Heteroaromatic carboxamide derivatives as plasma kallikrein inhibitors

Abstract
Disclosed are heteroaromatic carboxamides of formula (I),
Description
FIELD OF THE INVENTION

This invention relates to novel heteroaromatic carboxamide derivatives, and pharmaceutically acceptable salts thereof, that are plasma kallikrein inhibitors. In addition, the invention relates to intermediates of the synthesis of said compounds, to pharmaceutical compositions and combinations comprising said compounds and to their use in methods for the treatment of diseases which can be influenced by the inhibition of plasma kallikrein. Particularly, the pharmaceutical compositions of the invention are suitable for the prophylaxis and/or therapy of diabetic complications, ocular diseases and edema-associated diseases, in particular diabetic macular edema, age-related macular degeneration, choroidal neovascularization, hereditary angioedema, and brain edema after stroke.


BACKGROUND OF THE INVENTION

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


PKK is thought to play a role in a number of inflammatory disorders and may have numerous implications in disorders such as hereditary angioedema (HAE), retinopathy or diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), clinically significant macular edema (CSME), cystoid macular edema (CME), CME following cataract extraction, CME induced by cryotherapy, CME induced by uveitis, endophthalmitis, CME following vascular occlusion (e.g. central retina vein occlusion, branch retinal vein occlusion, or hemiretinal vein occlusion), retinal edema, complications related to cataract surgery in diabetic retinopathy, hypertensive retinopathy, retinal trauma, dry and wet age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV), choroidal neovascularization (CNV; e.g. non-exudative choroidal neovascularization), posterior vitreous detachment (PVD), ischemic reperfusion injuries, e.g. in all kind of contexts associated with tissue and/or organ transplantation, surgically-induced brain injury, focal cerebral ischemia, global cerebral ischemia, glioma-associated edema, spinal cord injury, pain, ischemia, focal brain 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 (including ACE-inhibitor induced edema as well as tissue plasminogen activator (tPA)-induced angioedemas), high altitude cerebral edema, cytotoxic cerebral edema, osmotic cerebral edema, obstructive hydrocephalus, radiation induced edema, lymph edema, traumatic brain injury, hemorrhagic stroke (e.g., cerebral stroke or subarachnoid stroke), intracerebral hemorrhage, hemorrhagic transformation of ischemic stroke, cerebral trauma associated with injury or surgery, brain aneurysm, arterio-venous malformation, reduction of blood losses during surgical procedures (e.g. cardiothoracic surgery, such as cardiopulmonary bypass or coronary artery bypass grafting), itch, disorders with an inflammation component (such as multiple sclerosis), epilepsy, encephalitis, Alzheimer's disease, excessive daytime sleepiness, essential hypertension, increased blood pressure associated with diabetes 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, feet, ankle vascular permeability), cerebral hemorrhage, blood coagulation disorders such as thrombosis, deep vein thrombosis, coagulation from post fibrinolytic treatments, angina, angioedema, sepsis, arthritis (e.g. rheumatoid arthritis, osteoarthritis, infection arthritis), lupus, gout, psoriasis, inflammatory bowel diseases (IBDs, such as 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, Creutzfeld-Jacob 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; serositis associated with systemic lupus erythematosus (SLE), acute respiratory distress syndrome (ARDS), coronavirus disease 2019 (COVID-19) related pneumonia, fibrotic disease, hepatic fibrosis, nonalcoholic steatohepatitis (NASH), renal injury, and other diseases. PKK is also thought to play an important role in hypersensitivity reactions and thrombosis during hemodialysis.


PKK inhibitors, like the compounds of the present invention, are considered to be useful in the treatment of a wide range of disorders, e.g. as mentioned hereinbefore; in particular, they should have utility as a treatment to reduce retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema or edema-associated diseases.


PKK inhibitors should be particularly useful in the treatment of edema formation in diseases, e.g. edema formation related to ischemic reperfusion injuries, retinopathy or edema-associated diseases, such as hereditary angioedema, macular edema and brain edema. PKK inhibitors are considered to be especially useful in the treatment of retinopathy, e.g. retinopathy associated with diabetes and/or hypertension, and in the treatment of macular edema, e.g. macular edema associated with diabetes and/or hypertension.


Other complications of diabetes such as cerebral hemorrhage, nephropathy, cardiomyopathy and neuropathy, all of which have associations with PKK, may also be considered as targets for a PKK inhibitor.


PKK inhibitors suitable for therapeutic and/or prophylactic use should bind potently and with high selectivity to PKK. They should be well absorbed from the gastrointestinal tract, be sufficiently metabolically stable and possess favorable pharmacokinetic properties. They should be non-toxic and demonstrate few side-effects.


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


SUMMARY OF THE INVENTION

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




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wherein


Y is selected from the group Y-G1 consisting of




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    • each of which is substituted with 1 or 2 independent substituents R1;


      R is selected from the group R-G1 consisting of

    • saturated 6- to 12-membered bicyclic ring systems containing 1 to 2 N atoms as ring members and optionally 1 ring member selected from the group consisting of C═O, O, S, S═O and SO2,

    • provided that the ring systems do not contain any heteroatom-heteroatom bonds between ring members,

    • wherein said ring systems are attached via an N atom to the group Y in formula (I), and

    • wherein said ring systems are optionally substituted with 1 to 6 F and optionally substituted with 1 to 3 substituents selected from the group consisting of C1-3-alkyl, CN, HO—C1-3-alkylene, OH, and C1-3-alkyl-O;


      Ar is selected from the group Ar-G1 consisting of

    • 5-membered heteroaryls, 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,

    • wherein said heteroaryls are attached to the carbonyl group in formula (I) via a C atom of the 5-membered ring and to the CH2 group in formula (I) via a non-adjacent C or N atom of the 5-membered ring, and

    • wherein said heteroaryls are optionally substituted with 1 substituent R3;


      R1 is selected from the group R1-G1 consisting of

    • H, halogen, C1-4-alkyl optionally substituted with 1 to 5 F, C3-4cycloalkyl optionally substituted with 1 CH3, CN or OH group, CN, O—C1-3-alkyl optionally substituted with 1 to 5 F, C1-3-alkyl optionally substituted with 1 substituent selected from the group consisting of CN, OH, and O—C1-3-alkyl;


      R3 is selected from the group R3-G1 consisting of

    • F, Cl, Br, CN, C1-4-alkyl optionally substituted with 1 to 5 F, C3-4-cycloalkyl, HO—C1-4-alkylene, C1-3-alkyl-O—C1-3-alkylene, and O—C1-4-alkyl optionally substituted with 1 to 5 F;


      wherein in any definition mentioned hereinbefore and if not specified otherwise, any alkyl or alkylene group or sub-group may be straight-chained or branched,


      the isoforms, tautomers, stereoisomers, metabolites, prodrugs, solvates, hydrates, cocrystals and the salts thereof, particularly the pharmaceutically acceptable cocrystals and salts thereof, or the combinations thereof.





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 their tautomers or pharmaceutically acceptable salts thereof, optionally together with one or more inert carriers and/or diluents.


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 their tautomers or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents, optionally together with one or more inert carriers and/or diluents.


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


In a fifth aspect, the present invention relates to a method for the treatment, i.e. therapy and/or prevention, of diseases or conditions which can be influenced by the inhibition of plasma kallikrein in a patient in need thereof, the method comprising administering to the patient one or more compounds of formula (I), as defined hereinbefore or hereinafter, and/or their tautomers or pharmaceutically acceptable salts thereof.


In addition, the present invention relates to the use of one or more compounds of formula (I), as defined hereinbefore or hereinafter, and/or their tautomers or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment, i.e. therapy and/or prevention, of diseases or conditions which can be influenced by the inhibition of plasma kallikrein.


Furthermore, the present invention relates to a compound of formula (I), as defined hereinbefore or hereinafter, and/or its tautomers or a pharmaceutically acceptable salt thereof for use in a method for the treatment, i.e. therapy and/or prevention, of diseases or conditions which can be influenced by the inhibition of plasma kallikrein, in a patient in need thereof.


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




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or a salt thereof,


which are valuable intermediates in the synthesis of compounds of formula (I).


Further aspects of the present invention will become apparent to the person skilled in the art directly from the foregoing and following description and the examples.


General Terms and Definitions

Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.


The terms “compound(s) according to this invention”, “compound(s) of formula (I)”, “compound(s) of the invention” and the like denote the compounds of formula (I) according to the present invention including their tautomers, stereoisomers and mixtures thereof and the salts thereof, in particular the pharmaceutically acceptable salts thereof, and the solvates, hydrates and cocrystals of such compounds, in particular the pharmaceutically acceptable cocrystals thereof, including the solvates, hydrates and cocrystals of such tautomers, stereoisomers and salts thereof.


Also, unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc. . . . ) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof, and solvates thereof, such as for instance hydrates, including solvates of the free compounds or solvates of a salt of the compound, and cocrystals thereof, including pharmaceutically acceptable cocrystals thereof and cocrystals of the free compounds or of a salt thereof.


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


As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral 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 which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, EtOAc, EtOH, isopropanol, or MeCN, or a mixture thereof.


Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts) also comprise a part of the invention.


As used herein, “pharmaceutically acceptable cocrystals” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making a cocrystal thereof with the help of one or more coformers. Also, cocrystals 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 cocrystals of the present invention can be synthesized from the parent compound by methods known to the one skilled in the art, including solid-based methods, such as solid state grinding, melt extrusion and melt crystallization, and liquid-based methods, such as solution crystallization, solvent evaporation, cooling crystallization, supercritical fluid assisted crystallization, ultrasound assisted crystallization, spray drying, liquid assisted grinding and planetary milling.


In case a compound of the present invention is depicted in form of a chemical name and as a formula, in case of any discrepancy the formula shall prevail.


In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C1-6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms.


An asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined. In the case of more than one attachment point, i.e. more than one asterisk, in a sub-formula, the asterisks may be further specified by a bracketed designation of the connected part of the core molecule.


The numeration of the atoms of a substituent starts with the atom which is 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:




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wherein the carboxy group is attached to the third carbon atom of the propyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or “cyclopropylmethyl-” group represent the following groups:




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The term “substituted” as used herein, means that any one or more hydrogens on the designated atom, radical or moiety is replaced with a selection from the indicated group, provided that the atom's normal valence is not exceeded, and that the substitution results in an acceptably stable compound.


In a definition of a group, the term “wherein each X, Y and Z group is optionally substituted with” and the like denotes that each group X, each group Y and each group Z either each as a separate group or each as part of a composed group may be substituted as defined. For example a definition “Rex denotes H, C1-3-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-3-alkyl or C1-3-alkyl-O—, wherein each alkyl group is optionally substituted with one or more Lex.” or the like means that in each of the beforementioned groups which comprise the term alkyl, i.e. in each of the groups C1-3-alkyl, C3-6-cycloalkyl-C1-3-alkyl and C1-3-alkyl-O—, the alkyl moiety may be substituted with Lex as defined.


The term “C1-n-alkyl”, wherein n is an integer from 1 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term C1-5-alkyl embraces the radicals H3C—, H3C—CH2—, H3C—CH2—CH2—, H3C—CH(CH3)—, H3C—CH2—CH2—CH2—, H3C—CH2—CH(CH3)—, H3C—CH(CH3)—CH2—, H3C—C(CH3)2—, H3C—CH2—CH2—CH2—CH2—, H3C—CH2—CH2—CH(CH3)—, H3C—CH2—CH(CH3)—CH2—, H3C—CH(CH3)—CH2—CH2—, H3C—CH2—C(CH3)2—, H3C—C(CH3)2—CH2—, H3C—CH(CH3)—CH(CH3)— and H3C—CH2—CH(CH2CH3)—.


The term “C1-n-alkylene” wherein n is an integer selected from 2, 3, 4, 5 or 6, preferably 4 or 6, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms. For example the term C1-4-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(CH(CH3))2— and —C(CH3)(CH2CH3)—.


The term “C3-n-cycloalkyl”, wherein n is an integer 3 to n, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms. The cyclic group may be mono-, bi-, tri- or spirocyclic, most preferably monocyclic. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclo-pentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1.]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.


The term “heteroaryl” means a mono- or polycyclic aromatic ring system containing one or more heteroatoms selected from N, O or S(O)r, wherein r=0, 1 or 2, consisting of 5 to 14 ring atoms wherein at least one of the heteroatoms is part of an aromatic ring. The term “heteroaryl” is intended to include all the possible isomeric forms.


Thus, the term “heteroaryl” includes the following exemplary structures; they are not depicted as radicals as each form is optionally attached through a covalent bond to any atom so long as appropriate valences are maintained:




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The term “bicyclic ring systems” means groups consisting of 2 joined cyclic substructures including spirocyclic, fused, and bridged ring systems.


The term halogen generally denotes fluorine, chlorine, bromine and iodine.


Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.


The terms “treatment” and “treating” as used herein embrace both therapeutic, i.e. curative and/or palliative, and preventive, i.e. prophylactic, treatment.


Therapeutic treatment refers to the treatment of patients having already developed one or more of said conditions in manifest, acute or chronic form. Therapeutic treatment may be symptomatic treatment in order to relieve the symptoms of the specific indication or causal treatment in order to reverse or partially reverse the conditions of the indication or to stop or slow down progression of the disease.


Preventive treatment (“prevention”) refers to the treatment of patients at risk of developing one or more of said conditions, prior to the clinical onset of the disease in order to reduce said risk.


The terms “treatment” and “treating” include the administration of one or more active compounds in order to prevent or delay the onset of the symptoms or complications and to prevent or delay the development of the disease, condition or disorder and/or in order to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the disease, condition or disorder.


When this invention refers to patients requiring treatment, it relates primarily to treatment in mammals, in particular humans.


The term “therapeutically effective amount” means an amount of a compound of the present invention that (i) treats or prevents the particular disease or condition, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease or condition, or (iii) prevents or delays the onset of one or more symptoms of the particular disease or condition described herein.







DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses novel heteroaromatic carboxamide derivatives, which are effective plasma kallikrein (PKK) inhibitors and possess suitable pharmacological and pharmacokinetic properties to use them as medicaments for the treatment of diseases and/or conditions that may be influenced by PKK inhibition, including but not limited to diabetic complications, ocular diseases and edema-associated diseases, in particular diabetic macular edema, age-related macular degeneration, choroidal neovascularization, hereditary angioedema, and brain edema after stroke.


The compounds of the present invention may provide 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 possibility to form stable salts.


Compounds of the Invention


In a first aspect of the present invention, it is found that compounds of formula (I)




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wherein Y, R, and Ar are defined as hereinbefore and hereinafter, are potent inhibitors of PKK and exhibit favorable properties with regard to selectivity, safety and tolerability, metabolic and/or chemical stability, pharmacokinetic and physicochemical characteristics, solubility, permeability, plasma protein binding, bioavailability and/or the possibility to form stable salts. In particular, they provide an advantageous combination of high potency on human PKK and significant selectivity, e.g. vs. various serine proteases, such as human tissue kallikrein 1 (TK1), as well as adequate solubilities at physiologically relevant pH values and high metabolic stabilities. In addition, advantageous safety features, such as low potential of mutagenicity, low inhibition of cytochrome P450 (CYP) enzymes like CYP3A4 and CYP2C8, and low propensity for mechanism based inhibition of CYP3A4, are exhibited.


Therefore, the 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 influenced by PKK inhibition.


Thus, according to one aspect of the present invention, a compound of formula (I)




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wherein Y, R, and Ar are defined as hereinbefore or hereinafter, is provided


as well as the isoforms, tautomers, stereoisomers, metabolites, prodrugs, solvates, hydrates, cocrystals, and the salts thereof, particularly the pharmaceutically acceptable cocrystals and salts thereof.


Unless otherwise stated, the groups, residues and substituents, particularly Y, R, Ar, R1, and R3 are defined as hereinbefore and hereinafter. Some preferred meanings of the substituents Y, R, Ar, R1, and R3 as well as of the stereochemistry of the compounds of formula (I) will be given hereinafter as embodiments of the invention. Any and each of these definitions and embodiments may be combined with one another.


Y:


According to one embodiment, Y is selected from the group Y-G1 consisting of




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each of which is substituted with 1 or 2 independent substituents R1.


According to another embodiment, Y is selected from the group Y-G2 consisting of




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each of which is substituted with 1 or 2 independent substituents R1 and


wherein the bonds with asterisk indicate the sites of attachment of R and the CH2 group of formula (I).


According to another embodiment, Y is selected from the group Y-G3 consisting of




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each of which is substituted with 1 or 2 substituents R1 and


wherein the bonds with asterisk and parentheses indicate the sites of attachment of R and the CH2 group of formula (I).


According to another embodiment, Y is selected from the group Y-G4 consisting of




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each of which is substituted with 1 substituent R1 and


wherein the bonds with asterisk and parentheses indicate the sites of attachment of R and the CH2 group of formula (I).


According to another embodiment, Y is selected from the group Y-G5 consisting of




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each of which is optionally substituted with 1 additional substituent R1 and


wherein the bonds with asterisk and parentheses indicate the sites of attachment of R and the CH2 group of formula (I).


According to another embodiment, Y is selected from the group Y-G6 consisting of




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which is optionally substituted with one additional substituent R1 and


wherein the bonds with asterisk and parentheses indicate the sites of attachment of R and the CH2 group of formula (I).


According to another embodiment, Y is selected from the group Y-G7 consisting of




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wherein the bonds with asterisk and parentheses indicate the sites of attachment of R and the CH2 group of formula (I).


R:


According to one embodiment, R is selected from the group R-G1 consisting of


saturated 6- to 12-membered bicyclic ring systems containing 1 to 2 N atoms as ring members and optionally 1 ring member selected from the group consisting of C═O, O, S, S═O and SO2,


provided that the ring systems do not contain any heteroatom-heteroatom bonds between ring members,


wherein said ring systems are attached via an N atom to the group Y in formula (I), and


wherein said ring systems are optionally substituted with 1 to 6 F and optionally substituted with 1 to 3 substituents selected from the group consisting of C1-3-alkyl, CN, HO—C1-3-alkylene, OH, and C1-3-alkyl-O.


According to another embodiment, R is selected from the group R-G2 consisting of


saturated 6- to 10-membered bicyclic ring systems containing 1 N atom and optionally 1 O atom as ring members,


wherein the ring systems are attached via the N atom to the group Y in formula (I), and


wherein the ring systems are optionally substituted with 1 substituent selected from the group consisting of F, C1-3-alkyl (preferably CH3), CN, HO—C1-3-alkylene (preferably HOCH2), OH, and C1-3-alkyl-O— (preferably CH3O), and


wherein the ring system is optionally additionally substituted with one substituent selected from the group consisting of F and CH3.


According to another embodiment, R is selected from the group R-G3 consisting of


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


each of which is attached via the N atom to the group Y in formula (I) and


each of which is optionally substituted with one substituent selected from the group consisting of F, CH3, CN, CH2OH, OH, and OCH3, preferably consisting of F and CH3, and


each of which is optionally substituted with one additional substituent selected from the group consisting of F and CH3.


According to another embodiment, R is selected from the group R-G4 consisting of




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According to another embodiment, R is selected from the group R-G5 consisting of




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According to another embodiment, R is selected from the group R-G6 consisting of




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According to another embodiment, R is selected from the group R-G7 consisting of




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According to another embodiment, R is selected from the group R-G8 consisting of




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Ar:


According to one embodiment, Ar is selected from the group Ar-G1 consisting of


5-membered heteroaryls, 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,


wherein said heteroaryls are attached to the carbonyl group in formula (I) via a C atom of the 5-membered ring and to the CH2 group in formula (I) via a non-adjacent C or N atom of the 5-membered ring, and


wherein said heteroaryls are optionally substituted with 1 substituent R3.


According to another embodiment, Ar is selected from the group Ar-G2 consisting of


5-membered heteroaryls, containing 1 to 3 N atoms or containing 1 O or S atom or containing 1 N atom and 1 O or S atom, and 9-membered heteroaryls, consisting of a 5-membered ring fused to a 6-membered ring and containing 1 to 3 N atoms,


wherein said heteroaryls are attached to the carbonyl group in formula (I) via a C atom of the 5-membered ring and to the CH2 group in formula (I) via a non-adjacent C or N atom of the 5-membered ring, and


wherein said heteroaryls are optionally substituted with 1 substituent R3.


According to another embodiment, Ar is selected from the group Ar-G3 consisting of




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and the tautomers thereof,


each of which is optionally substituted with 1 substituent R3 and


wherein the bonds with asterisk and parentheses indicate the sites of attachment of the groups C═O and CH2 of formula (I).


According to another embodiment, Ar is selected from the group Ar-G4 consisting of




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each of which is optionally substituted with 1 substituent R3 and


wherein the bonds with asterisk and parentheses indicate the sites of attachment of the groups C═O and CH2 of formula (I).


According to another embodiment, Ar is selected from the group Ar-G5 consisting of




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which is optionally substituted with 1 substituent R3 and


wherein the bonds with asterisk and parentheses indicate the sites of attachment of the groups C═O and CH2 of formula (I).


According to another embodiment, Ar is selected from the group Ar-G6 consisting of




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which is optionally substituted with 1 substituent R3 and


wherein the bonds with asterisk and parentheses indicate the sites of attachment of the groups C═O and CH2 of formula (I).


According to another embodiment, Ar is selected from the group Ar-G7 consisting of




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and the tautomers thereof,


each of which is optionally substituted with 1 substituent R3 and


wherein the bonds with asterisk and parentheses indicate the sites of attachment of the groups C═O and CH2 of formula (I).


According to another embodiment, Ar is selected from the group Ar-G8 consisting of




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which is optionally substituted with 1 substituent R3 and


wherein the bonds with asterisk and parentheses indicate the sites of attachment of the groups C═O and CH2 of formula (I).


According to another embodiment, Ar is selected from the group Ar-G9 consisting of




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each of which is optionally substituted with 1 substituent R3 and


wherein the bonds with asterisk and parentheses indicate the sites of attachment of the groups C═O and CH2 of formula (I).


According to another embodiment, Ar is selected from the group Ar-G10 consisting of




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each of which is optionally substituted with 1 substituent R3 and


wherein the bonds with asterisk and parentheses indicate the sites of attachment of the groups C═O and CH2 of formula (I).


According to another embodiment, Ar is selected from the group Ar-G11 consisting of




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which is optionally substituted with 1 substituent R3 and


wherein the bonds with asterisk and parentheses indicate the sites of attachment of the groups C═O and CH2 of formula (I).


R1:


According to one embodiment, R1 is selected from the group R1-G1 consisting of


H, halogen, C1-4-alkyl optionally substituted with 1 to 5 F, C3-4-cycloalkyl optionally substituted with 1 CH3, CN or OH group, CN, O—C1-3-alkyl optionally substituted with 1 to 5 F, C1-3-alkyl optionally substituted with 1 substituent selected from the group consisting of CN, OH, and O—C1-3-alkyl.


According to another embodiment, R1 is selected from the group R1-G2 consisting of H, F, Cl, Br, C1-2-alkyl optionally substituted with 1 to 5 F or with 1 CN, OH or O—C1-2-alkyl group, C3-4-alkyl optionally substituted with 1 CN or OH group, C3-4-cycloalkyl optionally substituted with 1 CH3, CN or OH group, O—C1-2-alkyl optionally substituted with 1 to 5 F.


According to another embodiment, R1 is selected from the group R1-G3 consisting of


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.


According to another embodiment, R1 is selected from the group R1-G4 consisting of


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


According to another embodiment, R1 is selected from the group R1-G5 consisting of H.


According to another embodiment, R1 is selected from the group R1-G6 consisting of F, Cl, and Br.


According to another embodiment, R1 is selected from the group R1-G7 consisting of CH3.


According to another embodiment, R1 is selected from the group R1-G8 consisting of CH2CH3.


According to another embodiment, R1 is selected from the group R1-G9 consisting of


CH2CH2CH3, CH2CH(CH3)2, cyclopropyl, and cyclobutyl.


According to another embodiment, R1 is selected from the group R1-G10 consisting of CHF2, and CF3.


According to another embodiment, R1 is selected from the group R1-G11 consisting of CN.


According to another embodiment, R1 is selected from the group R1-G12 consisting of


1-cyanocycloprop-1-yl, CH2CN, and C(CH3)2CN.


According to another embodiment, R1 is selected from the group R1-G13 consisting of CH2OH.


According to another embodiment, R1 is selected from the group R1-G14 consisting of


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


According to another embodiment, R1 is selected from the group R1-G15 consisting of


CH2OCH3, CH2OCH2CH3, O—CH3, O—CH2CH3, and O—CF3.


R3:


According to one embodiment, R3 is selected from the group R3-G1 consisting of


F, Cl, Br, CN, C1-4-alkyl optionally substituted with 1 to 5 F, C3-4-cycloalkyl, HO—C1-3-alkylene, C1-3-alkyl-O—C1-3-alkylene, and O—C1-4-alkyl optionally substituted with 1 to 5 F.


According to another embodiment, R3 is selected from the group R3-G2 consisting of


F, Cl, Br, CN, C1-3-alkyl optionally substituted with 1 to 3 F, HO—C1-4-alkylene, C1-2-alkyl-O—C1-2-alkylene, and O—C1-2-alkyl optionally substituted with 1 to 3 F.


According to another embodiment, R3 is selected from the group R3-G3 consisting of


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


According to another embodiment, R3 is selected from the group R3-G4 consisting of Cl and CN.


According to another embodiment, R3 is selected from the group R3-G5 consisting of CH3, CF3, CH2CH3, and CH(CH3)2.


According to another embodiment, R3 is selected from the group R3-G6 consisting of


CH2OH, CH2CH2OH, and C(CH3)2OH.


According to another embodiment, R3 is selected from the group R3-G7 consisting of CH2OCH3.


Stereochemistry:


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




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




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Further preferred subgeneric embodiments of the compounds of formula (I) are set forth as embodiments (I-a) to (I-r) in the following Table 1, wherein the above-mentioned substituent definitions are used. For example, the entry -G1 in column R1 and row (I-a) means that in embodiment (I-a) substituent R1 is selected from the definition designated R1-G1. The same applies analogously to the other variables incorporated in the general formulas.












TABLE 1










Substituents














Embodiment
Y
R
Ar
R1
R3







(I-a)
Y-G1
R-G1
Ar-G1
R1-G1
R3-G1



(I-b)
Y-G2
R-G2
Ar-G1
R1-G1
R3-G2



(I-c)
Y-G2
R-G2
Ar-G2
R1-G2
R3-G2



(I-d)
Y-G2
R-G3
Ar-G2
R1-G3
R3-G2



(I-e)
Y-G2
R-G4
Ar-G3
R1-G3
R3-G3



(I-f)
Y-G6
R-G5
Ar-G5
R1-G4
R3-G5



(I-g)
Y-G6
R-G5
Ar-G6
R1-G4
R3-G5



(I-h)
Y-G6
R-G5
Ar-G8
R1-G4
R3-G5



(I-i)
Y-G6
R-G6
Ar-G5
R1-G4
R3-G5



(I-j)
Y-G6
R-G6
Ar-G6
R1-G4
R3-G5



(I-k)
Y-G6
R-G6
Ar-G8
R1-G4
R3-G5



(I-m)
Y-G7
R-G5
Ar-G5
R1-G4
R3-G5



(I-n)
Y-G7
R-G5
Ar-G6
R1-G4
R3-G5



(I-o)
Y-G7
R-G5
Ar-G8
R1-G4
R3-G5



(I-p)
Y-G7
R-G6
Ar-G5
R1-G4
R3-G5



(I-q)
Y-G7
R-G6
Ar-G6
R1-G4
R3-G5



(I-r)
Y-G7
R-G6
Ar-G8
R1-G4
R3-G5










Particularly preferred are those subgeneric embodiments (I.1-a) to (I.1-r) which, in respect of the definitions of Y, R, Ar, R1, and R3 correspond to the subgeneric embodiments (I-a) to (I-r) of Table 1, but wherein the stereochemistry of the compounds is according to formula (I.1).


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


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


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


Particularly preferred compounds, including their tautomers, the salts thereof, or any solvates, hydrates or cocrystals thereof, are those described in the section Examples and Experimental Data.


Preparation


The compounds according to the invention and their intermediates may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis for example using methods described in “Comprehensive Organic Transformations”, 2nd Edition, Richard C. Larock, John Wiley & Sons, 2010, and “March's Advanced Organic Chemistry”, 7th Edition, Michael B. Smith, John Wiley & Sons, 2013. Preferably the compounds are obtained analogously to the methods of preparation explained more fully hereinafter, in particular as described in the experimental section. In some cases the sequence adopted in carrying out the reaction schemes may be varied. Variants of these reactions that are known to the skilled person but are not described in detail here may also be used. The general processes for preparing the compounds according to the invention will become apparent to the skilled person on studying the schemes that follow. Starting compounds are commercially available or may be prepared by methods that are described in the literature or herein, or may be prepared in an analogous or similar manner. Before the reaction is carried out, any corresponding functional groups in the starting compounds may be protected using conventional protecting groups. These protecting groups may be cleaved again at a suitable stage within the reaction sequence using methods familiar to the skilled person and described in the literature for example in “Protecting Groups”, 3rd Edition, Philip J. Kocienski, Thieme, 2005, and “Protective Groups in Organic Synthesis”, 4th Edition, Peter G. M. Wuts, Theodora W. Greene, John Wiley & Sons, 2006.




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Scheme 1: Compounds of formula (I′) can be prepared by reacting a suitable acid of formula (II) (either as free acid or carboxylate with a suitable metal cation such as Li+, Na+, K+, etc.) and a suitable amine of formula (III) (either as free amine or a salt such as hydrochloride, hydrobromide, etc.) in a suitable solvent (e.g., DCM, THF, 1,4-dioxane, DMF, N,N-dimethylacetamide, and 1-methyl-2-pyrrolidinone) in the presence of a suitable coupling agent (e.g., O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), (benzotriazol-1-yloxy)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 as defined hereinbefore. Alternatively, the carboxylic acid is transformed into a carboxylic chloride (using, e.g., oxalyl chloride or thionyl chloride in DCM) and coupled as such with amine (III) in the presence of a suited base (e.g., triethylamine, N,N-diisopropyl-ethylamine, pyridine, etc.).




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Scheme 2: Acids of formula (II), wherein Y, R, and Ar have the meanings as defined hereinbefore, are preferably prepared from the corresponding ester (IV) through hydrolysis or hydrogenolysis depending on the nature of R5. Lower alkyl group esters such as ethyl or methyl esters are preferably cleaved by hydrolysis with a hydroxide salt 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 mixtures of these) at ambient or elevated temperature. The acid may be isolated either as a salt with the metal cation or as free acid. A tert-butyl ester is 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 mixtures of these). A benzyl ester is preferably cleaved by hydrogenolysis with 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 to 5 bar).




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Scheme 3: Some of the compounds (II′) can be prepared by reaction of an alcohol (V) with an ester (VI) employing the conditions of the Mitsunobu reaction (e.g., triphenylphosphine or tri-n-butylphosphine combined with, e.g., 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 R3 in Scheme 3 have the meanings as defined hereinbefore. Alcohol (V) may bear the desired residue R on the heteroaromatic ring Y or a leaving group instead to introduce R later on. Alternatively, some of the compounds (II′) can be obtained by reacting alcohol (V) and ester (VI) in the presence of a Lewis acid or Brønsted acid (e.g., 4-toluenesulfonic acid) in a suited solvent (e.g., MeCN) at elevated temperature (20 to 120° C.).




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Scheme 4: Some of the compounds (II′) can also be prepared by reaction of compound (VII), bearing a leaving group at the heteroarylmethyl position such as Cl, Br, or mesyloxy (methanesulfonyloxy), with ester (VI) in the presence of a suitable base (e.g., sodium hydride, cesium carbonate, potassium carbonate, or triethylamine) in a suitable solvent (e.g., THF, DMF); Y, R, and R3 in Scheme 4 have the meanings as defined hereinbefore. Compound (VII) may bear the desired residue R on the heteroaromatic ring Y or a leaving group instead to introduce R later on.




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Scheme 5: Some esters of formula (II″), wherein Y and R have the meanings defined hereinbefore, can be prepared by treatment of a 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 a suitable propiolic acid 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, azide (VIII) can be obtained from an alcohol of formula (V) (or (VII) wherein Hal is OH) by treatment with diphenylphosphoryl azide in the presence of a suitable base such as DBU in a suitable solvent (e.g., THF or DMF). Compound (VII) may bear the desired residue R on the heteroaromatic ring Y or a leaving group instead to introduce R later on.




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Scheme 6: Esters of formula (II′″), wherein Y, R, and R3 have the meanings defined hereinbefore, can be prepared from alcohols (XII) by displacement of the hydroxyl group with hydrogen employing well known methods reported in the literature (e.g., triethylsilane and TFA or borontrifluoride etherate in DCM, or hydrogen in the presence of palladium on carbon in a solvent such as THF or EtOH). Alcohols (XII) may be prepared by adding magnesium halide (XI), or another organometal derivative, to aldehyde (IX), that, in turn, can be obtained from its corresponding alcohol by oxidation (e.g., Dess-Martin oxidation or Swern oxidation) in an inert solvent (e.g., THF, DCM, or diethyl ether) at low to ambient temperature. Magnesium halide (XI) may be obtained after a halogen metal exchange reaction from the corresponding bromide or iodide of (X) using isopropyl magnesium chloride optionally combined with lithium chloride in THF at low temperature. Alternatively, magnesium metal is inserted into the carbon halogen bond to provide magnesium halide (XI). Compounds (IX) and (XII) may bear the desired residue R on the heteroaromatic ring Y or a leaving group instead to introduce R later on.


Starting from the compounds (X′) and (X″) the corresponding analogs of compound (II′″) are accessible employing the principle proceeding delineated above (see Scheme 7 for (X′)).




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Scheme 7: Compounds of formula (II″″), wherein Y, R, and R3 have the meanings defined hereinbefore, can be prepared in an analogous fashion to the compounds delineated in Scheme 6 using the isomeric magnesium halide (XI′).




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Scheme 8: Intermediates of formula (XV) can be prepared from aromatic compound (XIII) and amine (XIV) via either a nucleophilic substitution reaction on the heteroaromatic ring or a transition metal catalyzed coupling reaction; Ar, R and R1 in Scheme 8 have the meanings defined hereinbefore. The nucleophilic substitution of a leaving group on the heteroaromatic ring in (XIII) with the N in compound (XIV) can be conducted 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. A transition metal catalyzed coupling reaction is preferably carried out in analogy to procedures reported in the literature of organic chemistry referred to as Ullmann or Buchwald/Hartwig coupling reaction using suitable copper or palladium salts or complexes thereof, optionally combined with additional ligands, in the presence of a base and in a suited solvent.




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Scheme 9: Enantiopure amine (III.1) can be prepared from ketone (XVI) as delineated in Scheme 9. The overall synthesis comprises 3 steps and starts with the condensation of the ketone with the enantiopure tert-butanesulfinamide in the presence of a dehydrating agent such as titanium alcoholate (e.g., Ti(OEt)4 or Ti(OiPr)4) in a suited solvent (e.g., THF, DCM, toluene, or neat) at ambient or elevated temperature to generate the corresponding enantiopure tert-butylsulfinylated imine (XVII). Imine (XVII) can be diastereoselectively reduced to the corresponding tert-butylsulfinylated amine (XVIII) using a hydride (e.g., lithium or sodium borohydride, L-selectride, diisobutylaluminum hydride, etc.) in a suited solvent (e.g., THF, toluene, MeOH, etc., depending on the hydride source used). The tert-butylsulfinyl group can be cleaved off using an acid (e.g., TFA or hydrochloric acid) in a suitable solvent (e.g., toluene, DCM, dioxane, alcohol, water, etc.) at ambient or elevated temperature.


The racemate (III) and the opposite enantiomer (III.2) are obtained by employing the racemic tert-butanesulfinamine and enantiopure (S)-tert-butanesulfinamine, respectively, in the route described above.


Alternatively, compound (III.1) and its enantiomer (III.2) can be obtained from ketone (XVI) via a 3-step synthesis sequence starting with an enantioselective reduction of the ketone moiety in compound (XVI) using conditions reported in the literature of organic chemistry (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 quoted therein) to give the corresponding enantiopure or enantioenriched alcohol. The thus formed hydroxyl group can then be replaced with a protected or masked ammonia group such as phthalimide or (tert-Bu-OCO)2N employing a stereospecific Mitsunobu or Mitsunobu-type reaction (using, e.g., triphenylphosphine or tri-n-butylphosphine combined with 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 heteroatom bearing C. Alternatively, a phosphoryl azide (e.g., diphenylphosphoryl azide) can be employed to replace the OH group with azide under inversion of the configuration. The amino group can be liberated from the phthalimide group by treatment with, e.g., 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 of these) with heating if necessary to give compound (III.1). tert-Bu-O—CO is preferably removed under acidic conditions (using, e.g., TFA or hydrochloric acid) to give the same amine (III.1). The azide can be reduced to the amine (III.1) with, e.g., hydrogen in the presence of a transition metal (e.g., Pd on carbon, Raney-Ni, PtO2, etc.) or a phosphine (e.g., triphenylphosphine). The racemate (III) is obtained upon reduction of compound (XVI) with an achiral reducing agent such as sodium borohydride and following the further route described above.




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Scheme 10: Compounds (XVI) can be obtained from ester (XIX) (or the corresponding lower or higher alkyl esters, e.g., methyl, n-propyl, isopropyl, or tert-butyl ester) in a sequence consisting of 3 or 4 reaction steps. Compound (XIX) can be brominated employing a suited electrophilic bromine source (e.g., N-bromosuccinimide (NBS) or Br2) in a suited solvent (e.g., AcOH, DCM, dichloroethane, dioxane, MeCN, DMF, etc.) at ambient or elevated temperature. For example, NBS in acetic acid at ambient temperature or NBS in HCCl3 at 65° C. provide the compound. Alternatively, treatment of compound (XIX) with NBS, sodium persulfate and palladium acetate in trifluoromethanesulfonic acid and 1,2-dichloroethane at 80° C. gives access to (XX) as well. Compound (XX) can then be transformed into ester (XXI) by applying a 1- or 2-step synthesis route encompassing a Fleck coupling reaction (broadly covered in the literature of organic chemistry, e.g., in Catalysts 2017, 7, 267 and references quoted therein) with either acrolein dialkyl acetal (e.g., acrolein diethyl acetal, →(XXI)) or an acrylic acid ester (e.g., acrylic ethyl ester, →(XXIII)); using the latter coupling partner requires an additional step to reduce the olefinic bond formed routinely achieved with hydrogen in the presence of a transition metal catalyst (e.g., Pd such as palladium on carbon, Ni such as Raney-Ni, Pt such as platinum oxide, Rh such as rhodium on carbon, etc.) in a suited solvent (e.g., DCM, dioxane, THF, EtOAc, alcohol such as MeOH, water, etc.). Ketoester (XXII) may be produced upon treatment of compound (XXI) with a base (e.g., a hydride such as sodium hydride, an alcoholate such as lithium methoxide or potassium tert-butylate, an organic amine such as DBU, a phosphazene such as P2Et phosphazene, an amide such as lithium diisopropylamide, lithium, sodium or potassium hexamethyldisilazide, etc.) in a suited solvent (e.g., benzene, toluene, dioxane, THF, alcohol, etc., depending on the base used) at low to elevated temperature (−78° C. to 100° C., depending on the base and solvent employed); 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 of these), 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 to 140° C. to give ketone (XVI).


The compounds of formula (I) may be resolved into their enantiomers and/or diastereomers as mentioned below. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers and racemic compounds may be separated into their enantiomers.


The cis/trans mixtures may be resolved, for example, by chromatography into the cis and trans isomers thereof. The compounds of formula (I) which occur as racemates may be separated by methods known per se into their optical antipodes and diastereomeric mixtures of compounds of general formula (I) may be resolved into their diastereomers by taking advantage of their different physico-chemical properties using methods known per se, e.g. chromatography and/or fractional crystallization; if the compounds obtained thereafter are racemates, they may be resolved into the enantiomers as mentioned below.


The racemates are preferably resolved by column chromatography on chiral phases or by crystallization from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as esters or amides with the racemic compound. Salts may 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, e.g. acids, their activated derivatives, or alcohols. Separation of the diastereomeric mixture of salts or derivatives thus obtained may be achieved by taking advantage of their different physico-chemical properties, e.g. differences in solubility; the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids commonly used for such a purpose as well as optically active alcohols applicable as auxiliary residues are known to those skilled in the art.


As mentioned above, the compounds of formula (I) may be converted into salts, particularly for pharmaceutical use into the pharmaceutically acceptable salts. As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.


The compounds according to the invention are advantageously also obtainable using the methods described in the examples that follow, which may also be combined for this purpose with methods known to the skilled person from the literature.


Thus, according to another aspect of the present invention, processes for the synthesis of compounds of formula (I) are provided.


According to another aspect of the present invention, intermediates of the synthesis of compounds of formula (I) are provided.


According to one embodiment, the invention relates to intermediates as depicted and described in Schemes 9 and/or 10.


According to another embodiment, the invention relates to one or more of the following intermediates




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Pharmacological Activity


The activity of the compounds of the invention may be demonstrated using the following assays:


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 Vila (FVIIa), or FVIIa complexed with Tissue Factor, phospholipids and CaCl2 (FVIIa/TF/PL/CaCl2) is determined using the following biochemical assays in assay buffer (100 mM Tris, 150 mM NaCL, adjusted to a pH of 7.8 with HCl, and containing 0.1% (w/v) BSA and 0.05% (v/v) Tween20) in the presence of 1% (v/v) DMSO:


Evaluation of the Inhibition of PKK Using an Endpoint Assay


Human PKK (0.01 U/mL; Enzyme Research Laboratories) or rat PKK (0.625 nM; produced in-house) is incubated for 1 h at room temperature with 0.10 μM fluorogenic substrate H-Pro-Phe-Arg-AMC (11295 from Bachem) and various concentrations of the test compound in assay buffer. 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 the wavelength excitation setting of 355 nm and the wavelength emission setting of 460 nm.


IC50 values for compounds according to the invention are shown in the following table. The number of the compound corresponds to the number of the Example in the experimental section.
















Example
IC50 (nM)



















1
1.3



2
3.1



3
1.7



4
0.9



5
1.1



6
0.9



7
1.4



8
2.3



9
3.8



10
2.5



11
2.1



12
3.4



13
1.1



14
1.0



15
1.1



16
0.6



17
2.0



18
2.1



19
14.2



20
0.7



21
0.9



22
0.5



23
1.1



24
1.0



25
2.0



26
4.9



27
0.9



28
0.6



29
2.6



30
0.9



31
5.3



32
1.1



33
2.5



34
0.9



35
2.2



36
0.5



37
0.9



38
3.4



39
0.7



40
1.2



41
3.4



42
0.6



43
0.9



44
1.8



45
0.7



46
1.0



47
0.8



48
2.8



49
2.5



50
1.7



51
1.0



52
1.1



53
2.0



54
0.7



55
2.3



56
1.8



57
0.6



58
2.5



59
0.4



60
18.8



61
3.1



62
14.0



63
3.0



64
0.7



65
1.4



66
0.7



67
3.1



68
1.4



69
0.9



70
0.8



71
151



72
3.3



73
9.6



74
6.9



75
0.5



76
0.6



77
3.3



78
6.8



79
5.5



80
4.7



81
1.3



82
0.8



83
1.7



84
0.7



85
0.8



86
1.2



87
3.3



88
0.9



89
77.5



90
0.7



91
2.1



92
2.8



93
1.4



94
10.8



95
5.5



96
1.5



97
1.4



98
1.5



99
3.7



100
5.6



101
0.6



102
2.1



103
0.7



104
3.2



105
0.5



106
9.8



107
1.0



108
1.7



109
0.8



110
0.9



111
8.6



112
12.6



113
9.9



114
1.8



115
4.1



116
0.4



117
2.2



118
0.3



119
1.2



120
2.4



121
1.6



122
1.5



123
0.9



124
2.4



125
1.1



126
0.6



127
1.2



128
5.1



129
23.7



130
20.0



131
4.3



132
1.9



133
1.6



134
1.7



135
4.2



136
2.0



137
4.4



138
2.2



139
9.6



140
5.8



141
2.0



142
5.8



143
0.6



144
0.8



145
0.7



146
1.1



147
1.4



148
1.4



149
1.6



150
1.0



151
3.6



152
1.2



153
0.5



154
9.9



155
15.4



156
0.8



157
1.2



158
4.6



159
3.5



160
2.2



161
1.5



162
1.1



163
2.2



164
1.8



165
0.8



166
1.0



167
1.3



168
1.5



169
0.6



170
0.8



171
2.6



172
8.1



173
0.6



174
1.9



175
2.9



176
4.2



177
5.5



178
5.0



179
4.2



180
2.6



181
10.9



182
7.1



183
19.4



184
13.5



185
10.9



186
10.9



187
12.2



188
19.8



189
22.1



190
1.5



191
169



192
1890



193
0.4



194
0.3



195
20.3



196
1.5



197
13.4



198
0.8



199
3.1



200
8.6



201
0.6



202
0.5



203
0.7



204
1.5



205
8.3



206
0.4



207
3.2



208
0.6



209
1.5



210
0.4



211
0.8



212
2.1



213
2.3



214
20.3



215
0.7



216
1.2



217
0.9



218
3.5



219
3.6



220
1.9



221
2.8



222
11.6



223
7540



224
302



225
232



226
35.7



227
45.3



228
126



229
110



230
53.7



231
223



232
512



233
81.4



234
350



235
214



236
222



237
111



238
123



239
123



240
52











Evaluation of the Inhibition of PKK in Kaolin Activated Human PPP


Platelet poor plasma (PPP) obtained from human wholeblood, anticoagulated with Na-Citrate, is incubated with various concentrations of the test compound together with either 25, 75, 250, or 750 pig/mL kaolin in assay buffer for 20 min at 37° C. such that for each kaolin dose used a concentration response is obtained for the test compound. Afterwards 0.25 mM fluorogenic substrate H-Pro-Phe-Arg-AMC (11295 from Bachem) is added to the mixture and measurements are performed in a kinetic interval every 2nd minute for 12 min using a Spectramax M5 (Molecular Devices) with the following settings of the wavelength excitation of 350 nm and wavelength emission of 450 nm. pIC50 and pIC90 values are obtained from 4 x/y-plots (x=log M, Compound; y=delta rfu/min) fitted with GraphPad prism 7.0 (Equation: log(agonist) vs. response—Find EC anything; the four concentration response curves obtained for the test compound, each obtained using a different kaolin dose, are fitted using a global fitting procedure yielding shared pIC50 or pIC90 values).


IC90 values for compounds according to the invention are shown in the following table. The number of the compound corresponds to the number of the Example in the experimental section.
















Example
IC50 (nM)



















1
290



2
253



3
210



4
184



5
278



6
1880



7
151



8
352



9
603



10
789



11
300



12
802



13
451



14
636



15
414



16
280



17
818



18
460



20
99



21
325



22
249



23
233



24
181



25
286



26
343



27
202



28
184



29
336



30
334



31
973



32
548



33
265



34
1190



35
259



36
180



37
125



39
380



40
543



41
488



42
195



43
308



44
444



45
151



46
162



47
173



48
612



49
254



50
110



51
213



52
155



53
203



54
109



55
250



56
586



57
166



62
769



63
203



64
221



65
1230



66
839



67
635



68
637



69
328



70
797



71
9310



72
831



73
498



74
321



75
192



76
270



77
197



78
317



79
249



80
495



81
117



82
117



83
594



84
209



85
132



86
597



87
177



88
139



89
3430



90
126



91
439



92
307



93
110



94
1760



95
577



96
134



97
766



98
282



99
2170



101
297



102
1440



103
531



104
706



105
117



106
1970



107
324



108
465



109
414



110
784



111
4150



112
2780



114
14700



115
2660



116
278



117
1540



118
157



119
1460



120
934



121
514



122
492



123
1320



124
823



125
2740



126
681



127
1680



128
1390



131
962



132
425



133
560



134
1030



135
909



136
310



137
756



139
774



140
760



141
621



142
731



143
1170



144
248



145
245



146
274



147
149



148
985



149
511



150
373



151
1140



152
430



153
280



154
4270



155
4100



158
2100



159
1140



160
967



161
431



162
231



163
470



164
443



165
342



166
193



167
272



168
1860



169
485



170
469



171
268



181
22300



182
6270



184
2310



185
2270



186
236



187
2450



188
1500



190
1080



193
253



194
183



196
350



198
398



199
808



201
130



202
157



203
202



204
818



206
138



207
745



208
80



173
729



174
1430



175
822



177
1180



178
844



179
389



180
207



209
432



210
128



211
590



212
1890



213
621



214
1040



215
194



216
>10000



217
624



218
646



219
776



220
525











Evaluation of the Inhibition of PKK (Ki)


Human PKK (1.78 nM or 0.025 U/mL; Enzyme Research Laboratories) is incubated at 24° C. with 0.25 mM fluorogenic substrate H-Pro-Phe-Arg-AMC (11295 from Bachem) and various concentrations of the test compound in assay buffer. Measurements are performed in a kinetic interval every 2nd minute for 16 min using a Spectramax M5 (Molecular Devices) with the following settings of the wavelength excitation of 350 nm and wavelength emission of 450 nm.


