, Ci- alkylthio, (6^)0-3 3-7 cycloalkyl, O-C3-6 cycloalkyl, aryl, O-aryl, NH-aryl, S-aryl, O-C1-4 alkyl-aryl, 61-4 alkyl-aryl, CF3, S-CF3, hydroxy, nitro amino, cyano and O-C1-4 alkyl-N(CH3)2; C2-C8 alkoxyalkyl, (CH2)o-4 alkylheteroaryl; (CH2)o- 4O-CF3, Ci-Ce hydroxyalkyl; n is 1 , 2 or 3; m is 0, 1 or 2;

[0023] R19 is H or is taken together with Rc or Rd as set out above; and

[0024] X is O, S, NRe, S(O), C(O), S(O)2, or a direct bond.

[0025] Description of the Invention

[0026] The term “alkyl” as used herein includes straight-chain and branched hydrocarbon groups. Examples are methyl, ethyl, propyl and isopropyl. Preferably, it contains 1 to 6, more preferably 1 to 4 carbon atoms.

[0027] The term “alkenyl” as used herein includes straight-chain and branched hydrocarbon groups as above with at least one carbon-carbon double bond (sp2). Preferably, it contains 2 to 6, more preferably 2 to 4 carbon atoms.

[0028] The term “alkynyl” as used herein includes straight-chain and branched hydrocarbon groups as above with at least one carbon-carbon triple bond (sp). Hydrocarbons having a mixture of double bonds and triple bonds are grouped as alkynyls herein. Preferably, it contains 2 to 6, more preferably 2 to 4 carbon atoms.

[0029] The term “alkoxy” as used herein includes straight-chain and branched alkyl groups with a terminal oxygen linking the alkyl group to the rest of the molecule. Alkyl is as defined above.

[0030] The term "aryl" as used herein includes any functional group or substituent comprising an aromatic ring and from 5 to 10 ring atoms. In particular the aryl may be selected from moieties comprising a phenyl, benzyl, naphtyl or biphenyl. The aryl may comprise one or more heteroatoms selected from N, O or S, in which case the aryl may be referred to as "heteroaryl". Preferred examples of heteroaryl groups include pyridine, furane, thiophene, pyrrole, imidazole, thiazole, oxazole, and triazole. The terms aryl and heteroaryl include bicyclic moieties.

[0031] The term “acyl” as used herein is an alkyl-CO group, where the alkyl group is as defined above.

[0032] The term “cycloalkyl” as used herein includes saturated or partially saturated, monocyclic, fused polycyclic, bridged or spiro polycyclic carbocycles having from 3 to 7 ring atoms per carbocycle. Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and bicyclo[2.1.1.]hex-2-ylidene.

[0033] The term “heterocyclic” refers to a monocyclic, or fused, bridged, or spiro polycyclic ring structure that is saturated or partially saturated and has from 4 to 8 ring atoms per ring structure selected from carbon atoms and up to three heteroatoms selected from nitrogen, oxygen and sulfur. The ring structure may optionally contain up to two oxo groups in carbon or sulfur ring members.

[0034] All groups defined above may be optionally substituted by one or more substituents (preferably 1 , 2 or 3, with the upper limit dependent on the valency of the member being substituted, and known to the skilled person) selected from halogen, C1-6 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-4 alkoxy, Ci- alkylthio, (CH2)o-3C3-7 cycloalkyl, O-C3-6 cycloalkyl, aryl, O-aryl, NH-aryl, S-aryl, O-C1-4 alkyl-aryl, C1-4 alkyl-aryl, CF3, S-CF3, hydroxy, nitro amino, cyano and O-C1-4 alkyl-N(CH3)2; C2-C8 alkoxyalkyl, (CH2)o-4 alkylheteroaryl; (CH2)o-40-CF3 or Ci-Ce hydroxyalkyl.

[0035] It is understood that substitutions and combinations of substitutions recited herein refer to substitutions that are consistent with the valency of the member being substituted.

[0036] Some preferred embodiments of the invention are described below.

[0037] Preferably, Re, R7, Rs, R3 and / or R2 are each independently selected from C1-C4 alkyl, or H.

[0038] Preferably, Y is N or CH. More preferably, Y is N.

[0039] In a preferred embodiment, is:

[0040] Preferably, R13 and / or R14 is independently selected from a halogen, preferably F.

[0041] Preferably, Rn, Ri2, R15, R16, R17 and / or Ris is H. Preferably, R2 and / or Ra is H. More preferably, R2 and Ra is H.

[0042] In a preferred embodiment, AR is:

[0043] In a preferred embodiment, R1 is selected from structures R, J, K, B, C and F, more preferably F, B and K.

[0044] In a preferred embodiment, R13 and R14 are F, and

[0045] R2, R3, Rii, Ri2, R15, R16, R17, RIS, R19, Ra, Rb, Rc, and Rd are H. The “pharmaceutically acceptable salt, ester or solvate thereof” refers to those salts, ester forms and solvates of the compounds of the present invention that would be apparent to the pharmaceutical chemist, i.e. those that are non-toxic and that would favourably affect the pharmacological properties of said compounds of the present invention. Those compounds having favourable pharmacological properties would be apparent to the pharmaceutical chemist, i.e. those that are non-toxic and that possess such pharmacological properties to provide sufficient palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, that are important in the selection are cost of raw materials, ease of crystallisation, yield, stability, hygroscopicity, and flowability of the resulting bulk drug.

[0046] Representative acids that may be used in the preparation of pharmaceutically acceptable salts include but are not limited to the following: acetic acid, 2,2-dichlorolactic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulphonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulphonic acid, (+)-(1S)-camphor-10-sulphonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulphuric acid, ethane-1,2- disulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L- glutamic acid, a-oxo-glutaric acid, glycolic acid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactid acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulphonic acid, naphthalene-2-sulphonic acid naphthalene-1,5-disulphonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulphuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulphonic acid and undecylenic acid.

[0047] Representative bases that may be used in the preparation of pharmaceutically acceptable salts include the following: ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1 H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2- hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

[0048] Examples of suitable esters include C1-7 alkyl, C5-7 cycloalkyl, phenyl, substituted phenyl, and phenyl-Ci-6 alkyl esters. Preferred esters include methyl esters.

[0049] Any formula given herein is also intended to represent unlabelled forms as well as isotopically labelled forms of the compounds. Isotopically labelled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,15N,18O,170,31P,32P,35S,18F,36CI,125l, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques [such as positron emission tomography (PET) or singlephoton emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F or11C labelled compound may be particularly preferred for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (i.e. ,2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labelled compounds of this invention can generally be prepared by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

[0050] The present invention includes prodrugs of the compounds of the invention. In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the bio-active compound. Thus, in the uses of the compounds for methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound that may not be specifically disclosed, but that converts to the specified compound in vivo after administration to the patient. Analogously, the term “compound”, when applied to compounds of this invention, shall encompass any specific compound according to the present invention or any compound (or prodrug) that converts to the specifically disclosed compound in vivo after administration, even if such prodrug is not explicitly disclosed herein.

[0051] Examples of prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, covalently joined through an amide or ester bond to a free amino or hydroxyl group of a compound of formula (I). Examples of amino acid residues include the twenty naturally occurring amino acids, commonly designated by three letter symbols, as well as 4-hydroxyproline, hydroxy lysine, desmosine, isodesmosine, 3-methylhistidine, norvalin, beta-alanine, gamma- aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone.

[0052] The present invention also relates to pharmaceutically active metabolites of compounds of formula (I), and uses of such metabolites in the methods of the invention. A "pharmaceutically active metabolite" means a pharmacologically active product of metabolism in the body of a compound of formula (I) or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini, et al., J. Med. Chem. 1997, 40, 2011-2016; Shan, et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 224-331 ; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers, 1991).

[0053] An active agent of the present invention may be administered to treat inflammation. Inflammation may be associated with various diseases, disorders, or conditions, such as inflammatory disorders, allergic disorders, dermatological disorders, autoimmune disease, lymphatic disorders, and immunodeficiency disorders and cancer, including the more specific conditions and diseases given below. Regarding the onset and evolution of inflammation, inflammatory diseases or inflammation-mediated diseases or conditions include, but are not limited to, acute inflammation, allergic inflammation, and chronic inflammation.

