TW202233592A - Heteroaromatic carboxamide derivatives as plasma kallikrein inhibitors - Google Patents

Abstract

Heteroaromatic carboxamides of formula (I), wherein Y, R, and Ar are as defined in the description and the claims, and pharmaceutically acceptable salts thereof can be used in methods for the treatment of diseases which can be influenced by the inhibition of plasma kallikrein.

Description

Heteroaromatic formamide derivatives as plasma kallikrein inhibitors

The present invention relates to novel heteroaromatic formamide derivatives and pharmaceutically acceptable salts thereof as plasma kallikrein inhibitors. Additionally, the present invention relates to intermediates for the synthesis of these compounds, to pharmaceutical compositions and combinations comprising these compounds and to their use in methods for the treatment of diseases that may be affected by inhibition of plasma kallikrein. Specifically, the pharmaceutical composition of the present invention is suitable for preventing and/or treating diabetic complications, ocular diseases and edema-related diseases, specifically diabetic macular edema, age-related macular degeneration, choroidal neovascularization, genetic Angioedema and cerebral edema after stroke.

Plasma kallikrein (PKK) is a trypsin-like serine protease secreted by hepatocytes in the liver as an inactive plasma kallikrein, either as a free zymogen in plasma or as bound to high molecular weight kinases. The heterodimeric complex of peptide pro-peptide circulates, and the high molecular weight kininogen is activated to generate active PKK which, in addition to processing other substrates, can also release kinin from kininogen. Kinins are powerful mediators of inflammation that act via G protein-coupled receptors such as the bradykinin receptor.

PKK is believed to play a role in, and may have many effects in, a variety of inflammatory disorders, such as hereditary angioedema (HAE), retinopathy or diabetic retinopathy, proliferative and non-proliferative retinas disease, diabetic macular edema (DME), clinically apparent macular edema (CSME), cystoid macular edema (CME), post-cataract extraction CME, cryotherapy-induced CME, uveitis-induced CME, endophthalmitis, CME following vascular occlusion (eg, central retinal vein occlusion, branch retinal vein occlusion, or semi-retinal vein occlusion), retinal edema, complications associated with cataract surgery in diabetic retinopathy, hypertensive retinopathy, Retinal trauma, dry and wet age-related macular degeneration (AMD), polypoid choroidal vasculopathy (PCV), choroidal neovascularization (CNV; e.g. non-exudative choroidal neovascularization), posterior vitreous detachment (PVD), e.g. Ischemia-reperfusion injury, surgery-induced brain injury, focal cerebral ischemia, global cerebral ischemia, glioma-related edema, spinal cord injury, pain, lack of Blood, cerebral ischemia, neurological and cognitive deficits, deep vein thrombosis, stroke (including post-stroke central nervous system edema), myocardial infarction, acquired angioedema, drug-related edema (including ACE-inhibitors) edema, inhibitors induced edema and tissue plasminogen activator (tPA)-induced angioedema), high altitude cerebral edema, cytotoxic cerebral edema, osmotic cerebral edema, obstructive hydrocephalus, radiation-induced edema, lymphedema, Traumatic brain injury, hemorrhagic stroke (eg, cerebral or subarachnoid stroke), intracerebral hemorrhage, hemorrhagic transformation of ischemic stroke, cerebral trauma associated with injury or surgery, cerebral aneurysm, arteriovenous malformation, in Reduction of blood loss during surgical procedures (eg, cardiothoracic surgery such as cardiopulmonary bypass or coronary artery bypass grafting), itching, conditions with an inflammatory component (such as multiple sclerosis), epilepsy, encephalitis, Alzheimer's Alzheimer's disease, excessive daytime sleepiness, essential hypertension, increased blood pressure associated with diabetes or hyperlipidemia, renal failure, chronic kidney disease, heart failure, microalbuminuria, albuminuria , proteinuria, disorders associated with increased vascular permeability (e.g. increased retinal vascular permeability, increased leg, foot, ankle vascular permeability), cerebral hemorrhage, blood clotting disorders such as thrombosis, deep vein thrombosis, Coagulation after fibrinolytic therapy, colic, angioedema, sepsis, arthritis (eg, rheumatoid arthritis, osteoarthritis, infectious arthritis), lupus, gout, psoriasis, inflammatory bowel disease (IBD) , such as ulcerative colitis (UC) and Crohn's disease (CD), diabetes, complications of diabetes, complications caused by metabolic syndrome, infectious diseases, astrocyte activation-related diseases such as Alzheimer's disease or multiple sclerosis), Parkinson's disease, amyotrophic lateral sclerosis, Creutzfeld-Jacob disease, stroke, epilepsy, and trauma (eg, brain trauma), such as Allergic edema with 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), coronary Viral disease 2019 (COVID-19) related pneumonia, fibrotic disease, liver fibrosis, nonalcoholic steatohepatitis (NASH), kidney damage and other diseases. PKK is also believed to play an important role in hypersensitivity reactions and thrombosis during hemodialysis.

PKK inhibitors, such as the compounds of the present invention, are considered useful in the treatment of a wide range of disorders, such as those mentioned above; in particular, they should have the effect of reducing the disease associated with diabetic retinopathy and diabetic macular edema or edema Efficacy of therapy related to retinal vascular permeability.

PKK inhibitors are particularly useful in the treatment of edema formation in diseases such as edema formation associated with ischemic reperfusion injury, retinopathy or edema-related diseases such as hereditary angioedema, macular edema and cerebral edema. PKK inhibitors are considered particularly useful in the treatment of retinopathy, such as those associated with diabetes and/or hypertension, and in the treatment of macular edema, such as those associated with diabetes and/or hypertension.

Other diabetic complications such as cerebral hemorrhage, nephropathy, cardiomyopathy, and neuropathy, all of which are associated with PKK, may also be targeted by PKK inhibitors.

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

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

， 其中 Y係選自由以下組成之群Y-G1：

， 其中之每一者經1或2個獨立取代基R ¹取代； R係選自由以下組成之群R-G1： 飽和6員至12員雙環系統，其含有作為環成員之1至2個N原子及選自由C=O、O、S、S=O及SO ₂組成之群之視情況選用之1個環成員， 其限制條件為該等環系統在環成員之間不含有任何雜原子-雜原子鍵， 其中該等環系統經由N原子與式(I)中之基團Y連接，且 其中該等環系統視情況經1至6個F取代且視情況經1至3個選自由C _{1 - 3}烷基、CN、HO-C _{1 - 3}伸烷基、OH及C _{1 - 3}烷基-O組成之群的取代基取代； Ar係選自由以下組成之群Ar-G1： 5員雜芳基，其含有1至4個N原子或含有1個O或S原子或含有1至2個N原子及1個O或S原子；及9員雜芳基，其由稠合至6員環之5員環組成且含有1至4個N原子， 其中該等雜芳基經由該5員環之C原子與式(I)中之羰基連接且經由該5員環之非鄰接C或N原子與式(I)中之CH ₂基團連接，且 其中該等雜芳基視情況經1個取代基R ³取代； R ¹係選自由以下組成之群R ¹-G1： H、鹵基、視情況經1至5個F取代之C _{1 - 4}烷基、視情況經1個CH ₃、CN或OH基團取代之C _{3 - 4}環烷基、CN、視情況經1至5個F取代之O-C _{1 - 3}烷基、視情況經選自由CN、OH及O-C _{1 - 3}烷基組成之群之1個取代基取代之C _{1 - 3}烷基； R ³係選自由以下組成之群R ³-G1： F、Cl、Br、CN、視情況經1至5個F取代之C _{1 - 4}烷基、C _{3 - 4}環烷基、HO-C _{1 - 4}伸烷基、C _{1 - 3}烷基-O-C _{1 - 3}伸烷基及視情況經1至5個F取代之O-C _{1 - 4}烷基； 其中，在上文提及之任何定義中且若未另外規定，任何烷基或伸烷基或亞基可為直鏈或分支鏈， 其同功異型物、互變異構體、立體異構體、代謝物、前驅藥、溶劑合物、水合物、共晶體及鹽，特定言之其醫藥學上可接受之共晶體及鹽，或其組合。 In a first aspect, the present invention relates to a compound of formula (I)

, where Y is selected from the group Y-G1 consisting of:

, each of which is substituted with ¹ or 2 independent substituents R1; R is selected from the group R-G1 consisting of: A saturated 6- to 12-membered bicyclic ring system containing 1 to 2 N as ring members Atom and optionally ₁ ring member selected from the group consisting of C=O, O, S, S=O and SO2, provided that such ring systems do not contain any heteroatoms between the ring members- Heteroatom bonds, wherein the ring systems are attached to the group Y in formula (I) via the N atom, and wherein the ring systems are optionally substituted with 1 to 6 F and optionally 1 to 3 are selected from C Substituent substitution of the group consisting _{of 1-3} alkyl, CN, HO _- C _1-3 alkylene, OH _and C _1-3 alkyl _- O _; Ar is selected from the group Ar-G1 consisting of: ₅ members Heteroaryl groups containing 1 to 4 N atoms or containing 1 O or S atom or containing 1 to 2 N atoms and 1 O or S atom; and 9-membered heteroaryl groups fused to 6-membered The 5-membered ring of the ring consists of and contains 1 to 4 N atoms, wherein the heteroaryl group is connected to the carbonyl group in formula (I) through a C atom of the 5-membered ring and through a non-adjacent C or N of the 5-membered ring Atom is attached to the CH ₂ group in formula (I), and wherein the heteroaryl groups are optionally substituted with 1 substituent R ³ ; R ¹ is selected from the group R ¹ -G1 consisting of: H, halo , C 1-4 alkyl substituted with 1 to 5 F as appropriate _{, C 3 - 4 cycloalkyl substituted} with ₁ CH ₃ , CN or OH group as appropriate, CN, optionally substituted with ₁ to 5 F _- substituted OC _1-3 alkyl, optionally C _1-3 alkyl substituted with ₁ substituent selected from the group consisting _of CN, OH _and OC _1-3 alkyl ^{; R 3} _{is selected} from the group consisting of Group ^R3 _- G1: F, Cl, Br, CN, _C1-4 alkyl optionally substituted with _{1 to 5 F} , _{C3-4cycloalkyl} , HO _{- C1-4alkylene} , C _1-3 alkyl _- OC _1-3 alkylene _and optionally OC _1-4 alkyl substituted with _{1 to 5} F _; wherein, in any of the definitions mentioned above and if not specified otherwise, any alkane The group or alkylene group or subunit can be straight chain or branched chain, its isoforms, tautomers, stereoisomers, metabolites, prodrugs, solvates, hydrates, co-crystals and salts, In particular, pharmaceutically acceptable co-crystals and salts thereof, or combinations thereof.

In a second aspect, the invention relates to compounds comprising one or more compounds of formula (I) and/or tautomers or pharmaceutically acceptable salts thereof, as the case may be and one or more as defined above or below Pharmaceutical compositions with various inert carriers and/or diluents.

In a third aspect, the present invention relates to compounds comprising one or more compounds of formula (I) and/or tautomers or pharmaceutically acceptable salts thereof as defined above or below and one or more additional treatments A pharmaceutical composition with one or more inert carriers and/or diluents, as appropriate.

In a fourth aspect, the present invention relates to a compound of formula (I) as defined above or below and/or a tautomer 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, ie, therapy and/or prevention, in a patient in need thereof, of a disease or condition that may be affected by inhibition of plasma kallikrein, the method comprising administering to the patient as above One or more compounds of formula (I) and/or tautomers or pharmaceutically acceptable salts thereof as defined herein or below.

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

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

或其鹽 其為式(I)化合物合成中之有價值中間物。 In a sixth aspect, the present invention relates to one or more compounds selected from the group consisting of:

or its salts, which are valuable intermediates in the synthesis of compounds of formula (I).

Other aspects of the invention will become apparent to those skilled in the art directly from the foregoing and following descriptions and examples. General terms and definitions

Terms not specifically defined herein should be given the meaning that one of ordinary skill in the art would assign to them in light of the invention and context. However, as used in this specification, unless stated to the contrary, the following terms have the meanings indicated and the following conventions will be followed.

The terms "compound(s) according to this invention/compound(s) of the invention", "compounds of formula (I)" and the like refer to compounds of formula (I) of the present invention, including their Tautomers, stereoisomers and mixtures thereof and their salts (in detail their pharmaceutically acceptable salts) and solvates, hydrates and co-crystals of these compounds (in their pharmacy Acceptable co-crystals include solvates, hydrates and co-crystals of such tautomers, stereoisomers and salts thereof).

Furthermore, unless specifically indicated otherwise, throughout this specification and the scope of the appended claims, a given formula or name shall encompass tautomers and all stereoisomers, optical isomers and geometric isomers (such as for Enantiomers, diastereomers, E/Z isomers, etc.) and their racemates, as well as mixtures of individual enantiomers in different proportions, mixtures of diastereomers, or the presence therein Mixtures of any of the foregoing forms of such isomers and enantiomers, as well as salts thereof (including pharmaceutically acceptable salts thereof) and solvates (such as hydrates, including solvates of the free compounds) compound or a solvate of a salt of the compound) and co-crystals thereof (including pharmaceutically acceptable co-crystals thereof and co-crystals of free compounds or salts thereof).

The phrase "pharmaceutically acceptable" is used herein to refer to compounds, substances, compositions and/or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with human and animal tissues without undue toxicity , irritation, allergic reactions, or other problems or complications, and are 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 preparing an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

For example, such salts include salts formed from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, cis-butyric acid Oleic 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 containing a basic or acidic moiety by conventional chemical methods. In general, the salts can be prepared by reacting the free acid or free base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent such as ether, EtOAc , EtOH, isopropanol or MeCN or mixtures thereof.

For example, salts of acids other than those described above (eg, trifluoroacetic acid salts) useful in purifying or isolating the compounds of the present invention also comprise a part of the present invention.

As used herein, "pharmaceutically acceptable co-crystals" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making co-crystals thereof by means of one or more configurational isomers. In addition, co-crystals of solvates and/or salts of the disclosed compounds are encompassed.

For example, configurational isomers include hydrogen bond donors such as carboxylic acids and hydrogen bond acceptors such as amines and amides.

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

Where the compounds of the present invention are depicted in the form of chemical names and chemical formulas, if there is any inconsistency, the chemical formulas shall prevail.

In a group, radical or moiety as defined below, the number of carbon atoms is generally indicated before the group, eg C1-6 alkyl means an alkyl group having _{1 to 6} carbon atoms.

An asterisk may be used in a subformula to indicate a bond to the core molecule as defined. In the case of more than one point of attachment in a subformula, ie more than one asterisk, the asterisk may be further specified by the parenthesized designation of the linking portion of the core molecule.

Substituent atoms are counted from the atom closest to the core or group to which the substituent is attached.

其中羧基連接至丙基之第三個碳原子。術語「1-甲基丙基-」、「2,2-二甲基丙基-」或「環丙基甲基-」基團表示以下基團：

。 For example, the term "3-carboxypropyl-group" refers to the following substituents:

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

.

The term "substituted" as used herein means that any one or more hydrogens on the specified atom, group or moiety are replaced with a selection from the specified group, provided that the normal valence of the atom is not exceeded and the substitution Yields acceptable stable compounds.

In the definition of groups, the term "wherein each X, Y and Z group is optionally substituted" and the like means: each group X, each group Y, and each group Z each as an independent A group or each as part of a constituent group may be substituted as defined. For example _, the definition " _R ^ex represents H _, C _1-3 alkyl _, C _3-6 cycloalkyl _, C _{3-6 cycloalkyl -} C _1-3 alkyl or C _{1-3 alkyl - O-} , wherein each alkyl group is optionally substituted with one or more ^Lex ." or the like means in each of the foregoing groups that include the term alkyl ₍ ie, _in groups _C1-3 in each _of alkyl _{, C3-6cycloalkyl - C1-3alkyl} , _{and C1-3alkyl -} O- ₎ , the alkyl moiety may be substituted with ^Lex as defined.

The term " _{Ci - n} alkyl" wherein n is an integer from 1 to n, alone or in combination with another group, denotes an acyclic saturated branched or straight chain hydrocarbon group having 1 to n C atoms. For example, the term _C1-5 alkyl encompasses the groups H3C-, H3C _- CH2-, H3C _{- CH2 -} CH2-, _{H3C - CH} ( _{CH3 ) -} , H ₃ C-CH ₂ -CH ₂ -CH ₂ -, H ₃ C-CH ₂ -CH(CH ₃ )-, H ₃ C-CH(CH ₃ )-CH ₂ -, H ₃ CC(CH ₃ ) ₂ - , H ₃ C-CH ₂ -CH ₂ -CH ₂ -CH ₂ -, H ₃ C-CH ₂ -CH ₂ -CH(CH ₃ )-, H ₃ C-CH ₂ -CH(CH ₃ )-CH ₂ -, H3C-CH( _CH3 ) _-CH2 -CH2-, H3C _{- CH2 -} C( _CH3 ) _2- , _H3CC ( _{CH3 ) 2 -} CH2-, _H3C -CH( _CH3 )-CH( _CH3 )- and H3C- _CH2 - _CH ( _{CH2CH3 )} -.

The term "Ci _{- nalkylene} " wherein _n is an integer selected from 2, 3, 4, 5 or 6, preferably 4 or 6, alone or in combination with another group, indicates that there are 1 to n carbon atoms Acyclic straight-chain or branched-chain divalent alkyl groups. For example, the term C1-4alkylene includes _-CH2- , _{-CH2 -} CH2-, -CH( _CH3 ) _- , _{-CH2 - CH2 -} CH2-, -C( _{CH3 )} ) ₂ -, -CH( _CH2CH3 )-, -CH( _CH3 ) _-CH2- , _-CH2 - _CH ( _{CH3 )} -, _-CH2 - _CH2 - _CH2 -CH2-, -CH ₂ -CH ₂ -CH(CH ₃ )-, -CH(CH ₃ )-CH ₂ -CH ₂ -, -CH ₂ -CH(CH ₃ )-CH ₂ -, -CH ₂ -C(CH ₃ ) ₂ -, -C(CH ₃ ) ₂ -CH ₂ -, -CH(CH ₃ )-CH(CH ₃ )-, -CH ₂ -CH(CH ₂ CH ₃ )-, -CH(CH ₂ CH ₃ )-CH ₂ -, -CH(CH ₂ CH ₂ CH ₃ )-, -CH(CH(CH ₃ )) ₂ - and -C(CH ₃ )(CH ₂ CH ₃ )-.

The term "C3-ncycloalkyl" wherein n is an integer from _{3 to n} , alone or in combination with another group, denotes a cyclic saturated unbranched hydrocarbon group having 3 to n C atoms. Cyclic groups can be mono-, bi-, tri- or spirocyclic, preferably monocyclic. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1.]octyl , spiro[4.5]decyl, norpinyl, norbornyl, norcarbenyl, adamantyl, etc.

The term "heteroaryl" means a monocyclic or polycyclic aromatic ring system containing one or more heteroatoms selected from N, O or S(O) _r , wherein r=0, 1 or 2, such monocyclic Or polycyclic aromatic ring systems are composed of 5 to 14 ring atoms, wherein at least one of the heteroatoms is part of the aromatic ring. The term "heteroaryl" is intended to include all possible isomeric forms.

。 Thus, the term "heteroaryl" includes the following exemplary structures; each form is not depicted as a group as it is optionally attached to any atom via a covalent bond, so long as the appropriate valences are maintained:

.

The term "bicyclic ring system" means a group consisting of 2 joined cyclic substructures including spiro, fused and bridged ring systems.

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

Many of the terms given above can be used repeatedly to define formulae or groups, and in each case independently of one another have one of the meanings given above.

The term "treatment/treating" as used herein encompasses both therapeutic (ie curative and/or palliative) treatment and prophylactic (ie prophylactic) treatment.

Therapeutic treatment refers to the treatment of a patient already suffering from one or more of these conditions in a distinctly acute or chronic form. Therapeutic treatment can be symptomatic treatment to relieve the symptoms of a particular indication, or causal treatment to reverse or partially reverse the condition of the indication or to arrest or slow disease progression.

Prophylactic treatment ("prophylaxis") refers to the treatment of patients at risk of developing one or more of these symptoms before the clinical onset of the disease in order to reduce that risk.

The term "treatment/treating" includes administration of one or more active compounds in order to prevent or delay the onset of symptoms or complications, and to prevent or delay the development of a disease, symptom or disorder, and/or to eliminate or control a disease, symptom or condition. Disorders, and alleviation of symptoms or complications associated with diseases, symptoms or disorders.

When the present invention refers to a patient in need of treatment, it primarily refers to treatment in mammals, especially humans.

The term "therapeutically effective amount" means (i) treatment or prevention of a particular disease or condition, (ii) alleviation, amelioration or elimination of one or more symptoms of a particular disease or condition, or (iii) prevention or delay as described herein The amount of a compound of the present invention at the onset of one or more symptoms of a particular disease or condition.

The present invention discloses novel heteroaromatic formamide derivatives that are potent plasma kallikrein (PKK) inhibitors and possess suitable pharmacological and pharmacokinetic properties for their use in the treatment of diseases that may be affected by PKK inhibition and/or conditions including, but not limited to, diabetic complications, ocular diseases and edema-related diseases, specifically diabetic macular edema, age-related macular degeneration, choroidal neovascularization, Hereditary angioedema and cerebral 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 profile and potential for stable salt formation. Compounds of the present invention

， 其中Y、R及X如上文及下文所定義，且該等式(I)化合物展現關於選擇性、安全性及耐受性、代謝及/或化學穩定性、藥物動力學及物理化學特徵、溶解度、滲透性、血漿蛋白結合、生物可用性及/或穩定鹽形成可能性之有利特性。特定言之，其提供對人類PKK及顯著選擇性之高效能之有利組合，例如對比多種絲胺酸蛋白酶，諸如人類組織激肽釋放酶1(TK1)，以及在生理學相關pH值下之適當溶解度及高代謝穩定性。此外，展現諸如低致突變性潛在性及低基於機制之細胞色素P450 3A4抑制傾向、低如CYP3A4及CYP2C8之細胞色素P450 (CYP)酶之抑制及低基於機制之CYP3A4之抑制的傾向之有利安全特點。 In a first aspect of the present invention, compounds of formula (I) were found to be potent PKK inhibitors,

, wherein Y, R and X are as defined above and below, and the compounds of formula (I) exhibit characteristics with respect to selectivity, safety and tolerability, metabolic and/or chemical stability, pharmacokinetics and physicochemical properties, Favorable properties of solubility, permeability, plasma protein binding, bioavailability and/or potential for stable salt formation. In particular, it provides an advantageous combination of high potency and remarkable selectivity for human PKK, eg, compared to various serine proteases, such as human tissue kallikrein 1 (TK1), and appropriate at physiologically relevant pH values. Solubility and high metabolic stability. In addition, exhibits favorable safety profiles such as low mutagenic potential and low propensity for mechanism-based inhibition of cytochrome P450 3A4, low inhibition of cytochrome P450 (CYP) enzymes such as CYP3A4 and CYP2C8, and low propensity for mechanism-based inhibition of CYP3A4 Features.

Accordingly, a compound of formula (I) as defined above or below, or a pharmaceutically acceptable salt thereof, is expected to be useful in the treatment of diseases and/or conditions that may be affected by PKK inhibition.

， 其中Y、R及X如上文或下文所定義， 以及其同功異型物、互變異構體、立體異構體、代謝物、前驅藥、溶劑合物、水合物、共晶體及鹽，特定言之其醫藥學上可接受之共晶體及鹽。 Therefore, according to one aspect of the present invention, there is provided a compound of formula (I)

, wherein Y, R and X are as defined above or below, and their isoforms, tautomers, stereoisomers, metabolites, prodrugs, solvates, hydrates, co-crystals and salts, specific In other words, its pharmaceutically acceptable co-crystals and salts.

Unless otherwise specified, groups, residues and substituents, in particular Y, R, Ar, ^R1 and ^R3 , are as defined above and below. Some preferred meanings of the substituents Y, R, Ar, R1 and ^R3 and the stereochemistry ^of the compounds of formula (I) are given below as examples of the present invention. Any and each of these definitions and embodiments may be combined with each other. Y :

， 其中之每一者經1或2個獨立取代基R ¹取代。 According to one embodiment, Y is selected from the group Y-G1 consisting of:

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

， 其中之每一者經1或2個獨立取代基R ¹取代，且 其中具有星號之鍵指示式(I)之R與CH ₂基團之連接位點。 According to another embodiment, Y is selected from the group Y-G2 consisting of:

, each of which is substituted with 1 or 2 independent substituents R ¹ , and wherein the bond with an asterisk indicates the site of attachment of R of formula (I) to the CH ₂ group.

， 其中之每一者經1或2個取代基R ¹取代，且 其中具有星號及圓括號之鍵指示式(I)之R與CH ₂基團之連接位點。 According to another embodiment, Y is selected from the group Y-G3 consisting of:

, each of which is substituted with 1 or 2 substituents R ¹ , and wherein the bond with an asterisk and parentheses indicates the site of attachment of R of formula (I) to the CH ₂ group.

， 其中之每一者經1個取代基R ¹取代，且 其中具有星號及圓括號之鍵指示式(I)之R與CH ₂基團之連接位點。 According to another embodiment, Y is selected from the group Y-G4 consisting of:

, each of which is substituted with 1 substituent R ¹ , and the bond with an asterisk and parentheses therein indicates the site of attachment of R of formula (I) to the CH ₂ group.

， 其中之每一者視情況經1個額外取代基R ¹取代，且 其中具有星號及圓括號之鍵指示式(I)之R與CH ₂基團之連接位點。 According to another embodiment, Y is selected from the group Y-G5 consisting of:

, each of which is optionally substituted with 1 additional substituent R ¹ , and wherein the bond with an asterisk and parentheses indicates the site of attachment of R of formula (I) to the CH ₂ group.

， 其視情況經一個額外取代基R ¹取代，及 其中具有星號及圓括號之鍵指示式(I)之R與CH ₂基團之連接位點。 According to another embodiment, Y is selected from the group Y-G6 consisting of:

, which is optionally substituted with one additional substituent R ¹ , and where the bond with an asterisk and parentheses indicates the point of attachment of R of formula (I) to the CH ₂ group.

， 其中具有星號及圓括號之鍵指示式(I)之R與CH ₂基團之連接位點。 R ： According to another embodiment, Y is selected from the group Y-G7 consisting of:

, wherein the bond with an asterisk and parentheses indicates the site of attachment of R of formula (I) to the CH ₂ group. R :

According to one embodiment, R is selected from the group R-G1 consisting of: a saturated 6- to 12-membered bicyclic ring system containing 1 to 2 N atoms as ring members and selected from C=O, O, S, S ₁ optional ring member of the group consisting of =O and SO2, with the limitation that these ring systems do not contain any heteroatom-heteroatom bonds between the ring members, wherein these ring systems are connected to each other through the N atom. The group Y in formula (I) is attached and wherein the ring systems are optionally substituted with 1 to 6 F and optionally with 1 to ₃ selected from C _{1 -3} alkyl, CN, HO-C _{1 -} Substituents of the group consisting of ₃ alkylene, OH and C _{1 - 3} alkyl-O.

According to another embodiment, R is selected from the group R-G2 consisting of: a saturated 6- to 10-membered bicyclic ring system containing 1 N atom and optionally 1 O atom as ring members, wherein the The ring system is attached to the group Y in formula (I) via the N atom, and wherein the ring system is optionally ₁ selected from F _{, C1-3} alkyl (preferably _CH3 ), CN, HO- Substituents of the group consisting of C _1-3 alkylene (preferably HOCH ₂ ), OH _and C _1-3 alkyl _- O- _{(preferably CH 3 O )} , and wherein the ring system is optionally additional 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-nitrogen Azaspiro[2.5]octane, 5-azaspiro[2.5]octane, 7-azaspiro[3.5]nonane, 3-azaspiro[4.1.0]heptane, 3-azaspiro[3.1 .1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane and 3-azabicyclo[3.2.1]octane, each of which is related to formula (I) via an N atom The groups Y in are connected, and each of which is optionally via a substituent selected from the group consisting _of F, _CH3 , CN, CH2OH, OH and _OCH3 , preferably F and _CH3 substituted, 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:

.

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

.

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

.

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

.

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

. Ar :

According to one embodiment, Ar is selected from the group Ar-G1 consisting of: 5-membered heteroaryl containing 1 to 4 N atoms or 1 O or S atom or 1 to 2 N atoms and 1 O or S atom; and a 9-membered heteroaryl group consisting of a 5-membered ring fused to a 6-membered ring and containing 1 to 4 N atoms, wherein the heteroaryl group is connected to the formula via the C atom of the 5-membered ring The carbonyl group in (I) is attached to the _CH2 group in formula (I) via a non-adjacent C or N atom of the 5-membered ring, and wherein the heteroaryl groups are optionally substituted with 1 substituent ^R3 .

According to another embodiment, Ar is selected from the group Ar-G2 consisting of: 5-membered heteroaryl containing 1 to 3 N atoms or 1 O or S atom or 1 N atom and 1 O or an S atom; and a 9-membered heteroaryl group consisting of a 5-membered ring fused to a 6-membered ring and containing 1 to 3 N atoms, wherein the heteroaryl groups are linked to the formula ( The carbonyl group in I) is attached to the _CH2 group in formula (I) via a non-adjacent C or N atom of the 5-membered ring, and wherein the heteroaryl groups are optionally substituted with 1 substituent ^R3 .

及其互變異構體， 其中之每一者視情況經1個取代基R ³取代，且 其中具有星號及圓括號之鍵指示式(I)之基團C=O與CH ₂之連接位點。 According to another embodiment, Ar is selected from the group Ar-G3 consisting of:

and tautomers thereof, each of which is optionally substituted with 1 substituent ^R3 , and wherein the bond with an asterisk and parentheses indicates the site of attachment of the group C=O and _CH2 of formula (I) .

， 其中之每一者視情況經1個取代基R ³取代，且 其中具有星號及圓括號之鍵指示式(I)之基團C=O與CH ₂之連接位點。 According to another embodiment, Ar is selected from the group Ar-G4 consisting of:

, each of which is optionally substituted with 1 substituent R ³ , and wherein the bond with an asterisk and parentheses indicates the site of attachment of the group C=O and CH ₂ of formula (I).

， 其視情況經1個取代基R ³取代，且 其中具有星號及圓括號之鍵指示式(I)之基團C=O與CH ₂之連接位點。 According to another embodiment, Ar is selected from the group Ar-G5 consisting of:

, which is optionally substituted with 1 substituent R ³ and wherein the bond with an asterisk and parentheses indicates the site of attachment of the group C=O and CH ₂ of formula (I).

， 其視情況經1個取代基R ³取代，且 其中具有星號及圓括號之鍵指示式(I)之基團C=O與CH ₂之連接位點。 According to another embodiment, Ar is selected from the group Ar-G6 consisting of:

, which is optionally substituted with 1 substituent R ³ and wherein the bond with an asterisk and parentheses indicates the site of attachment of the group C=O and CH ₂ of formula (I).

及其互變異構體， 其中之每一者視情況經1個取代基R ³取代，且 其中具有星號及圓括號之鍵指示式(I)之基團C=O與CH ₂之連接位點。 According to another embodiment, Ar is selected from the group Ar-G7 consisting of:

and tautomers thereof, each of which is optionally substituted with 1 substituent ^R3 , and wherein the bond with an asterisk and parentheses indicates the site of attachment of the group C=O and _CH2 of formula (I) .

， 其視情況經1個取代基R ³取代，且 其中具有星號及圓括號之鍵指示式(I)之基團C=O與CH ₂之連接位點。 According to another embodiment, Ar is selected from the group Ar-G8 consisting of:

, which is optionally substituted with 1 substituent R ³ and wherein the bond with an asterisk and parentheses indicates the site of attachment of the group C=O and CH ₂ of formula (I).

， 其中之每一者視情況經1個取代基R ³取代，且 其中具有星號及圓括號之鍵指示式(I)之基團C=O與CH ₂之連接位點。 According to another embodiment, Ar is selected from the group Ar-G9 consisting of:

, each of which is optionally substituted with 1 substituent R ³ , and wherein the bond with an asterisk and parentheses indicates the site of attachment of the group C=O and CH ₂ of formula (I).

， 其中之每一者視情況經1個取代基R ³取代，且 其中具有星號及圓括號之鍵指示式(I)之基團C=O與CH ₂之連接位點。 According to another embodiment, Ar is selected from the group Ar-G10 consisting of:

, each of which is optionally substituted with 1 substituent R ³ , and wherein the bond with an asterisk and parentheses indicates the site of attachment of the group C=O and CH ₂ of formula (I).

， 其視情況經1個取代基R ³取代，且 其中具有星號及圓括號之鍵指示式(I)之基團C=O與CH ₂之連接位點。 R ¹ ： According to another embodiment, Ar is selected from the group Ar-G11 consisting of:

, which is optionally substituted with 1 substituent R ³ and wherein the bond with an asterisk and parentheses indicates the site of attachment of the group C=O and CH ₂ of formula (I). ^R1 :

According to one embodiment, R ¹ is selected from the group R ¹ -G1 consisting of: H, halo, C _{1 -4} alkyl optionally substituted with 1 _to 5 F, optionally 1 CH ₃ , CN or OH group substituted C _{3 -4} cycloalkyl _, CN, optionally OC _{1 -3} alkyl substituted with 1 to 5 F, optionally selected from the group consisting _of CN, OH and OC _{1 - 3} alkyl C _{1-3 alkyl} substituted with one substituent _of the group.

According to another embodiment, R ¹ is selected from the group R ¹ -G2 consisting of: H, F, Cl, Br, optionally via 1 to 5 F or via ₁ CN, OH or OC _{1 -2} alkyl Substituted _C1-2 alkyl, _C3-4 alkyl optionally substituted with ₁ CN or OH group _{, C3-4 cycloalkyl} optionally substituted with _{1 CH3 , CN} or OH group , OC _{1 - 2} alkyl substituted with 1 to 5 F as appropriate.

According to another embodiment, R ¹ is selected from the group R ¹ -G3 consisting of H, F, Cl, Br, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH ₂ CH(CH ₃ ) ₂ , cyclopropyl, cyclobutyl, CHF ₂ , CF ₃ , CN, 1-cyanocyclopropan-1-yl, CH ₂ CN, C(CH ₃ ) ₂ CN, CH ₂ OH, CH ₂ CH ₂ OH , CH(OH)CH ₃ , CH ₂ CH ₂ CH ₂ OH, CH(CH ₃ )CH ₂ OH, C(OH)(CH ₃ ) ₂ , CH ₂ OCH ₃ , CH ₂ OCH ₂ CH ₃ , O-CH _3. O-CH ₂ CH ₃ and O-CF ₃ .

According to another embodiment, R ¹ is selected from the group R ¹ -G4 consisting of H, F, Cl, Br, CH ₃ , CH ₂ CH ₃ , CHF ₂ , CN, CH ₂ OH and CH ₂ OCH ₃ .

According to another embodiment, R ¹ is selected from the group consisting of H, R ¹ -G5.

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

According to another embodiment, R ¹ is selected from the group R ¹ -G7 consisting of CH ₃ .

According to another embodiment, R ¹ is selected from the group R ¹ -G8 consisting of CH ₂ CH ₃ .

According to another embodiment, R ¹ is selected from the group R ¹ -G9 consisting of CH ₂ CH ₂ CH ₃ , CH ₂ CH(CH ₃ ) ₂ , cyclopropyl and cyclobutyl.

According to another embodiment, R ¹ is selected from the group R ¹ -G10 consisting of CHF ₂ and CF ₃ .

According to another embodiment, R ¹ is selected from the group R ¹ -G11 consisting of CN.

According to another embodiment, R ¹ is selected from the group R ¹ -G12 consisting of 1-cyanocyclopropan-1-yl, CH ₂ CN and C(CH ₃ ) ₂ CN.

According to another embodiment, R ¹ is selected from the group R ¹ -G13 consisting of CH ₂ OH.

According to another embodiment, R ¹ is selected from the group R ¹ -G14 consisting of CH ₂ CH ₂ OH, CH(OH)CH ₃ , CH ₂ CH ₂ CH ₂ OH, CH(CH ₃ )CH ₂ OH, and C(OH)( _CH3 ) ₂ .

According to another embodiment, R ¹ is selected from the group R ¹ -G15 consisting of CH ₂ OCH ₃ , CH ₂ OCH ₂ CH ₃ , O-CH ₃ , O-CH ₂ CH ₃ and O-CF ₃ . ^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 cycloalkane group, HO _- Ci _{- 4alkylene} , C1-3alkyl _{- OC1-3 -} alkylene _and optionally _{OC1-4 -} alkyl substituted with _{1 to 5} Fs.

According to another embodiment, R ³ is selected from the group R ³ -G2 consisting of: F, Cl, Br, CN, C _{1 -3} alkyl optionally substituted with 1 to 3 F, HO _- C _{1 - 4 -} alkylene, _{C1-2alkyl - OC1-2alkylene ,} and optionally _OC1-2alkyl substituted with _{1 to 3} Fs.

According to another embodiment, R ³ is selected from the group R ³ -G3 consisting of Cl, CN, CH ₃ , CF ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH ₂ OH, CH ₂ CH ₂ OH, 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, R ³ is selected from the group R ³ -G5 consisting of CH ₃ , CF ₃ , CH ₂ CH ₃ and CH(CH ₃ ) ₂ .

According to another embodiment, R ³ is selected from the group R ³ -G6 consisting of CH ₂ OH, CH ₂ CH ₂ OH and C(CH ₃ ) ₂ OH.

According to another embodiment, R ³ is selected from the group R ³ -G7 consisting of CH ₂ OCH ₃ . Stereochemistry :

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

.

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

.

More preferred subgeneric examples of compounds of formula (I) are illustrated in Table 1 below as examples (Ia) to (Ir), wherein the definitions of substituents mentioned above are used. For example, the term ^-G1 in row R1 and column (Ia) means that in embodiment (Ia), the substituent R1 is selected from the specified definitions R1 ^{- G1} . The same applies similarly to other variables incorporated into the formula. Table 1 : Example Substituent Y R Ar R ^{1 R3} (Ia) Y-G1 R-G1 Ar-G1 R1 ^- G1 ^R3 -G1 (Ib) Y-G2 R-G2 Ar-G1 R1 ^- G1 ^R3 -G2 (Ic) Y-G2 R-G2 Ar-G2 R1 ^- G2 ^R3 -G2 (Id) Y-G2 R-G3 Ar-G2 R1 ^- G3 ^R3 -G2 (Ie) Y-G2 R-G4 Ar-G3 R1 ^- G3 ^R3 -G3 (If) Y-G6 R-G5 Ar-G5 R1 ^- G4 ^R3 -G5 (Ig) Y-G6 R-G5 Ar-G6 R1 ^- G4 ^R3 -G5 (Ih) Y-G6 R-G5 Ar-G8 R1 ^- G4 ^R3 -G5 (ii) Y-G6 R-G6 Ar-G5 R1 ^- G4 ^R3 -G5 (Ij) Y-G6 R-G6 Ar-G6 R1 ^- G4 ^R3 -G5 (Ik) Y-G6 R-G6 Ar-G8 R1 ^- G4 ^R3 -G5 (Im) Y-G7 R-G5 Ar-G5 R1 ^- G4 ^R3 -G5 (In) Y-G7 R-G5 Ar-G6 R1 ^- G4 ^R3 -G5 (Io) Y-G7 R-G5 Ar-G8 R1 ^- G4 ^R3 -G5 (Ip) Y-G7 R-G6 Ar-G5 R1 ^- G4 ^R3 -G5 (Iq) Y-G7 R-G6 Ar-G6 R1 ^- G4 ^R3 -G5 (Ir) Y-G7 R-G6 Ar-G8 R1 ^- G4 ^R3 -G5

Especially preferred are those subgeneric embodiments (I.1-a) to (I.1-r), which correspond to the subgroups of Table ¹ with respect to the definitions of Y, R, Ar, R1 and ^R3 Examples (Ia) to (Ir), but wherein the stereochemistry of the compound 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, their salts, or any solvates, hydrates or co-crystals thereof) are those described in the Examples and Experimental Information section. preparation

The compounds according to the invention and their intermediates can be synthesized using methods known to those skilled in the art and described in the organic synthesis literature, for example using those described in "Comprehensive Organic Transformations", 2nd Edition, Richard C. Larock, John Wiley & Sons, 2010 and the method in "March's Advanced Organic Chemistry", 7th edition, Michael B. Smith, John Wiley & Sons, 2013. Preferably, the compounds are obtained analogously to the preparation methods explained more fully below, especially as described in the experimental section. In some cases, the order in which the reaction schemes are carried out may vary. Variations of these reactions known to those skilled in the art but not described in detail herein may also be used. General procedures for the preparation of compounds according to the present invention will be apparent to those skilled in the art upon studying the following schemes. The starting compounds are commercially available or can be prepared by methods described in the literature or herein, or can be prepared in an analogous or analogous manner. Before carrying out the reaction, any corresponding functional groups in the starting compounds can be protected using conventional protecting groups. In addition, methods familiar to those skilled in the art and described in the literature, such as "Protecting Groups", 3rd edition, Philip J. Kocienski, Theime, 2005 and "Protective Groups in Organic Synthesis", 4th edition, Peter G. M. The method of Wuts, Theadora W. Greene, John Wiley and Sons, 2006, such protecting groups can be cleaved at an appropriate stage in the reaction sequence.

Process 1 :

-六氟磷酸鹽(HATU)、O-(苯并三唑-1-基)-N,N,N',N'-四甲

四氟硼酸鹽(TBTU)、(苯并三唑-1-基氧基)三吡咯啶鏻六氟磷酸鹽(PyBOP)、碳化二亞胺試劑等)及鹼(例如三乙胺、N,N-二異丙基-乙胺、吡啶等)之情況下，在適合溶劑(例如DCM、THF、1,4-二㗁烷、DMF、N,N-二甲基乙醯胺及1-甲基-2-吡咯啶酮)中，使式(II)合適酸(呈游離酸或具有諸如Li ⁺、Na ⁺、K ⁺等之合適金屬陽離子之羧酸鹽形式)與式(III)合適胺(呈游離胺或諸如鹽酸鹽、氫溴酸鹽等之鹽形式)反應以形成醯胺鍵；流程1中之Y、R及Ar具有如上文所定義之含義。可替代地，將羧酸轉化成羧酸氯(使用例如於DCM中之草醯氯或亞硫醯氯)，且因此在存在合適鹼(例如三乙胺、N,N-二異丙基-乙胺、吡啶等)之情況下與胺(III)偶合。 Scheme 1: Compounds of formula (I') can be prepared by: in the presence of a suitable coupling agent (eg O-(7-azabenzotriazol-1-yl)-N,N,N',N'- Sijia

- Hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl

Tetrafluoroborate (TBTU), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), carbodiimide reagents, etc.) and bases (such as triethylamine, N,N - in the case of diisopropyl-ethylamine, pyridine, etc.) in a suitable solvent such as DCM, THF, 1,4-diethane, DMF, N,N-dimethylacetamide and 1-methyl -2-pyrrolidone), a suitable acid of formula (II) (either as a free acid or as a carboxylate with a suitable metal cation such as Li ⁺ , Na ⁺ , K ⁺ etc.) is combined with a suitable amine of formula (III) ( in the form of the free amine or salts such as hydrochloride, hydrobromide, etc.) to form an amide bond; Y, R and Ar in Scheme 1 have the meanings as defined above. Alternatively, the carboxylic acid is converted to the carboxylic acid chloride (using eg oxalic chloride or thionium chloride in DCM), and thus in the presence of a suitable base (eg triethylamine, N,N-diisopropyl- In the case of ethylamine, pyridine, etc.), it is coupled with amine (III).

R ⁵= C _{1 - 4}烷基或苯甲基 Process 2 :

R ⁵ ₌ C _{1-4 alkyl} or benzyl

Scheme 2: Depending ^on the nature of R5, acids of formula (II) wherein Y, R and Ar have the meanings as defined above are preferably prepared from the corresponding ester (IV) via hydrolysis or hydrogenolysis. Preferably by using a solution such as NaOH, LiOH or KOH at ambient or elevated temperature in a mixture of water and a suitable miscible solvent such as THF, MeOH, EtOH, 1,4-dioxane or mixtures of these. Hydrolysis of hydroxide salts is carried out to cleave lower alkyl esters such as ethyl or methyl esters. The acid can be isolated as a salt with a metal cation or as a free acid. Tris are preferably cleaved by treatment with an acid such as hydrochloric acid or TFA in a suitable solvent such as DCM, 1,4-dioxane, MeOH, EtOH, THF, water or mixtures of these. grade butyl ester. The benzyl ester is preferably cleaved by hydrogenolysis under a hydrogen atmosphere (preferably 1 to 5 bar) with a suitable catalyst (eg palladium on carbon) in a suitable solvent (eg EtOH, MeOH, THF, DCM or EtOAC) .

T ¹及T ²彼此獨立地為N、C-H或C-R ³；或 T ¹及T ²一起形成成環苯并、吡啶或嘧啶環，其視情況經R ³單取代； T ³=CH或N； R ⁵= C _{1 - 4}烷基或苯甲基。 Process 3

T ¹ and T ² are independently of each other N, CH or CR ³ ; or T ¹ and T ² together form a cyclic benzo, pyridine or pyrimidine ring, which is optionally monosubstituted by R ³ ; T ³ =CH or N; R ⁵ ₌ C _1-4 alkyl or benzyl _.

Scheme 3: Some of compounds (II') can be prepared by using Mitsunobu reaction conditions (eg, with diazodicarboxylate in a solvent such as THF, 1,4-dioxane, toluene, etc.) Ethyl ester (DEAD), diisopropyl azodicarboxylate (DIAD) or di-tertiary butyl azodicarboxylate (DBAD) combined with triphenylphosphine or tri-n-butylphosphine) to make alcohol (V ) reacts with ester (VI); Y, R and R3 in Scheme ³ have the meanings as defined above. The alcohol (V) may carry the desired residue R on the heteroaromatic ring Y or alternatively leave the group for subsequent introduction of R. Alternatively, some of the compounds (II') can be obtained by Lewis acid or Brunsted acid ( Brønsted acid) (eg 4-toluenesulfonic acid) to react alcohol (V) with ester (VI).

T ¹及T ²彼此獨立地為N、C-H或C-R ³；或 T ¹及T ²一起形成成環苯并、吡啶或嘧啶環，其視情況經R ³單取代； T ³=CH或N； R ⁵= C _{1 - 4}烷基或苯甲基； Hal=脫離基，諸如Cl、Br、I、OSO ₂CH ₃。 Process 4

T ¹ and T ² are independently of each other N, CH or CR ³ ; or T ¹ and T ² together form a cyclic benzo, pyridine or pyrimidine ring, which is optionally monosubstituted by R ³ ; T ³ =CH or N; R ⁵ ₌ C _1-4 alkyl or benzyl _; Hal = leaving group, such as Cl, Br, I, OSO ₂ CH ₃ .

Scheme 4: Some of compounds (II') can also be prepared by: a suitable base (eg sodium hydride, cesium carbonate, potassium carbonate or triethylamine) in a suitable solvent (eg THF, DMF) Compound (VII) carrying a leaving group such as Cl, Br or mesyloxy/methanesulfonyloxy at the heteroarylmethyl position is reacted with ester (VI); Y, R in Scheme 4 and ^R3 has the meaning as defined above. Compound (VII) may carry the desired residue R on the heteroaromatic ring Y or alternatively leave the group for subsequent introduction of R.

R ⁵= C _{1 - 4}烷基或苯甲基； Hal=脫離基，諸如OH、Cl、Br、I、OSO ₂CH ₃ Process 5

R ⁵ ₌ C _1-4 alkyl or benzyl _; Hal = leaving group such as OH, Cl, Br, I, OSO ₂ CH ₃

Scheme 5: Some esters of formula (II'') wherein Y and R have the meanings defined above can be prepared by treating the corresponding alkyl halide with sodium azide in DMF or another suitable solvent (bromide or chloride) or sulfonates of formula (VII) (eg mesylate) to give intermediates of formula (VIII), which are subsequently reacted with appropriate propiolates (eg , mesylate) under copper mediated catalytic conditions Ethyl propiolate or tertiary butyl propioate is reacted with catalytic copper sulfate and sodium ascorbate in water/tertiary butanol) to give compound (II"). Alternatively, azide (VIII) can be converted from formula (V) (V) by treatment with diphenylphosphoryl azide in the presence of a suitable base such as DBU in a suitable solvent such as THF or DMF. or (VII), wherein Hal is an OH) alcohol obtained. Compound (VII) may carry the desired residue R on the heteroaromatic ring Y or alternatively leave the group for subsequent introduction of R.

對於化合物(X)、(XI)、(XII)及(II''')：T ¹及T ³係獨立地選自CH、C-R ³及N，且T ²係選自N-R ³、O及S； 對於化合物(X')：T ²及T ³係獨立地選自CH、C-R ³及N，且T ¹係選自N-R ³、O及S； 對於化合物(X'')：T ¹及T ²係獨立地選自CH、C-R ³及N，且T ³係選自N-R ³、O及S； R5=C _{1 - 4}烷基或苯甲基；Hal=Cl、Br、I Process 6

For compounds (X), (XI), (XII) and (II'''): T ¹ and T ³ are independently selected from CH, CR ³ and N, and T ² is selected from NR ³ , O and S ; For compound (X'): T ² and T ³ are independently selected from CH, CR ³ and N, and T ¹ is selected from NR ³ , O and S; For compound (X''): T ¹ and T ² is independently selected from CH, CR ³ and N, and T ³ is selected from NR ³ , O and S; R5 ₌ C _1-4 alkyl or benzyl _; Hal=Cl, Br, I

Scheme 6: Esters of formula (II''') wherein Y, R and ^R have the meanings defined above can be obtained by employing methods reported in the literature (palladium// in a solvent such as THF or EtOH). In the case of carbon, such as triethylsilane and TFA or boron trifluoride etherate or hydrogen in DCM, prepared from alcohol (XII) by replacing the hydroxyl group with hydrogen. The alcohol (XII) can be prepared by adding a magnesium halide (XI) or another organometallic derivative to the aldehyde (IX), which can then be prepared by adding a Diethyl ether) is obtained from its corresponding alcohol by oxidation (eg Dess-Martin oxidation or Swern oxidation). Magnesium halide (XI) can be obtained from the corresponding (X) bromide or iodide using isopropylmagnesium chloride optionally combined with lithium chloride in THF at low temperature after the halogen metal exchange reaction. Alternatively, intercalation of magnesium metal into carbon-halogen bonds yields magnesium halides (XI). Compounds (IX) and (XII) can carry the desired residue R on the heteroaromatic ring Y or alternatively leave the group for subsequent introduction of R.

Starting with compounds (X') and (X''), the corresponding analogs of compound (II''') can be obtained using the principles described above (see Scheme 7 for (X')).

Process 7

T ² and T ³ are independently selected from CH, CR ³ and N, and T ¹ is selected from NR ³ , O and S;

R5=C _{1 - 4} alkyl or benzyl; Hal=Cl, Br, I

Scheme 7 : Compounds of formula (II'''') wherein Y, R and ^R3 have the meanings defined above can be prepared using isomeric magnesium halides (XI') in a similar manner to the compounds depicted in Scheme 6 .

LG=脫離基，諸如F、Cl、Br、I；A ¹、A ²、A ³、A ⁴獨立地=N或C-R ¹R6=COOR ⁵、CHO、CH ₂OH、CH ₂-Ar-COOR ⁵；R ⁵=C _{1 - 4}-烷基或苯甲基 Process 8

LG=leaving group such as F, Cl, Br, I; A ¹ , A ² , A ³ , A ⁴ independently =N or CR ¹ R6=COOR ⁵ , CHO, CH ₂ OH, CH ₂ -Ar-COOR ⁵ ; R ⁵ =C _{1 - 4} -alkyl or benzyl

Scheme 8 : Intermediates of formula (XV) can be prepared from aromatic compounds (XIII) and amines (XIV) via nucleophilic substitution reactions on heteroaromatic rings or transition metal catalyzed coupling reactions; Ar, R and R ¹ has the meaning as defined above. Nucleophilic substitution of the leaving group on the heteroaromatic ring in (XIII) using the N in compound (XIV) can be carried out at ambient or elevated temperature in the presence of a suitable solvent such as THF, 1,4-dioxane, DMF, DMSO) in the presence of a suitable base such as sodium hydride, cesium carbonate, potassium carbonate, N,N-diisopropyl-ethylamine. The transition metal catalyzed coupling reaction is preferably carried out in a procedure similar to that reported in the organic chemistry literature known as the Ullmann or Bahafar/Hartwig coupling reaction, It is carried out in the presence of a base and in a suitable solvent using suitable copper or palladium salts or complexes thereof, optionally combined with additional ligands.

Process 9

Scheme 9 : Enantiopure amine (III.1) can be prepared as depicted in Scheme 9 from ketone (XVI). The overall synthesis consists of 3 steps and is carried out at ambient or elevated temperature in a suitable solvent such as THF, DCM, toluene or neat, such as a titanium alkoxide (eg, Ti(OEt) ₄ or Ti( ^OiPr ) ₄ ) starting with the condensation of the ketone with the enantiopure tertiary butanesulfinamide to yield the corresponding enantiopure tertiary butanesulfinylated amine (XVII). Amines (XVII) can be used in hydrides such as lithium or sodium borohydride, lithium tertiary butyl borohydride, dibutyl borohydride in suitable solvents such as THF, toluene, MeOH, etc. isobutylaluminum hydride, etc.) are diastereoselectively reduced to the corresponding tertiary butylsulfinylated amines (XVIII). The tertiary butylsulfinyl group can be cleaved off with an acid (eg, TFA or hydrochloric acid) in a suitable solvent (eg, toluene, DCM, diethane, alcohol, water, etc.) at ambient or elevated temperature.

Racemate (III) and opposite enantiomer (III.2) were obtained by employing racemic tertiary butanesulfinamide and enantiomerically pure (S)-tertiary butane, respectively, in the above route Alkyl sulfinamide to obtain.

Alternatively, compound (III.1) and its enantiomer (III.2) can be obtained from ketone (XVI) via a 3-step synthetic sequence using organic chemistry literature (eg, 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; . 2014, 55, 3635-40; and the references cited therein) under conditions reported to enable enantioselectivity of the ketone moiety in compound (XVI) to begin to yield correspondingly enantiopure or enantioenriched alcohols. Subsequently, a stereospecific Mitsunobu or Mitsunobu-type reaction can be employed using, for example, dimethyl azodicarboxylate, DEAD, DIAD, bis(4-chlorobenzyl) azodicarboxylate, diphenyl azodicarboxylate, DBAD, azodicarboxylate bis(dimethylamide), azodicarboxylate acid dipiperidine or dimorpholine azodicarboxylate combined with triphenylphosphine or tri-n-butylphosphine), the hydroxyl group thus formed is combined with, for example, phthalimide or (tertiary Bu-OCO) ₂ A protected or masked amino substitution of N causes configuration inversion at the C heteroatom bearing. Alternatively, a phosphonium azide (eg, diphenylphosphoryl azide) can be used to replace the OH group with an azide under configuration inversion. This can be achieved by using, for example, hydrazine, hydroxylamine, methyl alcohol in a suitable solvent such as EtOH, MeOH, MeCN, THF, diethane, DMSO, N,N-dimethylacetamide, water, or mixtures of these. Treatment with amine, n-butylamine or ethanolamine to liberate the amine group from the phthalimide group, and heating if necessary, affords compound (III.1). Tertiary Bu-O-CO is preferably removed under acidic conditions (using eg TFA or hydrochloric acid) to give the same amine (III.1). _The azide can be reduced to the amine (III. 1). Racemate (III) is obtained after reduction of compound (XVI) with an achiral reducing agent such as sodium borohydride and after another route described above.

Process 10

Scheme 10 : Compound (XVI) may consist of 3 or 4 reaction steps in sequence consisting of ester (XIX) (or corresponding lower or higher alkyl ester such as methyl, n-propyl, isopropyl or tris grade butyl ester) was obtained. Compound (XIX) can be employed at ambient or elevated temperature with a suitable electrophilic bromine source (eg, N-bromobutanedi) in a suitable solvent (eg, AcOH, DCM, dichloroethane, diethane, MeCN, DMF, etc.). imide (NBS) or Br ₂ ) bromination. For example, NBS in acetic acid at ambient temperature or NBS in HCCl ₃ at 65°C provides compounds. Alternatively, treatment of compound (XIX) with NBS, sodium persulfate and palladium acetate in trifluoromethanesulfonic acid and 1,2-dichloroethane at 80°C also affords (XX). Compound (XX) can then be converted to ester (XXI) using a 1-step or 2-step synthetic route encompassing compounds with acrolein dialkyl acetals (eg acrolein diethanol acetal, for example, acrolein diethanol acetal, -> (XXI)) or Heck coupling reaction of acrylates (e.g. ethyl acrylate, -> (XXIII)) (covered generally in e.g. Catalysts 2017, 7, 267 and references cited therein organic chemistry literature); the use of the latter coupling partner requires an additional step to reduce the olefinic bond formed, which can be obtained in the presence of a suitable solvent (e.g. DCM, dioxane, THF, EtOAc, alcohols such as MeOH, water etc.) using hydrogen in the case of transition metal catalysts (eg, Pd such as palladium/carbon, Ni such as Reynolds-Ni, Pt such as platinum oxide, Rh such as rhodium/carbon, etc.). Can be used in a suitable solvent (depending on the base used, such as benzene, toluene, diethane, THF, alcohol, etc.) at low temperature to high temperature (depending on the base and solvent used, -78°C to 100°C) bases (for example, hydrides such as sodium hydride, alcoholates such as lithium methoxide or potassium tertiary butoxide, organic amines such as DBU, phosphazenes such as _P2Et phosphazenes, lithium diisopropylamide, ketoester (XXII) after treatment of compound (XXI) with lithium hexamethyldisilazide, sodium hexamethyldisilazide or potassium hexamethyldisilazide amide, etc.; in THF at 20°C Among them, potassium hexamethyldisilazide is one of the better conditions for this conversion. The ester group in compound (XXII) can be hydrolyzed, followed by decarboxylation, by optionally in the presence of a base (such as sodium hydroxide), a halide salt (such as lithium iodide or lithium chloride) or an acid ( The compound is stirred in a solvent such as diethane, THF, ACN, DMF, N,N-dimethylacetamide, DMSO, alcohol, water, etc., or a mixture of these, in the case of hydrochloric acid, for example, to This is achieved by obtaining ketone (XVI).

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

Cis/trans mixtures can be resolved, eg by chromatography, into their cis and trans isomers. Compounds of formula (I) in racemic form can be separated into their optical antipodes by methods known per se, and by exploiting their different physicochemical properties using, for example, chromatography and/or fractional crystallization Diastereoisomeric mixtures of compounds of general formula (I) are decomposed into their diastereoisomers by methods known per se; if the compound obtained thereafter is a racemate, it can be decomposed as follows the mentioned enantiomers.

Preferably by column chromatography on the opposite chiral phase, or by crystallization from photoactive solvents, or by formation of salts or derivatives such as esters or amides with photoactive substances with racemic compounds ) reaction to resolve the racemate. Basic compounds can form salts with enantiomerically pure acids, and acidic compounds can form salts with enantiomerically pure bases. Diastereomeric derivatives are formed from enantiomerically pure auxiliary compounds (eg, acids, activated derivatives thereof, or alcohols). Separation of diastereomeric mixtures of salts or derivatives thus obtained can be achieved by exploiting their different physicochemical properties, such as differences in solubility; from pure diastereoisomers by the action of suitable reagents Sex salts or derivatives release the free enantiomer. Optically active acids commonly used for this purpose and optically active alcohols suitable as auxiliary residues are known to those skilled in the art.

