Isoxazolidines as RIPK1 inhibitors and uses thereof

Abstract

The present disclosure relates to compounds of formula (I) wherein R1 represents phenyl or monocyclic heteroaryl optionally substituted by one, two or three R3; r2 represents an aryl or heteroaryl group optionally substituted by one, two or three R6 groups; each R3 is independently selected from the group consisting of halogen, cyano, (C1-C4) alkyl, or (C1-C4) alkoxy; r4 and R5 are independently selected from halogen, (C1-C4) alkyl, (C1-C4) alkoxy, or R4 and R5 together form a (C1-C4) alkylene bridge; m and s are independently 0 or 1; p, q, r and t are independently 0 or 1; each R6 is independently selected from the group consisting of halogen, cyano,-NH2 group,-OH, (C1-C4) alkyl,-CF3,-C (O) NH2,-C (O) NH-(C1-C4) alkyl,-C (O) OH,-C (O) O-(C1-C4) alkyl,-SO2NH2, (C1-C4) alkoxy,-O-(C1-C4) alkylene-(C3-C6) cycloalkyl,-O-(C3-C6) cycloalkyl,-O-(C3-C6) heterocycloalkyl, (C3-C6) heterocycloalkyl, heteroaryl, and pendant oxygen groups; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. The present disclosure further relates to pharmaceutical compositions containing said novel compounds.

Description

Technical Field

[0001] This disclosure relates to novel isoxazolidine derivatives that can be used as pharmaceutical agents. These novel compounds are particularly effective as kinase inhibitors and even more particularly as RIPK1 inhibitors. They are highly effective for the treatment and / or prevention of acute and chronic neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS).

[0002] This disclosure further relates to pharmaceutical compositions containing the new compound. Technical Background While inflammation may be a protective mechanism in response to harmful stimuli such as pathogen invasion and tissue damage, chronic inflammation is a significant underlying factor in many human diseases, including neurodegenerative diseases, rheumatoid arthritis, autoimmune and inflammatory diseases, and cancer. Similarly, the initiation of cell death pathways such as necrosis and apoptosis (which can be used to eliminate infected or damaged cells) is also a significant underlying mechanism in human diseases, including acute and chronic neurodegenerative diseases. Receptor-interacting protein kinase 1 (UniProtKB Q13546) is a key regulator of inflammation, apoptosis, and necroptosis. Receptor-interacting protein kinase 1 plays an important role in regulating the inflammatory response mediated by the nuclear factor κ light chain enhancer (NF-κB) that initiates B cells. Recent studies have shown that its kinase activity controls necroptosis, a form of necrotic cell death that has traditionally been considered passive and unregulated and characterized by a distinctive morphology. Furthermore, receptor-interacting protein kinase 1 is part of a pro-apoptotic complex, suggesting its activity in regulating apoptosis.

[0004] Receptor-interacting protein kinase 1 (RIK1) is subject to a complex regulatory mechanism, including ubiquitination, deubiquitination, and phosphorylation. These regulatory events collectively determine whether a cell will survive and initiate an inflammatory response or die via apoptosis or necrotizing apoptosis. Dysregulation of RAK1 signaling can lead to excessive inflammation or cell death, and conversely, studies have shown that inhibiting RAK1 may be an effective therapy for diseases involving inflammation or cell death.

[0005] RIPK1 inhibition has been identified as a promising principle for treating various diseases such as rheumatoid arthritis (RA), psoriasis, multiple sclerosis, Alzheimer's disease, inflammatory bowel disease (such as Crohn's disease), amyotrophic lateral sclerosis (ALS), or ulcerative colitis (UC). For some of these diseases, such as multiple sclerosis (MS) and Alzheimer's disease, entry into the central nervous system (CNS) is required; while for others, such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD) (such as Crohn's disease or UC), entry into the CNS is generally unnecessary.

[0006] Different RIPK1 inhibitors have been described, for example, in patent applications WO 2014 / 125444, WO 2016 / 185423 or WO 2016 / 027253 (GSK).

[0007] The RIPK1 inhibitor GSK2982772 (an oxazepinone derivative disclosed in WO 2014 / 125444) was evaluated in a phase II clinical trial for RA, psoriasis, and UC.

[0008] GSK disclosed dihydropyrazole compounds with phenyl substituents on the dihydropyrazole and pyrimidine-piperidine components as RIPK1 inhibitors in WO 2018 / 092089. Other dihydropyrazole compounds as RIPK1 inhibitors were disclosed in WO 2020 / 224656.

[0009] GSK disclosed isoxazolidine compounds with phenyl substituents on the isoxazolidine and pyrimidine-piperidine components as RIPK1 inhibitors in WO 2019 / 130230. Similar isoxazolidine compounds were disclosed in KR 2020-087922 (Voronoi) and WO 2020 / 043173.

[0010] WO 2021 / 245070 discloses isoxazolidine compounds that have reduced ability to cross the blood-brain barrier as RIPK1 inhibitors.

[0011] WO 2022 / 194259 discloses compounds with cycloalkyl components as RIPK1 inhibitors. Summary of the Invention

[0012] For one of its purposes, this disclosure relates to compounds of formula (I): (I) in R1 represents a phenyl or monocyclic heteroaryl group optionally substituted with one, two, or three R3 groups; R2 represents an aryl or heteroaryl group that is optionally replaced by one, two, or three R6 groups; Each R3 is independently selected from halogen, cyano, (C1-C4)alkyl, or (C1-C4)alkoxy; R4 and R5 are independently selected from halogens, (C1-C4)alkyl groups, (C1-C4)alkoxy groups, or R4 and R5 together form a (C1-C4)alkylene bridge; m and s are independently 0 or 1; p, q, r, and t are independently 0 or 1; Each R6 is independently selected from halogen, cyano, -OH, -NH2 group, (C1-C4)alkyl, -CF3, -C(O)NH2, -C(O)NH-(C1-C4)alkyl, -C(O)OH, -C(O)O-(C1-C4)alkyl, -SO2NH2, (C1-C4)alkoxy, -O-(C1-C4)alkylene-(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -O-(C3-C6)heterocyclic alkyl, (C3-C6)heterocyclic alkyl, heteroaryl, and lateral oxy, wherein the (C1-C4)alkyl, (C1-C4)alkoxy, -O-(C3-C6)cycloalkyl, (C1-C4)alkyl, (C3-C6)heterocyclic alkyl, or heteroaryl is optionally substituted by one, two, three, or four R7s; Each R7 is independently a halogen, side radical, -OH, (C1-C4)alkyl, or (C1-C4)alkoxy. Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0013] In related aspects, this document provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

[0014] On the other hand, this paper provides a method for manufacturing compounds of formula (I) and intermediates thereof.

[0015] On the other hand, this article provides compounds of formula (I) or pharmaceutically acceptable salts, solvates or stereoisomers thereof for use as pharmaceutical agents.

[0016] On the other hand, this article provides compounds of formula (I) or pharmaceutically acceptable salts, solvates or stereoisomers thereof for the treatment and / or prevention of diseases, disorders or conditions mediated at least in part by receptor-interacting protein kinase 1.

[0017] On the other hand, this article provides compounds of formula (I) or pharmaceutically acceptable salts, solvates or stereoisomers thereof for the treatment and / or prevention of diseases selected from: Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS).

[0018] In another aspect, the present disclosure provides methods for inhibiting receptor-interacting protein kinase 1. Further provided are methods for treating a disease, disorder, or condition that is at least partially mediated by receptor-interacting protein kinase 1, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of formula (I) as described herein. The present disclosure also provides the use of a compound of formula (I) or a composition thereof in the manufacture of a medicament for treating a disease, disorder, or condition that is at least partially mediated by receptor-interacting protein kinase 1. Detailed Description

[0019] Definitions Unless otherwise indicated, the following terms used in the specification and claims have the following meanings set forth below.

[0020] In the present specification, the term "alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group having the indicated number of atoms. More particularly, (C x -C y )alkyl (where x and y are integers and x < y) is a straight-chain or branched-chain saturated aliphatic group containing from x to y carbon atoms. For example, (C1-C4)alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl, among others.

[0021] The term "alkylene" includes both straight-chain and branched-chain divalent alkyl groups. For example, "(C1-C4)alkylene" includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), methylmethylene (-CH(CH3)-), propylene, and butylene.

[0022] The term "alkoxy" denotes an alkyl group bonded to oxygen by a single bond. In particular, as used herein, "(C x -C y )alkoxy" refers to -O-(C x -C y )alkyl, where x and y are integers and x < y. For example, "(C1-C4)alkoxy" includes, but is not limited to, methoxy, ethoxy, isopropoxy, and tert-butoxy.

[0023] "Cycloalkyl" refers to a saturated or partially unsaturated optionally substituted cyclic hydrocarbon group having the indicated number of atoms. More particularly, (C3-C z )cycloalkyl (where z is an integer greater than or equal to 4) contains from 3 to z carbon atoms. For example, (C3-C8)cycloalkyl contains from 3 to 8 carbon atoms and is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cycloctyl.

[0024] The term "halogen" refers to a chlorine, fluorine, bromine, or iodine atom, and particularly refers to a chlorine or fluorine atom.

[0025] The terms “heterocyclic group,” “heterocyclic,” or “heterocyclic” refer to a non-aromatic, saturated, or partially unsaturated, optionally substituted monocyclic, fused, or bridged bicyclic system in which one to five (suitably one or two) carbon atoms are replaced by heteroatoms (such as oxygen, sulfur, or nitrogen atoms). For example, as used herein, “(C3-C6)heterocyclic alkyl” refers to such a (C3-C6)cycloalkyl group in which one or two carbon atoms are replaced by heteroatoms, particularly oxygen or nitrogen atoms. Examples of heterocyclic groups include, but are not limited to, cyclic ethers such as oxetane, oxetane, tetrahydrofuran, dioxane, and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azirone, pyrrolidin, piperidin, piperazine, tetrahydrotriazine, tetrahydropyrazol, etc. Typical sulfur-containing heterocycles include tetrahydrothiophene, dihydro-1,3-dithiol, tetrahydro-2H-thiaran, and hexahydrothiapan. Other heterocycles include tetrahydrooxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For sulfur-containing heterocycles, sulfur oxide heterocycles containing SO or SO2 groups are also included. Partially unsaturated heterocyclic base rings contain at least one double bond, such as one or two double bonds. Examples of partially unsaturated heterocyclic base rings include 1,6-dihydropyridinyl, 1,6-dihydropyridazinyl, and 2,3-dihydropyrroleyl. As those skilled in the art will understand, any heterocycle can be attached to another group via any suitable atom (e.g., via a carbon or nitrogen atom).

[0026] "Bridged ring system" refers to a ring system in which two rings share more than two atoms, see, for example, Advanced Organic Chemistry, Jerry March, 4th ed., Wiley Interscience, pp. 131-133, 1992. Specifically, as used herein, "bridging (C6-C)" 10 “Cycloalkyl” refers to a bicyclic or tricyclic compound in which the rings are cycloalkyl groups, the rings share three or more atoms, and the bridges contain at least one atom, such as 1 (also known as a C1-alkylene bridge), 2 (also known as a C2-alkylene bridge), or 3 atoms. Such bridged cycloalkyl groups may be substituted with one or more C1-C3 alkyl groups. Examples are, but are not limited to, norbornyl or bicyclic [2.2.2]octyl.

[0027] The term "heteroaryl" refers to an aromatic monocyclic, bicyclic, or polycyclic compound containing one or more (e.g., 1 to 4, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. Examples of heteroaryls are monocyclic and bicyclic groups containing five to twelve ring members, and more typically five to ten. A heteroaryl can be, for example, a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic, such as a bicyclic structure formed from a fused five-membered ring and a six-membered ring, or two fused six-membered rings. Each ring may contain up to about four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain up to three heteroatoms, more typically up to two, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one cyclic nitrogen atom. The nitrogen atom in the heteroaryl ring may be basic, as in the case of imidazole or pyridine, or inherently non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl group (including any amino substituent in the ring) will be less than five. Heteroaryl groups containing nitrogen atoms can exist as corresponding oxynitrides.