[0054] Illustrative types of inflammation treatable with a histamine H4 and / or Hi receptormodulating agent according to the invention include inflammation due to any one of a plurality of conditions such as allergy, asthma, dry eye, chronic obstructed pulmonary disease (COPD), atherosclerosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases (including colitis, Crohn's disease, and ulcerative colitis), psoriasis, pruritis, itchy skin, atopic dermatitis, urticaria (hives), ocular inflammation (e.g., post-surgical ocular inflammation), conjunctivitis (e.g. allergic conjunctivitis or vernal keratoconjunctivitis), dry eye, ocular allergy, nasal polyps, allergic rhinitis, nasal itch, scleroderma, autoimmune thyroid diseases, immune-mediated (also known as type 1) diabetes mellitus and lupus, which are characterised by excessive or prolonged inflammation at some stage of the disease. Other autoimmune diseases that lead to inflammation include Myasthenia gravis, autoimmune neuropathies, such as Guillain-Barre, autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, anti-phospholipid syndrome, vasculitides, such as Wegener's granulomatosis, Behcet's disease, dermatitis herpetiformis, pemphigus vulgaris, vitiligio, primary biliary cirrhosis, autoimmune hepatitis, autoimmune oophoritis and orchitis, autoimmune disease of the adrenal gland, polymyositis, dermatomyositis, spondyloarthropathies, such as ankylosing spondylitis, and Sjogren's syndrome.

[0055] Pruritis treatable with a histamine H4 receptor-modulating agent according to the invention includes that which is a symptom of cutaneous diseases (such as atopic dermatitis, urticaria and hives) and other metabolic disorders (such as chronic renal failure, hepatic cholestasis, and diabetes mellitus). Pruritis treatable with a histamine H4 receptor-modulating agent according to the invention includes that which is a side-effect of administered drugs (i.e. drug-induced pruritis). A well-known example is opiate-induced pruritis resulting from the administration of opiates.

[0056] In a preferred embodiment, an active agent of the present invention is administered to treat allergy, in particular ocular allergy, asthma, autoimmune diseases, or pruritis. Thus, the active agents may be used to treat subjects diagnosed with or suffering from a disease, disorder, or condition mediated through histamine H4 receptor activity. The term "treat" or "treating" as used herein is intended to refer to administration of an active agent or composition of the invention to a subject for the purpose of effecting a therapeutic or prophylactic benefit through modulation of histamine H4 and / or Hi receptor activity. Treating includes reversing, ameliorating, alleviating, inhibiting the progress of, lessening the severity of, or preventing a disease, disorder, or condition, or one or more symptoms of such disease, disorder or condition mediated through modulation of histamine H4 receptor activity. The term "subject" refers to a mammalian patient in need of such treatment, such as a human. "Modulators" include both inhibitors and activators, where "inhibitors" refer to compounds that decrease, prevent, inactivate, desensitize or down-regulate histamine H4 receptor expression or activity, and "activators" are compounds that increase, activate, facilitate, sensitize, or up- regulate histamine H4 receptor expression or activity.

[0057] In treatment methods according to the invention, an effective amount of at least one active agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition. An "effective amount" means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition. When referring to modulating the target receptor, an "effective amount" means an amount sufficient to affect the activity of such receptor. Measuring the activity of the target receptor may be performed by routine analytical methods. Target receptor modulation is useful in a variety of settings, including assays. Effective amounts or doses of the active agents of the present invention may be ascertained by routine methods such as modelling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. An exemplary dose is in the range of from about 0.001 to about 200 mg of active agent per kg of subject's body weight per day, preferably about 0.05 to 100 mg / kg / day, or about 1 to 35 mg / kg / day, or about 0.1 to 10 mg / kg daily in single or divided dosage units (e.g., BID, TID, QID). For a 70-kg human, an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g / day, or about 0.2 to about 2.5 g / day.

[0058] Once improvement of the patient's disease, disorder, or condition has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0059] In addition, the active agents of the invention may be used in combination with additional active ingredients in the treatment of the above conditions. The additional active ingredients may be co-administered separately with an active agent of formula (I) or included with such an agent in a pharmaceutical composition according to the invention. In an exemplary embodiment, additional active ingredients are those that are known or discovered to be effective in the treatment of conditions, disorders, or diseases mediated by histamine H4 receptor activity, such as another histamine H4 receptor modulator or a compound active against another target associated with the particular condition, disorder, or disease. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an agent according to the invention), decrease one or more side effects, or decrease the required dose of the active agent according to the invention.

[0060] The active agents of the invention are used, alone or in combination with one or more additional active ingredients, to formulate pharmaceutical compositions of the invention. A pharmaceutical composition of the invention comprises an effective amount of at least one active agent in accordance with the invention. Such compositions may further comprise a pharmaceutically acceptable excipient.

[0061] A "pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0062] Delivery forms of the pharmaceutical compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art. The compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation.

[0063] The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. Preferably, the compositions are formulated for intravenous infusion, topical administration, or oral administration.

[0064] For oral administration, the active agents of the invention can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. To prepare the oral compositions, the active agents may be formulated to yield a dosage of, e.g., from about 0.05 to about 50 mg / kg daily, or from about 0.05 to about 20 mg / kg daily, or from about 0.1 to about 10 mg / kg daily.

[0065] Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0066] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0067] Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilised or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

[0068] The active agents of this invention may also be administered by non-oral routes. For example, compositions may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the agents of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 [mu] / kg / m inute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

[0069] For topical administration, the agents may be mixed with a pharmaceutical carrier at a concentration of about 0.01% to about 10% of drug to vehicle. Another mode of administering the agents of the invention may utilize a patch formulation to affect transdermal delivery.

[0070] In particular embodiments, compositions of the present invention are suitable for topical application to mammalian eyes. For example, for ophthalmic administration, the formulation may be a solution, a suspension, a gel, water-in-oil and oil-in-water emulsions, or an ointment. Preferred compositions for ophthalmic administration will be aqueous solution in the form of drops. The term "aqueous" typically denotes an aqueous formulation wherein the excipient is >50%, more preferably >75% and in particular >90% by weight water. These drops may be delivered from a single dose ampoule which may preferably be sterile and thus render bacteriostatic components of the formulation unnecessary. Alternatively, the drops may be delivered from a multi-dose bottle which may preferably comprise a device which extracts preservative from the formulation as it is delivered, such devices being known in the art.

[0071] Compositions of the present invention may be administered topically (i.e. , local, organspecific delivery) or systemically by means of conventional topical or systemic compositions, such as solutions, suspensions or gels for the eye and ear; nasal sprays or mists for the nose; metered dose inhalers for the lung; solutions, gels, creams or lotions for the skin; oral dosage forms including tablets or syrups for the gastrointestinal tract; and parenteral dosage forms including injectable compositions. The concentration of the H1 and H4 receptor antagonists in the compositions of the present invention will depend on the selected route of administration and dosage form.

[0072] Active agents may alternatively be administered in methods of this invention by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.

[0073] The compounds of the invention can be prepared according to processes within the skill of the art and / or according to processes of this invention, such as those described in the schemes and examples that follow and by matrix or combinatorial methods.

[0074] Illustrative preparations are presented in the following Schemes. Other compounds of the invention may be made in the same general way, using modifications that will be apparent to those of ordinary skill in the art.

[0075] The following Examples illustrate the invention.

[0076] Examples Thiazol-5-ylmethanamine.

[0077] Reagents and conditions: (i) NH2OH, HCI, NaOAc, EtOH, rt. (iv) AcOH, Zn, rt.

[0078] Step A: Thiazole-5-carbaldehyde oxime. To a solution of thiazole-5-carbaldehyde (200 mg, 1.768 mmol) and ethanol (5 ml) in a 5 mL microwave tube, the hydroxylamine hydrochloride (221 mg, 3.18 mmol) and sodium acetate (290 mg, 3.54 mmol) were added. The reaction mixture was stirred at room temperature for 72 hours. The ethanol was evaporated in vacuum and water (5 mL) was added to the residue and the product was extracted with ethyl acetate (3 x 5 mL). The organic layers were dried with Na2SO4, filtered and concentrated under vacuum to yield thiazole-5-carbaldehyde oxime. Yield: 203 mg, 90%.1H NMR (400 MHz, MeOD) 5 ppm 9.09 (s, 1 H, major), 8.93 (s, 1 H, minor), 8.34 (s, 1 H, minor), 8.24 (s, 1 H, major), 7.99 (s, 1 H, minor), 7.89 (s, 1 H, major). MS (M+1) (ESI) m / z 129 (M+1).