Evaluation of the Inhibition of FXIIa (Ki)


Human FXIIa (47.5 nM or 1.1 U/mL; Enzyme Research Laboratories) is incubated at 24° C. with 0.5 mM chromogenic Substrate S2302 (Chromogenix) and various concentrations of the test compound in assay buffer. Measurements are performed in a kinetic interval every 2nd minute for 16 min using a Spectramax M5 (Molecular Devices) measuring the optical absorbance at 405 nm.


Evaluation of the Inhibition of FXIa (Ki)


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


Evaluation of the Inhibition of FXa (Ki)


Human FXa (0.86 nM or 0.01 U/mL; Enzyme Research Laboratories) is incubated at 24° C. with 0.5 mM chromogenic Substrate S2765 (Chromogenix) and various concentrations of the test compound in assay buffer. Measurements are performed in a kinetic interval every 2nd minute for 16 min using a Spectramax M5 (Molecular Devices) measuring the optical absorbance at 405 nm.


Evaluation of the Inhibition of FIIa (Ki)


Human FIIa (44.6 nM or 5 U/mL; Enzyme Research Laboratories) is incubated at 24° C. with 0.5 mM chromogenic Substrate S2238 (Chromogenix) and various concentrations of the test compound in assay buffer. Measurements are performed in a kinetic interval every 2nd minute for 16 min using a Spectramax M5 (Molecular Devices) measuring the optical absorbance at 405 nm.


Evaluation of the Inhibition of Plasmin (Ki)


Human plasmin (64.1 nM or 0.0275 U/mL; Enzyme Research Laboratories) is incubated at 24° C. with 0.3 mM chromogenic Substrate S2251 (Chromogenix) and various concentrations of the test compound in assay buffer. Measurements are performed in a kinetic interval every 2nd minute for 16 min using a Spectramax M5 (Molecular Devices) measuring the optical absorbance at 405 nm.


Evaluation of the Inhibition of Trypsin (Ki)


Human trypsin (4.54 nM or 250 U/mL; Calbiochem) is incubated at 24° C. with 0.5 mM chromogenic Substrate S2222 (Chromogenix) and various concentrations of the test compound in assay buffer. Measurements are performed in a kinetic interval every 2nd minute for 16 min using a Spectramax M5 (Molecular Devices) measuring the optical absorbance at 405 nm.


Evaluation of the Inhibition of Tk1 (Ki)


Prior to the assay, human TK1 (R&D Systems) is activated by incubation with human trypsin (Calbiochem) in a 1:10,000 ratio for 15 min at 37° C. For assaying TK1 inhibitory activity, activated TK1 (31.25 nM or 1 U/mL) is incubated at 24° C. with 0.1 mM fluorogenic substrate H-Pro-Phe-Arg-AMC (11295 from Bachem) and various concentrations of the test compound in assay buffer. Measurements are performed in a kinetic interval every 2nd minute for 16 min using a Spectramax M5 (Molecular Devices) with the following settings of the wavelength excitation of 350 nm and wavelength emission of 450 nm.


Ki values for compounds according to the invention are shown in the following table. The number of the compound corresponds to the number of the Example in the experimental section.
















Example
Ki (nM)



















4
>10000



16
>10000



20
>10000



22
>10000



23
>10000



24
>10000



27
>10000



36
>10000



47
>10000



49
>10000



51
>10000



52
>10000



75
>10000



80
>10000



86
>10000



90
>10000



107
>10000



108
>10000



110
>10000



113
>10000



114
>10000



115
>10000



116
871



117
>10000



118
>10000



119
1060



120
>10000



121
>10000



122
>10000



123
>10000



124
>10000



125
>10000



126
>10000



127
>10000



128
>10000



131
>10000



133
>10000



134
>10000



135
>10000



136
>10000



137
>10000



169
>10000



170
>10000



171
>10000



173
>10000



175
>10000



177
>10000



178
>10000



181
>10000



190
>10000



193
>10000



194
>10000



196
>10000



198
>10000



217
>10000



218
>10000



222
7280











Evaluation of the Inhibition of FVIIa (Ki)


Human FVIIa (0.86 nM or 0.01 U/mL; Enzyme Research Laboratories) is incubated at 24° C. with 1.5 mM chromogenic Pefachrome® FVIIa (Loxo) and various concentrations of the test compound in assay buffer. Measurements are performed in a kinetic interval every 2nd minute for 16 min using a Spectramax M5 (Molecular Devices) measuring the optical absorbance at 405 nm.


Evaluation of the Inhibition of FVIIa/TF/PL/CaCl2 (Ki)


Human FVIIa (300 nM or 585 U/mL; Enzyme Research Laboratories) together with 10 mM CaCl2*2H2O and 13.3% (v/v) Dade®Innovin® (Siemens; OQUMI94E0002(5534), which contains recombinant human tissue factor synthetic phospholipids (thromboplastin), is incubated at 24° C. with 1.5 mM chromogenic Pefachrome® FVIIa (Loxo) and various concentrations of the test compound in assay buffer. Measurements are performed in a kinetic interval every 2nd minute for 16 min using a Spectramax M5 (Molecular Devices) measuring the optical absorbance at 405 nm.


Calculation of pIC50 and pKi Values


The average Vmax values for the time interval from 2 to 12 min after initiation of the assay (expressed as either delta OD/min for assays using a chromogenic substrate or delta RFU/min for assays using a fluorigenic substrate, respectively) are plotted versus the Log of the concentration in molar of the evaluated inhibitor compound. The pIC50 values are then fitted using a four-parametric fitting procedure using GraphPad Prism (version 6; GraphPad Software, Inc.). Respective Ki values are obtained by correction of the IC50 values for the respective KM value of the used substrate (see Table A for the obtained KM values of the used substrates) using the following formula:







K
i

=


IC
50


1
+


[

Substrate
,
mM

]


K
M









Where the IC50 is in molar and the KM value in mM.









TABLE A







KM values obtained for the substrates used


in the enzymatic assays.











Enzyme
Substrate
KM (mM)







PKK
I1295
0.16



FXIIa
S2302
0.20



FXIa
I1575
0.29



FXa
S2765
1.31



FIIa
S2238
1.25



Plasmin
S2251
1.45



Trypsin
S2222
2.03



TK1
I1295
0.07



FVIIa
Pefachrome ® FVIIa
0.42



FVIIa/TF/PL/CaCl2
Pefachrome ® FVIIa
3.92











Evaluation of Permeability


Caco-2 cells (1-2×105 cells/1 cm2 area) are seeded on filter inserts (Costar transwell polycarbonate or PET filters, 0.4 μm pore size) and cultured (DMEM) for 10 to 25 days.


Compounds are dissolved in appropriate solvent (like DMSO, 1-20 mM stock solutions). Stock solutions are diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 4.17 mM NaHCO3, 1.19 mM Na2HPO4×7H2O, 0.41 mM NaH2PO4×H2O, 15 mM HEPES, 20 mM glucose, pH 7.2) containing 0.25% BSA to prepare the transport solutions (0.1-300 μM compound, final DMSO<=0.5%). The transport solution (TL) is applied to the apical or basolateral donor side for measuring A-B or B-A permeability (2 filter replicates), respectively. The receiver side contains HTP-4 buffer supplemented with 0.25% BSA. Samples are collected at the start and end of experiment from the donor and at various time intervals for up to 2 hours also from the receiver side for concentration measurement by HPLC-MS/MS or scintillation counting. Sampled receiver volumes are replaced with fresh receiver solution.


Evaluation of Metabolic Stability in Human or Rat Liver Microsomes


The metabolic degradation of the test compound is assayed at 37° C. with pooled human (HLM) or rat liver microsomes (RLM). The final incubation volume of 60 μl per time point contains TRIS buffer pH 7.6 at RT (0.1 M), magnesium chloride (5 mM), microsomal protein (HLM: 1 mg/mL, RLM: 0.5 mg/mL) and the test compound at a final concentration of 1 μM.


Following a short preincubation period at 37° C., the reactions are initiated by addition of beta-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH, 1 mM) and terminated by transferring an aliquot into solvent after different time points. Additionally, the NADPH-independent degradation is monitored in incubations without NADPH, terminated at the last time point. The quenched incubations are pelleted by centrifugation (10000 g, 5 min). An aliquot of the supernatant is assayed by LC-MS/MS for the amount of parent compound. The half-life (t½ INVITRO) is determined by the slope of the semilogarithmic plot of the concentration-time profile.


Evaluation of Metabolic Stability in Human or Rat Hepatocytes


The metabolic degradation of the test compound is assayed in a hepatocyte suspension. After recovery from cryopreservation, human or rat hepatocytes are incubated in Dulbecco's modified eagle medium supplemented with 3.5 μg glucagon/500 ml, 2.5 mg insulin/500 ml and 3.75 mg/500 ml hydrocortisone) containing 5% or 50% human or rat serum or in absence of serum.


Following a 30 min preincubation in a cell culture incubator (37° C., 10% CO2), test compound solution is spiked into the hepatocyte suspension to obtain a final cell density of 1.0*106 cells/ml, a final test compound concentration of 1 μM, and a final DMSO concentration of 0.05%.


The cells are incubated for six hours (incubator, horizontal shaker) and samples are removed from the incubation after 0, 0.5, 1, 2, 4 and 6 hours. Samples are quenched with acetonitrile and pelleted by centrifugation. The supernatant is transferred to a 96-deepwell plate, and prepared for analysis of decline of parent compound by HPLC-MS/MS.


CLint is calculated as follows:

CLint=Dose/AUC=(C0/CD)/(AUD+clast/k)×1000/60

C0: initial concentration in the incubation [μM], CD: cell density of vital cells [10e6 cells/ml], AUD: area under the data [μM×h], clast: concentration of last data point [μM], k: slope of the regression line for parent decline [h−1].


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


Evaluation of Plasma Protein Binding


The equilibrium dialysis (ED) technique is used to determine the approximate in vitro fractional binding of test compounds to plasma proteins applying Dianorm Teflon dialysis cells (micro 0.2). Each dialysis cell consists of a donor and an acceptor chamber, separated by an ultrathin semipermeable membrane with a 5 kDa molecular weight cutoff. Stock solutions for each test compound are prepared in DMSO at 1 mM and serially diluted to obtain a final test concentration of 1 μM. The subsequent dialysis solutions are prepared in plasma (supplemented with NaEDTA as anticoagulant), and aliquots of 200 μl test compound dialysis solution in plasma are dispensed into the donor (plasma) chambers. Aliquots of 200 μl dialysis buffer (100 mM potassium phosphate, pH 7.4) are dispensed into the buffer (acceptor) chamber. Incubation is carried out for 2 hours under rotation at 37° C. for establishing equilibrium.


At the end of the dialysis period, aliquots obtained from donor and acceptor chambers, respectively, are transferred into reaction tubes, spiked with Internal Standard solution and processed for HPLC-MS/MS analysis. Analyte concentrations are quantified in aliquots of samples by HPLC-MS/MS against external calibration curves.


Percent bound is calculated using the formula:

% bound=(plasma concentration−buffer concentration/plasma concentration)×100

Evaluation of Solubility


The aqueous solubility of the test compound is determined by comparing the amount dissolved in buffer to the amount in an ACN/water (1/1) solution. Starting from a 10 mM DMSO stock solution aliquots are diluted with acetonitrile/water (1/1) or buffer resp. After 24 h of shaking, the solutions are filtrated and analyzed by LC-UV. The amount dissolved in buffer is compared to the amount in the ACN solution.


Solubility will usually be measured from 0.001 to 0.125 mg/mL at a DMSO concentration of 2.5%. If more than 90% of the compound is dissolved in buffer, the value is marked with “>”.


Evaluation of Pharmacokinetic Characteristics in Rodents


The test compound is administered either intravenously to fed rats or orally to fasted rats. Blood samples are taken at several time points post application of the test compound, anticoagulated and centrifuged.


The concentration of analytes—the administered compound and/or metabolites—are quantified in the plasma samples. PK parameters are calculated using non compartment methods. AUC and Cmax are normalized to a dose of 1 μmol/kg.


Evaluation of Inhibition of Cytochrome P450 Isoenzyme-Catalysed Reactions


The inhibition of cytochrome P450 isoenzyme-catalysed reactions by the test compound is assayed at 37° C. with human liver microsomes. All assays are carried out on a robotic system in 384-well plates. Test compounds are directly spotted into incubation plates from DMSO stocks by acoustic liquid dispensing (using the Labyte ECHO® system). The final incubation volume contains TRIS buffer (0.1 M), MgCl2 (5 mM), human liver microsomes, specific cytochrome P450 isoenzyme-substrate and the test compound at five different concentrations or no compound (high control) in duplicate (e.g. highest concentration 50 μM with subsequent serial 1:4 dilutions). Following a short preincubation period, reactions are started with the cofactor (NADPH, 1 mM) and stopped by cooling the incubation down to 8° C. and subsequently by addition of one volume of acetonitrile. An internal standard solution—usually the stable isotope of the formed metabolite—is added after quenching of incubations. Peak area analyte (=metabolite formed) and internal standard is determined by LC-MS/MS. The resulting peak area ratio analyte to internal standard in these incubations is compared to a control activity containing no test compound. Within each of the assay runs, the IC50 of a positive control inhibitor is determined. Experimental IC50 values are calculated by least square regression according to the following equation:

% control activity=(100% control activity/(1+(I/IC50)S)))−b

with


I=inhibitor concentration


S=slope factor


B=background activity


If the inhibition of the reaction is already >50% at the lowest concentration of the test compound, the IC50 is assigned “< lowest concentration tested” (usually <0.2 μM). If the inhibition of the reaction is still <50% at the highest concentration of the test compound, the IC50 is assigned “> highest concentration tested” (usually >50 μM).


Evaluation of Mechanism-Based Inhibition (MBI) of Cytochrome P450 3A4-Catalysed Midazolam Turnover


The mechanism-based inhibition towards CYP3A4 is assayed in human liver microsomes (0.02 mg/ml) with Midazolam (15 uM) as a substrate.


The test compounds are preincubated at 37° C. in presence of NADPH with human liver microsomes (0.2 mg/ml) at a concentration of 5 uM and 25 uM for 0 min, 10 min or 30 min. After preincubation, the incubate is diluted 1:10 and the substrate Midazolam is added for the main incubation (15 min). The main incubation is quenched with acetonitrile and the formation of Hydroxy-Midazolam is quantified via LC/MS-MS.


The turnover rates in pmol/min/mg protein are calculated and the activity after 10 and 30 min preincubation time is compared to that of the 0 min preincubation of the respective compound/concentration (% CTRL=% of the 0 min control of the respective compound/concentration). Additionally, the turnover rate is expressed relative to the turnover rate of the substrate reaction without compound added (% TR=% of the turnover rate without compound), in order to recognize competitive inhibition effects.


Methods of Treatment


In another aspect of the present invention, it is found that compounds of formula (I) or pharmaceutically acceptable salts thereof possess suitable properties for use in therapy and/or prevention, i.e. for use as medicaments. In particular, compounds of formula (I) or pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions containing the same, may be useful for the treatment, i.e. therapy and/or prevention (prophylaxis), of diseases or conditions, which can be influenced by the inhibition of plasma kallikrein, e.g. which are mediated by unwanted PKK activity or in which inhibition of PKK is beneficial, in a patient.


Diseases and conditions which can be influenced by the inhibition of PKK, e.g. which are mediated by unwanted PKK activity or in which inhibition of PKK is beneficial, are, for instance, those mentioned in section Background of the Invention, in particular diabetic complications, diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), clinically significant macular edema (CSME), cystoid macular edema (CME), CME 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 related to cataract surgery in diabetic retinopathy, hypertensive retinopathy, retinal trauma, dry and wet age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV), choroidal neovascularization (CNV; e.g. non-exudative choroidal neovascularization), hereditary angioedema (HAE), acute respiratory distress syndrome (ARDS), hemorrhage and edema after stroke, e.g. brain edema after stroke, vascular dementia, Alzheimer's disease, fibrotic disease, colitis, arthritis and renal injury.


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 invention are particularly suitable for the treatment of edema, such as hereditary angioedema (HAE) and brain edema after stroke.


In particular, the compounds and pharmaceutical compositions according to the 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 brain edema after stroke.


The compounds and pharmaceutical compositions according to the invention are most particularly suitable for treating diabetic macular edema (DME), wet age-related macular degeneration (AMD), non-exudative choroidal neovascularization (CNV), hereditary angioedema (HAE), and brain edema after stroke.


For instance, they are particularly suitable for the prevention of diabetic macular edema (DME), wet age-related macular degeneration (AMD), hereditary angioedema (HAE), and brain edema after stroke as well as for the prevention of the conversion from non-exudative choroidal neovascularization (neCNV) to exudative choroidal neovascularization (eCNV).


The dose range of the compounds of formula (I) applicable per day is usually from 0.01 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 age and weight of the patient, route of administration and severity of disease. In any case the compound or composition will be administered at dosages and in a manner which allows a therapeutically effective amount to be delivered based upon patient's unique condition.


The compounds and compositions, including any combinations with one or more additional therapeutic agents, according to the invention may be administered by oral, intravitreal, transdermal, inhalative, parenteral or sublingual route. Of the possible methods of administration, oral or intravitreal administration is preferred. In case of intravitreal injection the preferred dose should not exceed 5 mg per eye.


The patient to be treated is preferably a mammal, most preferably a human patient.


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


In another aspect, the present invention provides a method for the treatment of a disease or condition, which is mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial, in a patient in need thereof.


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


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


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


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


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


According to one embodiment, the disease or condition, which is 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 retinopathy, 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, which is mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial, is selected from edema-associated diseases such as hereditary angioedema (HAE) and brain edema after stroke.


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


According to one embodiment, the patient is a human patient.


Pharmaceutical Compositions


In another aspect of the present invention, it is described that a compound of the invention or a pharmaceutically acceptable salt thereof may be used as active ingredients in pharmaceutical compositions.


Suitable preparations for administering the compounds of the invention, optionally in combination with one or more further therapeutic agents, will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders etc. Oral formulations, particularly solid forms such as e.g. tablets or capsules are preferred. For intravitreal injection, solutions are preferred. The content of the pharmaceutically active compound(s) is advantageously in the range from 0.1 to 90 wt.-%, for example from 1 to 70 wt.-% of the composition as a whole.


Suitable tablets may be obtained, for example, by mixing one or more compounds according to formula (I) with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants. The tablets may also consist of several layers. The particular excipients, carriers and/or diluents that are suitable for the desired preparations will be familiar to the skilled person on the basis of his specialist knowledge. The preferred ones are those that are suitable for the particular formulation and method of administration that are desired. The preparations or formulations according to the invention may be prepared using methods known per se that are familiar to the skilled person, such as 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.


Thus, according to another aspect of the present invention, pharmaceutical compositions comprising one or more compounds of formula (I) and/or their tautomers, or pharmaceutically acceptable salts thereof, optionally together with one or more inert carriers and/or diluents are provided.


Also, a pharmaceutical composition that comprises one or more of the above-mentioned compounds, or pharmaceutically acceptable salts thereof, optionally together with one or more inert carriers and/or diluents is provided for use in a method for the treatment of diseases or conditions which are mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial, in a patient in need thereof.


In particular, the invention provides a pharmaceutical composition according to this invention for use in a method for the treatment of ophthalmic indications such as diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV) and choroidal neovascularization (CNV) and of edema-associated diseases such as hereditary angioedema (HAE) and brain edema after stroke.


Furthermore, the present invention relates to the use of a pharmaceutical composition according to this invention for the treatment of diseases or conditions which are mediated by unwanted plasma kallikrein activity in a patient, preferably in a human.


Also, the present invention relates to the use of a pharmaceutical composition according to this invention for the treatment of diseases or conditions in which inhibition of plasma kallikrein is beneficial in a patient, preferably in a human.


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


Preferably, this composition comprises one compound of formula (I) and/or its tautomers or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents.


Combination Therapy


The compounds of the invention may 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 diseases or conditions described hereinbefore, in particular associated with metabolic diseases or conditions such as for example diabetes mellitus, obesity, diabetic complications, hypertension, hyperlipidemia, or therapeutic agents useful for the treatment of ocular diseases.


Additional therapeutic agents which are suitable for such combinations include in particular those which for example potentiate the therapeutic effect of one or more active substances with respect to one of the indications mentioned and/or which allow the dosage of one or more active substances to be reduced.


Therefore a compound of the 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 high blood pressure, heart failure and/or atherosclerosis and agents for the treatment of ocular diseases. Antidiabetic agents are for example metformin, sulphonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR-(alpha, gamma or alpha/gamma) agonists or modulators, alpha-glucosidase inhibitors, DPPIV inhibitors, SGLT2-inhibitors, insulin and insulin analogues, GLP-1 and GLP-1 analogues or amylin and amylin analogues, cycloset, 11β-HSD inhibitors. Other suitable combination partners are inhibitors of protein tyrosinephosphatase 1, substances that affect deregulated glucose production in the liver, such as e.g. inhibitors of glucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, alpha2-antagonists, CCR-2 antagonists or glucokinase activators. One or more lipid lowering agents are also suitable as combination partners, such as for example HMG-CoA-reductase inhibitors, fibrates, nicotinic acid and the derivatives thereof, PPAR-(alpha, gamma or alpha/gamma) agonists or modulators, PPAR-delta agonists, ACAT inhibitors or cholesterol absorption inhibitors such as, bile acid-binding substances such as, inhibitors of ileac bile acid transport, MTP inhibitors, or HDL-raising compounds such as CETP inhibitors or ABC1 regulators.


Therapeutic agents for the treatment of overweight and/or obesity are for example antagonists of the cannabinoid1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists, β3-agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor.


Therapeutic agents for the treatment of high blood pressure, chronic heart failure and/or atherosclerosis are for example A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics, β-blockers, Ca-antagonists, centrally acting antihypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors and others or combinations thereof are suitable. Angiotensin II receptor antagonists are preferably used for the treatment or prevention of high blood pressure and complications of diabetes, often combined with a diuretic such as hydrochlorothiazide.


Therapeutic agents for the treatment of ocular diseases may 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 factors 3, 5, B, and D inhibitors), Bradykinin receptor 1 antagonists, CCR-2 antagonists.


Additional treatments for ocular diseases may include laser coagulation therapy.


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


The dosage for the combination partners mentioned above is usually 1/5 of the lowest dose normally recommended up to 1/1 of the normally recommended dose.


The use of the compound according to the invention in combination with the additional therapeutic agent may take place simultaneously or at staggered times.


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


Thus, according to another aspect, this invention relates to a pharmaceutical composition which comprises one or more compounds according to the invention and one or more additional therapeutic agents described hereinbefore and hereinafter, 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, which is mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial, in a patient in need thereof, the method comprising administering to the patient one or more compounds of formula (I) and/or its tautomers or pharmaceutically acceptable salts thereof, in combination with one or more additional therapeutic agents described in hereinbefore and hereinafter,


preferably administering to the patient a therapeutically effective amount of one or more compounds of formula (I) and/or its tautomers or pharmaceutically acceptable salts thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents described in hereinbefore and hereinafter.


Likewise, the present invention provides a compound of formula (I) and/or its tautomers or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents described hereinbefore or hereinafter for use in a method for the treatment of a disease or condition, which is mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial, in a patient in need thereof.


Likewise, the present invention provides the use of a compound of formula (I) and/or its tautomers or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents described hereinbefore or hereinafter, in the manufacture of a medicament for use in a method for the treatment of a disease or condition, which is mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial, in a patient in need thereof.


Likewise, the present invention provides the use of a compound of formula (I) and/or its tautomers or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents described hereinbefore or hereinafter, in a method for the treatment of a disease or condition, which is mediated by unwanted plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial, in a patient in need thereof.


According to one embodiment, the method for the treatment comprises administering to the patient one or more compounds of formula (I) and/or its tautomers or pharmaceutically acceptable salts thereof, in combination with one or more additional therapeutic agents described in hereinbefore and hereinafter,


preferably administering to the patient a therapeutically effective amount of one or more compounds of formula (I) and/or its tautomers or pharmaceutically acceptable salts thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents described in hereinbefore and hereinafter.


According to another embodiment, the method for the treatment comprises administering to the patient a pharmaceutical composition comprising one or more compounds according to the invention and one or more additional therapeutic agents described hereinbefore and hereinafter, 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 high blood pressure, heart failure and/or atherosclerosis and agents for the treatment of ocular diseases, in particular from those agents specifically mentioned above.


According to one embodiment, the disease or condition, which is 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 retinopathy, diabetic macular edema (DME), age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV) and choroidal neovascularization (CNV);


from edema-associated diseases such as hereditary angioedema (HAE) and brain edema after stroke; or from diabetic complications such as retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.


According to one embodiment, the patient is a human patient.


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.


EXAMPLES AND EXPERIMENTAL DATA

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


Abbreviations



  • 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 medium

  • DMF N,N-dimethylformamide

  • DMSO dimethyl sulfoxide

  • EDTA ethylenediaminetetraacetate

  • ESI electrospray ionization (in MS)

  • 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 molar (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

  • Rf retardation factor

  • RFU relative fluorescence units

  • RP reverse phase

  • rt room temperature

  • tR retention time (in HPLC/LC)

  • SFC supercritical fluid chromatography

  • TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate

  • TFA trifluoroacetic acid

  • THF tetrahydrofuran

  • UV ultraviolet



The terms “ambient temperature” and “room temperature” are used interchangeably and designate a temperature of about 20° C., e.g. 15 to 25° C.


As a rule, 1H-NMR and/or mass spectra have been obtained for the compounds prepared.


Unless otherwise specified, compounds containing chiral centers have the stereochemistry depicted. The assignment of stereochemistry has been made either by use of a chiral starting material of known stereochemistry, by stereoselective synthesis of known stereochemistry or by biological activity.


Analytical Methods















Method:
1


Device:
Agilent 1200 with DA- and MS-Detector


Column:
XBridge C18, 3 × 30 mm, 2.5 μm


Column Supplier:
Waters














Gradient/






Solvent
% Solvent
% Solvent
Flow
Temperature


Time [min]
[H2O, 0.1% NH3]
[ACN]
[mL/min]
[° C.]





0.00
97
3
2.2
60


0.20
97
3
2.2
60


1.20
0
100
2.2
60


1.25
0
100
3
60


1.40
0
100
3
60






















Method:
2


Device:
Agilent 1200 with DA- and MS-Detector


Column:
Sunfire C18, 3 × 30 mm, 2.5 μm


Column Supplier:
Waters














Gradient/






Solvent
% Solvent
% Solvent
Flow
Temperature


Time [min]
[H2O, 0.1% TFA]
[ACN]
[mL/min]
[° C.]





0.00
97
3
2.2
60


0.20
97
3
2.2
60


1.20
0
100
2.2
60


1.25
0
100
3
60


1.40
0
100
3
60






















Method:
3


Device:
Agilent 1260 SFC with DA- and MS-Detector


Column:
CHIRAL ART ® Cellulose SC, 4.6 × 250 mm,



5 μm


Column Supplier:
YMC















Gradient/

% Solvent





Solvent
%
[MeOH,


Back


Time
Solvent
20 mM
Flow
Temperature
pressure


[min]
[scCO2]
NH3]
[mL/min]
[° C.]
[PSI]





0.00
65.0
35.0
4.0
40.0
2175.0


10.0
65.0
35.0
4.0
40.0
2175.0






















Method:
4


Device:
Waters Acquity, QDa Detector


Column:
XBridge C18, 3 × 30 mm, 2.5 μm


Column Supplier:
Waters














Gradient/






Solvent
% Solvent
% Solvent
Flow
Temperature


Time [min]
[H2O, 0.1% NH3]
[ACN]
[mL/min]
[° C.]





0.00
95
5
1.5
60


1.30
0
100
1.5
60


1.50
0
100
1.5
60


1.60
95
5
1.5
60






















Method:
5


Device:
Waters Acquity, QDa Detector


Column:
XBridge C18, 3 × 30 mm, 2.5 μm


Column Supplier:
Waters














Gradient/






Solvent
% Solvent
% Solvent
Flow
Temperature


Time [min]
[H2O, 0.1% NH3]
[ACN]
[mL/min]
[° C.]





0.00
95
5
1.5
60


1.30
0
100
1.5
60


1.50
0
100
1.5
60


1.60
95
5
1.5
60









SYNTHESIS OF INTERMEDIATES

The starting materials and intermediates that are used in the processes leading to the compounds according to the invention are either commercially available or they may be prepared by methods (or by analogous or similar methods to those) described in the following or already known to those skilled in the art from the literature, e.g. from WO 2017/072020, WO 2017/072021 and WO 2018/192866 which are hereby incorporated by reference in their entirety.


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



embedded image


Step 1: Methyl 5-bromo-1-methyl-1H-imidazole-4-carboxylate

Under 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 (Na2S2O8, 64.9 g) and palladium-II-acetate (Pd(OAc)2, 3.1 g) are added successively and the mixture is cooled to 0° C. Trifluoromethanesulfonic acid (CF3—SO3H, 42.2 mL) is added dropwise and thereafter the mixture is heated to 60° C. for 20 h. The mixture is diluted with DCM, cooled to 0° C. and treated carefully with saturated aqueous Na2CO3 until a pH-value 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 (MgSO4) and concentrated in vacuo. The residue is chromatographed on silica gel (EtOAc/MeOH 85:15→70:30). The product thus obtained is triturated with tert.-butyl-methyl-ether (50 mL) to give the title compound.


LC (Method 1): tR=0.69 min; Mass spectrum (ESI+): m/z=219 [M+H]+.


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-methyldicyclohexylamin (15.3 mL) are added and the mixture is purged for 5 minutes with argon. Dichlorobis(tri-o-tolylphosphine)palladium(II) (PdCl2[P(o-Tol)3]2, 1.9 g) is added and the mixture is stirred for 3 h at 120° C. Then the mixture is partitioned between water and EtOAc and filtered over celite. The aqueous phase is mixed with saturated aqueous NaHCO3 and extracted for 4 times with EtOAc. The combined organic phases are dried (MgSO4) and concentrated in vacuo. The residue is chromatographed on silica gel (EtOAc/MeOH 90:10→70:30) to give the title compound.


LC (Method 2): tR=0.55 min; Mass spectrum (ESI+): m/z=227 [M+H]+.


Step 3: Methyl 1-methyl-4-oxo-1H,4H,5H,6H-cyclopenta[d]imidazole-5-carboxylate

Under 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 solvents are evaporated in vacuo to give the title compound.


LC (Method 1): tR=0.25 min; Mass spectrum (ESI+): m/z=195 [M+H]+.


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 h. The solvents are evaporated in vacuo to give the title compound. LC (Method 1): tR=0.16 min; Mass spectrum (ESI+): m/z=137 [M+H]+.


Alternatively, the reaction can be conducted by heating the starting material in a mixture of hydrogen chloride and acetic acid at 120° C. After completion of the reaction the solvents are 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 (DCM/MeOH 20:1→5:1) to give the title compound.


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 for 4 h at reflux, cooled to rt and treated with saturated aqueous NaCl (30 mL). The mixture is stirred for 1 h and then filtered over celite. For two times the filter cake is stirred 10 minutes in MeOH (20 mL) and filtered over celite. The combined organic phases are concentrated and the residue is chromatographed on silica gel (DCM/MeOH 95:5). The product thus obtained is triturated from EtOAc to give the title compound.


LC (Method 3): tR=3.69 min; Mass spectrum (ESI+): m/z=240 [M+H]+.


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 h and then treated dropwise with MeOH (5 mL). The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (DCM/MeOH 95:5→80:20) to give the title compound.


LC (Method 2): tR=0.55 min; Mass spectrum (ESI+): m/z=242 [M+H]+. LC (Method 3): tR=3.71 min.


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 h. The precipitate is collected by filtration, washed successively with isopropanol and diethylether and dried in vacuo to give the title compound. Mass spectrum (ESI+): m/z=138 [M+H]+.


Intermediate 2
5-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridine-2-carbaldehyde



embedded image


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 rt, partitioned between water and EtOAc and the phases are separated. The aqueous phase is extracted twice with EtOAc, the combined organic phase are dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/EtOAc 100:0→60:40) to give the title compound. LC (Method 2): tR=0.68 min; Mass spectrum (ESI+): m/z=189 [M+H]+.


Intermediates 2-1 to 2-4 are prepared in analogy to Intermediate 2:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







2-1


embedded image


0.75
189
Method 2





2-2


embedded image


0.73
225
Method 2





2-3


embedded image


0.82
189
Method 2





2-4


embedded image


1.22
301
Method 1























Intermediate
Reaction comment









2-2
The reaction is conducted for 12 h at 115° C.



2-3
The reaction is conducted in DMF for 18 h at rt.



2-4
The reaction is conducted in DMF for 26 h at 80° C.

























Name of
Name of


Intermediate
Name
Starting Material 1
Starting Material 2







2-1
5-{5-Azaspiro[2.3]hexan-5-
5-Fluoropyridine-2-
5-Azaspiro[2.3]hexane



yl}pyridine-2-carbaldehyde
carbaldehyde
hemioxalate


2-2
5-{6,6-Difluoro-3-azabicyclo-
5-Fluoropyridine-2-
6,6-Difluoro-3-azabicyclo-



[3.1.0]hexan-3-yl}pyridine-2-
carbaldehyde
[3.1.0]hexane hydrochloride



carbaldehyde




2-3
6-{3-Azabicyclo[3.1.0]hexan-
6-Fluoropyridine-3-
3-Azabicyclo[3.1.0]hexane



3-yl}pyridine-3-carbaldehyde
carbaldehyde
hydrochloride


2-4
3-(5-Iodo-6-methylpyridin-2-
6-Fluoro-3-iodo-2-
3-Azabicyclo[3.1.0]hexane



yl)-3-azabicyclo[3.1.0]hexane
methylpyridine
hydrochloride









Intermediate 3
(5-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridin-2-yl)methanol



embedded image


NaBH4 (217 mg) is added portionwise to a ice-cooled 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 h at 0° C., treated with 1 M aqueous HCl (10 mL) and stirred for 30 minutes at rt. Then the mixture is 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): tR=0.59 min; Mass spectrum (ESI+): m/z=191 [M+H]+.


Intermediates 3-1 to 3-23 are prepared in analogy to Intermediate 3:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







3-1


embedded image


0.94
305
Method 2





3-2


embedded image


0.90
261
Method 2





3-3


embedded image


0.87
225
Method 2





3-4


embedded image


0.90
269
Method 2





3-5


embedded image


1.00
259
Method 2





3-6


embedded image


0.99
223
Method 1





3-7


embedded image


1.03
223
Method 2





3-8


embedded image


0.60
191
Method 2





3-9


embedded image


0.89
225
Method 1





3-10


embedded image


0.94
269
Method 2





3-11


embedded image


0.52
227
Method 2





3-12


embedded image


0.59
241
Method 2





3-13


embedded image


0.58
227
Method 2





3-14


embedded image


0.82
205
Method 1





3-15


embedded image


0.85
205
Method 1





3-16


embedded image


0.87
225
Method 1





3-17


embedded image


0.83
266
Method 2





3-18


embedded image


0.82
205
Method 1





3-19


embedded image


0.62
255
Method 2





3-20


embedded image


0.71
230
Method 2





3-21


embedded image


0.96
239
Method 2





3-22


embedded image


0.60
219
Method 2





3-23


embedded image


0.79
227
Method 2






















Intermediate
Reaction comment





3-1
The reaction is conducted in EtOH.


3-5
Methylether is formed during stirring in presence of 1N aqueous HCl.


3-6
Methylether is formed during stirring in presence of 1N aqueous HCl.


3-7
Methylether is formed during stirring in presence of 1N aqueous HCl.


3-10
The reaction is conducted in EtOH.


3-12
The reaction is conducted in EtOH.


3-14
The reaction is conducted in THF/EtOH 1:2.


3-15
The reaction is conducted in EtOH for 2 h at rt.


3-16
The reaction is conducted for 2 h at 0° C.


3-17
The reaction is conducted for 30 minutes at rt.


3-18
The reaction is conducted in EtOH for 1 h at rt.


3-19
The reaction is conducted for 45 minutes at rt.


3-20
The reaction is conducted for 45 minutes at 0° C.


3-21
The reaction is conducted for 1 h at 0° C.


3-22
The reaction is conducted in EtOH for 1.5 h at rt.


3-23
The reaction is conducted in EtOH for 1 h at rt.












Intermediate
Name
Name of Starting Material





3-1
(2-Bromo-6-{6,6-difluoro-3-azabicyclo-
2-Bromo-6-{6,6-difluoro-3-azabicyclo-



[3.1.0]hexan-3-yl}pyridin-3-yl)methanol
[3.1.0]hexan-3-yl}pyridine-3-carbaldehyde


3-2
(2-Chloro-6-{6,6-difluoro-3-azabicyclo-
2-Chloro-6-{6,6-difluoro-3-azabicyclo-



[3.1.0]hexan-3-yl}pyridin-3-yl)methanol
[3.1.0]hexan-3-yl}pyridine-3-carbaldehyde


3-3
(6-{5-Azaspiro[2.3]hexan-5-yl}-2-chloropyridin-
6-{5-Azaspiro[2.3]hexan-5-yl}-2-



3-yl)methanol
chloropyridine-3-carbaldehyde


3-4
(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
6-{5-Azaspiro[2.3]hexan-5-yl}-2-



bromopyridin-3-yl)methanol
bromopyridine-3-carbaldehyde


3-5
6,6-Difluoro-3-[6-fluoro-5-(methoxy-
6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-



methyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane
2-fluoropyridine-3-carbaldehyde


3-6
5-[6-Fluoro-5-(methoxymethyl)pyridin-2-yl]-5-
6-{5-Azaspiro[2.3]hexan-5-yl}-2-fluoropyridine-



azaspiro[2.3]hexane
3-carbaldehyde


3-7
3-[6-Fluoro-5-(methoxymethyl)pyridin-2-yl]-3-
6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



azabicyclo[3.1.0]hexane
fluoropyridine-3-carbaldehyde


3-8
(5-{5-Azaspiro[2.3]hexan-5-yl}pyridin-2-
5-{5-Azaspiro[2.3]hexan-5-yl}pyridine-2-



yl)methanol
carbaldehyde


3-9
(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



chloropyridin-3-yl)methanol
chloropyridine-3-carbaldehyde


3-10
(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



bromopyridin-3-yl)methanol
bromopyridine-3-carbaldehyde


3-11
(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-



yl}pyridin-3-yl)methanol
yl}pyridine-3-carbaldehyde


3-12
(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-



yl}-2-methylpyridin-3-yl)methanol
2-methylpyridine-3-carbaldehyde


3-13
(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
5-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-



yl}pyridin-2-yl)methanol
yl}pyridine-2-carbaldehyde


3-14
(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
6-{5-Azaspiro[2.3]hexan-5-yl}-2-



methylpyridin-3-yl)methanol
methylpyridine-3-carbaldehyde


3-15
(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methanol
methylpyridine-3-carbaldehyde


3-16
(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-
6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-



chloropyridin-3-yl)methanol
chloropyridine-3-carbaldehyde


3-17
2-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-
2-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-



5-(hydroxymethyl)-4-methylpyridine-3-
5-formyl-4-methylpyridine-3-carbonitrile



carbonitrile



3-18
(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-
6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-



methylpyridin-3-yl)methanol
methylpyridine-3-carbaldehyde


3-19
(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-



yl}-2,4-dimethylpyridin-3-yl)methanol
2,4-dimethylpyridine-3-carbaldehyde


3-20
2-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-(hydroxy-
2-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-formyl-4-



methyl)-4-methylpyridine-3-carbonitrile
methylpyridine-3-carbonitrile


3-21
{2-Chloro-6-[(1R,5S,6R)-6-methyl-3-aza-
2-Chloro-6-[(1R,5S,6R)-6-methyl-3-



bicyclo[3.1.0]hexan-3-yl]pyridin-3-yl}methanol
azabicyclo[3.1.0]hexan-3-yl]pyridine-3-carbaldehyde


3-22
(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



ethylpyridin-3-yl)methanol
ethylpyridine-3-carbaldehyde


3-23
(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-
6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-



yl}pyridin-3-yl)methanol
pyridine-3-carbaldehyde









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



embedded image


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 add (54 mg) in ACN (15 mL) is heated for 5 h to 120° C. After cooling to rt 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 reversed phase (ACN, water) to give the title compound.


LC (Method 2): tR=0.71 min; Mass spectrum (ESI+): m/z=313 [M+H]+.


Intermediates 4-1 to 4-61 are prepared in analogy to Intermediate 4:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







4-1


embedded image


1.02
384
Method 2





4-2


embedded image


1.03
348
Method 2





4-3


embedded image


1.05
392
Method 2





4-4


embedded image


0.85
367
Method 2





4-5


embedded image


0.94
314
Method 1





4-6


embedded image


0.76
313
Method 2





4-7


embedded image


1.00
332
Method 2





4-8


embedded image


0.95
331
Method 1





4-9


embedded image


1.06
331
Method 2





4-10


embedded image


1.11
391
Method 2





4-11


embedded image


1.04
428
Method 2





4-12


embedded image


1.06
427
Method 2





4-13


embedded image


0.99
391
Method 1





4-14


embedded image


0.78
388
Method 1





4-15


embedded image


1.01
332
Method 2





4-16


embedded image


1.04
367
Method 2





4-17


embedded image


0.97
347
Method 1





4-18


embedded image


1.08
347
Method 2





4-19


embedded image


0.99
368
Method 2





4-20


embedded image


0.98
427
Method 1





4-21


embedded image


0.93
416
Method 2





4-22


embedded image


1.08
392
Method 2





4-23


embedded image


0.83
356
Method 2





4-24


embedded image


1.07
348
Method 2





4-25


embedded image


0.68
350
Method 2





4-26


embedded image


0.98
327
Method 1





4-27


embedded image


0.95
363
Method 1





4-28


embedded image


1.01
397
Method 2





4-29


embedded image


0.92
391
Method 2





4-30


embedded image


1.14
391
Method 2





4-31


embedded image


0.78
349
Method 2





4-32


embedded image


1.10
383
Method 2





4-33


embedded image


1.05
347
Method 2





4-34


embedded image


0.72
349
Method 2





4-35


embedded image


0.97
383
Method 1





4-36


embedded image


1.21
397
Method 2





4-37


embedded image


0.90

Method 1





4-38


embedded image


0.91
347
Method 2





4-39


embedded image


0.92
313
Method 1





4-40


embedded image


1.07
338
Method 1





4-41


embedded image


1.05
347
Method 1





4-42


embedded image


1.02
388
Method 1





4-43


embedded image


0.92
388
Method 1





4-44


embedded image


1.09
331
Method 2





4-45


embedded image


0.93
327
Method 1





4-46


embedded image


0.98
377
Method 1





4-47


embedded image


0.79
377
Method 2





4-48


embedded image


1.05
361
Method 1





4-49


embedded image


1.03
338
Method 2





4-50


embedded image


0.97
383
Method 1





4-51


embedded image


1.04
352
Method 2





4-52


embedded image


0.94
352
Method 1





4-53


embedded image


0.96
347
Method 1





4-54


embedded image


1.00
381
Method 1





4-55


embedded image


1.11

Method 1





4-56


embedded image


1.17
405
Method 2





4-57


embedded image


0.89
364
Method 1





4-58


embedded image


0.90
350
Method 1





4-59


embedded image


0.85
328
Method 2





4-60


embedded image


0.93
327
Method 2





4-61


embedded image


0.89
328
Method 2




















Intermediate
Reaction comment







4-1
The reaction is conducted for 10 minutes at 70° C.


4-2
The reaction is conducted for 15 minutes at 70° C.


4-3
The reaction is conducted for 15 minutes at 70° C.


4-4
The reaction is conducted for 48 h at 90° C.


4-5
The reaction is conducted for 10 h at 130° C.


4-6
The reaction is conducted for 4 h at 120° C.


4-7
The reaction is conducted for 10 minutes at 70° C.


4-8
The reaction is conducted for 5 h at 70° C.


4-9
The reaction is conducted for 1 h at 70° C.


4-10
The reaction is conducted for 30 minutes at 80° C.


4-11
The reaction is conducted for 10 minutes at 70° C.


4-12
The reaction is conducted for 2 h at 80° C.


4-13
The reaction is conducted for 12 h at 80° C.


4-14
The reaction is conducted for 4 h at 80° C.


4-15
The reaction is conducted for 10 minutes at 70° C.


4-16
The reaction is conducted for 1 h at 70° C.


4-17
The reaction is conducted for 15 h at 80° C.


4-18
The reaction is conducted for 1 h at 70° C.


4-19
The reaction is conducted for 10 minutes at 70° C.


4-20
The reaction is conducted for 7 h at 80° C. and for 2 h



at 90° C.


4-21
Camphersulfonic acid is used instead of p-toluenesulfonic



acid. The reaction is conducted for 4 h at 80° C.


4-22
The reaction is conducted for 15 minutes at 70° C.


4-23
The reaction is conducted for 2 h at 90° C.


4-24
The reaction is conducted for 15 minutes at 70° C.


4-25
The reaction is conducted for 12 h at 70° C.


4-26
The reaction is conducted for 5 h at 90° C.


4-27
The reaction is conducted for 15 h at 90° C.


4-28
The reaction is conducted for 12 h at 90° C.


4-29
The reaction is conducted for 5 h at 80° C.


4-30
The reaction is conducted for 30 minutes at 80° C.


4-31
The reaction is conducted for 6 h at 120° C.


4-32
The reaction is conducted for 2 h at 80° C.


4-33
The reaction is conducted for 2 h at 60° C.


4-34
The reaction is conducted for 4 h at 120° C. and for 1 h



at 130° C.


4-35
The reaction is conducted for 15 h at 75° C. and for 12 h



at 80° C.


4-36
The reaction is conducted for 30 minutes at 70° C.


4-37
The reaction is conducted for 12 h at 70° C. and for 6 h



at 80° C.


4-38
The reaction is conducted for 12 h at 80° C.


4-39
The reaction is conducted for 12 h at 90° C.


4-40
The reaction is conducted for 12 h at 80° C.


4-41
The reaction is conducted for 22 h at 70° C.


4-42
The reaction is conducted for 12 h at 90° C.


4-43
The reaction is conducted for 48 h at 80° C.


4-44
The reaction is conducted for 3 h at 70° C.


4-45
The reaction is conducted for 20 h at 80° C.


4-46
The reaction is conducted for 4 h at 80° C.


4-47
The reaction is conducted for 2 h at 80° C.


4-48
The reaction is conducted for 20 h at 80° C.


4-49
The reaction is conducted for 5 h at 70° C.


4-50
The reaction is conducted for 5 h at 90° C.


4-51
The reaction is conducted for 16 h at 60° C.


4-52
The reaction is conducted for 12 h at 90° C.


4-53
The reaction is conducted for 22 h at 70° C.


4-54
The reaction is conducted for 22 h at 70° C.


4-55
The reaction is conducted for 20 h at 70° C.


4-56
The reaction is conducted for 12 h at 70° C.


4-57
The reaction is conducted for 4 h at 90° C.


4-58
The reaction is conducted for 13 h at 130° C.


4-59
The reaction is conducted for 5 h at 90° C.


4-60
The reaction is conducted for 5 h at 90° C.


4-61
The reaction is conducted for 5 h at 90° C.
