[0028] Non-limiting examples of heteroaryl groups include furanyl, pyrrolyl, thiophenyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl (pyridinyl), pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indoleyl, isoindoleyl, isoindolelinyl, benzothiophenyl, benzooxazolyl, benzimidazolyl, benzothiazolyl, indoleyl, purinyl, benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxolinyl, cinolinyl, pterinyl, and terpineyl. Pyridyl, naphthidyl, carbazolyl, phenazinyl, benzisoquinoline, pyridopyrazinyl, oxazolidinyl, imidazolyl, triazolopyridyl (e.g., [1,2,4]triazolo[1,5-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl), pyrrolopyridyl (e.g., 1H-pyrrolo[2,3-c]pyridyl, 1H-pyrrolo[3,2-b]pyridyl or 1H-pyrrolo[3,2-c]pyridyl), imidazopyridyl (e.g., imidazo[1,2-a]pyridyl), imidazopyridazine (e.g., imidazo[1,2-b]pyridazinyl), thiopheno[2,3]pyridyl [b]furanyl, 2Hfurano[3,2b]pyranyl, 5Hpyrido[2,3d]oxazinyl, 1Hpyrazolo[4,3d]oxazolyl, 4H imidazo[4,5d]thiazolyl, pyrazolo[2,3d]pyridazinyl, imidazo[2,1b]thiazolyl, imidazo[1,2b][1,2,4]triazinyl, pyrazolopyridyl (e.g., pyrazolo[4,3-b]pyridyl), triazolopyridazinyl (e.g., [1,2,4]triazolo[1,5-b]pyridazinyl), benzimidazolyl (e.g., 1H-benzi[d]imidazolyl).

[0029] Non-limiting examples of five-membered heteroaryl groups include, but are not limited to, pyrrole, furanyl, thiophene, imidazolyl, furazonyl, oxazolyl, oxadiazolyl, oxtriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl.

[0030] Non-limiting examples of six-membered heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0031] Non-limiting examples of bicyclic heteroaryl groups containing a six-membered ring fused with a five-membered ring include, but are not limited to, triazolopyridyl (e.g., [1,2,4]triazolo[1,5-a]pyridyl or [1,2,4]triazolo[4,3-a]pyridyl), pyrrolopyridyl (e.g., 1H-pyrrolo[2,3-c]pyridyl, 1H-pyrrolo[3,2-b]pyridyl or 1H-pyrrolo[3,2-c]pyridyl), benzimidazolyl (e.g., 1H-benzi[d]imidazolyl), benzoxoxane... Azolyl (e.g., oxobenzo[d]oxazol-3(2H)-yl), imidazopyridyl (e.g., imidazo[1,2-a]pyridyl), imidazopyridazinyl (e.g., imidazo[1,2-b]pyridazinyl), imidazoyl, indazole (e.g., indazole-1-yl or indazole-2-yl), indolyl (e.g., indol-1-yl), isoindololinyl, pyrazolopyridyl (e.g., pyrazolo[4,3-b]pyridyl), and triazolopyridazinyl (e.g., [1,2,4]triazolo[1,5-b]pyridazinyl). Non-limiting examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochronyl, chromanyl, isochronyl, benzodioxane, quinazinyl, benzooxazinyl, benzodiazinyl, pyridinylpyridinyl, quinoxolinyl, quinazolinyl, terolinyl, phthalazinyl, naphthidyl, and pteridylyl.

[0032] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 6 to 10 carbon atoms. The term aryl includes both monovalent and divalent types. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. Suitablely, aryl is phenyl.

[0033] This specification may also use compound terms to describe groups containing more than one functional group. Those skilled in the art will understand such terms. For example, heterocyclic C1-C4 alkyl includes C1-C4 alkyl groups substituted with heterocyclic groups.

[0034] The term "optionally substituted" refers to substituted and unsubstituted groups, structures, or molecules.

[0035] In the case where the optional substituents are selected from "one or more" groups, it should be understood that this definition includes all substituents being selected from one of the specified groups or substituents being selected from two or more of the specified groups. It should be understood that in the case of multiple substituents, the selected substituents may be the same or different.

[0036] Given a numerical range, it should be understood that the range includes end values.

[0037] The phrase “compounds of this disclosure” means those compounds that are disclosed herein, both generally and specifically.

[0038] The phrase “pharmaceutically acceptable” is used in this document to refer to compounds, materials, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with tissues in humans and animals without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0039] In this regard, the term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic and organic acid addition salt of the compounds of this disclosure. These salts can be prepared in situ in an application medium or during dosage form manufacturing, or by reacting a purified compound in its free base form with a suitable organic or inorganic acid alone and separating the resulting salt during a subsequent purification process.

[0040] As used herein, the term "pharmaceuticalally acceptable excipient" refers to a substance that facilitates the administration of an active agent to a subject. "Pharmaceutically acceptable" means that the excipient is compatible with other components of the formulation and is harmless to the recipient. Pharmaceutical excipients that may be used in this disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, flow aids, coatings, sweeteners, flavorings, and colorants.

[0041] As used herein, the phrase “pharmaceutically acceptable carrier” refers to pharmaceutically acceptable materials, compositions, or mediators, such as liquid or solid fillers, diluents, excipients, or solvent encapsulating materials, which participate in carrying or transporting the subject compound from one organ or part of the body to another organ or part of the body.

[0042] It should be understood that references to “treating” or “treatment” include the prevention and relief of established symptoms of a condition. Therefore, “treating” or “treatment” for a state, disorder, or condition includes: (1) preventing or delaying the onset of clinical symptoms of a state, disorder, or condition in a person who may have or is susceptible to the state, disorder, or condition but has not yet experienced or exhibited clinical or subclinical symptoms of the state, disorder, or condition; (2) suppressing the state, disorder, or condition, i.e., (in the case of maintenance treatment) preventing, reducing, or delaying the development of the disease, or its recurrence, or at least one of its clinical or subclinical symptoms; or (3) alleviating or reducing the disease, i.e., leading to the resolution of the state, disorder, or condition or at least one of its clinical or subclinical symptoms.

[0043] "Prevention" or "preventing" means any treatment that prevents the development of clinical symptoms of a disease or condition. In some implementations, the compound may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0044] "Subject" refers to a person who has become or will become a subject of treatment, observation, or experimentation. The methods described herein can be used in human therapeutics.

[0045] "Therapeutic effective amount" means the amount of a compound that is sufficient to achieve such treatment of a disease when applied to a mammal. The "therapeutic effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated, and can be readily determined by one of ordinary skill in the art.

[0046] As used herein, chemical names not otherwise defined have the meaning used in this technical field.

[0047] compound This article discloses compounds of formula (I): (I) in R1 represents a phenyl or monocyclic heteroaryl group optionally substituted with one, two, or three R3 groups; R2 represents an aryl or heteroaryl group that is optionally replaced by one, two, or three R6 groups; Each R3 is independently selected from halogen, cyano, (C1-C4)alkyl, or (C1-C4)alkoxy; R4 and R5 are independently selected from halogens, (C1-C4)alkyl groups, (C1-C4)alkoxy groups, or R4 and R5 together form a (C1-C4)alkylene bridge; m and s are independently 0 or 1; p, q, r, and t are independently 0 or 1; Each R6 is independently selected from halogen, cyano, -OH, (C1-C4)alkyl, -CF3, -C(O)NH2, -C(O)NH-(C1-C4)alkyl, -C(O)OH, -C(O)O-(C1-C4)alkyl, -SO2NH2, (C1-C4)alkoxy, -O-(C1-C4)alkylene-(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -O-(C3-C6)heterocyclic alkyl, heterocyclic alkyl, heteroaryl, and lateral oxy, wherein the (C1-C4)alkyl, (C1-C4)alkoxy, -O-(C3-C6)cycloalkyl, (C1-C4)alkyl, heterocyclic alkyl, or heteroaryl is optionally substituted by one, two, three, or four R7; Each R7 is independently a halogen, side radical, -OH, (C1-C4)alkyl, or (C1-C4)alkoxy. Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0048] This article discloses compounds of formula (I): (I) in R1 represents a phenyl or monocyclic heteroaryl group optionally substituted with one, two, or three R3 groups; R2 represents an aryl or heteroaryl group that is optionally replaced by one, two, or three R6 groups; Each R3 is independently selected from halogen, cyano, (C1-C4)alkyl, or (C1-C4)alkoxy; R4 and R5 are independently selected from halogens, (C1-C4)alkyl groups, (C1-C4)alkoxy groups, or R4 and R5 together form a (C1-C4)alkylene bridge; m and s are independently 0 or 1; p, q, r, and t are independently 0 or 1; Each R6 is independently selected from halogen, cyano, -OH, -NH2 group, (C1-C4)alkyl, -CF3, -C(O)NH2, -C(O)NH-(C1-C4)alkyl, -C(O)OH, -C(O)O-(C1-C4)alkyl, -SO2NH2, (C1-C4)alkoxy, -O-(C1-C4)alkylene-(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -O-(C3-C6)heterocyclic alkyl, (C3-C6)heterocyclic alkyl, heteroaryl, and lateral oxy, wherein the (C1-C4)alkyl, (C1-C4)alkoxy, -O-(C3-C6)cycloalkyl, (C1-C4)alkyl, (C3-C6)heterocyclic alkyl, or heteroaryl is optionally substituted by one, two, three, or four R7s; Each R7 is independently a halogen, side radical, -OH, (C1-C4)alkyl, or (C1-C4)alkoxy. Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0049] According to one embodiment, compounds of formula (I) are disclosed herein. in: R1 represents a phenyl or a 5- or 6-membered monocyclic heteroaryl group optionally substituted with one, two or three R3s; R2 represents a phenyl group, a 5- or 6-membered monocyclic heteroaryl group, or a 9- or 10-membered bicyclic heteroaryl group optionally substituted with one, two, or three R6 groups; Each R3 is independently selected from halogen, cyano, (C1-C4)alkyl, and (C1-C4)alkoxy; R4 and R5 together form a (C1-C4) alkylene bridge; m and s are independently 0 or 1; p, q, r, and t are independently 0 or 1; Each R6 is independently selected from halogen, cyano, -NH2 group, -OH, (C1-C4)alkyl, -C(O)NH2, -C(O)NH-(C1-C4)alkyl, (C1-C4)alkoxy, -O-(C1-C4)alkylene-(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -O-(C3-C6)heterocyclic alkyl, 4- or 5-membered heterocyclic alkyl, 5- or 6-membered heteroaryl and lateral oxy, wherein the (C1-C4)alkyl, (C1-C4)alkoxy, -O-(C3-C6)cycloalkyl, heterocyclic alkyl, heteroaryl are optionally substituted by one or two R7s; Each R7 is independently -OH, (C1-C4)alkyl, or (C1-C4)alkoxy. Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0050] According to one embodiment, compounds of formula (I) are disclosed herein. R1 is selected from furanyl, phenyl, pyrazinyl, pyridyl, pyrimidinyl, and thiazolyl, especially phenyl or pyridyl, which are optionally substituted with one, two, or three R3. R2 is selected from benzimidazolyl, benzoxazolyl, imidazolyl, imidazopyridinyl, imidazopyridinyl, indazole, indolyl, isoindololinyl, phenyl, pyrazinyl, pyridinyl, pyrazolopyridinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolopyridinyl, thiazolyl, triazolopyridinyl, triazolopyridinyl, triazolyl, especially phenyl; which may be optionally substituted with one, two or three R6. Each R3 is independently selected from fluorine, cyano, methyl, or methoxy; R4 and R5 together form a methylene bridge or an ethylene bridge; m and s are independently 0 or 1; p, q, r, and t are independently 0 or 1; Each R6 is independently selected from chlorine, fluorine, cyano, -OH, methyl, ethyl, -C(O)NH2, -C(O)NH-methyl, methoxy, ethoxy, lateral oxy, O-methylene-cyclopropyl, cyclopropoxy, oxetyloxybutyloxy, oxetyl, imidazolyl, pyrazolyl, wherein the ethoxy, methoxy, cyclopropoxy, ethyl, methyl, oxetyl, imidazolyl, or pyrazolyl is optionally substituted by one or two R7s; Each R7 is independently -OH, methyl, or methoxy. Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0051] According to one embodiment, R1 in formula (I) represents a phenyl or a 5- or 6-membered monocyclic heteroaryl group optionally substituted with one, two or three R3s.

[0052] According to another embodiment, R1 in formula (I) is selected from phenyl, oxazolyl, pyridyl, furanyl, pyrazinyl and thiazolyl, particularly phenyl, pyrazinyl and pyridinyl, which are optionally substituted with one, two or three R3.