[0079] Step B: Thiazol-5-ylmethanamine. In a 5 mL microwave tube was To a solution of the thiazole-5-carbaldehyde oxime (203 mg, 1.584 mmol) in acetic acid (3 mL), zinc (621 mg, 9.50 mmol) was added. The reaction mixture was stirred for 1 week at room temperature and heated for 6 hours at 90 °C. The reaction mixture was filtered through celite and concentrated in vacuum. The product was purified with SPE using Si-Propylsolfonic acid as the stationary phase, the impurities were removed by methanol and the product was eluted with ammonia in methanol. The ammonia in methanol was evaporated in vacuum to yield the title compound. Yield: 141 mg, 78 %.1H NMR (400 MHz, CDCI3) 6 ppm 8.72 (s, 1 H), 7.72 (s, 1 H), 4.13 (s, 2H), 2.79 (s, 3H). MS (M+1) (ESI) m / z 115.

[0080] 4,5,6,7-Tetrahydrothieno[2,3-c]pyridine.

[0081] Reagents and conditions: (i) NH4AC, NO2CH3, mw, 90 °C. (ii). UAIH4, THF, DEE, rt. (iii) H2CO, DCM, 45 to 75 °C, HCI 3M in DMF.

[0082] Step A: (E)-3-(2-nitrovinyl)thiophene. In a 5 mL microwave tube was thiophene-3- carbaldehyde (0.80 ml, 9.13 mmol), ammonium acetate (0.212 g, 2.75 mmol) in nitromethane (4 ml, 74.2 mmol) to give a white suspension. The tube was introduced into the microwave system at 90 °C for 60 min and a dark suspension was created. The reaction mixture was cooled and nitromethane was evaporated. The product was purified with silica gel column chromatography (eluted with gradient: ethyl acetate / methanol (3 / 1 to 2 / 1 , v / v) to yield a bright yellow solid of (E)-3-(2-nitrovinyl)thiophene. Yield: 455 mg, 32% yield.1H NMR (250 MHz, CDCI3) <5 ppm 8.01 (d, J = 13.6 Hz, 1 H), 7.73 (d, J = 2.2 Hz, 1 H), 7.48 (d, J = 13.6 Hz, 1 H), 7.46-7.40 (m, 1 H), 7.31-7.23 (m, 1 H). No mass seen of product on MS (M+1) (ESI) m / z.

[0083] Step B: 2-(Thiophen-3-yl)ethanamine. Under N2 atmosphere, in a 100 mL three-neck round-bottomed flask a 2.6 M solution in THF of lithium aluminum hydride (12.39 ml, 29.7 mmol) was added to diethyl ether (40 ml) to give a colorless solution. Then, a solution of (E)- 3-(2-nitrovinyl)thiophene (1.77 g, 11.44 mmol) in diethyl ether (25 ml) and THF (5 ml) was added with a dropping funnel at such a rate that the mixture was kept a gentle reflux. The mixture was stirred for 2 hours at room temperature and the excess of the lithium aluminum hydride was destroyed by cooling the mixture down to 0 °C, quenching it with ethyl acetate, diluted it with saturated Rochelle salt solution and stirred for 4 h. The organic layer was collected, dried with MgSCU, filtered, and concentrated under vacuum. The product was purified with silica column chromatography eluted with dichloromethane / triethylamine / methanol 90 / 5 / 5, v / v / v) to yield a yellow oil of 2-(thiophen-3-yl)ethanamine.

[0084] Yield: 550 mg, 38%.1H NMR (250 MHz, CDCI3) <5 ppm 7.27 (dd, J = 2.8 and 4.7 Hz, 1 H), 7.00 (dd, J = 0.8 and 2.4 HZ, 1 H), 6.95 (dd, J = 1 .0 and 4.9 Hz, 1 H), 2.96 (t, J = 6.6 Hz, 2H), 2.78 (t, J = 6.7 Hz, 2H), 1.58 (s, 2H). MS (M+1) (ESI) m / z 128 (M+1).

[0085] Step C: 4,5,6,7-tetrahydrothieno[2,3-c]pyridine. A solution of 2-(thiophen-3-yl)ethanamine (455 mg, 3.58 mmol) and dichloromethane (10 ml) in a 50 mL round-bottomed flask with dean-stark arrangement was stirred for 10 minutes at room temperature and paraformaldehyde (129 mg, 4.29 mmol) was added to the mixture. The reaction was refluxed overnight at 45 °C, cooled to room temperature and 3 M HCI (1.5 ml, 4.50 mmol) in DMF (diluted 12 M hydrochloric acid with DMF) was added. The reaction mixture stirred for 6 h at 75 °C overnight at 15 °C. The mixture was diluted with water, acidify (pH = 2) using 2M HCI; the water layer was taken and diluted again with DCM. The mixture was brought to pH 11 with 1 M NaOH and the organic layer was taken, dried with MgSCL, and concentrated under vacuum to yield 156 mg, crude yellow oil with 4,5,6,7-tetrahydrothieno[2,3-c]pyridine.

[0086] 4,5,6,7-Tetrahydrothieno[3,2-c]pyridine.

[0087] In a 50 mL round-bottomed flask with dean-stark arrangement was 2-(thiophen-2- yl)ethanamine (0.39 ml, 3.33 mmol) in DCE (10 ml) to give a yellow solution. The mixture was stirred for 10 minutes at room temperature and paraformaldehyde (120 mg, 4.00 mmol) was added to the mixture. The reaction was refluxed 4h at 45 °C and cooled to room temperature and 3 M HCI (1.5 ml, 4.50 mmol) in DMF (diluted 12 M hydrochloric acid with DMF) was added. The reaction mixture stirred overnight at 75 °C and 8 h at 15 °C. The mixture was diluted with water, acidified (pH = 2) using 2M HCI, the water layer was taken and diluted again with dichloromethane. The mixture was brought to pH = 11 using 1 M NaOH solution and the organic layer was taken, dried with MgSCU, and concentrated under vacuum to yield 4,5,6,7-tetrahydrothieno[3,2-c]pyridine as yellow oil, 328 mg.

[0088] 4,5,6,7-tetrahydrofuro[2,3-c]pyridine.

[0089] Reagents and conditions: (i) NH4AC, NO2CH3, mw, 90 °C. (ii). UAIH4, THF, DEE, rt. (iii) H2CO, DCM, 45 to 75 °C, HCI 3M in DMF.

[0090] Step A: (E)-3-(2-nitrovinyl)furan. In a 20 mL microwave tube was furan-3-carbaldehyde (2.70 ml, 31.2 mmol), ammonium acetate (0.73 g, 9.42 mmol) in nitromethane (7.00 ml, 130 mmol) to give a light yellow suspension. The tube was introduced into the microwave system at 90 °C for 60 min and a dark suspension was created. The reaction mixture was cooled and nitromethane was evaporated. The product was purified with silica gel column chromatography (eluted with gradient: ethyl acetate / methanol, 10 / 1 to 10 / 7(v / v) to yield a bright yellow solid of (E)-3-(2-nitrovinyl)furan. Yield: 3.55 g, 82 %.1H NMR (250 MHz, CDCh) 5 ppm 7.94 (d, J = 13.5 Hz, 1 H), 7.84 (s, 1 H), 7.52 (s, 1 H), 7.39 (d, J = 13.5 Hz, 1 H), 6.57 (d, J = 1.8 Hz, 1 H). No mass seen of product on MS (M+1) (ESI) m / z.

[0091] Step B: 2-(furan-3-yl)ethanamine. Under N2 atmosphere, in a 250 mL three-neck round- bottomed flask a 2.6 M solution in THF of lithium aluminum hydride (27.6 ml, 66.3 mmol) was added to diethyl ether (35 ml) to give a colorless solution. A solution of (E)-3-(2- nitrovinyl)furan (3.55 g, 25.5 mmol) in diethyl ether (25 ml) and THF (5 ml) was added with a dropping funnel at such a rate that the mixture was kept a gentle reflux. The mixture was stirred for 2 hours at room temperature and the excess of lithium aluminum hydride was destroyed by slow addition of the minimum required amount of water. The reaction mixture was filtered through celite, the filtrate was dried over MgSC>4 and concentrated under vacuum. The product was purified with silica gel column chromatography eluted with dichloromethane / triethylamine / methanol (90 / 5 / 5, v / v / v). The product was diluted in DCM and washed with aqueous NH4OH to get rid of the triethylamine salt, dried over MgSO4, filtered, and concentrated under vacuum to yield a yellow oil of 2-(furan-3-yl)ethanamine. Yield: 624 mg, 22%.1H NMR (250 MHz, CDCI3) <5 ppm 7.35 (s, 1 H), 7.24 (s, 1 H), 6.26 (s, 1 H), 2.86 (t, J = 6.7 Hz, 2H), 2.53 (t, J = 6.7 Hz, 2H), 1.32 (s, 2H). MS (M+1) (ESI) m / z 112. Step C: 4,5,6,7-tetrahydrofuro[2,3-c]pyridine. In a 50 mL round-bottomed flask was 37 % aqueous solution of formaldehyde (487 mg, 6.00 mmol), 2-(furan-3-yl)ethanamine (556 mg, 5.00 mmol) was added drop wise and the mixture stirred for 30 min at room temperature. The mixture was extracted with diethyl ether (3 x 8 mL).The combined organic layers were dried over Na2SC>4, filtered and concentrated to get a yellow oil. DMF (5 mL) was saturated with hydrogen chloride gas by passing hydrogen chloride through the solution overnight. The remaining oil was dissolved in DMF (1 mL) and added to 4 mL of the HCI / DMF solution and stirred at room temperature for 3 h, and the mixture was concentrated in vacuum. The resulting mixture was diluted in DCM (10 mL) and washed with water (10 mL) basified with pH 11 by addition of sat NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated to yield 105 mg of the title compound as crude yellow oil.