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

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

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

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

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

。 藥理學活性 According to another embodiment, the present invention relates to one or more of the following intermediates:

. pharmacological activity

The activity of the compounds of the present invention can be demonstrated using the following assays: Biological Methods

Compounds of formula (I) inhibit plasma kallikrein (PKK), factor XIIa (FXIIa), factor XIa (FXIa), factor Xa (FXa), factor IIa (α-thrombin; FIIa), plasmin, pancreatic The capacity of protease, tissue kallikrein 1 (TK1), factor VIIa (FVIIa) or FVIIa complexed with tissue factor, phospholipids and CaCl ₂ (FVIIa/TF/PL/CaCl ₂ ) was determined in the presence of 1% (v/ v) The following biochemical assays were used in the presence of DMSO in assay buffer (100 mM Tris, 150 mM NaCl, adjusted to pH 7.8 with HCl, and containing 0.1% (w/v) BSA and 0.05% (v/v) Tween20 ): Assessment of PKK Inhibition Using Endpoint Analysis

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

The _IC50 values of the compounds according to the invention are shown in the table below. The values of the compounds correspond to the values of the examples in the experimental section. example _IC50 (nM) example _IC50 (nM) Example _IC50 (nM) example _IC50 (nM) 1 1.3 61 3.1 121 1.6 181 10.9 2 3.1 62 14.0 122 1.5 182 7.1 3 1.7 63 3.0 123 0.9 183 19.4 4 0.9 64 0.7 124 2.4 184 13.5 5 1.1 65 1.4 125 1.1 185 10.9 6 0.9 66 0.7 126 0.6 186 10.9 7 1.4 67 3.1 127 1.2 187 12.2 8 2.3 68 1.4 128 5.1 188 19.8 9 3.8 69 0.9 129 23.7 189 22.1 10 2.5 70 0.8 130 20.0 190 1.5 11 2.1 71 151 131 4.3 191 169 12 3.4 72 3.3 132 1.9 192 1890 13 1.1 73 9.6 133 1.6 193 0.4 14 1.0 74 6.9 134 1.7 194 0.3 15 1.1 75 0.5 135 4.2 195 20.3 16 0.6 76 0.6 136 2.0 196 1.5 17 2.0 77 3.3 137 4.4 197 13.4 18 2.1 78 6.8 138 2.2 198 0.8 19 14.2 79 5.5 139 9.6 199 3.1 20 0.7 80 4.7 140 5.8 200 8.6 twenty one 0.9 81 1.3 141 2.0 201 0.6 twenty two 0.5 82 0.8 142 5.8 202 0.5 twenty three 1.1 83 1.7 143 0.6 203 0.7 twenty four 1.0 84 0.7 144 0.8 204 1.5 25 2.0 85 0.8 145 0.7 205 8.3 26 4.9 86 1.2 146 1.1 206 0.4 27 0.9 87 3.3 147 1.4 207 3.2 28 0.6 88 0.9 148 1.4 208 0.6 29 2.6 89 77.5 149 1.6 209 1.5 30 0.9 90 0.7 150 1.0 210 0.4 31 5.3 91 2.1 151 3.6 211 0.8 32 1.1 92 2.8 152 1.2 212 2.1 33 2.5 93 1.4 153 0.5 213 2.3 34 0.9 94 10.8 154 9.9 214 20.3 35 2.2 95 5.5 155 15.4 215 0.7 36 0.5 96 1.5 156 0.8 216 1.2 37 0.9 97 1.4 157 1.2 217 0.9 38 3.4 98 1.5 158 4.6 218 3.5 39 0.7 99 3.7 159 3.5 219 3.6 40 1.2 100 5.6 160 2.2 220 1.9 41 3.4 101 0.6 161 1.5 221 2.8 42 0.6 102 2.1 162 1.1 222 11.6 43 0.9 103 0.7 163 2.2 223 7540 44 1.8 104 3.2 164 1.8 224 302 45 0.7 105 0.5 165 0.8 225 232 46 1.0 106 9.8 166 1.0 226 35.7 47 0.8 107 1.0 167 1.3 227 45.3 48 2.8 108 1.7 168 1.5 228 126 49 2.5 109 0.8 169 0.6 229 110 50 1.7 110 0.9 170 0.8 230 53.7 51 1.0 111 8.6 171 2.6 231 223 52 1.1 112 12.6 172 8.1 232 512 53 2.0 113 9.9 173 0.6 233 81.4 54 0.7 114 1.8 174 1.9 234 350 55 2.3 115 4.1 175 2.9 235 214 56 1.8 116 0.4 176 4.2 236 222 57 0.6 117 2.2 177 5.5 237 111 58 2.5 118 0.3 178 5.0 238 123 59 0.4 119 1.2 179 4.2 239 123 60 18.8 120 2.4 180 2.6 240 52 Assessment of PKK inhibition in kaolin activated human PPP

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

The _IC90 values of the compounds according to the invention are shown in the table below. The values of the compounds correspond to the values of the examples in the experimental section. example _IC90 (nM) example _IC90 (nM) example _IC90 (nM) example _IC90 (nM) 1 290 53 203 108 465 164 443 2 253 54 109 109 414 165 342 3 210 55 250 110 784 166 193 4 184 56 586 111 4150 167 272 5 278 57 166 112 2780 168 1860 6 1880 62 769 114 14700 169 485 7 151 63 203 115 2660 170 469 8 352 64 221 116 278 171 268 9 603 65 1230 117 1540 181 22300 10 789 66 839 118 157 182 6270 11 300 67 635 119 1460 184 2310 12 802 68 637 120 934 185 2270 13 451 69 328 121 514 186 236 14 636 70 797 122 492 187 2450 15 414 71 9310 123 1320 188 1500 16 280 72 831 124 823 190 1080 17 818 73 498 125 2740 193 253 18 460 74 321 126 681 194 183 20 99 75 192 127 1680 196 350 twenty one 325 76 270 128 1390 198 398 twenty two 249 77 197 131 962 199 808 twenty three 233 78 317 132 425 201 130 twenty four 181 79 249 133 560 202 157 25 286 80 495 134 1030 203 202 26 343 81 117 135 909 204 818 27 202 82 117 136 310 206 138 28 184 83 594 137 756 207 745 29 336 84 209 139 774 208 80 30 334 85 132 140 760 173 729 31 973 86 597 141 621 174 1430 32 548 87 177 142 731 175 822 33 265 88 139 143 1170 177 1180 34 1190 89 3430 144 248 178 844 35 259 90 126 145 245 179 389 36 180 91 439 146 274 180 207 37 125 92 307 147 149 209 432 39 380 93 110 148 985 210 128 40 543 94 1760 149 511 211 590 41 488 95 577 150 373 212 1890 42 195 96 134 151 1140 213 621 43 308 97 766 152 430 214 1040 44 444 98 282 153 280 215 194 45 151 99 2170 154 4270 216 >10000 46 162 101 297 155 4100 217 624 47 173 102 1440 158 2100 218 646 48 612 103 531 159 1140 219 776 49 254 104 706 160 967 220 525 50 110 105 117 161 431 51 213 106 1970 162 231 52 155 107 324 163 470 Assessment of PKK inhibition (K _i )

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

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

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

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

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

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

Human trypsin (4.54 nM or 250 U/mL; Calbiochem) was incubated at 24°C with 0.5 mM chromogenic substrate S2222 (Chromogenix) in assay buffer and various concentrations of test compounds. Measurements were performed every 2 minutes for 16 minutes at kinetic intervals using a Spectramax M5 (Molecular Devices) that measures absorbance at 405 nm. Assessment of TK1 inhibition (K _i )

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

The K _i values of the compounds according to the invention are shown in the table below. The values of the compounds correspond to the values of the examples in the experimental section. Example Ki (nM) Example Ki (nM) Example Ki (nM) Example Ki (nM) 4 >10000 90 >10000 124 >10000 175 >10000 16 >10000 107 >10000 125 >10000 177 >10000 20 >10000 108 >10000 126 >10000 178 >10000 twenty two >10000 110 >10000 127 >10000 181 >10000 twenty three >10000 113 >10000 128 >10000 190 >10000 twenty four >10000 114 >10000 131 >10000 193 >10000 27 >10000 115 >10000 133 >10000 194 >10000 36 >10000 116 871 134 >10000 196 >10000 47 >10000 117 >10000 135 >10000 198 >10000 49 >10000 118 >10000 136 >10000 217 >10000 51 >10000 119 1060 137 >10000 218 >10000 52 >10000 120 >10000 169 >10000 222 7280 75 >10000 121 >10000 170 >10000 80 >10000 122 >10000 171 >10000 86 >10000 123 >10000 173 >10000 Assessment of FVIIa Inhibition (K _i )

Human FVIIa (0.86 nM or 0.01 U/mL; Enzyme Research Laboratories) was incubated with 1.5 mM chromogenic Pefachrome® FVIIa (Loxo) in assay buffer and various concentrations of test compounds at 24°C. Measurements were performed every 2 minutes for 16 minutes at kinetic intervals using a Spectramax M5 (Molecular Devices) that measures absorbance at 405 nm. Assessment of FVIIa/TF/PL/CaCl ₂ inhibition (K _i )

Human FVIIa (300 nM or 585 U/mL; Enzyme Research Laboratories) with ₁₀ mM _CaCl2 *2H2O and 13.3% (v/v) Dade® Innovin® (Siemens; OQUMI94E0002(5534) containing recombinant human Tissue factor synthetic phospholipids (thrombin)) were incubated with 1.5 mM chromogenic Pefachrome® FVIIa (Loxo) in assay buffer and various concentrations of test compounds at 24°C. Measurements were performed every 2 minutes for 16 minutes at kinetic intervals using a Spectramax M5 (Molecular Devices) that measures absorbance at 405 nm. Calculation of pIC ₅₀ and pK _i values

其中IC ₅₀以莫耳為單位且K _M值以mM為單位。 表A：針對用於酶分析中之底物獲得之K _M值 酶 底物 K _M(mM) PKK I1295 0.16 FXIIa S2302 0.20 FXIa I1575 0.29 FXa S2765 1.31 FIIa S2238 1.25 纖維蛋白溶酶 S2251 1.45 胰蛋白酶 S2222 2.03 TK1 I1295 0.07 FVIIa Pefachrome ^®FVIIa 0.42 FVIIa/TF/PL/CaCl ₂ Pefachrome ^®FVIIa 3.92 滲透性之評估 Mean _Vmax for the time interval from 2 to 12 minutes after the start of the analysis (expressed as delta OD/min for assays using chromogenic substrates or as delta OD/min for assays using fluorogenic substrates, respectively delta RFU/min) is plotted against the logarithm of the molar concentration of the evaluated inhibitor compound. _pIC50 values were then fitted using a four parameter fitting program using GraphPad Prism (version 6; GraphPad Software, Inc.). Individual _Ki values were obtained by correcting the _IC50 values for the individual _KM values for the substrates used (see Table A for the obtained _KM values for the substrates used) using the following formula:

where _IC50 is in molar and _KM value is in mM. Table A: K _M values obtained for substrates used in enzyme assays enzyme substrate K _M (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/CaCl ₂ ^Pefachrome® FVIIa 3.92 Penetration assessment

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

Compounds are dissolved in a suitable solvent (eg DMSO, 1 to 20 mM stock solution). with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO ₄ , 1.8 mM CaCl ₂ , 4.17 mM NaHCO ₃ , 1.19 mM Na ₂ HPO ₄ × 7H ₂ O, 0.41 mM NaH ₂ PO ₄ × H ₂ O, 15 mM HEPES, 20 mM glucose, pH 7.2) diluted stock solutions containing 0.25% BSA to prepare delivery solutions (0.1 to 300 μM compound, final DMSO <= 0.5%). Transport solution (TL) was applied to the apical or basolateral donor side for measurement of AB or BA permeability, respectively (filtration repeated 2 times). The receiver side contained HTP-4 buffer supplemented with 0.25% BSA. Samples were collected from the donor and also from the receiver side at the beginning and end of the experiment and at various time intervals (up to 2 hours) for concentration measurement by HPLC-MS/MS or scintillation counting. Replace the sampled receiver volume with fresh receiver solution. Assessment of Metabolic Stability in Human or Mouse Liver Microsomes

Test compounds were assayed for metabolic degradation against pooled human (HLM) or mouse liver microsomes (RLM) at 37°C. A final incubation volume of 60 µl for each time point contained TRIS buffer pH 7.6 (0.1 M), magnesium chloride (5 mM), microsomal proteins (HLM: 1 mg/mL, RLM: 0.5 mg/mL) at RT and final Test compound at a concentration of 1 µM.

After a brief pre-incubation period at 37°C, the reaction was initiated by addition of β-nicotinamide adenine dinucleotide phosphate (NADPH, 1 mM) in reduced form, and by isolating the An aliquot was transferred to the solvent to stop the reaction. Additionally, NADPH-independent degradation was monitored during incubation without NADPH, terminated at the last time point. The quenched incubations were pooled by centrifugation (10000 g, 5 min). Aliquots of the supernatant were analyzed for the amount of parent compound by LC-MS/MS. Half-life (t1/2 in vitro) was determined by the slope of the semi-logarithmic plot of the concentration-time profile. Assessment of metabolic stability in human or mouse hepatocytes

Test compounds were assayed for metabolic degradation in hepatocyte suspensions. After recovery from cryopreservation, human or rat hepatocytes were prepared in Dulbecco's modified Eagle supplemented with 3.5 µg glucagon/500 ml, 2.5 mg insulin/500 ml, and 3.75 mg/500 ml hydrocortisone Culture medium (Dulbecco's modified eagle medium) containing 5% or 50% human or rat serum or no serum.

After 30 minutes of pre-incubation in a cell incubator (37°C, 10% CO ₂ ), the test compound solution was spiked into the hepatocyte suspension to obtain a final cell density of 1.0 x 106 cells/ml, a final cell density of 1 µM Test compound concentrations and a final DMSO concentration of 0.05%.

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

CL _int is calculated as follows: CL _int = dose/AUC = (C0/CD) / (AUD + clast/k) x 1000/60 C0: initial concentration in incubation [μM], CD: cell density of viable cells [10e6cells/ ml], AUD: data area [μM×h], clast: concentration of last data point [μM], k: slope of regression line for maternal decline [h ^{− 1} ].

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

This Equilibrium Dialysis (ED) technique is used to determine the approximate in vitro fractional binding of test compounds to plasma proteins applied to Dianorm Teflon dialyzed cells (0.2 microns). Each dialyzed cell consists of donor and acceptor compartments separated by an ultrathin semipermeable membrane with a 5 kDa molecular weight cutoff. Stock solutions for each test compound were prepared at 1 mM in DMSO and serially diluted to obtain a final test concentration of 1 μM. Subsequent dialysis solutions were prepared in plasma (supplemented with NaEDTA as anticoagulant) and 200 μl aliquots of test compound dialysis solutions in plasma were dispensed into the donor (plasma) compartment. An aliquot of 200 μL of dialysis buffer (100 mM potassium phosphate, pH 7.4) was dispensed into the buffer (acceptor) chamber. Incubation was performed at 37°C for 2 hours with rotation to establish equilibrium.

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

% binding is calculated using the following formula: % binding = (plasma concentration - buffer concentration/plasma concentration) x 100 Solubility assessment

The water solubility of test compounds was determined by comparing the amount dissolved in the buffer with the amount dissolved in ACN/water (1/1) solution. Starting with a 10 mM DMSO stock solution, aliquots were diluted with acetonitrile/water (1/1) or buffer, respectively. After shaking for 24 hours, the solution was filtered and analyzed by LC-UV. Compare the amount dissolved in the buffer with the amount dissolved in the ACN solution.

Solubility is typically measured at 2.5% DMSO from 0.001 mg/mL to 0.125 mg/mL. If more than 90% of the compound is dissolved in the buffer, the value is marked with a ">". Evaluation of Pharmacokinetic Properties in Rodents

Test compounds are administered intravenously to fed mice or orally to fasted mice. Blood samples were taken at several time points following administration of test compounds, anticoagulated and centrifuged.

The concentrations of analytes - administered compounds and/or metabolites - are quantified in plasma samples.

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

Cytochrome P450 Evaluation of Inhibition of Reactions Catalyzed by Isozymes

Test compounds were assayed for inhibition of cytochrome P450 isoenzyme-catalyzed reactions using human liver microsomes at 37°C. All analyses were performed on a robotic system in 384-well plates. Test compounds were spotted directly from the DMSO feed into the incubation dish by acoustic liquid dispensing (using the Labyte ECHO® system). The final incubation volume contained TRIS buffer (0.1 M), _MgCl2 (5 mM), human liver microsomes, specific cytochrome P450 isoenzyme-substrates and five different concentrations of test compound or no compound in duplicate (high control) (eg highest concentration 50 µM for subsequent 1:4 serial dilutions). After a brief pre-incubation period, the reaction was started with cofactor (NADPH, 1 mM) and stopped by cooling the incubation down to 8°C and then by adding one volume of acetonitrile. An internal standard solution, usually a stable isotope of the metabolite formed, is added after the incubation quench. The peak areas of the analytes (= metabolites formed) and the internal standard were determined by LC-MS/MS. The peak area ratios of analyte to internal standard obtained in these incubations were compared to the control activity without test compound. Within each of the analytical runs, the _IC50 of the positive control inhibitor was determined. _IC50 experimental values were calculated by least squares regression according to the following equation: % control activity=(100% control activity/(1+(I/ _IC50 )S)))-b where I=inhibitor concentration S=slope factor B=Background Activity If the inhibition of the response has been >50% at the lowest concentration of test compound, assign an _IC50 as "<lowest test concentration" (usually <0.2 µM). IC50s were assigned ">highest test concentration" (usually > ₅₀ µM) if response inhibition was <50% at the highest concentration of test compound.

Cytochrome P450 3A4 Mechanism-based inhibition of catalyzed midazolam conversion ( MBI ) evaluation of

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

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

Conversion rates in pmol/min/mg protein were calculated and the activity after 10 and 30 min preincubation times was compared to the activity of the respective compound/concentration at 0 min preincubation (CTRL% = 0 min at respective compound/concentration % of the control). In addition, conversion is expressed relative to the conversion of substrate reactions without compound added (TR% = % conversion without compound) in order to identify competitive inhibition. treatment method

In another aspect of the present invention, compounds of formula (I), or pharmaceutically acceptable salts thereof, were found to have properties suitable for use in therapy and/or prevention, ie as a medicament. In particular, the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing it may be suitable for use in therapy, that is, therapy and/or prevention (prevention) may be inhibited by plasma kallikrein in patients Affected diseases or conditions that are, for example, mediated by undesired PKK activity or in which inhibition of PKK is beneficial.

Diseases or conditions that may be affected by PKK inhibition, such as those mediated by undesired PKK activity or in which inhibition of PKK is beneficial, are such diseases or conditions as those mentioned in the Background of the Invention section, especially diabetes complicated by disease, diabetic retinopathy, proliferative and nonproliferative retinopathy, diabetic macular edema (DME), clinically apparent macular edema (CSME), cystoid macular edema (CME), post-cataract CME, CME induced by cryotherapy, CME induced by uveitis, endophthalmitis, CME after vascular occlusion (eg, central retinal vein occlusion, branch retinal vein occlusion, or semi-retinal vein occlusion), retinal edema, and diabetic retinopathy Complications associated with cataract surgery, hypertensive retinopathy, retinal trauma, dry and wet age-related macular degeneration (AMD), polypoid choroidal vasculopathy (PCV), choroidal neovascularization (CNV; such as non-exudative Choroidal neovascularization), Hereditary Angioedema (HAE), Acute Respiratory Distress Syndrome (ARDS), such as cerebral edema after stroke, post-stroke hemorrhage and edema, vascular dementia, Alzheimer's disease, fibrotic disease, colon inflammation, arthritis and kidney damage.

Therefore, the compounds and pharmaceutical compositions of the present invention are particularly useful for the treatment of ocular diseases including: diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), retinal vein occlusion, age-related macular degeneration (AMD), polypoid choroidal vasculopathy (PCV), and choroidal neovascularization (CNV; eg, non-exudative choroidal neovascularization).

In addition, the compounds and pharmaceutical compositions of the present invention are particularly useful in the treatment of edema such as hereditary angioedema (HAE) and cerebral edema after stroke.

Specifically, the compounds and pharmaceutical compositions of the present invention are suitable for the treatment of diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), age-related macular degeneration (AMD), polypoid Choroidal vasculopathy (PCV), choroidal neovascularization (CNV), hereditary angioedema (HAE) and brain edema after stroke. .

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

For example, it is particularly useful for the prevention of diabetic macular edema (DME), wet age-related macular degeneration (AMD), hereditary angioedema (HAE) and brain edema after stroke and for the prevention of Conversion of exudative choroidal neovascularization (neCNV) to exudative choroidal neovascularization (eCNV).

Suitable daily dosages of compounds of formula (I) are generally in the range of 0.01 mg/kg body weight to 10 mg/kg body weight.

The actual therapeutically effective amount or dose will, of course, depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease. In any event, the compound or composition should be administered in a dose and manner that achieves a therapeutically effective amount according to the unique condition of the patient.

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

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

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

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

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

Likewise, the present invention provides the use of a compound of formula (I) and/or a tautomer or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in a method for treating a patient in need thereof Diseases or conditions that are mediated by undesired plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial.

Likewise, the present invention provides compounds of formula (I) and/or tautomers or pharmaceutically acceptable salts thereof for use in the treatment of patients in need thereof mediated by undesired plasma kallikrein activity or wherein plasma stimulation Use in a method in which the inhibition of peptidylase is beneficial for a disease or condition.

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

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

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

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

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

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

In another aspect of the present invention, it is described that a compound of the present invention or a pharmaceutically acceptable salt thereof can be used as an active ingredient in a pharmaceutical composition.

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

This can be done, for example, by mixing one or more compounds according to formula (I) with known excipients such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants to obtain the appropriate lozenge. A lozenge may also consist of several layers. Those skilled in the art will be familiar with specific excipients, carriers and/or diluents suitable for use in the desired formulation based on their expertise. Preferred are those suitable for the particular formulation and method of administration desired. The formulations or formulations of the present invention may be prepared using methods known per se with which the skilled artisan is familiar, such as by mixing or combining at least one compound of formula (I) of the present invention, or a pharmaceutically acceptable salt of such a compound, with a or various excipients, carriers and/or diluents.

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

In addition, there is provided a pharmaceutical composition comprising one or more of the above-mentioned compounds or a pharmaceutically acceptable salt thereof and optionally one or more inert carriers and/or diluents, for use in a kind of treatment for a patient in need In a method for a disease or condition mediated by undesired plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial.

In particular, the present invention provides methods for the treatment of diseases such as diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), age-related macular degeneration (AMD), polypoid choroidal vasculopathy ( The pharmaceutical composition according to the present invention in the method of ocular disorders of PCV) and choroidal neovascularization (CNV) and edema-related diseases such as hereditary angioedema (HAE) and cerebral edema after stroke.

Furthermore, the present invention relates to the use of a pharmaceutical composition according to the present invention for the treatment of a disease or condition mediated by undesired plasma kallikrein activity in a patient, preferably a human.

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

According to another embodiment, there is provided a compound comprising one or more compounds of formula (I) and/or tautomers or pharmaceutically acceptable salts thereof and one or more additional therapeutic agents, optionally and one or more inert carriers and/or diluent pharmaceutical compositions.

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

The compounds of the present invention may be further combined with one or more, preferably one, additional therapeutic agents.

According to one embodiment, the additional therapeutic agent is selected from the group of therapeutic agents suitable for the treatment of the diseases or symptoms described above, particularly associated with metabolic diseases or conditions, or the group of therapeutic agents suitable for the treatment of ocular diseases, such diseases Or symptoms such as diabetes, obesity, diabetic complications, hypertension, hyperlipidemia.

Additional therapeutic agents suitable for use in such combinations include, among others, those that potentiate the therapeutic effect of one or more actives mentioned in relation to one of the instructions and/or reduce the dose of one or more actives, for example.

Accordingly, the compounds of the present invention may be combined with one or more additional therapeutic agents selected from the group consisting of antidiabetic agents, agents for the treatment of overweight and/or obesity, for the treatment of hypertension, heart failure and/or Or drugs for atherosclerosis and drugs for the treatment of eye diseases.

For example, the antidiabetic agent is metformin, sulfonylurea, nateglinide, repaglinide, thiazolidinediones, PPAR-(alpha, gamma or alpha/gamma) agonists or modulators, alpha- Glucosidase inhibitors, DPPIV inhibitors, SGLT2-inhibitors, insulin and insulin analogs, GLP-1 and GLP-1 analogs or amyloid and amyloid analogs, cycloset, 11β-HSD inhibitor. Other suitable combination partners are protein tyrosine phosphatase 1, an inhibitor of substances that affect dysregulated glucose production in the liver (such as glucose-6-phosphatase or fructose-1,6-bisphosphatase, hepatic glucose phosphorylation enzyme, glucagon receptor antagonist inhibitor and phosphoenolpyruvate carboxykinase inhibitor), hepatic glucose synthase kinase or pyruvate dehydrogenase, α2-antagonist, CCR-2 antagonist or glucokinase activator . One or more lipid-lowering agents are also suitable as combination partners, such as HMG-CoA-reductase inhibitors, fibrates, nicotinic acid and 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 ileal bile acid transport inhibitors), MTP inhibitors or HDL raising compounds (such as CETP inhibitors or ABC1 modulators) agent).

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

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

Therapeutic agents used to treat ocular diseases may include, for example, intravitreal administration of corticosteroids, intravitreal administration of anti-VEGF therapeutics, anti-Ang2 inhibitors, dual anti-VEGF/anti-Ang2 inhibitors, anti-PDGF, dual Anti-VEGF/anti-PDGF, VAP-1 (AOC3) inhibitors, supplemental inhibitors (eg supplemental factor 3, 5, B and D inhibitors), bradykinin receptor 1 antagonists, CCR-2 antagonists.

Additional treatments for eye disease may include laser coagulation therapy.

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

The dosage of the above-mentioned combination partners is usually from 1/5 of the normal recommended minimum dose to as high as 1/1 of the normal recommended dose.

The use of the compounds according to the invention in combination with additional therapeutic agents can be performed simultaneously or at staggered times.

Both the compound according to the invention and the one or more additional therapeutic agents may be present together in one formulation (eg, a lozenge or capsule), or separately in two identical or different formulations (eg, as so-called separate packs) part of the set).

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

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

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

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

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

According to one embodiment, the method for treatment comprises administering to a patient one or more compounds of formula (I) and/or tautomers or pharmaceutically acceptable salts thereof and one or more additional A therapeutic agent, preferably a therapeutically effective amount of one or more compounds of formula (I) and/or a tautomer or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more compounds of formula (I) and/or a therapeutically effective amount thereof as described in the context the additional therapeutic agent.

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

According to one embodiment, the one or more additional therapeutic agents are selected from antidiabetic agents, agents for the treatment of overweight and/or obesity, agents for the treatment of hypertension, heart failure and/or atherosclerosis, and agents for Agents for the treatment of eye diseases are especially selected from those specifically mentioned above.

According to one embodiment, the disease or condition mediated by undesired plasma kallikrein activity or in which inhibition of plasma kallikrein is beneficial is selected from the group consisting of, for example, diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetes Ophthalmic disorders such as macular edema (DME), age-related macular degeneration (AMD), polypoid choroidal vasculopathy (PCV), and choroidal neovascularization (CNV); selected from such as hereditary angioedema (HAE) and stroke edema-related diseases followed by cerebral edema; or 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.

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 illustrative purposes only and are not intended to limit the scope of the invention in any way.

-六氟磷酸鹽 HPLC         高效液相層析 HPLC-MS   偶合高效液相層析-質譜分析 LC             液相層析法 LC-MS       耦合液相層析質譜法 LG             脫離基 M               莫耳(mol/L) MeOH        甲醇 min            分鐘 MS             質譜 NADPH      菸醯胺腺嘌呤二核苷酸磷酸 NMP          N-甲基-2-吡咯啶酮 NMR          核磁共掁 PET           聚對苯二甲酸伸乙酯 PyBop        (苯并三唑-1-基氧基)三吡咯啶鏻六氟磷酸鹽 R _f阻滯因子 RFU           相對螢光單位 RP             逆相 rt                室溫 t _R滯留時間(以HPLC/LC計) SFC           超臨界流體層析法 TBTU         四氟硼酸O-(苯并三唑-1-基)-N,N,N',N'-四甲基

TFA           三氟乙酸 THF           四氫呋喃 UV             紫外線 Abbreviations : Ac Acetyl ACN Acetonitrile AMC 7-amino-4-methylcoumarin Boc Tertiary Butoxycarbonyl BSA Bovine Serum Albumin Bzl Benzyl d-day DAD Dipole Array Detector DBAD Azo Ditertiary butyl dicarboxylate DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DBN 1,5-diazabicyclo[4.3.0]non-5-ene DCM Dichloromethane DEAD Diethyl azodicarboxylate DIAD Diisopropyl azodicarboxylate DIPEA N,N-diisopropylethylamine DMEM Dulbecco's modified Eagle's medium DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EDTA ethylenediaminetetraacetate ESI electrospray ionization (in MS) EtOAc ethyl acetate EtOH ethanol h HATU O-(7-azabenzotriazol-1-yl)-N,N, N',N'-Tetrajia

-Hexafluorophosphate HPLC High Performance Liquid Chromatography HPLC-MS Coupled High Performance Liquid Chromatography-Mass Spectrometry LC Liquid Chromatography LC-MS Coupled Liquid Chromatography Mass Spectrometry LG Leaving Group M Mole (mol/L) MeOH methanol min min MS mass spectrometry NADPH nicotinamide adenine dinucleotide phosphate NMP N-methyl-2-pyrrolidinone NMR nuclear magnetic resonance PET polyethylene terephthalate PyBop (benzotriazole-1- Oxy)tripyrrolidinium phosphonium hexafluorophosphate R _f retardation factor RFU relative fluorescence unit RP reverse phase rt room temperature t _R retention time (by HPLC/LC) SFC supercritical fluid chromatography TBTU tetrafluoroboric acid O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl

TFA Trifluoroacetic acid THF Tetrahydrofuran UV UV

The terms "ambient temperature" and "room temperature" are used interchangeably and refer to a temperature of about 20°C, eg, 15 to 25°C.

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

Unless otherwise specified, compounds containing parachiral centers have the stereochemistry depicted. Stereochemistry assignment has been carried out by using known stereochemistry of chiral starting materials, by stereoselective synthesis of known stereochemistry, or by biological activity.

Analytical method method: 1 Device: Agilent 1200 with DA- and MS-detectors column: XBridge C18, 3×30 mm, 2.5 µm Column Supplier: waters Gradient/Solvent time [minutes] Solvent % [H ₂ O, 0.1% NH3] Solvent% [ACN] Flow [ml/min] temperature [°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-detectors column: Sunfire C18, 3×30 mm, 2.5 µm Column Supplier: waters Gradient/Solvent time [minutes] Solvent % [H ₂ O, 0.1% TFA] Solvent% [ACN] Flow [ml/min] temperature [°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-detectors column: CHIRAL ART® Cellulose SC, 4.6×250 mm, 5 μm Column Supplier: YMC Gradient/Solvent time [minutes] Solvent % [scCO ₂ ] Solvent % [MeOH, 20mM _NH3 ] Flow [ml/min] temperature [°C] Back Pressure [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 time [minutes] Solvent % [H ₂ O, 0.1% NH3] Solvent% [ACN] Flow [ml/min] temperature [°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 time [minutes] Solvent % [H ₂ O, 0.1% NH3] Solvent% [ACN] Flow [ml/min] temperature [°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 used in the process of producing the compounds according to the invention are commercially available or they can be obtained by means of documents such as those described in the following documents from WO 2017/072020, WO 2017/072021 and WO 2018/192866 or prepared by methods already known to those skilled in the art (or by methods analogous or analogous to those methods), which are hereby incorporated by reference in their entirety.

Intermediate 1

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

step 1 : 5 - bromine - 1 - methyl - 1H - imidazole - 4 - methyl formate

Under argon atmosphere, methyl 1-methyl-1H-imidazole-4-carboxylate (19.1 g) was dissolved in DCM (230 mL). N-bromosuccinimide (29.1 g), sodium persulfate ( _Na2S2O8 , 64.9 _g ) and palladium-II-acetate (Pd(OAc) ₂ , 3.1 g ₎ were added successively and the mixture was mixed Cool to 0°C. Trifluoromethanesulfonic acid ( _CF3 - _SO3H , 42.2 mL) was added dropwise, and the mixture was then heated to 60°C for 20 hours. The mixture was diluted with DCM, cooled to 0 °C and treated carefully with saturated aqueous _Na2CO3 until pH ₈ was reached. The mixture was partitioned between water and DCM. The aqueous phase was extracted with DCM and the combined organic phases were dried ( _MgSO4 ) and concentrated in vacuo. The residue was chromatographed on silica gel (EtOAc/MeOH 85:15→70:30). The product thus obtained was triturated with tert-butyl-methyl-ether (50 mL) to give the title compound.

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

step 2 : 5 -( 3 - Methoxy - 3 - Pendant oxypropyl )- 1 - methyl - 1H - imidazole - 4 - methyl formate

Methyl 5-bromo-1-methyl-1H-imidazole-4-carboxylate (10.6 g) was dissolved in dimethylacetamide (80 mL) and water (20 mL). 3,3-Dimethoxyprop-1-ene (8.6 mL) and N-methyldicyclohexylamine (15.3 mL) were added and the mixture was purged with argon for 5 minutes. Dichlorobis(tri-o-tolylphosphine)palladium(II) ( _PdCl2 [P(o-Tol) ₃ ] ₂ , 1.9 g) was added and the mixture was stirred at 120°C for 3 hours. The mixture was then partitioned between water and EtOAc and filtered through celite. The aqueous phase was mixed with saturated aqueous _NaHCO3 and extracted 4 times with EtOAc. The combined organic phases were dried ( _MgSO4 ) and concentrated in vacuo. The residue was chromatographed on silica gel (EtOAc/MeOH 90:10→70:30) to give the title compound.

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

step 3 : 1 - methyl - 4 - side oxygen - 1H , 4H , 5H , 6H - Cyclopentane [ d ] imidazole - 5 - methyl formate

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

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

step 4 : 1 - methyl - 1H , 4H , 5H , 6H - Cyclopentane [ d ] imidazole - 4 - ketone

Methyl 1-methyl-4-oxy-1H,4H,5H,6H-cyclopenta[d]imidazole-5-carboxylate (4.0 g) in 1,4-dioxane (150 mL) was heated under reflux ) and water (15 mL) for 90 hours. The solvent was evaporated in vacuo to give the title compound. LC (Method 1): t _R = 0.16 min; Mass Spec (ESI ⁺ ): m/z = 137 [M+H] ⁺ .

Alternatively, the reaction can be carried out at 120°C by heating the starting material in a mixture of hydrogen chloride and acetic acid. After the reaction was complete, the solvent was evaporated in vacuo. _The residue was dissolved in MeOH and treated with K2CO3 until pH ₈ was reached. Filter, concentrate and chromatograph the mixture 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 - Cyclopentane [ d ] imidazole -4- subunit ] propane - 2 - Sulfenamide

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

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

step 6 : ( R )- 2 - methyl - N -[( 4R )- 1 - methyl - 1H , 4H , 5H , 6H - Cyclopentane [ d ] imidazole - 4 - base ] propane - 2 - Sulfenamide

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

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

step 7 : ( 4R )- 1 - methyl - 1H , 4H , 5H , 6H - Cyclopentane [ d ] imidazole - 4 - Amine dihydrochloride

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

Intermediate 2

5- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } pyridine - 2 - carbaldehyde _ _ _ _

5-Fluoropyridine-2-carbaldehyde (1.0 g), ₃ -azabicyclo[3.1.0]hexane hydrochloride (1.1 g) and K2CO3 (2.8 _g ) were suspended in NMP (10 mL) And heated to 120°C for 2 hours. The mixture was cooled to room temperature, partitioned between water and EtOAc, and the phases were separated. The aqueous phase was extracted twice with EtOAc and the combined organic phases were dried ( _MgSO4 ) and concentrated. The residue was chromatographed on silica gel (cyclohexane/EtOAc 100:0→60:40) to give the title compound. LC (Method 2): t _R = 0.68 min; Mass Spec (ESI ⁺ ): m/z = 189 [M+H] ⁺ .

0.75 189 方法2 2-2

0.73 225 方法2 2-3

0.82 189 方法2 2-4

1.22 301 方法1 中間物 反應備註 2-2 反應在115℃下進行12小時。 2-3 反應在室溫下在DMF中進行18小時。 2-4 反應在80℃下在DMF中進行26小時。 中間物 名稱 起始材料 1 之名稱 起始材料 2 之名稱 2-1  5-{5-氮雜螺[2.3]己-5-基}吡啶-2-甲醛 5-氟吡啶-2-甲醛 5-氮雜螺[2.3]己烷半草酸鹽 2-2  5-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}吡啶-2-甲醛  5-氟吡啶-2-甲醛  6,6-二氟-3-氮雜雙環-[3.1.0]己烷鹽酸鹽 2-3  6-{3-氮雜雙環[3.1.0]己-3-基}吡啶-3-甲醛  6-氟吡啶-3-甲醛  3-氮雜雙環[3.1.0]己烷鹽酸鹽 2-4 3-(5-碘-6-甲基吡啶-2-基)-3-氮雜雙環[3.1.0]己烷  6-氟-3-碘-2-甲基吡啶  3-氮雜雙環[3.1.0]己烷鹽酸鹽 Intermediates 2-1 to 2-4 were prepared analogously to Intermediate 2 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 2-1

0.75 189 Method 2 2-2

0.73 225 Method 2 2-3

0.82 189 Method 2 2-4

1.22 301 method 1 Intermediate Reaction Notes 2-2 The reaction was carried out at 115°C for 12 hours. 2-3 The reaction was carried out in DMF at room temperature for 18 hours. 2-4 The reaction was carried out in DMF at 80°C for 26 hours. Intermediate name Name of starting material 1 Name of starting material 2 2-1 5-{5-Azaspiro[2.3]hex-5-yl}pyridine-2-carbaldehyde 5-Fluoropyridine-2-carbaldehyde 5-Azaspiro[2.3]hexane hemioxalate 2-2 5-{6,6-Difluoro-3-azabicyclo-[3.1.0]hex-3-yl}pyridine-2-carbaldehyde 5-Fluoropyridine-2-carbaldehyde 6,6-Difluoro-3-azabicyclo-[3.1.0]hexane hydrochloride 2-3 6-{3-Azabicyclo[3.1.0]hex-3-yl}pyridine-3-carbaldehyde 6-Fluoropyridine-3-carbaldehyde 3-Azabicyclo[3.1.0]hexane hydrochloride 2-4 3-(5-iodo-6-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane 6-Fluoro-3-iodo-2-methylpyridine 3-Azabicyclo[3.1.0]hexane hydrochloride

Intermediate 3

( 5- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } pyridin - 2 - yl ) methanol _ _ _ _

NaBH4 (217 mg) was added portionwise to 5-{ ₃ -azabicyclo[3.1.0]hex-3-yl}pyridine-2-carbaldehyde (920 mg) in THF (10 mL) and MeOH (5 mL) in the ice-cold mixture. The mixture was stirred at 0°C for 1 hour, treated with 1 M aqueous HCl (10 mL) and stirred at room temperature for 30 minutes. The mixture was then partitioned between saturated aqueous _NaHCO3 and EtOAc. Separate the phases. The organic phase was dried ( _MgSO4 ) and concentrated to give the title compound. LC (Method 2): t _R = 0.59 min; Mass Spec (ESI ⁺ ): m/z = 191 [M+H] ⁺ .

中間物 反應備註 3-1 反應在EtOH中進行。 3-5 甲基醚在攪拌期間在1 N HCl水溶液存在下形成。 3-6 甲基醚在攪拌期間在1 N HCl水溶液存在下形成。 3-7 甲基醚在攪拌期間在1 N HCl水溶液存在下形成。 3-10 反應在EtOH中進行。 3-12 反應在EtOH中進行。 3-14 反應在THF/EtOH 1:2中進行。 3-15 反應在室溫下在EtOH中進行2小時。 3-16 反應在0℃下進行2小時。 3-17 反應在室溫下進行30分鐘。 3-18 反應在室溫下在EtOH中進行1小時。 3-19 反應在室溫下進行45分鐘。 3-20 反應在0℃下進行45分鐘。 3-21 反應在0℃下進行1小時。 3-22 反應在室溫下在EtOH中進行1.5小時。 3-23 反應在室溫下在EtOH中進行1小時。 中間物 名稱 起始材料 之名稱 3-1  (2-溴-6-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}吡啶-3-基)甲醇  2-溴-6-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}吡啶-3-甲醛 3-2  (2-氯-6-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}吡啶-3-基)甲醇  2-氯-6-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}吡啶-3-甲醛 3-3  (6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲醇  6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-甲醛 3-4  (6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-基)甲醇  6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-甲醛 3-5  6,6-二氟-3-[6-氟-5-(甲氧基-甲基)吡啶-2-基]-3-氮雜雙環[3.1.0]己烷  6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-甲醛 3-6  5-[6-氟-5-(甲氧基甲基)吡啶-2-基]-5-氮雜螺[2.3]己烷  6-{5-氮雜螺[2.3]己-5-基}-2-氟吡啶-3-甲醛 3-7  3-[6-氟-5-(甲氧基甲基)吡啶-2-基]-3-氮雜雙環[3.1.0]己烷  6-{3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-甲醛 3-8  (5-{5-氮雜螺[2.3]己-5-基}吡啶-2-基)甲醇  5-{5-氮雜螺[2.3]己-5-基}吡啶-2-甲醛 3-9  (6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲醇  6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-甲醛 3-10  (6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲醇  6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-甲醛 3-11  (6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲醇  6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-甲醛 3-12  (6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲醇  6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-甲醛 3-13  (5-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-2-基)甲醇  5-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-2-甲醛 3-14  (6-{5-氮雜螺[2.3]己-5-基}-2-甲基吡啶-3-基)甲醇  6-{5-氮雜螺[2.3]己-5-基}-2-甲基吡啶-3-甲醛 3-15  (6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲醇  6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-甲醛 3-16  (6-{3-氮雜雙環[3.1.0]己-3-基}-4-氯吡啶-3-基)甲醇  6-{3-氮雜雙環[3.1.0]己-3-基}-4-氯吡啶-3-甲醛 3-17  2-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-5-(羥基甲基)-4-甲基吡啶-3-甲腈  2-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-5-甲醯基-4-甲基吡啶-3-甲腈 3-18  (6-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基吡啶-3-基)甲醇  6-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基吡啶-3-甲醛 3-19  (6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2,4-二甲基吡啶-3-基)甲醇  6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2,4-二甲基吡啶-3-甲醛 3-20  2-{3-氮雜雙環[3.1.0]己-3-基-5-(羥基-甲基)-4-甲基吡啶-3-甲腈  2-{3-氮雜雙環[3.1.0]己-3-基}-5-甲醯基-4-甲基吡啶-3-甲腈 3-21 {2-氯-6-[(1R,5S,6R)-6-甲基-3-氮雜-雙環[3.1.0]己-3-基]吡啶-3-基}甲醇 2-氯-6-[(1R,5S,6R)-6-甲基-3-氮雜雙-環[3.1.0]己-3-基]吡啶-3-甲醛 3-22 (6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲醇 6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-甲醛 3-23 (6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲醇 6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-吡啶-3-甲醛 Intermediates 3-1 to 3-23 were prepared analogously to Intermediate 3 :

Intermediate Reaction Notes 3-1 The reaction was carried out in EtOH. 3-5 Methyl ether was formed during stirring in the presence of 1 N aqueous HCl. 3-6 Methyl ether was formed during stirring in the presence of 1 N aqueous HCl. 3-7 Methyl ether was formed during stirring in the presence of 1 N aqueous HCl. 3-10 The reaction was carried out in EtOH. 3-12 The reaction was carried out in EtOH. 3-14 The reaction was carried out in THF/EtOH 1:2. 3-15 The reaction was carried out in EtOH at room temperature for 2 hours. 3-16 The reaction was carried out at 0°C for 2 hours. 3-17 The reaction was carried out at room temperature for 30 minutes. 3-18 The reaction was carried out in EtOH at room temperature for 1 hour. 3-19 The reaction was carried out at room temperature for 45 minutes. 3-20 The reaction was carried out at 0°C for 45 minutes. 3-21 The reaction was carried out at 0°C for 1 hour. 3-22 The reaction was carried out in EtOH at room temperature for 1.5 hours. 3-23 The reaction was carried out in EtOH at room temperature for 1 hour. Intermediate name name of starting material 3-1 (2-Bromo-6-{6,6-difluoro-3-azabicyclo-[3.1.0]hex-3-yl}pyridin-3-yl)methanol 2-Bromo-6-{6,6-difluoro-3-azabicyclo-[3.1.0]hex-3-yl}pyridine-3-carbaldehyde 3-2 (2-Chloro-6-{6,6-difluoro-3-azabicyclo-[3.1.0]hex-3-yl}pyridin-3-yl)methanol 2-Chloro-6-{6,6-difluoro-3-azabicyclo-[3.1.0]hex-3-yl}pyridine-3-carbaldehyde 3-3 (6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methanol 6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridine-3-carbaldehyde 3-4 (6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methanol 6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridine-3-carbaldehyde 3-5 6,6-Difluoro-3-[6-fluoro-5-(methoxy-methyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane 6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridine-3-carbaldehyde 3-6 5-[6-Fluoro-5-(methoxymethyl)pyridin-2-yl]-5-azaspiro[2.3]hexane 6-{5-Azaspiro[2.3]hex-5-yl}-2-fluoropyridine-3-carbaldehyde 3-7 3-[6-Fluoro-5-(methoxymethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridine-3-carbaldehyde 3-8 (5-{5-Azaspiro[2.3]hex-5-yl}pyridin-2-yl)methanol 5-{5-Azaspiro[2.3]hex-5-yl}pyridine-2-carbaldehyde 3-9 (6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methanol 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridine-3-carbaldehyde 3-10 (6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methanol 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridine-3-carbaldehyde 3-11 (6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methanol 6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridine-3-carbaldehyde 3-12 (6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methanol 6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridine-3-carbaldehyde 3-13 (5-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methanol 5-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridine-2-carbaldehyde 3-14 (6-{5-Azaspiro[2.3]hex-5-yl}-2-methylpyridin-3-yl)methanol 6-{5-Azaspiro[2.3]hex-5-yl}-2-methylpyridine-3-carbaldehyde 3-15 (6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methanol 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridine-3-carbaldehyde 3-16 (6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-chloropyridin-3-yl)methanol 6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-chloropyridine-3-carbaldehyde 3-17 2-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-5-(hydroxymethyl)-4-methylpyridine-3-carbonitrile 2-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-5-carboxy-4-methylpyridine-3-carbonitrile 3-18 (6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyridin-3-yl)methanol 6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyridine-3-carbaldehyde 3-19 (6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2,4-lutidine-3-yl)methanol 6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2,4-lutidine-3-carbaldehyde 3-20 2-{3-Azabicyclo[3.1.0]hex-3-yl-5-(hydroxy-methyl)-4-methylpyridine-3-carbonitrile 2-{3-Azabicyclo[3.1.0]hex-3-yl}-5-carboxy-4-methylpyridine-3-carbonitrile 3-21 {2-Chloro-6-[(1R,5S,6R)-6-methyl-3-aza-bicyclo[3.1.0]hex-3-yl]pyridin-3-yl}methanol 2-Chloro-6-[(1R,5S,6R)-6-methyl-3-azabi-cyclo[3.1.0]hex-3-yl]pyridine-3-carbaldehyde 3-22 (6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methanol 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridine-3-carbaldehyde 3-23 (6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methanol 6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-pyridine-3-carbaldehyde

Intermediate 4

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

In a microwave vial, combine (5-{3-azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methanol (100 mg), methyl 1H-imidazole-4-carboxylate (77 mg) ) and p-toluenesulfonic acid (54 mg) in ACN (15 mL) was heated to 120 °C for 5 h. After cooling to room temperature, the mixture was partitioned between saturated aqueous _NaHCO3 and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic phases were dried ( _MgSO4 ) and concentrated. The residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

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

中間物 反應備註 4-1 反應在70℃下進行10分鐘。 4-2 反應在70℃下進行15分鐘。 4-3 反應在70℃下進行15分鐘。 4-4 反應在90℃下進行48小時。 4-5 反應在130℃下進行10小時。 4-6 反應在120℃下進行4小時。 4-7 反應在70℃下進行10分鐘。 4-8 反應在70℃下進行5小時。 4-9 反應在70℃下進行1小時。 4-10 反應在80℃下進行30分鐘。 4-11 反應在70℃下進行10分鐘。 4-12 反應在80℃下進行2小時。 4-13 反應在80℃下進行12小時。 4-14 反應在80℃下進行4小時。 4-15 反應在70℃下進行10分鐘。 4-16 反應在70℃下進行1小時。 4-17 反應在80℃下進行15小時。 4-18 反應在70℃下進行1小時。 4-19 反應在70℃下進行10分鐘。 4-20 反應在80℃下進行7小時且在90℃下進行2小時。 4-21 使用樟腦磺酸代替對甲苯磺酸。 反應在80℃下進行4小時。 4-22 反應在70℃下進行15分鐘。 4-23 反應在90℃下進行2小時。 4-24 反應在70℃下進行15分鐘。 4-25 反應在70℃下進行12小時。 4-26 反應在90℃下進行5小時。 4-27 反應在90℃下進行15小時。 4-28 反應在90℃下進行12小時。 4-29 反應在80℃下進行5小時。 4-30 反應在80℃下進行30分鐘。 4-31 反應在120℃下進行6小時。 4-32 反應在80℃下進行2小時。 4-33 反應在60℃下進行2小時。 4-34 反應在120℃下進行4小時且在130℃下進行1小時。 4-35 反應在75℃下進行15小時且在80℃下進行12小時。 4-36 反應在70℃下進行30分鐘。 4-37 反應在70℃下進行12小時且在80℃下進行6小時。 4-38 反應在80℃下進行12小時。 4-39 反應在90℃下進行12小時。 4-40 反應在80℃下進行12小時。 4-41 反應在70℃下進行22小時。 4-42 反應在90℃下進行12小時。 4-43 反應在80℃下進行48小時。 4-44 反應在70℃下進行3小時。 4-45 反應在80℃下進行20小時。 4-46 反應在80℃下進行4小時。 4-47 反應在80℃下進行2小時。 4-48 反應在80℃下進行20小時。 4-49 反應在70℃下進行5小時。 4-50 反應在90℃下進行5小時。 4-51 反應在60℃下進行16小時。 4-52 反應在90℃下進行12小時。 4-53 反應在70℃下進行22小時。 4-54 反應在70℃下進行22小時。 4-55 反應在70℃下進行20小時。 4-56 反應在70℃下進行12小時。 4-57 反應在90℃下進行4小時。 4-58 反應在130℃下進行13小時。 4-59 反應在90℃下進行5小時。 4-60 反應在90℃下進行5小時。 4-61 反應在90℃下進行5小時。 中間物 名稱 起始材料 1 之名稱 起始材料 2 之名稱 4-1  1-[(2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯  2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲醇  1H-1,2,3-三唑-4-甲酸乙酯 4-2  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯  (6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲醇  1H-1,2,3-三唑-4-甲酸乙酯 4-3  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯  (6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-基)甲醇  1H-1,2,3-三唑-4-甲酸乙酯 4-4  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  6,6-二氟-3-[6-氟基-5-(甲氧基甲基)吡啶-2-基]-3-氮雜雙環[3.1.0]己烷  1H-咪唑-4-甲酸乙酯 4-5  1-[(5-{3-氮雜雙環[3.1.0]-己-3-基}吡啶-2-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯  (5-{3-氮雜雙環[3.1.0]己-3-基}吡啶-2-基)甲醇  1H-1,2,3-三唑-4-甲酸乙酯 4-6  1-[(5-{3-氮雜雙環[3.1.0]-己-3-基}吡啶-2-基)甲基]-1H-吡唑-4-甲酸乙酯  (5-{3-氮雜雙環[3.1.0]己-3-基}吡啶-2-基)甲醇  1H-吡唑-4-甲酸乙酯 4-7  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氟吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯  5-[6-氟-5-(甲氧基甲基)吡啶-2-基]-5-氮雜螺[2.3]己烷  1H-1,2,3-三唑-4-甲酸乙酯 4-8  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氟吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  5-[6-氟-5-(甲氧基甲基)吡啶-2-基]-5-氮雜螺[2.3]己烷  1H-咪唑-4-甲酸乙酯 4-9  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氟吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  5-[6-氟-5-(甲氧基甲基)吡啶-2-基]-5-氮雜螺[2.3]己烷  1H-吡唑-4-甲酸乙酯 4-10  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  (6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-基)甲醇  1H-吡唑-4-甲酸乙酯 4-11  1-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯  (2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲醇  1H-1,2,3-三唑-4-甲酸乙酯 4-12  1-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  (2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲醇  1H-吡唑-4-甲酸乙酯 4-13  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  (6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-基)甲醇  1H-咪唑-4-甲酸乙酯 4-14  1-[(2-{3-氮雜雙環[3.1.0]-己-3-基}-4-[(1E)-2-苯基-乙烯基]嘧啶-5-基)甲基]-1H-咪唑-4-甲酸  (2-{3-氮雜雙環[3.1.0]己-3-基}-4-[(1E)-2-苯基乙烯基]-嘧啶-5-基)甲醇  1H-咪唑-4-甲酸 4-15  1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-2-氟吡啶-3-基)-甲基]-1H-1,2,3-三唑-4-甲酸乙酯  3-[6-氟-5-(甲氧基甲基)吡啶-2-基]-3-氮雜雙環[3.1.0]己烷  1H-1,2,3-三唑-4-甲酸乙酯 4-16  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  6,6-二氟-3-[6-氟基-5-(甲氧基甲基)吡啶-2-基]-3-氮雜雙環[3.1.0]己烷  1H-吡唑-4-甲酸乙酯 4-17  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  (6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲醇  1H-咪唑-4-甲酸乙酯 4-18  1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-2-氯吡啶-3-基)-甲基]-1H-吡唑-4-甲酸乙酯  (6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)-甲醇  1H-吡唑-4-甲酸乙酯 4-19  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯  6,6-二氟-3-[6-氟基-5-(甲氧基甲基)吡啶-2-基]-3-氮雜雙環[3.1.0]己烷  1H-1,2,3-三唑-4-甲酸乙酯 4-20  1-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  (2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-吡啶-3-基)甲醇  1H-咪唑-4-甲酸乙酯 4-21  1-[(2-{3-氮雜雙環[3.1.0]-己-3-基}-4-[(1E)-2-苯基-乙烯基]嘧啶-5-基)甲基]-1H-咪唑-4-甲酸乙酯  (2-{3-氮雜雙環[3.1.0]己-3-基}-4-[(1E)-2-苯基乙烯基]-嘧啶-5-基)甲醇  1H-咪唑-4-甲酸乙酯 4-22  1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-2-溴吡啶-3-基)-甲基]-1H-1,2,3-三唑-4-甲酸乙酯  (6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)-甲醇  1H-1,2,3-三唑-4-甲酸乙酯 4-23  1-[(6-{3-氮雜雙環[3.1.0]-六-3-基}-2-丙基吡啶-3-基)-甲基]-1H-咪唑-4-甲酸乙酯  (6-{3-氮雜雙環[3.1.0]己-3-基}-2-丙基吡啶-3-基)-甲醇  1H-咪唑-4-甲酸乙酯 4-24  1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-2-氯吡啶-3-基)-甲基]-1H-1,2,3-三唑-4-甲酸乙酯  (6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)-甲醇  1H-1,2,3-三唑-4-甲酸乙酯 4-25  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯  (6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-吡啶-3-基)甲醇  1H-1,2,3-三唑-4-甲酸乙酯 4-26  1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)-甲基]-1H-咪唑-4-甲酸乙酯  (6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)-甲醇  1H-咪唑-4-甲酸乙酯 4-27  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  (6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲醇  1H-咪唑-4-甲酸乙酯 4-28  1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-2-(三氟甲氧基)-吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  3-[5-(甲氧基甲基)-6-(三氟甲氧基)吡啶-2-基]-3-氮雜雙環[3.1.0]己烷  1H-咪唑-4-甲酸乙酯 4-29  1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-2-溴吡啶-3-基)-甲基]-1H-咪唑-4-甲酸乙酯  (6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)-甲醇  1H-咪唑-4-甲酸乙酯 4-30  1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-2-溴吡啶-3-基)-甲基]-1H-吡唑-4-甲酸乙酯  (6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)-甲醇  1H-吡唑-4-甲酸乙酯 4-31  1-[(5-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-2-基)甲基]-1H-吡唑-4-甲酸乙酯  (5-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-吡啶-2-基)甲醇  1H-吡唑-4-甲酸乙酯 4-32  1-[(2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  (2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-吡啶-3-基)甲醇  1H-吡唑-4-甲酸乙酯 4-33  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  (6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲醇  1H-吡唑-4-甲酸乙酯 4-34  1-[(5-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-2-基)甲基]-1H-咪唑-4-甲酸乙酯  (5-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-吡啶-2-基)甲醇  1H-咪唑-4-甲酸乙酯 4-35  1-[(2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  (2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-吡啶-3-基)甲醇  1H-咪唑-4-甲酸乙酯 4-36  1-[(6-{3-氮雙環[3.1.0]-己-3-基}-2-(三氟-甲氧基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  3-[5-(甲氧基甲基)-6-(三氟甲氧基)吡啶-2-基]-3-氮雜雙環[3.1.0]己烷  1H-吡唑-4-甲酸乙酯 4-37  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  (6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲醇  1H-咪唑-4-甲酸乙酯 4-38  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  (6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲醇  1H-咪唑-4-甲酸乙酯 4-39  1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  (6-{3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲醇  1H-咪唑-4-甲酸乙酯 4-40  1-[(6-{3-氮雜雙環-[3.1.0]己-3-基}-2-甲基-吡啶-3-基)甲基]-3-氰基-1H-吡唑-4-甲酸甲酯  (6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲醇  3-氰基-1H-吡唑-4-甲酸甲酯 4-41  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-氯吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  (6-{3-氮雜雙環[3.1.0]己-3-基}-4-氯吡啶-3-基)甲醇  1H-吡唑-4-甲酸乙酯 4-42  1-[(5-氰基-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-4-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  2-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-5-(羥基甲基)-4-甲基吡啶-3-甲腈  1H-吡唑-4-甲酸乙酯 4-43  1-[(5-氰基-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-4-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  2-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-5-(羥基甲基)-4-甲基吡啶-3-甲腈  1H-咪唑-4-甲酸乙酯 4-44  1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-2-氟吡啶-3-基)-甲基]-1H-吡唑-4-甲酸乙酯  3-[6-氟-5-(甲氧基甲基)吡啶-2-基]-3-氮雜雙環[3.1.0]己烷  1H-吡唑-4-甲酸乙酯 4-45  1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-4-甲基吡啶-3-基)-甲基]-1H-咪唑-4-甲酸乙酯  (6-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基吡啶-3-基)-甲醇  1H-咪唑-4-甲酸乙酯 4-46  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2,4-二甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  (6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2,4-二甲基吡啶-3-基)-甲醇  1H-咪唑-4-甲酸乙酯 4-47  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2,4-二甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  (6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2,4-二甲基吡啶-3-基)-甲醇  1H-吡唑-4-甲酸乙酯 4-48 1-({2-氯-6-[(1R,5S,6R)-6-甲基-3-氮雜雙環[3.1.0]己-3-基]吡啶-3-基}甲基)-1H-咪唑-4-甲酸乙酯 {2-氯-6-[(1R,5S,6R)-6-甲基-3-氮雜雙環[3.1.0]-己-3-基]吡啶-3-基}-甲醇 1H-咪唑-4-甲酸乙酯 4-49 1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-5-氰基吡啶-3-基)-甲基]-1H-吡唑-4-甲酸乙酯 2-{3-氮雜雙環[3.1.0]己-3-基}-5-(羥基甲基)吡啶-3-甲腈 1H-吡唑-4-甲酸乙酯 4-50 2-氯-1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 (6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲醇 2-氯-1H-咪唑-4-甲酸乙酯 4-51 1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-5-氰基-4-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 2-{3-氮雜雙環[3.1.0]己-3-基}-5-(羥基甲基)-4-甲基吡啶-3-甲腈 1H-吡唑-4-甲酸乙酯 4-52 1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-5-氰基-4-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 2-{3-氮雜雙環[3.1.0]己-3-基}-5-(羥基甲基)-4-甲基吡啶-3-甲腈 1H-咪唑-4-甲酸乙酯 4-53 1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-4-氯吡啶-3-基)-甲基]-1H-咪唑-4-甲酸乙酯 (6-{3-氮雜雙環[3.1.0]己-3-基}-4-氯吡啶-3-基)甲醇 1H-咪唑-4-甲酸乙酯 4-54 1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-4-(三氟甲基)-吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 (6-{3-氮雜雙環[3.1.0]己-3-基}-4-(三氟甲基)吡啶-3-基)甲醇 1H-咪唑-4-甲酸乙酯 4-55 1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-5-溴-2-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 (6-{3-氮雜雙環[3.1.0]己-3-基}-5-溴-2-甲基吡啶-3-基)甲醇 1H-咪唑-4-甲酸乙酯 4-56 1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-5-溴-2-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 (6-{3-氮雜雙環[3.1.0]己-3-基}-5-溴-2-甲基吡啶-3-基)甲醇 1H-吡唑-4-甲酸乙酯 4-57 1-[(2-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-1H-咪唑-4-甲酸乙酯 (2-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲醇 1H-咪唑-4-甲酸乙酯 4-58 1-[(5-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-2-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 (5-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-吡啶-2-基)甲醇 1H-1,2,3-三唑-4-甲酸乙酯 4-59 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲基嘧啶-3-基)-甲基]-1H-咪唑-4-甲酸乙酯 (2-{5-氮雜螺[2.3]己-5-基}-4-甲基嘧啶-5-基)-甲醇 1H-咪唑-4-甲酸乙酯 4-60 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 (2-{5-氮雜螺[2.3]己-5-基}-4-甲基吡啶-5-基)甲醇 1H-咪唑-4-甲酸乙酯 4-61 1-[(6-{3-氮雜環[3.1.0]-己-3-基}-2-甲基嘧啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 (6-{3-氮雜雙環[3.1.0]-己-3-基}-2-甲基-嘧啶-3-基)-甲醇 1H-咪唑-4-甲酸乙酯 Intermediates 4-1 to 4-61 were prepared analogously to Intermediate 4 :

