Heteroaromatic carboxamide derivatives as plasma kallikrein inhibitors

Abstract

The present invention relates to heteroaromatic carboxamides of formula (I), wherein Y, R and Ar are as defined in the specification and claims, and pharmaceutically acceptable salts thereof, which can be used in methods for treating diseases that may be affected by the inhibition of plasma kallikrein.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202180011395.3, invention name “Heteroaromatic carboxamide derivatives as plasma kallikrein inhibitors” and filing date February 11, 2021. [Technical field]

[0002] The present invention relates to novel heteroaromatic carboxamide derivatives and pharmaceutically acceptable salts thereof as plasma kallikrein inhibitors. In addition, the present invention relates to intermediates for the synthesis of said compounds, to pharmaceutical compositions and combinations comprising said compounds and to their use in methods for treating diseases that may be affected by the inhibition of plasma kallikrein. In particular, the pharmaceutical compositions of the present invention are suitable for preventing and / or treating diabetic complications, eye diseases and edema-related diseases, in particular diabetic macular edema, age-related macular degeneration, choroidal neovascularization, hereditary angioedema and brain edema after stroke.

[0003] [Prior Art]

[0004] Plasma kallikrein (PKK) is a trypsin-like serine protease secreted by hepatocytes in the liver as an inactive plasma kallikrein that circulates in plasma as a free zymogen or as a heterodimeric complex bound to a high molecular weight kininogen that is activated to generate active PKK, which can release kinins from the kininogen in addition to processing other substrates. Kinins are potent mediators of inflammation acting via G protein-coupled receptors such as the bradykinin receptor.

[0005] PKK is believed to play a role in a variety of inflammatory disorders and may have a number of influences in disorders such as hereditary angioedema (HAE), retinopathy or diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), clinically significant macular edema (CSME), cystoid macular edema (CME), CME after cataract extraction, CME induced by cryotherapy, CME induced by uveitis, endophthalmitis, CME after vascular occlusion (e.g., central retinal vein occlusion, branch retinal vein occlusion, or hemi-retinal vein occlusion), retinal edema, complications associated with cataract surgery in diabetic retinopathy, hypertensive retinopathy, retinal trauma, dry and wet age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV), choroidal neovascularization (CNV;choroidal neovascularization, such as non-exudative), posterior vitreous detachment (PVD), ischemic reperfusion injury in all kinds of situations, such as those associated with tissue and / or organ transplantation, surgery-induced brain injury, focal cerebral ischemia, global cerebral ischemia, glioma-related edema, spinal cord injury, pain, ischemia, cerebral ischemia, neurological and cognitive deficits, deep vein thrombosis, stroke (including edema of the central nervous system after stroke), myocardial infarction, acquired angioedema, drug-related edema (including ACE-inhibitor edema), inhibitor-induced edema, and tissue plasminogen activator (tPA)-induced edema. vasogenic edema), high altitude cerebral edema, cytotoxic cerebral edema, osmotic cerebral edema, obstructive hydrocephalus, radiation-induced edema, lymphedema, traumatic brain injury, hemorrhagic stroke (e.g., cerebral stroke or subarachnoid stroke), intracerebral hemorrhage, hemorrhagic transformation of ischemic stroke, brain trauma associated with injury or surgery, cerebral aneurysm, arteriovenous malformation, reduction of blood loss during surgical procedures (e.g., cardiothoracic surgery such as cardiopulmonary bypass or coronary artery bypass graft), itch, disorders with an inflammatory component (such as multiple sclerosis), epilepsy, encephalitis, Alzheimer's disease disease), excessive daytime sleepiness, essential hypertension, increased blood pressure associated with diabetes or hyperlipidemia, renal failure, chronic kidney disease, heart failure, microalbuminuria, albuminuria, proteinuria, conditions associated with increased vascular permeability (e.g., increased retinal vascular permeability, increased vascular permeability of the legs, feet, ankles), cerebral hemorrhage, blood clotting disorders such as thrombosis, deep vein thrombosis, coagulation after fibrinolytic therapy, angina, angioedema, sepsis, arthritis (e.g., rheumatoid arthritis, osteoarthritis, infectious arthritis), lupus, gout, psoriasis, inflammatory bowel disease (IBD, such as ulcerative colitis (UC) and Crohn's disease (CD)), diabetes, diabetic complications, complications caused by metabolic syndrome, infectious diseases, diseases associated with astrocyte activation (e.g., Alzheimer's disease or multiple sclerosis), Parkinson's disease (Parkinson's disease), amyotrophic lateral sclerosis, Creutzfeld-Jacob disease, stroke, epilepsy and trauma (e.g., brain trauma), allergic edema such as airflow obstruction in long-term allergic sinusitis or perennial rhinitis; airflow obstruction in acute asthma; serositis associated with systemic lupus erythematosus (SLE), acute respiratory distress syndrome (ARDS), pneumonia associated with coronavirus disease 2019 (COVID-19), fibrotic diseases, liver fibrosis, non-alcoholic steatohepatitis (NASH), renal injury and other diseases. PKK is also believed to play an important role in hypersensitivity reactions and thrombosis during hemodialysis. ;

[0006] PKK inhibitors, such as the compounds of the present invention, are considered useful in treating a wide range of disorders, such as those mentioned above; in particular, they should have therapeutic utility in reducing retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema or edema-related diseases.

[0007] PKK inhibitors are particularly useful for treating edema formation in diseases, such as edema formation associated with ischemic reperfusion injury, retinopathy, or edema-related diseases, such as hereditary angioedema, macular edema, and cerebral edema. PKK inhibitors are considered particularly useful for treating retinopathy, such as retinopathy associated with diabetes and / or hypertension, and for treating macular edema, such as macular edema associated with diabetes and / or hypertension.

[0008] Other diabetic complications such as cerebral hemorrhage, nephropathy, cardiomyopathy and neuropathy, all of which are linked to PKK, may also be considered targets for PKK inhibitors.

[0009] PKK inhibitors suitable for therapeutic and / or prophylactic use should bind to PKK potently and with high selectivity. They should be well absorbed by the gastrointestinal tract, have sufficient metabolic stability and have favorable pharmacokinetic properties. They should be non-toxic and exhibit few side effects.

[0010] Low molecular weight PKK inhibitors are known in the art, for example the compounds disclosed in WO 2009 / 097141, WO 2013 / 111107, WO 2013 / 111108, WO 2014 / 188211, WO 2017 / 072020, WO 2017 / 072021 and WO 2018 / 192866. [Summary of the invention]

[0011] In a first aspect, the present invention relates to a compound of formula (I)

[0012]

[0013] in

[0014] Y is selected from the group Y-G1 consisting of:

[0015]

[0016] Each of which is independently substituted by 1 or 2 groups R 1 replace;

[0017] R is selected from the group R-G1 consisting of:

[0018] a saturated 6- to 12-membered bicyclic ring system containing as ring members 1 to 2 N atoms and an optional 1 ring member selected from the group consisting of C═O, O, S, S═O and SO2,

[0019] The proviso is that the ring system does not contain any heteroatom-heteroatom bonds between the ring members,

[0020] wherein the ring system is connected to the group Y in formula (I) via the N atom, and

[0021] wherein the ring system is optionally substituted with 1 to 6 F and optionally substituted with 1 to 3 selected from C 1-3 Alkyl, CN, HO-C 1-3 Alkylene, OH and C 1-3 Substitution by substituents of the group consisting of alkyl-O;

[0022] Ar is selected from the group consisting of Ar-G1:

[0023] 5-membered heteroaryl containing 1 to 4 N atoms or containing 1 O or S atom or containing 1 to 2 N atoms and 1 O or S atom; and 9-membered heteroaryl consisting of a 5-membered ring fused to a 6-membered ring and containing 1 to 4 N atoms,

[0024] wherein the heteroaryl group is connected to the carbonyl group in formula (I) via a C atom of the 5-membered ring and is connected to the CH2 group in formula (I) via a non-adjacent C or N atom of the 5-membered ring, and

[0025] wherein the heteroaryl group is optionally substituted by 1 substituent R 3 replace;

[0026] R 1 is selected from the group R consisting of 1 -G1:

[0027] H, halogen, C optionally substituted with 1 to 5 F 1-4 alkyl, C optionally substituted with 1 CH3, CN or OH group 3-4 Cycloalkyl, CN, OC optionally substituted with 1 to 5 F 1-3 Alkyl, optionally selected from CN, OH and OC 1-3 A C substituted with one substituent of a group consisting of an alkyl group 1-3 alkyl;

[0028] R 3 is selected from the group R consisting of 3 -G1:

[0029] F, Cl, Br, CN, C optionally substituted with 1 to 5 F 1-4 Alkyl, C 3-4 Cycloalkyl, HO-C1-4 Alkylene, C 1-3 Alkyl-OC 1-3 alkylene and OC optionally substituted with 1 to 5 F 1-4 alkyl;

[0030] Wherein, in any of the definitions mentioned above and if not otherwise specified, any alkyl or alkylene group or substituent group may be straight chain or branched,

[0031] Its isomers, tautomers, stereoisomers, metabolites, prodrugs, solvates, hydrates, co-crystals and salts, in particular its pharmaceutically acceptable co-crystals and salts, or combinations thereof.

[0032] In a second aspect, the present invention relates to a pharmaceutical composition comprising one or more compounds of formula (I) and / or tautomers thereof or pharmaceutically acceptable salts thereof as defined above or below, optionally together with one or more inert carriers and / or diluents.

[0033] In a third aspect, the present invention relates to a pharmaceutical composition comprising one or more compounds of formula (I) and / or tautomers thereof or pharmaceutically acceptable salts thereof as defined above or below and one or more additional therapeutic agents, optionally together with one or more inert carriers and / or diluents.

[0034] In a fourth aspect, the present invention relates to a compound of formula (I) and / or a tautomer thereof or a pharmaceutically acceptable salt thereof as defined above or below for use as a medicament.

[0035] In a fifth aspect, the present invention relates to a method for the treatment, i.e. therapy and / or prevention of a disease or condition that may be affected by the inhibition of plasma kallikrein in a patient in need thereof, the method comprising administering to the patient one or more compounds of formula (I) and / or their tautomers or pharmaceutically acceptable salts thereof as defined above or below.

[0036] Furthermore, the present invention relates to the use of one or more compounds of formula (I) as defined above or below and / or their tautomers or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment, i.e. therapy and / or prevention of diseases or conditions that may be affected by the inhibition of plasma kallikrein.

[0037] Furthermore, the present invention relates to compounds of formula (I) and / or their tautomers or pharmaceutically acceptable salts thereof as defined above or below for use in a method for the treatment, i.e. therapy and / or prevention of a disease or condition that may be affected by the inhibition of plasma kallikrein in a patient in need thereof.

[0038] In a sixth aspect, the present invention relates to one or more compounds selected from the group consisting of:

[0039]

[0040] or its salts

[0041] It is a valuable intermediate in the synthesis of compounds of formula (I).

[0042] Other aspects of the present invention will become apparent to those skilled in the art directly from the foregoing and following descriptions and examples.

[0043] General Terms and Definitions

[0044] Terms not specifically defined herein should be given the meanings that those skilled in the art would give them based on the invention and context. However, as used in this specification, unless otherwise indicated, the following terms have the designated meanings and will follow the following conventions.

[0045] The terms "compound(s) according to this invention / compound(s) of the invention", "compound(s) of formula (I)" and similar forms refer to the compound(s) of formula (I) of the present invention, including its tautomers, stereoisomers and mixtures thereof, and salts thereof (in particular, pharmaceutically acceptable salts thereof), and solvates, hydrates and co-crystals of the compound (in particular, pharmaceutically acceptable co-crystals thereof, including solvates, hydrates and co-crystals of its tautomers, stereoisomers and salts thereof).

[0046] Furthermore, unless specifically indicated otherwise, throughout this specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereoisomers, optical isomers and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and racemates thereof, as well as mixtures of individual enantiomers in varying proportions, diastereomeric mixtures, or mixtures in which any of the aforementioned forms of said isomers and enantiomers is present, as well as salts thereof (including pharmaceutically acceptable salts thereof) and solvates (such as hydrates, including solvates of free compounds or solvates of salts of said compounds) and co-crystals thereof (including pharmaceutically acceptable co-crystals thereof and co-crystals of free compounds or their salts).

[0047] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0048] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by preparing acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

[0049] For example, such salts include those formed from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid.

[0050] Pharmaceutically acceptable salts of the present invention can be synthesized by the parent compound containing basic or acidic moieties by conventional chemical methods. Generally speaking, the salt can be prepared by reacting the free acid or free base form of these compounds with a sufficient amount of a suitable base or acid in water or in an organic diluent, such as ether, EtOAc, EtOH, isopropanol or MeCN or a mixture thereof.

[0051] Salts of acids other than those mentioned above, such as trifluoroacetate salts, which are useful, for example, in purifying or isolating the compounds of the invention, also comprise part of the invention.

[0052] As used herein, "pharmaceutically acceptable co-crystals" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making co-crystals thereof with the aid of one or more conformational isomers. In addition, co-crystals of solvates and / or salts of the disclosed compounds are contemplated.

[0053] For example, conformational isomers include hydrogen bond donors such as carboxylic acids and hydrogen bond acceptors such as amines and amides.

[0054] The pharmaceutically acceptable co-crystals of the present invention can be synthesized from the parent compounds by methods known to those skilled in the art, including solid-based methods such as solid state grinding, melt extrusion and melt crystallization and liquid-based methods such as solution crystallization, solvent evaporation, cooling crystallization, supercritical fluid-assisted crystallization, ultrasound-assisted crystallization, spray drying, liquid-assisted grinding and orbital milling.

[0055] Where compounds of the invention are depicted in terms of chemical name and chemical formula, if there is any inconsistency, the chemical formula shall prevail.

[0056] In the groups, radicals or moieties defined below, the number of carbon atoms is usually indicated before the group, e.g. 1-6 The alkyl group refers to an alkyl group having 1 to 6 carbon atoms.

[0057] An asterisk may be used in a subformula to indicate a bond to a core molecule as defined. In the event that there is more than one point of attachment, ie more than one asterisk, in a subformula, the asterisk may be further specified by a bracketed identification of the attachment portion of the core molecule.

[0058] The numbering of substituent atoms begins with the atom closest to the core or group to which the substituent is attached.

[0059] For example, the term "3-carboxypropyl-group" represents the following substituent:

[0060]

[0061] wherein the carboxyl group is attached to the third carbon atom of the propyl group. The term "1-methylpropyl-", "2,2-dimethylpropyl-" or "cyclopropylmethyl-" group refers to the following groups:

[0062]

[0063] The term "substitution" as used herein means that any one or more hydrogens on a designated atom, group or moiety is replaced with a selection from the designated group, provided that the normal valence of the atom is not exceeded and that the substitution results in an acceptable stable compound.

[0064] In the definition of a group, the term "wherein each X, Y and Z group is optionally substituted" and the like means that each group X, each group Y and each group Z, each as an independent group or each as part of a constituent group, may be substituted as defined. For example, in the definition "R ex Indicates H, C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl or C 1-3 Alkyl-O-, wherein each alkyl group is optionally substituted with one or more L ex substituted." or the like means that in each of the foregoing groups containing the term alkyl (i.e., in the group C 1-3 Alkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and C 1-3 In each of the alkyl-O-, the alkyl portion may be as defined by L ex replace.

[0065] The term "C" alone or in combination with another group wherein n is an integer from 1 to n 1-n "Alkyl" refers to a non-cyclic saturated branched or straight chain hydrocarbon group having 1 to n C atoms. For example, the term C 1-5Alkyl includes the groups H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[0066] The term "C" alone or in combination with another group wherein n is an integer selected from 2, 3, 4, 5 or 6, preferably 4 or 6. 1-n "Alkylene" refers to a non-cyclic straight or branched divalent alkyl group containing 1 to n carbon atoms. For example, the term C 1-4 Alkylene groups include -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH 3)-CH2-, -CH2-CH(CH3)-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH(CH3)-, -CH(CH3)-CH2-CH2 -, -CH2-CH(CH3)-CH2-, -CH2-C(CH3)2-, -C(CH3)2-CH2-, -CH(CH3)-CH(CH3)-, -CH2-CH( CH2CH3)-, -CH(CH2CH3)-CH2-, -CH(CH2CH2CH3)-, -CH(CH(CH3))2-, and -C(CH3)(CH2CH3)-.

[0067] The term "C" alone or in combination with another group wherein n is an integer from 3 to n 3-n "Cycloalkyl" refers to a cyclic, saturated, non-branched hydrocarbon radical having 3 to n C atoms. The cyclic radical may be mono-, bi-, tri- or spirocyclic, preferably monocyclic. Examples of the cycloalkyl radical include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1.]octyl, spiro[4.5]decyl, norpinyl, norbornyl, norcarboxyl, adamantyl, and the like.

[0068] The term "heteroaryl" refers to a group containing a radical selected from N, O or S(O) rA monocyclic or polycyclic aromatic ring system containing one or more heteroatoms, wherein r = 0, 1 or 2, and the monocyclic or polycyclic aromatic ring system is composed of 5 to 14 ring atoms, wherein at least one of the heteroatoms is part of an aromatic ring. The term "heteroaryl" is intended to include all possible isomeric forms.

[0069] Thus, the term "heteroaryl" includes the following exemplary structures; each form is not depicted as a radical as it is optionally attached to any atom via a covalent bond, as long as proper valence is maintained:

[0070]

[0071] The term "bicyclic ring system" refers to a group composed of two joined cyclic substructures including spiro, fused and bridged ring systems.

[0072] The term halogen generally refers to fluorine, chlorine, bromine and iodine.

[0073] Several of the terms given above may be used repeatedly to define a formula or a group and in each case independently of one another have one of the meanings given above.

[0074] The terms "treatment" or "treating" as used herein encompass both therapeutic (ie, curative and / or palliative) treatment and preventative (ie, prophylactic) treatment.

[0075] Therapeutic treatment refers to the treatment of a patient already suffering from one or more of the conditions described in an apparent acute or chronic form. Therapeutic treatment may be symptomatic treatment in order to relieve the symptoms of a particular indication, or may be causal treatment in order to reverse or partially reverse the condition of the indication or in order to arrest or slow disease progression.

[0076] Prophylactic treatment ("prevention") refers to treatment of a patient at risk of developing one or more of the described symptoms prior to the clinical onset of the disease in order to reduce that risk.

[0077] The terms "treatment" or "treating" include the administration of one or more active compounds to prevent or delay the onset of symptoms or complications, and to prevent or delay the onset of a disease, symptom or disorder, and / or to eliminate or control a disease, symptom or disorder, and to alleviate symptoms or complications associated with a disease, symptom or disorder.

[0078] When the present invention refers to a patient in need of treatment, it is primarily concerned with treatment in mammals, especially humans.

[0079] The term "therapeutically effective amount" refers to the amount of a compound of the invention that (i) treats or prevents a specific disease or condition, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease or condition, or (iii) prevents or delays the onset of one or more symptoms of a specific disease or condition as described herein. [Implementation Method]

[0080] Disclosed are novel heteroaromatic carboxamide derivatives which are potent plasma kallikrein (PKK) inhibitors and possess suitable pharmacological and pharmacokinetic properties to enable their use as agents for the treatment of diseases and / or conditions that may be affected by PKK inhibition, including but not limited to diabetic complications, ocular diseases and edema-related diseases, in particular diabetic macular edema, age-related macular degeneration, choroidal neovascularization, hereditary angioedema and cerebral edema following stroke.

[0081] The compounds of the present invention may offer several advantages, such as enhanced potency, high metabolic and / or chemical stability, high selectivity, safety and tolerability, enhanced solubility, enhanced permeability, desirable plasma protein binding, enhanced bioavailability, improved pharmacokinetic profile and the possibility of forming stable salts.

[0082] Compounds of the present invention

[0083] In a first aspect of the present invention, compounds of formula (I) were found to be potent PKK inhibitors.

[0084]

[0085] wherein Y, R and X are as defined above and below, and the compounds of formula (I) exhibit favorable properties with respect to selectivity, safety and tolerability, metabolic and / or chemical stability, pharmacokinetic and physicochemical characteristics, solubility, permeability, plasma protein binding, bioavailability and / or the possibility of stable salt formation. Specifically, they provide an advantageous combination of high potency against human PKK and significant selectivity, for example, versus a variety of serine proteases, such as human tissue kallikrein 1 (TK1), as well as appropriate solubility and high metabolic stability at physiologically relevant pH values. In addition, favorable safety features such as low mutagenic potential and low mechanism-based cytochrome P450 3A4 inhibition tendency, low inhibition of cytochrome P450 (CYP) enzymes such as CYP3A4 and CYP2C8, and low mechanism-based CYP3A4 inhibition tendency are exhibited.

[0086] Therefore, it is expected that the compounds of formula (I) or pharmaceutically acceptable salts thereof as defined above or below are useful in the treatment of diseases and / or conditions which may be affected by PKK inhibition.

[0087] Therefore, according to one aspect of the present invention, there is provided a compound of formula (I)

[0088]

[0089] wherein Y, R and X are as defined above or below,

[0090] and isomers, tautomers, stereoisomers, metabolites, prodrugs, solvates, hydrates, co-crystals and salts thereof, in particular pharmaceutically acceptable co-crystals and salts thereof.

[0091] Unless otherwise stated, groups, residues and substituents, particularly Y, R, Ar, R 1 and R 3 As defined above and below. 1 and R 3 As well as some preferred meanings of the stereochemistry of the compounds of formula (I) as embodiments of the present invention. Any and each of these definitions and embodiments can be combined with each other.

[0092] Y:

[0093] According to one embodiment, Y is selected from the group Y-G1 consisting of:

[0094]

[0095] Each of which is independently substituted by 1 or 2 groups R 1 replace.

[0096] According to another embodiment, Y is selected from the group Y-G2 consisting of:

[0097]

[0098] Each of which is independently substituted by 1 or 2 groups R 1 Replace, and

[0099] The bonds with an asterisk therein indicate the site of attachment to the R and CH2 groups of formula (I).

[0100] According to another embodiment, Y is selected from the group Y-G3 consisting of:

[0101]

[0102] Each of them is substituted by 1 or 2 substituents R 1 Replace, and

[0103] Bonds with an asterisk and parentheses therein indicate the site of attachment to the R and CH2 groups of formula (I).

[0104] According to another embodiment, Y is selected from the group Y-G4 consisting of:

[0105]

[0106] Each of them is substituted by a substituent R 1 Replace, and

[0107] Bonds with an asterisk and parentheses therein indicate the site of attachment to the R and CH2 groups of formula (I).

[0108] According to another embodiment, Y is selected from the group Y-G5 consisting of:

[0109]

[0110] Each of which is optionally substituted with 1 additional substituent R 1 Replace, and

[0111] Bonds with an asterisk and parentheses therein indicate the site of attachment to the R and CH2 groups of formula (I).

[0112] According to another embodiment, Y is selected from the group Y-G6 consisting of:

[0113]

[0114] It is optionally substituted by an additional substituent R 1 Replace, and

[0115] Bonds with an asterisk and parentheses therein indicate the site of attachment to the R and CH2 groups of formula (I).

[0116] According to another embodiment, Y is selected from the group Y-G7 consisting of:

[0117]

[0118] Bonds with an asterisk and parentheses therein indicate the site of attachment to the R and CH2 groups of formula (I).

[0119] R:

[0120] According to one embodiment, R is selected from the group R-G1 consisting of:

[0121] a saturated 6- to 12-membered bicyclic ring system containing as ring members 1 to 2 N atoms and an optional 1 ring member selected from the group consisting of C═O, O, S, S═O and SO2,

[0122] The proviso is that the ring system does not contain any heteroatom-heteroatom bonds between the ring members,

[0123] wherein the ring system is connected to the group Y in formula (I) via the N atom, and

[0124] wherein the ring system is optionally substituted with 1 to 6 F and optionally substituted with 1 to 3 selected from C 1-3 Alkyl, CN, HO-C 1-3 Alkylene, OH and C 1-3 The substituent is substituted by a group consisting of alkyl-O.

[0125] According to another embodiment, R is selected from the group R-G2 consisting of:

[0126] a saturated 6- to 10-membered bicyclic ring system containing 1 N atom and optionally 1 O atom as ring members,

[0127] wherein the ring system is connected to the group Y in formula (I) via the N atom, and

[0128] wherein the ring system is optionally substituted with 1 selected from the group consisting of F, C 1-3 Alkyl (preferably CH3), CN, HO-C 1-3 Alkylene (preferably HOCH2), OH and C 1-3 alkyl-O- (preferably CH3O), and

[0129] wherein the ring system is optionally further substituted with a substituent selected from the group consisting of F and CH3.

[0130] According to another embodiment, R is selected from the group R-G3 consisting of:

[0131] 5-azaspiro[2.3]hexane, 2-azaspiro[3.3]heptane, 5-azaspiro[2.4]heptane, 6-azaspiro[3.4]octane, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 6-azaspiro[2.5]octane, 5-azaspiro[2.5]octane, 7-azaspiro[3.5]nonane, 3-azaspiro[4.1.0]heptane, 3-azaspiro[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane and 3-azabicyclo[3.2.1]octane,

[0132] Each of them is connected to the group Y in formula (I) via an N atom, and

[0133] Each of which is optionally substituted with a substituent selected from the group consisting of F, CH3, CN, CH2OH, OH and OCH3, preferably consisting of F and CH3, and

[0134] Each of which is optionally substituted with one additional substituent selected from the group consisting of F and CH3.

[0135] According to another embodiment, R is selected from the group R-G4 consisting of:

[0136]

[0137] According to another embodiment, R is selected from the group R-G5 consisting of:

[0138]

[0139] According to another embodiment, R is selected from the group R-G6 consisting of:

[0140]

[0141] According to another embodiment, R is selected from the group R-G7 consisting of:

[0142]

[0143] According to another embodiment, R is selected from the group R-G8 consisting of:

[0144]

[0145] Ar:

[0146] According to one embodiment, Ar is selected from the group Ar-G1 consisting of:

[0147] 5-membered heteroaryl containing 1 to 4 N atoms or containing 1 O or S atom or containing 1 to 2 N atoms and 1 O or S atom; and 9-membered heteroaryl consisting of a 5-membered ring fused to a 6-membered ring and containing 1 to 4 N atoms,

[0148] wherein the heteroaryl group is connected to the carbonyl group in formula (I) via a C atom of the 5-membered ring and is connected to the CH2 group in formula (I) via a non-adjacent C or N atom of the 5-membered ring, and

[0149] wherein the heteroaryl group is optionally substituted by 1 substituent R 3 replace.

[0150] According to another embodiment, Ar is selected from the group Ar-G2 consisting of:

[0151] 5-membered heteroaryl containing 1 to 3 N atoms or containing 1 O or S atom or containing 1 N atom and 1 O or S atom; and 9-membered heteroaryl consisting of a 5-membered ring fused to a 6-membered ring and containing 1 to 3 N atoms,

[0152] wherein the heteroaryl group is connected to the carbonyl group in formula (I) via a C atom of the 5-membered ring and is connected to the CH2 group in formula (I) via a non-adjacent C or N atom of the 5-membered ring, and

[0153] wherein the heteroaryl group is optionally substituted by 1 substituent R 3 replace.

[0154] According to another embodiment, Ar is selected from the group Ar-G3 consisting of:

[0155] and its tautomers,

[0156] Each of which is optionally substituted with 1 substituent R3, and

[0157] The bond with an asterisk and parentheses indicates the point of attachment of the group C═O to CH 2 of formula (I).

[0158] According to another embodiment, Ar is selected from the group Ar-G4 consisting of:

[0159]

[0160] Each of them is optionally substituted by 1 substituent R 3 Replace, and

[0161] The bond with an asterisk and parentheses indicates the point of attachment of the group C═O to CH 2 of formula (I).

[0162] According to another embodiment, Ar is selected from the group Ar-G5 consisting of:

[0163]

[0164] It is optionally substituted by 1 substituent R 3 Replace, and

[0165] The bond with an asterisk and parentheses indicates the point of attachment of the group C═O to CH 2 of formula (I).

[0166] According to another embodiment, Ar is selected from the group Ar-G6 consisting of:

[0167]

[0168] It is optionally substituted by 1 substituent R 3 Replace, and

[0169] The bond with an asterisk and parentheses indicates the point of attachment of the group C═O to CH 2 of formula (I).

[0170] According to another embodiment, Ar is selected from the group Ar-G7 consisting of:

[0171] and its tautomers,

[0172] Each of them is optionally substituted by 1 substituent R 3 Replace, and

[0173] The bond with an asterisk and parentheses indicates the point of attachment of the group C═O to CH 2 of formula (I).

[0174] According to another embodiment, Ar is selected from the group Ar-G8 consisting of:

[0175]

[0176] It is optionally substituted by 1 substituent R 3 Replace, and

[0177] The bond with an asterisk and parentheses indicates the point of attachment of the group C═O to CH 2 of formula (I).

[0178] According to another embodiment, Ar is selected from the group Ar-G9 consisting of:

[0179]

[0180] Each of them is optionally substituted by 1 substituent R 3 Replace, and

[0181] The bond with an asterisk and parentheses indicates the point of attachment of the group C═O to CH 2 of formula (I).

[0182] According to another embodiment, Ar is selected from the group Ar-G10 consisting of:

[0183]

[0184] Each of them is optionally substituted by 1 substituent R 3 Replace, and

[0185] The bond with an asterisk and parentheses indicates the point of attachment of the group C═O to CH 2 of formula (I).

[0186] According to another embodiment, Ar is selected from the group Ar-G11 consisting of:

[0187]

[0188] It is optionally substituted by 1 substituent R 3 Replace, and

[0189] The bond with an asterisk and parentheses indicates the point of attachment of the group C═O to CH 2 of formula (I).

