Heteroaromatic carboxamide derivatives as plasma kallikrein inhibitors

Abstract

To provide novel heteroaromatic carboxamide derivatives that are plasma kallikrein inhibitors and pharmaceutically acceptable salts thereof.SOLUTION: Heteroaromatic carboxamides of formula (I) and pharmaceutically acceptable salts thereof can be used in methods for the treatment of diseases which can be influenced by the inhibition of plasma kallikrein.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to novel heteroaromatic carboxamide derivatives and pharmaceutically acceptable salts thereof, which are plasma kallikrein inhibitors. In addition, the invention relates to intermediates in the synthesis of said compounds, pharmaceutical compositions and combinations containing said compounds, and their use in methods for treating diseases that can be affected by the inhibition of plasma kallikrein. In particular, the pharmaceutical compositions of the invention are suitable for the prevention and / or treatment of diabetic complications, ocular diseases, and edema-related diseases, particularly diabetic macular edema, age-related macular degeneration, choroidal neovascularization, hereditary angioedema, and post-stroke cerebral edema. [Background technology]

[0002] Plasma kallikrein (PKK) is a trypsin-like serine protease secreted by hepatocytes in the liver as inactive plasma prekallikrein, which circulates in plasma either as a free zymogen or as a heterodimeric complex bound to high molecular weight kininogen, resulting in active PKK that can liberate kinins from kininogen in addition to processing other substrates. Kinins are potent mediators of inflammation that act through G protein-coupled receptors, such as the bradykinin receptor.

[0003] PKK appears to play a role in numerous inflammatory disorders, including hereditary angioedema (HAE), retinopathy or diabetic retinopathy, proliferative and non-proliferative retinopathies, diabetic macular edema (DME), clinically significant macular edema (CSME), cystoid macular edema (CME), CME following cataract extraction, CME induced by cryotherapy, CME induced by uveitis, endophthalmitis, CME following vascular occlusion (e.g., central retinal vein occlusion, branch retinal vein occlusion, or hemiretinal vein occlusion), retinal edema, complications of cataract surgery in diabetic retinopathy, hypertensive retinopathy, retinal trauma, dry and exudative age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV), and choroidal neovascularization (CNV;non-exudative choroidal neovascularization), posterior vitreous detachment (PVD), ischemia-reperfusion injury of all kinds, for example in the context of tissue and / or organ transplantation, surgically induced brain injury, focal cerebral ischemia, global cerebral ischemia, glioma-related edema, spinal cord injury, pain, ischemia, focal cerebral ischemia, neurological and cognitive deficits, deep vein thrombosis, stroke (including edema in the central nervous system after stroke), myocardial infarction, acquired angioedema, drug-related edema (ACE inhibitor-induced edema, as well as tissue plasminogen activator (tPA)-induced angioedema) including), high altitude cerebral edema, cytotoxic cerebral edema, osmotic cerebral edema, obstructive hydrocephalus, radiation-induced edema, lymphedema, traumatic brain injury, hemorrhagic stroke (e.g., cerebral apoplexy or subarachnoid stroke), intracerebral hemorrhage, hemorrhagic transformation of ischemic stroke, brain trauma associated with injury or surgery, cerebral aneurysms, arteriovenous malformations, reduction of blood loss during surgical procedures (e.g., cardiothoracic surgery, e.g., cardiopulmonary bypass or coronary artery bypass graft), itch, disorders with an inflammatory component (such as multiple sclerosis), epilepsy, encephalitis, Alzheimer's disease, excessive daytime sleepiness, increased blood pressure associated with essential hypertension, diabetes mellitus or hyperlipidemia, renal insufficiency, chronic kidney disease, heart failure, microalbuminuria, albuminuria, proteinuria, disorders associated with increased vascular permeability (e.g., increased retinal vascular permeability, increased leg, foot, or ankle vascular permeability), cerebral hemorrhage, blood clotting disorders, e.g., thrombosis, deep vein thrombosis, clotting after fibrinolytic treatment, angina pectoris, angioedema, sepsis, arthritis (e.g., rheumatoid arthritis, osteoarthritis, infectious arthritis), lupus, gout, psoriasis, inflammation Intestinal diseases (IBD, e.g., ulcerative colitis (UC) and Crohn's disease (CD)), diabetes, diabetic complications, complications arising from metabolic syndrome, infectious diseases, astrocyte activation-related diseases (e.g., Alzheimer's disease or multiple sclerosis), Parkinson's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, stroke, epilepsy and trauma (e.g., brain trauma), allergic edema, e.g., airflow obstruction in chronic allergic sinusitis or perennial rhinitis; airflow obstruction in acute asthma;PKK may have numerous implications in disorders such as serositis associated with systemic lupus erythematosus (SLE), acute respiratory distress syndrome (ARDS), coronavirus disease 2019 (COVID-19)-associated pneumonia, fibrotic diseases, liver fibrosis, nonalcoholic steatohepatitis (NASH), kidney injury, and other diseases. Furthermore, PKK appears to play an important role in hypersensitivity reactions and thrombosis during hemodialysis.

[0004] PKK inhibitors such as the compounds of the present invention are believed to be useful in the treatment of a wide range of disorders, for example, as described above; in particular, they should have utility as a treatment for reducing retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema or edema-related diseases. PKK inhibitors should be particularly useful in treating edema formation in diseases, such as the edema formation associated with ischemia-reperfusion injury, retinopathy or edema-related diseases, such as hereditary angioedema, macular edema and cerebral edema.PKC inhibitors are particularly useful in treating retinopathy, such as the retinopathy associated with diabetes and / or hypertension, and in treating macular edema, such as the macular edema associated with diabetes and / or hypertension.

[0005] Other complications of diabetes such as cerebral hemorrhage, nephropathy, cardiomyopathy and neuropathy have all been linked to PKK and may also be considered targets for PKK inhibitors. PKK inhibitors suitable for therapeutic and / or prophylactic use should bind to PKK potently and with high selectivity. They should be well absorbed from the gastrointestinal tract, sufficiently metabolically stable, and possess favorable pharmacokinetic properties. They should be non-toxic and demonstrate no side effects. Small molecular weight PKK inhibitors are known in the art, for example compounds disclosed in WO2009 / 097141, WO2013 / 111107, WO2013 / 111108, WO2014 / 188211, WO2017 / 072020, WO2017 / 072021 and WO2018 / 192866. Summary of the Invention

[0006] In a first aspect, the present invention provides a compound of formula (I) [ka] Compounds of (In the formula, Y is

[0007] [ka] and each of which is selected from the group Y-G1 consisting of one or two independent substituents R 1 is replaced by; R is A saturated 6- to 12-membered bicyclic ring system containing 1-2 N atoms as ring members and, optionally, one ring member selected from the group consisting of C=O, O, S, S=O, and SO2. selected from the group R-G1 consisting of provided that the ring system does not contain any heteroatom-to-heteroatom bonds between ring members; wherein said ring system is attached to the Y group in formula (I) via the N atom, wherein the ring system is optionally substituted with 1 to 6 F, and 1-3 -Alkyl, CN, HO-C 1-3 -Alkylene, OH, and C 1-3 -alkyl-O; Ar is 5-membered heteroaryl containing 1 to 4 N atoms, or containing one O or S atom, or containing 1 to 2 N atoms and one 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 selected from the group Ar-G1 consisting of: wherein said heteroaryl is attached to the carbonyl group in formula (I) via a C atom of the 5-membered ring and to the CH group in formula (I) via a non-adjacent C or N atom of the 5-membered ring; wherein the heteroaryl is a heteroaryl having one substituent R 3 may be substituted with; R 1 teeth, C optionally substituted with H, halogen, or 1 to 5 F 1-4 - alkyl, optionally substituted with one CH3, CN or OH group 3-4 -cycloalkyl, CN, OC optionally substituted with 1 to 5 F 1-3 -Alkyl, CN, OH and OC 1-3 -C optionally substituted with one substituent selected from the group consisting of alkyl 1-3 -Alkyl A group R consisting of 1 - Selected from G1; R 3 teeth, 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 A group R consisting of 3 - Selected from G1; wherein in any definition set forth in the preceding sentence, and unless otherwise specified, any alkyl or alkylene group or subgroup may be straight-chained or branched. It relates to isoforms, tautomers, stereoisomers, metabolites, prodrugs, solvates, hydrates, co-crystals and salts thereof, in particular pharmaceutically acceptable co-crystals and salts thereof, or combinations thereof.

[0008] In a second aspect, the present invention relates to a pharmaceutical composition comprising one or more compounds of formula (I) as defined hereinbefore or hereinafter, and / or a tautomer thereof or a pharmaceutically acceptable salt thereof, optionally together with one or more inert carriers and / or diluents.

[0009] In a third aspect, the present invention relates to a pharmaceutical composition comprising one or more compounds of formula (I) as defined hereinbefore or hereinafter, 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.

[0010] In a fourth aspect, the present invention relates to a compound of formula (I) as defined hereinbefore or hereinafter, and / or a tautomer thereof or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0011] 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 can be affected by the inhibition of plasma kallikrein in a patient in need thereof, which method comprises administering to the patient one or more compounds of formula (I) as defined hereinbefore or hereinafter, and / or a tautomer thereof or a pharmaceutically acceptable salt thereof. Additionally, the present invention relates to the use of one or more compounds of formula (I) as defined hereinbefore or hereinafter, and / or tautomers thereof or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment, i.e., the treatment and / or prevention, of a disease or condition that can be affected by the inhibition of plasma kallikrein. Furthermore, the present invention relates to a compound of formula (I) as defined hereinbefore or hereinafter, and / or a tautomer thereof or a pharmaceutically acceptable salt thereof, for use in a method for the treatment, i.e., the therapy and / or prevention, of a disease or condition that can be affected by the inhibition of plasma kallikrein in a patient in need thereof.

[0012] In a sixth aspect, the present invention provides a compound of formula (I) which is a valuable intermediate in the synthesis of the compound of formula (I) [ka] The present invention relates to one or more compounds selected from the group consisting of:

[0013] Further aspects of the present invention will become apparent to those skilled in the art directly from the foregoing and subsequent description and examples. DETAILED DESCRIPTION OF THE INVENTION

[0014] General Terms and Definitions Terms not specifically defined herein should be given the meaning that would be given them by one of ordinary skill in the art in light of the disclosure and context. As used herein, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are observed. The terms "compound(s) according to this invention", "compound(s) of formula (I)", "compound(s) of the invention" and the like refer to compounds of formula (I) according to the invention, including tautomers, stereoisomers and mixtures thereof and salts thereof, particularly pharmaceutically acceptable salts thereof, and solvates, hydrates and co-crystals of such compounds, particularly pharmaceutically acceptable co-crystals thereof, including solvates, hydrates and co-crystals of such tautomers, stereoisomers and salts thereof.

[0015] Moreover, unless specifically indicated otherwise, throughout this specification and the appended claims, a given chemical formula or name is intended to encompass tautomers and all stereo, optical, and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and racemates thereof, as well as mixtures of different proportions of separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms, where such isomers and enantiomers are present, as well as salts, including pharmaceutically acceptable salts thereof, and solvates thereof, such as, for example, hydrates, including solvates of the free compound or solvates of a salt of the compound, and pharmaceutically acceptable co-crystals thereof, including co-crystals of the free compound or a salt thereof. The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0016] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by making 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. For example, such salts include salts 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. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a sufficient amount of the appropriate base or acid in water or an organic diluent such as ether, EtOAc, EtOH, isopropanol, or MeCN, or mixtures thereof. Salts of acids other than those mentioned above that are useful, for example, to purify or isolate the compounds of the invention (eg, trifluoroacetate salts) also form part of this invention.

[0017] As used herein, "pharmaceutically acceptable co-crystals" refer to derivatives of the disclosed compounds in which the parent compound is modified with the aid of one or more co-formers to create the co-crystal. Additionally, co-crystals of solvates and / or salts of the disclosed compounds are encompassed. For example, coformers include hydrogen bond donors, such as carboxylic acids, and hydrogen bond acceptors, such as amines and amides. 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 milling, 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 milling and planetary milling. When a compound of the invention is depicted in the form of a chemical name and as a formula, the formula will prevail in the event of any conflict.

[0018] In the groups, radicals or moieties defined below, the number of carbon atoms is often specified preceding the group, e.g., C 1-6 -Alkyl means an alkyl group or radical having 1 to 6 carbon atoms. An asterisk can be used in a sub-formula to indicate a bond that is attached to the core molecule as defined. In the case of more than one attachment point in a sub-formula, i.e., more than one asterisk, the asterisk can be further specified by a parenthetical designation of the attachment portion of the core molecule. The calculation of the atoms of a substituent starts from the atom closest to the core or to the group to which the substituent is attached. For example, the term "3-carboxypropyl group" represents the following substituent:

[0019] [ka] where the carboxy group is attached to the third carbon atom of the propyl group. The terms "1-methylpropyl-", "2,2-dimethylpropyl-" or "cyclopropylmethyl-" represent the following groups:

[0020] [ka] The term "substituted," as used herein, means that any one or more hydrogens on the specified atom, group, or moiety have been replaced with a selection from the indicated group, provided that the normal valence of the atom is not exceeded and the substitution results in an acceptably stable compound.

[0021] In the definition of a group, a term such as "each X, Y and Z group may be substituted with" indicates that each X group, each Y group and each Z group may be substituted as defined, either as a separate group or as part of each constituent group. For example, "R ex is H, C 1-3 -Alkyl, C 3-6 -cycloalkyl, C 3-6 -Cycloalkyl-C 1-3 -Alkyl or C 1-3 -alkyl-O-, where each alkyl group may be selected from one or more L ex " and in each of the above groups containing the term alkyl, i.e., C 1-3 -Alkyl group, C 3-6 -Cycloalkyl-C 1-3 -Alkyl groups and C 1-3 In each of the -alkyl-O- groups, the alkyl moiety is L as defined ex This means that it may be substituted with.

[0022] "C" where n is an integer from 1 to n 1-n The term "-alkyl", either alone or in combination with another group, denotes an acyclic, saturated, branched or linear hydrocarbon group having 1 to n C atoms. For example, C 1-5-The term alkyl includes the H3C- group, H3C-CH2- group, H3C-CH2-CH2- group, H3C-CH(CH3)- group, H3C-CH2-CH2-CH2- group, H3C-CH2-CH2-CH2- group, 3C-CH2-CH(CH3)- group, H3C-CH(CH3)-CH2- group, H3C-C(CH3)2- group, H3C-CH2-CH2-CH2-CH2- group, H3C -CH2-CH2-CH(CH3)- group, H3C-CH2-CH(CH3)-CH2- group, H3C-CH(CH3)-CH2-CH2- group, H3C-CH2-C(C H3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-. n is an integer selected from 2, 3, 4, 5 or 6, preferably 4 or 6; 1-n The term "-alkylene", either alone or in combination with another group, denotes an acyclic, straight or branched chain divalent alkyl group containing 1 to n carbon atoms. For example, C 1-4 The term -alkylene includes -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH3)-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(CH2CH2CH3)-CH2-, -CH(CH2CH2CH3)-, -CH(CH(CH3))2- and -C(CH3)(CH2CH3)-.

[0023] "C" where n is an integer 3 to n 3-nThe term "cycloalkyl", either alone or in combination with another group, denotes a cyclic, saturated, unbranched hydrocarbon group having 3 to n C atoms. The cyclic group can be monocyclic, bicyclic, tricyclic or spirocyclic, most preferably monocyclic. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1.]octyl, spiro[4.5]decyl, norpinyl, norbornyl, norcaryl, adamantyl, etc.

[0024] The term "heteroaryl" refers to heteroaryls consisting of 5 to 14 ring atoms, where r=0, 1, or 2, such as N, O, or S(O). r " refers to a monocyclic or polycyclic aromatic ring system containing one or more heteroatoms selected from: wherein at least one of the heteroatoms is part of an aromatic ring. The term "heteroaryl" is intended to include all possible isomeric forms.

[0025] Thus, the term "heteroaryl" includes the following exemplary structures; they are not depicted as groups because each form may be attached via a covalent bond to any atom as long as appropriate valences are maintained:

[0026] [ka]

[0027] The term "bicyclic ring system" refers to a group consisting of two joined cyclic substructures, including spirocyclic, fused and bridged ring systems.

[0028] The term halogen generally refers to fluorine, chlorine, bromine and iodine. Many of the terms given above can be used repeatedly in the definitions of formulae or groups and in each case have, independently of one of the meanings given above. The terms "treatment" and "treating" as used herein include both therapeutic, ie, curative and / or palliative, and preventative, ie, prophylactic, treatment. Therapeutic treatment refers to the treatment of patients who have already developed one or more of the above conditions in overt, acute or chronic form. Therapeutic treatment can be symptomatic treatment to alleviate the symptoms of a specific indication, or causal treatment to reverse or partially reverse the condition of the indication, or to stop or slow the progression of the disease. Preventative treatment ("prevention") refers to treatment prior to the clinical onset of disease to reduce the risk of a patient at risk of developing one or more of the above conditions.

[0029] The terms "treatment" and "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, condition or disorder and / or to eliminate or control a disease, condition or disorder, as well as to alleviate the symptoms or complications associated with a disease, condition or disorder. When this invention refers to a patient in need of treatment, it primarily relates to treatment in mammals, particularly humans. The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents a particular disease or condition, (ii) reduces, ameliorate, or eliminates one or more symptoms of a particular disease or condition, or (iii) prevents or delays the onset of one or more symptoms of a particular disease or condition described herein.

[0030] Detailed Description of the Invention The present invention discloses novel heteroaromatic carboxamide derivatives that are effective plasma kallikrein (PKK) inhibitors and that have suitable pharmacological and pharmacokinetic properties for use as pharmaceuticals for the treatment of diseases and / or conditions that can be affected by PKK inhibition, including, but not limited to, diabetic complications, ocular diseases and edema-related diseases, particularly diabetic macular edema, age-related macular degeneration, choroidal neovascularization, hereditary angioedema and post-stroke cerebral edema. 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 profiles, and the potential for forming stable salts.

[0031] Compounds of the Invention In a first aspect of the present invention, a compound of formula (I) [ka] (wherein Y, R and Ar are defined as above and below) These compounds have been found to be potent inhibitors of PKK and to 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 potential for forming stable salts. In particular, they offer an advantageous combination of high potency and significant selectivity against human PKK, e.g., versus various serine proteases, e.g., human tissue kallikrein 1 (TK1), as well as adequate solubility and high metabolic stability at physiologically relevant pH values. In addition, they exhibit favorable safety features, such as low mutagenicity potential, low inhibition of cytochrome P450 (CYP) enzymes such as CYP3A4 and CYP2C8, and a low propensity for mechanism-based inhibition of CYP3A4.

[0032] As such, compounds of formula (I) as defined hereinbefore or hereinafter, or pharmaceutically acceptable salts thereof, are expected to be useful in the treatment of diseases and / or conditions that can be affected by PKK inhibition.

[0033] Thus, according to one aspect of the present invention, a compound of formula (I) [ka] (wherein Y, R and Ar are defined as above or below) as well as isoforms, tautomers, stereoisomers, metabolites, prodrugs, solvates, hydrates, co-crystals, and salts thereof, particularly pharmaceutically acceptable co-crystals and salts thereof.

[0034] Unless otherwise specified, groups, residues and substituents, in particular Y, R, Ar, R 1 and R 3 are defined as above and hereinafter. The substituents Y, R, Ar, R, as well as the stereochemistry of the compounds of formula (I) 1 and R 3 Some preferred meanings of are given hereinafter as embodiments of the present invention. Any and each of these definitions and embodiments can be combined with each other.

[0035] Y: According to one embodiment, Y is [ka] selected from the group Y-G1 consisting of Each of these may be one or two independent substituents R 1 is replaced by .

[0036] According to another embodiment, Y is [ka] selected from the group Y-G2 consisting of Each of these may be one or two independent substituents R1 is replaced by The bond marked with an asterisk indicates the site of attachment of the R and CH2 groups of formula (I). According to another embodiment, Y is [ka] selected from the group Y-G3 consisting of Each of these may contain one or two substituents R 1 is replaced by The asterisk and bracketed bond indicate the attachment sites of the R and CH2 groups of formula (I).

[0037] According to another embodiment, Y is [ka] selected from the group Y-G4 consisting of Each of these is a single substituent R 1 is replaced by The asterisk and bracketed bond indicate the attachment sites of the R and CH2 groups of formula (I). According to another embodiment, Y is [ka] selected from the group Y-G5 consisting of Each of these may contain one additional substituent R 1 may be substituted with The asterisk and bracketed bond indicate the attachment sites of the R and CH2 groups of formula (I).

[0038] According to another embodiment, Y is [ka] selected from the group Y-G6 consisting of This is because one additional substituent R 1 may be substituted with The asterisk and bracketed bond indicate the attachment sites of the R and CH2 groups of formula (I).

[0039] According to another embodiment, Y is [ka] selected from the group Y-G7 consisting of The asterisk and bracketed bond indicate the attachment sites of the R and CH2 groups of formula (I).

[0040] R: According to one embodiment, R is A saturated 6- to 12-membered bicyclic ring system containing 1 to 2 N atoms as ring members, and optionally one ring member selected from the group consisting of C=O, O, S, S=O and SO2. selected from the group R-G1 consisting of provided that the ring system does not contain any heteroatom-to-heteroatom bonds between ring members; wherein said ring system is attached to the Y group in formula (I) via the N atom, wherein the ring system is optionally substituted with 1 to 6 F, and 1-3 -Alkyl, CN, HO-C 1-3 -Alkylene, OH, and C 1-3 -alkyl-O.

[0041] According to another embodiment, R is Saturated 6- to 10-membered bicyclic ring systems containing one N atom and optionally one O atom as ring members selected from the group R-G2 consisting of wherein the ring system is attached to the Y group in formula (I) via the N atom, where the ring system is F, C 1-3 -Alkyl (preferably CH3), CN, HO-C 1-3 -Alkylene (preferably HOCH2), OH, and C 1-3 -alkyl-O- (preferably CHO), wherein the ring system may be additionally substituted with one substituent selected from the group consisting of F and CH3.

[0042] According to another embodiment, R is 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 selected from the group R-G3 consisting of each of which is attached to the Y group in formula (I) via an N atom; each of which may be substituted with one substituent selected from the group consisting of F, CH3, CN, CH2OH, OH and OCH3, preferably F and CH3; Each of these may be substituted with one additional substituent selected from the group consisting of F and CH3.

[0043] According to another embodiment, R is [ka] is selected from the group R-G4 consisting of:

[0044] According to another embodiment, R is [ka] is selected from the group R-G5 consisting of:

[0045] According to another embodiment, R is [ka] and is selected from the group R-G6 consisting of:

[0046] According to another embodiment, R is [ka] is selected from the group R-G7 consisting of:

[0047] According to another embodiment, R is [ka] is selected from the group R-G8 consisting of:

[0048] Ar: According to one embodiment, Ar is 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 selected from the group Ar-G1 consisting of: wherein said heteroaryl is attached to the carbonyl group in formula (I) via a C atom of the 5-membered ring and to the CH group in formula (I) via a non-adjacent C or N atom of the 5-membered ring; wherein the heteroaryl is a heteroaryl having one substituent R 3 may be substituted with

[0049] According to another embodiment, Ar is 5-membered heteroaryl containing 1 to 3 N atoms, or containing one O or S atom, or containing one N atom and one 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 selected from the group Ar-G2 consisting of wherein said heteroaryl is attached to the carbonyl group in formula (I) via a C atom of the 5-membered ring and to the CH group in formula (I) via a non-adjacent C or N atom of the 5-membered ring; wherein the heteroaryl is a heteroaryl having one substituent R 3 may be substituted with

[0050] According to another embodiment, Ar is [ka] and tautomers thereof, Each of these is a single substituent R 3 may be substituted with The asterisk and bracketed bond indicate the sites of attachment of the C=O and CH2 groups in formula (I).

[0051] According to another embodiment, Ar is [ka] selected from the group Ar-G4 consisting of: Each of these is a single substituent R 3 may be substituted with The asterisk and bracketed bond indicate the sites of attachment of the C=O and CH2 groups in formula (I).

[0052] According to another embodiment, Ar is [ka] selected from the group Ar-G5 consisting of: This is a group containing one substituent R 3 may be substituted with The asterisk and bracketed bond indicate the sites of attachment of the C=O and CH2 groups in formula (I).

[0053] According to another embodiment, Ar is [ka] selected from the group Ar-G6 consisting of This is a group containing one substituent R 3 may be substituted with The asterisk and bracketed bond indicate the sites of attachment of the C=O and CH2 groups in formula (I).

[0054] According to another embodiment, Ar is [ka] and tautomers thereof, Each of these is a single substituent R 3 may be substituted with The asterisk and bracketed bond indicate the sites of attachment of the C=O and CH2 groups in formula (I).

[0055] According to another embodiment, Ar is [ka] selected from the group Ar-G8 consisting of This is a group containing one substituent R 3 may be substituted with The asterisk and bracketed bond indicate the sites of attachment of the C=O and CH2 groups in formula (I).

[0056] According to another embodiment, Ar is [ka] selected from the group Ar-G9 consisting of: Each of these is a single substituent R 3 may be substituted with The asterisk and bracketed bond indicate the sites of attachment of the C=O and CH2 groups in formula (I).

[0057] According to another embodiment, Ar is [ka] selected from the group Ar-G10 consisting of Each of these is a single substituent R 3 may be substituted with The asterisk and bracketed bond indicate the sites of attachment of the C=O and CH2 groups in formula (I).

[0058] According to another embodiment, Ar is [ka] selected from the group Ar-G11 consisting of This is a group containing one substituent R 3 may be substituted with The asterisk and bracketed bond indicate the sites of attachment of the C=O and CH2 groups in formula (I).