Intermediate Reaction Notes 4-1 The reaction was carried out at 70°C for 10 minutes. 4-2 The reaction was carried out at 70°C for 15 minutes. 4-3 The reaction was carried out at 70°C for 15 minutes. 4-4 The reaction was carried out at 90°C for 48 hours. 4-5 The reaction was carried out at 130°C for 10 hours. 4-6 The reaction was carried out at 120°C for 4 hours. 4-7 The reaction was carried out at 70°C for 10 minutes. 4-8 The reaction was carried out at 70°C for 5 hours. 4-9 The reaction was carried out at 70°C for 1 hour. 4-10 The reaction was carried out at 80°C for 30 minutes. 4-11 The reaction was carried out at 70°C for 10 minutes. 4-12 The reaction was carried out at 80°C for 2 hours. 4-13 The reaction was carried out at 80°C for 12 hours. 4-14 The reaction was carried out at 80°C for 4 hours. 4-15 The reaction was carried out at 70°C for 10 minutes. 4-16 The reaction was carried out at 70°C for 1 hour. 4-17 The reaction was carried out at 80°C for 15 hours. 4-18 The reaction was carried out at 70°C for 1 hour. 4-19 The reaction was carried out at 70°C for 10 minutes. 4-20 The reaction was carried out at 80°C for 7 hours and at 90°C for 2 hours. 4-21 Camphorsulfonic acid was used instead of p-toluenesulfonic acid. The reaction was carried out at 80°C for 4 hours. 4-22 The reaction was carried out at 70°C for 15 minutes. 4-23 The reaction was carried out at 90°C for 2 hours. 4-24 The reaction was carried out at 70°C for 15 minutes. 4-25 The reaction was carried out at 70°C for 12 hours. 4-26 The reaction was carried out at 90°C for 5 hours. 4-27 The reaction was carried out at 90°C for 15 hours. 4-28 The reaction was carried out at 90°C for 12 hours. 4-29 The reaction was carried out at 80°C for 5 hours. 4-30 The reaction was carried out at 80°C for 30 minutes. 4-31 The reaction was carried out at 120°C for 6 hours. 4-32 The reaction was carried out at 80°C for 2 hours. 4-33 The reaction was carried out at 60°C for 2 hours. 4-34 The reaction was carried out at 120°C for 4 hours and at 130°C for 1 hour. 4-35 The reaction was carried out at 75°C for 15 hours and at 80°C for 12 hours. 4-36 The reaction was carried out at 70°C for 30 minutes. 4-37 The reaction was carried out at 70°C for 12 hours and at 80°C for 6 hours. 4-38 The reaction was carried out at 80°C for 12 hours. 4-39 The reaction was carried out at 90°C for 12 hours. 4-40 The reaction was carried out at 80°C for 12 hours. 4-41 The reaction was carried out at 70°C for 22 hours. 4-42 The reaction was carried out at 90°C for 12 hours. 4-43 The reaction was carried out at 80°C for 48 hours. 4-44 The reaction was carried out at 70°C for 3 hours. 4-45 The reaction was carried out at 80°C for 20 hours. 4-46 The reaction was carried out at 80°C for 4 hours. 4-47 The reaction was carried out at 80°C for 2 hours. 4-48 The reaction was carried out at 80°C for 20 hours. 4-49 The reaction was carried out at 70°C for 5 hours. 4-50 The reaction was carried out at 90°C for 5 hours. 4-51 The reaction was carried out at 60°C for 16 hours. 4-52 The reaction was carried out at 90°C for 12 hours. 4-53 The reaction was carried out at 70°C for 22 hours. 4-54 The reaction was carried out at 70°C for 22 hours. 4-55 The reaction was carried out at 70°C for 20 hours. 4-56 The reaction was carried out at 70°C for 12 hours. 4-57 The reaction was carried out at 90°C for 4 hours. 4-58 The reaction was carried out at 130°C for 13 hours. 4-59 The reaction was carried out at 90°C for 5 hours. 4-60 The reaction was carried out at 90°C for 5 hours. 4-61 The reaction was carried out at 90°C for 5 hours. Intermediate name Name of starting material 1 Name of starting material 2 4-1 1-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]-hex-3-yl}pyridin-3-yl)methyl]-1H-1,2 ,3-Triazole-4-ethyl carboxylate 2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methanol 1H-1,2,3-Triazole-4-carboxylic acid ethyl ester 4-2 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester (6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methanol 1H-1,2,3-Triazole-4-carboxylic acid ethyl ester 4-3 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester (6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methanol 1H-1,2,3-Triazole-4-carboxylic acid ethyl ester 4-4 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-imidazol-4- Ethyl formate 6,6-Difluoro-3-[6-fluoro-5-(methoxymethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane 1H-imidazole-4-carboxylic acid ethyl ester 4-5 1-[(5-{3-Azabicyclo[3.1.0]-hex-3-yl}pyridin-2-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester (5-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methanol 1H-1,2,3-Triazole-4-carboxylic acid ethyl ester 4-6 1-[(5-{3-Azabicyclo[3.1.0]-hex-3-yl}pyridin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (5-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methanol 1H-Pyrazole-4-carboxylic acid ethyl ester 4-7 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-fluoropyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester 5-[6-Fluoro-5-(methoxymethyl)pyridin-2-yl]-5-azaspiro[2.3]hexane 1H-1,2,3-Triazole-4-carboxylic acid ethyl ester 4-8 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-fluoropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-[6-Fluoro-5-(methoxymethyl)pyridin-2-yl]-5-azaspiro[2.3]hexane 1H-imidazole-4-carboxylic acid ethyl ester 4-9 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-fluoropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-[6-Fluoro-5-(methoxymethyl)pyridin-2-yl]-5-azaspiro[2.3]hexane 1H-Pyrazole-4-carboxylic acid ethyl ester 4-10 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methanol 1H-Pyrazole-4-carboxylic acid ethyl ester 4-11 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-1,2, Ethyl 3-triazole-4-carboxylate (2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methanol 1H-1,2,3-Triazole-4-carboxylic acid ethyl ester 4-12 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4 -Ethyl formate (2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methanol 1H-Pyrazole-4-carboxylic acid ethyl ester 4-13 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester (6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-14 1-[(2-{3-Azabicyclo[3.1.0]-hex-3-yl}-4-[(1E)-2-phenyl-vinyl]pyrimidin-5-yl)methyl]- 1H-imidazole-4-carboxylic acid (2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-[(1E)-2-phenylvinyl]-pyrimidin-5-yl)methanol 1H-imidazole-4-carboxylic acid 4-15 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-2-fluoropyridin-3-yl)-methyl]-1H-1,2,3-triazole- Ethyl 4-formate 3-[6-Fluoro-5-(methoxymethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane 1H-1,2,3-Triazole-4-carboxylic acid ethyl ester 4-16 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-pyrazole-4 -Ethyl formate 6,6-Difluoro-3-[6-fluoro-5-(methoxymethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane 1H-Pyrazole-4-carboxylic acid ethyl ester 4-17 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester (6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-18 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-2-chloropyridin-3-yl)-methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)-methanol 1H-Pyrazole-4-carboxylic acid ethyl ester 4-19 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-1,2, Ethyl 3-triazole-4-carboxylate 6,6-Difluoro-3-[6-fluoro-5-(methoxymethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane 1H-1,2,3-Triazole-4-carboxylic acid ethyl ester 4-20 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-pyridin-3-yl)methyl]-1H-imidazole- Ethyl 4-formate (2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-pyridin-3-yl)methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-21 1-[(2-{3-Azabicyclo[3.1.0]-hex-3-yl}-4-[(1E)-2-phenyl-vinyl]pyrimidin-5-yl)methyl]- 1H-imidazole-4-carboxylic acid ethyl ester (2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-[(1E)-2-phenylvinyl]-pyrimidin-5-yl)methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-22 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-2-bromopyridin-3-yl)-methyl]-1H-1,2,3-triazole- Ethyl 4-formate (6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)-methanol 1H-1,2,3-Triazole-4-carboxylic acid ethyl ester 4-23 1-[(6-{3-Azabicyclo[3.1.0]-hexa-3-yl}-2-propylpyridin-3-yl)-methyl]-1H-imidazole-4-carboxylic acid ethyl ester (6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)-methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-24 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-2-chloropyridin-3-yl)-methyl]-1H-1,2,3-triazole- Ethyl 4-formate (6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)-methanol 1H-1,2,3-Triazole-4-carboxylic acid ethyl ester 4-25 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-1,2,3-triazole -4-ethyl formate (6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-pyridin-3-yl)methanol 1H-1,2,3-Triazole-4-carboxylic acid ethyl ester 4-26 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)-methyl]-1H-imidazole-4-carboxylic acid ethyl ester (6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)-methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-27 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-imidazol-4 -Ethyl formate (6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-28 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-2-(trifluoromethoxy)-pyridin-3-yl)methyl]-1H-imidazole-4 -Ethyl formate 3-[5-(Methoxymethyl)-6-(trifluoromethoxy)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane 1H-imidazole-4-carboxylic acid ethyl ester 4-29 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-2-bromopyridin-3-yl)-methyl]-1H-imidazole-4-carboxylic acid ethyl ester (6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)-methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-30 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-2-bromopyridin-3-yl)-methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)-methanol 1H-Pyrazole-4-carboxylic acid ethyl ester 4-31 1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (5-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-pyridin-2-yl)methanol 1H-Pyrazole-4-carboxylic acid ethyl ester 4-32 1-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-pyridin-3-yl)methyl]-1H-pyrazole -4-ethyl formate (2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-pyridin-3-yl)methanol 1H-Pyrazole-4-carboxylic acid ethyl ester 4-33 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methanol 1H-Pyrazole-4-carboxylic acid ethyl ester 4-34 1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester (5-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-pyridin-2-yl)methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-35 1-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-pyridin-3-yl)methyl]-1H-imidazole- Ethyl 4-formate (2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-pyridin-3-yl)methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-36 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-2-(trifluoro-methoxy)pyridin-3-yl)methyl]-1H-pyrazole-4 -Ethyl formate 3-[5-(Methoxymethyl)-6-(trifluoromethoxy)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane 1H-Pyrazole-4-carboxylic acid ethyl ester 4-37 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester (6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-38 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester (6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-39 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester (6-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-40 1-[(6-{3-Azabicyclo-[3.1.0]hex-3-yl}-2-methyl-pyridin-3-yl)methyl]-3-cyano-1H-pyrazole- Methyl 4-carboxylate (6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methanol Methyl 3-cyano-1H-pyrazole-4-carboxylate 4-41 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-chloropyridin-3-yl)methanol 1H-Pyrazole-4-carboxylic acid ethyl ester 4-42 1-[(5-Cyano-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-4-methylpyridin-3-yl)methyl]- 1H-Pyrazole-4-carboxylic acid ethyl ester 2-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-5-(hydroxymethyl)-4-methylpyridine-3-carbonitrile 1H-Pyrazole-4-carboxylic acid ethyl ester 4-43 1-[(5-Cyano-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-4-methylpyridin-3-yl)methyl]- 1H-imidazole-4-carboxylic acid ethyl ester 2-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-5-(hydroxymethyl)-4-methylpyridine-3-carbonitrile 1H-imidazole-4-carboxylic acid ethyl ester 4-44 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-2-fluoropyridin-3-yl)-methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 3-[6-Fluoro-5-(methoxymethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane 1H-Pyrazole-4-carboxylic acid ethyl ester 4-45 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-4-methylpyridin-3-yl)-methyl]-1H-imidazole-4-carboxylic acid ethyl ester (6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyridin-3-yl)-methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-46 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2,4-lutidine-3-yl)methyl]-1H- Imidazole-4-carboxylate ethyl ester (6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2,4-lutidine-3-yl)-methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-47 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2,4-lutidine-3-yl)methyl]-1H- Ethyl pyrazole-4-carboxylate (6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2,4-lutidine-3-yl)-methanol 1H-Pyrazole-4-carboxylic acid ethyl ester 4-48 1-({2-Chloro-6-[(1R,5S,6R)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl]pyridin-3-yl}methyl)- 1H-imidazole-4-carboxylic acid ethyl ester {2-Chloro-6-[(1R,5S,6R)-6-methyl-3-azabicyclo[3.1.0]-hex-3-yl]pyridin-3-yl}-methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-49 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-5-cyanopyridin-3-yl)-methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 2-{3-Azabicyclo[3.1.0]hex-3-yl}-5-(hydroxymethyl)pyridine-3-carbonitrile 1H-Pyrazole-4-carboxylic acid ethyl ester 4-50 2-Chloro-1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazol-4- Ethyl formate (6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methanol 2-Chloro-1H-imidazole-4-carboxylic acid ethyl ester 4-51 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-5-cyano-4-methylpyridin-3-yl)methyl]-1H-pyrazole-4 -Ethyl formate 2-{3-Azabicyclo[3.1.0]hex-3-yl}-5-(hydroxymethyl)-4-methylpyridine-3-carbonitrile 1H-Pyrazole-4-carboxylic acid ethyl ester 4-52 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-5-cyano-4-methylpyridin-3-yl)methyl]-1H-imidazol-4- Ethyl formate 2-{3-Azabicyclo[3.1.0]hex-3-yl}-5-(hydroxymethyl)-4-methylpyridine-3-carbonitrile 1H-imidazole-4-carboxylic acid ethyl ester 4-53 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-4-chloropyridin-3-yl)-methyl]-1H-imidazole-4-carboxylic acid ethyl ester (6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-chloropyridin-3-yl)methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-54 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-4-(trifluoromethyl)-pyridin-3-yl)methyl]-1H-imidazol-4- Ethyl formate (6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-(trifluoromethyl)pyridin-3-yl)methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-55 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester (6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-bromo-2-methylpyridin-3-yl)methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-56 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4- Ethyl formate (6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-bromo-2-methylpyridin-3-yl)methanol 1H-Pyrazole-4-carboxylic acid ethyl ester 4-57 1-[(2-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-1H-imidazol-4 -Ethyl formate (2-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-58 1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-1H-1,2,3-triazole -4-ethyl formate (5-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-pyridin-2-yl)methanol 1H-1,2,3-Triazole-4-carboxylic acid ethyl ester 4-59 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-methylpyrimidin-3-yl)-methyl]-1H-imidazole-4-carboxylic acid ethyl ester (2-{5-Azaspiro[2.3]hex-5-yl}-4-methylpyrimidin-5-yl)-methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-60 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester (2-{5-Azaspiro[2.3]hex-5-yl}-4-methylpyridin-5-yl)methanol 1H-imidazole-4-carboxylic acid ethyl ester 4-61 1-[(6-{3-Azacyclo[3.1.0]-hex-3-yl}-2-methylpyrimidin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester (6-{3-Azabicyclo[3.1.0]-hex-3-yl}-2-methyl-pyrimidin-3-yl)-methanol 1H-imidazole-4-carboxylic acid ethyl ester

Intermediate 5

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

1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester (162 mg) was stirred at 50°C ), MeOH (1 mL), THF (1 mL) and KOH (4 M in water, 648 µL) for 3 hours. After cooling to room temperature, aqueous HCl (4 M, 648 μL) was added and the solvent was evaporated to give the crude product, which was used directly in the next step. LC (Method 2): t _R = 0.58 min; Mass Spec (ESI ⁺ ): m/z = 285 [M+H] ⁺ .

中間物 反應備註 5-1 反應在室溫下在EtOH中進行3小時。 5-2 使用NaOH代替KOH。反應在70℃下進行1.5小時。 5-3 使用NaOH代替KOH。反應在室溫下在EtOH中進行48小時。 藉由逆相HPLC (ACN，水)純化產物。 5-4 使用NaOH代替KOH。反應在70℃下進行2小時。 5-5 使用NaOH代替KOH。反應在70℃下進行1小時。 5-6 使用NaOH代替KOH。反應在70℃下進行1.5小時。 5-7 使用NaOH代替KOH。反應在70℃下進行1.5小時。 5-9 使用NaOH代替KOH。反應在70℃下進行1.5小時。 5-10 使用NaOH代替KOH。反應在70℃下進行1.5小時。 5-11 使用NaOH代替KOH。反應在70℃下進行1.5小時。 5-12 使用NaOH代替KOH。反應在70℃下進行2小時。 5-13 使用NaOH代替KOH。反應在70℃下進行1小時。 5-14 使用NaOH代替KOH。反應在70℃下在THF/EtOH中進行45分鐘。 5-15 使用NaOH代替KOH。反應在70℃下進行1.5小時。 5-16 使用NaOH代替KOH。反應在70℃下進行1小時。 5-17 使用NaOH代替KOH。反應在70℃下進行1.5小時。 5-19 使用NaOH代替KOH。反應在50℃下在THF/EtOH中進行2小時。 5-20 使用NaOH代替KOH。反應在70℃下在THF/EtOH中進行20分鐘。 5-21 使用NaOH代替KOH。反應在室溫下在MeOH中進行12小時。 5-22 使用NaOH代替KOH。反應在70℃下進行1小時。 5-23 使用NaOH代替KOH。反應在70℃下進行0.1小時。 5-24 使用NaOH代替KOH。反應在70℃下在THF/EtOH中進行45分鐘。 5-25 使用NaOH代替KOH。反應在50℃下在THF/EtOH中進行4小時。 5-26 使用NaOH代替KOH。反應在70℃下進行1小時。 5-27 使用NaOH代替KOH。反應在70℃下在THF/EtOH中進行2小時。 5-28 使用NaOH代替KOH。反應在70℃下進行1小時。 5-29 反應在70℃下進行1小時。 5-30 使用NaOH代替KOH。反應在室溫下在EtOH中進行3小時。 5-31 使用NaOH代替KOH。反應在50℃下進行1.5小時。 5-32 使用NaOH代替KOH。反應在70℃下進行1小時。 5-33 使用NaOH代替KOH。反應在50℃下進行1小時。 5-34 使用NaOH代替KOH。反應在50℃下進行1.5小時。 5-35 使用NaOH代替KOH。反應在50℃下在THF/EtOH中進行5小時。 5-36 使用NaOH代替KOH。反應在70℃下進行1小時。 5-37 使用NaOH代替KOH。反應在70℃下進行1小時。 5-38 使用NaOH代替KOH。反應在70℃下進行3小時。 5-40 使用NaOH代替KOH。反應在50℃下進行1小時。 5-41 使用NaOH代替KOH。反應在70℃下進行8小時。 5-42 使用NaOH代替KOH。反應在40℃下進行4小時。 5-43 使用NaOH代替KOH。反應在70℃下在THF/EtOH中進行45分鐘。 5-44 使用NaOH代替KOH。反應在70℃下在THF/EtOH中進行2小時。 5-45 使用NaOH代替KOH。反應在70℃下在THF/EtOH中進行45分鐘。 5-46 反應在50℃下在EtOH中進行48小時。 5-47 反應在50℃下在EtOH中進行4小時。 5-48 使用NaOH代替KOH。反應在70℃下在THF/EtOH中進行2小時。 5-49 反應在50℃下進行2小時。 5-50 使用NaOH代替KOH。反應在40℃下在EtOH中進行12小時。 5-51 使用NaOH代替KOH。反應在70℃下在THF/EtOH中進行1小時。 5-52 使用NaOH代替KOH。反應在70℃下在THF/EtOH中進行40分鐘。 5-53 使用NaOH代替KOH。反應在70℃下進行2小時。 5-54 使用NaOH代替KOH。反應在室溫下在EtOH中進行12小時。 5-55 使用NaOH代替KOH。反應在70℃下進5小時。 5-56 使用NaOH代替KOH。反應在50℃下進行2小時。 5-57 使用NaOH代替KOH。反應在80℃下在THF中進行4小時。 5-58 使用NaOH代替KOH。反應在50℃下在1,4-二㗁烷中進行3小時。 5-59 使用NaOH代替KOH。反應在70℃下在THF/EtOH中進行40分鐘。 5-60 使用NaOH代替KOH。反應在室溫下在EtOH中進行48小時。 5-61 使用NaOH代替KOH。反應在70℃下進行1小時。 5-62 使用NaOH代替KOH。反應在70℃下在THF/EtOH中進行2小時。 5-63 使用NaOH代替KOH。反應在50℃下在THF/EtOH中進行2小時。 5-64 使用NaOH代替KOH。反應在70℃下在THF/EtOH中進行2小時。 5-65 使用NaOH代替KOH。反應在70℃下在THF/EtOH中進行1.5小時。 5-66 使用NaOH代替KOH。反應在室溫下在MeOH中進行3小時。 5-67 使用NaOH代替KOH。反應在60℃下進行2小時。 5-68 使用NaOH代替KOH。反應在40℃下進行12小時。 5-69 使用NaOH代替KOH。反應在室溫下在MeOH中進行4小時。 5-70 使用NaOH代替KOH。反應在室溫下在MeOH中進行15小時。 5-71 使用NaOH代替KOH。反應在50℃下進行6小時。 5-72 使用NaOH代替KOH。反應在70℃下在THF/EtOH中進行2.5小時。 5-73 使用NaOH代替KOH。反應在70℃下在THF/EtOH中進行2.5小時。 5-74 使用NaOH代替KOH。反應在70℃下在THF/EtOH中進行2.5小時。 5-75 使用NaOH代替KOH。反應在50℃下在MeOH中進行12小時。 5-76 使用NaOH代替KOH。反應在室溫下在THF/EtOH中進行50分鐘。 5-77 使用NaOH代替KOH。反應在室溫下在MeOH中進行4小時。 5-78 使用NaOH代替KOH。反應在50℃下進行4小時。 5-79 反應在50℃下在EtOH中進行12小時。 5-80 使用NaOH代替KOH。反應在室溫下在EtOH中進行12小時。 5-81 使用NaOH代替KOH。 反應在THF中在80℃下進行6小時且在室溫下進行12小時。 5-82 使用LiOH代替KOH。反應在50℃下在THF/MeOH中進行12小時。 5-83 使用NaOH代替KOH。反應在40℃下進行2小時。 5-84 反應在40℃下進行4小時。 5-85 使用NaOH代替KOH。反應在室溫下在EtOH中進行12小時。 5-86 使用NaOH代替KOH。反應在室溫下在MeOH中進行6小時。 5-87 使用NaOH代替KOH。反應在70℃下進行3小時。 5-88 使用NaOH代替KOH。反應在70℃下進行2小時。 5-89 反應在50℃下在EtOH中進行12小時。 5-90 使用NaOH代替KOH。反應在50℃下進行4.5小時。 5-91 使用NaOH代替KOH。反應在50℃下進行2小時。 5-92 反應在50℃下進行12小時。 5-93 使用NaOH代替KOH。反應在室溫下在EtOH中進行2.5小時。 5-94 使用NaOH代替KOH。反應在90℃下在1,4-二㗁烷中進行1小時。 5-95 使用NaOH代替KOH。反應在室溫下在MeOH中進行12小時。 5-96 使用NaOH代替KOH。反應在70℃下進行1小時。 5-97 反應在50℃下在EtOH中進行12小時。 5-98 使用NaOH代替KOH。反應在70℃下進行2小時。 5-99 使用NaOH代替KOH。反應在70℃下進行1小時。 5-100 使用NaOH代替KOH。反應在70℃下進行1小時。 5-101 使用NaOH代替KOH。反應在70℃下進行1小時。 5-102 使用NaOH代替KOH。反應在70℃下進行1小時。 5-103 使用NaOH代替KOH。反應在70℃下進行1小時。 5-104 使用NaOH代替KOH。反應在60℃下進行1小時。 5-105 使用NaOH代替KOH。反應在室溫下在EtOH中進行12小時。 5-106 使用NaOH代替KOH。反應在60℃下進行1小時。 5-107 使用NaOH代替KOH。反應在70℃下進行2.5小時。 5-108 使用NaOH代替KOH。反應在70℃下進行2.5小時。 5-109 使用NaOH代替KOH。反應在40℃下在EtOH中進行12小時。 5-110 使用NaOH代替KOH。反應在60℃下進行7小時。 5-111 使用NaOH代替KOH。反應在70℃下進行1小時。 5-112 使用NaOH代替KOH。反應在50℃下進行20小時。 5-113 使用NaOH代替KOH。反應在40℃下在EtOH中進行12小時。 5-114 使用NaOH代替KOH。反應在60℃下進行2.5小時。 5-115 使用NaOH代替KOH。反應在50℃下進行2小時。 5-116 使用NaOH代替KOH。反應在70℃下進行1.5小時。 5-117 使用NaOH代替KOH。反應在70℃下在THF/EtOH中進行2小時。 5-118 使用NaOH代替KOH。反應在70℃下進行1小時。 5-119 使用NaOH代替KOH。反應在70℃下進行1.5小時。 5-120 使用NaOH代替KOH。反應在室溫下在EtOH中進行4小時。 5-121 使用LiOH代替KOH。反應在室溫下在THF/水中進行12小時。 5-122 反應在50℃下進行48小時。 5-123 使用NaOH代替KOH。反應在室溫下在MeOH中進行12小時。 5-124 使用NaOH代替KOH。反應在50℃下進行1.5小時。 5-125 使用NaOH代替KOH。反應在50℃下在EtOH中進行12小時。 5-126 反應在50℃下進行2小時。 5-127 使用NaOH代替KOH。反應在70℃下進行2天。 5-128 使用NaOH代替KOH。反應在70℃下進5天。 5-129 使用NaOH代替KOH。反應在70℃下進行35小時且在室溫下進行3天。 5-130 使用NaOH代替KOH。反應在70℃下進行24小時且在50℃下進行2天。 5-131 使用NaOH代替KOH。反應在室溫下進行小時。 5-132 使用NaOH代替KOH。反應在室溫下進行45分鐘。 5-133 使用NaOH代替KOH。反應在室溫下進行45分鐘。 5-134 使用NaOH代替KOH。反應在室溫下進行4小時。 5-135 使用NaOH代替KOH。反應在室溫下進行30分鐘。 5-136 使用NaOH代替KOH。反應在室溫下進行1.5小時。 5-137 使用NaOH代替KOH。反應在室溫下進行2.5小時。 5-138 使用NaOH代替KOH。反應在室溫下進行45分鐘。 5-139 使用NaOH代替KOH。反應在室溫下進行1.5小時。 5-140 使用NaOH代替KOH。反應在室溫下進行16小時。 5-141 使用NaOH代替KOH。反應在室溫下進行16小時。 5-142 使用NaOH代替KOH。反應在室溫下進行72小時。 5-143 使用NaOH代替KOH。反應在室溫下進行18小時。 5-144 使用NaOH代替KOH。反應在50℃下進行2小時。 5-145 使用NaOH代替KOH。反應在50℃下進行30分鐘。 5-146 使用NaOH代替KOH。反應在室溫下在MeOH中進行5小時。 5-147 使用NaOH代替KOH。反應在80℃下進行12小時。 5-148 使用NaOH代替KOH。反應在室溫下進行17小時。 5-149 使用NaOH代替KOH。反應在室溫下進行17小時。 5-150 使用NaOH代替KOH。反應在室溫下在EtOH中進行12小時。 5-151 使用NaOH代替KOH。反應在40℃下進行1.5小時。 5-152 使用NaOH代替KOH。反應在40℃下進行3小時。 5-153 使用NaOH代替KOH。反應在40℃下進行45分鐘。 5-154 使用NaOH代替KOH。反應在室溫下在MeOH中進行12小時。 5-155 使用NaOH代替KOH。反應在室溫下在EtOH中進行5天。 5-156 使用NaOH代替KOH。反應在室溫下在THF中進行16小時。 5-157 使用NaOH代替KOH。反應在40℃下在MeOH中進行1小時。 5-158 使用NaOH代替KOH。反應在室溫下在EtOH中進行2小時。 5-159 使用NaOH代替KOH。反應在40℃下在MeOH中進行1小時。 5-160 使用NaOH代替KOH。反應在室溫下在1,4-二㗁烷/水為2:1中進行3小時。 5-161 使用NaOH代替KOH。反應在50℃下在MeOH/二㗁烷中進行4小時。 藉由逆相HPLC (ACN，水)純化產物。 5-162 使用LiOH代替KOH。反應在75℃下在MeOH中進行6小時。 5-163 使用LiOH代替KOH。反應在75℃下在MeOH中進行16小時。 5-164 使用NaOH代替KOH。反應在70℃下進行1小時。 5-165 使用NaOH代替KOH。反應在70℃下進行2小時。 5-166 使用NaOH代替KOH。反應在70℃下進行1.5小時。 5-167 使用NaOH代替KOH。反應在70℃下進行1.5小時。 5-168 使用NaOH代替KOH。反應在室溫下在EtOH中進行3.5小時。 5-169 使用NaOH代替KOH。反應在70℃下進行1小時。 5-170 使用NaOH代替KOH。反應在50℃下進行2小時。 中間物 名稱 起始材料 之名稱 5-1 1-[[6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-2 1-[(2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-3 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-4 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-5 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-6 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-7 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}吡啶-2-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}-吡啶-2-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-8 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}吡啶-2-基)甲基]-1H-吡唑-4-甲酸 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}-吡啶-2-基)甲基]-1H-吡唑-4-甲酸乙酯 5-9 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氟吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氟吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-10 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氟吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氟吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-11 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氟吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氟吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-12 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-13 1-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-14 1-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-15 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-16 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-17 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-18 1-[(5-{5-氮雜螺[2.3]己-5-基}吡啶-2-基)甲基]-1H-吡唑-4-甲酸 1-[(5-{5-氮雜螺[2.3]己-5-基}吡啶-2-基)甲基]-1H-吡唑-4-甲酸乙酯 5-19 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-20 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-21 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-22 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-23 1-[(6-{5-氮雜螺[2.3]己-5-基}吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-24 1-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-25 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-(二氟甲基)嘧啶-5-基)甲基]-1H-咪唑-4-甲酸 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4(二氟甲基)嘧啶-5-基)甲基]-1H-咪唑-4-甲酸乙酯 5-26 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-27 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-丙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-丙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-28 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-29 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-30 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-31 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-32 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-33 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}-6-氰基吡啶-2-基)甲基]-1H-吡唑-4-甲酸 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}-6-氰基吡啶-2-基)甲基]-1H-吡唑-4-甲酸乙酯 5-34 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-35 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-36 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(三氟甲氧基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(三氟甲氧基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-37 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-38 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-39 1-[(5-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-2-基)甲基]-1H-吡唑-4-甲酸 1-[(5-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-2-基)甲基]-1H-吡唑-4-甲酸乙酯 5-40 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(1-氰基環丙基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(1-氰基環丙基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-41 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-42 1-[(2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-43 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-44 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-45 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-46 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-(二氟甲基)嘧啶-5-基)甲基]-1H-吡唑-4-甲酸 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-(二氟甲基)嘧啶-5-基)甲基]-1H-吡唑-4-甲酸乙酯 5-47 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-48 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-49 1-[(5-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-2-基)甲基]-1H-咪唑-4-甲酸 1-[(5-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-2-基)甲基]-1H-咪唑-4-甲酸乙酯 5-50 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(3-羥丙基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(3-羥丙基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-51 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-52 1-[(2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-53 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(三氟甲氧基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(三氟甲氧基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-54 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(1-羥基丙烯-2-基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(1-羥基丙烯-2-基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-55  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}噠𠯤-3-基)甲基]-1H-吡唑-4-甲酸  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-嗒𠯤-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-56  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-57  1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-(羥甲基)嘧啶-5-基)甲基]-1H-吡唑-4-甲酸  1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-(羥甲基)嘧啶-5-基)甲基]-1H-吡唑-4-甲酸乙酯 5-58  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-59  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-60  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(1-氰基-1-甲基乙基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(1-氰基-1-甲基乙基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-61  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-丙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-丙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-62  1-[(2-環丁基-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡唑-4-甲酸  1-[(2-環丁基-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-63  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-64  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-丙基吡啶-3-基)甲基]-1H-吡唑-4-甲酸  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-丙基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-65  1-[(5-{3-氮雜雙環[3.1.0]己-3-基}嘧啶-2-基)甲基]-1H-吡唑-4-甲酸  1-[(5-{3-氮雜雙環[3.1.0]己-3-基}-嘧啶-2-基)甲基]-1H-吡唑-4-甲酸乙酯 5-66  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-67  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-68  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-69  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸酯三氟乙酸乙酯 5-70  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(氰基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(氰基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-71  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(1-羥基乙基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(1-羥基乙基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-72  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-[(1R)-1-羥基乙基]吡啶-3-基)甲基]-1H-吡唑-4-甲酸  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-[(1R)-1-羥基乙基]吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-73  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-[(1S)-1-羥基乙基]吡啶-3-基)甲基]-1H-吡唑-4-甲酸  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-[(1R)-1-羥基乙基]吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-74  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(2-羥基丙烯-2-基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(2-羥基丙烯-2-基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-75  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(2-羥基乙基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(2-羥基乙基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-76  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-77  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-78  1-[(5-{3-氮雜雙環[3.1.0]己-3-基}-3-(羥基甲基)吡𠯤-2-基)甲基]-1H-吡唑-4-甲酸  1-[(5-{3-氮雜雙環[3.1.0]己-3-基}-3-(羥基甲基)吡𠯤-2-基)甲基]-1H-吡唑-4-甲酸乙酯 5-79  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-80  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-81  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(羥基甲基)吡啶-3-基)-甲基]-1H-吡唑-4-甲酸乙酯 5-82 1-[(5-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-3-甲基吡𠯤-2-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(5-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-3-甲基吡𠯤-2-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-83 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-84 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-85 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-86 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-氰基-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-氰基-1H-吡唑-4-甲酸甲酯 5-87 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-氯吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-氯吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-88 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(2-甲基丙基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(2-甲基丙基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-89 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-90 1-[(5-氰基-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-4-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(5-氰基-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-4-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-91 1-[(5-氰基-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-4-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(5-氰基-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-4-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-92 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-93 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-94 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-(羥基甲基)-1H-吡唑-4-甲酸 3-(氯甲基))-1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-95 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-(氰基甲基)-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-(氰基甲基)-1H-吡唑-4-甲酸乙酯 5-96 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-97 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-98 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-丙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-丙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-99 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2,4-二甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2,4-二甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-100 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2,4-二甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2,4-二甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-101 5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]噻吩-2-甲酸 5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)-甲基]噻吩-2-甲酸乙酯 5-102 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-103 2-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1,3-噻唑-5-甲酸 2-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲基]-1,3-噻唑-5-甲酸甲酯 5-104 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基-4-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基-4-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-105 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-環丙基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-環丙基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-106 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基-4-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基-4-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-107 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-氯吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-氯吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-108 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-(三氟甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-(三氟甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-109 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-110 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-(甲氧基甲基)-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-(甲氧基甲基)-1H-吡唑-4-甲酸乙酯 5-111 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基-2-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基-2-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-112 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-(甲氧基-甲基)-1H-吡唑-4-甲酸 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲基]-3-(甲氧基甲基)-1H-吡唑-4-甲酸乙酯 5-113 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-114 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-溴-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-溴-1H-吡唑-4-甲酸乙酯 5-115 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-溴-2-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-溴-2-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-116 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基-2-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基-2-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸甲酯 5-117 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-溴-2-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-溴-2-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-118 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2,5-二甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2,5-二甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸甲酯 5-119 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2,5-二甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2,5-二甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸甲酯 5-120 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氰基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氰基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-121 1-[(2-氯-4-甲基嘧啶-5-基)甲基]-1H-吡唑-4-甲酸 1-[(2-氯-4-甲基嘧啶-5-基)-甲基]-1H-吡唑-4-甲酸乙酯 5-122 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 5-123 1-[(2-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-1H-咪唑-4-甲酸 1-[(2-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-4-甲基嘧啶-5-基)甲基]-1H-咪唑-4-甲酸乙酯 5-124 1-[(2-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(2-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-4-甲基嘧啶-5-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-125 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-126 1-[(5-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-2-基)甲基]-1H-1,2,3-三唑-4-甲酸 1-[(5-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}吡啶-2-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 5-127 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡咯-3-甲酸 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}吡啶-3-基)甲基]-1H-吡咯-3-甲酸甲酯 5-128 5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡咯-3-甲酸 5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}吡啶-3-基)甲基]-1H-吡咯-3-甲酸甲酯 5-129 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1H-吡咯-3-甲酸 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲基]-1H-吡咯-3-甲酸甲酯 5-130 5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1H-吡咯-3-甲酸 5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲基]-1H-吡咯-3-甲酸甲酯 5-131 1-({2-乙基-6-[(1R,5S,6R)-6-甲基-3-氮雜雙環[3.1.0]己-3-基]吡啶-3-基}甲基)-1H-咪唑-4-甲酸 1-({2-乙基-6-[(1R,5S,6R)-6-甲基-3-氮雜雙環[3.1.0]己-3-基]吡啶-3-基}甲基)-1H-咪唑-4-甲酸乙酯 5-132 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 5-133 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 5-134 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 5-135 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 5-136 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 5-137 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 5-138 3-[(2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 3-[(2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 5-139 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 5-140 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 5-141 2-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1,3-㗁唑-5-甲酸 2-[1-(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)-2-甲氧基-2-側氧基乙基]-1,3-㗁唑-5-甲酸甲酯 5-142 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-乙基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 5-143 2-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1,3-㗁唑-5-甲酸 2-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲基]-1,3-㗁唑-5-甲酸乙酯 5-144 3-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 3-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 5-145 3-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 3-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 5-146 2-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1,3-㗁唑-5-甲酸 2-[1-(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)-2-甲氧基-2-側氧基乙基]-1,3-㗁唑-5-甲酸甲酯 5-147 5-[(2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡咯-3-甲酸 5-[(2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡咯-3-甲酸甲酯 5-148 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1-(丙烯-2-基)-1H-吡唑-5-甲酸 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-乙基吡啶-3-基)甲基]-1-(丙烯-2-基)-1H-吡唑-5-甲酸乙酯 5-149 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1-乙基-1H-吡唑-5-甲酸 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-乙基吡啶-3-基)甲基]-1-乙基-1H-吡唑-5-甲酸乙酯 5-150 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-5-甲酸及5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-3-甲酸(異構體之混合物) 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-5-甲酸乙酯及5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-3-甲酸乙酯(異構體之混合物) 5-151 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1-乙基-1H-吡唑-5-甲酸 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1-乙基-1H-吡唑-5-甲酸乙酯 5-152 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1-乙基-1H-吡唑-5-甲酸 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲基]-1-乙基-1H-吡唑-5-甲酸乙酯 5-153 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1-乙基-1H-吡唑-5-甲酸 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1-乙基-1H-吡唑-5-甲酸乙酯 5-154 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-吡唑-5-甲酸 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-吡唑-5-甲酸乙酯 5-155 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1-甲基-1H-吡唑-5-甲酸 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1-甲基-1H-吡唑-5-甲酸乙酯 5-156 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1-甲基-1H-吡唑-5-甲酸 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1-甲基-1H-吡唑-5-甲酸乙酯 5-157 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲基嘧啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲基嘧啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-158 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-159 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基嘧啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基嘧啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-160 2-氯-1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸 2-氯-1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 5-161 7-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-7H-吡咯并[2,3-d]嘧啶-5-甲酸 7-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-7H-吡咯并[2,3-d]嘧啶-5-甲酸甲酯 5-162 7-[(2-{6 ,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-7H-吡咯并[2,3-d]嘧啶-5-甲酸 7-[(2-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-4-甲基嘧啶-5-基)甲基]-7H-吡咯并[2,3-d]嘧啶-5-甲酸甲酯 5-163 7-[2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-7H-吡咯并[2,3-d]嘧啶-5-甲酸 7-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-7H-吡咯并[2,3-d]嘧啶-5-甲酸甲酯 5-164 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]呋喃-2-甲酸 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]呋喃-2-甲酸甲酯 5-165 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]呋喃-3-甲酸 5-[(6-{3-氮雜雙環氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]呋喃-3-甲酸乙酯 5-166 5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]呋喃-2-甲酸 5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲基]呋喃-2-甲酸甲酯 5-167 5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]呋喃-2-甲酸 5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-乙基吡啶-3-基)甲基]呋喃-2-甲酸甲酯 5-168 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基-吡啶-3-基)甲基]噻吩-2-甲酸 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]噻吩-2-甲酸乙酯 5-169 5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]噻吩-2-甲酸 5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-乙基吡啶-3-基)甲基]噻吩-2-甲酸乙酯 5-170 5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]噻吩-2-甲酸 5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(羥基甲基)-吡啶-3-基)甲基]噻吩-2-甲酸乙酯 Intermediates 5-1 to 5-170 were prepared analogously to Intermediate 5 :

Intermediate Reaction Notes 5-1 The reaction was carried out in EtOH at room temperature for 3 hours. 5-2 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1.5 hours. 5-3 Use NaOH instead of KOH. The reaction was carried out in EtOH at room temperature for 48 hours. The product was purified by reverse phase HPLC (ACN, water). 5-4 Use NaOH instead of KOH. The reaction was carried out at 70°C for 2 hours. 5-5 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-6 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1.5 hours. 5-7 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1.5 hours. 5-9 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1.5 hours. 5-10 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1.5 hours. 5-11 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1.5 hours. 5-12 Use NaOH instead of KOH. The reaction was carried out at 70°C for 2 hours. 5-13 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-14 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 70°C for 45 minutes. 5-15 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1.5 hours. 5-16 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-17 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1.5 hours. 5-19 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 50°C for 2 hours. 5-20 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 70°C for 20 minutes. 5-21 Use NaOH instead of KOH. The reaction was carried out in MeOH at room temperature for 12 hours. 5-22 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-23 Use NaOH instead of KOH. The reaction was carried out at 70°C for 0.1 hour. 5-24 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 70°C for 45 minutes. 5-25 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 50°C for 4 hours. 5-26 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-27 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 70°C for 2 hours. 5-28 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-29 The reaction was carried out at 70°C for 1 hour. 5-30 Use NaOH instead of KOH. The reaction was carried out in EtOH at room temperature for 3 hours. 5-31 Use NaOH instead of KOH. The reaction was carried out at 50°C for 1.5 hours. 5-32 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-33 Use NaOH instead of KOH. The reaction was carried out at 50°C for 1 hour. 5-34 Use NaOH instead of KOH. The reaction was carried out at 50°C for 1.5 hours. 5-35 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 50°C for 5 hours. 5-36 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-37 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-38 Use NaOH instead of KOH. The reaction was carried out at 70°C for 3 hours. 5-40 Use NaOH instead of KOH. The reaction was carried out at 50°C for 1 hour. 5-41 Use NaOH instead of KOH. The reaction was carried out at 70°C for 8 hours. 5-42 Use NaOH instead of KOH. The reaction was carried out at 40°C for 4 hours. 5-43 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 70°C for 45 minutes. 5-44 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 70°C for 2 hours. 5-45 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 70°C for 45 minutes. 5-46 The reaction was carried out in EtOH at 50°C for 48 hours. 5-47 The reaction was carried out in EtOH at 50°C for 4 hours. 5-48 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 70°C for 2 hours. 5-49 The reaction was carried out at 50°C for 2 hours. 5-50 Use NaOH instead of KOH. The reaction was carried out in EtOH at 40°C for 12 hours. 5-51 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 70°C for 1 hour. 5-52 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 70°C for 40 minutes. 5-53 Use NaOH instead of KOH. The reaction was carried out at 70°C for 2 hours. 5-54 Use NaOH instead of KOH. The reaction was carried out in EtOH at room temperature for 12 hours. 5-55 Use NaOH instead of KOH. The reaction was carried out at 70°C for 5 hours. 5-56 Use NaOH instead of KOH. The reaction was carried out at 50°C for 2 hours. 5-57 Use NaOH instead of KOH. The reaction was carried out in THF at 80°C for 4 hours. 5-58 Use NaOH instead of KOH. The reaction was carried out in 1,4-dioxane at 50°C for 3 hours. 5-59 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 70°C for 40 minutes. 5-60 Use NaOH instead of KOH. The reaction was carried out in EtOH at room temperature for 48 hours. 5-61 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-62 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 70°C for 2 hours. 5-63 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 50°C for 2 hours. 5-64 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 70°C for 2 hours. 5-65 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 70°C for 1.5 hours. 5-66 Use NaOH instead of KOH. The reaction was carried out in MeOH at room temperature for 3 hours. 5-67 Use NaOH instead of KOH. The reaction was carried out at 60°C for 2 hours. 5-68 Use NaOH instead of KOH. The reaction was carried out at 40°C for 12 hours. 5-69 Use NaOH instead of KOH. The reaction was carried out in MeOH at room temperature for 4 hours. 5-70 Use NaOH instead of KOH. The reaction was carried out in MeOH at room temperature for 15 hours. 5-71 Use NaOH instead of KOH. The reaction was carried out at 50°C for 6 hours. 5-72 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 70°C for 2.5 hours. 5-73 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 70°C for 2.5 hours. 5-74 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 70°C for 2.5 hours. 5-75 Use NaOH instead of KOH. The reaction was carried out in MeOH at 50°C for 12 hours. 5-76 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at room temperature for 50 minutes. 5-77 Use NaOH instead of KOH. The reaction was carried out in MeOH at room temperature for 4 hours. 5-78 Use NaOH instead of KOH. The reaction was carried out at 50°C for 4 hours. 5-79 The reaction was carried out in EtOH at 50°C for 12 hours. 5-80 Use NaOH instead of KOH. The reaction was carried out in EtOH at room temperature for 12 hours. 5-81 Use NaOH instead of KOH. The reaction was carried out in THF at 80°C for 6 hours and at room temperature for 12 hours. 5-82 Use LiOH instead of KOH. The reaction was carried out in THF/MeOH at 50°C for 12 hours. 5-83 Use NaOH instead of KOH. The reaction was carried out at 40°C for 2 hours. 5-84 The reaction was carried out at 40°C for 4 hours. 5-85 Use NaOH instead of KOH. The reaction was carried out in EtOH at room temperature for 12 hours. 5-86 Use NaOH instead of KOH. The reaction was carried out in MeOH at room temperature for 6 hours. 5-87 Use NaOH instead of KOH. The reaction was carried out at 70°C for 3 hours. 5-88 Use NaOH instead of KOH. The reaction was carried out at 70°C for 2 hours. 5-89 The reaction was carried out in EtOH at 50°C for 12 hours. 5-90 Use NaOH instead of KOH. The reaction was carried out at 50°C for 4.5 hours. 5-91 Use NaOH instead of KOH. The reaction was carried out at 50°C for 2 hours. 5-92 The reaction was carried out at 50°C for 12 hours. 5-93 Use NaOH instead of KOH. The reaction was carried out in EtOH at room temperature for 2.5 hours. 5-94 Use NaOH instead of KOH. The reaction was carried out in 1,4-dioxane at 90°C for 1 hour. 5-95 Use NaOH instead of KOH. The reaction was carried out in MeOH at room temperature for 12 hours. 5-96 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-97 The reaction was carried out in EtOH at 50°C for 12 hours. 5-98 Use NaOH instead of KOH. The reaction was carried out at 70°C for 2 hours. 5-99 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-100 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-101 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-102 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-103 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-104 Use NaOH instead of KOH. The reaction was carried out at 60°C for 1 hour. 5-105 Use NaOH instead of KOH. The reaction was carried out in EtOH at room temperature for 12 hours. 5-106 Use NaOH instead of KOH. The reaction was carried out at 60°C for 1 hour. 5-107 Use NaOH instead of KOH. The reaction was carried out at 70°C for 2.5 hours. 5-108 Use NaOH instead of KOH. The reaction was carried out at 70°C for 2.5 hours. 5-109 Use NaOH instead of KOH. The reaction was carried out in EtOH at 40°C for 12 hours. 5-110 Use NaOH instead of KOH. The reaction was carried out at 60°C for 7 hours. 5-111 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-112 Use NaOH instead of KOH. The reaction was carried out at 50°C for 20 hours. 5-113 Use NaOH instead of KOH. The reaction was carried out in EtOH at 40°C for 12 hours. 5-114 Use NaOH instead of KOH. The reaction was carried out at 60°C for 2.5 hours. 5-115 Use NaOH instead of KOH. The reaction was carried out at 50°C for 2 hours. 5-116 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1.5 hours. 5-117 Use NaOH instead of KOH. The reaction was carried out in THF/EtOH at 70°C for 2 hours. 5-118 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-119 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1.5 hours. 5-120 Use NaOH instead of KOH. The reaction was carried out in EtOH at room temperature for 4 hours. 5-121 Use LiOH instead of KOH. The reaction was carried out in THF/water at room temperature for 12 hours. 5-122 The reaction was carried out at 50°C for 48 hours. 5-123 Use NaOH instead of KOH. The reaction was carried out in MeOH at room temperature for 12 hours. 5-124 Use NaOH instead of KOH. The reaction was carried out at 50°C for 1.5 hours. 5-125 Use NaOH instead of KOH. The reaction was carried out in EtOH at 50°C for 12 hours. 5-126 The reaction was carried out at 50°C for 2 hours. 5-127 Use NaOH instead of KOH. The reaction was carried out at 70°C for 2 days. 5-128 Use NaOH instead of KOH. The reaction was carried out at 70°C for 5 days. 5-129 Use NaOH instead of KOH. The reaction was carried out at 70°C for 35 hours and at room temperature for 3 days. 5-130 Use NaOH instead of KOH. The reaction was carried out at 70°C for 24 hours and at 50°C for 2 days. 5-131 Use NaOH instead of KOH. The reaction was carried out at room temperature for 1 hour. 5-132 Use NaOH instead of KOH. The reaction was carried out at room temperature for 45 minutes. 5-133 Use NaOH instead of KOH. The reaction was carried out at room temperature for 45 minutes. 5-134 Use NaOH instead of KOH. The reaction was carried out at room temperature for 4 hours. 5-135 Use NaOH instead of KOH. The reaction was carried out at room temperature for 30 minutes. 5-136 Use NaOH instead of KOH. The reaction was carried out at room temperature for 1.5 hours. 5-137 Use NaOH instead of KOH. The reaction was carried out at room temperature for 2.5 hours. 5-138 Use NaOH instead of KOH. The reaction was carried out at room temperature for 45 minutes. 5-139 Use NaOH instead of KOH. The reaction was carried out at room temperature for 1.5 hours. 5-140 Use NaOH instead of KOH. The reaction was carried out at room temperature for 16 hours. 5-141 Use NaOH instead of KOH. The reaction was carried out at room temperature for 16 hours. 5-142 Use NaOH instead of KOH. The reaction was carried out at room temperature for 72 hours. 5-143 Use NaOH instead of KOH. The reaction was carried out at room temperature for 18 hours. 5-144 Use NaOH instead of KOH. The reaction was carried out at 50°C for 2 hours. 5-145 Use NaOH instead of KOH. The reaction was carried out at 50°C for 30 minutes. 5-146 Use NaOH instead of KOH. The reaction was carried out in MeOH at room temperature for 5 hours. 5-147 Use NaOH instead of KOH. The reaction was carried out at 80°C for 12 hours. 5-148 Use NaOH instead of KOH. The reaction was carried out at room temperature for 17 hours. 5-149 Use NaOH instead of KOH. The reaction was carried out at room temperature for 17 hours. 5-150 Use NaOH instead of KOH. The reaction was carried out in EtOH at room temperature for 12 hours. 5-151 Use NaOH instead of KOH. The reaction was carried out at 40°C for 1.5 hours. 5-152 Use NaOH instead of KOH. The reaction was carried out at 40°C for 3 hours. 5-153 Use NaOH instead of KOH. The reaction was carried out at 40°C for 45 minutes. 5-154 Use NaOH instead of KOH. The reaction was carried out in MeOH at room temperature for 12 hours. 5-155 Use NaOH instead of KOH. The reaction was carried out in EtOH at room temperature for 5 days. 5-156 Use NaOH instead of KOH. The reaction was carried out in THF at room temperature for 16 hours. 5-157 Use NaOH instead of KOH. The reaction was carried out in MeOH at 40°C for 1 hour. 5-158 Use NaOH instead of KOH. The reaction was carried out in EtOH at room temperature for 2 hours. 5-159 Use NaOH instead of KOH. The reaction was carried out in MeOH at 40°C for 1 hour. 5-160 Use NaOH instead of KOH. The reaction was carried out in 1,4-dioxane/water 2:1 at room temperature for 3 hours. 5-161 Use NaOH instead of KOH. The reaction was carried out in MeOH/diethane at 50°C for 4 hours. The product was purified by reverse phase HPLC (ACN, water). 5-162 Use LiOH instead of KOH. The reaction was carried out in MeOH at 75°C for 6 hours. 5-163 Use LiOH instead of KOH. The reaction was carried out in MeOH at 75°C for 16 hours. 5-164 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-165 Use NaOH instead of KOH. The reaction was carried out at 70°C for 2 hours. 5-166 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1.5 hours. 5-167 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1.5 hours. 5-168 Use NaOH instead of KOH. The reaction was carried out in EtOH at room temperature for 3.5 hours. 5-169 Use NaOH instead of KOH. The reaction was carried out at 70°C for 1 hour. 5-170 Use NaOH instead of KOH. The reaction was carried out at 50°C for 2 hours. Intermediate name name of starting material 5-1 1-[[6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]- 1H-Pyrazole-4-carboxylic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl] -1H-Pyrazole-4-carboxylic acid ethyl ester 5-2 1-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-1,2, 3-Triazole-4-carboxylic acid 1-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-1,2, Ethyl 3-triazole-4-carboxylate 5-3 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-1,2,3-triazole -4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-1,2,3-triazole -4-ethyl formate 5-4 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester 5-5 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester 5-6 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-imidazol-4- Formic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-imidazol-4- Ethyl formate 5-7 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}-pyridin-2-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester 5-8 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}-pyridin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-9 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-fluoropyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-fluoropyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester 5-10 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-fluoropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-fluoropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-11 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-fluoropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-fluoropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-12 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-13 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-1,2, 3-Triazole-4-carboxylic acid 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-1,2, Ethyl 3-triazole-4-carboxylate 5-14 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4 - Formic acid 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4 -Ethyl formate 5-15 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-16 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-1,2,3-triazole-4- Formic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-1,2,3-triazole-4- Ethyl formate 5-17 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-pyrazole-4 - Formic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-pyrazole-4 -Ethyl formate 5-18 1-[(5-{5-Azaspiro[2.3]hex-5-yl}pyridin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(5-{5-Azaspiro[2.3]hex-5-yl}pyridin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-19 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester 5-20 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-21 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-22 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-1,2, 3-Triazole-4-carboxylic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-1,2, Ethyl 3-triazole-4-carboxylate 5-23 1-[(6-{5-Azaspiro[2.3]hex-5-yl}pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester 5-24 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazol-4- Formic acid 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazol-4- Ethyl formate 5-25 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-(difluoromethyl)pyrimidin-5-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4(difluoromethyl)pyrimidin-5-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-26 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-1,2,3- Triazole-4-carboxylic acid 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-1,2,3- Ethyl triazole-4-carboxylate 5-27 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-28 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-1,2,3-triazole-4- Formic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-1,2,3-triazole-4- Ethyl formate 5-29 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-1,2,3-triazole -4-carboxylic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-1,2,3-triazole -4-ethyl formate 5-30 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-31 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-imidazol-4 - Formic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-imidazol-4 -Ethyl formate 5-32 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methyl]-1H-1,2,3-triazole-4- Formic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methyl]-1H-1,2,3-triazole-4- Ethyl formate 5-33 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}-6-cyanopyridin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}-6-cyanopyridin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-34 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole- 4-carboxylic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole- Ethyl 4-formate 5-35 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-36 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(trifluoromethoxy)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(trifluoromethoxy)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-37 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-38 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-39 1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-40 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(1-cyanocyclopropyl)pyridin-3-yl)methyl]-1H-pyrazole- 4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(1-cyanocyclopropyl)pyridin-3-yl)methyl]-1H-pyrazole- Ethyl 4-formate 5-41 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-42 1-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4 - Formic acid 1-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4 -Ethyl formate 5-43 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H -Imidazole-4-carboxylic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]- 1H-imidazole-4-carboxylic acid ethyl ester 5-44 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H - Pyrazole-4-carboxylic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]- 1H-Pyrazole-4-carboxylic acid ethyl ester 5-45 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-46 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-(difluoromethyl)pyrimidin-5-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-(difluoromethyl)pyrimidin-5-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-47 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-48 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-49 1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-50 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(3-hydroxypropyl)pyridin-3-yl)methyl]-1H-pyrazole-4- Formic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(3-hydroxypropyl)pyridin-3-yl)methyl]-1H-pyrazole-4- Ethyl formate 5-51 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-52 1-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazol-4- Formic acid 1-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazol-4- Ethyl formate 5-53 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(trifluoromethoxy)pyridin-3-yl)methyl]-1H-pyrazole-4- Formic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(trifluoromethoxy)pyridin-3-yl)methyl]-1H-pyrazole-4- Ethyl formate 5-54 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(1-hydroxypropen-2-yl)pyridin-3-yl)methyl]-1H-pyrazole -4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(1-hydroxypropen-2-yl)pyridin-3-yl)methyl]-1H-pyrazole -4-ethyl formate 5-55 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-56 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-triazole- 4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-triazole- Ethyl 4-formate 5-57 1-[(2-{3-azabicyclo[3.1.0]hex-3-yl}-4-(hydroxymethyl)pyrimidin-5-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-(hydroxymethyl)pyrimidin-5-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-58 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-59 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-60 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(1-cyano-1-methylethyl)pyridin-3-yl)methyl]-1H - Pyrazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(1-cyano-1-methylethyl)pyridin-3-yl)methyl]-1H - Pyrazole-4-carboxylic acid ethyl ester 5-61 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)methyl]-1H-imidazole-4 - Formic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)methyl]-1H-imidazole-4 -Ethyl formate 5-62 1-[(2-Cyclobutyl-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole -4-carboxylic acid 1-[(2-Cyclobutyl-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole -4-ethyl formate 5-63 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-methylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-methylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester 5-64 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)methyl]-1H-pyrazole- 4-carboxylic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)methyl]-1H-pyrazole- Ethyl 4-formate 5-65 1-[(5-{3-azabicyclo[3.1.0]hex-3-yl}pyrimidin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}-pyrimidin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-66 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-67 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-68 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-imidazol-4 - Formic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-imidazol-4 -Ethyl formate 5-69 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate tris Ethyl Fluoroacetate 5-70 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(cyanomethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(cyanomethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-71 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(1-hydroxyethyl)pyridin-3-yl)methyl]-1H-pyrazole-4- Formic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(1-hydroxyethyl)pyridin-3-yl)methyl]-1H-pyrazole-4- Ethyl formate 5-72 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-[(1R)-1-hydroxyethyl]pyridin-3-yl)methyl]-1H-pyridine oxazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-[(1R)-1-hydroxyethyl]pyridin-3-yl)methyl]-1H-pyridine Ethyl oxazole-4-carboxylate 5-73 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-[(1S)-1-hydroxyethyl]pyridin-3-yl)methyl]-1H-pyridine oxazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-[(1R)-1-hydroxyethyl]pyridin-3-yl)methyl]-1H-pyridine Ethyl oxazole-4-carboxylate 5-74 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(2-hydroxypropen-2-yl)pyridin-3-yl)methyl]-1H-pyrazole -4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(2-hydroxypropen-2-yl)pyridin-3-yl)methyl]-1H-pyrazole -4-ethyl formate 5-75 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(2-hydroxyethyl)pyridin-3-yl)methyl]-1H-pyrazole-4- Formic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(2-hydroxyethyl)pyridin-3-yl)methyl]-1H-pyrazole-4- Ethyl formate 5-76 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-77 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-78 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}-3-(hydroxymethyl)pyridine-2-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}-3-(hydroxymethyl)pyridine-2-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-79 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrazole- 4-carboxylic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrazole- Ethyl 4-formate 5-80 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-tri oxazole-4-carboxylic acid 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-tri Ethyl oxazole-4-carboxylate 5-81 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H- Pyrazole-4-carboxylic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)-methyl]- 1H-Pyrazole-4-carboxylic acid ethyl ester 5-82 1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-3-methylpyridine-2-yl)methyl]-1H-1, 2,3-Triazole-4-carboxylic acid 1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-3-methylpyridine-2-yl)methyl]-1H-1, 2,3-Triazole-4-carboxylic acid ethyl ester 5-83 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]- 1H-imidazole-4-carboxylic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl] -1H-imidazole-4-carboxylic acid ethyl ester 5-84 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H- imidazole-4-carboxylic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H -Imidazole-4-carboxylic acid ethyl ester 5-85 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H- 1,2,3-Triazole-4-carboxylic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H -1,2,3-Triazole-4-ethyl carboxylate 5-86 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-cyano-1H-pyrazole-4- Formic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-cyano-1H-pyrazole-4- methyl formate 5-87 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-88 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(2-methylpropyl)pyridin-3-yl)methyl]-1H-imidazol-4- Formic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(2-methylpropyl)pyridin-3-yl)methyl]-1H-imidazol-4- Ethyl formate 5-89 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4 - Formic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4 -Ethyl formate 5-90 1-[(5-Cyano-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-4-methylpyridin-3-yl)methyl]- 1H-Pyrazole-4-carboxylic acid 1-[(5-Cyano-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-4-methylpyridin-3-yl)methyl]- 1H-Pyrazole-4-carboxylic acid ethyl ester 5-91 1-[(5-Cyano-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-4-methylpyridin-3-yl)methyl]- 1H-imidazole-4-carboxylic acid 1-[(5-Cyano-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-4-methylpyridin-3-yl)methyl]- 1H-imidazole-4-carboxylic acid ethyl ester 5-92 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-93 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-94 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(hydroxymethyl yl)-1H-pyrazole-4-carboxylic acid 3-(Chloromethyl))-1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl) Methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-95 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(cyanomethyl)-1H-pyridine oxazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(cyanomethyl)-1H-pyridine Ethyl oxazole-4-carboxylate 5-96 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-97 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-1,2 ,3-triazole-4-carboxylic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-1,2 ,3-Triazole-4-ethyl carboxylate 5-98 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-99 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2,4-lutidine-3-yl)methyl]-1H- imidazole-4-carboxylic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2,4-lutidine-3-yl)methyl]-1H -Imidazole-4-carboxylic acid ethyl ester 5-100 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2,4-lutidine-3-yl)methyl]-1H- Pyrazole-4-carboxylic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2,4-lutidine-3-yl)methyl]-1H - Pyrazole-4-carboxylic acid ethyl ester 5-101 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]thiophene-2-carboxylic acid 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)-methyl]thiophene-2- Ethyl formate 5-102 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyanopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyanopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-103 2-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1,3-thiazole -5-carboxylic acid 2-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methyl]-1,3- Methyl thiazole-5-carboxylate 5-104 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyano-4-methylpyridin-3-yl)methyl]-1H-pyrazole-4- Formic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyano-4-methylpyridin-3-yl)methyl]-1H-pyrazole-4- Ethyl formate 5-105 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-cyclopropylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-cyclopropylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-106 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyano-4-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyano-4-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-107 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-108 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-(trifluoromethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-(trifluoromethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-109 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-110 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(methoxymethyl)-1H- Pyrazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(methoxymethyl)-1H- Ethyl pyrazole-4-carboxylate 5-111 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyano-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyano-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-112 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(methoxy yl-methyl)-1H-pyrazole-4-carboxylic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(methyl Oxymethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 5-113 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-114 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-bromo-1H-pyrazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-bromo-1H-pyrazole-4-carboxylic acid ethyl ester 5-115 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-116 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyano-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4- Formic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyano-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4- methyl formate 5-117 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-118 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2,5-lutidine-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2,5-lutidine-3-yl)methyl]-1H-imidazole-4-carboxylic acid methyl ester 5-119 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2,5-lutidine-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2,5-lutidine-3-yl)methyl]-1H-pyrazole-4-carboxylic acid methyl ester 5-120 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-cyanopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-cyanopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-121 1-[(2-Chloro-4-methylpyrimidin-5-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(2-Chloro-4-methylpyrimidin-5-yl)-methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-122 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 5-123 1-[(2-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-1H-imidazol-4 - Formic acid 1-[(2-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-1H-imidazole- Ethyl 4-formate 5-124 1-[(2-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-1H-1,2 ,3-triazole-4-carboxylic acid 1-[(2-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-1H-1, 2,3-Triazole-4-carboxylic acid ethyl ester 5-125 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-1H-1,2,3-triazole-4 - Formic acid 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-1H-1,2,3-triazole-4 -Ethyl formate 5-126 1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-1H-1,2,3-triazole -4-carboxylic acid 1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}pyridin-2-yl)methyl]-1H-1,2,3-tri Ethyl oxazole-4-carboxylate 5-127 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3-carboxylic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3-carboxylic acid methyl ester 5-128 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3-carboxylic acid 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3-carboxylic acid methyl ester 5-129 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrrole-3 - Formic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrrole- Methyl 3-carboxylate 5-130 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrrole-3 - Formic acid 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrrole- Methyl 3-carboxylate 5-131 1-({2-Ethyl-6-[(1R,5S,6R)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl]pyridin-3-yl}methyl) -1H-imidazole-4-carboxylic acid 1-({2-Ethyl-6-[(1R,5S,6R)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl]pyridin-3-yl}methyl) -1H-imidazole-4-carboxylic acid ethyl ester 5-132 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1,2-oxazole-5 - Formic acid 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1,2-oxazole-5 -Ethyl formate 5-133 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1 ,2-oxazole-5-carboxylic acid 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]- Ethyl 1,2-oxazole-5-carboxylate 5-134 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid ethyl ester 5-135 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1, 2-Oxazole-5-carboxylic acid 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1 ,2-ethyl oxazole-5-carboxylate 5-136 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid ethyl ester 5-137 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1,2-oxazole-5- Formic acid 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1,2-oxazole-5- Ethyl formate 5-138 3-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1,2-oxazole -5-carboxylic acid 3-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1,2-oxazole -5-ethyl formate 5-139 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-pyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid ethyl ester 5-140 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1,2-㗁oxazole-5-carboxylic acid 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methyl]-1,2- Ethyl oxazole-5-carboxylate 5-141 2-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1,3-oxazole-5-carboxylic acid 2-[1-(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)-2-methoxy-2-pendantoxyethyl ]-Methyl 1,3-oxazole-5-carboxylate 5-142 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1,2-㗁oxazole-5-carboxylic acid 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1,2- Ethyl oxazole-5-carboxylate 5-143 2-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1,3-㗁oxazole-5-carboxylic acid 2-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methyl]-1,3- Ethyl oxazole-5-carboxylate 5-144 3-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid 3-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid ethyl ester 5-145 3-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid 3-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid ethyl ester 5-146 2-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1,3-oxazole-5-carboxylic acid 2-[1-(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)-2-methoxy-2-side oxyethyl ]-Methyl 1,3-oxazole-5-carboxylate 5-147 5-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3- Formic acid 5-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3- methyl formate 5-148 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1-(propene- 2-yl)-1H-pyrazole-5-carboxylic acid 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1-(propene -2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester 5-149 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1-ethyl- 1H-Pyrazole-5-carboxylic acid 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1-ethyl -1H-Pyrazole-5-carboxylic acid ethyl ester 5-150 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1-{[2-(trimethyl silyl)ethoxy]methyl}-1H-pyrazole-5-carboxylic acid and 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl) yl)pyridin-3-yl)methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylic acid (mixture of isomers) 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1-{[2-(trimethyl Silyl)ethoxy]methyl}-1H-pyrazole-5-carboxylic acid ethyl ester and 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-( Hydroxymethyl)pyridin-3-yl)methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylic acid ethyl ester (of isomers mixture) 5-151 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1-ethyl-1H-pyrazole-5- Formic acid 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1-ethyl-1H-pyrazole-5- Ethyl formate 5-152 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1-ethyl- 1H-Pyrazole-5-carboxylic acid 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methyl]-1-ethyl -1H-Pyrazole-5-carboxylic acid ethyl ester 5-153 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1-ethyl-1H-pyrazole-5- Formic acid 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1-ethyl-1H-pyrazole-5- Ethyl formate 5-154 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole-5-carboxylic acid 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole-5-carboxylic acid ethyl ester 5-155 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1-methyl-1H-pyrazole-5- Formic acid 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1-methyl-1H-pyrazole-5- Ethyl formate 5-156 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1-methyl-1H-pyrazole-5- Formic acid 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1-methyl-1H-pyrazole-5- Ethyl formate 5-157 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-methylpyrimidin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-methylpyrimidin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-158 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-159 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyrimidin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyrimidin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 5-160 2-Chloro-1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazol-4- Formic acid 2-Chloro-1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazol-4- Ethyl formate 5-161 7-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidine -5-carboxylic acid 7-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidine -Methyl 5-carboxylate 5-162 7-[(2-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-7H-pyrrolo[ 2,3-d]pyrimidine-5-carboxylic acid 7-[(2-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-7H-pyrrolo Methyl [2,3-d]pyrimidine-5-carboxylate 5-163 7-[2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidine- 5-carboxylic acid 7-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidine -Methyl 5-carboxylate 5-164 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]furan-2-carboxylic acid Methyl 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]furan-2-carboxylate 5-165 5-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]furan-3-carboxylic acid Ethyl 5-[(6-{3-azabicycloazabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]furan-3-carboxylate 5-166 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]furan-2-carboxylic acid 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methyl]furan-2-carboxylic acid methyl ester 5-167 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]furan-2-carboxylic acid 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-ethylpyridin-3-yl)methyl]furan-2-carboxylic acid methyl ester 5-168 5-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethyl-pyridin-3-yl)methyl]thiophene-2-carboxylic acid Ethyl 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]thiophene-2-carboxylate 5-169 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]thiophene-2-carboxylic acid 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-ethylpyridin-3-yl)methyl]thiophene-2-carboxylic acid ethyl ester 5-170 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]thiophene-2 - Formic acid 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(hydroxymethyl)-pyridin-3-yl)methyl]thiophene -2-ethyl formate

Intermediate 6

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

Under an argon atmosphere, 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) for 12 h. The mixture was cooled to room temperature, concentrated in vacuo, partitioned between water and EtOAc, and the phases were separated. The organic phase was washed with brine, dried ( _MgSO4 ), concentrated and the residue was chromatographed on silica gel (petroleum ether/EtOAc 85:15→70:30) to give the title compound.