Name of
Name of


Intermediate
Name
Starting Material 1
Starting Material 2







4-1
Ethyl 1-[(2-chloro-6-{6,6-difluoro-3-
2-Chloro-6-{6,6-difluoro-3-
Ethyl 1H-1,2,3-triazole-



azabicyclo[3.1.0]-hexan-3-
azabicyclo[3.1.0]hexan-3-
4-carboxylate



yl}pyridin-3-yl)methyl]-1H-1,2,3-
yl}pyridin-3-yl)methanol




triazole-4-carboxylate




4-2
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-
(6-{5-Azaspiro[2.3]hexan-5-yl}-
Ethyl 1H-1,2,3-triazole-



5-yl}-2-chloropyridin-3-yl)methyl]-
2-chloropyridin-3-yl)methanol
4-carboxylate



1H-1,2,3-triazole-4-carboxylate




4-3
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-
(6-{5-Azaspiro[2.3]hexan-5-yl}-
Ethyl 1H-1,2,3-triazole-



5-yl}-2-bromopyridin-3-yl)methyl]-
2-bromopyridin-3-yl)methanol
4-carboxylate



1H-1,2,3-triazole-4-carboxylate




4-4
Ethyl 1-[(6-{6,6-difluoro-3-
6,6-Difluoro-3-[6-fluoro-5-
Ethyl 1H-imidazole-4-



azabicyclo[3.1.0]hexan-3-yl}-2-
(methoxymethyl)pyridin-2-yl]-3-
carboxylate



fluoropyridin-3-yl)methyl]-1H-
azabicyclo[3.1.0]hexane




imidazole-4-carboxylate




4-5
Ethyl 1-[(5-{3-azabicyclo[3.1.0]-
(5-{3-Azabicyclo[3.1.0]hexan-
Ethyl 1H-1,2,3-triazole-



hexan-3-yl}pyridin-2-yl)methyl]-1H-
3-yl}pyridin-2-yl)methanol
4-carboxylate



1,2,3-triazole-4-carboxylate




4-6
Ethyl 1-[(5-{3-azabicyclo[3.1.0]-
(5-{3-Azabicyclo[3.1.0]hexan-
Ethyl 1H-pyrazole-4-



hexan-3-yl}pyridin-2-yl)methyl]-1H-
3-yl}pyridin-2-yl)methanol
carboxylate



pyrazole-4-carboxylate




4-7
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-
5-[6-Fluoro-5-
Ethyl 1H-1,2,3-triazole-



5-yl}-2-fluoropyridin-3-yl)methyl]-
(methoxymethyl)pyridin-2-yl]-5-
4-carboxylate



1H-1,2,3-triazole-4-carboxylate
azaspiro[2.3]hexane



4-8
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-
5-[6-Fluoro-5-
Ethyl 1H-imidazole-4-



5-yl}-2-fluoropyridin-3-yl)methyl]-
(methoxymethyl)pyridin-2-yl]-5-
carboxylate



1H-imidazole-4-carboxylate
azaspiro[2.3]hexane



4-9
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-
5-[6-Fluoro-5-
Ethyl 1H-pyrazole-4-



5-yl}-2-fluoropyridin-3-yl)methyl]-
(methoxymethyl)pyridin-2-yl]-5-
carboxylate



1H-pyrazole-4-carboxylate
azaspiro[2.3]hexane



4-10
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-
(6-{5-Azaspiro[2.3]hexan-5-yl}-
Ethyl 1H-pyrazole-4-



5-yl}-2-bromopyridin-3-yl)methyl]-
2-bromopyridin-3-yl)methanol
carboxylate



1H-pyrazole-4-carboxylate




4-11
Ethyl 1-[(2-bromo-6-{6,6-difluoro-3-
(2-Bromo-6-{6,6-difluoro-3-
Ethyl 1H-1,2,3-triazole-



azabicyclo[3.1.0]hexan-3-yl}pyridin-
azabicyclo[3.1.0]hexan-3-
4-carboxylate



3-yl)methyl]-1H-1,2,3-triazole-4-
yl}pyridin-3-yl)methanol




carboxylate




4-12
Ethyl 1-[(2-bromo-6-{6,6-difluoro-3-
(2-Bromo-6-{6,6-difluoro-3-
Ethyl 1H-pyrazole-4-



azabicyclo[3.1.0]hexan-3-yl}pyridin-
azabicyclo[3.1.0]hexan-3-
carboxylate



3-yl)methyl]-1H-pyrazole-4-
yl}pyridin-3-yl)methanol




carboxylate




4-13
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-
(6-{5-Azaspiro[2.3]hexan-5-yl}-
Ethyl 1H-imidazole-4-



5-yl}-2-bromopyridin-3-yl)methyl]-
2-bromopyridin-3-yl)methanol
carboxylate



1H-imidazole-4-carboxylate




4-14
1-[(2-{3-Azabicyclo[3.1.0]-hexan-3-
(2-{3-Azabicyclo[3.1.0]hexan-
1H-imidazole-4-



yl}-4-[(1E)-2-phenyl-
3-yl}-4-[(1E)-2-phenylethenyl]-
carboxylic acid



ethenyl]pyrimidin-5-yl)methyl]-1H-
pyrimidin-5-yl)methanol




imidazole-4-carboxylic acid




4-15
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
3-[6-Fluoro-5-
Ethyl 1H-1,2,3-triazole-



hexan-3-yl}-2-fluoropyridin-3-yl)-
(methoxymethyl)pyridin-2-yl]-3-
4-carboxylate



methyl]-1H-1,2,3-triazole-4-
azabicyclo[3.1.0]hexane




carboxylate




4-16
Ethyl 1-[(6-{6,6-difluoro-3-
6,6-Difluoro-3-[6-fluoro-5-
Ethyl 1H-pyrazole-4-



azabicyclo[3.1.0]hexan-3-yl}-2-
(methoxymethyl)pyridin-2-yl]-3-
carboxylate



fluoropyridin-3-yl)methyl]-1H-
azabicyclo[3.1.0]hexane




pyrazole-4-carboxylate




4-17
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-
(6-{5-Azaspiro[2.3]hexan-5-yl}-
Ethyl 1H-imidazole-4-



5-yl}-2-chloropyridin-3-yl)methyl]-
2-chloropyridin-3-yl)methanol
carboxylate



1H-imidazole-4-carboxylate




4-18
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
(6-{3-Azabicyclo[3.1.0]hexan-
Ethyl 1H-pyrazole-4-



hexan-3-yl}-2-chloropyridin-3-yl)-
3-yl}-2-chloropyridin-3-yl)-
carboxylate



methyl]-1H-pyrazole-4-carboxylate
methanol



4-19
Ethyl 1-[(6-{6,6-difluoro-3-
6,6-Difluoro-3-[6-fluoro-5-
Ethyl 1H-1,2,3-triazole-



azabicyclo[3.1.0]hexan-3-yl}-2-
(methoxymethyl)pyridin-2-yl]-3-
4-carboxylate



fluoropyridin-3-yl)methyl]-1H-1,2,3-
azabicyclo[3.1.0]hexane




triazole-4-carboxylate




4-20
Ethyl 1-[(2-bromo-6-{6,6-difluoro-3-
(2-Bromo-6-{6,6-difluoro-3-
Ethyl 1H-imidazole-4-



azabicyclo[3.1.0]-hexan-3-yl}-
azabicyclo[3.1.0]hexan-3-yl}-
carboxylate



pyridin-3-yl)methyl]-1H-imidazole-
pyridin-3-yl)methanol




4-carboxylate




4-21
Ethyl 1-[(2-{3-azabicyclo[3.1.0]-
(2-{3-Azabicyclo[3.1.0]hexan-
Ethyl 1H-imidazole-4-



hexan-3-yl}-4-[(1E)-2-phenyl-
3-yl}-4-[(1E)-2-phenylethenyl]-
carboxylate



ethenyl]pyrimidin-5-yl)methyl]-1H-
pyrimidin-5-yl)methanol




imidazole-4-carboxylate




4-22
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
(6-{3-Azabicyclo[3.1.0]hexan-
Ethyl 1H-1,2,3-triazole-



hexan-3-yl}-2-bromopyridin-3-yl)-
3-yl}-2-bromopyridin-3-yl)-
4-carboxylate



methyl]-1H-1,2,3-triazole-4-
methanol




carboxylate




4-23
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
(6-{3-Azabicyclo[3.1.0]hexan-
Ethyl 1H-imidazole-4-



hexan-3-yl}-2-propylpyridin-3-yl)-
3-yl}-2-propylpyridin-3-yl)-
carboxylate



methyl]-1H-imidazole-4-carboxylate
methanol



4-24
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
(6-{3-Azabicyclo[3.1.0]hexan-
Ethyl 1H-1,2,3-triazole-



hexan-3-yl}-2-chloropyridin-3-yl)-
3-yl}-2-chloropyridin-3-yl)-
4-carboxylate



methyl]-1H-1,2,3-triazole-4-
methanol




carboxylate




4-25
Ethyl 1-[(6-{6,6-difluoro-3-
(6-{6,6-Difluoro-3-
Ethyl 1H-1,2,3-triazole-



azabicyclo[3.1.0]hexan-3-yl}pyridin-
azabicyclo[3.1.0]hexan-3-yl}-
4-carboxylate



3-yl)methyl]-1H-1,2,3-triazole-4-
pyridin-3-yl)methanol




carboxylate




4-26
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
(6-{3-Azabicyclo[3.1.0]hexan-
Ethyl 1H-imidazole-4-



hexan-3-yl}-2-methylpyridin-3-yl)-
3-yl}-2-methylpyridin-3-yl)-
carboxylate



methyl]-1H-imidazole-4-carboxylate
methanol



4-27
Ethyl 1-[(6-{6,6-difluoro-3-
(6-{6,6-Difluoro-3-
Ethyl 1H-imidazole-4-



azabicyclo[3.1.0]hexan-3-yl}-2-
azabicyclo[3.1.0]hexan-3-yl}-2-
carboxylate



methylpyridin-3-yl)methyl]-1H-
methylpyridin-3-yl)methanol




imidazole-4-carboxylate




4-28
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
3-[5-(Methoxymethyl)-6-
Ethyl 1H-imidazole-4-



hexan-3-yl}-2-(trifluoromethoxy)-
(trifluoromethoxy)pyridin-2-yl]-
carboxylate



pyridin-3-yl)methyl]-1H-imidazole-
3-azabicyclo[3.1.0]hexane




4-carboxylate




4-29
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
(6-{3-Azabicyclo[3.1.0]hexan-
Ethyl 1H-imidazole-4-



hexan-3-yl}-2-bromopyridin-3-yl)-
3-yl}-2-bromopyridin-3-yl)-
carboxylate



methyl]-1H-imidazole-4-carboxylate
methanol



4-30
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
(6-{3-Azabicyclo[3.1.0]hexan-
Ethyl 1H-pyrazole-4-



hexan-3-yl}-2-bromopyridin-3-yl)-
3-yl}-2-bromopyridin-3-yl)-
carboxylate



methyl]-1H-pyrazole-4-carboxylate
methanol



4-31
Ethyl 1-[(5-{6,6-difluoro-3-
(5-{6,6-Difluoro-3-
Ethyl 1H-pyrazole-4-



azabicyclo[3.1.0]hexan-3-yl}pyridin-
azabicyclo[3.1.0]hexan-3-yl}-
carboxylate



2-yl)methyl]-1H-pyrazole-4-
pyridin-2-yl)methanol




carboxylate




4-32
Ethyl 1-[(2-chloro-6-{6,6-difluoro-3-
(2-Chloro-6-{6,6-difluoro-3-
Ethyl 1H-pyrazole-4-



azabicyclo[3.1.0]-hexan-3-yl}-
azabicyclo[3.1.0]hexan-3-yl}-
carboxylate



pyridin-3-yl)methyl]-1H-pyrazole-4-
pyridin-3-yl)methanol




carboxylate




4-33
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-
(6-{5-Azaspiro[2.3]hexan-5-yl}-
Ethyl 1H-pyrazole-4-



5-yl}-2-chloropyridin-3-yl)methyl]-
2-chloropyridin-3-yl)methanol
carboxylate



1H-pyrazole-4-carboxylate




4-34
Ethyl 1-[(5-{6,6-difluoro-3-
(5-{6,6-Difluoro-3-
Ethyl 1H-imidazole-4-



azabicyclo[3.1.0]hexan-3-yl}pyridin-
azabicyclo[3.1.0]hexan-3-yl}-
carboxylate



2-yl)methyl]-1H-imidazole-4-
pyridin-2-yl)methanol




carboxylate




4-35
Ethyl 1-[(2-chloro-6-{6,6-difluoro-3-
(2-Chloro-6-{6,6-difluoro-3-
Ethyl 1H-imidazole-4-



azabicyclo[3.1.0]-hexan-3-yl}-
azabicyclo[3.1.0]hexan-3-yl}-
carboxylate



pyridin-3-yl)methyl]-1H-imidazole-
pyridin-3-yl)methanol




4-carboxylate




4-36
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
3-[5-(Methoxymethyl)-6-
Ethyl 1H-pyrazole-4-



hexan-3-yl}-2-(trifluoro-
(trifluoromethoxy)pyridin-2-yl]-
carboxylate



methoxy)pyridin-3-yl)methyl]-1H-
3-azabicyclo[3.1.0]hexane




pyrazole-4-carboxylate




4-37
Ethyl 1-[(6-{6,6-difluoro-3-
(6-{6,6-Difluoro-3-
Ethyl 1H-imidazole-4-



azabicyclo[3.1.0]hexan-3-yl}pyridin-
azabicyclo[3.1.0]hexan-3-
carboxylate



3-yl)methyl]-1H-imidazole-4-
yl}pyridin-3-yl)methanol




carboxylate




4-38
Ethyl 1-[(6-{3-
(6-{3-Azabicyclo[3.1.0]hexan-
Ethyl 1H-imidazole-4-



azabicyclo[3.1.0]hexan-3-yl}-2-
3-yl}-2-chloropyridin-3-
carboxylate



chloropyridin-3-yl)methyl]-1H-
yl)methanol




imidazole-4-carboxylate




4-39
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
(6-{3-Azabicyclo[3.1.0]hexan-
Ethyl 1H-imidazole-4-



hexan-3-yl}pyridin-3-yl)methyl]-1H-
3-yl}pyridin-3-yl)methanol
carboxylate



imidazole-4-carboxylate




4-40
Methyl 1-[(6-{3-azabicyclo-
(6-{3-Azabicyclo[3.1.0]hexan-
Methyl 3-cyano-1H-



[3.1.0]hexan-3-yl}-2-methyl-pyridin-
3-yl}-2-methylpyridin-3-
pyrazole-4-carboxylate



3-yl)methyl]-3-cyano-1H-pyrazole-
yl)methanol




4-carboxylate




4-41
Ethyl 1-[(6-{3-
(6-{3-Azabicyclo[3.1.0]hexan-
Ethyl 1H-pyrazole-4-



azabicyclo[3.1.0]hexan-3-yl}-4-
3-yl}-4-chloropyridin-3-
carboxylate



chloropyridin-3-yl)methyl]-1H-
yl)methanol




pyrazole-4-carboxylate




4-42
Ethyl 1-[(5-cyano-6-{6,6-difluoro-3-
2-{6,6-Difluoro-3-
Ethyl 1H-pyrazole-4-



azabicyclo[3.1.0]hexan-3-yl}-4-
azabicyclo[3.1.0]hexan-3-yl}-5-
carboxylate



methylpyridin-3-yl)methyl]-1H-
(hydroxymethyl)-4-




pyrazole-4-carboxylate
methylpyridine-3-carbonitrile



4-43
Ethyl 1-[(5-cyano-6-{6,6-difluoro-3-
2-{6,6-Difluoro-3-
Ethyl 1H-imidazole-4-



azabicyclo[3.1.0]hexan-3-yl}-4-
azabicyclo[3.1.0]hexan-3-yl}-5-
carboxylate



methylpyridin-3-yl)methyl]-1H-
(hydroxymethyl)-4-




imidazole-4-carboxylate
methylpyridine-3-carbonitrile



4-44
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
3-[6-Fluoro-5-
Ethyl 1H-pyrazole-4-



hexan-3-yl}-2-fluoropyridin-3-yl)-
(methoxymethyl)pyridin-2-yl]-3-
carboxylate



methyl]-1H-pyrazole-4-carboxylate
azabicyclo[3.1.0]hexane



4-45
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
(6-{3-Azabicyclo[3.1.0]hexan-
Ethyl 1H-imidazole-4-



hexan-3-yl}-4-methylpyridin-3-yl)-
3-yl}-4-methylpyridin-3-yl)-
carboxylate



methyl]-1H-imidazole-4-carboxylate
methanol



4-46
Ethyl 1-[(6-{6,6-difluoro-3-
(6-{6,6-Difluoro-3-
Ethyl 1H-imidazole-4-



azabicyclo[3.1.0]hexan-3-yl}-2,4-
azabicyclo[3.1.0]hexan-3-yl}-
carboxylate



dimethylpyridin-3-yl)methyl]-1H-
2,4-dimethylpyridin-3-yl)-




imidazole-4-carboxylate
methanol



4-47
Ethyl 1-[(6-{6,6-difluoro-3-
(6-{6,6-Difluoro-3-
Ethyl 1H-pyrazole-4-



azabicyclo[3.1.0]hexan-3-yl}-2,4-
azabicyclo[3.1.0]hexan-3-yl}-
carboxylate



dimethylpyridin-3-yl)methyl]-1H-
2,4-dimethylpyridin-3-yl)-




pyrazole-4-carboxylate
methanol



4-48
Ethyl 1-({2-chloro-6-[(1R,5S,6R)-6-
{2-Chloro-6-[(1R,5S,6R)-6-
Ethyl 1H-imidazole-4-



methyl-3-azabicyclo[3.1.0]hexan-3-
methyl-3-azabicyclo[3.1.0]-
carboxylat



yl]pyridin-3-yl}methyl)-1H-
hexan-3-yl]pyridin-3-yl}-




imidazole-4-carboxylate
methanol



4-49
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
2-{3-Azabicyclo[3.1.0]hexan-3-
Ethyl 1H-pyrazole-4-



hexan-3-yl}-5-cyanopyridin-3-yl)-
yl}-5-(hydroxymethyl)pyridine-
carboxylate



methyl]-1H-pyrazole-4-carboxylate
3-carbonitrile



4-50
Ethyl 2-chloro-1-[(6-{6,6-difluoro-3-
(6-{6,6-difluoro-3-
Ethyl 2-chloro-1H-



azabicyclo[3.1.0]hexan-3-yl}pyridin-
azabicyclo[3.1.0]hexan-3-
imidazole-4-carboxylate



3-yl)methyl]-1H-imidazole-4-
yl}pyridin-3-yl)methanol




carboxylate




4-51
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
2-{3-Azabicyclo[3.1.0]hexan-3-
Ethyl 1H-pyrazole-4-



hexan-3-yl}-5-cyano-4-
yl}-5-(hydroxymethyl)-4-
carboxylate



methylpyridin-3-yl)methyl]-1H-
methylpyridine-3-carbonitrile




pyrazole-4-carboxylate




4-52
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
2-{3-Azabicyclo[3.1.0]hexan-3-
Ethyl 1H-imidazole-4-



hexan-3-yl}-5-cyano-4-
yl}-5-(hydroxymethyl)-4-
carboxylate



methylpyridin-3-yl)methyl]-1H-
methylpyridine-3-carbonitrile




imidazole-4-carboxylate




4-53
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
(6-{3-Azabicyclo[3.1.0]hexan-
Ethyl 1H-imidazole-4-



hexan-3-yl}-4-chloropyridin-3-yl)-
3-yl}-4-chloropyridin-3-
carboxylate



methyl]-1H-imidazole-4-carboxylate
yl)methanol



4-54
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
(6-{3-Azabicyclo[3.1.0]hexan-
Ethyl 1H-imidazole-4-



hexan-3-yl}-4-(trifluoromethyl)-
3-yl}-4-(trifluoromethyl)pyridin-
carboxylate



pyridin-3-yl)methyl]-1H-imidazole-
3-yl)methanol




4-carboxylate




4-55
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
(6-{3-Azabicyclo[3.1.0]hexan-
Ethyl 1H-imidazole-4-



hexan-3-yl}-5-bromo-2-
3-yl}-5-bromo-2-methylpyridin-
carboxylate



methylpyridin-3-yl)methyl]-1H-
3-yl)methanol




imidazole-4-carboxylate




4-56
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
(6-{3-Azabicyclo[3.1.0]hexan-
Ethyl 1H-pyrazole-4-



hexan-3-yl}-5-bromo-2-
3-yl}-5-bromo-2-methylpyridin-
carboxylate



methylpyridin-3-yl)methyl]-1H-
3-yl)methanol




pyrazole-4-carboxylate




4-57
Ethyl 1-[(2-{6,6-difluoro-3-
(2-{6,6-Difluoro-3-
Ethyl 1H-imidazole-4-



azabicyclo[3.1.0]hexan-3-yl}-4-
azabicyclo[3.1.0]hexan-3-yl}-4-
carboxylat



methylpyrimidin-5-yl)methyl]-1H-
methylpyrimidin-5-yl)methanol




imidazole-4-carboxylate




4-58
Ethyl 1-[(5-{6,6-difluoro-3-
(5-{6,6-Difluoro-3-
Ethyl 1H-1,2,3-triazole-



azabicyclo[3.1.0]hexan-3-yl}pyridin-
azabicyclo[3.1.0]hexan-3-yl}-
4-carboxylate



2-yl)methyl]-1H-1,2,3-triazole-4-
pyridin-2-yl)methanol




carboxylate




4-59
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-
(2-{5-Azaspiro[2.3]hexan-5-yl}-
Ethyl 1H-imidazole-4-



5-yl}-2-methylpyrimidin-3-yl)-
4-methylpyrimidin-5-yl)-
carboxylat



methyl]-1H-imidazole-4-carboxylate
methanol



4-60
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-
(2-{5-Azaspiro[2.3]hexan-5-yl}-
Ethyl 1H-imidazole-4-



yl}-2-methylpyridin-3-yl)methyl]-1H-
4-methylpyridin-5-yl)methanol
carboxylate



imidazole-4-carboxylate




4-61
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
(6-{3-Azabicyclo[3.1.0]-hexan-
Ethyl 1H-imidazole-4-



hexan-3-yl}-2-methylpyrimidin-3-
3-yl}-2-methyl-pyrimidin-3-yl)-
carboxylate



yl)methyl]-1H-imidazole-4-
methanol




carboxylate









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



embedded image


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 for 3 h at 50° C. After cooling to rt aqueous HCl (4 M, 648 μL) is added and the solvents are evaporated to give the crude product, which is directly used in the next step. LC (Method 2): tR=0.58 min; Mass spectrum (ESI+): m/z=285 [M+H]+.


Intermediates 5-1 to 5-170 are prepared in analogy to Intermediate 5:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







5-1


embedded image


0.67
365
Method 2





5-2


embedded image


0.90
356
Method 2





5-3


embedded image


0.91
336
Method 2





5-4


embedded image


0.89
320
Method 2





5-5


embedded image


0.93
364
Method 2





5-6


embedded image


0.73

Method 2





5-7


embedded image


0.62
286
Method 2





5-8


embedded image


0.64
285
Method 2





5-9


embedded image


0.86
304
Method 2





5-10


embedded image


0.73

Method 2





5-11


embedded image


0.90
303
Method 2





5-12


embedded image


0.94
363
Method 2





5-13


embedded image


0.91
400
Method 2





5-14


embedded image


0.94
399
Method 1





5-15


embedded image


0.77

Method 2





5-16


embedded image


0.88
304
Method 2





5-17


embedded image


0.89
339
Method 2





5-18


embedded image


0.66
285
Method 2





5-19


embedded image


0.62
314
Method 2





5-20


embedded image


0.62

Method 1





5-21


embedded image


0.63
313
Method 2





5-22


embedded image


0.86
362 [M + Na]+
Method 2





5-23


embedded image


0.57
286
Method 2





5-24


embedded image


0.64

Method 1





5-25


embedded image


0.67
336
Method 2





5-26


embedded image


0.95
336
Method 2





5-27


embedded image


0.71
328
Method 1





5-28


embedded image


0.92
320
Method 2





5-29


embedded image


0.54
322
Method 2





5-30


embedded image


0.62
299
Method 1





5-31


embedded image


0.62
335
Method 1





5-32


embedded image


0.84
364
Method 2





5-33


embedded image


0.88
310
Method 2





5-34


embedded image



349













5-35


embedded image


Crude product is directly used in the next step














5-36


embedded image


0.88

Method 2





5-37


embedded image


0.79

Method 2





5-38


embedded image


0.97
363
Method 2





5-39


embedded image


0.66
321
Method 2





5-40


embedded image


0.87
350
Method 2





5-41


embedded image


0.66
335
Method 1





5-42


embedded image


0.96
355
Method 2





5-43


embedded image


0.65
371
Method 1





5-44


embedded image


0.65
371
Method 1





5-45


embedded image


0.64

Method 1





5-46


embedded image


0.62
336
Method 1





5-47


embedded image


0.67
313
Method 1





5-48


embedded image


0.64
335
Method 1





5-49


embedded image


0.58
321
Method 2





5-50


embedded image


0.62
343
Method 2





5-51


embedded image


0.62
319
Method 1





5-52


embedded image


0.63
377 [M + Na]+
Method 1





5-53


embedded image


1.06
369
Method 2





5-54


embedded image


0.65
343
Method 2





5-55


embedded image


0.51
286
Method 2





5-56


embedded image


0.56
316
Method 2





5-57


embedded image


0.66
316
Method 2





5-58


embedded image


0.55
321
Method 1





5-59


embedded image


0.66
335
Method 1





5-60


embedded image


1.04
352
Method 2





5-61


embedded image


0.60
363
Method 2





5-62


embedded image


0.73
375
Method 1





5-63


embedded image


0.59
300
Method 2





5-64


embedded image


0.70
363
Method 1





5-65


embedded image


0.41
286
Method 1





5-66


embedded image


0.28
285
Method 2





5-67


embedded image


0.40
313
Method 2





5-68


embedded image


0.73
349
Method 1





5-69


embedded image


0.60
315
Method 1





5-70


embedded image


0.76
324
Method 2





5-71


embedded image


0.61
329
Method 2





5-72


embedded image


0.60
329
Method 2





5-73


embedded image


0.60
329
Method 2





5-74


embedded image


0.63
343
Method 2





5-75


embedded image


0.58
329
Method 2





5-76


embedded image


0.71
343
Method 2





5-77


embedded image


0.59
315
Method 1





5-78


embedded image


0.77
316
Method 2





5-79


embedded image


0.62
335
Method 2





5-80


embedded image


0.33
316
Method 2












5-81


embedded image


Crude product is directly used in the next step














5-82


embedded image


0.83
337
Method 2





5-83


embedded image


0.59
365
Method 2





5-84


embedded image


0.24
351
Method 2





5-85


embedded image


0.44
352
Method 2





5-86


embedded image


0.69
324
Method 1





5-87


embedded image


0.66
319
Method 2





5-88


embedded image


0.62
341
Method 2





5-89


embedded image


0.60
314
Method 2





5-90


embedded image


0.90
360
Method 2





5-91


embedded image


0.75
382 [M + Na]+
Method 2





5-92


embedded image


0.92
303
Method 2





5-93


embedded image


0.65
299
Method 1





5-94


embedded image


0.59
365
Method 2





5-95


embedded image


0.64
338
Method 2





5-96


embedded image


0.75

Method 2





5-97


embedded image


0.63
350
Method 2





5-98


embedded image


0.57
327
Method 2





5-99


embedded image


0.64
349
Method 1





5-100


embedded image


0.67
349
Method 2





5-101


embedded image


0.72
351
Method 2





5-102


embedded image


0.86
310
Method 2





5-103


embedded image


0.64
352
Method 2





5-104


embedded image


0.87
324
Method 2





5-105


embedded image


0.70
325
Method 2





5-106


embedded image


0.73
322 [M − H]
Method 2





5-107


embedded image


0.56
319
Method 2





5-108


embedded image


0.71
353
Method 2





5-109


embedded image


0.78
319
Method 2





5-110


embedded image


0.63
343
Method 2





5-111


embedded image


0.78
324
Method 2





5-112


embedded image


0.64
379
Method 2





5-113


embedded image


0.97
319
Method 2





5-114


embedded image


0.67
378
Method 2





5-115


embedded image


0.97
377
Method 2





5-116


embedded image


0.95
324
Method 2





5-117


embedded image


0.74
377
Method 1





5-118


embedded image


0.68
313
Method 2





5-119


embedded image


0.65
313
Method 2





5-120


embedded image


0.65
310
Method 1





5-121


embedded image


0.68
253
Method 2





5-122


embedded image


0.60
299
Method 2





5-123


embedded image


0.67
336
Method 2





5-124


embedded image


0.74
337
Method 2





5-125


embedded image


0.65
301
Method 2





5-126


embedded image


0.65
322
Method 2





5-127


embedded image


0.62
320
Method 2





5-128


embedded image


0.62
320
Method 2





5-129


embedded image


0.65
334
Method 2





5-130


embedded image


0.65
334
Method 2





5-131


embedded image


0.73
327
Method 2





5-132


embedded image


0.70
336
Method 1





5-133


embedded image


0.72
372
Method 1





5-134


embedded image


0.65
314
Method 2





5-135


embedded image


0.64
352
Method 1





5-136


embedded image


0.65
320
Method 1





5-137


embedded image


0.65
316
Method 1





5-138


embedded image


0.99
356
Method 2





5-139


embedded image


0.61
286
Method 1





5-140


embedded image


0.64
336
Method 2





5-141


embedded image


0.61
300
Method 2





5-142


embedded image


0.68
350
Method 2





5-143


embedded image


0.62
336
Method 2





5-144


embedded image


0.98
320
Method 2





5-145


embedded image


0.67
314
Method 2





5-146


embedded image


0.64
314
Method 2





5-147


embedded image


0.94
354
Method 2





5-148


embedded image


0.78
391
Method 2





5-149


embedded image


0.74
377
Method 2





5-150


embedded image


0.82 and 0.84
445
Method 2








embedded image




Method 2






(mixture of isomers)








5-151


embedded image


0.73
341
Method 2





5-152


embedded image


0.71
363
Method 2





5-153


embedded image


0.70
327
Method 2





5-154


embedded image


0.65
313
Method 2





5-155


embedded image


0.71
327
Method 2





5-156


embedded image


0.67
313
Method 2





5-157


embedded image


0.58
300
Method 2





5-158


embedded image


0.63
299
Method 2





5-159


embedded image


0.60
300
Method 2





5-160


embedded image


0.65
355
Method 1





5-161


embedded image


0.63
350
Method 1





5-162


embedded image


0.77
387
Method 1





5-163


embedded image


0.68
351
Method 1





5-164


embedded image


0.67
299
Method 2





5-165


embedded image


0.68
299
Method 2





5-166


embedded image


0.69
335
Method 2





5-167


embedded image


0.72
349
Method 2





5-168


embedded image


0.72
329
Method 2





5-169


embedded image


0.75
365
Method 2





5-170


embedded image


0.69
367
Method 2




















Intermediate
Reaction comment







5-1
The reaction is conducted in EtOH for 3 h at rt.


5-2
NaOH is used instead of KOH. The reaction is conducted for 1.5 h at 70° C.


5-3
NaOH is used instead of KOH. The reaction is conducted in EtOH for 48 h at rt.



The product is purified by HPLC on reversed phase (ACN, water).


5-4
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 2 h.


5-5
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1 h.


5-6
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1.5 h.


5-7
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1.5 h.


5-9
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1.5 h.


5-10
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1.5 h.


5-11
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1.5 h.


5-12
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 2 h.


5-13
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1 h.


5-14
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 45 minutes at 70° C.


5-15
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1.5 h.


5-16
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1 h.


5-17
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1.5 h.


5-19
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 2 h at 50° C.


5-20
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 20 minutes at 70° C.


5-21
NaOH is used instead of KOH. The reaction is conducted in MeOH for 12 h at rt.


5-22
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1 h.


5-23
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 0.1 h.


5-24
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 45 minutes at 70° C.


5-25
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 4 h at 50° C.


5-26
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1 h.


5-27
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 2 h at 70° C.


5-28
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1 h.


5-29
The reaction is conducted at 70° C. for 1 h.


5-30
NaOH is used instead of KOH. The reaction is conducted in EtOH for 3 h at rt.


5-31
NaOH is used instead of KOH. The reaction is conducted for 1.5 h at 50° C.


5-32
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1 h.


5-33
NaOH is used instead of KOH. The reaction is conducted at 50° C. for 1 h.


5-34
NaOH is used instead of KOH. The reaction is conducted at 50° C. for 1.5 h.


5-35
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 5 h at 50° C.


5-36
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1 h.


5-37
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1 h.


5-38
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 3 h.


5-40
NaOH is used instead of KOH. The reaction is conducted at 50° C. for 1 h.


5-41
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 8 h.


5-42
NaOH is used instead of KOH. The reaction is conducted at 40° C. for 4 h.


5-43
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 45 minutes at 70° C.


5-44
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 2 h at 70° C.


5-45
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 45 minutes at 70° C.


5-46
The reaction is conducted in EtOH for 48 h at 50° C.


5-47
The reaction is conducted in EtOH for 4 h at 50° C.


5-48
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 2 h at 70° C.


5-49
The reaction is conducted for 2 h at 50° C.


5-50
NaOH is used instead of KOH. The reaction is conducted in EtOH for 12 h at 40° C.


5-51
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 1 h at 70° C.


5-52
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 40 minutes at 70° C.


5-53
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 2 h.


5-54
NaOH is used instead of KOH. The reaction is conducted in EtOH for 12 h at rt.


5-55
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 5 h.


5-56
NaOH is used instead of KOH. The reaction is conducted at 50° C. for 2 h.


5-57
NaOH is used instead of KOH. The reaction is conducted in THF for 4 h at 80° C.


5-58
NaOH is used instead of KOH. The reaction is conducted in 1,4-dioxane for 3 h at 50° C.


5-59
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 40 minutes at 70° C.


5-60
NaOH is used instead of KOH. The reaction is conducted in EtOH for 48 h at rt.


5-61
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1 h.


5-62
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 2 h at 70° C.


5-63
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 2 h at 50° C.


5-64
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 2 h at 70° C.


5-65
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 1.5 h at70° C.


5-66
NaOH is used instead of KOH. The reaction is conducted in MeOH for 3 h at rt.


5-67
NaOH is used instead of KOH. The reaction is conducted for 2 h at 60° C.


5-68
NaOH is used instead of KOH. The reaction is conducted for 12 h at 40° C.


5-69
NaOH is used instead of KOH. The reaction is conducted in MeOH for 4 h at rt.


5-70
NaOH is used instead of KOH. The reaction is conducted in MeOH for 15 h at rt.


5-71
NaOH is used instead of KOH. The reaction is conducted for 6 h at 50° C.


5-72
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 2.5 h at 70° C.


5-73
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 2.5 h at 70° C.


5-74
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 2.5 h at 70° C.


5-75
NaOH is used instead of KOH. The reaction is conducted in MeOH for 12 h at 50° C.


5-76
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 50 minutes at rt.


5-77
NaOH is used instead of KOH. The reaction is conducted in MeOH for 4 h at rt.


5-78
NaOH is used instead of KOH. The reaction is conducted for 4 h at 50° C.


5-79
The reaction is conducted in EtOH for 12 h at 50° C.


5-80
NaOH is used instead of KOH. The reaction is conducted in EtOH for 12 h at rt.


5-81
NaOH is used instead of KOH.



The reaction is conducted in THF for 6 h at 80° C. and for 12 h at rt.


5-82
LiOH is used instead of KOH. The reaction is conducted in THF/MeOH for 12 h at 50° C.


5-83
NaOH is used instead of KOH. The reaction is conducted for 2 h at 40° C.


5-84
The reaction is conducted for 4 h at 40° C.


5-85
NaOH is used instead of KOH. The reaction is conducted in EtOH for 12 h at rt.


5-86
NaOH is used instead of KOH. The reaction is conducted in MeOH for 6 h at rt.


5-87
NaOH is used instead of KOH. The reaction is conducted for 3 h at 70° C.


5-88
NaOH is used instead of KOH. The reaction is conducted for 2 h at 70° C.


5-89
The reaction is conducted in EtOH for 12 h at 50° C.


5-90
NaOH is used instead of KOH. The reaction is conducted for 4.5 h at 50° C.


5-91
NaOH is used instead of KOH. The reaction is conducted for 2 h at 50° C.


5-92
The reaction is conducted for 12 h at 50° C.


5-93
NaOH is used instead of KOH. The reaction is conducted in EtOH for 2.5 h at rt.


5-94
NaOH is used instead of KOH. The reaction is conducted in 1,4-dioxane for 1 h at 90° C.


5-95
NaOH is used instead of KOH. The reaction is conducted in MeOH for 12 h at rt.


5-96
NaOH is used instead of KOH. The reaction is conducted for 1 h at 70° C.


5-97
The reaction is conducted in EtOH for 12 h at 50° C.


5-98
NaOH is used instead of KOH. The reaction is conducted for 2 h at 70° C.


5-99
NaOH is used instead of KOH. The reaction is conducted for 1 h at 70° C.


5-100
NaOH is used instead of KOH. The reaction is conducted for 1 h at 70° C.


5-101
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1 h.


5-102
NaOH is used instead of KOH. The reaction is conducted for 1 h at 70° C.


5-103
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1 h.


5-104
NaOH is used instead of KOH. The reaction is conducted for 1 h at 60° C.


5-105
NaOH is used instead of KOH. The reaction is conducted in EtOH for 12 h at rt.


5-106
NaOH is used instead of KOH. The reaction is conducted for 1 h at 60° C.


5-107
NaOH is used instead of KOH. The reaction is conducted for 2.5 h at 70° C.


5-108
NaOH is used instead of KOH. The reaction is conducted for 2.5 h at 70° C.


5-109
NaOH is used instead of KOH. The reaction is conducted in EtOH for 12 h at 40° C.


5-110
NaOH is used instead of KOH. The reaction is conducted for 7 h at 60° C.


5-111
NaOH is used instead of KOH. The reaction is conducted for 1 h at 70° C.


5-112
NaOH is used instead of KOH. The reaction is conducted for 20 h at 50° C.


5-113
NaOH is used instead of KOH. The reaction is conducted in EtOH for 12 h at 40° C.


5-114
NaOH is used instead of KOH. The reaction is conducted for 2.5 h at 60° C.


5-115
NaOH is used instead of KOH. The reaction is conducted for 2 h at 50° C.


5-116
NaOH is used instead of KOH. The reaction is conducted for 1.5 h at 70° C.


5-117
NaOH is used instead of KOH. The reaction is conducted in THF/EtOH for 2 h at 70° C.


5-118
NaOH is used instead of KOH. The reaction is conducted for 1 h at 70° C.


5-119
NaOH is used instead of KOH. The reaction is conducted for 1.5 h at 70° C.


5-120
NaOH is used instead of KOH. The reaction is conducted in EtOH for 4 h at rt.


5-121
LiOH is used instead of KOH. The reaction is conducted in THF/water for 12 h at rt.


5-122
The reaction is conducted for 48 h at 50° C.


5-123
NaOH is used instead of KOH. The reaction is conducted in MeOH for 12 h at rt.


5-124
NaOH is used instead of KOH. The reaction is conducted for 1.5 h at 50° C.


5-125
NaOH is used instead of KOH. The reaction is conducted in EtOH for 12 h at 50° C.


5-126
The reaction is conducted for 2 h at 50° C.


5-127
NaOH is used instead of KOH. The reaction is conducted for 2 days at 70° C.


5-128
NaOH is used instead of KOH. The reaction is conducted for 5 days at 70° C.


5-129
NaOH is used instead of KOH. The reaction is conducted for 35 h at 70° C. and for 3 days at rt.


5-130
NaOH is used instead of KOH. The reaction is conducted for 24 h at 70° C. and for 2 days at 50° C.


5-131
NaOH is used instead of KOH. The reaction is conducted for h at rt.


5-132
NaOH is used instead of KOH. The reaction is conducted for 45 min at rt.


5-133
NaOH is used instead of KOH. The reaction is conducted for 45 min at rt.


5-134
NaOH is used instead of KOH. The reaction is conducted for 4 h at rt.


5-135
NaOH is used instead of KOH. The reaction is conducted for 30 min at rt.


5-136
NaOH is used instead of KOH. The reaction is conducted for 1.5 h at rt.


5-137
NaOH is used instead of KOH. The reaction is conducted for 2.5 h at rt.


5-138
NaOH is used instead of KOH. The reaction is conducted for 45 min at rt.


5-139
NaOH is used instead of KOH. The reaction is conducted for 1.5 h at rt.


5-140
NaOH is used instead of KOH. The reaction is conducted for 16 h at rt.


5-141
NaOH is used instead of KOH. The reaction is conducted for 16 h at rt.


5-142
NaOH is used instead of KOH. The reaction is conducted for 72 h at rt.


5-143
NaOH is used instead of KOH. The reaction is conducted for 18 h at rt.


5-144
NaOH is used instead of KOH. The reaction is conducted for 2 h at 50° C.


5-145
NaOH is used instead of KOH. The reaction is conducted for 30 min at 50° C.


5-146
NaOH is used instead of KOH. The reaction is conducted in MeOH for 5 h at rt.


5-147
NaOH is used instead of KOH. The reaction is conducted for 12 h at 80° C.


5-148
NaOH is used instead of KOH. The reaction is conducted for 17 h at rt.


5-149
NaOH is used instead of KOH. The reaction is conducted for 17 h at rt.


5-150
NaOH is used instead of KOH. The reaction is conducted in EtOH for 12 h at rt.


5-151
NaOH is used instead of KOH. The reaction is conducted for 1.5 h at 40° C.


5-152
NaOH is used instead of KOH. The reaction is conducted for 3 h at 40° C.


5-153
NaOH is used instead of KOH. The reaction is conducted for 45 minutes at 40° C.


5-154
NaOH is used instead of KOH. The reaction is conducted in MeOH for 12 h at rt.


5-155
NaOH is used instead of KOH. The reaction is conducted in EtOH for 5 days at rt.


5-156
NaOH is used instead of KOH. The reaction is conducted in THF for 16 h at rt.


5-157
NaOH is used instead of KOH. The reaction is conducted in MeOH for 1 h at 40° C.


5-158
NaOH is used instead of KOH. The reaction is conducted in EtOH for 2 h at rt.


5-159
NaOH is used instead of KOH. The reaction is conducted in MeOH for 1 h at 40° C.


5-160
NaOH is used instead of KOH. The reaction is conducted in 1,4-dioxane/water 2:1 for 3 h at rt.


5-161
NaOH is used instead of KOH. The reaction is conducted in MeOH/dioxane for 4 h at 50° C.



The product is purified by HPLC on reversed phase (ACN, water).


5-162
LiOH is used instead of KOH. The reaction is conducted in MeOH for 6 h at 75° C.


5-163
LiOH is used instead of KOH. The reaction is conducted in MeOH for 16 h at 75° C.


5-164
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1 h.


5-165
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 2 h.


5-166
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1.5 h.


5-167
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1.5 h.


5-168
NaOH is used instead of KOH. The reaction is conducted in EtOH at r.t. for 3.5 h.


5-169
NaOH is used instead of KOH. The reaction is conducted at 70° C. for 1 h.


5-170
NaOH is used instead of KOH. The reaction is conducted at 50° C. for 2 h.





