[0190] R 1 :

[0191] According to one embodiment, R 1 is selected from the group R consisting of 1 -G1:

[0192] H, halogen, C optionally substituted with 1 to 5 F 1-4 alkyl, C optionally substituted with 1 CH3, CN or OH group 3-4 Cycloalkyl, CN, OC optionally substituted with 1 to 5 F 1-3 Alkyl, optionally selected from CN, OH and OC 1-3 A C substituted with one substituent of a group consisting of an alkyl group 1-3 alkyl.

[0193] According to another embodiment, R 1 is selected from the group R consisting of 1 -G2:

[0194] H, F, Cl, Br, optionally with 1 to 5 F or with 1 CN, OH or OC 1-2 Alkyl substituted C 1-2 Alkyl, C optionally substituted with 1 CN or OH group 3-4 alkyl, C optionally substituted with 1 CH3, CN or OH group 3-4 Cycloalkyl, optionally substituted with 1 to 5 F 1-2 alkyl.

[0195] According to another embodiment, R 1 is selected from the group R consisting of 1 -G3:

[0196] H, F, Cl, Br, CH3, CH2CH3, CH2CH2CH3, CH2CH(CH3)2, cyclopropyl, cyclobutyl, CHF2, CF3, CN, 1-cyanocyclopropan-1-yl, CH2CN, C(CH3)2CN, CH2OH, CH2CH2OH, CH(OH)CH3, CH2CH2CH2OH, CH(CH3)CH2OH, C(OH)(CH3)2, CH2OCH3, CH2OCH2CH3, O-CH3, O-CH2CH3 and O-CF3.

[0197] According to another embodiment, R 1 is selected from the group R consisting of 1 -G4:

[0198] H, F, Cl, Br, CH3, CH2CH3, CHF2, CN, CH2OH and CH2OCH3.

[0199] According to another embodiment, R 1 is a group R consisting of H 1 -G5.

[0200] According to another embodiment, R 1 is selected from the group consisting of F, Cl and Br 1 -G6.

[0201] According to another embodiment, R 1 is selected from the group R consisting of CH3 1 -G7.

[0202] According to another embodiment, R 1 is selected from the group R consisting of CH2CH3 1 -G8.

[0203] According to another embodiment, R 1 is selected from the group R consisting of 1 -G9:

[0204] CH2CH2CH3, CH2CH(CH3)2, cyclopropyl and cyclobutyl.

[0205] According to another embodiment, R 1 is selected from the group consisting of CHF2 and CF3 1 -G10.

[0206] According to another embodiment, R 1 is a group R consisting of CN 1 -G11.

[0207] According to another embodiment, R 1 is selected from the group R consisting of 1 -G12:

[0208] 1-Cyanocyclopropan-1-yl, CH2CN and C(CH3)2CN.

[0209] According to another embodiment, R 1 is selected from the group R consisting of CH2OH 1 -G13.

[0210] According to another embodiment, R 1 is selected from the group R consisting of 1 -G14:

[0211] CH2CH2OH, CH(OH)CH3, CH2CH2CH2OH, CH(CH3)CH2OH and C(OH)(CH3)2.

[0212] According to another embodiment, R 1 is selected from the group R consisting of 1 -G15:

[0213] CH2OCH3, CH2OCH2CH3, O-CH3, O-CH2CH3 and O-CF3.

[0214] R 3 :

[0215] According to one embodiment, R 3 is selected from the group R consisting of 3 -G1:

[0216] F, Cl, Br, CN, C optionally substituted with 1 to 5 F 1-4 Alkyl, C 3-4 Cycloalkyl, HO-C 1-4 Alkylene, C 1-3 Alkyl-OC 1-3 -alkylene and OC optionally substituted with 1 to 5 F 1-4 -alkyl.

[0217] According to another embodiment, R 3 is selected from the group R consisting of 3 -G2:

[0218] F, Cl, Br, CN, C optionally substituted with 1 to 3 F 1-3 Alkyl, HO-C 1-4 Alkylene, C 1-2 Alkyl-OC 1-2 alkylene and OC optionally substituted with 1 to 3 F 1-2 alkyl.

[0219] According to another embodiment, R 3 is selected from the group R consisting of 3 -G3:

[0220] Cl, CN, CH3, CF3, CH2CH3, CH(CH3)2, CH2OH, CH2CH2OH, C(CH3)2OH and CH2OCH3.

[0221] According to another embodiment, R 3 is selected from the group consisting of Cl and CN 3 -G4.

[0222] According to another embodiment, R 3 R is selected from the group consisting of CH3, CF3, CH2CH3 and CH(CH3)2 3 -G5.

[0223] According to another embodiment, R 3 is selected from the group R consisting of 3 -G6:

[0224] CH2OH, CH2CH2OH and C(CH3)2OH.

[0225] According to another embodiment, R 3 is selected from the group R consisting of CH2OCH3 3 -G7.

[0226] Stereochemistry:

[0227] According to one embodiment, the stereochemistry of the compound of formula (I) is according to formula (I.1)

[0228]

[0229] According to another embodiment, the stereochemistry of the compound of formula (I) is according to formula (I.2)

[0230]

[0231] More preferred subgeneric embodiments of the compounds of formula (I) are set forth in Table 1 below as embodiments (Ia) to (Ir), wherein the above-mentioned definitions of substituents apply. 1 and the term -G1 in column (Ia) means that in embodiment (Ia), the substituent R 1 is selected from the definition specified by R 1 -G1. The same analogously applies to other variables incorporated in the general formula.

[0232] Table 1:

[0233]

[0234] Particularly preferred are those subgeneric embodiments (I.1-a) to (I.1-r) in which Y, R, Ar, R 1 and R 3 In terms of the definition of , they correspond to subgeneric embodiments (Ia) to (Ir) of Table 1, but wherein the stereochemistry of the compound is according to formula (I.1).

[0235] According to another preferred embodiment, the stereochemistry of the compounds of the invention is according to formula (I.1), wherein Ar is selected from the group Ar-G5.

[0236] According to another preferred embodiment, the stereochemistry of the compounds of the invention is according to formula (I.1), wherein Ar is selected from the group Ar-G6.

[0237] According to another preferred embodiment, the stereochemistry of the compounds of the invention is according to formula (I.1), wherein Ar is selected from the group Ar-G8.

[0238] Particularly preferred compounds (including tautomers, salts thereof or any solvates, hydrates or co-crystals thereof) are the compounds described in the Examples and Experimental Data section.

[0239] preparation

[0240] The compounds according to the present invention and their intermediates can be obtained using synthetic methods known to those skilled in the art and described in the literature of organic synthesis, for example, using methods described in "Comprehensive Organic Transformations", 2nd edition, Richard C.Larock, John Wiley & Sons, 2010 and "March's Advanced Organic Chemistry", 7th edition, Michael B.Smith, John Wiley & Sons, 2013. Preferably, the compounds are obtained similarly to the preparation methods explained more fully below, especially as described in the experimental section. In some cases, the order in which the reaction process is carried out can be changed. Variations of these reactions known to those skilled in the art but not described in detail herein can also be used. Based on studying the following scheme, the general process for preparing the compounds according to the present invention will be apparent to those skilled in the art. The starting compound is commercially available or can be prepared by methods described in the literature or herein, or can be prepared in a similar or similar manner. Before carrying out the reaction, any corresponding functional group in the starting compound can be protected using a conventional protecting group. Furthermore, these protecting groups can be cleaved off at a suitable stage in the reaction sequence using methods familiar to the person skilled in the art and described in the literature, for example in "Protecting Groups", 3rd edition, Philip J. Kocienski, Theime, 2005 and "Protective Groups in Organic Synthesis", 4th edition, Peter GM Wuts, Theadora W. Greene, John Wiley and Sons, 2006.

[0241] Process 1:

[0242]

[0243] Scheme 1: The compound of formula (I') can be prepared by reacting a suitable acid of formula (II) (as a free acid or with a catalytic activity such as Li) in the presence of a suitable coupling agent (e.g., O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), (benzotriazol-1-yloxy)tripyrrolidiniumphosphonium hexafluorophosphate (PyBOP), carbodiimide reagent, etc.) and a base (e.g., triethylamine, N,N-diisopropyl-ethylamine, pyridine, etc.) in a suitable solvent (e.g., DCM, THF, 1,4-dioxane, DMF, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone). + 、Na + , K + The carboxylate form of a suitable metal cation (such as a carboxylate salt of a suitable metal cation such as oxalyl chloride, thionyl chloride, etc.) is reacted with a suitable amine of formula (III) (in the form of a free amine or a salt such as hydrochloride, hydrobromide, etc.) to form an amide bond; Y, R and Ar in Scheme 1 have the meanings defined above. Alternatively, the carboxylic acid is converted into the carboxylic acid chloride (using, for example, oxalyl chloride or thionyl chloride in DCM) and thus coupled with the amine (III) in the presence of a suitable base (such as triethylamine, N,N-diisopropyl-ethylamine, pyridine, etc.).

[0244] Process 2:

[0245]

[0246] R 5 =C 1-4 Alkyl or benzyl

[0247] Process 2: Visual R 5 The acid of formula (II) in which Y, R and Ar have the meanings defined above is preferably prepared from the corresponding ester (IV) via hydrolysis or hydrogenolysis. Preferably, lower alkyl esters such as ethyl or methyl esters are cleaved by hydrolysis with hydroxide salts such as NaOH, LiOH or KOH in a mixture of water and a suitable miscible solvent such as THF, MeOH, EtOH, 1,4-dioxane or a mixture of these substances at ambient temperature or elevated temperature. The acid can be separated into salts with metal cations or into free acids. Preferably, tertiary butyl esters are cleaved by treatment with an acid such as hydrochloric acid or TFA in a suitable solvent such as DCM, 1,4-dioxane, MeOH, EtOH, THF, water or a mixture of these substances. Preferably, benzyl esters are cleaved by hydrogenolysis with a suitable catalyst such as palladium on carbon in a suitable solvent such as EtOH, MeOH, THF, DCM or EtOAC under a hydrogen atmosphere such as preferably 1 to 5 bar.

[0248] Process 3

[0249]

[0250] T 1 and T 2 N, CH or CR independently of each other 3 :or

[0251] T 1 and T 2 Together they form a cyclobenzo, pyridine or pyrimidine ring, which is optionally substituted by R 3 Single substitution;

[0252] T 3 =CH or N:

[0253] R 5 =C 1-4 Alkyl or benzyl.

[0254] Scheme 3: Some of the compounds (II′) can be prepared by reacting alcohol (V) with ester (VI) using Mitsunobu reaction conditions (e.g., triphenylphosphine or tri-n-butylphosphine in combination with, for example, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), or di-tert-butyl azodicarboxylate (DBAD) in a solvent such as THF, 1,4-dioxane, toluene, etc.); Y, R and R in Scheme 3 3 has the meaning defined above. Alcohol (V) may carry the desired residue R on the heteroaromatic ring Y or alternatively leave the group for subsequent introduction of R. Alternatively, some of compounds (II′) may be obtained by reacting a Lewis acid or a Brønsted acid at elevated temperature (20 to 120° C.) in a suitable solvent (e.g. MeCN). In the case of 4-toluenesulfonic acid (for example, 4-toluenesulfonic acid), the alcohol (V) is reacted with the ester (VI).

[0255] Process 4

[0256]

[0257] T 1 and T 2 N, CH or CR independently of each other 3 ;or

[0258] T 1 and T 2 Together they form a cyclobenzo, pyridine or pyrimidine ring, which is optionally substituted by R 3 Single substitution;

[0259] T 3 =CH or N;

[0260] R 5 =C 1-4 Alkyl or benzyl;

[0261] Hal = leaving group, such as Cl, Br, I, OSO2CH3.

[0262] Scheme 4: Some of the compounds (II') can also be prepared by reacting a compound (VII) carrying a leaving group such as Cl, Br or mesyloxy / methanesulfonyloxy at the heteroarylmethyl position with an ester (VI) in the presence of a suitable base (e.g. sodium hydride, cesium carbonate, potassium carbonate or triethylamine) in a suitable solvent (e.g. THF, DMF); Y, R and R3 in Scheme 4 have the meanings defined above. Compound (VII) may carry the desired residue R on the heteroaromatic ring Y or alternatively a leaving group to subsequently introduce R.

[0263] Process 5

[0264]

[0265] R 5 =C 1-4 Alkyl or benzyl;

[0266] Hal = leaving group, such as OH, Cl, Br, I, OSO2CH3

[0267] Scheme 5: Some esters of formula (II″) wherein Y and R have the meanings defined above can be prepared by treating the corresponding alkyl halide (bromide or chloride) or sulfonate of formula (VII) (e.g. mesylate) with sodium azide in DMF or another suitable solvent to give an intermediate of formula (VIII), which is then reacted with a suitable propiolate (e.g. ethyl propiolate or tert-butyl propiolate with catalytic copper sulfate and sodium ascorbate in water / tert-butanol) under copper-mediated catalytic conditions to give compound (II″). Alternatively, azide (VIII) can be obtained from alcohol of formula (V) (or (VII), wherein Hal is OH) by treatment with diphenylphosphoryl azide in the presence of a suitable base (such as DBU) in a suitable solvent (e.g. THF or DMF). Compound (VII) may carry the desired residue R on the heteroaromatic ring Y or alternatively a leaving group for subsequent introduction of R.

[0268] Process 6

[0269]

[0270] For compounds (X), (XI), (XII) and (II″′): T 1 and T 3are independently selected from CH, CR 3 and N, and T 2 Is selected from NR 3 , O and S;

[0271] For compound (X'): T 2 and T 3 are independently selected from CH, CR 3 and N, and T 1 Is selected from NR 3 , O and S;

[0272] For compound (X″): T 1 and T 2 are independently selected from CH, CR 3 and N, and T 3 Is selected from NR 3 , O and S;

[0273] R5=C 1-4 Alkyl or benzyl; Hal=Cl, Br, I

[0274] Process 6: Where Y, R and R 3 Esters of formula (II'') having the meanings defined above can be prepared from alcohols (XII) by replacing the hydroxyl group with hydrogen using methods reported in the literature (e.g. triethylsilane and TFA or boron trifluoride etherate or hydrogen in DCM in the presence of palladium on carbon in a solvent such as THF or EtOH). Alcohols (XII) can be prepared by adding a magnesium halide (XI) or another organometallic derivative to an aldehyde (IX) followed by oxidation (e.g. Dess-Martin oxidation or Swern oxidation) in an inert solvent such as THF, DCM or diethyl ether at low to ambient temperature. The magnesium halide (XI) can be obtained from the corresponding (X) bromide or iodide using isopropylmagnesium chloride optionally in combination with lithium chloride in THF at low temperature after a halogen metal exchange reaction. Alternatively, magnesium metal is inserted into the carbon-halogen bond to obtain the magnesium halide (XI). Compounds (IX) and (XII) may carry the desired residue R on the heteroaromatic ring Y or alternatively leave the group for subsequent introduction of R.

[0275] Starting with compounds (X') and (X"), the corresponding analogs of compounds (II'") can be obtained using the principles depicted above (see Scheme 7 for (X')).

[0276] Process 7

[0277]

[0278] T2 and T 3 are independently selected from CH, CR 3 and N, and T 1 Is selected from NR 3 , O and S;

[0279] R5=C 1-4 Alkyl or benzyl; Hal=Cl, Br, I

[0280] Process 7: Where Y, R and R 3 Compounds of formula (II"") having the meanings defined above can be prepared in an analogous manner to the compounds depicted in Scheme 6 using isomeric magnesium halides (XI').

[0281] Process 8

[0282]

[0283] LG = leaving group, such as F, Cl, Br, I; A 1 , A 2 , A 3 , A 4 Independently = N or CR 1

[0284] R6=COOR 5 、CHO、CH2OH、CH2-Ar-COOR 5 ; R 5 =C 1-4 -alkyl or benzyl

[0285] Scheme 8: The intermediate of formula (XV) can be prepared from an aromatic compound (XIII) and an amine (XIV) via a nucleophilic substitution reaction on a heteroaromatic ring or a transition metal-catalyzed coupling reaction; Ar, R and R in Scheme 8 are 1 has the meaning defined above. The nucleophilic substitution of the leaving group on the heteroaromatic ring in (XIII) by N in compound (XIV) can be carried out at ambient or elevated temperature in the presence of a suitable base (e.g. sodium hydride, cesium carbonate, potassium carbonate, N,N-diisopropyl-ethylamine) in a suitable solvent (e.g. THF, 1,4-dioxane, DMF, DMSO). The transition metal-catalyzed coupling reaction is preferably carried out in a manner similar to that reported in the organic chemistry literature, which is known as the Ullmann or Bachfa / Hartwig coupling reaction, which is carried out in the presence of a base and in a suitable solvent using a suitable copper or palladium salt or a complex thereof, optionally in combination with an additional ligand.

[0286] Process 9

[0287]

[0288] Scheme 9: Enantiopure amines (III.1) can be prepared from ketones (XVI) as depicted in Scheme 9. The overall synthesis comprises three steps and is carried out at ambient or elevated temperature in a suitable solvent such as THF, DCM, toluene or pure titanium alkoxide (e.g., Ti(OEt)4 or Ti(O i Pr)4) in the presence of a dehydrating agent to condense the ketone with an enantiomerically pure tertiary butanesulfinamide to produce the corresponding enantiomerically pure tertiary butylsulfinylated amine (XVII). The amine (XVII) can be diastereoselectively reduced to the corresponding tertiary butylsulfinylated amine (XVIII) using a hydride (e.g., lithium or sodium borohydride, lithium tris-butyl borohydride, diisobutylaluminum hydride, etc.) in a suitable solvent (e.g., THF, toluene, MeOH, etc., depending on the source of the hydride used). The tertiary butylsulfinyl group can be cleaved off using an acid (e.g., TFA or hydrochloric acid) in a suitable solvent (e.g., toluene, DCM, dioxane, alcohol, water, etc.) at ambient or elevated temperature.

[0289] The racemate (III) and the opposite enantiomer (III.2) are obtained by using racemic tert-butanesulfenamide and enantiomerically pure (S)-tert-butanesulfenamide, respectively, in the above-mentioned pathway.

[0290] Alternatively, compound (III.1) and its enantiomer (III.2) can be obtained from ketone (XVI) via a 3-step synthetic sequence, starting with the enantioselective reaction of the ketone portion in compound (XVI) using conditions reported in the organic chemistry literature (e.g., J. Am. Chem. Soc. 1995, 117, 7562-3; Org. Lett. 2010, 12, 1756-9; Org. Proc. Res. Dev. 2006, 10, 949-958; Tetrahedron: Asymmetry 2003, 14, 2659-2681; Tetrahedron Lett. 2014, 55, 3635-40; and references cited therein) to give the corresponding enantiopure or enantiomerically enriched alcohol. The hydroxyl group thus formed can then be replaced with a protected or masked amino group such as phthalimide or (tertiary Bu-OCO)2N in a stereospecific Mitsunobu or Mitsunobu-type reaction (using, for example, triphenylphosphine or tri-n-butylphosphine in combination with dimethyl azodicarboxylate, DEAD, DIAD, bis(4-chlorobenzyl) azodicarboxylate, diphenylmethyl azodicarboxylate, DBAD, bis(dimethylamide) azodicarboxylate, dipiperidine azodicarboxylate, or dimorpholine azodicarboxylate in a suitable solvent such as THF, 1,4-dioxane, EtOAc, benzene, toluene, etc.), resulting in an inversion of the configuration at the C-bearing heteroatom. Alternatively, a phosphoryl azide (e.g., diphenylphosphoryl azide) can be used to replace the OH group with an azide under inversion of the configuration. The amine group can be released from the phthalimide group by treatment with, for example, hydrazine, hydroxylamine, methylamine, n-butylamine or ethanolamine in a suitable solvent such as EtOH, MeOH, MeCN, THF, dioxane, DMSO, N,N-dimethylacetamide, water or a mixture of these substances, and heating if necessary to give compound (III.1). The tertiary Bu-O-CO is preferably removed under acidic conditions (using, for example, TFA or hydrochloric acid) to give the same amine (III.1). The azide can be reduced to the amine (III.1) with, for example, hydrogen in the presence of a transition metal (e.g., palladium / carbon, Raney-Ni, PtO2, etc.) or a phosphine (e.g., triphenylphosphine). The racemate (III) is obtained after reduction of compound (XVI) with an achiral reducing agent such as sodium borohydride and following another route described above.

[0291] Process 10

[0292]

[0293] Scheme 10: Compound (XVI) can be obtained from ester (XIX) (or the corresponding low- or high-carbon alkyl ester, such as methyl, n-propyl, isopropyl or tert-butyl ester) in a sequence consisting of 3 or 4 reaction steps. Compound (XIX) can be brominated with a suitable electrophilic bromine source (e.g., N-bromosuccinimide (NBS) or Br2) in a suitable solvent (e.g., AcOH, DCM, dichloroethane, dioxane, MeCN, DMF, etc.) at ambient temperature or elevated temperature. For example, NBS in acetic acid at ambient temperature or NBS in HCCl3 at 65°C provides the compound. Alternatively, treatment of compound (XIX) with NBS in trifluoromethanesulfonic acid and 1,2-dichloroethane, sodium persulfate and palladium acetate at 80°C also provides (XX). Subsequently, compound (XX) can be converted to ester (XXI) using a 1-step or 2-step synthetic route covering Heck coupling reactions (generally covered in the organic chemistry literature such as Catalysts 2017, 7, 267 and references cited therein) with acrolein dialkyl acetals (e.g. acrolein diethyl acetal, -> (XXI)) or acrylates (e.g. ethyl acrylate, -> (XXIII)); use of the latter coupling partner requires an additional step to reduce the formed olefin bond, which can be obtained using hydrogen in the presence of a transition metal catalyst (e.g., Pd such as palladium / carbon, Ni such as Raegle-Ni, Pt such as platinum oxide, Rh such as rhodium / carbon, etc.) in a suitable solvent (e.g., DCM, dioxane, THF, EtOAc, alcohols such as MeOH, water, etc.). Compound (XXI) can be treated with a base (e.g., a hydride such as sodium hydride, an alcoholate such as lithium methoxide or potassium tert-butoxide, an organic amine such as DBU, a phosphazene such as P2Et phosphazene, an amide such as lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide or potassium hexamethyldisilazide, etc.) in a suitable solvent (depending on the base and solvent used, e.g., benzene, toluene, dioxane, THF, alcohol, etc.) at low to high temperatures (depending on the base and solvent used, -78°C to 100°C); potassium hexamethyldisilazide in THF at 20°C is one of the more preferred conditions for this transformation. The hydrolysis of the ester group in compound (XXII) followed by decarboxylation can be achieved by stirring the compound in a solvent (e.g., dioxane, THF, ACN, DMF, N,N-dimethylacetamide, DMSO, alcohol, water, etc., or a mixture of these) at 0 to 140° C., optionally in the presence of a base (e.g., sodium hydroxide), a halide salt (such as lithium iodide or lithium chloride), or an acid (e.g., hydrochloric acid) to give ketone (XVI).

[0294] The compounds of formula (I) may be resolved into their enantiomers and / or diastereomers as mentioned below. Thus, for example, a cis / trans mixture may be resolved into its cis and trans isomers, and a racemic compound may be resolved into its enantiomers.

[0295] Cis / trans mixtures can be resolved into their cis and trans isomers, for example, by chromatography. Compounds of formula (I) which occur in racemic form can be separated into their optical antipodes by methods known per se, and diastereomeric mixtures of compounds of general formula (I) can be resolved into their diastereomers by methods known per se which exploit their different physicochemical properties, for example using chromatography and / or fractional crystallization; if the compound obtained thereafter is a racemate, it can be resolved into the enantiomers as mentioned below.

[0296] The racemate is preferably resolved by column chromatography on a chiral phase, or by crystallization from a photoactive solvent, or by reaction with a photoactive substance (which forms a salt or a derivative such as an ester or amide with the racemic compound). The basic compound can form a salt with an enantiomerically pure acid, and the acidic compound can form a salt with an enantiomerically pure alkali. The diastereomeric derivative is formed by an enantiomerically pure auxiliary compound (e.g., an acid, an activated derivative thereof, or an alcohol). The separation of the diastereomeric mixture of the salt or derivative thus obtained can be achieved by utilizing their different physicochemical properties (e.g., differences in solubility); the free enantiomer can be released from the pure diastereomeric salt or derivative by the action of a suitable reagent. Optically active acids commonly used for this purpose and optically active alcohols suitable for use as auxiliary residues are known to those skilled in the art.

[0297] As mentioned above, compounds of formula (I) can be converted into salts, especially into pharmaceutically acceptable salts for pharmaceutical use. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by preparing acid or base salts thereof.

[0298] The compounds according to the invention can also be obtained expediently using the methods described in the examples below, which methods can also be combined for this purpose with methods known to the skilled worker from the literature.

[0299] Therefore, according to another aspect of the present invention, there is provided a process for synthesizing a compound of formula (I).

[0300] According to another aspect of the present invention, an intermediate for the synthesis of the compound of formula (I) is provided.

[0301] According to one embodiment, the present invention pertains to intermediates as depicted and described in Schemes 9 and / or 10.

[0302] According to another embodiment, the present invention relates to one or more of the following intermediates:

[0303]

[0304] Pharmacological activity

[0305] The activity of the compounds of the invention can be demonstrated using the following assays:

[0306] Biological methods

[0307] The ability of the compounds of formula (I) to inhibit plasma kallikrein (PKK), factor XIIa (FXIIa), factor XIa (FXIa), factor Xa (FXa), factor IIa (α-thrombin; FIIa), plasmin, trypsin, tissue kallikrein 1 (TK1), factor VIIa (FVIIa) or FVIIa complexed with tissue factor, phospholipids and CaCl2 (FVIIa / TF / PL / CaCl2) was determined in the presence of 1% (v / v) DMSO using the following biochemical assay in assay buffer (100 mM Tris, 150 mM NaCL, adjusted to pH 7.8 with HCl, and containing 0.1% (w / v) BSA and 0.05% (v / v) Tween 20):

[0308] Assessment of PKK inhibition using endpoint analysis

[0309] Human PKK (0.01 U / mL; Enzyme Research Laboratories) or rat PKK (0.625 nM; homemade) was incubated with 0.10 μM of the fluorescent substrate H-Pro-Phe-Arg-AMC (I1295 from Bachem) and various concentrations of the test compound in assay buffer for 1 hour at room temperature. Subsequently, PPACK II (Calbiochem) was added as a stop solution to achieve a final concentration of 1 μM, and fluorescence was measured using an Envision Reader (PerkinElmer) with wavelength excitation set to 355 nm and wavelength emission set to 460 nm.

[0310] IC of the compounds according to the invention 50 The values ​​are shown in the table below. The values ​​of the compounds correspond to the values ​​of the examples in the experimental part.

[0311]

[0312]

[0313] Evaluation of PKK inhibition in kaolin-activated human PPP

[0314] Platelet-poor plasma (PPP) obtained from human whole blood anticoagulated with Na-Citrate was incubated with various concentrations of test compounds and 25, 75, 250 or 750 μg / mL kaolin in assay buffer at 37° C. for 20 minutes, so that for each kaolin dose used, a concentration effect for the test compound was obtained. Afterwards, 0.25 mM of the fluorescent substrate H-Pro-Phe-Arg-AMC (I1295 from Bachem) was added to the mixture, and measurements were performed every 2 minutes for 12 minutes using a Spectramax M5 (Molecular Devices) with the following wavelength excitation set to 350 nm and wavelength emission set to 450 nm for kinetic intervals. pIC50 and pIC90 values ​​were obtained from 4 x / y-plots (x = log M, compound; y = Δrfu / min) fitted with GraphPad Prism 7.0 (Equation: log(agonist) vs. response - FindECanything; four concentration response curves obtained for the test compound (each obtained using a different kaolin dose) were fitted using the global fitting procedure to obtain a shared pIC50 or pIC90 value).

[0315] IC of the compounds according to the invention 90 The values ​​are shown in the table below. The values ​​of the compounds correspond to the values ​​of the examples in the experimental part.

[0316]

[0317]

[0318] PKK inhibition (K i )

[0319] Human PKK (1.78 nM or 0.025 U / mL; Enzyme Research Laboratories) was incubated with 0.25 mM fluorescent substrate H-Pro-Phe-Arg-AMC (I1295 from Bachem) and various concentrations of test compounds in assay buffer at 24° C. Measurements were performed at kinetic intervals every 2 minutes for 16 minutes using a Spectramax M5 (Molecular Devices) with wavelength excitation set to 350 nm and wavelength emission set to 450 nm.

[0320] FXIIa inhibition (K i )

[0321] Human FXIIa (47.5 nM or 1.1 U / mL; Enzyme Research Laboratories) was incubated with 0.5 mM chromogenic substrate S2302 (Chromogenix) and various concentrations of test compounds in assay buffer at 24° C. Measurements were performed every 2 minutes for 16 minutes at kinetic intervals using a Spectramax M5 (Molecular Devices) measuring absorbance at 405 nm.

[0322] FXIa inhibition (K i )

[0323] Human FXIa (0.5 nM or 0.016 U / mL; Enzyme Research Laboratories) was incubated with 0.25 mM fluorescent substrate Boc-Glu(OBzl)-Ala-Arg-AMC·HCl (I1575 from Bachem) and various concentrations of test compounds in assay buffer at 24° C. Measurements were performed every 2 minutes for 16 minutes at kinetic intervals using a Spectramax M5 (Molecular Devices) with wavelength excitation set to 350 nm and wavelength emission set to 450 nm.

[0324] FXa inhibition (K i )

[0325] Human FXa (0.86 nM or 0.01 U / mL; Enzyme Research Laboratories) was incubated with 0.5 mM chromogenic substrate S2765 (Chromogenix) and various concentrations of test compounds in assay buffer at 24° C. Measurements were performed every 2 minutes for 16 minutes at kinetic intervals using a Spectramax M5 (Molecular Devices) measuring absorbance at 405 nm.