LC (Method 2): t _R = 1.03 min; Mass Spec (ESI ⁺ ): m/z = 303 [M+H] ⁺ .

中間物 反應備註 6-4 使用K ₂CO ₃代替DIPEA作為鹼。反應在室溫下進行2小時。 6-5 使用K ₂CO ₃代替DIPEA作為鹼。反應在室溫下進行2小時。 6-6 使用K ₂CO ₃代替DIPEA作為鹼。反應在室溫下進行2小時。 6-7 反應在90℃下進行6小時。 6-8 反應在室溫下進行12小時。 6-9 使用K ₂CO ₃代替DIPEA作為鹼。反應在80℃下進行12小時。 6-10 使用KHCO ₃代替DIPEA作為鹼。反應在80℃下在DMSO中進行12小時。 6-11 使用KHCO ₃代替DIPEA作為鹼。反應在80℃下在DMSO中進行12小時。 6-12 使用KHCO ₃代替DIPEA作為鹼。反應在45℃下在DMSO中進行48小時。 6-13 使用KHCO ₃代替DIPEA作為鹼。反應在45℃下在DMSO中進行4小時。 6-14 反應在60℃下在DMSO中進行12小時。 6-15 使用KHCO ₃代替DIPEA作為鹼。反應在60℃下在DMSO中進行12小時。 6-16 反應在70℃下進行24小時。 6-17 反應在50℃下進行18小時。 6-18 反應在50℃下進行2小時。 中間物 名稱 起始材料 1 之名稱 起始材料 2 之名稱 6-1  2-氯-6-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}-吡啶-3-甲醛  2,6-二氯吡啶-3-甲醛  6,6-二氟-3-氮雜雙環-[3.1.0]己烷鹽酸鹽 6-2  6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-甲醛  2,6-二氯吡啶-3-甲醛  5-氮雜螺[2.3]己烷三氟乙酸鹽 6-3  6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-甲醛  2,6-二溴吡啶-3-甲醛  5-氮雜螺[2.3]己烷三氟乙酸鹽 6-4  6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-甲醛  2,6-二氟吡啶-3-甲醛  6,6-二氟-3-氮雜雙環-[3.1.0]己烷鹽酸鹽 6-5  6-{5-氮雜螺[2.3]己-5-基}-2-氟吡啶-3-甲醛  2,6-二氟吡啶-3-甲醛  5-氮雜螺[2.3]己烷半草酸鹽 6-6  6-{3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-甲醛  2,6-二氟吡啶-3-甲醛  3-氮雜雙環[3.1.0]己烷鹽酸鹽 6-7  6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-甲醛  2,6-二氯吡啶-3-甲醛  3-氮雜雙環[3.1.0]己烷鹽酸鹽 6-8  6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-甲醛  2,6-二溴吡啶-3-甲醛  3-氮雜雙環[3.1.0]己烷鹽酸鹽 6-9  6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-甲醛  6-氯吡啶-3-甲醛  6,6-二氟-3-氮雜雙環-[3.1.0]己烷鹽酸鹽 6-10  6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-甲醛  6-氯-2-甲基-吡啶-3-甲醛  6,6-二氟-3-氮雜雙環-[3.1.0]己烷鹽酸鹽 6-11  6-{5-氮雜螺[2.3]己-5-基}-2-甲基吡啶-3-甲醛  6-氯-2-甲基-吡啶-3-甲醛  5-氮雜螺[2.3]己烷三氟乙酸鹽 6-12  6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-甲醛  6-氯-2-甲基-吡啶-3-甲醛  3-氮雜雙環[3.1.0]己烷鹽酸鹽 6-13  6-{3-氮雜雙環[3.1.0]己-3-基}-4-氯吡啶-3-甲醛  4,6-二氯吡啶-3-甲醛  3-氮雜雙環[3.1.0]己烷鹽酸鹽 6-14  2-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}-5-碘-4-甲基吡啶-3-甲腈  2-氯-5-碘-4-甲基吡啶-3-甲腈  6,6-二氟-3-氮雜雙環-[3.1.0]己烷鹽酸鹽 6-15  6-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基吡啶-3-甲醛  6-氯-4-甲基-吡啶-3-甲醛  3-氮雜雙環[3.1.0]己烷鹽酸鹽 6-16  6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2,4-二甲基吡啶-3-甲醛  6-氯-2,4-二甲基-吡啶-3-甲醛  6,6-二氟-3-氮雜雙環-[3.1.0]己烷鹽酸鹽 6-17  2-{3-氮雜雙環[3.1.0]己-3-基}-5-碘-4-甲基吡啶-3-甲腈  2-氯-5-碘-4-甲基吡啶-3-甲腈  3-氮雜雙環[3.1.0]己烷鹽酸鹽 6-18  2-氯-6-[(1R,5S,6R)-6-甲基-3-氮雜雙環[3.1.0]己-3-基]吡啶-3-甲醛  2,6-二氯吡啶-3-甲醛  (1R,5S,6R)-6-甲基-3-氮雜雙環[3.1.0]己烷鹽酸鹽  (藉由標準RP層析法分離6-甲基-3-氮雜雙環氮雜雙環[3.1.0]己烷-3-甲酸三級丁酯之非對映異構體且用HCl於EtOAc中裂解保護基來獲得) 6-19  6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-甲醛  6-氟吡啶-3-甲醛  6,6-二氟-3-氮雜雙環-[3.1.0]己烷鹽酸鹽 Intermediates 6-1 to 6-19 were prepared analogously to Intermediate 6 :

Intermediate Reaction Notes 6-4 _K2CO3 was used instead _of DIPEA as the base. The reaction was carried out at room temperature for 2 hours. 6-5 _K2CO3 was used instead _of DIPEA as the base. The reaction was carried out at room temperature for 2 hours. 6-6 _K2CO3 was used instead _of DIPEA as the base. The reaction was carried out at room temperature for 2 hours. 6-7 The reaction was carried out at 90°C for 6 hours. 6-8 The reaction was carried out at room temperature for 12 hours. 6-9 _K2CO3 was used instead _of DIPEA as the base. The reaction was carried out at 80°C for 12 hours. 6-10 _KHCO3 was used instead of DIPEA as the base. The reaction was carried out in DMSO at 80°C for 12 hours. 6-11 _KHCO3 was used instead of DIPEA as the base. The reaction was carried out in DMSO at 80°C for 12 hours. 6-12 _KHCO3 was used instead of DIPEA as the base. The reaction was carried out in DMSO at 45°C for 48 hours. 6-13 _KHCO3 was used instead of DIPEA as the base. The reaction was carried out in DMSO at 45°C for 4 hours. 6-14 The reaction was carried out in DMSO at 60°C for 12 hours. 6-15 _KHCO3 was used instead of DIPEA as the base. The reaction was carried out in DMSO at 60°C for 12 hours. 6-16 The reaction was carried out at 70°C for 24 hours. 6-17 The reaction was carried out at 50°C for 18 hours. 6-18 The reaction was carried out at 50°C for 2 hours. Intermediate name Name of starting material 1 Name of starting material 2 6-1 2-Chloro-6-{6,6-difluoro-3-azabicyclo-[3.1.0]hex-3-yl}-pyridine-3-carbaldehyde 2,6-Dichloropyridine-3-carbaldehyde 6,6-Difluoro-3-azabicyclo-[3.1.0]hexane hydrochloride 6-2 6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridine-3-carbaldehyde 2,6-Dichloropyridine-3-carbaldehyde 5-Azaspiro[2.3]hexane trifluoroacetate 6-3 6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridine-3-carbaldehyde 2,6-Dibromopyridine-3-carbaldehyde 5-Azaspiro[2.3]hexane trifluoroacetate 6-4 6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridine-3-carbaldehyde 2,6-Difluoropyridine-3-carbaldehyde 6,6-Difluoro-3-azabicyclo-[3.1.0]hexane hydrochloride 6-5 6-{5-Azaspiro[2.3]hex-5-yl}-2-fluoropyridine-3-carbaldehyde 2,6-Difluoropyridine-3-carbaldehyde 5-Azaspiro[2.3]hexane hemioxalate 6-6 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridine-3-carbaldehyde 2,6-Difluoropyridine-3-carbaldehyde 3-Azabicyclo[3.1.0]hexane hydrochloride 6-7 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridine-3-carbaldehyde 2,6-Dichloropyridine-3-carbaldehyde 3-Azabicyclo[3.1.0]hexane hydrochloride 6-8 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridine-3-carbaldehyde 2,6-Dibromopyridine-3-carbaldehyde 3-Azabicyclo[3.1.0]hexane hydrochloride 6-9 6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridine-3-carbaldehyde 6-Chloropyridine-3-carbaldehyde 6,6-Difluoro-3-azabicyclo-[3.1.0]hexane hydrochloride 6-10 6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridine-3-carbaldehyde 6-Chloro-2-methyl-pyridine-3-carbaldehyde 6,6-Difluoro-3-azabicyclo-[3.1.0]hexane hydrochloride 6-11 6-{5-Azaspiro[2.3]hex-5-yl}-2-methylpyridine-3-carbaldehyde 6-Chloro-2-methyl-pyridine-3-carbaldehyde 5-Azaspiro[2.3]hexane trifluoroacetate 6-12 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridine-3-carbaldehyde 6-Chloro-2-methyl-pyridine-3-carbaldehyde 3-Azabicyclo[3.1.0]hexane hydrochloride 6-13 6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-chloropyridine-3-carbaldehyde 4,6-Dichloropyridine-3-carbaldehyde 3-Azabicyclo[3.1.0]hexane hydrochloride 6-14 2-{6,6-Difluoro-3-azabicyclo-[3.1.0]hex-3-yl}-5-iodo-4-methylpyridine-3-carbonitrile 2-Chloro-5-iodo-4-methylpyridine-3-carbonitrile 6,6-Difluoro-3-azabicyclo-[3.1.0]hexane hydrochloride 6-15 6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyridine-3-carbaldehyde 6-Chloro-4-methyl-pyridine-3-carbaldehyde 3-Azabicyclo[3.1.0]hexane hydrochloride 6-16 6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2,4-lutidine-3-carbaldehyde 6-Chloro-2,4-dimethyl-pyridine-3-carbaldehyde 6,6-Difluoro-3-azabicyclo-[3.1.0]hexane hydrochloride 6-17 2-{3-Azabicyclo[3.1.0]hex-3-yl}-5-iodo-4-methylpyridine-3-carbonitrile 2-Chloro-5-iodo-4-methylpyridine-3-carbonitrile 3-Azabicyclo[3.1.0]hexane hydrochloride 6-18 2-Chloro-6-[(1R,5S,6R)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl]pyridine-3-carbaldehyde 2,6-Dichloropyridine-3-carbaldehyde (1R,5S,6R)-6-Methyl-3-azabicyclo[3.1.0]hexane hydrochloride (isolation of 6-methyl-3-azabicycloazabicyclo by standard RP chromatography [3.1.0] Diastereomer of tert-butyl hexane-3-carboxylate and obtained by cleavage of the protecting group with HCl in EtOAc) 6-19 6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridine-3-carbaldehyde 6-Fluoropyridine-3-carbaldehyde 6,6-Difluoro-3-azabicyclo-[3.1.0]hexane hydrochloride

Intermediate 7

( 6- { 6,6 - Difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - vinylpyridin - 3 - yl ) methanol _ _ _ _ _ _

In a microwave vial, purge (2-bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methanol (100 mg), potassium vinyltrifluoroborate (60 _mg ), K2CO3 (125 mg) and THF ( ₅ mL) for 10 minutes. 1,1'-Bis(diphenylphosphino)ferrocene palladium(II) dichloride (Pd(dppf)Cl2, ₁₅ mg) was added, the vial was sealed and the mixture was stirred at 60°C for 12 hours. After cooling to room temperature, the mixture was diluted with MeOH and purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t _R = 0.61 min; Mass Spec (ESI ⁺ ): m/z = 253 [M+H] ⁺ .

0.74 340 方法2 7-2

0.76 339 方法2 7-3

1.02 215 方法1 7-4

0.77 339 方法2 7-5

1.07 340 方法2 7-6

0.27 217 方法2 7-7

0.92 375 方法2 7-8

0.81 375 方法2 7-9

(異構體之混合物) 0.96 及 0.98 469 方法2 中間物 反應備註 7-1 反應在80℃下進行。 7-2 反應在80℃下進行。 7-4 反應在90℃下進行。 7-5 反應在100℃下進行14小時。 7-6 反應在80℃下進行。 7-7 使用Na ₂CO ₃代替K ₂CO ₃、乙烯基硼酸頻哪醇酯代替乙烯基三氟硼酸鉀及1,4-二㗁烷代替THF。反應在100℃下進行12小時。 7-8 反應在100℃下進行4小時。 7-9 反應在80℃下進行3天。 獲得作為異構體之混合物之產物且按原樣用於下一步驟中。 中間物 名稱 起始材料 之名稱 7-1 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙烯基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 7-2 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙烯基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 7-3 6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-甲醛 6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-甲醛 7-4  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 7-5  1-[(5-{3-氮雜雙環[3.1.0]己-3-基}-3-乙烯基吡啶-2-基)甲基]-1H-吡唑-4-甲酸乙酯  1-[(5-{3-氮雜雙環[3.1.0]己-3-基}-3-氯吡𠯤-2-基)甲基]-1H-吡唑-4-甲酸乙酯 7-6  (6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲醇  (6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲醇 7-7  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  1-[(2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 7-8 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 1-[(2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 7-9 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-5-甲酸乙酯及5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-3-甲酸乙酯 (異構體之混合物) 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-5-甲酸乙酯及5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-3-甲酸乙酯 (異構體之混合物) Intermediates 7-1 to 7-9 were prepared analogously to Intermediate 7 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 7-1

0.74 340 Method 2 7-2

0.76 339 Method 2 7-3

1.02 215 method 1 7-4

0.77 339 Method 2 7-5

1.07 340 Method 2 7-6

0.27 217 Method 2 7-7

0.92 375 Method 2 7-8

0.81 375 Method 2 7-9

(mixture of isomers) 0.96 and 0.98 469 Method 2 Intermediate Reaction Notes 7-1 The reaction was carried out at 80°C. 7-2 The reaction was carried out at 80°C. 7-4 The reaction was carried out at 90°C. 7-5 The reaction was carried out at 100°C for 14 hours. 7-6 The reaction was carried out at 80°C. 7-7 Na ₂ CO ₃ was used instead of K ₂ CO ₃ , pinacol vinylborate instead of potassium vinyltrifluoroborate, and 1,4-dioxane instead of THF. The reaction was carried out at 100°C for 12 hours. 7-8 The reaction was carried out at 100°C for 4 hours. 7-9 The reaction was carried out at 80°C for 3 days. The product was obtained as a mixture of isomers and used as such in the next step. Intermediate name name of starting material 7-1 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-vinylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester 7-2 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-vinylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 7-3 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridine-3-carbaldehyde 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridine-3-carbaldehyde 7-4 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 7-5 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}-3-vinylpyridin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}-3-chloropyridine-2-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 7-6 (6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methanol (6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methanol 7-7 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1H-pyrazole- Ethyl 4-formate 1-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4 -Ethyl formate 7-8 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1H-imidazol-4 -Ethyl formate 1-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazol-4- Ethyl formate 7-9 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1-{[2-(trimethylsilyl )ethoxy]methyl}-1H-pyrazole-5-carboxylic acid ethyl ester and 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridine- 3-yl)methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylic acid ethyl ester (mixture of isomers) 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1-{[2-(trimethylsilyl) Ethoxy]methyl}-1H-pyrazole-5-carboxylic acid ethyl ester and 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloropyridine-3- ethyl)methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylic acid ethyl ester (mixture of isomers)

Intermediate 8

1 - [ ( 6- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - vinylpyridin - 3 - yl ) methyl ] -1H - pyridine _ _ _ _ Ethyl oxazole - 4 - carboxylate

Under argon atmosphere, (6-{6,6-difluoro-3-azabicyclo[3.1.0]hexyl-3-yl}-2-vinylpyridin-3-yl)methanol (877 mg) and DIPEA (1.6 mL) were dissolved in DCM (25 mL). The mixture was cooled to 0 °C and treated dropwise with methanesulfonyl chloride ( _{CH3 -} SO2Cl, 318 µL). After stirring for 15 minutes, 1H-pyrazole-4-carboxylic acid ethyl ester (555 mg) was added and the mixture was stirred at room temperature for 3 hours. The mixture was then partitioned between water and DCM. The organic phase was dried ( _MgSO4 ), concentrated and the residue was chromatographed on silica gel (petroleum ether/EtOAc 100:0→70:30) to give the title compound. LC (Method 2): t _R = 0.93 min; Mass Spec (ESI ⁺ ): m/z = 375 [M+H] ⁺ .

Intermediate 9

1 - [ ( 6- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - carboxypyridin - 3 - yl ) methyl ] -1H- _ _ _ _ _ Pyrazole- 4 - ethyl carboxylate

OsO ₄ (4% in water, 283 µL) was added to 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridine -3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (700 mg) in a mixture of 1,4-dioxane (3.4 mL) and water (3.4 mL). The mixture was stirred for 30 minutes, treated with _NaIO4 (1.2 g) and stirred at room temperature for 3 hours. The mixture was partitioned between water and EtOAc/MeOH (9:1). After separation of the phases, the organic phase was dried ( _MgSO4 ) and concentrated to give the title compound. LC (Method 2): t _R = 1.06 min; Mass Spec (ESI ⁺ ): m/z = 377 [M+H] ⁺ .

中間物 反應備註 9-3 在添加NaIO ₄之後，攪拌混合物12小時。 9-9 在添加NaIO ₄之後，攪拌混合物12小時。 9-10 在添加NaIO ₄之後，攪拌混合物12小時。 9-13 在添加NaIO ₄之後，攪拌混合物12小時。 9-16 在添加NaIO ₄之後，攪拌混合物16小時。 9-18 在添加NaIO ₄之後，攪拌混合物12小時。 獲得作為異構體之混合物之產物。 中間物 名稱 起始材料 之名稱 9-1  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲醯基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙烯基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 9-2 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲醯基嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-[(1E)-2-苯基乙烯基]嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊-[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 9-3 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲醯基嘧啶-5-基)甲基]-1H-咪唑-4-甲酸乙酯 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-[(1E)-2-苯基乙烯基]嘧啶-5-基)甲基]-1H-咪唑-4-甲酸乙酯 9-4 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲醯基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 9-5 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲醯基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 9-6 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲醯基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙烯基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 9-7 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲醯基嘧啶-5-基)甲基]-1H-吡唑-4-甲酸乙酯 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-[(1E)-2-苯基乙烯基]嘧啶-5-基)甲基]-1H-吡唑-4-甲酸乙酯 9-8 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲醯基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙烯基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 9-9 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲醯基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 9-10 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲醯基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙烯基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 9-11 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲醯基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 9-12 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}-3-甲醯基吡𠯤-2-基)甲基]-1H-吡唑-4-甲酸乙酯 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}-3-乙烯基吡啶-2-基)甲基]-1H-吡唑-4-甲酸乙酯 9-13 1-[(6-{3-氮雜環[3.1.0]己-3-基}-2-甲醯基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 1-[(6-{3-氮雜環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 9-14 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲醯基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 9-15 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲醯基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 9-16 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲醯基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 3-[(6-{3-氮雜環[3.1.0]己-3-基}-2-[(1E)-2-苯基乙烯基]吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 9-17 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲醯基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-[(1E)-2-苯基乙烯基]吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 9-18 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲醯基吡啶-3-基)甲基]-1-{[2-(三甲基-矽烷基)乙氧基]甲基}-1H-吡唑-5-甲酸乙酯 及 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲醯基吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)-乙氧基]甲基}-1H-吡唑-3-甲酸乙酯 (異構體之混合物) 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]-1-{[2-(三甲基-矽烷基)乙氧基]甲基}-1H-吡唑-5-甲酸乙酯 及 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]-1-{[2-(三甲基-矽烷基)乙氧基]甲基}-1H-吡唑-3-甲酸乙酯 (異構體之混合物) Intermediates 9-1 to 9-18 were prepared analogously to Intermediate 9 :

Intermediate Reaction Notes 9-3 After the addition of _NaIO4 , the mixture was stirred for 12 hours. 9-9 After the addition of _NaIO4 , the mixture was stirred for 12 hours. 9-10 After the addition of _NaIO4 , the mixture was stirred for 12 hours. 9-13 After the addition of _NaIO4 , the mixture was stirred for 12 hours. 9-16 After the addition of _NaIO4 , the mixture was stirred for 16 hours. 9-18 After the addition of _NaIO4 , the mixture was stirred for 12 hours. The product is obtained as a mixture of isomers. Intermediate name name of starting material 9-1 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-carboxypyridin-3-yl)methyl]-1H-1,2,3-triazole-4- Ethyl formate 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-vinylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester 9-2 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-carboxypyrimidin-5-yl)methyl]-N-[(4R)-1-methyl -1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(2-{3-azabicyclo[3.1.0]hex-3-yl}-4-[(1E)-2-phenylvinyl]pyrimidin-5-yl)methyl]-N- [(4R)-1-Methyl-1H,4H,5H,6H-cyclopent-[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 9-3 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-carboxypyrimidin-5-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-[(1E)-2-phenylvinyl]pyrimidin-5-yl)methyl]-1H- Imidazole-4-carboxylate ethyl ester 9-4 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 9-5 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1H-imidazole- Ethyl 4-formate 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1H-imidazol-4 -Ethyl formate 9-6 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-carboxypyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-vinylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 9-7 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-carboxypyrimidin-5-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-[(1E)-2-phenylvinyl]pyrimidin-5-yl)methyl]-1H- Ethyl pyrazole-4-carboxylate 9-8 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-carboxypyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-vinylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 9-9 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1H-1, Ethyl 2,3-triazole-4-carboxylate 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1H-1,2 ,3-Triazole-4-ethyl carboxylate 9-10 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-carboxypyridin-3-yl)methyl]-1H-1,2,3-triazole-4- Ethyl formate 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-vinylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester 9-11 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 9-12 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}-3-carboxypyridine-2-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}-3-vinylpyridin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 9-13 1-[(6-{3-Azacyclo[3.1.0]hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1H-1,2,3-triazole- Ethyl 4-formate 1-[(6-{3-Azacyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4 -Ethyl formate 9-14 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1H-pyridine Ethyl oxazole-4-carboxylate 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1H-pyrazole- Ethyl 4-formate 9-15 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1H-imidazole -4-ethyl formate 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1H-imidazol-4 -Ethyl formate 9-16 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid ethyl ester 3-[(6-{3-Azacyclo[3.1.0]hex-3-yl}-2-[(1E)-2-phenylvinyl]pyridin-3-yl)methyl]-1, Ethyl 2-oxazole-5-carboxylate 9-17 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1,2- Ethyl oxazole-5-carboxylate 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-[(1E)-2-phenylvinyl]pyridine-3- ethyl)methyl]-1,2-oxazole-5-carboxylic acid ethyl ester 9-18 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1-{[2-(trimethyl- Silyl)ethoxy]methyl}-1H-pyrazole-5-carboxylic acid ethyl ester and 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-carboxylate pyridin-3-yl)methyl]-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-pyrazole-3-carboxylic acid ethyl ester (mixture of isomers) 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1-{[2-(trimethyl-silane ethyl)ethoxy]methyl}-1H-pyrazole-5-carboxylic acid ethyl ester and 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridine -3-yl)methyl]-1-{[2-(trimethyl-silyl)ethoxy]methyl}-1H-pyrazole-3-carboxylic acid ethyl ester (mixture of isomers)

Intermediate 10

1 - [ ( 6- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2- ( hydroxymethyl ) pyridin - 3 - yl ) methyl ] - _ _ _ 1H - Pyrazole - 4 - ethylcarboxylate

NaBH4 ( ₄₀ mg) was added portionwise to 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-carboxypyridine-3 -yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (200 mg) in an ice-cold mixture of EtOH (5 mL). The mixture was stirred at room temperature for 2 hours, cooled to 0 °C, treated with 4 M aqueous HCl (599 μL) and stirred for 5 minutes. 4 M aqueous NaOH (599 µL) was added and the mixture was diluted with EtOAc. After drying ( _{MgSO4 )} , the mixture was filtered and concentrated. The residue was partitioned between EtOAc and saturated aqueous _NaHCO3 . The organic phase was dried ( _MgSO4 ) and concentrated to give the title compound. LC (Method 2): t _R = 0.75 min; Mass Spec (ESI ⁺ ): m/z = 379 [M+H] ⁺ .

0.99 343 方法1 10-2

0.71 380 方法2 10-3

0.68 344 方法2 10-4

0.82 344 方法2 10-5

0.91 344 方法1 10-6

0.66 344 方法2 10-7

0.75 379 方法2 10-8

0.67 379 方法2 10-9

1.01 380 方法1 10-10

1.05 344 方法1 10-11

(異構體之混合物) 0.89 及 0.93 473 方法2 中間物 反應備註 10-3 反應在THF/EtOH 2:1中進行。 10-3 反應在室溫下在THF中進行12小時。 10-5 反應在室溫下在THF/EtOH中進行30分鐘。 10-7 反應在室溫下在THF/EtOH中進行1小時。 10-8 反應在室溫下在THF/水 10:1中進行12小時。 10-9 反應在室溫下進行15分鐘。 用NaHCO ₃飽和水溶液代替HCl淬滅反應。 10-10 反應在室溫下進行45分鐘。 用NaHCO ₃飽和水溶液代替HCl淬滅反應。 10-11 獲得作為異構體之混合物之產物。 中間物 名稱 起始材料 之名稱 10-1  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲醯基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 10-2  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲醯基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 10-3  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲醯基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 10-4  1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-(羥甲基)嘧啶-5-基)甲基]-1H-吡唑-4-甲酸乙酯  1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲醯基嘧啶-5-基)甲基]-1H-吡唑-4-甲酸乙酯 10-5  1-[(5-{3-氮雜雙環[3.1.0]己-3-基}-3-(羥基甲基)吡𠯤-2-基)甲基]-1H-吡唑-4-甲酸乙酯  1-[(5-{3-氮雜雙環[3.1.0]己-3-基}-3-甲醯基吡𠯤-2-基)甲基]-1H-吡唑-4-甲酸乙酯 10-6  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯  1-[(6-{3-氮雜環[3.1.0]己-3-基}-2-甲醯基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 10-7  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲醯基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 10-8  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲醯基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 10-9  3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯  3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲醯基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 10-10  3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯  3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲醯基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 10-11  3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-5-甲酸乙酯 及  5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-3-甲酸乙酯  (異構體之混合物)  3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲醯基吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)-乙氧基]甲基}-1H-吡唑-5-甲酸乙酯 及  5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲醯基吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)-乙氧基]甲基}-1H-吡唑-3-甲酸乙酯  (異構體之混合物) Intermediates 10-1 to 10-11 were prepared analogously to Intermediate 10 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 10-1

0.99 343 method 1 10-2

0.71 380 Method 2 10-3

0.68 344 Method 2 10-4

0.82 344 Method 2 10-5

0.91 344 method 1 10-6

0.66 344 Method 2 10-7

0.75 379 Method 2 10-8

0.67 379 Method 2 10-9

1.01 380 method 1 10-10

1.05 344 method 1 10-11

(mixture of isomers) 0.89 and 0.93 473 Method 2 Intermediate Reaction Notes 10-3 The reaction was carried out in THF/EtOH 2:1. 10-3 The reaction was carried out in THF at room temperature for 12 hours. 10-5 The reaction was carried out in THF/EtOH at room temperature for 30 minutes. 10-7 The reaction was carried out in THF/EtOH at room temperature for 1 hour. 10-8 The reaction was carried out in THF/water 10:1 at room temperature for 12 hours. 10-9 The reaction was carried out at room temperature for 15 minutes. The reaction was quenched with saturated aqueous _NaHCO3 instead of HCl. 10-10 The reaction was carried out at room temperature for 45 minutes. The reaction was 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 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 10-2 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H -1,2,3-Triazole-4-ethyl carboxylate 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1H-1 ,2,3-Triazole-4-ethyl carboxylate 10-3 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-triazole- Ethyl 4-formate 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-carboxypyridin-3-yl)methyl]-1H-1,2,3-triazole-4- Ethyl formate 10-4 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-(hydroxymethyl)pyrimidin-5-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-carboxypyrimidin-5-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 10-5 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}-3-(hydroxymethyl)pyridine-2-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}-3-carboxypyridine-2-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 10-6 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-tri Ethyl oxazole-4-carboxylate 1-[(6-{3-Azacyclo[3.1.0]hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1H-1,2,3-triazole- Ethyl 4-formate 10-7 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H - Pyrazole-4-carboxylic acid ethyl ester 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1H-pyridine Ethyl oxazole-4-carboxylate 10-8 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H -Imidazole-4-carboxylic acid ethyl ester 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1H-imidazole -4-ethyl formate 10-9 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1 ,2-ethyl oxazole-5-carboxylate 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1,2 -Ethyl oxazole-5-carboxylate 10-10 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1,2-oxazole-5- Ethyl formate 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid ethyl ester 10-11 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1-{[2-(trimethyl Silyl)ethoxy]methyl}-1H-pyrazole-5-carboxylic acid ethyl ester and 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-( Hydroxymethyl)pyridin-3-yl)methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylic acid ethyl ester (of isomers mixture) 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1-{[2-(trimethylsilane ethyl)-ethoxy]methyl}-1H-pyrazole-5-carboxylate and 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-carboxylate pyridin-3-yl)methyl]-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-pyrazole-3-carboxylic acid ethyl ester (mixture of isomers)

Intermediate 11

1 - [ ( 6- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2- ( methoxymethyl ) pyridin - 3 - yl ) methyl _ _ _ _ ] -1H - Pyrazole - 4 - ethylcarboxylate

To 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methane at 0 °C To a solution of ethyl]-1H-pyrazole-4-carboxylate (89 mg) in DMF (250 µL) was added NaH (60% in mineral oil, 23 mg). The mixture was stirred for 15 minutes, treated with _CH3I (17 μL) and stirred at room temperature for 12 hours. The solvent was evaporated in vacuo to give the crude product, which was used directly in the next step.

LC (Method 2): t _R = 0.83 min; Mass Spec (ESI ⁺ ): m/z = 393 [M+H] ⁺ .

0.75 393 方法2 中間物 反應備註 11-1 在添加CH ₃I之後，在室溫下攪拌反應物1小時。 中間物 名稱 起始材料之名稱 11-1  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 Intermediate 11-1 was prepared analogously to Intermediate 11 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 11-1

0.75 393 Method 2 Intermediate Reaction Notes 11-1 After the addition of _CH3I , the reaction was stirred at room temperature for 1 hour. Intermediate name name of starting material 11-1 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl] -1H-imidazole-4-carboxylic acid ethyl ester 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H -Imidazole-4-carboxylic acid ethyl ester

Intermediate 12

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

In a microwave vial, add 1-[(6-{5-azaspiro[2.3]hex-5-yl}-2-carboxypyridin-3-yl]-1H-1,2,3-triazole Ethyl-4-carboxylate (763 mg) was dissolved in DCM (10 mL). Diethylaminosulfur trifluoride (DAST, 1 mL) was added, the vial was sealed and the mixture was heated to 50°C for 12 hours. After cooling to room temperature, the mixture was cautiously treated with 1 N aqueous NaHCO ₃ until gas evolution ceased. The mixture was then partitioned between saturated aqueous NaHCO ₃ and DCM. The phases were separated and the aqueous phase was extracted with DCM. The combined organic The phases were washed with brine, dried ( _MgSO4 ) and concentrated. The residue was chromatographed on silica gel (petroleum ether/EtOAc 70:30→30:70) to give the title compound.

LC (Method 2): t _R = 1.05 min; Mass Spec (ESI ⁺ ): m/z = 364 [M+H] ⁺ .

0.88 364 方法2 12-2

1.08 363 方法2 12-3

0.99 399 方法1 12-4

1.07 399 方法1 12-5

1.00 363 方法1 12-6

1.10 364 方法2 12-7

1.09 363 方法1 12-8

1.03 363 方法1 12-9

1.17 364 方法1 12-10

1.12 400 方法1 中間物 反應備註 12-9 在0℃下進行反應且攪拌1小時。 12-10 在0℃下進行反應且攪拌30分鐘。 中間物 名稱 起始材料 之名稱 12-1  1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-(二氟甲基)嘧啶-5-基)甲基]-1H-咪唑-4-甲酸乙酯  1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲醯基嘧啶-5-基)甲基]-1H-咪唑-4-甲酸乙酯 12-2  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲醯基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 12-3  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲醯基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 12-4  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲醯基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 12-5  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲醯基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 12-6  1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-(二氟甲基)嘧啶-5-基)甲基]-1H-吡唑-4-甲酸乙酯  1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲醯基嘧啶-5-基)甲基]-1H-吡唑-4-甲酸乙酯 12-7  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲醯基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 12-8  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲醯基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 12-9  3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯  3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲醯基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 12-10  3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(二氟甲基)吡啶-3-基)-甲基]-1,2-㗁唑-5-甲酸乙酯  3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲醯基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 Intermediates 12-1 to 12-10 were prepared analogously to Intermediate 12 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 12-1

0.88 364 Method 2 12-2

1.08 363 Method 2 12-3

0.99 399 method 1 12-4

1.07 399 method 1 12-5

1.00 363 method 1 12-6

1.10 364 Method 2 12-7

1.09 363 method 1 12-8

1.03 363 method 1 12-9

1.17 364 method 1 12-10

1.12 400 method 1 Intermediate Reaction Notes 12-9 The reaction was carried out at 0°C and stirred for 1 hour. 12-10 The reaction was carried out at 0°C and stirred for 30 minutes. Intermediate name name of starting material 12-1 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-(difluoromethyl)pyrimidin-5-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-carboxypyrimidin-5-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 12-2 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 12-3 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]- 1H-imidazole-4-carboxylic acid ethyl ester 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1H-imidazole -4-ethyl formate 12-4 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]- 1H-Pyrazole-4-carboxylic acid ethyl ester 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1H-pyridine Ethyl oxazole-4-carboxylate 12-5 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-carboxypyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 12-6 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-(difluoromethyl)pyrimidin-5-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-carboxypyrimidin-5-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 12-7 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-carboxypyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 12-8 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 12-9 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1,2-oxazole-5 -Ethyl formate 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid ethyl ester 12-10 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)-methyl] -1,2-Ethyl oxazole-5-carboxylate 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-carboxypyridin-3-yl)methyl]-1,2 -Ethyl oxazole-5-carboxylate

Intermediate 13

Ethyl 2 - chloro - 4 -[( 1E ) -2 - phenylvinyl ] pyrimidine - 5 - carboxylate

In a microwave vial, purge with argon 2,4-dichloropyrimidine-5-carboxylic acid ethyl ester (2.5 g), trans-beta-styryl potassium trifluoroborate (2.5 g), Na ₂ CO ₃ ( 2 M in water, 12.5 mL) and 1,4-dioxane (50 mL) for 10 min. Bis(di-tertiarybutyl(4-dimethylaminophenyl)phosphine)dichloropalladium( _II ) (Pd( _amphos )2Cl2, 300 mg) was added, the vial was sealed and the mixture was heated to 50°C for 2 hours. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried ( _MgSO4 ) and concentrated. The residue was chromatographed on silica gel (petroleum ether/EtOAc 80:20→60:40) to give the title compound.

LC (Method 2): t _R = 1.21 min; Mass Spec (ESI ⁺ ): m/z = 289 [M+H] ⁺ .

1.27 416 方法1 13-2

1.20 452 方法1 中間物 反應備註 13-1 反應在75℃下進行15小時。 13-2 反應在80℃下進行18小時。 中間物 名稱 起始材料之名稱 13-1 3-[(6-{3-氮雜環[3.1.0]己-3-基}-2-[(1E)-2-苯基乙烯基]吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 13-2 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-[(1E)-2-苯基乙烯基]吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 3-[(2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 Intermediates 13-1 to 13-2 were prepared analogously to Intermediate 13 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 13-1

1.27 416 method 1 13-2

1.20 452 method 1 Intermediate Reaction Notes 13-1 The reaction was carried out at 75°C for 15 hours. 13-2 The reaction was carried out at 80°C for 18 hours. Intermediate name name of starting material 13-1 3-[(6-{3-Azacyclo[3.1.0]hex-3-yl}-2-[(1E)-2-phenylvinyl]pyridin-3-yl)methyl]-1, Ethyl 2-oxazole-5-carboxylate 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid ethyl ester 13-2 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-[(1E)-2-phenylvinyl]pyridine-3- ethyl)methyl]-1,2-oxazole-5-carboxylic acid ethyl ester 3-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1,2-oxazole -5-ethyl formate

Intermediate 14

Ethyl 2- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -4 - [ ( 1E ) -2 - phenylvinyl ] pyrimidine - 5 - carboxylate _

Under argon atmosphere, 2-chloro-4-[(1E)-2-phenylvinyl]pyrimidine-5-carboxylic acid ethyl ester (2.56 g), 3-azabicyclo[3.1.0 ] A mixture of hexane hydrochloride (1.3 g) and _KHCO3 (2.3 g) in THF (30 mL) for 12 hours. The mixture was partitioned between saturated aqueous _NH4Cl and EtOAc and the phases were separated. The organic phase was washed with brine, dried ( _MgSO4 ), concentrated and the residue was chromatographed on silica gel (petroleum ether/EtOAc 80:20→60:40) to give the title compound.

LC (Method 2): t _R = 1.27 min; Mass Spec (ESI ⁺ ): m/z = 336 [M+H] ⁺ .

Intermediate 15

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

2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-[ was treated dropwise with diisobutylaluminum hydride (DIBAH, 1 M in THF, 25 mL) under argon atmosphere A mixture of (1E)-ethyl 2-phenylvinyl]pyrimidine-5-carboxylate (1.96 g) in THF (40 mL). The mixture was stirred at room temperature for 2 hours, cooled to 0 °C, and treated dropwise with 4 M aqueous HCl (15 mL). The mixture was then stirred for 5 minutes and 4 M aqueous NaOH (15 mL) was added. The mixture was partitioned between brine and DCM, and the layers were separated. The organic phase was dried ( _MgSO4 ), concentrated and the residue was chromatographed on silica gel (DCM/MeOH 98:2→90:10) to give the title compound.

LC (Method 2): t _R = 0.84 min; Mass Spec (ESI ⁺ ): m/z = 294 [M+H] ⁺ .

0.72 234 方法2 15-2

0.60 206 方法1 中間物 名稱 起始材料之名稱 15-1 (6-{3-氮雜雙環[3.1.0]己-3-基}-2-丙基吡啶-3-基)甲醇  6-{3-氮雜雙環[3.1.0]己-3-基}-2-丙基吡啶-3-甲酸乙酯 15-2  (2-{5-氮雜螺[2.3]己-5-基}-4-甲基嘧啶-5-基)甲醇  2-{5-氮雜螺[2.3]己-5-基}-4-甲基嘧啶-5-甲酸乙酯 Intermediates 15-1 to 15-2 were prepared analogously to Intermediate 15 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 15-1

0.72 234 Method 2 15-2

0.60 206 method 1 Intermediate name name of starting material 15-1 (6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)methanol 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-propylpyridine-3-carboxylic acid ethyl ester 15-2 (2-{5-Azaspiro[2.3]hex-5-yl}-4-methylpyrimidin-5-yl)methanol 2-{5-Azaspiro[2.3]hex-5-yl}-4-methylpyrimidine-5-carboxylic acid ethyl ester

Intermediate 16

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

-六氟磷酸酯(HATU，280 mg)處理1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-[(1E)-2-苯基乙烯基]嘧啶5-基)-甲基]-1H-咪唑-4-甲酸(240 mg)及DIPEA(380 µL)於DMF(3 mL)中之混合物。攪拌混合物5分鐘且接著用(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-胺二鹽酸鹽(145 mg)處理。在攪拌1小時之後，將混合物分配於水與DCM之間。有機相用鹽水洗滌，乾燥(MgSO ₄)，濃縮且在矽膠(DCM/MeOH 98:2 → 70:30)上層析殘餘物，得到標題化合物。LC(方法1): t _R= 1.02分鐘；質譜(ESI ⁺): m/z = 507 [M+H] ⁺。 Under argon atmosphere, with O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl

- Hexafluorophosphate (HATU, 280 mg) treated 1-[(2-{3-azabicyclo[3.1.0]hex-3-yl}-4-[(1E)-2-phenylvinyl] A mixture of pyrimidin 5-yl)-methyl]-1H-imidazole-4-carboxylic acid (240 mg) and DIPEA (380 µL) in DMF (3 mL). The mixture was stirred for 5 minutes and then treated with (4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-amine dihydrochloride (145 mg). After stirring for 1 hour, the mixture was partitioned between water and DCM. The organic phase was washed with brine, dried ( _MgSO4 ), concentrated and the residue was chromatographed on silica gel (DCM/MeOH 98:2→70:30) to give the title compound. LC (Method 1): t _R = 1.02 min; Mass Spec (ESI ⁺ ): m/z = 507 [M+H] ⁺ .

Intermediate 17

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

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

0.99 338 方法1 中間物 名稱 起始材料 1 之名稱 起始材料 2 之名稱 17-1 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}-6-氰基吡啶-2-基)甲基]-1H-吡唑-4-甲酸乙酯 3-{3-氮雜雙環[3.1.0]己-3-基}-6-(羥基甲基)吡啶-2-甲腈 1H-吡唑-4-甲酸乙酯 Intermediate 17-1 was prepared analogously to Intermediate 17 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 17-1

0.99 338 method 1 Intermediate name Name of starting material 1 Name of starting material 2 17-1 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}-6-cyanopyridin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 3-{3-azabicyclo[3.1.0]hex-3-yl}-6-(hydroxymethyl)pyridine-2-carbonitrile 1H-Pyrazole-4-carboxylic acid ethyl ester

Intermediate 18

1 - [ ( 6- { 5 - azaspiro [ 2.3 ] hex - 5 - yl } -2 - ethylpyridin - 3 - yl ) methyl ] -1H - 1,2,3 - triazole - 4 _ _ _ _ -Ethyl formate

In a microwave vial, purge 1-[(6-{5-azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-1,2 with argon A mixture of ethyl ,3-triazole-4-carboxylate (85 mg), ethylboronic acid (55 mg), K2CO3 (170 _mg ) and 1,4-dioxane ( ₃ mL) for 10 minutes. 1,1'-Bis(diphenylphosphino)ferrocene palladium(II) dichloride (Pd(dppf)Cl2, ₁₄ mg) was added, the vial was sealed and the mixture was heated to 80°C for 12 hours. Ethylboronic _acid (65 _mg ), K2CO3 (100 mg) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (Pd(dppf)Cl2 ₎ were added, 16 mg) and the mixture was heated to 90°C for 5 hours. After cooling to room temperature, the mixture was partitioned between water and EtOAc. The organic phase was washed with brine, dried ( _MgSO4 ), concentrated and the residue was chromatographed on silica gel (petroleum ether/EtOAc 85:15→60:40) to give the title compound. LC (Method 2): t _R = 0.72 min; Mass Spec (ESI ⁺ ): m/z = 342 [M+H] ⁺ .

0.72 342 方法2 18-2

0.76 378 方法2 18-3

0.66 217 方法2 18-4

0.86 253 方法2 中間物 反應備註 18-1 反應在80℃下進行12小時。 18-2 反應在80℃下進行12小時。 18-3 反應在70℃下進行5小時。 18-4 反應在80℃下進行16小時。 中間物 名稱 起始材料之名稱 18-1  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 18-2  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-乙基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯  1-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯 18-3  6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-甲醛  6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-甲醛 18-4  6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-甲醛  2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}吡啶-3-甲醛 Intermediates 18-1 to 18-4 were prepared analogously to Intermediate 18 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 18-1

0.72 342 Method 2 18-2

0.76 378 Method 2 18-3

0.66 217 Method 2 18-4

0.86 253 Method 2 Intermediate Reaction Notes 18-1 The reaction was carried out at 80°C for 12 hours. 18-2 The reaction was carried out at 80°C for 12 hours. 18-3 The reaction was carried out at 70°C for 5 hours. 18-4 The reaction was carried out at 80°C for 16 hours. Intermediate name name of starting material 18-1 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4 -Ethyl formate 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methyl]-1H-1,2,3-triazole-4- Ethyl formate 18-2 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-1, Ethyl 2,3-triazole-4-carboxylate 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-1,2, Ethyl 3-triazole-4-carboxylate 18-3 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridine-3-carbaldehyde 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridine-3-carbaldehyde 18-4 6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridine-3-carbaldehyde 2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]-hex-3-yl}pyridine-3-carbaldehyde

Intermediate 19

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

In a microwave vial, purge 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-pyridine with argon A mixture of oxazole-4-carboxylate (1.43 g), diethylzinc (1 M in n-hexane, 6.18 mL) and 1,4-dioxane (60 mL) for 10 minutes. 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (Pd(dppf)Cl2, 150 _mg ) was added, the vial was sealed and the mixture was heated to 70°C for 1 hour. After cooling to room temperature, the mixture was cautiously treated with saturated aqueous _NH4Cl . The mixture was partitioned between saturated aqueous _NH4Cl and EtOAc. The aqueous phase was extracted twice with EtOAc. The organic phase was washed with brine, dried ( _MgSO4 ), concentrated and the residue was chromatographed on silica gel (petroleum ether/EtOAc 95:5→0:100) to give the title compound. LC (Method 2): t _R = 0.75 min; Mass Spec (ESI ⁺ ): m/z = 341 [M+H] ⁺ .

中間物 反應備註 19-4 使用溴化正丙基鋅代替二乙基鋅。 19-5 使用溴化環丁基鋅代替二乙基鋅。 19-6 使用溴化正丙基鋅代替二乙基鋅。 19-7 反應在LiCL存在下以與二乙基鋅相同之莫耳量進行。 將反應加熱至60℃持續2小時。 19-9 使用溴化2-甲基丙基鋅代替二乙基鋅及使用二氯[1,3-雙(2,6-二-3-戊基苯基)咪唑-2-亞甲基] (3-氯吡啶基)鈀(II) (Pd-PEPPSI-IPent)代替1,1'-雙(二苯基膦基)二氯化二茂鐵鈀(II) (Pd(dppf)Cl ₂)。 反應在LiCL存在下以與二乙基鋅相同之莫耳量進行。 將反應加熱至60℃持續2小時。 19-10 使用溴化正丙基鋅代替二乙基鋅及使用二氯[1,3-雙(2,6-二-3-戊基苯基)咪唑-2-亞基](3-氯吡啶基)鈀(II) (Pd-PEPPSI-IPent)代替1,1'-雙(二苯基膦基)二氯化二茂鐵鈀(II) (Pd(dppf)Cl ₂)。 反應在LiCL存在下以與二乙基鋅相同之莫耳量進行。 將反應加熱至60℃持續2小時。 19-11 使用溴化環丙基鋅代替二乙基鋅。 19-12 使用二氯[1,3-雙(2,6-二-3-戊基苯基)咪唑-2-亞基](3-氯吡啶基)鈀(II) (Pd-PEPPSI-IPent)代替1,1'-雙(二苯基膦基)二氯化二茂鐵鈀(II) (Pd(dppf)Cl ₂)。反應在LiCL存在下以與二乙基鋅相同之莫耳量進行。將反應加熱至60℃持續1小時。 19-13 反應在80℃下進行2.5小時。 中間物 名稱 起始材料之名稱 19-1  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  1-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 19-2  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 19-3  (6-{5-氮雜螺[2.3]己-5-基}-2-乙基吡啶-3-基)甲醇  (6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲醇 19-4  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-丙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  1-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 19-5  1-[(2-環丁基-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  1-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 19-6  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-丙基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  1-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 19-7  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 19-8  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-六-3-基}-2-乙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  1-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)-甲基]-1H-咪唑-4-甲酸乙酯 19-9  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(2-甲基丙基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 19-10  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-丙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 19-11  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-環丙基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 19-12  1-({2-乙基-6-[(1R,5S,6R)-6-甲基-3-氮雜雙環[3.1.0]己-3-基]吡啶-3-基}甲基)-1H-咪唑-4-甲酸乙酯  1-({2-氯-6-[(1R,5S,6R)-6-甲基-3-氮雜雙環[3.1.0]己-3-基]吡啶-3-基}甲基)-1H-咪唑-4-甲酸乙酯 19-13  3-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯  3-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 19-14  5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-乙基吡啶-3-基)甲基]呋喃-2-甲酸甲酯  5-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]呋喃-2-甲酸甲酯 19-15  5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]噻吩-2-甲酸乙酯  5-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]噻吩-2-甲酸乙酯 Intermediates 19-1 to 19-15 were prepared analogously to Intermediate 19 :

Intermediate Reaction Notes 19-4 Use n-propylzinc bromide instead of diethylzinc. 19-5 Cyclobutylzinc bromide was used instead of diethylzinc. 19-6 Use n-propylzinc bromide instead of diethylzinc. 19-7 The reaction was carried out in the presence of LiCL at the same molar amount as diethylzinc. The reaction was heated to 60°C for 2 hours. 19-9 Using 2-methylpropylzinc bromide instead of diethylzinc and using dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-methylene](3- Chlorpyridyl)palladium(II) (Pd-PEPPSI-IPent) was used in place of 1,1'-bis(diphenylphosphino)ferrocene palladium( _II ) chloride (Pd(dppf)Cl2). The reaction was carried out in the presence of LiCL at the same molar amount as diethylzinc. The reaction was heated to 60°C for 2 hours. 19-10 Using n-propylzinc bromide instead of diethylzinc and using dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl) Palladium(II) (Pd-PEPPSI-IPent) was used in place of 1,1'-bis(diphenylphosphino)ferrocene palladium( _II ) (Pd(dppf)Cl2). The reaction was carried out in the presence of LiCL at the same molar amount as diethylzinc. The reaction was heated to 60°C for 2 hours. 19-11 Cyclopropylzinc bromide was used instead of diethylzinc. 19-12 Use dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (Pd-PEPPSI-IPent) in place of 1 ,1'-bis(diphenylphosphino)dichloroferrocene palladium( _II ) (Pd(dppf)Cl2). The reaction was carried out in the presence of LiCL at the same molar amount as diethylzinc. The reaction was heated to 60°C for 1 hour. 19-13 The reaction was carried out at 80°C for 2.5 hours. Intermediate name name of starting material 19-1 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole- Ethyl 4-formate 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4 -Ethyl formate 19-2 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 19-3 (6-{5-Azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methanol (6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methanol 19-4 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)methyl]-1H-imidazole-4 -Ethyl formate 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazol-4- Ethyl formate 19-5 1-[(2-Cyclobutyl-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole -4-ethyl formate 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4 -Ethyl formate 19-6 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)methyl]-1H-pyrazole- Ethyl 4-formate 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4 -Ethyl formate 19-7 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 19-8 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hexa-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-imidazole- Ethyl 4-formate 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)-methyl]-1H-imidazol-4 -Ethyl formate 19-9 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(2-methylpropyl)pyridin-3-yl)methyl]-1H-imidazol-4- Ethyl formate 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 19-10 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 19-11 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-cyclopropylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 19-12 1-({2-Ethyl-6-[(1R,5S,6R)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl]pyridin-3-yl}methyl) -1H-imidazole-4-carboxylic acid ethyl ester 1-({2-Chloro-6-[(1R,5S,6R)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl]pyridin-3-yl}methyl)- 1H-imidazole-4-carboxylic acid ethyl ester 19-13 3-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid ethyl ester 3-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid ethyl ester 19-14 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-ethylpyridin-3-yl)methyl]furan-2-carboxylic acid methyl ester Methyl 5-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]furan-2-carboxylate 19-15 Ethyl 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]thiophene-2-carboxylate ester 5-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]thiophene-2-carboxylic acid ethyl ester

Intermediate 20

1 - [ ( 6- { 5 - azaspiro [ 2.3 ] hex - 5 - yl } pyridin - 3 - yl ) methyl ] -1H - 1,2,3 - triazole - 4 - ethyl carboxylate _ _ _

1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methyl]-1H- A mixture of 1,2,3-triazole-4-carboxylic acid ethyl ester (150 mg), 10% palladium on carbon (20 mg) in EtOH (4 mL) and THF (4 mL) for 3.5 hours. The mixture was filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t _R = 0.68 min; Mass Spec (ESI ⁺ ): m/z = 314 [M+H] ⁺ .

Intermediate twenty one

1 - [ ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2- ( difluoromethyl ) pyridin - 3 - yl ) methyl ] -1H - 1,2 , _ _ _ _ 3 - Triazole - 4 - ethylcarboxylate

In a microwave vial, treat 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-bromopyridine-3- with difluoromethyltrimethylsilane (435 µL) A mixture of ethyl)-1H-1,2,3-triazole-4-carboxylate (250 mg), CsF (290 mg) and CuF (121 mg) in NMP (4 mL). The vial was sealed and the mixture was heated to 120°C for 1.5 hours. The mixture was partitioned between half-saturated aqueous _NaHCO3 and EtOAc. The mixture was then filtered through celite and the filter cake was washed with EtOAc. The phases were separated and the aqueous phase was extracted twice with EtOAc. The combined organic phases were dried ( _MgSO4 ), concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t _R = 1.10 min; Mass Spec (ESI ⁺ ): m/z = 364 [M+H] ⁺ .

Intermediate twenty two

2 - Chloro - 4 - propylpyrimidine - 5 - carboxylic acid ethyl ester

In a microwave vial, 2,4-dichloropyrimidine-5-carboxylic acid ethyl ester (1 g), n-propylzinc bromide (0.5 M in THF, 9.5 mL) and 1,1' were purged with argon - A mixture of bis(diphenylphosphino)ferrocene palladium(II) dichloride (Pd(dppf)Cl2, 66 _mg ) in 1,4-dioxane (25 mL) for 10 min. The vial was sealed and the mixture was heated to 70°C for 1 hour. Then n-propylzinc bromide (0.5 M in THF, 5 mL) was added and the mixture was heated to 70°C for 45 minutes. After cooling to room temperature, the mixture was partitioned between EtOAc and saturated aqueous _NH4Cl . The aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried ( _MgSO4 ) and concentrated. The residue was chromatographed on silica gel (petroleum ether/EtOAc 98:2→90:10) to give the title compound.

LC (Method 2): t _R = 1.10 min; Mass Spec (ESI ⁺ ): m/z = 229 [M+H] ⁺ .

Intermediate twenty three

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

Under argon atmosphere, 2-chloro-4-propylpyrimidine-5-carboxylic acid ethyl ester (546 mg), 3-azabicyclo[3.1.0]hexane hydrochloride (328 mg) were stirred at room temperature and a mixture _of K2CO3 (663 mg) in DMF (15 mL) for ₂ hours. The mixture was partitioned between water and EtOAc and the phases were separated. The aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried ( _MgSO4 ), concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

LC (Method 2): t _R = 1.09 min; Mass Spec (ESI ⁺ ): m/z = 276 [M+H] ⁺ .

Intermediate twenty four

Methyl 5- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -6 - cyanopyridine - 2 - carboxylate _ _ _

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

Intermediate 25

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

NaBH ₄ (131 mg) was added portionwise to methyl 5-{3-azabicyclo[3.1.0]hex-3-yl}-6-cyanopyridine-2-carboxylate (280 mg) and CaCl ₂ ( 507 mg) in a mixture of THF (8 mL) and EtOH (8 mL). The mixture was stirred at room temperature for 2 hours and at 45°C for 1 hour. The mixture was then partitioned between saturated aqueous _NaHCO3 and EtOAc. The precipitate was filtered off. The aqueous phase was extracted with EtOAc. The combined organic phases were dried ( _MgSO4 ), concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

LC (Method 1): t _R = 0.81 min; Mass Spec (ESI ⁺ ): m/z = 216 [M+H] ⁺ .