Intermediate
Name
Name of Starting Material







5-1 
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1H-
hexan-3-yl}-2-(methoxymethyl)pyridin-3-



pyrazole-4-carboxylic acid
yl)methyl]-1H-pyrazole-4-carboxylate


5-2 
1-[(2-Chloro-6-{6,6-difluoro-3-
Ethyl 1-[(2-chloro-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}pyridin-3-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid
yl)methyl]-1H-1,2,3-triazole-4-carboxylate


5-3 
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



(difluoromethyl)pyridin-3-yl)methyl]-1H-1,2,3-
(difluoromethyl)pyridin-3-yl)methyl]-1H-1,2,3-



triazole-4-carboxylic acid
triazole-4-carboxylate


5-4 
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



chloropyridin-3-yl)methyl]-1H-1,2,3-triazole-4-
chloropyridin-3-yl)methyl]-1H-1,2,3-triazole-4-



carboxylic acid
carboxylate


5-5 
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



bromopyridin-3-yl)methyl]-1H-1,2,3-triazole-4-
bromopyridin-3-yl)methyl]-1H-1,2,3-triazole-4-



carboxylic acid
carboxylate


5-6 
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-



yl}-2-fluoropyridin-3-yl)methyl]-1H-imidazole-
azabicyclo[3.1.0]hexan-3-yl}-2-fluoropyridin-3-



4-carboxylic acid
yl)methyl]-1H-imidazole-4-carboxylate


5-7 
1-[(5-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridin-2-
Ethyl 1-[(5-{3-azabicyclo[3.1.0]hexan-3-yl}-



yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid
pyridin-2-yl)methyl]-1H-1,2,3-triazole-4-




carboxylate


5-8 
1-[(5-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridin-2-
Ethyl 1-[(5-{3-azabicyclo[3.1.0]hexan-3-yl}-



yl)methyl]-1H-pyrazole-4-carboxylic acid
pyridin-2-yl)methyl]-1H-pyrazole-4-carboxylate


5-9 
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



fluoropyridin-3-yl)methyl]-1H-1,2,3-triazole-4-
fluoropyridin-3-yl)methyl]-1H-1,2,3-triazole-4-



carboxylic acid
carboxylate


5-10
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



fluoropyridin-3-yl)methyl]-1H-imidazole-4-
fluoropyridin-3-yl)methyl]-1H-imidazole-4-



carboxylic acid
carboxylate


5-11
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



fluoropyridin-3-yl)methyl]-1H-pyrazole-4-
fluoropyridin-3-yl)methyl]-1H-pyrazole-4-



carboxylic acid
carboxylate


5-12
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



bromopyridin-3-yl)methyl]-1H-pyrazole-4-
bromopyridin-3-yl)methyl]-1H-pyrazole-4-



carboxylic acid
carboxylate


5-13
1-[(2-Bromo-6-{6,6-difluoro-3-
Ethyl 1-[(2-bromo-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}pyridin-3-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid
yl)methyl]-1H-1,2,3-triazole-4-carboxylate


5-14
1-[(2-Bromo-6-{6,6-difluoro-3-
Ethyl 1-[(2-bromo-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}pyridin-3-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl)methyl]-1H-pyrazole-4-carboxylic acid
yl)methyl]-1H-pyrazole-4-carboxylate


5-15
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



bromopyridin-3-yl)methyl]-1H-imidazole-4-
bromopyridin-3-yl)methyl]-1H-imidazole-4-



carboxylic acid
carboxylate


5-16
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



fluoropyridin-3-yl)methyl]-1H-1,2,3-triazole-4-
fluoropyridin-3-yl)methyl]-1H-1,2,3-triazole-4-



carboxylic acid
carboxylate


5-17
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-



yl}-2-fluoropyridin-3-yl)methyl]-1H-pyrazole-4-
azabicyclo[3.1.0]hexan-3-yl}-2-fluoropyridin-3-



carboxylic acid
yl)methyl]-1H-pyrazole-4-carboxylate


5-18
1-[(5-{5-Azaspiro[2.3]hexan-5-yl}pyridin-2-
Ethyl 1-[(5-{5-azaspiro[2.3]hexan-5-yl}pyridin-



yl)methyl]-1H-pyrazole-4-carboxylic acid
2-yl)methyl]-1H-pyrazole-4-carboxylate


5-19
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



ethylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-
ethylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-



carboxylic acid
carboxylate


5-20
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



chloropyridin-3-yl)methyl]-1H-imidazole-4-
chloropyridin-3-yl)methyl]-1H-imidazole-4-



carboxylic acid
carboxylate


5-21
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



ethylpyridin-3-yl)methyl]-1H-pyrazole-4-
ethylpyridin-3-yl)methyl]-1H-pyrazole-4-



carboxylic acid
carboxylate


5-22
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-



yl}-2-fluoropyridin-3-yl)methyl]-1H-1,2,3-
azabicyclo[3.1.0]hexan-3-yl}-2-fluoropyridin-3-



triazole-4-carboxylic acid
yl)methyl]-1H-1,2,3-triazole-4-carboxylate


5-23
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}pyridin-3-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}pyridin-



yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid
3-yl)methyl]-1H-1,2,3-triazole-4-carboxylate


5-24
1-[(2-Bromo-6-{6,6-difluoro-3-
Ethyl 1-[(2-bromo-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}pyridin-3-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl)methyl]-1H-imidazole-4-carboxylic acid
yl)methyl]-1H-imidazole-4-carboxylate


5-25
1-[(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-
Ethyl 1-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-



(difluoromethyl)pyrimidin-5-yl)methyl]-1H-
4(difluoromethyl)pyrimidin-5-yl)methyl]-1H-



imidazole-4-carboxylic acid
imidazole-4-carboxylate


5-26
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(difluoromethyl)pyridin-3-yl)methyl]-1H-1,2,3-
(difluoromethyl)pyridin-3-yl)methyl]-1H-1,2,3-



triazole-4-carboxylic acid
triazole-4-carboxylate


5-27
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



propylpyridin-3-yl)methyl]-1H-imidazole-4-
propylpyridin-3-yl)methyl]-1H-imidazole-4-



carboxylic acid
carboxylate


5-28
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



chloropyridin-3-yl)methyl]-1H-1,2,3-triazole-4-
chloropyridin-3-yl)methyl]-1H-1,2,3-triazole-4-



carboxylic acid
carboxylate


5-29
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-



yl}pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



carboxylic acid
yl)methyl]-1H-1,2,3-triazole-4-carboxylate


5-30
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methyl]-1H-imidazole-4-
methylpyridin-3-yl)methyl]-1H-imidazole-4-



carboxylic acid
carboxylate


5-31
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-



yl}-2-methylpyridin-3-yl)methyl]-1H-imidazole-
azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-



4-carboxylic acid
3-yl)methyl]-1H-imidazole-4-carboxylate


5-32
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



bromopyridin-3-yl)methyl]-1H-1,2,3-triazole-4-
bromopyridin-3-yl)methyl]-1H-1,2,3-triazole-4-



carboxylic acid
carboxylate


5-33
1-[(5-{3-Azabicyclo[3.1.0]hexan-3-yl}-6-
Ethyl 1-[(5-{3-azabicyclo[3.1.0]hexan-3-yl}-6-



cyanopyridin-2-yl)methyl]-1H-pyrazole-4-
cyanopyridin-2-yl)methyl]-1H-pyrazole-4-



carboxylic acid
carboxylate


5-34
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-



yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole-4-
azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-



carboxylic acid
yl)methyl]-1H-pyrazole-4-carboxylate


5-35
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



ethylpyridin-3-yl)methyl]-1H-imidazole-4-
ethylpyridin-3-yl)methyl]-1H-imidazole-4-



carboxylic acid
carboxylate


5-36
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(trifluoromethoxy)pyridin-3-yl)methyl]-1H-
(trifluoromethoxy)pyridin-3-yl)methyl]-1H-



imidazole-4-carboxylic acid
imidazole-4-carboxylate


5-37
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



bromopyridin-3-yl)methyl]-1H-imidazole-4-
bromopyridin-3-yl)methyl]-1H-imidazole-4-



carboxylic acid
carboxylate


5-38
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



bromopyridin-3-yl)methyl]-1H-pyrazole-4-
bromopyridin-3-yl)methyl]-1H-pyrazole-4-



carboxylic acid
carboxylate


5-39
1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(5-{6,6-difluoro-3-



yl}pyridin-2-yl)methyl]-1H-pyrazole-4-
azabicyclo[3.1.0]hexan-3-yl}pyridin-2-



carboxylic acid
yl)methyl]-1H-pyrazole-4-carboxylate


5-40
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(1-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



cyanocyclopropyl)pyridin-3-yl)methyl]-1H-
(1-cyanocyclopropyl)pyridin-3-yl)methyl]-1H-



pyrazole-4-carboxylic acid
pyrazole-4-carboxylate


5-41
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(difluoromethyl)pyridin-3-yl)methyl]-1H-
(difluoromethyl)pyridin-3-yl)methyl]-1H-



pyrazole-4-carboxylic acid
pyrazole-4-carboxylate


5-42
1-[(2-Chloro-6-{6,6-difluoro-3-
Ethyl 1-[(2-chloro-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}pyridin-3-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl)methyl]-1H-pyrazole-4-carboxylic acid
yl)methyl]-1H-pyrazole-4-carboxylate


5-43
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-
hexan-3-yl}-2-(difluoromethyl)pyridin-3-



imidazole-4-carboxylic acid
yl)methyl]-1H-imidazole-4-carboxylate


5-44
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-
hexan-3-yl}-2-(difluoromethyl)pyridin-3-



pyrazole-4-carboxylic acid
yl)methyl]-1H-pyrazole-4-carboxylate


5-45
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



(difluoromethyl)pyridin-3-yl)methyl]-1H-
(difluoromethyl)pyridin-3-yl)methyl]-1H-



imidazole-4-carboxylic acid
imidazole-4-carboxylate


5-46
1-[(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-
Ethyl 1-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-



(difluoromethyl)pyrimidin-5-yl)methyl]-1H-
(difluoromethyl)pyrimidin-5-yl)methyl]-1H-



pyrazole-4-carboxylic acid
pyrazole-4-carboxylate


5-47
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



ethylpyridin-3-yl)methyl]-1H-pyrazole-4-
ethylpyridin-3-yl)methyl]-1H-pyrazole-4-



carboxylic acid
carboxylate


5-48
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



(difluoromethyl)pyridin-3-yl)methyl]-1H-
(difluoromethyl)pyridin-3-yl)methyl]-1H-



pyrazole-4-carboxylic acid
pyrazole-4-carboxylate


5-49
1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(5-{6,6-difluoro-3-



yl}pyridin-2-yl)methyl]-1H-imidazole-4-
azabicyclo[3.1.0]hexan-3-yl}pyridin-2-



carboxylic acid
yl)methyl]-1H-imidazole-4-carboxylate


5-50
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(3-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



hydroxypropyl)pyridin-3-yl)methyl]-1H-
(3-hydroxypropyl)pyridin-3-yl)methyl]-1H-



pyrazole-4-carboxylic acid
pyrazole-4-carboxylate


5-51
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



chloropyridin-3-yl)methyl]-1H-pyrazole-4-
chloropyridin-3-yl)methyl]-1H-pyrazole-4-



carboxylic acid
carboxylate


5-52
1-[(2-Chloro-6-{6,6-difluoro-3-
Ethyl 1-[(2-chloro-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}pyridin-3-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl)methyl]-1H-imidazole-4-carboxylic acid
yl)methyl]-1H-imidazole-4-carboxylate


5-53
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(trifluoromethoxy)pyridin-3-yl)methyl]-1H-
(trifluoromethoxy)pyridin-3-yl)methyl]-1H-



pyrazole-4-carboxylic acid
pyrazole-4-carboxylate


5-54
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(1-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



hydroxypropan-2-yl)pyridin-3-yl)methyl]-1H-
(1-hydroxypropan-2-yl)pyridin-3-yl)methyl]-1H-



pyrazole-4-carboxylic acid
pyrazole-4-carboxylate


5-55
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridazin-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-



3-yl)methyl]-1H-pyrazole-4-carboxylic acid
pyridazin-3-yl)methyl]-1H-pyrazole-4-




carboxylate


5-56
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



(hydroxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-
(hydroxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-



triazole-4-carboxylic acid
triazole-4-carboxylate


5-57
1-[(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-
Ethyl 1-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-



(hydroxymethyl)pyrimidin-5-yl)methyl]-1H-
(hydroxymethyl)pyrimidin-5-yl)methyl]-1H-



pyrazole-4-carboxylic acid
pyrazole-4-carboxylate


5-58
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-



yl}pyridin-3-yl)methyl]-1H-imidazole-4-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



carboxylic acid
yl)methyl]-1H-imidazole-4-carboxylate


5-59
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(difluoromethyl)pyridin-3-yl)methyl]-1H-
(difluoromethyl)pyridin-3-yl)methyl]-1H-



imidazole-4-carboxylic acid
imidazole-4-carboxylate


5-60
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(1-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



cyano-1-methylethyl)pyridin-3-yl)methyl]-1H-
(1-cyano-1-methylethyl)pyridin-3-yl)methyl]-



pyrazole-4-carboxylic acid
1H-pyrazole-4-carboxylate


5-61
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-



yl}-2-propylpyridin-3-yl)methyl]-1H-imidazole-
azabicyclo[3.1.0]hexan-3-yl}-2-propylpyridin-3-



4-carboxylic acid
yl)methyl]-1H-imidazole-4-carboxylate


5-62
1-[(2-Cyclobutyl-6-{6,6-difluoro-3-
Ethyl 1-[(2-cyclobutyl-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}pyridin-3-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl)methyl]-1H-pyrazole-4-carboxylic acid
yl)methyl]-1H-pyrazole-4-carboxylate


5-63
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



methylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-
methylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-



carboxylic acid
carboxylate


5-64
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-



yl}-2-propylpyridin-3-yl)methyl]-1H-pyrazole-4-
azabicyclo[3.1.0]hexan-3-yl}-2-propylpyridin-3-



carboxylic acid
yl)methyl]-1H-pyrazole-4-carboxylate


5-65
1-[(5-{3-Azabicyclo[3.1.0]hexan-3-yl}pyrimidin-
Ethyl 1-[(5-{3-azabicyclo[3.1.0]hexan-3-yl}-



2-yl)methyl]-1H-pyrazole-4-carboxylic acid
pyrimidin-2-yl)methyl]-1H-pyrazole-4-




carboxylate


5-66
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridin-3-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-



yl)methyl]-1H-imidazole-4-carboxylic acid
pyridin-3-yl)methyl]-1H-imidazole-4-




carboxylate


5-67
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



ethylpyridin-3-yl)methyl]-1H-imidazole-4-
ethylpyridin-3-yl)methyl]-1H-imidazole-4-



carboxylic acid
carboxylate


5-68
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-



yl}-2-ethylpyridin-3-yl)methyl]-1H-imidazole-4-
azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-



carboxylic acid
yl)methyl]-1H-imidazole-4-carboxylate


5-69
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



(hydroxymethyl)pyridin-3-yl)methyl]-1H-
(hydroxymethyl)pyridin-3-yl)methyl]-1H-



pyrazole-4-carboxylic acid
pyrazole-4-carboxylatetrifluoroacetate


5-70
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(cyanomethyl)pyridin-3-yl)methyl]-1H-
(cyanomethyl)pyridin-3-yl)methyl]-1H-



pyrazole-4-carboxylic acid
pyrazole-4-carboxylate


5-71
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(1-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



hydroxyethyl)pyridin-3-yl)methyl]-1H-pyrazole-
(1-hydroxyethyl)pyridin-3-yl)methyl]-1H-



4-carboxylic acid
pyrazole-4-carboxylate


5-72
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-[(1R)-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



1-hydroxyethyl]pyridin-3-yl)methyl]-1H-
[(1R)-1-hydroxyethyl]pyridin-3-yl)methyl]-1H-



pyrazole-4-carboxylic acid
pyrazole-4-carboxylate


5-73
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-[(1S)-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



1-hydroxyethyl]pyridin-3-yl)methyl]-1H-
[(1R)-1-hydroxyethyl]pyridin-3-yl)methyl]-1H-



pyrazole-4-carboxylic acid
pyrazole-4-carboxylate


5-74
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



hydroxypropan-2-yl)pyridin-3-yl)methyl]-1H-
(2-hydroxypropan-2-yl)pyridin-3-yl)methyl]-1H-



pyrazole-4-carboxylic acid
pyrazole-4-carboxylate


5-75
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



hydroxyethyl)pyridin-3-yl)methyl]-1H-pyrazole-
(2-hydroxyethyl)pyridin-3-yl)methyl]-1H-



4-carboxylic acid
pyrazole-4-carboxylate


5-76
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(hydroxymethyl)pyridin-3-yl)methyl]-1H-
(hydroxymethyl)pyridin-3-yl)methyl]-1H-



pyrazole-4-carboxylic acid
pyrazole-4-carboxylate


5-77
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



(hydroxymethyl)pyridin-3-yl)methyl]-1H-
(hydroxymethyl)pyridin-3-yl)methyl]-1H-



imidazole-4-carboxylic acid
imidazole-4-carboxylate


5-78
1-[(5-{3-Azabicyclo[3.1.0]hexan-3-yl}-3-
Ethyl 1-[(5-{3-azabicyclo[3.1.0]hexan-3-yl}-3-



(hydroxymethyl)pyrazin-2-yl)methyl]-1H-
(hydroxymethyl)pyrazin-2-yl)methyl]-1H-



pyrazole-4-carboxylic acid
pyrazole-4-carboxylate


5-79
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-



yl}-2-methylpyridin-3-yl)methyl]-1H-pyrazole-
azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-



4-carboxylic acid
3-yl)methyl]-1H-pyrazole-4-carboxylate


5-80
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(hydroxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-
(hydroxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-



triazole-4-carboxylic acid
triazole-4-carboxylate


5-81
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-
hexan-3-yl}-2-(hydroxymethyl)pyridin-3-yl)-



pyrazole-4-carboxylic acid
methyl]-1H-pyrazole-4-carboxylate


5-82
1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(5-{6,6-difluoro-3-



yl}-3-methylpyrazin-2-yl)methyl]-1H-1,2,3-
azabicyclo[3.1.0]hexan-3-yl}-3-methylpyrazin-



triazole-4-carboxylic acid
2-yl)methyl]-1H-1,2,3-triazole-4-carboxylate


5-83
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1H-
hexan-3-yl}-2-(methoxymethyl)pyridin-3-



imidazole-4-carboxylic acid
yl)methyl]-1H-imidazole-4-carboxylate


5-84
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-
hexan-3-yl}-2-(hydroxymethyl)pyridin-3-



imidazole-4-carboxylic acid
yl)methyl]-1H-imidazole-4-carboxylate


5-85
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-
hexan-3-yl}-2-(hydroxymethyl)pyridin-3-



1,2,3-triazole-4-carboxylic acid
yl)methyl]-1H-1,2,3-triazole-4-carboxylate


5-86
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Methyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methyl]-3-cyano-1H-
methylpyridin-3-yl)methyl]-3-cyano-1H-



pyrazole-4-carboxylic acid
pyrazole-4-carboxylate


5-87
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-4-



chloropyridin-3-yl)methyl]-1H-pyrazole-4-
chloropyridin-3-yl)methyl]-1H-pyrazole-4-



carboxylic acid
carboxylate


5-88
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



methylpropyl)pyridin-3-yl)methyl]-1H-
(2-methylpropyl)pyridin-3-yl)methyl]-1H-



imidazole-4-carboxylic acid
imidazole-4-carboxylate


5-89
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



ethylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-
ethylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-



carboxylic acid
carboxylate


5-90
1-[(5-Cyano-6-{6,6-difluoro-3-
Ethyl 1-[(5-cyano-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}-4-methylpyridin-
azabicyclo[3.1.0]hexan-3-yl}-4-methylpyridin-



3-yl)methyl]-1H-pyrazole-4-carboxylic acid
3-yl)methyl]-1H-pyrazole-4-carboxylate


5-91
1-[(5-Cyano-6-{6,6-difluoro-3-
Ethyl 1-[(5-cyano-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}-4-methylpyridin-
azabicyclo[3.1.0]hexan-3-yl}-4-methylpyridin-



3-yl)methyl]-1H-imidazole-4-carboxylic acid
3-yl)methyl]-1H-imidazole-4-carboxylate


5-92
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



fluoropyridin-3-yl)methyl]-1H-pyrazole-4-
fluoropyridin-3-yl)methyl]-1H-pyrazole-4-



carboxylic acid
carboxylate


5-93
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-4-



methylpyridin-3-yl)methyl]-1H-imidazole-4-
methylpyridin-3-yl)methyl]-1H-imidazole-4-



carboxylic acid
carboxylate


5-94
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 3-(chloromethyl)-1-[(6-{6,6-difluoro-3-



yl}-2-methylpyridin-3-yl)methyl]-3-
azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-



(hydroxymethyl)-1H-pyrazole-4-carboxylic acid
3-yl)methyl]-1H-pyrazole-4-carboxylate


5-95
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methyl]-3-(cyanomethyl)-
methylpyridin-3-yl)methyl]-3-(cyanomethyl)-



1H-pyrazole-4-carboxylic acid
1H-pyrazole-4-carboxylate


5-96
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



fluoropyridin-3-yl)methyl]-1H-imidazole-4-
fluoropyridin-3-yl)methyl]-1H-imidazole-4-



carboxylic acid
carboxylate


5-97
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-



yl}-2-ethylpyridin-3-yl)methyl]-1H-1,2,3-
azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-



triazole-4-carboxylic acid
yl)methyl]-1H-1,2,3-triazole-4-carboxylate


5-98
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



propylpyridin-3-yl)methyl]-1H-imidazole-4-
propylpyridin-3-yl)methyl]-1H-imidazole-4-



carboxylic acid
carboxylate


5-99
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2,4-dimethylpyridin-3-yl)methyl]-1H-
hexan-3-yl}-2,4-dimethylpyridin-3-yl)methyl]-



imidazole-4-carboxylic acid
1H-imidazole-4-carboxylate


 5-100
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2,4-dimethylpyridin-3-yl)methyl]-1H-
hexan-3-yl}-2,4-dimethylpyridin-3-yl)methyl]-



pyrazole-4-carboxylic acid
1H-pyrazole-4-carboxylate


 5-101
5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 5-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-methylpyridin-3-yl)methyl]thiophene-2-
hexan-3-yl}-2-methylpyridin-3-yl)-



carboxylic acid
methyl]thiophene-2-carboxylate


 5-102
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-



cyanopyridin-3-yl)methyl]-1H-pyrazole-4-
cyanopyridin-3-yl)methyl]-1H-pyrazole-4-



carboxylic acid
carboxylate


 5-103
2-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Methyl 2-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-methylpyridin-3-yl)methyl]-1,3-thiazole-5-
hexan-3-yl}-2-methylpyridin-3-yl)methyl]-1,3-



carboxylic acid
thiazole-5-carboxylate


 5-104
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-cyano-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-



4-methylpyridin-3-yl)methyl]-1H-pyrazole-4-
cyano-4-methylpyridin-3-yl)methyl]-1H-



carboxylic acid
pyrazole-4-carboxylate


 5-105
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



cyclopropylpyridin-3-yl)methyl]-1H-pyrazole-4-
cyclopropylpyridin-3-yl)methyl]-1H-pyrazole-4-



carboxylic acid
carboxylate


 5-106
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-cyano-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-



4-methylpyridin-3-yl)methyl]-1H-imidazole-4-
cyano-4-methylpyridin-3-yl)methyl]-1H-



carboxylic acid
imidazole-4-carboxylate


 5-107
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-4-



chloropyridin-3-yl)methyl]-1H-imidazole-4-
chloropyridin-3-yl)methyl]-1H-imidazole-4-



carboxylic acid
carboxylate


 5-108
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-4-



(trifluoromethyl)pyridin-3-yl)methyl]-1H-
(trifluoromethyl)pyridin-3-yl)methyl]-1H-



imidazole-4-carboxylic acid
imidazole-4-carboxylate


 5-109
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



chloropyridin-3-yl)methyl]-1H-imidazole-4-
chloropyridin-3-yl)methyl]-1H-imidazole-4-



carboxylic acid
carboxylate


 5-110
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methyl]-3-(methoxymethyl)-
methylpyridin-3-yl)methyl]-3-(methoxymethyl)-



1H-pyrazole-4-carboxylic acid
1H-pyrazole-4-carboxylate


 5-111
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-cyano-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-



2-methylpyridin-3-yl)methyl]-1H-imidazole-4-
cyano-2-methylpyridin-3-yl)methyl]-1H-



carboxylic acid
imidazole-4-carboxylate


 5-112
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-methylpyridin-3-yl)methyl]-3-(methoxy-
hexan-3-yl}-2-methylpyridin-3-yl)methyl]-3-



methyl)-1H-pyrazole-4-carboxylic acid
(methoxymethyl)-1H-pyrazole-4-carboxylate


 5-113
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



chloropyridin-3-yl)methyl]-1H-pyrazole-4-
chloropyridin-3-yl)methyl]-1H-pyrazole-4-



carboxylic acid
carboxylate


 5-114
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methyl]-3-bromo-1H-
methylpyridin-3-yl)methyl]-3-bromo-1H-



pyrazole-4-carboxylic acid
pyrazole-4-carboxylate


 5-115
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-



bromo-2-methylpyridin-3-yl)methyl]-1H-
bromo-2-methylpyridin-3-yl)methyl]-1H-



pyrazole-4-carboxylic acid
pyrazole-4-carboxylate


 5-116
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-cyano-
Methyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-



2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-
cyano-2-methylpyridin-3-yl)methyl]-1H-



carboxylic acid
pyrazole-4-carboxylate


 5-117
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-



bromo-2-methylpyridin-3-yl)methyl]-1H-
bromo-2-methylpyridin-3-yl)methyl]-1H-



imidazole-4-carboxylic acid
imidazole-4-carboxylate


 5-118
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2,5-
Methyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-



dimethylpyridin-3-yl)methyl]-1H-imidazole-4-
2,5-dimethylpyridin-3-yl)methyl]-1H-imidazole-



carboxylic acid
4-carboxylate


 5-119
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2,5-
Methyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-



dimethylpyridin-3-yl)methyl]-1H-pyrazole-4-
2,5-dimethylpyridin-3-yl)methyl]-1H-pyrazole-



carboxylic acid
4-carboxylate


 5-120
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



cyanopyridin-3-yl)methyl]-1H-pyrazole-4-
cyanopyridin-3-yl)methyl]-1H-pyrazole-4-



carboxylic acid
carboxylate


 5-121
1-[(2-Chloro-4-methylpyrimidin-5-yl)methyl]-
Ethyl 1-[(2-chloro-4-methylpyrimidin-5-yl)-



1H-pyrazole-4-carboxylic acid
methyl]-1H-pyrazole-4-carboxylate


 5-122
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methyl]-1H-pyrazole-4-
methylpyridin-3-yl)methyl]-1H-pyrazole-4-



carboxylic acid
carboxylate


 5-123
1-[(2-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(2-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-4-methylpyrimidin-5-yl)methyl]-1H-
hexan-3-yl}-4-methylpyrimidin-5-yl)methyl]-



imidazole-4-carboxylic acid
1H-imidazole-4-carboxylate


 5-124
1-[(2-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(2-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-4-methylpyrimidin-5-yl)methyl]-1H-1,2,3-
hexan-3-yl}-4-methylpyrimidin-5-yl)methyl]-



triazole-4-carboxylic acid
1H-1,2,3-triazole-4-carboxylate


 5-125
1-[(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-
Ethyl 1-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-



methylpyrimidin-5-yl)methyl]-1H-1,2,3-triazole-
methylpyrimidin-5-yl)methyl]-1H-1,2,3-triazole-



4-carboxylic acid
4-carboxylate


 5-126
1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(5-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}pyridin-2-yl)methyl]-1H-1,2,3-triazole-4-
hexan-3-yl}pyridin-2-yl)methyl]-1H-1,2,3-



carboxylic acid
triazole-4-carboxylate


 5-127
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Methyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}pyridin-3-yl)methyl]-1H-pyrrole-3-carboxylic
hexan-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3-



acid
carboxylate


 5-128
5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Methyl 5-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}pyridin-3-yl)methyl]-1H-pyrrole-3-carboxylic
hexan-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3-



acid
carboxylate


 5-129
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Methyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-methylpyridin-3-yl)methyl]-1H-pyrrole-3-
hexan-3-yl}-2-methylpyridin-3-yl)methyl]-1H-



carboxylic acid
pyrrole-3-carboxylate


 5-130
5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Methyl 5-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-methylpyridin-3-yl)methyl]-1H-pyrrole-3-
hexan-3-yl}-2-methylpyridin-3-yl)methyl]-1H-



carboxylic acid
pyrrole-3-carboxylate


 5-131
1-({2-Ethyl-6-[(1R,5S,6R)-6-methyl-3-
Ethyl 1-({2-ethyl-6-[(1R,5S,6R)-6-methyl-3-



azabicyclo[3.1.0]hexan-3-yl]pyridin-3-
azabicyclo[3.1.0]hexan-3-yl]pyridin-3-



yl}methyl)-1H-imidazole-4-carboxylic acid
yl}methyl)-1H-imidazole-4-carboxylate


 5-132
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(difluoromethyl)pyridin-3-yl)methyl]-1,2-
(difluoromethyl)pyridin-3-yl)methyl]-1,2-



oxazole-5-carboxylic acid
oxazole-5-carboxylate


 5-133
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1,2-
hexan-3-yl}-2-(difluoromethyl)pyridin-3-



oxazole-5-carboxylic acid
yl)methyl]-1,2-oxazole-5-carboxylate


 5-134
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



ethylpyridin-3-yl)methyl]-1,2-oxazole-5-
ethylpyridin-3-yl)methyl]-1,2-oxazole-5-



carboxylic acid
carboxylate


 5-135
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1,2-
hexan-3-yl}-2-(hydroxymethyl)pyridin-3-



oxazole-5-carboxylic acid
yl)methyl]-1,2-oxazole-5-carboxylate


 5-136
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



chloropyridin-3-yl)methyl]-1,2-oxazole-5-
chloropyridin-3-yl)methyl]-1,2-oxazole-5-



carboxylic acid
carboxylate


 5-137
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(hydroxymethyl)pyridin-3-yl)methyl]-1,2-
(hydroxymethyl)pyridin-3-yl)methyl]-1,2-



oxazole-5-carboxylic acid
oxazole-5-carboxylate


 5-138
3-[(2-Chloro-6-{6,6-difluoro-3-
Ethyl 3-[(2-chloro-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}pyridin-3-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl)methyl]-1,2-oxazole-5-carboxylic acid
yl)methyl]-1,2-oxazole-5-carboxylate


 5-139
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridin-3-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-



yl)methyl]-1,2-oxazole-5-carboxylic acid
pyridin-3-yl)methyl]-1,2-oxazole-5-carboxylate


 5-140
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-methylpyridin-3-yl)methyl]-1,2-oxazole-5-
hexan-3-yl}-2-methylpyridin-3-yl)methyl]-1,2-



carboxylic acid
oxazole-5-carboxylate


 5-141
2-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Methyl 2-[1-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-



methylpyridin-3-yl)methyl]-1,3-oxazole-5-
2-methylpyridin-3-yl)-2-methoxy-2-oxoethyl]-



carboxylic acid
1,3-oxazole-5-carboxylate


 5-142
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-ethylpyridin-3-yl)methyl]-1,2-oxazole-5-
hexan-3-yl}-2-ethylpyridin-3-yl)methyl]-1,2-



carboxylic acid
oxazole-5-carboxylate


 5-143
2-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 2-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-methylpyridin-3-yl)methyl]-1,3-oxazole-5-
hexan-3-yl}-2-methylpyridin-3-yl)methyl]-1,3-



carboxylic acid
oxazole-5-carboxylate


 5-144
3-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 3-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



chloropyridin-3-yl)methyl]-1,2-oxazole-5-
chloropyridin-3-yl)methyl]-1,2-oxazole-5-



carboxylic acid
carboxylate


 5-145
3-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 3-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



ethylpyridin-3-yl)methyl]-1,2-oxazole-5-
ethylpyridin-3-yl)methyl]-1,2-oxazole-5-



carboxylic acid
carboxylate


 5-146
2-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Methyl 2-[1-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-



ethylpyridin-3-yl)methyl]-1,3-oxazole-5-
2-ethylpyridin-3-yl)-2-methoxy-2-oxoethyl]-



carboxylic acid
1,3-oxazole-5-carboxylate


 5-147
5-[(2-Chloro-6-{6,6-difluoro-3-
Methyl 5-[(2-chloro-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}pyridin-3-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl)methyl]-1H-pyrrole-3-carboxylic acid
yl)methyl]-1H-pyrrole-3-carboxylate


 5-148
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-ethylpyridin-3-yl)methyl]-1-(propan-2-yl)-
hexan-3-yl}-2-ethylpyridin-3-yl)methyl]-1-



1H-pyrazole-5-carboxylic acid
(propan-2-yl)-1H-pyrazole-5-carboxylate


 5-149
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-ethylpyridin-3-yl)methyl]-1-ethyl-1H-
hexan-3-yl}-2-ethylpyridin-3-yl)methyl]-1-ethyl-



pyrazole-5-carboxylic acid
1H-pyrazole-5-carboxylate


 5-150
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(hydroxymethyl)pyridin-3-yl)methyl]-1-{[2-
(hydroxymethyl)pyridin-3-yl)methyl]-1-{[2-



(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-
(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-



carboxylic acid and
carboxylate and



5-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(hydroxymethyl)pyridin-3-yl)methyl]-1-{[2-
(hydroxymethyl)pyridin-3-yl)methyl]-1-{[2-



(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-
(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-



carboxylic acid (mixture of isomers)
carboxylate (mixture of isomers)


 5-151
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



ethylpyridin-3-yl)methyl]-1-ethyl-1H-pyrazole-
ethylpyridin-3-yl)methyl]-1-ethyl-1H-pyrazole-



5-carboxylic acid
5-carboxylate


 5-152
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-methylpyridin-3-yl)methyl]-1-ethyl-1H-
hexan-3-yl}-2-methylpyridin-3-yl)methyl]-1-



pyrazole-5-carboxylic acid
ethyl-1H-pyrazole-5-carboxylate


 5-153
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methyl]-1-ethyl-1H-
methylpyridin-3-yl)methyl]-1-ethyl-1H-



pyrazole-5-carboxylic acid
pyrazole-5-carboxylate


 5-154
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



ethylpyridin-3-yl)methyl]-1H-pyrazole-5-
ethylpyridin-3-yl)methyl]-1H-pyrazole-5-



carboxylic acid
carboxylate


 5-155
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



ethylpyridin-3-yl)methyl]-1-methyl-1H-
ethylpyridin-3-yl)methyl]-1-methyl-1H-



pyrazole-5-carboxylic acid
pyrazole-5-carboxylate


 5-156
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methyl]-1-methyl-1H-
methylpyridin-3-yl)methyl]-1-methyl-1H-



pyrazole-5-carboxylic acid
pyrazole-5-carboxylate


 5-157
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



methylpyrimidin-3-yl)methyl]-1H-imidazole-4-
methylpyrimidin-3-yl)methyl]-1H-imidazole-4-



carboxylic acid
carboxylate


 5-158
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



methylpyridin-3-yl)methyl]-1H-imidazole-4-
methylpyridin-3-yl)methyl]-1H-imidazole-4-



carboxylic acid
carboxylate


 5-159
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyrimidin-3-yl)methyl]-1H-imidazole-4-
methylpyrimidin-3-yl)methyl]-1H-imidazole-4-



carboxylic acid
carboxylate


 5-160
2-chloro-1-[(6-{6,6-difluoro-3-
Ethyl 2-chloro-1-[(6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}pyridin-3-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl)methyl]-1H-imidazole-4-carboxylic acid
yl)methyl]-1H-imidazole-4-carboxylate


 5-161
7-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Methyl 7-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methyl]-7H-pyrrolo[2,3-
methylpyridin-3-yl)methyl]-7H-pyrrolo[2,3-



d]pyrimidine-5-carboxylic acid
d]pyrimidine-5-carboxylate


 5-162
7-[(2-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Methyl 7-[(2-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-4-methylpyrimidin-5-yl)methyl]-7H-
hexan-3-yl}-4-methylpyrimidin-5-yl)methyl]-



pyrrolo[2,3-d]pyrimidine-5-carboxylic acid
7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate


 5-163
7-[(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-
Methyl 7-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-



methylpyrimidin-5-yl)methyl]-7H-pyrrolo[2,3-
methylpyrimidin-5-yl)methyl]-7H-pyrrolo[2,3-



d]pyrimidine-5-carboxylic acid
d]pyrimidine-5-carboxylate


 5-164
5-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Methyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methyl]furan-2-carboxylic
methylpyridin-3-yl)methyl]furan-2-carboxylate



acid



 5-165
5-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methyl]furan-3-carboxylic
methylpyridin-3-yl)methyl]furan-3-carboxylate



acid



 5-166
5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Methyl 5-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-methylpyridin-3-yl)methyl]furan-2-
hexan-3-yl}-2-methylpyridin-3-yl)methyl]furan-



carboxylic acid
2-carboxylate


 5-167
5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Methyl 5-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-ethylpyridin-3-yl)methyl]furan-2-
hexan-3-yl}-2-ethylpyridin-3-yl)methyl]furan-2-



carboxylic acid
carboxylate


 5-168
5-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-ethyl-
Ethyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]thiophene-2-carboxylic acid
ethylpyridin-3-yl)methyl]thiophene-2-




carboxylate


 5-169
5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 5-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-ethylpyridin-3-yl)methyl]thiophene-2-
hexan-3-yl}-2-ethylpyridin-3-



carboxylic acid
yl)methyl]thiophene-2-carboxylate


 5-170
5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 5-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-(hydroxymethyl)pyridin-3-
hexan-3-yl}-2-(hydroxymethyl)-pyridin-3-



yl)methyl]thiophene-2-carboxylic acid
yl)methyl]thiophene-2-carboxylate









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



embedded image


Under 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 rt, concentrated in vacuo, partitioned between water and EtOAc and the phases are separated. The organic phase is washed with brine, dried (MgSO4), concentrated and the residue is chromatographed on silica gel (petroleum ether/EtOAc 85:15→70:30) to give the title compound.


LC (Method 2): tR=1.03 min; Mass spectrum (ESI+): m/z=303 [M+H]+.


Intermediates 6-1 to 6-19 are prepared in analogy to Intermediate 6:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







6-1


embedded image


1.02
259
Method 2





6-2


embedded image


1.03
223
Method 2





6-3


embedded image


1.05
267
Method 2





6-4


embedded image


0.94
243
Method 2





6-5


embedded image


0.95
207
Method 2





6-6


embedded image


0.95
207
Method 2





6-7


embedded image


0.99
223
Method 2





6-8


embedded image


1.04
267
Method 2





6-9


embedded image


0.65
225
Method 2





6-10


embedded image


0.70
239
Method 2





6-11


embedded image


0.91
203
Method 1





6-12


embedded image


0.59
203
Method 2





6-13


embedded image


0.87
223
Method 1





6-14


embedded image


1.16
362
Method 1





6-15


embedded image


0.91
203
Method 1





6-16


embedded image


0.98
253
Method 1





6-17


embedded image


1.17
326
Method 1





6-18


embedded image


1.10
237
Method 2





6-19


embedded image


0.86
225
Method 2




















Intermediate
Reaction comment







6-4 
K2CO3 is used as base instead of DIPEA.



The reaction is conducted for 2 h at rt.


6-5 
K2CO3 is used as base instead of DIPEA.



The reaction is conducted for 2 h at rt.


6-6 
K2CO3 is used as base instead of DIPEA.



The reaction is conducted for 2 h at rt.


6-7 
The reaction is conducted for 6 h at 90° C.


6-8 
The reaction is conducted for 12 h at rt.


6-9 
K2CO3 is used as base instead of DIPEA.



The reaction is conducted for 12 h at 80° C.


6-10
KHCO3 is used as base instead of DIPEA.



The reaction is conducted in DMSO for 12 h at 80° C.


6-11
KHCO3 is used as base instead of DIPEA.



The reaction is conducted in DMSO for 12 h at 80° C.


6-12
KHCO3 is used as base instead of DIPEA.



The reaction is conducted in DMSO for 48 h at 45° C.


6-13
KHCO3 is used as base instead of DIPEA.



The reaction is conducted in DMSO for 4 h at 45° C.


6-14
The reaction is conducted in DMSO for 12 h at 60° C.


6-15
KHCO3 is used as base instead of DIPEA.



The reaction is conducted in DMSO for 12 h at 60° C.


6-16
The reaction is conducted for 24 h at 70° C.


6-17
The reaction is conducted for 18 h at 50° C.


6-18
The reaction is conducted for 2 h at 50° C.
























Name of
Name of


Intermediate
Name
Starting Material 1
Starting Material 2


















6-1 
2-Chloro-6-{6,6-difluoro-3-azabicyclo-
2,6-Dichloropyridine-3-
6,6-Difluoro-3-azabicyclo-



[3.1.0]hexan-3-yl}-pyridine-3-carbaldehyde
carbaldehyde
[3.1.0]hexane hydrochloride


6-2 
6-{5-Azaspiro[2.3]hexan-5-yl}-2-
2,6-Dichloropyridine-3-
5-Azaspiro[2.3]hexane



chloropyridine-3-carbaldehyde
carbaldehyde
trifluoroacetate


6-3 
6-{5-Azaspiro[2.3]hexan-5-yl}-2-
2,6-Dibromopyridine-3-
5-Azaspiro[2.3]hexane



bromopyridine-3-carbaldehyde
carbaldehyde
trifluoroacetate


6-4 
6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-
2,6-Difluoropyridine-3-
6,6-Difluoro-3-azabicyclo-



3-yl}-2-fluoropyridine-3-carbaldehyde
carbaldehyde
[3.1.0]hexane hydrochloride


6-5 
6-{5-Azaspiro[2.3]hexan-5-yl}-2-
2,6-Difluoropyridine-3-
5-Azaspiro[2.3]hexane



fluoropyridine-3-carbaldehyde
carbaldehyde
hemioxalate


6-6 
6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
2,6-Difluoropyridine-3-
3-Azabicyclo[3.1.0]hexane



fluoropyridine-3-carbaldehyde
carbaldehyde
hydrochloride


6-7 
6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
2,6-Dichloropyridine-3-
3-Azabicyclo[3.1.0]hexane



chloropyridine-3-carbaldehyde
carbaldehyde
hydrochloride


6-8 
6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
2,6-Dibromopyridine-3-
3-Azabicyclo[3.1.0]hexane



bromopyridine-3-carbaldehyde
carbaldehyde
hydrochloride


6-9 
6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-
6-Chloropyridine-3-
6,6-Difluoro-3-azabicyclo-



3-yl}pyridine-3-carbaldehyde
carbaldehyde
[3.1.0]hexane hydrochloride


6-10
6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-
6-Chloro-2-methyl-
6,6-Difluoro-3-azabicyclo-



3-yl}-2-methylpyridine-3-carbaldehyde
pyridine-3-carbaldehyde
[3.1.0]hexane hydrochloride


6-11
6-{5-Azaspiro[2.3]hexan-5-yl}-2-
6-Chloro-2-methyl-
5-Azaspiro[2.3]hexane



methylpyridine-3-carbaldehyde
pyridine-3-carbaldehyde
trifluoroacetate


6-12
6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
6-Chloro-2-methyl-
3-Azabicyclo[3.1.0]hexane



methylpyridine-3-carbaldehyde
pyridine-3-carbaldehyde
hydrochloride


6-13
6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-
4,6-Dichloropyridine-3-
3-Azabicyclo[3.1.0]hexane



chloropyridine-3-carbaldehyde
carbaldehyde
hydrochloride


6-14
2-{6,6-Difluoro-3-azabicyclo-[3.1.0]hexan-
2-Chloro-5-iodo-4-
6,6-Difluoro-3-azabicyclo-



3-yl}-5-iodo-4-methylpyridine-3-
methylpyridine-3-
[3.1.0]hexane hydrochloride



carbonitrile
carbonitrile



6-15
6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-
6-Chloro-4-methyl-
3-Azabicyclo[3.1.0]hexane



methylpyridine-3-carbaldehyde
pyridine-3-carbaldehyde
hydrochloride


6-16
6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-
6-Chloro-2,4-dimethyl-
6,6-Difluoro-3-azabicyclo-



3-yl}-2,4-dimethylpyridine-3-carbaldehyde
pyridine-3-carbaldehyde
[3.1.0]hexane hydrochloride


6-17
2-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-iodo-
2-Chloro-5-iodo-4-
3-Azabicyclo[3.1.0]hexane



4-methylpyridine-3-carbonitrile
methylpyridine-3-
hydrochloride




carbonitrile



6-18
2-Chloro-6-[(1R,5S,6R)-6-methyl-3-
2,6-Dichloropyridine-3-
(1R,5S,6R)-6-Methyl-3-



azabicyclo[3.1.0]hexan-3-yl]pyridine-3-
carbaldehyde
azabicyclo[3.1.0]hexane



carbaldehyde

hydrochloride





(Obtained by separation of





the diastereomers of tert-





butyl 6-methyl-3-





azabicyclo[3.1.0]hexane-3-





carboxylate by standard RP





chromatography and





cleavage of the protecting





group with HCl in EtOAc)


6-19
6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
6-Fluoropyridine-3-
6,6-Difluoro-3-azabicyclo-



yl}pyridine-3-carbaldehyde
carbaldehyde
[3.1.0]hexane hydrochloride









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



embedded image


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 for 10 minutes with argon. 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 h. After cooling to rt the mixture is diluted with MeOH and purified by HPLC on reversed phase (ACN, water) to give the title compound. LC (Method 2): tR=0.61 min; Mass spectrum (ESI+): m/z=253 [M+H]+.


Intermediates 7-1 to 7-9 are prepared in analogy to Intermediate 7:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







7-1


embedded image


0.74
340
Method 2





7-2


embedded image


0.76
339
Method 2





7-3


embedded image


1.02
215
Method 1





7-4


embedded image


0.77
339
Method 2





7-5


embedded image


1.07
340
Method 2





7-6


embedded image


0.27
217
Method 2





7-7


embedded image


0.92
375
Method 2





7-8


embedded image


0.81
375
Method 2





7-9


embedded image


0.96 and 0.98
469
Method 2








embedded image











(mixture of isomers)




















Intermediate
Reaction comment







7-1
The reaction is conducted at 80° C.


7-2
The reaction is conducted at 80° C.


7-4
The reaction is conducted at 90° C.


7-5
The reaction is conducted at 100° C. for 14 h.


7-6
The reaction is conducted at 80° C.


7-7
Na2CO3 is used instead of K2CO3, vinylboronic acid



pinacolester instead of potassium vinyltrifluoroborate and



1,4-dioxane instead of THF. The reaction is conducted at



100° C. for 12 h.


7-8
The reaction is conducted at 100° C. for 4 h.


7-9
The reaction is conducted at 80° C. for 3 days. The



product is obtained as a mixture of isomers and used as



such in the next step.





















Intermediate
Name
Name of Starting Material







7-1
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



ethenylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-
chloropyridin-3-yl)methyl]-1H-1,2,3-triazole-4-



carboxylate
carboxylate


7-2
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



ethenylpyridin-3-yl)methyl]-1H-pyrazole-4-
chloropyridin-3-yl)methyl]-1H-pyrazole-4-



carboxylate
carboxylate


7-3
6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



ethenylpyridine-3-carbaldehyde
chloropyridine-3-carbaldehyde


7-4
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



ethenylpyridin-3-yl)methyl]-1H-pyrazole-4-
chloropyridin-3-yl)methyl]-1H-pyrazole-4-



carboxylate
carboxylate


7-5
Ethyl 1-[(5-{3-azabicyclo[3.1.0]hexan-3-yl}-3-
Ethyl 1-[(5-{3-azabicyclo[3.1.0]hexan-3-yl}-3-



ethenylpyrazin-2-yl)methyl]-1H-pyrazole-4-
chloropyrazin-2-yl)methyl]-1H-pyrazole-4-



carboxylate
carboxylate


7-6
(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



ethenylpyridin-3-yl)methanol
bromopyridin-3-yl)methanol


7-7
Ethyl 1-[(6-{6,6-difluoro-3-
Ethyl 1-[(2-chloro-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}-2-ethenylpyridin-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



3-yl)methyl]-1H-pyrazole-4-carboxylate
yl)methyl]-1H-pyrazole-4-carboxylate


7-8
Ethyl 1-[(6-{6,6-difluoro-3-
Ethyl 1-[(2-chloro-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}-2-ethenylpyridin-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



3-yl)methyl]-1H-imidazole-4-carboxylate
yl)methyl]-1H-imidazole-4-carboxylate


7-9
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



ethenylpyridin-3-yl)methyl]-1-{[2-
chloropyridin-3-yl)methyl]-1-{[2-



(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-
(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-



carboxylate and
carboxylate and



Ethyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



ethenylpyridin-3-yl)methyl]-1-{[2-
chloropyridin-3-yl)methyl]-1-{[2-



(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-
(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-



carboxylate (mixture of isomers)
carboxylate (mixture of isomers)









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



embedded image


Under 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 methanesulfonylchloride (CH3—SO2Cl, 318 μL). After stirring for 15 minutes ethyl 1H-pyrazole-4-carboxylate (555 mg) is added and the mixture is stirred for 3 h at rt. Then the mixture is partitioned between water and DCM. The organic phase is dried (MgSO4), concentrated and the residue is chromatographed on silica gel (petroleum ether/EtOAc 100:0→70:30) to give the title compound. LC (Method 2): tR=0.93 min; Mass spectrum (ESI+): m/z=375 [M+H]+.


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



embedded image


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 h at rt. The mixture is partitioned between water and EtOAc/MeOH (9:1). After separation of the phases, the organic phase is dried (MgSO4) and concentrated to give the title compound. LC (Method 2): tR=1.06 min; Mass spectrum (ESI+): m/z=377 [M+H]+.


Intermediates 9-1 to 9-18 are prepared in analogy to Intermediate 9:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







9-1


embedded image


0.90
342
Method 2





9-2


embedded image


0.81

Method 1





9-3


embedded image


0.87
342
Method 1





9-4


embedded image


1.08
341
Method 1





9-5


embedded image


0.95
377
Method 1





9-6


embedded image


0.95
341
Method 1





9-7


embedded image



342






9-8


embedded image


0.87
341
Method 2





9-9


embedded image


1.00
378
Method 2





9-10


embedded image


0.99
340 [M − H]
Method 1





9-11


embedded image


0.98
341
Method 1





9-12


embedded image


0.98
342
Method 1





9-13


embedded image


0.88
342
Method 2





9-14


embedded image


1.05
377
Method 2





9-15


embedded image


0.87
377
Method 2





9-16


embedded image


1.12
342
Method 1





9-17


embedded image


1.08
378
Method 1





9-18


embedded image


1.08 and 1.15
471
Method 2








embedded image











(mixure of isomers)























Intermediate
Reaction comment









9-3 
The mixture is stirred for 12 h after addition of NalO4.



9-9 
The mixture is stirred for 12 h after addition of NalO4.



9-10
The mixture is stirred for 12 h after addition of NalO4.



9-13
The mixture is stirred for 12 h after addition of NalO4.



9-16
The mixture is stirred for 16 h after addition of NalO4.



9-18
The mixture is stirred for 12 h after addition of NalO4.




The product is obtained as a mixture of isomers.






