[0326] FIIa inhibition (K i )

[0327] Human FIIa (44.6 nM or 5 U / mL; Enzyme Research Laboratories) was incubated with 0.5 mM chromogenic substrate S2238 (Chromogenix) and various concentrations of test compounds in assay buffer at 24° C. Measurements were performed every 2 minutes for 16 minutes using a Spectramax M5 (Molecular Devices) measuring absorbance at 405 nm.

[0328] Plasmin inhibitor (K i )

[0329] Human plasmin (64.1 nM or 0.0275 U / mL; Enzyme Research Laboratories) was incubated with 0.3 mM chromogenic substrate S2251 (Chromogenix) and various concentrations of test compounds in assay buffer at 24° C. Measurements were performed every 2 minutes for 16 minutes at kinetic intervals using a Spectramax M5 (Molecular Devices) measuring absorbance at 405 nm.

[0330] Trypsin inhibition (K i )

[0331] Human trypsin (4.54 nM or 250 U / mL; Calbiochem) was incubated with 0.5 mM chromogenic substrate S2222 (Chromogenix) and various concentrations of test compounds in assay buffer at 24° C. Measurements were performed every 2 minutes for 16 minutes at kinetic intervals using a Spectramax M5 (Molecular Devices) measuring absorbance at 405 nm.

[0332] TK1 inhibition (K i )

[0333] Prior to analysis, human TK1 (R&D system) was activated by incubation with human trypsin (Calbiochem) at a ratio of 1:10,000 at 37°C for 15 minutes. For analysis of TK1 inhibitory activity, activated TK1 (31.25 nM or 1 U / mL) was incubated with 0.1 mM fluorescent substrate H-Pro-Phe-Arg-AMC (I1295 from Bachem) and various concentrations of test compounds in assay buffer at 24°C. Measurements were performed every 2 minutes for 16 minutes at kinetic intervals using a Spectramax M5 (Molecular Devices) with the following wavelength excitation set to 350 nm and wavelength emission set to 450 nm.

[0334] The Ki values ​​of the compounds according to the invention are shown in the table below. The values ​​for the compounds correspond to the values ​​of the examples in the experimental part.

[0335]

[0336] FVIIa inhibition (K i )

[0337] Human FVIIa (0.86 nM or 0.01 U / mL; Enzyme Research Laboratories) was developed with 1.5 mM in assay buffer at 24°C. FVIIa(Loxo) was incubated with various concentrations of the test compound. Measurements were performed at kinetic intervals every 2 minutes for 16 minutes using a Spectramax M5 (Molecular Devices) measuring absorbance at 405 nm.

[0338] FVIIa / TF / PL / CaCl2 inhibition (K i )

[0339] Human FVIIa (300 nM or 585 U / mL; Enzyme Research Laboratories) with 10 mM CaCl2*2H2O and 13.3% (v / v) (Siemens; OQUMI94E0002 (5534), which contains recombinant human tissue factor synthetic phospholipids (thromboplastin)) was developed at 24°C with 1.5 mM FVIIa(Loxo) was incubated with various concentrations of the test compound. Measurements were performed at kinetic intervals every 2 minutes for 16 minutes using a Spectramax M5 (Molecular Devices) measuring absorbance at 405 nm.

[0340] pIC 50 and pK i Calculation of values

[0341] Mean V for the time interval from 2 to 12 minutes after the start of the analysis max The pIC values ​​(expressed as δOD / min for assays using chromogenic substrates or δRFU / min for assays using fluorogenic substrates, respectively) are plotted against the logarithm of the molar concentration of the inhibitor compound being evaluated. 50 The values ​​were then fitted using a four parameter fitting program using GraphPad Prism (version 6; GraphPad Software, Inc.). The individual Ki values ​​were calculated for the individual K values ​​of the substrates used using the formula M Values ​​(see obtained K for the substrate used) M Table A) Correction IC 50 The value is obtained:

[0342]

[0343] Among them, IC 50 In units of molar concentration and K M Values ​​are in mM.

[0344] Table A: K obtained for substrates used in enzyme assays M value

[0345]

[0346] Permeability assessment

[0347] Caco-2 cells (1-2×10 5 Cells / 1cm 2 area) were seeded on filter inserts (Costar transwell polycarbonate or PET filters, 0.4 μm pore size) and cultured (DMEM) for 10 to 25 days.

[0348] Compounds were dissolved in a suitable solvent (e.g., DMSO, 1 to 20 mM stock solution). The stock solution was diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 4.17 mM NaHCO3, 1.19 mM Na2HPO4×7H2O, 0.41 mM NaH2PO4×H2O, 15 mM HEPES, 20 mM glucose, pH 7.2) containing 0.25% BSA to prepare transport solutions (0.1 to 300 μM compound, final DMSO <= 0.5%). The transport solution (TL) was applied to the apical or basolateral donor side for measuring AB or BA permeability, respectively (repeat 2 filtrations). The receiver side contained HTP-4 buffer supplemented with 0.25% BSA. Samples were collected from the donor and also from the receiver side at the beginning and end of the experiment and at various time intervals (up to 2 hours) for concentration measurement by HPLC-MS / MS or scintillation counting. The receiver volume after sampling was replaced with fresh receiver solution.

[0349] Assessment of metabolic stability in human or mouse liver microsomes

[0350] Metabolic degradation of test compounds was analyzed on pooled human (HLM) or mouse liver microsomes (RLM) at 37° C. The final incubation volume of 60 μl for each time point contained TRIS buffer pH 7.6 (0.1 M), magnesium chloride (5 mM), microsomal proteins (HLM: 1 mg / mL, RLM: 0.5 mg / mL) at RT and test compound at a final concentration of 1 μM.

[0351] After a brief pre-incubation at 37°C for a certain period of time, the reaction was initiated by adding the reduced form of β-nicotinamide adenine dinucleotide phosphate (NADPH, 1 mM), and the reaction was terminated by transferring aliquots to the solvent after different time points. In addition, NADPH-independent degradation was monitored during the incubation without NADPH, terminating at the last time point. The quenched incubation solution was collected by centrifugation (10000g, 5 minutes). The amount of parent compound in aliquots of the supernatant was analyzed by LC-MS / MS. The half-life (t1 / 2 in vitro) was determined by the slope of the semi-logarithmic plot of the concentration-time characteristic curve.

[0352] Assessment of metabolic stability in human or mouse hepatocytes

[0353] Metabolic degradation of test compounds was analyzed in hepatocyte suspensions. After recovery from cryopreservation, human or rat hepatocytes were cultured in Dulbecco's modified eagle medium supplemented with 3.5 μg glucagon / 500 ml, 2.5 mg insulin / 500 ml and 3.75 mg / 500 ml hydrocortisone, containing 5% or 50% human or rat serum or in the absence of serum.

[0354] After pre-incubation for 30 min in a cell incubator (37°C, 10% CO2), the test compound solution was spiked into the hepatocyte suspension to obtain a final cell density of 1.0×106 cells / mL, a final test compound concentration of 1 μM and a final DMSO concentration of 0.05%.

[0355] Cells were incubated for six hours (incubator, horizontal shaker), and samples were removed after 0, 0.5, 1, 2, 4, and 6 hours. Samples were quenched with acetonitrile and pelleted by centrifugation. The supernatant was transferred to a 96-deep well plate and prepared for analysis of the reduction of the parent compound by HPLC MS / MS.

[0356] CL int It is calculated as follows:

[0357] CL int =Dose / AUC=(C0 / CD) / (AUD+clast / k)×1000 / 60

[0358] C0: initial concentration in the culture [μM], CD: cell density of viable cells [10e6 cells / ml], AUD: data area [μM×h], clast: concentration of the last data point [μM], k: slope of the regression line for maternal decay [h -1 ].

[0359] The calculated in vitro hepatic intrinsic clearance can be scaled up to the in vivo intrinsic hepatic clearance and used to predict the in vivo hepatic blood clearance (CL) by using a liver model (well-stirred model).

[0360] Assessment of plasma protein binding

[0361] This equilibrium dialysis (ED) technique is used to measure the approximate in vitro partial binding of test compounds to plasma proteins applying Dianorm Teflon (Teflon) dialysis cells (0.2 microns). Each dialysis cell consists of a donor and a receptor chamber, which is separated by an ultrathin semipermeable membrane with a 5kDa molecular weight cutoff. A stock solution for each test compound is prepared with 1mM in DMSO and serially diluted to obtain a final test concentration of 1μM. Subsequent dialysis solutions are prepared in plasma (supplemented with NaEDTA as an anticoagulant), and aliquots of 200μl test compound dialysis solutions in plasma are distributed to the donor (plasma) chamber. An aliquot of 200μL dialysis buffer (100mM potassium phosphate, pH 7.4) is distributed to the buffer (receptor) chamber. Cultivate 2 hours at 37°C under rotation to establish equilibrium.

[0362] At the end of the dialysis period, aliquots obtained from the donor and acceptor compartments, respectively, were transferred to reaction tubes, spiked with internal standard solution and processed for HPLCMS / MS analysis. Analyte concentrations were quantified in sample aliquots by HPLC-MS / MS against an external calibration curve.

[0363] The binding % is calculated using the formula:

[0364] % binding = (plasma concentration - buffer concentration / plasma concentration) × 100

[0365] Solubility Assessment

[0366] The water solubility of the test compound is measured by comparing the amount dissolved in the buffer with the amount dissolved in the ACN / water (1 / 1) solution. Starting from the 10mM DMSO stock solution, aliquots are diluted with acetonitrile / water (1 / 1) or buffer respectively. After 24 hours of vibration, the solution is filtered and analyzed by LC-UV. Compare the amount dissolved in the buffer with the amount dissolved in the ACN solution.

[0367] The solubility is usually measured at 2.5% DMSO concentration between 0.001 mg / mL and 0.125 mg / mL. If more than 90% of the compound is dissolved in the buffer, the value is marked by a ">".

[0368] Evaluation of pharmacokinetic properties in rodents

[0369] Test compounds were administered intravenously to fed mice or orally to fasted mice. Blood samples were obtained at several time points after administration of the test compounds, anticoagulated and centrifuged.

[0370] The concentration of the analyte - the administered compound and / or metabolite - is quantified in the plasma samples.

[0371] PK parameters were calculated using a non-compartmental approach. AUC and Cmax were normalized to a dose of 1 μmol / kg.

[0372] Evaluation of inhibition of reactions catalyzed by cytochrome P450 isozymes

[0373] Human liver microsomes were used at 37°C to analyze the inhibition of reactions catalyzed by cytochrome P450 isozymes by test compounds. All analyses were performed on a robotic system in 384-well plates. Test compounds were spotted directly from DMSO stock into culture plates by acoustic liquid dispensing (using Labyte system). The final incubation volume contains TRIS buffer (0.1 M), MgCl2 (5 mM), human liver microsomes, specific cytochrome P450 isozyme-substrate and five different concentrations of test compound or no compound (high control) in duplicate (e.g. highest concentration 50 μM with subsequent 1:4 serial dilutions). After a short pre-incubation period, the reaction is started with cofactor (NADPH, 1 mM) and stopped by cooling the incubation down to 8°C and subsequently by adding one volume of acetonitrile. After the incubation quench, an internal standard solution is added, usually a stable isotope of the metabolite formed. The analyte (= metabolite formed) and internal target peak areas are determined by LC-MS / MS. The peak area ratios of analyte to internal standard obtained in these incubations are compared to the control activity without test compound. Within each of the analytical runs, the IC of the positive control inhibitor is determined. 50 IC was calculated by least squares regression according to the following formula 50 Experimental value:

[0374] % control activity = (100% control activity / (1 + (I / IC50) S))) - b

[0375] in

[0376] I = inhibitor concentration

[0377] S = slope factor

[0378] B = Background activity

[0379] If inhibition of the reaction is >50% at the lowest concentration of the test compound, an IC is assigned. 50IC is "< the lowest concentration tested" (usually < 0.2 μM). If the inhibition of the reaction is still < 50% at the highest concentration of the test compound, then the IC is assigned 50 is ">highest tested concentration" (usually >50 μM).

[0380] Evaluation of mechanism-based inhibition (MBI) of cytochrome P450 3A4-catalyzed midazolam conversion

[0381] Mechanism-based inhibition against CYP3A4 was analyzed in human liver microsomes (0.02 mg / ml) with midazolam (15 μM) as substrate.

[0382] Test compounds were pre-incubated with human liver microsomes (0.2 mg / ml) at concentrations of 5 uM and 25 uM for 0, 10 or 30 minutes at 37°C in the presence of NADPH. After the pre-incubation, the incubation was diluted 1:10 and the substrate midazolam was added for the main incubation (15 minutes). The main incubation was quenched with acetonitrile and the formation of hydroxy-midazolam was quantified by LC / MS-MS.

[0383] The conversion rate was calculated in pmol / min / mg protein and the activity after 10 and 30 minutes pre-incubation time was compared to the activity of 0 minutes pre-incubation for the respective compound / concentration (CTRL% = % of 0 minutes control for the respective compound / concentration). In addition, the conversion rate was expressed relative to the conversion rate of the substrate reaction without added compound (TR% = % of conversion without compound) in order to identify competitive inhibition.

[0384] Treatment

[0385] In another aspect of the invention, the compounds of formula (I) or pharmaceutically acceptable salts thereof are found to have properties suitable for therapy and / or prevention, i.e., for use as medicaments. In particular, the compounds of formula (I) or pharmaceutically acceptable salts thereof and pharmaceutical compositions containing them may be suitable for treatment, i.e., therapy and / or prevention (prevention and treatment) of diseases or conditions that may be affected by the inhibition of plasma kallikrein in patients, such as those mediated by undesirable PKK activity or in which the inhibition of PKK is beneficial.

[0386] Diseases or conditions that may be affected by PKK inhibition, e.g., diseases or conditions mediated by undesired PKK activity or in which inhibition of PKK is beneficial, are, for example, those mentioned in the section on the background of the invention, in particular diabetic complications, diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), clinically significant macular edema (CSME), cystoid macular edema (CME), CME after cataract extraction, CME induced by cryotherapy, CME induced by uveitis, endophthalmitis, vascular occlusions (e.g., central retinal vein occlusion, retinal retinal edema, complications associated with cataract surgery in diabetic retinopathy, hypertensive retinopathy, retinal trauma, dry and wet age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV), choroidal neovascularization (CNV; e.g., non-exudative choroidal neovascularization), hereditary angioedema (HAE), acute respiratory distress syndrome (ARDS), post-stroke hemorrhage and edema such as post-stroke cerebral edema, vascular dementia, Alzheimer's disease, fibrotic diseases, colitis, arthritis, and renal injury.

[0387] Therefore, the compounds and pharmaceutical compositions of the present invention are particularly suitable for treating ocular diseases including diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), retinal vein occlusion, age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV) and choroidal neovascularization (CNV; e.g., non-exudative choroidal neovascularization).

[0388] Additionally, the compounds and pharmaceutical compositions of the present invention are particularly useful for treating edema such as hereditary angioedema (HAE) and cerebral edema following stroke.

[0389] In particular, the compounds and pharmaceutical compositions of the present invention are suitable for treating diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV), choroidal neovascularization (CNV), hereditary angioedema (HAE) and brain edema after stroke.

[0390] The compounds and pharmaceutical compositions of the present invention are most particularly useful for treating diabetic macular edema (DME), wet age-related macular degeneration (AMD), non-exudative choroidal neovascularization (CNV), hereditary angioedema (HAE), and brain edema following stroke.

[0391] For example, it is particularly suitable for preventing diabetic macular edema (DME), wet age-related macular degeneration (AMD), hereditary angioedema (HAE) and brain edema after stroke, and for preventing the transformation from non-exudative choroidal neovascularization (neCNV) to exudative choroidal neovascularization (eCNV).

[0392] The dosage range of the compound of formula (I) used per day is usually 0.01 mg / kg to 10 mg / kg body weight.

[0393] The actual therapeutically effective amount or therapeutic dose will of course depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease. In any case, the compound or composition should be administered in a dosage and manner that can achieve a therapeutically effective amount according to the patient's unique condition.

[0394] The compounds and compositions according to the present invention (including any combination with one or more additional therapeutic agents) can be administered by oral, intravitreal, transdermal, inhalation, parenteral or sublingual routes. Of the possible administration methods, oral or intravitreal administration is preferred. In the case of intravitreal injection, the preferred dose should not exceed 5 mg per eye.

[0395] The patient to be treated is preferably a mammal, especially a human patient.

[0396] Therefore, in another aspect, the present invention provides a compound of formula (I) and its tautomers, including pharmaceutically acceptable salts thereof, suitable for use as a medicament.

[0397] In another aspect, the invention provides a method for treating a disease or condition mediated by undesirable plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial in a patient in need thereof.

[0398] Likewise, the present invention provides a compound of formula (I) and / or its tautomer or a pharmaceutically acceptable salt thereof for use in a method for treating a disease or condition mediated by undesirable plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial in a patient in need thereof.

[0399] Likewise, the present invention provides the use of a compound of formula (I) and / or its tautomers or pharmaceutically acceptable salts thereof for the manufacture of a medicament for use in a method for treating a disease or condition mediated by undesirable plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial in a patient in need thereof.

[0400] Likewise, the present invention provides the use of a compound of formula (I) and / or a tautomer thereof or a pharmaceutically acceptable salt thereof in a method for treating a disease or condition mediated by undesirable plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial in a patient in need thereof.

[0401] According to one embodiment, the method of treatment comprises administering to a patient one or more compounds of formula (I) and / or tautomers thereof or pharmaceutically acceptable salts thereof, preferably administering to a patient a therapeutically effective amount of one or more compounds of formula (I) and / or tautomers thereof or pharmaceutically acceptable salts thereof.

[0402] According to another embodiment, the method for treatment comprises administering to a patient a pharmaceutical composition according to the invention.

[0403] According to one embodiment, the disease or condition mediated by undesirable plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial is selected from ophthalmic disorders such as diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV) and choroidal neovascularization (CNV).

[0404] According to another embodiment, the disease or condition mediated by undesirable plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial is selected from edema-related diseases, such as hereditary angioedema (HAE) and cerebral edema following stroke.

[0405] According to another embodiment, the disease or condition mediated by undesirable plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial is selected from diabetic complications, such as retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

[0406] According to one embodiment, the patient is a human patient.

[0407] Pharmaceutical composition

[0408] In another aspect of the present invention, it is described that the compounds of the present invention or pharmaceutically acceptable salts thereof can be used as active ingredients in pharmaceutical compositions.

[0409] Suitable formulations for administering the compounds of the invention (optionally in combination with one or more other therapeutic agents) will be apparent to those of ordinary skill in the art, and include, for example, tablets, pills, capsules, suppositories, lozenges, sugar-coated tablets, solutions, syrups, elixirs, sachets, injectables, inhalants, and powders, etc. Oral formulations, in particular solid forms such as tablets or capsules, are preferred. For intravitreal injection, solutions are preferred. The content of one or more pharmaceutically active compounds is advantageously in the range of 0.1 wt% to 90 wt% of the overall composition, for example 1 wt% to 70 wt% of the overall composition.

[0410] Suitable tablets can be obtained, for example, by mixing one or more compounds according to formula (I) with known excipients (e.g., inert diluents, carriers, disintegrants, adjuvants, surfactants, adhesives and / or lubricants). Tablets can also consist of several layers. Those skilled in the art will be familiar with specific excipients, carriers and / or diluents suitable for the desired formulation based on their professional knowledge. Preferred are those suitable for the desired specific formulation and method of administration. The preparations or formulations of the present invention can be prepared using methods known to the skilled person, such as by mixing or combining at least one compound of formula (I) of the present invention or a pharmaceutically acceptable salt of such a compound with one or more excipients, carriers and / or diluents.

[0411] Therefore, according to another aspect of the present invention, there is provided a pharmaceutical composition comprising one or more compounds of formula (I) and / or tautomers thereof or pharmaceutically acceptable salts thereof, optionally together with one or more inert carriers and / or diluents.

[0412] In addition, provided is a pharmaceutical composition comprising one or more of the above compounds or pharmaceutically acceptable salts thereof and optionally one or more inert carriers and / or diluents for use in a method for treating a disease or condition mediated by undesirable plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial in a patient in need thereof.

[0413] In particular, the present invention provides a pharmaceutical composition according to the present invention for use in a method for treating ocular disorders such as diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV) and choroidal neovascularization (CNV), and edema-related diseases such as hereditary angioedema (HAE) and cerebral edema after stroke.

[0414] Furthermore, the present invention relates to the use of a pharmaceutical composition according to the present invention for treating a disease or condition mediated by undesirable plasma kallikrein activity in a patient, preferably a human.

[0415] Furthermore, the present invention relates to the use of a pharmaceutical composition according to the invention for the treatment of a disease or condition which may be affected by the inhibition of plasma kallikrein in a preferably human patient.

[0416] According to another embodiment, there is provided a pharmaceutical composition comprising one or more compounds of formula (I) and / or tautomers thereof or pharmaceutically acceptable salts thereof and one or more additional therapeutic agents, optionally together with one or more inert carriers and / or diluents.

[0417] Preferably, the composition comprises a compound of formula (I) and / or a tautomer thereof or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents.

[0418] Combination therapy

[0419] The compounds of the present invention may further be combined with one or more, preferably one, additional therapeutic agent.

[0420] According to one embodiment, the additional therapeutic agent is selected from the group of therapeutic agents useful for treating the diseases or symptoms described above, in particular associated with metabolic diseases or symptoms, or therapeutic agents useful for treating ocular diseases, such as diabetes, obesity, diabetic complications, hypertension, hyperlipidemia.

[0421] Suitable additional therapeutic agents for use in these combinations include in particular those which, for example, potentiate the therapeutic effect of one or more active substances mentioned in connection with one of the indications and / or allow a dosage reduction of one or more active substances.

[0422] Thus, the compounds of the invention may be combined with one or more additional therapeutic agents selected from the group consisting of antidiabetic agents, agents for treating overweight and / or obesity, agents for treating hypertension, heart failure and / or atherosclerosis, and agents for treating ocular diseases.

[0423] For example, antidiabetic agents are metformin, sulfonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR-(α, γ or α / γ) agonists or modulators, α-glucosidase inhibitors, DPPIV inhibitors, SGLT2-inhibitors, insulin and insulin analogs, GLP-1 and GLP-1 analogs or amylin and amylin analogs, cycloset, 11β-HSD inhibitors. Other suitable combination partners are protein tyrosine phosphatase 1, inhibitors of substances that affect unregulated glucose production in the liver (such as glucose-6-phosphatase or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonist inhibitors and phosphoenolpyruvate carboxykinase inhibitors), glycogen synthase kinase or pyruvate dehydrogenase, α2-antagonists, CCR-2 antagonists or glucokinase activators. One or more lipid lowering agents are also suitable as combination partners, such as HMG-CoA-reductase inhibitors, fibrate esters, nicotinic acid and its derivatives, PPAR-(α, γ or α / γ) agonists or modulators, PPAR-δ agonists, ACAT inhibitors or cholesterol absorption inhibitors (such as bile acid binding substances, such as ileal bile acid transport inhibitors), MTP inhibitors or HDL raising compounds (such as CETP inhibitors or ABC1 modulators).

[0424] For example, therapeutic agents for treating overweight and / or obesity are cannabinoid receptor 1 antagonists, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists, β3-agonists, leptin or leptin mimetics, 5HT2c receptor agonists.

[0425] For example, therapeutic agents for the treatment of hypertension, chronic heart failure and / or atherosclerosis are A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics, β-blockers, Ca-antagonists, central antihypertensive agents, α-2-adrenergic receptor antagonists, neutral endopeptidase inhibitors, thrombocyte aggregation inhibitors and others or combinations thereof are suitable. Angiotensin II receptor antagonists are preferably used to treat or prevent hypertension and diabetic complications, often in combination with diuretics such as hydrochlorothiazide.

[0426] Therapeutic agents for treating ocular diseases may include, for example, intravitreally administered corticosteroids, intravitreally administered anti-VEGF therapeutics, anti-Ang2 inhibitors, dual anti-VEGF / anti-Ang2 inhibitors, anti-PDGF, dual anti-VEGF / anti-PDGF, VAP-1 (AOC3) inhibitors, complement inhibitors (e.g., complement factor 3, 5, B and D inhibitors), bradykinin receptor 1 antagonists, CCR-2 antagonists.

[0427] Additional treatments for eye diseases may include laser photocoagulation.

[0428] Preferably, the compounds of the present invention and / or pharmaceutical compositions comprising the compounds of the present invention, optionally in combination with one or more additional therapeutic agents, are administered in conjunction with exercise and / or diet.

[0429] The dosage of the above combination partners is usually 1 / 5 of the normally recommended minimum dosage to as high as 1 / 1 of the normally recommended dosage.

[0430] The use of the compounds according to the invention in combination with the additional therapeutic agent may be carried out simultaneously or at staggered times.

[0431] The compound according to the invention and the one or more additional therapeutic agents may both be present together in one formulation (eg a tablet or capsule) or separately in two identical or different formulations (eg as a so-called kit of parts).

[0432] In another aspect, the present invention relates to a pharmaceutical composition comprising one or more compounds according to the present invention and one or more additional therapeutic agents as described above and below and optionally one or more inert carriers and / or diluents.

[0433] According to another aspect, the present invention provides a method for treating a disease or condition mediated by undesirable plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial in a patient in need thereof, the method comprising administering to the patient one or more compounds of formula (I) and / or tautomers thereof or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents as described above and below. Preferably, one or more compounds of formula (I) and / or tautomers thereof or pharmaceutically acceptable salts thereof, and a therapeutically effective amount of one or more additional therapeutic agents as described above and below are administered to the patient.

[0434] Likewise, the present invention provides a compound of formula (I) and / or its tautomer or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents as described above and below, for use in a method for treating a disease or condition mediated by undesirable plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial in a patient in need thereof.

[0435] Likewise, the present invention provides the use of a compound of formula (I) and / or its tautomer or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents as described above and below, for the manufacture of a medicament for use in a method for treating a disease or condition mediated by undesirable plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial in a patient in need thereof.

[0436] Likewise, the present invention provides a compound of formula (I) and / or its tautomer or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents as described above and below, for use in a method for treating a disease or condition mediated by undesirable plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial in a patient in need thereof.

[0437] According to one embodiment, the method for treatment comprises administering to a patient one or more compounds of formula (I) and / or tautomers thereof or pharmaceutically acceptable salts thereof and one or more additional therapeutic agents as described above and below, preferably administering to a patient a therapeutically effective amount of one or more compounds of formula (I) and / or tautomers thereof or pharmaceutically acceptable salts thereof and a therapeutically effective amount of one or more additional therapeutic agents as described above and below.

[0438] According to another embodiment, the method for treatment comprises administering to a patient a pharmaceutical composition comprising one or more compounds according to the invention and one or more additional therapeutic agents as described above and below and optionally one or more inert carriers and / or diluents.

[0439] According to one embodiment, the one or more additional therapeutic agents are chosen from antidiabetic agents, agents for the treatment of overweight and / or obesity, agents for the treatment of hypertension, heart failure and / or atherosclerosis and agents for the treatment of eye diseases, in particular from those specifically mentioned above.

[0440] According to one embodiment, the disease or condition mediated by undesired plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial is selected from ophthalmic disorders such as diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV) and choroidal neovascularization (CNV); from edema-associated diseases such as hereditary angioedema (HAE) and cerebral edema after stroke; or from diabetic complications such as retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

[0441] According to one embodiment, the patient is a human patient.

[0442] Other features and advantages of the present invention will become apparent from the following more detailed examples which illustrate, by way of example, the principles of the invention.

[0443] Examples and experimental data

[0444] The following examples are for the purpose of illustrating the present invention only and are not intended to limit the scope of the present invention in any way.

[0445] abbreviation:

[0446] Acyl

[0447] ACN Acetonitrile

[0448] AMC 7-amino-4-methylcoumarin

[0449] Boc tertiary butoxycarbonyl

[0450] BSA bovine serum albumin

[0451] Bzl Benzyl

[0452] d day

[0453] DAD Diode Array Detector

[0454] DBAD Di-tertiary butyl azodicarboxylate

[0455] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0456] DBN 1,5-diazabicyclo[4.3.0]non-5-ene

[0457] DCM Dichloromethane

[0458] DEAD Diethyl azodicarboxylate

[0459] DIAD Diisopropyl azodicarboxylate

[0460] DIPEA N,N-Diisopropylethylamine

[0461] DMEM Dulbecco's Modified Eagle's Medium

[0462] DMF N,N-Dimethylformamide

[0463] DMSO Dimethyl sulfoxide

[0464] EDTA Ethylenediaminetetraacetate

[0465] ESI Electrospray ionization (in MS)

[0466] EtOAc Ethyl acetate

[0467] EtOH

[0468] h hour

[0469] HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0470] HPLC High Performance Liquid Chromatography

[0471] HPLC-MS coupled high performance liquid chromatography-mass spectrometry

[0472] LC Liquid Chromatography

[0473] LC-MS coupled liquid chromatography mass spectrometry

[0474] LG leaves the base

[0475] M molar concentration (mol / L)

[0476] MeOH Methanol

[0477] min

[0478] MS

[0479] NADPH Nicotinamide adenine dinucleotide phosphate

[0480] NMP N-Methyl-2-pyrrolidone

[0481] NMR Nuclear Magnetic Resonance

[0482] PET Polyethylene terephthalate

[0483] PyBop (Benzotriazol-1-yloxy)tripyrrolidiniumphosphonium hexafluorophosphate

[0484] R f Blocking factor

[0485] RFU relative fluorescence unit

[0486] RP Invert

[0487] rt room temperature

[0488] t R Retention time (by HPLC / LC)

[0489] SFC Supercritical Fluid Chromatography

[0490] TBTU O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate

[0491] TFA Trifluoroacetic acid

[0492] THF Tetrahydrofuran

[0493] UV

[0494] The terms "ambient temperature" and "room temperature" are used interchangeably and refer to a temperature of about 20°C, such as 15 to 25°C.