[0053] According to another embodiment, R1 in formula (I) is selected from phenyl, pyrazinyl and pyridinyl groups optionally substituted with one, two or three R3 groups.

[0054] According to another embodiment, R1 in formula (I) is a phenyl group optionally substituted with one, two, or three R3s.

[0055] According to one embodiment, R1 in equation (I) is unsubstituted. According to another embodiment, R1 in equation (I) is substituted by one, two, or three R3, particularly by one or two R3.

[0056] According to one embodiment, R2 in formula (I) represents a phenyl, a 5- or 6-membered monocyclic heteroaryl, or a 9- or 10-membered bicyclic heteroaryl, optionally substituted with one, two, or three R6.

[0057] According to another embodiment, R2 in formula (I) is selected from benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), benzoxazolyl (e.g., benzo[d]oxazol-3(2H)-yl), imidazolyl, imidazopyridazinyl (e.g., imidazo[1,2-b]pyridazinyl), imidazopyridyl (e.g., imidazo[1,2-a]pyridyl), indazole, indolyl, isoindololinyl, phenyl, pyrazinyl, pyridazinyl, pyrazolopyridyl (e.g., pyrazolo[4,3-b]pyridyl), pyrazolyl, pyridyl, pyrimidinyl, pyrrolopyridyl The following groups are pyridyl groups (e.g., 1H-pyrrolo[2,3-c]pyridyl, 1H-pyrrolo[3,2-b]pyridyl or 1H-pyrrolo[3,2-c]pyridyl), thiazolyl, triazolopyridinyl (e.g., [1,2,4]triazolo[1,5-b]pyridinyl), triazolopyridinyl (e.g., [1,2,4]triazolo[1,5-a]pyridinyl or [1,2,4]triazolo[4,3-a]pyridinyl), triazolyl (e.g., 1,2,3-triazolyl), pyrazolopyridinyl, imidazopyridinyl, phenyl, pyridinyl, and thiazolyl. In particular, R2 is selected from imidazopyridazinyl (e.g., imidazo[1,2-b]pyridazinyl), indazole, pyrazolyl, pyridinyl, pyrimidinyl, triazolopyridazinyl (e.g., [1,2,4]triazolo[1,5-b]pyridazinyl), and triazolopyridinyl (e.g., [1,2,4]triazolo[1,5-a]pyridinyl or [1,2,4]triazolo[4,3-a]pyridinyl).

[0058] According to one embodiment, R2 in equation (I) is unsubstituted. According to another embodiment, R2 in equation (I) is substituted by one, two, or three R6, particularly by one or two R6.

[0059] According to one embodiment, each R3 is independently selected from halogen, cyano, (C1-C4)alkyl, and (C1-C4)alkoxy.

[0060] According to another implementation, each R3 is independently selected from fluorine, cyano, methyl, or methoxy.

[0061] According to one embodiment, R4 and R5 in formula (I) together form a (C1-C4) alkylene bridge, particularly a methylene or ethylene bridge.

[0062] According to one embodiment, each R6 is independently selected from halogen, cyano, -NH2 group, -OH, (C1-C4)alkyl, -C(O)NH2, -C(O)NH-(C1-C4)alkyl, (C1-C4)alkoxy, -O-(C1-C4)alkylene-(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -O-(C3-C6)heterocyclic alkyl, 4- or 5-membered heterocyclic alkyl, 5- or 6-membered heteroaryl, and sideoxy, wherein the (C1-C4)alkyl, (C1-C4)alkoxy, -O-(C3-C6)cycloalkyl, heterocyclic alkyl, and heteroaryl are optionally substituted by one, two, three, or four R7s.

[0063] According to another embodiment, each R6 is independently selected from chlorine, fluorine, cyano, -NH2 group, -OH, methyl, ethyl, -C(O)NH2, -C(O)NH-methyl, methoxy, ethoxy, lateral oxy, O-methylene-cyclopropyl, cyclopropoxy, oxetyloxy, oxetyl, imidazolyl, pyrazolyl, wherein the ethoxy, methoxy, cyclopropoxy, ethyl, methyl, oxetyl, imidazolyl, or pyrazolyl is optionally substituted by one, two, three, or four R7s.

[0064] In one implementation, each R6 is unreplaced. In another implementation, each R6 is replaced by one or two R7s.

[0065] According to one embodiment, each R7 is independently -OH, (C1-C4)alkyl, or (C1-C4)alkoxy, and in particular, each R7 is independently -OH, methyl, or methoxy.

[0066] According to one implementation scheme, each R7 is independently -OH, methyl, or methoxy.

[0067] According to one implementation, p, q, r, and t are independently 0 or 1, wherein at least one of p, q, r, and t is 0.

[0068] According to one implementation scheme, p, q, r, and t are all equal to 0.

[0069] According to this embodiment, the compound of formula (I) more particularly has the following formula (Ia): (Ia) R1, R2, R4, R5, m, and s are as defined above, or their pharmaceutically acceptable salts, solvates, or stereoisomers.

[0070] According to one embodiment, the compound according to this disclosure has formula (Ia), wherein: R1 is a phenyl group that is optionally substituted with one or two R3s; R2 is a 9-membered bicyclic heteroaryl group optionally substituted with one or two R6 groups, particularly benzimidazolyl; Each R3 is independently selected from halogen, cyano or (C1-C4) alkyl, and in particular each R3 is independently selected from fluorine, cyano or methyl; m and s are 0; Each R6 is a halogen, especially fluorine. Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0071] According to one embodiment, the compound according to this disclosure has formula (Ia), wherein: R1 is a phenyl group that is optionally substituted with one or two R3s; R2 is a benzimidazole group that is optionally substituted with one or two R6 groups; Each R3 is independently selected from fluorine, cyano, or methyl; m and s are 0; Each R6 is fluorine. Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0072] According to one implementation, r, q, and t are 0 and p is 1, or r, q, and p are 0 and t is 1.

[0073] According to this embodiment, the compound of formula (I) more particularly has the following formula (Ib): (Ib) R1, R2, R4, R5, m, and s are as defined above, or their pharmaceutically acceptable salts, solvates, or stereoisomers.

[0074] According to one implementation, one of q and r is 1 and the other is 0, and one of t and p is 1 and the other is 0.

[0075] According to this embodiment, the compound of formula (I) more particularly has the following formula (Ic): (Ic) R1, R2, R4, R5, m, and s are as defined above, or their pharmaceutically acceptable salts, solvates, or stereoisomers.

[0076] According to one embodiment, the compound according to this disclosure has formula (Ic), wherein: R1 is a phenyl or a 6-membered monocyclic heteroaryl group optionally substituted with one or two R3 groups, preferably a phenyl, pyrazinyl, pyridinyl or pyrimidinyl, thiazolyl or oxazolyl group optionally substituted with one or two R3 groups. R2 is a 5- or 6-membered monocyclic heteroaryl or a 9-membered bicyclic heteroaryl, optionally substituted with one or two R6s; in particular, R2 is imidazopyridazinyl, indazole, pyrazolyl, pyridinyl, pyrimidinyl, triazolpyridazinyl, triazolpyridinyl, pyrazolpyridinyl, imidazopyridinyl, phenyl, pyridazinyl, or thiazolyl. Each R3 is independently selected from halogen, cyano or (C1-C4)alkyl or (C1-C4)alkoxy, preferably each R3 is independently selected from fluorine, cyano, methoxy or methyl; m and s are 0 or m is 0 and s is 1, and R4 is a methyl group; Each R6 is independently selected from halogen, cyano, -NH2 group, (C1-C4)alkyl, (C1-C4)alkoxy, -CF3, and (C3-C6) heterocyclic alkyl optionally substituted with one, two, three, or four R7s, preferably each R7 is independently a halogen, side group, -OH, methyl, or methoxy group, and in particular each R6 is independently selected from fluorine, cyano, methyl, methoxy, or hydroxyoxetane. Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0077] According to one embodiment, the compound according to this disclosure has formula (Ic), wherein: R1 is a phenyl, pyrazinyl, pyridinyl, thiazolyl, oxazolyl, or pyrimidinyl group that is optionally substituted with one or two R3 groups. R2 is an imidazopyridinyl, indazole, pyrazolyl, pyridinyl, pyrimidinyl, triazolpyridinyl, or triazolpyridinyl, pyrazolpyridinyl, imidazopyridinyl, phenyl, pyridinyl, or thiazolyl, optionally substituted with one or two R6 groups. Each R3 is independently selected from fluorine, cyano, methoxy, or methyl; m and s are 0 or m is 0 and s is 1, and R4 is a methyl group; Each R6 is independently selected from fluorine, cyano, -NH2 group, methyl, -CF3, methoxy or hydroxyoxetane; Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0078] According to one embodiment, the compound according to this disclosure has formula (Ic), wherein: R1 is a phenyl group that is optionally substituted with one or two R3s; R2 is an imidazopyridazinyl, indazole, pyrazolyl, pyridinyl, pyrimidinyl, triazolpyridazinyl, triazolpyridinyl, pyrazolpyridinyl, imidazopyridinyl, phenyl, pyridazinyl, or thiazolyl group optionally substituted with one or two R6 groups. Each R3 is independently selected from fluorine, cyano, or methyl; m and s are 0 or m is 0 and s is 1, and R4 is a methyl group; Each R6 is independently selected from fluorine, cyano, methyl, or methoxy; Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0079] According to one implementation, t and p are equal to 1, and one of q and r is 1 while the other is 0.

[0080] According to this embodiment, the compound of formula (I) more particularly has the following formula (Id): R1, R2, R4, R5, m, and s are as defined above, or their pharmaceutically acceptable salts, solvates, or stereoisomers.

[0081] According to one embodiment, the compound of formula (Ig) is further disclosed herein: (Ig) in R1, R2, R4, R5, r, q, p, t, m and s are as defined in compounds of formula (I), or pharmaceutically acceptable salts, solvates or stereoisomers thereof.

[0082] According to this embodiment, the compound of formula (I) more particularly has the following formula (Ie): (Ie) R1, R2, R4, R5, m, and s are as defined above, or their pharmaceutically acceptable salts, solvates, or stereoisomers.

[0083] According to one embodiment, the compound according to this disclosure has formula (Ie), wherein: R1 is a phenyl or a 6-membered monocyclic heteroaryl group optionally substituted with one or two R3 groups, preferably a phenyl, pyrazinyl, pyridinyl or pyrimidinyl, thiazolyl or oxazolyl group optionally substituted with one or two R3 groups. R2 is a 5- or 6-membered monocyclic heteroaryl or a 9-membered bicyclic heteroaryl, optionally substituted with one or two R6s; in particular, R2 is imidazopyridazinyl, indazole, pyrazolyl, pyridinyl, pyrimidinyl, triazolpyridazinyl, triazolpyridinyl, pyrazolpyridinyl, imidazopyridinyl, phenyl, pyridazinyl, or thiazolyl. Each R3 is independently selected from halogen, cyano or (C1-C4)alkyl or (C1-C4)alkoxy, preferably each R3 is independently selected from fluorine, cyano, methoxy or methyl; m and s are 0 or m is 0 and s is 1, and R4 is a methyl group; Each R6 is independently selected from halogen, cyano, -NH2 group, (C1-C4)alkyl, (C1-C4)alkoxy, -CF3, and (C3-C6) heterocyclic alkyl optionally substituted with one, two, three, or four R7s, preferably each R7 is independently a halogen, a side group, -OH, methyl, or methoxy, and R6 is independently selected from fluorine, cyano, methyl, methoxy, or hydroxyoxetane. Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0084] According to one embodiment, the compound according to this disclosure has formula (Ie), wherein: R1 is a phenyl, pyrazinyl, pyridinyl, thiazolyl, oxazolyl, or pyrimidinyl group that is optionally substituted with one or two R3 groups. R2 is an imidazopyridinyl, indazole, pyrazolyl, pyridinyl, pyrimidinyl, triazolpyridinyl, or triazolpyridinyl, pyrazolpyridinyl, imidazopyridinyl, phenyl, pyridinyl, or thiazolyl, optionally substituted with one or two R6 groups. Each R3 is independently selected from fluorine, cyano, methoxy, or methyl; m and s are 0 or m is 0 and s is 1, and R4 is a methyl group; Each R6 is independently selected from fluorine, cyano, -NH2 group, methyl, -CF3, methoxy or hydroxyoxetane; Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0085] According to one embodiment, the compound according to this disclosure has formula (Ie), wherein: R1 is a phenyl group that is optionally substituted with one or two R3s; R2 is an imidazopyridazinyl, indazole, pyrazolyl, pyridinyl, pyrimidinyl, triazolpyridazinyl, triazolpyridinyl, pyrazolpyridinyl, imidazopyridinyl, phenyl, pyridazinyl, or thiazolyl group optionally substituted with one or two R6 groups. Each R3 is independently selected from fluorine, cyano, or methyl; m and s are 0 or m is 0 and s is 1, and R4 is a methyl group; Each R6 is independently selected from fluorine, cyano, methyl, or methoxy; Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0086] According to one implementation, t and p are equal to 1, and one of q and r is 1 while the other is 0.