Intermediate
Name
Name of Starting Material







9-1 
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



formylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-
ethenylpyridin-3-yl)methyl]-1H-1,2,3-triazole-



carboxylate
4-carboxylate


9-2 
1-[(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-
1-[(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-[(1E)-



formylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-
2-phenylethenyl]pyrimidin-5-yl)methyl]-N-



1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-
[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta-



imidazole-4-carboxamide
[d]imidazol-4-yl]-1H-imidazole-4-carboxamide


9-3 
Ethyl 1-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-
Ethyl 1-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-



formylpyrimidin-5-yl)methyl]-1H-imidazole-4-
[(1E)-2-phenylethenyl]pyrimidin-5-yl)methyl]-



carboxylate
1H-imidazole-4-carboxylate


9-4 
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



formylpyridin-3-yl)methyl]-1H-pyrazole-4-
ethenylpyridin-3-yl)methyl]-1H-pyrazole-4-



carboxylate
carboxylate


9-5 
Ethyl 1-[(6-{6,6-difluoro-3-
Ethyl 1-[(6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}-2-formylpyridin-3-
azabicyclo[3.1.0]hexan-3-yl}-2-ethenylpyridin-



yl)methyl]-1H-imidazole-4-carboxylate
3-yl)methyl]-1H-imidazole-4-carboxylate


9-6 
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



formylpyridin-3-yl)methyl]-1H-imidazole-4-
ethenylpyridin-3-yl)methyl]-1H-imidazole-4-



carboxylate
carboxylate


9-7 
Ethyl 1-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-
Ethyl 1-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-



formylpyrimidin-5-yl)methyl]-1H-pyrazole-4-
[(1E)-2-phenylethenyl]pyrimidin-5-yl)methyl]-



carboxylate
1H-pyrazole-4-carboxylate


9-8 
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



formylpyridin-3-yl)methyl]-1H-pyrazole-4-
ethenylpyridin-3-yl)methyl]-1H-pyrazole-4-



carboxylate
carboxylate


9-9 
Ethyl 1-[(6-{6,6-difluoro-3-
Ethyl 1-[(6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}-2-formylpyridin-3-
azabicyclo[3.1.0]hexan-3-yl}-2-ethenylpyridin-



yl)methyl]-1H-1,2,3-triazole-4-carboxylate
3-yl)methyl]-1H-1,2,3-triazole-4-carboxylate


9-10
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



formylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-
ethenylpyridin-3-yl)methyl]-1H-1,2,3-triazole-



carboxylate
4-carboxylate


9-11
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



formylpyridin-3-yl)methyl]-1H-imidazole-4-
ethenylpyridin-3-yl)methyl]-1H-imidazole-4-



carboxylate
carboxylate


9-12
Ethyl 1-[(5-{3-azabicyclo[3.1.0]hexan-3-yl}-3-
Ethyl 1-[(5-{3-azabicyclo[3.1.0]hexan-3-yl}-3-



formylpyrazin-2-yl)methyl]-1H-pyrazole-4-
ethenylpyrazin-2-yl)methyl]-1H-pyrazole-4-



carboxylate
carboxylate


9-13
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



formylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-
ethenylpyridin-3-yl)methyl]-1H-1,2,3-triazole-



carboxylate
4-carboxylate


9-14
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Ethyl 1-[(6-{6,6-difluoro-3-



hexan-3-yl}-2-formylpyridin-3-yl)methyl]-1H-
azabicyclo[3.1.0]hexan-3-yl}-2-ethenylpyridin-



pyrazole-4-carboxylate
3-yl)methyl]-1H-pyrazole-4-carboxylate


9-15
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Ethyl 1-[(6-{6,6-difluoro-3-



hexan-3-yl}-2-formylpyridin-3-yl)methyl]-1H-
azabicyclo[3.1.0]hexan-3-yl}-2-ethenylpyridin-



imidazole-4-carboxylate
3-yl)methyl]-1H-imidazole-4-carboxylate


9-16
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



formylpyridin-3-yl)methyl]-1,2-oxazole-5-
[(1E)-2-phenylethenyl]pyridin-3-yl)methyl]-1,2-



carboxylate
oxazole-5-carboxylate


9-17
Ethyl 3-[(6-{6,6-difluoro-3-
Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



azabicyclo[3.1.0]hexan-3-yl}-2-formylpyridin-3-
hexan-3-yl}-2-[(1E)-2-phenylethenyl]pyridin-3-



yl)methyl]-1,2-oxazole-5-carboxylate
yl)methyl]-1,2-oxazole-5-carboxylate


9-18
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



formylpyridin-3-yl)methyl]-1-{[2-(trimethyl-
ethenylpyridin-3-yl)methyl]-1-{[2-(trimethyl-



silyl)ethoxy]methyl}-1H-pyrazole-5-carboxylate and
silyl)ethoxy]methyl}-1H-pyrazole-5-carboxylate and



Ethyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



formylpyridin-3-yl)methyl]-1-{[2-(trimethylsilyl)-
ethenylpyridin-3-yl)methyl]-1-{[2-(trimethyl-



ethoxy]methyl}-1H-pyrazole-3-carboxylate
silyl)ethoxy]methyl}-1H-pyrazole-3-carboxylate



(mixture of isomers)
(mixture of isomers)









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



embedded image


NaBH4 (40 mg) is added portionwise to a ice-cooled 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 for 2 h at rt, 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): tR=0.75 min; Mass spectrum (ESI+): m/z=379 [M+H]+.


Intermediates 10-1 to 10-11 are prepared in analogy to Intermediate 10:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







10-1


embedded image


0.99
343
Method 1





10-2


embedded image


0.71
380
Method 2





10-3


embedded image


0.68
344
Method 2





10-4


embedded image


0.82
344
Method 2





10-5


embedded image


0.91
344
Method 1





10-6


embedded image


0.66
344
Method 2





10-7


embedded image


0.75
379
Method 2





10-8


embedded image


0.67
379
Method 2





10-9


embedded image


1.01
380
Method 1





10-10


embedded image


1.05
344
Method 1





10-11


embedded image


0.89 and 0.93
473
Method 2








embedded image











(mixture of isomers)




















Intermediate
Reaction comment







10-3
The reaction is conducted in THF/MeOH 2:1.


10-3
The reaction is conducted in THF for 12 h at rt.


10-5
The reaction is conducted in THF/EtOH for 30



minutes at rt.


10-7
The reaction is conducted in THF/MeOH for



1 h at rt.


10-8
The reaction is conducted in THF/water 10:1 for



12 h at rt.


10-9
The reaction is conducted for 15 minutes at rt.



The reaction is quenched with saturated aqueous



NaHCO3 instead of HCl.


10-10
The reaction is conducted for 45 minutes at rt.



The reaction is quenched with saturated aqueous



NaHCO3 instead of HCl.


10-11
The product is obtained as a mixture of isomers.





















Intermediate
Name
Name of Starting Material







10-1
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(hydroxymethyl)pyridin-3-yl)methyl]-1H-
formylpyridin-3-yl)methyl]-1H-pyrazole-4-



pyrazole-4-carboxylate
carboxylate


10-2
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



hexan-3-yl}-2-(hydroxymethyl)pyridin-3-
hexan-3-yl}-2-formylpyridin-3-yl)methyl]-1H-



yl)methyl]-1H-1,2,3-triazole-4-carboxylate
1,2,3-triazole-4-carboxylate


10-3
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



(hydroxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-
formylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-



triazole-4-carboxylate
carboxylate


10-4
Ethyl 1-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-
Ethyl 1-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-



(hydroxymethyl)pyrimidin-5-yl)methyl]-1H-
formylpyrimidin-5-yl)methyl]-1H-pyrazole-4-



pyrazole-4-carboxylate
carboxylate


10-5
Ethyl 1-[(5-{3-azabicyclo[3.1.0]hexan-3-yl}-3-
Ethyl 1-[(5-{3-azabicyclo[3.1.0]hexan-3-yl}-3-



(hydroxymethyl)pyrazin-2-yl)methyl]-1H-
formylpyrazin-2-yl)methyl]-1H-pyrazole-4-



pyrazole-4-carboxylate
carboxylate


10-6
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(hydroxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-
formylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-



triazole-4-carboxylate
carboxylate


10-7
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



hexan-3-yl}-2-(hydroxymethyl)pyridin-3-
hexan-3-yl}-2-formylpyridin-3-yl)methyl]-1H-



yl)methyl]-1H-pyrazole-4-carboxylate
pyrazole-4-carboxylate


10-8
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



hexan-3-yl}-2-(hydroxymethyl)pyridin-3-
hexan-3-yl}-2-formylpyridin-3-yl)methyl]-1H-



yl)methyl]-1H-imidazole-4-carboxylate
imidazole-4-carboxylate


10-9
Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



hexan-3-yl}-2-(hydroxymethyl)pyridin-3-
hexan-3-yl}-2-formylpyridin-3-yl)methyl]-1,2-



yl)methyl]-1,2-oxazole-5-carboxylate
oxazole-5-carboxylate


10-10
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(hydroxymethyl)pyridin-3-yl)methyl]-1,2-
formylpyridin-3-yl)methyl]-1,2-oxazole-5-



oxazole-5-carboxylate
carboxylate


10-11
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(hydroxymethyl)pyridin-3-yl)methyl]-1-{[2-
formylpyridin-3-yl)methyl]-1-{[2-(trimethylsilyl)-



(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-
ethoxy]methyl}-1H-pyrazole-5-carboxylate



carboxylate
and



and
Ethyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



Ethyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
formylpyridin-3-yl)methyl]-1-{[2-(trimethylsilyl)-



(hydroxymethyl)pyridin-3-yl)methyl]-1-{[2-
ethoxy]methyl}-1H-pyrazole-3-carboxylate



(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-
(mixture of isomers)



carboxylate




(mixture of isomers)









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



embedded image


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 at 0° C. NaH (60% in mineral oil, 23 mg). The mixture is stirred for 15 minutes, treated with CH3I (17 μL) and stirred for 12 h at rt. The solvents are evaporated in vacuo to give the crude product, which is directly used in the next step.


LC (Method 2): tR=0.83 min; Mass spectrum (ESI+): m/z=393 [M+H]+.


Intermediate 11-1 is prepared in analogy to Intermediate 11:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







11-1


embedded image


0.75
393
Method 2























Intermediate
Reaction comment









11-1
The reaction is stirred for




1 h at rt after addition of CH3I.






















Intermediate
Name
Name of Starting Material







11-1
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



hexan-3-yl}-2-(methoxymethyl)pyridin-3-
hexan-3-yl}-2-(hydroxymethyl)pyridin-3-



yl)methyl]-1H-imidazole-4-carboxylate
yl)methyl]-1H-imidazole-4-carboxylate









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



embedded image


In a microwave vial ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-formylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylate (763 mg) is dissolved in DCM (10 mL). Diethylaminosulfurtrifluoride (DAST, 1 mL) is added, the vial is sealed and the mixture is heated to 50° C. for 12 h. After cooling to rt the mixture is carefully treated with 1 N aqueous NaHCO3 until gas evolution has stopped. Then the mixture is 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 (petroleum ether/EtOAc 70:30→30:70) to give the title compound.


LC (Method 2): tR=1.05 min; Mass spectrum (ESI+): m/z=364 [M+H]+.


Intermediates 12-1 to 12-10 are prepared in analogy to Intermediate 12:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







12-1


embedded image


0.88
364
Method 2





12-2


embedded image


1.08
363
Method 2





12-3


embedded image


0.99
399
Method 1





12-4


embedded image


1.07
399
Method 1





12-5


embedded image


1.00
363
Method 1





12-6


embedded image


1.10
364
Method 2





12-7


embedded image


1.09
363
Method 1





12-8


embedded image


1.03
363
Method 1





12-9


embedded image


1.17
364
Method 1





12-10


embedded image


1.12
400
Method 1






















Intermediate
Reaction comment





12-9
The reaction is conducted at 0° C. and is stirred for 1 h.


12-10
The reaction is conducted at 0° C. and is stirred for 30 minutes.












Intermediate
Name
Name of Starting Material





12-1
Ethyl 1-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-
Ethyl 1-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-



(difluoromethyl)pyrimidin-5-yl)methyl]-1H-
formylpyrimidin-5-yl)methyl]-1H-imidazole-4-



imidazole-4-carboxylate
carboxylate


12-2
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(difluoromethyl)pyridin-3-yl)methyl]-1H-
formylpyridin-3-yl)methyl]-1H-pyrazole-4-



pyrazole-4-carboxylate
carboxylate


12-3
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



hexan-3-yl}-2-(difluoromethyl)pyridin-3-
hexan-3-yl}-2-formylpyridin-3-yl)methyl]-1H-



yl)methyl]-1H-imidazole-4-carboxylate
imidazole-4-carboxylate


12-4
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



hexan-3-yl}-2-(difluoromethyl)pyridin-3-
hexan-3-yl}-2-formylpyridin-3-yl)methyl]-1H-



yl)methyl]-1H-pyrazole-4-carboxylate
pyrazole-4-carboxylate


12-5
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



(difluoromethyl)pyridin-3-yl)methyl]-1H-
formylpyridin-3-yl)methyl]-1H-imidazole-4-



imidazole-4-carboxylate
carboxylate


12-6
Ethyl 1-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-
Ethyl 1-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-



(difluoromethyl)pyrimidin-5-yl)methyl]-1H-
formylpyrimidin-5-yl)methyl]-1H-pyrazole-4-



pyrazole-4-carboxylate
carboxylate


12-7
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



(difluoromethyl)pyridin-3-yl)methyl]-1H-
formylpyridin-3-yl)methyl]-1H-pyrazole-4-



pyrazole-4-carboxylate
carboxylate


12-8
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(difluoromethyl)pyridin-3-yl)methyl]-1H-
formylpyridin-3-yl)methyl]-1H-imidazole-4-



imidazole-4-carboxylate
carboxylate


12-9
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(difluoromethyl)pyridin-3-yl)methyl]-1,2-
formylpyridin-3-yl)methyl]-1,2-oxazole-5-



oxazole-5-carboxylate
carboxylate


12-10
Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



hexan-3-yl}-2-(difluoromethyl)pyridin-3-yl)-
hexan-3-yl}-2-formylpyridin-3-yl)methyl]-1,2-



methyl]-1,2-oxazole-5-carboxylate
oxazole-5-carboxylate









Intermediate 13
Ethyl 2-chloro-4-[(1E)-2-phenylethenyl]pyrimidine-5-carboxylate



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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 for 10 minutes with argon. 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 h. After cooling to rt 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 (petroleum ether/EtOAc 80:20→60:40) to give the title compound.


LC (Method 2): tR=1.21 min; Mass spectrum (ESI+): m/z=289 [M+H]+.


Intermediates 13-1 to 13-2 are prepared in analogy to Intermediate 13:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







13-1


embedded image


1.27
416
Method 1





13-2


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1.20
452
Method 1






















Intermediate
Reaction comment





13-1
The reaction is conducted for 15 h at 75° C.


13-2
The reaction is conducted for 18 h at 80° C.












Intermediate
Name
Name of Starting Material





13-1
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



[(1E)-2-phenylethenyl]pyridin-3-yl)methyl]-1,2-
chloropyridin-3-yl)methyl]-1,2-oxazole-5-



oxazole-5-carboxylate
carboxylate


13-2
Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Ethyl 3-[(2-chloro-6-{6,6-difluoro-3-



hexan-3-yl}-2-[(1E)-2-phenylethenyl]pyridin-3-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl)methyl]-1,2-oxazole-5-carboxylate
yl)methyl]-1,2-oxazole-5-carboxylate









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



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Under 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 KHCO3 (2.3 g) in THF (30 mL) is stirred for 12 h at rt. The mixture is partitioned between saturated aqueous NH4Cl and EtOAc and the phases are separated. The organic phase is washed with brine, dried (MgSO4), concentrated and the residue is chromatographed on silica gel (petroleum ether/EtOAc 80:20→60:40) to give the title compound.


LC (Method 2): tR=1.27 min; Mass spectrum (ESI+): m/z=336 [M+H]+.


Intermediate 15
(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-[(1E)-2-phenylethenyl]pyrimidin-5-yl)methanol



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Under 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 diisobutylaluminiumhydride (DIBAH, 1 M in THF, 25 mL). The mixture is stirred for 2 h at rt, cooled to 0° C. and treated dropwise with 4 M aqueous HCl (15 mL). Then the mixture is 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 (MgSO4), concentrated and the residue is chromatographed on silica gel (DCM/MeOH 98:2→90:10) to give the title compound.


LC (Method 2): tR=0.84 min; Mass spectrum (ESI+): m/z=294 [M+H]+.


Intermediates 15-1 to 15-2 are prepared in analogy to Intermediate 15:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







15-1


embedded image


0.72
234
Method 2





15-2


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0.60
206
Method 1





















Intermediate
Name
Name of Starting Material







15-1
(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



propylpyridin-3-yl)methanol
propylpyridine-3-carboxylate


15-2
(2-{5-Azaspiro[2.3]hexan-5-yl}-4-
Ethyl 2-{5-azaspiro[2.3]hexan-5-yl}-4-



methylpyrimidin-5-yl)methanol
methylpyrimidine-5-carboxylate









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



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Under 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) is treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphat (HATU, 280 mg). The mixture is 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 h the mixture is partitioned between water and DCM. The organic phase is washed with brine, dried (MgSO4), concentrated and the residue is chromatographed on silica gel (DCM/MeOH 98:2→70:30) to give the title compound. LC (Method 1): tR=1.02 min; Mass spectrum (ESI+): m/z=507 [M+H]+.


Intermediate 17
Ethyl 1-[(5-{5-azaspiro[2.3]hexan-5-yl}pyridin-2-yl)methyl]-1H-pyrazole-4-carboxylate



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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 at 0° C. DIAD (222 μL). The mixture is stirred for 1 h while warming to rt. Then the mixture is diluted with MeOH and purified by HPLC on reversed phase (ACN, water) to give the title compound. LC (Method 2): tR=0.79 min; Mass spectrum (ESI+): m/z=313 [M+H]+.


Intermediate 17-1 is prepared in analogy to Intermediate 17:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







17-1


embedded image


0.99
338
Method 1

























Name of


Intermediate
Name
Name of Starting Material 1
Starting Material 2







17-1
Ethyl 1-[(5-{3-azabicyclo[3.1.0]hexan-
3-{3-Azabicyclo[3.1.0]hexan-3-
Ethyl 1H-pyrazole-4-



3-yl}-6-cyanopyridin-2-yl)methyl]-1H-
yl}-6-(hydroxymethyl)pyridine-
carboxylate



pyrazole-4-carboxylate
2-carbonitrile









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



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


Intermediates 18-1 to 18-4 are prepared in analogy to Intermediate 18:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







18-1


embedded image


0.72
342
Method 2





18-2


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0.76
378
Method 2





18-3


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0.66
217
Method 2





18-4


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0.86
253
Method 2























Intermediate
Reaction comment









18-1
The reaction is conducted for 12 h at 80° C.



18-2
The reaction is conducted for 12 h at 80° C.



18-3
The reaction is conducted for 5 h at 70° C.



18-4
The reaction is conducted for 16 h at 80° C.






















Intermediate
Name
Name of Starting Material







18-1
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



ethylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-
bromopyridin-3-yl)methyl]-1H-1,2,3-triazole-4-



carboxylate
carboxylate


18-2
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Ethyl 1-[(2-bromo-6-{6,6-difluoro-3-



hexan-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



1,2,3-triazole-4-carboxylate
yl)methyl]-1H-1,2,3-triazole-4-carboxylate


18-3
6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



ethylpyridine-3-carbaldehyde
chloropyridine-3-carbaldehyde


18-4
6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-
2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]-



2-ethylpyridine-3-carbaldehyde
hexan-3-yl}pyridine-3-carbaldehyde









Intermediate 19
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate



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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 for minutes with argon. 1,1′-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)Cl2, 150 mg) is added, the vial is sealed and the mixture is heated to 70° C. for 1 h. After cooling to rt 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 (petroleum ether/EtOAc 95:5→0:100) to give the title compound. LC (Method 2): tR=0.75 min; Mass spectrum (ESI+): m/z=341 [M+H]+.


Intermediates 19-1 to 19-15 are prepared in analogy to Intermediate 19:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







19-1


embedded image



377






19-2


embedded image


0.67
341
Method 2





19-3


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0.59
219
Method 2





19-4


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1.06

Method 1





19-5


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1.18
403
Method 1





19-6


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1.14
391
Method 1





19-7


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0.66
341
Method 2





19-8


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0.68

Method 2





19-9


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0.70

Method 2





19-10


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0.66

Method 2





19-11


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0.85
353
Method 2





19-12


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1.10
355
Method 1





19-13


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0.80
342
Method 2





19-14


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0.80
363
Method 2





19-15


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0.87
393
Method 2




















Intermediate
Reaction comment







19-4
n-Propylzinc bromide is used instead of diethylzinc.


19-5
Cyclobutylzinc bromide is used instead of diethylzinc.


19-6
n-Propylzinc bromide is used instead of diethylzinc.


19-7
The reaction is conducted in the presence of LiCL in the same molar amount as diethylzinc.



The reaction is heated for 2 h to 60° C.


19-9
2-Methylpropylzinc bromide is used instead of diethylzinc and dichloro[1,3-bis(2,6-Di-3-



pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (Pd-PEPPSI-IPent) is used



instead of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)Cl2).



The reaction is conducted in the presence of LiCL in the same molar amount as diethylzinc.



The reaction is heated for 2 h to 60° C.


19-10
n-Propylzinc bromide is used instead of diethylzinc and dichloro[1,3-bis(2,6-Di-3-



pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (Pd-PEPPSI-IPent) is used



instead of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)Cl2).



The reaction is conducted in the presence of LiCL in the same molar amount as diethylzinc.



The reaction is heated for 2 h to 60° C.


19-11
Cyclopropylzinc bromide is used instead of diethylzinc.


19-12
Dichloro[1,3-bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (Pd-



PEPPSI-IPent) is used instead of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride



(Pd(dppf)Cl2). The reaction is conducted in the presence of LiCL in the same molar amount as



diethylzinc. The reaction is heated for 1 h to 60° C.


19-13
The reaction is conducted for 2.5 h at 80° C.





















Intermediate
Name
Name of Starting Material







19-1
Ethyl 1-[(6-{6,6-difluoro-3-
Ethyl 1-[(2-bromo-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl)methyl]-1H-pyrazole-4-carboxylate
yl)methyl]-1H-pyrazole-4-carboxylate


19-2
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



ethylpyridin-3-yl)methyl]-1H-imidazole-4-
chloropyridin-3-yl)methyl]-1H-imidazole-4-



carboxylate
carboxylate


19-3
(6-{5-Azaspiro[2.3]hexan-5-yl}-2-ethylpyridin-
(6-{5-Azaspiro[2.3]hexan-5-yl}-2-chloropyridin-



3-yl)methanol
3-yl)methanol


19-4
Ethyl 1-[(6-{6,6-difluoro-3-
Ethyl 1-[(2-bromo-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}-2-propylpyridin-3-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl)methyl]-1H-imidazole-4-carboxylate
yl)methyl]-1H-imidazole-4-carboxylate


19-5
Ethyl 1-[(2-cyclobutyl-6-{6,6-difluoro-3-
Ethyl 1-[(2-bromo-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}pyridin-3-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl)methyl]-1H-pyrazole-4-carboxylate
yl)methyl]-1H-pyrazole-4-carboxylate


19-6
Ethyl 1-[(6-{6,6-difluoro-3-
Ethyl 1-[(2-bromo-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}-2-propylpyridin-3-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl)methyl]-1H-pyrazole-4-carboxylate
yl)methyl]-1H-pyrazole-4-carboxylate


19-7
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



ethylpyridin-3-yl)methyl]-1H-imidazole-4-
bromopyridin-3-yl)methyl]-1H-imidazole-4-



carboxylate
carboxylate


19-8
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Ethyl 1-[(2-bromo-6-{6,6-difluoro-3-



hexan-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)-



imidazole-4-carboxylate
methyl]-1H-imidazole-4-carboxylate


19-9
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(2-methylpropyl)pyridin-3-yl)methyl]-1H-
bromopyridin-3-yl)methyl]-1H-imidazole-4-



imidazole-4-carboxylate
carboxylate


19-10
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



propylpyridin-3-yl)methyl]-1H-imidazole-4-
bromopyridin-3-yl)methyl]-1H-imidazole-4-



carboxylate
carboxylate


19-11
Ethyl 1-[(6-{3-azabicyclo[3.1 0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



cyclopropylpyridin-3-yl)methyl]-1H-pyrazole-4-
bromopyridin-3-yl)methyl]-1H-pyrazole-4-



carboxylate
carboxylate


19-12
Ethyl 1-({2-ethyl-6-[(1R,5S,6R)-6-methyl-3-
Ethyl 1-({2-chloro-6-[(1R,5S,6R)-6-methyl-3-



azabicyclo[3.1.0]hexan-3-yl]pyridin-3-
azabicyclo[3.1.0]hexan-3-yl]pyridin-3-



yl}methyl)-1H-imidazole-4-carboxylate
yl}methyl)-1H-imidazole-4-carboxylate


19-13
Ethyl 3-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-
Ethyl 3-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



ethylpyridin-3-yl)methyl]-1,2-oxazole-5-
chloropyridin-3-yl)methyl]-1,2-oxazole-5-



carboxylate
carboxylate


19-14
Methyl 5-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Methyl 5-[(2-bromo-6-{6,6-difluoro-3-



hexan-3-yl}-2-ethylpyridin-3-yl)methyl]furan-2-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



carboxylate
yl)methyl]furan-2-carboxylate


19-15
Ethyl 5-[(6-{6,6-difluoro-3-
Ethyl 5-[(2-bromo-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl)methyl]thiophene-2-carboxylate
yl)methyl]thiophene-2-carboxylate









Intermediate 20
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylate



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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 hydrogen atmosphere (3 bar) at rt for 3.5 h. The mixture is filtered, the filtrate is concentrated and the residue is purified by HPLC on reversed phase (ACN, water) to give the title compound. LC (Method 2): tR=0.68 min; Mass spectrum (ESI+): m/z=314 [M+H]+.


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



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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 half-saturated aqueous NaHCO3 and EtOAc. Then the mixture is 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 reversed phase (ACN, water) to give the title compound. LC (Method 2): tR=1.10 min; Mass spectrum (ESI+): m/z=364 [M+H]+.


Intermediate 22
Ethyl 2-chloro-4-propylpyrimidine-5-carboxylate



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In a microwave vial a mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (1 g), n-propylzinc bromide (0.5 M in THF, 9.5 mL) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)Cl2, 66 mg) in 1,4-dioxane (25 mL) is purged for 10 minutes with argon. The vial is sealed and the mixture is heated to 70° C. for 1 h. Then n-propylzinc bromide (0.5 M in THF, 5 mL) is added and the mixture is heated for 45 minutes to 70° C. After cooling to rt the mixture is partitioned between EtOAc and saturated aqueous NH4Cl. The aqueous phase is extracted twice with EtOAc. The combined organic phases are washed with brine, dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (petroleum ether/EtOAc 98:2→90:10) to give the title compound.


LC (Method 2): tR=1.10 min; Mass spectrum (ESI+): m/z=229 [M+H]+.


Intermediate 23
Ethyl 2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-propylpyrimidine-5-carboxylate



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Under argon atmosphere a mixture of ethyl 2-chloro-4-propylpyrimidine-5-carboxylate (546 mg), 3-azabicyclo[3.1.0]hexane hydrochloride (328 mg) and K2CO3 (663 mg) in DMF (15 mL) is stirred for 2 h at rt. 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 reversed phase (ACN, water) to give the title compound.


LC (Method 2): tR=1.09 min; Mass spectrum (ESI+): m/z=276 [M+H]+.


Intermediate 24
Methyl 5-{3-azabicyclo[3.1.0]hexan-3-yl}-6-cyanopyridine-2-carboxylate



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Under argon atmosphere a mixture of methyl 5-bromo-6-cyanopyridine-2-carboxylate (500 mg), 3-azabicyclo[3.1.0]hexane hydrochloride (289 mg) and K2CO3 (717 mg) in NMP (5 mL) is stirred for 12 h at 80° C. 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): tR=0.92 min; Mass spectrum (ESI+): m/z=244 [M+H]+.


Intermediate 25
3-{3-Azabicyclo[3.1.0]hexan-3-yl}-6-(hydroxymethyl)pyridine-2-carbonitrile



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NaBH4 (131 mg) is added portionwise 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 h at rt and for 1 h at 45° C. Then the mixture is 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), concentrated and the residue is purified by HPLC on reversed phase (ACN, water) to give the title compound.


LC (Method 1): tR=0.81 min; Mass spectrum (ESI+): m/z=216 [M+H]+.


Intermediate 25-1 is prepared in analogy to Intermediate 25:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







25-1


embedded image


0.83
395
Method 2























Intermediate
Reaction comment









25-1
The reaction is conducted at rt for 24 h.






















Intermediate
Name
Name of Starting Material







25-1
Ethyl 5-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Ethyl 6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-



hexan-3-yl}-2-(hydroxymethyl)-pyridin-3-
3-yl}-3-{[5-(ethoxycarbonyl)thiophen-2-



yl)methyl]thiophene-2-carboxylate
yl]methyl}pyridine-2-carboxylate









Intermediate 26
Methyl 6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(trifluoromethoxy)pyridine-3-carboxylate



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Under argon atmosphere a mixture of methyl 6-chloro-2-(trifluoromethoxy)pyridine-3-carboxylate (1 g), 3-azabicyclo[3.1.0]hexane hydrochloride (538 mg) and K2CO3 (1.1 g) in DMF (20 mL) is stirred for 4 h at rt. 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 reversed phase (ACN, water) to give the title compound. LC (Method 2): tR=1.18 min; Mass spectrum (ESI+): m/z=303 [M+H]+.


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



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LiBH4 (250 mg) is added portionwise 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 for 12 h at rt. Then the mixture is poured into 1 N aqueous HCl and stirred vigorously for 20 minutes. Thereafter the mixture is partitioned between saturated aqueous NaHCO3 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 reversed phase (ACN, water) to give the title compound. LC (Method 2): tR=1.22 min; Mass spectrum (ESI+): m/z=289 [M+H]+.


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



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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 (5.62 g), vinylboronic acid pinacolester (2.9 mL), Na2CO3 (1 M aqueous solution, 40.5 mL) and 1,4-dioxane (75 mL) is purged for 10 minutes with argon. 1,1′-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)Cl2, 662 mg) is added, the vial is sealed and the mixture is heated to 100° C. for 12 h. After cooling to rt 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 chromatographed on silica gel (petroleum ether/EtOAc 100:0→50:50) to give the title compound.


LC (Method 2): tR=0.78 min; Mass spectrum (ESI+): m/z=339 [M+H]+.


Intermediates 28-1 to 28-5 are prepared in analogy to Intermediate 28:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







28-1


embedded image


0.99

Method 1





28-2


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1.01
339
Method 1





28-3


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0.79
353
Method 2





28-4


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1.04
339
Method 1





28-5


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0.82
367
Method 2























Intermediate
Reaction comment









28-3
Isopropenylboronic acid pinacolester is used




instead of vinylboronic acid pinacolester.



28-5
Isopropenylboronic acid pinacolester is used




instead of vinylboronic acid pinacolester. The




reaction is conducted for 18 h at 80° C.






















Intermediate
Name
Name of Starting Material







28-1
Ethyl 1-[(6-{6,6-difluoro-3-
Ethyl 1-[(2-bromo-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}-2-ethenylpyridin-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



3-yl)methyl]-1H-imidazole-4-carboxylate
yl)methyl]-1H-imidazole-4-carboxylate


28-2
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



ethenylpyridin-3-yl)methyl]-1H-imidazole-4-
chloropyridin-3-yl)methyl]-1H-imidazole-4-



carboxylate
carboxylate


28-3
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(prop-1-en-2-yl)pyridin-3-yl)methyl]-1H-
chloropyridin-3-yl)methyl]-1H-pyrazole-4-



pyrazole-4-carboxylate
carboxylate


28-4
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



ethenylpyridin-3-yl)methyl]-1H-imidazole-4-
chloropyridin-3-yl)methyl]-1H-imidazole-4-



carboxylate
carboxylate


28-5
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methyl]-3-(prop-1-en-2-yl)-
methylpyridin-3-yl)methyl]-3-bromo-1H-



1H-pyrazole-4-carboxylate
pyrazole-4-carboxylate









Intermediate 29
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(cyanomethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate



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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 successively and the mixture is stirred again for 45 minutes. Then the mixture is diluted with THF and purified by HPLC on reversed phase (ACN, water) to give the title compound. LC (Method 2): tR=0.97 min; Mass spectrum (ESI+): m/z=352 [M+H]+.


Intermediate 30
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(1-cyanocyclopropyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate



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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 rt, cooled to 0° C. and treated with 1,2-dibromoethane (80 μL). Then the mixture is stirred for 1 h at rt. After cooling to 0° C. the mixture is treated with saturated aqueous NH4Cl. 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 (petroleum ether/EtOAc 90:10→60:40) to give the title compound.


LC (Method 2): tR=1.06 min; Mass spectrum (ESI+): m/z=378 [M+H]+.


Intermediate 30-1 is prepared in analogy to Intermediate 30:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







30-1


embedded image


1.16
380
Method 1























Intermediate
Reaction comment









30-1
The reaction is conducted in DMF. CH3I




is used instead of 1,2-dibromoethane.






















Intermediate
Name
Name of Starting Material







30-1
Ethyl 1-[(6-{3-azabicyclo
Ethyl 1-[(6-{3-azabicyclo



[3.1.0]hexan-3-yl}-2-
[3.1.0]hexan-3-yl}-2-



(1-cyano-1-methylethyl)
(cyanomethyl)pyridin-



pyridin-3-yl)methyl]-
3-yl)methyl]-1H-



1H-pyrazole-4-carboxylate
pyrazole-4-carboxylate









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



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SOCl2 (5 mL) is added under argon atmosphere 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). The mixture is heated to 60° C. for 3 h, cooled to rt and concentrated in vacuo. The residue is taken up 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 h at rt the mixture is partitioned between water and DCM. The organic phase is washed with brine, dried (MgSO4), concentrated and the residue is chromatographed on silica gel (petroleum ether/EtOAc 50:50→0:100) to give the title compound.


LC (Method 2): tR=1.06 min; Mass spectrum (ESI+): m/z=416 [M+H]+.


Intermediate 32
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid



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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 at 0° C. NaH (60% in mineral oil, 263 mg). The mixture is stirred for 30 minutes, treated with CH3I (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 rt 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 (MgSO4), concentrated and the residue is purified by HPLC on reversed phase (ACN, water) to give the title compound. LC (Method 2): tR=0.62 min; Mass spectrum (ESI+): m/z=329 [M+H]+.


Intermediates 32-1 to 32-3 are prepared in analogy to Intermediate 32:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







32-1


embedded image


0.63
329
Method 1





32-2


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0.63
329
Method 1





32-3


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0.85 and 0.86
459
Method 2








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(mixture of isomers)




















Intermediate
Reaction comment







32-3
After addition of CH3I the mixture is stirred for 12 h at rt.



Then water is added and the mixture is purified by HPLC



on reversed phase (ACN, water) to give the title



compounds as a mixture of isomers.





















Intermediate
Name
Name of Starting Material







32-1
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



(methoxymethyl)pyridin-3-yl)methyl]-1H-
(hydroxymethyl)pyridin-3-yl)methyl]-1H-



imidazole-4-carboxylic acid
imidazole-4-carboxylate


32-2
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



(methoxymethyl)pyridin-3-yl)methyl]-1H-
(hydroxymethyl)pyridin-3-yl)methyl]-1H-



pyrazole-4-carboxylic acid
pyrazole-4-carboxylate trifluoroacetate


32-3
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(methoxymethyl)pyridin-3-yl)methyl]-1-{[2-
(hydroxymethyl)pyridin-3-yl)methyl]-1-{[2-



(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-
(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-



carboxylic acid
carboxylate



and
and



5-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(methoxymethyl)pyridin-3-yl)methyl]-1-{[2-
(hydroxymethyl)pyridin-3-yl)methyl]-1-{[2-



(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-
(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-



carboxylic acid
carboxylate



(mixture of isomers)
(mixture of isomers)









Intermediate 33
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate



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To a 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 minutes. Saturated aqueous NaHCO3 is added and the mixture is stirred vigorously for 5 minutes. Then the mixture is filtered over celite. The aqueous phase is extracted twice with EtOAc and the combined organic phases are washed with brine and dried (MgSO4). The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (petroleum ether/EtOAc 70:30→0:100) to give the title compound.


LC (Method 2): tR=0.78 min; Mass spectrum (ESI+): m/z=341 [M+H]+.


Intermediates 33-1 to 33-5 are prepared in analogy to Intermediate 33:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







33-1


embedded image


1.14
405
Method 1





33-2


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0.73
327
Method 2





33-3


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0.65
364
Method 1





33-4


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0.84
401
Method 1





33-5


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0.77
365
Method 1




















Intermediate
Reaction comment







33-1
DBAD is added to the reaction mixture at 0° C. The



mixture is stirred for 12 h while warming to rt.


33-4
DBAD is added to the reaction mixture at 0° C. The



mixture is stirred for 12 h while warming to rt.


33-5
DBAD is added to the reaction mixture at 0° C. The



mixture is stirred for 12 h while warming to rt.
























Name of
Name of


Intermediate
Name
Starting Material 1
Starting Material 2







33-1
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-hexan-
(6-{3-Azabicyclo[3.1.0]-
Ethyl 3-bromo-1H-



3-yl}-2-methylpyridin-3-yl)methyl]-3-
hexan-3-yl}-2-methylpyridin-
pyrazole-4-carboxylate



bromo-1H-pyrazole-4-carboxylate
3-yl)methanol



33-2
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-hexan-
(6-{3-Azabicyclo[3.1.0]-
Ethyl 1H-pyrazole-4-



3-yl}-2-methylpyridin-3-yl)methyl]-1H-
hexan-3-yl}-2-methylpyridin-
carboxylate



pyrazole-4-carboxylate
3-yl)methanol



33-3
Methyl 7-[(6-{3-azabicyclo[3.1.0]-
(6-{3-Azabicyclo[3.1.0]-
Methyl 7H-pyrrolo[2,3-



hexan-3-yl}-2-methylpyridin-3-yl)-
hexan-3-yl}-2-methyl-
d]pyrimidine-5-



methyl]-7H-pyrrolo[2,3-d]pyrimidine-5-
pyridin-3-yl)methanol
carboxylate



carboxylate




33-4
Methyl 7-[(2-{6,6-difluoro-3-
(2-{6,6-Difluoro-3-
Methyl 7H-pyrrolo[2,3-



azabicyclo[3.1.0]hexan-3-yl}-4-
azabicyclo[3.1.0]hexan-3-
d]pyrimidine-5-



methylpyrimidin-5-yl)methyl]-7H-
yl}-4-methylpyrimidin-5-
carboxylate



pyrrolo[2,3-d]pyrimidine-5-carboxylate
yl)methanol



33-5
Methyl 7-[(2-{3-azabicyclo[3.1.0]-
(2-{3-Azabicyclo[3.1.0]-
Methyl 7H-pyrrolo[2,3-



hexan-3-yl}-4-methylpyrimidin-5-yl)-
hexan-3-yl}-4-methyl-
d]pyrimidine-5-



methyl]-7H-pyrrolo[2,3-d]pyrimidine-5-
pyrimidin-5-yl)methanol
carboxylate



carboxylate









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



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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 for 10 minutes with argon. 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 h. After cooling to rt 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 (petroleum ether/EtOAc 70:30→0:100) to give the title compound.


LC (Method 2): tR=0.95 min; Mass spectrum (ESI+): m/z=459 [M+H]+.


Intermediate 35
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(3-hydroxypropyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate



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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 hydrogen atmosphere (3 bar) at rt for 12 h. The mixture is filtered, the filtrate is concentrated and the residue is chromatographed on silica gel (petroleum ether/EtOAc 70:30→0:100) to give the title compound.


LC (Method 2): tR=0.73 min; Mass spectrum (ESI+): m/z=371 [M+H]+.


Intermediate 36
3-[5-(Azidomethyl)-6-ethenylpyridin-2-yl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane



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Under argon atmosphere diphenylphosphorylazide (1.4 mL) is added dropwise to an ice-cooled 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 h while warming to rt. Then 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 (petroleum ether/EtOAc 99:1→50:50) to give the title compound. LC (Method 2): tR=0.88 min; Mass spectrum (ESI+): m/z=278 [M+H]+.


Intermediates 36-1 to 36-5 are prepared in analogy to Intermediate 36:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







36-1


embedded image


0.69
230
Method 2





36-2


embedded image


0.72
242
Method 2





36-3


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1.00
267
Method 2





36-4


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0.97
267
Method 2





36-5


embedded image


0.75
231
Method 2






















Intermediate
Reaction comment








36-3
The reaction is conducted in toluene/ACN 1:1.



36-4
The reaction is conducted in toluene/ACN 1:1.



36-5
The reaction is conducted in toluene/ACN 1:1.





















Intermediate
Name
Name of Starting Material







36-1
5-[5-(Azidomethyl)-6-methylpyridin-2-yl]-5-
(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



azaspiro[2.3]hexane
methylpyridin-3-yl)methanol


36-2
3-[5-(Azidomethyl)-6-ethenylpyridin-2-yl]-3-
(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



azabicyclo[3.1.0]hexane
ethenylpyridin-3-yl)methanol


36-3
3-[5-(Azidomethyl)-6-methylpyrazin-2-yl]-6,6-
(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-



difluoro-3-azabicyclo[3.1.0]hexane
yl}-3-methylpyrazin-2-yl)methanol


36-4
3-[5-(Azidomethyl)-4-methylpyrimidin-2-yl]-
(2-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-



6,6-difluoro-3-azabicyclo[3.1.0]hexane
yl}-4-methylpyrimidin-5-yl)methanol


36-5
3-[5-(Azidomethyl)-4-methylpyrimidin-2-yl]-3-
(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-



azabicyclo[3.1.0]hexane
methylpyrimidin-5-yl)methanol









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



embedded image


A mixture of 3-[5-(azidomethyl)-6-ethenylpyridin-2-yl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane (794 mg), propiolic acid ethylester (320 μL), CuSO4 (92 mg) and sodium (L)-ascorbate (568 mg) in tert.-butanol (8 mL) and water (8 mL) is stirred at rt for 48 h. 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 (petroleum ether/EtOAc 99:1→50:50) to give the title compound.


LC (Method 2): tR=0.89 min; Mass spectrum (ESI+): m/z=376 [M+H]+.


Intermediates 37-1 to 37-5 are prepared in analogy to Intermediate 37:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







37-1


embedded image


0.69
328
Method 2





37-2


embedded image


0.74
340
Method 2





37-3


embedded image


0.95
365
Method 2





37-4


embedded image


0.87
365
Method 2





37-5


embedded image


0.79
329
Method 2






















Intermediate
Reaction comment








37-3
The reaction is conducted for 12 h.



37-5
The reaction is conducted for 5 days.





















Intermediate
Name
Name of Starting Material







37-1
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-methyl-
5-[5-(Azidomethyl)-6-methylpyridin-2-yl]-



pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylate
5-azaspiro[2.3]hexane


37-2
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
3-[5-(Azidomethyl)-6-ethenylpyridin-2-yl]-



ethenylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-
3-azabicyclo[3.1.0]hexane



carboxylate



37-3
Ethyl 1-[(5-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-
3-[5-(Azidomethyl)-6-methylpyrazin-2-yl]-



3-yl}-3-methylpyrazin-2-yl)methyl]-1H-1,2,3-
6,6-difluoro-3-azabicyclo[3.1.0]hexane



triazole-4-carboxylate



37-4
Ethyl 1- [(2-{6,6-difluoro-3-azabicyclo[3.1.0]-hexan-
3-[5-(Azidomethyl)-4-methylpyrimidin-2-



3-yl}-4-methylpyrimidin-5-yl)methyl]-1H-1,2,3-
yl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane



triazole-4-carboxylate



37-5
Ethyl 1-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-
3-[5-(Azidomethyl)-4-methylpyrimidin-2-



methylpyrimidin-5-yl)methyl]-1H-1,2,3-triazole-4-
yl]-3-azabicyclo[3.1.0]hexane



carboxylate









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



embedded image


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 at 0° C. NaH (60% in mineral oil, 45 mg). The mixture is stirred for 30 minutes at rt, treated with CH3I (30 μL) and stirred for 12 h at rt. Water is added and the mixture is concentrated in vacuo. The residue is taken up in DCM/isopropanol 1:1 and filtered. The filtrate is dried (MgSO4) and concentrated in vacuo to give the title compound.


LC (Method 2): tR=0.65 min; Mass spectrum (ESI+): m/z=366 [M+H]+.


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



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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 for 48 h at rt. 9-Borabicyclo(3.3.1)nonane (6 mL) is added and stirring is continued for 12 h. The mixture is cooled to 0° C. and treated dropwise with water (3 mL) and H2O2 (35% in water, 3.35 mL). Then the mixture is stirred for 30 minutes at rt. Aqueous NaOH (2 M, 340 μL) is added, the mixture is stirred for 20 minutes and then cooled to 0° C. Saturated aqueous Na2S2O3 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 (petroleum ether/EtOAc 80:20→0:100) to give the title compound. LC (Method 2): tR=0.76 min; Mass spectrum (ESI+): m/z=371 [M+H]+.


Intermediate 39-1 is prepared in analogy to Intermediate 39:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







39-1


embedded image


0.98
357
Method 1






















Intermediate
Reaction comment








39-1
The hydroboration is conducted for 3 h at rt.





















Intermediate
Name
Name of Starting Material







39-1
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(2-hydroxyethyl)pyridin-3-yl)methyl]-1H-
ethenylpyridin-3-yl)methyl]-1H-pyrazole-4-



pyrazole-4-carboxylate
carboxylate









Intermediate 40
Methyl 6-{3-azabicyclo[3.1.0]hexan-3-yl}pyridazine-3-carboxylate



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Under argon atmosphere a mixture of methyl 6-chloropyridazine-3-carboxylate (2.5 g), 3-azabicyclo[3.1.0]hexane hydrochloride (1.99 g) and K2CO3 (4.02 g) in DMF (50 mL) is stirred for 12 h at rt. 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): tR=0.60 min; Mass spectrum (ESI+): m/z=220 [M+H]+.


Intermediates 40-1 to 40-8 are prepared in analogy to Intermediate 40:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







40-1


embedded image


0.68
219
Method 2





40-2


embedded image


0.96
219
Method 1





40-3


embedded image


0.93
254
Method 2





40-4


embedded image


0.93
270
Method 2





40-5


embedded image


1.07
287
Method 1





40-6


embedded image


1.02
284
Method 2





40-7


embedded image


1.02
248
Method 2





40-8


embedded image


1.00
248
Method 1




















Intermediate
Reaction comment







40-1
The reaction is conducted at 90° C. for 12 h.


40-3
The reaction is conducted for 48 h at rt.


40-4
The reaction is conducted at 90° C. for 12 h.


40-5
KHCO3 is used instead of K2CO3 and DMSO instead of



DMF. The reaction is conducted at 45° C. for 4 h.


40-6
The reaction is conducted at 90° C. for 1 h.


40-7
The reaction is conducted at 90° C. for 1 h.
























Name of
Name of


Intermediate
Name
Starting Material 1
Starting Material 2







40-1
Methyl 6-{3-azabicyclo[3.1.0]-
Methyl 6-chloropyridine-3-
3-Azabicyclo[3.1.0]hexane



hexan-3-yl}pyridine-3-carboxylate
carboxylate
hydrochloride


40-2
Methyl 6-{5-azaspiro[2.3]hexan-
Methyl 6-fluororopyridine-3-
5-Azaspiro[2.3]hexane



5-yl}pyridine-3-carboxylate
carboxylate
trifluoroacetate


40-3
Methyl 5-{3-azabicyclo[3.1.0]-
Methyl 3,5-dichloropyrazine-
3-Azabicyclo[3.1.0]hexane



hexan-3-yl}-3-chloropyrazine-2-
2-carboxylate
hydrochloride



carboxylate




40-4
Methyl 5-{6,6-difluoro-3-
Methyl 5-chloro-3-
6,6-Difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}-3-
methylpyrazine-2-
azabicyclo[3.1.0]hexane



methylpyrazine-2-carboxylate
carboxylate
hydrochloride


40-5
Methyl 6-{3-azabicyclo[3.1.0]-
Methyl 6-chloro-4-
3-Azabicyclo[3.1.0]hexane



hexan-3-yl}-4-(trifluoromethyl)-
(trifluoromethyl)pyridine-3-
hydrochloride



pyridine-3-carboxylate
carboxylate



40-6
Ethyl 2-{6,6-difluoro-3-
Ethyl 2-chloro-4-
6,6-Difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}-4-
methylpyrimidine-5-
azabicyclo[3.1.0]hexane



methylpyrimidine-5-carboxylate
carboxylate
hydrochloride


40-7
Ethyl 2-{3-
Ethyl 2-chloro-4-
3-Azabicyclo[3.1.0]hexane



azabicyclo[3.1.0]hexan-3-yl}-4-
methylpyrimidine-5-
hydrochloride



methylpyrimidine-5-carboxylate
carboxylate



40-8
Ethyl 2-{5-azaspiro[2.3]hexan-5-
Ethyl 2-chloro-4-
5-azaspiro[2.3]hexane



yl}-4-methylpyrimidine-5-
methylpyrimidine-5-
trifluoroacetate



carboxylate
carboxylate









Intermediate 41
(6-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridazin-3-yl)methanol



embedded image


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 for 24 h at 70° C. After cooling to rt 1 M aqueous HCl is added until a pH-value of 2 is reached. The mixture is stirred for 15 minutes and then partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous phase is extracted twice with EtOAc and twice with EtOAc/isopropanol 1:1. The combined organic phases are dried (MgSO4), concentrated in vacuo and the residue is purified by HPLC on reversed phase (ACN, water) to give the title compound.


LC (Method 1): tR=0.67 min; Mass spectrum (ESI+): m/z=192 [M+H]+.


Intermediate 41-1 is prepared in analogy to Intermediate 41:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M+H]+
LC Method







41-1


embedded image


0.67
379
Method 2




















Intermediate
Reaction comment







41-1
The reaction is conducted in THF/EtOH 1:1 for 8 h at rt.





















Intermediate
Name
Name of Starting Material







41-1
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Ethyl 6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-



hexan-3-yl}-2-(hydroxymethyl)pyridin-3-
3-yl}-3-{[4-(ethoxycarbonyl)-1H-imidazol-1-



yl)methyl]-1H-imidazole-4-carboxylate
yl]methyl}pyridine-2-carboxylate









Intermediate 42
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}pyridazin-3-yl)methyl]-1H-pyrazole-4-carboxylate



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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 h, diluted with DMF and purified by HPLC on reversed phase (ACN, water) to give the title compound.