[0495] Typically, the compounds prepared have been obtained 1H-NMR and / or mass spectrometry.

[0496] Unless otherwise specified, compounds containing chiral centers have the depicted stereochemistry. Assignments of stereochemistry have been made by using chiral starting materials of known stereochemistry, by stereoselective synthesis of known stereochemistry, or by biological activities.

[0497] Analytical methods

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504] Synthesis of intermediates:

[0505] The starting materials and intermediates used in the process for producing the compounds according to the present invention are commercially available or they can be prepared by methods described in the literature, for example from the following documents WO 2017 / 072020, WO 2017 / 072021 and WO 2018 / 192866, or already known to those skilled in the art (or by methods similar or analogous to those methods), which are hereby incorporated by reference in their entirety.

[0506] Intermediate 1

[0507] (4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-amine dihydrochloride

[0508]

[0509] Step 1: 5-Bromo-1-methyl-1H-imidazole-4-carboxylic acid methyl ester

[0510] Under argon atmosphere, methyl 1-methyl-1H-imidazole-4-carboxylate (19.1 g) was dissolved in DCM (230 mL). N-bromosuccinimide (29.1 g), sodium persulfate (Na2S2O8, 64.9 g) and palladium-II-acetate (Pd(OAc)2, 3.1 g) were added successively and the mixture was cooled to 0°C. Trifluoromethanesulfonic acid (CF3-SO3H, 42.2 mL) was added dropwise and the mixture was then heated to 60°C for 20 hours. The mixture was diluted with DCM, cooled to 0°C and carefully treated with saturated aqueous Na2CO3 until the pH reached 8. The mixture was partitioned between water and DCM. The aqueous phase was extracted with DCM, the combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica gel (EtOAc / MeOH 85:15→70:30). The product thus obtained was triturated with tert-butyl-methyl-ether (50 mL) to afford the title compound.

[0511] LC (method 1): t R = 0.69 min; mass spectrometry (ESI + ): m / z = 219 [M + H] + .

[0512] Step 2: 5-(3-methoxy-3-oxopropyl)-1-methyl-1H-imidazole-4-carboxylic acid methyl ester

[0513] Methyl 5-bromo-1-methyl-1H-imidazole-4-carboxylate (10.6 g) was dissolved in dimethylacetamide (80 mL) and water (20 mL). 3,3-Dimethoxyprop-1-ene (8.6 mL) and N-methyldicyclohexylamine (15.3 mL) were added and the mixture was purged with argon for 5 minutes. Dichlorobis(tri-o-tolylphosphine)palladium(II) (PdCl2[P(o-Tol)3]2, 1.9 g) was added and the mixture was stirred at 120°C for 3 hours. The mixture was then partitioned between water and EtOAc and filtered through celite. The aqueous phase was mixed with a saturated aqueous solution of NaHCO3 and extracted 4 times with EtOAc. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica gel (EtOAc / MeOH 90:10→70:30) to give the title compound.

[0514] LC (method 2): t R = 0.55 min; mass spectrometry (ESI + ): m / z = 227 [M + H] + .

[0515] Step 3: 1-methyl-4-oxo-1H,4H,5H,6H-cyclopenta[d]imidazole-5-carboxylic acid methyl ester

[0516] Under argon atmosphere, potassium 5-(3-methoxy-3-oxopropyl)-1-methyl-1H-imidazole-4-carboxylate (4.5 g) was dissolved in THF (100 mL) and treated with potassium bis(trimethylsilyl)amide (40 mL of a 1 M solution in THF). The mixture was stirred for 30 minutes and then poured into a cooled mixture of EtOAc (800 mL) and acetic acid (7 mL). After stirring for 40 minutes, the mixture was filtered. The solvent was evaporated in vacuo to give the title compound.

[0517] LC (method 1): t R = 0.25 min; mass spectrometry (ESI + ): m / z = 195 [M + H] + .

[0518] Step 4: 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-one

[0519] A solution of methyl 1-methyl-4-oxo-1H,4H,5H,6H-cyclopenta[d]imidazole-5-carboxylate (4.0 g) in 1,4-dioxane (150 mL) and water (15 mL) was heated at reflux for 90 hours. The solvent was evaporated in vacuo to give the title compound. LC (Method 1): t R = 0.16 min; mass spectrometry (ESI + ): m / z = 137 [M + H] + .

[0520] Alternatively, the reaction can be carried out at 120°C by heating the starting material in a mixture of hydrogen chloride and acetic acid. After the reaction is complete, the solvent is evaporated in vacuo. The residue is dissolved in MeOH and treated with K2CO3 until the pH reaches 8. Filter, concentrate and chromatograph the mixture on silica gel (DCM / MeOH 20:1→5:1) to give the title compound.

[0521] Step 5: (R)-2-methyl-N-[(4E)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-ylidene]propane-2-sulfenamide

[0522] 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-one (2.94 g), toluene (120 mL) and tetraethoxytitanium (Ti(OEt)4, 13.6 mL) were stirred for 15 minutes and then treated with (R)-2-methylpropane-2-sulfinamide (5.25 g). The mixture was heated under reflux for 4 hours, cooled to room temperature and treated with saturated aqueous NaCl solution (30 mL). The mixture was stirred for 1 hour and then filtered through celite. The filter cake was stirred twice in MeOH (20 mL) for 10 minutes and filtered through celite. The combined organic phases were concentrated and the residue was chromatographed on silica gel (DCM / MeOH 95:5). The product thus obtained was triturated with EtOAc to give the title compound.

[0523] LC (method 3): t R = 3.69 minutes; mass spectrometry (ESI + ): m / z = 240 [M + H] + .

[0524] Step 6: (R)-2-methyl-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]propane-2-sulfenamide

[0525] Lithium tris(2-butylborohydride) (1 M in THF, 45 mL) was dissolved in THF (75 mL) and treated portionwise with (R)-2-methyl-N-[(4E)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-ylidene]propane-2-sulfenamide (7.2 g). The mixture was stirred for 1 hour and then treated dropwise with MeOH (5 mL). The solvent was evaporated in vacuo and the residue was chromatographed on silica gel (DCM / MeOH 95:5→80:20) to give the title compound.

[0526] LC (method 2): t R = 0.55 min; mass spectrometry (ESI + ): m / z = 242 [M + H] + LC (Method 3): t R =3.71 minutes.

[0527] Step 7: (4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-amine dihydrochloride

[0528] A mixture of (R)-2-methyl-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]propane-2-sulfenamide (7.25 g) in isopropanol (50 mL) was treated with a 1.25 M solution of HCl in isopropanol (50 mL) and stirred for 2 hours. The precipitate was collected by filtration, washed sequentially with isopropanol and diethyl ether and dried in vacuo to give the title compound. Mass Spectrum (ESI + ): m / z = 138 [M + H] + .

[0529] Intermediate 2

[0530] 5-{3-azabicyclo[3.1.0]hexan-3-yl}pyridine-2-carbaldehyde

[0531]

[0532] 5-Fluoropyridine-2-carbaldehyde (1.0 g), 3-azabicyclo[3.1.0]hexane hydrochloride (1.1 g) and K2CO3 (2.8 g) were suspended in NMP (10 mL) and heated to 120°C for 2 h. The mixture was cooled to room temperature, partitioned between water and EtOAc, and the phases were separated. The aqueous phase was extracted twice with EtOAc, the combined organic phases were dried (MgSO4) and concentrated. The residue was chromatographed on silica gel (cyclohexane / EtOAc 100:0→60:40) to give the title compound. LC (Method 2): t R = 0.68 min; mass spectrometry (ESI + ): m / z = 189 [M + H] + .

[0533] Intermediates 2-1 to 2-4 were prepared similarly to Intermediate 2:

[0534]

[0535]

[0536]

[0537] Intermediate 3

[0538] (5-{3-azabicyclo[3.1.0]hexan-3-yl}pyridin-2-yl)methanol

[0539]

[0540] NaBH4 (217 mg) was added portionwise to an ice-cold mixture of 5-{3-azabicyclo[3.1.0]hex-3-yl}pyridine-2-carbaldehyde (920 mg) in THF (10 mL) and MeOH (5 mL). The mixture was stirred at 0°C for 1 hour, treated with 1M aqueous HCl (10 mL) and stirred at room temperature for 30 minutes. The mixture was then partitioned between saturated aqueous NaHCO3 and EtOAc. The phases were separated. The organic phase was dried (MgSO4) and concentrated to give the title compound. LC (Method 2): t R = 0.59 min; mass spectrometry (ESI + ): m / z = 191 [M + H] + .

[0541] Intermediates 3-1 to 3-23 were prepared similarly to Intermediate 3:

[0542]

[0543]

[0544]

[0545]

[0546] Intermediate Reaction Notes 3-1 The reaction was carried out in EtOH. 3-5 The methyl ether was formed during stirring in the presence of 1 N aqueous HCl. 3-6 The methyl ether was formed during stirring in the presence of 1 N aqueous HCl. 3-7 The methyl ether was formed during stirring in the presence of 1 N aqueous HCl. 3-10 The reaction was carried out in EtOH. 3-12 The reaction was carried out in EtOH. 3-14 The reaction was carried out in THF / EtOH 1:2. 3-15 The reaction was carried out in EtOH at room temperature for 2 hours. 3-16 The reaction was carried out at 0°C for 2 hours. 3-17 The reaction was carried out at room temperature for 30 minutes. 3-18 The reaction was carried out in EtOH at room temperature for 1 hour. 3-19 The reaction was carried out at room temperature for 45 minutes. 3-20 The reaction was carried out at 0°C for 45 minutes. 3-21 The reaction was carried out at 0°C for 1 hour. 3-22 The reaction was carried out in EtOH at room temperature for 1.5 hours. 3-23 The reaction was carried out in EtOH at room temperature for 1 hour.

[0547]

[0548]

[0549] Intermediate 4

[0550] 1-[(5-{3-azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-1H-imidazole-4-carboxylic acid methyl ester

[0551]

[0552] In a microwave vial, a mixture of (5-{3-azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methanol (100 mg), methyl 1H-imidazole-4-carboxylate (77 mg) and p-toluenesulfonic acid (54 mg) in ACN (15 mL) was heated to 120° C. for 5 hours. After cooling to room temperature, the mixture was partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried (MgSO4) and concentrated. The residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

[0553] LC (method 2): t R= 0.71 min; mass spectrometry (ESI + ):m / z=313[M+H] + .

[0554] Intermediates 4-1 to 4-61 were prepared similarly to Intermediate 4:

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571] Intermediate 5

[0572] 1-[(5-{3-azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-1H-imidazole-4-carboxylic acid

[0573]

[0574] A mixture of ethyl 1-[(5-{3-azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-1H-imidazole-4-carboxylate (162 mg), MeOH (1 mL), THF (1 mL) and KOH (4 M aqueous solution, 648 μL) was stirred at 50° C. for 3 h. After cooling to room temperature, aqueous HCl (4 M, 648 μL) was added and the solvent was evaporated to give the crude product, which was used directly in the next step. LC (Method 2): t R = 0.58 min; mass spectrometry (ESI + ): m / z = 285 [M + H] + .

[0575] Intermediates 5-1 to 5-170 were prepared similarly to Intermediate 5:

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616] Intermediate 6

[0617] 2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridine-3-carbaldehyde

[0618]

[0619] A mixture of 2,6-dibromopyridine-3-carbaldehyde (5.0 g), 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride (3.0 g) and DIPEA (8 mL) in DMF (50 mL) was stirred at 50° C. under argon atmosphere for 12 hours. The mixture was cooled to room temperature, concentrated in vacuo, partitioned between water and EtOAc, and the phases were separated. The organic phase was washed with brine, dried (MgSO 4 ), concentrated, and the residue was chromatographed on silica gel (petroleum ether / EtOAc 85:15→70:30) to give the title compound.

[0620] LC (method 2): t R = 1.03 min; mass spectrometry (ESI + ): m / z = 303 [M + H] + .

[0621] Intermediates 6-1 to 6-19 were prepared similarly to Intermediate 6:

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629] Intermediate 7

[0630] (6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-vinylpyridin-3-yl)methanol

[0631]

[0632] In a microwave vial, a mixture of (2-bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methanol (100 mg), potassium vinyl trifluoroborate (60 mg), K2CO3 (125 mg) and THF (5 mL) was purged with argon for 10 min. 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)Cl2, 15 mg) was added, the vial was sealed and the mixture was stirred at 60° C. for 12 h. After cooling to room temperature, the mixture was diluted with MeOH and purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t R = 0.61 min; mass spectrometry (ESI + ): m / z = 253 [M + H] + .

[0633] Intermediates 7-1 to 7-9 were prepared similarly to Intermediate 7:

[0634]

[0635]

[0636]

[0637]

[0638] Intermediate 8

[0639] 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0640]

[0641] Under argon atmosphere, (6-{6,6-difluoro-3-azabicyclo[3.1.0]hexyl-3-yl}-2-vinylpyridin-3-yl)methanol (877 mg) and DIPEA (1.6 mL) were dissolved in DCM (25 mL). The mixture was cooled to 0°C and treated dropwise with methanesulfonyl chloride (CH3-SO2Cl, 318 μL). After stirring for 15 minutes, 1H-pyrazole-4-carboxylic acid ethyl ester (555 mg) was added and the mixture was stirred at room temperature for 3 hours. The mixture was then partitioned between water and DCM. The organic phase was dried (MgSO4), concentrated and the residue was chromatographed on silica gel (petroleum ether / EtOAc 100:0→70:30) to give the title compound. LC (Method 2): t R = 0.93 min; mass spectrometry (ESI + ): m / z = 375 [M + H]+ .

[0642] Intermediate 9

[0643] 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-formylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0644]

[0645] OsO4 (4% in water, 283 μL) was added to a mixture of ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (700 mg) in 1,4-dioxane (3.4 mL) and water (3.4 mL). The mixture was stirred for 30 minutes, treated with NaIO4 (1.2 g) and stirred at room temperature for 3 hours. The mixture was partitioned between water and EtOAc / MeOH (9:1). After separation of the phases, the organic phase was dried (MgSO4) and concentrated to give the title compound. LC (Method 2): t R = 1.06 min; mass spectrometry (ESI + ): m / z = 377 [M + H] + .

[0646] Intermediates 9-1 to 9-18 were prepared similarly to Intermediate 9:

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653] Intermediate 10

[0654] 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0655]

[0656] NaBH4 (40 mg) was added portionwise to an ice-cold mixture of ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-formylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (200 mg) in EtOH (5 mL). The mixture was stirred at room temperature for 2 hours, cooled to 0°C, treated with 4M aqueous HCl (599 μL) and stirred for 5 minutes. 4M aqueous NaOH (599 μL) was added and the mixture was diluted with EtOAc. After drying (MgSO4), the mixture was filtered and concentrated. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was dried (MgSO4) and concentrated to give the title compound. LC (Method 2): t R = 0.75 min; mass spectrometry (ESI + ): m / z = 379 [M + H] + .

[0657] Intermediates 10-1 to 10-11 were prepared similarly to Intermediate 10:

[0658]

[0659]

[0660]

[0661]

[0662]

[0663] Intermediate 11

[0664] 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0665]

[0666] To a solution of ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (89 mg) in DMF (250 μL) was added NaH (60% in mineral oil, 23 mg) at 0°C. The mixture was stirred for 15 minutes, treated with CH3I (17 μL) and stirred at room temperature for 12 hours. The solvent was evaporated in vacuo to give the crude product, which was used directly in the next step.

[0667] LC (method 2): t R= 0.83 min; mass spectrometry (ESI + ): m / z = 393 [M + H] + .

[0668] Intermediate 11-1 was prepared similarly to Intermediate 11:

[0669]

[0670] Intermediate Reaction Notes 11-1 <![CDATA[After adding CH3I, the reactants were stirred at room temperature for 1 hour.]]>

[0671]

[0672] Intermediate 12

[0673] 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester

[0674]

[0675] In a microwave vial, ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-formylpyridin-3-yl]-1H-1,2,3-triazole-4-carboxylate (763 mg) was dissolved in DCM (10 mL). Diethylaminosulfur trifluoride (DAST, 1 mL) was added, the vial was sealed and the mixture was heated to 50° C. for 12 hours. After cooling to room temperature, the mixture was cautiously treated with 1N aqueous NaHCO 3 solution until gas evolution ceased. The mixture was then partitioned between saturated aqueous NaHCO 3 and DCM. The phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried (MgSO 4 ) and concentrated. The residue was chromatographed on silica gel (petroleum ether / EtOAc 70:30→30:70) to give the title compound.

[0676] LC (method 2): t R = 1.05 min; mass spectrometry (ESI + ): m / z = 364 [M + H] + .

[0677] Intermediates 12-1 to 12-10 were prepared similarly to Intermediate 12:

[0678]

[0679]

[0680] Intermediate Reaction Notes 12-9 The reaction was carried out at 0°C and stirred for 1 hour. 12-10 The reaction was carried out at 0°C and stirred for 30 minutes.

[0681]

[0682]

[0683] Intermediate 13

[0684] 2-Chloro-4-[(1E)-2-phenylvinyl]pyrimidine-5-carboxylic acid ethyl ester

[0685]

[0686] In a microwave vial, a mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (2.5 g), potassium trans-β-phenylyltrifluoroborate (2.5 g), Na2CO3 (2M aqueous solution, 12.5 mL) and 1,4-dioxane (50 mL) was purged with argon for 10 minutes. Bis(di-tributyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Pd(amphos)2Cl2, 300 mg) was added, the vial was sealed and the mixture was heated to 50°C for 2 hours. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel (petroleum ether / EtOAc 80:20→60:40) to give the title compound.

[0687] LC (method 2): t R = 1.21 min; mass spectrometry (ESI + ): m / z = 289 [M + H] + .

[0688] Intermediates 13-1 to 13-2 were prepared similarly to Intermediate 13:

[0689]

[0690]

[0691]

[0692] Intermediate 14

[0693] 2-{3-azabicyclo[3.1.0]hex-3-yl}-4-[(1E)-2-phenylvinyl]pyrimidine-5-carboxylic acid ethyl ester

[0694]

[0695] Under argon atmosphere, a mixture of ethyl 2-chloro-4-[(1E)-2-phenylvinyl]pyrimidine-5-carboxylate (2.56 g), 3-azabicyclo[3.1.0]hexane hydrochloride (1.3 g) and KHCO (2.3 g) in THF (30 mL) was stirred at room temperature for 12 hours. The mixture was partitioned between saturated aqueous NH4Cl and EtOAc and the phases were separated. The organic phase was washed with brine, dried (MgSO4), concentrated and the residue was chromatographed on silica gel (petroleum ether / EtOAc 80:20→60:40) to give the title compound.

[0696] LC (method 2): t R = 1.27 minutes; mass spectrometry (ESI + ): m / z = 336 [M + H] + .

[0697] Intermediate 15

[0698] (2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-[(1E)-2-phenylvinyl]pyrimidin-5-yl)methanol

[0699]

[0700] A mixture of ethyl 2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-[(1E)-2-phenylvinyl]pyrimidine-5-carboxylate (1.96 g) in THF (40 mL) was treated dropwise with diisobutylaluminum hydride (DIBAH, 1 M in THF, 25 mL) under argon atmosphere. The mixture was stirred at room temperature for 2 hours, cooled to 0°C, and treated dropwise with 4M aqueous HCl solution (15 mL). The mixture was then stirred for 5 minutes and 4M aqueous NaOH solution (15 mL) was added. The mixture was partitioned between brine and DCM, and the layers were separated. The organic phase was dried (MgSO4), concentrated, and the residue was chromatographed on silica gel (DCM / MeOH 98:2→90:10) to give the title compound.

[0701] LC (method 2): t R = 0.84 min; mass spectrometry (ESI + ): m / z = 294 [M + H] + .

[0702] Intermediates 15-1 to 15-2 were prepared similarly to Intermediate 15:

[0703]

[0704]

[0705] Intermediate 16

[0706] 1-[(2-{3-azabicyclo[3.1.0]hex-3-yl}-4-[(1E)-2-phenylvinyl]pyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide

[0707]

[0708] Under argon atmosphere, a mixture of 1-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-[(1E)-2-phenylvinyl]pyrimidin-5-yl)-methyl]-1H-imidazole-4-carboxylic acid (240 mg) and DIPEA (380 μL) in DMF (3 mL) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (HATU, 280 mg). The mixture was stirred for 5 minutes and then treated with (4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-amine dihydrochloride (145 mg). After stirring for 1 hour, the mixture was partitioned between water and DCM. The organic phase was washed with brine, dried (MgSO4), concentrated and the residue was chromatographed on silica gel (DCM / MeOH 98:2→70:30) to give the title compound. LC (Method 1): t R = 1.02 min; mass spectrometry (ESI + ): m / z = 507 [M + H] + .

[0709] Intermediate 17

[0710] 1-[(5-{5-azaspiro[2.3]hexan-5-yl}pyridin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0711]

[0712] To a solution of (5-{5-azaspiro[2.3]hexan-5-yl}pyridin-2-yl)methanol (110 mg), ethyl 1H-pyrazole-4-carboxylate (122 mg) and triphenylphosphine (296 mg) in THF (2 mL) was added DIAD (222 μL) at 0°C. The mixture was stirred for 1 hour while warming to room temperature. The mixture was then diluted with MeOH and purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t R = 0.79 min; mass spectrometry (ESI + ): m / z = 313 [M + H] + .

[0713] Intermediate 17-1 was prepared similarly to Intermediate 17:

[0714]

[0715]

[0716] Intermediate 18

[0717] 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-ethylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester

[0718]

[0719] In a microwave vial, a mixture of ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-chloropyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylate (85 mg), ethylboronic acid (55 mg), K2CO3 (170 mg) and 1,4-dioxane (3 mL) was purged with argon for 10 min. 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)Cl2, 14 mg) was added, the vial was sealed and the mixture was heated to 80° C. for 12 h. Ethylboronic acid (65 mg), K2CO3 (100 mg) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)Cl2, 16 mg) were added and the mixture was heated to 90° C. for 5 h. After cooling to room temperature, the mixture was partitioned between water and EtOAc. The organic phase was washed with brine, dried (MgSO4), concentrated and the residue was chromatographed on silica gel (petroleum ether / EtOAc 85:15→60:40) to give the title compound. LC (Method 2): t R = 0.72 min; mass spectrometry (ESI + ): m / z = 342 [M + H] + .

[0720] Intermediates 18-1 to 18-4 were prepared similarly to Intermediate 18:

[0721]

[0722] Intermediate Reaction Notes 18-1 The reaction was carried out at 80°C for 12 hours. 18-2 The reaction was carried out at 80°C for 12 hours. 18-3 The reaction was carried out at 70°C for 5 hours. 18-4 The reaction was carried out at 80°C for 16 hours.

[0723]

[0724]

[0725] Intermediate 19

[0726] 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0727]

[0728] In a microwave vial, a mixture of 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (1.43 g), diethylzinc (1M in n-hexane, 6.18 mL) and 1,4-dioxane (60 mL) was purged with argon for 10 minutes. 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)Cl, 150 mg) was added, the vial was sealed and the mixture was heated to 70° C. for 1 hour. After cooling to room temperature, the mixture was cautiously treated with saturated aqueous NH4Cl solution. The mixture was partitioned between saturated aqueous NH4Cl solution and EtOAc. The aqueous phase was extracted twice with EtOAc. The organic phase was washed with brine, dried (MgSO4), concentrated and the residue was chromatographed on silica gel (petroleum ether / EtOAc 95:5→0:100) to give the title compound. LC (Method 2): t R = 0.75 min; mass spectrometry (ESI + ): m / z = 341 [M + H] + .

[0729] Intermediates 19-1 to 19-15 were prepared similarly to Intermediate 19:

[0730]

[0731]

[0732]

[0733]

[0734]

[0735] Intermediate 20

[0736] 1-[(6-{5-azaspiro[2.3]hexan-5-yl}pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester

[0737]

[0738] A mixture of ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-bromopyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylate (150 mg), 10% palladium on carbon (20 mg) in EtOH (4 mL) and THF (4 mL) was shaken at room temperature under a hydrogen atmosphere (3 bar) for 3.5 h. The mixture was filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): tR = 0.68 min; mass spectrum (ESI + ): m / z = 314 [M + H] + .

[0739] Intermediate 21

[0740] 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester

[0741]

[0742] In a microwave vial, a mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-bromopyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylate (250 mg), CsF (290 mg) and CuF (121 mg) in NMP (4 mL) was treated with difluoromethyltrimethylsilane (435 μL). The vial was sealed and the mixture was heated to 120° C. for 1.5 hours. The mixture was partitioned between a half-saturated aqueous solution of NaHCO 3 and EtOAc. The mixture was then filtered through celite and the filter cake was washed with EtOAc. The phases were separated and the aqueous phase was extracted twice with EtOAc. The combined organic phases were dried (MgSO 4 ), concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t R = 1.10 min; mass spectrometry (ESI + ): m / z = 364 [M + H] + .

[0743] Intermediate 22

[0744] 2-Chloro-4-propylpyrimidine-5-carboxylic acid ethyl ester

[0745]

[0746] In a microwave vial, a mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (1 g), n-propylzinc bromide (0.5 M in THF, 9.5 mL) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)Cl, 66 mg) in 1,4-dioxane (25 mL) was purged with argon for 10 minutes. The vial was sealed and the mixture was heated to 70° C. for 1 hour. Then n-propylzinc bromide (0.5 M in THF, 5 mL) was added and the mixture was heated to 70° C. for 45 minutes. After cooling to room temperature, the mixture was partitioned between EtOAc and saturated aqueous NH4Cl. The aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel (petroleum ether / EtOAc 98:2→90:10) to give the title compound.

[0747] LC (method 2): t R = 1.10 min; mass spectrometry (ESI + ): m / z = 229 [M + H] + .

[0748] Intermediate 23

[0749] 2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-propylpyrimidine-5-carboxylic acid ethyl ester

[0750]

[0751] Under argon atmosphere, a mixture of ethyl 2-chloro-4-propylpyrimidine-5-carboxylate (546 mg), 3-azabicyclo[3.1.0]hexane hydrochloride (328 mg) and KCO (663 mg) in DMF (15 mL) was stirred at room temperature for 2 hours. The mixture was partitioned between water and EtOAc and the phases were separated. The aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried (MgSO), concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

[0752] LC (method 2): t R = 1.09 min; mass spectrometry (ESI + ): m / z = 276 [M + H] + .

[0753] Intermediate 24

[0754] 5-{3-azabicyclo[3.1.0]hex-3-yl}-6-cyanopyridine-2-carboxylic acid methyl ester

[0755]

[0756] Under argon atmosphere, a mixture of methyl 5-bromo-6-cyanopyridine-2-carboxylate (500 mg), 3-azabicyclo[3.1.0]hexane hydrochloride (289 mg) and K2CO3 (717 mg) in NMP (5 mL) was stirred at 80°C for 12 hours. The mixture was poured into water. The precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound. LC (Method 2): t R = 0.92 min; mass spectrometry (ESI + ): m / z = 244 [M + H] + .

[0757] Intermediate 25

[0758] 3-{3-Azabicyclo[3.1.0]hex-3-yl}-6-(hydroxymethyl)pyridine-2-carbonitrile

[0759]

[0760] NaBH4 (131 mg) was added portionwise to a mixture of 5-{3-azabicyclo[3.1.0]hex-3-yl}-6-cyanopyridine-2-carboxylic acid methyl ester (280 mg) and CaCl2 (507 mg) in THF (8 mL) and EtOH (8 mL). The mixture was stirred at room temperature for 2 hours and at 45°C for 1 hour. The mixture was then partitioned between a saturated aqueous solution of NaHCO3 and EtOAc. The precipitate was filtered off. The aqueous phase was extracted with EtOAc. The combined organic phases were dried (MgSO4), concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

[0761] LC (method 1): t R = 0.81 min; mass spectrometry (ESI + ): m / z = 216 [M + H] + .

[0762] Intermediate 25-1 was prepared similarly to Intermediate 25:

[0763]

[0764]

[0765]

[0766] Intermediate 26

[0767] 6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(trifluoromethoxy)pyridine-3-carboxylic acid methyl ester

[0768]

[0769] Under argon atmosphere, a mixture of methyl 6-chloro-2-(trifluoromethoxy)pyridine-3-carboxylate (1 g), 3-azabicyclo[3.1.0]hexane hydrochloride (538 mg) and K2CO3 (1.1 g) in DMF (20 mL) was stirred at room temperature for 4 hours. The mixture was partitioned between water and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried (MgSO4), concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t R = 1.18 min; mass spectrometry (ESI + ): m / z = 303 [M + H] + .

[0770] Intermediate 27

[0771] 3-[5-(Methoxymethyl)-6-(trifluoromethoxy)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane

[0772]

[0773] LiBH4 (250 mg) was added portionwise to a mixture of methyl 6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(trifluoromethoxy)pyridine-3-carboxylate (384 mg) in THF (5 mL). The mixture was stirred at room temperature for 12 hours. The mixture was then poured into a 1N aqueous HCl solution and stirred vigorously for 20 minutes. Thereafter, the mixture was partitioned between a saturated aqueous solution of NaHCO3 and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried (MgSO4), concentrated, and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t R = 1.22 minutes; mass spectrometry (ESI + ): m / z = 289 [M + H] + .