[0087] According to this embodiment, the compound of formula (I) more particularly has the following formula (Id): R1, R2, R4, R5, m, and s are as defined above, or their pharmaceutically acceptable salts, solvates, or stereoisomers.

[0088] According to one implementation, m and s in equation (I) above are equal, that is, m and s are 0 or m and s are 1. According to another implementation, at most one of m and s is 1.

[0089] According to one embodiment, this document further discloses compounds of formula (I) having the following formulas (Ib), (Ic), and particularly formulas (Ie) or (Id): (Ib) (Ic) (Ie) (Id) Where R1, R2, R4, R5, m, and s are as defined above. Or its pharmaceutically acceptable salts, solvates or stereoisomers; In particular, it has: Equation (Ib), Formula (Ic), and more specifically formula (Ie) or Formula (Id), Or its pharmaceutically acceptable salts, solvates or stereoisomers; More particularly: Equation (Ib), Formula (Ic), and more specifically formula (Ie), Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0090] According to one embodiment, this document further discloses compounds of formula (I), wherein when the group When the cyclobutyl group is optionally substituted, R4 and R5 are independently selected from halogens, (C1-C4)alkyl groups, or (C1-C4)alkoxy groups.

[0091] According to one embodiment, the compound of formula (If) is further disclosed herein: (If) in R1, R2, R4, R5, m, and s are as defined above, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

[0092] The following compounds (1) through (411) were named according to the rules of the International Union of Pure and Applied Chemistry. The prefixes “cis” and “trans” are also used to specify the relative stereochemistry of two adjacent chiral centers.