LC (Method 2): tR=0.68 min; Mass spectrum (ESI+): m/z=314 [M+H]+.


Intermediates 42-1 to 42-2 are prepared in analogy to Intermediate 42:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M+H]+
LC Method







42-1


embedded image


1.04
348
Method 2





42-2


embedded image


0.89
281
Method 2




















Intermediate
Reaction comment







42-1
The reaction mixture is chromatographed on silica



gel (petroleum ether/EtOAc 95:5 → 45:55) to



give the title compound.


42-2
The reaction mixture is stirred for 12 h at rt. The crude



product is chromatographed on silica gel (cyclohexane/



EtOAc 50:50 → 0:100) to give the title compound.
























Name of
Name of


Intermediate
Name
Starting Material 1
Starting Material 2


















42-1
Ethyl 1-[(5-{3-azabicyclo[3.1.0]-hexan-3-
(5-{3-Azabicyclo[3.1.0]-hexan-3-
Ethyl 1H-pyrazole-



yl}-3-chloropyrazin-2-yl)methyl]-1H-
yl}-3-chloropyrazin-2-yl)methanol
4-carboxylate



pyrazole-4-carboxylate




42-2
Ethyl 1-[(2-chloro-4-methyl-pyrimidin-5-
(2-Chloro-4-methyl-pyrimidin-5-
Ethyl 1H-pyrazole-



yl)methyl]-1H-pyrazole-4-carboxylate
yl)methanol
4-carboxylate









Intermediate 43
Ethyl 1-[(5-bromopyrimidin-2-yl)methyl]-1H-pyrazole-4-carboxylate



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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 for 1.5 h at rt. The mixture is diluted with THF and filtered over celite. The filter cake is washed twice with THF. The combined filtrates are concentrated and the residue is chromatographed on silica gel (petroleum ether/EtOAc 80:20→0:100) to give the title compound.


LC (Method 1): tR=0.85 min; Mass spectrum (ESI+): m/z=311 [M+H]+.


Intermediate 44
Ethyl 1-[(5-{3-azabicyclo[3.1.0]hexan-3-yl}pyrimidin-2-yl)methyl]-1H-pyrazole-4-carboxylate



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In a microwave vial a mixture of ethyl 1-[(5-bromopyrimidin-2-yl)methyl]-1H-pyrazole-4-carboxylate (500 mg), 3-azabicyclo[3.1.0]hexane hydrochloride (384 mg), Cs2CO3 (1.6 g), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3, 74 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 93 mg) in DMF (1.3 mL) and toluene (3.8 mL) is purged for 10 minutes with argon. The vial is sealed and the mixture is heated to 90° C. for 2 h. Then the mixture is 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 (petroleum ether/EtOAc 90:10→20:80) to give the title compound. LC (Method 1): tR=0.91 min; Mass spectrum (ESI+): m/z=314 [M+H]+.


Intermediate 45
(6-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methanol



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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 for 12 h at 60° C. LiBH4 (2 M solution in THF, 5 mL) is added and the mixture is stirred for 2 h at 60° C. Then the mixture is 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 (DCM/MeOH 0:100→90:10) to give the title compound. LC (Method 1): tR=0.79 min; Mass spectrum (ESI+): m/z=191 [M+H]+.


Intermediates 45-1 to 45-3 are prepared in analogy to Intermediate 45:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M+H]+
LC Method







45-1


embedded image


0.80
191
Method 1





45-2


embedded image


0.71
242
Method 2





45-3


embedded image


0.62
242
Method 2




















Intermediate
Reaction comment







45-2
The reaction is conducted in



1,4-dioxane/MeOH 15:1 for 3 h at rt.


45-3
The reaction is conducted for 12 h at 50° C.





















Intermediate
Name
Name of Starting Material







45-1
(6-{5-Azaspiro[2.3]hexan-5-yl}pyridin-3-yl)-
Methyl 6-{5-azaspiro[2.3]hexan-5-yl}pyridine-



methanol
3-carboxylate


45-2
(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-
Methyl 5-{6,6-difluoro-3-azabicyclo[3.1.0]-



3-methylpyrazin-2-yl)methanol
hexan-3-yl}-3-methylpyrazine-2-carboxylate


45-3
(2-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-
Ethyl 2-{6,6-difluoro-3-azabicyclo[3.1.0]-



4-methylpyrimidin-5-yl)methanol
hexan-3-yl}-4-methylpyrimidine-5-carboxylate









Intermediate 46
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid trifluoroacetate



embedded image


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 h. Then the mixture is concentrated in vacuo. The residue is taken up in MeOH (10 mL) and aqueous NaOH (1 M, 5 mL) and stirred for 2 h at rt. After neutralization with trifluoroacetic acid the crude product is purified by HPLC on reversed phase (ACN, water) to give the title compound.


LC (Method 1): tR=0.65 min; Mass spectrum (ESI+): m/z=285 [M+H]+.


Intermediate 47
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid trifluoroacetate



embedded image


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 for 48 h to 75° C., for 3 h to 90° C., for 3 h to 100° C. and for 12 h to 80° C. After cooling to rt 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 h at rt the mixture is neutralized with trifluoroacetic and purified by HPLC on reversed phase (ACN, water) to give the title compound. LC (Method 2): tR=0.40 min; Mass spectrum (ESI+): m/z=285 [M+H]+.


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



embedded image


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 for 3 h at rt. The mixture is partitioned between saturated aqueous NaHCO3 and DCM. The aqueous phase is extracted with DCM for three times. The combined organic phases are dried (Na2SO4) and concentrated in vacuo to give the title compound.


LC (Method 1): tR=0.89 min; Mass spectrum (ESI+): m/z=469 [M+H]+.


Intermediate 48-1 is prepared in analogy to Intermediate 48:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M+H]+
LC Method







48-1


embedded image


1.10
355
Method 2




















Intermediate
Reaction comment







48-1
The crude product is chromatographed on silica



gel (petroleum ether/EtOAc 95:5 → 70:30) to



give the title compound.





















Intermediate
Name
Name of Starting Material







48-1
Ethyl 1-[(2-acetyl-6-{3-azabicyclo[3.1.0]hexan-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4-
(1-hydroxyethyl)pyridin-3-yl)methyl]-1H-



carboxylate
pyrazole-4-carboxylate









Intermediate 49
Ethyl 6-{5-azaspiro[2.3]hexan-5-yl}-3-{[4-(ethoxycarbonyl)-1H-imidazol-1-yl]methyl}pyridine-2-carboxylate



embedded image


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 under a carbonmonoxide atmosphere of 10 bar to 130° C. for 5 h. The solvents are evaporated in vacuo and the residue is purified by HPLC on reversed phase (ACN, water) to give the title compound.


LC (Method 2): tR=0.89 min; Mass spectrum (ESI+): m/z=385 [M+H]+.


Intermediates 49-1 to 49-4 are prepared in analogy to Intermediate 49:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M+H]+
LC Method







49-1


embedded image


1.03
385
Method 2





49-2


embedded image


0.89
385
Method 2





49-3


embedded image


0.89
421
Method 2





49-4


embedded image


0.91
385
Method 2




















Intermediate
Reaction comment







49-3
The reaction is conducted under a



carbonmonoxide atmosphere of 5 bar at 90° C.


49-4
The reaction is conducted under a



carbonmonoxide atmosphere of 4 bar at 100° C. for 14 h.





















Intermediate
Name
Name of Starting Material







49-1
Ethyl 6-{5-azaspiro[2.3]hexan-5-yl}-3-{[4-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



(ethoxycarbonyl)-1H-pyrazol-1-
chloropyridin-3-yl)methyl]-1H-pyrazole-4-



yl]methyl}pyridine-2-carboxylate
carboxylate


49-2
Ethyl 6-{5-azaspiro[2.3]hexan-5-yl}-3-{[4-
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-



(ethoxycarbonyl)-1H-imidazol-1-
chloropyridin-3-yl)methyl]-1H-imidazole-4-



yl]methyl}pyridine-2-carboxylate
carboxylate


49-3
Ethyl 6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-
Ethyl 1-[(2-bromo-6-{6,6-difluoro-3-



3-yl}-3-{[4-(ethoxycarbonyl)-1H-imidazol-1-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl]methyl}pyridine-2-carboxylate
yl)methyl]-1H-imidazole-4-carboxylate


49-4
Ethyl 6-{3-azabicyclo[3.1.0]hexan-3-yl}-3-{[4-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(ethoxycarbonyl)-1H-imidazol-1-
bromopyridin-3-yl)methyl]-1H-imidazole-4-



yl]methyl}pyridine-2-carboxylate
carboxylate









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



embedded image


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


LC (Method 1): tR=0.91 min; Mass spectrum (ESI+): m/z=343 [M+H]+.


Intermediates 50-1 to 50-2 are prepared in analogy to Intermediate 50:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M+H]+
LC Method







50-1


embedded image


1.00
343
Method 1





50-2


embedded image


0.91
343
Method 1





















Intermediate
Name
Name of Starting Material







50-1
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-
Ethyl 6-{5-azaspiro[2.3]hexan-5-yl}-3-{[4-



(hydroxymethyl)pyridin-3-yl)methyl]-1H-
(ethoxycarbonyl)-1H-pyrazol-1-



pyrazole-4-carboxylate trifluoroacetate
yl]methyl}pyridine-2-carboxylate


50-2
Ethyl 1-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-
Ethyl 6-{5-azaspiro[2.3]hexan-5-yl}-3-{[4-



(hydroxymethyl)pyridin-3-yl)methyl]-1H-
(ethoxycarbonyl)-1H-imidazol-1-



imidazole-4-carboxylate
yl]methyl}pyridine-2-carboxylate









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



embedded image


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 is then treated with aqueous NaOH (4 M, 750 μL). After stirring for 12 h at rt, aqueous HCl (4 M, 750 μL) is added and the mixture is purified by HPLC on reversed phase (ACN, water) to give the title compound. LC (Method 2): tR=0.63 min; Mass spectrum (ESI+): m/z=321 [M+H]+.


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



embedded image


CH3MgBr (3 M in diethylether, 1.22 mL) is added dropwise at −40° C. 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). 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): tR=0.73 min; Mass spectrum (ESI+): m/z=357 [M+H]+.


Intermediate 52-1 is prepared in analogy to Intermediate 52:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M+H]+
LC Method







52-1


embedded image


1.10
371
Method 1




















Intermediate
Reaction comment







52-1
The reaction is conducted at −10° C.























Name of


Intermediate
Name
Starting Material







52-1
Ethyl 1-[(6-{3-azabicyclo
Ethyl 1-[(2-acetyl-6-



[3.1.0]hexan-3-yl}-2-(2-
{3-azabicyclo[3.1.0]



hydroxypropan-
hexan-3-yl}pyridin-



2-yl)pyridin-3-yl)methyl]-
3-yl)methyl]-1H-



1H-pyrazole-4-carboxylate
pyrazole-4-carboxylate









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



embedded image


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


LC (Method 1): tR=1.03 min; Mass spectrum (ESI+): m/z=357 [M+H]+.


Intermediate 53-1 is prepared in analogy to Intermediate 53:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M+H]+
LC Method







53-1


embedded image


1.03
357
Method 1




















Intermediate
Reaction comment







53-1
RuCl[(S,S)-Tsdpen(mesitylene) is used instead



of RuCl[(R,R)-Tsdpen(mesitylene).





















Intermediate
Name
Name of Starting Material







53-1
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(2-acetyl-6-{3-azabicyclo[3.1.0]hexan-



[(1S)-1-hydroxyethyl]pyridin-3-yl)methyl]-1H-
3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4-



pyrazole-4-carboxylate
carboxylate









Intermediate 54
(5-{3-Azabicyclo[3.1.0]hexan-3-yl}-3-chloropyrazin-2-yl)methanol



embedded image


LiBH4 (744 mg) is added portionwise to an ice-cooled 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 for 2 h at rt. After cooling to 0° C. aqueous HCl (4 M, 10 mL) is added and the mixture is stirred for 10 minutes. Then the mixture is partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous phase is extracted twice with EtOAc. The combined organic phases are dried (MgSO4), concentrated in vacuo and the residue is chromatographed on silica gel (petroleum ether/EtOAc 80:20→50:50) to give the title compound. LC (Method 2): tR=0.85 min; Mass spectrum (ESI+): m/z=226 [M+H]+.


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



embedded image


Under argon atmosphere an ice-cooled 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 CH3SO2Cl (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 h at rt the mixture is partitioned between water and DCM. The organic phase is dried (MgSO4) and concentrated in vacuo to give the crude product which is directly used in the next step.


LC (Method 2): tR=0.76 min; Mass spectrum (ESI+): m/z=363 [M+H]+.


Intermediate 55-1 is prepared in analogy to Intermediate 55:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M+H]+
LC Method







55-1


embedded image


1.02
327
Method 1




















Intermediate
Reaction comment







55-1
After the addition of ethyl 1H-pyrazole-4-carboxylate



the reaction mixture is stirred for 12 h at rt.
























Name of
Name of


Intermediate
Name
Starting Material 1
Starting Material 2


















55-1
Ethyl 1-[(6-{3-azabicyclo[3.1.0]-
(6-{3-Azabicyclo[3.1.0]hexan-
Ethyl 1H-pyrazole-4-



hexan-3-yl}-4-methylpyridin-3-
3-yl}-4-methylpyridin-3-yl)-
carboxylate



yl)-methyl]-1H-pyrazole-4-
methanol




carboxylate









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



embedded image


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 at 0° C. NaH (60% in mineral oil, 25 mg). The mixture is stirred for 30 minutes at rt, treated with CH3I (16 μL) and stirred for 12 h. Water is carefully added. The mixture is concentrated in vacuo and the residue is taken up in DCM/isopropanol 1:1. Then the mixture is filtered and the filtrate is concentrated in vacuo to give the crude product which is directly used in the next step.


LC (Method 2): tR=0.58 min; Mass spectrum (ESI+): m/z=330 [M+H]+.


Intermediates 56-1 to 56-2 are prepared in analogy to Intermediate 56:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M+H]+
LC Method










56-1


embedded image


0.71
379
Method 2





56-2


embedded image


0.53
329
Method 2




















Intermediate
Reaction comment







56-1
Iodoethane is used instead of CH3I.


56-2
After addition of CH3I the mixture is stirred for 4 h.



Then aqueous NaOH (4M) is added until pH of 12 is



reached and the mixture is stirred for 1 h at 50° C. The



mixture is neutralized by addition of acetic acid and



purified by HPLC on reversed phase (ACN, water).





















Intermediate
Name
Name of Starting Material







56-1
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-2-(ethoxymethyl)pyridin-3-yl)methyl]-1H-
hexan-3-yl}-2-(hydroxymethyl)pyridin-3-



pyrazole-4-carboxylic acid
yl)methyl]-1H-pyrazole-4-carboxylate


56-2
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



(methoxymethyl)pyridin-3-yl)methyl]-1H-
(hydroxymethyl)pyridin-3-yl)methyl]-1H-



imidazole-4-carboxylic acid
imidazole-4-carboxylate









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



embedded image


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 for 2.5 h to 155° C. and for 3 h to 165° C. Purification by HPLC on reversed phase (ACN, water) gives the title compound. LC (Method 2): tR=0.84 min.


Intermediate 57-1 is prepared in analogy to Intermediate 57:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M+H]+
LC Method







57-1


embedded image


0.85

Method 2






















Intermediate
Reaction comment





57-1
NaOCH2CH3 in EtOH is used instead of NaOCH3 in MeOH.



The reaction is conducted for 12 h at 150° C.












Intermediate
Name
Name of Starting Material





57-1
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
Ethyl 1-[(2-chloro-6-{6,6-difluoro-3-



yl}-2-ethoxypyridin-3-yl)methyl]-1H-imidazole-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



4-carboxylic acid
yl)methyl]-1H-imidazole-4-carboxylate









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



embedded image


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 for 14 h at rt, cooled to 0° C. and treated with aqueous HCl (1 M, 5 mL). Then the mixture is neutralized by addition of NaOH (4 M) and purified by HPLC on reversed phase (ACN, water) to give the title compounds.


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

LC (Method 1): tR=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): tR=0.94 min; Mass spectrum (ESI+): m/z=343 [M+H]+.


Intermediate 59
2-Hydroxy-5-iodo-4-methylpyridine-3-carbonitrile



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Under argon atmosphere an ice-cooled mixture of 2-hydroxy-4-methylpyridine-3-carbonitrile (3 g) in DCM (100 mL) is treated with trifluoroacetic acid (5 mL). Then N-iodosuccinimide (7.55 g) is added portionwise. The mixture is stirred for 3 h while warming to rt. The mixture is concentrated in vacuo, half-saturated aqueous Na2S2O3 is added and the mixture is stirred for 10 minutes. The precipitate is collected by filtration, washed with water and diethylether and dried in vacuo to give the title compound. LC (Method 2): tR=0.72 min; Mass spectrum (ESI+): m/z=261 [M+H]+.


Intermediate 60
2-Chloro-5-iodo-4-methylpyridine-3-carbonitrile



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A mixture of 2-hydroxy-5-iodo-4-methylpyridine-3-carbonitrile (6.27 g) in POCl3 is stirred for 5 h at 100° C. The mixture is concentrated in vacuo. The residue is taken up in DCM (200 mL) and treated with water. Then the mixture is neutralized by careful addition of saturated aqueous NaHCO3. The phases are separated and the aqueous phase is extracted twice with DCM. The combined organic phases are washed with saturated aqueous NaHCO3, dried (MgSO4) and concentrated in vacuo to give the crude product which is directly used in the next step.


LC (Method 1): tR=1.02 min; Mass spectrum (ESI+): m/z=278 [M+H]+.


Intermediate 61
2-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-5-formyl-4-methylpyridine-3-carbonitrile



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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., treated dropwise with isopropylmagnesium chloride (iPrMgCl, 2 M solution in THF, 3.82 mL) and stirred for 30 minutes. Then the mixture is 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 half-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 directly used in the next step.


LC (Method 2): tR=0.96 min; Mass spectrum (ESI+): m/z=264 [M+H]+.


Intermediate 61-1 is prepared in analogy to Intermediate 61:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







61-1


embedded image


0.98
228
Method 2





















Intermediate
Name
Name of Starting Material







61-1
2-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-formyl-4-
2-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-iodo-4-



methylpyridine-3-carbonitrile
methylpyridine-3-carbonitrile









Intermediate 62
N′-[(E)-(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methylidene]acetohydrazide



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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 h. The mixture is concentrated in vacuo, taken up in toluene, treated with p-toluenesulfonic acid (100 mg) and refluxed in a Dean-Stark apparatus for 16 h. After cooling to rt the precipitate is collected by filtration, washed with tert.-butyl-methyl-ether and dried in vacuo to give the title compound. LC (Method 2): tR=0.64 min; Mass spectrum (ESI+): m/z=295 [M+H]+.


Intermediate 62-1 is prepared in analogy to Intermediate 62:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







62-1


embedded image


0.61
259
Method 2





















Intermediate
Name
Name of Starting Material







62-1
N′-[(E)-(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methylidene]acetohydrazide
methylpyridine-3-carbaldehyde









Intermediate 63
N′-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]acetohydrazide



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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 hydrogen atmosphere (3 bar) at rt for 3.5 h. The mixture is filtered, the filtrate is concentrated and the residue is taken up in tert.-butyl-methyl-ether (100 mL) and EtOAc (10 mL). After stirring for 3 h the precipitate is collected by filtration, washed with tert.-butyl-methyl-ether and dried in vacuo to give the title compound.


LC (Method 2): tR=0.58 min; Mass spectrum (ESI+): m/z=297 [M+H]+.


Intermediate 63-1 is prepared in analogy to Intermediate 63:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







63-1


embedded image


0.57
261
Method 2





















Intermediate
Name
Name of Starting Material







63-1
N′-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
N′-[(E)-(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methyl]acetohydrazide
methylpyridin-3-yl)methylidene]acetohydrazide









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



embedded image


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 for 12 h at rt. The mixture is concentrated and then partitioned between DCM and saturated aqueous Na2CO3. 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): tR=0.82 min; Mass spectrum (ESI+): m/z=411 [M+H]+.


Intermediate 64-1 is prepared in analogy to Intermediate 64:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







64-1


embedded image


0.81
375
Method 2





















Intermediate
Name
Name of Starting Material







64-1
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
N′-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methyl]-3-(chloromethyl)-
methylpyridin-3-yl)methyl]acetohydrazide



1H-pyrazole-4-carboxylate









Intermediate 65
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]-3-(cyanomethyl)-1H-pyrazole-4-carboxylate



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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 h. The mixture is partitioned between water and EtOAc. The aqueous phase is extracted 4 times with EtOAc. The combined organic phases are washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound.


LC (Method 2): tR=0.74 min; Mass spectrum (ESI+): m/z=366 [M+H]+.


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



embedded image


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-hexafluorophosphat (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 (DCM/(DCM/MeOH/7 N NH3 in MeOH 50:48:2) 90:10→60:40) to give the title compound.


LC (Method 2): tR=0.63 min; Mass spectrum (ESI+): m/z=457 [M+H]+.


Intermediates 66-1 to 66-4 are prepared in analogy to Intermediate 66:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







66-1


embedded image


0.97
496
Method 1





66-2


embedded image


0.64
372
Method 2





66-3


embedded image


0.78
578
Method 2








embedded image








(mixture of isomers)








66-4


embedded image


0.76
564
Method 2








embedded image








(mixture of isomers)




















Intermediate
Reaction comment







66-3
The product is obtained as a mixture of isomers.


66-4
The product is obtained as a mixture of isomers.





















Intermediate
Name
Name of Starting Material







66-1
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methyl]-3-bromo-N-[(4R)-1-
methylpyridin-3-yl)methyl]-3-bromo-1H-



methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-
pyrazole-4-carboxylic acid



yl]-1H-pyrazole-4-carboxamide



66-2
1-[(2-Chloro-4-methylpyrimidin-5-yl)methyl]-N-
1-[(2-Chloro-4-methylpyrimidin-5-yl)methyl]-



[(4R)-1-methyl-1H,4H,5H,6H-cydopenta[d]-
1H-pyrazole-4-carboxylic acid



imidazol-4-yl]-1H-pyrazole-4-carboxamide



66-3
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



(methoxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1-
(methoxymethyl)pyridin-3-yl)methyl]-1-{[2-



methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-
(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-



yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-
carboxylic acid



pyrazole-5-carboxamide
and



and
5-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



5-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
(methoxymethyl)pyridin-3-yl)methyl]-1-{[2-



(methoxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1-
(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-



methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-
carboxylic acid



yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-
(mixture of isomers)



pyrazole-3-carboxamide




(mixture of isomers)



66-4
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



(hydroxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1-
(hydroxymethyl)pyridin-3-yl)methyl]-1-{[2-



methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-
(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-



yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-
carboxylic acid



pyrazole-5-carboxamide
and



and
5-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



5-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
(hydroxymethyl)pyridin-3-yl)methyl]-1-{[2-



(hydroxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1-
(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-



methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-
carboxylic acid



yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-
(mixture of isomers)



pyrazole-3-carboxamide




(mixture of isomers)









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



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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 for 1 h to 110° C. The mixture is cooled to rt treated with aqueous NaOH (4 M, 15 mL) and stirred for 10 minutes. Then aqueous HCl (4 M, 15 mL) is 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 minutes. After cooling to rt the mixture is neutralized with aqueous NaOH (1 M), concentrated in vacuo and the residue is chromatographed on silica gel (cyclohexane/EtOAc 90:10→70:30) to give the title compound.


LC (Method 2): tR=0.63 min; Mass spectrum (ESI+): m/z=490 [M+H]+.


Intermediate 68
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-imidazole-4-carboxylate



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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 h. After cooling to rt the mixture is partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous phase is extracted for 4 times with EtOAc. The combined organic phases are concentrated in vacuo and purified by HPLC on reversed phase (AON, water) to give the title compound. LC (Method 1): tR=0.96 min.


Intermediate 69
2-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-bromopyridine-3-carbonitrile



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Under argon atmosphere a mixture of 5-bromo-2-chloropyridine-3-carbonitrile (1.0 g), 3-azabicyclo[3.1.0]hexane hydrochloride (605 mg) and DIPEA (2 mL) in DMF (10 mL) is heated to 80° C. for 2 h. The mixture is cooled, concentrated, partitioned between water and EtOAc and the phases are separated. The aqueous is extracted twice with EtOAc. The combined organic phases are washed with brine, dried (MgSO4), concentrated and the residue is chromatographed on silica gel (petroleum ether/EtOAc 98:2→95:5) to give the title compound.


LC (Method 2): tR=1.13 min; Mass spectrum (ESI+): m/z=264 [M+H]+.


Intermediate 69-1 is prepared in analogy to Intermediate 69:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







69-1


embedded image


1.25
311
Method 1























Intermediate
Reaction comment









69-1
The reaction is conducted for 12 h at 80° C.























Intermediate
Name
Name of Starting Material 1
Name of Starting Material 2







69-1
Methyl 6-{3-azabicyclo[3.1.0]-
Methyl 5-bromo-6-chloro-2-
3-azabicyclo[3.1.0]hexane



hexan-3-yl}-5-bromo-2-
methylpyridine-3-carboxylate
hydrochloride



methylpyridine-3-carboxylate









Intermediate 70
Methyl 6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-cyanopyridine-3-carboxylate



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Under argon atmosphere a mixture of 2-{3-azabicyclo[3.1.0]hexan-3-yl}-5-bromopyridine-3-carbonitrile (773 mg) and triethylamine (489 μL) and (1,1′-bis(diphenylphosphino)ferrocene)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, concentrated in vacuo and the residue is purified by HPLC on reversed phase (ACN, water) to give the title compound.


LC (Method 1): tR=0.99 min; Mass spectrum (ESI+): m/z=244 [M+H]+.


Intermediates 70-1 to 70-3 are prepared in analogy to Intermediate 70:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







70-1


embedded image


0.64
476
Method 2





70-2


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1.14
437
Method 2





70-3


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0.72
366
Method 2




















Intermediate
Reaction comment







70-1
MeOH is used instead of a DMF/MeOH mixture.



The reaction is conducted at 100° C. for 2 h under a CO atmosphere of 12 bar


70-2
EtOH is used instead of MeOH. Bis(triphenylphosphine)palladium(II) dichloride



is used instead of (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride.



The reaction is conducted at 90° C. for 17 h under a CO atmosphere of 5 bar.


70-3
The reaction is conducted at 90° C. for 6 h.





















Intermediate
Name
Name of Starting Material







70-1
Methyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methyl]-4-{[(4R)-1-methyl-
methylpyridin-3-yl)methyl]-3-bromo-N-[(4R)-1-



1H,4H,5H,6H-cyclopenta[d]imidazol-4-
methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-



yl]carbamoyl}-1H-pyrazole-3-carboxylate
yl]-1H-pyrazole-4-carboxamide


70-2
Ethyl 6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-
Ethyl 5-[(2-bromo-6-{6,6-difluoro-3-



3-yl}-3-{[5-(ethoxycarbonyl)thiophen-2-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl]methyl}pyridine-2-carboxylate
yl)methyl]thiophene-2-carboxylate


70-3
Methyl 2-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
3-{5-[(5-Bromo-1,3-thiazol-2-yl)methyl]-6-



hexan-3-yl}-2-methylpyridin-3-yl)methyl]-1,3-
methylpyridin-2-yl}-6,6-difluoro-3-



thiazole-5-carboxylate
azabicyclo[3.1.0]hexane









Intermediate 71
2-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-(hydroxymethyl)pyridine-3-carbonitrile



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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 LiAlH4 (1 M solution in THF, 1.4 mL). The mixture is stirred for 3 h 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 (MgSO4), concentrated and purified by HPLC on reversed phase (ACN, water) to give the title compound.


LC (Method 1): tR=0.81 min; Mass spectrum (ESI+): m/z=216 [M+H]+.


Intermediates 71-1 to 71-2 are prepared in analogy to Intermediate 71:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







71-1


embedded image


0.93
259
Method 1





71-2


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0.77
283
Method 2




















Intermediate
Reaction comment







71-1
The reaction is conducted for 3 h at −25° C. Then 10% NH4Cl in water is carefully added. The



mixture is partitioned between water and EtOAc and filtered over celite. The phases are separated



and 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.





















Intermediate
Name
Name of Starting Material







71-1
(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-
Methyl 6-{3-azabicyclo[3.1.0]hexan-3-yl}-4-



(trifluoromethyl)pyridin-3-yl)methanol
(trifluoromethyl)pyridine-3-carboxylate


71-2
(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-
Methyl 6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-



bromo-2-methylpyridin-3-yl)methanol
bromo-2-methylpyridine-3-carboxylate









Intermediate 72
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]-3-(methoxymethyl)-1H-pyrazole-4-carboxylate



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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 under argon atmosphere in a microwave vial at 90° C. for 12 h. The mixture is diluted with MeOH and water and purified by HPLC on reversed phase (ACN, water) to give the title compound. LC (Method 1): tR=1.07 min; Mass spectrum (ESI+): m/z=371 [M+H]+.


Intermediate 72-1 is prepared in analogy to Intermediate 72:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







72-1


embedded image


1.04
407
Method 1























Intermediate
Reaction comment









72-1
The reaction is conducted at 100° C.






















Intermediate
Name
Name of Starting Material







72-1
Ethyl 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Ethyl 3-(chloromethyl)-1-[(6-{6,6-difluoro-3-



hexan-3-yl}-2-methylpyridin-3-yl)methyl]-3-
azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-



(methoxymethyl)-1H-pyrazole-4-carboxylate
yl)methyl]-1H-pyrazole-4-carboxylate









Intermediate 73
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-cyano-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylate



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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 rt 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 reversed phase (ACN, water) to give the title compound.


LC (Method 1): tR=0.99 min; Mass spectrum (ESI+): m/z=352 [M+H]+.


Intermediate 73-1 is prepared in analogy to Intermediate 73:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







73-1


embedded image


1.04
338
Method 1





















Intermediate
Name
Name of Starting Material







73-1
Methyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-
Methyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-



cyano-2-methylpyridin-3-yl)methyl]-1H-
bromo-2-methylpyridin-3-yl)methyl]-1H-



pyrazole-4-carboxylate
pyrazole-4-carboxylate









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



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A mixture of ethyl 1-[(6-{3-azabicycio[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 directly used in the next step.


LC (Method 2): tR=0.67 min; Mass spectrum (ESI+): m/z=357 [M+H]+.


Intermediate 75
Methyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate



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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 H2SO4 (182 μL) in MeOH (10 mL) is heated to 40° C. for 12 h. After cooling to rt the mixture is partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous phase is extracted with EtOAc. The combined organic phases are dried (MgSO4), concentrated and the residue is purified by HPLC on reversed phase (ACN, water) to give the title compound.


LC (Method 1): tR=1.17 min; Mass spectrum (ESI+): m/z=391 [M+H]+.


Intermediate 75-1 is prepared in analogy to Intermediate 75:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







75-1


embedded image


1.07

Method 1




















Intermediate
Reaction comment







75-1
The reaction is conducted for 12 h at 70° C.





















Intermediate
Name
Name of Starting Material







75-1
Methyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-



bromo-2-methylpyridin-3-yl)methyl]-1H-
bromo-2-methylpyridin-3-yl)methyl]-1H-



imidazole-4-carboxylate
imidazole-4-carboxylic acid









Intermediate 76
Methyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2,5-dimethylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylate



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In a microwave vial 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 for minutes with argon. Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 71 mg) is added, the vial is sealed and the mixture is heated for 12 h to 110° C. After cooling to rt the mixture is partitioned between half-saturated aqueous NaCl 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 reversed phase (ACN, water) to give the title compound.


LC (Method 2): tR=0.63 min; Mass spectrum (ESI+): m/z=327 [M+H]+.


Intermediate 76-1 is prepared in analogy to Intermediate 76:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







76-1


embedded image


1.10
327
Method 1





















Intermediate
Name
Name of Starting Material







76-1
Methyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-
Methyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-5-



2,5-dimethylpyridin-3-yl)methyl]-1H-pyrazole-
bromo-2-methylpyridin-3-yl)methyl]-1H-



4-carboxylate
pyrazole-4-carboxylate









Intermediate 77
Ethyl 1-[(6-chloro-2-cyanopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate



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A mixture of 6-chloro-3-(chloromethyl)pyridine-2-carbonitrile (37 mg), ethyl 1H-pyrazole-4-carboxylate (30 mg) and Cs2CO3 (100 mg) in THF (2 mL) is stirred for 8 h at rt. Then the mixture is neutralized by addition of trifluoroacetic acid and purified by HPLC on reversed phase (ACN, water) to give the title compound.


LC (Method 1): tR=0.94 min; Mass spectrum (ESI+): m/z=291 [M+H]+.


Intermediate 78
Ethyl 1-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-cyanopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate



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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 for 12 h at 140° C. After cooling to rt the mixture is partitioned between water and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic phases are washed with water, dried (MgSO4), concentrated and the residue is purified by HPLC on reversed phase (ACN, water) to give the title compound. LC (Method 1): tR=1.04 min; Mass spectrum (ESI+): m/z=338 [M+H]+.


Intermediate 79
2-Chloro-4-methylpyrimidine-5-carboxylic acid



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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 h. After cooling to rt 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): tR=0.68 min; Mass spectrum (ESI+): m/z=173 [M+H]+.


Intermediate 80
(2-Chloro-4-methylpyrimidin-5-yl)methanol



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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 isobutylchloroformate (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 rt and then partitioned between water and EtOAc. The aqueous phase is extracted with EtOAc for 3 times. The combined organic phases are washed with brine, dried (MgSO4), concentrated and the residue is chromatographed on silica gel (petroleum ether/(EtOAc/MeOH 8:2) 70:30) to give the title compound. LC (Method 2): tR=0.51 min; Mass spectrum (ESI+): m/z=159 [M+H]+.


Intermediate 81
(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-methylpyrimidin-5-yl)methanol



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Diisobutylaluminiumhydride (1 M in THF, 80 mL) is added dropwise at −10° C. 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). The mixture is stirred for 1 h while warming to 0° C. This mixture is then added dropwise under ice-cooling to a mixture of aqueous NaOH (4 M, 6 mL) in water (150 mL). After stirring for 1 h the mixture is filtered over celite. The filter cake is washed with EtOAc/MeOH 9:1. The combined filtrates are dried (MgSO4), concentrated and the residue is chromatographed on silica gel (EtOAc/MeOH 95:5→95:5) to give the title compound.


LC (Method 2): tR=0.59 min; Mass spectrum (ESI+): m/z=206 [M+H]+.


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



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Under argon atmosphere a mixture of (6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methanol (1.2 g), DIPEA (1.8 mL) in DCM (5 mL) is treated dropwise with CH3SO2Cl (513 μL). The mixture is stirred for 15 minutes and then added dropwise to a mixture obtained by treatment of 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 rt. Then the mixture is partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous phase is extracted twice with EtOAc. The combined organic phases are dried (MgSO4), concentrated in vacuo and purified by HPLC on reversed phase (ACN, water) to give the title compounds.


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): tR=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): tR=0.70 min; Mass spectrum (ESI+): m/z=334 [M+H]+.


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



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Under argon atmosphere a mixture of (6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methanol (1.1 g), DIPEA (1.2 mL) in DCM (15 mL) is treated dropwise with CH3SO2Cl (656 μL). The mixture is stirred for 15 minutes and then added dropwise to a mixture obtained by treatment of 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 h at rt. Then the mixture is partitioned between saturated aqueous NaHCO3 and DCM. The aqueous phase is extracted twice with DCM. The combined organic phases are dried (MgSO4), concentrated in vacuo and the residue is chromatographed on silica gel (petroleum ether/EtOAc 90:10→50:50) 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): tR=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): tR=0.73 min; Mass spectrum (ESI+): m/z=348 [M+H]+.


Intermediate 86
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloropyridin-3-yl)methyl]-1,2-oxazole-5-carboxylate



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A mixture of 3-[6-chloro-5-(2-nitroethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane (2.58 g), Boc2O (4.42 g), ethyl propiolate (3.03 mL), DMAP (176 mg), and ACN (60 mL) is stirred for 18 h at 23° C. Purification by HPLC on reversed phase (ACN, water) gives the title compound. LC (Method 1): tR=1.15 min; Mass spectrum (ESI+): m/z=348[M+H]+.


Intermediates 86-1 to 86-2 are prepared in analogy to Intermediate 86:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







86-1


embedded image


1.11
384
Method 1





86-2


embedded image


1.14
348
Method 2





















Intermediate
Name
Name of Starting Material







86-1
Ethyl 3-[(2-chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]-
3-[6-Chloro-5-(2-nitroethyl)pyridin-2-yl]-



hexan-3-yl}pyridin-3-yl)-methyl]-1,2-oxazole-5-
6,6-difluoro-3-azabicyclo[3.1.0]hexane



carboxylate



86-2
Ethyl 3-[(6-{5-azaspiro[2.3]hexan-5-yl}-2-
5-[6-Chloro-5-(2-nitroethyl)pyridin-2-yl]-



chloropyridin-3-yl)methyl]-1,2-oxazole-5-carboxylate
5-azaspiro[2.3]hexane









Intermediate 87
3-[6-Chloro-5-(2-nitroethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane



embedded image


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 min at 0° C., and for 1 h at rt. 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), concentrated and the residue is chromatographed on silica gel (cyclohexane/EtOAc 100:0→30:70) to give the title compound.


LC (Method 2): tR=1.10 min. Mass spectrum (ESI+): m/z=268 [M+H]+.


Intermediates 87-1 to 87-2 are prepared in analogy to Intermediate 87:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







87-1


embedded image


1.07
304
Method 2





87-2


embedded image


1.07
268
Method 2





















Intermediate
Name
Name of Starting Material







87-1
3-[6-Chloro-5-(2-nitroethyl)pyridin-2-yl]-6,6-
3-{6-Chloro-5-[(1E)-2-nitroethenyl]pyridin-2-



difluoro-3-azabicyclo[3.1.0]hexane
yl}-6,6-difluoro-3-azabicyclo[3.1.0]hexane


87-2
5-[6-Chloro-5-(2-nitroethyl)pyridin-2-yl]-5-
5-{6-Chloro-5-[(1E)-2-nitroethenyl]pyridin-2-



azaspiro[2.3]hexane
yl}-5-azaspiro[2.3]hexane









Intermediate 88
3-{6-Chloro-5-[(1E)-2-nitroethenyl]pyridin-2-yl}-3-azabicyclo[3.1.0]hexane



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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 for 18 h at 100° C. The mixture is cooled to rt 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): tR=1.14 min. Mass spectrum (ESI+): m/z=266 [M+H]+.


Intermediates 88-1 to 88-2 are prepared in analogy to Intermediate 88:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







88-1


embedded image


1.10
302
Method 2





88-2


embedded image


1.11
266
Method 2





















Intermediate
Name
Name of Starting Material







88-1
3-{6-Chloro-5-[(1E)-2-nitroethenyl]pyridin-2-
2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]-



yl}-6,6-difluoro-3-azabicyclo[3.1.0]hexane
hexan-3-yl}pyridine-3-carbaldehyde


88-2
5-{6-Chloro-5-[(1E)-2-nitroethenyl]pyridin-2-
6-{5-Azaspiro[2.3]hexan-5-yl}-2-



yl}-5-azaspiro[2.3]hexane
chloropyridine-3-carbaldehyde









Intermediate 89
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)methyl]-1,2-oxazole-5-carboxylate



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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), aqueous NaOCl 15% (34 mL), and THF (20 mL) is stirred for 3 h at rt. 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 (MgSO4), concentrated and the residue is chromatographed on silica gel (petroleum ether/EtOAc 99:1→70:30) to give the title compound.


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


Intermediates 89-1 to 89-2 are prepared in analogy to Intermediate 89:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







89-1


embedded image


1.04
314
Method 1





89-2


embedded image


0.76
364
Method 2




















Intermediate
Reaction comment







89-1
The reaction is conducted in DCM instead of THF.





















Intermediate
Name
Name of Starting Material







89-1
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-
(E,Z)-N-[2-(6-{3-Azabicyclo[3.1.0]hexan-3-



pyridin-3-yl)methyl]-1,2-oxazole-5-carboxylate
yl}pyridin-3-yl)ethylidene]hydroxylamine


89-2
Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
(E,Z)-N-[2-(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



hexan-3-yl}-2-methylpyridin-3-yl)methyl]-1,2-
hexan-3-yl}-2-methylpyridin-3-yl)-



oxazole-5-carboxylate
ethylidene]hydroxylamine









Intermediate 90
(E,Z)-N-[2-(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)ethylidene]hydroxylamine



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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 for 2 h at rt. 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): tR=0.62 and 0.64 min. Mass spectrum (ESI+): m/z=246 [M+H]+.


Intermediates 90-1 to 90-3 are prepared in analogy to Intermediate 90:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







90-1


embedded image


0.82 and 0.84
218
Method 1





90-2


embedded image


0.61 and 0.63
268
Method 2





90-3


embedded image


0.65
282
Method 2





















Intermediate
Name
Name of Starting Material







90-1
(E,Z)-N-[2-(6-{3-Azabicyclo[3.1.0]hexan-3-
2-(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-pyridin-



yl}pyridin-3-yl)ethylidene]hydroxylamine
3-yl)acetaldehyde


90-2
(E,Z)-N-[2-(6-{6,6-Difluoro-3-
2-(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-



azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-
3-yl}-2-methylpyridin-3-yl)acetaldehyde



yl)ethylidene]hydroxylamine



90-3
(E,Z)-N-[2-(6-{6,6-Difluoro-3-
2-(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-



azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-
3-yl}-2-ethylpyridin-3-yl)acetaldehyde



yl)ethylidene]hydroxylamine









Intermediate 91
2-(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)acetaldehyde



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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 for 1 h at rt. 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.


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


Intermediates 91-1 to 91-3 are prepared in analogy to Intermediate 91:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







91-1


embedded image


0.83
203
Method 1





91-2


embedded image


0.60
253
Method 2





91-3


embedded image


0.62
267
Method 2





















Intermediate
Name
Name of Starting Material







91-1
2-(6-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridin-3-
3-[5-(2-Methoxyethenyl)pyridin-2-yl]-3-



yl)acetaldehyde
azabicyclo[3.1.0]hexane


91-2
2-(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
6,6-Difluoro-3-[5-(2-methoxyethenyl)-6-



yl}-2-methylpyridin-3-yl)acetaldehyde
methylpyridin-2-yl]-3-azabicyclo[3.1.0]hexane


91-3
2-(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
3-[6-Ethyl-5-(2-methoxyethenyl)pyridin-2-yl]-



yl}-2-ethylpyridin-3-yl)acetaldehyde
6,6-difluoro-3-azabicyclo[3.1.0]hexane









Intermediate 92
3-[6-Ethyl-5-(2-methoxyethenyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane



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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 argon atmosphere, and stirred for 15 minutes at this temperature. 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. Then the mixture is warmed over 4 h to rt. 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 diisopropylether and the precipitate is filtered off. The filtrate is concentrate, and the residue is chromatographed on silica gel (petroleum ether/EtOAc 99:1→70:30) to give the title compound as a mixture of isomers.


LC (Method 2): tR=0.74 and 0.76 min (mixture of isomers). Mass spectrum (ESI+): m/z=245 [M+H]+.


Intermediates 92-1 to 92-3 are prepared in analogy to Intermediate 92:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







92-1


embedded image


0.99 and 1.01
217
Method 1





92-2


embedded image


0.73 and 0.74
267
Method 2





92-3


embedded image


0.75
281
Method 2





















Intermediate
Name
Name of Starting Material







92-1
3-[5-(2-Methoxyethenyl)pyridin-2-yl]-3-
6-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridine-3-



azabicyclo[3.1.0]hexane
carbaldehyde


92-2
6,6-Difluoro-3-[5-(2-methoxyethenyl)-6-
6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-



methylpyridin-2-yl]-3-azabicyclo[3.1.0]hexane
2-methylpyridine-3-carbaldehyde


92-3
3-[6-Ethyl-5-(2-methoxyethenyl)pyridin-2-yl]-
6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-



6,6-difluoro-3-azabicyclo[3.1.0]hexane
2-ethylpyridine-3-carbaldehyde









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



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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 (2M in THF, 1.1 mL), at −78° C. under argon atmosphere and is stirred for 15 minutes at this temperature. 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 is then warmed over 18 h to rt. 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 (petroleum ether/EtOAc 80:20→20:80) to give the title compound. LC (Method 2): tR=0.72 min. Mass spectrum (ESI+): m/z=372 [M+H]+.


Intermediates 93-1 to 93-2 are prepared in analogy to Intermediate 93:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







93-1


embedded image


0.75
408
Method 2





93-2


embedded image


0.77
386
Method 2





















Intermediate
Name
Name of Starting Material







93-1
Methyl 2-[1-(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Methyl 2-(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



hexan-3-yl}-2-methylpyridin-3-yl)-2-methoxy-2-
hexan-3-yl}-2-methylpyridin-3-yl)acetate



oxoethyl]-1,3-oxazole-5-carboxylate



93-2
Methyl 2-[1-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-
Methyl 2-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



2-ethylpyridin-3-yl)-2-methoxy-2-oxoethyl]-1,3-
ethylpyridin-3-yl)acetate



oxazole-5-carboxylate









Intermediate 94
Methyl 2-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)acetate



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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 SOCl2 (575 μL) at rt, and the mixture is stirred for 6 h, before being treated with saturated aqueous NaHCO3. The aqueous phase is extracted twice with DCM, and the combined organic layers are washed with brine, dried (MgSO4) and concentrated to give the title compound. LC (Method 2): tR=0.64 min. Mass spectrum (ESI+): m/z=247 [M+H]+.


Intermediates 94-1 to 94-2 are prepared in analogy to Intermediate 94:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







94-1


embedded image


0.66
283
Method 2





94-2


embedded image


0.69
261
Method 2




















Intermediate
Reaction comment







94-1
The reaction is conducted for 18 h at 50° C.


94-2
The reaction is conducted for 24 h.





















Intermediate
Name
Name of Starting Material







94-1
Methyl 2-(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
2-(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-



hexan-3-yl}-2-methylpyridin-3-yl)acetate
yl}-2-methylpyridin-3-yl)acetonitrile


94-2
Methyl 2-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
2-(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



ethylpyridin-3-yl)acetate
ethylpyridin-3-yl)acetonitrile









Intermediate 95
2-(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)acetonitrile



embedded image


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 for 66 h at rt 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 (petroleum ether/EtOAc 90:10→80:20) to give the title compound.


LC (Method 1: tR=0.97 min. Mass spectrum (ESI+): m/z=214 [M+H]+.


Intermediates 95-1 to 95-2 are prepared in analogy to Intermediate 95:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







95-1


embedded image


0.95
250
Method 1





95-2


embedded image


0.63
228
Method 2























Intermediate
Reaction comment









95-1
The reaction is conducted for 18 h at rt.



95-2
The reaction is conducted for 12 h at rt.






















Intermediate
Name
Name of Starting Material







95-1
2-(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-
(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-



yl}-2-methylpyridin-3-yl)acetonitrile
yl}-2-methylpyridin-3-yl)methanol


95-2
2-(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



ethylpyridin-3-yl)acetonitrile
ethylpyridin-3-yl)methanol









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



embedded image


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), Na2CO3 (57 mg), NaCl (23 mg), MeOH (2 mL) and water (100 μL) is stirred for 5 h at rt, and concentrated. The residue is partitioned between water and EtOAc. The organic phase is washed with brine, dried (MgSO4), concentrated and the residue is chromatographed on silica gel (petroleum ether/EtOAc 99:01→50:50) to give the title compound.


LC (Method 2): tR=0.81 min. Mass spectrum (ESI+): m/z=378 [M+H]+.


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



embedded image


Under 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), DIPEA (782 μL) in DCM (1.5 mL) is treated dropwise with CH3SO2Cl (222 μL). The mixture is stirred for 15 minutes and then added dropwise to a mixture obtained by treatment of 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 h at 40° C. Then the mixture is partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous phase is extracted twice with EtOAc. The combined organic phases are dried (MgSO4), concentrated in vacuo and the residue is purified by HPLC on reversed phase (AON, water) to give the title compound.


LC (Method 2): tR=1.05 min; Mass spectrum (ESI+): m/z=368 [M+H]+.