[0092] General synthetic scheme

[0093] Reagents and conditions: (i) dimethyl carboxylate, NaH, THF, rt. (ii) Ammonium acetate, MeOH, rt. (iii) Phosgene 20% in PhCH3, NH4OH 30% in water, 50°C. (iv) POCI3, D. (v) NHR1R2, DIEA, CHCN3, Mw, 70°C. (vi) NHR3R4, DIEA, 1 ,4-dioxane, microwave heating, 150°C.

[0094] General remarks

[0095] Chemicals and reagents were obtained from commercial suppliers and were used without further purification. Yields given are isolated yields unless mentioned otherwise. All1H-NMR and13C-NMR spectra were measured on a Bruker AC250, Bruker Advance 400 or Bruker Ascend 500. Microwave assisted chemistry was performed with a Biotage Initiator typically using 2 or 5 ml vials obtained from Biotage.

[0096] LCMS analyses were performed with a Shimadzu LCMS-2010 EV mass spectrometer, a Shimadzu LC-20 AB pump system, a SPD-M20 A diode array detector and a CTO-20 AC column oven using an XBridge column (C18, 5 pm, 4,6 x 50 mm). An aqueous buffer (pH 8) of 0.04% NH4HCO3 (solvent A) and a mixture of 90% MeCN and 10% of a 0.4% NH4HCO3 buffer (pH 8, solvent B) were used. The runs started with 5% B with a linear gradient to 90% B in 4.5 minutes, then continuing for 1.5 minutes with 90% B and finally a linear gradient to 5% B in 0.5 minutes. Total run time 8 minutes.

[0097] Chemical names were generated using ChemBioDraw Ultra 13 (CambridgeSoft, Cambridge, MA).

[0098] Example 1 : 4-Aminomethylthienyl-6,6-difluoro-2-(4-methyl-piperazinyl)-5, 6,7,8- tetrahydroquinazoline

[0099] Step A: Methyl 5, 5-difluoro-2-oxocyclohexane-1 -carboxylate. To a flamed-dried flask, 4,4- difluorocyclohexanone (4.0 g, 29.8 mmol) in 6 mL benzene was added along with NaH (1.8 g, 75 mmol) in 60 mL benzene and diethyl carbonate (62.5 mmol). After the mixture was refluxed for 2h, the reaction was quenched by the addition of crushed ice, and 12 mL of acetic acid. The mixture was diluted with ethyl acetate (100 mL) and washed with water and brine. The organic layer was dried and concentrated to afford methyl 5,5-difluoro-2-oxocyclohexane- 1 -carboxylate (quantitative).

[0100] Step B: Methyl 2-amino-5,5-difluorocyclohex-1-ene-1 -carboxylate. A mixture of methyl 5,5-difluoro-2-oxocyclohexane-1-carboxylate (5.7 g, 29.7 mmol) and ammonium acetate (11.4 g, 148 mmol) in MeOH (250 mL) was stirred at room temperature until the starting material had disappeared. The whole reaction mixture was then concentrated. The residue was redissolved in CH2CI2 (200 mL). The remaining solid was filtered and washed with ample CH2CI2. The combined CH2CI2 layers were washed with water and brine and dried over sodium sulfate. The solution was concentrated under vacuum to give methyl 2-amino-5,5- difluorocyclohex-1-ene-1 -carboxylate, which was used without further purification.

[0101] Step C: 6,6-Difluoro-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione. To a cool (0°C) solution of methyl 2-amino-5,5-difluorocyclohex-1-ene-1 -carboxylate (4.20 g, 20.8 mmol), pyridine (9.6 mL, 119 mmol) and 1,2-dichloroethane (150 mL), phosgene (20% in toluene) (105 mL, 35.6 mmol) was added in one portion. The mixture was maintained at 0°C for 3h. Then 28% NH4OH (41.9 mL, 1.1 mol) was added cautiously down the side of the flask and the mixture was gently stirred for 3 h and subsequently heated at 50°C for 16 h. Next water (50 mL) was added and the phases were separated. The organic phase was extracted with 1% NH4OH (2 x 25 mL). The combined aqueous phases were washed with dichloromethane (3 x 20mL) and concentrated, which caused the product to precipitate. The precipitate was filtered, rinsed with a small amount water / MeOH, 1 / 1 (v / v), acetone (to remove water) and dried under high vacuum to afford 6,6-difluoro-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)- dione in 58% yield.1H NMR (400 MHz, DMSO) 57.48 (s, 2H), 2.67 (t, J = 14.4 Hz, 2H), 2.58 (t, J = 6.8 Hz, 2H), 2.23-2.13 (m, 2H). MS (M+1) (ESI) m / z 202.90. Step D: 2,4-Dichloro-6,6-difluoro-5,6,7,8-tetrahydroquinazoline. The mixture of 6,6- difluoro-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (1.0 g, 5.0 mmol) and POCh (1.84 mL, 9.8 mmol) was refluxed for 4 hours. The mixture was poured on crushed ice and extracted with CHCI3, the organic phases washed with brine, dried over MgSCL, filtered and the solvent was removed by evaporation to obtain 2,4-dichloro-6,6-difluoro-5,6,7,8- tetrahydroquinazoline (1 d), which was purified by silica gel column chromatography (eluent: 1 / 1 , EA / Hex; yield 76%).1H NMR (400 MHz, CDCI3) 63.18 (t, J = 14.4 Hz, 2H), 3.11-3.09 (m, 2H), 2.31-2.23 (m, 2H). MS (M+1) (ESI) m / z 238.80.

[0102] Step E: 2-Chloro-6,6-difluoro-N-(thiophen-2-ylmethyl)-5,6,7,8-tetrahydroquinazolin-4- amine. The mixture of 2,4-dichloro-6,6-difluoro-5,6,7,8-tetrahydroquinazoline 1d (0.3 g, 1.25 mmol), thiophen-2-ylmethanamine (0.14 g, 1.25 mmol), DIEA (0.34 g, 2.64 mmol) and acetonitrile (10 mL) was stirred at 70°C microwave heating for 30 min. Then, the solvent was removed by evaporation. The residue was purified by silica gel chromatography eluted by gradient of hexane / EA, 1 / 0, 2 / 1 , 1 / 1 , to give 2-chloro-6,6-difluoro-N-(thiophen-2-ylmethyl)- 5,6,7,8-tetrahydroquinazolin-4-amine.1H NMR (400 MHz, CDCI3) 67.20 (m, 1 H), 7.00 (d, J =

[0103] 4.8 Hz, 1 H), 6.91 (m, 1H), 4.81 (s, 2H), 2.91 (m, 2H), 2.71 (t, J = 14.0 Hz, 2H), 2.18-2.10 (m, 2H). MS (M+1) (ESI) m / z 319.85.

[0104] Step F: 2-Chloro-6,6-difluoro-N-(thiophen-2-ylmethyl)-5,6,7,8-tetrahydroquinazolin-4-amine was redissolved in 1,4-dioxane. Next, 4-methyl piperazine (0.13 g, 1.25 mmol) was added and the mixture was heated twice in a microwave for 60 min at 150 °C. The mixture was diluted with ethyl acetate (20 mL) and the solution was washed with, brine, ammonium chloride and water. The organic phase was dried, filtered and the solvent removed by evaporation. The residue was purified by silica gel column cromatography (eluent: gradient of ethyl acetate / MeO, 95 / 5 to ethyl acetate / triethylamine / MeO, 90 / 5 / 5) to give 4- aminomethylthienyl-6,6-difluoro-2-(4-methyl-piperazinyl)-5,6,7,8-tetrahydroquinazoline (Example 1) in 42%.