0.83 395 方法2 中間物 反應備註 25-1 反應在室溫下進行24小時。 中間物 名稱 起始材料之名稱 25-1  5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(羥基甲基)-吡啶-3-基)甲基]噻吩-2-甲酸乙酯  6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-3-{[5-(乙氧羰基)噻吩-2-基]甲基}吡啶-2-甲酸乙酯 Intermediate 25-1 was prepared analogously to Intermediate 25 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 25-1

0.83 395 Method 2 Intermediate Reaction Notes 25-1 The reaction was carried out at room temperature for 24 hours. Intermediate name name of starting material 25-1 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(hydroxymethyl)-pyridin-3-yl)methyl]thiophene -2-ethyl formate 6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-3-{[5-(ethoxycarbonyl)thiophen-2-yl]methyl}pyridine-2 -Ethyl formate

Intermediate 26

Methyl 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2- ( trifluoromethoxy ) pyridine - 3 - carboxylate _ _ _

Under argon atmosphere, methyl 6-chloro-2-(trifluoromethoxy)pyridine-3-carboxylate (1 g), 3-azabicyclo[3.1.0]hexane hydrochloride was stirred at room temperature A mixture of salt (538 mg) and K2CO3 (1.1 _g ) in DMF (20 mL) for ₄ hours. The mixture was partitioned between water and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried ( _MgSO4 ), concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t _R = 1.18 min; Mass Spec (ESI ⁺ ): m/z = 303 [M+H] ⁺ .

Intermediate 27

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

_LiBH4 (250 mg) was added portionwise to methyl 6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(trifluoromethoxy)pyridine-3-carboxylate (384 mg) In a mixture in THF (5 mL). The mixture was stirred at room temperature for 12 hours. The mixture was then poured into 1 N aqueous HCl and stirred vigorously for 20 minutes. The mixture was then partitioned between saturated aqueous _NaHCO3 and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried ( _MgSO4 ), concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t _R = 1.22 min; Mass Spec (ESI ⁺ ): m/z = 289 [M+H] ⁺ .

Intermediate 28

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

In a microwave vial, purge 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-pyridine with argon A mixture of methyl oxazole-4-carboxylate (5.62 g), pinacol vinylboronate (2.9 mL), Na ₂ CO ₃ (1 M aq, 40.5 mL) and 1,4-dioxane (75 mL) 10 minutes. 1,1'- Bis(diphenylphosphino)ferrocene palladium(II) dichloride (Pd(dppf)Cl2, 662 _mg ) was added, the vial was sealed and the mixture was heated to 100°C for 12 hours. After cooling to room temperature, the mixture was partitioned between water and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried ( _MgSO4 ), concentrated and the residue was chromatographed on silica gel (petroleum ether/EtOAc 100:0→50:50) to give the title compound.

LC (Method 2): t _R = 0.78 min; Mass Spec (ESI ⁺ ): m/z = 339 [M+H] ⁺ .

0.99    方法1 28-2

1.01 339 方法1 28-3

0.79 353 方法2 28-4

1.04 339 方法1 28.5

0.82 367 方法2 中間物 反應備註 28-3 使用異丙烯基硼酸頻哪醇酯代替乙烯基硼酸頻哪醇酯。 28-5 使用異丙烯基硼酸頻哪醇酯代替乙烯基硼酸頻哪醇酯。 反應在80℃下進行18小時。 中間物 名稱 起始材料之名稱 28-1  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  1-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 28-2  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙烯基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 28-3  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(丙-1-烯-2-基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 28-4  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 28-5  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-(丙-1-烯-2-基)-1H-吡唑-4-甲酸乙酯  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-溴-1H-吡唑-4-甲酸乙酯 Intermediates 28-1 to 28-5 were prepared analogously to Intermediate 28 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 28-1

0.99 method 1 28-2

1.01 339 method 1 28-3

0.79 353 Method 2 28-4

1.04 339 method 1 28.5

0.82 367 Method 2 Intermediate Reaction Notes 28-3 Use pinacol isopropenyl borate instead of vinyl borate pinacol. 28-5 Use pinacol isopropenyl borate instead of vinyl borate pinacol. The reaction was carried out at 80°C for 18 hours. Intermediate name name of starting material 28-1 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1H-imidazol-4 -Ethyl formate 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazol-4- Ethyl formate 28-2 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-vinylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 28-3 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(prop-1-en-2-yl)pyridin-3-yl)methyl]-1H-pyridine Ethyl oxazole-4-carboxylate 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 28-4 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 28-5 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(prop-1-en-2-yl )-1H-Pyrazole-4-carboxylic acid ethyl ester 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-bromo-1H-pyrazole-4-carboxylic acid ethyl ester

Intermediate 29

1 - [ ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2- ( cyanomethyl ) pyridin - 3 - yl ) methyl ] -1H - pyrazole - 4 _ _ -Ethyl formate

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

Intermediate 30

1 - [ ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2- ( 1 - cyanocyclopropyl ) pyridin - 3 - yl ) methyl ] -1H - pyridine _ _ Ethyl oxazole - 4 - carboxylate

1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(cyanomethyl)pyridin-3-yl)methyl]-1H-pyrazol-4- A mixture of ethyl formate (212 mg) in DMSO (7 mL) was cooled to 10 °C and treated portionwise with NaH (60% in mineral oil, 60 mg). The mixture was stirred at room temperature for 15 minutes, cooled to 0 °C and treated with 1,2-dibromoethane (80 µL). The mixture was then stirred at room temperature for 1 hour. After cooling to 0°C, the mixture was treated with saturated aqueous _NH4Cl . The mixture was then extracted twice with EtOAc. The combined organic phases were washed with water, dried ( _MgSO4 ), concentrated and the residue was chromatographed on silica gel (petroleum ether/EtOAc 90:10→60:40) to give the title compound.

LC (Method 2): t _R = 1.06 min; Mass Spec (ESI ⁺ ): m/z = 378 [M+H] ⁺ .

1.16 380 方法1 中間物 反應備註 30-1 反應在DMF中進行。使用CH ₃I代替1,2-二溴乙烷。 中間物 名稱 起始材料之名稱 30-1 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(1-氰基-1-甲基乙基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(氰基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 Intermediate 30-1 was prepared analogously to Intermediate 30 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 30-1

1.16 380 method 1 Intermediate Reaction Notes 30-1 The reaction was carried out in DMF. _CH3I was used instead of 1,2-dibromoethane. Intermediate name name of starting material 30-1 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(1-cyano-1-methylethyl)pyridin-3-yl)methyl]-1H - Pyrazole-4-carboxylic acid ethyl ester 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(cyanomethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

Intermediate 31

1 - [( 2- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -4 - [ ( 1E ) -2 - phenylethenyl ] pyrimidin - 5 - yl ) methyl ] - 1H - Pyrazole - 4 - ethylcarboxylate

_SOCl2 (5 mL) was added to (2-{3-azabicyclo[3.1.0]hex-3-yl}-4-[(1E)-2 in toluene (20 mL) under argon atmosphere A mixture of -phenylvinyl]pyrimidin-5-yl)methanol (1.89 g). The mixture was heated to 60°C for 3 hours, cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (20 mL) and added dropwise to a mixture of lH-pyrazole-4-carboxylic acid ethyl ester (950 mg) and DIPEA (2.2 mL) in DCM (20 mL). After stirring at room temperature for 12 hours, the mixture was partitioned between water and DCM. The organic phase was washed with brine, dried ( _MgSO4 ), concentrated and the residue was chromatographed on silica gel (petroleum ether/EtOAc 50:50→0:100) to give the title compound.

LC (Method 2): t _R = 1.06 min; Mass Spec (ESI ⁺ ): m/z = 416 [M+H] ⁺ .

Intermediate 32

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

To 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-pyrazole at 0 °C To a solution of ethyl-4-carboxylate (900 mg) in DMF (10 mL) was added NaH (60% in mineral oil, 263 mg). The mixture was stirred for 30 minutes, treated with _CH3I (222 μL) and stirred at 0 °C for 1.5 hours. EtOH (4 mL) and aqueous NaOH (4 M, 4.2 mL) were added and the mixture was stirred at 70 °C for 12 h. After cooling to room temperature, aqueous HCl (4 M, 3 mL) was added and the mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried ( _MgSO4 ), concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t _R = 0.62 min; Mass Spec (ESI ⁺ ): m/z = 329 [M+H] ⁺ .

0.63 329 方法1 32-2

0.63 329 方法1 32-3   

(異構體之混合物) 0.85及0.86 459 方法2 中間物 反應備註 32-3 在添加CH ₃I之後，在室溫下攪拌混合物12小時。接著添加水且藉由逆相HPLC (ACN，水)純化混合物，得到作為異構體之混合物之標題化合物。 中間物 名稱 起始材料之名稱 32-1 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 32-2 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸酯三氟乙酸乙酯 32-3 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-5-甲酸 及 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-3-甲酸 (異構體之混合物) 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-5-甲酸乙酯 及 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-3-甲酸乙酯 (異構體之混合物) Intermediates 32-1 to 32-3 were prepared analogously to Intermediate 32 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 32-1

0.63 329 method 1 32-2

0.63 329 method 1 32-3

(mixture of isomers) 0.85 and 0.86 459 Method 2 Intermediate Reaction Notes 32-3 After the addition of _CH3I , the mixture was stirred at room temperature for 12 hours. Water was then added and the mixture was purified by reverse phase HPLC (ACN, water) to give the title compound as a mixture of isomers. Intermediate name name of starting material 32-1 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 32-2 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate tris Ethyl Fluoroacetate 32-3 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1-{[2-( Trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carboxylic acid and 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-( Methoxymethyl)pyridin-3-yl)methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylic acid (of isomers) mixture) 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1-{[2-(trimethyl Silyl)ethoxy]methyl}-1H-pyrazole-5-carboxylic acid ethyl ester and 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-( Hydroxymethyl)pyridin-3-yl)methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylic acid ethyl ester (of isomers mixture)

Intermediate 33

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

To (6-{5-azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methanol (400 mg), 1H-pyrazole-4-carboxylic acid ethyl ester (800 mg) DBAD (1.35 g) was added dropwise to an ice-cold solution of tributylphosphine (1.6 mL) in THF (10 mL). The mixture was stirred for 45 minutes. Saturated aqueous _NaHCO3 was added and the mixture was stirred vigorously for 5 minutes. The mixture was then filtered through diatomaceous earth. The aqueous phase was extracted twice with EtOAc, and the combined organic phases were washed with brine and dried ( _MgSO4 ). The solvent was evaporated in vacuo and the residue was chromatographed on silica gel (petroleum ether/EtOAc 70:30→0:100) to give the title compound.

LC (Method 2): t _R = 0.78 min; Mass Spec (ESI ⁺ ): m/z = 341 [M+H] ⁺ .

1.14 405 方法1 33-2

0.73 327 方法2 33-3

0.65 364 方法1 33-4

0.84 401 方法1 33-5

0.77 365 方法1 中間物 反應備註 33-1 在0℃下將DBAD添加至反應混合物中。在升溫至室溫時攪拌混合物12小時。 33-4 在0℃下將DBAD添加至反應混合物中。在升溫至室溫時攪拌混合物12小時。 33-5 在0℃下將DBAD添加至反應混合物中。在升溫至室溫時攪拌混合物12小時。 中間物 名稱 起始材料 1 之名稱 起始材料 2 之名稱 33-1  1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲基]-3-溴-1H-吡唑-4-甲酸乙酯  (6-{3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲醇  3-溴-1H-吡唑-4-甲酸乙酯 33-2  1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  (6-{3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲醇  1H-吡唑-4-甲酸乙酯 33-3  7-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)-甲基]-7H-吡咯并[2,3-d]嘧啶-5-甲酸甲酯  (6-{3-氮雜雙環[3.1.0]-己-3-基}-2-甲基-吡啶-3-基)甲醇  7H-吡咯并[2,3-d]嘧啶-5-甲酸甲酯 33-4  7-[2,{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-7H-吡咯并[2,3-d]嘧啶-5-甲酸甲酯  (2-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲醇  7H-吡咯并[2,3-d]嘧啶-5-甲酸甲酯 33-5  7-[2-{3-氮雜雙環[3.1.0]-己-3-基}-4-甲基嘧啶-5-基)-甲基]-7H-吡咯并[2,3-d]嘧啶-5-甲酸甲酯  (2-{3-氮雜雙環[3.1.0]-己-3-基}-4-甲基-嘧啶-5-基)甲醇  7H-吡咯并[2,3-d]嘧啶-5-甲酸甲酯 Intermediates 33-1 to 33-5 were prepared analogously to Intermediate 33 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 33-1

1.14 405 method 1 33-2

0.73 327 Method 2 33-3

0.65 364 method 1 33-4

0.84 401 method 1 33-5

0.77 365 method 1 Intermediate Reaction Notes 33-1 DBAD was added to the reaction mixture at 0°C. The mixture was stirred for 12 hours while warming to room temperature. 33-4 DBAD was added to the reaction mixture at 0°C. The mixture was stirred for 12 hours while warming to room temperature. 33-5 DBAD was added to the reaction mixture at 0°C. The mixture was stirred for 12 hours while warming to room temperature. Intermediate name Name of starting material 1 Name of starting material 2 33-1 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-bromo-1H-pyrazole-4- Ethyl formate (6-{3-Azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methanol 3-Bromo-1H-pyrazole-4-carboxylic acid ethyl ester 33-2 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (6-{3-Azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methanol 1H-Pyrazole-4-carboxylic acid ethyl ester 33-3 7-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)-methyl]-7H-pyrrolo[2,3-d ]pyrimidine-5-carboxylic acid methyl ester (6-{3-Azabicyclo[3.1.0]-hex-3-yl}-2-methyl-pyridin-3-yl)methanol 7H-Pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester 33-4 7-[2,{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-7H-pyrrolo[2 ,3-d]Pyrimidine-5-carboxylate methyl ester (2-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methanol 7H-Pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester 33-5 7-[2-{3-Azabicyclo[3.1.0]-hex-3-yl}-4-methylpyrimidin-5-yl)-methyl]-7H-pyrrolo[2,3-d] Methyl pyrimidine-5-carboxylate (2-{3-Azabicyclo[3.1.0]-hex-3-yl}-4-methyl-pyrimidin-5-yl)methanol 7H-Pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester

Intermediate 34

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

In a microwave vial, purge 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-pyridine with argon Ethyl oxazole-4-carboxylate (100 mg), (E)-3-(benzyloxy)propan-1-yl potassium trifluoroborate (88 mg), K ₂ CO ₃ (100 mg) and THF (5 mL) for 10 minutes. 1,1'- Bis(diphenylphosphino)ferrocene palladium(II) dichloride (Pd(dppf)Cl2, ₁₅ mg) was added, the vial was sealed and the mixture was heated to 80°C for 15 hours. After cooling to room temperature, the mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried ( _MgSO4 ), concentrated in vacuo and the residue was chromatographed on silica gel (petroleum ether/EtOAc 70:30→0:100) to give the title compound.

LC (Method 2): t _R = 0.95 min; Mass Spec (ESI ⁺ ): m/z = 459 [M+H] ⁺ .

Intermediate 35

1 - [ ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2- ( 3 - hydroxypropyl ) pyridin - 3 - yl ) methyl ] -1H - pyrazole- _ _ _ 4 - ethyl formate

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

LC (Method 2): t _R = 0.73 min; Mass Spec (ESI ⁺ ): m/z = 371 [M+H] ⁺ .

Intermediate 36

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

Under argon atmosphere, diphenylphosphorylazide (1.4 mL) was added dropwise to (6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl] In an ice-cold mixture of }-2-vinylpyridin-3-yl)methanol (1.34 g) and DBU (1.05 mL) in toluene (10 mL) and ACN (10 mL). The mixture was stirred for 12 hours while warming to room temperature. The mixture was then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried ( _MgSO4 ), concentrated in vacuo and the residue chromatographed on silica gel (petroleum ether/EtOAc 99:1→50:50) to give the title compound. LC (Method 2): t _R = 0.88 min; Mass Spec (ESI ⁺ ): m/z = 278 [M+H] ⁺ .

0.69 230 方法2 36-2

0.72 242 方法2 36-3

1.00 267 方法2 36-4

0.97 267 方法2 36-5

0.75 231 方法2 中間物 反應備註 36-3 反應在甲苯/ACN 1:1中進行。 36-4 反應在甲苯/ACN 1:1中進行。 36-5 反應在甲苯/ACN 1:1中進行。 中間物 名稱 起始材料之名稱 36-1  5-[5-(疊氮基甲基)-6-甲基吡啶-2-基]-5-氮雜螺[2.3]己烷  (6-{5-氮雜螺[2.3]己-5-基}-2-甲基吡啶-3-基)甲醇 36-2  3-[5-(疊氮基甲基)-6-乙烯基吡啶-2-基]-3-氮雜雙環[3.1.0]己烷  (6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲醇 36-3  3-[5-(疊氮基甲基)-6-甲基吡𠯤-2-基]-6,6-二氟-3-氮雜雙環[3.1.0]己烷  (5-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-3-甲基吡𠯤-2-基)甲醇 36-4  3-[5-(疊氮基甲基)-4-甲基嘧啶-2-基]-6,6-二氟-3-氮雜雙環[3.1.0]己烷  (2-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲醇 36-5  3-[5-(疊氮基甲基)-4-甲基嘧啶-2-基]-3-氮雜雙環[3.1.0]己烷  (2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲醇 Intermediates 36-1 to 36-5 were prepared analogously to Intermediate 36 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 36-1

0.69 230 Method 2 36-2

0.72 242 Method 2 36-3

1.00 267 Method 2 36-4

0.97 267 Method 2 36-5

0.75 231 Method 2 Intermediate Reaction Notes 36-3 The reaction was carried out in toluene/ACN 1:1. 36-4 The reaction was carried out in toluene/ACN 1:1. 36-5 The reaction was carried out in toluene/ACN 1:1. Intermediate name name of starting material 36-1 5-[5-(Azidomethyl)-6-methylpyridin-2-yl]-5-azaspiro[2.3]hexane (6-{5-Azaspiro[2.3]hex-5-yl}-2-methylpyridin-3-yl)methanol 36-2 3-[5-(Azidomethyl)-6-vinylpyridin-2-yl]-3-azabicyclo[3.1.0]hexane (6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methanol 36-3 3-[5-(Azidomethyl)-6-methylpyridine-2-yl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane (5-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-3-methylpyridin-2-yl)methanol 36-4 3-[5-(Azidomethyl)-4-methylpyrimidin-2-yl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane (2-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methanol 36-5 3-[5-(Azidomethyl)-4-methylpyrimidin-2-yl]-3-azabicyclo[3.1.0]hexane (2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methanol

Intermediate 37

1 - [ ( 6- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - vinylpyridin - 3 - yl ) methyl ] -1H - 1 _ _ _ _ , 2 , 3 - Triazole - 4 - ethyl carboxylate

3-[5-(Azidomethyl)-6-vinylpyridin-2-yl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane (794 mg), ethyl propiolate (320 µL), CuSO4 ₍ 92 mg) and (L)-sodium ascorbate (568 mg) in tertiary butanol (8 mL) and water (8 mL) for 48 hours . The mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried ( _MgSO4 ), concentrated in vacuo and the residue chromatographed on silica gel (petroleum ether/EtOAc 99:1→50:50) to give the title compound.

LC (Method 2): t _R = 0.89 min; Mass Spec (ESI ⁺ ): m/z = 376 [M+H] ⁺ .

0.69 328 方法2 37-2

0.74 340 方法2 37-3

0.95 365 方法2 37-4

0.87 365 方法2 37-5

0.79 329 方法2 中間物 反應備註 37-3 反應進行12小時。 37-5 反應進行5天。 中間物 名稱 起始材料之名稱 37-1  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲基-吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯  5-[5-(疊氮基甲基)-6-甲基吡啶-2-基]-5-氮雜螺[2.3]己烷 37-2  1-[(6-{3-氮雜環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯  3-[5-(疊氮基甲基)-6-乙烯基吡啶-2-基]-3-氮雜雙環[3.1.0]己烷 37-3  1-[(5-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-3-甲基吡𠯤-2-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯  3-[5-(疊氮基甲基)-6-甲基吡𠯤-2-基]-6,6-二氟-3-氮雜雙環[3.1.0]己烷 37-4  1-[(2-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-4-甲基嘧啶-5-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯  3-[5-(疊氮基甲基)-4-甲基嘧啶-2-基]-6,6-二氟-3-氮雜雙環[3.1.0]己烷 37-5  1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-1H-1,2,3-三唑-4-甲酸乙酯  3-[5-(疊氮基甲基)-4-甲基嘧啶-2-基]-3-氮雜雙環[3.1.0]己烷 Intermediates 37-1 to 37-5 were prepared analogously to Intermediate 37 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 37-1

0.69 328 Method 2 37-2

0.74 340 Method 2 37-3

0.95 365 Method 2 37-4

0.87 365 Method 2 37-5

0.79 329 Method 2 Intermediate Reaction Notes 37-3 The reaction was carried out for 12 hours. 37-5 The reaction was carried out for 5 days. Intermediate name name of starting material 37-1 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-methyl-pyridin-3-yl)methyl]-1H-1,2,3-triazole-4- Ethyl formate 5-[5-(Azidomethyl)-6-methylpyridin-2-yl]-5-azaspiro[2.3]hexane 37-2 1-[(6-{3-Azacyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4 -Ethyl formate 3-[5-(Azidomethyl)-6-vinylpyridin-2-yl]-3-azabicyclo[3.1.0]hexane 37-3 1-[(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-3-methylpyridine-2-yl)methyl]-1H-1, Ethyl 2,3-triazole-4-carboxylate 3-[5-(Azidomethyl)-6-methylpyridine-2-yl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane 37-4 1-[(2-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-1H-1, Ethyl 2,3-triazole-4-carboxylate 3-[5-(Azidomethyl)-4-methylpyrimidin-2-yl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane 37-5 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-1H-1,2,3-triazole-4 -Ethyl formate 3-[5-(Azidomethyl)-4-methylpyrimidin-2-yl]-3-azabicyclo[3.1.0]hexane

Intermediate 38

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

To 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methane at 0 °C To a solution of ethyl]-1H-1,2,3-triazole-4-carboxylate (175 mg) in DMF (2 mL) was added NaH (60% in mineral oil, 45 mg). The mixture was stirred at room temperature for 30 minutes, treated with _CH3I (30 μL) and stirred at room temperature for 12 hours. Water was added and the mixture was concentrated in vacuo. The residue was dissolved in DCM/isopropanol 1:1 and filtered. The filtrate was dried ( _MgSO4 ) and concentrated in vacuo to give the title compound.

LC (Method 2): t _R = 0.65 min; Mass Spec (ESI ⁺ ): m/z = 366 [M+H] ⁺ .

Intermediate 39

1 - [ ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2- ( 1 - hydroxypropen - 2 - yl ) pyridin - 3 - yl ) methyl ] -1H- _ _ _ Pyrazole- 4 - ethyl carboxylate

Stir 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(prop-1-en-2-yl)pyridin-3-yl)methyl at room temperature A mixture of ]-1H-pyrazole-4-carboxylic acid ethyl ester (270 mg) and 9-borabicyclo(3.3.1)nonane (3.1 mL) for 48 hours. 9-borabicyclo(3.3.1)nonane (6 mL) was added and stirring was continued for 12 hours. The mixture was cooled to ₀ °C and treated dropwise with water ( ₃ mL) and H2O2 (35% in water, 3.35 mL). The mixture was then stirred at room temperature for 30 minutes. Aqueous NaOH (2 M, 340 μL) was added, the mixture was stirred for 20 min and then cooled to 0 °C. _Saturated aqueous _Na2S2O3 was added _slowly and the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried ( _MgSO4 ), concentrated in vacuo and the residue was chromatographed on silica gel (petroleum ether/EtOAc 80:20→0:100) to give the title compound. LC (Method 2): t _R = 0.76 min; Mass Spec (ESI ⁺ ): m/z = 371 [M+H] ⁺ .

0.98 357 方法1 中間物 反應備註 39-1 硼氫化在室溫下進行3小時。 中間物 名稱 起始材料之名稱 39-1 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(2-羥基乙基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 Intermediate 39-1 was prepared analogously to Intermediate 39 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 39-1

0.98 357 method 1 Intermediate Reaction Notes 39-1 Hydroboration was carried out at room temperature for 3 hours. Intermediate name name of starting material 39-1 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(2-hydroxyethyl)pyridin-3-yl)methyl]-1H-pyrazole-4- Ethyl formate 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

Intermediate 40

6- { 3 - azabicyclo [ 3.1.0 ] hexyl - 3 - yl } pyridin - 3 - carboxylate methyl ester _ _ _

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

0.68 219 方法2 40-2

0.96 219 方法1 40-3

0.93 254 方法2 40-4

0.93 270 方法2 40-5

1.07 287 方法1 40-6

1.02 284 方法2 40-7

1.02 248 方法2 40-8

1.00 248 方法1 中間物 反應備註 40-1 反應在90℃下進行12小時。 40-3 反應在室溫下進行48小時。 40-4 反應在90℃下進行12小時。 40-5 使用KHCO ₃代替K ₂CO ₃及DMSO代替DMF。 反應在45℃下進行4小時。 40-6 反應在90℃下進行1小時。 40-7 反應在90℃下進行1小時。 中間物 名稱 起始材料 1 之名稱 起始材料 2 之名稱 40-1  6-{3-氮雜雙環[3.1.0]-己-3-基}吡啶-3-甲酸甲酯  6-氯吡啶-3-甲酸甲酯  3-氮雜雙環[3.1.0]己烷鹽酸鹽 40-2  6-{5-氮雜螺[2.3]己-5-基}吡啶-3-甲酸甲酯  6-氟吡啶-3-甲酸甲酯  5-氮雜螺[2.3]己烷三氟乙酸鹽 40-3  5-{3-氮雜雙環[3.1.0]-己-3-基}-3-氯吡𠯤-2-甲酸甲酯  3,5-二氯吡𠯤-2-甲酸甲酯  3-氮雜雙環[3.1.0]己烷鹽酸鹽 40-4  5-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-3-甲基吡𠯤-2-甲酸甲酯  5-氯-3-甲基吡𠯤-2-甲酸甲酯  6,6-二氟-3-氮雜雙環[3.1.0]己烷鹽酸鹽 40-5  6-{3-氮雜雙環[3.1.0]-己-3-基}-4-(三氟甲基)-吡啶-3-甲酸甲酯  6-氯-4-(三氟甲基)吡啶-3-甲酸甲酯  3-氮雜雙環[3.1.0]己烷鹽酸鹽 40-6  2-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-甲酸乙酯  2-氯-4-甲基嘧啶-5-甲酸乙酯  6,6-二氟-3-氮雜雙環[3.1.0]己烷鹽酸鹽 40-7  2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-甲酸乙酯  2-氯-4-甲基嘧啶-5-甲酸乙酯  3-氮雜雙環[3.1.0]己烷鹽酸鹽 40-8  2-{5-氮雜螺[2.3]己-5-基}-4-甲基嘧啶-5-甲酸乙酯  2-氯-4-甲基嘧啶-5-甲酸乙酯  5-氮雜螺[2.3]己烷三氟乙酸鹽 Intermediates 40-1 to 40-8 were prepared analogously to Intermediate 40 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 40-1

0.68 219 Method 2 40-2

0.96 219 method 1 40-3

0.93 254 Method 2 40-4

0.93 270 Method 2 40-5

1.07 287 method 1 40-6

1.02 284 Method 2 40-7

1.02 248 Method 2 40-8

1.00 248 method 1 Intermediate Reaction Notes 40-1 The reaction was carried out at 90°C for 12 hours. 40-3 The reaction was carried out at room temperature for 48 hours. 40-4 The reaction was carried out at 90°C for 12 hours. 40-5 Use _KHCO3 instead _{of K2CO3} and DMSO instead of DMF. The reaction was carried out at 45°C for 4 hours. 40-6 The reaction was carried out at 90°C for 1 hour. 40-7 The reaction was carried out at 90°C for 1 hour. Intermediate name Name of starting material 1 Name of starting material 2 40-1 Methyl 6-{3-azabicyclo[3.1.0]-hex-3-yl}pyridine-3-carboxylate Methyl 6-chloropyridine-3-carboxylate 3-Azabicyclo[3.1.0]hexane hydrochloride 40-2 Methyl 6-{5-azaspiro[2.3]hex-5-yl}pyridine-3-carboxylate Methyl 6-fluoropyridine-3-carboxylate 5-Azaspiro[2.3]hexane trifluoroacetate 40-3 Methyl 5-{3-azabicyclo[3.1.0]-hex-3-yl}-3-chloropyridine-2-carboxylate Methyl 3,5-dichloropyridine-2-carboxylate 3-Azabicyclo[3.1.0]hexane hydrochloride 40-4 Methyl 5-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-3-methylpyridine-2-carboxylate Methyl 5-chloro-3-methylpyridine-2-carboxylate 6,6-Difluoro-3-azabicyclo[3.1.0]hexane hydrochloride 40-5 6-{3-Azabicyclo[3.1.0]-hex-3-yl}-4-(trifluoromethyl)-pyridine-3-carboxylic acid methyl ester Methyl 6-chloro-4-(trifluoromethyl)pyridine-3-carboxylate 3-Azabicyclo[3.1.0]hexane hydrochloride 40-6 2-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidine-5-carboxylic acid ethyl ester 2-Chloro-4-methylpyrimidine-5-carboxylic acid ethyl ester 6,6-Difluoro-3-azabicyclo[3.1.0]hexane hydrochloride 40-7 2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidine-5-carboxylic acid ethyl ester 2-Chloro-4-methylpyrimidine-5-carboxylic acid ethyl ester 3-Azabicyclo[3.1.0]hexane hydrochloride 40-8 2-{5-Azaspiro[2.3]hex-5-yl}-4-methylpyrimidine-5-carboxylic acid ethyl ester 2-Chloro-4-methylpyrimidine-5-carboxylic acid ethyl ester 5-Azaspiro[2.3]hexane trifluoroacetate

Intermediate 41

( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } pyridin - 3 - yl ) methanol _ _ _ _ _

NaBH4 (76 mg) was added portionwise to methyl 6-{ ₃ -azabicyclo[3.1.0]hex-3-yl}pyridin-3-carboxylate (200 mg) and _CaCl2 (54 mg) to in MeOH (4 mL). The mixture was stirred at 70°C for 24 hours. After cooling to room temperature, 1 M aqueous HCl was added until pH 2 was reached. The mixture was stirred for 15 minutes and then partitioned between saturated aqueous _NaHCO3 and EtOAc. The aqueous phase was extracted twice with EtOAc and twice with EtOAc/isopropanol 1:1. The combined organic phases were dried ( _MgSO4 ), concentrated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

LC (Method 1): _tR = 0.67 min; Mass Spec (ESI ⁺ ): m/z = 192 [M+H] ⁺ .

0.67 379 方法2 中間物 反應備註 41-1 反應在室溫下在THF/EtOH 1:1中進行8小時。 中間物 名稱 起始材料之名稱 41-1  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-3-{[4-(乙氧羰基)-1H-咪唑-1-基]甲基}吡啶-2-甲酸乙酯 Intermediate 41-1 was prepared analogously to Intermediate 41 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 41-1

0.67 379 Method 2 Intermediate Reaction Notes 41-1 The reaction was carried out in THF/EtOH 1:1 at room temperature for 8 hours. Intermediate name name of starting material 41-1 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H -Imidazole-4-carboxylic acid ethyl ester 6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-3-{[4-(ethoxycarbonyl)-1H-imidazol-1-yl]methyl} Ethyl pyridine-2-carboxylate

Intermediate 42

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

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

LC (Method 2): t _R = 0.68 min; Mass Spec (ESI ⁺ ): m/z = 314 [M+H] ⁺ .

1.04 348 方法2 42-2

0.89 281 方法2 中間物 反應備註 42-1 在矽膠(石油醚/EtOAc 95:5 → 45:55)上層析反應混合物，得到標題化合物。 42-2 在室溫下攪拌反應混合物12小時。在矽膠(環己烷/EtOAc 50:50 → 0:100)上層析粗產物，得到標題化合物。 中間物 名稱 起始材料 1 之名稱 起始材料 2 之名稱 42-1 1-[(5-{3-氮雜雙環[3.1.0]-己-3-基}-3-氯吡𠯤-2-基)甲基]-1H-吡唑-4-甲酸乙酯 (5-{3-氮雜雙環[3.1.0]-己-3-基}-3-氯吡𠯤-2-基)甲醇 1H-吡唑-4-甲酸乙酯 42-2 1-[(2-氯-4-甲基-嘧啶-5-基)甲基]-1H-吡唑-4-甲酸乙酯 (2-氯-4-甲基-嘧啶-5-基)甲醇 1H-吡唑-4-甲酸乙酯 Intermediates 42-1 to 42-2 were prepared analogously to Intermediate 42 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 42-1

1.04 348 Method 2 42-2

0.89 281 Method 2 Intermediate Reaction Notes 42-1 The reaction mixture was chromatographed on silica gel (petroleum ether/EtOAc 95:5→45:55) to give the title compound. 42-2 The reaction mixture was stirred at room temperature for 12 hours. The crude product was chromatographed on silica gel (cyclohexane/EtOAc 50:50→0:100) to give the title compound. Intermediate name Name of starting material 1 Name of starting material 2 42-1 1-[(5-{3-Azabicyclo[3.1.0]-hex-3-yl}-3-chloropyridine-2-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (5-{3-Azabicyclo[3.1.0]-hex-3-yl}-3-chloropyridine-2-yl)methanol 1H-Pyrazole-4-carboxylic acid ethyl ester 42-2 1-[(2-Chloro-4-methyl-pyrimidin-5-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (2-Chloro-4-methyl-pyrimidin-5-yl)methanol 1H-Pyrazole-4-carboxylic acid ethyl ester

Intermediate 43

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

Stir 5-bromo-2-(bromomethyl)pyrimidine (1.5 g), K ₂ CO ₃ (2.4 g) and 1H-pyrazole-4-carboxylic acid ethyl ester (814 mg) in DMF (20 mL) at room temperature ) for 1.5 hours. The mixture was diluted with THF and filtered through celite. The filter cake was washed twice with THF. The combined filtrates were concentrated and the residue was chromatographed on silica gel (petroleum ether/EtOAc 80:20→0:100) to give the title compound.

LC (Method 1): _tR = 0.85 min; Mass Spec (ESI ⁺ ): m/z = 311 [M+H] ⁺ .

Intermediate 44

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

In a microwave vial, purge 1-[(5-bromopyrimidin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (500 mg), 3-azabicyclo[3.1. 0] Hexane hydrochloride (384 mg), Cs ₂ CO ₃ (1.6 g), gins(dibenzylideneacetone)dipalladium(0) (Pd ₂ dba ₃ , 74 mg) and 4,5-bis A mixture of (diphenylphosphino)-9,9-dimethyldibenzopyran (Xantphos, 93 mg) in DMF (1.3 mL) and toluene (3.8 mL) for 10 minutes. The vial was sealed and the mixture was heated to 90°C for 2 hours. The mixture was then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were dried ( _MgSO4 ), concentrated in vacuo and the residue was chromatographed on silica gel (petroleum ether/EtOAc 90:10→20:80) to give the title compound. LC (method 1): t _R = 0.91 min; mass spectrum (ESI ⁺ ): m/z = 314 [M+H] ⁺ .

Intermediate 45

( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } pyridin - 3 - yl ) methanol _ _ _ _

Methyl 6-{3-azabicyclo[3.1.0]hex-3-yl}pyridine-3-carboxylate (8 g) and _LiBH4 (2 M in THF, 20 mL) in THF ( 60 mL) and MeOH (3 mL) for 12 h. _LiBH4 (2 M in THF, 5 mL) was added and the mixture was stirred at 60°C for 2 hours. The mixture was then cooled to 0°C and treated cautiously with water. The mixture was concentrated and the residue was partitioned between water and EtOAc. The organic phase was dried ( _MgSO4 ), concentrated and the residue was chromatographed on silica gel (DCM/MeOH 0:100→90:10) to give the title compound. LC (Method 1): _tR = 0.79 min; Mass Spec (ESI ⁺ ): m/z = 191 [M+H] ⁺ .

0.80 191 方法1 45-2

0.71 242 方法2 45-3

0.62 242 方法2 中間物 反應備註 45-2 反應在室溫下在1,4-二㗁烷/MeOH 15:1中進行3小時。 45-3 反應在50℃下進行12小時。 中間物 名稱 起始材料之名稱 45-1  (6-{5-氮雜螺[2.3]己-5-基}吡啶-3-基)-甲醇  6-{5-氮雜螺[2.3]己-5-基}吡啶-3-甲酸甲酯 45-2  (5-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-3-甲基吡𠯤-2-基)甲醇  5-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-3-甲基吡𠯤-2-甲酸甲酯 45-3  (2-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲醇  2-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-4-甲基嘧啶-5-甲酸乙酯 Intermediates 45-1 to 45-3 were prepared analogously to Intermediate 45 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 45-1

0.80 191 method 1 45-2

0.71 242 Method 2 45-3

0.62 242 Method 2 Intermediate Reaction Notes 45-2 The reaction was carried out in 1,4-dioxane/MeOH 15:1 at room temperature for 3 hours. 45-3 The reaction was carried out at 50°C for 12 hours. Intermediate name name of starting material 45-1 (6-{5-Azaspiro[2.3]hex-5-yl}pyridin-3-yl)-methanol Methyl 6-{5-azaspiro[2.3]hex-5-yl}pyridine-3-carboxylate 45-2 (5-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-3-methylpyridin-2-yl)methanol Methyl 5-{6,6-difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-3-methylpyridine-2-carboxylate 45-3 (2-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methanol 2-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-4-methylpyrimidine-5-carboxylic acid ethyl ester

Intermediate 46

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

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

LC (Method 1): t _R = 0.65 min; Mass Spec (ESI ⁺ ): m/z = 285 [M+H] ⁺ .

Intermediate 47

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

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

Intermediate 48

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

1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methan was stirred at room temperature Base]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide Amine (19 mg) and 1,1,1-para(acetoxy)-1,1-dihydro-1,2-benzoiodooxolan-3-(1H)-one (Dess- A mixture of Dess-Martin periodinane, 26 mg) in DCM (2 ml) for 3 hours. The mixture was partitioned between saturated aqueous _NaHCO3 and DCM. The aqueous phase was extracted three times with DCM. The combined organic phases were dried ( _{Na2SO4 )} and concentrated in vacuo to give the title compound.

LC (Method 1): _tR = 0.89 min; Mass Spec (ESI ⁺ ): m/z = 469 [M+H] ⁺ .

1.10 355 方法2 中間物 反應備註 48-1 在矽膠(石油醚/EtOAc 95:5 → 70:30)上層析粗產物，得到標題化合物。 中間物 名稱 起始材料之名稱 48-1 1-[(2-乙醯基-6-{3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(1-羥基乙基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 Intermediate 48-1 was prepared analogously to Intermediate 48 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 48-1

1.10 355 Method 2 Intermediate Reaction Notes 48-1 The crude product was chromatographed on silica gel (petroleum ether/EtOAc 95:5→70:30) to give the title compound. Intermediate name name of starting material 48-1 1-[(2-Acetyl-6-{3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(1-hydroxyethyl)pyridin-3-yl)methyl]-1H-pyrazole-4- Ethyl formate

Intermediate 49

6- { 5 - Azaspiro [ 2.3 ] hex - 5 - yl } -3 - { [ 4- ( ethoxycarbonyl ) -1H - imidazol - 1 - yl ] methyl } pyridine - 2 - carboxylate

1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid under 10 bar carbon monoxide atmosphere Ethyl ester (860 mg), bis(triphenylphosphine)palladium(II) dichloride (Pd( _PPh3 ) _2Cl2 , ₂₀₀ mg) and triethylamine (1.1 mL) in EtOH (60 mL) The mixture was brought to 130°C for 5 hours. The solvent was evaporated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

LC (Method 2): t _R = 0.89 min; Mass Spec (ESI ⁺ ): m/z = 385 [M+H] ⁺ .

1.03 385 方法2 49-2

0.89 385 方法2 49-3

0.89 421 方法2 49-4

0.91 385 方法2 中間物 反應備註 49-3 反應在5巴之一氧化碳氛圍下在90℃下進行。 49-4 反應在4巴之一氧化碳氛圍下在100℃下進行14小時。 中間物 名稱 起始材料之名稱 49-1 6-{5-氮雜螺[2.3]己-5-基}-3-{[4-(乙氧羰基)-1H-吡唑-1-基]甲基}吡啶-2-甲酸乙酯 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 49-2 6-{5-氮雜螺[2.3]己-5-基}-3-{[4-(乙氧羰基)-1H-咪唑-1-基]甲基}吡啶-2-甲酸乙酯 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 49-3 6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-3-{[4-(乙氧羰基)-1H-咪唑-1-基]甲基}吡啶-2-甲酸乙酯 1-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 49-4 6-{3-氮雜雙環[3.1.0]己-3-基}-3-{[4-(乙氧羰基)-1H-咪唑-1-基]甲基}吡啶-2-甲酸乙酯 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 Intermediates 49-1 to 49-4 were prepared analogously to Intermediate 49 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 49-1

1.03 385 Method 2 49-2

0.89 385 Method 2 49-3

0.89 421 Method 2 49-4

0.91 385 Method 2 Intermediate Reaction Notes 49-3 The reaction was carried out at 90°C under a 5 bar carbon monooxide atmosphere. 49-4 The reaction was carried out at 100°C for 14 hours under an atmosphere of 4 bar carbon monooxide. Intermediate name name of starting material 49-1 6-{5-Azaspiro[2.3]hex-5-yl}-3-{[4-(ethoxycarbonyl)-1H-pyrazol-1-yl]methyl}pyridine-2-carboxylic acid ethyl ester 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester 49-2 6-{5-Azaspiro[2.3]hex-5-yl}-3-{[4-(ethoxycarbonyl)-1H-imidazol-1-yl]methyl}pyridine-2-carboxylic acid ethyl ester 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 49-3 6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-3-{[4-(ethoxycarbonyl)-1H-imidazol-1-yl]methyl} Ethyl pyridine-2-carboxylate 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazol-4- Ethyl formate 49-4 6-{3-Azabicyclo[3.1.0]hex-3-yl}-3-{[4-(ethoxycarbonyl)-1H-imidazol-1-yl]methyl}pyridine-2-carboxylic acid ethyl ester 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

Intermediate 50

1 - [ ( 6- { 5 - azaspiro [ 2.3 ] hex - 5 - yl } -2- ( hydroxymethyl ) pyridin - 3 - yl ) methyl ] -1H - imidazole - 4 - carboxylate Bistrifluoroacetate

_LiBH4 (150 mg) was added portionwise to 6-{5-azaspiro[2.3]hex-5-yl}-3-{[4-(ethoxycarbonyl)-1H-imidazol-1-yl]methane In a mixture of ethyl}pyridine-2-carboxylate (705 mg) in THF (15 mL). The mixture was stirred at room temperature for 2 hours, cooled to 0 °C, treated with aqueous HCl (4 M, 2 mL) and purified by reverse phase HPLC (ACN, water) to give the title compound.

LC (Method 1): _tR = 0.91 min; Mass Spec (ESI ⁺ ): m/z = 343 [M+H] ⁺ .

1.00 343 方法1 50-2

0.91 343 方法1 中間物 名稱 起始材料之名稱 50-1  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸酯三氟乙酸乙酯  6-{5-氮雜螺[2.3]己-5-基}-3-{[4-(乙氧羰基)-1H-吡唑-1-基]甲基}吡啶-2-甲酸乙酯 50-2  1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯  6-{5-氮雜螺[2.3]己-5-基}-3-{[4-(乙氧羰基)-1H-咪唑-1-基]甲基}吡啶-2-甲酸乙酯 Intermediates 50-1 to 50-2 were prepared analogously to Intermediate 50 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 50-1

1.00 343 method 1 50-2

0.91 343 method 1 Intermediate name name of starting material 50-1 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylate tris Ethyl fluoroacetate 6-{5-Azaspiro[2.3]hex-5-yl}-3-{[4-(ethoxycarbonyl)-1H-pyrazol-1-yl]methyl}pyridine-2-carboxylic acid ethyl ester 50-2 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester 6-{5-Azaspiro[2.3]hex-5-yl}-3-{[4-(ethoxycarbonyl)-1H-imidazol-1-yl]methyl}pyridine-2-carboxylic acid ethyl ester

Intermediate 51

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

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

Intermediate 52

1 - [ ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2- ( 1 - hydroxyethyl ) pyridin - 3 - yl ) methyl ] -1H - pyrazole- _ _ _ 4 - ethyl formate

CH3MgBr ( ₃ M in diethyl ether, 1.22 mL) was added dropwise to 1-[(6-{3-azabicyclo[3.1.0]-hex-3-yl}-2 at -40°C In a mixture of -carboxypyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (1 g) in THF (20 mL). The mixture was stirred for 25 minutes while warming to -25°C. Aqueous HCl (1 M, 4 mL) was added. After stirring for 5 minutes, the mixture was partitioned between saturated aqueous _NaHCO3 and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried ( _MgSO4 ) and concentrated in vacuo to give the title compound.

LC (Method 2): t _R = 0.73 min; Mass Spec (ESI ⁺ ): m/z = 357 [M+H] ⁺ .

1.10 371 方法1 中間物 反應備註 52-1 反應在-10℃下進行。 中間物 名稱 起始材料之名稱 52-1  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(2-羥基丙烯-2-基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  1-[(2-乙醯基-6-{3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 Intermediate 52-1 was prepared analogously to Intermediate 52 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 52-1

1.10 371 method 1 Intermediate Reaction Notes 52-1 The reaction was carried out at -10°C. Intermediate name name of starting material 52-1 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(2-hydroxypropen-2-yl)pyridin-3-yl)methyl]-1H-pyrazole -4-ethyl formate 1-[(2-Acetyl-6-{3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

Intermediate 53

1 - [ ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - [ ( 1R ) -1 - hydroxyethyl ] pyridin - 3 - yl ) methyl ] -1H -Pyrazole - 4 - ethyl formate

Triethylamine (246 µL) was dissolved in DCM (3 mL), cooled to 0 °C and washed successively with formic acid (75 µL), 1-[(2-acetoxy-6-[3-azabicyclo[3.1 .0]Hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (200 mg) and chloro[(1R,2R)-(-)-2-amino -1,2-Diphenylethyl](4-Tosylsulfonyl)amido}(R)ruthenium(II) (RuCl[(R,R)-Tsdpen(R,R)-Tsdpen(R, R), 23 mg] treated The mixture was stirred for 24 hours while warming to room temperature. The mixture was concentrated, dissolved in THF (5 mL) and treated with a solution of _NH3 in MeOH (7 M, 1 mL) and water (1 mL). The mixture was purified by reverse phase HPLC (ACN, water) to give the title compound.

LC (Method 1): t _R = 1.03 min; Mass Spec (ESI ⁺ ): m/z = 357 [M+H] ⁺ .

1.03 357 方法1 中間物 反應備註 53-1 使用RuCl[(S,S)-Tsdpen(艸米)代替RuCl[(R,R)-Tsdpen(艸米)。 中間物 名稱 起始材料之名稱 53-1  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-[(1S)-1-羥基乙基]吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯  1-[(2-乙醯基-6-{3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 Intermediate 53-1 was prepared analogously to Intermediate 53 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 53-1

1.03 357 method 1 Intermediate Reaction Notes 53-1 Use RuCl[(S,S)-Tsdpen(艸米) instead of RuCl[(R,R)-Tsdpen(艸米). Intermediate name name of starting material 53-1 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-[(1S)-1-hydroxyethyl]pyridin-3-yl)methyl]-1H-pyridine Ethyl oxazole-4-carboxylate 1-[(2-Acetyl-6-{3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

Intermediate 54

( 5- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -3 - chloropyridine - 2 - yl ) methanol _ _ _ _ _

_LiBH4 (744 mg) was added portionwise to methyl 5-{3-azabicyclo[3.1.0]hex-3-yl}-3-chloropyridine-2-carboxylate (4.33 g) in THF (80 mL) in the ice-cold mixture. The mixture was stirred at room temperature for 2 hours. After cooling to 0 °C, aqueous HCl (4 M, 10 mL) was added and the mixture was stirred for 10 minutes. The mixture was then partitioned between saturated aqueous _NaHCO3 and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried ( _MgSO4 ), concentrated in vacuo and the residue was chromatographed on silica gel (petroleum ether/EtOAc 80:20→50:50) to give the title compound. LC (Method 2): t _R = 0.85 min; Mass Spec (ESI ⁺ ): m/z = 226 [M+H] ⁺ .

Intermediate 55

1 - [ ( 6- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - methylpyridin - 3 - yl ) methyl ] -1H - pyridine _ _ _ _ Ethyl oxazole - 4 - carboxylate

(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex- ₃ -yl} _-2 -methyl) was treated dropwise with CH3SO2Cl (7.2 mL) under argon atmosphere An ice-cold mixture of pyridin-3-yl)methanol (20 g) and DIPEA (32 mL) in DCM (400 mL). The mixture was stirred for 15 minutes and then treated with 1H-pyrazole-4-carboxylic acid ethyl ester (12 g). After stirring at room temperature for 4 hours, the mixture was partitioned between water and DCM. The organic phase was dried ( _MgSO4 ) and concentrated by evaporation in vacuo to give the crude product, which was used directly in the next step.

LC (Method 2): t _R = 0.76 min; Mass Spec (ESI ⁺ ): m/z = 363 [M+H] ⁺ .

1.02 327 方法1 中間物 反應備註 55-1 在添加1H-吡唑-4-甲酸乙酯之後，在室溫下攪拌反應混合物12小時。 中間物 名稱 起始材料 1 之名稱 起始材料 2 之名稱 55-1 1-[(6-{3-氮雜雙環[3.1.0]-己-3-基}-4-甲基吡啶-3-基)-甲基]-1H-吡唑-4-甲酸乙酯 (6-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基吡啶-3-基)-甲醇 1H-吡唑-4-甲酸乙酯 Intermediate 55-1 was prepared analogously to Intermediate 55 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 55-1

1.02 327 method 1 Intermediate Reaction Notes 55-1 After addition of 1H-pyrazole-4-carboxylic acid ethyl ester, the reaction mixture was stirred at room temperature for 12 hours. Intermediate name Name of starting material 1 Name of starting material 2 55-1 1-[(6-{3-Azabicyclo[3.1.0]-hex-3-yl}-4-methylpyridin-3-yl)-methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyridin-3-yl)-methanol 1H-Pyrazole-4-carboxylic acid ethyl ester

Intermediate 56

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

To 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-1 at 0 °C, To a solution of ethyl 2,3-triazole-4-carboxylate (86 mg) in DMF (2 mL) was added NaH (60% in mineral oil, 25 mg). The mixture was stirred at room temperature for 30 minutes, treated with _CH3I (16 μL) and stirred for 12 hours. Add water sparingly. The mixture was concentrated in vacuo and the residue was dissolved in DCM/isopropanol 1:1. The mixture was then filtered and the filtrate was concentrated in vacuo to give the crude product, which was used directly in the next step.

LC (Method 2): t _R = 0.58 min; Mass Spec (ESI ⁺ ): m/z = 330 [M+H] ⁺ .

0.71 379 方法2 56-2

0.53 329 方法2 中間物 反應備註 56-1 使用碘乙烷代替CH ₃I。 56-2 在添加CH ₃I之後，將混合物4小時。接著添加NaOH水溶液(4 M)直至pH達至12為止，且在50℃下攪拌混合物1小時。藉由添加乙酸來中和混合物且藉由逆相HPLC (ACN，水)純化。 中間物 名稱 起始材料之名稱 56-1 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-(乙氧基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 56-2 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 Intermediates 56-1 to 56-2 were prepared analogously to Intermediate 56 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 56-1

0.71 379 Method 2 56-2

0.53 329 Method 2 Intermediate Reaction Notes 56-1 Iodoethane was used instead of _CH3I . 56-2 After the addition of _CH3I , the mixture was allowed to stand for 4 hours. Aqueous NaOH (4 M) was then added until the pH reached 12, and the mixture was stirred at 50°C for 1 hour. The mixture was neutralized by addition of acetic acid and purified by reverse phase HPLC (ACN, water). Intermediate name name of starting material 56-1 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(ethoxymethyl)pyridin-3-yl)methyl]- 1H-Pyrazole-4-carboxylic acid 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H - Pyrazole-4-carboxylic acid ethyl ester 56-2 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

Intermediate 57

1 - [ ( 6- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - methoxypyridin - 3 - yl ) methyl ] -1H- _ _ _ _ _ Imidazole - 4 - carboxylic acid

1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazol-4 - A mixture of ethyl formate (190 mg) and NaOCH3 ( ₁ M in MeOH, 4.5 mL) was heated to 155 °C for 2.5 h and to 165 °C for 3 h. Purification by reverse phase HPLC (ACN, water) afforded the title compound. LC (Method 2): _tR = 0.84 min.

0.85    方法2 中間物 反映備註 57-1 使用EtOH中之NaOCH ₂CH ₃代替MeOH中之NaOCH ₃。 反應在150℃下進行12小時。 中間物 名稱 起始材料之名稱 57-1  1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙氧基吡啶-3-基)甲基]-1H-咪唑-4-甲酸  1-[(2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸乙酯 Intermediate 57-1 was prepared analogously to Intermediate 57 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 57-1

0.85 Method 2 Intermediate reflect remarks 57-1 _NaOCH2CH3 in _EtOH was used instead _of NaOCH3 in MeOH. The reaction was carried out at 150°C for 12 hours. Intermediate name name of starting material 57-1 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethoxypyridin-3-yl)methyl]-1H-imidazole- 4-carboxylic acid 1-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazol-4- Ethyl formate

Intermediate 58

1 -[( 6 -{ 3 - azabicyclo [ 3 . 1 . 0 ] already - 3 - base }- 2 -( Hydroxymethyl ) Pyridine - 3 - base ) methyl ]- 1H - imidazole - 4 - Formic acid

Intermediate 58 - 1

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

_LiBH4 (356 mg) was added portionwise to 6-{3-azabicyclo[3.1.0]hex-3-yl}-3-{[4-(ethoxycarbonyl)-1H-imidazol-1-yl ]methyl}pyridine-2-carboxylic acid ethyl ester (1.65 g) in THF (25 mL). The mixture was stirred at room temperature for 14 hours, cooled to 0 °C, and treated with aqueous HCl (1 M, 5 mL). The mixture was then neutralized by addition of NaOH (4 M) and purified by reverse phase HPLC (ACN, water) to give the title compound.

1 -[( 6 -{ 3 - azabicyclo [ 3 . 1 . 0 ] already - 3 - base }- 2 -( Hydroxymethyl ) Pyridine - 3 - base ) methyl ]- 1H - imidazole - 4 - Formic acid :

LC (Method 1): _tR = 0.64 min; Mass Spec (ESI ⁺ ): m/z = 315 [M+H] ⁺ .

1 -[( 6 -{ 3 - azabicyclo [ 3 . 1 . 0 ] already - 3 - base }- 2 -( Hydroxymethyl ) Pyridine - 3 - base ) methyl ]- 1H - imidazole - 4 - Ethyl formate :

LC (Method 1): _tR = 0.94 min; Mass Spec (ESI ⁺ ): m/z = 343 [M+H] ⁺ .

Intermediate 59

2 - Hydroxy - 5 - iodo - 4 - picoline - 3 - carbonitrile

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

Intermediate 60

2 - Chloro - 5 - iodo - 4 - picoline - 3 - carbonitrile

A mixture of 2-hydroxy-5-iodo-4-methylpyridine-3-carbonitrile (6.27 g) in _POCl3 was stirred at 100°C for 5 hours. The mixture was concentrated in vacuo. The residue was dissolved in DCM (200 mL) and treated with water. The mixture was then neutralized by cautious addition of saturated aqueous _NaHCO3 . The phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were washed with saturated aqueous _NaHCO3 , dried ( _MgSO4 ) and concentrated in vacuo to give the crude product, which was used directly in the next step.

LC (Method 1): t _R = 1.02 min; Mass Spec (ESI ⁺ ): m/z = 278 [M+H] ⁺ .

Intermediate 61

2- { 6,6 - Difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -5 - carboxy - 4 - methylpyridine - 3 - carbonitrile _ _ _ _ _ _

2-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-5-iodo-4-methylpyridine-3-carbonitrile (2.3 g) was dissolved in THF (30 The mixture in mL) was cooled to -78°C, treated dropwise with isopropylmagnesium chloride (iPrMgCl, 2 M in THF, 3.82 mL) and stirred for 30 minutes. The mixture was then warmed to 0°C, treated dropwise with DMF (2.47 mL) and stirred for 40 minutes. Water was added cautiously and the mixture was partitioned between half-saturated aqueous _NH4Cl and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic phases were concentrated in vacuo to give the crude product, which was used directly in the next step.

LC (Method 2): t _R = 0.96 min; Mass Spec (ESI ⁺ ): m/z = 264 [M+H] ⁺ .

0.98 228 方法2 中間物 名稱 起始材料之名稱 61-1  2-{3-氮雜雙環[3.1.0]己-3-基}-5-甲醯基-4-甲基吡啶-3-甲腈  2-{3-氮雜雙環[3.1.0]己-3-基}-5-碘-4-甲基吡啶-3-甲腈 Intermediate 61-1 was prepared analogously to Intermediate 61 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 61-1

0.98 228 Method 2 Intermediate name name of starting material 61-1 2-{3-Azabicyclo[3.1.0]hex-3-yl}-5-carboxy-4-methylpyridine-3-carbonitrile 2-{3-Azabicyclo[3.1.0]hex-3-yl}-5-iodo-4-methylpyridine-3-carbonitrile

Intermediate 62

N ' - [ ( E ) - ( 6- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - methylpyridin - 3 - yl ) methylene _ base ] acetohydrazine

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

0.61 259 方法2 中間物 名稱 起始材料之名稱 62-1  N'-[(E)-(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)亞甲基]乙醯肼  6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-甲醛 Intermediate 62-1 was prepared analogously to Intermediate 62 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 62-1

0.61 259 Method 2 Intermediate name name of starting material 62-1 N'-[(E)-(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methylene]acetohydrazine 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridine-3-carbaldehyde

Intermediate 63

N ' - [ ( 6- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - methylpyridin - 3 - yl ) methyl ] acetamide _ _ _

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

LC (Method 2): t _R = 0.58 min; Mass Spec (ESI ⁺ ): m/z = 297 [M+H] ⁺ .

0.57 261 方法2 中間物 名稱 起始材料之名稱 63-1  N'-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]乙醯肼  N'-[(E)-(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)亞甲基]乙醯肼 Intermediate 63-1 was prepared analogously to Intermediate 63 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 63-1

0.57 261 Method 2 Intermediate name name of starting material 63-1 N'-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]acethydrazine N'-[(E)-(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methylene]acetohydrazine

Intermediate 64

3- ( chloromethyl ) ) - 1 - [ ( 6- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - methylpyridine - 3- _ _ _ yl ) methyl ] -1H - pyrazole - 4 - ethylcarboxylate

Stir N'-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl] at room temperature A mixture of acethydrazide (1.9 g) and ethyl 4-chloro-2-(ethoxymethylene)-3-pendoxobutanoate (1.68 g) in EtOH (30 mL) for 12 hours. _The mixture was concentrated and then partitioned between DCM and saturated aqueous _Na2CO3 . The aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried ( _MgSO4 ) and concentrated in vacuo to give the title compound. LC (Method 2): t _R = 0.82 min; Mass Spec (ESI ⁺ ): m/z = 411 [M+H] ⁺ .

0.81 375 方法2 中間物 名稱 起始材料之名稱 64-1  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-(氯甲基)-1H-吡唑-4-甲酸乙酯  N'-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]乙醯肼 Intermediate 64-1 was prepared analogously to Intermediate 64 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 64-1

0.81 375 Method 2 Intermediate name name of starting material 64-1 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(chloromethyl)-1H-pyrazole -4-ethyl formate N'-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]acethydrazine

Intermediate 65

1 - [ ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - methylpyridin - 3 - yl ) methyl ] -3- ( cyanomethyl ) -1H _ _ -Pyrazole - 4 - ethyl formate

1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(chloromethyl)-1H-pyridine A mixture of ethyl oxazole-4-carboxylate (700 mg) and KCN (250 mg) in DMSO (5 mL) and water (2 mL) was heated to 85 °C for 2 h. The mixture was partitioned between water and EtOAc. The aqueous phase was extracted 4 times with EtOAc. The combined organic phases were washed with brine, dried ( _MgSO4 ) and concentrated in vacuo to give the title compound.

LC (Method 2): t _R = 0.74 min; Mass Spec (ESI ⁺ ): m/z = 366 [M+H] ⁺ .

Intermediate 66

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

-六氟磷酸鹽(HATU，272 mg)於DMF (4 mL)中之混合物5分鐘。添加(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-胺二鹽酸鹽(143 mg)且攪拌混合物2小時。將混合物分配於水與EtOAc之間。用EtOAc萃取水相三次。合併之有機相用鹽水洗滌，乾燥(MgSO ₄)，在真空中濃縮且在矽膠(DCM/(於MeOH中之DCM/MeOH/7 N NH ₃50:48:2) 90:10 → 60:40)，得到標題化合物。 Stir 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(cyanomethyl)-1H- Pyrazole-4-carboxylic acid (230 mg), DIPEA (466 µL) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl

- A mixture of hexafluorophosphate (HATU, 272 mg) in DMF (4 mL) for 5 minutes. (4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-amine dihydrochloride (143 mg) was added and the mixture was stirred for 2 hours. The mixture was partitioned between water and EtOAc. The aqueous phase was extracted three times with EtOAc. The combined organic phases were washed with brine, dried ( _MgSO4 ), concentrated in vacuo and washed on silica gel (DCM/(DCM/MeOH/7N _NH3 in MeOH 50:48:2) 90:10→60:40 ) to obtain the title compound.