Intermediate 98
Ethyl 5-iodo-1H-pyrazole-3-carboxylate



embedded image


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


LC (Method 2): tR=0.86 min. Mass spectrum (ESI+): m/z=267 [M+H]+.


Intermediate 98-1 is prepared in analogy to Intermediate 98:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







98-1


embedded image


1.02
281
Method 2





















Intermediate
Name
Name of Starting Material







98-1
Ethyl 3-iodo-1-methyl-
Ethyl 3-amino-1-methyl-



1H-pyrazole-5-carboxylate
1H-pyrazole-5-carboxylate




hydrochloride









Intermediate 99
Ethyl 3-iodo-1-(propan-2-yl)-1H-pyrazole-5-carboxylate



embedded image


NaH (60% in mineral oil, 180 mg) is added portionwise at 0° C. to a mixture of ethyl 5-iodo-1H-pyrazole-3-carboxylate (1.0 g) in DMF (15 mL). The mixture is stirred for 30 minutes and then treated with 2-iodopropane (451 μL). The mixture is stirred for 4 h while warming to rt. Then the mixture is partitioned between saturated aqueous NH4Cl and EtOAc. The aqueous phase is extracted twice with EtOAc. The combined organic phases are dried (MgSO4), concentrated in vacuo and the residue is purified by HPLC on reversed phase (ACN, water) to give the title compound.


LC (Method 2): tR=1.08 min. Mass spectrum (ESI+): m/z=309 [M+H]+.


Intermediates 99-1 to 99-2 are prepared in analogy to Intermediate 99:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







99-1


embedded image


1.02
295
Method 2





99-2


embedded image


1.24
397
Method 2























Intermediate
Reaction comment









99-1
Iodoethane is used instead of 2-iodopropane.



99-2
(2-Chloromethoxy-ethyl)-trimethyl-silane




(SEM-CI) is used instead of 2-iodopropane.






















Intermediate
Name
Name of Starting Material







99-1
Ethyl 1-ethyl-3-iodo-1H-pyrazole-5-carboxylate
Ethyl 5-iodo-1H-pyrazole-3-carboxylate


99-2
Ethyl 3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-
Ethyl 5-iodo-1H-pyrazole-3-carboxylate



1H-pyrazole-5-carboxylate









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



embedded image


A mixture of ethyl 3-iodo-1-(propan-2-yl)-1H-pyrazole-5-carboxylate (100 mg) in THF (2 mL) is treated dropwise at −40° C. under argon atmosphere with iPrMgCl×LiCl (1.3 M in THF, 300 μL). 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 h 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 directly used in the next step.


LC (Method 2): tR=0.85 min. Mass spectrum (ESI+): m/z=435 [M+H]+.


Intermediates 100-1 to 100-8 are prepared in analogy to Intermediate 100:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







100-1


embedded image


0.81
421
Method 2





100-2


embedded image


1.20
493
Method 2





100-3


embedded image


0.78
383
Method 2





100-4


embedded image


0.77
407
Method 2





100-5


embedded image


0.71
371
Method 2





100-6


embedded image


0.94
487
Method 2





100-7


embedded image


0.77
371
Method 2





100-8


embedded image



357




















Intermediate
Reaction comment







100-2
The aldehyde is added to the reaction mixture at −78° C., then the mixture is stirred for 1 h while



warming to rt. The crude reaction product is purified by chromatography on silica gel (petroleum



ether/EtOAc 99:1 → 50:50).


100-3
The reaction is conducted for 30 minutes at −40° C. and for 30 minutes at rt.


100-4
The reaction is conducted for 30 minutes at −40° C. and for 30 minutes at rt.


100-5
The reaction is conducted for 30 minutes at −40° C. and for 30 minutes at rt.


100-6
The aldehyde is added to the reaction mixture at −78° C., then the mixture is stirred for 1 h while



warming to rt. The crude reaction product is purified by chromatography on silica gel (petroleum



ether/EtOAc 90:10 → 70:30).


100-7
The aldehyde is added to the reaction mixture at −78° C., then the mixture is stirred for 1 h while



warming to rt. The crude reaction product is purified by chromatography on silica gel (petroleum



ether/EtOAc 60:40 → 0:100).


100-8
The aldehyde is added to the reaction mixture at −78° C., then the mixture is stirred for 2 h while



warming to rt. The crude reaction product is purified by chromatography on silica gel (cyclohexane/



EtOAc 90:10 → 50:50).
























Name of
Name of


Intermediate
Name
Starting Material 1
Starting Material 2







100-1
Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Ethyl 1-ethyl-3-iodo-
6-{6,6-Difluoro-3-azabicyclo-



hexan-3-yl}-2-ethylpyridin-3-yl)(hydroxy)-
1H-pyrazole-5-
[3.1.0]hexan-3-yl}-2-ethyl-



methyl]-1-ethyl-1H-pyrazole-5-carboxylate
carboxylate
pyridine-3-carbaldehyde


100-2
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-
Ethyl 3-iodo-1-{[2-
6-{3-Azabicyclo[3.1.0]hexan-



2-chloropyridin-3-yl)(hydroxy)-methyl]-1-
(trimethylsilyl)ethoxy]
3-yl}-2-chloropyridine-3-



{[2-(trimethylsilyl)ethoxy]-methyl}-1H-
methyl}-1H-pyrazole-5-
carbaldehyde



pyrazole-5-carboxylate
carboxylate



100-3
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-
Ethyl 1-ethyl-3-iodo-
6-{3-Azabicyclo[3.1.0]hexan-



2-ethenylpyridin-3-yl)(hydroxy)-methyl]-1-
1H-pyrazole-5-
3-yl}-2-ethenylpyridine-3-



ethyl-1H-pyrazole-5-carboxylate
carboxylate
carbaldehyde


100-4
Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-
Ethyl 1-ethyl-3-iodo-
6-{6,6-Difluoro-3-azabicyclo-



hexan-3-yl}-2-methylpyridin-3-yl)(hydroxy)-
1H-pyrazole-5-
[3.1.0]hexan-3-yl}-2-methyl-



methyl]-1-ethyl-1H-pyrazole-5-carboxylate
carboxylate
pyridine-3-carbaldehyde


100-5
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-
Ethyl 1-ethyl-3-iodo-
6-{3-Azabicyclo[3.1.0]hexan-



2-methylpyridin-3-yl)(hydroxy)-methyl]-1-
1H-pyrazole-5-
3-yl}-2-methylpyridine-3-



ethyl-1H-pyrazole-5-carboxylate
carboxylate
carbaldehyde


100-6
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-
Ethyl 3-iodo-1-{[2-
6-{3-Azabicyclo[3.1.0]hexan-



2-ethylpyridin-3-yl)(hydroxy)methyl]-1-{[2-
(trimethylsilyl)ethoxy]
3-yl}-2-ethylpyridine-3-



(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-
methyl}-1H-pyrazole-5-
carbaldehyde



5-carboxylate
carboxylate



100-7
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-
Ethyl 3-iodo-1-methyl-
6-{3-Azabicyclo[3.1.0]-



2-ethylpyridin-3-yl)(hydroxy)methyl]-1-
1H-pyrazole-5-
hexan-3-yl}-2-ethylpyridine-



methyl-1H-pyrazole-5-carboxylate
carboxylate
3-carbaldehyde


100-8
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-
Ethyl 3-iodo-1-methyl-
6-{3-Azabicyclo[3.1.0]-



2-methylpyridin-3-yl)(hydroxy)-methyl]-1-
1H-pyrazole-5-
hexan-3-yl}-2-methyl-



methyl-1H-pyrazole-5-carboxylate
carboxylate
pyridine-3-carbaldehyde









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



embedded image


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 under argon atmosphere for 30 minutes at rt. The mixture is concentrated in vacuo to give the crude product, which is directly used in the next step.


LC (Method 2): tR=0.90 min. Mass spectrum (ESI+): m/z=419 [M+H]+.


Intermediates 101-1 to 101-12 are prepared in analogy to Intermediate 101:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







101-1


embedded image


0.86
405
Method 2





101-2


embedded image


0.84
367
Method 2





101-3


embedded image


0.82
391
Method 2





101-4


embedded image


0.82
355
Method 2





101-5


embedded image


0.74
313
Method 2





101-6


embedded image


1.19
327
Method 1





101-7


embedded image


0.77
349
Method 2





101-8


embedded image


1.12
413
Method 1





101-9


embedded image


0.85
355
Method 2





101-10


embedded image


1.22
443
Method 2





101-11


embedded image


0.84
379
Method 2





101-12


embedded image


0.78
386
Method 2























Intermediate
Reaction comment









101-1
The reaction is conducted for 2 h at rt.



101-2
The reaction is conducted for 4 h at 30° C.



101-3
The reaction is conducted for 45 minutes at 30° C.



101-4
The reaction is conducted for 30 minutes at 30° C.



100-5
The reaction is conducted at 40° C. for 20 h.




The product is purified by HPLC on reversed phase




(ACN, water).



101-6
The reaction is conducted at 50° C. for 2 h.



101-7
The reaction is conducted at 50° C. for 30 minutes.



101-8
The reaction is conducted at 50° C. for 30 minutes.



101-9
The reaction is conducted at rt for 1.5 h.



101-10
The reaction is conducted at 30° C. for 2 h.



101-11
The reaction is conducted at 50° C. for 30 minutes.



101-12
The reaction is conducted at 70° C. for 2 h.






















Intermediate
Name
Name of Starting Material







101-1
Ethyl 3-[(6-{6,6-difluoro-3-
Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-
hexan-3-yl}-2-ethylpyridin-3-yl)(hydroxy)-



yl)methyl]-1-ethyl-1H-pyrazole-5-carboxylate
methyl]-1-ethyl-1H-pyrazole-5-carboxylate


101-2
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicydo[3.1.0]hexan-3-yl}-2-



ethenylpyridin-3-yl)methyl]-1-ethyl-1H-
ethenylpyridin-3-yl)(hydroxy)methyl]-1-ethyl-



pyrazole-5-carboxylate
1H-pyrazole-5-carboxylate


101-3
Ethyl 3-[(6-{6,6-difluoro-3-
Ethyl 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]-



azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-
hexan-3-yl}-2-methylpyridin-3-yl)(hydroxy)-



3-yl)methyl]-1-ethyl-1H-pyrazole-5-carboxylate
methyl]-1-ethyl-1H-pyrazole-5-carboxylate


101-4
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 3-[(6-{3-azabicydo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methyl]-1-ethyl-1H-
methylpyridin-3-yl)(hydroxy)methyl]-1-ethyl-



pyrazole-5-carboxylate
1H-pyrazole-5-carboxylate


101-5
Methyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Methyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methyl]furan-2-carboxylate
methylpyridin-3-yl)(hydroxy)methyl]furan-2-




carboxylate


101-6
Ethyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 5-[(6-{3-azabicydo[3.1.0]hexan-3-yl}-2-



methylpyridin-3-yl)methyl]furan-3-carboxylate
methylpyridin-3-yl)(hydroxy)methyl]furan-3-




carboxylate


101-7
Methyl 5-[(6-{6,6-difluoro-3-
Methyl 5-[(6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-
azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-



3-yl)methyl]furan-2-carboxylate
3-yl)(hydroxy)methyl]furan-2-carboxylate


101-8
Methyl 5-[(2-bromo-6-{6,6-difluoro-3-
Methyl 5-[(2-bromo-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}pyridin-3-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl)methyl]furan-2-carboxylate
yl)(hydroxy)methyl]furan-2-carboxylate


101-9
Ethyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
Ethyl 5-[(6-{3-azabicydo[3.1.0]hexan-3-yl}-2-



ethenylpyridin-3-yl)methyl]thiophene-2-
ethenylpyridin-3-yl)(hydroxy)methyl]thiophene-



carboxylate
2-carboxylate


101-10
Ethyl 5-[(2-bromo-6-{6,6-difluoro-3-
Ethyl 5-[(2-bromo-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}pyridin-3-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



yl)methyl]thiophene-2-carboxylate
yl)(hydroxy)methyl]thiophene-2-carboxylate


101-11
Ethyl 5-[(6-{6,6-difluoro-3-
Ethyl 5-[(6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-
azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-



3-yl)methyl]thiophene-2-carboxylate
3-yl)(hydroxy)methyl]thiophene-2-carboxylate


101-12
3-{5-[(5-Bromo-1,3-thiazol-2-yl)methyl]-6-
(5-Bromo-1,3-thiazol-2-yl)(6-{6,6-difluoro-3-



methylpyridin-2-yl}-6,6-difluoro-3-
azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-



azabicyclo[3.1.0]hexane
3-yl)methanol









Intermediate 102
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-5-carboxylate



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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 borontrifluoride-diethyletherate (BF3×OEt2, 2.3 mL) in DCM (8 mL) is stirred under argon atmosphere for 12 h at rt. 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 (petroleum ether/EtOAc 80:20→0:100) to give the title compound.


LC (Method 2): tR=1.05 min. Mass spectrum (ESI+): m/z=347 [M+H]+.


Intermediates 102-1 to 102-3 are prepared in analogy to Intermediate 102:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







102-1


embedded image


0.75
341
Method 2





102-2


embedded image


0.82
355
Method 2





102-3


embedded image


1.15
341
Method 1























Intermediate
Reaction comment









102-3
The reaction is conducted at 0° C. The mixture




is stirred for 1.5 h while warming to rt.






















Intermediate
Name
Name of Starting Material







102-1
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-ethyl-



yl}-2-ethylpyridin-3-yl)methyl]-1H-
pyridin-3-yl)(hydroxy)methyl]-1-{[2-(trimethylsilyl)-



pyrazole-5-carboxylate
ethoxy]methyl}-1H-pyrazole-5-carboxylate


102-2
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



yl}-2-ethylpyridin-3-yl)methyl]-1-methyl-
ethylpyridin-3-yl)(hydroxy)methyl]-1-methyl-1H-



1H-pyrazole-5-carboxylate
pyrazole-5-carboxylate


102-3
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-
Ethyl 3-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



yl}-2-methylpyridin-3-yl)methyl]-1-
methylpyridin-3-yl)(hydroxy)methyl]-1-methyl-1H-



methyl-1H-pyrazole-5-carboxylate
pyrazole-5-carboxylate









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)



embedded image


NaH (60% in mineral oil, 73 mg) is added under argon atmosphere at 0° C. 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). 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 h while warming to rt. Then the mixture is 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 (petroleum ether/EtOAc 99:1→70:30) to give the title compounds as a mixture of isomers.


LC (Method 2): tR=1.05 min. Mass spectrum (ESI+): m/z=347 [M+H]+.


Intermediate 104
Ethyl 3-[{6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl}methyl]-1-ethyl-1H-pyrazole-5-carboxylate



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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 hydrogen atmosphere (3 bar) at rt for 4.5 h. The mixture is filtered and the filtrate is concentrated in vacuo to give the crude product, which is directly used in the next step. LC (Method 2): tR=0.84 min; Mass spectrum (ESI+): m/z=369 [M+H]+.


Intermediates 104-1 is prepared in analogy to Intermediate 104:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







104-1


embedded image


0.75
357
Method 2




















Intermediate
Reaction comment







104-1
The reaction is conducted at rt for 4 h under 1 bar



hydrogen atmosphere. The product is purified by



HPLC on reversed phase (ACN, water).





















Intermediate
Name
Name of Starting Material







104-1
Ethyl 5-[(6-{3-azabicydo[3.1.0]hexan-3-yl}-2-
Ethyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



ethylpyridin-3-yl)methyl]thiophene-2-carboxylate
ethenylpyridin-3-yl)methyl]thiophene-2-carboxylate









Intermediate 105
Ethyl 3-[(6-fluoro-2-methylpyridin-3-yl)(hydroxy)methyl]-1-methyl-1H-pyrazole-5-carboxylate



embedded image


A mixture of 6-fluoro-3-iodo-2-methylpyridine (550 mg) in THF (25 mL) is treated dropwise at −50° C. under argon atmosphere with iPrMgCl×LiCl (1.3 M in THF, 2.2 mL). The mixture is stirred for 1 h 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 h 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), concentrated in vacuo and the residue is chromatographed on silica gel (petroleum ether/EtOAc 90:10→50:50) to give the title compound.


LC (Method 2): tR=0.89 min. Mass spectrum (ESI+): m/z=294 [M+H]+.


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



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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 for 48 h to 150° C. After cooling to rt the mixture is diluted with ACN, filtered and purified by HPLC on reversed phase (ACN, water) to give the title compound. LC (Method 2): tR=0.63 min; Mass spectrum (ESI+): m/z=365 [M+H]+.


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



embedded image


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 borontrifluoride-diethyletherate (BF3×OEt2, 293 μL) in DCM (3 mL) and THF (1 mL) is stirred under argon atmosphere for 12 h at rt. The mixture is diluted with water and purified by HPLC on reversed phase (ACN, water) to give the title compound.


LC (Method 2): tR=0.69 min. Mass spectrum (ESI+): m/z=349 [M+H]+.


Intermediate 108
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid



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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 tributyl phosphine (9 mL) are added. Di-tert.-butyl-azodicarboxylate (DBAD, 7.4 g) is slowly added portionwise, the mixture is stirred at rt for 45 min and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/EtOAc) to give the title compound.


LC (Method 2): tR=0.88 min; Mass spectrum (ESI+): m/z=264 [M+H]+.


Step 2: 1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-methylpyridin-3-yl)methyl]-1 FI-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 for 16 h at 100° C. and additional 5 h at 120° C. After cooling to rt, the N,N-diisopropyl-ethylamine phase is removed, 4 M NaOH (4 mL) is added and stirred at 60° C. for 2 h. Aqueous HCl (4 M, 4 mL) is added and the mixture is purified by HPLC on reversed phase (ACN, water) to give the title compound. LC (Method 1): tR=0.68 min; Mass spectrum (ESI+): m/z=299 [M+H]+.


Intermediate 109
Methyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)(hydroxy)methyl]furan-2-carboxylate



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A mixture of methyl 5-bromofuran-2-carboxylate (500 mg) in THF (15 mL) is treated dropwise at −50° C. with iPrMgCl×LiCl (1.3 M in THF, 1.95 mL). The mixture is stirred at 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 h 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), concentrated in vacuo and the residue is chromatographed on silica gel (petroleum ether/EtOAc 85:15→50:50) to give the title compound.


LC (Method 2): tR=0.70 min. Mass spectrum (ESI+): m/z=329 [M+H]+.


Intermediates 109-1 to 109-7 are prepared in analogy to Intermediate 109:



















Mass spectrum (ESI+):



Intermediate
Structure
tR
m/z [M + H]+
LC Method







109-1


embedded image


1.05 
343
Method 1





109-2


embedded image


0.97 
365
Method 1





109-3


embedded image


1.04 
429
Method 2





109-4


embedded image


0.80 
371
Method 2





109-5


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1.12 
459
Method 2





109-6


embedded image


0.807
395
Method 2





109-7


embedded image


0.74 
402
Method 2




















Intermediate
Reaction comment







109-1
After addition of iPrMgClxLiCl the mixture is



slowly warmed to −10° C. over 2 h. Then the



mixture is cooled to −30° C. and the aldehyde is



added, followed by stirring for 1 h while



warming to −10° C.


109-3
The reaction is conducted at −78° C.



The product is purified by HPLC on reversed



phase (ACN, water).


109-4
The reaction is conducted at −60° C. instead of



−50° C. and warmed after the addition to rt over



17 h.


109-5
The reaction is conducted at −78° C.


109-6
The reaction is conducted at −78° C.



The product is purified by HPLC on reversed



phase (ACN, water).


109-7
The reaction is conducted at −78° C.



The product is purified by HPLC on reversed



phase (ACN, water).






















Inter-

Name of
Name of


mediate
Name
Starting Material 1
Starting Material 2







109-1
Ethyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-
3-(5-Iodo-6-methyl-
Ethyl 5-formylfuran-3-



2-methylpyridin-3-yl)-
pyridin-2-yl)-3-aza-
carboxylate



(hydroxy)methyl]furan-3-carboxylate
bicyclo[3.1.0]hexane



109-2
Methyl 5-[(6-{6,6-difluoro-3-azabicyclo-
Methyl 5-bromofuran-
6-{6,6-Difluoro-3-azabicyclo-



[3.1.0]hexan-3-yl}-2-methyl-pyridin-3-
2-carboxylate
[3.1.0]hexan-3-yl}-2-methyl-



yl)(hydroxy)methyl]furan-2-carboxylate

pyridine-3-carbaldehyde


109-3
Methyl 5-[(2-bromo-6-{6,6-difluoro-3-
Methyl 5-bromofuran-
2-Bromo-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}pyridin-3-
2-carboxylate
azabicyclo[3.1.0]hexan-3-



yl)(hydroxy)methyl]furan-2-carboxylate

yl}pyridine-3-carbaldehyde


109-4
Ethyl 5-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-
Ethyl 5-
6-{3-Azabicyclo[3.1.0]hexan-



2-ethenylpyridin-3-yl)(hydroxy)-
bromothiophene-2-
3-yl}-2-ethenylpyridine-3-



methyl]thiophene-2-carboxylate
carboxylate
carbaldehyde


109-5
Ethyl 5-[(2-bromo-6-{6,6-difluoro-3-
Ethyl 5-
2-Bromo-6-{6,6-difluoro-3-



azabicyclo[3.1.0]hexan-3-yl}pyridin-3-
bromothiophene-2-
azabicyclo[3.1.0]hexan-3-



yl)(hydroxy)methyl]thiophene-2-carboxylate
carboxylate
yl}pyridine-3-carbaldehyde


109-6
Ethyl 5-[(6-{6,6-difluoro-3-azabicyclo-
Ethyl 5-
6-{6,6-Difluoro-3-azabicyclo-



[3.1.0]hexan-3-yl}-2-methylpyridin-3-
bromothiophene-2-
[3.1.0]hexan-3-yl}-2-methyl-



yl)(hydroxy)methyl]-thiophene-2-carboxylate
carboxylate
pyridine-3-carbaldehyde


109-7
(5-Bromo-1,3-thiazol-2-yl)(6-{6,6-difluoro-
2,5-Dibromo-1,3-
6-{6,6-Difluoro-3-azabicyclo-



3-azabicyclo[3.1.0]hexan-3-yl}-2-
thiazole
[3.1.0]hexan-3-yl}-2-methyl-



methylpyridin-3-yl)methanol

pyridine-3-carbaldehyde









Intermediate 110
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-3-cyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid



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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 analogous 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 analogous to that described in Step 4 of Intermediate 118.


LC (Method 2): tR=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 analogous 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 analogous to that described in Step 4 of Intermediate 111.


Intermediate 111
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid



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

A mixture of 3,4,5-trifluorobenzaldehyde (1.50 g), 3-azabicyclo[3.1.0]hexane hydrochloride (1.23 g), iPr2NEt (4 mL), and DMF (15 mL) is stirred at 70° C. overnight. After cooling to rt, water is added and the resulting mixture is extracted with ethyl acetate (3×). The combined extract is dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (petroleum ether/EtOAc 98:2→95:5) to give the title compound.


LC (Method 2): tR=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 portionwise 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 for 1 h in the cooling bath and another 30 min at rt before aqueous HCl solution (1 mol/L) is added. The mixture is stirred for 30 min before it is neutralized with aqueous NaHCO3 solution. The mixture is extracted with ethyl acetate (2×), and the combined extract is dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (petroleum ether/EtOAc 95:5→85:15) to give the title compound.


LC (Method 2): tR=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 and depending on the degree of conversion the temperature is increased and/or reaction time is extended). After cooling to room temperature, the mixture is concentrated, water is added, and the resulting mixture is neutralized with aqueous NaHCO3 solution. The resulting mixture is extracted with ethyl acetate (3×), and the combined extract is dried (Na2SO4) and concentrated. The residue is chromatographed (HPLC; ACN/water/ammonia) to give the title compound. LC (Method 2): tR=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 h. 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 value of ca. 5 with aq. NaOH. The precipitate formed is separated and 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): tR=1.04 min; Mass spectrum (ESI+): m/z=320 [M+H]+.


Intermediate 112
2-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-3,5-difluorophenyl)methyl]-1H-imidazole-5-carboxylic acid



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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), SOCl2 (0.04 mL), and dichloromethane (1 mL) is stirred at room temperature for 30 min. The mixture is concentrated, taken up in toluene, concentrated again, and used as is 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

LiOtBu (21 mg) is added to a mixture of ethyl 1H-imidazole-4-carboxylate (37 mg), BuOH (0.4 mL), and DCM (1.6 mL) chilled in an ice bath. The mixture is stirred for 5 min prior to the addition of 3-[4-(chloromethyl)-2,6-difluorophenyl]-3-azabicyclo[3.1.0]hexane (65 mg, crude product from Step 1) in DCM (0.4 mL). The cooling bath is removed, and the mixture is stirred at 40° C. overnight. After cooling to rt, water and DCM are added. The organic phase is separated, and the aqueous phase is extracted with DCM (2×). The combined organic extract is concentrated, and the residue is chromatographed (HPLC; ACN/water/ammonia) to give the title compound.


LC (Method 2): tR=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 analogous to that described in Step 4 of Intermediate 111.


LC (Method 2): tR=0.82 min; Mass spectrum (ESI+): m/z=320 [M+H]+.


Intermediate 113
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid



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Step 1: 6-Fluoro-3-formyl-2-methylbenzonitrile


iPrMgCl*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 prior to the addition of another portion of iPrMgCl*LiCl (Turbo Grignard; 1.3 mol/L in THF, 1.0 mL). The cooling bath is removed, and the mixture is stirred for another 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 solution at rt. The mixture is extracted with EtOAc (3×), and the combined extract is dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/EtOAc 24:1→3:1) to give the title compound. LC (Method 2): tR=0.87 min.


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 h. After cooling to rt, water is added, and the mixture is stirred for 30 min. The precipitate is separated by filtration, washed with water (2×), and dried at 65° C. to give the title compound. LC (Method 1): tR=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 portionwise 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 rt. The mixture is stirred for 1 h before aqueous HCl solution (1 mol/L) is added. The mixture is stirred for 1 h before it is neutralized with aqueous NaHCO3 solution. The mixture is extracted with EtOAc (2×), and the combined extract is dried (Na2SO4) and concentrated to afford a mixture of the title compound and 6-{3-azabicyclo[3.1.0]hexan-3-yl}-3-(methoxymethyl)-2-methylbenzonitrile that is used as is in the next reaction step (both components are competent starting materials for the next step).


LC (Method 1): tR=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 obtained in Step 3 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, and ethyl 1H-pyrazole-4-carboxylate following a procedure analogous to that described in Step 3 of Intermediate 111.


LC (Method 1): tR=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 analogous to that described in Step 4 of Intermediate 111.


LC (Method 2): tR=0.96 min; Mass spectrum (ESI+): m/z=323 [M+H]+.


Intermediate 114
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-imidazole-4-carboxylic acid



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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 obtained in Step 3 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, and ethyl 1H-imidazole-4-carboxylate following a procedure analogous to that described in Step 3 of Intermediate 111.


LC (Method 1): tR=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 analogous to that described in Step 4 of Intermediate 111.


LC (Method 2): tR=0.80 min; Mass spectrum (ESI+): m/z=323 [M+H]+.


Intermediate 115
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-3-cyano-5-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid



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Step 1: 2,3-Difluoro-5-formylbenzonitrile

The title compound is prepared from 5-bromo-2,3-difluorobenzonitrile following a procedure analogous to that described in Step 1 of Intermediate 113. LC (Method 2): tR=0.84 min.


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 analogous to that described in Step 1 of Intermediate 111.


LC (Method 2): tR=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 analogous to that described in Step 2 of Intermediate 111.


LC (Method 2): tR=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 analogous to that described in Step 3 of Intermediate 111.


LC (Method 2): tR=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 analogous to that described in Step 4 of Intermediate 111.


LC (Method 2): tR=0.99 min; Mass spectrum (ESI+): m/z=327 [M+H]+.


Intermediate 116
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid



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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 analogous 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 analogous to that described in Step 4 of Intermediate 111.


Intermediate 117
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-3,5-dicyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid



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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 h. After cooling to rt, water is added, and the resulting mixture is extracted with ethyl acetate (3×). The combined extract is dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (petroleum ether/EtOAc 95:51→70:30) 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 analogous to that described in Step 1 of Intermediate 111.


LC (Method 2): tR=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 analogous to that described in Step 2 of Intermediate 111.


LC (Method 2): tR=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 analogous to that described in Step 3 of Intermediate 111.


LC (Method 2): tR=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 analogous to that described in Step 4 of Intermediate 111.


LC (Method 2): tR=0.92 min; Mass spectrum (ESI+): m/z=334 [M+H]+.


Intermediate 118
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid



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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 h and then cooled to rt. 20% Aqueous HCl solution is added, and the resulting mixture is extracted with diethyl ether. The combined extract is dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/EtOAc 7:3) to give the title compound. LC (Method 2): tR=1.01 min.


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 analogous to that described in Step 1 of Intermediate 111.


LC (Method 2): tR=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), PdCl2(dppf) (72 mg), NEt3 (0.3 mL), and MeOH (6 mL) is stirred under an atmosphere of carbon monoxide (10 bar) at 80° C. overnight. After cooling to rt, the mixture is filtered, and the filtrate is concentrated. The residue is chromatographed on silica gel (cyclohexane/EtOAc 6:4) to give the title compound.


LC (Method 2): tR=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 LiAlH4 in THF (2.3 mol/L; 0.70 mL) at −50° C. The mixture is stirred while warming to −20° C. for 1.5 h and then quenched by the addition of aqueous HCl solution (1 mol/L). The resulting mixture is extracted with EtOAc (3×), and the combined extract is dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/EtOAc 1:0→1:1) 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 also or exclusively obtained; the latter can be analogously used in the next reaction step. Mass spectrum (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 following a procedure analogous to that described in Step 3 of Intermediate 111.


LC (Method 1): tR=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 analogous to that described in Step 4 of Intermediate 111.


LC (Method 2): tR=0.94 min; Mass spectrum (ESI+): m/z=349 [M+Na]+.


Intermediate 119
1-[(4-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid



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Step 1: 4-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-methylbenzaldehyde

The title compound is prepared from 4-fluoro-2-methylbenzaldehyde and 6,6-difluoro-3-azabicyclo[3.1.0]hexane following a procedure analogous to that described in Step 1 of Intermediate 111; K2CO3 instead of Hünig's base is used at 130° C. LC (Method 2): tR=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 analogous 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 analogous to that described in Step 3 of Intermediate 111.


LC (Method 2): tR=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 analogous to that described in Step 4 of Intermediate 111.


LC (Method 2): tR=0.98 min; Mass spectrum (ESI+): m/z=334 [M+H]+.


Intermediate 120
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid



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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 rt. The mixture is stirred at rt for 24 h. The mixture is cooled to 0° C. and then slowly poured into an ice-cold solution of aqueous NaOH solution (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): tR=1.07 min.


Step 2: 2-Chloro-5-formyl-4-methylbenzonitrile

The title compound is prepared from 5-bromo-2-chloro-4-methylbenzonitrile following a procedure analogous to that described in Step 1 of Intermediate 113. LC (Method 1): tR=0.90 min; Mass spectrum (ESI): m/z=178 [M−H].


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 analogous to that described in Step 1 of Intermediate 111.


LC (Method 2): tR=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 analogous to that described in Step 2 of Intermediate 111.


LC (Method 2): tR=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 analogous to that described in Step 3 of Intermediate 111.


LC (Method 1): tR=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 analogous to that described in Step 4 of Intermediate 111.


LC (Method 1): tR=0.68 min; Mass spectrum (ESI+): m/z=323 [M+H]+.


Intermediate 121
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylic acid



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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 is 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 analogous to that described in Step 3 of Intermediate 111; the reaction is conducted at 140° C. in a microwave oven. LC (Method 1): tR=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 analogous to that described in Step 4 of Intermediate 111.


LC (Method 2): tR=0.78 min; Mass spectrum (ESI+): m/z=327 [M+H]+.


Intermediate 122
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-cyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid



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Step 1: 3-Bromo-2,6-dichlorobenzonitrile

KBrO3 (7.28 g) is added in portions to 2,6-dichlorobenzonitrile (2.50 g) in concentrated sulfuric acid chilled in an ice bath. The mixture is warmed in the cooling bath to rt and then stirred at this temperature overnight. The mixture is poured onto ice, and saturated aqueous K2CO3 solution is added to neutralize the solution. The resulting mixture is extracted with DCM (3×), and the combined extract is dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/EtOAc 1:0→7:3) to give the title compound.


LC (Method 2): tR=1.09 min.


Step 2: Methyl 2,4-dichloro-3-cyanobenzoate

The title compound is prepared from 3-bromo-2,6-dichlorobenzonitrile following a procedure analogous to that described in Step 3 of Intermediate 118; the reaction is conducted in a mixture of DMF and MeOH.


LC (Method 2): tR=1.00 min.


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 analogous to that described in Step 1 of Intermediate 111.


LC (Method 2): tR=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 analogous to that described in Step 4 of Intermediate 118.


LC (Method 2): tR=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 analogous to that described in Step 3 of Intermediate 111.


LC (Method 2): tR=1.10 min.


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 following a procedure analogous to that described in Step 4 of Intermediate 111. LC (Method 2): tR=0.96 min.


Intermediate 123
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid



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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 following a procedure analogous to that described in Step 3 of Intermediate 111; the reaction is conducted at 100° C. LC (Method 1): tR=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 analogous to that described in Step 4 of Intermediate 111.


LC (Method 2): tR=0.80 min; Mass spectrum (ESI+): m/z=343 [M+H]+.


Intermediate 124
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylic acid



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Step 1: 4-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-bromobenzaldehyde

The title compound is prepared from 2-bromo-4-fluorobenzaldehyde and 3-azabicyclo[3.1.0]hexane hydrochloride following a procedure analogous to that described in Step 1 of Intermediate 111; K2CO3 instead of Hünig's base and NMP instead of DMF are used at 120° C.


LC (Method 2): tR=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 analogous to that described in Step 2 of Intermediate 111.


LC (Method 2): tR=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 analogous to that described in Step 3 of Intermediate 111.


LC (Method 2): tR=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 analogous to that described in Step 4 of Intermediate 111.


LC (Method 2): tR=0.85 min.


Intermediate 125
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-methylphenyl)methyl]-1H-imidazole-4-carboxylic acid



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Step 1: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylphenyl)methyl]-1H-imidazole-4-carboxylate

A flask charged with 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), Cs2CO3 (0.25 g), and 1,4-dioxane (1.5 mL) is flushed with Ar for 10 min. PdCl2(dppf) (21 mg) is added, the flask is sealed, and the mixture is stirred at 110° C. for 1.5 h. After cooling to rt, the mixture is diluted with MeOH and chromatographed (HPLC; ACN/water/ammonia) to give the title compound.


LC (Method 2): tR=0.91 min.


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 analogous to that described in Step 4 of Intermediate 111.


LC (Method 2): tR=0.81 min.


Intermediate 126
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid



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Step 1: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-cyanophenyl)methyl]-1H-imidazole-4-carboxylate

A flask charged with a stir bar, ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylate (100 mg), Zn(CN)2 (60 mg), zinc (8 mg), Pd2(dba)3 (23 mg), and tBu3P*HBF4 (15 mg) 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 rt, the mixture is diluted with DMF and chromatographed (HPLC; ACN/water/ammonia) to give the title compound.


LC (Method 2): tR=0.90 min; Mass spectrum (ESI+): m/z=337 [M+H]+.


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 analogous to that described in Step 4 of Intermediate 111.


LC (Method 2): tR=0.79 min; Mass spectrum (ESI+): m/z=309 [M+H]+.


Intermediate 127
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)phenyl)methyl]-1H-imidazole-4-carboxylic acid



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Step 1: Ethyl 1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-ethenylphenyl)methyl]-1H-imidazole-4-carboxylate

A flask charged with 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), aq. Na2CO3 solution (1 mol/L; 3.2 mL), and 1,4-dioxane (9 mL) is flushed with Ar for 10 min. PdCl2(dppf) (53 mg) is added, the flask is sealed, and the mixture is stirred at 100° C. for 2.5 h. After cooling to rt, the mixture is diluted with brine, and the resulting mixture is extracted with EtOAc (3×). The combined extract is dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/EtOAc 4:1→0:1) to give the title compound. LC (Method 2): tR=0.93 min.


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. After stirring the mixture for 10 min, NaIO4 (0.57 g) is added. The mixture is stirred for 2.5 h, and then ethyl acetate/methanol (9:1; 20 mL) and water (20 mL) are added. The mixture is extracted with ethyl acetate (3×), and the combined extract is dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 70:30 →0:1) to give the title compound.


LC (Method 1): tR=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 analogous to that described in Step 2 of Intermediate 111.


LC (Method 1): tR=0.81 min.


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 analogous to that described in Step 4 of Intermediate 111.


LC (Method 2): tR=0.72 min.


Intermediate 128
1-[(2-Cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-pyrazole-4-carboxylic acid



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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 analogous to that described in Step 1 of Intermediate 126.


LC (Method 1): tR=1.03 min.


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 analogous to that described in Step 4 of Intermediate 111.


LC (Method 1): tR=0.63 min.


Intermediate 129
1-[(2-Bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-pyrazole-4-carboxylic acid



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Step 1: 2-Bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}benzaldehyde

The title compound is prepared from 2-bromo-4-fluorobenzaldehyde and 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride following a procedure analogous to that described in Step 1 of Intermediate 111; K2CO3 instead of Hünig's base and NMP instead of DMF are used at 120° C.


LC (Method 2): tR=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 analogous to that described in Step 2 of Intermediate 111.


LC (Method 2): tR=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 analogous to that described in Step 3 of Intermediate 111.


LC (Method 2): tR=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 analogous to that described in Step 4 of Intermediate 111.


LC (Method 1): tR=0.68 min.


Intermediate 130
1-[(2-Cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylic acid



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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 analogous to that described in Step 3 of Intermediate 111.


LC (Method 2): tR=0.91 min.


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 following a procedure analogous to that described in Step 1 of Intermediate 126. LC (Method 1): tR=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 analogous to that described in Step 4 of Intermediate 111.


LC (Method 1): tR=0.64 min; Mass spectrum (ESI+): m/z=345 [M+H]+.


Intermediate 131
1-[(2-Chloro-4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylic acid



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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 h. After cooling to rt, the mixture is diluted with water and extracted with EtOAc (3×). The combined extract is dried (Na2SO4) and concentrated. The residue is chromatographed (HPLC; ACN/water/ammonia) to give the title compound.


LC (Method 2): tR=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 analogous to that described in Step 4 of Intermediate 111.


LC (Method 1): tR=0.67 min; Mass spectrum (ESI): m/z=352 [M−H].


Intermediate 132
1-[(4-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylic acid



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Step 1:4-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorobenzaldehyde

The title compound is prepared from 2,4-difluorobenzaldehyde and 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride following a procedure analogous to that described in Step 1 of Intermediate 111; K2CO3 instead of Hünig's base and NMP instead of DMF are used. 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 analogous 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 analogous 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 analogous to that described in Step 4 of Intermediate 111.


LC (Method 2): tR=0.79 min.


Intermediate 133
1-[(4-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid



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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 analogous to that described in Step 3 of Intermediate 111.


LC (Method 2): tR=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 analogous to that described in Step 4 of Intermediate 111.


SYNTHESIS OF EXAMPLES
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



embedded image


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-hexafluorophosphat (HATU, 57 mg) in DMF (1 mL) is stirred for 5 min. (4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-amine dihydrochloride (33 mg) is added and the mixture is stirred for 1 h. The mixture is purified by HPLC on reversed phase (ACN, water) to give the title compound.


LC (Method 1): tR=0.91 min; Mass spectrum (ESI+): m/z=475 [M+H]+.


Examples 2 to 213 are prepared in analogy to example 1:



















Mass



Ex-


spectrum (ESI+):
LC


ample
Structure
tR
m/z [M + H]+
Method



















2


embedded image


0.64
484
Method 2





3


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0.62
404
Method 2





4


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0.95
455
Method 1





5


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0.78
439
Method 2





6


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0.80
483
Method 2





7


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0.73
458
Method 2





8


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0.64
405
Method 2





9


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0.62
407
Method 2





10


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0.77
423
Method 2





11


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0.73
422
Method 2





12


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0.77
422
Method 2





13


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0.79
482
Method 2





14


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0.93
519
Method 1





15


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0.92
518
Method 1





16


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0.76
482
Method 2





17


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0.78
423
Method 2





18


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0.77
458
Method 2





19


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0.64
404
Method 2





20


embedded image


0.94
433
Method 1





21


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0.91
438
Method 1





22


embedded image


0.96
432
Method 1





23


embedded image


0.55
418
Method 2





24


embedded image


0.89
454
Method 1





25


embedded image


0.77
459
Method 2





26


embedded image


0.59
405
Method 2





27


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0.90
455
Method 1





28


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0.92
518
Method 1





29


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0.74
455
Method 2





30


embedded image


0.82
455
Method 2





31


embedded image


0.95
447
Method 1





32


embedded image


0.80
439
Method 2





33


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0.58
441
Method 2





34


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0.81
483
Method 2





35


embedded image


0.75
429
Method 2





36


embedded image


0.64
468
Method 2





37


embedded image


0.93
432
Method 1





38


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0.84
488
Method 2





39


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0.77
482
Method 2





40


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0.81
482
Method 2





41


embedded image


0.82
440
Method 1





42


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0.76
469
Method 2





43


embedded image


0.95
454
Method 1





44


embedded image


0.79
474
Method 2





45


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0.93
490
Method 1





46


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0.92
490
Method 1





47


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0.93
454
Method 1





48


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0.79
455
Method 2





49


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0.90
448
Method 1





50


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0.84
471
Method 1





51


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0.92
432
Method 1





52


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0.78
454
Method 2





53


embedded image


0.62
440
Method 2





54


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0.67
462
Method 1





55


embedded image


0.90
485
Method 1





56


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0.78
438
Method 2





57


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0.91
474
Method 1





58


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0.88
488
Method 2





59


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0.90
462
Method 1





60


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0.55
405
Method 2





61


embedded image


0.59
435
Method 2





62


embedded image


0.64
435
Method 2





63


embedded image


0.58
440
Method 4





64


embedded image


0.95
454
Method 1





65


embedded image


1.00
471
Method 1





66


embedded image


0.98
482
Method 1





67


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1.02
494
Method 1





68


embedded image


0.87
419
Method 1





69


embedded image


0.98
482
Method 1





70


embedded image


0.97
443
Method 1





71


embedded image


0.79
405
Method 1





72


embedded image


0.87
404
Method 1





73


embedded image


0.86
404
Method 1





74


embedded image


0.86
404
Method 1





75


embedded image


0.60
432
Method 2





76


embedded image


0.60
468
Method 2





77


embedded image


0.63
448
Method 5





78


embedded image


0.62
448
Method 5





79


embedded image


0.58
434
Method 5





80


embedded image


0.58
440
Method 5





81


embedded image


0.89
443
Method 1





82


embedded image


0.89
448
Method 1





83


embedded image


0.89
448
Method 1





84


embedded image


0.61
462
Method 2





85


embedded image


0.85
448
Method 1





86


embedded image


0.85
434
Method 1





87


embedded image


0.52
434
Method 5





88


embedded image


0.89
448
Method 1





89


embedded image


0.69
435
Method 2





90


embedded image


0.62
454
Method 2





91


embedded image


0.86
435
Method 1





92


embedded image


0.93
449
Method 1





93


embedded image


0.60
470
Method 2





94


embedded image


0.76
456
Method 2





95


embedded image


0.64
484
Method 2





96


embedded image


0.59
470
Method 2





97


embedded image


0.73
470
Method 5





98


embedded image


0.88
434
Method 1





99


embedded image


0.89
438
Method 1





100


embedded image


0.65
460
Method 2





101


embedded image


0.99
433
Method 1





102


embedded image


0.83
484
Method 2





103


embedded image


0.88
479
Method 1





104


embedded image


0.78
422
Method 2





105


embedded image


0.87
479
Method 1





106


embedded image


0.87
418
Method 1





107


embedded image


0.88
484
Method 1





108


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0.74
422
Method 2





109


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0.96
469
Method 1





110


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0.62
446
Method 2





111


embedded image


0.62
468
Method 2





112


embedded image


0.64
468
Method 2





113


embedded image


0.63
418
Method 4





114


embedded image


0.75
429
Method 2





115


embedded image


0.93
472
Method 1





116


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0.76
443
Method 2





117


embedded image


0.66
444
Method 2





118


embedded image


0.74
443
Method 2





119


embedded image


0.81
486
Method 5





120


embedded image


0.89
438
Method 1





121


embedded image


0.93
472
Method 1





122


embedded image


0.77
437
Method 2





123


embedded image


0.94
462
Method 1





124


embedded image


0.77
443
Method 2





125


embedded image


0.97
476
Method 1





126


embedded image


0.93
498
Method 1





127


embedded image


0.92
438
Method 1





128


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0.93
443
Method 1





129


embedded image


0.97
432
Method 1





130


embedded image


0.97
432
Method 1





131


embedded image


0.59
404
Method 5





132


embedded image


0.67
429
Method 5





133


embedded image


0.89
418
Method 1





134


embedded image


0.80
472
Method 5





135


embedded image


0.61
405
Method 5





136


embedded image


0.69
455
Method 2





137


embedded image


0.86
420
Method 1





138


embedded image


0.64
441
Method 2





139


embedded image


0.60
439
Method 2





140


embedded image


0.60
439
Method 2





141


embedded image


0.62
453
Method 2





142


embedded image


0.63
453
Method 2





143


embedded image


1.02
446
Method 1





144


embedded image


1.01
455
Method 1





145


embedded image


0.98
491
Method 1





146


embedded image


1.03
433
Method 1





147


embedded image


0.88
471
Method 1





148


embedded image


0.98
439
Method 1





149


embedded image


0.91
435
Method 1





150


embedded image


0.96
475
Method 1





151


embedded image


0.88
405
Method 1





152


embedded image


0.94
455
Method 1





153


embedded image


1.06
469
Method 1





154


embedded image


0.91
419
Method 1





155


embedded image


0.89
455
Method 1





156


embedded image


0.97
433
Method 1





157


embedded image


0.95
439
Method 1





158


embedded image


0.78
433
Method 5





159


embedded image


0.82
473
Method 2





160


embedded image


1.07
510
Method 1





161


embedded image


1.03
496
Method 1





162


embedded image


1.05
460
Method 1





163


embedded image


0.97
482
Method 1





164


embedded image


0.98
446
Method 1





165


embedded image


0.96
432
Method 1





166


embedded image


0.66
446
Method 2





167


embedded image


0.94
468
Method 1





168


embedded image


0.96
432
Method 1





169


embedded image


0.62
418
Method 5





170


embedded image


0.62
418
Method 5





171


embedded image


0.59
419
Method 5





172


embedded image


0.55
419
Method 5





173


embedded image


0.71
469
Method 5





174


embedded image


0.64
470
Method 5





175


embedded image


0.63
506
Method 5





176


embedded image


0.66
474
Method 5





177


embedded image


0.59
419
Method 5





178


embedded image


0.62
456
Method 5





179


embedded image


0.92
498
Method 1





180


embedded image


0.90
448
Method 1





181


embedded image


0.63
418
Method 2





182


embedded image


0.63
418
Method 2





183


embedded image


1.08
448
Method 1





184


embedded image


0.69
484
Method 2





185


embedded image


0.65
486
Method 2





186


embedded image


0.67
468
Method 2





187


embedded image


0.67
470
Method 2





188


embedded image


0.66
471
Method 2





189


embedded image


0.66
454
Method 2





190


embedded image


0.80
428
Method 2





191


embedded image


0.98
439
Method 5





192


embedded image


0.98
439
Method 1





193


embedded image


0.92
442
Method 1





194


embedded image


0.92
442
Method 1





195


embedded image


0.83
446
Method 2





196


embedded image


0.78
428
Method 2





197


embedded image


0.79
453
Method 2





198


embedded image


0.59
446
Method 5





199


embedded image


0.84
453
Method 2





200


embedded image


0.72
442
Method 5





201


embedded image


0.67
446
Method 4





202


embedded image


0.83
462
Method 2





203


embedded image


0.54
462
Method 5





204


embedded image


0.82
481/483 (Br)
Method 2





205


embedded image


0.78
417
Method 2





206


embedded image


0.69
428
Method 1





207


embedded image


0.87
433
Method 1





208


embedded image


0.90
464
Method 1





209


embedded image


0.95
517/519 (Br)
Method 1





210


embedded image


0.65
464
Method 5





211


embedded image


0.74
473
Method 5





212


embedded image


0.70
457
Method 4





213


embedded image


0.81
457
Method 2





















Example
Name
Name of Starting Material

















2
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-



(methoxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1-methyl-
azabicyclo[3.1.0]hexan-3-yl}-2-