[0105] 1H NMR (400 MHz, CDCI3) 67.14 (dd, J = 5.1Hz, 1H), 6.94 (d, J = 3.0 Hz, 1 H), 6.89 (dd, J =

[0106] 4.9 Hz, 1 H), 4.88 (d, J = 5.4 Hz, 1 H), 4.77 (d, J = 5.6 Hz, 2H), 3.83-3.67 (m, 4H), 3.32 (t, J = 7.1 Hz, 2H), 2.70-2.68 (m, 3H), 2.43-2.35 (m, 4H), 2.34-2.26 (m, 5H), 2.20-2.05 (m, 2H), 1.97 (dd, J = 15.1 Hz, 7.6 Hz, 2H). MS (M+1) (ESI) m / z 380.5.

[0107] The compounds in Examples 2-26 were prepared using methods analogous to those described in Example 1. 6,6-difluoro-2-(piperazin-1-yl)-N-(thiophen-2-ylmethyl)-5,6,7,8-tetrahydroquinazolin-4- amine (Example 2)

[0108] Yield: 130 mg, 56%.1H NMR (400 MHz, CDCI3) <57.20 (dd, J = 5.1Hz, 1H), 6.99 (d, J = 3.0 Hz, 1 H), 6.94 (dd, J = 4.9 Hz, 1 H),6.89 (dd, J = 4.9 Hz, 1 H), 4.81 (d, J = 5.4 Hz, 2H), 4.62 (t, J = 5.6 Hz, 1 H), 3.87-3.70 (m, 4H), 2.98-2.85 (m, 4H), 2.80 (t, J = 6.8 Hz, 2H), 2.72 (t, J = 14.4 Hz, 2H), 2.28-2.08 (m, 3H), MS (M+1) (ESI) m / z 365.9.

[0109] 2-(1,4-diazepan-1-yl)-6,6-difluoro-N-(thiophen-2-ylmethyl)-5,6,7,8-tetrahydroquinazolin-

[0110] 4-amine (Example 3)

[0111] Yield: 44 mg, 37%.1H NMR (400 MHz, CDCI3) 6 ppm 7.19 (d, J = 5.0 Hz, 1 H), 6.98 (s, 1 H), 6.97-6.83 (m, 1 H), 4.82 (d, J = 5.5 Hz, 2H), 4.69 (m, 1 H), 3.83 (t, J = 5.7 Hz, 4H), 3.04-2.98 (m, 2H), 2.88-2.83 (m, 2H), 2.80 (t, J = 6.9 Hz, 2H), 2.74 (t, J = 14.6 Hz, 2H), 2.25-2.08 (m, 2H), 1.90-1.76 (m, 2H). MS (M+1) (ESI) m / z 380.

[0112] 6,6-difluoro-2-(4-methyl-1,4-diazepan-1-yl)-N-(thiophen-2-ylmethyl)-5,6,7,8- tetrahydroquinazolin-4-amine (Example 4)

[0113] Yield: 73 mg, 59%.1H NMR (400 MHz, CDCI3) 6 ppm 7.18 (d, J = 5.1 Hz, 1 H), 6.97 (s, 1 H), 6.95-6.88 (m, 1 H), 4.81 (d, J = 5.4 Hz, 2H), 4.71 (d, J = 5.4 Hz, 1 H), 3.97-3.86 (m, 2H), 3.80 (t, J = 6.6 Hz, 2H), 2.79 (t, J = 6.6, 2H), 2.72 (t, J = 14.5 Hz, 2H), 2.68-2.63 (m, 2H), 2.60- 2.49 (m, 2H), 2.35 (s, 3H), 2.17 (dt, J = 6.7 Hz, 13.4 Hz, 2H), 1.96 (dd, J = 5.5 Hz, 10.7 Hz, 2H). MS (M+1) (ESI) m / z 394.5. 2-(3-(dimethylamino)azetidin-1-yl)-6,6-difluoro-N-(thiophen-2-ylmethyl)-5, 6,7,8- tetrahydroquinazolin-4-amine (Example 5)

[0114] Yield: 31 mg, 26%.1H NMR (400 MHz, CDCI3) <5ppm 7.21 (d, J= 5.0 Hz, 1H), 7.00 (d, J = 3.1 Hz, 1H), 6.99-6.83 (m, 1H), 4.82 (d, J= 5.6 Hz, 2H), 4.72 (d, J= 5.4 Hz, 1H), 4.17-4.07 (m, 2H), 3.97-3.95(m, 2H), 3.15 (m, 1H), 2.82 (t, J= 6.8 Hz, 2H), 2.72 (t, J= 14.4 Hz, 2H), 2.25-2.19 (m, 2H), 2.17 (s, 6H). MS (M+1) (ESI) m / z 380.50.

[0115] 6,6-difluoro-2-(1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-N-(thiophen-2- ylmethyl)-5,6,7,8-tetrahydroquinazolin-4-amine (Example 6)

[0116] (3aR, 6aR)

[0117] Yield: 73 mg, 57%.1H NMR (400 MHz, CDCI3) <5ppm 7.19 (d, J= 5.1 Hz, 1H), 7.04-6.97 (m, 1H), 6.98-6.88 (m, 1H), 4.83 (d, J= 5.6 Hz, 2H), 4.66 (t, J= 5.4 Hz, 1H), 3.90-3.72 (m, 2H), 3.56-3.37 (m, 2H), 3.12 (t, J= 8.4 Hz, 1H), 2.92-2.77 (m, 4H), 2.72 (t, J= 14.4 Hz, 2H), 2.40 (s, 3H), 2.24-2.01 (m, 4H), 1.74 (ddd, J= 4.5 Hz, 10.4 Hz, 17.2 Hz, 1H). MS (M+1) (ESI) m / z 406.5.

[0118] 6,6-difluoro-2-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(thiophen-2- ylmethyl)-5,6,7,8-tetrahydroquinazolin-4-amine (Example 7)

[0119] Yield: 30 mg, 24%.1H NMR (400 MHz, CDCI3) 5 ppm 7.19 (dd, J= 5.1 Hz, 1H), 6.99 (d, J = 3.3 Hz, 1H), 6.93 (dd, J= 3.6 Hz, 5.0 Hz, 1H), 4.84 (d, J= 5.6 Hz, 2H), 4.73 (t, J= 5.4 Hz, 1H), 3.84-3.71 (m, 2H), 3.68-3.55 (m, 2H), 3.31 (dd, J=4.8Hz, 11.1, 1H), 2.82 (t, J=6.8 Hz, 2H), 2.72 (t, J= 14.4 Hz, 2H), 2.27-2.06 (m, 4H), 1.89-1.61 (m, 3H). MS (M+1) (ESI) m / z 392.5 (R)-2-(3-aminopyrrolidin-1-yl)-6,6-difluoro-N-(thiophen-2-ylmethyl)-5, 6,7,8- tetrahydroquinazolin-4-amine (Example 8)

[0120] Yield: 45 mg, 19%.1H NMR (400 MHz, CDCI3) <5ppm 7.21 (d, J= 5.1 Hz, 1H), 7.01 (d, J = 3.0 Hz, 1H), 7.00-6.84 (m, 1H), 4.84 (d, J= 5.6 Hz, 2H), 4.64 (s, 1H), 3.74 (dd, J= 7.2 Hz, 11.5, 2H), 3.61-3.43 (m, 2H), 3.13 (dd, J= 5.9 Hz, 10.8 Hz, 2H), 2.94-2.80 (m, 3H), 2.74 (t, J = 14.4 Hz, 2H), 2.32-2.08 (m, 2H). MS (M+1) (ESI) m / z 366.44.

[0121] (S)-2-(3-aminopyrrolidin-1-yl)-6,6-difluoro-N-(thiophen-2-ylmethyl)-5, 6,7,8- tetrahydroquinazolin-4-amine (Example 9)

[0122] Yiled.65 mg, 28%.1H NMR (400 MHz, CDCI3) <5ppm 7.21 (d, J= 5.1 Hz, 1H), 7.01 (d, J = 3.3 Hz, 1H), 6.95 (dd, J= 3.6 Hz, 4.9, 1H), 4.85 (d, J= 5.6 Hz, 2H), 4.64 (d, J= 5.4 Hz, 1H), 3.86-3.68 (m, 2H), 3.63 (dt, J= 6.3 Hz, 11.6, 2H), 3.32 (dd, J= 4.8 Hz, 11.1, 1H), 2.83 (t, J = 6.8 Hz, 2H), 2.74 (t, J= 14.4 Hz, 2H), 2.19 (m, 2H), 1.86-1.57 (m, 2H). MS (M+1) (ESI) m / z 366.44.