LC (Method 2): t _R = 0.63 min; Mass Spec (ESI ⁺ ): m/z = 457 [M+H] ⁺ .

0.97 496 方法1 66-2

0.64 372 方法2 66-3  

(異構體之混合物) 0.78 578 方法2 66-4

(異構體之混合物) 0.76 564 方法2 中間物 反應備註 66-3 獲得作為異構體之混合物之產物。 66-4 獲得作為異構體之混合物之產物。 中間物 名稱 起始材料之名稱 66-1 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-溴-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-溴-1H-吡唑-4-甲酸 66-2 1-[(2-氯-4-甲基嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]-咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(2-氯-4-甲基嘧啶-5-基)甲基]-1H-吡唑-4-甲酸 66-3 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-5-甲醯胺 及 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-3-甲醯胺 (異構體之混合物) 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-5-甲酸 及 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-3-甲酸 (異構體之混合物) 66-4 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-5-甲醯胺 及 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-3-甲醯胺 (異構體之混合物) 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-5-甲酸 及 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-3-甲酸 (異構體之混合物) Intermediates 66-1 to 66-4 were prepared analogously to Intermediate 66 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 66-1

0.97 496 method 1 66-2

0.64 372 Method 2 66-3

(mixture of isomers) 0.78 578 Method 2 66-4

(mixture of isomers) 0.76 564 Method 2 Intermediate Reaction Notes 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]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-bromo-N-[(4R)-1 -Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-bromo-1H-pyrazole-4-carboxylic acid 66-2 1-[(2-Chloro-4-methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]-imidazole- 4-yl]-1H-pyrazole-4-carboxamide 1-[(2-Chloro-4-methylpyrimidin-5-yl)methyl]-1H-pyrazole-4-carboxylic acid 66-3 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-N-[(4R)- 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole -5-Carboxamide and 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]- N-[(4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl yl}-1H-pyrazole-3-carboxamide (mixture of isomers) 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1-{[2-( Trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carboxylic acid and 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-( Methoxymethyl)pyridin-3-yl)methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylic acid (of isomers) mixture) 66-4 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1- Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5 -Carboxamide and 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-N-[( 4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H - Pyrazole-3-carboxamide (mixture of isomers) 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1-{[2-(trimethyl silyl)ethoxy]methyl}-1H-pyrazole-5-carboxylic acid and 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl) yl)pyridin-3-yl)methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylic acid (mixture of isomers)

Intermediate 67

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

1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(cyanomethyl)-N- [(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide (330 mg) in _CH3COOH (2 mL) and concentrated aqueous HCl (2 mL) was heated to 110 °C for 1 h. The mixture was cooled to room temperature, treated with aqueous NaOH (4 M, 15 mL) and stirred for 10 minutes. Then aqueous HCl (4 M, 15 mL) was added and the mixture was washed twice with EtOAc. The aqueous phase was concentrated in vacuo and the residue was added to a mixture of acetyl chloride (50 μL) in MeOH (10 mL). The mixture was heated to 90°C for 90 minutes. After cooling to room temperature, the mixture was neutralized with aqueous NaOH (1 M), concentrated in vacuo and the residue was chromatographed on silica gel (cyclohexane/EtOAc 90:10→70:30) to give the title compound.

LC (Method 2): t _R = 0.63 min; Mass Spec (ESI ⁺ ): m/z = 490 [M+H] ⁺ .

Intermediate 68

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

1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester (200 mg ) and tetrabutylammonium fluoride trihydrate (269 mg) in DMF (2 mL) was heated to 80 °C for 12 h. After cooling to room temperature, the mixture was partitioned between saturated aqueous _NaHCO3 and EtOAc. The aqueous phase was extracted 4 times with EtOAc. The combined organic phases were concentrated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 1): t _R = 0.96 min.

Intermediate 69

2- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -5 - bromopyridine - 3 - carbonitrile _ _ _ _

Under argon, 5-bromo-2-chloropyridine-3-carbonitrile (1.0 g), 3-azabicyclo[3.1.0]hexane hydrochloride (605 mg) and DIPEA (2 mL) were combined The mixture in DMF (10 mL) was heated to 80°C for 2 hours. The mixture was cooled, concentrated, partitioned between water and EtOAc and the phases were separated. The aqueous material was extracted twice with EtOAc. The combined organic phases were washed with brine, dried ( _MgSO4 ), concentrated and the residue was chromatographed on silica gel (petroleum ether/EtOAc 98:2→95:5) to give the title compound.

LC (Method 2): t _R = 1.13 min; Mass Spec (ESI ⁺ ): m/z = 264 [M+H] ⁺ .

1.25 311 方法1 中間物 反應備註 69-1 反應在80℃下進行12小時。 中間物 名稱 起始材料 1 之名稱 起始材料 2 之名稱 69-1 6-{3-氮雜雙環[3.1.0]-己-3-基}-5-溴-2-甲基吡啶-3-甲酸甲酯 5-溴-6-氯-2-甲基吡啶-3-甲酸甲酯 3-氮雜雙環[3.1.0]己烷鹽酸鹽 Intermediate 69-1 was prepared analogously to Intermediate 69 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 69-1

1.25 311 method 1 Intermediate Reaction Notes 69-1 The reaction was carried out at 80°C for 12 hours. Intermediate name Name of starting material 1 Name of starting material 2 69-1 6-{3-Azabicyclo[3.1.0]-hex-3-yl}-5-bromo-2-methylpyridine-3-carboxylic acid methyl ester 5-Bromo-6-chloro-2-methylpyridine-3-carboxylic acid methyl ester 3-Azabicyclo[3.1.0]hexane hydrochloride

Intermediate 70

Methyl 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -5 - cyanopyridine - 3 - carboxylate _ _ _

Under argon, 2-{3-azabicyclo[3.1.0]hex-3-yl}-5-bromopyridine-3-carbonitrile (773 mg) and triethyl A mixture of amine (489 µL) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (119 mg) in DMF (15 mL) and MeOH (15 mL) Heated to 80°C for 22 hours. The mixture was cooled, concentrated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

LC (Method 1): _tR = 0.99 min; Mass Spec (ESI ⁺ ): m/z = 244 [M+H] ⁺ .

0.64 476 方法2 70-2

1.14 437 方法2 70-3

0.72 366 方法2 中間物 反應備註 70-1 使用MeOH代替DMF/MeOH混合物。 反應在100℃下在12巴之CO氛圍下進行2小時。 70-2 使用EtOH代替MeOH。使用雙(三苯基膦)二氯化鈀(II)代替(1,1'-雙(二苯基膦基)二茂鐵)二氯化鈀(II)。 反應在90℃下在5巴之CO氛圍下進行17小時。 70-3 反應在90℃下進行6小時。 中間物 名稱 起始材料之名稱 70-1 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-4-{[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]胺甲醯基}-1H-吡唑-3-甲酸甲酯 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-溴-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 70-2 6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-3-{[5-(乙氧羰基)噻吩-2-基]甲基}吡啶-2-甲酸乙酯 5-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]噻吩-2-甲酸乙酯 70-3 2-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲基]-1,3-噻唑-5-甲酸甲酯 3-{5-[(5-溴-1,3-噻唑-2-基)甲基]-6-甲基吡啶-2-基}-6,6-二氟-3-氮雜雙環[3.1.0]己烷 Intermediates 70-1 to 70-3 were prepared analogously to Intermediate 70 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 70-1

0.64 476 Method 2 70-2

1.14 437 Method 2 70-3

0.72 366 Method 2 Intermediate Reaction Notes 70-1 MeOH was used instead of the DMF/MeOH mixture. The reaction was carried out at 100°C under a CO atmosphere of 12 bar for 2 hours. 70-2 EtOH was used instead of MeOH. Instead of (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride, bis(triphenylphosphino)palladium(II) dichloride was used. The reaction was carried out at 90°C under a CO atmosphere of 5 bar for 17 hours. 70-3 The reaction was carried out at 90°C for 6 hours. Intermediate name name of starting material 70-1 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-4-{[(4R)-1-methyl -1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]aminocarbamoyl}-1H-pyrazole-3-carboxylic acid methyl ester 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-bromo-N-[(4R)-1 -Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 70-2 6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-3-{[5-(ethoxycarbonyl)thiophen-2-yl]methyl}pyridine-2 -Ethyl formate 5-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]thiophene-2-carboxylic acid ethyl ester 70-3 2-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methyl]-1,3- Methyl thiazole-5-carboxylate 3-{5-[(5-Bromo-1,3-thiazol-2-yl)methyl]-6-methylpyridin-2-yl}-6,6-difluoro-3-azabicyclo[3.1 .0]Hexane

Intermediate 71

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

A mixture of methyl 6-{3-azabicyclo[3.1.0]hex-3-yl}-5-cyanopyridine-3-carboxylate (300 mg) in THF (5 mL) was cooled to -50°C and treated dropwise with LiAlH4 ( ₁ M in THF, 1.4 mL). The mixture was stirred at -20°C for 3 hours and then cautiously treated with water (1 mL). After dilution with DCM, the mixture was stirred for 30 minutes. The precipitate was filtered and the filter cake was washed with DCM. The combined filtrates were diluted with water. Separate the phases. The aqueous phase was extracted twice with DCM. The combined organic phases were dried ( _MgSO4 ), concentrated and purified by reverse phase HPLC (ACN, water) to give the title compound.

LC (Method 1): t _R = 0.81 min; Mass Spec (ESI ⁺ ): m/z = 216 [M+H] ⁺ .

0.93 259 方法1 71-2

0.77 283 方法2 中間物 反應備註 71-1 反應在-25℃下進行3小時。接著謹慎地添加含10% NH ₄Cl之水。使混合物分配於水與EtOAc之間且經矽藻土過濾。分離各相且用EtOAc萃取水相。合併之有機相經乾燥(MgSO ₄)且在真空中蒸發濃縮，得到粗產物，其直接用於下一步驟中。 中間物 名稱 起始材料之名稱 71-1 (6-{3-氮雜雙環[3.1.0]己-3-基}-4-(三氟甲基)吡啶-3-基)甲醇 6-{3-氮雜雙環[3.1.0]己-3-基}-4-(三氟甲基)吡啶-3-甲酸甲酯 71-2 (6-{3-氮雜雙環[3.1.0]己-3-基}-5-溴-2-甲基吡啶-3-基)甲醇 6-{3-氮雜雙環[3.1.0]己-3-基}-5-溴-2-甲基吡啶-3-甲酸甲酯 Intermediates 71-1 to 71-2 were prepared analogously to Intermediate 71 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 71-1

0.93 259 method 1 71-2

0.77 283 Method 2 Intermediate Reaction Notes 71-1 The reaction was carried out at -25°C for 3 hours. Then 10% _NH4Cl in water was added cautiously. The mixture was partitioned between water and EtOAc and filtered through celite. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried ( _MgSO4 ) and concentrated by evaporation in vacuo to give the crude product, which was used directly in the next step. Intermediate name name of starting material 71-1 (6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-(trifluoromethyl)pyridin-3-yl)methanol Methyl 6-{3-azabicyclo[3.1.0]hex-3-yl}-4-(trifluoromethyl)pyridine-3-carboxylate 71-2 (6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-bromo-2-methylpyridin-3-yl)methanol Methyl 6-{3-azabicyclo[3.1.0]hex-3-yl}-5-bromo-2-methylpyridine-3-carboxylate

Intermediate 72

1 - [ ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - methylpyridin - 3 - yl ) methyl ] -3- ( methoxymethyl ) - _ 1H - Pyrazole - 4 - ethylcarboxylate

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

1.04 407 方法1 中間物 反應備註 72-1 反應在100℃下進行。 中間物 名稱 起始材料之名稱 72-1 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲基]-3-(甲氧基甲基)-1H-吡唑-4-甲酸乙酯 3-(氯甲基))-1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸乙酯 Intermediate 72-1 was prepared analogously to Intermediate 72 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 72-1

1.04 407 method 1 Intermediate Reaction Notes 72-1 The reaction was carried out at 100°C. Intermediate name name of starting material 72-1 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(methyl Oxymethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 3-(Chloromethyl))-1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl) Methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

Intermediate 73

1 - [ ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -5 - cyano - 2 - methylpyridin - 3 - yl ) methyl ] -1H - imidazol - 4 _ _ -Ethyl formate

In a microwave vial, add N,N,N',N'-tetramethylethylenediamine (196 µL) to 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl }-5-Bromo-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester (530 mg), NaCN (77 mg), CuCN (25 mg) and KI (43 mg) ) in a mixture of toluene (15 mL). The vial was sealed and the mixture was heated to 130°C for 18 hours. After cooling to room temperature, the mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were dried ( _MgSO4 ), concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

LC (Method 1): _tR = 0.99 min; Mass Spec (ESI ⁺ ): m/z = 352 [M+H] ⁺ .

1.04 338 方法1 中間物 名稱 起始材料之名稱 73-1  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基-2-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸甲酯  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-溴-2-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸甲酯 Intermediate 73-1 was prepared analogously to Intermediate 73 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 73-1

1.04 338 method 1 Intermediate name name of starting material 73-1 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyano-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4- methyl formate 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid methyl ester

Intermediate 74

1 - [ ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - methylpyridin - 3 - yl ) methyl ] -3- ( 2 - hydroxypropene - 2- _ _ _ _ yl ) -1H - pyrazole- 4 - carboxylate hydrochloride

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

LC (Method 2): t _R = 0.67 min; Mass Spec (ESI ⁺ ): m/z = 357 [M+H] ⁺ .

Intermediate 75

1 - [ ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -5 - bromo - 2 - methylpyridin - 3 - yl ) methyl ] -1H - pyrazole - 4 _ _ - Methyl formate

1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl]-1H-pyrazol-4- A mixture of formic acid (920 _mg ) and concentrated aqueous _H2SO4 (182 µL) in MeOH (10 mL) was heated to 40 °C for 12 h. After cooling to room temperature, the mixture was partitioned between EtOAc and saturated aqueous _NaHCO3 . The aqueous phase was extracted with EtOAc. The combined organic phases were dried ( _MgSO4 ), concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

LC (Method 1): _tR = 1.17 min; Mass Spec (ESI ⁺ ): m/z = 391 [M+H] ⁺ .

1.07    方法1 中間物 反應備註 75-1 反應在70℃下進行12小時。 中間物 名稱 起始材料之名稱 75-1  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-溴-2-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸甲酯  1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-溴-2-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 Intermediate 75-1 was prepared analogously to Intermediate 75 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 75-1

1.07 method 1 Intermediate Reaction Notes 75-1 The reaction was carried out at 70°C for 12 hours. Intermediate name name of starting material 75-1 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid methyl ester 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid

Intermediate 76

1 - [ ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2,5 - lutidine - 3 - yl ) methyl ] -1H - imidazole - 4 - carboxylic acid _ _ _ methyl ester

In a microwave vial, purge 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl with argon A mixture of methyl]-1H-imidazole-4-carboxylate (120 mg), trimethylcyclotriboroxane (77 mg) and K2CO3 (127 _mg ) in DMF ( ₄ mL) for 5 min. Four(triphenylphosphine)palladium(0) (Pd( _PPh3 ) ₄ , 71 mg) was added, the vial was sealed and the mixture was heated to 110°C for 12 hours. After cooling to room temperature, the mixture was partitioned between half-saturated aqueous NaCl and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were dried ( _MgSO4 ), concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

LC (Method 2): t _R = 0.63 min; Mass Spec (ESI ⁺ ): m/z = 327 [M+H] ⁺ .

1.10 327 方法1 中間物 名稱 起始材料之名稱 76-1 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2,5-二甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸甲酯 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-溴-2-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸甲酯 Intermediate 76-1 was prepared analogously to Intermediate 76 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 76-1

1.10 327 method 1 Intermediate name name of starting material 76-1 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2,5-lutidine-3-yl)methyl]-1H-pyrazole-4-carboxylic acid methyl ester 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-bromo-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid methyl ester

Intermediate 77

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

6-Chloro-3-(chloromethyl)pyridine-2-carbonitrile (37 mg), 1H-pyrazole-4-carboxylic acid ethyl ester (30 mg) and Cs ₂ CO ₃ (100 mg) were stirred at room temperature Mixture in THF (2 mL) for 8 hours. The mixture was then neutralized by addition of trifluoroacetic acid and purified by reverse phase HPLC (ACN, water) to give the title compound.

LC (Method 1): t _R = 0.94 min; Mass Spec (ESI ⁺ ): m/z = 291 [M+H] ⁺ .

Intermediate 78

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

1-[(6-Chloro-2-cyanopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (1 g), 3-azabicyclo[3.1. A mixture of 0]-hexane hydrochloride (411 mg) and DIPEA (1.8 mL) in NMP (20 mL) for 12 h. After cooling to room temperature, the mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with water, dried ( _MgSO4 ), concentrated and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 1): t _R = 1.04 min; Mass Spec (ESI ⁺ ): m/z = 338 [M+H] ⁺ .

Intermediate 79

2 - Chloro - 4 - methylpyrimidine - 5 - carboxylic acid

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

LC (Method 2): t _R = 0.68 min; Mass Spec (ESI ⁺ ): m/z = 173 [M+H] ⁺ .

Intermediate 80

( 2 - Chloro - 4 - methylpyrimidin - 5 - yl ) methanol

A mixture of 2-chloro-4-methylpyrimidine-5-carboxylic acid (8.5 g) and N-methylpyridine (5.14 mL) in 1,2-dimethoxyethane (200 mL) was cooled to - 10°C and treated dropwise with isobutyl chloroformate (6.2 mL). The mixture was stirred for 30 minutes and then treated dropwise with a solution of NaBH4 ₍ 1.81 g) in water (20 mL). The mixture was stirred for 30 minutes while warming to room temperature, and then partitioned between water and EtOAc. The aqueous phase was extracted 3 times with EtOAc. The combined organic phases were washed with brine, dried ( _MgSO4 ), concentrated and the residue chromatographed on silica gel (petroleum ether/(EtOAc/MeOH 8:2) 70:30) to give the title compound. LC (Method 2): t _R = 0.51 min; Mass Spec (ESI ⁺ ): m/z = 159 [M+H] ⁺ .

Intermediate 81

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

Diisobutylaluminum hydride (1 M in THF, 80 mL) was added dropwise to 2-{3-azabicyclo[3.1.0]hex-3-yl}-4-methyl at -10 °C In a mixture of pyrimidine-5-carboxylic acid ethyl ester (8.7 g) in THF (70 mL). The mixture was stirred for 1 hour while warming to 0°C. This mixture was then added dropwise to a mixture of aqueous NaOH (4 M, 6 mL) in water (150 mL) under ice cooling. After stirring for 1 hour, the mixture was filtered through celite. The filter cake was washed with EtOAc/MeOH 9:1. The combined filtrates were dried ( _MgSO4 ), concentrated and the residue was chromatographed on silica gel (EtOAc/MeOH 95:5→95:5) to give the title compound.

LC (Method 2): t _R = 0.59 min; Mass Spec (ESI ⁺ ): m/z = 206 [M+H] ⁺ .

Intermediate 82

1 - [ ( 6- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } pyridin - 3 - yl ) methyl ] -1H - pyrrole - 3 - carboxylate _ _ _ _ Ester and

Intermediate 83

5 - [ ( 6- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } pyridin - 3 - yl ) methyl ] -1H - pyrrole - 3 - carboxylate _ _ _ _ ester

(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex- ₃ -yl}pyridine- _3- was treated dropwise with CH3SO2Cl (513 µL) under argon atmosphere base) a mixture of methanol (1.2 g), DIPEA (1.8 mL) in DCM (5 mL). The mixture was stirred for 15 minutes and then added dropwise to the mixture obtained by treating a solution of 1H-pyrrole-3-carboxylic acid methyl ester (863 mg) in DMF (15 mL) with KOtBu (893 mg). The thus obtained mixture was stirred at room temperature for 5 days. The mixture was then partitioned between saturated aqueous _NaHCO3 and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried ( _MgSO4 ), concentrated in vacuo and purified by reverse phase HPLC (ACN, water) to give the title compound.

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

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

Intermediate 84

1 - [ ( 6- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - methylpyridin - 3 - yl ) methyl ] -1H - pyrrole _ _ _ _ - Methyl 3 - formate and

Intermediate 85

5 - [ ( 6- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - methylpyridin - 3 - yl ) methyl ] -1H - pyrrole _ _ _ _ - Methyl 3 - formate

(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex- ₃ -yl} _-2 -methyl) was treated dropwise with CH3SO2Cl (656 µL) under argon atmosphere A mixture of pyridin-3-yl)methanol (1.1 g), DIPEA (1.2 mL) in DCM (15 mL). The mixture was stirred for 15 minutes and then added dropwise to the mixture obtained by treating a solution of 1H-pyrrole-3-carboxylic acid methyl ester (745 mg) in DMF (30 mL) with KOtBu (771 mg). The thus obtained mixture was stirred at room temperature for 1 hour. The mixture was then partitioned between saturated aqueous _NaHCO3 and DCM. The aqueous phase was extracted twice with DCM. The combined organic phases were dried ( _MgSO4 ), concentrated in vacuo and the residue was chromatographed on silica gel (petroleum ether/EtOAc 90:10→50:50) to give the title compound.

1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrrole-3 - Methyl formate (Intermediate 84): LC (Method 2): t _R = 0.74 min; Mass Spec (ESI+): m/z = 348 [M+H] ⁺ .

5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrrole-3 - Methyl formate (Intermediate 85): LC (Method 2): t _R = 0.73 min; Mass Spec (ESI+): m/z = 348 [M+H] ⁺ .

Intermediate 86

Ethyl 3 - [ ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - chloropyridin - 3 - yl ) methyl ] -1,2 - oxazole - 5 - carboxylate _ _ _ ester

3-[6-Chloro-5-(2-nitroethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane (2.58 g), Boc ₂ O ( A mixture of 4.42 g), ethyl propiolate (3.03 mL), DMAP (176 mg) and ACN (60 mL) was stirred for 18 hours. Purification by reverse phase HPLC (ACN, water) afforded the title compound. LC (Method 1): _tR = 1.15 min; Mass Spec (ESI ⁺ ): m/z = 348 [M+H] ⁺ .

1.11 384 方法1 86-2

1.14 348 方法2 中間物 名稱 起始材料之名稱 86-1  3-[(2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}吡啶-3-基)-甲基]-1,2-㗁唑-5-甲酸乙酯  3-[6-氯-5-(2-硝基乙基)吡啶-2-基]-6,6-二氟-3-氮雜雙環[3.1.0]己烷 86-2  3-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯  5-[6-氯-5-(2-硝基乙基)吡啶-2-基]-5-氮雜螺[2.3]己烷 Intermediates 86-1 to 86-2 were prepared analogously to Intermediate 86 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 86-1

1.11 384 method 1 86-2

1.14 348 Method 2 Intermediate name name of starting material 86-1 3-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]-hex-3-yl}pyridin-3-yl)-methyl]-1,2- Ethyl oxazole-5-carboxylate 3-[6-Chloro-5-(2-nitroethyl)pyridin-2-yl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane 86-2 3-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid ethyl ester 5-[6-Chloro-5-(2-nitroethyl)pyridin-2-yl]-5-azaspiro[2.3]hexane

Intermediate 87

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

3-{6-Chloro-5-[(1E)-2-nitrovinyl]pyridin-2-yl}-3-azabicyclo[3.1.0]hexane (4.0 g), _A mixture of NaBH4 (726 mg), acetic acid (5 mL) and DMSO (30 mL) for 30 minutes and stirred at room temperature for 1 hour. The mixture was diluted with water and EtOAc and the phases were separated. The aqueous phase was extracted three times with EtOAc. The combined organic phases were washed with brine, dried ( _MgSO4 ), concentrated and the residue was chromatographed on silica gel (cyclohexane/EtOAc 100:0→30:70) to give the title compound.

LC (Method 2): _tR = 1.10 min. Mass spectrum (ESI ⁺ ): m/z = 268 [M+H] ⁺ .

1.07 304 方法2 87-2

1.07 268 方法2 中間物 名稱 起始材料之名稱 87-1 3-[6-氯-5-(2-硝基乙基)吡啶-2-基]-6,6-二氟-3-氮雜雙環[3.1.0]己烷 3-{6-氯-5-[(1E)-2-硝基乙烯基]吡啶-2-基}-6,6-二氟-3-氮雜雙環[3.1.0]己烷 87-2 5-[6-氯-5-(2-硝基乙基)吡啶-2-基]-5-氮雜螺[2.3]己烷 5-{6-氯-5-[(1E)-2-硝基乙烯基]吡啶-2-基}-5-氮雜螺[2.3]己烷 Intermediates 87-1 to 87-2 were prepared analogously to Intermediate 87 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 87-1

1.07 304 Method 2 87-2

1.07 268 Method 2 Intermediate name name of starting material 87-1 3-[6-Chloro-5-(2-nitroethyl)pyridin-2-yl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane 3-{6-Chloro-5-[(1E)-2-nitrovinyl]pyridin-2-yl}-6,6-difluoro-3-azabicyclo[3.1.0]hexane 87-2 5-[6-Chloro-5-(2-nitroethyl)pyridin-2-yl]-5-azaspiro[2.3]hexane 5-{6-Chloro-5-[(1E)-2-nitrovinyl]pyridin-2-yl}-5-azaspiro[2.3]hexane

Intermediate 88

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

6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridine-3-carbaldehyde (500 mg), nitromethane (1.6 mL), ammonium acetate (346 mg) were stirred at 100°C mg) and acetic acid (10 mL) for 18 hours. The mixture was cooled to room temperature and added dropwise to a cold mixture of EtOAc, water and saturated aqueous _NaHCO3 . The phases were separated and the aqueous phase was extracted three times with EtOAc. The combined organic phases were washed with brine, dried ( _MgSO4 ) and concentrated to give the crude title compound.

LC (Method 2): t _R = 1.14 min. Mass spectrum (ESI ⁺ ): m/z = 266 [M+H] ⁺ .

1.10 302 方法2 88-2

1.11 266 方法2 中間物 名稱 起始材料之名稱 88-1  3-{6-氯-5-[(1E)-2-硝基乙烯基]吡啶-2-基}-6,6-二氟-3-氮雜雙環[3.1.0]己烷  2-氯-6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}吡啶-3-甲醛 88-2  5-{6-氯-5-[(1E)-2-硝基乙烯基]吡啶-2-基}-5-氮雜螺[2.3]己烷  6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-甲醛 Intermediates 88-1 to 88-2 were prepared analogously to Intermediate 88 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 88-1

1.10 302 Method 2 88-2

1.11 266 Method 2 Intermediate name name of starting material 88-1 3-{6-Chloro-5-[(1E)-2-nitrovinyl]pyridin-2-yl}-6,6-difluoro-3-azabicyclo[3.1.0]hexane 2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]-hex-3-yl}pyridine-3-carbaldehyde 88-2 5-{6-Chloro-5-[(1E)-2-nitrovinyl]pyridin-2-yl}-5-azaspiro[2.3]hexane 6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridine-3-carbaldehyde

Intermediate 89

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

Stir (E,Z)-N-[2-(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)ethylene at room temperature ] A mixture of hydroxylamine (2.45 g), ethylprop-2-ynoic acid (2.0 mL), NaOCl 15% in water (34 mL) and THF (20 mL) for 3 hours. The mixture was diluted with EtOAc and water, and the aqueous phase was extracted three times with EtOAc. The combined organic phases were washed with brine, dried ( _MgSO4 ), concentrated and the residue was chromatographed on silica gel (petroleum ether/EtOAc 99:1→70:30) to give the title compound.

LC (Method 2): t _R = 0.79 min. Mass spectrum (ESI ⁺ ): m/z = 342 [M+H] ⁺ .

1.04 314 方法1 89-2

0.76 364 方法2 中間物 反應備註 89-1 反應在DCM而非THF中進行。 中間物 名稱 起始材料之名稱 89-1 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 (E,Z)-N-[2-(6-{3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)亞乙基]羥胺 89-2 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸乙酯 (E,Z)-N-[2-(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)-亞乙基]羥胺 Intermediates 89-1 to 89-2 were prepared analogously to Intermediate 89 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 89-1

1.04 314 method 1 89-2

0.76 364 Method 2 Intermediate Reaction Notes 89-1 The reaction was carried out in DCM instead of THF. Intermediate name name of starting material 89-1 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-pyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid ethyl ester (E,Z)-N-[2-(6-{3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)ethylene]hydroxylamine 89-2 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methyl]-1,2- Ethyl oxazole-5-carboxylate (E,Z)-N-[2-(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl) -Ethylene]hydroxylamine

Intermediate 90

( E , Z ) -N- [ 2- ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - ethylpyridin - 3 - yl ) ethylene ] hydroxylamine _ _ _ _

2-(6-{3-Azabicyclo[3.1.0]hex-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) mixture for 2 h. The mixture was concentrated and the residue was treated with water, stirred for 15 minutes and filtered. The precipitate was washed with water and dried in a desiccator to give the title compound as a mixture of isomers.

LC (Method 2): _tR = 0.62 min and 0.64 min. Mass spectrum (ESI ⁺ ): m/z = 246 [M+H] ⁺ .

0.82及0.84 218 方法1 90-2

0.61及0.63 268 方法2 90-3

0.65 282 方法2 中間物 名稱 起始材料之名稱 90-1  (E,Z)-N-[2-(6-{3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)亞乙基]羥胺  2-(6-{3-氮雜雙環[3.1.0]己-3-基}-吡啶-3-基)乙醛 90-2 (E,Z)-N-[2-(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)亞乙基]羥胺 2-(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)乙醛 90-3 (E,Z)-N-[2-(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)亞乙基]羥胺 2-(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)乙醛 Intermediates 90-1 to 90-3 were prepared analogously to Intermediate 90 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 90-1

0.82 and 0.84 218 method 1 90-2

0.61 and 0.63 268 Method 2 90-3

0.65 282 Method 2 Intermediate name name of starting material 90-1 (E,Z)-N-[2-(6-{3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)ethylene]hydroxylamine 2-(6-{3-Azabicyclo[3.1.0]hex-3-yl}-pyridin-3-yl)acetaldehyde 90-2 (E,Z)-N-[2-(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)idene ethyl]hydroxylamine 2-(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)acetaldehyde 90-3 (E,Z)-N-[2-(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)idene ethyl]hydroxylamine 2-(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)acetaldehyde

Intermediate 91

2- ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - ethylpyridin - 3 - yl ) acetaldehyde _ _ _ _

3-[6-ethyl-5-(2-methoxyvinyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane (2.36 g) was stirred at room temperature, concentrated HCl (4.0 mL) and 1,4-dioxane (24 mL) for 1 hour. The mixture was neutralized cautiously with saturated aqueous _NaHCO3 , and the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried ( _MgSO4 ) and concentrated to give the title compound.

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

0.83 203 方法1 91-2

0.60 253 方法2 91-3

0.62 267 方法2 中間物 名稱 起始材料之名稱 91-1 2-(6-{3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)乙醛 3-[5-(2-甲氧基乙烯基)吡啶-2-基]-3-氮雜雙環[3.1.0]己烷 91-2 2-(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)乙醛 6,6-二氟-3-[5-(2-甲氧基乙烯基)-6-甲基吡啶-2-基]-3-氮雜雙環[3.1.0]己烷 91-3 2-(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)乙醛 3-[6-乙基-5-(2-甲氧基乙烯基)吡啶-2-基]-6,6-二氟-3-氮雜雙環[3.1.0]己烷 Intermediates 91-1 to 91-3 were prepared analogously to Intermediate 91 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 91-1

0.83 203 method 1 91-2

0.60 253 Method 2 91-3

0.62 267 Method 2 Intermediate name name of starting material 91-1 2-(6-{3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)acetaldehyde 3-[5-(2-Methoxyvinyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane 91-2 2-(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)acetaldehyde 6,6-Difluoro-3-[5-(2-methoxyvinyl)-6-methylpyridin-2-yl]-3-azabicyclo[3.1.0]hexane 91-3 2-(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)acetaldehyde 3-[6-Ethyl-5-(2-methoxyvinyl)pyridin-2-yl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane

Intermediate 92

3- [ 6 - Ethyl - 5- ( 2 - methoxyvinyl ) pyridin - 2 - yl ] -3 - azabicyclo [ 3.1.0 ] hexane _ _ _ _

(Methoxymethyl)triphenylphosphonium chloride (10.0 g) in THF (80 mL) was treated dropwise with NaHMDS (2 M in THF, 14.6 mL) at -40 °C under argon atmosphere The mixture was stirred at this temperature for 15 minutes. A mixture of 6-{3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridine-3-carbaldehyde (2.09 g) in THF (20 mL) was added dropwise at -40°C Process this mixture. The mixture was then warmed to room temperature over 4 hours. The mixture was diluted with EtOAc and the organic layer was washed with brine and water, dried ( _MgSO4 ) and concentrated. The residue was stirred in diisopropyl ether and the precipitate was filtered. The filtrate was concentrated and the residue was chromatographed on silica gel (petroleum ether/EtOAc 99:1→70:30) to give the title compound as a mixture of isomers.

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

0.99 及1.01 217 方法1 92-2

0.73及0.74 267 方法2 92-3

0.75 281 方法2 中間物 名稱 起始材料之名稱 92-1  3-[5-(2-甲氧基乙烯基)吡啶-2-基]-3-氮雜雙環[3.1.0]己烷  6-{3-氮雜雙環[3.1.0]己-3-基}吡啶-3-甲醛 92-2  6,6-二氟-3-[5-(2-甲氧基乙烯基)-6-甲基吡啶-2-基]-3-氮雜雙環[3.1.0]己烷  6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-甲醛 92-3  3-[6-乙基-5-(2-甲氧基乙烯基)吡啶-2-基]-6,6-二氟-3-氮雜雙環[3.1.0]己烷  6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-甲醛 Intermediates 92-1 to 92-3 were prepared analogously to Intermediate 92 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 92-1

0.99 and 1.01 217 method 1 92-2

0.73 and 0.74 267 Method 2 92-3

0.75 281 Method 2 Intermediate name name of starting material 92-1 3-[5-(2-Methoxyvinyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane 6-{3-Azabicyclo[3.1.0]hex-3-yl}pyridine-3-carbaldehyde 92-2 6,6-Difluoro-3-[5-(2-methoxyvinyl)-6-methylpyridin-2-yl]-3-azabicyclo[3.1.0]hexane 6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridine-3-carbaldehyde 92-3 3-[6-Ethyl-5-(2-methoxyvinyl)pyridin-2-yl]-6,6-difluoro-3-azabicyclo[3.1.0]hexane 6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridine-3-carbaldehyde

Intermediate 93

2- [ 1- ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - methylpyridin - 3 - yl ) -2 - methoxy - 2 - pendantoxy _ _ _ _ Ethyl ] -1 , 3 - oxazole - 5 - carboxylate methyl ester

Methyl 2-(6-{3-azabicyclo[3.1.0]hex-3-yl} was treated dropwise with NaHMDS (2 M in THF, 1.1 mL) at -78 °C under argon atmosphere - A mixture of methyl 2-methylpyridin-3-yl)acetate (460 mg) in THF (5 mL) and stirred at this temperature for 15 minutes. This mixture was treated dropwise with a mixture of methyl 2-chloro-1,3-oxazole-5-carboxylate (305 mg) in THF (3 mL) at -78°C and then warmed to room temperature over 18 hours. The mixture was quenched with saturated aqueous _NH4Cl and the aqueous phase was extracted twice with EtOAc. The combined organic phases were dried ( _MgSO4 ), concentrated and the residue was chromatographed on silica gel (petroleum ether/EtOAc 80:20→20:80) to give the title compound. LC (Method 2): t _R = 0.72 min. Mass spectrum (ESI ⁺ ): m/z = 372 [M+H] ⁺ .

0.75 408 方法2 93-2

0.77 386 方法2 中間物 名稱 起始材料之名稱 93-1 2-[1-(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)-2-甲氧基-2-側氧基乙基]-1,3-㗁唑-5-甲酸甲酯 2-(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)乙酸甲酯 93-2 2-[1-(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)-2-甲氧基-2-側氧基乙基]-1,3-㗁唑-5-甲酸甲酯 2-(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)乙酸甲酯 Intermediates 93-1 to 93-2 were prepared analogously to Intermediate 93 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 93-1

0.75 408 Method 2 93-2

0.77 386 Method 2 Intermediate name name of starting material 93-1 2-[1-(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)-2-methoxy -2-Oxyethyl]-1,3-oxazole-5-carboxylic acid methyl ester Methyl 2-(6-{6,6-difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)acetate 93-2 2-[1-(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)-2-methoxy-2-side oxyethyl ]-Methyl 1,3-oxazole-5-carboxylate Methyl 2-(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)acetate

Intermediate 94

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

_2- (6-{ ₃ -azabicyclo[3.1.0]hex-3-yl}-2-methylpyridine- A mixture of 3-yl)acetonitrile (473 mg) in MeOH (5 mL), and the mixture was stirred for 6 hours. The aqueous phase was extracted twice with DCM and the combined organic layers were washed with brine, dried ( _MgSO4 ) and concentrated to give the title compound. LC (Method 2): t _R = 0.64 min. Mass spectrum (ESI ⁺ ): m/z = 247 [M+H] ⁺ .

0.66 283 方法2 94-2

0.69 261 方法2 中間物 反應備註 94-1 反應在50℃下進行18小時。 94-2 反應進行24小時。 中間物 名稱 起始材料之名稱 94-1 2-(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)乙酸甲酯 2-(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)乙腈 94-2 2-(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)乙酸甲酯 2-(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)乙腈 Intermediates 94-1 to 94-2 were prepared analogously to Intermediate 94 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 94-1

0.66 283 Method 2 94-2

0.69 261 Method 2 Intermediate Reaction Notes 94-1 The reaction was carried out at 50°C for 18 hours. 94-2 The reaction was carried out for 24 hours. Intermediate name name of starting material 94-1 Methyl 2-(6-{6,6-difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)acetate 2-(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)acetonitrile 94-2 Methyl 2-(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)acetate 2-(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)acetonitrile

Intermediate 95

2- ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - methylpyridin - 3 - yl ) acetonitrile _ _ _ _

(6-{ ₃ -azabicyclo[3.1. 0] A mixture of hex-3-yl}-2-methylpyridin-3-yl)methanol (1.96 g) in THF (15 mL). The mixture was stirred at room temperature for 66 hours and quenched with saturated aqueous _NaHCO3 . The aqueous phase was extracted with EtOAc. The organic phase was washed with brine, dried ( _MgSO4 ), concentrated and the residue was chromatographed on silica gel (petroleum ether/EtOAc 90:10→80:20) to give the title compound.

LC (Method 1): t _R = 0.97 min. Mass spectrum (ESI ⁺ ): m/z = 214 [M+H] ⁺ .

0.95 250 方法1 95-2

0.63 228 方法2 中間物 反應備註 95-1 反應在室溫下進行18小時。 95-2 反應在室溫下進行12小時。 中間物 名稱 起始材料之名稱 95-1 2-(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)乙腈 (6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲醇 95-2 2-(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)乙腈 (6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲醇 Intermediates 95-1 to 95-2 were prepared analogously to Intermediate 95 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 95-1

0.95 250 method 1 95-2

0.63 228 Method 2 Intermediate Reaction Notes 95-1 The reaction was carried out at room temperature for 18 hours. 95-2 The reaction was carried out at room temperature for 12 hours. Intermediate name name of starting material 95-1 2-(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)acetonitrile (6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methanol 95-2 2-(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)acetonitrile (6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methanol

Intermediate 96

3 - [ ( 6- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - ethylpyridin - 3 - yl ) methyl ] -1,2 _ _ _ _ _ _ -Oxazole - 5 - ethyl formate

Stir N-[2-(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)ethylene at room temperature [methyl]hydroxylamine (100 mg), ethylprop-2-ynoic acid (47 µL), potassium hydrogen persulfate (328 mg), Na ₂ CO ₃ (57 mg), NaCl (23 mg), MeOH (2 mL) and water (100 µL) for 5 hours and concentrated. The residue was partitioned between water and EtOAc. The organic phase was washed with brine, dried ( _MgSO4 ), concentrated and the residue chromatographed on silica gel (petroleum ether/EtOAc 99:01→50:50) to give the title compound.

LC (Method 2): t _R = 0.81 min. Mass spectrum (ESI ⁺ ): m/z = 378 [M+H] ⁺ .

Intermediate 97

5 - [ ( 2 - Chloro - 6- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } pyridin - 3 - yl ) methyl ] -1H - pyrrole- _ _ _ _ _ Methyl 3 - formate

( ₂ -Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex- ₃ -yl} was treated dropwise with CH3SO2Cl (222 µL) under argon atmosphere A mixture of pyridin-3-yl)methanol (300 mg), DIPEA (782 µL) in DCM (1.5 mL). The mixture was stirred for 15 minutes and then added dropwise to the mixture obtained by treating a solution of 1H-pyrrole-3-carboxylic acid methyl ester (187 mg) in DMF (4 mL) with KOtBu (194 mg). The thus obtained mixture was stirred at 40°C for 12 hours. The mixture was then partitioned between saturated aqueous _NaHCO3 and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried ( _MgSO4 ), concentrated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

LC (Method 2): t _R = 1.05 min; Mass Spec (ESI ⁺ ): m/z = 368 [M+H] ⁺ .

Intermediate 98

Ethyl 5 - iodo - 1H - pyrazole - 3 - carboxylate

5-Amino-lH-pyrazole-3-carboxylic acid ethyl ester (10 g) was added portionwise to a mixture of water (240 mL) and concentrated aqueous _H2SO4 ( ₁₂₀ mL) at 0 °C. To this mixture was added a solution of NaNO2 (4.65 _g ) in water (10 mL) dropwise. The mixture was stirred for 2 hours and then treated dropwise with a solution of KI (12.0 g) in water (10 mL). The mixture was stirred for 3 hours while warming to room temperature. The mixture was then cooled to ₀ °C by cautious addition _of saturated aqueous K2CO3 and the mixture was neutralized. The mixture was extracted twice with EtOAc. _The combined organic phases _were washed with Na2S2O3 ₂₀ % aqueous solution, dried ( _MgSO4 ), concentrated and the residue was chromatographed on silica gel (petroleum ether/EtOAc 95:5→70:30) to give the title compound.

LC (Method 2): t _R = 0.86 min. Mass spectrum (ESI ⁺ ): m/z = 267 [M+H] ⁺ .

1.02 281 方法2 中間物 名稱 起始材料之名稱 98-1 3-碘-1-甲基-1H-吡唑-5-甲酸乙酯 3-胺基-1-甲基-1H-吡唑-5-甲酸乙酯鹽酸鹽 Intermediate 98-1 was prepared analogously to Intermediate 98 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 98-1

1.02 281 Method 2 Intermediate name name of starting material 98-1 3-Iodo-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester 3-Amino-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester hydrochloride

Intermediate 99

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

NaH (60% in mineral oil, 180 mg) was added portionwise to a mixture of ethyl 5-iodo-1-pyrazole-3-carboxylate (1.0 g) in DMF (15 mL) at 0 °C. The mixture was stirred for 30 minutes and then treated with 2-iodopropane (451 μL). The mixture was stirred for 4 hours while warming to room temperature. The mixture was then partitioned between saturated aqueous _NH4Cl and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried ( _MgSO4 ), concentrated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

LC (Method 2): t _R = 1.08 min. Mass spectrum (ESI ⁺ ): m/z = 309 [M+H] ⁺ .

1.02 295 方法2 99-2

1.24 397 方法2 中間物 反應備註 99-1 使用碘乙烷代替2-碘丙烷。 99-2 使用(2-氯甲氧基-乙基)-三甲基-矽烷(SEM-Cl)代替2-碘丙烷。 中間物 名稱 起始材料之名稱 99-1 1-乙基-3-碘-1H-吡唑-5-甲酸乙酯 5-碘-1H-吡唑-3-甲酸乙酯 99-2 3-碘-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-5-甲酸乙酯 5-碘-1H-吡唑-3-甲酸乙酯 Intermediates 99-1 to 99-2 were prepared analogously to Intermediate 99 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 99-1

1.02 295 Method 2 99-2

1.24 397 Method 2 Intermediate Reaction Notes 99-1 Use iodoethane instead of 2-iodopropane. 99-2 (2-Chloromethoxy-ethyl)-trimethyl-silane (SEM-Cl) was used instead of 2-iodopropane. Intermediate name name of starting material 99-1 1-Ethyl-3-iodo-1H-pyrazole-5-carboxylic acid ethyl ester Ethyl 5-iodo-1H-pyrazole-3-carboxylate 99-2 3-Iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carboxylic acid ethyl ester Ethyl 5-iodo-1H-pyrazole-3-carboxylate

Intermediate 100

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

Ethyl 3-iodo-1-(propen-2-yl)-1H-pyrazole-5-carboxylate was treated dropwise with iPrMgClxLiCl (1.3 M in THF, 300 µL) at -40 °C under argon atmosphere (100 mg) in THF (2 mL). The mixture was stirred for 30 minutes and then treated with 6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridine-3-carbaldehyde (90 mg) in THF ( 2 mL) was treated dropwise. After stirring at -40°C for 3 hours, the mixture was partitioned between saturated aqueous _NH4Cl and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were dried ( _MgSO4 ) and concentrated by evaporation in vacuo to give the crude product, which was used directly in the next step.

LC (Method 2): t _R = 0.85 min. Mass spectrum (ESI ⁺ ): m/z = 435 [M+H] ⁺ .

0.81 421 方法2 100-2

1.20 493 方法2 100-3

0.78 383 方法2 100-4

0.77 407 方法2 100-5

0.71 371 方法2 100-6

0.94 487 方法2 100-7

0.77 371 方法2 100-8

   357    中間物 反應備註 100-2 在-78℃下將醛添加至反應混合物中，接著在升溫至室溫時攪拌混合物1小時。藉由矽膠(石油醚/EtOAc 99:1 → 50:50)上之層析純化粗反應產物。 100-3 反應在-40℃下進行30分鐘且在室溫下進行30分鐘。 100-4 反應在-40℃下進行30分鐘且在室溫下進行30分鐘。 100-5 反應在-40℃下進行30分鐘且在室溫下進行30分鐘。 100-6 在-78℃下將醛添加至反應混合物中，接著在升溫至室溫時攪拌混合物1小時。藉由矽膠(石油醚/EtOAc 90:10 → 70:30)之層析純化粗反應產物。 100-7 在-78℃下將醛添加至反應混合物中，接著在升溫至室溫時攪拌混合物1小時。藉由矽膠(石油醚/EtOAc 60:40 → 0:100)之層析純化粗反應產物。 100-8 在-78℃下將醛添加至反應混合物中，接著在升溫至室溫時攪拌混合物2小時。藉由矽膠(石油醚/EtOAc 90:10 → 50:50)上之層析純化粗反應產物。 中間物 名稱 起始材料 1 之名稱 起始材料 2 之名稱 100-1 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-乙基吡啶-3-基)(羥基)-甲基]-1-乙基-1H-吡唑-5-甲酸乙酯 1-乙基-3-碘-1H-吡唑-5-甲酸乙酯 6-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}-2-乙基-吡啶-3-甲醛 100-2 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)(羥基)-甲基]-1-{[2-(三甲基矽烷基)乙氧基]-甲基}-1H-吡唑-5-甲酸乙酯 3-碘-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-5-甲酸乙酯 6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-甲醛 100-3 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)(羥基)-甲基]-1-乙基-1H-吡唑-5-甲酸乙酯 1-乙基-3-碘-1H-吡唑-5-甲酸乙酯 6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-甲醛 100-4 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)(羥基)-甲基]-1-乙基-1H-吡唑-5-甲酸乙酯 1-乙基-3-碘-1H-吡唑-5-甲酸乙酯 6-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}-2-甲基-吡啶-3-甲醛 100-5 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)(羥基)-甲基]-1-乙基-1H-吡唑-5-甲酸乙酯 1-乙基-3-碘-1H-吡唑-5-甲酸乙酯 6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-甲醛 100-6 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)(羥基)甲基]-1-{[2-(三甲基矽烷基)乙氧基]甲基-1H-吡唑-5-甲酸乙酯 3-碘-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-5-甲酸乙酯 6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-甲醛 100-7 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)(羥基)甲基]-1-甲基-1H-吡唑-5-甲酸乙酯 3-碘-1-甲基-1H-吡唑-5-甲酸乙酯 6-{3-氮雜雙環[3.1.0]-己-3-基}-2-乙基吡啶-3-甲醛 100-8 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)(羥基)-甲基]-1-甲基-1H-吡唑-5-甲酸乙酯 3-碘-1-甲基-1H-吡唑-5-甲酸乙酯 6-{3-氮雜雙環[3.1.0]-己-3-基}-2-甲基-吡啶-3-甲醛 Intermediates 100 - 1 to 100 - 8 were prepared analogously to Intermediate 100: Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 100-1

0.81 421 Method 2 100-2

1.20 493 Method 2 100-3

0.78 383 Method 2 100-4

0.77 407 Method 2 100-5

0.71 371 Method 2 100-6

0.94 487 Method 2 100-7

0.77 371 Method 2 100-8

357 Intermediate Reaction Notes 100-2 The aldehyde was added to the reaction mixture at -78°C, then the mixture was stirred for 1 hour while warming to room temperature. The crude reaction product was purified by chromatography on silica gel (petroleum ether/EtOAc 99:1→50:50). 100-3 The reaction was carried out at -40°C for 30 minutes and at room temperature for 30 minutes. 100-4 The reaction was carried out at -40°C for 30 minutes and at room temperature for 30 minutes. 100-5 The reaction was carried out at -40°C for 30 minutes and at room temperature for 30 minutes. 100-6 The aldehyde was added to the reaction mixture at -78°C, then the mixture was stirred for 1 hour while warming to room temperature. The crude reaction product was purified by chromatography on silica gel (petroleum ether/EtOAc 90:10→70:30). 100-7 The aldehyde was added to the reaction mixture at -78°C, then the mixture was stirred for 1 hour while warming to room temperature. The crude reaction product was purified by chromatography on silica gel (petroleum ether/EtOAc 60:40→0:100). 100-8 The aldehyde was added to the reaction mixture at -78°C, then the mixture was stirred for 2 hours while warming to room temperature. The crude reaction product was purified by chromatography on silica gel (petroleum ether/EtOAc 90:10→50:50). Intermediate name Name of starting material 1 Name of starting material 2 100-1 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-ethylpyridin-3-yl)(hydroxy)-methyl]- 1-Ethyl-1H-pyrazole-5-carboxylic acid ethyl ester 1-Ethyl-3-iodo-1H-pyrazole-5-carboxylic acid ethyl ester 6-{6,6-Difluoro-3-azabicyclo-[3.1.0]hex-3-yl}-2-ethyl-pyridine-3-carbaldehyde 100-2 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)(hydroxy)-methyl]-1-{[2-(trimethyl Silyl)ethoxy]-methyl}-1H-pyrazole-5-carboxylic acid ethyl ester 3-Iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carboxylic acid ethyl ester 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridine-3-carbaldehyde 100-3 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)(hydroxy)-methyl]-1-ethyl-1H-pyridine Ethyl oxazole-5-carboxylate 1-Ethyl-3-iodo-1H-pyrazole-5-carboxylic acid ethyl ester 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridine-3-carbaldehyde 100-4 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)(hydroxy)-methyl]- 1-Ethyl-1H-pyrazole-5-carboxylic acid ethyl ester 1-Ethyl-3-iodo-1H-pyrazole-5-carboxylic acid ethyl ester 6-{6,6-Difluoro-3-azabicyclo-[3.1.0]hex-3-yl}-2-methyl-pyridine-3-carbaldehyde 100-5 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)(hydroxy)-methyl]-1-ethyl-1H-pyridine Ethyl oxazole-5-carboxylate 1-Ethyl-3-iodo-1H-pyrazole-5-carboxylic acid ethyl ester 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridine-3-carbaldehyde 100-6 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)(hydroxy)methyl]-1-{[2-(trimethyl Silyl)ethoxy]methyl-1H-pyrazole-5-carboxylic acid ethyl ester 3-Iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carboxylic acid ethyl ester 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridine-3-carbaldehyde 100-7 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)(hydroxy)methyl]-1-methyl-1H-pyrazole -5-ethyl formate 3-Iodo-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester 6-{3-Azabicyclo[3.1.0]-hex-3-yl}-2-ethylpyridine-3-carbaldehyde 100-8 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)(hydroxy)-methyl]-1-methyl-1H-pyridine Ethyl oxazole-5-carboxylate 3-Iodo-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester 6-{3-Azabicyclo[3.1.0]-hex-3-yl}-2-methyl-pyridine-3-carbaldehyde

Intermediate 101

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

3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridine-3- (hydroxy)methyl]-1-(propen-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester (141 mg), triethylsilane (492 µL) and trifluoroacetic acid (594 µL) Mixture in 1,2-dichloroethane (1.18 mL) for 30 minutes. The mixture was concentrated in vacuo to give the crude product, which was used directly in the next step.

LC (Method 2): t _R = 0.90 min. Mass spectrum (ESI ⁺ ): m/z = 419 [M+H] ⁺ .

0.86 405 方法2 101-2

0.84 367 方法2 101-3

0.82 391 方法2 101-4

0.82 355 方法2 101-5

0.74 313 方法2 101-6

1.19 327 方法1 101-7

0.77 349 方法2 101-8

1.12 413 方法1 101-9

0.85 355 方法2 101-10

1.22 443 方法2 101-11

0.84 379 方法2 101-12

0.78 386 方法2 中間物 反應備註 101-1 反應在室溫下進行2小時。 101-2 反應在30℃下進行4小時。 101-3 反應在30℃下進行45分鐘。 101-4 反應在30℃下進行30分鐘。 100-5 反應在40℃下進行20小時。 藉由逆相HPLC (ACN，水)純化產物。 101-6 反應在50℃下進行2小時。 101-7 反應在50℃下進行30分鐘。 101-8 反應在50℃下進行30分鐘。 101-9 反應在室溫下進行1.5小時。 101-10 反應在30℃下進行2小時。 101-11 反應在50℃下進行30分鐘。 101-12 反應在70℃下進行2小時。 中間物 名稱 起始材料之名稱 101-1 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1-乙基-1H-吡唑-5-甲酸乙酯 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-乙基吡啶-3-基)(羥基)-甲基]-1-乙基-1H-吡唑-5-甲酸乙酯 101-2 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]-1-乙基-1H-吡唑-5-甲酸乙酯 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)(羥基)甲基]-1-乙基-1H-吡唑-5-甲酸乙酯 101-3 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1-乙基-1H-吡唑-5-甲酸乙酯 3-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)(羥基)-甲基]-1-乙基-1H-吡唑-5-甲酸乙酯 101-4 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1-乙基-1H-吡唑-5-甲酸乙酯 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)(羥基)甲基]-1-乙基-1H-吡唑-5-甲酸乙酯 101-5 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]呋喃-2-甲酸甲酯 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)(羥基)甲基]呋喃-2-甲酸甲酯 101-6 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]呋喃-3-甲酸乙酯 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)(羥基)甲基]呋喃-3-甲酸乙酯 101-7 5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]呋喃-2-甲酸甲酯 5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)(羥基)甲基]呋喃-2-甲酸甲酯 101-8 5-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]呋喃-2-甲酸甲酯 5-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)(羥基)甲基]呋喃-2-甲酸甲酯 101-9  5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]噻吩-2-甲酸乙酯  5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)(羥基)甲基]噻吩-2-甲酸乙酯 101-10  5-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]噻吩-2-甲酸乙酯 5-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)(羥基)甲基]噻吩-2-甲酸乙酯 101-11 5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]噻吩-2-甲酸乙酯 5-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)(羥基)甲基]噻吩-2-甲酸乙酯 101-12 3-{5-[(5-溴-1,3-噻唑-2-基)甲基]-6-甲基吡啶-2-基}-6,6-二氟-3-氮雜雙環[3.1.0]己烷 (5-溴-1,3-噻唑-2-基)(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲醇 Intermediates 101-1 to 101-12 were prepared analogously to Intermediate 101 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 101-1

0.86 405 Method 2 101-2

0.84 367 Method 2 101-3

0.82 391 Method 2 101-4

0.82 355 Method 2 101-5

0.74 313 Method 2 101-6

1.19 327 method 1 101-7

0.77 349 Method 2 101-8

1.12 413 method 1 101-9

0.85 355 Method 2 101-10

1.22 443 Method 2 101-11

0.84 379 Method 2 101-12

0.78 386 Method 2 Intermediate Reaction Notes 101-1 The reaction was carried out at room temperature for 2 hours. 101-2 The reaction was carried out at 30°C for 4 hours. 101-3 The reaction was carried out at 30°C for 45 minutes. 101-4 The reaction was carried out at 30°C for 30 minutes. 100-5 The reaction was carried out at 40°C for 20 hours. The product was purified by reverse phase HPLC (ACN, water). 101-6 The reaction was carried out at 50°C for 2 hours. 101-7 The reaction was carried out at 50°C for 30 minutes. 101-8 The reaction was carried out at 50°C for 30 minutes. 101-9 The reaction was carried out at room temperature for 1.5 hours. 101-10 The reaction was carried out at 30°C for 2 hours. 101-11 The reaction was carried out at 50°C for 30 minutes. 101-12 The reaction was carried out at 70°C for 2 hours. Intermediate name name of starting material 101-1 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1-ethyl- 1H-Pyrazole-5-carboxylic acid ethyl ester 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-ethylpyridin-3-yl)(hydroxy)-methyl]- 1-Ethyl-1H-pyrazole-5-carboxylic acid ethyl ester 101-2 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]-1-ethyl-1H-pyrazole-5- Ethyl formate 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)(hydroxy)methyl]-1-ethyl-1H-pyrazole -5-ethyl formate 101-3 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1-ethyl- 1H-Pyrazole-5-carboxylic acid ethyl ester 3-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)(hydroxy)-methyl]- 1-Ethyl-1H-pyrazole-5-carboxylic acid ethyl ester 101-4 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1-ethyl-1H-pyrazole-5- Ethyl formate 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)(hydroxy)methyl]-1-ethyl-1H-pyrazole -5-ethyl formate 101-5 Methyl 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]furan-2-carboxylate Methyl 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)(hydroxy)methyl]furan-2-carboxylate 101-6 Ethyl 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]furan-3-carboxylate Ethyl 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)(hydroxy)methyl]furan-3-carboxylate 101-7 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]furan-2-carboxylic acid methyl ester 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)(hydroxy)methyl]furan-2 - Methyl formate 101-8 Methyl 5-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]furan-2-carboxylate 5-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)(hydroxy)methyl]furan-2- methyl formate 101-9 Ethyl 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]thiophene-2-carboxylate Ethyl 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)(hydroxy)methyl]thiophene-2-carboxylate 101-10 5-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]thiophene-2-carboxylic acid ethyl ester 5-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)(hydroxy)methyl]thiophene-2- Ethyl formate 101-11 Ethyl 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]thiophene-2-carboxylate ester 5-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)(hydroxy)methyl]thiophene-2 -Ethyl formate 101-12 3-{5-[(5-Bromo-1,3-thiazol-2-yl)methyl]-6-methylpyridin-2-yl}-6,6-difluoro-3-azabicyclo[3.1 .0]Hexane (5-Bromo-1,3-thiazol-2-yl)(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridine-3 -base) methanol

Intermediate 102

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

3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)(hydroxy)methyl] was stirred at room temperature under argon atmosphere -1-{[2-(Trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carboxylic acid ethyl ester (848 mg), triethylsilane (1.38 mL), trifluoroacetic acid ( 663 µL) and a mixture of boron trifluoride-diethyl etherate (BF ₃ xOEt ₂ , 2.3 mL) in DCM (8 mL) for 12 h. The mixture was partitioned between water and DCM. The aqueous phase was extracted twice with DCM. The combined organic phases were washed with brine, dried ( _MgSO4 ), concentrated in vacuo and the residue was chromatographed on silica gel (petroleum ether/EtOAc 80:20→0:100) to give the title compound.

LC (Method 2): t _R = 1.05 min. Mass spectrum (ESI ⁺ ): m/z = 347 [M+H] ⁺ .

0.75 341 方法2 102-2

0.82 355 方法2 102-3

1.15 341 方法1 中間物 反應備註 102-3 反應在0℃下進行。在升溫至室溫時攪拌混合物1.5小時。 中間物 名稱 起始材料之名稱 102-1  3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-吡唑-5-甲酸乙酯 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基-吡啶-3-基)(羥基)甲基]-1-{[2-(三甲基矽烷基)-乙氧基]甲基}-1H-吡唑-5-甲酸乙酯 102-2 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1-甲基-1H-吡唑-5-甲酸乙酯 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)(羥基)甲基]-1-甲基-1H-吡唑-5-甲酸乙酯 102-3 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1-甲基-1H-吡唑-5-甲酸乙酯 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)(羥基)甲基]-1-甲基-1H-吡唑-5-甲酸乙酯 Intermediates 102-1 to 102-3 were prepared analogously to Intermediate 102 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 102-1

0.75 341 Method 2 102-2

0.82 355 Method 2 102-3

1.15 341 method 1 Intermediate Reaction Notes 102-3 The reaction was carried out at 0°C. The mixture was stirred for 1.5 hours while warming to room temperature. Intermediate name name of starting material 102-1 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole-5-carboxylic acid ethyl ester 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-ethyl-pyridin-3-yl)(hydroxy)methyl]-1-{[2-(tri Methylsilyl)-ethoxy]methyl}-1H-pyrazole-5-carboxylic acid ethyl ester 102-2 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1-methyl-1H-pyrazole-5- Ethyl formate 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)(hydroxy)methyl]-1-methyl-1H-pyrazole -5-ethyl formate 102-3 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1-methyl-1H-pyrazole-5- Ethyl formate 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)(hydroxy)methyl]-1-methyl-1H-pyrazole -5-ethyl formate

Intermediate 103

3 - [ ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - chloropyridin - 3 - yl ) methyl ] -1 - { [ 2- ( trimethylsilane ethyl ) ethoxy ] methyl } -1H - pyrazole- 5 - carboxylate and

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

NaH (60% in mineral oil, 73 mg) was added to 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}- at 0 °C under argon atmosphere In a mixture of 2-chloropyridin-3-yl)methyl]-1H-pyrazole-5-carboxylic acid ethyl ester (500 mg) in DMF (3 mL). The mixture was stirred for 30 minutes and then treated dropwise with (2-chloromethoxy-ethyl)-trimethyl-silane (SEM-Cl, 313 μL). The mixture was stirred for 2 hours while warming to room temperature. The mixture was then partitioned between saturated aqueous _NH4Cl and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried ( _MgSO4 ), concentrated in vacuo and the residue chromatographed on silica gel (petroleum ether/EtOAc 99:1→70:30) to give the title compound as a mixture of isomers .