[0774] Intermediate 28

[0775] 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0776]

[0777] In a microwave vial, a mixture of methyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (5.62 g), vinylboronic acid pinacol ester (2.9 mL), Na2CO3 (1M aqueous solution, 40.5 mL) and 1,4-dioxane (75 mL) was purged with argon for 10 minutes. 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)Cl2, 662 mg) was added, the vial was sealed and the mixture was heated to 100°C for 12 hours. After cooling to room temperature, the mixture was partitioned between water and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried (MgSO4), concentrated and the residue was chromatographed on silica gel (petroleum ether / EtOAc 100:0→50:50) to give the title compound.

[0778] LC (method 2): t R = 0.78 min; mass spectrometry (ESI + ): m / z = 339 [M + H] + .

[0779] Intermediates 28-1 to 28-5 were prepared similarly to Intermediate 28:

[0780]

[0781]

[0782]

[0783]

[0784] Intermediate 29

[0785] 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(cyanomethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0786]

[0787] To a solution of ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (400 mg), 2-hydroxy-2-methylpropionitrile (140 μL) and triphenylphosphine (460 mg) in THF (6 mL) was added DBAD (360 μL) dropwise. The mixture was stirred for 45 minutes. 2-Hydroxy-2-methylpropionitrile (140 μL), triphenylphosphine (460 mg) and DBAD (360 μL) were added successively and the mixture was stirred for another 45 minutes. The mixture was then diluted with THF and purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t R = 0.97 min; mass spectrometry (ESI + ): m / z = 352 [M + H] + .

[0788] Intermediate 30

[0789] 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(1-cyanocyclopropyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0790]

[0791] A mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(cyanomethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (212 mg) in DMSO (7 mL) was cooled to 10° C. and treated with NaH (60% in mineral oil, 60 mg) portionwise. The mixture was stirred at room temperature for 15 minutes, cooled to 0° C. and treated with 1,2-dibromoethane (80 μL). The mixture was then stirred at room temperature for 1 hour. After cooling to 0° C., the mixture was treated with saturated aqueous NH4Cl. The mixture was then extracted twice with EtOAc. The combined organic phases were washed with water, dried (MgSO4), concentrated and the residue was chromatographed on silica gel (petroleum ether / EtOAc 90:10→60:40) to give the title compound.

[0792] LC (method 2): t R = 1.06 min; mass spectrometry (ESI + ): m / z = 378 [M + H] + .

[0793] Intermediate 30-1 was prepared similarly to Intermediate 30:

[0794]

[0795] Intermediate Reaction Notes 30-1 <![CDATA[The reaction was carried out in DMF. CH3I was used instead of 1,2-dibromoethane.]]>

[0796]

[0797] Intermediate 31

[0798] 1-[(2-{3-azabicyclo[3.1.0]hex-3-yl}-4-[(1E)-2-phenylvinyl]pyrimidin-5-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0799]

[0800] SOCl2 (5 mL) was added to a mixture of (2-{3-azabicyclo[3.1.0]hex-3-yl}-4-[(1E)-2-phenylvinyl]pyrimidin-5-yl)methanol (1.89 g) in toluene (20 mL) under argon atmosphere. The mixture was heated to 60°C for 3 hours, cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (20 mL) and added dropwise to a mixture of ethyl 1H-pyrazole-4-carboxylate (950 mg) and DIPEA (2.2 mL) in DCM (20 mL). After stirring at room temperature for 12 hours, the mixture was partitioned between water and DCM. The organic phase was washed with brine, dried (MgSO4), concentrated and the residue was chromatographed on silica gel (petroleum ether / EtOAc 50:50→0:100) to give the title compound.

[0801] LC (method 2): t R = 1.06 min; mass spectrometry (ESI + ): m / z = 416 [M + H] + .

[0802] Intermediate 32

[0803] 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid

[0804]

[0805] To a solution of ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (900 mg) in DMF (10 mL) was added NaH (60% in mineral oil, 263 mg) at 0°C. The mixture was stirred for 30 minutes, treated with CH3I (222 μL) and stirred at 0°C for 1.5 hours. EtOH (4 mL) and aqueous NaOH solution (4 M, 4.2 mL) were added and the mixture was stirred at 70°C for 12 hours. After cooling to room temperature, aqueous HCl solution (4 M, 3 mL) was added and the mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t R = 0.62 min; mass spectrometry (ESI + ): m / z = 329 [M + H] + .

[0806] Intermediates 32-1 to 32-3 were prepared similarly to Intermediate 32:

[0807]

[0808]

[0809]

[0810] Intermediate 33

[0811] 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0812]

[0813] To an ice-cold solution of (6-{5-azaspiro[2.3]hexan-5-yl}-2-ethylpyridin-3-yl)methanol (400 mg), ethyl 1H-pyrazole-4-carboxylate (800 mg) and tributylphosphine (1.6 mL) in THF (10 mL) was added DBAD (1.35 g) dropwise. The mixture was stirred for 45 minutes. Saturated aqueous NaHCO3 was added and the mixture was stirred vigorously for 5 minutes. The mixture was then filtered through celite. The aqueous phase was extracted twice with EtOAc, and the combined organic phases were washed with brine and dried (MgSO4). The solvent was evaporated in vacuo and the residue was chromatographed on silica gel (petroleum ether / EtOAc 70:30→0:100) to give the title compound.

[0814] LC (method 2): tR = 0.78 min; mass spectrometry (ESI + ): m / z = 341 [M + H] + .

[0815] Intermediates 33-1 to 33-5 were prepared analogously to Intermediate 33:

[0816]

[0817]

[0818]

[0819]

[0820]

[0821] Intermediate 34

[0822] 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-[(1E)-3-(benzyloxy)prop-1-en-1-yl]pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0823]

[0824] In a microwave vial, a mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (100 mg), potassium (E)-3-(benzyloxy)propan-1-yl trifluoroborate (88 mg), K2CO3 (100 mg) and THF (5 mL) was purged with argon for 10 minutes. 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)Cl2, 15 mg) was added, the vial was sealed and the mixture was heated to 80°C for 15 hours. After cooling to room temperature, the mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), concentrated in vacuo and the residue was chromatographed on silica gel (petroleum ether / EtOAc 70:30→0:100) to give the title compound.

[0825] LC (method 2): t R = 0.95 min; mass spectrometry (ESI + ): m / z = 459 [M + H] + .

[0826] Intermediate 35

[0827] 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(3-hydroxypropyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0828]

[0829] A mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-[(1E)-3-(benzyloxy)prop-1-en-1-yl]pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (60 mg), 10% palladium on carbon (6 mg) in THF (2 mL) and acetic acid (8 μL) was shaken at room temperature under a hydrogen atmosphere (3 bar) for 12 hours. The mixture was filtered, the filtrate was concentrated and the residue was chromatographed on silica gel (petroleum ether / EtOAc 70:30→0:100) to give the title compound.

[0830] LC (method 2): t R = 0.73 min; mass spectrometry (ESI + ): m / z = 371 [M + H] + .

[0831] Intermediate 36

[0832] 3-[5-(Azidomethyl)-6-vinylpyridin-2-yl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane

[0833]

[0834] Under argon atmosphere, diphenylphosphoryl azide (1.4 mL) was added dropwise to an ice-cold mixture of (6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methanol (1.34 g) and DBU (1.05 mL) in toluene (10 mL) and ACN (10 mL). The mixture was stirred for 12 hours while warming to room temperature. The mixture was then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), concentrated in vacuo and the residue was chromatographed on silica gel (petroleum ether / EtOAc 99:1→50:50) to give the title compound. LC (Method 2): t R = 0.88 min; mass spectrometry (ESI + ): m / z = 278 [M + H] + .

[0835] Intermediates 36-1 to 36-5 were prepared similarly to Intermediate 36:

[0836]

[0837]

[0838]

[0839]

[0840] Intermediate 37

[0841] 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-vinylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester

[0842]

[0843] A mixture of 3-[5-(azidomethyl)-6-vinylpyridin-2-yl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane (794 mg), ethyl propiolate (320 μL), CuSO4 (92 mg) and (L)-sodium ascorbate (568 mg) in tert-butyl alcohol (8 mL) and water (8 mL) was stirred at room temperature for 48 hours. The mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), concentrated in vacuo and the residue was chromatographed on silica gel (petroleum ether / EtOAc 99:1→50:50) to give the title compound.

[0844] LC (method 2): t R = 0.89 min; mass spectrometry (ESI + ): m / z = 376 [M + H] + .

[0845] Intermediates 37-1 to 37-5 were prepared analogously to Intermediate 37:

[0846]

[0847]

[0848] Intermediate Reaction Notes 37-3 The reaction was carried out for 12 hours. 37-5 The reaction was carried out for 5 days.

[0849]

[0850] Intermediate 38

[0851] 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid

[0852]

[0853] To a solution of ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylate (175 mg) in DMF (2 mL) was added NaH (60% in mineral oil, 45 mg) at 0°C. The mixture was stirred at room temperature for 30 minutes, treated with CH3I (30 μL) and stirred at room temperature for 12 hours. Water was added and the mixture was concentrated in vacuo. The residue was dissolved in DCM / isopropanol 1:1 and filtered. The filtrate was dried (MgSO4) and concentrated in vacuo to give the title compound.

[0854] LC (method 2): t R = 0.65 min; mass spectrometry (ESI + ): m / z = 366 [M + H] + .

[0855] Intermediate 39

[0856] 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(1-hydroxypropen-2-yl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0857]

[0858] A mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(prop-1-en-2-yl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (270 mg) and 9-borabicyclo(3.3.1)nonane (3.1 mL) was stirred at room temperature for 48 hours. 9-borabicyclo(3.3.1)nonane (6 mL) was added and stirring was continued for 12 hours. The mixture was cooled to 0°C and treated dropwise with water (3 mL) and H2O2 (35% in water, 3.35 mL). The mixture was then stirred at room temperature for 30 minutes. Aqueous NaOH solution (2 M, 340 μL) was added, the mixture was stirred for 20 minutes and then cooled to 0°C. A saturated aqueous solution of Na2S2O3 was slowly added and the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), concentrated in vacuo and the residue was chromatographed on silica gel (petroleum ether / EtOAc 80:20→0:100) to give the title compound. LC (Method 2): t R = 0.76 min; mass spectrometry (ESI + ): m / z = 371 [M + H] + .

[0859] Intermediate 39-1 was prepared similarly to Intermediate 39:

[0860]

[0861]

[0862]

[0863] Intermediate 40

[0864] 6-{3-azabicyclo[3.1.0]hexan-3-yl}pyridazine-3-carboxylic acid methyl ester

[0865]

[0866] Under argon atmosphere, a mixture of methyl 6-chloropyridazine-3-carboxylate (2.5 g), 3-azabicyclo[3.1.0]hexane hydrochloride (1.99 g) and K2CO3 (4.02 g) in DMF (50 mL) was stirred at room temperature for 12 hours. The mixture was partitioned between water and EtOAc and stirred for 20 minutes. The precipitate was collected by filtration and dried in vacuo to give the title compound. LC (Method 2): t R = 0.60 min; mass spectrometry (ESI + ): m / z = 220 [M + H] + .

[0867] Intermediates 40-1 to 40-8 were prepared similarly to Intermediate 40:

[0868]

[0869]

[0870]

[0871]

[0872]

[0873] Intermediate 41

[0874] (6-{3-azabicyclo[3.1.0]hexan-3-yl}pyridazin-3-yl)methanol

[0875]

[0876] NaBH4 (76 mg) was added portionwise to a mixture of methyl 6-{3-azabicyclo[3.1.0]hex-3-yl}pyridazine-3-carboxylate (200 mg) and CaCl2 (54 mg) in MeOH (4 mL). The mixture was stirred at 70°C for 24 hours. After cooling to room temperature, 1M aqueous HCl was added until the pH reached 2. The mixture was stirred for 15 minutes and then partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous phase was extracted twice with EtOAc and twice with EtOAc / isopropanol 1:1. The combined organic phases were dried (MgSO4), concentrated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

[0877] LC (method 1): t R = 0.67 min; mass spectrometry (ESI + ): m / z = 192 [M + H] + .

[0878] Intermediate 41-1 was prepared similarly to Intermediate 41:

[0879]

[0880]

[0881] Intermediate Reaction Notes 41-1 The reaction was carried out in THF / EtOH 1:1 at room temperature for 8 hours.

[0882]

[0883] Intermediate 42

[0884] 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}pyridazin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0885]

[0886] To a solution of (6-{3-azabicyclo[3.1.0]hexan-3-yl}pyridazin-3-yl)methanol (105 mg), ethyl 1H-pyrazole-4-carboxylate (81 mg) and triphenylphosphine (166 mg) in THF (2 mL) was added DBAD (139 mg). The mixture was stirred for 1.5 h, diluted with DMF and purified by reverse phase HPLC (ACN, water) to give the title compound.

[0887] LC (method 2): t R = 0.68 min; mass spectrometry (ESI + ): m / z = 314 [M + H] + .

[0888] Intermediates 42-1 to 42-2 were prepared similarly to Intermediate 42:

[0889]

[0890]

[0891]

[0892] Intermediate 43

[0893] 1-[(5-bromopyrimidin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0894]

[0895] A mixture of 5-bromo-2-(bromomethyl)pyrimidine (1.5 g), KCO (2.4 g) and ethyl 1H-pyrazole-4-carboxylate (814 mg) in DMF (20 mL) was stirred at room temperature for 1.5 h. The mixture was diluted with THF and filtered through celite. The filter cake was washed twice with THF. The combined filtrate was concentrated and the residue was chromatographed on silica gel (petroleum ether / EtOAc 80:20→0:100) to give the title compound.

[0896] LC (method 1): t R = 0.85 min; mass spectrometry (ESI + ): m / z = 311 [M + H] + .

[0897] Intermediate 44

[0898] 1-[(5-{3-azabicyclo[3.1.0]hexan-3-yl}pyrimidin-2-yl,)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0899]

[0900] In a microwave vial, a mixture of ethyl 1-[(5-bromopyrimidin-2-yl)methyl]-1H-pyrazole-4-carboxylate (500 mg), 3-azabicyclo[3.1.0]hexane hydrochloride (384 mg), Cs2CO3 (1.6 g), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3, 74 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (Xantphos, 93 mg) in DMF (1.3 mL) and toluene (3.8 mL) was purged with argon for 10 minutes. The vial was sealed and the mixture was heated to 90° C. for 2 hours. The mixture was then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were dried (MgSO 4 ), concentrated in vacuo and the residue was chromatographed on silica gel (petroleum ether / EtOAc 90:10→20:80) to give the title compound. LC (Method 1 ): t R = 0.91 min; mass spectrometry (ESI + ): m / z = 314 [M + H] + .

[0901] Intermediate 45

[0902] (6-{3-azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methanol

[0903]

[0904] A mixture of methyl 6-{3-azabicyclo[3.1.0]hex-3-yl}pyridine-3-carboxylate (8 g) and LiBH4 (2M THF solution, 20 mL) in THF (60 mL) and MeOH (3 mL) was stirred at 60°C for 12 hours. LiBH4 (2M THF solution, 5 mL) was added and the mixture was stirred at 60°C for 2 hours. The mixture was then cooled to 0°C and carefully treated with water. The mixture was concentrated and the residue was partitioned between water and EtOAc. The organic phase was dried (MgSO4), concentrated and the residue was chromatographed on silica gel (DCM / MeOH 0:100→90:10) to give the title compound. LC (Method 1): t R = 0.79 min; mass spectrometry (ESI + ): m / z = 191 [M + H] + .

[0905] Intermediates 45-1 to 45-3 were prepared similarly to Intermediate 45:

[0906]

[0907] Intermediate Reaction Notes 45-2 The reaction was carried out in 1,4-dioxane / MeOH 15:1 at room temperature for 3 hours. 45-3 The reaction was carried out at 50°C for 12 hours.

[0908]

[0909] Intermediate 46

[0910] 1-[(6-{5-azaspiro[2.3]hexan-5-yl}pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid trifluoroacetate

[0911]

[0912] To an ice-cold solution of (6-{5-azaspiro[2.3]hexan-5-yl}pyridin-3-yl)methanol (170 mg), ethyl 1H-pyrazole-4-carboxylate (130 mg) and tributylphosphine (450 μL) in THF (5 mL) was added DBAD (338 mg) dropwise. The mixture was stirred for 48 hours. The mixture was then concentrated in vacuo. The residue was dissolved in MeOH (10 mL) and aqueous NaOH solution (1 M, 5 mL) and stirred at room temperature for 2 hours. After neutralization with trifluoroacetic acid, the crude product was purified by reverse phase HPLC (ACN, water) to give the title compound.

[0913] LC (method 1): t R = 0.65 min; mass spectrometry (ESI + ): m / z = 285 [M + H] + .

[0914] Intermediate 47

[0915] 1-[(6-{5-azaspiro[2.3]hexan-5-yl}pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid trifluoroacetate

[0916]

[0917] In a microwave vial, a mixture of (6-{5-azaspiro[2.3]hex-5-yl}pyridin-3-yl)methanol (85 mg), ethyl 1H-imidazole-4-carboxylate (76 mg) and p-toluenesulfonic acid (90 mg) in ACN (4 mL) was heated to 75 ° C for 48 hours, to 90 ° C for 3 hours, to 100 ° C for 3 hours and to 80 ° C for 12 hours. After cooling to room temperature, the mixture was diluted with ACN and purified by reverse phase HPLC (ACN, water). The product thus obtained was dissolved in MeOH (2 mL) and aqueous NaOH solution (1 M, 500 μL). After stirring at room temperature for 2 hours, the mixture was neutralized with trifluoroacetic acid and purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t R = 0.40 min; mass spectrometry (ESI + ): m / z = 285 [M + H] +.

[0918] Intermediate 48

[0919] 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-formylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide

[0920]

[0921] A mixture of 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide (19 mg) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzoiodooxol-3-(1H)-one (Dess-Martinperiodinane, 26 mg) in DCM (2 ml) was stirred at room temperature for 3 hours. The mixture was partitioned between saturated aqueous NaHCO3 and DCM. The aqueous phase was extracted three times with DCM. The combined organic phases were dried (Na2SO4) and concentrated in vacuo to give the title compound.

[0922] LC (method 1): t R = 0.89 min; mass spectrometry (ESI + ): m / z = 469 [M + H] + .

[0923] Intermediate 48-1 was prepared similarly to Intermediate 48:

[0924]

[0925] Intermediate Reaction Notes 48-1 The crude product was chromatographed on silica gel (petroleum ether / EtOAc 95:5→70:30) to give the title compound.

[0926]

[0927] Intermediate 49

[0928] Ethyl 6-{5-azaspiro[2.3]hexan-5-yl}-3-{[4-(ethoxycarbonyl)-1H-imidazol-1-yl]methyl}pyridine-2-carboxylate

[0929]

[0930] A mixture of ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylate (860 mg), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2, 200 mg) and triethylamine (1.1 mL) in EtOH (60 mL) was heated to 130° C. under 10 bar of carbon monoxide for 5 hours. The solvent was evaporated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

[0931] LC (method 2): t R = 0.89 min; mass spectrometry (ESI + ): m / z = 385 [M + H] + .

[0932] Intermediates 49-1 to 49-4 were prepared analogously to Intermediate 49:

[0933]

[0934]

[0935] Intermediate Reaction Notes 49-3 The reaction was carried out at 90°C under 5 bar of carbon monoxide atmosphere. 49-4 The reaction was carried out at 100°C for 14 hours under 4 bar of carbon monoxide atmosphere.

[0936]

[0937] Intermediate 50

[0938] 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylate bis(trifluoroacetic acid)ethyl ester

[0939]

[0940] LiBH4 (150 mg) was added portionwise to a mixture of ethyl 6-{5-azaspiro[2.3]hexan-5-yl}-3-{[4-(ethoxycarbonyl)-1H-imidazol-1-yl]methyl}pyridine-2-carboxylate (705 mg) in THF (15 mL). The mixture was stirred at room temperature for 2 h, cooled to 0°C, treated with aqueous HCl (4 M, 2 mL) and purified by reverse phase HPLC (ACN, water) to give the title compound.

[0941] LC (method 1): t R = 0.91 min; mass spectrometry (ESI + ): m / z = 343 [M + H] + .

[0942] Intermediates 50-1 to 50-2 were prepared similarly to Intermediate 50:

[0943]

[0944]

[0945] Intermediate 51

[0946] 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid trifluoroacetate

[0947]

[0948] To an ice-cold solution of (6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methanol (158 mg), ethyl 1H-pyrazole-4-carboxylate (100 mg) and tributylphosphine (210 μL) in THF (2 mL) was added DBAD (190 mg) dropwise. The mixture was stirred for 30 minutes and then treated with aqueous NaOH (4 M, 750 μL). After stirring at room temperature for 12 hours, aqueous HCl (4 M, 750 μL) was added and the mixture was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t R = 0.63 min; mass spectrometry (ESI + ): m / z = 321 [M + H] + .

[0949] Intermediate 52

[0950] 1-[(6-{3-azabicyclo[3-1.0]hex-3-yl}-2-(1-hydroxyethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0951]

[0952] CH3MgBr (3M in diethyl ether, 1.22 mL) was added dropwise to a mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]-hex-3-yl}-2-formylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (1 g) in THF (20 mL) at -40°C. The mixture was stirred for 25 minutes while warming to -25°C. Aqueous HCl (1 M, 4 mL) was added. After stirring for 5 minutes, the mixture was partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound.

[0953] LC (method 2): t R= 0.73 min; mass spectrometry (ESI + ): m / z = 357 [M + H] + .

[0954] Intermediate 52-1 was prepared similarly to Intermediate 52:

[0955]

[0956] Intermediate Reaction Notes 52-1 The reaction was carried out at -10°C.

[0957]

[0958] Intermediate 53

[0959] 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-[(1R)-1-hydroxyethyl]pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0960]

[0961] Triethylamine (246 μL) was dissolved in DCM (3 mL), cooled to 0°C and treated successively with formic acid (75 μL), ethyl 1-[(2-acetyl-6-[3-azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (200 mg) and chloro[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}(grass rice)ruthenium(II) (RuCI[(R,R)-Tsdpen(grass rice), 23 mg]. The mixture was stirred for 24 h while warming to room temperature. The mixture was concentrated, dissolved in THF (5 mL) and treated with a solution of NH3 in MeOH (7 M, 1 mL) and water (1 mL). The mixture was then purified by reverse phase HPLC (ACN, water) to give the title compound.

[0962] LC (method 1): t R = 1.03 min; mass spectrometry (ESI + ): m / z = 357 [M + H] + .

[0963] Intermediate 53-1 was prepared similarly to Intermediate 53:

[0964]

[0965] Intermediate Reaction Notes 53-1 RuCl[(S,S)-Tsdpen(grass rice) was used instead of RuCl[(R,R)-Tsdpen(grass rice).

[0966]

[0967] Intermediate 54

[0968] (5-{3-azabicyclo[3.1.0]hexan-3-yl}-3-chloropyrazin-2-yl)methanol

[0969]

[0970] LiBH4 (744 mg) was added portionwise to an ice-cold mixture of 5-{3-azabicyclo[3.1.0]hex-3-yl}-3-chloropyrazine-2-carboxylic acid methyl ester (4.33 g) in THF (80 mL). The mixture was stirred at room temperature for 2 hours. After cooling to 0°C, an aqueous solution of HCl (4M, 10 mL) was added and the mixture was stirred for 10 minutes. The mixture was then partitioned between a saturated aqueous solution of NaHCO3 and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried (MgSO4), concentrated in vacuo and the residue was chromatographed on silica gel (petroleum ether / EtOAc 80:20→50:50) to give the title compound. LC (Method 2): t R = 0.85 min; mass spectrometry (ESI + ): m / z = 226 [M + H] + .

[0971] Intermediate 55

[0972] 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0973]

[0974] Under argon atmosphere, an ice-cold mixture of (6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methanol (20 g) and DIPEA (32 mL) in DCM (400 mL) was treated dropwise with CH3SO2Cl (7.2 mL). The mixture was stirred for 15 minutes and then treated with 1H-pyrazole-4-carboxylic acid ethyl ester (12 g). After stirring at room temperature for 4 hours, the mixture was partitioned between water and DCM. The organic phase was dried (MgSO4) and concentrated by evaporation in vacuo to give the crude product, which was used directly in the next step.

[0975] LC (method 2): t R = 0.76 min; mass spectrometry (ESI + ): m / z = 363 [M + H] + .

[0976] Intermediate 55-1 was prepared similarly to Intermediate 55:

[0977]

[0978] Intermediate Reaction Notes 55-1 After addition of ethyl 1H-pyrazole-4-carboxylate, the reaction mixture was stirred at room temperature for 12 hours.

[0979]

[0980] Intermediate 56

[0981] 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid

[0982]

[0983] To a solution of ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylate (86 mg) in DMF (2 mL) was added NaH (60% in mineral oil, 25 mg) at 0°C. The mixture was stirred at room temperature for 30 minutes, treated with CH3I (16 μL) and stirred for 12 hours. Water was added cautiously. The mixture was concentrated in vacuo and the residue was dissolved in DCM / isopropanol 1:1. The mixture was then filtered and the filtrate was concentrated in vacuo to give the crude product, which was used directly in the next step.

[0984] LC (method 2): t R = 0.58 min; mass spectrometry (ESI + ): m / z = 330 [M + H] + .

[0985] Intermediates 56-1 to 56-2 were prepared similarly to Intermediate 56:

[0986]

[0987]

[0988]

[0989] Intermediate 57

[0990] 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methoxypyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid

[0991]

[0992] A mixture of ethyl 1-[(2-bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazole-4-carboxylate (190 mg) and NaOCH3 (1 M in MeOH, 4.5 mL) was heated to 155°C for 2.5 hours and to 165°C for 3 hours. Purification by reverse phase HPLC (ACN, water) gave the title compound. LC (Method 2): t R =0.84 minutes.

[0993] Intermediate 57-1 was prepared similarly to Intermediate 57:

[0994]

[0995]

[0996]

[0997] Intermediate 58

[0998] 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid

[0999] Intermediate 58-1

[1000] 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

[1001]

[1002] LiBH4 (356 mg) was added portionwise to a mixture of ethyl 6-{3-azabicyclo[3.1.0]hexan-3-yl}-3-{[4-(ethoxycarbonyl)-1H-imidazol-1-yl]methyl}pyridine-2-carboxylate (1.65 g) in THF (25 mL). The mixture was stirred at room temperature for 14 hours, cooled to 0°C, and treated with aqueous HCl (1 M, 5 mL). The mixture was then neutralized by the addition of NaOH (4 M) and purified by reverse phase HPLC (ACN, water) to give the title compound.

[1003] 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid:

[1004] LC (method 1): t R = 0.64 min; mass spectrometry (ESI + ): m / z = 315 [M + H]+ .

[1005] 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester:

[1006] LC (method 1): t R = 0.94 min; mass spectrometry (ESI + ): m / z = 343 [M + H] + .

[1007] Intermediate 59

[1008] 2-Hydroxy-5-iodo-4-methylpyridine-3-carbonitrile

[1009]

[1010] Under argon atmosphere, an ice-cold mixture of 2-hydroxy-4-methylpyridine-3-carbonitrile (3 g) in DCM (100 mL) was treated with trifluoroacetic acid (5 mL). N-iodosuccinimide (7.55 g) was then added portionwise. The mixture was stirred for 3 hours while warming to room temperature. The mixture was concentrated in vacuo, a half-saturated aqueous solution of Na2S2O3 was added and the mixture was stirred for 10 minutes. The precipitate was collected by filtration, washed with water and diethyl ether and dried in vacuo to give the title compound. LC (Method 2): t R = 0.72 min; mass spectrometry (ESI + ): m / z = 261 [M + H] + .

[1011] Intermediate 60

[1012] 2-Oxy-5-iodo-4-methylpyridine-3-carbonitrile

[1013]

[1014] The mixture of 2-hydroxy-5-iodo-4-methylpyridine-3-carbonitrile (6.27 g) in POCl was stirred at 100 ° C for 5 hours. The mixture was concentrated in vacuo. The residue was dissolved in DCM (200 mL) and treated with water. Then the mixture was neutralized by carefully adding NaHCO saturated aqueous solution. Each phase was separated and the aqueous phase was extracted twice with DCM. The combined organic phase was washed with NaHCO saturated aqueous solution, dried (MgSO ) and concentrated in vacuo to give a crude product, which was directly used in the next step.

[1015] LC (method 1): t R = 1.02 min; mass spectrometry (ESI + ): m / z = 278 [M + H]+ .

[1016] Intermediate 61

[1017] 2-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-5-formyl-4-methylpyridine-3-carbonitrile

[1018]

[1019] A mixture of 2-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-5-iodo-4-methylpyridine-3-carbonitrile (2.3 g) in THF (30 mL) was cooled to -78 °C, treated dropwise with isopropylmagnesium chloride (iPrMgCl, 2M THF solution, 3.82 mL) and stirred for 30 minutes. The mixture was then warmed to 0 °C, treated dropwise with DMF (2.47 mL) and stirred for 40 minutes. Water was carefully added and the mixture was partitioned between a half-saturated aqueous solution of NH4Cl and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic phases were concentrated in vacuo to give the crude product, which was used directly in the next step.

[1020] LC (method 2): t R = 0.96 min; mass spectrometry (ESI + ): m / z = 264 [M + H] + .