[0059] R 1 : According to one embodiment, R 1 teeth, C optionally substituted with H, halogen, or 1 to 5 F 1-4 - alkyl, optionally substituted with one CH3, CN or OH group 3-4 -cycloalkyl, CN, OC optionally substituted with 1 to 5 F 1-3 -Alkyl, CN, OH and OC 1-3 -C optionally substituted with one substituent selected from the group consisting of alkyl 1-3 -Alkyl A group R consisting of 1 -G1. According to another embodiment, R 1 teeth, H, F, Cl, Br, 1 to 5 F or 1 CN, OH or OC 1-2 -C optionally substituted with alkyl group 1-2 -alkyl, C optionally substituted with one CN or OH group 3-4 - alkyl, optionally substituted with one CH3, CN or OH group 3-4 -cycloalkyl, OC optionally substituted with 1 to 5 F 1-2-Alkyl A group R consisting of 1 -G2. According to another embodiment, R 1 teeth, H, F, Cl, Br, CH3, CH2CH3, CH2CH2CH3, CH2CH(CH3)2, cyclopropyl, cyclobutyl, CHF2, CF3, CN, 1-cyanocycloprop-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 A group R consisting of 1 -G3.

[0060] According to another embodiment, R 1 teeth, H, F, Cl, Br, CH3, CH2CH3, CHF2, CN, CH2OH, and CH2OCH3 A group R consisting of 1 -G4. According to another embodiment, R 1 is a group R consisting of H 1 -G5 is selected. According to another embodiment, R 1 is the group R consisting of F, Cl and Br 1 -G6 is selected. According to another embodiment, R 1 is a group R consisting of CH3 1 -G7 is selected. According to another embodiment, R 1 is a group R consisting of CH2CH3 1 -G8 is selected. According to another embodiment, R 1 teeth, CH2CH2CH3, CH2CH(CH3)2, cyclopropyl and cyclobutyl A group R consisting of 1 -G9 is selected.

[0061] According to another embodiment, R 1 is a group R consisting of CHF2 and CF3 1 -G10 is selected. According to another embodiment, R 1 is a group R consisting of CN 1 -G11. According to another embodiment, R 1 teeth, 1-Cyanocycloprop-1-yl, CH2CN, and C(CH3)2CN A group R consisting of 1 -G12. According to another embodiment, R 1 is a group R consisting of CH2OH 1 -G13. According to another embodiment, R 1 teeth, CH2CH2OH, CH(OH)CH3, CH2CH2CH2OH, CH(CH3)CH2OH, and C(OH)(CH3)2 A group R consisting of 1 -G14. According to another embodiment, R 1 teeth, CH2OCH3, CH2OCH2CH3, O-CH3, O-CH2CH3, and O-CF3 A group R consisting of 1 -G15.

[0062] R 3 : According to one embodiment, R 3 teeth, 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 A group R consisting of 3 -G1. According to another embodiment, R3 teeth, 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 A group R consisting of 3 -G2.

[0063] According to another embodiment, R 3 teeth, Cl, CN, CH3, CF3, CH2CH3, CH(CH3)2, CH2OH, CH2CH2OH, C(CH3)2OH, and CH2OCH3 A group R consisting of 3 -G3. According to another embodiment, R 3 is a group R consisting of Cl and CN 3 -G4. According to another embodiment, R 3 is the group R consisting of CH3, CF3, CH2CH3, and CH(CH3)2 3 -G5 is selected. According to another embodiment, R 3 teeth, CH2OH, CH2CH2OH, and C(CH3)2OH A group R consisting of 3 -G6 is selected. According to another embodiment, R 3 is a group R consisting of CH2OCH3 3 -G7 is selected. Stereochemistry:

[0064] According to one embodiment, the stereochemistry of the compounds of formula (I) is of formula (I.1) [ka] Follow.

[0065] According to another embodiment, the stereochemistry of the compound of formula (I) is that of formula (I.2) [ka] Follow.

[0066] Further preferred subgeneric embodiments of compounds of formula (I) are set forth below in Table 1 as embodiments (Ia) through (Ir), where the substituent definitions set forth above are used. For example, in column R 1 and entry G1 in column (Ia) represents, in embodiment (Ia), the substituent R 1 But R 1 -G1 means selected from the definitions specified. The same applies to other variables incorporated into the general formula as well.

[0067] [Table 1]

[0068] Particularly preferred are Y, R, Ar, R 1 and R 3 Subgeneric embodiments (I.1-a) to (I.1-r) as corresponding to subgeneric embodiments (Ia) to (Ir) in Table 1, with respect to the definition of (I.1), wherein the stereochemistry of the compounds is according to formula (I.1).

[0069] According to another preferred embodiment, the stereochemistry of the compounds of the invention is according to formula (I.1) in which Ar is selected from the group Ar-G5. According to another preferred embodiment, the stereochemistry of the compounds of the invention is according to formula (I.1) in which Ar is selected from the group Ar-G6.

[0070] According to another preferred embodiment, the stereochemistry of the compounds of the invention is according to formula (I.1) in which Ar is selected from the group Ar-G8. Particularly preferred compounds are those described in the Examples section and experimental data, including their tautomers, their salts, or any solvates, hydrates or co-crystals thereof.

[0071] preparation The compounds according to the invention and intermediates thereto can be prepared using synthetic methods known to those skilled in the art and described in the organic synthesis literature, for example, in "Comprehensive Organic Transformations", 2 nd Edition, Richard C. Larock, John Wiley & Sons, 2010 and “March's Advanced Organic Chemistry”, 7 th Edition, Michael B. Smith, John Wiley & Sons, 2013. Preferably, the compounds are obtained analogously to the methods of preparation more fully described hereinafter, in particular the methods of preparation as described in the experimental section. In some cases, the order adopted in carrying out the reaction schemes can be varied. Variants of these reactions known to those skilled in the art but not described in detail herein can also be used. The general process for preparing the compounds according to the present invention will be apparent to those skilled in the art upon studying the schemes that follow. The starting compounds are commercially available or can be prepared by methods described in the literature or herein, or can be prepared in a similar or analogous manner. Before the reaction is carried out, any corresponding functional groups in the starting compounds can be protected using conventional protecting groups. These protecting groups will be obvious to those skilled in the art and can be found in the literature, for example, in "Protecting Groups", 3 rd Edition, Philip J. Kocienski, Thieme, 2005 and “Protective Groups in Organic Synthesis”, 4 th The reaction can be cleaved again at an appropriate stage in the reaction sequence using methods described in The Journal of Biological Chemistry, Vol. 1, No. 1, pp. 111-115, 1997. Edition, Peter GM Wuts, Theodora W. Greene, John Wiley & Sons, 2006.

[0072] [ka] Scheme 1: Compounds of formula (I') can be prepared by reacting a compound of formula (II) with an appropriate acid (free acid, or Li + , Na + , K. + and a suitable amine of formula (III) (either as the free amine or as a salt such as the hydrochloride, hydrobromide, etc.) in a suitable solvent (e.g., DCM, THF, 1,4-dioxane, DMF, N,N-dimethylacetamide, and 1-methyl-2-pyrrolidinone) with a suitable coupling agent (e.g., O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate (HATU), O-( ... (triazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), carbodiimide reagents, etc.) and a base (e.g., triethylamine, N,N-diisopropyl-ethylamine, pyridine, etc.) to form an amide bond; Y, R, and Ar in Scheme 1 have the meanings defined above. Alternatively, the carboxylic acid can be converted to a carboxylic acid chloride (e.g., using oxalyl chloride or thionyl chloride in DCM) and coupled directly with amine (III) in the presence of a suitable base (e.g., triethylamine, N,N-diisopropyl-ethylamine, pyridine, etc.).

[0073] [ka] R 5 =C 1-4 -Alkyl or benzyl Scheme 2: Acids of formula (II) in which Y, R and Ar have the meanings as defined above are preferably selected from R 5The acid is prepared from the corresponding ester (IV) via hydrolysis or hydrogenolysis, depending on the nature of the ester. Lower alkyl esters, such as ethyl or methyl esters, are preferably cleaved by hydrolysis using hydroxide salts such as NaOH, LiOH, or KOH in a mixture of water and a suitable miscible solvent (e.g., THF, MeOH, EtOH, 1,4-dioxane, or a mixture thereof) at ambient or elevated temperatures. The acid can be isolated either as a salt with a metal cation or as the free acid. tert-Butyl esters are preferably cleaved by treatment with an acid (e.g., hydrochloric acid or TFA) in a suitable solvent (e.g., DCM, 1,4-dioxane, MeOH, EtOH, THF, water, or a mixture thereof). Benzyl esters are preferably cleaved by hydrogenolysis using a suitable catalyst (e.g., palladium on carbon) in a suitable solvent (e.g., EtOH, MeOH, THF, DCM, or EtOAc) under an atmosphere of hydrogen (preferably 1-5 bar).

[0074] [ka] T 1 and T 2 are, independently of each other, N, CH or CR 3 or T 1 and T 2 together form a fused benzo, pyrido, or pyrimido ring, which is represented by R 3 optionally monosubstituted with; T 3 =CH or N; R 5 =C 1-4 - alkyl or benzyl. Scheme 3: Some of the compounds (II') can be prepared by the reaction of alcohols (V) with esters (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 as defined above. Alcohol (V) can carry the desired residue R on the heteroaromatic ring Y or on the leaving group instead of later introducing R. Alternatively, some of compounds (II') can be obtained by reacting alcohol (V) and ester (VI) in the presence of a Lewis acid or Bronsted acid (e.g., 4-toluenesulfonic acid) in a suitable solvent (e.g., MeCN) at elevated temperatures (20°C to 120°C).

[0075] [ka] T 1 and T 2 are, independently of one another, N, CH or CR 3 or T 1 and T 2 together form a fused benzo, pyrido, or pyrimido ring, which is represented by R 3 optionally monosubstituted with; T 3 =CH or N; R 5 =C 1-4 - alkyl or benzyl; Hal = leaving group such as Cl, Br, I, OSO2CH3. Scheme 4: Some of the compounds (II') can also be prepared by the reaction of compounds (VII) bearing a leaving group at the heteroarylmethyl position, such as Cl, Br, or mesyloxy (methanesulfonyloxy), with esters (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 R in Scheme 4 can be prepared by the reaction of esters (VI) with esters (VI) in the presence of a suitable base (e.g., sodium hydride, cesium carbonate, potassium carbonate, or triethylamine). 3 has the meaning as defined above. Compound (VII) can carry the desired residue R on the heteroaromatic ring Y or on the leaving group instead of introducing R later.

[0076] [ka] R 5 =C 1-4 - alkyl or benzyl; Hal = leaving group such as OH, Cl, Br, I, OSO2CH3. Scheme 5: Some esters of formula (II"), in which Y and R have the meanings defined above, can be prepared by treatment of the corresponding alkyl halide (bromide or chloride) or sulfonate (e.g., mesylate) of formula (VII) with sodium azide in DMF or another suitable solvent to give an intermediate of formula (VIII), which is then reacted with an appropriate propiolate ester under copper-mediated conditions (e.g., ethyl propiolate or tert-butyl propiolate with catalytic copper sulfate and sodium ascorbate in water / tert-butanol) to give compound (II"). Alternatively, azides (VIII) can be obtained from alcohols of formula (V) (or (VII) in which Hal is OH) by treatment with diphenylphosphoryl azide in a suitable solvent (e.g., THF or DMF) in the presence of a suitable base such as DBU. Compound (VII) can carry the desired residue R on the heteroaromatic ring Y or on the leaving group, instead of later introducing R.

[0077] [ka] For compounds (X), (XI), (XII) and (II'"): T 1 and T 3 , CH, CR 3 and N are independently selected from T 2 is NR 3 , O and S; Regarding compound (X'): 2 and T 3 , CH, CR 3 and N are independently selected from T 1 is NR 3 , O and S; Regarding compound (X"): 1 and T 2 , CH, CR 3 and N are independently selected from T 3 is NR 3 , O and S; R 5 =C 1-4 - alkyl or benzyl; Hal = Cl, Br, I. Scheme 6: Y, R and R 3Esters of formula (II'"), where , has the meaning defined above, can be prepared from alcohols (XII) by displacement of the hydroxyl group with hydrogen using well-known methods reported in the literature (e.g., triethylsilane and TFA or boron trifluoride etherate in DCM, or hydrogen in the presence of palladium on carbon in solvents such as THF or EtOH). Alcohols (XII) can be prepared by adding magnesium halide (XI) or another organometallic derivative to aldehydes (IX), which can in turn be obtained from the corresponding alcohol by oxidation (e.g., Dess-Martin or Swern oxidation) in inert solvents (e.g., THF, DCM, or diethyl ether) at low to ambient temperatures. Magnesium halides (XI) can be obtained from the corresponding bromides or iodides of (X) at low temperatures using isopropylmagnesium chloride, optionally in combination with lithium chloride in THF, after a halogen-metal exchange reaction. Alternatively, magnesium metal can be inserted into the carbon-halogen bond to provide magnesium halide (XI). Compounds (IX) and (XII) can carry the desired residue R on the heteroaromatic ring Y or on the leaving group instead of later introducing R.

[0078] Starting from compounds (X') and (X"), the corresponding analogs of compounds (II'") are accessible using the principles outlined above (see Scheme 7 for (X')).

[0079] [ka] T 2 and T 3 , CH, CR 3 and N are independently selected from T 1 is NR 3 , O and S; R 5 =C 1-4 - alkyl or benzyl; Hal = Cl, Br, I. Scheme 7: Y, R and R 3 Compounds of formula (II″”), wherein R has the meaning defined above, can be prepared in a manner similar to that detailed in Scheme 6 using isomeric magnesium halides (XI′).

[0080] [ka] LG = leaving group such as F, Cl, Br, I; A 1 , A 2 , A 3 , A 4 = N or CR independently 1 R 6 =COOR 5 , CHO, CH2OH, CH2-Ar-COOR 5 ;R 5 =C 1-4 -Alkyl or benzyl Scheme 8: Intermediates of formula (XV) can be prepared from aromatic compounds (XIII) and amines (XIV) either via nucleophilic substitution on the heteroaromatic ring or via transition metal catalyzed coupling reactions; Ar, R and R in Scheme 8 1 has the meaning defined above. Nucleophilic displacement of the leaving group on the heteroaromatic ring in (XIII) with N in compound (XIV) can be carried out 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) at ambient or elevated temperature. The transition metal-catalyzed coupling reaction is preferably carried out in the presence of a base and in a suitable solvent using an appropriate copper or palladium salt or complex thereof, optionally in combination with an additional ligand, similar to procedures reported in the organic chemistry literature referred to as the Ullmann or Buchwald-Hartwig coupling reaction.

[0081] [ka] Scheme 9: Enantiopure amines (III.1) can be prepared from ketones (XVI) as detailed in Scheme 9. The overall synthesis involves three steps, from the condensation of the ketone with enantiopure tert-butanesulfinamide to give titanium alcoholates (e.g., Ti(OEt) or Ti(O i In the presence of a dehydrating agent such as HCl, ...

[0082] The racemate (III) and the opposite enantiomer (III.2) can be obtained by using racemic tert-butanesulfinamine and enantiopure (S)-tert-butanesulfinamine, respectively, via the routes described above.

[0083] Alternatively, compound (III.1) and its enantiomer (III.2) can be obtained from ketone (XVI) via a three-step synthetic sequence, starting with the enantioselective reduction of the ketone moiety in compound (XVI) to give the corresponding enantiopure or enantiomerically enriched alcohol 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). The hydroxyl group thus formed can then be displaced with a protected or masked ammonia group, such as phthalimide or (tert-Bu-OCO)N, using a stereospecific Mitsunobu or Mitsunobu-type reaction (e.g., using tri-n-butylphosphine in combination with triphenylphosphine or dimethyl azodicarboxylate, DEAD, DIAD, di-(4-chlorobenzyl)azodicarboxylate, dibenzyl azodicarboxylate, DBAD, azodicarboxylic acid bis-(dimethylamide), azodicarboxylic acid dipiperidide, or azodicarboxylic acid dimorpholide in a suitable solvent (e.g., THF, 1,4-dioxane, EtOAc, benzene, toluene, etc.)), leading to inversion of the configuration at the C-bearing heteroatom. Alternatively, phosphoryl azides (e.g., diphenylphosphoryl azide) can be used to displace the OH group with an azide under inversion of the configuration. The amino group can be liberated from the phthalimido group by treatment with, for example, hydrazine, hydroxylamine, methylamine, n-butylamine or ethanolamine in a suitable solvent (e.g., EtOH, MeOH, MeCN, THF, dioxane, DMSO, N,N-dimethylacetamide, water, or mixtures thereof) with heating if necessary, to give compound (III.1).The tert-Bu-O-CO is preferably removed under acidic conditions (e.g., using TFA or hydrochloric acid) to give the same amine (III.1). The azide can be reduced to the amine (III.1), for example, with hydrogen in the presence of a transition metal (e.g., Pd on carbon, Raney-Ni, PtO, etc.) or a phosphine (e.g., triphenylphosphine). The racemate (III) is obtained by reduction of compound (XVI) with an achiral reducing agent such as sodium borohydride and following the further route described above.

[0084] [ka] Scheme 10: Compound (XVI) can be obtained from ester (XIX) (or the corresponding lower or higher alkyl ester, e.g., methyl, n-propyl, isopropyl, or tert-butyl ester) in a sequence of three or four reaction steps. Compound (XIX) can be brominated with a suitable electrophilic bromine source (e.g., N-bromosuccinimide (NBS) or Br) in a suitable solvent (e.g., AcOH, DCM, dichloroethane, dioxane, MeCN, DMF, etc.) at ambient or elevated temperatures. For example, NBS in acetic acid at ambient temperature or NBS in HCl at 65°C provides the compound. Alternatively, treatment of compound (XIX) with NBS, sodium persulfate, and palladium acetate in trifluoromethanesulfonic acid and 1,2-dichloroethane at 80°C similarly provides access to (XX). Compound (XX) can then be converted to ester (XXI) by applying one- or two-step synthetic routes involving Heck coupling reactions with acrolein dialkyl acetals (e.g., acrolein diethyl acetal → (XXI)) or acrylates (e.g., acrylic ethyl ester → (XXIII)) (extensively covered in the organic chemistry literature, e.g., Catalysts 2017, 7, 267 and references cited therein); using the latter coupling partner requires an additional step to reduce the formed olefinic bond, which is routinely achieved with hydrogen in a suitable solvent (e.g., DCM, dioxane, THF, EtOAc, alcohols (e.g., MeOH, water, etc.) in the presence of a transition metal catalyst (e.g., Pd, e.g., palladium on carbon; Ni, e.g., Raney-Ni; Pt, e.g., platinum oxide; Rh, e.g., rhodium on carbon, etc.).Ketoesters (XXII) can be produced by treatment of compound (XXI) with a base (e.g., hydrides such as sodium hydride, alcoholates such as lithium methoxide or potassium tert-butylate, organic amines such as DBU, phosphazenes such as P2Et phosphazenes, amides such as lithium diisopropylamide, lithium, sodium or potassium hexamethyldisilazide, etc.) in a suitable solvent (e.g., benzene, toluene, dioxane, THF, alcohols, etc., depending on the base used) at low to elevated temperatures (-78°C to 100°C, depending on the base and solvent used); potassium hexamethyldisilazide in THF at 20°C is one of the more preferred conditions for this transformation. 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 mixtures thereof) optionally in the presence of a base (e.g., sodium hydroxide), a halide salt such as lithium iodide or chloride, or an acid (e.g., hydrochloric acid) at 0°C to 140°C to give ketone (XVI).

[0085] The compounds of formula (I) can be resolved into their enantiomers and / or diastereomers as described below. Thus, for example, cis / trans mixtures can be resolved into their cis and trans isomers and racemates can be separated into their enantiomers.

[0086] Cis / trans mixtures can be resolved into their cis and trans isomers, for example, by chromatography. Compounds of formula (I) that occur as racemates 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 taking advantage of their different physicochemical properties, for example, using methods known per se, for example, chromatography and / or fractional crystallization; if the compounds obtained subsequently are racemic, they can be resolved into their enantiomers as described below.

[0087] Racemates are preferably resolved by column chromatography on chiral phases, by crystallization from optically active solvents, or by reaction with optically active substances that form salts or derivatives, such as esters or amides, with the racemate. Salts can be formed with enantiomerically pure acids for basic compounds and with enantiomerically pure bases for acidic compounds. Diastereomeric derivatives are formed with enantiomerically pure auxiliary compounds, such as acids, their activated derivatives, or alcohols. Separation of the diastereomeric mixtures of salts or derivatives thus obtained can be achieved by exploiting their different physicochemical properties, such as differences in solubility; the free antipode can be released from the pure diastereomeric salt or derivative by the action of an appropriate agent. Optically active acids commonly used for such purposes, as well as optically active alcohols applicable as auxiliary residues, are known to those skilled in the art. As described above, the compounds of formula (I) can be converted into salts, particularly pharmaceutically acceptable salts for pharmaceutical use. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by making acid or base salts thereof. The compounds according to the invention are furthermore advantageously obtained using the methods described in the examples that follow, which may also be combined with methods known to those skilled in the art from the literature for this purpose. Thus, according to another aspect of the present invention there is provided a process for the synthesis of compounds of formula (I). According to another aspect of the present invention, there are provided intermediates in the synthesis of compounds of formula (I). According to one embodiment, the present invention relates to intermediates as depicted and described in Schemes 9 and / or 10.

[0088] According to another embodiment, the present invention provides the following intermediate [ka] relating to one or more of the following:

[0089] Pharmacological activity The activity of the compounds of the present invention can be demonstrated using the following assays:

[0090] biological methods The ability of compounds of formula (I) to inhibit plasma kallikrein (PKK), factor XIIa (FXIIa), factor XIa (FXIa), factor Xa (FXa), factor IIa (alpha-thrombin; FIIa), plasmin, trypsin, tissue kallikrein 1 (TK1), factor VIIa (FVIIa), or the FVIIa complex with tissue factor, phospholipids, and CaCl2 (FVIIa / TF / PL / CaCl2) is determined in the presence of 1% (v / v) DMSO in assay buffer (100 mM Tris, 150 mM NaCL, adjusted to a pH of 7.8 with HCl, containing 0.1% (w / v) BSA and 0.05% (v / v) Tween 20) using the following biochemical assay:

[0091] Evaluation of PKK inhibition using an AN endpoint assay Human PKK (0.01 U / mL; Enzyme Research Laboratories) or rat PKK (0.625 nM; homemade) is incubated in assay buffer with 0.10 μM fluorogenic substrate H-Pro-Phe-Arg-AMC (I1295 from Bachem) and various concentrations of test compound for 1 hour at room temperature. Subsequently, PPACK II (Calbiochem) is added as a stop solution to achieve a final concentration of 1 μM, and fluorescence is measured using an Envision Reader (PerkinElmer) with excitation and emission wavelengths of 355 nm and 460 nm, respectively.

[0092] IC for compounds according to the invention 50 The values ​​are shown in the table below, where the compound numbers correspond to the example numbers in the experimental section.

[0093] [Table 2-1] [Table 2-2]

[0094] Evaluation of PKK inhibition in kaolin-activated human PPP Platelet-poor plasma (PPP) from human whole blood anticoagulated with sodium citrate was incubated with various concentrations of test compound in assay buffer at 37°C for 20 minutes with either 25 μg / mL, 75 μg / mL, 250 μg / mL, or 750 μg / mL kaolin to obtain a concentration response for the test compound for each kaolin dose used. 0.25 mM fluorogenic substrate H-Pro-Phe-Arg-AMC (I1295 from Bachem) was then added to the mixture, and measurements were taken at 2-minute kinetic intervals for 12 minutes using a Spectramax M5 (Molecular Devices) with the following settings: excitation wavelength 350 nm, emission wavelength 450 nm. pIC50 and pIC90 values ​​are obtained from 4 x / y-plots (x = log M compound; y = delta rfu / min) fitted in GraphPad Prism 7.0 (equation: log(agonist) vs. response--Find ECanything; four concentration-response curves obtained for the test compound, each obtained using a different kaolin dose, are fitted using a global fitting procedure to obtain a common pIC50 or pIC90 value).

[0095] IC for compounds according to the invention 90 The values ​​are shown in the table below, where the compound numbers correspond to the example numbers in the experimental section.

[0096] [Table 3-1] [Table 3-2]

[0097] PKK (K i ) inhibition evaluation Human PKK (1.78 nM or 0.025 U / mL; Enzyme Research Laboratories) is incubated in assay buffer with 0.25 mM fluorogenic substrate H-Pro-Phe-Arg-AMC (I1295 from Bachem) and various concentrations of test compound at 24° C. Measurements are taken every 2 minutes for 16 minutes with kinetic intervals using a Spectramax M5 (Molecular Devices) with the following settings: excitation wavelength of 350 nm and emission wavelength of 450 nm.

[0098] FXIIa(K i ) inhibition evaluation Human FXIIa (47.5 nM or 1.1 U / mL; Enzyme Research Laboratories) is incubated in assay buffer with 0.5 mM chromogenic substrate S2302 (Chromogenix) and various concentrations of test compound at 24° C. Measurements are taken every 2 minutes for 16 minutes at kinetic intervals using a Spectramax M5 (Molecular Devices) measuring the absorbance band at 405 nm.

[0099] FXIa(K i ) inhibition evaluation Human FXIa (0.5 nM or 0.016 U / mL; Enzyme Research Laboratories) is incubated in assay buffer with 0.25 mM fluorogenic substrate Boc-Glu(OBzl)-Ala-Arg-AMC·HCl (I1575 from Bachem) and various concentrations of test compound at 24°C. Measurements are performed every 2 minutes for 16 minutes using a Spectramax M5 (Molecular Devices) with the following settings: excitation wavelength 350 nm and emission wavelength 450 nm.

[0100] FXa(K i ) inhibition evaluation Human FXa (0.86 nM or 0.01 U / mL; Enzyme Research Laboratories) is incubated in assay buffer with 0.5 mM chromogenic substrate S2765 (Chromogenix) and various concentrations of test compound at 24° C. Measurements are taken every 2 minutes for 16 minutes at kinetic intervals using a Spectramax M5 (Molecular Devices) measuring the absorbance band at 405 nm.