[0093] According to one embodiment, the compounds of formula (I) are selected from: (1) trans-3-[(3S)-2-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile; (2) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxynitrile, (3) trans-1-((4-((S)-3-(5-fluoropyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxynitrile, (4) trans-1-((4-((S)-3-(5-fluoropyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-4-methyl-1H-imidazol-5-carboxynitrile, (5) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazolium-5-carboxynitrile, (6) trans-1-((4-((S)-3-(5-fluoropyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazol-5-carboxynitrile, (7) trans-3-((S)-2-(4-((1H-benzo[d]imidazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)-5-fluorobenzonitrile, (8) trans-(4-((1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl)((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)methyl ketone, (9) trans-(4-((1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl)((S)-3-(5-fluoropyridin-3-yl)isoxazolidine-2-yl)methyl ketone, (10) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-benzo[d]imidazolium-5-carboxynitrile, (11) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-benzo[d]imidazolium-5-carboxynitrile, (12) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-benzo[d]imidazolium-6-carboxynitrile, (13) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-benzo[d]imidazolium-6-carboxynitrile, (14) trans-3-((S)-2-(4-((1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolide-3-yl)-5-fluorobenzonitrile, (15) trans-3-((S)-2-(4-((1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolide-3-yl)-5-fluorobenzonitrile, (16) Inverse - 3-((S)-2-(4-((1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)-5-fluorobenzonitrile, (17) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxynitrile, (18) trans-3-fluoro-5-((S)-2-(4-((2-oxobenzo[d]oxazol-3(2H)-yl)methyl)cyclohexane-1-carbonyl)isooxazolidine-3-yl)benzonitrile, (19) trans-3-((S)-2-(4-((6-chloro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)-5-fluorobenzonitrile, (20) trans-3-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)benzo[d]oxazol-2(3H)-one, (21) trans-(4-((6-chloro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexyl)((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)methyl ketone, (22) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-indole-6-carboxynitrile, (23) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-indole-6-carboxynitrile, (24) trans-2-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-2H-pyrazolo[4,3-b]pyridine-6-carboxynitrile, (25) trans-2-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-2H-pyrazolo[4,3-b]pyridine-6-carboxynitrile, (26) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-pyrazolo[4,3-b]pyridine-6-carboxynitrile, (27) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-pyrazolo[4,3-b]pyridine-6-carboxynitrile, (28) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-indazole-6-carboxynitrile, (29) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-indazole-6-carboxynitrile, (30) trans-2-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-2H-indazole-6-carboxynitrile, (31) trans-2-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-2H-indazole-6-carboxynitrile, (32) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-indazole-6-carboxynitrile, (33) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-indazole-6-carboxynitrile, (34) trans-2-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-2H-indazole-6-carboxynitrile, (35) trans-2-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-2H-indazole-6-carboxynitrile, (36) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-benzo[d]imidazolium-6-carboxynitrile, (37) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-benzo[d]imidazolium-6-carboxynitrile, (38) trans-4-fluoro-1-((4-((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazol-6-carboxynitrile, (39) trans-5-fluoro-1-((4-((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazol-6-carboxynitrile, (40) trans-6-fluoro-1-((4-((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazol-5-carboxynitrile, (41) trans-2-((4-((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-2H-indazole-6-carboxynitrile, (42) trans-4-fluoro-2-((4-((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-2H-indazole-6-carboxynitrile, (43) trans-1-((4-((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-indazole-6-carboxynitrile, (44) trans-4-fluoro-1-((4-((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-indazole-6-carboxynitrile, (45) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-indole-6-carboxynitrile, (46) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-indole-6-carboxynitrile, (47) trans-4-fluoro-1-((4-((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-indole-6-carboxynitrile, (48) trans-3-fluoro-5-((S)-2-(4-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)benzonitrile, (49) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl) ketone, (50) trans-3-fluoro-5-((S)-2-(4-((5-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)benzonitrile, (51) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((5-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl) ketone, (52) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-indazole-5-carboxynitrile, (53) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-indazole-5-carboxynitrile, (54) trans-3-fluoro-5-((S)-2-(4-((5-fluoro-1H-indazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)benzonitrile, (55) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((5-fluoro-1H-indazol-1-yl)methyl)cyclohexyl) ketone, (56) trans-3-fluoro-5-((S)-2-(4-(((5-fluoro-2H-indazol-2-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)benzonitrile, (57) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((5-fluoro-2H-indazol-2-yl)methyl)cyclohexyl) ketone, (58) trans-2-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-2H-indazole-5-carboxynitrile, (59) trans-2-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-2H-indazole-5-carboxynitrile, (60) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((3-methyl-1H-indazol-1-yl)methyl)cyclohexyl) ketone, (61) trans-3-fluoro-5-((S)-2-(4-((3-methyl-1H-indazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)benzonitrile, (62) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((3-methyl-2H-indazol-2-yl)methyl)cyclohexyl) ketone, (63) trans-3-fluoro-5-((S)-2-(4-((3-methyl-2H-indazol-2-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)benzonitrile, (64) trans-1-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-benzo[d]imidazol-6-carboxynitrile, (65) trans-1-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-benzo[d]imidazol-5-carboxynitrile, (66) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-indazole-5-carboxynitrile, (67) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-indazole-5-carboxynitrile, (68) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-6-fluoro-3-methyl-1H-indazole-5-carboxynitrile, (69) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-6-fluoro-3-methyl-1H-indazole-5-carboxynitrile, (70) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-benzo[d]imidazolium-6-carboxamide, (71) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-benzo[d]imidazolium-6-carboxamide, (72) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-indazole-5-carboxamide, (73) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-indazole-5-carboxamide, (74) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-benzo[d]imidazol-5-carboxamide, (75) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-benzo[d]imidazol-5-carboxamide, (76) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-indole-6-carboxamide, (77) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-indole-6-carboxamide, (78) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-pyrazolo[4,3-b]pyridine-6-carboxamide, (79) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-pyrazolo[4,3-b]pyridine-6-carboxamide, (80) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-benzo[d]imidazolium-6-carboxamide, (81) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-benzo[d]imidazolium-6-carboxamide, (82) trans-3-((S)-2-(4-((4,5-dimethyl-1H-imidazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)-5-fluorobenzonitrile, (83) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((4,5-dimethyl-1H-imidazol-1-yl)methyl)cyclohexyl) ketone, (84) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-3-methyl-1H-indazole-6-carboxynitrile, (85) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-3-methyl-1H-indazole-6-carboxynitrile, (86) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-indazole-6-carboxynitrile, (87) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-indazole-6-carboxynitrile, (88) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-methyl-1H-imidazolium-5-carboxynitrile, (89) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-methyl-1H-imidazolium-5-carboxynitrile, (90) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-methyl-1H-imidazolium-4-carboxynitrile, (91) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-methyl-1H-imidazolium-4-carboxynitrile, (92) trans-(4-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl)((S)-3-(pyrazin-2-yl)isoxazolidine-2-yl)methyl ketone, (93) trans-3-fluoro-5-((S)-2-(4-((6-fluoro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)benzonitrile, (94) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((6-fluoro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexyl) ketone, (95) trans-3-fluoro-5-((S)-2-(4-(((5-fluoro-1H-indol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolide-3-yl)benzonitrile, (96) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((5-fluoro-1H-indol-1-yl)methyl)cyclohexyl) ketone, (97) trans-6-fluoro-1-((4-((S)-3-(pyrazin-2-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazol-5-carboxynitrile, (98) trans-5-fluoro-1-((4-((S)-3-(pyrazin-2-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazol-6-carboxynitrile, (99) trans-1-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]pyrrolo[3,2-b]pyridine-5-carboxynitrile, (100) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-3-methyl-1H-indazole-6-carboxynitrile, (101) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-3-methyl-1H-indazole-6-carboxynitrile, (102) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-4-fluoro-3-methyl-1H-indazole-6-carboxamide, (103) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-3-methyl-1H-indazole-6-carboxamide, (104) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-indole-6-carboxamide, (105) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-indole-6-carboxamide, (106) trans-5-((S)-2-(4-((6-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)nicotinonitrile, (107) trans-5-((S)-2-(4-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)nicotinonitrile, (108) trans-1-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxynitrile, (109) trans-5-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-2-methylbenzonitrile, (110) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-3-methyl-1H-indole-6-carboxamide, (111) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-3-methyl-1H-indole-6-carboxamide, (112) trans-3-fluoro-5-((S)-2-(4-((6-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)benzonitrile, (113) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((6-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl) ketone, (114) trans-(3-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclobutyl)((S)-3-(p-tolyl)isoxazoline-2-yl)methyl ketone, (115) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(3-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclobutyl) ketone, (116) trans-3-fluoro-5-((S)-2-(3-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclobutane-1-carbonyl)isoxazoline-3-yl)benzonitrile, (117) trans-(4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)cyclohexyl)((S)-3-(p-tolyl)isoxazoline-2-yl)methyl ketone, (118) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)cyclohexyl) ketone, (119) trans-3-((S)-2-(4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)-5-fluorobenzonitrile, (120) trans-3-fluoro-5-[(3S)-2-[4-[(5-methoxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (121) trans-2-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxynitrile, (122) trans-1-[[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-6-sideoxy-pyridine-3-carboxynitrile, (123) trans-5-((S)-2-(4-((6-fluoro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)nicotinonitrile, (124) trans-3-[(3S)-2-[4-[[6-(3,5-dimethylpyrazol-1-yl)pyrimidin-4-yl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]-5-fluorobenzonitrile, (125) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[[6-(3,5-dimethylpyrazol-1-yl)pyrimidin-4-yl]methyl]cyclohexyl] ketone, (126) trans-5-((S)-2-(4-((5-fluoro-1H-indazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)nicotinonitrile, (127) trans-2-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-2H-indazole-6-carboxynitrile, (128) trans-3-fluoro-5-[(3S)-2-[4-[(6-methoxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (129) trans-3-fluoro-5-[(3S)-2-[4-[(6-hydroxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (130) trans-1-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-indole-6-carboxynitrile, (131) trans-2-methyl-5-[[4-[(3S)-3-(p-tolyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]benzamide, (132) trans-5-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-2-methylbenzamide, (133) trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-2-methyl-benzamide, (134) trans-1-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrrolo[3,2-b]pyridine-6-carboxynitrile, (135) trans-3-fluoro-5-[(3S)-2-[4-[[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (136) trans-[4-[[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]methyl]cyclohexyl]-[(3S)-3-(p-tolyl)isoxazoline-2-yl] ketone, (137) trans-1-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrazolo[4,3-b]pyridine-6-carboxynitrile, (138) trans-2-methyl-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]benzamide, (139) trans-2-methyl-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]benzonitrile, (140) trans-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]pyridine-3-carboxynitrile, (141) trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]pyridine-3-carboxynitrile, (142) trans-3-fluoro-5-[(3S)-2-[4-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (143) trans-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]-[4-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)cyclohexyl] ketone, (144) trans-3-fluoro-5-[(3S)-2-[4-[(3-oxoisoindololin-5-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (145) trans-6-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]isoindololin-1-one, (146) trans-3-fluoro-5-[(3S)-2-[4-[[6-(oxecyclobutane-3-yloxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (147) trans-[4-[(5-fluoro-3-pyridinyl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (148) trans-3-fluoro-5-[(3S)-2-[4-[(5-fluoro-3-pyridyl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (149) trans-3-fluoro-5-[(3S)-2-[4-[[6-(2-methoxyethoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (150) trans-3-fluoro-5-[(3S)-2-[4-[(1-methylpyrazol-4-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (151) trans-[4-[(1-methylpyrazol-4-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (152) trans-3-[(3S)-2-[4-[[6-(cyclopropylmethoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]-5-fluorobenzonitrile, (153) trans-3-fluoro-5-[(3S)-2-[4-[[6-(2-hydroxyethoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (154) trans-6-[[4-[(3S)-3-(4-fluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]isoindololin-1-one, (155) trans-6-[[4-[(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]isoindololin-1-one, (156) trans-6-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]isoindololin-1-one, (157) trans-6-[[4-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]isoindololin-1-one, (158) trans-5-[[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-2-methylbenzamide, (159) trans-2-methyl-5-[[4-[(3S)-3-(2-methylthiazolyl-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]benzamide, (160) trans-3-fluoro-5-[[4-[(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-N-methyl-benzamide, (161) trans-3-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-5-fluoro-N-methylbenzamide, (162) trans-3-fluoro-N-methyl-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]benzamide, (163) trans-3-[[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-5-fluoro-N-methylbenzamide, (164) trans-3-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-5-fluoro-N-methyl-benzamide, (165) trans-3-fluoro-5-[[4-[(3S)-3-(4-fluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-N-methyl-benzamide, (166) trans-5-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-2-methylbenzamide, (167) trans-3-fluoro-5-[(3S)-2-[4-[(3-methylimidazol-4-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (168) trans-5-[(3S)-2-[4-[(3-methylimidazol-4-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]pyridin-3-carboxynitrile, (169) trans-3-fluoro-5-[(3S)-2-[4-[[4-(3-hydroxyoxetane-3-yl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (170) trans-[(3S)-3-(4-fluorophenyl)isoxazoline-2-yl]-[4-[[4-(3-hydroxyoxetane-3-yl)phenyl]methyl]cyclohexyl] ketone, (171) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[[4-(3-hydroxyoxetane-3-yl)phenyl]methyl]cyclohexyl] ketone, (172) trans-4-fluoro-3-[[4-[(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-N-methyl-benzamide, (173) trans-4-fluoro-3-[[4-[(3S)-3-(4-fluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-N-methyl-benzamide, (174) trans-3-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-4-fluoro-N-methylbenzamide, (175) trans-4-fluoro-N-methyl-3-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]benzamide, (176) trans-3-[[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-4-fluoro-N-methyl-benzamide, (177) trans-3-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-4-fluoro-N-methyl-benzamide, (178) trans-[4-[(5-fluoro-2-methyl-3-pyridyl)methyl]cyclohexyl]-[(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-yl] methyl ketone, (179) trans-[4-[(5-fluoro-2-methyl-3-pyridyl)methyl]cyclohexyl]-[(3S)-3-(4-fluorophenyl)isoxazoline-2-yl] methyl ketone, (180) trans-[4-[(5-fluoro-2-methyl-3-pyridinyl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (181) trans-3-fluoro-5-[(3S)-2-[4-[(5-fluoro-2-methyl-3-pyridyl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (182) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(5-fluoro-2-methyl-3-pyridyl)methyl]cyclohexyl] ketone, (183) trans-5-[(3S)-2-[4-[[4-(3-hydroxyoxetane-3-yl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]pyridine-3-carboxynitrile, (184) trans-3-fluoro-5-[(3S)-2-[4-[[6-(1-methylcyclopropoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (185) trans-1-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrrolo[3,2-b]pyridine-6-carboxynitrile, (186) trans-1-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrazolo[4,3-b]pyridine-6-carboxynitrile, (187) trans-1-[[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrazolo[4,3-b]pyridine-6-carboxynitrile, (188) trans-1-[[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrrolo[3,2-b]pyridine-6-carboxynitrile, (189) trans-2-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxynitrile, (190) trans-1-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxynitrile, (191) trans-2-fluoro-5-[[4-[(3S)-3-(4-fluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]benzamide, (192) trans-5-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-2-fluoro-benzamide, (193) trans-2-fluoro-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]benzamide, (194) trans-5-[[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-2-fluoro-benzamide, (195) trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-2-fluoro-benzamide, (196) trans-2-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxynitrile, (197) trans-5-[(3S)-2-[4-[(5-fluoro-2-methyl-3-pyridinyl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]pyridin-3-carboxynitrile, (198) trans-1-[[4-[(3S)-3-(2-methylthiazolyl-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrrolo[3,2-b]pyridine-6-carboxynitrile, (199) trans-1-[[4-[(3S)-3-(2-methylthiazolyl-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrazolo[4,3-b]pyridine-6-carboxynitrile, (200) trans-1-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxynitrile, (201) trans-1-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxamide, (202) trans-1-[[4-[(3S)-3-(2-methylthiazolyl-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-5-carboxynitrile, (203) trans-2-[[4-[(3S)-3-(2-methylthiazolyl-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxynitrile, (204) trans-1-[[4-[(3S)-3-(2-methylthiazolyl-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxynitrile, (205) trans-[4-[(8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (206) trans-3-fluoro-5-[(3S)-2-[4-[(8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (207) trans-[4-[[3-fluoro-5-(2-methylimidazol-1-yl)phenyl]methyl]cyclohexyl]-[(3S)-3-(4-fluorophenyl)isoxazoline-2-yl] ketone, (208) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[[3-fluoro-5-(2-methylimidazol-1-yl)phenyl]methyl]cyclohexyl] ketone, (209) trans-[4-[[3-fluoro-5-(2-methylimidazol-1-yl)phenyl]methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (210) trans-5-[(3S)-2-[4-[[3-fluoro-5-(2-methylimidazol-1-yl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]pyridin-3-carboxynitrile, (211) trans-[4-[[3-fluoro-5-(2-methylpyrazol-3-yl)phenyl]methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (212) trans-4-fluoro-6-[[4-[(3S)-3-(4-fluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]isoindololin-1-one, (213) trans-4-fluoro-6-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]isoindoline-1-one, (214) trans-3-fluoro-5-[(3S)-2-[4-[[3-fluoro-5-(2-methylpyrazol-3-yl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (215) trans-1-[[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxynitrile, (216) trans-3-fluoro-5-[(3S)-2-[4-[[3-fluoro-5-(2-methylimidazol-1-yl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (217) trans-1-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-5-carboxynitrile, (218) trans-1-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-5-carboxynitrile, (219) trans-3-fluoro-5-[(3S)-2-[4-[(7-fluoro-3-oxo-isoindololin-5-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (220) trans-[4-[[3-fluoro-5-(2-methylimidazol-1-yl)phenyl]methyl]cyclohexyl]-[(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-yl] ketone, (221) trans-3-fluoro-5-[(3S)-2-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (222) trans-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (223) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (224) trans-3-fluoro-5-[(3S)-2-[4-[(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (225) trans-3-fluoro-5-[(3S)-2-[4-[(2-methylimidazo[1,2-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (226) trans-[4-[(2-methylimidazo[1,2-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl] ketone, (227) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(2-methylimidazo[1,2-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (228) trans-2-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxamide, (229) trans-1-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxamide, (230) trans-1-[[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxamide, (231) trans-1-[[4-[(3S)-3-(4-cyano-2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxamide, (232) trans-2-[[4-[(3S)-3-(4-cyano-2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxamide, (233) trans-2-[[4-[(3S)-3-(2-methylthiazolyl-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxamide, (234) trans-1-[[4-[(3S)-3-(2-methylthiazolyl-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxamide, (235) trans-5-[(3S)-2-[4-[(1-methylpyrazol-4-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]pyridin-3-carboxynitrile, (236) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(1-methylpyrazol-4-yl)methyl]cyclohexyl] ketone, (237) trans-3-fluoro-5-[(3S)-2-[4-[(2-methylpyrazol-3-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (238) trans-[4-[(2-methylpyrazol-3-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (239) trans-3-fluoro-5-[(3S)-2-[4-[(2-methylthiazolyl-4-yl)methyl]cyclohexanecarbonyl]isoxazolyl-3-yl]benzonitrile, (240) trans-[4-[(2-methylthiazolyl-4-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (241) trans-1-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indole-6-carboxynitrile, (242) trans-2-fluoro-5-[[4-[(3S)-3-(4-fluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]benzonitrile, (243) trans-2-fluoro-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]benzonitrile, (244) trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-2-fluorobenzonitrile, (245) trans-3-fluoro-5-[(3S)-2-[4-(pyrazin-2-ylmethyl)cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (246) trans-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]-[4-(pyrazin-2-ylmethyl)cyclohexyl] ketone, (247) trans-3-fluoro-5-[(3S)-2-[4-(pyrimidin-5-ylmethyl)cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (248) trans-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]-[4-(pyrimidin-5-ylmethyl)cyclohexyl] ketone, (249) trans-3-fluoro-5-[(3S)-2-[4-[(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]-1,2-oxazolidine-3-yl]benzonitrile, (250) trans-[4-[(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidine-2-yl] ketone, (251) trans-1-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]indole-5-carboxamide, (252) trans-1-[[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indole-5-carboxamide, (253) trans-1-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indole-5-carboxamide, (254) trans-1-[[4-[(3S)-3-(2-methylthiazolyl-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indole-5-carboxamide, (255) trans-1-[[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indole-5-carboxamide, (256) trans-3-fluoro-5-[(3S)-2-[4-[[3-fluoro-5-(hydroxymethyl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (257) trans-5-[(3S)-2-[4-[[3-fluoro-5-(hydroxymethyl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]pyridin-3-carboxynitrile, (258) trans-3-fluoro-5-[(3S)-2-[4-[(1-methyltriazol-4-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (259) trans-[4-[[3-fluoro-5-(hydroxymethyl)phenyl]methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (260) trans-[(3S)-3-(4-fluorophenyl)isoxazoline-2-yl]-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (261) trans-[(3S)-3-(3,4-difluorophenyl)isoxazoline-2-yl]-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (262) trans-5-[(3S)-2-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]pyridin-3-carboxynitrile, (263) trans-3-fluoro-5-[(3S)-2-[4-[(2-methylpyrimidin-5-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (264) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(2-methylpyrimidin-5-yl)methyl]cyclohexyl] ketone, (265) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[[3-fluoro-4-(hydroxymethyl)phenyl]methyl]cyclohexyl] ketone, (266) trans-3-fluoro-5-[(3S)-2-[4-[[3-fluoro-4-(hydroxymethyl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (267) trans-5-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-2-methylpyridine-3-carboxylonitrile, (268) trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-2-methylpyridine-3-carboxylonitrile, (269) 