[1021] Intermediate 61-1 was prepared similarly to Intermediate 61:

[1022]

[1023]

[1024] Intermediate 62

[1025] N′-[(E)-(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methylene]acetohydrazide

[1026]

[1027] A mixture of 6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridine-3-carbaldehyde (5.8 g) and acetic hydrazide (2.36 g) in MeOH (100 mL) was refluxed for 12 h. The mixture was concentrated in vacuo, dissolved in toluene, treated with p-toluenesulfonic acid (100 mg) and refluxed in a Dean-Stark apparatus for 16 h. The precipitate was collected by filtration, washed with tertiary butyl-methyl-ether and dried in vacuo to give the title compound. LC (Method 2): tR = 0.64 min; mass spectrum (ESI + ): m / z = 295 [M + H] + .

[1028] Intermediate 62-1 was prepared similarly to Intermediate 62:

[1029]

[1030]

[1031] Intermediate 63

[1032] N′-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]acetohydrazide

[1033]

[1034] A mixture of N'-[(E)-(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methylene]acetohydrazide (5.6 g) and 10% palladium / carbon (300 mg) in MeOH (80 mL) and THF (20 mL) was shaken at room temperature under a hydrogen atmosphere (3 bar) for 3.5 hours. The mixture was filtered, the filtrate was concentrated and the residue was dissolved in tert-butyl-methyl-ether (100 mL) and EtOAc (10 mL). After stirring for 3 hours, the precipitate was collected by filtration, washed with tert-butyl-methyl-ether and dried in vacuo to give the title compound.

[1035] LC (method 2): t R = 0.58 min; mass spectrometry (ESI + ): m / z = 297 [M + H] + .

[1036] Intermediate 63-1 was prepared similarly to Intermediate 63:

[1037]

[1038]

[1039] Intermediate 64

[1040] 3-(Chloromethyl)-1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[1041]

[1042] A mixture of N'-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]acetohydrazide (1.9 g) and ethyl 4-chloro-2-(ethoxymethylene)-3-oxobutanoate (1.68 g) in EtOH (30 mL) was stirred at room temperature for 12 hours. The mixture was concentrated and then partitioned between DCM and saturated aqueous Na2CO3. The aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound. LC (Method 2): t R = 0.82 min; mass spectrometry (ESI + ): m / z = 411 [M + H] + .

[1043] Intermediate 64-1 was prepared similarly to Intermediate 64:

[1044]

[1045]

[1046] Intermediate 65

[1047] 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(cyanomethyl)-1H-pyrazole-4-carboxylic acid ethyl ester

[1048]

[1049] A mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(chloromethyl)-1H-pyrazole-4-carboxylate (700 mg) and KCN (250 mg) in DMSO (5 mL) and water (2 mL) was heated to 85° C. for 2 hours. The mixture was partitioned between water and EtOAc. The aqueous phase was extracted 4 times with EtOAc. The combined organic phases were washed with brine, dried (MgSO ) and concentrated in vacuo to give the title compound.

[1050] LC (method 2): tR = 0.74 min; mass spectrometry (ESI + ): m / z = 366 [M + H] + .

[1051] Intermediate 66

[1052] 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(cyanomethyl)-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide

[1053]

[1054] A mixture of 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(cyanomethyl)-1H-pyrazole-4-carboxylic acid (230 mg), DIPEA (466 μL) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (HATU, 272 mg) in DMF (4 mL) was stirred for 5 minutes. (4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-amine dihydrochloride (143 mg) was added and the mixture was stirred for 2 hours. The mixture was partitioned between water and EtOAc. The aqueous phase was extracted three times with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), concentrated in vacuo and purified on silica gel (DCM / (DCM / MeOH / 7N NH3 in MeOH 50:48:2) 90:10→60:40) to give the title compound.

[1055] LC (method 2): t R = 0.63 min; mass spectrometry (ESI + ): m / z = 457 [M + H] + .

[1056] Intermediates 66-1 to 66-4 were prepared analogously to Intermediate 66:

[1057]

[1058]

[1059] Intermediate Reaction Notes 66-3 The product was obtained as a mixture of isomers. 66-4 The product was obtained as a mixture of isomers.

[1060]

[1061]

[1062] Intermediate 67

[1063] 2-{1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-4-{[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]carbamoyl}-1H-pyrazol-3-yl}acetate

[1064]

[1065] A mixture of 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(cyanomethyl)-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide (330 mg) in CHCOOH (2 mL) and concentrated aqueous HCl (2 mL) was heated to 110° C. for 1 hour. The mixture was cooled to room temperature, treated with aqueous NaOH (4 M, 15 mL) and stirred for 10 minutes. Aqueous HCl (4 M, 15 mL) was then added and the mixture was washed twice with EtOAc. The aqueous phase was concentrated in vacuo and the residue was added to a mixture of acetyl chloride (50 μL) in MeOH (10 mL). The mixture was heated to 90° C. for 90 minutes. After cooling to room temperature, the mixture was neutralized with aqueous NaOH solution (1 M), concentrated in vacuo and the residue was chromatographed on silica gel (cyclohexane / EtOAc 90:10→70:30) to give the title compound.

[1066] LC (method 2): t R = 0.63 min; mass spectrometry (ESI + ): m / z = 490 [M + H] + .

[1067] Intermediate 68

[1068] 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

[1069]

[1070] A mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylate (200 mg) and tetrabutylammonium fluoride trihydrate (269 mg) in DMF (2 mL) was heated to 80° C. for 12 hours. After cooling to room temperature, the mixture was partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous phase was extracted 4 times with EtOAc. The combined organic phases were concentrated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 1): t R =0.96 minutes.

[1071] Intermediate 69

[1072] 2-{3-Azabicyclo[3.1.0]hex-3-yl}-5-bromopyridine-3-carbonitrile

[1073]

[1074] Under argon atmosphere, a mixture of 5-bromo-2-chloropyridine-3-carbonitrile (1.0 g), 3-azabicyclo[3.1.0]hexane hydrochloride (605 mg) and DIPEA (2 mL) in DMF (10 mL) was heated to 80° C. for 2 hours. The mixture was cooled, concentrated, partitioned between water and EtOAc and the phases were separated. The aqueous material was extracted twice with EtOAc. The combined organic phases were washed with brine, dried (MgSO ), concentrated and the residue was chromatographed on silica gel (petroleum ether / EtOAc 98:2→95:5) to give the title compound.

[1075] LC (method 2): t R = 1.13 min; mass spectrometry (ESI + ): m / z = 264 [M + H] + .

[1076] Intermediate 69-1 was prepared similarly to Intermediate 69:

[1077]

[1078] Intermediate Reaction Notes 69-1 The reaction was carried out at 80°C for 12 hours.

[1079]

[1080] Intermediate 70

[1081] 6-{3-azabicyclo[3.1.0]hex-3-yl}-5-cyanopyridine-3-carboxylic acid methyl ester

[1082]

[1083] Under argon, a mixture of 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-bromopyridine-3-carbonitrile (773 mg) and triethylamine (489 μL) and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (119 mg) in DMF (15 mL) and MeOH (15 mL) was heated to 80° C. for 22 hours under 10 bar of CO. The mixture was cooled, concentrated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

[1084] LC (method 1): t R = 0.99 min; mass spectrometry (ESI + ): m / z = 244 [M + H] + .

[1085] Intermediates 70-1 to 70-3 were prepared similarly to Intermediate 70:

[1086]

[1087]

[1088]

[1089]

[1090] Intermediate 71

[1091] 2-{3-Azabicyclo[3.1.0]hex-3-yl}-5-(hydroxymethyl)pyridine-3-carbonitrile

[1092]

[1093] A mixture of 6-{3-azabicyclo[3.1.0]hex-3-yl}-5-cyanopyridine-3-carboxylic acid methyl ester (300 mg) in THF (5 mL) was cooled to -50 ° C and treated dropwise with LiAlH4 (1M THF solution, 1.4 mL). The mixture was stirred at -20 ° C for 3 hours and then carefully treated with water (1 mL). After dilution with DCM, the mixture was stirred for 30 minutes. The precipitate was filtered and the filter cake was washed with DCM. The combined filtrate was diluted with water. The phases were separated. The aqueous phase was extracted twice with DCM. The combined organic phase was dried (MgSO4), concentrated and purified by reverse phase HPLC (ACN, water) to give the title compound.

[1094] LC (method 1): t R = 0.81 min; mass spectrometry (ESI + ): m / z = 216 [M + H] + .

[1095] Intermediates 71-1 to 71-2 were prepared analogously to Intermediate 71:

[1096]

[1097]

[1098]

[1099]

[1100] Intermediate 72

[1101] 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(methoxymethyl)-1H-pyrazole-4-carboxylic acid ethyl ester

[1102]

[1103] In a microwave vial, a mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(chloromethyl)-1H-pyrazole-4-carboxylate (100 mg) and NaI (10 mg) in MeOH (4 mL) was heated at 90 °C under argon atmosphere for 12 hours. The mixture was then diluted with MeOH and purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 1): t R = 1.07 min; mass spectrometry (ESI + ): m / z = 371 [M + H] + .

[1104] Intermediate 72-1 was prepared similarly to Intermediate 72:

[1105]

[1106] Intermediate Reaction Notes 72-1 The reaction was carried out at 100°C.

[1107]

[1108] Intermediate 73

[1109] 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-cyano-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

[1110]

[1111] In a microwave vial, N,N,N',N'-tetramethylethylenediamine (196 μL) was added to a mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylate (530 mg), NaCN (77 mg), CuCN (25 mg) and KI (43 mg) in toluene (15 mL). The vial was sealed and the mixture was heated to 130 °C for 18 hours. After cooling to room temperature, the mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were dried (MgSO4), concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

[1112] LC (method 1): t R = 0.99 min; mass spectrometry (ESI + ): m / z = 352 [M + H] + .

[1113] Intermediate 73-1 was prepared similarly to Intermediate 73:

[1114]

[1115]

[1116] Intermediate 74

[1117] 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(2-hydroxypropen-2-yl)-1H-pyrazole-4-carboxylic acid hydrochloride

[1118]

[1119] A mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(prop-1-en-2-yl)-1H-pyrazole-4-carboxylate (66 mg) in aqueous HCl (4M, 5 mL) was heated to 60° C. for 12 hours. The mixture was concentrated in vacuo to give the crude product, which was used directly in the next step.

[1120] LC (method 2): t R = 0.67 min; mass spectrometry (ESI + ): m / z = 357 [M + H] + .

[1121] Intermediate 75

[1122] 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid methyl ester

[1123]

[1124] A mixture of 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid (920 mg) and concentrated aqueous H2SO4 (182 μL) in MeOH (10 mL) was heated to 40° C. for 12 hours. After cooling to room temperature, the mixture was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous phase was extracted with EtOAc. The combined organic phases were dried (MgSO4), concentrated, and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

[1125] LC (method 1): t R = 1.17 min; mass spectrometry (ESI + ): m / z = 391 [M + H] + .

[1126] Intermediate 75-1 was prepared similarly to Intermediate 75:

[1127]

[1128] Intermediate Reaction Notes 75-1 The reaction was carried out at 70°C for 12 hours.

[1129]

[1130] Intermediate 76

[1131] 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2,5-dimethylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid methyl ester

[1132]

[1133] In a microwave vial, a mixture of methyl 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylate (120 mg), trimethylcyclotriboroxine (77 mg) and K2CO3 (127 mg) in DMF (4 mL) was purged with argon for 5 min. Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 71 mg) was added, the vial was sealed and the mixture was heated to 110°C for 12 h. After cooling to room temperature, the mixture was partitioned between a half-saturated aqueous solution of NaCl and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were dried (MgSO4), concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

[1134] LC (method 2): t R = 0.63 min; mass spectrometry (ESI + ): m / z = 327 [M + H] + .

[1135] Intermediate 76-1 was prepared similarly to Intermediate 76:

[1136]

[1137]

[1138] Intermediate 77

[1139] 1-[(6-Chloro-2-cyano-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[1140]

[1141] A mixture of 6-chloro-3-(chloromethyl)pyridine-2-carbonitrile (37 mg), ethyl 1H-pyrazole-4-carboxylate (30 mg) and Cs2CO3 (100 mg) in THF (2 mL) was stirred at room temperature for 8 h. The mixture was then neutralized by the addition of trifluoroacetic acid and purified by reverse phase HPLC (ACN, water) to give the title compound.

[1142] LC (method 1): t R = 0.94 min; mass spectrometry (ESI + ): m / z = 291 [M + H] + .

[1143] Intermediate 78

[1144] 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-oxypyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[1145]

[1146] A mixture of ethyl 1-[(6-chloro-2-cyanopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (1 g), 3-azabicyclo[3.1.0]-hexane hydrochloride (411 mg) and DIPEA (1.8 mL) in NMP (20 mL) was stirred at 140° C. for 12 hours. After cooling to room temperature, the mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with water, dried (MgSO 4 ), concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 1): t R = 1.04 min; mass spectrometry (ESI + ): m / z = 338 [M + H] + .

[1147] Intermediate 79

[1148] 2-Chloro-4-methylpyrimidine-5-carboxylic acid

[1149]

[1150] A mixture of ethyl 2-chloro-4-methylpyrimidine-5-carboxylate (25 g) and NaOH (6.5 g) in water (200 mL) was stirred at 40° C. for 3 h. After cooling to room temperature, the mixture was treated with aqueous HCl (4 M) until the pH reached 2. The precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound.

[1151] LC (method 2): t R = 0.68 min; mass spectrometry (ESI + ): m / z = 173 [M + H] + .

[1152] Intermediate 80

[1153] (2-Chloro-4-methylpyrimidin-5-yl)methanol

[1154]

[1155] A mixture of 2-chloro-4-methylpyrimidine-5-carboxylic acid (8.5 g) and N-methylpyrimidine (5.14 mL) in 1,2-dimethoxyethane (200 mL) was cooled to -10 ° C and treated dropwise with isobutyl chloroformate (6.2 mL). The mixture was stirred for 30 minutes and then treated dropwise with a solution of NaBH4 (1.81 g) in water (20 mL). The mixture was stirred for 30 minutes while warming to room temperature and then partitioned between water and EtOAc. The aqueous phase was extracted 3 times with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), concentrated and the residue was chromatographed on silica gel (petroleum ether / (EtOAc / MeOH 8:2) 70:30) to give the title compound. LC (Method 2): t R = 0.51 min; mass spectrometry (ESI + ): m / z = 159 [M + H] + .

[1156] Intermediate 81

[1157] (2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-methylpyrimidin-5-yl)methanol

[1158]

[1159] Diisobutylaluminum hydride (1M in THF, 80 mL) was added dropwise to a mixture of ethyl 2-{3-azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidine-5-carboxylate (8.7 g) in THF (70 mL) at -10°C. The mixture was stirred for 1 hour while warming to 0°C. This mixture was then added dropwise to a mixture of aqueous NaOH solution (4M, 6 mL) in water (150 mL) under ice-cold cooling. After stirring for 1 hour, the mixture was filtered through celite. The filter cake was washed with EtOAc / MeOH 9:1. The combined filtrate was dried (MgSO4), concentrated and the residue was chromatographed on silica gel (EtOAc / MeOH 95:5→95:5) to give the title compound.

[1160] LC (method 2): t R = 0.59 min; mass spectrometry (ESI + ): m / z = 206 [M + H] + .

[1161] Intermediate 82

[1162] 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3-carboxylic acid methyl ester

[1163] and

[1164] Intermediate 83

[1165] 5-[(6-{6,6-di-fluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3-carboxylic acid methyl ester

[1166]

[1167] Under argon atmosphere, a mixture of (6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methanol (1.2 g), DIPEA (1.8 mL) in DCM (5 mL) was treated dropwise with CH3SO2Cl (513 μL). The mixture was stirred for 15 minutes and then added dropwise to a mixture obtained by treating a solution of 1H-pyrrole-3-carboxylic acid methyl ester (863 mg) in DMF (15 mL) with KOtBu (893 mg). The mixture thus obtained was stirred at room temperature for 5 days. The mixture was then distributed between a saturated aqueous solution of NaHCO3 and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried (MgSO4), concentrated in vacuo and purified by reverse phase HPLC (ACN, water) to give the title compound.

[1168] 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3-carboxylic acid methyl ester (Intermediate 82): LC (Method 2): t R = 0.71 min; mass spectrum (ESI+): m / z = 334 [M+H] + .

[1169] 5-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3-carboxylic acid methyl ester (Intermediate 83): LC (Method 2): t R = 0.70 min; mass spectrum (ESI+): m / z = 334 [M+H] + .

[1170] Intermediate 84

[1171] 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrrole-3-carboxylic acid methyl ester

[1172] and

[1173] Intermediate 85

[1174] 5-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrrole-3-carboxylic acid methyl ester

[1175]

[1176] Under argon atmosphere, a mixture of (6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methanol (1.1 g), DIPEA (1.2 mL) in DCM (15 mL) was treated dropwise with CH3SO2Cl (656 μL). The mixture was stirred for 15 minutes and then added dropwise to a mixture obtained by treating a solution of 1H-pyrrole-3-carboxylic acid methyl ester (745 mg) in DMF (30 mL) with KOtBu (771 mg). The mixture thus obtained was stirred at room temperature for 1 hour. The mixture was then partitioned between a saturated aqueous solution of NaHCO3 and DCM. The aqueous phase was extracted twice with DCM. The combined organic phases were dried (MgSO4), concentrated in vacuo and the residue was chromatographed on silica gel (petroleum ether / EtOAc 90:10→50:50) to give the title compound.

[1177] 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrrole-3-carboxylic acid methyl ester (Intermediate 84): LC (Method 2): t R = 0.74 min; mass spectrum (ESI+): m / z = 348 [M+H] + .

[1178] 5-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrrole-3-carboxylic acid methyl ester (Intermediate 85): LC (Method 2): t R = 0.73 min; mass spectrum (ESI+): m / z = 348 [M+H] + .

[1179] Intermediate 86

[1180] 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid ethyl ester

[1181]

[1182] A mixture of 3-[6-chloro-5-(2-nitroethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane (2.58 g), Boc2O (4.42 g), ethyl propiolate (3.03 mL), DMAP (176 mg) and ACN (60 mL) was stirred at 23°C for 18 hours. Purification by reverse phase HPLC (ACN, water) gave the title compound. LC (Method 1): t R = 1.15 min; mass spectrometry (ESI + ): m / z = 348 [M + H] + .

[1183] Intermediates 86-1 to 86-2 were prepared similarly to Intermediate 86:

[1184]

[1185]

[1186] Intermediate 87

[1187] 3-[6-Chloro-5-(2-nitroethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane

[1188]

[1189] A mixture of 3-{6-chloro-5-[(1E)-2-nitrovinyl]pyridin-2-yl}-3-azabicyclo[3.1.0]hexane (4.0 g), NaBH4 (726 mg), acetic acid (5 mL) and DMSO (30 mL) was stirred at 0°C for 30 minutes and at room temperature for 1 hour. The mixture was diluted with water and EtOAc and the phases were separated. The aqueous phase was extracted three times with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), concentrated and the residue was chromatographed on silica gel (cyclohexane / EtOAc 100:0→30:70) to give the title compound.

[1190] LC (method 2): t R = 1.10 min. Mass spectrometry (ESI + ): m / z = 268 [M + H] + .

[1191] Intermediates 87-1 to 87-2 were prepared analogously to Intermediate 87:

[1192]

[1193]

[1194] Intermediate 88

[1195] 3-{6-chloro-5-[(1E)-2-nitrovinyl]pyridin-2-yl}-3-azabicyclo[3.1.0]hexane

[1196]

[1197] A mixture of 6-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloropyridine-3-carbaldehyde (500 mg), nitromethane (1.6 mL), ammonium acetate (346 mg) and acetic acid (10 mL) was stirred at 100° C. for 18 hours. The mixture was cooled to room temperature and added dropwise to a cold mixture of EtOAc, water and a saturated aqueous solution of NaHCO 3 . The phases were separated and the aqueous phase was extracted three times with EtOAc. The combined organic phases were washed with brine, dried (MgSO 4 ) and concentrated to give the crude title compound.

[1198] LC (method 2): t R = 1.14 minutes. Mass spectrometry (ESI + ): m / z = 266 [M + H] + .

[1199] Intermediates 88-1 to 88-2 were prepared similarly to Intermediate 88:

[1200]

[1201]

[1202]

[1203] Intermediate 89

[1204] 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid ethyl ester

[1205]

[1206] A mixture of (E,Z)-N-[2-(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)ethylidene]hydroxylamine (2.45 g), ethylprop-2-ynoic acid (2.0 mL), NaOCl 15% aqueous solution (34 mL) and THF (20 mL) was stirred at room temperature for 3 hours. The mixture was diluted with EtOAc and water, and the aqueous phase was extracted three times with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), concentrated and the residue was chromatographed on silica gel (petroleum ether / EtOAc 99:1→70:30) to give the title compound.

[1207] LC (method 2): tR = 0.79 min. Mass spectrometry (ESI + ): m / z = 342 [M + H] + .

[1208] Intermediates 89-1 to 89-2 were prepared analogously to Intermediate 89:

[1209]

[1210] Intermediate Reaction Notes 89-1 The reaction was carried out in DCM rather than THF.

[1211]

[1212] Intermediate 90

[1213] (E,Z)-N-[2-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)ethylidene]hydroxylamine

[1214]

[1215] A mixture of 2-(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)acetaldehyde (2.22 g), hydroxylamine hydrochloride (1.35 g), NaCO (1.23 g) water (8.0 mL) and MeOH (40 mL) was stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was treated with water, stirred for 15 minutes and filtered. The precipitate was washed with water and dried in a desiccator to give the title compound as a mixture of isomers.

[1216] LC (method 2): t R = 0.62 minutes and 0.64 minutes. Mass Spectrometry (ESI + ): m / z = 246 [M + H] + .

[1217] Intermediates 90-1 to 90-3 were prepared similarly to Intermediate 90:

[1218]

[1219]

[1220]

[1221] Intermediate 91

[1222] 2-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)acetaldehyde

[1223]

[1224] A mixture of 3-[6-ethyl-5-(2-methoxyvinyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane (2.36 g), concentrated HCl (4.0 mL) and 1,4-dioxane (24 mL) was stirred at room temperature for 1 hour. The mixture was carefully neutralized with saturated aqueous NaHCO3 and the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried (MgSO4) and concentrated to give the title compound.

[1225] LC (method 2): t R = 0.58 min. Mass spectrometry (ESI + ): m / z = 231 [M + H] + .

[1226] Intermediates 91-1 to 91-3 were prepared similarly to Intermediate 91:

[1227]

[1228]

[1229]

[1230] Intermediate 92

[1231] 3-[6-ethyl-5-(2-methoxyvinyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane

[1232]

[1233] Under argon atmosphere, a mixture of (methoxymethyl)triphenylphosphine chloride (10.0 g) in THF (80 mL) was treated dropwise with NaHMDS (2 M in THF, 14.6 mL) at -40°C and stirred at this temperature for 15 minutes. This mixture was treated dropwise with a mixture of 6-{3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridine-3-carbaldehyde (2.09 g) in THF (20 mL) at -40°C. The mixture was then warmed to room temperature over 4 hours. The mixture was diluted with EtOAc, and the organic layer was washed with brine and water, dried (MgSO4) and concentrated. The residue was stirred in diisopropyl ether and the precipitate was filtered. The filtrate was concentrated, and the residue was chromatographed on silica gel (petroleum ether / EtOAc 99:1→70:30) to give the title compound as a mixture of isomers.

[1234] LC (method 2): t R = 0.74 and 0.76 minutes (mixture of isomers). Mass spectrum (ESI+): m / z = 245 [M+H] + .

[1235] Intermediates 92-1 to 92-3 were prepared similarly to Intermediate 92:

[1236]

[1237]

[1238]

[1239] Intermediate 93

[1240] 2-[1-(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)-2-methoxy-2-oxoethyl]-1,3-oxazole-5-carboxylic acid methyl ester

[1241]

[1242] Under argon atmosphere, a mixture of methyl 2-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)acetate (460 mg) in THF (5 mL) was treated dropwise with NaHMDS (2 M in THF, 1.1 mL) at -78 ° C and stirred at this temperature for 15 minutes. This mixture was treated dropwise with a mixture of methyl 2-chloro-1,3-oxazole-5-carboxylate (305 mg) in THF (3 mL) at -78 ° C and then warmed to room temperature over 18 hours. The mixture was quenched with saturated aqueous NH4Cl and the aqueous phase was extracted twice with EtOAc. The combined organic phases were dried (MgSO4), concentrated and the residue was chromatographed on silica gel (petroleum ether / EtOAc 80:20→20:80) to give the title compound. LC (Method 2): t R = 0.72 min. Mass spectrometry (ESI + ): m / z = 372 [M + H] + .

[1243] Intermediates 93-1 to 93-2 were prepared similarly to Intermediate 93:

[1244]

[1245]

[1246] Intermediate 94

[1247] Methyl 2-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)acetate

[1248]

[1249] A mixture of 2-(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)acetonitrile (473 mg) in MeOH (5 mL) was treated with SOCl (575 μL) at room temperature before treatment with saturated aqueous NaHCO3 and the mixture was stirred for 6 hours. The aqueous phase was extracted twice with DCM and the combined organic layers were washed with brine, dried (MgSO4) and concentrated to give the title compound. LC (Method 2): t R = 0.64 min. Mass spectrometry (ESI + ): m / z = 247 [M + H] + .

[1250] Intermediates 94-1 to 94-2 were prepared similarly to Intermediate 94:

[1251]

[1252]

[1253] Intermediate Reaction Notes 94-1 The reaction was carried out at 50°C for 18 hours. 94-2 The reaction was allowed to proceed for 24 hours.

[1254]

[1255] Intermediate 95

[1256] 2-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)acetonitrile

[1257]

[1258] A mixture of (6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methanol (1.96 g) in THF (15 mL) was treated with 2-hydroxy-2-methylpropionitrile (895 mg), triphenylphosphine (PPh3, 3.80 g) and DIAD (2.36 g) at 0°C. The mixture was stirred at room temperature for 66 hours and quenched with saturated aqueous NaHCO3. The aqueous phase was extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), concentrated and the residue was chromatographed on silica gel (petroleum ether / EtOAc 90:10→80:20) to give the title compound.

[1259] LC (method 1): t R = 0.97 min. Mass spectrometry (ESI + ): m / z = 214 [M + H] + .

[1260] Intermediates 95-1 to 95-2 were prepared analogously to Intermediate 95:

[1261]

[1262]

[1263] Intermediate Reaction Notes 95-1 The reaction was carried out at room temperature for 18 hours. 95-2 The reaction was carried out at room temperature for 12 hours.

[1264]

[1265] Intermediate 96

[1266] 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid ethyl ester

[1267]

[1268] A mixture of N-[2-(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)ethylidene]hydroxylamine (100 mg), ethylprop-2-ynoic acid (47 μL), potassium persulfate (328 mg), Na2CO3 (57 mg), NaCl (23 mg), MeOH (2 mL) and water (100 μL) was stirred at room temperature for 5 hours and concentrated. The residue was partitioned between water and EtOAc. The organic phase was washed with brine, dried (MgSO4), concentrated and the residue was chromatographed on silica gel (petroleum ether / EtOAc 99:01→50:50) to give the title compound.

[1269] LC (method 2): t R = 0.81 min. Mass spectrometry (ESI + ): m / z = 378 [M + H] + .

[1270] Intermediate 97

[1271] 5-[(2-chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3-carboxylic acid methyl ester

[1272]

[1273] Under argon atmosphere, a mixture of (2-chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methanol (300 mg), DIPEA (782 μL) in DCM (1.5 mL) was treated dropwise with CH3SO2Cl (222 μL). The mixture was stirred for 15 minutes and then added dropwise to a mixture obtained by treating a solution of 1H-pyrrole-3-carboxylic acid methyl ester (187 mg) in DMF (4 mL) with KOtBu (194 mg). The mixture thus obtained was stirred at 40°C for 12 hours. The mixture was then partitioned between a saturated aqueous solution of NaHCO3 and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried (MgSO4), concentrated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

[1274] LC (method 2): t R = 1.05 min; mass spectrometry (ESI + ): m / z = 368 [M + H] + .

[1275] Intermediate 98

[1276] 5-Iodo-1H-pyrazole-3-carboxylic acid ethyl ester

[1277]

[1278] Ethyl 5-amino-1H-pyrazole-3-carboxylate (10 g) was added portionwise to a mixture of water (240 mL) and concentrated H2SO4 aqueous solution (120 mL) at 0°C. To this mixture was added a solution of NaNO2 (4.65 g) in water (10 mL) dropwise. The mixture was stirred for 2 hours and then treated dropwise with a solution of KI (12.0 g) in water (10 mL). The mixture was stirred for 3 hours while warming to room temperature. The mixture was then cooled to 0°C and neutralized by cautious addition of a saturated aqueous solution of K2CO3. The mixture was extracted twice with EtOAc. The combined organic phases were washed with Na2S2O3 20% aqueous solution, dried (MgSO4), concentrated and the residue was chromatographed on silica gel (petroleum ether / EtOAc 95:5→70:30) to give the title compound.

[1279] LC (method 2): t R = 0.86 min. Mass spectrometry (ESI + ): m / z = 267 [M + H] + .

[1280] Intermediate 98-1 was prepared similarly to Intermediate 98:

[1281]

[1282]

[1283] Intermediate 99

[1284] 3-Iodo-1-(propen-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester

[1285]

[1286] NaH (60% in mineral oil, 180 mg) was added portionwise to a mixture of 5-iodo-1-pyrazole-3-carboxylic acid ethyl ester (1.0 g) in DMF (15 mL) at 0°C. The mixture was stirred for 30 minutes and then treated with 2-iodopropane (451 μL). The mixture was stirred for 4 hours while warming to room temperature. The mixture was then partitioned between NH4Cl saturated aqueous solution and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried (MgSO4), concentrated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

[1287] LC (method 2): t R = 1.08 min. Mass spectrometry (ESI + ): m / z = 309 [M + H] + .