[0101] FIIa(K i ) inhibition evaluation Human Fila (44.6 nM or 5 U / mL; Enzyme Research Laboratories) is incubated in assay buffer with 0.5 mM chromogenic substrate S2238 (Chromogenix) and various concentrations of test compound at 24° C. Measurements are taken every 2 minutes for 16 minutes at kinetic intervals using a Spectramax M5 (Molecular Devices) measuring the absorbance band at 405 nm.

[0102] Plasmin (K i ) inhibition evaluation Human plasmin (64.1 nM or 0.0275 U / mL; Enzyme Research Laboratories) is incubated in assay buffer with 0.3 mM chromogenic substrate S2251 (Chromogenix) and various concentrations of test compound at 24° C. Measurements are taken every 2 minutes for 16 minutes at kinetic intervals using a Spectramax M5 (Molecular Devices) measuring the absorbance band at 405 nm.

[0103] Trypsin (K i ) inhibition evaluation Human trypsin (4.54 nM or 250 U / mL; Calbiochem) is incubated in assay buffer with 0.5 mM chromogenic substrate S2222 (Chromogenix) and various concentrations of test compound at 24° C. Measurements are taken every 2 minutes for 16 minutes at kinetic intervals using a Spectramax M5 (Molecular Devices) measuring the absorbance band at 405 nm.

[0104] TK1(K i ) inhibition evaluation Prior to the assay, human TK1 (R&D Systems) is activated by incubation with human trypsin (Calbiochem) at a ratio of 1:10,000 for 15 minutes at 37°C. To assay TK1 inhibitory activity, activated TK1 (31.25 nM or 1 U / mL) is incubated with 0.1 mM fluorogenic substrate H-Pro-Phe-Arg-AMC (I1295 from Bachem) and various concentrations of test compound in assay buffer at 24°C. Measurements are performed every 2 minutes for 16 minutes with a dynamic interval using a Spectramax M5 (Molecular Devices) with the following settings: excitation wavelength 350 nm and emission wavelength 450 nm. K for compounds according to the invention i The values ​​are shown in the table below, where the compound numbers correspond to the example numbers in the experimental section.

[0105] [Table 4]

[0106] FVIIa(K i ) inhibition evaluation Human FVIIa (0.86 nM or 0.01 U / mL; Enzyme Research Laboratories) is incubated in assay buffer with 1.5 mM chromogenic Pefachrome® FVIIa (Loxo) and various concentrations of test compound at 24° C. Measurements are taken every 2 minutes for 16 minutes at kinetic intervals using a Spectramax M5 (Molecular Devices) measuring the light absorption band at 405 nm.

[0107] FVIIa / TF / PL / CaCl2(K i ) inhibition evaluation Recombinant human tissue factor synthetic phospholipid (thromboplastin) containing 10 mM CaCl * Human FVIIa (300 nM or 585 U / mL; Enzyme Research Laboratories) with 2H2O and 13.3% (v / v) Dade® Innovin® (Siemens; OQUMI94E0002 (5534)) is incubated in assay buffer with 1.5 mM chromogenic Pefachrome® FVIIa (Loxo) and various concentrations of test compound at 24°C. Measurements are taken every 2 minutes for 16 minutes at kinetic intervals using a Spectramax M5 (Molecular Devices) measuring the light absorption band at 405 nm.

[0108] pIC 50 value and pK i Calculating values The average V for the time interval 2 to 12 minutes after the start of the assay max Values ​​(expressed as either delta OD / min for assays using chromogenic substrates or delta RFU / min for assays using fluorogenic substrates, respectively) are plotted versus the log of the molar concentration of the inhibitor compound being evaluated. 50 The values ​​are then fitted using a four-parameter fitting procedure using GraphPad Prism (version 6; GraphPad Software, Inc.). iThe K values ​​for each of the substrates used were calculated using the following equation: M IC for Value 50 The value obtained by correcting the K M See Table A for values):

[0109]

number

[0110] [Table 5]

[0111] Permeability assessment Caco-2 cells (1~2×10 5 cells / 1cm 2 area) are seeded onto filter inserts (Costar Transwell polycarbonate or PET filters, 0.4 μm pore size) and cultured (in DMEM) for 10–25 days. Compounds are dissolved in an appropriate solvent (e.g., DMSO, 1-20 mM stock solution) and diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO, 1.8 mM CaCl, 4.17 mM NaHCO, 1.19 mM NaHPO x 7H2O, 0.41 mM NaHPO x 7H2O, 15 mM HEPES, 20 mM glucose, pH 7.2) containing 0.25% BSA to prepare transport solutions (0.1-300 µM compound, final DMSO <= 0.5%). Transport solution (TL) is applied to the apical or basolateral donor side to measure AB or BA permeability (two filter replicates), respectively. The receiver side contains HTP-4 buffer supplemented with 0.25% BSA. Samples are collected from the donor at the beginning and end of the experiment, and from the receiver side at various time intervals up to 2 h, for concentration measurement by HPLC-MS / MS or scintillation counting. The sampled receiver volume is replaced with fresh receiver solution.

[0112] Assessment of metabolic stability in human or rat liver microsomes Metabolic degradation of test compounds is assayed using pooled human (HLM) or rat liver microsomes (RLM) at 37° C. A final incubation volume of 60 μl per time point contains Tris buffer pH 7.6 (0.1 M), magnesium chloride (5 mM), microsomal protein (HLM: 1 mg / mL, RLM: 0.5 mg / mL), and test compound at a final concentration of 1 μM at room temperature. Following a short pre-incubation period at 37°C, the reaction is initiated by the addition of beta-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH, 1 mM), and terminated by transferring aliquots into solvent after different time points. Additionally, NADPH-independent degradation is monitored in incubations without NADPH, which are terminated at the end of the incubation period. The quenched incubations are pelleted by centrifugation (10,000g, 5 minutes). An aliquot of the supernatant is assayed for the amount of parent compound by LC-MS / MS. The half-life (t1 / 2 INVITRO) is determined by the slope of a semi-logarithmic plot of the concentration-time profile.

[0113] Assessment of metabolic stability in human or rat hepatocytes The metabolic degradation of test compounds is assayed in suspension hepatocytes. After recovery from cryopreservation, human or rat hepatocytes are incubated in Dulbecco's modified Eagle's medium (supplemented with 3.5 μg glucagon / 500 ml, 2.5 mg insulin / 500 ml, and 3.75 mg hydrocortisone / 500 ml) containing 5% or 50% human or rat serum or in the absence of serum. Following a 30-minute preincubation in a cell culture incubator (37°C, 10% CO2), the test compound solution was spiked into the hepatocyte suspension to give a 1.0 * A final cell density of 10 6 cells / ml, a final test compound concentration of 1 μM, and a final DMSO concentration of 0.05% is obtained. The cells are incubated (incubator, horizontal shaker) for 6 hours, and samples are removed from the incubation at 0, 0.5, 1, 2, 4, and 6 hours. The samples are quenched with acetonitrile and pelleted by centrifugation. The supernatant is transferred to a 96-deep-well plate and prepared for analysis of parent compound decay by HPLC-MS / MS.

[0114] CL intis calculated as follows: CL int =Dose / AUC=(C0 / CD) / (AUD+clast / k)×1000 / 60 C0: initial concentration in incubation [μM], CD: viable cell density [10e6cells / ml], AUD: area under the data [μM × h], clast: concentration of the last data point [μM], k: slope of the regression line for parent fading [h -1 ].

[0115] The calculated in vitro hepatic intrinsic clearance can be scaled to the intrinsic in vivo hepatic clearance and used to predict hepatic in vivo blood clearance (CL) by use of a liver model (well-stirred model).

[0116] Evaluation of plasma protein binding The equilibrium dialysis (ED) technique was used to determine the approximate in vitro fractional binding of test compounds to plasma proteins using Dianorm Teflon dialysis cells (micro 0.2). Each dialysis cell consisted of a donor and acceptor chamber separated by an ultrathin semipermeable membrane with a molecular weight cutoff of 5 kDa. A stock solution for each test compound was prepared at 1 mM in DMSO and serially diluted to obtain a final test concentration of 1 μM. Subsequent dialysis solutions were prepared in plasma (supplemented with NaEDTA as an anticoagulant), and 200 μl aliquots of the test compound dialysis solution in plasma were dispensed into the donor (plasma) chamber. 200 μl aliquots of dialysis buffer (100 mM potassium phosphate, pH 7.4) were dispensed into the buffer (acceptor) chamber. Incubation was carried out at 37 °C under rotation for 2 h to establish equilibrium. At the end of the dialysis period, aliquots from the donor and acceptor chambers, respectively, are transferred into reaction tubes, spiked with an internal standard solution, and processed for HPLC-MS / MS analysis. Analyte concentrations are quantified in the sample aliquots by HPLC-MS / MS against an external calibration curve. Percent binding is calculated using the following formula: Binding % = (Plasma concentration - Buffer concentration / Plasma concentration) x 100

[0117] Solubility assessment The water solubility of the test compound is determined by comparing the amount dissolved in the buffer with the amount in the ACN / water (1 / 1) solution. Starting from a 10 mM DMSO stock solution, an aliquot is diluted with acetonitrile / water (1 / 1) or buffer, respectively. After shaking for 24 hours, the solution is filtered and analyzed by LC-UV. The amount dissolved in the buffer is compared with the amount in the ACN solution. Solubility is usually measured at 0.001 mg to 0.125 mg / mL at a DMSO concentration of 2.5%. If more than 90% of the compound is dissolved in the buffer, the value is marked with ">".

[0118] Evaluation of pharmacokinetic characteristics in rodents Test compounds are administered either intravenously to fed rats or orally to fasted rats. Blood samples are taken at several time points after application of the test compound, anticoagulated, and centrifuged. The concentration of the analyte—the administered compound and / or metabolite—is quantified in the plasma sample. PK parameters are calculated using non-compartmental methods. AUC and Cmax are normalized to a dose of 1 μmol / kg.

[0119] Evaluation of inhibition of cytochrome P450 isoenzyme-catalyzed reactions Inhibition of cytochrome P450 isoenzyme-catalyzed reactions by test compounds is assayed using human liver microsomes at 37°C. All assays are performed on a robotic system in 384-well plates. Test compounds are spotted directly into incubation plates from DMSO stocks by acoustic liquid dispensing (using the Labyte ECHO® system). The final incubation volume contains, in duplicate, Tris buffer (0.1 M), MgCl2 (5 mM), human liver microsomes, specific cytochrome P450 isoenzyme substrates, and test compounds at five different concentrations, or no compound (high control) (e.g., using a top concentration of 50 μM followed by serial 1:4 dilutions). Following a short preincubation period, the reaction is initiated with the cofactor (NADPH, 1 mM) and stopped by cooling the incubation to 8°C and subsequently adding one volume of acetonitrile. An internal standard solution—usually a stable isotope of the metabolite formed—is added after quenching the incubation. The peak areas of the analyte (= metabolite formed) and the internal standard are determined by LC-MS / MS. The resulting peak area ratios of the analyte to the internal standard in these incubations are compared to a control activity that does not contain the test compound. Within each assay run, the IC of the positive control inhibitor is calculated. 50 is determined. Experimental IC50 values ​​are calculated by least squares regression according to the following equation: % control activity = (100% control activity / (1 + (I / IC 50 )S)))-b where: I = inhibitor concentration S=slope factor B = background activity If the inhibition of the response is already >50% at the lowest concentration of the test compound, the IC 50 If inhibition of the response is still <50% at the highest concentration of test compound, then the IC50 is assigned to the "highest concentration tested" (usually >50 μM).

[0120] Evaluation of mechanism-based inhibition (MBI) of cytochrome P450 3A4-catalyzed midazolam turnover Mechanism-based inhibition towards CYP3A4 is assayed in human liver microsomes (0.02 mg / ml) with midazolam (15 uM) as substrate.

[0121] Test compounds are preincubated with human liver microsomes (0.2 mg / ml) in the presence of NADPH at concentrations of 5 μM and 25 μM for 0, 10, or 30 minutes at 37°C. After preincubation, the incubate is diluted 1:10 and the substrate midazolam is added for the main incubation (15 minutes). The main incubation is quenched with acetonitrile, and the formation of hydroxy-midazolam is quantified via LC / MS-MS. The turnover rate in pmol / min / mg protein was calculated, and the activity after 10 and 30 min preincubation times was compared to that of the 0 min preincubation with each compound / concentration (%CTRL = % of the 0 min control for each compound / concentration). Additionally, the turnover rate is expressed relative to the turnover rate of the substrate reaction without added compound (%TR = % of the turnover rate without compound) to recognize competitive inhibition effects.

[0122] Treatment method In another aspect of the present invention, it has been found that the compound of formula (I) or a pharmaceutically acceptable salt thereof has suitable properties for use in therapy and / or prevention, i.e., for use as a pharmaceutical. In particular, the compound of formula (I) or a pharmaceutically acceptable salt thereof, as well as pharmaceutical compositions containing same, may be useful in the treatment, i.e., treatment and / or prevention (prophylaxis) of diseases or conditions in patients that can be affected by inhibition of plasma kallikrein, for example, that are mediated by unwanted PKK activity, or in which inhibition of PKK is beneficial. Diseases and conditions that can be affected by inhibition of PKK, e.g., those mediated by unwanted PKK activity or in which inhibition of PKK would be beneficial, include, for example, those described in the Background of the Invention section, particularly diabetic complications, diabetic retinopathy, proliferative and non-proliferative retinopathies, diabetic macular edema (DME), clinically significant macular edema (CSME), cystoid macular edema (CME), CME following cataract extraction, CME induced by cryotherapy, CME induced by uveitis, endophthalmitis, vascular occlusion (e.g., central retinal vein occlusion), and the like. These include CME following retinal vein occlusion (branch retinal vein occlusion or hemiretinal vein occlusion), retinal edema, complications associated with cataract surgery in diabetic retinopathy, hypertensive retinopathy, retinal trauma, dry and exudative age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV), choroidal neovascularization (CNV; e.g., nonexudative choroidal neovascularization), hereditary angioedema (HAE), acute respiratory distress syndrome (ARDS), post-stroke hemorrhage and edema, e.g., post-stroke cerebral edema, vascular dementia, Alzheimer's disease, fibrotic diseases, colitis, arthritis, and renal damage.

[0123] Thus, 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). In addition, the compounds and pharmaceutical compositions according to the present invention are particularly suitable for the treatment of edema, such as hereditary angioedema (HAE) and post-stroke cerebral edema. In particular, the compounds and pharmaceutical compositions according to the present invention are suitable for the treatment of 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 post-stroke cerebral edema.

[0124] The compounds and pharmaceutical compositions according to the present invention are particularly suitable for treating diabetic macular edema (DME), wet age-related macular degeneration (AMD), nonexudative choroidal neovascularization (CNV), hereditary angioedema (HAE), and post-stroke cerebral edema. For example, they are particularly suitable for preventing diabetic macular edema (DME), exudative age-related macular degeneration (AMD), hereditary angioedema (HAE) and post-stroke cerebral edema, as well as for preventing the conversion of non-exudative choroidal neovascularization (neCNV) to exudative choroidal neovascularization (eCNV). The applicable daily dose range of the compound of formula (I) is usually 0.01 mg to 10 mg per kg body weight. The actual therapeutically effective amount or therapeutic dosage will, of course, depend on factors known by those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease, etc. In any case, the compound or composition will be administered in a dosage and manner that allows a therapeutically effective amount to be delivered based on the patient's unique condition.

[0125] The compound and composition of the present invention, including any combination with one or more additional therapeutic agents, can be administered orally, intravitreal, transdermal, inhalation, parenteral or sublingually.Among possible administration methods, oral or intravitreal administration is preferred.In the case of intravitreal injection, the preferred dose should not exceed 5mg per eye. The patient to be treated is preferably a mammal, most preferably a human patient.

[0126] Thus, in another aspect, the present invention provides compounds of formula (I) and tautomers thereof, including pharmaceutically acceptable salts thereof, for use as pharmaceuticals. In another aspect, the present invention provides a method for the treatment of a disease or condition in a patient in need thereof that is mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial. Similarly, the present invention provides a compound of formula (I) and / or a tautomer thereof or a pharmaceutically acceptable salt thereof for use in a method for the treatment of a disease or condition in a patient in need thereof that is mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial. Similarly, the invention provides the use of a compound of formula (I) and / or a tautomer thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method for the treatment, in a patient in need thereof, of a disease or condition mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial. Similarly, 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 the treatment of a disease or condition in a patient in need thereof that is mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial.

[0127] According to one embodiment, the method for treatment comprises administering to the patient one or more compounds of formula (I) and / or tautomers thereof or pharmaceutically acceptable salts thereof, preferably administering to the patient a therapeutically effective amount of one or more compounds of formula (I) and / or tautomers thereof or pharmaceutically acceptable salts thereof. According to another embodiment, the method for treatment comprises administering to a patient a pharmaceutical composition according to the invention.

[0128] According to one embodiment, the disease or condition mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial is selected from ophthalmic indications such as diabetic retinopathy, proliferative and non-proliferative retinopathies, diabetic macular edema (DME), age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV) and choroidal neovascularization (CNV). According to another embodiment, the disease or condition mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial is selected from edema-related diseases such as hereditary angioedema (HAE) and post-stroke cerebral edema. According to another embodiment, the disease or condition mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial is selected from diabetic complications such as diabetic retinopathy and retinal vascular permeability associated with diabetic macular edema. According to one embodiment, the patient is a human patient.

[0129] Pharmaceutical Composition In another aspect of the present invention, it is provided that the compounds of the present invention, or pharmaceutically acceptable salts thereof, can be used as the active ingredient in pharmaceutical compositions. Suitable preparations for administering the compounds of the present invention, optionally in combination with one or more additional therapeutic agents, will be apparent to those of ordinary skill in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injections, inhalants, and powders. Oral preparations, particularly solid forms such as tablets or capsules, are preferred. For intravitreal injection, solutions are preferred. The content of the pharmaceutically active compound(s) is advantageously in the range of 0.1 to 90 wt.-% of the total composition, for example, 1 wt.-% to 70 wt.-%.

[0130] Suitable tablets can be obtained, for example, by mixing one or more compounds according to formula (I) with known excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants. Tablets can also consist of several layers. The specific excipients, carriers and / or diluents suitable for the desired preparation will be obvious to those skilled in the art based on their expert knowledge. Preference is given to those suitable for the particular formulation and the desired method of administration. Preparations or formulations according to the invention can be prepared using methods known per se and obvious to those skilled in the art, for example, by mixing or combining at least one compound of formula (I) according to the invention, or a pharmaceutically acceptable salt of such a compound, and one or more excipients, carriers and / or diluents.

[0131] Thus, 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. Moreover, pharmaceutical compositions comprising one or more of the above-described compounds, or pharmaceutically acceptable salts thereof, optionally together with one or more inert carriers and / or diluents, are provided for use in methods for the treatment of diseases or conditions in a patient in need thereof that are mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial. In particular, the present invention provides pharmaceutical compositions according to this invention for use in methods for the treatment of ophthalmic indications, such as diabetic retinopathy, proliferative and non-proliferative retinopathies, diabetic macular edema (DME), age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV) and choroidal neovascularization (CNV), and for the treatment of edema-related diseases, such as hereditary angioedema (HAE) and post-stroke cerebral edema.

[0132] Furthermore, the present invention relates to the use of a pharmaceutical composition according to this invention for the treatment of a disease or condition mediated by unwanted plasma kallikrein activity in a patient, preferably a human. Moreover, the present invention relates to the use of a pharmaceutical composition according to this invention for the treatment of a disease or condition in a patient, preferably a human, in which inhibition of plasma kallikrein is beneficial. 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. Preferably, the composition comprises one compound of formula (I) and / or a tautomer thereof or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

[0133] Combination Therapy The compounds of the present invention can further be combined with one or more, preferably one, additional therapeutic agent. According to one embodiment, the additional therapeutic agent is selected from the group of therapeutic agents useful in the treatment of the diseases or conditions described above, in particular diseases or conditions associated with metabolic diseases or conditions such as diabetes mellitus, obesity, diabetic complications, hypertension, hyperlipidemia, or therapeutic agents useful in the treatment of ocular diseases. Additional therapeutic agents that are suitable for such combinations include, in particular, those that enhance the therapeutic effect of one or more active substances, e.g., for one of the described indications, and / or those that allow the dosage of one or more active substances to be reduced. As such, the compounds of the present invention may be combined with one or more additional therapeutic agents selected from the group consisting of 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 ocular diseases.

[0134] Antidiabetic agents include, for example, metformin, sulfonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR (alpha, gamma, or alpha / gamma) agonists or modulators, alpha-glucosidase inhibitors, DPPIV inhibitors, SGLT2 inhibitors, insulin and insulin analogs, GLP-1 and GLP-1 analogs, or amylin and amylin analogs, cyclostearate, and 11β-HSD inhibitors. Other suitable combination partners are inhibitors of protein tyrosine phosphatase 1, substances that affect deregulated glucose production in the liver, such as inhibitors of glucose-6-phosphatase or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists, and inhibitors of phosphoenolpyruvate carboxykinase, glycogen synthase kinase, or pyruvate dehydrokinase, alpha2 antagonists, CCR-2 antagonists, or glucokinase activators. Also suitable as combination partners are one or more lipid-lowering agents, such as, for example, HMG-CoA-reductase inhibitors, fibrates, nicotinic acid and its derivatives, PPAR-(alpha, gamma or alpha / gamma) agonists or modulators, PPAR-delta agonists, ACAT inhibitors or cholesterol absorption inhibitors, e.g., bile acid binding substances, e.g., inhibitors of ileal bile acid transport, MTP inhibitors, or HDL-raising compounds, e.g., CETP inhibitors or ABC1 modulators.

[0135] Therapeutic agents for the treatment of overweight and / or obesity are, for example, antagonists of the cannabinoid 1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists, β3 agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor.

[0136] Therapeutic agents for the treatment of hypertension, chronic heart failure, and / or atherosclerosis include, for example, A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics, β-blockers, Ca antagonists, centrally acting antihypertensive agents, alpha-2-adrenergic receptor antagonists, neutral endopeptidase inhibitors, platelet aggregation inhibitors, and others, or combinations thereof. Angiotensin II receptor antagonists are preferably used in combination with diuretics such as hydrochlorothiazide for the treatment or prevention of hypertension and diabetic complications.

[0137] Therapeutic agents for the treatment of ocular diseases can include, for example, intravitreally administered corticosteroids, intravitreally administered anti-VEGF therapy, 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. Additional treatments for eye diseases can include laser coagulation therapy. Preferably, the compounds of the invention and / or pharmaceutical compositions comprising the compounds of the invention are administered in conjunction with exercise and / or diet, optionally in combination with one or more additional therapeutic agents.

[0138] Dosages for the combination partners described above are usually from 1 / 5 of the lowest normally recommended dose to a maximum of 1 / 1 of the normally recommended dose. The use of the compounds according to the present invention in combination with additional therapeutic agents may be done simultaneously or at staggered times. The compound according to the invention and the one or more additional therapeutic agents can both be present together in one formulation, e.g., a tablet or capsule, or separately in two identical or different formulations, e.g., as a so-called kit of parts.

[0139] Therefore, according to another aspect, the present invention relates to pharmaceutical compositions comprising one or more compounds according to the invention as described above and below, and one or more additional therapeutic agents, optionally together with one or more inert carriers and / or diluents. According to another aspect, the present invention provides a method for the treatment of a disease or condition in a patient in need thereof that is mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial, comprising administering to the patient one or more compounds of formula (I) and / or tautomers thereof or pharmaceutically acceptable salts thereof in combination with one or more additional therapeutic agents as described above and below; Preferably, a therapeutically effective amount of one or more compounds of formula (I) and / or tautomers thereof or pharmaceutically acceptable salts thereof is administered to a patient in combination with a therapeutically effective amount of one or more additional therapeutic agents described above and below. The present invention provides a method comprising: Similarly, the present invention provides compounds of formula (I) and / or tautomers thereof or pharmaceutically acceptable salts thereof, in combination with one or more additional therapeutic agents described above or below, for use in a method for the treatment of a disease or condition in a patient in need thereof that is mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial. Similarly, the invention provides the use of a compound of formula (I) and / or a tautomer thereof or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents described above or below in the manufacture of a medicament for use in a method for the treatment, in a patient in need thereof, of a disease or condition mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial. Similarly, the present invention provides the use of a compound of formula (I) and / or a tautomer thereof or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents described above or below in a method for the treatment of a disease or condition in a patient in need thereof that is mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial.

[0140] 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 in combination with one or more additional therapeutic agents as described above and below; Preferably, a therapeutically effective amount of one or more compounds of formula (I) and / or tautomers thereof or pharmaceutically acceptable salts thereof is administered to a patient in combination with a therapeutically effective amount of one or more additional therapeutic agents described above and below. Includes:

[0141] 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, optionally together with one or more inert carriers and / or diluents. According to one embodiment, the one or more additional therapeutic agents are selected 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 ocular diseases, in particular from agents specifically described above.

[0142] According to one embodiment, the disease or condition mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial is selected from ophthalmic indications, such as diabetic retinopathy, proliferative and non-proliferative retinopathies, diabetic macular edema (DME), age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV) and choroidal neovascularization (CNV); from edema-related diseases, such as hereditary angioedema (HAE) and post-stroke cerebral edema; or Diabetic complications, such as retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema be selected. According to one embodiment, the patient is a human patient.