[0123] (R)-6,6-difluoro-2-(3-(methylamino)pyrrolidin-1 -yl)-N-(thiophen-2-ylmethyl)-5, 6,7,8- tetrahydroquinazolin-4-amine (Example 10)

[0124] Yield: 40 m, 17%.1H NMR (400 MHz, CDCI3) 5 ppm 7.25-7.12 (m, 1H), 7.01 (d, J= 3.0 Hz, 1H), 6.95 (dd, J= 3.5 Hz, 5.0 Hz, 1H), 4.85 (d, J= 5.6 Hz, 2H), 4.61 (m, 1H), 3.82 (m, 1H), 3.72 (m, 1H), 3.60 (m, 1H), 3.44-3.21 (m, 2H), 2.83 (t, J= 6.8, 2H), 2.73 (t, J= 14.4, 2H), 2.49 (s, 3H), 2.19-2.17 (m, 3H), 1.81-1.78 (m, 1H). MS (M+1) (ESI) m / z 380.5.

[0125] (S)-6,6-difluoro-2-(3-(methylamino)pyrrolidin-1-yl)-N-(thiophen-2-ylmethyl)-5,6,7,8- tetrahydroquinazolin-4-amine (Example 11)

[0126] Yield: 63 mg, 26%.1H NMR (400 MHz, CDCI3) <5ppm 7.19 (d, J= 5.1 Hz, 1H), 7.00 (d, J = 2.6 H, 1H), 6.94 (dd, J= 3.7 Hz, 4.8 Hz, 1H), 4.84 (d, J= 5.6 Hz, 2H), 4.67 (t, J= 5.3 Hz, 1H), 3.81-3.79 (m, 1H), 3.77-3.65 (m, 1H), 3.58-3.55 (m, 1H), 3.39-3.36 (m, 1H), 3.35-3.15 (m, 1H), 2.82 (t, J= 6.8 Hz, 2H), 2.73 (t, J= 14.4 Hz, 2H), 2.47 (s, 3H), 2.18-2.16 (m, 3H), 1.81- 1.79 (m, 1H). MS (M+1) (ESI) m / z 380.5.

[0127] (R)-6,6-difluoro-2-(3-methylpiperazin-1-yl)-N-(thiophen-2-ylmethyl)-5, 6,7,8- tetrahydroquinazolin-4-amine (Example 12)

[0128] Yield: 49 mg, 20%.1H NMR (400 MHz, CDCI3) <5ppm 7.21 (d, J= 5.1 Hz, 1H), 7.00 (d, J = 2.9 Hz, 1H), 6.95 (dd, J= 3.6 Hz, 4.9 Hz, 1H), 4.82 (d, J= 5.7 Hz, 2H), 4.70-4.52 (m, 3H), 2.91-2.78 (m, 6H), 2.73 (t, J= 14.5 Hz, 2H), 2.49 (dd, J= 10.4 Hz, 12.7 Hz, 1H), 2.29-2.01 (m, 2H), 1.12 (d, J = 6.3, 3H). MS (M+1) (ESI) m / z 380.5.

[0129] (S)-6,6-difluoro-2-(3-methylpiperazin-1-yl)-N-(thiophen-2-ylmethyl)-5, 6,7,8- tetrahydroquinazolin-4-amine (Example 13)

[0130] Yield: 29 mg, 12%.1H NMR (400 MHz, CDCI3) 5 ppm 7.21 (d, J= 5.1 Hz, 1H), 7.00 (d, J = 3.3 Hz, 1H), 6.95 (dd, J= 3.7 Hz, 4.8 Hz, 1H), 4.83 (d, J= 5.6, 2H), 4.73-4.50 (m, 3H), 3.05 (d, J= 8.1 Hz, 1H), 2.92-2.78 (m, 5H), 2.73 (t, J= 14.4 Hz, 2H), 2.49 (dd, J= 10.4 Hz, 12.7 Hz, 1H), 2.28-1.99 (m, 2H), 1.12 (d, J=6.3, 3H). MS (M+1) (ESI) m / z 380.5.

[0131] 6,6-difluoro-2-(3-(methylamino)azetidin-1-yl)-N-(thiophen-2-ylmethyl)-5,6,7,8- tetrahydroquinazolin-4-amine (Example 14)

[0132] Yield: 37 mg, 32%.1H NMR (400 MHz, CDCI3) <5 ppm 7.24-7.13 (m, 1H), 7.00 (d, J = 3.2 Hz, 1 H), 6.94 (dd, J = 3.6 Hz, 4.9 Hz, 1H), 4.81 (s, 3H), 4.34-4.22 (m, 2H), 3.84 (dd, J = 4.9, 9.1, 2H), 3.65 (dd, J = 3.5, 8.4, 1 H), 2.83 (t, J = 6.8, 2H), 2.73 (t, J = 14.3, 2H), 2.44 (s, 3H), 2.31- 2.07 (m, 2H). MS (M+1) (ESI) m / z 365.4.

[0133] 6,6-difluoro-2-(4-methylpiperazin-1-yl)-N-((5-methylthiophen-2-yl)methyl)-5,6,7,8- tetrahydroquinazolin-4-amine (Example 15)

[0134] Yield: 70 mg, 85% from 0.494 mmol of the starting material.1H NMR (250 MHz, CDCI3) 5 ppm 6.77 (d, J = 3.3 Hz, 1 H), 6.58 (d, J = 2.3 Hz, 1 H), 4.72 (d, J = 5.5 Hz, 2H), 4.55 (d, J = 5.4 Hz, 1H), 3.89 (brs, 4H), 2.78 (dd, J = 10.6 and 17.3 Hz, 4H), 2.60-2.48 (m, 4H), 2.42 (m, 5H), 2.27-2.05 (m, 2H). MS (M+1) (ESI) m / z 394.5.

[0135] 6,6-difluoro-2-(4-methylpiperazin-1-yl)-N-((3-methylthiophen-2-yl)methyl)-5,6,7,8- tetrahydroquinazolin-4-amine (Example 16)

[0136] Yield: 94 mg, 38% from 0.361 mmol of the starting material.1H NMR (250 MHz, CDCh) 5 ppm 7.12 (d, J = 5.1 Hz, 1 H), 6.82 (d, J = 5.1 Hz, 1 H), 4.73 (d, J = 5.2 Hz, 2H), 4.39 (t, J = 5.0 Hz,1 H), 3.89 -3.76(m, 4H), 2.84-2.62(m, 4H), 2.52-2.41(m, 4H), 2.34 (s, 3H), 2.24 (s, 3H), 2.23-2.07 (m, 2H). MS (M+1) (ESI) m / z 394.5.

[0137] 5-(((6,6-difluoro-2-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-4- yl)amino)methyl)thiophene-2-carbonitrile (Example 17)

[0138] Yield: 30 mg, 15%, from 0.51 mmol of the starting material.1H NMR (250 MHz, CDCI3) 67.47 (d, J = 4.0 Hz, 1 H), 6.99 (d, J = 4.0 Hz, 1 H), 4.85 (m, 3H), 3.83-3.79 (m, 4H), 2.83-2.69 (m, 4H), 2.48-2.31 (m, 4H), 2.36 (s, 3H), 2.21-2.18 (m, 2H). MS (M+1) (ESI) m / z 405.48.

[0139] 6,6-difluoro-2-(4-methylpiperazin-1-yl)-N-(thiazol-2-ylmethyl)-5,6,7,8- tetrahydroquinazolin-4-amine (Example 18)

[0140] Yield: 11 mg, 13% yield, from 0.22 mmol of the starting material.1H NMR (250 MHz, CDCh) 5 ppm 7.69 (d, J = 3.3 Hz, 1H), 7.34-7.17 (m, 1H), 5.33 (t, J = 5.6 Hz, 1 H), 4.94 (d, J = 5.7 Hz, 2H), 3.87 - 3.72 (m, 4H), 2.86-2.67 (m, 4H), 2.50-2.39 (m, 4H), 2.33 (s, 3H), 2.18 (m, 2H). MS (M+1) (ESI) m / z 381 (M+1).

[0141] 6,6-difluoro-2-(4-methylpiperazin-1-yl)-N-(thiazol-5-ylmethyl)-5,6,7,8- tetrahydroquinazolin-4-amine (Example 19)

[0142] Yield: 303 mg, 97%, from 0.069 mmol of the starting material.1H NMR (250 MHz, CDCI3) 5 ppm 8.69 (s, 1H), 7.78 (s, 1 H), 4.86 (d, J = 5.7 Hz, 2H), 4.82-4.70 (m, 1H), 3.94-3.80 (m, 4H), 2.85-2.65 (m, 4H), 2.58-2.46 (m, 4H), 2.38 (s, 3H), 2.28-2.10 (m, 2H). MS (M+1) (ESI) m / z 381.