LC (Method 2): t _R = 1.05 min. Mass spectrum (ESI ⁺ ): m/z = 347 [M+H] ⁺ .

Intermediate 104

3 - [ ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - ethylpyridin - 3 - yl ) methyl ] -1 - ethyl - 1H - pyrazole- _ _ _ 5 - ethyl formate

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

0.75 357 方法2 中間物 反應備註 104-1 在1巴氫氣氛圍下在室溫下進行反應4小時。 藉由逆相HPLC (ACN，水)純化產物。 中間物 名稱 起始材料之名稱 104-1 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]噻吩-2-甲酸乙酯 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)甲基]噻吩-2-甲酸乙酯 Intermediate 104-1 was prepared analogously to Intermediate 104 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 104-1

0.75 357 Method 2 Intermediate Reaction Notes 104-1 The reaction was carried out at room temperature for 4 hours under a hydrogen atmosphere of 1 bar. The product was purified by reverse phase HPLC (ACN, water). Intermediate name name of starting material 104-1 Ethyl 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]thiophene-2-carboxylate Ethyl 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)methyl]thiophene-2-carboxylate

Intermediate 105

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

6-Fluoro-3-iodo-2-methylpyridine (550 mg) in THF (25 mL) was treated dropwise with iPrMgClxLiCl (1.3 M in THF, 2.2 mL) at -50 °C under argon atmosphere of the mixture. The mixture was stirred for 1 hour and then treated dropwise with a mixture of 3-carboxy-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (300 mg) in THF (1 mL). After stirring at -50°C for 1 hour, the mixture was partitioned between saturated aqueous _NH4Cl and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were dried ( _MgSO4 ), concentrated in vacuo and the residue was chromatographed on silica gel (petroleum ether/EtOAc 90:10→50:50) to give the title compound.

LC (Method 2): t _R = 0.89 min. Mass spectrum (ESI ⁺ ): m/z = 294 [M+H] ⁺ .

Intermediate 106

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

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

Intermediate 107

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

Under argon atmosphere, 3-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridine-3- (hydroxy)methyl]-1-methyl-1H-pyrazole-5-carboxylic acid (173 mg), triethylsilane (380 µL), trifluoroacetic acid (185 µL) and boron trifluoride-difluoride A mixture of ethyl etherate ( _BF3xOEt2 , 293 µL) in DCM ( ₃ mL) and THF (1 mL) for 12 h. The mixture was diluted with water and purified by reverse phase HPLC (ACN, water) to give the title compound.

LC (Method 2): t _R = 0.69 min. Mass spectrum (ESI ⁺ ): m/z = 349 [M+H] ⁺ .

Intermediate 108

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

step 1 : 1 -[( 6 - fluorine - 2 - picoline - 3 - base ) methyl ]- 1H - Pyrazole - 4 - Ethyl formate

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

LC (Method 2): t _R = 0.88 min; Mass Spec (ESI ⁺ ): m/z = 264 [M+H] ⁺ .

step 2 : 1 -[( 6 -{ 5 - Azaspiro [ 2 . 3 ] already - 5 - base }- 2 - picoline - 3 - base ) methyl ]- 1H - Pyrazole - 4 - Formic acid

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

Intermediate 109

Methyl 5 - [ ( 6- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - methylpyridin - 3 - yl ) ( hydroxy ) methyl ] furan - 2 - carboxylate

A mixture of methyl 5-bromofuran-2-carboxylate (500 mg) in THF (15 mL) was treated dropwise with iPrMgClxLiCl (1.3 M in THF, 1.95 mL) at -50°C. The mixture was stirred at -50°C for 30 minutes and then cooled to -78°C. 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridine-3-carbaldehyde (592 mg) in THF (8 mL) was added and the mixture was stirred at -78°C 1 hour and then stirred at 0°C for 30 minutes. The reaction was quenched with saturated aqueous _NH4Cl and water. The mixture was extracted with EtOAc. The combined organic phases were dried ( _MgSO4 ), concentrated in vacuo and the residue was chromatographed on silica gel (petroleum ether/EtOAc 85:15→50:50) to give the title compound.

LC (Method 2): t _R = 0.70 min. Mass spectrum (ESI ⁺ ): m/z = 329 [M+H] ⁺ .

1.05 343 方法1 109-2

0.97 365 方法1 109-3

1.04 429 方法2 109-4

0.80 371 方法2 109-5

1.12 459 方法2 109-6

0.807 395 方法2 109-7

0.74 402 方法2 中間物 反應備註 109-1 在添加iPrMgClxLiCl之後，將混合物經2小時緩慢升溫至-10℃。接著將混合物冷卻至-30℃且添加醛，隨後在升溫至-10℃時攪拌1小時。 109-3 反應在-78℃下進行。 藉由逆相HPLC (ACN，水)純化產物。 109-4 反應在-60℃而非-50℃下進行且在添加後歷經17小時升溫至室溫。 109-5 反應在-78℃下進行。 109-6 反應在-78℃下進行。 藉由逆相HPLC (ACN，水)純化產物。 109-7 反應在-78℃下進行。 藉由逆相HPLC (ACN，水)純化產物。 中間物 名稱 起始材料 1 之名稱 起始材料 2 之名稱 109-1 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)-(羥基)甲基]呋喃-3-甲酸乙酯 3-(5-碘-6-甲基-吡啶-2-基)-3-氮雜-雙環[3.1.0]己烷 5-甲醯基呋喃-3-甲酸乙酯 109-2 5-[(6-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}-2-甲基-吡啶-3-基)(羥基)甲基]呋喃-2-甲酸甲酯 5-溴呋喃-2-甲酸甲酯 6-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}-2-甲基-吡啶-3-甲醛 109-3 5-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)(羥基)甲基]呋喃-2-甲酸甲酯 5-溴呋喃-2-甲酸甲酯 2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-甲醛 109-4 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-基)(羥基)-甲基]噻吩-2-甲酸乙酯 5-溴噻吩-2-甲酸乙酯 6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙烯基吡啶-3-甲醛 109-5 5-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)(羥基)甲基]噻吩-2-甲酸乙酯 5-溴噻吩-2-甲酸乙酯 2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-甲醛 109-6 5-[(6-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}-2-甲基吡啶-3-基)(羥基)甲基]-噻吩-2-甲酸乙酯 5-溴噻吩-2-甲酸乙酯 6-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}-2-甲基-吡啶-3-甲醛 109-7 (5-溴-1,3-噻唑-2-基)(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲醇 2,5-二溴-1,3-噻唑 6-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}-2-甲基-吡啶-3-甲醛 Intermediates 109-1 to 109-7 were prepared analogously to Intermediate 109 : Intermediate structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 109-1

1.05 343 method 1 109-2

0.97 365 method 1 109-3

1.04 429 Method 2 109-4

0.80 371 Method 2 109-5

1.12 459 Method 2 109-6

0.807 395 Method 2 109-7

0.74 402 Method 2 Intermediate Reaction Notes 109-1 After the addition of iPrMgClxLiCl, the mixture was slowly warmed to -10°C over 2 hours. The mixture was then cooled to -30°C and the aldehyde was added, followed by stirring for 1 hour while warming to -10°C. 109-3 The reaction was carried out at -78°C. The product was purified by reverse phase HPLC (ACN, water). 109-4 The reaction was run at -60°C instead of -50°C and warmed to room temperature over 17 hours after addition. 109-5 The reaction was carried out at -78°C. 109-6 The reaction was carried out at -78°C. The product was purified by reverse phase HPLC (ACN, water). 109-7 The reaction was carried out at -78°C. The product was purified by reverse phase HPLC (ACN, water). Intermediate name Name of starting material 1 Name of starting material 2 109-1 Ethyl 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)-(hydroxy)methyl]furan-3-carboxylate 3-(5-Iodo-6-methyl-pyridin-2-yl)-3-aza-bicyclo[3.1.0]hexane Ethyl 5-Methylaminofuran-3-carboxylate 109-2 5-[(6-{6,6-Difluoro-3-azabicyclo-[3.1.0]hex-3-yl}-2-methyl-pyridin-3-yl)(hydroxy)methyl]furan -Methyl 2-carboxylate Methyl 5-bromofuran-2-carboxylate 6-{6,6-Difluoro-3-azabicyclo-[3.1.0]hex-3-yl}-2-methyl-pyridine-3-carbaldehyde 109-3 5-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)(hydroxy)methyl]furan-2- methyl formate Methyl 5-bromofuran-2-carboxylate 2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridine-3-carbaldehyde 109-4 5-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridin-3-yl)(hydroxy)-methyl]thiophene-2-carboxylic acid ethyl ester Ethyl 5-bromothiophene-2-carboxylate 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-vinylpyridine-3-carbaldehyde 109-5 5-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)(hydroxy)methyl]thiophene-2- Ethyl formate Ethyl 5-bromothiophene-2-carboxylate 2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridine-3-carbaldehyde 109-6 5-[(6-{6,6-Difluoro-3-azabicyclo-[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)(hydroxy)methyl]-thiophene -2-ethyl formate Ethyl 5-bromothiophene-2-carboxylate 6-{6,6-Difluoro-3-azabicyclo-[3.1.0]hex-3-yl}-2-methyl-pyridine-3-carbaldehyde 109-7 (5-Bromo-1,3-thiazol-2-yl)(6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridine-3 -base) methanol 2,5-Dibromo-1,3-thiazole 6-{6,6-Difluoro-3-azabicyclo-[3.1.0]hex-3-yl}-2-methyl-pyridine-3-carbaldehyde

Intermediate 110

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

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

Following procedures similar to those described in Step 1 of Intermediate 111, the title compound was prepared from methyl 3-cyano-4-fluorobenzoate and 3-azabicyclo[3.1.0]hexane hydrochloride.

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

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

LC (Method 2): t _R = 0.92 min; Mass Spec (ESI ⁺ ): m/z = 215 [M+H] ⁺ .

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

Following a procedure similar to that described in Step 3 of Intermediate 111, from 2-{3-azabicyclo[3.1.0]hex-3-yl}-5-(hydroxymethyl)benzonitrile and 1H-pyridine The title compound was prepared from ethyl oxazole-4-carboxylate.

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

Following a procedure analogous to that described in Step 4 of Intermediate 111 from 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyanophenyl)methyl] -1H-Pyrazole-4-carboxylic acid ethyl ester The title compound was prepared.

Intermediate 111

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

Step 1 : 4-{3-Azabicyclo[3.1.0]hex-3-yl}-3,5-difluorobenzaldehyde

Stir 3,4,5-trifluorobenzaldehyde (1.50 g), 3-azabicyclo[3.1.0]hexane hydrochloride (1.23 g), ^iPr ₂ NEt (4 mL) and DMF at 70°C (15 mL) of the mixture overnight. After cooling to room temperature, water was added and the resulting mixture was extracted with ethyl acetate (3 times). Dry ( _{Na2SO4 )} and concentrate the combined extracts. The residue was chromatographed on silica gel (petroleum ether/EtOAc 98:2→95:5) to give the title compound.

LC (Method 2): t _R = 1.13 min; Mass Spec (ESI ⁺ ): m/z = 224 [M+H] ⁺ .

Step 2 : (4-{3-Azabicyclo[3.1.0]hex-3-yl}-3,5-difluorophenyl)methanol

NaBH4 (0.18 g) was added portionwise to _4- {3-azabicyclo[3.1.0]hex-3-yl}-3,5-difluorobenzaldehyde (0.97 g) in THF at 0°C (10 mL) and methanol (10 mL). The mixture was stirred in a cooling bath for 1 hour and at room temperature for a further 30 minutes before adding aqueous HCl (1 mol/L). The mixture was stirred for 30 minutes and then neutralized with aqueous _NaHCO3 . The mixture was extracted with ethyl acetate (2 times), and the combined extracts were dried ( _{Na2SO4 )} and concentrated. The residue was chromatographed on silica gel (petroleum ether/EtOAc 95:5→85:15) to give the title compound.

LC (Method 2): t _R = 1.04 min; Mass Spec (ESI ⁺ ): m/z = 226 [M+H] ⁺ .

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

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

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

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

LC (Method 2): t _R = 1.04 min; Mass Spec (ESI ⁺ ): m/z = 320 [M+H] ⁺ .

Intermediate 112

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

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

Stir (4-{3-azabicyclo[3.1.0]hex-3-yl}-3,5-difluorophenyl)methanol (60 mg), _SOCl2 (0.04 mL) and dichloro at room temperature A mixture of methane (1 mL) for 30 minutes. The mixture was concentrated, dissolved in toluene, concentrated again, and used as is in the next reaction step.

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

^LiOtBu (21 mg) was added to a mixture of lH-imidazole-4-carboxylic acid ethyl ester (37 mg), ^tBuOH (0.4 mL) and DCM (1.6 mL), the mixture was refrigerated in an ice bath. The mixture was stirred for 5 minutes, followed by the addition of 3-[4-(chloromethyl)-2,6-difluorophenyl]-3-azabicyclo[3.1.0]hexane in DCM (0.4 mL) (65 mg, crude product from step 1). The cooling bath was removed and the mixture was stirred at 40°C overnight. After cooling to room temperature, water and DCM were added. The organic phase was separated and the aqueous phase was extracted with DCM (2 times). The combined organic extracts were concentrated and the residue was chromatographed (HPLC; ACN/water/ammonia) to give the title compound.

LC (Method 2): t _R = 0.89 min; Mass Spec (ESI ⁺ ): m/z = 348 [M+H] ⁺ .

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

Following a procedure analogous to that described in Step 4 of Intermediate 111, from 2-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3,5-difluorophenyl)methan The title compound was prepared from ethyl]-1H-imidazole-5-carboxylate.

LC (Method 2): t _R = 0.82 min; Mass Spec (ESI ⁺ ): m/z = 320 [M+H] ⁺ .

Intermediate 113

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

Step 1 : 6-Fluoro-3-carbamoyl-2-methylbenzonitrile

^iPrMgCl *LiCl (Turbo Grignard; 1.3 mol/L in THF, 3.8 mL) was added dropwise to a solution containing 3-bromo-6-fluoro-2-methylbenzonitrile (1.0 g) at -20 °C in THF (25 mL). The mixture was warmed to 0°C over a period of 1.3 hours before another portion of ^iPrMgCl *LiCl (Turbo Grignard; 1.3 mol/L in THF, 1.0 mL) was added. The cooling bath was removed and the mixture was stirred for an additional 45 minutes. The mixture was cooled to -20°C and DMF (0.8 mL) was added. After stirring for 50 minutes, the cooling bath was removed and the reaction was quenched by addition of aqueous _NH4Cl at room temperature. The mixture was extracted with EtOAc (3 times), and the combined extracts were dried ( _{Na2SO4 )} and concentrated. The residue was chromatographed on silica gel (cyclohexane/EtOAc 24:1→3:1) to give the title compound. LC (Method 2): _tR = 0.87 min.

Step 2 : 6-{3-Azabicyclo[3.1.0]hex-3-yl}-3-carbamoyl-2-methylbenzonitrile

6-Fluoro-3-carbamoyl-2-toluenecarbonitrile (515 mg), _KHCO3 (0.79 g), 3-azabicyclo[3.1.0]hexane hydrochloride (453 mg) were stirred at 70°C ) and DMSO (10 mL) for 1.3 hours. After cooling to room temperature, water was added and the mixture was stirred for 30 minutes. The precipitate was isolated by filtration, washed with water (2 times) and dried at 65°C to give the title compound. LC (Method 1): _tR = 0.97 min; Mass Spec (ESI ⁺ ): m/z = 227 [M+H] ⁺ .

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

NaBH4 ₍ 0.21 g) was added portionwise at room temperature to 6-{3-azabicyclo[3.1.0]hex-3-yl}-3-carbamoyl-2-methylbenzonitrile ( 0.63 g) in THF (10 mL) and MeOH (5 mL). The mixture was stirred for 1 hour, then aqueous HCl (1 mol/L) was added. The mixture was stirred for 1 hour, then the mixture was neutralized with aqueous _NaHCO3 . The mixture was extracted with EtOAc (2 times), and the combined extracts were dried ( _{Na2SO4 )} and concentrated to provide the title compound and 6-{3-azabicyclo[3.1.0]hex-3-yl}-3- A mixture of (methoxymethyl)-2-methylbenzonitrile, which was used as such in the next reaction step (both components were competent starting materials for the next step).

LC (Method 1): t _R = 1.27 min; Mass Spec (ESI ⁺ ): m/z = 439 [M+H] ⁺ .

Step 4 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-pyrazol-4- Ethyl formate

Following a procedure similar to that described in Step 3 of Intermediate 111, 6-{3-azabicyclo[3.1.0]hex-3-yl}-3-{[( 4-{3-Azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-methylphenyl)methoxy]methyl}-2-methylbenzonitrile and 6- A mixture of {3-azabicyclo[3.1.0]hex-3-yl}-3-(methoxymethyl)-2-methylbenzonitrile and 1H-pyrazole-4-carboxylic acid ethyl ester prepared the title compound.

LC (Method 1): _tR = 1.08 min; Mass Spec (ESI ⁺ ): m/z = 351 [M+H] ⁺ .

Step 5 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-pyrazol-4- Formic acid

Following a procedure analogous to that described in Step 4 of Intermediate 111 from 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-methylbenzene yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester to prepare the title compound.

LC (Method 2): t _R = 0.96 min; Mass Spec (ESI ⁺ ): m/z = 323 [M+H] ⁺ .

Intermediate 114

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

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

Following a procedure similar to that described in Step 3 of Intermediate 111, 6-{3-azabicyclo[3.1.0]hex-3-yl}-3-{[( 4-{3-Azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-methylphenyl)methoxy]methyl}-2-methylbenzonitrile and 6- The title compound was prepared from a mixture of {3-azabicyclo[3.1.0]hex-3-yl}-3-(methoxymethyl)-2-methylbenzonitrile and 1H-imidazole-4-carboxylic acid ethyl ester .

LC (Method 1): _tR = 0.99 min; Mass Spec (ESI ⁺ ): m/z = 351 [M+H] ⁺ .

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

Following a procedure analogous to that described in Step 4 of Intermediate 111 from 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-methylbenzene yl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester to prepare the title compound.

LC (Method 2): t _R = 0.80 min; Mass Spec (ESI ⁺ ): m/z = 323 [M+H] ⁺ .

Intermediate 115

1 - [ ( 4- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -3 - cyano - 5 - fluorophenyl ) methyl ] -1H - pyrazole - 4 - carboxylic acid _

Step 1 : 2,3-Difluoro-5-carbamoylbenzonitrile

Following a procedure analogous to that described in Step 1 of Intermediate 113, the title compound was prepared from 5-bromo-2,3-difluorobenzonitrile. LC (Method 2): _tR = 0.84 min.

Step 2 : 2-{3-Azabicyclo[3.1.0]hex-3-yl}-3-fluoro-5-carboxybenzonitrile

Following procedures analogous to those described in Step 1 of Intermediate 111, the title compound was prepared from 2,3-difluoro-5-carboxybenzonitrile and 3-azabicyclo[3.1.0]hexane hydrochloride .

LC (Method 2): t _R = 1.03 min; Mass Spec (ESI ⁺ ): m/z = 231 [M+H] ⁺ .

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

Prepared from 2-{3-azabicyclo[3.1.0]hex-3-yl}-3-fluoro-5-carbamoylbenzonitrile following procedures analogous to those described in Step 2 of Intermediate 111 title compound.

LC (Method 2): t _R = 0.99 min; Mass Spec (ESI ⁺ ): m/z = 233 [M+H] ⁺ .

Step 4 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-3-cyano-5-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

Following a procedure similar to that described in Step 3 of Intermediate 111, from 2-{3-azabicyclo[3.1.0]hex-3-yl}-3-fluoro-5-(hydroxymethyl)benzyl The title compound was prepared from nitrile and 1H-pyrazole-4-carboxylic acid ethyl ester.

LC (Method 2): t _R = 1.10 min; Mass Spec (ESI ⁺ ): m/z = 355 [M+H] ⁺ .

Step 5 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-3-cyano-5-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid

Following a procedure analogous to that described in Step 4 of Intermediate 111 from 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyano-5-fluorophenyl )methyl]-1H-pyrazole-4-carboxylic acid ethyl ester to prepare the title compound.

LC (Method 2): t _R = 0.99 min; Mass Spec (ESI ⁺ ): m/z = 327 [M+H] ⁺ .

Intermediate 116

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

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

Following a procedure similar to that described in Step 3 of Intermediate 111 from 2-{3-azabicyclo[3.1.0]hex-3-yl}-5-(hydroxymethyl)benzonitrile and 1H-imidazole -4-Ethyl carboxylate The title compound was prepared.

Step 2 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid

Following a procedure analogous to that described in Step 4 of Intermediate 111 from 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyanophenyl)methyl] -1H-imidazole-4-carboxylic acid ethyl ester The title compound was prepared.

Intermediate 117

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

Step 1 : 2-Fluoro-5-carboxybenzene-1,3-dicarbonitrile

A mixture of 4-fluoro3,5-diiodobenzaldehyde (2.00 g), copper(I) cyanide (1.05 g) and DMF (25 mL) was stirred at 120°C for 24 hours. After cooling to room temperature, water was added and the resulting mixture was extracted with ethyl acetate (3 times). Dry ( _{Na2SO4 )} and concentrate the combined extracts. The residue was chromatographed on silica gel (petroleum ether/EtOAc 95:51→70:30) to give the title compound.

Step 2 : 2-{3-Azabicyclo[3.1.0]hex-3-yl}-5-carbamoylbenzene-1,3-dicarbonitrile

Following a procedure similar to that described in Step 1 of Intermediate 111 from 2-fluoro-5-carboxybenzene-1,3-dicarbonitrile and 3-azabicyclo[3.1.0]hexane hydrochloride The title compound was prepared.

LC (Method 2): t _R = 0.95 min; Mass Spec (ESI ⁺ ): m/z = 238 [M+H] ⁺ .

Step 3 : 2-{3-Azabicyclo[3.1.0]hex-3-yl}-5-(hydroxymethyl)benzene-1,3-dicarbonitrile

Following a procedure similar to that described in Step 2 of Intermediate 111 from 2-{3-azabicyclo[3.1.0]hex-3-yl}-5-carbamoylbenzene-1,3-dicarbonitrile The title compound was prepared.

LC (Method 2): t _R = 0.92 min; Mass Spec (ESI ⁺ ): m/z = 240 [M+H] ⁺ .

Step 4 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-3,5-dicyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

Following a procedure similar to that described in Step 3 of Intermediate 111, from 2-{3-azabicyclo[3.1.0]hex-3-yl}-5-(hydroxymethyl)benzene-1,3-di The title compound was prepared from carbonitrile and 1H-pyrazole-4-carboxylic acid ethyl ester.

LC (Method 2): t _R = 1.07 min; Mass Spec (ESI ⁺ ): m/z = 362 [M+H] ⁺ .

Step 5 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-3,5-dicyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid

Following a procedure analogous to that described in Step 4 of Intermediate 111 from 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3,5-dicyanophenyl) Methyl]-1H-pyrazole-4-carboxylic acid ethyl ester prepared the title compound.

LC (Method 2): t _R = 0.92 min; Mass Spec (ESI ⁺ ): m/z = 334 [M+H] ⁺ .

Intermediate 118

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

Step 1 : 3-Bromo-2,6-difluorobenzonitrile

3-Amino-2,6-difluorobenzonitrile (2.50 g) dissolved in ACN (45 mL) was added dropwise to copper(II) bromide (4.49 g), tertiary nitrite at 65°C in a mixture of ester (3.8 mL) and ACN (45 mL). The reaction mixture was stirred at 65°C for 1 hour and then cooled to room temperature. 20% aqueous HCl was added, and the resulting mixture was extracted with diethyl ether. Dry ( _{Na2SO4 )} and concentrate the combined extracts. The residue was chromatographed on silica gel (cyclohexane/EtOAc 7:3) to give the title compound. LC (Method 2): t _R = 1.01 min.

Step 2 : 6-{3-Azabicyclo[3.1.0]hex-3-yl}-3-bromo-2-fluorobenzonitrile

Following procedures similar to those described in Step 1 of Intermediate 111, the title compound was prepared from 3-bromo-2,6-difluorobenzonitrile and 3-azabicyclo[3.1.0]hexane hydrochloride.

LC (Method 2): t _R = 1.17 min; Mass Spec (ESI ⁺ ): m/z = 281/283 (Br) [M+H] ⁺ .

Step 3 : Methyl 4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-fluorobenzoate

6-{3-Azabicyclo[3.1.0]hex-3-yl}-3-bromo-2-fluorobenzonitrile (500 mg), PdCl were stirred at 80 °C under a carbon monoxide atmosphere (10 bar) A mixture of ₂ (dppf) (72 mg), _NEt3 (0.3 mL) and MeOH (6 mL) overnight. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel (cyclohexane/EtOAc 6:4) to give the title compound.

LC (Method 2): t _R = 1.05 min; Mass Spec (ESI ⁺ ): m/z = 261 [M+H] ⁺ .

Step 4 : 6-{3-azabicyclo[3.1.0]hex-3-yl}-3-{[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3- Cyano-2-fluorophenyl)methoxy]-methyl}-2-fluorobenzonitrile

4-{3-Azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-fluorobenzoate (0.42 g) dissolved in THF (5 mL) at -50°C LiAlH4 in THF (2.3 mol/L; 0.70 mL) was added dropwise _. The mixture was stirred for 1.5 hours while warming to -20°C, and then quenched by addition of aqueous HCl (1 mol/L). The resulting mixture was extracted with EtOAc (3 times), and the combined extracts were dried ( _{Na2SO4 )} and concentrated. The residue was chromatographed on silica gel (cyclohexane/EtOAc 1:0→1:1) to give the title compound. Depending on the processing procedure, only 6-{3-azabicyclo[3.1.0]hex-3-yl}-2-fluoro-3-(hydroxymethyl)benzonitrile is obtained; the latter can be obtained analogously used in the next reaction step. Mass spectrum (ESI ⁺ ): m/z = 447 [M+H] ⁺ .

Step 5 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester

Following a procedure similar to that described in Step 3 of Intermediate 111, from 6-{3-azabicyclo[3.1.0]hex-3-yl}-3-{[(4-{3-azabicyclo[ 3.1.0] Hex-3-yl}-3-cyano-2-fluorophenyl)methoxy]methyl}-2-fluorobenzonitrile and 1H-pyrazole-4-carboxylic acid ethyl ester to prepare the title compound .

LC (Method 1): _tR = 1.06 min; Mass Spec (ESI ⁺ ): m/z = 355 [M+H] ⁺ .

Step 6 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid

Following a procedure analogous to that described in Step 4 of Intermediate 111 from 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-fluorophenyl )methyl]-1H-pyrazole-4-carboxylic acid ethyl ester to prepare the title compound.

LC (Method 2): t _R = 0.94 min; Mass Spec (ESI ⁺ ): m/z = 349 [M+H] ⁺ .

Intermediate 119

1 - [ ( 4- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - methylphenyl ) methyl ] -1H - pyrazole - 4 _ _ _ _ - Formic acid

Step 1 : 4-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylbenzaldehyde

Following a procedure analogous to that described in Step 1 of Intermediate 111, the title compound was prepared from 4-fluoro-2-methylbenzaldehyde and 6,6-difluoro-3-azabicyclo[3.1.0]hexane; K2CO3 was used instead _{of Hünig} 's base at 130°C. LC (Method 2): t _R = 1.01 min; Mass Spec (ESI ⁺ ): m/z = 238 [M+H] ⁺ .

Step 2 : (4-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylphenyl)methanol

Prepared from 4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylbenzaldehyde following procedures analogous to those described in Step 2 of Intermediate 111 title compound.

Step 3 : 1-[(4-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylphenyl)methyl]-1H-pyrazole- Ethyl 4-formate

Following a procedure analogous to that described in Step 3 of Intermediate 111, from (4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylphenyl ) methanol and 1H-pyrazole-4-carboxylic acid ethyl ester to prepare the title compound.

LC (Method 2): t _R = 1.13 min; Mass Spec (ESI ⁺ ): m/z = 362 [M+H] ⁺ .

Step 4 : 1-[(4-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylphenyl)methyl]-1H-pyrazole- 4-carboxylic acid

Following a procedure analogous to that described in Step 4 of Intermediate 111 from 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methyl The title compound was prepared from ethyl phenyl)methyl]-1H-pyrazole-4-carboxylate.

LC (Method 2): t _R = 0.98 min; Mass Spec (ESI ⁺ ): m/z = 334 [M+H] ⁺ .

Intermediate 120

1 - [ ( 4- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -5 - cyano - 2 - methylphenyl ) methyl ] -1H - pyrazole - 4 - carboxylic acid _

Step 1 : 5-Bromo-2-chloro-4-methylbenzonitrile

N-bromosuccinimide (3.50 g) and trifluoroacetic acid (25 mL) were added to 2-chloro-4-methylbenzonitrile (2.50 g) in concentrated sulfuric acid at room temperature. The mixture was stirred at room temperature for 24 hours. The mixture was cooled to 0 °C and then poured slowly into an ice-cold solution of aqueous NaOH (4 mol/L; 125 mL). The precipitate was isolated by filtration and purified by silica gel chromatography (cyclohexane/EtOAc) to give the title compound.

LC (Method 1): t _R = 1.07 min.

Step 2 : 2-Chloro-5-carbamoyl-4-methylbenzonitrile

Following a procedure analogous to that described in Step 1 of Intermediate 113, the title compound was prepared from 5-bromo-2-chloro-4methylbenzonitrile. LC (Method 1): t _R = 0.90 min; Mass Spec (ESI ⁻ ): m/z = 178 [MH] ⁻ .

Step 3 : 2-{3-Azabicyclo[3.1.0]hex-3-yl}-5-carbamoyl-4-methylbenzonitrile

Prepared from 2-chloro-5-carboxy-4-methylbenzonitrile and 3-azabicyclo[3.1.0]hexane hydrochloride following procedures analogous to those described in Step 1 of Intermediate 111 title compound.

LC (Method 2): t _R = 1.02 min; Mass Spec (ESI ⁺ ): m/z = 227 [M+H] ⁺ .

Step 4 : 2-{3-Azabicyclo[3.1.0]hex-3-yl}-5-(hydroxymethyl)-4-methylbenzonitrile

Prepared from 2-{3-azabicyclo[3.1.0]hex-3-yl}-5-carbamoyl-4-methylbenzonitrile following a procedure analogous to that described in Step 2 of Intermediate 111 title compound.

LC (Method 2): t _R = 0.96 min; Mass Spec (ESI ⁺ ): m/z = 229 [M+H] ⁺ .

Step 5 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyano-2-methylphenyl)methyl]-1H-pyrazol-4- Ethyl formate

Following a procedure analogous to that described in Step 3 of Intermediate 111, from 2-{3-azabicyclo[3.1.0]hex-3-yl}-5-(hydroxymethyl)-4-methylbenzyl The title compound was prepared from nitrile and 1H-pyrazole-4-carboxylic acid ethyl ester.

LC (Method 1): t _R = 1.08 min; Mass Spec (ESI ⁺ ): m/z = 351 [M+H] ⁺ .

Step 6 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyano-2-methylphenyl)methyl]-1H-pyrazol-4- Formic acid

Following a procedure analogous to that described in Step 4 of Intermediate 111 from 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-5-cyano-2-methylbenzene yl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester to prepare the title compound.

LC (Method 1): t _R = 0.68 min; Mass Spec (ESI ⁺ ): m/z = 323 [M+H] ⁺ .

Intermediate 121

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

Step 1 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

Following a procedure similar to that described in step 3 of intermediate 111, 6-{3-azabicyclo[3.1.0]hex-3-yl}-3-{ was obtained after treatment of step 4 of intermediate 118 [(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-fluorophenyl)methoxy]methyl}-2-fluorobenzonitrile and 6- The title compound was prepared from a mixture of {3-azabicyclo[3.1.0]hex-3-yl}-2-fluoro-3-(hydroxymethyl)benzonitrile and 1H-imidazole-4-carboxylic acid ethyl ester; in Reactions were carried out at 140°C in a microwave oven. LC (method 1): t _R = 0.90 min; mass spectrum (ESI ⁺ ): m/z = 355 [M+H] ⁺ .

Step 2 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylic acid

Following a procedure analogous to that described in Step 4 of Intermediate 111 from 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-3-cyano-2-fluorophenyl )methyl]-1H-imidazole-4-carboxylic acid ethyl ester to prepare the title compound.

LC (Method 2): t _R = 0.78 min; Mass Spec (ESI ⁺ ): m/z = 327 [M+H] ⁺ .

Intermediate 122

1 - [ ( 4- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - chloro - 3 - cyanophenyl ) methyl ] -1H - pyrazole - 4 - carboxylic acid _

Step 1 : 3-Bromo-2,6-dichlorobenzonitrile

KBrO3 ₍ 7.28 g) was added portionwise to concentrated sulfuric acid refrigerated in an ice bath containing 2,6-dichlorobenzonitrile (2.50 g). The mixture was warmed to room temperature in a cooling bath and then stirred at this temperature overnight. _The mixture was poured onto ice, and saturated aqueous _K2CO3 was added to neutralize the solution. The mixture was extracted with DCM (3 times), and the combined extracts were dried ( _{Na2SO4 )} and concentrated. The residue was 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 was prepared from 3-bromo-2,6-dichlorobenzonitrile following a procedure analogous to that described in Step 3 of Intermediate 118; the reaction was carried out in a mixture of DMF and MeOH.

LC (Method 2): t _R = 1.00 min.

Step 3 : Methyl 4-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-cyanobenzoate

Following procedures similar to those described in Step 1 of Intermediate 111, the title compound was prepared from methyl 2,4-dichloro-3-cyanobenzoate and 3-azabicyclo[3.1.0]hexane hydrochloride .

LC (Method 2): t _R = 1.07 min; Mass Spec (ESI ⁺ ): m/z = 277 [M+H] ⁺ .

Step 4 : 6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-(hydroxymethyl)benzonitrile

The title was prepared from methyl 4-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-cyanobenzoate following a procedure analogous to that described in Step 4 of Intermediate 118 compound.

LC (Method 2): t _R = 0.96 min; Mass Spec (ESI ⁺ ): m/z = 249 [M+H] ⁺ .

Step 5 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-cyano-6-methylphenyl)methyl]-1H-pyridine Ethyl oxazole-4-carboxylate

Following a procedure similar to that described in Step 3 of Intermediate 111 from 6-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-(hydroxymethyl)benzonitrile and 1H-pyrazole-4-carboxylic acid ethyl ester to prepare the title compound.

LC (Method 2): t _R = 1.10 min.

Step 6 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-cyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid

Following a procedure analogous to that described in Step 4 of Intermediate 111 from 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-cyano-6 -methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester The title compound was prepared. LC (Method 2): _tR = 0.96 min.

Intermediate 123

1 - [ ( 4- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - chloro - 3 - cyanophenyl ) methyl ] -1H - imidazole - 4 - carboxylic acid _

Step 1 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

Following a procedure analogous to that described in Step 3 of Intermediate 111 from 6-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-(hydroxymethyl)benzonitrile and 1H-imidazole-4-carboxylic acid ethyl ester to prepare the title compound; the reaction was carried out at 100°C. LC (Method 1): _tR = 0.98 min; Mass Spec (ESI ⁺ ): m/z = 371 [M+H] ⁺ .

Step 2 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid

Following a procedure analogous to that described in Step 4 of Intermediate 111 from 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-chloro-3-cyanophenyl )methyl]-1H-imidazole-4-carboxylic acid ethyl ester to prepare the title compound.

LC (Method 2): t _R = 0.80 min; Mass Spec (ESI ⁺ ): m/z = 343 [M+H] ⁺ .

Intermediate 124

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

Step 1 : 4-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromobenzaldehyde

The title compound was prepared from 2-bromo-4-fluorobenzaldehyde and 3-azabicyclo[3.1.0]hexane hydrochloride following a procedure analogous to that described in Step 1 of Intermediate 111; used at 120°C K ₂ CO ₃ was used instead of Schönig's base and NMP was used instead of DMF.

LC (Method 2): t _R = 1.08 min; Mass Spec (ESI ⁺ ): m/z = 266/268 (Br) [M+H] ⁺ .

Step 2 : (4-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromophenyl)methanol

The title compound was prepared from 4-{3-azabicyclo[3.1.0]hex-3-yl}-2-bromobenzaldehyde following a procedure analogous to that described in Step 2 of Intermediate 111.

LC (Method 2): t _R = 1.01 min; Mass Spec (ESI ⁺ ): m/z = 268/270 (Br) [M+H] ⁺ .

Step 3 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

Following a procedure similar to that described in Step 3 of Intermediate 111 from (4-{3-azabicyclo[3.1.0]hex-3-yl}-2-bromophenyl)methanol and 1H-imidazol-4 - Ethyl formate Prepare the title compound.

LC (Method 2): t _R = 0.96 min; Mass Spec (ESI ⁺ ): m/z = 390/392 (Br) [M+H] ⁺ .

Step 4 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylic acid

Following a procedure analogous to that described in Step 4 of Intermediate 111, from 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-bromophenyl)methyl]- The title compound was prepared from 1H-imidazole-4-carboxylic acid ethyl ester.

LC (Method 2): t _R = 0.85 min.

Intermediate 125

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

Step 1 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylphenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

Rinse with Ar with stirring bar, ethyl 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylic acid A flask of ester (100 mg), methylboronic acid ( ₂₃ mg), _Cs2CO3 (0.25 g) and 1,4-dioxane (1.5 mL) for 10 min. PdCl ₂ (dppf) (21 mg) was added, the flask was sealed, and the mixture was stirred at 110° C. for 1.5 hours. After cooling to room temperature, the mixture was diluted with MeOH and chromatographed (HPLC; ACN/water/ammonia) to give the title compound.

LC (Method 2): t _R = 0.91 min.

Step 2 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylphenyl)methyl]-1H-imidazole-4-carboxylic acid

Following a procedure analogous to that described in Step 4 of Intermediate 111 from 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylphenyl)methyl] -1H-imidazole-4-carboxylic acid ethyl ester The title compound was prepared.

LC (Method 2): _tR = 0.81 min.

Intermediate 126

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

Step 1 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-2-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

Rinse with Ar with stirring bar, ethyl 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylic acid Flask of ester (100 mg), Zn(CN) ₂ (60 mg), zinc (8 mg), Pd2(dba _{)3 ( 23} mg) and ^tBu3P *HBF4 ( ₁₅ mg) for 10 minutes. NMP (1 mL) was added, the flask was sealed, and the mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the mixture was diluted with DMF and chromatographed (HPLC; ACN/water/ammonia) to give the title compound.

LC (Method 2): t _R = 0.90 min; Mass Spec (ESI ⁺ ): m/z = 337 [M+H] ⁺ .

Step 2 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-2-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid

Following a procedure analogous to that described in Step 4 of Intermediate 111 from 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-cyanophenyl)methyl] -1H-imidazole-4-carboxylic acid ethyl ester The title compound was prepared.

LC (Method 2): t _R = 0.79 min; Mass Spec (ESI ⁺ ): m/z = 309 [M+H] ⁺ .

Intermediate 127

1 - [ ( 4- { 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2- ( hydroxymethyl ) phenyl ) methyl ] -1H - imidazole - 4 - carboxylic acid _

Step 1 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-2-vinylphenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

Rinse with Ar with stirring bar, ethyl 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylic acid A flask of ester (500 mg), vinylboronic acid (0.25 mL), aqueous _Na2CO3 ( ₁ mol/L; 3.2 mL) and 1,4-dioxane (9 mL) for 10 min. PdCl ₂ (dppf) (53 mg) was added, the flask was sealed, and the mixture was stirred at 100° C. for 2.5 hours. After cooling to room temperature, the mixture was diluted with brine and the resulting mixture was extracted with EtOAc (3 times). Dry ( _{Na2SO4 )} and concentrate the combined extracts. The residue was chromatographed on silica gel (cyclohexane/EtOAc 4:1→0:1) to give the title compound. LC (Method 2): _tR = 0.93 min.

Step 2 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-2-carbamoylphenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

_OsO4 (4% in water; 0.14 mL) was added to 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-vinylphenyl)methane at room temperature In a mixture of ethyl]-1H-imidazole-4-carboxylate (300 mg), water (4 mL) and 1,4-dioxane (4 mL). After stirring the mixture for 10 minutes, _NaIO4 (0.57 g) was added. The mixture was stirred for 2.5 hours, and then ethyl acetate/methanol (9:1; 20 mL) and water (20 mL) were added. The mixture was extracted with ethyl acetate (3 times), and the combined extracts were dried ( _{Na2SO4 )} and concentrated. The residue was chromatographed on silica gel (cyclohexane/ethyl acetate 70:30->0:1) to give the title compound.

LC (Method 1): _tR = 0.99 min; Mass Spec (ESI ⁺ ): m/z = 340 [M+H] ⁺ .

Step 3 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)phenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester

Following a procedure analogous to that described in Step 2 of Intermediate 111 from 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-carbylphenyl)methyl ]-1H-imidazole-4-carboxylic acid ethyl ester to prepare the title compound.

LC (Method 1): _tR = 0.81 min.

Step 4 : 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)phenyl)methyl]-1H-imidazole-4-carboxylic acid

Following a procedure analogous to that described in Step 4 of Intermediate 111, from 1-[(4-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)phenyl) Methyl]-1H-imidazole-4-carboxylic acid ethyl ester prepared the title compound.

LC (Method 2): _tR = 0.72 min.

Intermediate 128

1 - [ ( 2 - Cyano - 4- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hexyl - 3- ) methyl ] -1H - pyrazole - 4 - carboxylic acid _ _ _

Step 1 : 1-[(2-Cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-pyrazole- Ethyl 4-formate

Following a procedure analogous to that described in Step 1 of Intermediate 126 from 1-[(2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl} Phenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester The title compound was prepared.

LC (Method 1): t _R = 1.03 min.

Step 2 : 1-[(2-Cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-pyrazole- 4-carboxylic acid

Following a procedure similar to that described in Step 4 of Intermediate 111 from 1-[(2-cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl }Phenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester The title compound was prepared.

LC (Method 1): _tR = 0.63 min.

Intermediate 129

1 - [ ( 2 - Bromo - 4- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } phenyl ) methyl ] -1H - pyrazole - 4- _ _ _ _ _ Formic acid

Step 1 : 2-Bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}benzaldehyde

The title was prepared from 2-bromo-4-fluorobenzaldehyde and 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride following a procedure analogous to that described in Step 1 of Intermediate 111 Compound; K2CO3 was used in place _{of Schönig} 's base and NMP in place of DMF at 120°C.

LC (Method 2): t _R = 1.02 min; Mass Spec (ESI ⁺ ): m/z = 302/304 (Br) [M+H] ⁺ .

Step 2 : (2-Bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methanol

The title was prepared from 2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}benzaldehyde following a procedure analogous to that described in Step 2 of Intermediate 111 compound.

LC (Method 2): t _R = 0.96 min; Mass Spec (ESI ⁺ ): m/z = 304/306 (Br) [M+H] ⁺ .

Step 3 : 1-[(2-Bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-pyrazole-4 -formate

Following a procedure analogous to that described in Step 3 of Intermediate 111 from (2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl) The title compound was prepared from methanol and 1H-pyrazole-4-carboxylic acid ethyl ester.

LC (Method 2): t _R = 1.09 min; Mass Spec (ESI ⁺ ): m/z = 426/428 (Br) [M+H] ⁺ .

Step 4 : 1-[(2-Bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-pyrazole-4 - Formic acid

Following a procedure analogous to that described in Step 4 of Intermediate 111 from 1-[(2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl} Phenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester The title compound was prepared.

LC (Method 1): _tR = 0.68 min.

Intermediate 130

1 - [ ( 2 - cyano - 4- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } phenyl ) methyl ] -1H - imidazol - 4- _ _ _ _ _ Formic acid

Step 1 : 1-[(2-Bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-imidazol-4- Ethyl formate

Following a procedure analogous to that described in Step 3 of Intermediate 111 from (2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl) The title compound was prepared from methanol and 1H-imidazole-4-carboxylic acid ethyl ester.

LC (Method 2): t _R = 0.91 min.

Step 2 : 1-[(2-Cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-imidazole-4 -Ethyl formate

Following a procedure similar to that described in Step 1 of Intermediate 126 from 1-[(2-bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl} Phenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester and zinc(II) cyanide to prepare the title compound. LC (Method 1): _tR = 0.95 min; Mass Spec (ESI ⁺ ): m/z = 373 [M+H] ⁺ .

Step 3 : 1-[(2-Cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-imidazole-4 - Formic acid

Following a procedure similar to that described in Step 4 of Intermediate 111 from 1-[(2-cyano-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl }Phenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester The title compound was prepared.

LC (method 1): t _R = 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 ] hex - 3 - yl } phenyl ) methyl ] -1H - imidazole - 4 - carboxylic acid _ _ _

Step 1 : 1-[(2-Chloro-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-imidazol-4- Ethyl formate

1-[(2-Bromo-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-imidazole- A mixture of ethyl 4-carboxylate (200 mg), copper(I) chloride (92 mg) and NMP for 2.5 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (3 times). Dry ( _{Na2SO4 )} and concentrate the combined extracts. Chromatography (HPLC; ACN/water/ammonia) of the residue gave the title compound.

LC (Method 2): t _R = 0.92 min; Mass Spec (ESI ⁺ ): m/z = 382 [M+H] ⁺ .

Step 2 : 1-[(2-Chloro-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-imidazol-4- Formic acid

Following a procedure analogous to that described in Step 4 of Intermediate 111 from 1-[(2-chloro-4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl} Phenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester to prepare the title compound.

LC (Method 1): t _R = 0.67 min; Mass Spec (ESI ⁻ ): m/z = 352 [MH] ⁻ .

Intermediate 132

1 - [ ( 4- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - fluorophenyl ) methyl ] -1H - imidazole - 4 - carboxylic acid _ _ _

Step 1 : 4-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluorobenzaldehyde

Following procedures analogous to those described in Step 1 of Intermediate 111, the title compound was prepared from 2,4-difluorobenzaldehyde and 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride ; Use K ₂ CO ₃ instead of Schonegg's base and NMP instead of DMF. Mass spectrum (ESI ⁺ ): m/z = 242 [M+H] ⁺ .

Step 2 : (4-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluorophenyl)methanol

The title was prepared from 4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluorobenzaldehyde following a procedure analogous to that described in Step 2 of Intermediate 111 compound.

LC (Method 2): t _R = 0.93 min; Mass Spec (ESI ⁺ ): m/z = 244 [M+H] ⁺ .

Step 3 : 1-[(4-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluorophenyl)methyl]-1H-imidazole-4- Ethyl formate

Following procedures analogous to those described in Step 3 of Intermediate 111 from (4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluorophenyl) The title compound was prepared from methanol and 1H-imidazole-4-carboxylic acid ethyl ester.

Step 4 : 1-[(4-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluorophenyl)methyl]-1H-imidazole-4- Formic acid

Following a procedure analogous to that described in Step 4 of Intermediate 111 from 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluoro Phenyl)methyl]-1H-imidazole-4-carboxylic acid ethyl ester to prepare the title compound.

LC (Method 2): _tR = 0.79 min.

Intermediate 133

1 - [ ( 4- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2 - fluorophenyl ) methyl ] -1H - pyrazole - 4- _ _ _ _ _ Formic acid

Step 1 : 1-[(4-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluorophenyl)methyl]-1H-pyrazole-4 -Ethyl formate

Following procedures analogous to those described in Step 3 of Intermediate 111 from (4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluorophenyl) The title compound was prepared from methanol and 1H-pyrazole-4-carboxylic acid ethyl ester.

LC (Method 2): t _R = 1.10 min; Mass Spec (ESI ⁺ ): m/z = 366 [M+H] ⁺ .

Step 2 : 1-[[4-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluorophenyl)methyl]-1H-pyrazole-4 - Formic acid

Following a procedure analogous to that described in Step 4 of Intermediate 111 from 1-[(4-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluoro Phenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester The title compound was prepared. Synthetic example:

Example 1

1 - [ ( 2 - Chloro - 6- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } pyridin - 3 - yl ) methyl ] -N - [ ( _ _ 4R ) -1 - methyl - 1H , 4H , 5H , 6H - cyclopenta [ d ] imidazol - 4 - yl ] -1H - 1,2,3 - triazole - 4 - carboxamide _ _ _ _

-六氟磷酸(HATU, 57 mg)於DMF (1 mL)中之混合物5分鐘。添加(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-胺二鹽酸鹽(33 mg)且攪拌混合物1小時。藉由藉由反相HPLC (ACN，水)純化混合物。得到標題化合物。Stir 1-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-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'-tetramethyl

- A mixture of hexafluorophosphoric acid (HATU, 57 mg) in DMF (1 mL) for 5 minutes. (4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-amine dihydrochloride (33 mg) was added and the mixture was stirred for 1 hour. The mixture was purified by reverse phase HPLC (ACN, water). The title compound was obtained.

LC (method 1): t _R = 0.91 min; mass spectrum (ESI ⁺ ): m/z = 475 [M+H] ⁺ .

實例 名稱 起始材料 之名稱 2 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]-咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[[6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 3 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}吡啶-2-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}吡啶-2-基)甲基]-1H-咪唑-4-甲酸 4 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(二氟甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環-戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 5 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環-戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 6 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環-戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 7 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}-2-氟吡啶-3-基)-甲基]-1H-咪唑-4-甲酸 8 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}吡啶-2-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}吡啶-2-基)甲基]-1H-1,2,3-三唑-4-甲酸 9 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}吡啶-2-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}吡啶-2-基)甲基]-1H-吡唑-4-甲酸 10 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氟吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環-戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氟吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 11 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氟吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氟吡啶-3-基)甲基]-1H-咪唑-4-甲酸 12 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氟吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氟吡啶-3-基)甲基]-1H-吡唑-4-甲酸 13 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-基)甲基]-1H-吡唑-4-甲酸 14 1-[(2-溴-6-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(2-溴-6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 15 1-[(2-溴-6-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(2-溴-6-{6,6-二氟-3-氮雜-雙環[3.1.0]己-3-基}吡啶-3-基)-甲基]-1H-吡唑-4-甲酸 16 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-溴吡啶-3-基)甲基]-1H-咪唑-4-甲酸 17 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環-戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 18 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}-2-氟吡啶-3-基)-甲基]-1H-吡唑-4-甲酸 19 1-[(5-{5-氮雜螺[2.3]己-5-基}吡啶-2-基)-甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(5-{5-氮雜螺[2.3]己-5-基}吡啶-2-基)甲基]-1H-吡唑-4-甲酸 20 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環-戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 21 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1H-咪唑-4-甲酸 22 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 23 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 24 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}-2-甲基吡啶-3-基)-甲基]-1H-咪唑-4-甲酸 25 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 26 1-[(6-{5-氮雜螺[2.3]己-5-基}吡啶-3-基)-甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 27 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 28 1-[(2-溴-6-{6,6-二氟-3-氮雜雙環-[3.1.0]己-3-基}吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(2-溴-6-{6,6-二氟-3-氮雜-雙環[3.1.0]己-3-基}吡啶-3-基)-甲基]-1H-咪唑-4-甲酸 29 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-(二氟甲基)-嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-(二氟甲基)嘧啶-5-基)甲基]-1H-咪唑-4-甲酸 30 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環-戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 31 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-丙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-丙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 32 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊-[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 33 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環-戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環-[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 34 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊-[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 35 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}-6-氰基吡啶-2-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}-6-氰基吡啶-2-基)甲基]-1H-吡唑-4-甲酸 36 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環-[3.1.0]己-3-基}-2-乙基吡啶-3-基)-甲基]-1H-吡唑-4-甲酸 37 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 38 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(三氟甲氧基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(三氟甲氧基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 39 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲基]-1H-咪唑-4-甲酸 40 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-溴吡啶-3-基)甲基]-1H-吡唑-4-甲酸 41 1-[(5-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}吡啶-2-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(5-{6,6-二氟-3-氮雜環-[3.1.0]己-3-基}吡啶-2-基)甲基]-1H-吡唑-4-甲酸 42 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(1-氰基環丙-基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(1-氰基環丙基)吡啶-3-基)-甲基]-1H-吡唑-4-甲酸 43 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 44 1-[(2-氯-6-{6,6-二氟-3-氮雜環-[3.1.0]己-3-基}吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(2-氯-6-{6,6-二氟-3-氮雜-二環[3.1.0]己-3-基}吡啶-3-基)-甲基]-1H-吡唑-4-甲酸 45 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊-[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 46 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊-[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 47 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(二氟甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 48 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 49 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(甲氧基甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 50 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]-咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 51 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 52 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(二氟甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 53 1-[(5-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}吡啶-2-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(5-{6,6-二氟-3-氮雜環-[3.1.0]己-3-基}吡啶-2-基)甲基]-1H-咪唑-4-甲酸 54 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(3-羥基丙基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(3-羥基丙基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 55 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]-咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 56 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1H-吡唑-4-甲酸 57 1-[(2-氯-6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(2-氯-6-{6,6-二氟-3-氮雜-二環[3.1.0]己-3-基}吡啶-3-基)-甲基]-1H-咪唑-4-甲酸 58 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(三氟甲氧基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(三氟甲氧基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 59 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(1-羥基丙烯 -2-基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(1-羥基丙烯-2-基)吡啶-3-基)-甲基]-1H-吡唑-4-甲酸 60 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}噠𠯤-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}噠𠯤-3-基)甲基]-1H-吡唑-4-甲酸 61 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(羥基甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環-戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 62 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-(羥基甲基)-嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-(羥基甲基)嘧啶-5-基)甲基]-1H-吡唑-4-甲酸 63 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環-[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸 64 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 65 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(1-氰基-1-甲基乙基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]-咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(1-氰基-1-甲基乙基)吡啶-3-基)-甲基]-1H-吡唑-4-甲酸 66 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-丙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H -環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環-[3.1.0]己-3-基}-2-丙基吡啶-3-基)-甲基]-1H-咪唑-4-甲酸 67 1-[(2-環丁基-6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(2-環丁基-6-{6,6-二氟-3-氮雜-二環[3.1.0]己-3-基}吡啶-3-基)-甲基]-1H-吡唑-4-甲酸 68 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲基吡啶-3-基)-甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環-戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 69 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-丙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H -環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-丙基吡啶-3-基)-甲基]-1H-吡唑-4-甲酸 70 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-氰基-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-氰基-1H-吡唑-4-甲酸 71 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}嘧啶-2-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}嘧啶-2-基)甲基]-1H-吡唑-4-甲酸 72 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸 73 1-[(6-{5-氮雜螺[2.3]己-5-基}吡啶-3-基)-甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}吡啶-3-基)甲基]-1H-吡唑-4-甲酸三氟乙酸鹽 74 1-[(6-{5-氮雜螺[2.3]己-5-基}吡啶-3-基)-甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}吡啶-3-基)甲基]-1H-咪唑-4-甲酸三氟乙酸鹽 75 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 76 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環-[3.1.0]己-3-基}-2-乙基吡啶-3-基)-甲基]-1H-咪唑-4-甲酸 77 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(甲氧基甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 78 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(甲氧基甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 79 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(羥基甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 80 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}吡啶-3-基)甲基]-1H-吡唑-4-甲酸三氟乙酸鹽 81 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(氰基甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(氰基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 82 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-[(1R)-1-羥基-乙基]吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-[(1R)-1-羥基乙基]吡啶-3-基)-甲基]-1H-吡唑-4-甲酸 83 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-[(1S)-1-羥基-乙基]吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-[(1S)-1-羥基乙基]吡啶-3-基)-甲基]-1H-吡唑-4-甲酸 84 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(2-羥基丙烯 -2-基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(2-羥基丙烯-2-基)吡啶-3-基)-甲基]-1H-吡唑-4-甲酸 85 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(2-羥基乙基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(2-羥基乙基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 86 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 87 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(羥基甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 88 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(1-羥基乙基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(1-羥基乙基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 89 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}-3-(羥基甲基)-吡𠯤-2-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(5-{3-氮雜雙環[3.1.0]己-3-基}-3-(羥基甲基)吡𠯤-2-基)甲基]-1H-吡唑-4-甲酸 90 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H -環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)-甲基]-1H-吡唑-4-甲酸 91 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環-戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 92 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(甲氧基甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環-戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 93 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊-[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 94 1-[(5-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-3-甲基吡𠯤-2-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(5-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-3-甲基吡𠯤-2-基)甲基]-1H-1,2,3-三唑-4-甲酸 95 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊-[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 96 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊-[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 97 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-甲氧基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-甲氧基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 98 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 99 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-氯吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-氯吡啶-3-基)甲基]-1H-吡唑-4-甲酸 100 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(2-甲基丙基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(2-甲基丙基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 101 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環-戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 102 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-乙氧基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H -環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-乙氧基吡啶-3-基)-甲基]-1H-咪唑-4-甲酸 103 1-[(5-氰基-6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-4-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊-[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(5-氰基-6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-4-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 104 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)-甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-1H-吡唑-4-甲酸 105 1-[(5-氰基-6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-4-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊-[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(5-氰基-6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-4-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 106 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 107 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-(羥基甲基)-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲基]-3-(羥基甲基)-1H-吡唑-4-甲酸 108 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氟吡啶-3-基)甲基]-1H-咪唑-4-甲酸 109 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-乙基-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環-戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-乙基吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 110 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-丙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-丙基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 111 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2,4-二-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H -環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2,4-二甲基吡啶-3-基)-甲基]-1H-咪唑-4-甲酸 112 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2,4-二-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H -環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2,4-二甲基吡啶-3-基)-甲基]-1H-吡唑-4-甲酸 113 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 114 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 115 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-(三氟甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-(三氟甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸, 鋰鹽 116 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基-4-甲基-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基-4-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 117 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-環丙基-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-環丙基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 118 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基-4-甲基-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基-4-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 119 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-3-(三氟甲基)-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-(三氟甲基)-1H-吡唑-4-甲酸 120 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-氯吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-氯吡啶-3-基)甲基]-1H-咪唑-4-甲酸 121 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-(三氟甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-4-(三氟甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 122 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-1H-咪唑-4-甲酸 123 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-(甲氧基甲基)-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊-[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-(甲氧基-甲基)-1H-吡唑-4-甲酸 124 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基-2-甲基-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基-2-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 125 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-(2-羥基丙烯-2-基)-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊-[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-(2-羥基丙烯-2-基)-1H-吡唑-4-甲酸 126 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-3-(甲氧基甲基)-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲基]-3-(甲氧基甲基)-1H-吡唑-4-甲酸 127 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-1H-吡唑-4-甲酸 128 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基-2-甲基-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-5-氰基-2-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 129 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2,5-二甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2,5-二甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 130 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2,5-二甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2,5-二甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 131 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡唑-4-甲酸 132 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氰基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氰基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 133 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 134 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(三氟甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(三氟甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 135 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-1,2,3-三唑-4-甲酸 136 1-[(2-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(2-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-4-甲基嘧啶-5-基)-甲基]-1H-咪唑-4-甲酸 137 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環-戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-1H-1,2,3-三唑-4-甲酸 138 1-[(5-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}吡啶-2-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環-戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(5-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}吡啶-2-基)甲基]-1H-1,2,3-三唑-4-甲酸 139 5-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡咯-3-甲醯胺 5-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡咯-3-甲酸 140 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡咯-3-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡咯-3-甲酸 141 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H -環戊[d]咪唑-4-基]-1H-吡咯-3-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)-甲基]-1H-吡咯-3-甲酸 142 5-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H -環戊[d]咪唑-4-基]-1H-吡咯-3-甲醯胺 5-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲基]-1H-吡咯-3-甲酸 143 1-({2-乙基-6-[(1R,5S,6R)-6-甲基-3-氮雜環[3.1.0]-己-3-基]吡啶-3-基}甲基)-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊-[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-({2-乙基-6-[(1R,5S,6R)-6-甲基-3-氮雜環[3.1.0]己-3-基]吡啶-3-基}甲基)-1H-咪唑-4-甲酸 144 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1,2-㗁唑-5-甲醯胺 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 145 3-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊-[d]咪唑-4-基]-1,2-㗁唑-5-甲醯胺 3-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-(二氟甲基)吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 146 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1,2-㗁唑-5-甲醯胺 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 147 3-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊-[d]咪唑-4-基]-1,2-㗁唑-5-甲醯胺 3-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 148 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1,2-㗁唑-5-甲醯胺 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-氯吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 149 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1,2-㗁唑-5-甲醯胺 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 150 3-[(2-氯-6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊-[d]咪唑-4-基]-1,2-㗁唑-5-甲醯胺 3-[(2-氯-6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 151 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1,2-㗁唑-5-甲醯胺 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 152 3-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H -環戊[d]咪唑-4-基]-1,2-㗁唑-5-甲醯胺 3-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 153 3-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1,2-㗁唑-5-甲醯胺 3-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-乙基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 154 2-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1,3-㗁唑-5-甲醯胺 2-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1,3-㗁唑-5-甲酸 155 2-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H -環戊[d]咪唑-4-基]-1,3-㗁唑-5-甲醯胺 2-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲基]-1,3-㗁唑-5-甲酸 156 3-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1,2-㗁唑-5-甲醯胺 3-[(6-{5-氮雜螺[2.3]己-5-基}-2-乙基吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 157 3-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1,2-㗁唑-5-甲醯胺 3-[(6-{5-氮雜螺[2.3]己-5-基}-2-氯吡啶-3-基)甲基]-1,2-㗁唑-5-甲酸 158 2-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1,3-㗁唑-5-甲醯胺 2-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1,3-㗁唑-5-甲酸 159 5-[(2-氯-6-{6,6-二氟-3-氮雜環-[3.1.0]己-3-基}吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡咯-3-甲醯胺 5-[(2-氯-6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}吡啶-3-基)甲基]-1H-吡咯-3-甲酸 160 3-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1-(丙烯-2-基)-1H-吡唑-5-甲醯胺 3-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-乙基吡啶-3-基)甲基]-1-(丙烯-2-基)-1H-吡唑-5-甲酸 161 3-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1-乙基-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-5-甲醯胺 3-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-乙基吡啶-3-基)甲基]-1-乙基-1H-吡唑-5-甲酸 162 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1-乙基-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-5-甲醯胺 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1-乙基-1H-吡唑-5-甲酸 163 3-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1-乙基-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-5-甲醯胺 3-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)甲基]-1-乙基-1H-吡唑-5-甲酸 164 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1-乙基-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-5-甲醯胺 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1-乙基-1H-吡唑-5-甲酸 165 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-5-甲醯胺 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1H-吡唑-5-甲酸 166 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1-甲基-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-5-甲醯胺 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-1-甲基-1H-吡唑-5-甲酸 167 3-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1-甲基-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊-[d]咪唑-4-基]-1H-吡唑-5-甲醯胺 3-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)-甲基]-1-甲基-1H-吡唑-5-甲酸 168 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1-甲基-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-5-甲醯胺 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-1-甲基-1H-吡唑-5-甲酸 169 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲基吡啶-3-基)甲基]-1H-吡唑-4-甲酸 170 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{5-氮雜螺[2.3]己-5-基}-2-甲基吡啶-3-基)甲基]-1H-咪唑-4-甲酸 171 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-1H-咪唑-4-甲酸 172 1-[(2-{5-氮雜螺[2.3]己-5-基}-4-甲基嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(2-{5-氮雜螺[2.3]己-5-基}-4-甲基嘧啶-5-基)甲基]-1H-咪唑-4-甲酸 173 7-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]-咪唑-4-基]-7H-吡咯并[2,3-d]嘧啶-5-甲醯胺 7-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-7H-吡咯并-[2,3-d]嘧啶-5-甲酸 174 7-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]-咪唑-4-基]-7H-吡咯并[2,3-d]嘧啶-5-甲醯胺 7-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-7H-吡咯并-[2,3-d]嘧啶-5-甲酸 175 7-[(2-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-7H-吡咯并[2,3-d]嘧啶-5-甲醯胺 7-[(2-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-4-甲基嘧啶-5-基)-甲基]-7H-吡咯并[2,3-d]嘧啶-5-甲酸 176 2-氯-1-[(6-{6,6-二氟-3-氮雜環-[3.1.0]己-3-基}吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 2-氯-1-[(6-{6,6-二氟-3-氮雜-二環[3.1.0]己-3-基}吡啶-3-基)-甲基]-1H-咪唑-4-甲酸 177 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(2-{3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-1H-吡唑-4-甲酸 178 1-[(2-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-1,2,3-三唑-4-甲醯胺 1-[(2-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-4-甲基嘧啶-5-基)-甲基]-1H-1,2,3-三唑-4-甲酸 179 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-(乙氧基甲基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-(乙氧基甲基)吡啶-3-基)甲基]-1H-吡唑-4-甲酸 180 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(甲氧基甲基)-吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(甲氧基甲基)吡啶-3-基)甲基]-1H-咪唑-4-甲酸 181 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]呋喃-2-甲醯胺 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]呋喃-2-甲酸 182 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]呋喃-3-甲醯胺 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]呋喃-3-甲酸 183 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]噻吩-2-甲醯胺 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]噻吩-2-甲酸 184 5-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]噻吩-2-甲醯胺 5-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-乙基吡啶-3-基)-甲基]噻吩-2-甲酸 185 5-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊-[d]咪唑-4-基]噻吩-2-甲醯胺 5-[(6-{6,6-二氟-3-氮雜環-[3.1.0]己-3-基}-2-(羥基甲基)-吡啶-3-基)-甲基]噻吩-2-甲酸 186 5-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]呋喃-2-甲醯胺 5-[(6-{6,6-二氟-3-氮雜環-[3.1.0]己-3-基}-2-乙基吡啶-3-基)甲基]呋喃-2-甲酸 187 5-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H -環戊[d]咪唑-4-基]噻吩-2-甲醯胺 5-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)-甲基]噻吩-2-甲酸 188 2-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H -環戊[d]咪唑-4-基]-1,3-噻唑-5-甲醯胺 2-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)-甲基]-1,3-噻唑-5-甲酸 189 5-[(6-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-甲基吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H -環戊[d]咪唑-4-基]呋喃-2-甲醯胺 5-[(6-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-甲基吡啶-3-基)-甲基]呋喃-2-甲酸 190 1-[(4-{3-氮雜雙環[3.1.0]己-3-基}-3-氰基苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(4-{3-氮雜雙環[3.1.0]己-3-基}-3-氰基苯基)甲基]-1H-吡唑-4-甲酸 191 1-[(4-{3-氮雜雙環[3.1.0]己-3-基}-3,5-二氟苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(4-{3-氮雜雙環[3.1.0]己-3-基}-3,5-二氟苯基)甲基]-1H-吡唑-4-甲酸 192 2-[(4-{3-氮雜環[3.1.0]己-3-基}-3,5-二氟苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 2-[(4-{3-氮雜環[3.1.0]己-3-基}-3,5-二氟苯基)甲基]-1H-咪唑-4-甲酸 193 1-[(4-{3-氮雜環[3.1.0]己-3-基}-3-氰基-2-甲基苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(4-{3-氮雜環[3.1.0]己-3-基}-3-氰基-2-甲基苯基)甲基]-1H-吡唑-4-甲酸 194 1-[(4-{3-氮雜環[3.1.0]己-3-基}-3-氰基-2-甲基苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(4-{3-氮雜環[3.1.0]己-3-基}-3-氰基-2-甲基苯基)甲基]-1H-咪唑-4-甲酸 195 1-[(4-{3-氮雜環[3.1.0]己-3-基}-3-氰基-5-氟苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(4-{3-氮雜環[3.1.0]己-3-基}-3-氰基-5-氟苯基)甲基]-1H-吡唑-4-甲酸 196 1-[(4-{3-氮雜環[3.1.0]己-3-基}-3-氰基苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(4-{3-氮雜環[3.1.0]己-3-基}-3-氰基苯基)甲基]-1H-咪唑-4-甲酸 197 1-[(4-{3-氮雜環[3.1.0]己-3-基}-3,5-二氰基苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(4-{3-氮雜環[3.1.0]己-3-基}-3,5-二氰基苯基)甲基]-1H-吡唑-4-甲酸 198 1-[(4-{3-氮雜環[3.1.0]己-3-基}-3-氰基-2-氟苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(4-{3-氮雜環[3.1.0]己-3-基}-3-氰基-2-氟苯基)甲基]-1H-吡唑-4-甲酸 199 1-[(4-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-甲基苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(4-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-甲基苯基)甲基]-1H-吡唑-4-甲酸 200 1-[(4-{3-氮雜環[3.1.0]己-3-基}-5-氰基-2-甲基苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(4-{3-氮雜環[3.1.0]己-3-基}-5-氰基-2-甲基苯基)甲基]-1H-吡唑-4-甲酸 201 1-[(4-{3-氮雜環[3.1.0]己-3-基}-3-氰基-2-氟苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(4-{3-氮雜環[3.1.0]己-3-基}-3-氰基-2-氟苯基)甲基]-1H-咪唑-4-甲酸 202 1-[(4-{3-氮雜環[3.1.0]己-3-基}-2-氯-3-氰基苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(4-{3-氮雜環[3.1.0]己-3-基}-2-氯-3-氰基苯基)甲基]-1H-吡唑-4-甲酸 203 1-[(4-{3-氮雜環[3.1.0]己-3-基}-2-氯-3-氰基苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(4-{3-氮雜環[3.1.0]己-3-基}-2-氯-3-氰基苯基)甲基]-1H-咪唑-4-甲酸 204 1-[(4-{3-氮雜環[3.1.0]己-3-基}-2-溴苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(4-{3-氮雜環[3.1.0]己-3-基}-2-溴苯基)甲基]-1H-咪唑-4-甲酸 205 1-[(4-{3-氮雜環[3.1.0]己-3-基}-2-甲基苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(4-{3-氮雜環[3.1.0]己-3-基}-2-甲基苯基)甲基]-1H-咪唑-4-甲酸 206 1-[(4-{3-氮雜環[3.1.0]己-3-基}-2-氰基苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(4-{3-氮雜環[3.1.0]己-3-基}-2-氰基苯基)甲基]-1H-咪唑-4-甲酸 207 1-[(4-{3-氮雜環[3.1.0]己-3-基}-2-(羥基甲基)-苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(4-{3-氮雜環[3.1.0]己-3-基}-2-(羥基甲基)苯基)甲基]-1H-咪唑-4-甲酸 208 1-[(2-氰基-4-{6,6-二氟-3-氮雜環-[3.1.0]己-3-基}苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(2-氰基-4-{6,6-二氟-3-氮雜-二環[3.1.0]己-3-基}苯基)甲基]-1H-吡唑-4-甲酸 209 1-[(2-溴-4-{6,6-二氟-3-氮雜環-[3.1.0]己-3-基}苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(2-溴-4-{6,6-二氟-3-氮雜-二環[3.1.0]己-3-基}苯基)甲基]-1H-吡唑-4-甲酸 210 1-[(2-氰基-4-{6,6-二氟-3-氮雜環-[3.1.0]己-3-基}苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(2-氰基-4-{6,6-二氟-3-氮雜-二環[3.1.0]己-3-基}苯基)甲基]-1H-咪唑-4-甲酸 211 1-[(2-氯-4-{6,6-二氟-3-氮雜環-[3.1.0]己-3-基}苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(2-氯-4-{6,6-二氟-3-氮雜-二環[3.1.0]己-3-基}苯基)甲基]-1H-咪唑-4-甲酸 212 1-[(4-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-氟苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-咪唑-4-甲醯胺 1-[(4-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-氟苯基)甲基]-1H-咪唑-4-甲酸 213 1-[(4-{6,6-二氟-3-氮雜環[3.1.0]己-3-基}-2-氟苯基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 1-[(4-{6,6-二氟-3-氮雜環[3.1.0]-己-3-基}-2-氟苯基)甲基]-1H-吡唑-4-甲酸 Examples 2 to 213 were prepared analogously to Example 1:

Example name name of starting material 2 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]- N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]-imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[[6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]- 1H-Pyrazole-4-carboxylic acid 3 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H ,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-1H-imidazole-4-carboxylic acid 4 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(difluoromethyl)-pyridin-3-yl)methyl]-N-[(4R)-1- Methyl-1H,4H,5H,6H-cyclo-penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-1,2,3-triazole -4-carboxylic acid 5 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H ,5H,6H-cyclo-penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid 6 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H ,5H,6H-cyclo-penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid 7 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-N-[(4R) -1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(6-{6,6-Difluoro-3-azabicyclo-[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)-methyl]-1H-imidazole- 4-carboxylic acid 8 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H ,6H-Cyclopenta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid 9 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H ,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid 10 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-fluoropyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H ,5H,6H-cyclo-penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-fluoropyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid 11 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-fluoropyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H ,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-fluoropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 12 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-fluoropyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H ,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-fluoropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 13 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H ,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 14 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo-[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-1,2, 3-Triazole-4-carboxylic acid 15 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo-[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(2-Bromo-6-{6,6-difluoro-3-aza-bicyclo[3.1.0]hex-3-yl}pyridin-3-yl)-methyl]-1H-pyrazole -4-carboxylic acid 16 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H ,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-bromopyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 17 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H ,4H,5H,6H-cyclo-penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-1,2,3-triazole-4- Formic acid 18 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-N-[(4R) -1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{6,6-Difluoro-3-azabicyclo-[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)-methyl]-1H-pyrazole -4-carboxylic acid 19 1-[(5-{5-Azaspiro[2.3]hex-5-yl}pyridin-2-yl)-methyl]-N-[(4R)-1-methyl-1H,4H,5H, 6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(5-{5-Azaspiro[2.3]hex-5-yl}pyridin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid 20 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H, 4H,5H,6H-cyclo-penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid twenty one 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H ,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid twenty two 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid twenty three 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid twenty four 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-N-[(4R )-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(6-{6,6-Difluoro-3-azabicyclo-[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)-methyl]-1H-imidazole -4-carboxylic acid 25 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-N-[(4R) -1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-1,2, 3-Triazole-4-carboxylic acid 26 1-[(6-{5-Azaspiro[2.3]hex-5-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 1-[(6-{5-Azaspiro[2.3]hex-5-yl}pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid 27 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-1,2 ,3-triazole-4-carboxylic acid 28 1-[(2-Bromo-6-{6,6-difluoro-3-azabicyclo-[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[(4R )-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(2-Bromo-6-{6,6-difluoro-3-aza-bicyclo[3.1.0]hex-3-yl}pyridin-3-yl)-methyl]-1H-imidazole- 4-carboxylic acid 29 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-(difluoromethyl)-pyrimidin-5-yl)methyl]-N-[(4R)- 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-(difluoromethyl)pyrimidin-5-yl)methyl]-1H-imidazole-4-carboxylic acid 30 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)-pyridin-3-yl)methyl]-N-[(4R)- 1-Methyl-1H,4H,5H,6H-cyclo-penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-1,2,3- Triazole-4-carboxylic acid 31 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 32 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H ,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-1,2,3-triazole-4- Formic acid 33 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl yl-1H,4H,5H,6H-cyclo-penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{6,6-Difluoro-3-azacyclo-[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-1,2,3-tri oxazole-4-carboxylic acid 34 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H ,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methyl]-1H-1,2,3-triazole-4- Formic acid 35 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}-6-cyanopyridin-2-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}-6-cyanopyridin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid 36 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{6,6-Difluoro-3-azacyclo-[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)-methyl]-1H-pyridine oxazole-4-carboxylic acid 37 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H, 4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 38 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(trifluoromethoxy)-pyridin-3-yl)methyl]-N-[(4R) -1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(trifluoromethoxy)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 39 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H ,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 40 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H ,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-bromopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 41 1-[(5-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-N-[(4R)-1-methyl yl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(5-{6,6-Difluoro-3-azacyclo-[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid 42 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(1-cyanocyclopropyl-yl)-pyridin-3-yl)methyl]-N-[ (4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(1-cyanocyclopropyl)pyridin-3-yl)-methyl]-1H-pyrazole -4-carboxylic acid 43 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)-pyridin-3-yl)methyl]-N-[(4R)- 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 44 1-[(2-Chloro-6-{6,6-difluoro-3-azacyclo-[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(2-Chloro-6-{6,6-difluoro-3-aza-bicyclo[3.1.0]hex-3-yl}pyridin-3-yl)-methyl]-1H-pyridine oxazole-4-carboxylic acid 45 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-N -[(4R)-1-Methyl-1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H -Imidazole-4-carboxylic acid 46 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-N -[(4R)-1-Methyl-1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H - Pyrazole-4-carboxylic acid 47 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(difluoromethyl)-pyridin-3-yl)methyl]-N-[(4R)-1- Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 48 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)-pyridin-3-yl)methyl]-N-[(4R)- 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 49 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)-pyridin-3-yl)methyl]-N-[(4R) -1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4- Formic acid 50 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-N- [(4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]-imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{6,6-Difluoro-3-azaheterocycle[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H- 1,2,3-Triazole-4-carboxylic acid 51 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H, 4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 52 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(difluoromethyl)-pyridin-3-yl)methyl]-N-[(4R)-1- Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 53 1-[(5-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-N-[(4R)-1-methyl yl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(5-{6,6-Difluoro-3-azacyclo-[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-1H-imidazole-4-carboxylic acid 54 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(3-hydroxypropyl)-pyridin-3-yl)methyl]-N-[(4R) -1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(3-hydroxypropyl)pyridin-3-yl)methyl]-1H-pyrazole-4- Formic acid 55 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]- N-[(4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]-imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]- 1H-1,2,3-triazole-4-carboxylic acid 56 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H ,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 57 1-[(2-Chloro-6-{6,6-difluoro-3-azacyclo[3.1.0]-hex-3-yl}pyridin-3-yl)methyl]-N-[(4R )-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(2-Chloro-6-{6,6-difluoro-3-aza-bicyclo[3.1.0]hex-3-yl}pyridin-3-yl)-methyl]-1H-imidazole -4-carboxylic acid 58 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(trifluoromethoxy)-pyridin-3-yl)methyl]-N-[(4R) -1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(trifluoromethoxy)pyridin-3-yl)methyl]-1H-pyrazole-4- Formic acid 59 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(1-hydroxypropen-2-yl)pyridin-3-yl)methyl]-N-[( 4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(1-hydroxypropen-2-yl)pyridin-3-yl)-methyl]-1H-pyridine oxazole-4-carboxylic acid 60 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H, 5H,6H-Cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 61 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(hydroxymethyl)-pyridin-3-yl)methyl]-N-[(4R)-1-methyl yl-1H,4H,5H,6H-cyclo-penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-triazole- 4-carboxylic acid 62 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-(hydroxymethyl)-pyrimidin-5-yl)methyl]-N-[(4R)-1 -Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-(hydroxymethyl)pyrimidin-5-yl)methyl]-1H-pyrazole-4-carboxylic acid 63 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl yl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{6,6-Difluoro-3-azacyclo-[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 64 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)-pyridin-3-yl)methyl]-N-[(4R)- 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 65 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(1-cyano-1-methylethyl)pyridin-3-yl)methyl]-N -[(4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]-imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(1-cyano-1-methylethyl)pyridin-3-yl)-methyl]- 1H-Pyrazole-4-carboxylic acid 66 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(6-{6,6-Difluoro-3-azacyclo-[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)-methyl]-1H-imidazole -4-carboxylic acid 67 1-[(2-Cyclobutyl-6-{6,6-difluoro-3-azacyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[( 4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(2-Cyclobutyl-6-{6,6-difluoro-3-aza-bicyclo[3.1.0]hex-3-yl}pyridin-3-yl)-methyl]-1H - Pyrazole-4-carboxylic acid 68 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-methylpyridin-3-yl)-methyl]-N-[(4R)-1-methyl-1H ,4H,5H,6H-cyclo-penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-methylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid 69 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-propylpyridin-3-yl)-methyl]-1H-pyridine oxazole-4-carboxylic acid 70 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-cyano-N-[(4R)- 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-cyano-1H-pyrazole-4- Formic acid 71 1-[(5-{3-azabicyclo[3.1.0]hex-3-yl}pyrimidin-2-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H ,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(5-{3-azabicyclo[3.1.0]hex-3-yl}pyrimidin-2-yl)methyl]-1H-pyrazole-4-carboxylic acid 72 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H ,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 73 1-[(6-{5-Azaspiro[2.3]hex-5-yl}pyridin-3-yl)-methyl]-N-[(4R)-1-methyl-1H,4H,5H, 6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid trifluoroacetate 74 1-[(6-{5-Azaspiro[2.3]hex-5-yl}pyridin-3-yl)-methyl]-N-[(4R)-1-methyl-1H,4H,5H, 6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid trifluoroacetate 75 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 76 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-N-[(4R )-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(6-{6,6-Difluoro-3-azacyclo-[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)-methyl]-1H-imidazole -4-carboxylic acid 77 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(methoxymethyl)-pyridin-3-yl)methyl]-N-[(4R)-1 -Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 78 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(methoxymethyl)-pyridin-3-yl)methyl]-N-[(4R)-1 -Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 79 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(hydroxymethyl)-pyridin-3-yl)methyl]-N-[(4R)-1-methyl yl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 80 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl yl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid tris Fluoroacetate 81 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(cyanomethyl)-pyridin-3-yl)methyl]-N-[(4R)- 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(cyanomethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 82 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-[(1R)-1-hydroxy-ethyl]pyridin-3-yl)methyl]-N- [(4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-[(1R)-1-hydroxyethyl]pyridin-3-yl)-methyl]-1H- Pyrazole-4-carboxylic acid 83 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-[(1S)-1-hydroxy-ethyl]pyridin-3-yl)methyl]-N- [(4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-[(1S)-1-hydroxyethyl]pyridin-3-yl)-methyl]-1H- Pyrazole-4-carboxylic acid 84 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(2-hydroxypropen-2-yl)pyridin-3-yl)methyl]-N-[( 4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(2-hydroxypropen-2-yl)pyridin-3-yl)-methyl]-1H-pyridine oxazole-4-carboxylic acid 85 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(2-hydroxyethyl)-pyridin-3-yl)methyl]-N-[(4R) -1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(2-hydroxyethyl)pyridin-3-yl)methyl]-1H-pyrazole-4- Formic acid 86 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)-pyridin-3-yl)methyl]-N-[(4R)-1 -Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 87 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(hydroxymethyl)-pyridin-3-yl)methyl]-N-[(4R)-1-methyl yl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 88 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(1-hydroxyethyl)-pyridin-3-yl)methyl]-N-[(4R) -1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(1-hydroxyethyl)pyridin-3-yl)methyl]-1H-pyrazole-4- Formic acid 89 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}-3-(hydroxymethyl)-pyridin-2-yl)methyl]-N-[(4R)- 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(5-{3-Azabicyclo[3.1.0]hex-3-yl}-3-(hydroxymethyl)pyridine-2-yl)methyl]-1H-pyrazole-4-carboxylic acid 90 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)-methyl]-1H-pyridine oxazole-4-carboxylic acid 91 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)-pyridin-3-yl)methyl]-N-[(4R)-1 -Methyl-1H,4H,5H,6H-cyclo-penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-1,2,3-tri oxazole-4-carboxylic acid 92 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)-pyridin-3-yl)methyl]-N-[(4R) -1-Methyl-1H,4H,5H,6H-cyclo-penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1H-1,2,3 -Triazole-4-carboxylic acid 93 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-N- [(4R)-1-Methyl-1H,4H,5H,6H-cyclopent-[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{6,6-Difluoro-3-azaheterocycle[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H- Pyrazole-4-carboxylic acid 94 1-[(5-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-3-methylpyridine-2-yl)methyl]-N-[( 4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(5-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-3-methylpyridin-2-yl)methyl]-1H-1, 2,3-Triazole-4-carboxylic acid 95 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]- N-[(4R)-1-Methyl-1H,4H,5H,6H-cyclopent-[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]- 1H-imidazole-4-carboxylic acid 96 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-N- [(4R)-1-Methyl-1H,4H,5H,6H-cyclopent-[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{6,6-Difluoro-3-azaheterocycle[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H- imidazole-4-carboxylic acid 97 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-methoxypyridin-3-yl)methyl]-N-[( 4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-methoxypyridin-3-yl)methyl]-1H-imidazole- 4-carboxylic acid 98 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)-pyridin-3-yl)methyl]-N-[(4R)-1 -Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 99 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-chloropyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H ,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 100 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(2-methylpropyl)-pyridin-3-yl)methyl]-N-[(4R )-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(2-methylpropyl)pyridin-3-yl)methyl]-1H-imidazol-4- Formic acid 101 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclo-penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4 - Formic acid 102 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-ethoxypyridin-3-yl)methyl]-N-[( 4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-ethoxypyridin-3-yl)-methyl]-1H- imidazole-4-carboxylic acid 103 1-[(5-Cyano-6-{6,6-difluoro-3-azacyclo[3.1.0]-hex-3-yl}-4-methylpyridin-3-yl)methyl] -N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(5-Cyano-6-{6,6-difluoro-3-azacyclo[3.1.0]hex-3-yl}-4-methylpyridin-3-yl)methyl]- 1H-Pyrazole-4-carboxylic acid 104 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)-methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 105 1-[(5-Cyano-6-{6,6-difluoro-3-azacyclo[3.1.0]-hex-3-yl}-4-methylpyridin-3-yl)methyl] -N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(5-Cyano-6-{6,6-difluoro-3-azacyclo[3.1.0]hex-3-yl}-4-methylpyridin-3-yl)methyl]- 1H-imidazole-4-carboxylic acid 106 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 107 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(hydroxymethyl base)-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{6,6-Difluoro-3-azaheterocycle[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(hydroxy Methyl)-1H-pyrazole-4-carboxylic acid 108 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H ,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-fluoropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 109 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-ethyl-pyridin-3-yl)methyl]-N-[( 4R)-1-Methyl-1H,4H,5H,6H-cyclo-penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-1, 2,3-Triazole-4-carboxylic acid 110 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-propylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 111 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2,4-di-methylpyridin-3-yl)methyl]-N -[(4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{6,6-Difluoro-3-azaheterocycle[3.1.0]-hex-3-yl}-2,4-lutidine-3-yl)-methyl]- 1H-imidazole-4-carboxylic acid 112 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2,4-di-methylpyridin-3-yl)methyl]-N -[(4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{6,6-Difluoro-3-azaheterocycle[3.1.0]-hex-3-yl}-2,4-lutidine-3-yl)-methyl]- 1H-Pyrazole-4-carboxylic acid 113 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 114 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyanopyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyanopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 115 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-(trifluoromethyl)-pyridin-3-yl)methyl]-N-[(4R)- 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-(trifluoromethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid , Lithium salt 116 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyano-4-methyl-pyridin-3-yl)methyl]-N-[(4R) -1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyano-4-methylpyridin-3-yl)methyl]-1H-pyrazole-4- Formic acid 117 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-cyclopropyl-pyridin-3-yl)methyl]-N-[(4R)-1-methyl yl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-cyclopropylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 118 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyano-4-methyl-pyridin-3-yl)methyl]-N-[(4R) -1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyano-4-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 119 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-3-(trifluoromethyl)-1H-pyrazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(trifluoromethyl)-1H-pyridine oxazole-4-carboxylic acid 120 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-chloropyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H ,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 121 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-(trifluoromethyl)-pyridin-3-yl)methyl]-N-[(4R)- 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-4-(trifluoromethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 122 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H ,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 123 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(methoxymethyl)-N- [(4R)-1-Methyl-1H,4H,5H,6H-cyclopent-[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(methoxy-methyl)-1H - Pyrazole-4-carboxylic acid 124 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyano-2-methyl-pyridin-3-yl)methyl]-N-[(4R) -1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyano-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 125 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(2-hydroxypropen-2-yl) -N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(2-hydroxypropen-2-yl) -1H-Pyrazole-4-carboxylic acid 126 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(methoxy ylmethyl)-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methyl]-3-(methyl oxymethyl)-1H-pyrazole-4-carboxylic acid 127 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H ,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 128 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyano-2-methyl-pyridin-3-yl)methyl]-N-[(4R) -1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-5-cyano-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4- Formic acid 129 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2,5-lutidine-3-yl)methyl]-N-[(4R)-1- Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2,5-lutidine-3-yl)methyl]-1H-imidazole-4-carboxylic acid 130 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2,5-lutidine-3-yl)methyl]-N-[(4R)-1- Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2,5-lutidine-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 131 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H ,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 132 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-cyanopyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-cyanopyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 133 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 134 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(trifluoromethyl)-pyridin-3-yl)methyl]-N-[(4R)- 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(trifluoromethyl)pyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 135 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H ,6H-Cyclopenta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxylic acid 136 1-[(2-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-N-[(4R )-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(2-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-4-methylpyrimidin-5-yl)-methyl]-1H-imidazole -4-carboxylic acid 137 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclo-penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-1H-1,2,3-triazole-4 - Formic acid 138 1-[(5-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}pyridin-2-yl)methyl]-N-[(4R)-1-methyl yl-1H,4H,5H,6H-cyclo-penta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(5-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}pyridin-2-yl)methyl]-1H-1,2,3-tri oxazole-4-carboxylic acid 139 5-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl yl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrrole-3-carboxamide 5-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3-carboxylic acid 140 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl yl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrrole-3-carboxamide 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3-carboxylic acid 141 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrrole-3-carboxamide 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)-methyl]-1H-pyrrole -3-carboxylic acid 142 5-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrrole-3-carboxamide 5-[(6-{6,6-Difluoro-3-azaheterocycle[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrrole- 3-carboxylic acid 143 1-({2-Ethyl-6-[(1R,5S,6R)-6-methyl-3-azacyclo[3.1.0]-hex-3-yl]pyridin-3-yl}methyl )-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-({2-Ethyl-6-[(1R,5S,6R)-6-methyl-3-azacyclo[3.1.0]hex-3-yl]pyridin-3-yl}methyl) -1H-imidazole-4-carboxylic acid 144 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)-pyridin-3-yl)methyl]-N-[(4R)- 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1,2-oxazole-5-carboxamide 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1,2-oxazole-5 - Formic acid 145 3-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-N -[(4R)-1-Methyl-1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1,2-oxazole-5-carboxamide 3-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-(difluoromethyl)pyridin-3-yl)methyl]-1 ,2-oxazole-5-carboxylic acid 146 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-Cyclopenta[d]imidazol-4-yl]-1,2-oxazole-5-carboxamide 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid 147 3-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-N- [(4R)-1-Methyl-1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1,2-oxazole-5-carboxamide 3-[(6-{6,6-Difluoro-3-azaheterocycle[3.1.0]-hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1 ,2-oxazole-5-carboxylic acid 148 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H ,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1,2-oxazole-5-carboxamide 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-chloropyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid 149 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)-pyridin-3-yl)methyl]-N-[(4R)-1 -Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1,2-oxazole-5-carboxamide 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-1,2-oxazole-5- Formic acid 150 3-[(2-Chloro-6-{6,6-difluoro-3-azacyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[(4R) -1-Methyl-1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1,2-oxazole-5-carboxamide 3-[(2-Chloro-6-{6,6-difluoro-3-azacyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1,2-oxazole -5-carboxylic acid 151 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H ,6H-Cyclopenta[d]imidazol-4-yl]-1,2-oxazole-5-carboxamide 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid 152 3-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1,2-oxazole-5-carboxamide 3-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methyl]-1,2- Oxazole-5-carboxylic acid 153 3-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1,2-oxazole-5-carboxamide 3-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1,2- Oxazole-5-carboxylic acid 154 2-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1,3-oxazole-5-carboxamide 2-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1,3-oxazole-5-carboxylic acid 155 2-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1,3-oxazole-5-carboxamide 2-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methyl]-1,3- Oxazole-5-carboxylic acid 156 3-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H, 4H,5H,6H-Cyclopenta[d]imidazol-4-yl]-1,2-oxazole-5-carboxamide 3-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-ethylpyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid 157 3-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H,4H ,5H,6H-cyclopenta[d]imidazol-4-yl]-1,2-oxazol-5-carboxamide 3-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-chloropyridin-3-yl)methyl]-1,2-oxazole-5-carboxylic acid 158 2-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1,3-oxazole-5-carboxamide 2-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1,3-oxazole-5-carboxylic acid 159 5-[(2-Chloro-6-{6,6-difluoro-3-azacyclo-[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrrole-3-carboxamide 5-[(2-Chloro-6-{6,6-difluoro-3-azacyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-1H-pyrrole-3- Formic acid 160 3-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1-(propen-2-yl)-1H-pyrazole-5-carboxamide 3-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1-(propene -2-yl)-1H-pyrazole-5-carboxylic acid 161 3-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1-ethyl- N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-5-carboxamide 3-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1-ethyl -1H-Pyrazole-5-carboxylic acid 162 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1-ethyl-N-[(4R)- 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-5-carboxamide 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1-ethyl-1H-pyrazole-5- Formic acid 163 3-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1-ethyl- N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-5-carboxamide 3-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)methyl]-1-ethyl -1H-Pyrazole-5-carboxylic acid 164 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1-ethyl-N-[(4R)- 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-5-carboxamide 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1-ethyl-1H-pyrazole-5- Formic acid 165 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-5-carboxamide 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1H-pyrazole-5-carboxylic acid 166 3-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1-methyl-N-[(4R)- 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-5-carboxamide 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-1-methyl-1H-pyrazole-5- Formic acid 167 3-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1-methyl- N-[(4R)-1-Methyl-1H,4H,5H,6H-cyclopenta-[d]imidazol-4-yl]-1H-pyrazol-5-carboxamide 3-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)-methyl]-1-methyl yl-1H-pyrazole-5-carboxylic acid 168 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1-methyl-N-[(4R)- 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-5-carboxamide 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-1-methyl-1H-pyrazole-5- Formic acid 169 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H, 4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-methylpyridin-3-yl)methyl]-1H-pyrazole-4-carboxylic acid 170 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl-1H, 4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(6-{5-Azaspiro[2.3]hex-5-yl}-2-methylpyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 171 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-1H-imidazole-4-carboxylic acid 172 1-[(2-{5-Azaspiro[2.3]hex-5-yl}-4-methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H, 4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(2-{5-Azaspiro[2.3]hex-5-yl}-4-methylpyrimidin-5-yl)methyl]-1H-imidazole-4-carboxylic acid 173 7-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]-imidazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 7-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-7H-pyrrolo-[2,3-d] Pyrimidine-5-carboxylic acid 174 7-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]-imidazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 7-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-7H-pyrrolo-[2,3-d] Pyrimidine-5-carboxylic acid 175 7-[(2-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 7-[(2-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-4-methylpyrimidin-5-yl)-methyl]-7H-pyrrole Do[2,3-d]pyrimidine-5-carboxylic acid 176 2-Chloro-1-[(6-{6,6-difluoro-3-azacyclo-[3.1.0]hex-3-yl}pyridin-3-yl)methyl]-N-[(4R )-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 2-Chloro-1-[(6-{6,6-Difluoro-3-aza-bicyclo[3.1.0]hex-3-yl}pyridin-3-yl)-methyl]-1H-imidazole -4-carboxylic acid 177 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(2-{3-Azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-1H-pyrazole-4-carboxylic acid 178 1-[(2-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-1,2,3-triazole-4-carboxamide 1-[(2-{6,6-Difluoro-3-azaheterocycle[3.1.0]-hex-3-yl}-4-methylpyrimidin-5-yl)-methyl]-1H-1 ,2,3-Triazole-4-carboxylic acid 179 1-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-(ethoxymethyl)pyridin-3-yl)methyl]- N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(6-{6,6-Difluoro-3-azaheterocycle[3.1.0]-hex-3-yl}-2-(ethoxymethyl)pyridin-3-yl)methyl] -1H-Pyrazole-4-carboxylic acid 180 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)-pyridin-3-yl)methyl]-N-[(4R) -1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-1H-imidazole-4-carboxylic acid 181 5-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]furan-2-carboxamide 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]furan-2-carboxylic acid 182 5-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]furan-3-carboxamide 5-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]furan-3-carboxylic acid 183 5-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]thiophene-2-carboxamide 5-[(6-{3-Azabicyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]thiophene-2-carboxylic acid 184 5-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]thiophene-2-carboxamide 5-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-ethylpyridin-3-yl)-methyl]thiophene-2- Formic acid 185 5-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-N- [(4R)-1-Methyl-1H,4H,5H,6H-cyclopent-[d]imidazol-4-yl]thiophene-2-carboxamide 5-[(6-{6,6-Difluoro-3-azacyclo-[3.1.0]hex-3-yl}-2-(hydroxymethyl)-pyridin-3-yl)-methyl] Thiophene-2-carboxylic acid 186 5-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]furan-2-carboxamide 5-[(6-{6,6-Difluoro-3-azacyclo-[3.1.0]hex-3-yl}-2-ethylpyridin-3-yl)methyl]furan-2-carboxylic acid 187 5-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]thiophene-2-carboxamide 5-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)-methyl]thiophene-2- Formic acid 188 2-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1,3-thiazole-5-carboxamide 2-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)-methyl]-1,3 - Thiazole-5-carboxylic acid 189 5-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-methylpyridin-3-yl)methyl]-N-[(4R )-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]furan-2-carboxamide 5-[(6-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-methylpyridin-3-yl)-methyl]furan-2- Formic acid 190 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-3-cyanophenyl)methyl]-N-[(4R)-1-methyl-1H,4H ,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-3-cyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid 191 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-3,5-difluorophenyl)methyl]-N-[(4R)-1-methyl-1H ,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(4-{3-Azabicyclo[3.1.0]hex-3-yl}-3,5-difluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid 192 2-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-3,5-difluorophenyl)methyl]-N-[(4R)-1-methyl-1H ,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 2-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-3,5-difluorophenyl)methyl]-1H-imidazole-4-carboxylic acid 193 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-3-cyano-2-methylphenyl)methyl]-N-[(4R)-1-methyl yl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid 194 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-3-cyano-2-methylphenyl)methyl]-N-[(4R)-1-methyl yl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-3-cyano-2-methylphenyl)methyl]-1H-imidazole-4-carboxylic acid 195 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-3-cyano-5-fluorophenyl)methyl]-N-[(4R)-1-methyl -1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-3-cyano-5-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid 196 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-3-cyanophenyl)methyl]-N-[(4R)-1-methyl-1H,4H ,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid 197 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-3,5-dicyanophenyl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-3,5-dicyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid 198 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-3-cyano-2-fluorophenyl)methyl]-N-[(4R)-1-methyl -1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid 199 1-[(4-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-methylphenyl)methyl]-N-[(4R)-1 -Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(4-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-methylphenyl)methyl]-1H-pyrazole-4- Formic acid 200 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-5-cyano-2-methylphenyl)methyl]-N-[(4R)-1-methyl yl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-5-cyano-2-methylphenyl)methyl]-1H-pyrazole-4-carboxylic acid 201 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-3-cyano-2-fluorophenyl)methyl]-N-[(4R)-1-methyl -1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-3-cyano-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylic acid 202 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-2-chloro-3-cyanophenyl)methyl]-N-[(4R)-1-methyl -1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-2-chloro-3-cyanophenyl)methyl]-1H-pyrazole-4-carboxylic acid 203 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-2-chloro-3-cyanophenyl)methyl]-N-[(4R)-1-methyl -1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-2-chloro-3-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid 204 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-2-bromophenyl)methyl]-N-[(4R)-1-methyl-1H,4H, 5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-2-bromophenyl)methyl]-1H-imidazole-4-carboxylic acid 205 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-2-methylphenyl)methyl]-N-[(4R)-1-methyl-1H,4H ,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-2-methylphenyl)methyl]-1H-imidazole-4-carboxylic acid 206 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-2-cyanophenyl)methyl]-N-[(4R)-1-methyl-1H,4H ,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-2-cyanophenyl)methyl]-1H-imidazole-4-carboxylic acid 207 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)-phenyl)methyl]-N-[(4R)-1-methyl -1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(4-{3-Azacyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)phenyl)methyl]-1H-imidazole-4-carboxylic acid 208 1-[(2-Cyano-4-{6,6-difluoro-3-azacyclo-[3.1.0]hex-3-yl}phenyl)methyl]-N-[(4R)- 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(2-Cyano-4-{6,6-difluoro-3-aza-bicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-pyrazole-4 - Formic acid 209 1-[(2-Bromo-4-{6,6-difluoro-3-azacyclo-[3.1.0]hex-3-yl}phenyl)methyl]-N-[(4R)-1 -Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(2-Bromo-4-{6,6-difluoro-3-aza-bicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-pyrazole-4- Formic acid 210 1-[(2-Cyano-4-{6,6-difluoro-3-azacyclo-[3.1.0]hex-3-yl}phenyl)methyl]-N-[(4R)- 1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazole-4-carboxamide 1-[(2-Cyano-4-{6,6-difluoro-3-aza-bicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-imidazole-4- Formic acid 211 1-[(2-Chloro-4-{6,6-difluoro-3-azacyclo-[3.1.0]hex-3-yl}phenyl)methyl]-N-[(4R)-1 -Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(2-Chloro-4-{6,6-difluoro-3-aza-bicyclo[3.1.0]hex-3-yl}phenyl)methyl]-1H-imidazole-4-carboxylic acid 212 1-[(4-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-fluorophenyl)methyl]-N-[(4R)-1- Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide 1-[(4-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-fluorophenyl)methyl]-1H-imidazole-4-carboxylic acid 213 1-[(4-{6,6-Difluoro-3-azacyclo[3.1.0]hex-3-yl}-2-fluorophenyl)methyl]-N-[(4R)-1- Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 1-[(4-{6,6-Difluoro-3-azacyclo[3.1.0]-hex-3-yl}-2-fluorophenyl)methyl]-1H-pyrazole-4-carboxylic acid

Example 214

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

To 1-[(2-{3-azabicyclo[3.1.0]hex-3-yl}-4-carboxypyrimidin-5-yl)methyl]-N-[(4R)-1-methyl To a mixture of yl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-imidazol-4-carboxamide (24 mg) in THF ( ₂ mL) was added NaBH4. The mixture was stirred at room temperature for 12 hours and then treated with aqueous HCl (1 M, 500 μL). After stirring for 10 minutes, aqueous NaOH (1 M, 500 µL) was added. The mixture was diluted with MeOH and purified by reverse phase (ACN, water) HPLC to give the title compound. LC (Method 1): _tR = 0.78 min; Mass Spec (ESI ⁺ ): m/z = 435 [M+H] ⁺ .

Example 215

1 - [ ( 6- { 6,6 - difluoro - 3 - azabicyclo [ 3.1.0 ] hex - 3 - yl } -2- ( 1 - hydroxyethyl ) pyridin - 3 - yl ) methyl _ _ _ _ ] -N - [ ( 4R ) -1 - methyl - 1H , 4H , 5H , 6H - cyclopenta [ d ] imidazol - 4 - yl ] -1H - 1,2,3 - triazole - 4 - carboxamide _ _

CH ₃ MgBr (3 M in THF, 92 µL) was added dropwise under argon atmosphere to 1-[(6-{6,6-difluoro-3-azabicyclo[3.1.0]hexan- 3-yl}-2-carbylpyridin-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 an ice-cold mixture of THF (5 mL). The mixture was stirred for 12 hours while warming to room temperature. The mixture was then partitioned between saturated aqueous _NH4Cl and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were dried ( _{Na2SO4 )} , concentrated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

LC (Method 1): t _R = 0.88 min; Mass Spec (ESI ⁺ ): m/z = 485 [M+H] ⁺ .

Example 216

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

LiAlH4 ( ₁ M in THF, 200 µL) was added dropwise to 2-{1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2 under argon atmosphere -Methylpyridin-3-yl)methyl]-4-{[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]aminocarboxyl} Methyl -1H-pyrazol-3-yl}acetate (90 mg) in a cold mixture of -78°C in THF (1 mL). The mixture was stirred for 12 hours while warming to room temperature. Water (14 µL), aqueous NaOH (4 M, 14 µL) and additional water (14 µL) were added successively to the mixture. After vigorous stirring for 15 minutes, the mixture was filtered through celite, and the filter cake was washed with THF. The combined filtrates were concentrated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t _R = 0.66 min; Mass Spec (ESI ⁺ ): m/z = 462 [M+H] ⁺ .

example 217

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

LiAlH4 ( ₁ M in THF, 200 µL) was added dropwise to 1-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-methyl under argon atmosphere Pyridin-3-yl)methyl]-4-{[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]aminocarboxy}-1H- Methyl pyrazole-3-carboxylate (25 mg) in an ice-cold mixture of THF (2 mL). The mixture was stirred for 30 minutes. Water (50 µL) and aqueous NaOH (4 M, 25 µL) were added successively to the mixture. After vigorous stirring for 15 minutes, the mixture was filtered through celite, and the filter cake was washed with THF. The combined filtrates were concentrated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 1): _tR = 0.89 min; Mass Spec (ESI ⁺ ): m/z = 448 [M+H] ⁺ .

Example 218

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

Stir 1-[(2-Chloro-4-methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[ d] Imidazol-4-yl]-1H-pyrazol-4-carboxamide (33 mg), 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride (27 mg) and a mixture of DIPEA (75 µL) in DMSO (1 mL) for 8 hours. After cooling to room temperature, the mixture was diluted with DMSO and purified by reverse phase HPLC (ACN, water) to give the title compound.

LC (Method 1): _tR = 0.86 min; Mass Spec (ESI ⁺ ): m/z = 454 [M+H] ⁺ .

Example 219

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

3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl]-N-[(4R) -1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyridine oxazol-5-carboxamide and 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(methoxymethyl)pyridin-3-yl)methyl] -N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1-{[2-(trimethylsilyl)ethoxy] Methyl}-1H-pyrazol-3-carboxamide (mixture of isomers) (20 mg) was dissolved in DCM (3 mL). Trifluoroacetic acid (1 mL) was added and the mixture was stirred at room temperature for 12 hours. The mixture was then concentrated in vacuo, dissolved in MeOH (1 mL) and treated with _NH3 (7 M in MeOH, 3 mL). The mixture was heated to 80°C for 12 hours in a sealed microwave vial. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC (ACN, water) to give the title compound.

LC (Method 1): _tR = 0.91 min; Mass Spec (ESI ⁺ ): m/z = 448 [M+H] ⁺ .

0.87 434 方法1 實例 名稱 起始材料之名稱 220 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-5-甲醯胺 3-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-5-甲醯胺 及 5-[(6-{3-氮雜雙環[3.1.0]己-3-基}-2-(羥基甲基)吡啶-3-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-3-甲醯胺 (異構體之混合物) Example 220 was prepared analogously to Intermediate 219: Example structure _tR Mass Spec (ESI+): m/z [M+H] ⁺ LC method 220

0.87 434 method 1 example name name of starting material 220 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1- Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-5-carboxamide 3-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-N-[(4R)-1- Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5 -Carboxamide and 5-[(6-{3-azabicyclo[3.1.0]hex-3-yl}-2-(hydroxymethyl)pyridin-3-yl)methyl]-N-[( 4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H - Pyrazole-3-carboxamide (mixture of isomers)

Example 221

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

1-[(2-Chloro-6-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}pyridin-3-yl)methyl]- N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide (50 mg) and NaOCH ₃ ( A mixture of 1 M in MeOH, 2 mL) was heated to 165 °C for 6 h. After cooling to room temperature, the mixture was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 2): t _R = 0.86 min; Mass Spec (ESI ⁺ ): m/z = 470 [M+H] ⁺ .

Example 222

1 - [( 2- { 5 - azaspiro [ 2.3 ] hex - 5 - yl } -4 - methylpyrimidin - 5 - yl ) methyl ] -N - [ ( 4R ) -1 - methyl- 1H , 4H , 5H , 6H - cyclopenta [ d ] imidazol - 4 - yl ] -1H - pyrazole - 4 - carboxamide

Stir 1-[(2-Chloro-4-methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[ d]Imidazol-4-yl]-1H-pyrazol-4-carboxamide (40 mg), DIPEA (100 µL) and 5-azaspiro[2.3]hexane; trifluoroacetate (32 mg) in The mixture was mixed in DMSO (2 mL) for 16 hours. The mixture was purified by reverse phase HPLC (ACN, water) to give the title compound. LC (Method 5): t _R = 0.56 min; Mass Spec (ESI ⁺ ): m/z = 419 [M+H] ⁺ .

實例 名稱 起始材料 之名稱 223 1-[(2-{2-羥基-2-甲基-7-氮雜螺[3.5]壬烷-7-基}-4-甲基嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 2-甲基-7-氮雜螺[3.5]壬-2-醇鹽酸鹽 224 1-({2-[(1R,5S,6S)-6-氰基-3-氮雜雙環[3.1.0]己-3-基]-4-甲基嘧啶-5-基}甲基)-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d] 咪唑-4-基]-1H-吡唑-4-甲醯胺 (1R,5S,6S)-3-氮雜雙環[3.1.0]己烷-6-甲腈鹽酸鹽 225 1-({2-[(1R,5S)-1,5-二甲基-3-氮雜雙環[3.1.0]己-3-基]-4-甲基嘧啶-5-基}甲基)-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 (1R,5S)-1,5-二甲基-3-氮雜雙環[3.1.0]己烷鹽酸鹽 226 1-[(2-{2-氮雜螺[3.3]庚-2-基}-4-甲基嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 雙(2-氮雜螺[3.3]庚烷)草酸 227 1-[(2-{3-氮雜雙環[4.1.0]庚-3-基}-4-甲基嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 3-氮雜雙環[4.1.0]庚烷鹽酸鹽 228 1-[(2-{6,6-二甲基-3-氮雜雙環[3.1.0]己-3-基}-4-甲基嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 6,6-二甲基-3-氮雜雙環[3.1.0]己烷 229 N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1-({4-甲基-2-[(1R,5S,6R)-6-甲基-3-氮雜雙環[3.1.0]己-3-基]嘧啶-5-基}甲基)-1H-吡唑-4-甲醯胺 (1R,5S,6R)-6-甲基-3-氮雜雙環-[3.1.0]己烷鹽酸鹽 (藉由標準RP層析及用含HCl之EtOAc的保護基之裂解的藉由6-甲基-3-氮雜雙環[3.1.0]己烷-3-甲酸三級丁酯之非對映異構體之分離而獲得) 230 1-[(2-{5-氮雜螺[2.4]庚-5-基}-4-甲基嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 5-氮雜螺[2.4]庚烷鹽酸鹽 231 N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1-[(4-甲基-2-{6-氧雜-3-氮雜雙環[3.1.1]庚-3-基}嘧啶-5-基)甲基]-1H-吡唑-4-甲醯胺 6-氧雜-3-氮雜雙環[3.1.1]庚烷; 4-甲基苯-1-磺酸 232 1-[(2-{5-氮雜螺[2.5]辛-5-基}-4-甲基嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 5-氮雜螺[2.5]辛烷 233 1-[(2-{6-甲氧基-3-氮雜雙環[3.1.1]庚-3-基}-4-甲基嘧啶-5-基)甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 6-甲氧基-3-氮雜雙環[3.1.1]庚烷鹽酸鹽 234 1-({2-[(1R,5S,8R)-8-甲氧基-3-氮雜雙環[3.2.1]辛-3-基]-4-甲基嘧啶-5-基}甲基)-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 (1R,5S,8S)-8-甲氧基-3-氮雜雙環[3.2.1]辛烷鹽酸鹽 235 1-({2-[(1R,5S,6S)-6-(羥基甲基)-3-氮雜雙環[3.1.0]-己-3-基]-4-甲基嘧啶-5-基}甲基)-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 [(1R,5S,6S)-3-氮雜雙環[3.1.0]己-6-基]甲醇 236 1-({2-[(1R,5S,6S)-6-羥基-3-氮雜雙環[3.1.0]己-3-基]-4-甲基嘧啶-5-基}甲基)-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 (1R,5S,6S)-3-氮雜雙環[3.1.0]己-6-醇鹽酸鹽 237 1-[(2-{6-氮雜螺[2.5]辛-6-基}-4-甲基嘧啶-5-基)-甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 6-氮雜螺[2.5]辛烷鹽酸鹽 238 1-[(2-{3-氮雜雙環[3.2.0]庚-3-基}-4-甲基嘧啶-5-基)-甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 3-氮雜雙環[3.2.0]庚烷鹽酸鹽 239 N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1-[(4-甲基-2-{八氫環戊并[c] 吡咯-2-基}嘧啶-5-基)甲基]-1H-吡唑-4-甲醯胺 八氫環戊并[c]吡咯 240 1-[(2-{6-氮雜螺[3.4]辛-6-基}-4-甲基嘧啶-5-基)-甲基]-N-[(4R)-1-甲基-1H,4H,5H,6H-環戊[d]咪唑-4-基]-1H-吡唑-4-甲醯胺 6-氮雜螺[3.4]辛烷 Examples 223-240 were prepared analogously to Example 222:

example name name of starting material 223 1-[(2-{2-Hydroxy-2-methyl-7-azaspiro[3.5]nonan-7-yl}-4-methylpyrimidin-5-yl)methyl]-N-[( 4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 2-Methyl-7-azaspiro[3.5]nonan-2-ol hydrochloride 224 1-({2-[(1R,5S,6S)-6-cyano-3-azabicyclo[3.1.0]hex-3-yl]-4-methylpyrimidin-5-yl}methyl) -N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide (1R,5S,6S)-3-azabicyclo[3.1.0]hexane-6-carbonitrile hydrochloride 225 1-({2-[(1R,5S)-1,5-dimethyl-3-azabicyclo[3.1.0]hex-3-yl]-4-methylpyrimidin-5-yl}methyl )-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide (1R,5S)-1,5-dimethyl-3-azabicyclo[3.1.0]hexane hydrochloride 226 1-[(2-{2-Azaspiro[3.3]hept-2-yl}-4-methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H, 4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide Bis(2-azaspiro[3.3]heptane)oxalic acid 227 1-[(2-{3-Azabicyclo[4.1.0]hept-3-yl}-4-methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl- 1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 3-Azabicyclo[4.1.0]heptane hydrochloride 228 1-[(2-{6,6-Dimethyl-3-azabicyclo[3.1.0]hex-3-yl}-4-methylpyrimidin-5-yl)methyl]-N-[( 4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 6,6-Dimethyl-3-azabicyclo[3.1.0]hexane 229 N-[(4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1-({4-methyl-2-[(1R,5S,6R )-6-Methyl-3-azabicyclo[3.1.0]hex-3-yl]pyrimidin-5-yl}methyl)-1H-pyrazole-4-carboxamide (1R,5S,6R)-6-methyl-3-azabicyclo-[3.1.0]hexane hydrochloride (by standard RP chromatography and cleavage of the protecting group with HCl in EtOAc) 6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester obtained by separation of diastereomers) 230 1-[(2-{5-Azaspiro[2.4]hept-5-yl}-4-methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H, 4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 5-Azaspiro[2.4]heptane hydrochloride 231 N-[(4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1-[(4-methyl-2-{6-oxa-3 -azabicyclo[3.1.1]hept-3-yl}pyrimidin-5-yl)methyl]-1H-pyrazol-4-carboxamide 6-oxa-3-azabicyclo[3.1.1]heptane; 4-methylbenzene-1-sulfonic acid 232 1-[(2-{5-Azaspiro[2.5]oct-5-yl}-4-methylpyrimidin-5-yl)methyl]-N-[(4R)-1-methyl-1H, 4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 5-Azaspiro[2.5]octane 233 1-[(2-{6-Methoxy-3-azabicyclo[3.1.1]hept-3-yl}-4-methylpyrimidin-5-yl)methyl]-N-[(4R) -1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazole-4-carboxamide 6-Methoxy-3-azabicyclo[3.1.1]heptane hydrochloride 234 1-({2-[(1R,5S,8R)-8-methoxy-3-azabicyclo[3.2.1]oct-3-yl]-4-methylpyrimidin-5-yl}methyl )-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide (1R,5S,8S)-8-methoxy-3-azabicyclo[3.2.1]octane hydrochloride 235 1-({2-[(1R,5S,6S)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]-hex-3-yl]-4-methylpyrimidin-5-yl }methyl)-N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide [(1R,5S,6S)-3-azabicyclo[3.1.0]hex-6-yl]methanol 236 1-({2-[(1R,5S,6S)-6-hydroxy-3-azabicyclo[3.1.0]hex-3-yl]-4-methylpyrimidin-5-yl}methyl)- N-[(4R)-1-methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide (1R,5S,6S)-3-azabicyclo[3.1.0]hexan-6-ol hydrochloride 237 1-[(2-{6-Azaspiro[2.5]oct-6-yl}-4-methylpyrimidin-5-yl)-methyl]-N-[(4R)-1-methyl-1H ,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 6-Azaspiro[2.5]octane hydrochloride 238 1-[(2-{3-Azabicyclo[3.2.0]hept-3-yl}-4-methylpyrimidin-5-yl)-methyl]-N-[(4R)-1-methyl -1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 3-Azabicyclo[3.2.0]heptane hydrochloride 239 N-[(4R)-1-Methyl-1H,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1-[(4-methyl-2-{octahydrocyclopento[ c]pyrrol-2-yl}pyrimidin-5-yl)methyl]-1H-pyrazole-4-carboxamide Octahydrocyclopenta[c]pyrrole 240 1-[(2-{6-Azaspiro[3.4]oct-6-yl}-4-methylpyrimidin-5-yl)-methyl]-N-[(4R)-1-methyl-1H ,4H,5H,6H-cyclopenta[d]imidazol-4-yl]-1H-pyrazol-4-carboxamide 6-Azaspiro[3.4]octane

Claims (17)

A compound of formula (I)

, where Y is selected from the group Y-G1 consisting of:

, each of which is substituted with ¹ or 2 independent substituents R1; R is selected from the group R-G1 consisting of: A saturated 6- to 12-membered bicyclic ring system containing 1 to 2 N as ring members Atom and optionally ₁ ring member selected from the group consisting of C=O, O, S, S=O and SO2, provided that such ring systems do not contain any heteroatoms between the ring members- Heteroatom bonds, wherein the ring systems are attached to the group Y in formula (I) via the N atom, and wherein the ring systems are optionally substituted with 1 to 6 F and optionally 1 to 3 are selected from C Substituent substitution of the group consisting _{of 1-3} alkyl, CN, HO _- C _1-3 alkylene, OH _and C _1-3 alkyl _- O _; Ar is selected from the group Ar-G1 consisting of: ₅ members Heteroaryl groups containing 1 to 4 N atoms or containing 1 O or S atom or containing 1 to 2 N atoms and 1 O or S atom; and 9-membered heteroaryl groups fused to 6-membered The 5-membered ring of the ring consists of and contains 1 to 4 N atoms, wherein the heteroaryl group is connected to the carbonyl group in formula (I) through a C atom of the 5-membered ring and through a non-adjacent C or N of the 5-membered ring The atom is attached to the CH ₂ group in formula (I), and wherein the heteroaryl groups are optionally substituted with a substituent R ³ ; R ¹ is selected from the group R ¹ -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, optionally substituted with ₁ to 5 F Substituted OC _1-3 alkyl _, optionally C _1-3 alkyl substituted with ₁ substituent selected from the group consisting _of CN, OH _and OC _1-3 alkyl ^{; R 3} _{is selected} from the group consisting of R ³ -G1 _: F, Cl, Br, CN, C _{1 -4} alkyl optionally substituted with 1 _to 5 F, C _{3 -4} cycloalkyl, HO _- C _{1 -4} alkylene, C _{1 - 3alkyl - OC1-3alkylene} and optionally _OC1-4alkyl substituted with _{1 to 5} F; or a salt thereof. The compound of claim 1, wherein Y is selected from the group Y-G2 consisting of:

, each of which is substituted with 1 or 2 independent substituents R ¹ , and wherein the bond with an asterisk indicates the site of attachment of R of formula (I) to the CH ₂ group; or a salt thereof. The compound of claim 1, wherein 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-azaspiro Bicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, and 3-azabicyclo[3.2.1]octane, each of which is linked via an N atom to the formula The groups Y in (I) are linked, and each of which is optionally one selected from the group consisting of F, _CH3 , CN, CH2OH, OH and _OCH3 , preferably the group consisting _of F and _CH3 , each of which is optionally substituted with an additional substituent selected from the group consisting _of F and CH ; or a salt thereof. The compound of claim 1, wherein Ar is selected from the group Ar-G3 consisting of:

and tautomers thereof, each of which is optionally substituted with 1 substituent ^R3 , and wherein the bond with an asterisk and parentheses indicates the site of attachment of the group C=O and _CH2 of formula (I) ; or a salt thereof. The compound of any one of claims 1 to 4, wherein R ¹ is selected from the group R ¹ -G2 consisting of: H, F, Cl, Br, optionally via 1 to 5 F or via 1 CN, C _1-2 alkyl substituted with OH or OC _1-2 alkyl _, C _3-4 alkyl substituted with ₁ CN or OH group as _{appropriate, substituted with 1 CH 3 , CN or OH} group as appropriate C _{3 - 4} cycloalkyl, OC _{1 - 2} alkyl substituted with 1 to 5 F as the case may be; or a salt thereof. The compound of any one of claims 1 to 4, wherein R ³ is selected from the group R ³ -G2 consisting of: F, Cl, Br, CN, C _{1 -3} optionally substituted with 1 to ₃ Fs _Alkyl , HO _{- C1-4alkylene} , _{C1-2alkyl - OC1-2alkylene ,} and optionally _OC1-2alkyl substituted with _{1 to 3} F _; or a salt thereof. The compound of any one of claims 1 to 4, wherein the stereochemistry of the compound is according to formula (I.1)

or its salt. A pharmaceutically acceptable salt of a compound of any one of claims 1 to 7. A pharmaceutical composition comprising one or more compounds as claimed in any one of claims 1 to 7, or a pharmaceutically acceptable salt as claimed in claim 8, optionally together with one or more inert carriers and/or dilutions agent. A pharmaceutical composition comprising one or more compounds as claimed in any one of claims 1 to 7, or a pharmaceutically acceptable salt as claimed in claim 8, and one or more additional therapeutic agents, optionally and one or Various inert carriers and/or diluents. As in the pharmaceutical composition of claim 10, wherein the one or more additional therapeutic agents are selected from the group consisting of: antidiabetic agents, agents for the treatment of overweight and/or obesity; agents for the treatment of hypertension, heart failure and/or atherosclerosis, and Medicines used to treat eye diseases. The compound of any one of claims 1 to 4 for use as a medicament. The pharmaceutically acceptable salt of claim 8 is used as a medicament. A use of one or more compounds as claimed in any one or more of items 1 to 7 or a pharmaceutically acceptable salt as claimed in item 8 for the manufacture of an eye disease, preferably for the treatment of diabetes Agents for macular edema, age-related macular degeneration and/or choroidal neovascularization. The compound according to any one of claims 1 to 4, for use in a method for treating eye diseases, preferably diabetic macular edema, age-related macular degeneration and/or choroidal neovascularization, the method comprising One or more compounds of any one of claims 1-4 are administered to the patient. The pharmaceutically acceptable salt of claim 8, which is used in a method for treating eye diseases, preferably diabetic macular edema, age-related macular degeneration and/or choroidal neovascularization, the method comprising A pharmaceutically acceptable salt of claim 8 is administered to the patient. A compound selected from the group consisting of:

or its salt.