[0143] 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. [Example]

[0144] Examples and Experimental Data The following examples are for illustrative purposes only and are not intended to limit the scope of the present invention in any way. Abbreviation: Ac Acetyl ACN Acetonitrile AMC 7-amino-4-methylcoumarin Boc tert-butyloxycarbonyl BSA Bovine serum albumin Bzl Benzyl d day(s) DAD Diode Array Detector DBAD Di-tert-butyl azodicarboxylate DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DBN 1,5-diazabicyclo[4.3.0]non-5-ene DCM dichloromethane DEAD Diethyl azodicarboxylate DIAD Diisopropyl azodicarboxylate DIPEA N,N-Diisopropylethylamine DMEM Dulbecco's Modified Eagle's Medium DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EDTA Ethylenediaminetetraacetate ESI electrospray ionization (inMS) EtOAc ethyl acetate EtOH ethanol h hour(s) HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate HPLC High Performance Liquid Chromatography HPLC-MS Coupled High Performance Liquid Chromatography-Mass Spectrometry LC liquid chromatography LC-MS Coupled Liquid Chromatography-Mass Spectrometry LG leaving group M mole (mol / L) MeOH Methanol min minute(s) MS mass spectrometry NADPH Nicotinamide adenine dinucleotide phosphate NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance PET polyethylene terephthalate PyBop (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate R f Retardation Coefficient RFU Relative Fluorescence Units RP reverse phase rt room temperature t R Retention time (HPLC / LC) SFC Supercritical Fluid Chromatography TBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate TFA trifluoroacetic acid THF tetrahydrofuran UV ultraviolet

[0145] The terms "ambient temperature" and "room temperature" are used interchangeably and designate a temperature of about 20°C, e.g., 15-25°C. generally, 1 H-NMR and / or mass spectra were obtained for the compounds prepared. Unless otherwise specified, compounds containing chiral centers have the stereochemistry shown. The assignment of stereochemistry was made either by the use of chiral starting materials of known stereochemistry, by stereoselective synthesis of known stereochemistry, or by biological activity.

[0146] Analysis method [Table 6]

[0147] [Table 7]

[0148] [Table 8]

[0149] [Table 9]

[0150] [Table 10]

[0151] Synthesis of intermediates: The starting materials and intermediates used in the processes leading to the compounds according to the invention are either commercially available or they can be prepared by (or by methods analogous or similar to) the methods described below or already known to those skilled in the art from the literature, for example WO2017 / 072020, WO2017 / 072021 and WO2018 / 192866, which are hereby incorporated by reference in their entireties.

[0152] Intermediate 1 (4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-amine dihydrochloride [ka] Step 1: Methyl 5-bromo-1-methyl-1H-imidazole-4-carboxylate Under an argon atmosphere, methyl 1-methyl-1H-imidazole-4-carboxylate (19.1 g) is dissolved in DCM (230 mL). N-Bromosuccinimide (29.1 g), sodium persulfate (NaSO, 64.9 g), and palladium-II-acetate (Pd(OAc), 3.1 g) are added sequentially, and the mixture is cooled to 0 °C. Trifluoromethanesulfonic acid (CF-SOH, 42.2 mL) is added dropwise, and the mixture is then heated to 60 °C for 20 h. The mixture is diluted with DCM, cooled to 0 °C, and carefully treated with saturated aqueous NaCO until a pH of 8 is reached. The mixture is partitioned between water and DCM. The aqueous phase is extracted with DCM, and the combined organic phases are dried (MgSO) and concentrated in vacuo. The residue is chromatographed on silica gel (85:15 -> 70:30 EtOAc / MeOH). The product thus obtained is triturated with tert.-butyl-methyl-ether (50 mL) to give the title compound. LC (method 1):t R = 0.69 min; Mass spectrum (ESI + ): m / z=219[M+H] + .

[0153] Step 2: Methyl 5-(3-methoxy-3-oxopropyl)-1-methyl-1H-imidazole-4-carboxylate Methyl 5-bromo-1-methyl-1H-imidazole-4-carboxylate (10.6 g) is dissolved in dimethylacetamide (80 mL) and water (20 mL). 3,3-Dimethoxyprop-1-ene (8.6 mL) and N-methyldicyclohexylamine (15.3 mL) are added, and the mixture is purged with argon for 5 minutes. Dichlorobis(tri-o-tolylphosphine)palladium(II) (PdCl2[P(o-Tol)3]2, 1.9 g) is added, and the mixture is stirred at 120 °C for 3 hours. The mixture is then partitioned between water and EtOAc and filtered over Celite. The aqueous phase is mixed with saturated aqueous NaHCO3 and extracted four times with EtOAc. The combined organic phases are dried (MgSO4) and concentrated in vacuo. The residue is chromatographed on silica gel (90:10 to 70:30 EtOAc / MeOH) to give the title compound. LC (Method 2):t R = 0.55 min; Mass spectrum (ESI + ): m / z=227[M+H] + .

[0154] Step 3: Methyl 1-methyl-4-oxo-1H,4H,5H,6H-cyclopenta[d]imidazole-5-carboxylate Under an argon atmosphere, methyl 5-(3-methoxy-3-oxopropyl)-1-methyl-1H-imidazole-4-carboxylate (4.5 g) is dissolved in THF (100 mL) and treated with potassium bis(trimethylsilyl)amide (40 mL of a 1 M solution in THF). The mixture is 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 is filtered. The solvent is evaporated in vacuo to give the title compound. LC (method 1):t R = 0.25 min; Mass spectrum (ESI + ): m / z=195[M+H] + .

[0155] Step 4: 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-one 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) is heated under reflux for 90 hours. The solvent is evaporated in vacuo to give the title compound. LC (Method 1): R = 0.16 min; Mass spectrum (ESI + ): m / z=137[M+H] + . Alternatively, the reaction can be carried out by heating the starting material in a mixture of hydrogen chloride and acetic acid at 120 °C. After completion of the reaction, the solvent is evaporated in vacuo. The residue is dissolved in MeOH and treated with K2CO3 until a pH value of 8 is reached. The mixture is filtered, concentrated, and chromatographed on silica gel (20:1 → 5:1 DCM / MeOH) to give the title compound.

[0156] Step 5: (R)-2-Methyl-N-[(4E)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-ylidene]propane-2-sulfinamide 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-one (2.94 g), toluene (120 mL), and titanium tetraethoxide (Ti(OEt)4, 13.6 mL) are stirred for 15 minutes and then treated with (R)-2-methylpropane-2-sulfinamide (5.25 g). The mixture is heated at reflux for 4 hours, cooled to room temperature, and treated with saturated aqueous NaCl (30 mL). The mixture is stirred for 1 hour and then filtered over Celite. The filter cake is twice stirred for 10 minutes in MeOH (20 mL) and filtered over Celite. The combined organic phases are concentrated, and the residue is chromatographed on silica gel (95:5 DCM / MeOH). The product thus obtained is triturated from EtOAc to give the title compound. LC (method 3):t R = 3.69 min; Mass Spectrum (ESI + ): m / z=240[M+H] + .

[0157] Step 6: (R)-2-methyl-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]propane-2-sulfinamide L-Selectride (1 M in THF, 45 mL) is 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-sulfinamide (7.2 g). The mixture is stirred for 1 hour and then treated dropwise with MeOH (5 mL). The solvent is evaporated in vacuo, and the residue is chromatographed on silica gel (DCM / MeOH 95:5 to 80:20) to give the title compound. LC (Method 2):t R = 0.55 min; Mass spectrum (ESI + ): m / z=242[M+H] + . LC (method 3):t R =3.71 minutes.

[0158] Step 7: (4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-amine dihydrochloride A mixture of (R)-2-methyl-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]propane-2-sulfinamide (7.25 g) in isopropanol (50 mL) is treated with a 1.25 M solution of HCl in isopropanol (50 mL) and stirred for 2 hours. The precipitate is collected by filtration, washed successively with isopropanol and diethyl ether, and dried in vacuo to give the title compound. Mass spectrum (ESI) + ): m / z=138[M+H] + .

[0159] Intermediate 2 5-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridine-2-carbaldehyde [ka] 5-Fluoropyridine-2-carbaldehyde (1.0 g), 3-azabicyclo[3.1.0]hexane hydrochloride (1.1 g), and K2CO3 (2.8 g) are suspended in NMP (10 mL) and heated to 120 °C for 2 h. The mixture is cooled to room temperature, partitioned between water and EtOAc, and the phases are separated. The aqueous phase is extracted twice with EtOAc, and the combined organic phases are dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (100:0 → 60:40 cyclohexane / EtOAc) to give the title compound. LC (Method 2):t R = 0.68 min; Mass spectrum (ESI+): m / z = 189 [M+H] + .

[0160] Intermediates 2-1 to 2-4 are prepared analogously to Intermediate 2: [Table 11]

[0161] [Table 12]

[0162] [Table 13]

[0163] Intermediate 3 (5-{3-azabicyclo[3.1.0]hexan-3-yl}pyridin-2-yl)methanol [ka] NaBH4 (217 mg) is added in portions to an ice-cold mixture of 5-{3-azabicyclo[3.1.0]hexan-3-yl}pyridine-2-carbaldehyde (920 mg) in THF (10 mL) and MeOH (5 mL). The mixture is stirred for 1 hour at 0°C, treated with 1 M aqueous HCl (10 mL), and stirred for 30 minutes at room temperature. The mixture is then partitioned between saturated aqueous NaHCO3 and EtOAc. The phases are separated. The organic phase is dried (MgSO4) and concentrated to give the title compound. LC (Method 2):t R = 0.59 min; Mass spectrum (ESI+): m / z = 191 [M+H] + .

[0164] Intermediates 3-1 to 3-23 are prepared analogously to Intermediate 3: [Table 14-1] [Table 14-2] [Table 14-3]

[0165] [Table 15]

[0166] [Table 16-1] [Table 16-2] [Table 16-3]

[0167] Intermediate 4 Ethyl 1-[(5-{3-azabicyclo[3.1.0]hexan-3-yl}pyridin-2-yl)methyl]-1H-imidazole-4-carboxylate

[0168] [ka] In a microwave vial, a mixture of (5-{3-azabicyclo[3.1.0]hexan-3-yl}pyridin-2-yl)methanol (100 mg), ethyl 1H-imidazole-4-carboxylate (77 mg), and p-toluenesulfonic acid (54 mg) in ACN (15 mL) is heated to 120 °C for 5 h. After cooling to room temperature, the mixture is partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous phase is extracted with EtOAc, and the combined organic phases are dried (MgSO4) and concentrated. The residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2):t R = 0.71 min; Mass spectrum (ESI+): m / z = 313 [M+H] + .

[0169] Intermediates 4-1 to 4-61 are prepared analogously to Intermediate 4: [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4] [Table 17-5] [Table 17-6] [Table 17-7]

[0170] [Table 18-1]

Table 18-2

[0171]

Table 19-1

Table 19-2

Table 19-3

Table 19-4

Table 19-5

Table 19-6

Table 19-7

Table 19-8

Table 19-9

Table 19-10

Table 19-11

Table 19-12

Table 19-13

[0172] Intermediate 5 1-[(5-{3-azabicyclo[3.1.0]hexan-3-yl}pyridin-2-yl)methyl]-1H-imidazole-4-carboxylic acid

[0173] [ka] A mixture of ethyl 1-[(5-{3-azabicyclo[3.1.0]hexan-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) is stirred at 50° C. for 3 hours. After cooling to room temperature, aqueous HCl (4 M, 648 μL) is added and the solvent is evaporated to give the crude product, which is used directly in the next step. LC (Method 2): R = 0.58 min; Mass spectrum (ESI+): m / z = 285 [M+H] + .

[0174] Intermediates 5-1 to 5-170 are prepared analogously to Intermediate 5: [Table 20-1] [Table 20-2] [Table 20-3] [Table 20-4] [Table 20-5] [Table 20-6] [Table 20-7] [Table 20-8]

Table 20-9

Table 20-10

Table 20-11

Table 20-12

Table 20-13

Table 20-14

Table 20-15

Table 20-16

Table 20-17

Table 20-18

Table 20-19

[0175]

Table 21-1

Table 21-2

Table 21-3

Table 21-4

Table 21-5

Table 21-6

[0176]

Table 22-1

Table 22-2

Table 22-3

Table 22-4

Table 22-5

Table 22-6

Table 22-7

Table 22-8

Table 22-9

Table 22-10

Table 22-11

Table 22-12

Table 22-13

Table 22-14

Table 22-15

Table 22-16

[0177] Intermediate 6 2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridine-3-carbaldehyde

[0178] [ka] Under an argon atmosphere, 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) is stirred at 50 °C for 12 h. The mixture is cooled to room temperature, concentrated in vacuo, and partitioned between water and EtOAc, and the phases are separated. The organic phase is washed with brine, dried (MgSO), concentrated, and the residue is chromatographed on silica gel (85:15 to 70:30 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 1.03 min; Mass spectrum (ESI+): m / z = 303 [M+H] + .

[0179] Intermediates 6-1 to 6-19 are prepared analogously to Intermediate 6: [Table 23-1] [Table 23-2] [Table 23-3]

[0180] [Table 24]

[0181] [Table 25-1] [Table 25-2]

[0182] Intermediate 7 (6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-ethenylpyridin-3-yl)methanol

[0183] [ka] In a microwave vial, a mixture of (2-bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methanol (100 mg), potassium vinyltrifluoroborate (60 mg), K2CO3 (125 mg), and THF (5 mL) is purged with argon for 10 minutes. 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)Cl2, 15 mg) is added, the vial is sealed, and the mixture is stirred at 60 °C for 12 hours. After cooling to room temperature, the mixture is diluted with MeOH and purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2): R = 0.61 min; Mass spectrum (ESI+): m / z = 253 [M+H] + .

[0184] Intermediates 7-1 to 7-9 are prepared analogously to Intermediate 7: [Table 26]

[0185] [Table 27]

[0186] [Table 28-1] [Table 28-2]

[0187] Intermediate 8 Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-ethenylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate

[0188] [ka] Under an argon atmosphere, (6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-ethenylpyridin-3-yl)methanol (877 mg) and DIPEA (1.6 mL) are dissolved in DCM (25 mL). The mixture is cooled to 0 °C and treated dropwise with methanesulfonyl chloride (CH3-SO2Cl, 318 μL). After stirring for 15 minutes, ethyl 1H-pyrazole-4-carboxylate (555 mg) is added, and the mixture is stirred at room temperature for 3 hours. The mixture is then partitioned between water and DCM. The organic phase is dried (MgSO4), concentrated, and the residue is chromatographed on silica gel (100:0 → 70:30 petroleum ether / EtOAc) to give the title compound. LC (Method 2): R = 0.93 min; Mass spectrum (ESI+): m / z = 375 [M+H] + .

[0189] Intermediate 9 Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-formylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate

[0190] [ka] OsO4 (4% in water, 283 μL) is added to a mixture of ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-ethenylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (700 mg) in 1,4-dioxane (3.4 mL) and water (3.4 mL). The mixture is stirred for 30 minutes, treated with NaIO4 (1.2 g), and stirred for 3 hours at room temperature. The mixture is partitioned between water and EtOAc / MeOH (9:1). After phase separation, the organic phase is dried (MgSO4) and concentrated to give the title compound. LC (Method 2):t R = 1.06 min; Mass spectrum (ESI+): m / z = 377 [M+H]+ .

[0191] Intermediates 9-1 to 9-18 are prepared analogously to Intermediate 9: [Table 29-1] [Table 29-2] [Table 29-3]

[0192] [Table 30]

[0193] [Table 31-1] [Table 31-2] [Table 31-3]

[0194] Intermediate 10 Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate

[0195] [ka] NaBH4 (40 mg) is added portionwise to an ice-cold mixture of ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-formylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (200 mg) in EtOH (5 mL). The mixture is stirred at room temperature for 2 hours, cooled to 0 °C, treated with 4 M aqueous HCl (599 μL) and stirred for 5 minutes. 4 M aqueous NaOH (599 μL) is added and the mixture is diluted with EtOAc. After drying (MgSO4), the mixture is filtered and concentrated. The residue is partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase is dried (MgSO4) and concentrated to give the title compound. LC (Method 2):t R = 0.75 min; Mass spectrum (ESI+): m / z = 379 [M+H] + .

[0196] Intermediates 10-1 to 10-11 are prepared analogously to Intermediate 10: [Table 32-1] [Table 32-2]

[0197] [Table 33]

[0198] [Table 34-1] [Table 34-2]

[0199] Intermediate 11 Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate

[0200] [ka] 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) is added NaH (60% in mineral oil, 23 mg) at 0 ° C. The mixture is stirred for 15 minutes, treated with CHI (17 μL), and stirred at room temperature for 12 hours. The solvent is evaporated in vacuo to give the crude product, which is used directly in the next step. LC (Method 2):t R = 0.83 min; Mass spectrum (ESI+): m / z = 393 [M+H] + .

[0201] Intermediate 11-1 is prepared analogously to Intermediate 11: [Table 35]

[0202] [Table 36]

[0203] Intermediate 12 Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylate

[0204] [ka] In a microwave vial, ethyl 1-[(6-{5-azaspiro[2.3]hexane-5-yl}-2-formylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylate (763 mg) is dissolved in DCM (10 mL). Diethylaminosulfur trifluoride (DAST, 1 mL) is added, the vial is sealed, and the mixture is heated to 50 °C for 12 h. After cooling to room temperature, the mixture is carefully treated with 1N aqueous NaHCO3 until gas evolution ceases. The mixture is then partitioned between saturated aqueous NaHCO3 and DCM. The phases are separated, and the aqueous phase is extracted with DCM. The combined organic phases are washed with brine, dried (MgSO4), and concentrated. The residue is chromatographed on silica gel (70:30 → 30:70 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 1.05 min; Mass spectrum (ESI+): m / z = 364 [M+H] + .

[0205] Intermediates 12-1 to 12-10 are prepared analogously to Intermediate 12: [Table 37]

[0206] [Table 38]

[0207] [Table 39-1] [Table 39-2]

[0208] Intermediate 13 Ethyl 2-chloro-4-[(1E)-2-phenylethenyl]pyrimidine-5-carboxylate [ka] In a microwave vial, a mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (2.5 g), potassium trans-beta-styryltrifluoroborate (2.5 g), Na2CO3 (2 M aqueous solution, 12.5 mL), and 1,4-dioxane (50 mL) is purged with argon for 10 minutes. Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Pd(amphos)2Cl2, 300 mg) is added, the vial is sealed, and the mixture is heated to 50 °C for 2 hours. After cooling to room temperature, the mixture is partitioned between EtOAc and water. The organic phase is washed with brine, dried (MgSO4), and concentrated. The residue is chromatographed on silica gel (80:20 → 60:40 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 1.21 min; Mass spectrum (ESI+): m / z = 289 [M+H] + .

[0209] Intermediates 13-1 to 13-2 are prepared analogously to Intermediate 13: [Table 40]

[0210] [Table 41]

[0211] [Table 42]

[0212] Intermediate 14 Ethyl 2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-[(1E)-2-phenylethenyl]pyrimidine-5-carboxylate

[0213] [ka] Under an argon atmosphere, a mixture of ethyl 2-chloro-4-[(1E)-2-phenylethenyl]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) is stirred at room temperature for 12 hours. The mixture is partitioned between saturated aqueous NH Cl and EtOAc, and the phases are separated. The organic phase is washed with brine, dried (MgSO), and concentrated, and the residue is chromatographed on silica gel (80:20 → 60:40 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 1.27 min; Mass spectrum (ESI+): m / z = 336 [M+H] + .

[0214] Intermediate 15 (2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-[(1E)-2-phenylethenyl]pyrimidin-5-yl)methanol [ka] Under an argon atmosphere, a mixture of ethyl 2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-[(1E)-2-phenylethenyl]pyrimidine-5-carboxylate (1.96 g) in THF (40 mL) is treated dropwise with diisobutylaluminum hydride (DIBAH, 1 M in THF, 25 mL). The mixture is stirred at room temperature for 2 hours, cooled to 0 °C, and treated dropwise with 4 M aqueous HCl (15 mL). The mixture is then stirred for 5 minutes, and 4 M aqueous NaOH (15 mL) is added. The mixture is partitioned between brine and DCM, and the phases are separated. The organic phase is dried (MgSO 4 ), concentrated, and the residue is chromatographed on silica gel (98:2 → 90:10 DCM / MeOH) to give the title compound. LC (Method 2):t R = 0.84 min; Mass spectrum (ESI+): m / z = 294 [M+H] + .

[0215] Intermediates 15-1 to 15-2 are prepared analogously to Intermediate 15: [Table 43]

[0216] [Table 44]

[0217] Intermediate 16 1-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-[(1E)-2-phenylethenyl]pyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide

[0218] [ka] Under an argon atmosphere, a mixture of 1-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-[(1E)-2-phenylethenyl]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 is washed with brine, dried (MgSO4), concentrated and the residue is chromatographed on silica gel (98:2 to 70:30 DCM / MeOH) to give the title compound. LC (Method 1): R = 1.02 min; Mass spectrum (ESI+): m / z = 507 [M+H] + .

[0219] Intermediate 17 Ethyl 1-[(5-{5-azaspiro[2.3]hexan-5-yl}pyridin-2-yl)methyl]-1H-pyrazole-4-carboxylate [ka] 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) is added dropwise DIAD (222 μL) at 0° C. The mixture is stirred for 1 hour while warming to room temperature. The mixture is then diluted with MeOH and purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2): R = 0.79 min; Mass spectrum (ESI+): m / z = 313 [M+H] + .

[0220] Intermediate 17-1 is prepared analogously to Intermediate 17: [Table 45]

[0221] [Table 46]

[0222] Intermediate 18 Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-ethylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylate

[0223] [ka] 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 in a microwave vial. 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) are added, and the mixture is heated to 90 °C for 5 h. After cooling to room temperature, the mixture is partitioned between water and EtOAc. The organic phase is washed with brine, dried (MgSO4), and concentrated, and the residue is chromatographed on silica gel (85:15 to 60:40 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 0.72 min; Mass spectrum (ESI+): m / z = 342 [M+H] + .

[0224] Intermediates 18-1 to 18-4 are prepared analogously to Intermediate 18: [Table 47]

[0225] [Table 48]

[0226] [Table 49]

[0227] Intermediate 19 Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate [ka] In a microwave vial, a mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (1.43 g), diethylzinc (1 M solution in n-hexane, 6.18 mL), and 1,4-dioxane (60 mL) is purged with argon for 10 minutes. 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)Cl, 150 mg) is added, the vial is sealed, and the mixture is heated to 70 °C for 1 hour. After cooling to room temperature, the mixture is carefully treated with saturated aqueous NH4Cl. The mixture is partitioned between saturated aqueous NH4Cl and EtOAc. The aqueous phase is extracted twice with EtOAc. The combined organic phases are washed with brine, dried (MgSO4), concentrated, and the residue is chromatographed on silica gel (95:5 to 0:100 petroleum ether / EtOAc) to give the title compound. LC (Method 2): R = 0.75 min; Mass spectrum (ESI+): m / z = 341 [M+H] + .

[0228] Intermediates 19-1 to 19-15 are prepared analogously to Intermediate 19: [Table 50-1] [Table 50-2]

[0229] [Table 51]

[0230] [Table 52-1] [Table 52-2] [Table 52-3]

[0231] Intermediate 20 Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylate [ka] 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) is shaken under a hydrogen atmosphere (3 bar) at room temperature for 3.5 hours. The mixture is filtered, the filtrate is concentrated, and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2): R = 0.68 min; Mass spectrum (ESI+): m / z = 314 [M+H] + .

[0232] Intermediate 21 Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylate [ka] 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) is treated with difluoromethyltrimethylsilane (435 μL). The vial is sealed, and the mixture is heated to 120 °C for 1.5 h. The mixture is partitioned between semi-saturated aqueous NaHCO3 and EtOAc. The mixture is then filtered over Celite, and the filter cake is washed with EtOAc. The phases are separated, and the aqueous phase is extracted twice with EtOAc. The combined organic phases are dried (MgSO4), concentrated, and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2): R = 1.10 min; Mass spectrum (ESI+): m / z = 364 [M+H] + .

[0233] Intermediate 22 Ethyl 2-chloro-4-propylpyrimidine-5-carboxylate [ka] In a microwave vial, a mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (1 g), n-butylzinc 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) is purged with argon for 10 minutes. The vial is sealed, and the mixture is heated to 70 °C for 1 hour. Then, n-butylzinc bromide (0.5 M in THF, 5 mL) is added, and the mixture is heated to 70 °C for 45 minutes. After cooling to room temperature, the mixture is partitioned between EtOAc and saturated aqueous NH Cl. The aqueous phase is extracted twice with EtOAc. The combined organic phases are washed with brine, dried (MgSO), and concentrated. The residue is chromatographed on silica gel (98:2 to 90:10 petroleum ether / EtOAc) to give the title compound. LC (Method 2):tR = 1.10 min; Mass spectrum (ESI+): m / z = 229 [M+H] + .

[0234] Intermediate 23 Ethyl 2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-propylpyrimidine-5-carboxylate [ka] Under an argon atmosphere, a mixture of ethyl 2-chloro-4-propylpyrimidine-5-carboxylate (546 mg), 3-azabicyclo[3.1.0]hexane hydrochloride (328 mg), and K2CO3 (663 mg) in DMF (15 mL) is stirred at room temperature for 2 hours. The mixture is partitioned between water and EtOAc, and the phases are separated. The aqueous phase is extracted twice with EtOAc. The combined organic phases are washed with brine, dried (MgSO4), concentrated, and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2):t R = 1.09 min; Mass spectrum (ESI+): m / z = 276 [M+H] + .

[0235] Intermediate 24 Methyl 5-{3-azabicyclo[3.1.0]hexan-3-yl}-6-cyanopyridine-2-carboxylate [ka] Under an 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) is stirred at 80°C for 12 hours. The mixture is poured into water. The precipitate is collected by filtration, washed with water, and dried in vacuo to give the title compound. LC (Method 2): R = 0.92 min; Mass spectrum (ESI+): m / z = 244 [M+H] + .

[0236] Intermediate 25 3-{3-azabicyclo[3.1.0]hexan-3-yl}-6-(hydroxymethyl)pyridine-2-carbonitrile [ka] NaBH4 (131 mg) is added in portions to a mixture of methyl 5-{3-azabicyclo[3.1.0]hexan-3-yl}-6-cyanopyridine-2-carboxylate (280 mg) and CaCl2 (507 mg) in THF (8 mL) and EtOH (8 mL). The mixture is stirred for 2 hours at room temperature and for 1 hour at 45 °C. The mixture is then partitioned between saturated aqueous NaHCO3 and EtOAc. The precipitate is filtered off. The aqueous phase is extracted with EtOAc. The combined organic phases are dried (MgSO4) and concentrated, and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (method 1):t R = 0.81 min; Mass spectrum (ESI+): m / z = 216 [M+H] + .