[0143] 6,6-difluoro-2-(4-methylpiperazin-1-yl)-N-(thiazol-4-ylmethyl)-5,6,7,8- tetrahydroquinazolin-4-amine (Example 20)

[0144] Yield: 30.3 mg, 97%.1H NMR (250 MHz, CDCI3) <5 ppm 8.78 (d, J = 1.9 Hz, 1 H), 7.19 (d, J = 1.2 Hz, 1 H), 5.03 (t, J = 5.1 Hz, 1 H), 4.79 (d, J = 5.3 Hz, 2H), 3.87-3.74 (m, 4H), 2.85-2.69 (m, 4H), 2.52-2.44 (m, 4H), 2.35 (s, 3H), 2.27-2.09 (m, 2H). MS (M+1) (ESI) m / z 381.

[0145] 6,6-difluoro-N-((5-methylfuran-2-yl)methyl)-2-(4-methylpiperazin-1-yl)-5,6,7,8- tetrahydroquinazolin-4-amine (Example 21)

[0146] Yield: 112 mg, 47% from 0.630 mmol of the starting material.1H NMR (250 MHz, CDCh) 5 ppm 6.10 (d, J = 3.0 Hz, 1H), 5.93-5.84 (m, 1 H), 4.56 (d, J = 4.9 Hz, 2H), 4.50 (d, J = 4.7 Hz, 1 H), 3.88 -3.74 (m, 4H), 2.84 -2.64 (m, 4H), 2.49 -2.39 (m, 4H), 2.30 (s, 3H), 2.27 (s, 3H), 2.24 -2.11 (m, 2H). MS (M+1) (ESI) m / z 378.44.

[0147] 5-(6, 6-difluoro-2-(4-methylpiperazin-1-yl)-5, 6,7, 8-tetrahydroquinazolin-4-yl)-4, 5,6,7- tetrahydrothieno[3,2-c]pyridine (Example 22)

[0148] Yield: 37 mg, 31%.1H NMR (250 MHz, CDCI3) <5 ppm 7.13 (d, J = 5.1 Hz, 1 H), 6.81 (d, J = 5.1 Hz, 1H), 4.41 (s, 2H), 4.01-3.85 (m, 4H), 3.58 (t, J = 5.6 Hz, 2H), 3.03 (t, J = 13.6 Hz, 4H), 2.88 (t, J = 7.1 Hz, 2H), 2.73 - 2.58 (m, 4H), 2.47 (s, 3H), 2.34-2.14 (m, 2H). MS (M+1) (ESI) m / z 406.

[0149] 6-(6,6-difluoro-2-(4-methylpiperazin-1 -yl)-5, 6,7, 8-tetrahydroquinazolin-4-yl)-4, 5,6,7- tetrahydrothieno[2,3-c]pyridine (Example 23)

[0150] Yield: 183 mg, 84%.1H NMR (250 MHz, CDCI3) 6 ppm 7.13 (d, J = 5.1 Hz, 1 H), 6.82 (d, J = 5.1 Hz, 1H), 4.54 (s, 2H), 3.87-3.74 (m, 4H), 3.51 (t, J = 5.6, 2H), 3.02 (t, J = 13.7, 2H), 2.88 (dd, J = 5.3 and 8.8, 4H), 2.51-2.39 (m, 4H), 2.34 (s, 3H), 2.29-2.08 (m, 2H). MS (M+1) (ESI) m / z 406.

[0151] 5-(6,6-difluoro-2-(4-methylpiperazin-1-yl)-5, 6,7, 8-tetrahydroquinazolin-4-yl)-4, 5,6,7- tetrahydrofuro[3,2-c]pyridine (Example 24)

[0152] Yield: 21 mg, 31%.1H NMR (250 MHz, CDCI3) 6 ppm 7.30 (d, J = 1.6 Hz, 1 H), 6.28 (d, J = 1.7Hz , 1H), 4.36 (s, 2H), 3.85-3.76 (m, 4H), 3.45 (t, J = 5.5 Hz , 2H), 3.00 (t, J = 13.7 Hz, 2H), 2.88 (t, J = 7.1 Hz, 2H), 2.68 (t, J = 5.3 Hz, 2H), 2.54-2.46 (m, 4H), 2.36 (s, 3H), 2.32- 3.15 (m, 2H). MS (M+1) (ESI) m / z 390.

[0153] 2-(piperazin-1-yl)-N-(thiophen-2-ylmethyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- amine (Example 25)

[0154] Yield: 77 mg, 23%.1H NMR (250 MHz, CDCI3) 67.21 (d, J = 4.0 Hz, 1 H), 7.01 (se, 1H), 6.96 (d, J = 4.0 Hz, 1 H), 4.83 (d, J = 5.6 Hz, 2H), 4.6 (m, 1 H), 3.84 (m, 4H), 2.95 (m, 4H), 2.76 (m, 2H), 2.54 (m, 2H), 2.04 (m, 2H). MS (M+1) (ESI) m / z 316.15.

[0155] 2-(piperazin-1-yl)-N-(thiophen-2-ylmethyl)-5,6,7,8-tetrahydroquinazolin-4-amine

[0156] (Example 26)

[0157] 2-(piperazin-1 -yl)-A / -(thiophen-2-ylmethyl)- 5,6,7,8-tetrahydroquinazolin-4-amine

[0158] Yield: 20 mg, 17%.1H NMR (400 MHz, CDCI3) <5 ppm 7.18 (d, J = 5.1 Hz, 1 H), 7.01-6.82 (m, 2H), 4.81 (d, J = 5.6 Hz, 2H), 4.72-4.70 (m, 1H), 3.82-3.62 (m, 4H), 2.91 (s, 4H), 2.56-2.50 (m, 4H), 1.84-1.60 (m, 4H). MS (M+1) (ESI) m / z 330.17.

[0159] Examples 1-26 were evaluated for their ability to bind the human H4R and H1 R. Compounds displayed binding affinities between 1-10 micomolar, designated as affinity class “A”, or below 1 micromolar, designated as affinity class “B”. The affinity of Examples 1-26 at the human H4R and H1R can be measured in a radioligand displacement or binding assay.

[0160] Typical radioligand displacement studies at the human H4 receptor [3H]histamine binding assay

[0161] Affinity of ligands (expressed as Ki or pKi) for the H4R receptor can be determined in a radioligand binding assay. The [3H]histamine binding assay is performed using the human histamine H4 receptor (hH4R) transiently expressed in HEK 293T cells. The assay challenges the binding of approximately 9 nM [3H]histamine to the hH4R with 8 different concentrations (ranging from 10'11M to 10'4M) of unlabelled test compound. The assay is performed using 96 well-plates and in 50 mM Tris-HCI buffer (pH 7.4), to a total volume of 200 pL. The reactions are incubated at room temperature (~22°C) for 1 hour and terminated by filtration on 96-well GF / C plates (PerkinElmer) pretreated with 0.5% polyethyleneimine (PEI), followed by three washes (300 pL each time) with ice-cold 50 mM Tris-HCI buffer containing 150 mM NaCI (pH 7.4, 4°C). To each well of the dried plates is added 25 pL of MicroScint (PerkinElmer) and the residual radioactivity is counted in a Trilux 10 Microbeta counter (PerkinElmer). These data are analyzed with Prism (Prism Graphpad 6.0) to determine the Ki or pKi values of the test compounds.

[0162] Typical [3H] pyrilamine binding assay for the human Hi receptor

[0163] This assay follows the same protocol as above except that test compounds challenge the binding of approximately 1 nM [3H] pyrilamine in a buffer containing 50 mM Na / K-phosphate (pH 7.4). The reactions are incubated for 2 hours and terminated by filtration on pre-treated 96-well GF / B plates (PerkinElmer). Results for the compounds tested in this assay are presented in Table 1.

[0164] Table 1 Compounds are also evaluated for their intrinsic activity (a value / pECso) and antagonism against 100nM histamine (pICso / pKb). This is done at the human H4 receptor using a [35S]GTPyS binding assay and at the human Hi receptor using an NFAT-Luciferase assay.