1H,4H,5H,6H-cyclopenta[d]-imidazol-4-yl]-1H-pyrazole-4-
(methoxymethyl)pyridin-3-yl)methyl]-



carboxamide
1H-pyrazole-4-carboxylic acid


3
1-[(5-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridin-2-yl)methyl]-
1-[(5-{3-Azabicyclo[3.1.0]hexan-3-



N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-
yl}pyridin-2-yl)methyl]-1H-imidazole-4-



yl]-1H-imidazole-4-carboxamide
carboxylic acid


4
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-(difluoromethyl)-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclo-
(difluoromethyl)pyridin-3-yl)methyl]-1H-



penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide
1,2,3-triazole-4-carboxylic acid


5
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-chloropyridin-3-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclo-
chloropyridin-3-yl)methyl]-1H-1,2,3-



penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide
triazole-4-carboxylic acid


6
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-bromopyridin-3-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclo-
bromopyridin-3-yl)methyl]-1H-1,2,3-



penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide
triazole-4-carboxylic acid


7
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-azabicyclo-



fluoropyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
[3.1.0]hexan-3-yl}-2-fluoropyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
methyl]-1H-imidazole-4-carboxylic acid


8
1-[(5-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridin-2-yl)methyl]-
1-[(5-{3-Azabicyclo[3.1.0]hexan-3-



N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-
yl}pyridin-2-yl)methyl]-1H-1,2,3-



yl]-1H-1,2,3-triazole-4-carboxamide
triazole-4-carboxylic acid


9
1-[(5-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridin-2-yl)methyl]-
1-[(5-{3-Azabicyclo[3.1.0]hexan-3-



N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-
yl}pyridin-2-yl)methyl]-1H-pyrazole-4-



yl]-1H-pyrazole-4-carboxamide
carboxylic acid


10
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-fluoropyridin-3-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclo-
fluoropyridin-3-yl)methyl]-1H-1,2,3-



penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide
triazole-4-carboxylic acid


11
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-fluoropyridin-3-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
fluoropyridin-3-yl)methyl]-1H-imidazole-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
4-carboxylic acid


12
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-fluoropyridin-3-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
fluoropyridin-3-yl)methyl]-1H-pyrazole-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
4-carboxylic acid


13
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-bromopyridin-3-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
bromopyridin-3-yl)methyl]-1H-pyrazole-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
4-carboxylic acid


14
1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo-[3.1.0]hexan-3-
1-[(2-Bromo-6-{6,6-difluoro-3-



yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



cyclopenta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-
yl)methyl]-1H-1,2,3-triazole-4-



carboxamide
carboxylic acid


15
1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo-[3.1.0]hexan-3-
1-[(2-Bromo-6-{6,6-difluoro-3-aza-



yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
bicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
methyl]-1H-pyrazole-4-carboxylic acid


16
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-bromopyridin-3-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
bromopyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


17
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-fluoropyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclo-
fluoropyridin-3-yl)methyl]-1H-1,2,3-



penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide
triazole-4-carboxylic acid


18
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-azabicyclo-



fluoropyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
[3.1.0]hexan-3-yl}-2-fluoropyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
methyl]-1H-pyrazole-4-carboxylic acid


19
1-[(5-{5-Azaspiro[2.3]hexan-5-yl}pyridin-2-yl)-methyl]-N-
1-[(5-{5-Azaspiro[2.3]hexan-5-



[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-
yl}pyridin-2-yl)methyl]-1H-pyrazole-4-



1H-pyrazole-4-carboxamide
carboxylic acid


20
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-ethylpyridin-3-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclo-
ethylpyridin-3-yl)methyl]-1H-1,2,3-



penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide
triazole-4-carboxylic acid


21
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-chloropyridin-3-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
chloropyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


22
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
ethylpyridin-3-yl)methyl]-1H-pyrazole-4-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
carboxylic acid


23
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
methylpyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


24
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-azabicyclo-



methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
methyl]-1H-imidazole-4-carboxylic acid


25
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-



fluoropyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
azabicyclo[3.1.0]hexan-3-yl}-2-



cyclopenta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-
fluoropyridin-3-yl)methyl]-1H-1,2,3-



carboxamide
triazole-4-carboxylic acid


26
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}pyridin-3-yl)-methyl]-N-
1-[(6-{5-Azaspiro[2.3]hexan-5-



[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-
yl}pyridin-3-yl)methyl]-1H-1,2,3-



1H-1,2,3-triazole-4-carboxamide
triazole-4-carboxylic acid


27
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-



methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-
azabicyclo[3.1.0]hexan-3-yl}-2-



1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-1,2,3-
methylpyridin-3-yl)methyl]-1H-1,2,3-



triazole-4-carboxamide
triazole-4-carboxylic acid


28
1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo-[3.1.0]hexan-3-
1-[(2-Bromo-6-{6,6-difluoro-3-aza-



yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
bicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
methyl]-1H-imidazole-4-carboxylic acid


29
1-[(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-(difluoromethyl)-
1-[(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-



pyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(difluoromethyl)pyrimidin-5-yl)methyl]-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
1H-imidazole-4-carboxylic acid


30
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(difluoromethyl)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclo-
(difluoromethyl)pyridin-3-yl)methyl]-1H-



penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide
1,2,3-triazole-4-carboxylic acid


31
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-propylpyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
propylpyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


32
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-chloropyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta-
chloropyridin-3-yl)methyl]-1H-1,2,3-



[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide
triazole-4-carboxylic acid


33
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-
1-[(6-{6,6-Difluoro-3-azabicyclo-



3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclo-
[3.10]hexan-3-yl}pyridin-3-yl)methyl]-



penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide
1H-1,2,3-triazole-4-carboxylic acid


34
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-bromopyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta-
bromopyridin-3-yl)methyl]-1H-1,2,3-



[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide
triazole-4-carboxylic acid


35
1-[(5-{3-Azabicyclo[3.1.0]hexan-3-yl}-6-cyanopyridin-2-
1-[(5-{3-Azabicyclo[3.1.0]hexan-3-yl}-6-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
cyanopyridin-2-yl)methyl]-1H-pyrazole-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
4-carboxylic acid


36
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-azabicyclo-



ethylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
methyl]-1H-pyrazole-4-carboxylic acid


37
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-ethylpyridin-3-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
ethylpyridin-3-yl)methyl]-1H-imidazole-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
4-carboxylic acid


38
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(trifluoromethoxy)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(trifluoromethoxy)pyridin-3-yl)methyl]-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
1H-imidazole-4-carboxylic acid


39
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-bromopyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
bromopyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


40
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-bromopyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
bromopyridin-3-yl)methyl]-1H-pyrazole-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
4-carboxylic acid


41
1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-
1-[(5-{6,6-Difluoro-3-azabicyclo-



2-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
[3.10]hexan-3-yl}pyridin-2-yl)methyl]-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
1H-pyrazole-4-carboxylic acid


42
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(1-cyanocyclopro-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyl)-pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(1-cyanocyclopropyl)pyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
methyl]-1H-pyrazole-4-carboxylic acid


43
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(difluoromethyl)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(difluoromethyl)pyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


44
1-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo-[3.1.0]hexan-3-
1-[(2-Chloro-6-{6,6-difluoro-3-aza-



yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
bicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
methyl]-1H-pyrazole-4-carboxylic acid


45
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-



(difluoromethyl)pyridin-3-yl)methyl]-N-[(4R)-1-methyl-
azabicyclo[3.1.0]hexan-3-yl}-2-



1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-imidazole-
(difluoromethyl)pyridin-3-yl)methyl]-1H-



4-carboxamide
imidazole-4-carboxylic acid


46
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-



(difluoromethyl)pyridin-3-yl)methyl]-N-[(4R)-1-methyl-
azabicyclo[3.1.0]hexan-3-yl}-2-



1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-pyrazole-4-
(difluoromethyl)pyridin-3-yl)methyl]-1H-



carboxamide
pyrazole-4-carboxylic acid


47
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-(difluoromethyl)-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(difluoromethyl)pyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


48
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(difluoromethyl)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(difluoromethyl)pyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


49
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(methoxymethyl)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(methoxymethyl)pyridin-3-yl)methyl]-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
1H-pyrazole-4-carboxylic acid


50
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-



(hydroxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1-methyl-
azabicyclo[3.1.0]hexan-3-yl}-2-



1H,4H,5H,6H-cyclopenta[d]-imidazol-4-yl]-1H-1,2,3-
(hydroxymethyl)pyridin-3-yl)methyl]-1H-



triazole-4-carboxamide
1,2,3-triazole-4-carboxylic acid


51
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-ethylpyridin-3-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
ethylpyridin-3-yl)methyl]-1H-pyrazole-4-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
carboxylic acid


52
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-(difluoromethyl)-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(difluoromethyl)pyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


53
1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-
1-[(5-{6,6-Difluoro-3-azabicyclo-



2-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
[3.10]hexan-3-yl}pyridin-2-yl)methyl]-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
1H-imidazole-4-carboxylic acid


54
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(3-hydroxypropyl)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(3-hydroxypropyl)pyridin-3-yl)methyl]-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
1H-pyrazole-4-carboxylic acid


55
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-



(methoxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1-methyl-
azabicyclo[3.1.0]hexan-3-yl}-2-



1H,4H,5H,6H-cyclopenta[d]-imidazol-4-yl]-1H-1,2,3-
(methoxymethyl)pyridin-3-yl)methyl]-



triazole-4-carboxamide
1H-1,2,3-triazole-4-carboxylic acid


56
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-chloropyridin-3-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
chloropyridin-3-yl)methyl]-1H-pyrazole-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
4-carboxylic acid


57
1-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]-hexan-3-
1-[(2-Chloro-6-{6,6-difluoro-3-aza-



yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
bicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
methyl]-1H-imidazole-4-carboxylic acid


58
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(trifluoromethoxy)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(trifluoromethoxy)pyridin-3-yl)methyl]-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
1H-pyrazole-4-carboxylic acid


59
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(1-hydroxypropan-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



2-yl)pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(1-hydroxypropan-2-yl)pyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
methyl]-1H-pyrazole-4-carboxylic acid


60
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridazin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
yl}pyridazin-3-yl)methyl]-1H-pyrazole-4-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
carboxylic acid


61
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-(hydroxymethyl)-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclo-
(hydroxymethyl)pyridin-3-yl)methyl]-1H-



penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide
1,2,3-triazole-4-carboxylic acid


62
1-[(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-(hydroxymethyl)-
1-[(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-



pyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(hydroxymethyl)pyrimidin-5-yl)methyl]-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
1H-pyrazole-4-carboxylic acid


63
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-
1-[(6-{6,6-Difluoro-3-azabicyclo-



3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
[3.10]hexan-3-yl}pyridin-3-yl)methyl]-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
1H-imidazole-4-carboxylic acid


64
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(difluoromethyl)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(difluoromethyl)pyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


65
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(1-cyano-1-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



methylethyl)pyridin-3-yl)methyl]-N-[(4R)-1-methyl-
(1-cyano-1-methylethyl)pyridin-3-yl)-



1H,4H,5H,6H-cyclopenta[d]-imidazol-4-yl]-1H-pyrazole-4-
methyl]-1H-pyrazole-4-carboxylic acid



carboxamide



66
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-azabicyclo-



propylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
[3.1.0]hexan-3-yl}-2-propylpyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
methyl]-1H-imidazole-4-carboxylic acid


67
1-[(2-Cydobutyl-6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-
1-[(2-Cyclobutyl-6-{6,6-difluoro-3-aza-



3-yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
bicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
methyl]-1H-pyrazole-4-carboxylic acid


68
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-methylpyridin-3-yl)-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclo-
methylpyridin-3-yl)methyl]-1H-1,2,3-



penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide
triazole-4-carboxylic acid


69
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



propylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexan-3-yl}-2-propylpyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
methyl]-1H-pyrazole-4-carboxylic acid


70
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-3-cyano-N-[(4R)-1-methyl-1H,4H,5H,6H-
methylpyridin-3-yl)methyl]-3-cyano-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


71
1-[(5-{3-Azabicyclo[3.1.0]hexan-3-yl}pyrimidin-2-
1-[(5-{3-Azabicyclo[3.1.0]hexan-3-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
yl}pyrimidin-2-yl)methyl]-1H-pyrazole-4-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
carboxylic acid


72
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methyl]-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-



N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-
yl}pyridin-3-yl)methyl]-1H-imidazole-4-



yl]-1H-imidazole-4-carboxamide
carboxylic acid


73
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}pyridin-3-yl)-methyl]-N-
1-[(6-{5-Azaspiro[2.3]hexan-5-



[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-
yl}pyridin-3-yl)methyl]-1H-pyrazole-4-



1H-pyrazole-4-carboxamide
carboxylic acid trifluoroacetate


74
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}pyridin-3-yl)-methyl]-N-
1-[(6-{5-Azaspiro[2.3]hexan-5-



[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-
yl}pyridin-3-yl)methyl]-1H-imidazole-4-



1H-imidazole-4-carboxamide
carboxylic acid trifluoroacetate


75
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
ethylpyridin-3-yl)methyl]-1H-imidazole-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
4-carboxylic acid


76
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-azabicyclo-



ethylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
[3.1.0]hexan-3-yl}-2-ethylpyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
methyl]-1H-imidazole-4-carboxylic acid


77
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-(methoxymethyl)-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(methoxymethyl)pyridin-3-yl)methyl]-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
1H-imidazole-4-carboxylic acid


78
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-(methoxymethyl)-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(methoxymethyl)pyridin-3-yl)methyl]-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
1H-pyrazole-4-carboxylic acid


79
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-(hydroxymethyl)-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(hydroxymethyl)pyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


80
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexan-3-yl}pyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid trifluoroacetate


81
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(cyanomethyl)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(cyanomethyl)pyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


82
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-[(1R)-1-hydroxy-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



ethyl]pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
[(1R)-1-hydroxyethyl]pyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
methyl]-1H-pyrazole-4-carboxylic acid


83
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-[(1S)-1-hydroxy-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



ethyl]pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
[(1S)-1-hydroxyethyl]pyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
methyl]-1H-pyrazole-4-carboxylic acid


84
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(2-hydroxypropan-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



2-yl)pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(2-hydroxypropan-2-yl)pyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
methyl]-1H-pyrazole-4-carboxylic acid


85
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(2-hydroxyethyl)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(2-hydroxyethyl)pyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


86
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(hydroxymethyl)pyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


87
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-(hydroxymethyl)-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(hydroxymethyl)pyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


88
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(1-hydroxyethyl)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(1-hydroxyethyl)pyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


89
1-[(5-{3-Azabicyclo[3.1.0]hexan-3-yl}-3-(hydroxymethyl)-
1-[(5-{3-Azabicyclo[3.1.0]hexan-3-yl}-3-



pyrazin-2-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(hydroxymethyl)pyrazin-2-yl)methyl]-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
1H-pyrazole-4-carboxylic acid


90
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexan-3-yl}-2-methylpyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
methyl]-1H-pyrazole-4-carboxylic acid


91
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclo-
(hydroxymethyl)pyridin-3-yl)methyl]-1H-



penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide
1,2,3-triazole-4-carboxylic acid


92
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(methoxymethyl)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclo-
(methoxymethyl)pyridin-3-yl)methyl]-



penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide
1H-1,2,3-triazole-4-carboxylic acid


93
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-



(hydroxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1-methyl-
azabicyclo[3.1.0]hexan-3-yl}-2-



1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-pyrazole-4-
(hydroxymethyl)pyridin-3-yl)methyl]-1H-



carboxamide
pyrazole-4-carboxylic acid


94
1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-3-
1-[(5-{6,6-Difluoro-3-



methylpyrazin-2-yl)methyl]-N-[(4R)-1-methyl-
azabicyclo[3.1.0]hexan-3-yl}-3-



1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-1,2,3-
methylpyrazin-2-yl)methyl]-1H-1,2,3-



triazole-4-carboxamide
triazole-4-carboxylic acid


95
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-



(methoxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1-methyl-
azabicyclo[3.1.0]hexan-3-yl}-2-



1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-imidazole-
(methoxymethyl)pyridin-3-yl)methyl]-



4-carboxamide
1H-imidazole-4-carboxylic acid


96
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-



(hydroxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1-methyl-
azabicyclo[3.1.0]hexan-3-yl}-2-



1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-imidazole-
(hydroxymethyl)pyridin-3-yl)methyl]-1H-



4-carboxamide
imidazole-4-carboxylic acid


97
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-



methoxypyridin-3-yl)methyl]-N-[(4R)-1-methyl-
azabicyclo[3.1.0]hexan-3-yl}-2-



1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-
methoxypyridin-3-yl)methyl]-1H-



carboxamide
imidazole-4-carboxylic acid


98
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(hydroxymethyl)pyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


99
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-chloropyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
chloropyridin-3-yl)methyl]-1H-pyrazole-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
4-carboxylic acid


100
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(2-methylpropyl)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(2-methylpropyl)pyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


101
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclo-
ethylpyridin-3-yl)methyl]-1H-1,2,3-



penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide
triazole-4-carboxylic acid


102
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



ethoxypyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexan-3-yl}-2-ethoxypyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
methyl]-1H-imidazole-4-carboxylic acid


103
1-[(5-Cyano-6-{6,6-difluoro-3-azabicyclo[3.1.0]-hexan-3-
1-[(5-Cyano-6-{6,6-difluoro-3-



yl}-4-methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-
azabicyclo[3.1.0]hexan-3-yl}-4-



1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-pyrazole-4-
methylpyridin-3-yl)methyl]-1H-pyrazole-



carboxamide
4-carboxylic acid


104
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-fluoropyridin-3-yl)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
fluoropyridin-3-yl)methyl]-1H-pyrazole-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
4-carboxylic acid


105
1-[(5-Cyano-6-{6,6-difluoro-3-azabicyclo[3.1.0]-hexan-3-
1-[(5-Cyano-6-{6,6-difluoro-3-



yl}-4-methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-
azabicyclo[3.1.0]hexan-3-yl}-4-



1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-imidazole-
methylpyridin-3-yl)methyl]-1H-



4-carboxamide
imidazole-4-carboxylic acid


106
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-methylpyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
methylpyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


107
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



methylpyridin-3-yl)methyl]-3-(hydroxymethyl)-N-[(4R)-1-
hexan-3-yl}-2-methylpyridin-3-



methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-
yl)methyl]-3-(hydroxymethyl)-1H-



pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


108
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-fluoropyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
fluoropyridin-3-yl)methyl]-1H-imidazole-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
4-carboxylic acid


109
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-ethyl-
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclo-
hexan-3-yl}-2-ethylpyridin-3-yl)methyl]-



penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide
1H-1,2,3-triazole-4-carboxylic acid


110
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-propylpyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
propylpyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


111
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2,4-di-
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexan-3-yl}-2,4-dimethylpyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
methyl]-1H-imidazole-4-carboxylic acid


112
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2,4-di-
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexan-3-yl}-2,4-dimethylpyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
methyl]-1H-pyrazole-4-carboxylic acid


113
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-methylpyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
methylpyridin-3-yl)methyl]-1H-pyrazole-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
4-carboxylic acid


114
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-cyanopyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
cyanopyridin-3-yl)methyl]-1H-pyrazole-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
4-carboxylic acid


115
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-(trifluoromethyl)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(trifluoromethyl)pyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid, lithium salt


116
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-cyano-4-methyl-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
cyano-4-methylpyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


117
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-cyclopropyl-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
cyclopropylpyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


118
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-cyano-4-methyl-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
cyano-4-methylpyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


119
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
methylpyridin-3-yl)methyl]-3-



cyclopenta[d]imidazol-4-yl]-3-(trifluoromethyl)-1H-
(trifluoromethyl)-1H-pyrazole-4-



pyrazole-4-carboxamide
carboxylic acid


120
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-chloropyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
chloropyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


121
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-(trifluoromethyl)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(trifluoromethyl)pyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


122
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-chloropyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
chloropyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


123
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-3-(methoxymethyl)-N-[(4R)-1-methyl-
methylpyridin-3-yl)methyl]-3-(methoxy-



1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-pyrazole-4-
methyl)-1H-pyrazole-4-carboxylic acid



carboxamide



124
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-cyano-2-methyl-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
cyano-2-methylpyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


125
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-3-(2-hydroxypropan-2-yl)-N-[(4R)-1-methyl-
methylpyridin-3-yl)methyl]-3-(2-



1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-pyrazole-4-
hydroxypropan-2-yl)-1H-pyrazole-4-



carboxamide
carboxylic acid


126
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



methylpyridin-3-yl)methyl]-3-(methoxymethyl)-N-[(4R)-1-
hexan-3-yl}-2-methylpyridin-3-



methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-
yl)methyl]-3-(methoxymethyl)-1H-



pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


127
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-chloropyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
chloropyridin-3-yl)methyl]-1H-pyrazole-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
4-carboxylic acid


128
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-cyano-2-methyl-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-5-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
cyano-2-methylpyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


129
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2,5-dimethylpyridin-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-



3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
2,5-dimethylpyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


130
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2,5-dimethylpyridin-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-



3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
2,5-dimethylpyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


131
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methyl]-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-



N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-
yl}pyridin-3-yl)methyl]-1H-pyrazole-4-



yl]-1H-pyrazole-4-carboxamide
carboxylic acid


132
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-cyanopyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
cyanopyridin-3-yl)methyl]-1H-pyrazole-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
4-carboxylic acid


133
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
methylpyridin-3-yl)methyl]-1H-pyrazole-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
4-carboxylic acid


134
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(trifluoromethyl)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(trifluoromethyl)pyridin-3-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


135
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methyl]-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-



N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-
yl}pyridin-3-yl)methyl]-1H-1,2,3-



yl]-1H-1,2,3-triazole-4-carboxamide
triazole-4-carboxylic acid


136
1-[(2-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-4-
1-[(2-{6,6-Difluoro-3-azabicyclo[3.1.0]-



methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-
hexan-3-yl}-4-methylpyrimidin-5-yl)-



1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-
methyl]-1H-imidazole-4-carboxylic acid



carboxamide



137
1-[(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-methylpyrimidin-
1-[(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-



5-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclo-
methylpyrimidin-5-yl)methyl]-1H-1,2,3-



penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide
triazole-4-carboxylic acid


138
1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-
1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]-



2-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclo-
hexan-3-yl}pyridin-2-yl)methyl]-1H-



penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide
1,2,3-triazole-4-carboxylic acid


139
5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-
5-[(6-{6,6-Difluoro-3-



3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



cyclopenta[d]imidazol-4-yl]-1H-pyrrole-3-carboxamide
yl)methyl]-1H-pyrrole-3-carboxylic acid


140
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}pyridin-
1-[(6-{6,6-Difluoro-3-



3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



cyclopenta[d]imidazol-4-yl]-1H-pyrrole-3-carboxamide
yl)methyl]-1H-pyrrole-3-carboxylic acid


141
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexan-3-yl}-2-methylpyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-pyrrole-3-carboxamide
methyl]-1H-pyrrole-3-carboxylic acid


142
5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexan-3-yl}-2-methylpyridin-3-



cyclopenta[d]imidazol-4-yl]-1H-pyrrole-3-carboxamide
yl)methyl]-1H-pyrrole-3-carboxylic acid


143
1-({2-Ethyl-6-[(1R,5S,6R)-6-methyl-3-azabicyclo[3.1.0]-
1-({2-Ethyl-6-[(1R,5S,6R)-6-methyl-3-



hexan-3-yl]pyridin-3-yl}methyl)-N-[(4R)-1-methyl-
azabicyclo[3.1.0]hexan-3-yl]pyridin-3-



1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-imidazole-
yl}methyl)-1H-imidazole-4-carboxylic



4-carboxamide
acid


144
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(difluoromethyl)-
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(difluoromethyl)pyridin-3-yl)methyl]-1,2-



cyclopenta[d]imidazol-4-yl]-1,2-oxazole-5-carboxamide
oxazole-5-carboxylic acid


145
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
3-[(6-{6,6-Difluoro-3-



(difluoromethyl)pyridin-3-yl)methyl]-N-[(4R)-1-methyl-
azabicyclo[3.1.0]hexan-3-yl}-2-



1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1,2-oxazole-5-
(difluoromethyl)pyridin-3-yl)methyl]-1,2-



carboxamide
oxazole-5-carboxylic acid


146
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
ethylpyridin-3-yl)methyl]-1,2-oxazole-5-



cyclopenta[d]imidazol-4-yl]-1,2-oxazole-5-carboxamide
carboxylic acid


147
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



(hydroxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1-methyl-
hexan-3-yl}-2-(hydroxymethyl)pyridin-3-



1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1,2-oxazole-5-
yl)methyl]-1,2-oxazole-5-carboxylic acid



carboxamide



148
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-chloropyridin-3-
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
chloropyridin-3-yl)methyl]-1,2-oxazole-



cyclopenta[d]imidazol-4-yl]-1,2-oxazole-5-carboxamide
5-carboxylic acid


149
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)-
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(hydroxymethyl)pyridin-3-yl)methyl]-1,2-



cyclopenta[d]imidazol-4-yl]-1,2-oxazole-5-carboxamide
oxazole-5-carboxylic acid


150
3-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-
3-[(2-Chloro-6-{6,6-difluoro-3-



yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



cyclopenta-[d]imidazol-4-yl]-1,2-oxazole-5-carboxamide
yl)methyl]-1,2-oxazole-5-carboxylic acid


151
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)methyl]-
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-



N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-
yl}pyridin-3-yl)methyl]-1,2-oxazole-5-



yl]-1,2-oxazole-5-carboxamide
carboxylic acid


152
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexan-3-yl}-2-methylpyridin-3-



cyclopenta[d]imidazol-4-yl]-1,2-oxazole-5-carboxamide
yl)methyl]-1,2-oxazole-5-carboxylic acid


153
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



ethylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexan-3-yl}-2-ethylpyridin-3-yl)methyl]-



cyclopenta[d]imidazol-4-yl]-1,2-oxazole-5-carboxamide
1,2-oxazole-5-carboxylic acid


154
2-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-
2-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
methylpyridin-3-yl)methyl]-1,3-oxazole-



cyclopenta[d]imidazol-4-yl]-1,3-oxazole-5-carboxamide
5-carboxylic acid


155
2-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
2-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexan-3-yl}-2-methylpyridin-3-



cyclopenta[d]imidazol-4-yl]-1,3-oxazole-5-carboxamide
yl)methyl]-1,3-oxazole-5-carboxylic acid


156
3-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-ethylpyridin-3-
3-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
ethylpyridin-3-yl)methyl]-1,2-oxazole-5-



cyclopenta[d]imidazol-4-yl]-1,2-oxazole-5-carboxamidef
carboxylic acid


157
3-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-chloropyridin-3-
3-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
chloropyridin-3-yl)methyl]-1,2-oxazole-



cyclopenta[d]imidazol-4-yl]-1,2-oxazole-5-carboxamide
5-carboxylic acid


158
2-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-
2-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
ethylpyridin-3-yl)methyl]-1,3-oxazole-5-



cyclopenta[d]imidazol-4-yl]-1,3-oxazole-5-carboxamide
carboxylic acid


159
5-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo-[3.1.0]hexan-3-
5-[(2-Chloro-6-{6,6-difluoro-3-



yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
azabicyclo[3.1.0]hexan-3-yl}pyridin-3-



cyclopenta[d]imidazol-4-yl]-1H-pyrrole-3-carboxamide
yl)methyl]-1H-pyrrole-3-carboxylic acid


160
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



ethylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexan-3-yl}-2-ethylpyridin-3-yl)methyl]-



cyclopenta[d]imidazol-4-yl]-1-(propan-2-yl)-1H-pyrazole-
1-(propan-2-yl)-1H-pyrazole-5-



5-carboxamide
carboxylic acid


161
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



ethylpyridin-3-yl)methyl]-1-ethyl-N-[(4R)-1-methyl-
hexan-3-yl}-2-ethylpyridin-3-yl)methyl]-



1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-5-
1-ethyl-1H-pyrazole-5-carboxylic acid



carboxamide



162
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-1-ethyl-N-[(4R)-1-methyl-1H,4H,5H,6H-
ethylpyridin-3-yl)methyl]-1-ethyl-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-5-carboxamide
pyrazole-5-carboxylic acid


163
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



methylpyridin-3-yl)methyl]-1-ethyl-N-[(4R)-1-methyl-
hexan-3-yl}-2-methylpyridin-3-



1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-5-
yl)methyl]-1-ethyl-1H-pyrazole-5-



carboxamide
carboxylic acid


164
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-1-ethyl-N-[(4R)-1-methyl-1H,4H,5H,6H-
methylpyridin-3-yl)methyl]-1-ethyl-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-5-carboxamide
pyrazole-5-carboxylic acid


165
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
ethylpyridin-3-yl)methyl]-1H-pyrazole-5-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-5-carboxamide
carboxylic acid


166
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-1-methyl-N-[(4R)-1-methyl-1H,4H,5H,6H-
ethylpyridin-3-yl)methyl]-1-methyl-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-5-carboxamide
pyrazole-5-carboxylic acid


167
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



methylpyridin-3-yl)methyl]-1-methyl-N-[(4R)-1-methyl-
hexan-3-yl}-2-methylpyridin-3-yl)-



1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-pyrazole-5-
methyl]-1-methyl-1H-pyrazole-5-



carboxamide
carboxylic acid


168
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-1-methyl-N-[(4R)-1-methyl-1H,4H,5H,6H-
methylpyridin-3-yl)methyl]-1-methyl-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-5-carboxamide
pyrazole-5-carboxylic acid


169
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-methylpyridin-3-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
methylpyridin-3-yl)methyl]-1H-pyrazole-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
4-carboxylic acid


170
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-methylpyridin-3-
1-[(6-{5-Azaspiro[2.3]hexan-5-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
methylpyridin-3-yl)methyl]-1H-imidazole-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
4-carboxylic acid


171
1-[(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-methylpyrimidin-5-
1-[(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
methylpyrimidin-5-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


172
1-[(2-{5-Azaspiro[2.3]hexan-5-yl}-4-methylpyrimidin-5-
1-[(2-{5-Azaspiro[2.3]hexan-5-yl}-4-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
methylpyrimidin-5-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


173
7-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl]-2-methylpyridin-3-
7-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]-
methylpyridin-3-yl)methyl]-7H-pyrrolo-



imidazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
[2,3-d]pyrimidine-5-carboxylic acid


174
7-[(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-methylpyrimidin-5-
7-[(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]-
methylpyrimidin-5-yl)methyl]-7H-pyrrolo-



imidazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
[2,3-d]pyrimidine-5-carboxylic acid


175
7-[(2-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-4-
7-[(2-{6,6-Difluoro-3-azabicyclo[3.1.0]-



methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-
hexan-3-yl}-4-methylpyrimidin-5-yl)-



1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-7H-pyrrolo[2,3-
methyl]-7H-pyrrolo[2,3-d]pyrimidine-5-



d]pyrimidine-5-carboxamide
carboxylic acid


176
2-Chloro-1-[(6-{6,6-difluoro-3-azabicyclo-[3.1.0]hexan-3-
2-Chloro-1-[(6-{6,6-difluoro-3-aza-



yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
bicyclo[3.1.0]hexan-3-yl}pyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
methyl]-1H-imidazole-4-carboxylic acid


177
1-[(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-methylpyrimidin-
1-[(2-{3-Azabicyclo[3.1.0]hexan-3-yl}-4-



5-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
methylpyrimidin-5-yl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


178
1-[(2-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-4-
1-[(2-{6,6-Difluoro-3-azabicyclo[3.1.0]-



methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-
hexan-3-yl}-4-methylpyrimidin-5-yl)-



1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-1,2,3-
methyl]-1H-1,2,3-triazole-4-carboxylic



triazole-4-carboxamide
acid


179
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



(ethoxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1-methyl-
hexan-3-yl}-2-(ethoxymethyl)pyridin-3-



1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-
yl)methyl]-1H-pyrazole-4-carboxylic



carboxamide
acid


180
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-(methoxymethyl)-
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(methoxymethyl)pyridin-3-yl)methyl]-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
1H-imidazole-4-carboxylic acid


181
5-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-
5-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
methylpyridin-3-yl)methyl]furan-2-



cyclopenta[d]imidazol-4-yl]furan-2-carboxamide
carboxylic


182
5-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-
5-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
methylpyridin-3-yl)methyl]furan-3-



cyclopenta[d]imidazol-4-yl]furan-3-carboxamide
carboxylic acid


183
5-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-ethylpyridin-3-
5-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
ethylpyridin-3-yl)methyl]thiophene-2-



cyclopenta[d]imidazol-4-yl]thiophene-2-carboxamide
carboxylic acid


184
5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



ethylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexan-3-yl}-2-ethylpyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]thiophene-2-carboxamide
methyl]thiophene-2-carboxylic acid


185
5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
5-[(6-{6,6-Difluoro-3-azabicyclo-



(hydroxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1-methyl-
[3.1.0]hexan-3-yl}-2-(hydroxymethyl)-



1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]thiophene-2-
pyridin-3-yl)-methyl]thiophene-2-



carboxamide
carboxylic acid


186
5-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
5-[(6-{6,6-Difluoro-3-azabicyclo-



ethylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
[3.1.0]hexan-3-yl}-2-ethylpyridin-3-



cyclopenta[d]imidazol-4-yl]furan-2-carboxamide
yl)methyl]furan-2-carboxylic acid


187
5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexan-3-yl}-2-methylpyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]thiophene-2-carboxamide
methyl]thiophene-2-carboxylic acid


188
2-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
2-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexan-3-yl}-2-methylpyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]-1,3-thiazole-5-carboxamide
methyl]-1,3-thiazole-5-carboxylic acid


189
5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-



methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexan-3-yl}-2-methylpyridin-3-yl)-



cyclopenta[d]imidazol-4-yl]furan-2-carboxamide
methyl]furan-2-carboxylic acid


190
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-3-
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-3-



cyanophenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
cyanophenyl)methyl]-1H-pyrazole-4-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
carboxylic acid


191
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-3,5-
1-[(4-{3-Azabicyclo[3.1.0]hexan-3-yl}-



difluorophenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
3,5-difluorophenyl)methyl]-1H-pyrazole-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
4-carboxylic acid


192
2-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-
2-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-



difluorophenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
3,5-difluorophenyl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


193
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-



methylphenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
cyano-2-methylphenyl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


194
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-



methylphenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
cyano-2-methylphenyl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


195
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-5-
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-



fluorophenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
cyano-5-fluorophenyl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


196
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-



cyanophenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
cyanophenyl)methyl]-1H-imidazole-4-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
carboxylic acid


197
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3,5-
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-



dicyanophenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
3,5-dicyanophenyl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


198
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-



fluorophenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
cyano-2-fluorophenyl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


199
1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]-



methylphenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexan-3-yl}-2-methylphenyl)methyl]-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
1H-pyrazole-4-carboxylic acid


200
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-5-cyano-2-
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-5-



methylphenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
cyano-2-methylphenyl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


201
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-cyano-2-
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-3-



fluorophenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
cyano-2-fluorophenyl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


202
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



cyanophenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
chloro-3-cyanophenyl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid


203
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloro-3-
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



cyanophenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
chloro-3-cyanophenyl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


204
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



bromophenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
bromophenyl)methyl]-1H-imidazole-4-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
carboxylic acid


205
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



methylphenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
methylphenyl)methyl]-1H-imidazole-4-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
carboxylic acid


206
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



cyanophenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
cyanophenyl)methyl]-1H-imidazole-4-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
carboxylic acid


207
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-(hydroxymethyl)-
1-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-2-



phenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
(hydroxymethyl)phenyl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


208
1-[(2-cyano-4-{6,6-difluoro-3-azabicyclo-[3.1.0]hexan-3-
1-[(2-cyano-4-{6,6-difluoro-3-aza-



yl}phenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
bicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
1H-pyrazole-4-carboxylic acid


209
1-[(2-bromo-4-{6,6-difluoro-3-azabicyclo-[3.1.0]hexan-3-
1-[(2-bromo-4-{6,6-difluoro-3-aza-



yl}phenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
bicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
1H-pyrazole-4-carboxylic acid


210
1-[(2-cyano-4-{6,6-difluoro-3-azabicyclo-[3.1.0]hexan-3-
1-[(2-cyano-4-{6,6-difluoro-3-aza-



yl}phenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
bicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
1H-imidazole-4-carboxylic acid


211
1-[(2-chloro-4-{6,6-difluoro-3-azabicyclo-[3.1.0]hexan-3-
1-[(2-chloro-4-{6,6-difluoro-3-aza-



yl}phenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
bicyclo[3.1.0]hexan-3-yl}phenyl)methyl]-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
1H-imidazole-4-carboxylic acid


212
1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]-



fluorophenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexan-3-yl}-2-fluorophenyl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide
imidazole-4-carboxylic acid


213
1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-
1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]-



fluorophenyl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexan-3-yl}-2-fluorophenyl)methyl]-1H-



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
pyrazole-4-carboxylic acid









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



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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 for 12 h at rt 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 reversed phase (ACN, water) to give the title compound. LC (Method 1): tR=0.78 min; Mass spectrum (ESI+): m/z=435 [M+H]+.


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



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CH3MgBr (3 M in THF, 92 μL) is added dropwise under argon atmosphere to an ice-cooled 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). The mixture is stirred for 12 h while warming to rt. Then the mixture is partitioned between saturated aqueous NH4Cl and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic phases are dried (Na2SO4), concentrated in vacuo and the residue is purified by HPLC on reversed phase (ACN, water) to give the title compound.


LC (Method 1): tR=0.88 min; Mass spectrum (ESI+): m/z=485 [M+H]+.


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



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LiAlH4 (1 M in THF, 200 μL) is added dropwise under argon atmosphere to a −78° C. cold 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). The mixture is stirred for 12 h while warming to rt. To the mixture are successively added water (14 μL), aqueous NaOH (4 M, 14 μL) and again water (14 μL). After vigorous 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 reversed phase (ACN, water) to give the title compound. LC (Method 2): tR=0.66 min; Mass spectrum (ESI+): m/z=462 [M+H]+.


Example 217
1-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]-3-yl)hydroxymethyl)-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide



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LiAlH4 (1 M in THF, 200 μL) is added dropwise under argon atmosphere to an ice-cooled 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). The mixture is stirred for 30 minutes. To the mixture are successively added water (50 μL) and aqueous NaOH (4 M, 25 μL). After vigorous 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 reversed phase (ACN, water) to give the title compound. LC (Method 1): tR=0.89 min; Mass spectrum (ESI+): m/z=448 [M+H]+.


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



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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 h at 60° C. After cooling to rt the mixture is diluted with DMSO and purified by HPLC on reversed phase (ACN, water) to give the title compound.


LC (Method 1): tR=0.86 min; Mass spectrum (ESI+): m/z=454 [M+H]+.


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



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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) are dissolved in DCM (3 mL). Trifluoroacetic acid (1 mL) is added and the mixture is stirred for 12 h at rt. 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 for 12 h to 80° C. in a sealed microwave vial. After cooling to rt the mixture is concentrated in vacuo and the residue is purified by HPLC on reversed phase (ACN, water) to give the title compound.


LC (Method 1): tR=0.91 min; Mass spectrum (ESI+): m/z=448 [M+H]+.


Example 220 is prepared in analogy to Intermediate 219:



















Mass spectrum (ESI+):



Example
Structure
tR
m/z [M + H]+
LC Method







220


embedded image


0.87
434
Method 1





















Example
Name
Name of Starting Material







220
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-
3-[(6-{3-Azabicyclo[3.1.0]hexan-3-yl}-2-



(hydroxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1-
(hydroxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1-



methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-
methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-



yl]-1H-pyrazole-5-carboxamide
1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-




5-carboxamide and




5-[(6-{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]-




1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-




3-carboxamide (mixture of isomers)









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



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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 in a sealed microwave vial to 165° C. for 6 h. After cooling to rt the mixture is purified by HPLC on reversed phase (ACN, water) to give the title compound. LC (Method 2): tR=0.86 min; Mass spectrum (ESI+): m/z=470 [M+H]+.


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



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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 h. The mixture is purified by HPLC on reversed phase (ACN, water) to give the title compound. LC (Method 5): tR=0.56 min; Mass spectrum (ESI+): m/z=419 [M+H]+.


Examples 223 to 240 are prepared in analogy to example 222:



















Mass spectrum (ESI+):



Example
Structure
tR
m/z [M + H]+
LC Method



















223


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0.58
491
Method 5





224


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0.51
444
Method 5





225


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0.73
447
Method 5





226


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0.62
433
Method 5





227


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0.69
433
Method 5





228


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0.72
447
Method 5





229


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0.67
433
Method 5





230


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0.65
433
Method 5





231


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0.46
435
Method 5





232


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0.75
447
Method 5





233


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0.61
463
Method 5





234


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0.67
477
Method 5





235


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0.44
449
Method 5





236


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0.42
435
Method 5





237


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0.76
447
Method 5





238


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0.67
433
Method 5





239


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0.71
447
Method 5





240


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0.71
447
Method 5





















Example
Name
Name of Starting Material







223
1-[(2-{2-Hydroxy-2-methyl-7-azaspiro[3.5]nonan-7-yl}-4-
2-Methyl-7-azaspiro[3.5]nonan-2-ol



methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hydrochloride



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide



224
1-({2-[(1R,5S,6S)-6-Cyano-3-azabicyclo[3.1.0]Lhexan-3-yl]-4-
(1R,5S,6S)-3-Azabicyclo[3.1.0]



methylpyrimidin-5-yl}methyl)-N-[(4R)-1-methyl-1H,4H,5H,6H-
hexane-6-carbonitrile hydrochloride



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide



225
1-({2-[(1R,5S)-1,5-Dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-4-
(1R,5S)-1,5-Dimethyl-3-



methylpyrimidin-5-yl}methyl)-N-[(4R)-1-methyl-1H,4H,5H,6H-
azabicyclo[3.1.0]hexane



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
hydrochloride


226
1-[(2-{2-Azaspiro[3.3]heptan-2-yl}-4-methylpyrimidin-5-
Bis(2-azaspiro[3.3]heptane) oxalic



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
acid



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide



227
1-[(2-{3-Azabicyclo[4.1.0]heptan-3-yl]-4-methylpyrimidin-5-
3-Azabicyclo[4.1.0]heptane



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hydrochloride



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide



228
1-[(2-{6,6-Dimethyl-3-azabicyclo[3.1.0]hexan-3-yl}-4-
6,6-Dimethyl-3-



methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
azabicyclo[3.1.0]hexane



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide



229
N-[(4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1-
(1R,5S,6R)-6-Methyl-3-azabicyclo-



({4-methyl-2-[(1R,5S,6R)-6-methyl-3-azabicyclo[3.1.0]hexan-
[3.1.0]hexanehydrochloride



3-yl]pyrimidin-5-yl}methyl)-1H-pyrazole-4-carboxamide
(Obtained by separation of the




diastereomers of tert-butyl 6-methyl-




3-azabicyclo[3.1.0]hexane-3-




carboxylate by standard RP




chromatography and cleavage of the




protecting group with HCl in EtOAc)


230
1-[(2-{5-Azaspiro[2.4]heptan-5-yl}-4-methylpyrimidin-5-
5-Azaspiro[2.4]heptane hydrochloride



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-




cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide



231
N-[(4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1-
6-Oxa-3-azabicyclo[3.1.1]heptane; 4-



[(4-methyl-2-{6-oxa-3-azabicyclo[3.1.1]heptan-3-yl}pyrimidin-
methylbenzene-1-sulfonic acid



5-yl)methyl]-1H-pyrazole-4-carboxamide



232
1-[(2-{5-Azaspiro[2.5]octan-5-yl}-4-methylpyrimidin-5-
5-Azaspiro[2.5]octane



yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-




cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide



233
1-[(2-{6-Methoxy-3-azabicyclo[3.1.1]heptan-3-yl}-4-
6-Methoxy-3-azabicyclo



methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
[3.1.1]heptane hydrochloride



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide



234
1-({2-[(1R,5S,8R)-8-Methoxy-3-azabicyclo[3.2.1]octan-3-yl]-4-
(1R,5S,8S)-8-Methoxy-3-



methylpyrimidin-5-yl}methyl)-N-[(4R)-1-methyl-1H,4H,5H,6H-
azabicyclo[3.2.1]octane



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
hydrochloride


235
1-({2-[(1R,5S,6S)-6-(Hydroxymethyl)-3-azabicyclo[3.1.0]-
[(1R,5S,6S)-3-



hexan-3-yl]-4-methylpyrimidin-5-yl}methyl)-N-[(4R)-1-methyl-
Azabicyclo[3.1.0]hexan-6-yl]methanol



1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-




carboxamide



236
1-({2-[(1R,5S,6S)-6-Hydroxy-3-azabicyclo[3.1.0]hexan-3-yl]-4-
(1R,5S,6S)-3-



methylpyrimidin-5-yl}methyl)-N-[(4R)-1-methyl-1H,4H,5H,6H-
Azabicyclo[3.1.0]hexan-6-ol



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide
hydrochloride


237
1-[(2-{6-Azaspiro[2.5]octan-6-yl}-4-methylpyrimidin-5-yl)-
6-Azaspiro[2.5]octane hydrochloride



methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-




cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide



238
1-[(2-{3-Azabicyclo[3.2.0]heptan-3-yl}-4-methylpyrimidin-5-yl)-
3-Azabicyclo[3.2.0]heptane



methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-
hydrochloride



cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide



239
N-[(4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1-
Octahydrocyclopenta[c]pyrrole



[(4-methyl-2-{octahydrocyclopenta[c]pyrrol-2-yl}pyrimidin-5-




yl)methyl]-1H-pyrazole-4-carboxamide



240
1-[(2-{6-Azaspiro[3.4]octan-6-yl}-4-methylpyrimidin-5-yl)-
6-Azaspiro[3.4]octane



methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-




cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide








Claims
  • 1. A compound of formula (I)
  • 2. The compound according to claim 1, wherein Y is selected from the group consisting of
  • 3. The compound according to claim 1, wherein Y is selected from the group consisting of
  • 4. The compound according to claim 3, wherein R is selected from the group consisting of
  • 5. The compound according to claim 3, wherein R is selected from the group consisting of
  • 6. The compound according to claim 4, wherein R is selected from the group consisting of
  • 7. The compound according to claim 6, wherein R1 is selected from the group consisting ofH, 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;or a salt thereof.
  • 8. The compound according to claim 7, wherein R1 is selected from the group consisting ofH, F, Cl, Br, CH3, CH2CH3, CHF2, CN, CH2OH, and CH2OCH3;or a salt thereof.
  • 9. The compound according to claim 1, wherein R3 is selected from the group consisting ofCl, CN, CH3, CF3, CH2CH3, CH(CH3)2, CH2OH, CH2CH2OH, C(CH3)2OH, and CH2OCH3;or a salt thereof.
  • 10. The compound according to claim 8, wherein R3 is selected from the group consisting of Cl and CN;or a salt thereof.
  • 11. The compound according to claim 1, whereinY is
  • 12. The compound according to claim 1, wherein Y is
  • 13. The compound according to claim 1, wherein the stereochemistry of the compound is according to formula (I.1)
  • 14. A compound selected from:
  • 15. A compound of formula:
  • 16. A compound of formula:
  • 17. A compound of formula:
  • 18. A compound of formula:
  • 19. A compound of formula:
  • 20. A pharmaceutically acceptable salt of the compound according to claim 1.
  • 21. A pharmaceutically acceptable salt of the compound according to claim 15.
  • 22. A pharmaceutically acceptable salt of the compound according to claim 16.
  • 23. A pharmaceutically acceptable salt of the compound according to claim 17.
  • 24. A pharmaceutically acceptable salt of the compound according to claim 18.
  • 25. A pharmaceutically acceptable salt of the compound according to claim 19.
  • 26. A compound of formula:
  • 27. A compound of formula:
  • 28. A compound of formula:
  • 29. A compound of formula:
  • 30. A compound of formula:
Priority Claims (1)
Number Date Country Kind
20 157 259 Feb 2020 EP regional
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Related Publications (1)
Number Date Country
20210292301 A1 Sep 2021 US