5-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]norbornene-1-yl]methyl]-2-methylbenzamide, (270) 5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]norbornene-1-yl]methyl]-2-methylbenzamide, (271) 2-Methyl-5-[[4-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]norbornen-1-yl]methyl]benzamide, (272) 2-Methyl-5-[[4-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-bicyclo[2.2.2]octyl]methyl]benzamide, (273) 5-[[4-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]-1-bicyclo[2.2.2]octyl]methyl]-2-methylbenzamide, (274) 5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]-1-bicyclo[2.2.2]octyl]methyl]-2-methyl-benzamide, (275) trans-5-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-4-methylpyridine-3-carboxylonitrile, (276) trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-4-methylpyridine-3-carboxylonitrile, (277) trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-6-methylpyridine-3-carboxylonitrile, (278) trans-5-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-6-methylpyridine-3-carboxynitrile carboxylate, (279) trans-3-fluoro-5-[(3S)-2-[4-[[3-fluoro-4-(2-hydroxyethyl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (280) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[[3-fluoro-4-(2-hydroxyethyl)phenyl]methyl]cyclohexyl] ketone, (281) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (282) trans-3-fluoro-5-[(3S)-2-[4-[[3-fluoro-5-(2-hydroxyethyl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (283) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[[3-fluoro-5-(2-hydroxyethyl)phenyl]methyl]cyclohexyl] ketone, (284) trans-3-fluoro-5-[(3S)-2-[4-[(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (285) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (286) trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-4-methyl-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-2-methyl-pyridine-3-carboxylonitrile, (287) trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-4-methyl-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-4-methyl-pyridine-3-carboxylonitrile, (288) trans-3-[(3S)-2-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]-5-fluorobenzonitrile, (289) trans-4-fluoro-3-[(3S)-2-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (290) trans-3-[(3S)-2-[4-[(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]-5-fluorobenzonitrile, (291) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)methyl]cyclohexyl] ketone, (292) trans-3-[(3S)-2-[4-[(2,7-dimethylimidazo[1,2-b]pyridazin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]-5-fluorobenzonitrile, (293) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(2,7-dimethylimidazo[1,2-b]pyridazin-6-yl)methyl]cyclohexyl] ketone, (294) trans-3-fluoro-5-[(3S)-2-[4-[(1-methylindazol-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (295) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(1-methylindazole-6-yl)methyl]cyclohexyl] ketone, (296) trans-3-fluoro-5-[(3S)-2-[4-[(1-methylpyrazolo[4,3-b]pyridin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (297) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(1-methylpyrazolo[4,3-b]pyridin-6-yl)methyl]cyclohexyl] ketone, (298) 6-Fluoro-1-[[trans-4-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-5-carboxynitrile, (299) trans-2-fluoro-5-[[4-[(3S)-3-(6-methylpyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]benzamide, (300) trans-3-[(3S)-2-[4-[(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]-1,2-oxazolidine-3-yl]-5-fluorobenzonitrile, (301) trans-[4-[(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidine-2-yl]methyl ketone, (302) trans-3-fluoro-5-[(3S)-2-[4-[(6-methylpyridazin-4-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (303) trans-3-fluoro-5-[(3S)-2-[4-[(6-methylpyridazin-3-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (304) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(6-methylpyridazin-3-yl)methyl]cyclohexyl] ketone, (305) trans-[4-[[5-(2,5-dimethylpyrazol-3-yl)-3-pyridinyl]methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (306) trans-[(3S)-3-(4-fluorophenyl)isoxazoline-2-yl]-[4-[(2-methylpyrazol-3-yl)methyl]cyclohexyl] ketone, (307) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(2-methylpyrazol-3-yl)methyl]cyclohexyl] ketone, (308) trans-[4-[[5-(1,3-dimethylpyrazol-4-yl)-3-pyridinyl]methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (309) trans-[(3S)-3-(3,4-difluorophenyl)isoxazoline-2-yl]-[4-[(2-methylpyrimidin-5-yl)methyl]cyclohexyl] ketone, (310) trans-[(3S)-3-(3,4-difluorophenyl)isoxazoline-2-yl]-[4-[(2-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)methyl]cyclohexyl] ketone, (311) trans-[(3S)-3-(3,4-difluorophenyl)isoxazoline-2-yl]-[4-[(2-methylpyrazol-3-yl)methyl]cyclohexyl] ketone, (312) trans-3-[(3S)-2-[4-[(2,6-dimethylpyrimidin-4-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]-5-fluorobenzonitrile, (313) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(6-methylpyrimidin-4-yl)methyl]cyclohexyl] ketone, (314) trans-[4-[(8-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidine-2-yl] ketone, (315) trans-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidin-2-yl]-[4-[(2-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)methyl]cyclohexyl] ketone, (316) trans-[4-[(5-fluoro-2-methyl-3-pyridinyl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyrazin-2-yl)isoxazolidine-2-yl]methyl ketone, (317) trans-[4-[(3,7-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(3-fluorophenyl)isoxazoline-2-yl] methyl ketone, (318) trans-[(3S)-3-(3,4-difluorophenyl)isoxazoline-2-yl]-[4-[(3,7-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (319) trans-[4-[(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(4-fluorophenyl)isoxazoline-2-yl] ketone, (320) trans-[4-[(8-fluoro-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(4-fluorophenyl)isoxazoline-2-yl] ketone, (321) trans-[(3S)-3-(4-fluorophenyl)isoxazoline-2-yl]-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)methyl]cyclohexyl] ketone, (322) trans-[2-cyano-4-[(3S)-2-[4-[(2-methylimidazo[1,2-b]pyridazin-7-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]phenyl], (323) trans-[2-fluoro-4-[(3S)-2-[4-[(2-methylimidazo[1,2-b]pyridazin-7-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]phenyl], (324) trans-[4-[(3S)-2-[4-[(2-methylimidazo[1,2-b]pyridazin-7-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]phenyl], (325) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazoline-2-yl] ketone, (326) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (327) trans-[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-yl]-[4-[(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (328) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyrazin-2-yl)isoxazolidin-2-yl] methyl ketone, (329) trans-[4-[(1-methylpyrazolo[4,3-b]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (330) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (331) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-fluoropyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (332) trans-[4-[(2,5-dimethylpyridin-4-yl)methyl]cyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl] ketone, (333) trans-[4-[(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (334) trans-[(3S)-3-(5-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (335) trans-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (336) trans-[(3S)-3-(5-fluoropyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (337) trans-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl]-[4-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)cyclohexyl] ketone, (338) trans-[(3S)-3-(5-fluoropyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)cyclohexyl] ketone, (339) trans-[4-[(2,5-dimethylpyridin-4-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyrazin-2-yl)-1,2-oxazolidin-2-yl] methyl ketone, (340) trans-[4-[(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidine-2-yl] ketone, (341) trans-[4-[(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (342) trans-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl]-[4-[(8-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (343) trans-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(2-methylpyrimidin-5-yl)methyl]cyclohexyl] ketone, (344) trans-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(2-methylpyrimidin-5-yl)methyl]cyclohexyl] ketone, (345) trans-[(3S)-3-(5-fluoropyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(8-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (346) trans-[4-[(2-methylpyrimidin-5-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidin-2-yl]methyl ketone, (347) trans-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (348) trans-[4-[[4-(3-hydroxyoxetane-3-yl)phenyl]methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl] ketone, (349) trans-[4-[(2-methylimidazo[1,2-b]pyridazin-7-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidin-2-yl]methyl ketone, (350) trans-[4-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-ylmethyl)-cyclohexyl]-((S)-3-pyrazin-2-yl-isoxazolidine-2-yl)-methyl ketone, (351) trans-[4-[(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (352) trans-[4-[[4-(3-hydroxyoxetane-3-yl)phenyl]methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidin-2-yl]methyl ketone, (353) trans-[4-[(2-methylimidazo[1,2-b]pyridazin-7-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl] ketone, (354) trans-[4-(2,5-dimethyl-pyridin-4-ylmethyl)-cyclohexyl]-[(S)-3-(6-methyl-pyridin-3-yl)-isoxazolidine-2-yl]-methyl ketone, (355) trans-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)methyl]cyclohexyl]-[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazoline-2-yl]-methyl ketone (356) trans-[4-(2,5-dimethyl-pyridin-4-ylmethyl)-cyclohexyl]-((S)-3-pyrazin-2-yl-isoxazolidine-2-yl)-methyl ketone, (357) trans-[4-[(6-methylpyridazin-3-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (358) trans-[4-[(3,5-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidine-2-yl] ketone, (359) trans-[4-[(8-fluoro-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidine-2-yl] ketone, (360) trans-(S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(2-methyl-1,3-thiazolyl-4-yl)methyl]cyclohexyl] ketone, (361) trans-[4-(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)-cyclohexyl]-[(S)-3-(2-methyl-thiazolyl-4-yl)isoxazolidine-2-yl]-methyl ketone, (362) trans-[(S)-3-(2-methyl-thiazolyl-4-yl)-isoxazolidine-2-yl]-[4-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)cyclohexyl]-methyl ketone, (363) trans-[4-(8-fluoro-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylmethyl)-cyclohexyl]-[(S)-3-(2-methyl-thiazolyl-4-yl)isoxazolidine-2-yl]-methyl ketone, (364) trans-[4-(8-fluoro-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylmethyl)-cyclohexyl]-[(S)-3-(6-methyl-pyridin-3-yl)-isoxazolidine-2-yl]-methyl ketone, (365) trans-[4-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylmethyl)-cyclohexyl]-[(S)-3-(6-methyl-pyridin-3-yl)-isoxazoline-2-yl]-methyl ketone, (366) trans-[4-(2,5-dimethyl-pyridin-4-ylmethyl)-cyclohexyl]-[(S)-3-(2-methyl-thiazolyl-4-yl)-isoxazolidine-2-yl]-methyl ketone, (367) trans-[4-(8-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)-cyclohexyl]-[(S)-3-(2-methyl-thiazolyl-4-yl)isoxazoline-2-yl]-methyl ketone, (368) trans-[4-(8-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)-cyclohexyl]-[(S)-3-(6-methyl-pyridin-3-yl)-isoxazolidine-2-yl]-methyl ketone, (369) trans-{4-[4-(3-hydroxy-oxacyclobutane-3-yl)-benzyl]-cyclohexyl}-[(S)-3-(2-methyl-thiazolyl-4-yl)-isoxazolyl-2-yl]-methyl ketone, (370) trans-[4-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-ylmethyl)-cyclohexyl]-[(S)-3-(2-methyl-thiazo-4-yl)-isoxazolidine-2-yl]-methyl ketone, (371) trans-[4-(2-methyl-imidazo[1,2-b]pyridazin-7-ylmethyl)-cyclohexyl]-[(S)-3-(2-methyl-thiazo-4-yl)-isoxazolidine-2-yl]-methyl ketone, (372) trans-[(S)-3-(2-methyl-thiazolyl-4-yl)-isoxazolidine-2-yl]-[4-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)cyclohexyl]-methyl ketone, (373) trans-[(S)-3-(6-methyl-pyridin-3-yl)-isoxazolidine-2-yl]-[4-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)cyclohexyl]-methyl ketone, (374) trans-[4-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-cyclohexyl]-((S)-3-pyrazin-2-yl-isoxazolidine-2-yl)-methyl ketone, (375) trans-[4-(3,5-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylmethyl)-cyclohexyl]-[(S)-3-(2-methyl-thiazolyl-4-yl)isoxazoline-2-yl]-methyl ketone, (376) trans-[4-(3,5-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylmethyl)-cyclohexyl]-[(S)-3-(6-methyl-pyridin-3-yl)-isoxazoline-2-yl]-methyl ketone, (377) trans-[4-[(2,5-dimethylpyridin-4-yl)methyl]cyclohexyl]-[(3S)-3-(2-methyl-1,3-oxazol-4-yl)-1,2-oxazolidine-2-yl] ketone, (378) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (379) trans-[4-[(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyrazin-2-yl)-1,2-oxazolidine-2-yl] ketone, (380) trans-[4-[(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-fluoropyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (381) trans-[4-[(8-chloro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (382) trans-[4-[(8-chloro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-fluoropyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (383) trans-[4-[(8-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (384) trans-[4-[(5-fluoro-2-methylpyridin-4-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyrazin-2-yl)-1,2-oxazolidin-2-yl] methyl ketone, (385) trans-[4-[(5-chloro-2-methylpyridin-4-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyrazin-2-yl)-1,2-oxazolidin-2-yl] methyl ketone, (386) trans-[4-[(5-fluoro-2-methylpyridin-4-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl] ketone, (387) trans-[4-[(6-methylpyridazin-3-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl] methyl ketone, (388) trans-[4-[(6-methylpyridazin-3-yl)methyl]cyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl] ketone, (389) trans-[4-[(5-chloro-2-methylpyridin-4-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl] ketone, (390) trans-[4-[(8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (391) trans-[4-[(2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (392) trans-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (393) trans-[4-[(2,4-dimethylpyrimidin-5-yl)methyl]cyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl] methyl ketone, (394) trans-[4-[(5-fluoro-2-methylpyridin-4-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidin-2-yl] ketone, (395) trans-[(3S)-3-(5-methylpyrazin-2-yl)-1,2-oxazolidin-2-yl]-[4-[(2-methylpyrazin-3-yl)methyl]cyclohexyl] ketone, (396) trans-[4-[(5-chloro-2-methylpyridin-4-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidin-2-yl] methyl ketone, (397) trans-[4-[(2-methylpyrazol-3-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] methyl ketone, (398) trans-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(6-methylpyridazin-4-yl)methyl]cyclohexyl] ketone, (399) trans-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[[2-methyl-4-(trifluoromethyl)pyrimidin-5-yl]methyl]cyclohexyl] ketone, (400) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]-1-methylcyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (401) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]-1-methylcyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (402) cis-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]-1-methylcyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (403) cis-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]-1-methylcyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (404) trans-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(2-methylpyrazol-3-yl)methyl]cyclohexyl] ketone, (405) cis-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]-4-methylcyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (406) cis-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]-4-methylcyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (407) cis-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]-4-methylcyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (408) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]-4-methylcyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (409) trans-[(3S)-3-(5-methylpyrazin-2-yl)-1,2-oxazolidin-2-yl]-[4-[(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (410) trans-[4-[(1,3-dimethylpyrazolo[4,3-b]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyrazin-2-yl)-1,2-oxazolidine-2-yl] methyl ketone, and (411) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyrazin-2-yl)isoxazolidin-2-yl] ketone; Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0094] Among the compounds of formula (I), the following compounds may be specifically mentioned: compounds (1), (2), (3), (7), (8), (10), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (26), (27), (28), (29), (31), (32), (33), (35), (36), (37), (38), (39), (43), (44), (45), (46), (47), (48), (49), (50), (51), (52), (53), (54), (55), (57), (58), (60), ( 61), (62), (63), (64), (66), (67), (68), (69), (72), (73), (75), (76), (77), (79), (83), (84), (85), (86), (87), (89), (93), (94), (95), (96), (99), (100), (101), (102), (103), (104), (105), (108), (109), (110), (111), (112), (113), (118), (120), (121), (123), (125), (126), (127), (128), (12 9), (130), (131), (132), (133), (134), (136), (137), (138), (139), (141), (142), (144), (145), (146), (147), (148), (149), (150), (152), (153), (154), (155), (156), (158), (159), (160), (161), (162), (163), (164), (165), (166), (169), (170), (171), (172), (173), (174), (175), (176), (177) ),(178),(179),(180),(181),(182),(183),(184),(185),(186),(190),(191),(192),(193),(194),(195),(197),(198),(200),(202),(204),(206),(208),(210),(211),(212),(213),(214),(215),(216),(217),(218),(219),(220),(221),(222),(223),(224),(225),(226),(227),(231)(236), (239), (242), (243), (244), (245), (249), (250), (251), (256), (257), (259), (260), (261), (264), (265), (266), (267), (268), (269), (273), (274), (275), (276), (277), (278), (279), (280), (281), (282), (283), (284), (285), (286), (287), (288), (290), (291) 、(292),(293),(294),(295),(296),(297),(298),(299),(300),(301),(302),(303),(304),(305),(306),(307),(308),(309),(310),(311),(312),(313),(314),(315),(316),(317),(318),(319),(320),(321),(322),(323),(324),(325),(326),(327),(328),(329) 、(330),(331),(332),(333),(334),(335),(336),(337),(338),(339),(340),(341),(342),(343),(344),(345),(346),(347),(348),(349),(350),(351),(352),(353),(354),(355),(356),(357),(358),(359),(360),(361),(362),(363),(364),(365),(366),(367) , (368), (369), (370), (371), (372), (373), (374), (375), (376), (377), (378), (379), (380), (381), (382), (383), (384), (385), (386) , (387), (388), (389), (390), (391), (392), (393), (394), (395), (396), (397), (398), (399), (400), (401), (402), (403), (404), (405) and (406), (407), (408), (409), (410) and (411), Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0095] According to another specific embodiment of this disclosure, the compound of formula (I) is selected from compounds (1), (3), (7), (17), (18), (20), (21), (22), (23), (26), (27), (28), (29), (31), (32), (33), (36), (37), (43), (44), (45), (46), (47), (48), (49), (52), (53), (54), (55), (60), (61), (62), (66), (67), (68), (69), (73), (76), (77), (79), (84), (85), (86), (87), (93), (94), (95), (96), (87), (93), (94), (95), (96), (97), (96), (97), (98), (9 ... 6), (100), (101), (103), (104), (105), (109), (110), (112), (113), (125), (128), (130), (131), (132), (133), (138), (139), (141), (144), (148), (149), (150), (152), (153), (155), (156), (160), (161), (162), (163), (164), (165), (170), (171), (172), (173), (174), (175), (176), (177) (180), (190), (191), (192), (193), (194), (195), (197), (198), (204), (206), (208), (210), (211), (212), (213), (214), (215), (216), (217), (218), (219), (221), (223), (225), (227), (236), (242), (243), (244), (245), (249), (250), (251), (256), (257), (259), (260), (261), (264), (26 5), (266), (267), (268), (273), (275), (276), (277), (278), (279), (280), (281), (282), (283), (285), (286), (287), (288), (290), (291), (292), (293), (294), (295), (296), (297), (298), (299), (300), (303), (306), (307), (309), (310), (311), (312), (313), (314), (315), (316), (317)(318), (319), (320), (321), (322), (323), (324), (325), (326), (327), (328), (329), (330), (331), (332), (333), (334), (335), (336), (337), (338), (339), (340), (341), (342), (343), (344), (345), (346), (347), (348), (349), (350), (351), (352), (353), (354), (355), (356), (357), (358), (359), (360), (361) 、(362),(363),(364),(365),(366),(367),(368),(369),(370),(371),(372),(373),(374),(375),(376),(377),(378),(379),(380),(381),(382),(383),(384),(385),(386),(387),(388),(389),(390),(391),(392),(393),(394),(395),(396),(397),(398),(399),(400),(401),(402),(403),(404),(405) (406), (407), (408), (409), (410), and (411), Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0096] According to another specific embodiment of this disclosure, the compound of formula (I) is selected from compounds (1), (180), (260), (288), (298), (306), (307), (309), (310), (311), (312), (313), (314), (315), (316), (317), (318), (319), (320), (321), (322), (323), and (324) or pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