[0165] Typical [35S] GTPyS functional assay for the human H4 receptor The activity of the human H4 receptor is measured as accumulation of [35S]GTPyS binding to Gai proteins, using receptors transiently expressed in HEK 293T cells. The intrinsic activity of a compound at the human H4 receptor can be agonistic, neutral antagonistic, or inverse agonistic. Histamine is used as the reference agonist and thioperamide as the inverse agonist. Each compound is tested at eight concentrations (10-11M to 10'4M) in a buffer containing 20 mM HEPES, 150 mM NaCI, 10 mM MgCh, 1 pM GDP, 0.01 mg / ml saponin (pH 7.4 at room temperature) and 0.1 nM [35S]GTPyS. The reactions are performed in 96-well plates in a total volume of 200 pl and are incubated for 1 hour at room temperature (22°C) and then harvested on 96-well GF / B plates (Perkin-Elmer). Plates are then washed three times using ice-cold buffer containing 50 mM Tris-HCI and 150 mM NaCI (pH 7.4 at 4°C). The radioactivity retained on the filters was measured by liquid scintillation counting in a Microbeta counter (Perkin-Elmer). Compounds are tested for antagonism at the human H4 receptor by performing the assay in the presence of 100nM histamine and using thioperamide as the reference antagonist

[0166] Typical NFAT-Luciferase functional assay for the human Hi receptor

[0167] In this assay the activity of the human H1 receptor is measured by the extent to which it triggers NFAT-mediated transcription of a luciferase reporter gene. The human H1 receptor and an NFAT-Luc reporter vector are transiently expressed in HEK 293T cells. Transfected cells are plated at 4x105 / well and after an overnight incubation are stimulated with the test compounds diluted to eight concentrations (10-11M to 10'4M) for a period of 4-6 hours. The assay is performed in poly-L-lysine coated 96 well plates in a final volume of 200ul of Dulbecco’s Modified Eagle’s Medium supplemented with 1% Penicillin / Streptomyocin and 5% Fetal Bovine Serum. Incubations are carried out at 37°C and 5%CO2.

[0168] Luciferase activity is measured following the addition of 25ul / well of Luciferase Assay Reagent (LAR) containing 0.23mg / ml D-Luciferine (Duchefa) in a VICTORS counter (Perkin Elmer). As for the GTPyS assay, intrinsic activity of compounds is measured in the absence of histamine and antagonism in the presence of 100nM histamine.

[0169] Data analysis

[0170] The pharmacological values (EC50 and IC50) of the test compounds were calculated using non-linear regression (Graphpad Prism 6.0, Graphpad Software, Inc., CA, USA). The Kd of histamine used for Kb calculations at the mouse and guinea pig H4R are 78 and 11nM, respectively. Kb is a parameter suggested for estimation of affinity of a compound from a pharmacological blocking experiment (Neubig et al., 2003), it is calculated according to the Cheng-Prusoff equation (Cheng and Prusoff, 1973). Standard errors of the mean (SEM) were determined by dividing the standard deviation by the square root of the number of experiments.

Claims

CLAIMS1. A compound of formula (I):or a prodrug, metabolite, or pharmaceutically acceptable salt or ester thereof; wherein:Y is CRgor N;Ri isRe, R7 and Rs are independently selected from H, C1-4 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-4 alkoxy, C1-4 alkylthio, (CH2)o-3C3-7cycloalkyl, aryl, C1-4 alkyl-aryl and heteroaryl; R9 is H, halogen or C1-C5 alkyl;R2, and R3 are independently selected from H, CM alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-4 alkoxy, C1-4 alkylthio, (CH2)o-3C3-7cycloalkyl, aryl, C1-4 alkyl-aryl, CF3, cyano, heteroaryl, Ci- 04 alkyl-heteroaryl, Ci-C4 alkyl-heteroaryl or R2 and R3 taken together with the attached C- atoms form a 3-6 membered cycloalkyl ring;AR iswherein Xa is O or S; wherein Za is CRc or N; wherein Zb is CRb or N; wherein Ra, Rb, Rc and Rd are each independently selected from H, halogen, C1-4 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-4 alkoxy, C1-4 alkylthio, (CH2)o-3C3-7cycloalkyl, aryl, heteroaryl, C1-4 alkyl-aryl, cyano, heteroaryl, C1-C4 alkyl-heteroaryl or Ra and Rb, or Rb and Rc taken together with the attached C atoms form a 5-7 membered cycloalkyl ring, a 5-6 membered aryl ring, a 5-6 membered heteroaryl ring or a 4 to 8 membered nonaromatic heterocyclic group, one or more substituents independently selected from C1- ealkyl, (CH2)O-3C3-7 cycloalkyl, alkoxyalkyl containing 2 to 8 carbon atoms, C1-C4 alkyl- heteroaryl, Ci-4alkylOCF3, (CH2)i-4aryl and C1-6 hydroxyalkyl, or Rc and R19 or Rd and R19 taken together areto^orm ag memberedrjng;is one of the structures shown below:wherein Rn, R12, 13, 14, R15, 16, R17 and R18 are independently selected from H, F, OH, C1-4 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-4 alkoxy, C1-4 alkylthio, (CH2)o-3C3-7cycloalkyl, O- C3-6 cycloalkyl, aryl, NH-Ci-Ce acyl, O-aryl, NH-aryl, S-aryl, O-C1-4 alkyl-aryl, C1-4 alkyl-aryl, CF3, O-CF3, S-CF3, hydroxy, O-C1-4 alkyl-N(CH3)2, heteroaryl, O-heteroaryl, NH-heteroaryl, S-heteroaryl, C1-C4 alkyl-heteroaryl, Ci-C4 alkyl-heteroaryl and NRmRn, wherein Rm and Rn are independently selected from H, C1-4 alkyl, aryl and phenethyl; wherein any alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic group can independently be optionally substituted with one or more substituents selected from halogen, C1-6 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-4 alkoxy, Ci- alkylthio, (6^)0-3 3-7 cycloalkyl, O-C3-6 cycloalkyl, aryl, O-aryl, NH-aryl, S-aryl, O-C1-4 alkyl-aryl, 61-4 alkyl-aryl, CF3, S-CF3, hydroxy, nitro amino, cyano and O-C1-4 alkyl-N(CH3)2; C2-C8 alkoxyalkyl, (CH2)o-4 alkylheteroaryl; (CH2)o- 4O-CF3, Ci-Ce hydroxyalkyl; n is 1 , 2 or 3; m is 0, 1 or 2;R19 is H or is taken together with Rc or Rd as set out above; andX is O, S, NRe, S(O), C(O), S(O)2 or a direct bond, wherein the term “aryl” includes any functional group or substituent comprising an aromatic ring and from 5 to 10 ring atoms, wherein the term “cycloalkyl” includes saturated or partially saturated, monocyclic, fused polycyclic, bridged or spiro polycyclic carbocycles having from 3 to 7 ring atoms per carbocycle.

2. A compound according to claim 1 , wherein R1 is selected from structures R, J, K, B, C and F.

3. A compound according to claim 1 or claim 2, wherein Re, R7, Rs, R3 and / or R2 are each independently selected from C1-C4 alkyl, C1-C4 alkylaryl or H.

4. A compound according to any preceding claim, whereinis:

5. A compound according to any preceding claim, wherein R13 and / or R14 is independently selected from a halogen, preferably F.

6. A compound according to any preceding claim, wherein Rn, R12, R15, R16, R17 and / or Ris is H.

7. A compound according to any preceding claim, wherein R2 and / or R3 is H.

8. A compound according to any preceding claim, wherein AR is:

9. A compound according to any preceding claim, wherein Ra, Rb, Rcand / or Rd is H.

10. A compound according to any preceding claim, wherein Y is N.

11. A compound according to claims 4 - 10.

12. A compound according to any preceding claim, which is a compound exemplified herein.

13. A pharmaceutical composition comprising a compound according to any preceding claim and a pharmaceutically acceptable excipient.

14. A compound according to any preceding claim, for use in therapy.

15. A compound according to any preceding claim, for use in the treatment of inflammatory disorders, allergic disorders, dermatological disorders, autoimmune disease, lymphatic disorders, and immunodeficiency disorders, preferably wherein the condition is selected from allergy, asthma, dry eye, chronic obstructive pulmonary disease (COPD), atherosclerosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases (including colitis, Crohn's disease, and ulcerative colitis), psoriasis, pruritis, itchy skin, atopic dermatitis, urticaria (hives), ocular inflammation (e.g., post-surgical ocular inflammation), (allergic) conjunctivitis, dry eye, nasal polyps, allergic rhinitis, nasal itch, scleroderma, autoimmune thyroid diseases, immune-mediated (also known as type 1) diabetes mellitus, lupus, myasthenia gravis, autoimmune neuropathies, such as Guillain-Barre, autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, anti-phospholipid syndrome, vasculitides, such as Wegener's granulomatosis, Behcet's disease, dermatitis herpetiformis, pemphigus vulgaris, vitiligio, primary biliary cirrhosis, autoimmune hepatitis, autoimmune oophoritis and orchitis, autoimmune disease of the adrenal gland, polymyositis, dermatomyositis, spondyloarthropathies, such as ankylosing spondylitis, Sjogren's syndrome, allergic asthma, atopic dermatitis, pruritus or rheumatoid arthritis.

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