[0237] Intermediate 25-1 is prepared analogously to Intermediate 25: [Table 53]

[0238] [Table 54]

[0239] [Table 55]

[0240] Intermediate 26 Methyl 6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(trifluoromethoxy)pyridine-3-carboxylate [ka] Under an 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) is stirred at room temperature for 4 hours. The mixture is partitioned between water and EtOAc. The aqueous phase is extracted twice with EtOAc. The combined organic phases are dried (MgSO4), concentrated, and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2):t R = 1.18 min; Mass spectrum (ESI+): m / z = 303 [M+H] + .

[0241] Intermediate 27 3-[5-(methoxymethyl)-6-(trifluoromethoxy)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane

[0242] [ka] LiBH4 (250 mg) is added in portions to a mixture of methyl 6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(trifluoromethoxy)pyridine-3-carboxylate (384 mg) in THF (5 mL). The mixture is stirred at room temperature for 12 hours. The mixture is then poured into 1N aqueous HCl and stirred vigorously for 20 minutes. The mixture is then partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous phase is extracted twice with EtOAc. The combined organic phases are dried (MgSO4) and concentrated, and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2):t R = 1.22 min; Mass spectrum (ESI+): m / z = 289 [M+H] + .

[0243] Intermediate 28 Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-ethenylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate

[0244] [ka] A mixture of ethyl 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 (1 M aqueous solution, 40.5 mL), and 1,4-dioxane (75 mL) is purged with argon for 10 minutes in a microwave vial. 1,1'-Bis(diphenylphosphino)ferrocene palladium(II) dichloride (Pd(dppf)Cl2, 662 mg) is added, the vial is sealed, and the mixture is heated to 100 °C for 12 hours. After cooling to room temperature, the mixture is partitioned between water and EtOAc. The aqueous phase is extracted twice with EtOAc. The combined organic phases are dried (MgSO4) and concentrated, and the residue is chromatographed on silica gel (100:0 to 50:50 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 0.78 min; Mass spectrum (ESI+): m / z = 339 [M+H] + .

[0245] Intermediates 28-1 to 28-5 are prepared analogously to Intermediate 28: [Table 56]

[0246] [Table 57]

[0247] [Table 58]

[0248] Intermediate 29 Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(cyanomethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate [ka] 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-methylpropanenitrile (140 μL), and triphenylphosphine (460 mg) in THF (6 mL) is added dropwise DBAD (360 μL). The mixture is stirred for 45 minutes. 2-Hydroxy-2-methylpropanenitrile (140 μL), triphenylphosphine (460 mg), and DBAD (360 μL) are added sequentially, and the mixture is stirred again for 45 minutes. The mixture is then diluted with THF and purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2):t R = 0.97 min; Mass spectrum (ESI+): m / z = 352 [M+H] + .

[0249] Intermediate 30 Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(1-cyanocyclopropyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate [ka] A mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(cyanomethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (212 mg) in DMSO (7 mL) is cooled to 10 °C and treated portionwise with NaH (60% in mineral oil, 60 mg). The mixture is stirred for 15 minutes at room temperature, cooled to 0 °C, and treated with 1,2-dibromoethane (80 μL). The mixture is then stirred for 1 hour at room temperature. After cooling to 0 °C, the mixture is treated with saturated aqueous NH4Cl solution. The mixture is then extracted twice with EtOAc. The combined organic phases are washed with water, dried (MgSO4), concentrated, and the residue is chromatographed on silica gel (90:10 to 60:40 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 1.06 min; Mass spectrum (ESI+): m / z = 378 [M+H] + .

[0250] Intermediate 30-1 is prepared analogously to intermediate 30: [Table 59]

[0251] [Table 60]

[0252] [Table 61]

[0253] Intermediate 31 Ethyl 1-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-[(1E)-2-phenylethenyl]pyrimidin-5-yl)methyl]-1H-pyrazole-4-carboxylate

[0254] [ka] SOCl2 (5 mL) is added to a mixture of (2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-[(1E)-2-phenylethenyl]pyrimidin-5-yl)methanol (1.89 g) in toluene (20 mL) under an argon atmosphere. The mixture is heated to 60 °C for 3 hours, cooled to room temperature, and concentrated in vacuo. The residue is 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 for 12 hours at room temperature, the mixture is partitioned between water and DCM. The organic phase is washed with brine, dried (MgSO4), and concentrated, and the residue is chromatographed on silica gel (50:50 to 0:100 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 1.06 min; Mass spectrum (ESI+): m / z = 416 [M+H] + .

[0255] Intermediate 32 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid [ka] 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) is added NaH (60% in mineral oil, 263 mg) at 0 °C. The mixture is stirred for 30 min, treated with CHI (222 μL), and stirred for 1.5 h at 0 °C. EtOH (4 mL) and aqueous NaOH (4 M, 4.2 mL) are added, and the mixture is stirred for 12 h at 70 °C. After cooling to room temperature, aqueous HCl (4 M, 3 mL) is added, and the mixture is partitioned between water and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic phases are washed with brine, dried (MgSO), concentrated, and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2):t R = 0.62 min; Mass spectrum (ESI+): m / z = 329 [M+H] + .

[0256] Intermediates 32-1 to 32-3 are prepared analogously to Intermediate 32: [Table 62]

[0257] [Table 63]

[0258] [Table 64]

[0259] Intermediate 33 Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate [ka] To an ice-cooled 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) is added dropwise DBAD (1.35 g). The mixture is stirred for 45 min. Saturated aqueous NaHCO3 is added, and the mixture is stirred vigorously for 5 min. The mixture is then filtered over Celite. The aqueous phase is extracted twice with EtOAc, and the combined organic phases are washed with brine and dried (MgSO4). The solvent is evaporated in vacuo, and the residue is chromatographed on silica gel (70:30 to 0:100 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 0.78 min; Mass spectrum (ESI+): m / z = 341 [M+H] + .

[0260] Intermediates 33-1 to 33-5 are prepared analogously to intermediate 33: [Table 65]

[0261] [Table 66]

[0262] [Table 67]

[0263] Intermediate 34 Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-[(1E)-3-(benzyloxy)prop-1-en-1-yl]pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate [ka] In a microwave vial, a mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (100 mg), potassium (E)-3-(benzyloxy)prop-1-enyltrifluoroborate (88 mg), K2CO3 (100 mg), and THF (5 mL) is purged with argon for 10 minutes. 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)Cl2, 15 mg) is added, the vial is sealed, and the mixture is heated to 80 °C for 15 hours. After cooling to room temperature, the mixture is partitioned between water and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic phases are washed with brine, dried (MgSO4), concentrated in vacuo and the residue is chromatographed on silica gel (70:30 to 0:100 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 0.95 min; Mass spectrum (ESI+): m / z = 459 [M+H] + .

[0264] Intermediate 35 Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(3-hydroxypropyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate [ka] A mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-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) is shaken under a hydrogen atmosphere (3 bar) at room temperature for 12 hours. The mixture is filtered, the filtrate is concentrated, and the residue is chromatographed on silica gel (70:30 to 0:100 petroleum ether / EtOAc) to give the title compound. LC (Method 2):tR = 0.73 min; Mass spectrum (ESI+): m / z = 371 [M+H] + .

[0265] Intermediate 36 3-[5-(azidomethyl)-6-ethenylpyridin-2-yl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane [ka] Under an argon atmosphere, diphenylphosphoryl azide (1.4 mL) is added dropwise to an ice-cold mixture of (6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-ethenylpyridin-3-yl)methanol (1.34 g) and DBU (1.05 mL) in toluene (10 mL) and ACN (10 mL). The mixture is stirred for 12 hours while warming to room temperature. The mixture is then partitioned between water and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic phases are washed with brine, dried (MgSO4), and concentrated in vacuo, and the residue is chromatographed on silica gel (99:1 to 50:50 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 0.88 min; Mass spectrum (ESI+): m / z = 278 [M+H] + .

[0266] Intermediates 36-1 to 36-5 are prepared analogously to Intermediate 36: [Table 68]

[0267] [Table 69]

[0268] [Table 70]

[0269] Intermediate 37 Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-ethenylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylate [ka] A mixture of 3-[5-(azidomethyl)-6-ethenylpyridin-2-yl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane (794 mg), propiolic acid ethyl ester (320 μL), CuSO (92 mg), and sodium (L)-ascorbate (568 mg) in tert.-butanol (8 mL) and water (8 mL) is stirred at room temperature for 48 hours. The mixture is partitioned between water and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic phases are washed with brine, dried (MgSO), and concentrated in vacuo, and the residue is chromatographed on silica gel (99:1 → 50:50 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 0.89 min; Mass spectrum (ESI+): m / z = 376 [M+H] + .

[0270] Intermediates 37-1 to 37-5 are prepared analogously to Intermediate 37: [Table 71]

[0271] [Table 72]

[0272] [Table 73]

[0273] Intermediate 38 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid

[0274] [ka] 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) is added NaH (60% in mineral oil, 45 mg) at 0 °C. The mixture is stirred for 30 min at room temperature, treated with CHI (30 μL), and stirred for 12 h at room temperature. Water is added, and the mixture is concentrated in vacuo. The residue is dissolved in 1:1 DCM / isopropanol and filtered. The filtrate is dried (MgSO) and concentrated in vacuo to give the title compound. LC (Method 2):t R = 0.65 min; Mass spectrum (ESI+): m / z = 366 [M+H] + .

[0275] Intermediate 39 Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(1-hydroxypropan-2-yl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate

[0276] [ka] A mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-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) is stirred at room temperature for 48 hours. 9-Borabicyclo(3.3.1)nonane (6 mL) is added, and stirring is continued for 12 hours. The mixture is cooled to 0 °C and treated dropwise with water (3 mL) and H2O2 (35% in water, 3.35 mL). The mixture is then stirred at room temperature for 30 minutes. Aqueous NaOH (2 M, 340 μL) is added, and the mixture is stirred for 20 minutes and then cooled to 0 °C. Saturated aqueous Na2SO3 solution is slowly added, and the aqueous phase is extracted twice with EtOAc. The combined organic phases are washed with brine, dried (MgSO4), concentrated in vacuo, and the residue is chromatographed on silica gel (80:20 to 0:100 petroleum ether / EtOAc) to give the title compound. LC (Method 2): R = 0.76 min; Mass spectrum (ESI+): m / z = 371 [M+H] + .

[0277] Intermediate 39-1 is prepared analogously to intermediate 39: [Table 74]

[0278] [Table 75]

[0279] [Table 76]

[0280] Intermediate 40 Methyl 6-{3-azabicyclo[3.1.0]hexan-3-yl}pyridazine-3-carboxylate [ka] Under an 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) is stirred at room temperature for 12 hours. The mixture is partitioned between water and EtOAc and stirred for 20 minutes. The precipitate is collected by filtration and dried in vacuo to give the title compound. LC (Method 2):t R = 0.60 min; Mass spectrum (ESI+): m / z = 220 [M+H] + .

[0281] Intermediates 40-1 to 40-8 are prepared analogously to intermediate 40: [Table 77]

[0282] [Table 78]

[0283] [Table 79-1] [Table 79-2]

[0284] Intermediate 41 (6-{3-azabicyclo[3.1.0]hexan-3-yl}pyridazin-3-yl)methanol [ka] NaBH4 (76 mg) is added portionwise to a mixture of methyl 6-{3-azabicyclo[3.1.0]hexan-3-yl}pyridazine-3-carboxylate (200 mg) and CaCl2 (54 mg) in MeOH (4 mL). The mixture is stirred at 70 °C for 24 h. After cooling to room temperature, 1 M aqueous HCl is added until a pH value of 2 is reached. The mixture is stirred for 15 min and then partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous phase is extracted twice with EtOAc and twice with 1:1 EtOAc / isopropanol. The combined organic phases are dried (MgSO4) and concentrated in vacuo, and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (method 1):t R = 0.67 min; Mass spectrum (ESI+): m / z = 192 [M+H] + .

[0285] Intermediate 41-1 is prepared analogously to intermediate 41: [Table 80]

[0286] [Table 81]

[0287] [Table 82]

[0288] Intermediate 42 Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}pyridazin-3-yl)methyl]-1H-pyrazole-4-carboxylate [ka] 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) is added DBAD (139 mg). The mixture is stirred for 1.5 hours, diluted with DMF, and purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2):t R = 0.68 min; Mass spectrum (ESI+): m / z = 314 [M+H] + .

[0289] Intermediates 42-1 to 42-2 are prepared analogously to intermediate 42: [Table 83]

[0290] [Table 84]

[0291] [Table 85]

[0292] Intermediate 43 Ethyl 1-[(5-bromopyrimidin-2-yl)methyl]-1H-pyrazole-4-carboxylate [ka] A mixture of 5-bromo-2-(bromomethyl)pyrimidine (1.5 g), K2CO3 (2.4 g), and ethyl 1H-pyrazole-4-carboxylate (814 mg) in DMF (20 mL) is stirred at room temperature for 1.5 h. The mixture is diluted with THF and filtered over Celite. The filter cake is washed twice with THF. The combined filtrate is concentrated, and the residue is chromatographed on silica gel (80:20 to 0:100 petroleum ether / EtOAc) to give the title compound. LC (method 1):t R = 0.85 min; Mass spectrum (ESI+): m / z = 311 [M+H] + .

[0293] Intermediate 44 Ethyl 1-[(5-{3-azabicyclo[3.1.0]hexan-3-yl}pyrimidin-2-yl)methyl]-1H-pyrazole-4-carboxylate [ka] 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)palladium(0) (Pd2dba3, 74 mg), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 93 mg) in DMF (1.3 mL) and toluene (3.8 mL) is purged with argon for 10 minutes. The vial is sealed, and the mixture is heated to 90 °C for 2 hours. The mixture is then partitioned between water and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic phases are dried (MgSO4), concentrated in vacuo, and the residue is chromatographed on silica gel (90:10 to 20:80 petroleum ether / EtOAc) to give the title compound. LC (Method 1): R = 0.91 min; Mass spectrum (ESI+): m / z = 314 [M+H] + .

[0294] Intermediate 45 (6-{3-azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methanol [ka] A mixture of methyl 6-{3-azabicyclo[3.1.0]hexan-3-yl}pyridine-3-carboxylate (8 g) and LiBH4 (2 M solution in THF, 20 mL) in THF (60 mL) and MeOH (3 mL) is stirred at 60 °C for 12 hours. LiBH4 (2 M solution in THF, 5 mL) is added, and the mixture is stirred at 60 °C for 2 hours. The mixture is then cooled to 0 °C and carefully treated with water. The mixture is concentrated, and the residue is partitioned between water and EtOAc. The organic phase is dried (MgSO4), concentrated in vacuo, and the residue is chromatographed on silica gel (0:100 → 90:10 DCM / MeOH) to give the title compound. LC (Method 1):t R = 0.79 min; Mass spectrum (ESI+): m / z = 191 [M+H] + .

[0295] Intermediates 45-1 to 45-3 are prepared analogously to Intermediate 45: [Table 86]

[0296] [Table 87]

[0297] [Table 88]

[0298] Intermediate 46 1-[(6-{5-azaspiro[2.3]hexan-5-yl}pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid trifluoroacetate [ka] To an ice-cooled 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) is added dropwise DBAD (338 mg). The mixture is stirred for 48 hours. The mixture is then concentrated in vacuo. The residue is dissolved in MeOH (10 mL) and aqueous NaOH (1 M, 5 mL) and stirred for 2 hours at room temperature. After neutralization with trifluoroacetic acid, the crude product is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (method 1):t R = 0.65 min; Mass spectrum (ESI+): m / z = 285 [M+H] + .

[0299] Intermediate 47 1-[(6-{5-azaspiro[2.3]hexan-5-yl}pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid trifluoroacetate [ka] In a microwave vial, a mixture of (6-{5-azaspiro[2.3]hexan-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) is heated to 75°C for 48 hours, 90°C for 3 hours, 100°C for 3 hours, and 80°C for 12 hours. After cooling to room temperature, the mixture is diluted with ACN and purified by HPLC on reversed phase (ACN, water). The product thus obtained is dissolved in MeOH (2 mL) and aqueous NaOH (1 M, 500 μL). After stirring for 2 hours at room temperature, the mixture is neutralized with trifluoroacetic acid and purified by HPLC on reversed phase (ACN, water) to give the title compound. LC (Method 2): R = 0.40 min; Mass spectrum (ESI+): m / z = 285 [M+H] + .

[0300] Intermediate 48 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

[0301] [ka] A mixture of 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-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-benziodoxol-3-(1H)-one (Dess-Martin periodinane, 26 mg) in DCM (2 mL) is stirred at room temperature for 3 hours. The mixture is partitioned between saturated aqueous NaHCO3 and DCM. The aqueous phase is extracted three times with DCM. The combined organic phases are dried (Na2SO4) and concentrated in vacuo to give the title compound. LC (method 1):t R = 0.89 min; Mass spectrum (ESI+): m / z = 469 [M+H] + .

[0302] Intermediate 48-1 is prepared analogously to intermediate 48: [Table 89]

[0303] [Table 90]

[0304] [Table 91]

[0305] Intermediate 49 Ethyl 6-{5-azaspiro[2.3]hexan-5-yl}-3-{[4-(ethoxycarbonyl)-1H-imidazol-1-yl]methyl}pyridine-2-carboxylate [ka] 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) is heated to 130 °C under a carbon monoxide atmosphere at 10 bar for 5 h. The solvent is evaporated in vacuo, and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2):t R = 0.89 min; Mass spectrum (ESI+): m / z = 385 [M+H] + .

[0306] Intermediates 49-1 to 49-4 are prepared analogously to intermediate 49: [Table 92]

[0307] [Table 93]

[0308] [Table 94]

[0309] Intermediate 50 Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylate bistrifluoroacetate

[0310] [ka] LiBH4 (150 mg) is added in portions 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 is stirred at room temperature for 2 hours, cooled to 0 °C, treated with aqueous HCl (4 M, 2 mL), and purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (method 1):t R = 0.91 min; Mass spectrum (ESI+): m / z = 343 [M+H] + .

[0311] Intermediates 50-1 to 50-2 are prepared analogously to Intermediate 50: [Table 95]

[0312] [Table 96]

[0313] Intermediate 51 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid trifluoroacetate

[0314] [ka] To an ice-cooled solution of (6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methanol (158 mg), ethyl 1H-pyrazole-4-carboxylate (100 mg), and tributylphosphine (210 μL) in THF (2 mL) is added dropwise DBAD (190 mg). The mixture is 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) is added and the mixture is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2):t R = 0.63 min; Mass spectrum (ESI+): m / z = 321 [M+H] + .

[0315] Intermediate 52 Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(1-hydroxyethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate

[0316] [ka] CH3MgBr (3 M in diethyl ether, 1.22 mL) is added dropwise to a mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]-hexan-3-yl}-2-formylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (1 g) in THF (20 mL) at -40 °C. The mixture is stirred for 25 minutes while warming to -25 °C. Aqueous HCl (1 M, 4 mL) is added. After stirring for 5 minutes, the mixture is partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic phases are washed with brine, dried (MgSO4), and concentrated in vacuo to give the title compound. LC (Method 2):t R = 0.73 min; Mass spectrum (ESI+): m / z = 357 [M+H] + .

[0317] Intermediate 52-1 is prepared analogously to intermediate 52: [Table 97]

[0318] [Table 98]

[0319] [Table 99]

[0320] Intermediate 53 Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-[(1R)-1-hydroxyethyl]pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate [ka] Triethylamine (246 μL) was dissolved in DCM (3 mL), cooled to 0° C., and treated 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)amide.}(mesitylene)ruthenium(II) (RuCl[(R,R)-Tsdpen(mesitylene), 23 mg]). The mixture is stirred for 24 h while warming to room temperature. The mixture is concentrated, dissolved in THF (5 mL), and treated with a solution of NH in MeOH (7 M, 1 mL) and water (1 mL). The mixture is then purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (method 1):t R = 1.03 min; Mass spectrum (ESI+): m / z = 357 [M+H] + .

[0321] Intermediate 53-1 is prepared analogously to intermediate 53: [Table 100]

[0322] [Table 101]

[0323] [Table 102]

[0324] Intermediate 54 (5-{3-azabicyclo[3.1.0]hexan-3-yl}-3-chloropyrazin-2-yl)methanol [ka] LiBH4 (744 mg) is added in portions to an ice-cold mixture of methyl 5-{3-azabicyclo[3.1.0]hexan-3-yl}-3-chloropyrazine-2-carboxylate (4.33 g) in THF (80 mL). The mixture is stirred at room temperature for 2 hours. After cooling to 0 °C, aqueous HCl (4 M, 10 mL) is added and the mixture is stirred for 10 minutes. The mixture is then partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous phase is extracted twice with EtOAc. The combined organic phases are dried (MgSO4) and concentrated in vacuo, and the residue is chromatographed on silica gel (80:20 → 50:50 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 0.85 min; Mass spectrum (ESI+): m / z = 226 [M+H] + .

[0325] Intermediate 55 Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate [ka] Under an 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) is treated dropwise with CHSOCl (7.2 mL). The mixture is stirred for 15 minutes and then treated with ethyl 1H-pyrazole-4-carboxylate (12 g). After stirring for 4 hours at room temperature, the mixture is partitioned between water and DCM. The organic phase is dried (MgSO) and concentrated in vacuo to give the crude product, which is used directly in the next step. LC (Method 2):t R = 0.76 min; Mass spectrum (ESI+): m / z = 363 [M+H] + .

[0326] Intermediate 55-1 is prepared analogously to intermediate 55: [Table 103]

[0327] [Table 104]

[0328] [Table 105]

[0329] Intermediate 56 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid [ka] 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) is added NaH (60% in mineral oil, 25 mg) at 0 °C. The mixture is stirred for 30 minutes at room temperature, treated with CHI (16 μL), and stirred for 12 hours. Water is carefully added. The mixture is concentrated in vacuo, and the residue is dissolved in 1:1 DCM / isopropanol. The mixture is then filtered, and the filtrate is concentrated in vacuo to give the crude product, which is used directly in the next step. LC (Method 2):t R = 0.58 min; Mass spectrum (ESI+): m / z = 330 [M+H] + .

[0330] Intermediates 56-1 to 56-2 are prepared analogously to Intermediate 56: [Table 106]

[0331] [Table 107]

[0332] [Table 108]

[0333] Intermediate 57 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methoxypyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid [ka] A mixture of ethyl 1-[(2-bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methyl]-1H-imidazole-4-carboxylate (190 mg) and NaOCH3 (1 M in MeOH, 4.5 mL) is heated to 155°C for 2.5 hours and 165°C for 3 hours. Purification by HPLC on reverse phase (ACN, water) gives the title compound. LC (Method 2): R =0.84 minutes.

[0334] Intermediate 57-1 is prepared analogously to intermediate 57: [Table 109]

[0335] [Table 110]

[0336] [Table 111]

[0337] Intermediate 58 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid Intermediate 58-1 Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylate [ka] LiBH4 (356 mg) is 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 is stirred at room temperature for 14 hours, cooled to 0 °C, and treated with aqueous HCl (1 M, 5 mL). The mixture is then neutralized by the addition of NaOH (4 M) and purified by HPLC on reverse phase (ACN, water) to give the title compound. 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid: LC (method 1):t R = 0.64 min; Mass spectrum (ESI+): m / z = 315 [M+H] + . Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylate: LC (method 1):t R = 0.94 min; Mass spectrum (ESI+): m / z = 343 [M+H] + .

[0338] Intermediate 59 2-Hydroxy-5-iodo-4-methylpyridine-3-carbonitrile [ka] Under an argon atmosphere, an ice-cold mixture of 2-hydroxy-4-methylpyridine-3-carbonitrile (3 g) in DCM (100 mL) is treated with trifluoroacetic acid (5 mL). N-iodosuccinimide (7.55 g) is then added portionwise. The mixture is stirred for 3 hours while warming to room temperature. The mixture is concentrated in vacuo, half-saturated aqueous NaSO solution is added, and the mixture is stirred for 10 minutes. The precipitate is collected by filtration, washed with water and diethyl ether, and dried in vacuo to give the title compound. LC (Method 2):R = 0.72 min; Mass spectrum (ESI+): m / z = 261 [M+H] + .

[0339] Intermediate 60 2-Chloro-5-iodo-4-methylpyridine-3-carbonitrile [ka]

[0340] A mixture of 2-hydroxy-5-iodo-4-methylpyridine-3-carbonitrile (6.27 g) in POCl3 is stirred at 100 °C for 5 hours. The mixture is concentrated in vacuo. The residue is dissolved in DCM (200 mL) and treated with water. The mixture is then neutralized by careful addition of saturated aqueous NaHCO3 solution. The phases are separated and the aqueous phase is extracted twice with DCM. The combined organic phases are washed with saturated aqueous NaHCO3 solution, dried (MgSO4), and concentrated in vacuo to give the crude product, which is used directly in the next step. LC (method 1):t R = 1.02 min; Mass spectrum (ESI+): m / z = 278 [M+H] + .

[0341] Intermediate 61 2-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-5-formyl-4-methylpyridine-3-carbonitrile [ka] A mixture of 2-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-5-iodo-4-methylpyridine-3-carbonitrile (2.3 g) in THF (30 mL) is cooled to -78 °C and treated dropwise with isopropylmagnesium chloride (iPrMgCl, 2 M solution in THF, 3.82 mL) and stirred for 30 minutes. The mixture is then warmed to 0 °C, treated dropwise with DMF (2.47 mL), and stirred for 40 minutes. Water is carefully added, and the mixture is partitioned between semi-saturated aqueous NH4Cl and EtOAc. The aqueous phase is extracted with EtOAc, and the combined organic phases are concentrated in vacuo to give the crude product, which is used directly in the next step. LC (Method 2):t R = 0.96 min; Mass spectrum (ESI+): m / z = 264 [M+H] + .