[0097] According to another specific embodiment of this disclosure, the compound of formula (I) is selected from compounds (316), (326), (327), (328), (332), (334), (335), (337), (339), (343), (354), (384), (385), (392), (393), (395) and (411) or pharmaceutically acceptable salts, solvates or stereoisomers thereof.

[0098] Some of the compounds in this disclosure are described in Table 1 below, which is illustrative only and does not limit the scope of this disclosure.

[0099] The NMR and LC / MS data in Table 1 were obtained according to the methods detailed in the experimental section provided for the detailed example synthesis.

[0100] Table 1. Structure and analytical characterization of compounds (1) to (411) Manufacturing method Compounds of formula (I) can be prepared using the methods disclosed herein and their conventional modifications (which will be clear given the content of this disclosure) and methods well known in the art.

[0101] Scheme 1: General synthesis of compounds of formula (I) (where R1, R2, R4, R5, m, s, p, q, r, and t are as defined above). According to the first synthetic method (SM1), the compound of formula (I) can be obtained from the alkyl ester of formula (III). Step 2 involves the hydrolysis of the alkyl ester of formula (III) to form the compound of formula (IIa) and can be carried out under well-known conditions using, for example, lithium hydroxide or sodium hydroxide in water or solvent mixtures (such as THF / water or THF / water / MeOH). Step 1a is an amide coupling between a suitably substituted isoxazolidine compound of formula (A) and a compound of formula (IIa). It can be carried out in aprotic solvents (such as DMF, DMSO, acetonitrile, etc.) using, for example, ethyl cyanohydroxyimino(IIa), acyl chloride, HOBt, HATU, HBTU, PyBOP or 1-propylphosphonic anhydride (T3P) under basic conditions (e.g., diisopropylethylamine, etc.) by standard acid activation to form the compound of formula (I).

[0102] The substituted isoxazolidine of formula (A) can be synthesized by known procedures from literature (e.g., WO 2017096301, WO2019130230 and WO 2021245070).

[0103] According to the second synthetic method (SM2), the compound of formula (I) can be obtained from the isoxazolidine derivative of formula (IIb) (where the leaving group can represent a fluorine, chlorine, iodine or bromine atom, a sulfonate group, an O-nonafluorobutyrate sulfonate or an O-trifluoromethanesulfonate).

[0104] Where R2 represents an optionally substituted heteroaryl group containing a nitrogen atom, the compound of formula (I) can be obtained from the isoxazolidine derivative of formula (IIb) via alkylation step 1b. Compound (IIb) is reacted with a suitable heteroaryl compound containing a nitrogen atom in an inert solvent (such as, for example, DMF or THF) in the presence of a base (such as NaH, Cs2CO3 or K2CO3).

[0105] Where R2 represents an aryl or heteroaryl group that does not contain a nitrogen atom, the compound of formula (I) can be used, for example, by photoredox catalysis (described in detail in...). JACS (2016, 138, 8084-8087) or cross-electrophilic coupling (detailed in...) ACS Catal (2020, 10, 12642-12656) obtained from the isoxazolidine derivative of formula (IIb) via step 1c.

[0106] Compounds of formula (IIb) can be synthesized by procedures known in the literature or as described herein.

[0107] Scheme 2: Synthesis of the compound of formula (III) (where R2 is an optional substituted benzimidazole group). R2 indicates that the compound of formula (I) with an optional substituted imidazole group can be synthesized starting from an optional substituted o-fluoronitrobenzene (B) and a compound of formula (IVa). In scheme 2, R4, R5, R6, m, s, p, q, r, and t are as defined above for formula (I), o is 0, 1, 2, or 3, R8 represents a hydrogen atom or an R6 group as defined above, and R9 represents a hydrogen atom or a group selected from the following groups: halogen, cyano, -OH, (C1-C4)alkyl, CF3, -C(O)NH2, C(O)NH(C1C4)-alkyl, -C(O)OH, -C(O)O-(C1-C4)alkyl, SO2NH2, and (C1-C4)alkoxy.

[0108] Step 5 is the S process carried out in a suitable solvent (such as acetonitrile) in the presence of a base (such as diisopropylethylamine). N Ar reaction. The resulting nitroaniline compound (Va) can then be converted (step 4) to the corresponding aminoaniline compound (IVa), which can be achieved, for example, by palladium-catalyzed reduction in a suitable solvent (such as methanol) under a hydrogen atmosphere. Step 3 allows for the yield of compound (IIIa) via condensation with a suitable orthoester or acyl halide bearing an R8 group (e.g., acetyl chloride or trimethyl orthoformate). This type of reaction can be carried out in solvents such as methanol or dioxane, respectively.

[0109] Optionally substituted o-fluoronitrobenzene (B) can be synthesized using known procedures in the literature.

[0110] Compounds of formula (VIa) can be synthesized using known procedures in the literature or as described herein.

[0111] Scheme 3: Synthesis of compounds of formula (III) (where R2 represents an optional substituted aryl or heteroaryl group different from benzimidazolyl). Compounds of general formula (IIIb) (where R2 represents an optionally substituted heteroaryl group containing a nitrogen atom) can be synthesized from compound (IVb) by alkylation (step 6a) under the same conditions as detailed above with respect to step 1b for SM2. The leaving group can be an iodine or bromine atom, or a sulfonate group.

[0112] In the case where R2 represents an aryl or heteroaryl group without a nitrogen atom, the compound of formula (IIIb) can be obtained from compound (IVb) via step 6b by photoredox catalysis or cross-electrophilic coupling similar to step 1c of the general procedure SM2.

[0113] Compounds of formula (IVb) can be synthesized by means of literature (such as March's Advanced Organic Chemistry, John Wiley & Sons; 2019) or by known procedures as described herein.