[1288] Intermediates 99-1 to 99-2 were prepared analogously to Intermediate 99:

[1289]

[1290] Intermediate Reaction Notes 99-1 Ethyl iodide was used instead of 2-iodopropane. 99-2 (2-Chloromethoxy-ethyl)-trimethyl-silane (SEM-C1) was used instead of 2-iodopropane.

[1291]

[1292] Intermediate 100

[1293] 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)(hydroxy)methyl]-1-(propen-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester

[1294]

[1295] Under argon atmosphere, a mixture of ethyl 3-iodo-1-(propylene-2-yl)-1H-pyrazole-5-carboxylate (100 mg) in THF (2 mL) was treated dropwise with iPrMgClxLiCl (1.3 M in THF, 300 μL) at -40°C. The mixture was stirred for 30 minutes and then treated dropwise with a mixture of 6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridine-3-carboxaldehyde (90 mg) in THF (2 mL). After stirring at -40°C for 3 hours, the mixture was partitioned between saturated aqueous NH4Cl solution and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were dried (MgSO4) and concentrated by evaporation in vacuo to give the crude product, which was used directly in the next step.

[1296] LC (method 2): t R = 0.85 min. Mass spectrometry (ESI + ): m / z = 435 [M + H] + .

[1297] Intermediates 100-1 to 100-8 were prepared similarly to Intermediate 100:

[1298]

[1299]

[1300]

[1301]

[1302]

[1303] Intermediate 101

[1304] 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1-(propen-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester

[1305]

[1306] A mixture of ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)(hydroxy)methyl]-1-(propen-2-yl)-1H-pyrazole-5-carboxylate (141 mg), triethylsilane (492 μL) and trifluoroacetic acid (594 μL) in 1,2-dichloroethane (1.18 mL) was stirred at room temperature for 30 minutes under argon atmosphere. The mixture was concentrated in vacuo to give the crude product, which was used directly in the next step.

[1307] LC (method 2): t R = 0.90 min. Mass spectrometry (ESI + ): m / z = 419 [M + H] + .

[1308] Intermediates 101-1 to 101-12 were prepared similarly to Intermediate 101:

[1309]

[1310]

[1311]

[1312]

[1313] Intermediate 102

[1314] 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-5-carboxylic acid ethyl ester

[1315]

[1316] A mixture of ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloropyridin-3-yl)(hydroxy)methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carboxylate (848 mg), triethylsilane (1.38 mL), trifluoroacetic acid (663 μL) and boron trifluoride-diethyl etherate (BF3xOEt2, 2.3 mL) in DCM (8 mL) was stirred at room temperature under argon atmosphere for 12 hours. The mixture was partitioned between water and DCM. The aqueous phase was extracted twice with DCM. The combined organic phases were washed with brine, dried (MgSO4), concentrated in vacuo and the residue was chromatographed on silica gel (petroleum ether / EtOAc 80:20→0:100) to give the title compound.

[1317] LC (method 2): t R = 1.05 min. Mass spectrometry (ESI + ): m / z = 347 [M + H] + .

[1318] Intermediates 102-1 to 102-3 were prepared similarly to Intermediate 102:

[1319]

[1320] Intermediate Reaction Notes 102-3 The reaction was carried out at 0° C. The mixture was stirred for 1.5 hours while warming to room temperature.

[1321]

[1322] Intermediate 103

[1323] 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carboxylic acid ethyl ester

[1324] and

[1325] 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1-({[2-(trimethylsilyl)ethyl]amino}methyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylic acid ethyl ester (mixture of isomers)

[1326]

[1327] Under argon atmosphere, NaH (60% in mineral oil, 73 mg) was added to a mixture of ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-5-carboxylate (500 mg) in DMF (3 mL) at 0°C. The mixture was stirred for 30 minutes and then treated dropwise with (2-chloromethoxy-ethyl)-trimethyl-silane (SEM-Cl, 313 μL). The mixture was stirred for 2 hours while warming to room temperature. The mixture was then partitioned between saturated aqueous NH4Cl and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), concentrated in vacuo and the residue was chromatographed on silica gel (petroleum ether / EtOAc 99:1→70:30) to give the title compound as a mixture of isomers.

[1328] LC (method 2): t R = 1.05 min. Mass spectrometry (ESI + ): m / z = 347 [M + H] + .

[1329] Intermediate 104

[1330] 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1-ethyl-1H-pyrazole-5-carboxylic acid ethyl ester

[1331]

[1332] A mixture of ethyl 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1-ethyl-1H-pyrazole-5-carboxylate (40 mg), 10% palladium / carbon (5 mg) in MeOH (3 mL) was shaken at room temperature for 4.5 hours under a hydrogen atmosphere (3 bar). The mixture was filtered and the filtrate was concentrated in vacuo to give the crude product, which was used directly in the next step. LC (Method 2): t R = 0.84 min; mass spectrometry (ESI + ): m / z = 369 [M + H] + .

[1333] Intermediate 104-1 was prepared similarly to Intermediate 104:

[1334]

[1335]

[1336]

[1337] Intermediate 105

[1338] 3-[(6-Fluoro-2-methylpyridin-3-yl)(hydroxy)methyl]-1-methyl-1-pyrazole-5-carboxylic acid ethyl ester

[1339]

[1340] Under argon atmosphere, a mixture of 6-fluoro-3-iodo-2-methylpyridine (550 mg) in THF (25 mL) was treated dropwise with iPrMgClxLiCl (1.3 M in THF, 2.2 mL) at -50 ° C. The mixture was stirred for 1 hour and then treated dropwise with a mixture of ethyl 3-formyl-1-methyl-1H-pyrazole-5-carboxylate (300 mg) in THF (1 mL). After stirring at -50 ° C for 1 hour, the mixture was partitioned between saturated aqueous NH4Cl solution and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were dried (MgSO4), concentrated in vacuo and the residue was chromatographed on silica gel (petroleum ether / EtOAc 90:10→50:50) to give the title compound.

[1341] LC (method 2): t R = 0.89 min. Mass spectrometry (ESI + ): m / z = 294 [M + H] + .

[1342] Intermediate 106

[1343] 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)(hydroxy)methyl]-1-methyl-1H-pyrazole-5-carboxylic acid

[1344]

[1345] A mixture of ethyl 3-[(6-fluoro-2-methylpyridin-3-yl)(hydroxy)methyl]-1-methyl-1-pyrazole-5-carboxylate (430 mg), 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride (1.36 g) and K2CO3 (2.4 g) in DMSO (10 mL) was heated to 150°C for 48 hours. After cooling to room temperature, the mixture was diluted with ACN and purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t R = 0.63 min; mass spectrometry (ESI + ): m / z = 365 [M + H] + .

[1346] Intermediate 107

[1347] 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]-1-methyl-1H-pyrazole-5-carboxylic acid

[1348]

[1349] A mixture of 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)(hydroxy)methyl]-1-methyl-1H-pyrazole-5-carboxylic acid (173 mg), triethylsilane (380 μL), trifluoroacetic acid (185 μL) and boron trifluoride-diethyl etherate (BF3xOEt2, 293 μL) in DCM (3 mL) and THF (1 mL) was stirred at room temperature for 12 hours under argon atmosphere. The mixture was diluted with water and purified by reverse phase HPLC (ACN, water) to give the title compound.

[1350] LC (method 2): t R = 0.69 min. Mass spectrometry (ESI + ): m / z = 349 [M + H] + .

[1351] Intermediate 108

[1352] 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid

[1353]

[1354] Step 1: 1-[(6-Fluoro-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[1355] (6-Fluoro-2-methylpyridin-3-yl)methanol (4.12 g) was dissolved in THF (50 mL) and cooled to -10 °C. 1H-pyrazole-4-carboxylic acid ethyl ester (4.43 g) and tributylphosphine (9 mL) were added. Di-tert-butyl-azodicarboxylate (DBAD, 7.4 g) was added slowly in portions, the mixture was stirred at room temperature for 45 minutes and concentrated in vacuo. The residue was chromatographed on silica gel (cyclohexane / EtOAc) to give the title compound.

[1356] LC (method 2): t R = 0.88 min; mass spectrometry (ESI + ): m / z = 264 [M + H] + .

[1357] Step 2: 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid

[1358] 1-[(6-Fluoro-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.5 g) was dissolved in DMSO (2 mL). 5-Azaspiro[2.3]hexane trifluoroacetate (1.2 g) and DIPEA (2 mL) were added and the mixture was stirred at 100 °C for 16 hours and at 120 °C for another 5 hours. After cooling to room temperature, the N,N-diisopropyl-ethylamine phase was removed, 4M NaOH (4 mL) was added and stirred at 60 °C for 2 hours. Aqueous HCl (4 M, 4 mL) was added and the mixture was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 1): t R = 0.68 min; mass spectrometry (ESI + ): m / z = 299 [M + H] + .

[1359] Intermediate 109

[1360] 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)(hydroxy)methyl]furan-2-carboxylic acid methyl ester

[1361]

[1362] A mixture of methyl 5-bromofuran-2-carboxylate (500 mg) in THF (15 mL) was treated dropwise with iPrMgClxLiCl (1.3 M in THF, 1.95 mL) at -50°C. The mixture was stirred at -50°C for 30 minutes and then cooled to -78°C. 6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridine-3-carbaldehyde (592 mg) in THF (8 mL) was added and the mixture was stirred at -78°C for 1 hour and then at 0°C for 30 minutes. The reaction was quenched with saturated aqueous NH4Cl and water. The mixture was extracted with EtOAc. The combined organic phases were dried (MgSO4), concentrated in vacuo and the residue was chromatographed on silica gel (petroleum ether / EtOAc 85:15→50:50) to give the title compound.

[1363] LC (method 2): t R = 0.70 min. Mass spectrometry (ESI + ): m / z = 329 [M + H] + .

[1364] Intermediates 109-1 to 109-7 were prepared similarly to Intermediate 109:

[1365]

[1366]

[1367]

[1368]

[1369]

[1370] Intermediate 110

[1371] 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1372]

[1373] Step 1: Methyl 4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyanobenzoate

[1374] The title compound was prepared following analogous procedures to those described in step 1 of intermediate 111 from methyl 3-cyano-4-fluorobenzoate and 3-azabicyclo[3.1.0]hexane hydrochloride.

[1375] Step 2: 2-{3-azabicyclo[3.1.0]hex-3-yl}-5-(hydroxymethyl)benzonitrile

[1376] The title compound was prepared following a procedure analogous to that described in step 4 of intermediate 118 from methyl 4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyanobenzoate.

[1377] LC (method 2): t R = 0.92 min; mass spectrometry (ESI + ): m / z = 215 [M + H] + .

[1378] Step 3: 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[1379] The title compound was prepared following the procedure analogous to that described in step 3 of intermediate 111 from 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-(hydroxymethyl)benzonitrile and ethyl 1H-pyrazole-4-carboxylate.

[1380] Step 4: 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1381] The title compound was prepared following analogous procedures to those described in step 4 of intermediate 111 from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyanophenyl)methyl]-1H-pyrazole-4-carboxylate.

[1382] Intermediate 111

[1383] 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3,5-difluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1384]

[1385] Step 1: 4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorobenzaldehyde

[1386] 3,4,5-trifluorobenzaldehyde (1.50 g), 3-azabicyclo[3.1.0]hexane hydrochloride (1.23 g), i A mixture of Pr2NEt (4 mL) and DMF (15 mL) was added overnight. After cooling to room temperature, water was added and the resulting mixture was extracted with ethyl acetate (3 times). The combined extracts were dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel (petroleum ether / EtOAc 98:2→95:5) to give the title compound.

[1387] LC (method 2): t R = 1.13 min; mass spectrometry (ESI + ): m / z = 224 [M + H] + .

[1388] Step 2: (4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methanol

[1389] NaBH4 (0.18 g) was added portionwise to THF (10 mL) and methanol (10 mL) containing 4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorobenzaldehyde (0.97 g) at 0°C. The mixture was stirred in a cooling bath for 1 hour and at room temperature for an additional 30 minutes before adding aqueous HCl (1 mol / L). The mixture was stirred for 30 minutes before neutralizing the mixture with aqueous NaHCO3. The mixture was extracted with ethyl acetate (2 times) and the combined extracts were dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel (petroleum ether / EtOAc 95:5→85:15) to give the title compound.

[1390] LC (method 2): t R = 1.04 min; mass spectrometry (ESI + ): m / z = 226 [M + H] + .

[1391] Step 3: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[1392] A mixture of 4-{3-azabicyclo[3.1.0]hex-3-yl}-3,5-difluorophenyl)methanol (0.62 g), ethyl 1H-pyrazole-4-carboxylate (0.48 g), p-toluenesulfonic acid (0.28 g) and MeCN (5 mL) was stirred at 70° C. for 1.5 h (if the reaction was not complete and depending on the degree of conversion, the temperature and / or reaction time were increased). After cooling to room temperature, the mixture was concentrated, water was added and the resulting mixture was neutralized with aqueous NaHCO3. The resulting mixture was extracted with ethyl acetate (3 times) and the combined extracts were dried (Na2SO4) and concentrated. Chromatography (HPLC; ACN / water / ammonia) of the residue gave the title compound. LC (Method 2): t R = 1.20 min; mass spectrometry (ESI + ): m / z = 348 [M + H] + .

[1393] Step 4: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1394] A mixture of ethyl 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3,5-difluorophenyl)methyl]-1H-pyrazole-4-carboxylate (0.10 g), aqueous NaOH solution (4 mol / L; 0.5 mL), THF (2 mL) and EtOH (2 mL) was stirred at 70° C. for 1.5 hours. After cooling to room temperature, the mixture was concentrated. Water (2 mL) and aqueous HCl solution (4 mol / L; 0.5 mL) were added, and the resulting mixture was adjusted to a pH of approximately 5 with aqueous NaOH solution. The precipitate formed was separated and dried and used as such in the next reaction step; or, if no precipitate was formed, the aqueous phase was concentrated and the remainder was used as such in the next reaction step.

[1395] LC (method 2): t R = 1.04 min; mass spectrometry (ESI + ): m / z = 320 [M + H] + .

[1396] Intermediate 112

[1397] 2-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methyl]-1H-imidazole-5-carboxylic acid

[1398]

[1399] Step 1: 3-[4-(Chloromethyl)-2,6-difluorophenyl]-3-azabicyclo[3.1.0]hexane

[1400] A mixture of (4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methanol (60 mg), SOCl2 (0.04 mL) and dichloromethane (1 mL) was stirred at room temperature for 30 min. The mixture was concentrated, dissolved in toluene, concentrated again, and used as is in the next reaction step.

[1401] Step 2: 2-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methyl]-1H-imidazole-5-carboxylic acid ethyl ester

[1402] LiO t Bu (21 mg) was added to 1H-imidazole-4-carboxylic acid ethyl ester (37 mg), tThe mixture was stirred for 5 minutes and then 3-[4-(chloromethyl)-2,6-difluorophenyl]-3-azabicyclo[3.1.0]hexane (65 mg, crude product from step 1) in DCM (0.4 mL) was added. The cooling bath was removed and the mixture was stirred at 40° C. overnight. After cooling to room temperature, water and DCM were added. The organic phase was separated and the aqueous phase was extracted with DCM (2 times). The combined organic extracts were concentrated and the residue was chromatographed (HPLC; ACN / water / ammonia) to give the title compound.

[1403] LC (method 2): t R = 0.89 min; mass spectrometry (ESI + ): m / z = 348 [M + H] + .

[1404] Step 3: 2-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methyl]-1H-imidazole-5-carboxylic acid

[1405] The title compound was prepared following analogous procedures to those described in step 4 of intermediate 111 from ethyl 2-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methyl]-1H-imidazole-5-carboxylate.

[1406] LC (method 2): t R = 0.82 min; mass spectrometry (ESI + ): m / z = 320 [M + H] + .

[1407] Intermediate 113

[1408] 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1409]

[1410] Step 1: 6-Fluoro-3-formyl-2-methylbenzonitrile

[1411] At -20℃ i PrMgCl*LiCl (Turbo Grignard; 1.3 mol / L in THF, 3.8 mL) was added dropwise to 3-bromo-6-fluoro-2-methylbenzonitrile (1.0 g) in THF (25 mL). The mixture was warmed to 0° C. over a period of 1.3 hours before another portion of iPrMgCl*LiCl (Turbo Grignard; 1.3 mol / L in THF, 1.0 mL). The cooling bath was removed and the mixture was stirred for an additional 45 minutes. The mixture was cooled to -20°C and DMF (0.8 mL) was added. After stirring for 50 minutes, the cooling bath was removed and the reaction was quenched by adding aqueous NH4Cl at room temperature. The mixture was extracted with EtOAc (3 times), and the combined extracts were dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel (cyclohexane / EtOAc 24:1→3:1) to give the title compound. LC (Method 2): t R =0.87 minutes.

[1412] Step 2: 6-{3-azabicyclo[3.1.0]hexan-3-yl}-3-formyl-2-methylbenzonitrile

[1413] A mixture of 6-fluoro-3-formyl-2-toluonitrile (515 mg), KHCO3 (0.79 g), 3-azabicyclo[3.1.0]hexane hydrochloride (453 mg) and DMSO (10 mL) was stirred at 70°C for 1.3 hours. After cooling to room temperature, water was added and the mixture was stirred for 30 minutes. The precipitate was isolated by filtration, washed with water (2 times) and dried at 65°C to give the title compound. LC (Method 1): t R = 0.97 min; mass spectrometry (ESI + ): m / z = 227 [M + H] + .

[1414] Step 3: 6-{3-azabicyclo[3.1.0]hex-3-yl}-3-{[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-methylphenyl)methoxy]methyl}-2-methylbenzonitrile

[1415] NaBH4 (0.21 g) was added portionwise to THF (10 mL) and MeOH (5 mL) containing 6-{3-azabicyclo[3.1.0]hex-3-yl}-3-formyl-2-methylbenzonitrile (0.63 g) at room temperature. The mixture was stirred for 1 hour, then aqueous HCl (1 mol / L) was added. The mixture was stirred for 1 hour, then the mixture was neutralized with aqueous NaHCO3. The mixture was extracted with EtOAc (2 times), and the combined extracts were dried (Na2SO4) and concentrated to provide a mixture of the title compound and 6-{3-azabicyclo[3.1.0]hex-3-yl}-3-(methoxymethyl)-2-methylbenzonitrile, which was used as is in the next reaction step (both components were competent starting materials for the next step).

[1416] LC (method 1): tR = 1.27 minutes; mass spectrometry (ESI + ): m / z = 439 [M + H] + .

[1417] Step 4: 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[1418] The title compound was prepared from a mixture of 6-{3-azabicyclo[3.1.0]hex-3-yl}-3-{[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-methylphenyl)methoxy]methyl}-2-methylbenzonitrile and 6-{3-azabicyclo[3.1.0]hex-3-yl}-3-(methoxymethyl)-2-methylbenzonitrile and ethyl 1H-pyrazole-4-carboxylate obtained in step 3 of intermediate 113 following a procedure analogous to that described in step 3 of intermediate 111.

[1419] LC (method 1): t R = 1.08 min; mass spectrometry (ESI + ): m / z = 351 [M + H] + .

[1420] Step 5: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1421] The title compound was prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylate following analogous procedures to those described in step 4 of intermediate 111.

[1422] LC (method 2): t R = 0.96 min; mass spectrometry (ESI + ): m / z = 323 [M + H] + .

[1423] Intermediate 114

[1424] 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-imidazole-4-carboxylic acid

[1425]

[1426] Step 1: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

[1427] The title compound was prepared from a mixture of 6-{3-azabicyclo[3.1.0]hexan-3-yl}-3-{[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-methylphenyl)methoxy]methyl}-2-methylbenzonitrile and 6-{3-azabicyclo[3.1.0]hexan-3-yl}-3-(methoxymethyl)-2-methylbenzonitrile and ethyl 1H-imidazole-4-carboxylate obtained in step 3 of intermediate 113 following a procedure analogous to that described in step 3 of intermediate 111.

[1428] LC (method 1): t R = 0.99 min; mass spectrometry (ESI + ): m / z = 351 [M + H] + .

[1429] Step 2: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-imidazole-4-carboxylic acid

[1430] The title compound was prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-imidazole-4-carboxylate following the procedure analogous to that described in step 4 of intermediate 111.

[1431] LC (method 2): t R = 0.80 min; mass spectrometry (ESI + ): m / z = 323 [M + H] + .

[1432] Intermediate 115

[1433] 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyano-5-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1434]

[1435] Step 1: 2,3-Difluoro-5-formylbenzonitrile

[1436] The title compound was prepared from 5-bromo-2,3-difluorobenzonitrile following a procedure analogous to that described in step 1 of intermediate 113. LC (Method 2): t R =0.84 minutes.

[1437] Step 2: 2-{3-azabicyclo[3.1.0]hexan-3-yl}-3-fluoro-5-formylbenzonitrile

[1438] The title compound was prepared following analogous procedures to those described in step 1 of intermediate 111 from 2,3-difluoro-5-formylbenzonitrile and 3-azabicyclo[3.1.0]hexane hydrochloride.

[1439] LC (method 2): t R = 1.03 min; mass spectrometry (ESI + ): m / z = 231 [M + H] + .

[1440] Step 3: 2-{3-azabicyclo[3.1.0]hex-3-yl}-3-fluoro-5-(hydroxymethyl)benzonitrile

[1441] The title compound was prepared from 2-{3-azabicyclo[3.1.0]hex-3-yl}-3-fluoro-5-formylbenzonitrile following analogous procedures to those described in step 2 of intermediate 111.

[1442] LC (method 2): t R = 0.99 min; mass spectrometry (ESI + ): m / z = 233 [M + H] + .

[1443] Step 4: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-5-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[1444] The title compound was prepared from 2-{3-azabicyclo[3.1.0]hexan-3-yl}-3-fluoro-5-(hydroxymethyl)benzonitrile and 1H-pyrazole-4-carboxylic acid ethyl ester following the procedure analogous to that described in step 3 of intermediate 111.

[1445] LC (method 2): t R = 1.10 min; mass spectrometry (ESI + ): m / z = 355 [M + H] + .

[1446] Step 5: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-5-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1447] The title compound was prepared following analogous procedures to those described in step 4 of intermediate 111 from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-5-fluorophenyl)methyl]-1H-pyrazole-4-carboxylate.

[1448] LC (method 2): t R = 0.99 min; mass spectrometry (ESI +): m / z = 327 [M + H] + .

[1449] Intermediate 116

[1450] 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid

[1451]

[1452] Step 1: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

[1453] The title compound was prepared following analogous procedures to those described in step 3 of intermediate 111 from 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-(hydroxymethyl)benzonitrile and ethyl 1H-imidazole-4-carboxylate.

[1454] Step 2: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid

[1455] The title compound was prepared following analogous procedures to those described in step 4 of intermediate 111 from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylate.

[1456] Intermediate 117

[1457] 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-dicyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1458]

[1459] Step 1: 2-Fluoro-5-formylbenzene-1,3-dicarbonitrile

[1460] A mixture of 4-fluoro-3,5-diiodobenzaldehyde (2.00 g), copper(I) cyanide (1.05 g) and DMF (25 mL) was stirred at 120° C. for 24 h. After cooling to room temperature, water was added and the resulting mixture was extracted with ethyl acetate (3 times). The combined extracts were dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel (petroleum ether / EtOAc 95:51→70:30) to give the title compound.

[1461] Step 2: 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-formylbenzene-1,3-dicarbonitrile

[1462] The title compound was prepared following analogous procedures to those described in step 1 of intermediate 111 from 2-fluoro-5-formylbenzene-1,3-dicarbonitrile and 3-azabicyclo[3.1.0]hexane hydrochloride.

[1463] LC (method 2): t R = 0.95 min; mass spectrometry (ESI + ): m / z = 238 [M + H] + .

[1464] Step 3: 2-{3-azabicyclo[3.1.0]hex-3-yl}-5-(hydroxymethyl)benzene-1,3-dicarbonitrile

[1465] The title compound was prepared from 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-formylbenzene-1,3-dicarbonitrile following analogous procedures to those described in step 2 of intermediate 111.

[1466] LC (method 2): t R = 0.92 min; mass spectrometry (ESI + ): m / z = 240 [M + H] + .

[1467] Step 4: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-dicyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[1468] The title compound was prepared from 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-(hydroxymethyl)benzene-1,3-dicarbonitrile and ethyl 1H-pyrazole-4-carboxylate following the procedure analogous to that described in step 3 of intermediate 111.

[1469] LC (method 2): t R = 1.07 min; mass spectrometry (ESI + ): m / z = 362 [M + H] + .

[1470] Step 5: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-dicyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1471] The title compound was prepared following analogous procedures to those described in step 4 of intermediate 111 from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-dicyanophenyl)methyl]-1H-pyrazole-4-carboxylate.

[1472] LC (method 2): t R= 0.92 min; mass spectrometry (ESI + ): m / z = 334 [M + H] + .

[1473] Intermediate 118

[1474] 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1475]

[1476] Step 1: 3-Bromo-2,6-difluorobenzonitrile

[1477] 3-Amino-2,6-difluorobenzonitrile (2.50 g) dissolved in ACN (45 mL) was added dropwise to a mixture of copper (II) bromide (4.49 g), tert-butyl nitrite (3.8 mL) and ACN (45 mL) at 65° C. The reaction mixture was stirred at 65° C. for 1 hour and then cooled to room temperature. A 20% aqueous HCl solution was added and the resulting mixture was extracted with diethyl ether. The combined extracts were dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel (cyclohexane / EtOAc 7:3) to give the title compound. LC (Method 2): t R =1.01 minutes.

[1478] Step 2: 6-{3-azabicyclo[3.1.0]hex-3-yl}-3-bromo-2-fluorobenzonitrile

[1479] The title compound was prepared following analogous procedures to those described in step 1 of intermediate 111 from 3-bromo-2,6-difluorobenzonitrile and 3-azabicyclo[3.1.0]hexane hydrochloride.

[1480] LC (method 2): t R = 1.17 min; mass spectrometry (ESI + ): m / z = 281 / 283 (Br) [M + H] + .

[1481] Step 3: 4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorobenzoic acid methyl ester

[1482] Under carbon monoxide atmosphere (10 bar), a mixture of 6-{3-azabicyclo[3.1.0]hex-3-yl}-3-bromo-2-fluorobenzonitrile (500 mg), PdCl2(dppf) (72 mg), NEt3 (0.3 mL) and MeOH (6 mL) was stirred at 80°C overnight. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was chromatographed on silica gel (cyclohexane / EtOAc 6:4) to give the title compound.

[1483] LC (method 2): t R = 1.05 min; mass spectrometry (ESI + ): m / z = 261 [M + H] + .

[1484] Step 4: 6-{3-Azabicyclo[3.1.0]hex-3-yl}-3-{[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-fluorophenyl)methoxy]-methyl}-2-fluorobenzonitrile

[1485] 4-{3-Azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-fluorobenzoate (0.42 g) dissolved in THF (5 mL) was added dropwise to LiAlH4 in THF (2.3 mol / L; 0.70 mL) at -50°C. The mixture was stirred for 1.5 hours while warming to -20°C and then quenched by adding aqueous HCl (1 mol / L). The resulting mixture was extracted with EtOAc (3 times), and the combined extracts were dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel (cyclohexane / EtOAc 1:0→1:1) to give the title compound. Depending on the workup, either only 6-{3-azabicyclo[3.1.0]hex-3-yl}-2-fluoro-3-(hydroxymethyl)benzonitrile was obtained; the latter can be used similarly in the next reaction step. Mass spectrometry (ESI + ): m / z = 447 [M + H] + .

[1486] Step 5: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[1487] The title compound was prepared from 6-{3-azabicyclo[3.1.0]hexan-3-yl}-3-{[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorophenyl)methoxy]methyl}-2-fluorobenzonitrile and 1H-pyrazole-4-carboxylic acid ethyl ester following the procedure analogous to that described in step 3 of intermediate 111.

[1488] LC (method 1): tR = 1.06 min; mass spectrometry (ESI + ): m / z = 355 [M + H] + .

[1489] Step 6: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1490] The title compound was prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylate following analogous procedures to those described in step 4 of intermediate 111.

[1491] LC (method 2): t R = 0.94 min; mass spectrometry (ESI + ): m / z = 349 [M + H] + .

[1492] Intermediate 119

[1493] 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1494]

[1495] Step 1: 4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylbenzaldehyde

[1496] The title compound was prepared from 4-fluoro-2-methylbenzaldehyde and 6,6-difluoro-3-azabicyclo[3.1.0]hexane following a procedure analogous to that described in step 1 of intermediate 111; K2CO3 was used instead of Hünig's base at 130°C. LC (Method 2): t R = 1.01 min; mass spectrometry (ESI + ): m / z = 238 [M + H] + .

[1497] Step 2: (4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylphenyl)methanol

[1498] The title compound was prepared from 4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylbenzaldehyde following analogous procedures to those described in step 2 of intermediate 111.

[1499] Step 3: 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[1500] The title compound was prepared from (4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylphenyl)methanol and 1H-pyrazole-4-carboxylic acid ethyl ester following the procedure analogous to that described in step 3 of intermediate 111.

[1501] LC (method 2): t R = 1.13 min; mass spectrometry (ESI + ): m / z = 362 [M + H] + .

[1502] Step 4: 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1503] The title compound was prepared following analogous procedures to those described in step 4 of intermediate 111 from ethyl 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylate.

[1504] LC (method 2): t R = 0.98 min; mass spectrometry (ESI + ): m / z = 334 [M + H] + .