[0342] Intermediate 61-1 is prepared analogously to Intermediate 61: [Table 112]

[0343] [Table 113]

[0344] Intermediate 62 N'-[(E)-(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methylidene]acetohydrazide [ka] A mixture of 6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridine-3-carbaldehyde (5.8 g) and acetohydrazide (2.36 g) in MeOH (100 mL) is refluxed for 12 hours. The mixture is concentrated in vacuo, dissolved in toluene, treated with p-toluenesulfonic acid (100 mg), and refluxed in a Dean-Stark apparatus for 16 hours. After cooling to room temperature, the precipitate is collected by filtration, washed with tert.-butyl-methyl-ether, and dried in vacuo to give the title compound. LC (Method 2): R = 0.64 min; Mass spectrum (ESI+): m / z = 295 [M+H] + .

[0345] Intermediate 62-1 is prepared analogously to intermediate 62: [Table 114]

[0346] [Table 115]

[0347] Intermediate 63 N'-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]acetohydrazide [ka] A mixture of N'-[(E)-(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methylidene]acetohydrazide (5.6 g) and 10% palladium on carbon (300 mg) in MeOH (80 mL) and THF (20 mL) is shaken under a hydrogen atmosphere (3 bar) at room temperature for 3.5 hours. The mixture is filtered, the filtrate is concentrated, and the residue is dissolved in tert.-butyl methyl ether (100 mL) and EtOAc (10 mL). After stirring for 3 hours, the precipitate is collected by filtration, washed with tert.-butyl methyl ether, and dried in vacuo to give the title compound. LC (Method 2):t R = 0.58 min; Mass spectrum (ESI+): m / z = 297 [M+H] + .

[0348] Intermediate 63-1 is prepared analogously to intermediate 63: [Table 116]

[0349] [Table 117]

[0350] Intermediate 64 Ethyl 3-(chloromethyl)-1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate [ka] A mixture of N'-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]acetohydrazide (1.9 g) and ethyl 4-chloro-2-(ethoxymethylidene)-3-oxobutanoate (1.68 g) in EtOH (30 mL) is stirred at room temperature for 12 hours. The mixture is concentrated and then partitioned between DCM and saturated aqueous Na2CO3 solution. The aqueous phase is extracted with DCM. The combined organic phases are washed with brine, dried (MgSO4), and concentrated in vacuo to give the title compound. LC (Method 2):t R = 0.82 min; Mass spectrum (ESI+): m / z = 411 [M+H] + .

[0351] Intermediate 64-1 is prepared analogously to intermediate 64: [Table 118]

[0352] [Table 119]

[0353] Intermediate 65 Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]-3-(cyanomethyl)-1H-pyrazole-4-carboxylate [ka] A mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-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) is heated to 85° C. for 2 hours. The mixture is partitioned between water and EtOAc. The aqueous phase is extracted four times with EtOAc. The combined organic phases are washed with brine, dried (MgSO), and concentrated in vacuo to give the title compound. LC (Method 2):t R = 0.74 min; Mass spectrum (ESI+): m / z = 366 [M+H] + .

[0354] Intermediate 66 1-[(6-{3-azabicyclo[3.1.0]hexan-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

[0355] [ka] A mixture of 1-[(6-{3-azabicyclo[3.1.0]hexan-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) is stirred for 5 min. (4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-amine dihydrochloride (143 mg) is added, and the mixture is stirred for 2 h. The mixture is partitioned between water and EtOAc. The aqueous phase is extracted three times with EtOAc. The combined organic phases are washed with brine, dried (MgSO4), concentrated in vacuo and chromatographed on silica gel (90:10 to 60:40 DCM / (50:48:2 DCM / MeOH / 7N NH3 in MeOH)) to give the title compound. LC (Method 2):t R = 0.63 min; Mass spectrum (ESI + ): m / z=457[M+H] + .

[0356] Intermediates 66-1 to 66-4 are prepared analogously to Intermediate 66: [Table 120]

[0357] [Table 121]

[0358] [Table 122-1] [Table 122-2]

[0359] Intermediate 67 Methyl 2-{1-[(6-{3-azabicyclo[3.1.0]hexan-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 [ka] A mixture of 1-[(6-{3-azabicyclo[3.1.0]hexan-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 CH3COOH (2 mL) and concentrated aqueous HCl (2 mL) is heated to 110 °C for 1 h. The mixture is cooled to room temperature, treated with aqueous NaOH (4 M, 15 mL), and stirred for 10 min. Aqueous HCl (4 M, 15 mL) is then added, and the mixture is washed twice with EtOAc. The aqueous phase is concentrated in vacuo, and the residue is added to a mixture of acetyl chloride (50 μL) in MeOH (10 mL). The mixture is heated to 90 °C for 90 min. After cooling to room temperature, the mixture is neutralized with aqueous NaOH (1 M), concentrated in vacuo, and the residue is chromatographed on silica gel (90:10 to 70:30 cyclohexane / EtOAc) to give the title compound. LC (Method 2):tR = 0.63 min; Mass spectrum (ESI + ): m / z=490[M+H] + .

[0360] Intermediate 68 Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-imidazole-4-carboxylate [ka] A mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylate (200 mg) and tetrabutylammonium fluoride trihydrate (269 mg) in DMF (2 mL) is heated to 80° C. for 12 hours. After cooling to room temperature, the mixture is partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous phase is extracted four times with EtOAc. The combined organic phases are concentrated in vacuo and purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 1):t R =0.96 minutes.

[0361] Intermediate 69 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-bromopyridine-3-carbonitrile [ka] Under an 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) is heated to 80 °C for 2 h. The mixture is cooled, concentrated, and partitioned between water and EtOAc, and the phases are separated. The aqueous phase is extracted twice with EtOAc. The combined organic phases are washed with brine, dried (MgSO), concentrated, and the residue is chromatographed on silica gel (98:2 to 95:5 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 1.13 min; Mass spectrum (ESI+): m / z = 264 [M+H] + .

[0362] Intermediate 69-1 is prepared analogously to intermediate 69: [Table 123]

[0363] [Table 124]

[0364] [Table 125]

[0365] Intermediate 70 Methyl 6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-cyanopyridine-3-carboxylate [ka] Under an argon atmosphere, a mixture of 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-bromopyridine-3-carbonitrile (773 mg), triethylamine (489 μL), and (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (119 mg) in DMF (15 mL) and MeOH (15 mL) is heated to 80° C. for 22 h under a CO atmosphere of 10 bar. The mixture is cooled and concentrated in vacuo, and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (method 1):t R = 0.99 min; Mass spectrum (ESI+): m / z = 244 [M+H] + .

[0366] Intermediates 70-1 to 70-3 are prepared analogously to Intermediate 70: [Table 126]

[0367] [Table 127]

[0368] [Table 128]

[0369] Intermediate 71 2-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-(hydroxymethyl)pyridine-3-carbonitrile [ka] A mixture of methyl 6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-cyanopyridine-3-carboxylate (300 mg) in THF (5 mL) is cooled to -50 °C and treated dropwise with LiAlH (1.4 mL of a 1 M solution in THF). The mixture is stirred for 3 hours at -20 °C and then carefully treated with water (1 mL). After dilution with DCM, the mixture is stirred for 30 minutes. The precipitate is filtered off and the filter cake is washed with DCM. The combined filtrates are diluted with water. The phases are separated. The aqueous phase is extracted twice with DCM. The combined organic phases are dried (MgSO), concentrated, and purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (method 1):t R = 0.81 min; Mass spectrum (ESI+): m / z = 216 [M+H] + .

[0370] Intermediates 71-1 to 71-2 are prepared analogously to Intermediate 71: [Table 129]

[0371] [Table 130]

[0372] [Table 131]

[0373] Intermediate 72 Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]-3-(methoxymethyl)-1H-pyrazole-4-carboxylate [ka] A mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]-3-(chloromethyl)-1H-pyrazole-4-carboxylate (100 mg) and NaI (10 mg) in MeOH (4 mL) is heated in a microwave vial at 90° C. for 12 hours under an argon atmosphere. The mixture is diluted with MeOH and water and purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 1): R = 1.07 min; Mass spectrum (ESI+): m / z = 371 [M+H] + .

[0374] Intermediate 72-1 is prepared analogously to Intermediate 72: [Table 132]

[0375] [Table 133]

[0376] [Table 134]

[0377] Intermediate 73 Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-cyano-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylate [ka] In a microwave vial, N,N,N',N'-tetramethylethylenediamine (196 μL) is 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 is sealed, and the mixture is heated to 130 °C for 18 h. After cooling to room temperature, the mixture is partitioned between water and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic phases are dried (MgSO4), concentrated, and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (method 1):t R = 0.99 min; Mass spectrum (ESI+): m / z = 352 [M+H] + .

[0378] Intermediate 73-1 is prepared analogously to intermediate 73: [Table 135]

[0379] [Table 136]

[0380] Intermediate 74 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]-3-(2-hydroxypropan-2-yl)-1H-pyrazole-4-carboxylic acid hydrochloride [ka] A mixture of ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]-3-(prop-1-en-2-yl)-1H-pyrazole-4-carboxylate (66 mg) in aqueous HCl (4 M, 5 mL) is heated to 60° C. for 12 h. The mixture is concentrated in vacuo to give the crude product, which is used directly in the next step. LC (Method 2):t R = 0.67 min; Mass spectrum (ESI+): m / z = 357 [M+H] + .

[0381] Intermediate 75 Methyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate [ka] A mixture of 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid (920 mg) and concentrated aqueous HSO (182 μL) in MeOH (10 mL) is heated to 40 °C for 12 h. After cooling to room temperature, the mixture is partitioned between EtOAc and saturated aqueous NaHCO. The aqueous phase is extracted with EtOAc. The combined organic phases are dried (MgSO) and concentrated, and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (method 1):t R = 1.17 min; Mass spectrum (ESI+): m / z = 391 [M+H] + .

[0382] Intermediate 75-1 is prepared analogously to Intermediate 75: [Table 137]

[0383] [Table 138]

[0384] [Table 139]

[0385] Intermediate 76 Methyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2,5-dimethylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylate [ka] A mixture of methyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylate (120 mg), trimethylboroxine (77 mg), and K2CO3 (127 mg) in DMF (4 mL) is purged with argon for 5 minutes in a microwave vial. Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 71 mg) is added, the vial is sealed, and the mixture is heated to 110 °C for 12 hours. After cooling to room temperature, the mixture is partitioned between semisaturated aqueous NaCl and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic phases are dried (MgSO4) and concentrated, and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2):t R = 0.63 min; Mass spectrum (ESI+): m / z = 327 [M+H] + .

[0386] Intermediate 76-1 is prepared analogously to Intermediate 76: [Table 140]

[0387] [Table 141]

[0388] Intermediate 77 Ethyl 1-[(6-chloro-2-cyanopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate [ka] A mixture of 6-chloro-3-(chloromethyl)pyridine-2-carbonitrile (37 mg), ethyl 1H-pyrazole-4-carboxylate (30 mg), and CsCO (100 mg) in THF (2 mL) is stirred at room temperature for 8 hours. The mixture is then neutralized by the addition of trifluoroacetic acid and purified by HPLC on reverse phase (ACN, water) to give the title compound.

[0389] LC (method 1):t R = 0.94 min; Mass spectrum (ESI+): m / z = 291 [M+H] + .

[0390] Intermediate 78 Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-cyanopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate [ka] 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) is stirred at 140° C. for 12 hours. After cooling to room temperature, the mixture is partitioned between water and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic phases are washed with water, dried (MgSO 4 ), concentrated, and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 1):t R = 1.04 min; Mass spectrum (ESI+): m / z = 338 [M+H] +.

[0391] Intermediate 79 2-chloro-4-methylpyrimidine-5-carboxylic acid [ka] A mixture of ethyl 2-chloro-4-methylpyrimidine-5-carboxylate (25 g) and NaOH (6.5 g) in water (200 mL) is stirred at 40° C. for 3 hours. After cooling to room temperature, the mixture is treated with aqueous HCl (4 M) until a pH value of 2 is reached. The precipitate is collected by filtration, washed with water, and dried in vacuo to give the title compound. LC (Method 2):t R = 0.68 min; Mass spectrum (ESI+): m / z = 173 [M+H] + .

[0392] Intermediate 80 (2-chloro-4-methylpyrimidin-5-yl)methanol [ka] A mixture of 2-chloro-4-methylpyrimidine-5-carboxylic acid (8.5 g) and N-methylmorpholine (5.14 mL) in 1,2-dimethoxyethane (200 mL) is cooled to -10°C and treated dropwise with isobutyl chloroformate (6.2 mL). The mixture is stirred for 30 minutes and then treated dropwise with a solution of NaBH4 (1.81 g) in water (20 mL). The mixture is stirred for 30 minutes while warming to room temperature and then partitioned between water and EtOAc. The aqueous phase is extracted three times with EtOAc. The combined organic phases are washed with brine, dried (MgSO4), concentrated, and the residue is chromatographed on silica gel (70:30 petroleum ether / (8:2 EtOAc / MeOH)) to give the title compound. LC (Method 2):t R = 0.51 min; Mass spectrum (ESI+): m / z = 159 [M+H] + .

[0393] Intermediate 81 (2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-methylpyrimidin-5-yl)methanol [ka] Diisobutylaluminum hydride (1 M in THF, 80 mL) is added dropwise to a mixture of ethyl 2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-methylpyrimidine-5-carboxylate (8.7 g) in THF (70 mL) at −10° C. The mixture is stirred for 1 hour while warming to 0° C. This mixture is then added dropwise to a mixture of aqueous NaOH (4 M, 6 mL) in water (150 mL) under ice cooling. After stirring for 1 hour, the mixture is filtered over Celite. The filter cake is washed with 9:1 EtOAc / MeOH. The combined filtrates are dried (MgSO4) and concentrated, and the residue is chromatographed on silica gel (95:5 to 95:5 EtOAc / MeOH) to give the title compound. LC (Method 2):t R = 0.59 min; Mass spectrum (ESI+): m / z = 206 [M+H] + .

[0394] Intermediate 82 Methyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3-carboxylate and Intermediate 83 Methyl 5-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3-carboxylate [ka] Under an argon atmosphere, a mixture of (6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methanol (1.2 g) and DIPEA (1.8 mL) in DCM (5 mL) is treated dropwise with CHSOCl (513 μL). The mixture is stirred for 15 minutes and then added dropwise to a mixture obtained by treating a solution of methyl 1H-pyrrole-3-carboxylate (863 mg) in DMF (15 mL) with KOtBu (893 mg). The mixture thus obtained is stirred for 5 days at room temperature. The mixture is then partitioned between saturated aqueous NaHCO and EtOAc. The aqueous phase is extracted twice with EtOAc. The combined organic phases are dried (MgSO), concentrated in vacuo, and purified by HPLC on reverse phase (ACN, water) to give the title compound. Methyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3-carboxylate (Intermediate 82): LC (Method 2): R = 0.71 min; Mass spectrum (ESI+): m / z = 334 [M+H] + . Methyl 5-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3-carboxylate (Intermediate 83): LC (Method 2): R = 0.70 min; Mass spectrum (ESI+): m / z = 334 [M+H] + .

[0395] Intermediate 84 Methyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrrole-3-carboxylate and Intermediate 85 Methyl 5-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrrole-3-carboxylate [ka] Under an 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) and DIPEA (1.2 mL) in DCM (15 mL) is treated dropwise with CHSOCl (656 μL). The mixture is stirred for 15 minutes and then added dropwise to a mixture obtained by treating a solution of methyl 1H-pyrrole-3-carboxylate (745 mg) in DMF (30 mL) with KOtBu (771 mg). The mixture thus obtained is stirred for 1 hour at room temperature. The mixture is then partitioned between saturated aqueous NaHCO and DCM. The aqueous phase is extracted twice with DCM. The combined organic phases are dried (MgSO) and concentrated in vacuo, and the residue is chromatographed on silica gel (90:10 → 50:50 petroleum ether / EtOAc) to give the title compound. Methyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrrole-3-carboxylate (Intermediate 84): LC (Method 2):t R = 0.74 min; Mass spectrum (ESI+): m / z = 348 [M+H] + . Methyl 5-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrrole-3-carboxylate (Intermediate 85): LC (Method 2): t R = 0.73 min; Mass spectrum (ESI+): m / z = 348 [M+H] + .

[0396] Intermediate 86 Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloropyridin-3-yl)methyl]-1,2-oxazole-5-carboxylate [ka] A mixture of 3-[6-chloro-5-(2-nitroethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane (2.58 g), BocO (4.42 g), ethyl propionate (3.03 mL), DMAP (176 mg), and ACN (60 mL) is stirred at 23° C. for 18 hours. Purification by HPLC on reverse phase (ACN, water) affords the title compound. LC (Method 1): R = 1.15 min; Mass spectrum (ESI+): m / z = 348 [M+H] + .

[0397] Intermediates 86-1 to 86-2 are prepared analogously to Intermediate 86: [Table 142]

[0398] [Table 143]

[0399] Intermediate 87 3-[6-chloro-5-(2-nitroethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane [ka] A mixture of 3-{6-chloro-5-[(1E)-2-nitroethenyl]pyridin-2-yl}-3-azabicyclo[3.1.0]hexane (4.0 g), NaBH4 (726 mg), acetic acid (5 mL), and DMSO (30 mL) is stirred for 30 minutes at 0 °C and for 1 hour at room temperature. The mixture is diluted with water and EtOAc, and the phases are separated. The aqueous phase is extracted three times with EtOAc. The combined organic phases are washed with brine, dried (MgSO4), and concentrated, and the residue is chromatographed on silica gel (100:0 to 30:70 cyclohexane / EtOAc) to give the title compound. LC (Method 2):t R = 1.10 min. Mass spectrum (ESI+): m / z = 268 [M+H] + .

[0400] Intermediates 87-1 to 87-2 are prepared analogously to Intermediate 87: [Table 144]

[0401] [Table 145]

[0402] Intermediate 88 3-{6-chloro-5-[(1E)-2-nitroethenyl]pyridin-2-yl}-3-azabicyclo[3.1.0]hexane [ka] A mixture of 6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloropyridine-3-carbaldehyde (500 mg), nitromethane (1.6 mL), ammonium acetate (346 mg), and acetic acid (10 mL) is stirred at 100 °C for 18 h. The mixture is cooled to room temperature and added dropwise to a cold mixture of EtOAc, water, and saturated aqueous NaHCO3. The phases are separated, and the aqueous phase is extracted three times with EtOAc. The combined organic phases are washed with brine, dried (MgSO4), and concentrated to give the crude title compound. LC (Method 2):t R = 1.14 min. Mass spectrum (ESI+): m / z = 266 [M+H] + .

[0403] Intermediates 88-1 to 88-2 are prepared analogously to Intermediate 88: [Table 146]

[0404] [Table 147]

[0405] Intermediate 89 Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)methyl]-1,2-oxazole-5-carboxylate [ka] A mixture of (E,Z)-N-[2-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)ethylidene]hydroxylamine (2.45 g), ethyl prop-2-ynoate (2.0 mL), 15% aqueous NaOCl (34 mL), and THF (20 mL) is stirred at room temperature for 3 hours. The mixture is diluted with EtOAc and water, and the aqueous phase is extracted three times with EtOAc. The combined organic phases are washed with brine, dried (MgSO), and concentrated, and the residue is chromatographed on silica gel (99:1 to 70:30 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 0.79 min. Mass spectrum (ESI+): m / z = 342 [M+H] + .

[0406] Intermediates 89-1 to 89-2 are prepared analogously to intermediate 89: [Table 148]

[0407] [Table 149]

[0408] [Table 150]

[0409] Intermediate 90 (E,Z)-N-[2-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)ethylidene]hydroxylamine [ka] A mixture of 2-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)acetaldehyde (2.22 g), hydroxylamine hydrochloride (1.35 g), Na2CO3 (1.23 g), water (8.0 mL), and MeOH (40 mL) is stirred at room temperature for 2 hours. The mixture is concentrated, and the residue is treated with water, stirred for 15 minutes, and filtered. The precipitate is washed with water and dried in a desiccator to give the title compound as a mixture of isomers. LC (Method 2):t R = 0.62 min and 0.64 min. Mass spectrum (ESI+): m / z = 246 [M+H] + .

[0410] Intermediates 90-1 to 90-3 are prepared analogously to Intermediate 90: [Table 151]

[0411] [Table 152]

[0412] Intermediate 91 2-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)acetaldehyde [ka] A mixture of 3-[6-ethyl-5-(2-methoxyethenyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane (2.36 g), concentrated HCl (4.0 mL), and 1,4-dioxane (24 mL) is stirred at room temperature for 1 hour. The mixture is carefully neutralized with a saturated aqueous solution of NaHCO3, and the aqueous phase is extracted twice with EtOAc. The combined organic phases are washed with brine, dried (MgSO4), and concentrated to give the title compound.

[0413] LC (Method 2):t R = 0.58 min. Mass spectrum (ESI+): m / z = 231 [M+H] + .

[0414] Intermediates 91-1 to 91-3 are prepared analogously to Intermediate 91: [Table 153]

[0415] [Table 154]

[0416] Intermediate 92 3-[6-ethyl-5-(2-methoxyethenyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane [ka] A mixture of (methoxymethyl)triphenylphosphonium chloride (10.0 g) in THF (80 mL) is treated dropwise with NaHMDS (2 M in THF, 14.6 mL) at −40° C. under an argon atmosphere and stirred at this temperature for 15 minutes. This mixture is treated dropwise with a mixture of 6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridine-3-carbaldehyde (2.09 g) in THF (20 mL) at −40° C. The mixture is then warmed to room temperature over 4 hours. The mixture is diluted with EtOAc, and the organic layer is washed with water and brine, dried (MgSO4), and concentrated. The residue is stirred in diisopropyl ether, and the precipitate is filtered off. The filtrate is concentrated, and the residue is chromatographed on silica gel (99:1 to 70:30 petroleum ether / EtOAc) to give the title compound as a mixture of isomers. LC (Method 2):t R = 0.74 and 0.76 min (mixture of isomers). Mass spectrum (ESI+): m / z = 245 [M+H] + .

[0417] Intermediates 92-1 to 92-3 are prepared analogously to Intermediate 92: [Table 155]

[0418] [Table 156]

[0419] Intermediate 93 Methyl 2-[1-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)-2-methoxy-2-oxoethyl]-1,3-oxazole-5-carboxylate [ka] 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) is treated dropwise with NaHMDS (2 M in THF, 1.1 mL) at −78° C. under an argon atmosphere and stirred at this temperature for 15 minutes. This mixture is 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 allowed to warm to room temperature over 18 hours. The mixture is quenched with saturated aqueous NH4Cl, and the aqueous phase is extracted twice with EtOAc. The combined organic phases are dried (MgSO4), concentrated, and the residue is chromatographed on silica gel (80:20 to 20:80 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 0.72 min. Mass spectrum (ESI+): m / z = 372 [M+H] + .

[0420] Intermediates 93-1 to 93-2 are prepared analogously to Intermediate 93: [Table 157]

[0421] [Table 158]

[0422] Intermediate 94 Methyl 2-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)acetate [ka] A mixture of 2-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)acetonitrile (473 mg) in MeOH (5 mL) is treated with SOCl (575 mL) at room temperature, and the mixture is stirred for 6 hours before being treated with saturated aqueous NaHCO. The aqueous phase is extracted twice with DCM, and the combined organic layers are washed with brine, dried (MgSO), and concentrated to give the title compound. LC (Method 2): R = 0.64 min. Mass spectrum (ESI+): m / z = 247 [M+H] + .

[0423] Intermediates 94-1 to 94-2 are prepared analogously to Intermediate 94: [Table 159]

[0424] [Table 160]

[0425] [Table 161]

[0426] Intermediate 95 2-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)acetonitrile [ka] A mixture of (6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methanol (1.96 g) in THF (15 mL) is treated with 2-hydroxy-2-methylpropionitrile (895 mg), triphenylphosphine (PPh3, 3.80 g), and DIAD (2.36 g) at 0 °C. The mixture is stirred at room temperature for 66 h and quenched with a saturated aqueous solution of NaHCO3. The aqueous phase is extracted with EtOAc. The organic phase is washed with brine, dried (MgSO4), concentrated, and the residue is chromatographed on silica gel (90:10 to 80:20 petroleum ether / EtOAc) to give the title compound. LC(Method 1:t R = 0.97 min. Mass spectrum (ESI+): m / z = 214 [M+H] + .

[0427] Intermediates 95-1 to 95-2 are prepared analogously to Intermediate 95: [Table 162]

[0428] [Table 163]

[0429] [Table 164]

[0430] Intermediate 96 Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)methyl]-1,2-oxazole-5-carboxylate [ka] A mixture of N-[2-(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)ethylidene]hydroxylamine (100 mg), ethyl prop-2-ynoate (47 μL), oxone (328 mg), NaCO (57 mg), NaCl (23 mg), MeOH (2 mL), and water (100 μL) is stirred at room temperature for 5 hours and concentrated. The residue is partitioned between water and EtOAc. The organic phase is washed with brine, dried (MgSO), concentrated, and the residue is chromatographed on silica gel (99:01 to 50:50 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 0.81 min. Mass spectrum (ESI+): m / z = 378 [M+H] + .

[0431] Intermediate 97 Methyl 5-[(2-chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3-carboxylate [ka] Under an argon atmosphere, a mixture of (2-chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methanol (300 mg) and DIPEA (782 μL) in DCM (1.5 mL) is treated dropwise with CHSOCl (222 μL). The mixture is stirred for 15 minutes and then added dropwise to a mixture obtained by treating a solution of methyl 1H-pyrrole-3-carboxylate (187 mg) in DMF (4 mL) with KOtBu (194 mg). The mixture thus obtained is stirred for 12 hours at 40 °C. The mixture is then partitioned between saturated aqueous NaHCO and EtOAc. The aqueous phase is extracted twice with EtOAc. The combined organic phases are dried (MgSO) and concentrated in vacuo, and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2):t R= 1.05 min; Mass spectrum (ESI+): m / z = 368 [M+H] + .

[0432] Intermediate 98 Ethyl 5-iodo-1H-pyrazole-3-carboxylate [ka] Ethyl 5-amino-1H-pyrazole-3-carboxylate (10 g) is added in portions to a mixture of water (240 mL) and concentrated aqueous HSO (120 mL) at 0 °C. A solution of NaNO (4.65 g) in water (10 mL) is added dropwise to this mixture. The mixture is stirred for 2 hours and then treated dropwise with a solution of KI (12.0 g) in water (10 mL). The mixture is stirred for 3 hours while warming to room temperature. The mixture is then cooled to 0 °C and neutralized by careful addition of saturated aqueous KCO solution. The mixture is extracted twice with EtOAc. The combined organic phases are washed with 20% NaSO in water, dried (MgSO), concentrated, and the residue is chromatographed on silica gel (95:5 to 70:30 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 0.86 min. Mass spectrum (ESI+): m / z = 267 [M+H] + .

[0433] Intermediate 98-1 is prepared analogously to Intermediate 98: [Table 165]

[0434] [Table 166]

[0435] Intermediate 99 Ethyl 3-iodo-1-(propan-2-yl)-1H-pyrazole-5-carboxylate [ka] NaH (60% in mineral oil, 180 mg) is added portionwise to a mixture of ethyl 5-iodo-1H-pyrazole-3-carboxylate (1.0 g) in DMF (15 mL) at 0° C. The mixture is stirred for 30 minutes and then treated with 2-iodopropane (451 μL). The mixture is stirred for 4 hours while warming to room temperature. The mixture is then partitioned between saturated aqueous NH4Cl and EtOAc. The aqueous phase is extracted twice with EtOAc. The combined organic phases are dried (MgSO4) and concentrated in vacuo, and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2):t R = 1.08 min. Mass spectrum (ESI+): m / z = 309 [M+H] + .

[0436] Intermediates 99-1 to 99-2 are prepared analogously to Intermediate 99: [Table 167]

[0437] [Table 168]

[0438] [Table 169]

[0439] Intermediate 100 Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)(hydroxy)methyl]-1-(propan-2-yl)-1H-pyrazole-5-carboxylate [ka] A mixture of ethyl 3-iodo-1-(propan-2-yl)-1H-pyrazole-5-carboxylate (100 mg) in THF (2 mL) is treated dropwise with iPrMgClxLiCl (1.3 M in THF, 300 μL) at −40° C. under an argon atmosphere. The mixture is stirred for 30 minutes and then treated dropwise with a mixture of 6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridine-3-carbaldehyde (90 mg) in THF (2 mL). After stirring for 3 hours at −40° C., the mixture is partitioned between saturated aqueous NH4Cl and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic phases are dried (MgSO4) and concentrated in vacuo to give the crude product, which is used directly in the next step. LC (Method 2):t R = 0.85 min. Mass spectrum (ESI+): m / z = 435 [M+H] + .

[0440] Intermediates 100-1 to 100-8 are prepared analogously to Intermediate 100: [Table 170]

[0441] [Table 171]

[0442] [Table 172-1] [Table 172-2]

[0443] Intermediate 101 Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)methyl]-1-(propan-2-yl)-1H-pyrazole-5-carboxylate [ka] A mixture of ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)(hydroxy)methyl]-1-(propan-2-yl)-1H-pyrazole-5-carboxylate (141 mg), triethylsilane (492 μL) and trifluoroacetic acid (594 μL) in 1,2-dichloroethane (1.18 mL) is stirred at room temperature for 30 minutes under an argon atmosphere. The mixture is concentrated in vacuo to give the crude product, which is used directly in the next step. LC (Method 2):t R = 0.90 min. Mass spectrum (ESI+): m / z = 419 [M+H] + .

[0444] Intermediates 101-1 to 101-12 are prepared analogously to Intermediate 101: [Table 173-1] [Table 173-2]

[0445] [Table 174]

[0446] [Table 175-1] [Table 175-2]

[0447] Intermediate 102 Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-5-carboxylate [ka] 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) is stirred at room temperature under an argon atmosphere for 12 hours. The mixture is partitioned between water and DCM. The aqueous phase is extracted twice with DCM. The combined organic phases are washed with brine, dried (MgSO4), concentrated in vacuo, and the residue is chromatographed on silica gel (80:20 → 0:100 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 1.05 min. Mass spectrum (ESI+): m / z = 347 [M+H] + .

[0448] Intermediates 102-1 to 102-3 are prepared analogously to Intermediate 102: [Table 176]

[0449] [Table 177]

[0450] [Table 178]

[0451] Intermediate 103 Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloropyridin-3-yl)methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carboxylate and Ethyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloropyridin-3-yl)methyl]-1-({[2-(trimethylsilyl)ethyl]amino}methyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylate (mixture of isomers) [ka] NaH (60% in mineral oil, 73 mg) is 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 under an argon atmosphere. The mixture is stirred for 30 minutes and then treated dropwise with (2-chloromethoxy-ethyl)-trimethyl-silane (SEM-Cl, 313 μL). The mixture is stirred for 2 hours while warming to room temperature. The mixture is then partitioned between saturated aqueous NH4Cl and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic phases are washed with brine, dried (MgSO4), concentrated in vacuo, and the residue is chromatographed on silica gel (99:1 to 70:30 petroleum ether / EtOAc) to give the title compound as a mixture of isomers. LC (Method 2):t R = 1.05 min. Mass spectrum (ESI+): m / z = 347 [M+H] + .

[0452] Intermediate 104 Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)methyl]-1-ethyl-1H-pyrazole-5-carboxylate [ka] A mixture of ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-ethenylpyridin-3-yl)methyl]-1-ethyl-1H-pyrazole-5-carboxylate (40 mg), 10% palladium on carbon (5 mg) in MeOH (3 mL) is shaken under a hydrogen atmosphere (3 bar) at room temperature for 4.5 hours. The mixture is filtered and the filtrate is concentrated in vacuo to give the crude product, which is used directly in the next step. LC (Method 2): R = 0.84 min; Mass spectrum (ESI+): m / z = 369 [M+H] + .

[0453] Intermediate 104-1 is prepared analogously to intermediate 104: [Table 179]

[0454] [Table 180]

[0455] [Table 181]

[0456] Intermediate 105 Ethyl 3-[(6-fluoro-2-methylpyridin-3-yl)(hydroxy)methyl]-1-methyl-1H-pyrazole-5-carboxylate [ka] A mixture of 6-fluoro-3-iodo-2-methylpyridine (550 mg) in THF (25 mL) is treated dropwise with iPrMgClxLiCl (1.3 M in THF, 2.2 mL) at -50 °C under an argon atmosphere. The mixture is 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 for 1 hour at -50 °C, the mixture is partitioned between saturated aqueous NH4Cl and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic phases are dried (MgSO4) and concentrated in vacuo, and the residue is chromatographed on silica gel (90:10 to 50:50 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 0.89 min. Mass spectrum (ESI+): m / z = 294 [M+H] + .

[0457] Intermediate 106 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 [ka] A mixture of ethyl 3-[(6-fluoro-2-methylpyridin-3-yl)(hydroxy)methyl]-1-methyl-1H-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) is heated to 150 °C for 48 hours. After cooling to room temperature, the mixture is diluted with ACN, filtered, and purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2): R = 0.63 min; Mass spectrum (ESI+): m / z = 365 [M+H] + .

[0458] Intermediate 107 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 [ka] 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) is stirred at room temperature for 12 hours under an argon atmosphere. The mixture is diluted with water and purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2):t R = 0.69 min. Mass spectrum (ESI+): m / z = 349 [M+H] + .

[0459] Intermediate 108 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid [ka] Step 1: Ethyl 1-[(6-fluoro-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (6-Fluoro-2-methylpyridin-3-yl)methanol (4.12 g) is dissolved in THF (50 mL) and cooled to -10 ° C. Ethyl 1H-pyrazole-4-carboxylate (4.43 g) and tributylphosphine (9 mL) are added. Di-tert.-butyl-azodicarboxylate (DBAD, 7.4 g) is added slowly in small portions, the mixture is stirred at room temperature for 45 minutes and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane / EtOAc) to give the title compound. LC (Method 2):t R = 0.88 min; Mass spectrum (ESI + ): m / z=264[M+H] + .

[0460] Step 2: 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid Ethyl 1-[(6-fluoro-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate (0.5 g) is dissolved in DMSO (2 mL). 5-Azaspiro[2.3]hexane trifluoroacetate (1.2 g) and DIPEA (2 mL) are added, and the mixture is stirred at 100° C. for 16 hours and at 120° C. for an additional 5 hours. After cooling to room temperature, the N,N-diisopropyl-ethylamine phase is removed, 4 M NaOH (4 mL) is added, and the mixture is stirred at 60° C. for 2 hours. Aqueous HCl (4 M, 4 mL) is added, and the mixture is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 1): R = 0.68 min; Mass spectrum (ESI + ): m / z=299[M+H] + .

[0461] Intermediate 109 Methyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)(hydroxy)methyl]furan-2-carboxylate [ka] A mixture of methyl 5-bromofuran-2-carboxylate (500 mg) in THF (15 mL) is treated dropwise with iPrMgClxLiCl (1.3 M in THF, 1.95 mL) at −50° C. The mixture is stirred for 30 minutes at −50° C. and then cooled to −78° C. 6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridine-3-carbaldehyde (592 mg) in THF (8 mL) is added, and the mixture is stirred for 1 hour at −78° C. and then for 30 minutes at 0° C. The reaction is quenched with saturated aqueous NH4Cl and water. The mixture is extracted with EtOAc. The combined organic phases are dried (MgSO4) and concentrated in vacuo, and the residue is chromatographed on silica gel (85:15 to 50:50 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 0.70 min. Mass spectrum (ESI+): m / z = 329 [M+H] + .

[0462] Intermediates 109-1 to 109-7 are prepared analogously to intermediate 109: [Table 182]

[0463] [Table 183]

[0464] [Table 184-1] [Table 184-2]

[0465] Intermediate 110 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid [ka] Step 1: Methyl 4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyanobenzoate The title compound is prepared from methyl 3-cyano-4-fluorobenzoate and 3-azabicyclo[3.1.0]hexane hydrochloride following a procedure similar to that described in Step 1 of Intermediate 111. Step 2: 2-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-(hydroxymethyl)benzonitrile The title compound is prepared from methyl 4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyanobenzoate following a procedure similar to that described in Step 4 of Intermediate 118. LC (Method 2):t R = 0.92 min; Mass spectrum (ESI + ): m / z=215[M+H] + . Step 3: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyanophenyl)methyl]-1H-pyrazole-4-carboxylate The title compound is prepared from 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-(hydroxymethyl)benzonitrile and ethyl 1H-pyrazole-4-carboxylate following a procedure similar to that described in Step 3 of Intermediate 111. Step 4: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyanophenyl)methyl]-1H-pyrazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111.

[0466] Intermediate 111 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid [ka] Step 1: 4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorobenzaldehyde 3,4,5-trifluorobenzaldehyde (1.50 g), 3-azabicyclo[3.1.0]hexane hydrochloride (1.23 g), i A mixture of PrNEt (4 mL) and DMF (15 mL) is stirred at 70 °C overnight. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate (3x). The combined extracts are dried (NaSO) and concentrated. The residue is chromatographed on silica gel (98:2 to 95:5 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 1.13 min; Mass spectrum (ESI + ): m / z=224[M+H] + . Step 2: (4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methanol NaBH4 (0.18 g) is added in portions to 4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorobenzaldehyde (0.97 g) in THF (10 mL) and methanol (10 mL) at 0 °C. The mixture is stirred in the cooling bath for 1 hour and at room temperature for another 30 minutes, after which aqueous HCl (1 mol / L) is added. After the mixture is stirred for 30 minutes, it is neutralized with aqueous NaHCO3. The mixture is extracted with ethyl acetate (2x), and the combined extracts are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (95:5 → 85:15 petroleum ether / EtOAc) to give the title compound. LC (Method 2):t R = 1.04 min; Mass spectrum (ESI + ): m / z=226[M+H]+ . Step 3: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methyl]-1H-pyrazole-4-carboxylate A mixture of (4-{3-azabicyclo[3.1.0]hexan-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) is stirred at 70 °C for 1.5 h (if the reaction is not complete, increase the temperature and / or extend the reaction time depending on the degree of conversion). After cooling to room temperature, the mixture is concentrated, water is added, and the resulting mixture is neutralized with aqueous NaHCO3. The resulting mixture is extracted with ethyl acetate (3x), and the combined extracts are dried (Na2SO4), and concentrated. The residue is chromatographed (HPLC; ACN / water / ammonia) to give the title compound. LC (Method 2):t R = 1.20 min; Mass Spectrum (ESI + ): m / z=348[M+H] + . Step 4: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid A mixture of ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methyl]-1H-pyrazole-4-carboxylate (0.10 g), aqueous NaOH (4 mol / L; 0.5 mL), THF (2 mL), and EtOH (2 mL) is stirred at 70° C. for 1.5 hours. After cooling to room temperature, the mixture is concentrated. Water (2 mL) and aqueous HCl (4 mol / L; 0.5 mL) are added, and the resulting mixture is adjusted to a pH of about 5 with aqueous NaOH. The precipitate formed is separated, dried, and used as is in the next reaction step; alternatively, if no precipitate forms, the aqueous phase is concentrated, and the remainder is used as is in the next reaction step. LC (Method 2):t R= 1.04 min; Mass spectrum (ESI + ): m / z=320[M+H] + .

[0467] Intermediate 112 2-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methyl]-1H-imidazole-5-carboxylic acid [ka] Step 1: 3-[4-(chloromethyl)-2,6-difluorophenyl]-3-azabicyclo[3.1.0]hexane A mixture of (4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methanol (60 mg), SOCl (0.04 mL), and dichloromethane (1 mL) is stirred at room temperature for 30 minutes. The mixture is concentrated, dissolved in toluene, concentrated again, and used directly in the next reaction step. Step 2: Ethyl 2-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methyl]-1H-imidazole-5-carboxylate LiO t Bu (21 mg) was added to ethyl 1H-imidazole-4-carboxylate (37 mg) cooled in an ice bath. t Add to a mixture of BuOH (0.4 mL) and DCM (1.6 mL). After stirring the mixture for 5 minutes, add 3-[4-(chloromethyl)-2,6-difluorophenyl]-3-azabicyclo[3.1.0]hexane (65 mg, crude product from Step 1) in DCM (0.4 mL). Remove the cooling bath and stir the mixture at 40 °C overnight. After cooling to room temperature, add water and DCM. Separate the organic phase and extract the aqueous phase with DCM (2x). Concentrate the combined organic extracts and chromatograph the residue (HPLC; ACN / water / ammonia) to give the title compound. LC (Method 2):t R = 0.89 min; Mass spectrum (ESI + ): m / z=348[M+H]+ . Step 3: 2-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methyl]-1H-imidazole-5-carboxylic acid The title compound is prepared from ethyl 2-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methyl]-1H-imidazole-5-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111. LC (Method 2):t R = 0.82 min; Mass spectrum (ESI + ): m / z=320[M+H] + .

[0468] Intermediate 113 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid [ka] Step 1: 6-Fluoro-3-formyl-2-methylbenzonitrile i PrMgCl * LiCl (Turbo Grignard; 1.3 mol / L in THF, 3.8 mL) is added dropwise to 3-bromo-6-fluoro-2-methylbenzonitrile (1.0 g) in THF (25 mL) at −20° C. The mixture is warmed to 0° C. over a period of 1.3 h, after which another aliquot i PrMgCl *LiCl (Turbo Grignard; 1.3 mol / L in THF, 1.0 mL) is added. The cooling bath is removed and the mixture is stirred for an additional 45 min. The mixture is cooled to -20°C and DMF (0.8 mL) is added. After stirring for 50 min, the cooling bath is removed and the reaction is quenched by adding aqueous NH4Cl at room temperature. The mixture is extracted with EtOAc (3x) and the combined extracts are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (24:1 → 3:1 cyclohexane / EtOAc) to give the title compound. LC (Method 2):t R =0.87 minutes. Step 2: 6-{3-azabicyclo[3.1.0]hexan-3-yl}-3-formyl-2-methylbenzonitrile A mixture of 6-fluoro-3-formyl-2-methylbenzonitrile (515 mg), KHCO3 (0.79 g), 3-azabicyclo[3.1.0]hexane hydrochloride (453 mg), and DMSO (10 mL) is stirred at 70°C for 1.3 hours. After cooling to room temperature, water is added and the mixture is stirred for 30 minutes. The precipitate is separated by filtration, washed with water (2x), and dried at 65°C to give the title compound. LC (Method 1): R = 0.97 min; Mass spectrum (ESI + ): m / z=227[M+H] + . Step 3: 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 NaBH4 (0.21 g) is added in portions to 6-{3-azabicyclo[3.1.0]hexan-3-yl}-3-formyl-2-methylbenzonitrile (0.63 g) in THF (10 mL) and MeOH (5 mL) at room temperature. After stirring the mixture for 1 hour, aqueous HCl (1 mol / L) is added. After stirring the mixture for 1 hour, it is neutralized with aqueous NaHCO3. The mixture is extracted with EtOAc (2x), and the combined extracts are dried (Na2SO4) and concentrated to give a mixture of the title compound and 6-{3-azabicyclo[3.1.0]hexan-3-yl}-3-(methoxymethyl)-2-methylbenzonitrile, which is used directly in the next reaction step (both components are suitable starting materials for the next step). LC (method 1):t R = 1.27 min; Mass spectrum (ESI + ): m / z=439[M+H] + . Step 4: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylate The title compound is prepared from the mixture of intermediate 113, 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 obtained in step 3, and ethyl 1H-pyrazole-4-carboxylate, according to a procedure similar to that described in step 3 of intermediate 111. LC (method 1):t R = 1.08 min; Mass spectrum (ESI + ): m / z=351[M+H] + . Step 5: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111. LC (Method 2):t R = 0.96 min; Mass spectrum (ESI + ): m / z=323[M+H] + .

[0469] Intermediate 114 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-imidazole-4-carboxylic acid [ka] Step 1: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-imidazole-4-carboxylate The title compound is prepared from the mixture of intermediate 113, 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 obtained in step 3, and ethyl 1H-imidazole-4-carboxylate, according to a procedure similar to that described in step 3 of intermediate 111. LC (method 1):t R = 0.99 min; Mass spectrum (ESI + ): m / z=351[M+H] + . Step 2: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-imidazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-imidazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111. LC (Method 2):t R = 0.80 min; Mass Spectrum (ESI + ): m / z=323[M+H] + .

[0470] Intermediate 115 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-5-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid [ka] Step 1: 2,3-Difluoro-5-formylbenzonitrile The title compound is prepared from 5-bromo-2,3-difluorobenzonitrile following a procedure similar to that described in Step 1 of Intermediate 113. LC (Method 2): R =0.84 minutes. Step 2: 2-{3-azabicyclo[3.1.0]hexan-3-yl}-3-fluoro-5-formylbenzonitrile The title compound is prepared from 2,3-difluoro-5-formylbenzonitrile and 3-azabicyclo[3.1.0]hexane hydrochloride following a procedure similar to that described in Step 1 of Intermediate 111. LC (Method 2):t R = 1.03 min; Mass spectrum (ESI + ): m / z=231[M+H] + . Step 3: 2-{3-azabicyclo[3.1.0]hexan-3-yl}-3-fluoro-5-(hydroxymethyl)benzonitrile The title compound is prepared from 2-{3-azabicyclo[3.1.0]hexan-3-yl}-3-fluoro-5-formylbenzonitrile following a procedure similar to that described in Step 2 of Intermediate 111. LC (Method 2):t R = 0.99 min; Mass spectrum (ESI + ): m / z=233[M+H] + . Step 4: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-5-fluorophenyl)methyl]-1H-pyrazole-4-carboxylate The title compound is prepared from 2-{3-azabicyclo[3.1.0]hexan-3-yl}-3-fluoro-5-(hydroxymethyl)benzonitrile and ethyl 1H-pyrazole-4-carboxylate following a procedure similar to that described in Step 3 of Intermediate 111. LC (Method 2):t R = 1.10 min; Mass spectrum (ESI + ): m / z=355[M+H] + . Step 5: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-5-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-5-fluorophenyl)methyl]-1H-pyrazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111. LC (Method 2):t R = 0.99 min; Mass spectrum (ESI + ): m / z=327[M+H] + .

[0471] Intermediate 116 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid [ka] Step 1: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylate The title compound is prepared from 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-(hydroxymethyl)benzonitrile and ethyl 1H-imidazole-4-carboxylate following a procedure similar to that described in Step 3 of Intermediate 111. Step 2: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111.

[0472] Intermediate 117 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-dicyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid [ka] Step 1: 2-Fluoro-5-formylbenzene-1,3-dicarbonitrile A mixture of 4-fluoro-3,5-diiodobenzaldehyde (2.00 g), copper(I) cyanide (1.05 g), and DMF (25 mL) is stirred at 120° C. for 24 hours. After cooling to room temperature, water is added, and the resulting mixture is extracted with ethyl acetate (3×). The combined extracts are dried (NaSO) and concentrated. The residue is chromatographed on silica gel (95:51 to 70:30 petroleum ether / EtOAc) to give the title compound. Step 2: 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-formylbenzene-1,3-dicarbonitrile The title compound is prepared from 2-fluoro-5-formylbenzene-1,3-dicarbonitrile and 3-azabicyclo[3.1.0]hexane hydrochloride following a procedure similar to that described in Step 1 of Intermediate 111. LC (Method 2):t R = 0.95 min; Mass spectrum (ESI + ): m / z=238[M+H] + . Step 3: 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-(hydroxymethyl)benzene-1,3-dicarbonitrile The title compound is prepared from 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-formylbenzene-1,3-dicarbonitrile following a procedure similar to that described in Step 2 of Intermediate 111. LC (Method 2):t R = 0.92 min; Mass spectrum (ESI + ): m / z=240[M+H] + . Step 4: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-dicyanophenyl)methyl]-1H-pyrazole-4-carboxylate The title compound is prepared from 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-(hydroxymethyl)benzene-1,3-dicarbonitrile and ethyl 1H-pyrazole-4-carboxylate following a procedure similar to that described in Step 3 of Intermediate 111. LC (Method 2):t R = 1.07 min; Mass spectrum (ESI + ): m / z=362[M+H] + . Step 5: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-dicyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-dicyanophenyl)methyl]-1H-pyrazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111. LC (Method 2):t R = 0.92 min; Mass spectrum (ESI + ): m / z=334[M+H] + .

[0473] Intermediate 118 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid [ka] Step 1: 3-Bromo-2,6-difluorobenzonitrile 3-Amino-2,6-difluorobenzonitrile (2.50 g) dissolved in ACN (45 mL) is added dropwise to a mixture of copper(II) bromide (4.49 g), tert-butyl nitrite (3.8 mL), and ACN (45 mL) stirred at 65° C. The mixture is stirred at 65° C. for 1 hour and then cooled to room temperature. 20% aqueous HCl is added, and the resulting mixture is extracted with diethyl ether. The combined extracts are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (7:3 cyclohexane / EtOAc) to give the title compound. LC (Method 2):t R =1.01 minutes. Step 2: 6-{3-azabicyclo[3.1.0]hexan-3-yl}-3-bromo-2-fluorobenzonitrile The title compound is prepared from 3-bromo-2,6-difluorobenzonitrile and 3-azabicyclo[3.1.0]hexane hydrochloride following a procedure similar to that described in Step 1 of Intermediate 111. LC (Method 2):t R = 1.17 min; Mass spectrum (ESI +): m / z = 281 / 283 (Br) [M+H] + . Step 3: Methyl 4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorobenzoate A mixture of 6-{3-azabicyclo[3.1.0]hexan-3-yl}-3-bromo-2-fluorobenzonitrile (500 mg), PdCl(dppf) (72 mg), NEt (0.3 mL), and MeOH (6 mL) is stirred overnight at 80 °C under an atmosphere of carbon monoxide (10 bar). After cooling to room temperature, the mixture is filtered and the filtrate is concentrated. The residue is chromatographed on silica gel (6:4 cyclohexane / EtOAc) to give the title compound. LC (Method 2):t R = 1.05 min; Mass spectrum (ESI + ): m / z=261[M+H] + . Step 4: 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 Methyl 4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorobenzoate (0.42 g) dissolved in THF (5 mL) is added dropwise to LiAlH in THF (2.3 mol / L; 0.70 mL) at −50° C. The mixture is stirred with warming to −20° C. for 1.5 h and then quenched by the addition of aqueous HCl (1 mol / L). The resulting mixture is extracted with EtOAc (3×), and the combined extracts are dried (NaSO) and concentrated. The residue is chromatographed on silica gel (1:0 → 1:1 cyclohexane / EtOAc) to give the title compound. Depending on the workup procedure, 6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-fluoro-3-(hydroxymethyl)benzonitrile is obtained in addition or exclusively; the latter can be used analogously in the next reaction step. Mass spectrometry (ESI) + ): m / z=447[M+H]+ . Step 5: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylate The title compound is 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 ethyl 1H-pyrazole-4-carboxylate according to a procedure similar to that described in Step 3 of Intermediate 111. LC (method 1):t R = 1.06 min; Mass spectrum (ESI + ): m / z=355[M+H] + . Step 6: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111. LC (Method 2):t R = 0.94 min; Mass spectrum (ESI + ): m / z=349[M+Na] + .