[1505] Intermediate 120

[1506] 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-5-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1507]

[1508] Step 1: 5-Bromo-2-chloro-4-methylbenzonitrile

[1509] N-Bromosuccinimide (3.50 g) and trifluoroacetic acid (25 mL) were added to concentrated sulfuric acid containing 2-chloro-4-methylbenzonitrile (2.50 g) at room temperature. The mixture was stirred at room temperature for 24 hours. The mixture was cooled to 0°C and then slowly poured into an ice-cold solution of aqueous NaOH solution (4 mol / L; 125 mL). The precipitate was isolated by filtration and purified by silica gel chromatography (cyclohexane / EtOAc) to give the title compound.

[1510] LC (method 1): tR =1.07 minutes.

[1511] Step 2: 2-Chloro-5-formyl-4-methylbenzonitrile

[1512] The title compound was prepared from 5-bromo-2-chloro-4-methylbenzonitrile following a procedure analogous to that described in step 1 of intermediate 113. LC (Method 1): t R = 0.90 min; mass spectrometry (ESI - ): m / z = 178 [MH] - .

[1513] Step 3: 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-formyl-4-methylbenzonitrile

[1514] The title compound was prepared following analogous procedures to those described in step 1 of intermediate 111 from 2-chloro-5-formyl-4-methylbenzonitrile and 3-azabicyclo[3.1.0]hexane hydrochloride.

[1515] LC (method 2): t R = 1.02 min; mass spectrometry (ESI + ): m / z = 227 [M + H] + .

[1516] Step 4: 2-{3-azabicyclo[3.1.0]hex-3-yl}-5-(hydroxymethyl)-4-methylbenzonitrile

[1517] The title compound was prepared from 2-{3-azabicyclo[3.1.0]hex-3-yl}-5-formyl-4-methylbenzonitrile following analogous procedures to those described in step 2 of intermediate 111.

[1518] LC (method 2): t R = 0.96 min; mass spectrometry (ESI + ): m / z = 229 [M + H] + .

[1519] Step 5: 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-5-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[1520] The title compound was prepared from 2-{3-azabicyclo[3.1.0]hex-3-yl}-5-(hydroxymethyl)-4-methylbenzonitrile and ethyl 1H-pyrazole-4-carboxylate following the procedure analogous to that described in step 3 of intermediate 111.

[1521] LC (method 1): t R = 1.08 min; mass spectrometry (ESI+ ): m / z = 351 [M + H] + .

[1522] Step 6: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-5-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1523] The title compound was prepared following analogous procedures to those described in step 4 of intermediate 111 from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-5-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylate.

[1524] LC (method 1): t R = 0.68 min; mass spectrometry (ESI + ): m / z = 323 [M + H] + .

[1525] Intermediate 121

[1526] 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylic acid

[1527]

[1528] Step 1: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

[1529] The title compound was prepared from a mixture of 6-{3-azabicyclo[3.1.0]hex-3-yl}-3-{[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-fluorophenyl)methoxy]methyl}-2-fluorobenzonitrile and 6-{3-azabicyclo[3.1.0]hex-3-yl}-2-fluoro-3-(hydroxymethyl)benzonitrile and ethyl 1H-imidazole-4-carboxylate following a procedure analogous to that described in step 3 of intermediate 111; the reaction was carried out in a microwave oven at 140°C. LC (Method 1): t R = 0.90 min; mass spectrometry (ESI + ): m / z = 355 [M + H] + .

[1530] Step 2: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylic acid

[1531] The title compound was prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylate following analogous procedures to those described in step 4 of intermediate 111.

[1532] LC (method 2): t R = 0.78 min; mass spectrometry (ESI + ): m / z = 327 [M + H] + .

[1533] Intermediate 122

[1534] 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-cyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1535]

[1536] Step 1: 3-Bromo-2,6-dichlorobenzonitrile

[1537] KBrO (7.28 g) was added portionwise to concentrated sulfuric acid refrigerated in an ice bath containing 2,6-dichlorobenzonitrile (2.50 g). The mixture was warmed to room temperature in a cooling bath and then stirred overnight at this temperature. The mixture was poured onto ice and a saturated aqueous solution of KCO was added to neutralize the solution. The mixture was extracted with DCM (3 times) and the combined extracts were dried (NaSO) and concentrated. The residue was chromatographed on silica gel (cyclohexane / EtOAc 1:0→7:3) to give the title compound.

[1538] LC (method 2): t R =1.09 minutes.

[1539] Step 2: Methyl 2,4-dichloro-3-cyanobenzoate

[1540] The title compound was prepared from 3-bromo-2,6-dichlorobenzonitrile following an analogous procedure to that described in step 3 of intermediate 118; the reaction was carried out in a mixture of DMF and MeOH.

[1541] LC (method 2): t R =1.00 min.

[1542] Step 3: Methyl 4-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-cyanobenzoate

[1543] The title compound was prepared following analogous procedures to those described in step 1 of intermediate 111 from methyl 2,4-dichloro-3-cyanobenzoate and 3-azabicyclo[3.1.0]hexane hydrochloride.

[1544] LC (method 2): t R = 1.07 min; mass spectrometry (ESI + ): m / z = 277 [M + H] + .

[1545] Step 4: 6-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-(hydroxymethyl)benzonitrile

[1546] The title compound was prepared following a procedure analogous to that described in step 4 of intermediate 118 from methyl 4-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-cyanobenzoate.

[1547] LC (method 2): t R = 0.96 min; mass spectrometry (ESI + ): m / z = 249 [M + H] + .

[1548] Step 5: 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-cyano-6-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[1549] The title compound was prepared from 6-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-(hydroxymethyl)benzonitrile and ethyl 1H-pyrazole-4-carboxylate following the procedure analogous to that described in step 3 of intermediate 111.

[1550] LC (method 2): t R =1.10 minutes.

[1551] Step 6: 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-cyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1552] The title compound was prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-cyano-6-methylphenyl)methyl]-1H-pyrazole-4-carboxylate following a procedure analogous to that described in step 4 of intermediate 111. LC (Method 2): tR=0.96 min.

[1553] Intermediate 123

[1554] 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid

[1555]

[1556] Step 1: 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

[1557] The title compound was prepared from 6-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-(hydroxymethyl)benzonitrile and 1H-imidazole-4-carboxylic acid ethyl ester following a procedure analogous to that described in step 3 of intermediate 111; the reaction was carried out at 100°C. LC (Method 1): t R = 0.98 min; mass spectrometry (ESI + ): m / z = 371 [M + H] + .

[1558] Step 2: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid

[1559] The title compound was prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylate following analogous procedures to those described in step 4 of intermediate 111.

[1560] LC (method 2): t R = 0.80 min; mass spectrometry (ESI + ): m / z = 343 [M + H] + .

[1561] Intermediate 124

[1562] 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylic acid

[1563]

[1564] Step 1: 4-{3-azabicyclo[3.1.0]hex-3-yl}-2-bromobenzaldehyde

[1565] The title compound was prepared from 2-bromo-4-fluorobenzaldehyde and 3-azabicyclo[3.1.0]hexane hydrochloride following a procedure analogous to that described in step 1 of intermediate 111; using K2CO3 instead of Huenegg's base and NMP instead of DMF at 120°C.

[1566] LC (method 2): t R = 1.08 min; mass spectrometry (ESI + ): m / z = 266 / 268 (Br) [M + H] + .

[1567] Step 2: (4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-bromophenyl)methanol

[1568] The title compound was prepared from 4-{3-azabicyclo[3.1.0]hex-3-yl}-2-bromobenzaldehyde following analogous procedures to those described in step 2 of intermediate 111.

[1569] LC (method 2): t R = 1.01 min; mass spectrometry (ESI + ): m / z = 268 / 270 (Br) [M + H] + .

[1570] Step 3: 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

[1571] The title compound was prepared from (4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-bromophenyl)methanol and ethyl 1H-imidazole-4-carboxylate following the procedure analogous to that described in step 3 of intermediate 111.

[1572] LC (method 2): t R = 0.96 min; mass spectrometry (ESI + ): m / z = 390 / 392 (Br) [M + H] + .

[1573] Step 4: 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylic acid

[1574] The title compound was prepared following analogous procedures to those described in step 4 of intermediate 111 from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylate.

[1575] LC (method 2): t R =0.85 minutes.

[1576] Intermediate 125

[1577] 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylphenyl)methyl]-1H-imidazole-4-carboxylic acid

[1578]

[1579] Step 1: 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylphenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

[1580] A flask containing a stirring bar, ethyl 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylate (100 mg), methylboronic acid (23 mg), Cs2CO3 (0.25 g) and 1,4-dioxane (1.5 mL) was flushed with Ar for 10 min. PdCl2(dppf) (21 mg) was added, the flask was sealed, and the mixture was stirred at 110°C for 1.5 h. After cooling to room temperature, the mixture was diluted with MeOH and chromatographed (HPLC; ACN / water / ammonia) to give the title compound.

[1581] LC (method 2): t R =0.91 minutes.

[1582] Step 2: 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylphenyl)methyl]-1H-imidazole-4-carboxylic acid

[1583] The title compound was prepared following analogous procedures to those described in step 4 of intermediate 111 from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylphenyl)methyl]-1H-imidazole-4-carboxylate.

[1584] LC (method 2): t R =0.81 minutes.

[1585] Intermediate 126

[1586] 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid

[1587]

[1588] Step 1: 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

[1589] A flask containing a stirring bar, ethyl 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylate (100 mg), Zn(CN)2 (60 mg), zinc (8 mg), Pd2(dba)3 (23 mg) and tBu3P*HBF4 (15 mg) was added to the flask for 10 minutes. NMP (1 mL) was added, the flask was sealed, and the mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the mixture was diluted with DMF and chromatographed (HPLC; ACN / water / ammonia) to give the title compound.

[1590] LC (method 2): t R = 0.90 min; mass spectrometry (ESI + ): m / z = 337 [M + H] + .

[1591] Step 2: 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid

[1592] The title compound was prepared following analogous procedures to those described in step 4 of intermediate 111 from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-cyanophenyl)methyl]-1H-imidazole-4-carboxylate.

[1593] LC (method 2): t R = 0.79 min; mass spectrometry (ESI + ): m / z = 309 [M + H] + .

[1594] Intermediate 127

[1595] 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)phenyl)methyl]-1H-imidazole-4-carboxylic acid

[1596]

[1597] Step 1: 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-vinylphenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

[1598] A flask containing a stirring bar, ethyl 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylate (500 mg), vinylboronic acid (0.25 mL), aqueous Na2CO3 (1 mol / L; 3.2 mL) and 1,4-dioxane (9 mL) was flushed with Ar for 10 minutes. PdCl2(dppf) (53 mg) was added, the flask was sealed, and the mixture was stirred at 100°C for 2.5 hours. After cooling to room temperature, the mixture was diluted with brine and the resulting mixture was extracted with EtOAc (3 times). The combined extracts were dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel (cyclohexane / EtOAc 4:1→0:1) to give the title compound. LC (Method 2): t R =0.93 minutes.

[1599] Step 2: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-formylphenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

[1600] OsO4 (4% in water; 0.14 mL) was added to a mixture of ethyl 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-vinylphenyl)methyl]-1H-imidazole-4-carboxylate (300 mg), water (4 mL) and 1,4-dioxane (4 mL) at room temperature. After stirring the mixture for 10 minutes, NaIO4 (0.57 g) was added. The mixture was stirred for 2.5 hours, and then ethyl acetate / methanol (9:1; 20 mL) and water (20 mL) were added. The mixture was extracted with ethyl acetate (3 times), and the combined extracts were dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel (cyclohexane / ethyl acetate 70:30->0:1) to give the title compound.

[1601] LC (method 1): t R = 0.99 min; mass spectrometry (ESI + ): m / z = 340 [M + H] + .

[1602] Step 3: 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)phenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

[1603] The title compound was prepared following analogous procedures to those described in step 2 of intermediate 111 from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-formylphenyl)methyl]-1H-imidazole-4-carboxylate.

[1604] LC (method 1): t R=0.81 minutes.

[1605] Step 4: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)phenyl)methyl]-1H-imidazole-4-carboxylic acid

[1606] The title compound was prepared following the procedure analogous to that described in step 4 of intermediate 111 from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)phenyl)methyl]-1H-imidazole-4-carboxylate.

[1607] LC (method 2): t R =0.72 minutes.

[1608] Intermediate 128

[1609] 1-[(2-Cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-)methyl]-1H-pyrazole-4-carboxylic acid

[1610]

[1611] Step 1: 1-[(2-cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[1612] The title compound was prepared following analogous procedures to those described in step 1 of intermediate 126 from ethyl 1-[(2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-pyrazole-4-carboxylate.

[1613] LC (method 1): t R =1.03 minutes.

[1614] Step 2: 1-[(2-Cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1615] The title compound was prepared following analogous procedures to those described in step 4 of intermediate 111 from ethyl 1-[(2-cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-pyrazole-4-carboxylate.

[1616] LC (method 1): t R =0.63 minutes.

[1617] Intermediate 129

[1618] 1-[(2-Bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1619]

[1620] Step 1: 2-Bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}benzaldehyde

[1621] The title compound was prepared from 2-bromo-4-fluorobenzaldehyde and 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride following a procedure analogous to that described in Step 1 of Intermediate 111; using K2CO3 instead of Huenegg's base and NMP instead of DMF at 120°C.

[1622] LC (method 2): t R = 1.02 min; mass spectrometry (ESI + ): m / z = 302 / 304 (Br) [M + H] + .

[1623] Step 2: (2-Bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methanol

[1624] The title compound was prepared from 2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}benzaldehyde following analogous procedures to those described in step 2 of intermediate 111.

[1625] LC (method 2): t R = 0.96 min; mass spectrometry (ESI + ): m / z = 304 / 306 (Br) [M + H] + .

[1626] Step 3: 1-[(2-Bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-pyrazole-4-carboxylate

[1627] The title compound was prepared from (2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methanol and 1H-pyrazole-4-carboxylic acid ethyl ester following the procedure analogous to that described in step 3 of intermediate 111.

[1628] LC (method 2): t R = 1.09 min; mass spectrometry (ESI + ): m / z = 426 / 428 (Br) [M + H] + .

[1629] Step 4: 1-[(2-Bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1630] The title compound was prepared following analogous procedures to those described in step 4 of intermediate 111 from ethyl 1-[(2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-pyrazole-4-carboxylate.

[1631] LC (method 1): t R =0.68 minutes.

[1632] Intermediate 130

[1633] 1-[(2-Cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylic acid

[1634]

[1635] Step 1: 1-[(2-Bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

[1636] The title compound was prepared from (2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methanol and ethyl 1H-imidazole-4-carboxylate following the procedure analogous to that described in step 3 of intermediate 111.

[1637] LC (method 2): t R =0.91 minutes.

[1638] Step 2: 1-[(2-cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

[1639] The title compound was prepared from ethyl 1-[(2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylate and zinc(II) cyanide following a procedure analogous to that described in step 1 of intermediate 126. LC (Method 1): t R = 0.95 min; mass spectrometry (ESI + ): m / z = 373 [M + H] + .

[1640] Step 3: 1-[(2-Cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylic acid

[1641] The title compound was prepared following analogous procedures to those described in step 4 of intermediate 111 from ethyl 1-[(2-cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylate.

[1642] LC (method 1): t R = 0.64 min; mass spectrometry (ESI + ): m / z = 345 [M + H] + .

[1643] Intermediate 131

[1644] 1-[(2-Chloro-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylic acid

[1645]

[1646] Step 1: 1-[(2-chloro-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

[1647] A mixture of ethyl 1-[(2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylate (200 mg), copper(I) chloride (92 mg) and NMP was stirred at 160° C. for 2.5 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (3 times). The combined extracts were dried (Na2SO4) and concentrated. Chromatography (HPLC; ACN / water / ammonia) of the residue gave the title compound.

[1648] LC (method 2): t R = 0.92 min; mass spectrometry (ESI + ): m / z = 382 [M + H] + .

[1649] Step 2: 1-[(2-Chloro-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylic acid

[1650] The title compound was prepared following analogous procedures to those described in step 4 of intermediate 111 from ethyl 1-[(2-chloro-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylate.

[1651] LC (method 1): t R = 0.67 min; mass spectrum (ESI-): m / z = 352 [MH]-.

[1652] Intermediate 132

[1653] 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylic acid

[1654]

[1655] Step 1: 4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluorobenzaldehyde

[1656] The title compound was prepared from 2,4-difluorobenzaldehyde and 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride following a procedure analogous to that described in step 1 of intermediate 111; using K2CO3 instead of Hunig's base and NMP instead of DMF. Mass Spectrum (ESI + ): m / z = 242 [M + H] + .

[1657] Step 2: (4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methanol

[1658] The title compound was prepared from 4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluorobenzaldehyde following analogous procedures to those described in step 2 of intermediate 111.

[1659] LC (method 2): t R = 0.93 min; mass spectrometry (ESI + ): m / z = 244 [M + H] + .

[1660] Step 3: 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

[1661] The title compound was prepared from (4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methanol and ethyl 1H-imidazole-4-carboxylate following the procedure analogous to that described in step 3 of intermediate 111.

[1662] Step 4: 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylic acid

[1663] The title compound was prepared following analogous procedures to those described in step 4 of intermediate 111 from ethyl 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylate.

[1664] LC (method 2): t R =0.79 minutes.

[1665] Intermediate 133

[1666] 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1667]

[1668] Step 1: 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[1669] The title compound was prepared from (4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methanol and 1H-pyrazole-4-carboxylic acid ethyl ester following the procedure analogous to that described in step 3 of intermediate 111.

[1670] LC (method 2): t R = 1.10 min; mass spectrometry (ESI + ): m / z = 366 [M + H] + .

[1671] Step 2: 1-[[4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid

[1672] The title compound was prepared following analogous procedures to those described in step 4 of intermediate 111 from ethyl 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylate.

[1673] Synthesis Example:

[1674] Example 1

[1675] 1-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide

[1676]

[1677] A mixture of 1-[(2-chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid (46 mg), DIPEA (111 μL) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (HATU, 57 mg) in DMF (1 mL) was stirred for 5 minutes. (4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-amine dihydrochloride (33 mg) was added and the mixture was stirred for 1 hour. The mixture was purified by reverse phase HPLC (ACN, water). The title compound was obtained.

[1678] LC (method 1): t R = 0.91 min; mass spectrometry (ESI + ): m / z = 475 [M + H] + .

[1679] Examples 2 to 213 were prepared similarly to Example 1:

[1680]

[1681]

[1682]

[1683]

[1684]

[1685]

[1686]

[1687]

[1688]

[1689]

[1690]

[1691]

[1692]

[1693]

[1694]

[1695]

[1696]

[1697]

[1698]

[1699]

[1700]

[1701]

[1702]

[1703]

[1704]

[1705]

[1706]

[1707]

[1708]

[1709]

[1710]

[1711]

[1712]

[1713]

[1714]

[1715]

[1716]

[1717]

[1718]

[1719]

[1720]

[1721]

[1722]

[1723]

[1724]

[1725] Embodiment 214

[1726] 1-[(2-{3-azabicyclo[3.1.0]hex-3-yl}-4-(hydroxymethyl)pyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide

[1727]

[1728] To a mixture of 1-[(2-{3-azabicyclo[3.1.0]hex-3-yl}-4-formylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide (24 mg) in THF (2 mL) was added NaBH4. The mixture was stirred at room temperature for 12 hours and then treated with aqueous HCl (1 M, 500 μL). After stirring for 10 minutes, aqueous NaOH (1 M, 500 μL) was added. The mixture was diluted with MeOH and purified by reverse phase (ACN, water) HPLC to give the title compound. LC (Method 1): t R = 0.78 min; mass spectrometry (ESI + ): m / z = 435 [M + H] + .

[1729] Embodiment 215

[1730] 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(1-hydroxyethyl)pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide

[1731]

[1732] To an ice-cold mixture of 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-formylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide (13 mg) in THF (5 mL) was added dropwise under argon atmosphere. The mixture was stirred for 12 hours while warming to room temperature. The mixture was then partitioned between saturated aqueous NH4Cl and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were dried (Na2SO4), concentrated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

[1733] LC (method 1): t R = 0.88 min; mass spectrometry (ESI + ): m / z = 485 [M + H] + .

[1734] Embodiment 216

[1735] 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(2-hydroxyethyl N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide

[1736]

[1737] LiA1H4 (1 M in THF, 200 μL) was added dropwise to a -78°C cold mixture of methyl 2-{1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-4-{[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]carbamoyl}-1H-pyrazol-3-yl}acetate (90 mg) in THF (1 mL) under argon atmosphere. The mixture was stirred for 12 hours while warming to room temperature. To the mixture was added water (14 μL), aqueous NaOH solution (4 M, 14 μL) and additional water (14 μL) successively. After vigorous stirring for 15 minutes, the mixture was filtered through celite, and the filter cake was washed with THF. The combined filtrates were concentrated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t R = 0.66 min; mass spectrometry (ESI + ): m / z = 462 [M + H] + .

[1738] Embodiment 217

[1739] 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(hydroxymethyl)-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide

[1740]

[1741] LiAlH4 (1 M in THF, 200 μL) was added dropwise to an ice-cold mixture of 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-4-{[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]carbamoyl}-1H-pyrazole-3-carboxylic acid methyl ester (25 mg) in THF (2 mL) under argon atmosphere. The mixture was stirred for 30 minutes. To the mixture were added water (50 μL) and aqueous NaOH solution (4 M, 25 μL) successively. After vigorous stirring for 15 minutes, the mixture was filtered through celite and the filter cake was washed with THF. The combined filtrates were concentrated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (method 1): tR = 0.89 min; mass spectrometry (ESI + ): m / z = 448 [M + H] + .

[1742] Embodiment 218

[1743] 1-[(2-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide

[1744]

[1745] A mixture of 1-[(2-chloro-4-methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide (33 mg), 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride (27 mg) and DIPEA (75 μL) in DMSO (1 mL) was stirred at 60° C. for 8 h. After cooling to room temperature, the mixture was diluted with DMSO and purified by reverse phase HPLC (ACN, water) to give the title compound.

[1746] LC (method 1): t R = 0.86 min; mass spectrometry (ESI + ): m / z = 454 [M + H] + .

[1747] Embodiment 219

[1748] 3-I (6-{3-azabicyclo [3.1.0] hex-3-yl}-2-(methoxymethyl) pyridin-3-yl) methyl] -N- [(4R) -1-methyl-1H, 4H, 5H, 6H-cyclopenta [d] imidazol-4-yl] -1H-pyrazole-5-carboxamide

[1749]

[1750] 3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carboxamide and 5-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxamide (mixture of isomers) (20 mg) were dissolved in DCM (3 mL). Trifluoroacetic acid (1 mL) was added and the mixture was stirred at room temperature for 12 h. The mixture was then concentrated in vacuo, dissolved in MeOH (1 mL) and treated with NH3 (7 M in MeOH, 3 mL). The mixture was heated to 80 °C for 12 h in a sealed microwave vial. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

[1751] LC (method 1): t R = 0.91 min; mass spectrometry (ESI + ): m / z = 448 [M + H] + .

[1752] Example 220 was prepared similarly to Intermediate 219:

[1753]

[1754]

[1755]

[1756] Embodiment 221

[1757] 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methoxypyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide

[1758]

[1759] A mixture of 1-[(2-chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide (50 mg) and NaOCH3 (1 M in MeOH, 2 mL) was heated to 165°C for 6 hours in a sealed microwave vial. After cooling to room temperature, the mixture was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t R = 0.86 min; mass spectrometry (ESI + ): m / z = 470 [M + H] + .

[1760] Embodiment 222

[1761] 1-[(2-{5-azaspiro[2.3]hexan-5-yl}-4-methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide

[1762]

[1763] A mixture of 1-[(2-chloro-4-methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide (40 mg), DIPEA (100 μL) and 5-azaspiro[2.3]hexane; trifluoroacetate (32 mg) in DMSO (2 mL) was stirred at 60° C. for 16 hours. The mixture was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 5): t R = 0.56 min; mass spectrometry (ESI + ): m / z = 419 [M + H] + .

[1764] Examples 223 to 240 were prepared similarly to Example 222:

[1765]

[1766]

[1767]

[1768]

[1769]

[1770]

Claims

1. A compound of formula (I) in Y is selected from the group consisting of: Each of which is independently substituted by 1 or 2 groups R 1 Replace, and The bonds with an asterisk indicate the sites of attachment to the R and CH2 groups of formula (I); R is selected from the group consisting of: 5-azaspiro[2.3]hexane, 2-azaspiro[3.3]heptane, 5-azaspiro[2.4]heptane, 6-azaspiro[3.4]octane, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 6-azaspiro[2.5]octane, 5-azaspiro[2.5]octane, 7-azaspiro[3.5]nonane, 3-azabicyclo[4.1.0]heptane, 3-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane and 3-azabicyclo[3.2.1]octane, Each of them is connected to the group Y in formula (I) via an N atom, and Each of which is optionally substituted with a substituent selected from the group consisting of F, CH3, CN, CH2OH, OH and OCH3, and Each of which is optionally substituted with an additional substituent selected from the group consisting of F and CH3; Ar is selected from the group consisting of: Each of them is optionally substituted by 1 substituent R 3 Replace, and The bond with an asterisk and parentheses indicates the site of attachment of the group C═O to CH2 of formula (I); R 1 Select from the group consisting of: H, halogen, C optionally substituted with 1 to 5 F 1-4 alkyl, C optionally substituted with 1 CH3, CN or OH group 3-4 Cycloalkyl, CN, OC optionally substituted with 1 to 5 F 1-3 Alkyl, optionally selected from CN, OH and OC 1-3 A C substituted with one substituent of a group consisting of an alkyl group 1-3 alkyl; and R 3 Select from the group consisting of: F, Cl, Br, CN, C optionally substituted with 1 to 3 F 1-3 Alkyl, HO-C 1-4 Alkylene, C 1-2 Alkyl-OC 1-2 alkylene, and OC optionally substituted with 1 to 3 F 1-2 alkyl; or a salt thereof.

2. The compound according to claim 1, Wherein Y is selected from the group consisting of: Each of which is independently substituted by 1 or 2 groups R 1 Replace, and The bonds with asterisks and parentheses indicate the sites of attachment to the R and CH2 groups of formula (I); or a salt thereof.

3. The compound according to claim 2, Wherein Y is selected from the group consisting of: It is optionally substituted by an additional substituent R 1 Replace, and The bonds with asterisks and parentheses indicate the sites of attachment to the R and CH2 groups of formula (I); or a salt thereof.

4. A compound according to any one of claims 1 to 3, Where R is selected from the group consisting of: or a salt thereof.

5. The compound according to claim 4, Where R is selected from the group consisting of: or a salt thereof.

6. The compound according to claim 4, Where R is selected from the group consisting of: or a salt thereof.

7. A compound according to any one of claims 1 to 3, Where R 1 Select from the group consisting of: H, F, Cl, Br, CH3, CH2CH3, CH2CH2CH3, CH2CH(CH3)2, cyclopropyl, cyclobutyl, CHF2, CF3, CN, 1-cyanocyclopropan-1-yl, CH2CN, C(CH3)2CN, CH2OH, CH2CH2OH, CH(OH)CH3, CH2CH2CH2OH, CH(CH3)CH2OH, C(OH)(CH3)2, CHOCH3, CHOCH2CH3, O-CH3, O-CH2CH3, and O-CF3; or a salt thereof.

8. The compound according to claim 7, Where R 1 Select from the group consisting of: H, F, Cl, Br, CH3, CH2CH3, CHF2, CN, CH2OH, and CH2OCH3; or a salt thereof.

9. A compound according to any one of claims 1 to 3, Where R 3 Select from the group consisting of: Cl, CN, CH3, CF3, CH2CH3, CH(CH3)2, CH2OH, CH2CH2OH, C(CH3)2OH, and CH2OCH3; or a salt thereof.

10. The compound according to claim 9, Where R 3 Selected from the group consisting of: Cl and CN; or a salt thereof.

11. The compound of claim 1, wherein Y is The bonds with asterisks and parentheses indicate the sites of attachment to the R and CH2 groups of formula (I); R is Ar wherein the bond with an asterisk and parentheses indicates the point of attachment of the group C═O to CH2 of formula (I); and R 1 Selected from the group consisting of: H, F, Cl, Br, CH3, CH2CH3, CHF2, CN, CH2OH, and CH2OCH3; or a salt thereof.

12. The compound of claim 1, wherein Y is The bonds with asterisks and parentheses indicate the sites of attachment to the R and CH2 groups of formula (I); R is selected from the group consisting of: Ar wherein the bond with an asterisk and parentheses indicates the point of attachment of the group C═O to CH2 of formula (I); and R 1 Selected from the group consisting of: H, F, Cl, Br, CH3, CH2CH3, CHF2, CN, CH2OH, and CH2OCH3; or a salt thereof.

13. The compound according to claim 1 or 11, The stereochemistry of the compound is according to formula (I.1) or a salt thereof.

14. The compound of claim 1, wherein the compound is selected from: or a salt thereof.

15. The compound of claim 14, wherein the compound is 16. The compound of claim 14, wherein the compound is 17. The compound of claim 14, wherein the compound is 18. The compound of claim 14, wherein the compound is 19. The compound of claim 14, wherein the compound is 20. A pharmaceutically acceptable salt which is a pharmaceutically acceptable salt of a compound according to any one of claims 1 to 19.

21. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 19 or a pharmaceutically acceptable salt according to claim 20, and one or more inert carriers and / or diluents.

22. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt according to claim 20 in the preparation of a medicament for treating eye diseases and / or edema-related diseases.

23. The use according to claim 22, wherein the medicament is for the treatment of diabetic macular edema, age-related macular degeneration, choroidal neovascularization, hereditary angioedema and / or cerebral edema after stroke.

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