[0474] Intermediate 119 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid [ka] Step 1: 4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylbenzaldehyde The title compound was prepared from 4-fluoro-2-methylbenzaldehyde and 6,6-difluoro-3-azabicyclo[3.1.0]hexane following a procedure similar to that described in Step 1 of Intermediate 111; KCO was used instead of Hunig's base at 130 °C. LC (Method 2): R = 1.01 min; Mass spectrum (ESI + ): m / z=238[M+H] + . Step 2: (4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylphenyl)methanol The title compound is prepared from 4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylbenzaldehyde following a procedure similar to that described in Step 2 of Intermediate 111. Step 3: Ethyl 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylate The title compound is prepared from (4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylphenyl)methanol and ethyl 1H-pyrazole-4-carboxylate following a procedure similar to that described in Step 3 of Intermediate 111. LC (Method 2):t R = 1.13 min; Mass spectrum (ESI + ): m / z=362[M+H] + . Step 4: 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111. LC (Method 2):t R= 0.98 min; Mass spectrum (ESI + ): m / z=334[M+H] + .

[0475] Intermediate 120 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-5-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid [ka] Step 1: 5-Bromo-2-chloro-4-methylbenzonitrile N-Bromosuccinimide (3.50 g) and trifluoroacetic acid (25 mL) are added to 2-chloro-4-methylbenzonitrile (2.50 g) in concentrated sulfuric acid at room temperature. The mixture is stirred at room temperature for 24 hours. The mixture is cooled to 0° C. and then slowly poured into an ice-cold solution of aqueous NaOH (4 mol / L; 125 mL). The precipitate is separated by filtration and purified by chromatography on silica gel (cyclohexane / EtOAc) to give the title compound. LC (method 1):t R =1.07 minutes. Step 2: 2-Chloro-5-formyl-4-methylbenzonitrile The title compound is prepared from 5-bromo-2-chloro-4-methylbenzonitrile following a procedure similar to that described in Step 1 of Intermediate 113. LC (Method 1): R = 0.90 min; Mass Spectrum (ESI - ): m / z=178[MH] - . Step 3: 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-formyl-4-methylbenzonitrile The title compound is prepared from 2-chloro-5-formyl-4-methylbenzonitrile and 3-azabicyclo[3.1.0]hexane hydrochloride following a procedure similar to that described in Step 1 of Intermediate 111. LC (Method 2):t R = 1.02 min; Mass spectrum (ESI+ ): m / z=227[M+H] + . Step 4: 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-(hydroxymethyl)-4-methylbenzonitrile The title compound is prepared from 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-formyl-4-methylbenzonitrile following a procedure similar to that described in Step 2 of Intermediate 111. LC (Method 2):t R = 0.96 min; Mass spectrum (ESI + ): m / z=229[M+H] + . Step 5: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-5-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylate The title compound is prepared from 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-(hydroxymethyl)-4-methylbenzonitrile and ethyl 1H-pyrazole-4-carboxylate following a procedure similar to that described in Step 3 of Intermediate 111. LC (method 1):t R = 1.08 min; Mass spectrum (ESI + ): m / z=351[M+H] + . Step 6: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-5-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-5-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111. LC (method 1):t R = 0.68 min; Mass spectrum (ESI + ): m / z=323[M+H] + .

[0476] Intermediate 121 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylic acid [ka] Step 1: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylate 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-fluorophenyl)methoxy]methyl}-2-fluorobenzonitrile and 6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-fluoro-3-(hydroxymethyl)benzonitrile, obtained after workup in step 4 of intermediate 118, and ethyl 1H-imidazole-4-carboxylate, following a procedure similar 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 Spectrum (ESI + ): m / z=355[M+H] + . Step 2: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111. LC (Method 2):t R = 0.78 min; Mass spectrum (ESI + ): m / z=327[M+H] + .

[0477] Intermediate 122 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-cyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid [ka] Step 1: 3-Bromo-2,6-dichlorobenzonitrile KBrO3 (7.28 g) is added in one portion to 2,6-dichlorobenzonitrile (2.50 g) in concentrated sulfuric acid cooled in an ice bath. The mixture is warmed to room temperature in the cooling bath and then stirred at this temperature overnight. The mixture is poured onto ice, and the solution is neutralized by adding saturated aqueous K2CO3 solution. The resulting mixture is extracted with DCM (3x), and the combined extracts are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (1:0 → 7:3 cyclohexane / EtOAc) to give the title compound. LC (Method 2):t R =1.09 minutes. Step 2: Methyl 2,4-dichloro-3-cyanobenzoate The title compound is prepared from 3-bromo-2,6-dichlorobenzonitrile following a procedure similar to that described in Step 3 of Intermediate 118; the reaction is carried out in a mixture of DMF and MeOH. LC (Method 2):t R =1.00 minutes. Step 3: Methyl 4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-cyanobenzoate The title compound is prepared from methyl 2,4-dichloro-3-cyanobenzoate and 3-azabicyclo[3.1.0]hexane hydrochloride following a procedure similar to that described in Step 1 of Intermediate 111. LC (Method 2):t R = 1.07 min; Mass spectrum (ESI + ): m / z=277[M+H] + . Step 4: 6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-(hydroxymethyl)benzonitrile The title compound is prepared from methyl 4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-cyanobenzoate following a procedure similar to that described in Step 4 of Intermediate 118. LC (Method 2):t R = 0.96 min; Mass spectrum (ESI + ): m / z=249[M+H] + . Step 5: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-cyano-6-methylphenyl)methyl]-1H-pyrazole-4-carboxylate The title compound is prepared from 6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-(hydroxymethyl)benzonitrile and ethyl 1H-pyrazole-4-carboxylate following a procedure similar to that described in Step 3 of Intermediate 111. LC (Method 2):t R =1.10 minutes. Step 6: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-cyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-cyano-6-methylphenyl)methyl]-1H-pyrazole-4-carboxylate according to a procedure similar to that described in Step 4 of Intermediate 111. LC (Method 2): R =0.96 minutes.

[0478] Intermediate 123 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid [ka] Step 1: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylate The title compound is prepared from 6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-(hydroxymethyl)benzonitrile and ethyl 1H-imidazole-4-carboxylate according to a procedure similar to that described in Step 3 of Intermediate 111; the reaction is carried out at 100° C. LC (Method 1): R = 0.98 min; Mass spectrum (ESI + ): m / z=371[M+H] + . Step 2: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111. LC (Method 2):t R = 0.80 min; Mass Spectrum (ESI + ): m / z=343[M+H] + .

[0479] Intermediate 124 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylic acid [ka] Step 1: 4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-bromobenzaldehyde Prepare the title compound from 2-bromo-4-fluorobenzaldehyde and 3-azabicyclo[3.1.0]hexane hydrochloride following a procedure similar to that described in Step 1 of Intermediate 111; using KCO instead of Hunig's base and NMP instead of DMF at 120 °C. LC (Method 2):t R = 1.08 min; Mass spectrum (ESI + ): m / z = 266 / 268 (Br) [M+H] + . Step 2: (4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-bromophenyl)methanol The title compound is prepared from 4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-bromobenzaldehyde following a procedure similar to that described in Step 2 of Intermediate 111. LC (Method 2):t R = 1.01 min; Mass spectrum (ESI + ): m / z = 268 / 270 (Br) [M+H] + . Step 3: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylate The title compound is prepared from (4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-bromophenyl)methanol and ethyl 1H-imidazole-4-carboxylate following a procedure similar to that described in Step 3 of Intermediate 111. LC (Method 2):t R = 0.96 min; Mass spectrum (ESI + ): m / z = 390 / 392 (Br) [M+H] + . Step 4: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111. LC (Method 2):t R =0.85 minutes.

[0480] Intermediate 125 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylphenyl)methyl]-1H-imidazole-4-carboxylic acid [ka] Step 1: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylphenyl)methyl]-1H-imidazole-4-carboxylate A flask containing a stir bar, ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylate (100 mg), methylboronic acid (23 mg), CsCO (0.25 g), and 1,4-dioxane (1.5 mL) is flushed with Ar for 10 minutes. PdCl(dppf) (21 mg) is added, the flask is sealed, and the mixture is stirred at 110 °C for 1.5 hours. After cooling to room temperature, the mixture is diluted with MeOH and chromatographed (HPLC; ACN / water / ammonia) to give the title compound. LC (Method 2):t R =0.91 minutes. Step 2: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylphenyl)methyl]-1H-imidazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylphenyl)methyl]-1H-imidazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111. LC (Method 2):tR =0.81 minutes.

[0481] Intermediate 126 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid [ka] Step 1: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-cyanophenyl)methyl]-1H-imidazole-4-carboxylate A stirring bar, ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylate (100 mg), Zn(CN) (60 mg), zinc (8 mg), Pd(dba) (23 mg), and t Bu3P * A flask containing HBF (15 mg) is flushed with Ar for 10 min. NMP (1 mL) is added, the flask is sealed, and the mixture is stirred at 80 °C for 2 h. After cooling to room temperature, the mixture is diluted with DMF and chromatographed (HPLC; ACN / water / ammonia) to give the title compound. LC (Method 2):t R = 0.90 min; Mass Spectrum (ESI + ): m / z=337[M+H] + .

[0482] Step 2: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-cyanophenyl)methyl]-1H-imidazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111. LC (Method 2):t R = 0.79 min; Mass spectrum (ESI +): m / z=309[M+H] + .

[0483] Intermediate 127 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)phenyl)methyl]-1H-imidazole-4-carboxylic acid [ka] Step 1: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-ethenylphenyl)methyl]-1H-imidazole-4-carboxylate A flask containing a stir bar, ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylate (500 mg), vinylboronic acid (0.25 mL), aqueous NaCO (1 mol / L; 3.2 mL), and 1,4-dioxane (9 mL) is flushed with Ar for 10 minutes. PdCl(dppf) (53 mg) is added, the flask is sealed, and the mixture is stirred at 100 °C for 2.5 hours. After cooling to room temperature, the mixture is diluted with brine, and the resulting mixture is extracted with EtOAc (3x). The combined extracts are dried (NaSO) and concentrated. The residue is chromatographed on silica gel (4:1 → 0:1 cyclohexane / EtOAc) to give the title compound. LC (Method 2): R =0.93 minutes. Step 2: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-formylphenyl)methyl]-1H-imidazole-4-carboxylate OsO4 (4% in water; 0.14 mL) is added to a mixture of ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-ethenylphenyl)methyl]-1H-imidazole-4-carboxylate (300 mg), water (4 mL), and 1,4-dioxane (4 mL) at room temperature. The mixture is stirred for 10 minutes, and then NaIO4 (0.57 g) is added. The mixture is stirred for 2.5 hours, and then ethyl acetate / methanol (9:1; 20 mL) and water (20 mL) are added. The mixture is extracted with ethyl acetate (3x), and the combined extracts are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (70:30 → 0:1 cyclohexane / ethyl acetate) to give the title compound. LC (method 1):t R = 0.99 min; Mass spectrum (ESI + ): m / z=340[M+H] + . Step 3: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)phenyl)methyl]-1H-imidazole-4-carboxylate The title compound is prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-formylphenyl)methyl]-1H-imidazole-4-carboxylate following a procedure similar to that described in Step 2 of Intermediate 111. LC (method 1):t R =0.81 minutes. Step 4: 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)phenyl)methyl]-1H-imidazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)phenyl)methyl]-1H-imidazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111. LC (Method 2):t R =0.72 minutes.

[0484] Intermediate 128 1-[(2-cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-pyrazole-4-carboxylic acid [ka] Step 1: Ethyl 1-[(2-cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-pyrazole-4-carboxylate The title compound is prepared from ethyl 1-[(2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-pyrazole-4-carboxylate following a procedure similar to that described in Step 1 of Intermediate 126. LC (method 1):t R =1.03 minutes. Step 2: 1-[(2-cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-pyrazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(2-cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-pyrazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111. LC (method 1):t R =0.63 minutes.

[0485] Intermediate 129 1-[(2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-pyrazole-4-carboxylic acid [ka] Step 1: 2-Bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}benzaldehyde Prepare the title compound from 2-bromo-4-fluorobenzaldehyde and 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride following a procedure similar to that described in Step 1 of Intermediate 111; using KCO instead of Hunig's base and NMP instead of DMF at 120 °C. LC (Method 2):t R = 1.02 min; Mass spectrum (ESI + ): m / z = 302 / 304 (Br) [M+H] + . Step 2: (2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methanol The title compound is prepared from 2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}benzaldehyde following a procedure similar to that described in Step 2 of Intermediate 111. LC (Method 2):t R = 0.96 min; Mass spectrum (ESI + ): m / z = 304 / 306 (Br) [M+H] + . Step 3: Ethyl 1-[(2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-pyrazole-4-carboxylate The title compound is prepared from (2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methanol and ethyl 1H-pyrazole-4-carboxylate following a procedure similar to that described in Step 3 of Intermediate 111. LC (Method 2):t R = 1.09 min; Mass spectrum (ESI + ): m / z = 426 / 428 (Br) [M+H] + . Step 4: 1-[(2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-pyrazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-pyrazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111. LC (method 1):t R =0.68 minutes.

[0486] Intermediate 130 1-[(2-cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylic acid [ka] Step 1: Ethyl 1-[(2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylate The title compound is prepared from (2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methanol and ethyl 1H-imidazole-4-carboxylate following a procedure similar to that described in Step 3 of Intermediate 111. LC (Method 2):t R =0.91 minutes. Step 2: Ethyl 1-[(2-cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylate The title compound is prepared from ethyl 1-[(2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylate and zinc(II) cyanide according to a procedure similar to that described in Step 1 of Intermediate 126. LC (Method 1): R = 0.95 min; Mass spectrum (ESI + ): m / z=373[M+H] + . Step 3: 1-[(2-cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(2-cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111. LC (method 1):t R = 0.64 min; Mass spectrum (ESI + ): m / z=345[M+H] + .

[0487] Intermediate 131 1-[(2-chloro-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylic acid [ka] Step 1: Ethyl 1-[(2-chloro-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylate A mixture of ethyl 1-[(2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylate (200 mg), copper(I) chloride (92 mg), and NMP is stirred at 160° C. for 2.5 hours. After cooling to room temperature, the mixture is diluted with water and extracted with EtOAc (3×). The combined extracts are dried (NaSO) and concentrated. The residue is chromatographed (HPLC; ACN / water / ammonia) to give the title compound. LC (Method 2):t R = 0.92 min; Mass spectrum (ESI + ): m / z=382[M+H] + . Step 2: 1-[(2-chloro-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(2-chloro-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111. LC (method 1):t R = 0.67 min; Mass spectrum (ESI - ): m / z=352[MH] - .

[0488] Intermediate 132 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylic acid [ka] Step 1: 4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorobenzaldehyde The title compound was prepared from 2,4-difluorobenzaldehyde and 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride following a procedure similar to that described in Step 1 of Intermediate 111; using KCO instead of Hunig's base and NMP instead of DMF. Mass spectrum (ESI) + ): m / z=242[M+H] + . Step 2: (4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methanol The title compound is prepared from 4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorobenzaldehyde following a procedure similar to that described in Step 2 of Intermediate 111. LC (Method 2):tR = 0.93 min; Mass spectrum (ESI + ): m / z=244[M+H] + . Step 3: Ethyl 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylate The title compound is prepared from (4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methanol and ethyl 1H-imidazole-4-carboxylate following a procedure similar to that described in Step 3 of Intermediate 111. Step 4: 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111. LC (Method 2):t R =0.79 minutes.

[0489] Intermediate 133 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid [ka] Step 1: Ethyl 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylate The title compound is prepared from (4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methanol and ethyl 1H-pyrazole-4-carboxylate following a procedure similar to that described in Step 3 of Intermediate 111. LC (Method 2):t R = 1.10 min; Mass spectrum (ESI + ): m / z=366[M+H] + . Step 2: 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid The title compound is prepared from ethyl 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylate following a procedure similar to that described in Step 4 of Intermediate 111.

[0490] Example Synthesis: Example 1 1-[(2-chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-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 [ka] 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) is stirred for 5 minutes. (4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-amine dihydrochloride (33 mg) is added, and the mixture is stirred for 1 hour. The mixture is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (method 1):t R = 0.91 min; Mass spectrum (ESI + ): m / z=475[M+H] + .

[0491] Examples 2-213 are prepared analogously to Example 1: [Table 185-1] [Table 185-2] [Table 185-3] [Table 185-4] [Table 185-5] [Table 185-6] [Table 185-7] [Table 185-8] [Table 185-9]

Table 185-10

Table 185-11

Table 185-12

Table 185-13

Table 185-14

Table 185-15

Table 185-16

Table 185-17

Table 185-18

Table 185-19

Table 185-20

Table 185-21

Table 185-22

Table 185-23

Table 185-24

Table 185-25

[0492]

Table 186-1

Table 186-2

Table 186-3

Table 186-4

Table 186-5

Table 186-6

Table 186-7

Table 186-8

Table 186-9

Table 186-10

Table 186-11

Table 186-12

Table 186-13

Table 186-14

Table 186-15

Table 186-16

Table 186-17

Table 186-18

Table 186-19

Table 186-20

Table 186-21

Table 186-22

Table 186-23

Table 186-24

Table 186-25

Table 186-26

Table 186-27

Table 186-28

Table 186-29

Table 186-30

Table 186-31

Table 186-32

[0493] (Example 214) 1-[(2-{3-azabicyclo[3.1.0]hexan-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

[0494] [ka] To a mixture of 1-[(2-{3-azabicyclo[3.1.0]hexan-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) is added NaBH4. The mixture is 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) is added. The mixture is diluted with MeOH and purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 1):t R = 0.78 min; Mass spectrum (ESI + ): m / z=435[M+H]+ .

[0495] (Example 215) 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-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

[0496] [ka] CHClMgBr (3 M in THF, 92 μL) is added dropwise 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) under an argon atmosphere. The mixture is stirred for 12 hours while warming to room temperature. The mixture is then partitioned between saturated aqueous NHCl and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic phases are dried (NaSO) and concentrated in vacuo, and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (method 1):t R = 0.88 min; Mass spectrum (ESI + ): m / z=485[M+H] + .

[0497] (Example 216) 1-[(6-{3-azabicyclo[3.1.0]hexan-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

[0498] [ka] LiAlH4 (1 M in THF, 200 μL) was added dropwise to a cooled mixture of methyl 2-{1-[(6-{3-azabicyclo[3.1.0]hexan-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) at −78 °C under an argon atmosphere. The mixture was stirred for 12 h while warming to room temperature. Water (14 μL), aqueous NaOH (4 M, 14 μL), and water (14 μL) were added sequentially to the mixture. After vigorously stirring for 15 min, the mixture was filtered over Celite, and the filter cake was washed with THF. The combined filtrates are concentrated in vacuo and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2): R = 0.66 min; Mass spectrum (ESI + ): m / z=462[M+H] + .

[0499] Example 217 1-[(6-{3-azabicyclo[3.1.0]hexan-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

[0500] [ka] LiAlH4 (1M in THF, 200 μL) is added dropwise to an ice-cold mixture of methyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]-4-{[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]carbamoyl}-1H-pyrazole-3-carboxylate (25 mg) in THF (2 mL) under an argon atmosphere. The mixture is stirred for 30 minutes. Water (50 μL) and aqueous NaOH (4M, 25 μL) are added sequentially to the mixture. After vigorously stirring for 15 minutes, the mixture is filtered over Celite and the filter cake is washed with THF. The combined filtrates are concentrated in vacuo, and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 1):t R = 0.89 min; Mass spectrum (ESI + ): m / z=448[M+H] + .

[0501] Example 218 1-[(2-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-4-methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide

[0502] [ka] 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) is stirred for 8 hours at 60° C. After cooling to room temperature, the mixture is diluted with DMSO and purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (method 1):t R= 0.86 min; Mass spectrum (ESI+): m / z = 454 [M+H] + .

[0503] (Example 219) 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]-1H-pyrazole-5-carboxamide

[0504] [ka] 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) is dissolved in DCM (3 mL). Trifluoroacetic acid (1 mL) is added and the mixture is stirred at room temperature for 12 hours. The mixture is then concentrated in vacuo, dissolved in MeOH (1 mL), and treated with NH3 (7 M in MeOH, 3 mL). The mixture is heated to 80 °C in a sealed microwave vial for 12 hours. After cooling to room temperature, the mixture is concentrated in vacuo, and the residue is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (method 1):t R = 0.91 min; Mass spectrum (ESI+): m / z = 448 [M+H] + .

[0505] Example 220 is prepared analogously to intermediate 219: [Table 187]

[0506] [Table 188]

[0507] Example 221 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methoxypyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide

[0508] [ka] A mixture of 1-[(2-chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-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) is heated to 165°C for 6 hours in a sealed microwave vial. After cooling to room temperature, the mixture is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 2): R = 0.86 min; Mass spectrum (ESI+): m / z = 470 [M+H] + .

[0509] Example 222 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

[0510] [ka] 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) is stirred at 60° C. for 16 hours. The mixture is purified by HPLC on reverse phase (ACN, water) to give the title compound. LC (Method 5): R = 0.56 min; Mass spectrum (ESI + ): m / z=419[M+H] + .

[0511] Examples 223-240 are prepared analogously to Example 222: [Table 189-1] [Table 189-2] [Table 189-3]

[0512] [Table 190-1] [Table 190-2] [Table 190-3] [Table 190-4]

Claims

1. Formula (I) 【Chemical 1】 or a salt thereof. (In the ceremony Y is, 【Chemistry 2】 selected from the group Y-G1 consisting of: Each of these may be one or two independent substituents R 1 is substituted with; R is 1 to 2 N atoms as ring members, and optionally C═O, O, S, S═O and SO 2 A saturated 6- to 12-membered bicyclic ring system containing one ring member selected from the group consisting of selected from the group R-G1 consisting of: provided that the ring system does not contain any heteroatom-to-heteroatom bonds between ring members; wherein said ring system is attached to the Y group in formula (I) via the N atom, wherein said ring system is optionally substituted with 1 to 6 F, and 1-3 -Alkyl, CN, HO-C 1-3 - alkylene, OH, and C 1-3 -alkyl-O; Ar is 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 heteroaryls consisting of a 5-membered ring fused to a 6-membered ring and containing 1 to 4 N atoms. is selected from the group Ar-G1 consisting of: wherein said heteroaryl is connected to the carbonyl group in formula (I) via a C atom of the 5-membered ring and to the CH group in formula (I) via a non-adjacent C atom or N atom of the 5-membered ring. 2 is attached to the base, wherein the heteroaryl is one substituent R 3 optionally substituted with; R 1 teeth, C optionally substituted with H, halogen, or 1 to 5 F 1-4 - alkyl, 1 CH 3 , C optionally substituted with a CN or OH group 3-4 -cycloalkyl, CN, O—C optionally substituted with 1 to 5 F 1-3 -Alkyl, CN, OH and O—C 1-3 -C optionally substituted with one substituent selected from the group consisting of alkyl 1-3 -Alkyl A group R consisting of 1 - selected from G1; R 3 teeth, 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-O-C 1-3 -alkylene, and O—C optionally substituted with 1 to 5 F 1-4 -Alkyl A group R consisting of 3 -G1)

2. Y, 【Chemistry 3】 selected from the group Y-G2 consisting of: Each of these may be one or two independent substituents R 1 is replaced by The bond marked with an asterisk represents the R and CH groups of formula (I). 2 indicates the attachment site of the group, The compound according to claim 1 or a salt thereof.

3. R is, 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 selected from the group R-G3 consisting of: each of which is attached to the Y group in formula (I) via an N atom; Each of these is F, CH 3 , C.N., C.H. 2 OH, OH and OCH 3 preferably consisting of F and CH 3 and optionally substituted with one substituent selected from the group consisting of: Each of these is F and CH 3 and optionally substituted with one additional substituent selected from the group consisting of: The compound according to any one of claims 1 to 2, or a salt thereof.

4. Ar is, 【Chemistry 4】 and tautomers thereof; Each of these is a single substituent R 3 may be substituted with The asterisk and the bracketed bond represent the C=O group and CH 2 indicates the attachment site of the group, The compound or salt thereof according to any one of claims 1 to 3.

5. R 1 but, H, F, Cl, Br, 1 to 5 F or 1 CN, OH or O—C 1-2 -C optionally substituted with an alkyl group 1-2 - alkyl, C optionally substituted with one CN or OH group 3-4 - alkyl, 1 CH 3 , C optionally substituted with a CN or OH group 3-4 -cycloalkyl, O—C optionally substituted with 1 to 5 F 1-2 -Alkyl A group R consisting of 1 - selected from G2, The compound or salt thereof according to any one of claims 1 to 4.

6. R 3 but, F, Cl, Br, CN, C optionally substituted with 1 to 3 F 1-3 -Alkyl, HO-C 1-4 - alkylene, C 1-2 -Alkyl-O-C 1-2 -alkylene, and O—C optionally substituted with 1 to 3 F 1-2 -Alkyl A group R consisting of 3 - selected from G2, The compound or salt thereof according to any one of claims 1 to 5.

7. The stereochemistry of the compound is 【Chemistry 5】 Follow The compound or salt thereof according to any one of claims 1 to 6.

8. A pharmaceutically acceptable salt of the compound according to any one of claims 1 to 7.

9. 9. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 8, or pharmaceutically acceptable salts thereof, optionally together with one or more inert carriers and / or diluents.

10. 9. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 8 or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents, optionally together with one or more inert carriers and / or diluents.

11. the one or more additional therapeutic agents are selected from the group consisting of 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 ocular diseases; The pharmaceutical composition of claim 10.

12. 9. A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for use as a medicine.

13. 10. A method for the treatment of an ocular disease, preferably for the treatment of diabetic macular edema, age-related macular degeneration and / or choroidal neovascularization, in a patient in need thereof, comprising administering to the patient one or more compounds according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

14. 9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of an ocular disease, preferably for the treatment of diabetic macular edema, age-related macular degeneration and / or choroidal neovascularization, comprising administering to a patient one or more compounds according to any one of claims 1 to 8 and / or tautomers thereof, or pharmaceutically acceptable salts thereof.

15. 【Chemical 6】 A compound selected from the group consisting of: or a salt thereof.

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