[0114] The functional groups (such as acids, esters, amides, nitriles, halogens) in a compound can be transformed (interconverted) into other functional groups using standard methods (such as esterification, saponification, halogenation, Suzuki reaction) to obtain other compounds of formula (I).

[0115] The synthesis of the typical compounds described herein can be carried out as illustrated in the examples below. Reagents can be commercially available, for example, from Sigma Aldrich or other chemical suppliers, if applicable. It should be understood that other method conditions may also be used, unless otherwise specified, given typical or preferred method conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.). Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0116] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, a variety of protecting groups are described in Wuts, PGM, Greene, TW, & Greene, TW (2006), Greene's protective groups in organicsynthesis, Hoboken, NJ, Wiley-Interscience, and the references cited therein.

[0117] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Therefore, such compounds can be prepared or isolated as pure stereoisomers, i.e., individual enantiomers or diastereomers or mixtures rich in stereoisomers, if desired. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included within the scope of this disclosure. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, photoactive starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0118] The starting materials used in the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Other preparations can be made using procedures described in standard reference texts or their obvious modifications, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1–15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1–5, and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1–40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry (John Wiley, and Sons, 5th edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). The terms “solvent,” “inert organic solvent,” or “inert solvent” refer to solvents that are inert under the reaction conditions described herein (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, dichloromethane (or dichloromethane, “DCM”), diethyl ether, methanol, pyridine, etc.). Unless otherwise specified, the solvents used in the reactions described herein are inert organic solvents, and the reactions are carried out under an inert gas, preferably argon.

[0119] Pharmaceutical Composition The compounds described herein are typically administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions comprising one or more of the compounds described herein or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof, and one or more pharmaceutically acceptable mediators selected from carriers, adjuvants, and excipients are also provided herein.

[0120] According to another aspect, pharmaceutical compositions comprising the compounds described herein as active ingredients are disclosed. The compounds of this disclosure will generally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient, and these pharmaceutical compositions comprise an effective dose of at least one compound as defined herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0121] The excipient is selected from conventional excipients known to those skilled in the art, depending on the desired form of the drug and the method of administration.

[0122] In these pharmaceutical compositions intended for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal, or rectal administration, the active ingredient is a compound of formula (I) above or a salt or solvate thereof, which may be administered in unit doses to subjects (e.g., humans) in a mixture with conventional pharmaceutical excipients for the prevention or treatment of diseases or disorders or conditions at least partially mediated by receptor-interacting protein kinase 1, and particularly acute and chronic neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS).

[0123] Unit application Appropriate forms of administration include oral forms such as tablets, soft or hard gel capsules, powders, granules, and oral solutions or suspensions; sublingual, buccal, intratracheal, intraocular, and intranasal forms; forms for inhalation, external, transdermal, subcutaneous, intramuscular, or intravenous administration; rectal forms; and implants.

[0124] When prepared in unit-dosage form, the pharmaceutical compositions of this disclosure typically contain 1 mg to 1000 mg of active ingredient. The amount of active ingredient combined with one or more excipients to produce a single unit-dosage form will vary as necessary depending on the host being treated and the specific route of administration. For example, formulations intended for oral administration to humans will generally contain, for example, 0.5 mg to 0.5 g of active ingredient, compounded with an appropriate and convenient amount of excipients (which will vary from about 5% to about 98% by weight of the total composition).

[0125] As an example, a unit administration form of the compounds described herein in tablet form may contain the following components: Compound 50.0 mg Mannitol 223.75 mg Cross-linked carboxymethyl cellulose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg When using the compounds of this disclosure for therapeutic or preventative purposes, taking into account that if fractionated administration is required, their administration would typically result in a daily dose ranging from, for example, 0.1 mg / kg to 75 mg / kg body weight.

[0126] Generally, smaller doses are administered when the route is parenteral. Therefore, for example, for intravenous or intraperitoneal administration, doses in the range of 0.1 mg / kg to 30 mg / kg body weight will generally be used. Oral administration, particularly in tablet form, is also suitable. Typically, a unit dosage form will contain about 0.5 mg to 0.5 g of the compound described in this disclosure.

[0127] There may be exceptional cases where a higher or lower dose is appropriate; such a dose does not depart from the scope of this disclosure. In accordance with usual practice, the appropriate dose for each patient is determined by the physician based on the method of administration and the patient's weight and response.

[0128] Treatment In other embodiments, this document provides methods for treating receptor-interacting protein kinase 1-mediated diseases or disorders. The methods include administering a therapeutically effective amount of a compound or pharmaceutical composition as described herein to a subject in need. In some embodiments, the receptor-interacting protein kinase 1-mediated disease or disorder is Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS).

[0129] Therefore, the receptor-interacting protein kinase 1 inhibitors of this disclosure may be used to treat diseases and conditions mediated by receptor-interacting protein kinase 1, including but not limited to neurodegenerative diseases and central nervous system (CNS) diseases.

[0130] Neurodegenerative diseases and CNS diseases The receptor-interacting protein kinase 1 inhibitors described in this article can also be used to treat neurodegenerative diseases. Neurodegenerative diseases can affect many bodily functions, such as balance, movement, speech, breathing, and heart function. Neurodegenerative diseases can be hereditary or caused by medical conditions such as alcoholism, tumors, stroke, toxins, chemicals, and viruses. Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease.

[0131] In some embodiments, the compounds and compositions of this disclosure can be used to treat Alzheimer's disease. In some embodiments, the compounds and compositions of this disclosure can be used to treat Parkinson's disease. In some embodiments, the compounds and compositions of this disclosure can be used to treat amyotrophic lateral sclerosis (ALS).

[0132] More generally, the receptor-interacting protein kinase 1 inhibitors described herein can be used to maintain neuronal viability and promote axonal growth and neural function within the central nervous system (CNS). Therefore, these compounds can be used to reduce or even reverse the loss of cognitive, motor, and sensory function associated with CNS diseases or disorders by maintaining neuronal viability and / or promoting axonal regeneration and / or neural function.

[0133] If desired, the effective daily dose of the active compound can be administered as two, three, four, five, six or more sub-dose, said sub-dose being administered at appropriate intervals throughout the day, optionally in a single dosage form. In some embodiments, this disclosure relates to compounds for inhibiting cell death, said compounds being represented by formula (I). In some embodiments, the compounds of this disclosure are cell death inhibitors. In any case, the compounds of this disclosure exert their inhibitory effect on cell death at a concentration of less than about 50 μmol in another embodiment, more in another embodiment at a concentration of less than about 10 μmol, and most in another embodiment at a concentration of less than 1 μmol. The compounds of this disclosure can be used in standard animal models of stroke and standard protocols (such as those described by Hara, H. et al.). Proc. Natl. Acad. Sci.USA The test was conducted in accordance with the description in , 1997.94(5): 2007-12.

[0134] When the compounds of this disclosure are administered to humans and animals as medicines, they may be administered on their own or as a pharmaceutical composition comprising, for example, 0.1% to 99.5% (more in another embodiment, 0.5% to 90%) of an active ingredient and a pharmaceutically acceptable carrier.

[0135] The compounds or combinations thereof described herein may be administered once, twice, three or four times daily using any of the suitable modes described above. Furthermore, administration of the compound or treatment with the compound may continue for several days; for example, for a treatment cycle, treatment typically lasts at least 7, 14, or 28 days. Treatment cycles are well known and often alternate between cycles with a withdrawal period of approximately 1 to 28 days, typically about 7 days or about 14 days. In some embodiments, treatment cycles may also be continuous.

[0136] When administered orally, the total daily dose for human subjects can be between 1 mg and 1,000 mg, approximately 1,000–2,000 mg / day, approximately 10–500 mg / day, approximately 50–300 mg / day, approximately 75–200 mg / day, or approximately 100–150 mg / day.

[0137] The daily dose can also be described as the total amount of the compound described herein administered per dose or per day. The daily dose of the compound can be between about 1 mg and 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day. In some embodiments, the method includes administering an initial daily dose of about 1 to 800 mg of the compound described herein to the subject, and increasing the dose in increments until clinical efficacy is achieved. The dose can be increased in increments of about 5, 10, 25, 50, or 100 mg. The dose can be increased daily, every other day, twice a week, or once a week.

[0138] In some embodiments, the compound or pharmaceutical preparation is administered orally. In some embodiments, the compound or pharmaceutical preparation is administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration.

[0139] The formulations of this disclosure can be administered orally, parenterally, topically, or rectally. The formulations are, of course, administered in a form suitable for each route of administration. For example, they may be administered as tablets or capsules, by injection, inhalation, eye wash, ointment, suppository, etc.; by injection, infusion, or inhalation; by topical application as a wash or ointment; and by rectal administration as a suppository. In some embodiments, administration is oral.

[0140] [Example] The following examples illustrate embodiments of the present disclosure that are currently best known. However, it should be understood that the following are merely examples or illustrations of the application of the principles of the present disclosure. Those skilled in the art can devise various modifications and alternative compositions, methods, and systems without departing from the spirit and scope of the present disclosure. Therefore, while the present disclosure has been specifically described above, the following examples provide further details related to what is currently considered the most practical embodiment of the present disclosure.

[0141] abbreviation: silica gel chromatography Silica gel chromatography was performed using the CombiFlash® Rf (Teledyne ISCO), the Biotage Isolera One automated rapid purification system, or two Büchi systems (a combination of C-660, C-605, C-620, and C-635, and a combination of C-660, C-605, C-615, and C-630) with pre-packaged columns.

[0142] Preparative reversed-phase HPLC For preparative reversed-phase HPLC, use an Agilent 1200 preparative HPLC system, a Gilson device (GX-271 liquid processor, 331 / 332-pump, UV / VIS-155), or a Waters automated purification LC preparative system.

[0143] Preparative RP-LC Reversed-phase liquid chromatography was performed using a C18 column and a water (0.1% formic acid) / acetonitrile gradient on a Biotage device.

[0144] NMR 400 MHz: Recorded on a Bruker AVANCE II 400 spectrometer operating at a proton frequency of 400.23 MHz. 1 1H NMR spectroscopy. The instrument is equipped with a 5 mm BBI room temperature probe. Alternatively, a Bruker AVANCE III HD400 MHz or a Bruker AVANCE NEO 400 MHz probe can be used.

[0145] 600 MHz: Recorded on a Bruker AVANCE III 600 spectrometer operating at a proton frequency of 600.05 MHz. 1 H NMR spectroscopy. The instrument is equipped with a 5 mm BBI room temperature probe.

[0146] Analytical LC / MS equipment for method A Retention time and mass determination were performed on a Waters Acquity UHPLC system coupled with a Waters SQD mass detector. The injection volume was 1.0 μl. Molecular weights are given in grams per mole [g / mol], and the detected mass is given in mass / charge [m / z].

[0147] Analytical LC / MS equipment for methods B, D, and E For retention time and mass determination, LC / MS systems from Agilent were used (LC 1200 series / MS 6120 quadrupole LC / MS, LC 1260 infinity / MS 6120 quadrupole LC / MS, or LC 1260 Infinity II / MSD InfinityLab). Molecular weights are given in grams per mole [g / mol], and the detected mass is given in mass / charge [m / z].

[0148] Analytical LC / MS equipment for methods C, Q, R, and S. Retention time and quality testing were performed on a SHIMADZU LC-30AD system coupled with a PDA or DAD quality detector.

[0149] For retention time and mass determination, LC / MS systems from Agilent were used (LC 1200 series / MS 6120 quadrupole LC / MS, LC 1260 infinity / MS 6120 quadrupole LC / MS, or LC 1260 Infinity II / MSD InfinityLab). Molecular weights are given in grams per mole [g / mol], and the detected mass is given in mass / charge [m / z].

[0150] Chiral analysis equipment for methods F, I, M, Y, AE, AF, AG, AR, and AS. For retention time, use the SFC: SHIMADZU LC-30AD sf system.

[0151] Analytical LC / MS equipment for methods P, W, X, Z, AC, and AH. For retention time, use the LC system (Agilent-1260 series system) from Agilent.

[0152] Analytical LC / MS equipment for method A Retention time and mass determination were performed on a Waters Acquity UHPLC system coupled with a Waters SQD mass detector. The injection volume was 1.0 μl. Molecular weights are given in grams per mole [g / mol], and the detected mass is given in mass / charge [m / z].

[0153] Analytical LC / MS equipment for methods B and C For retention time and mass determination, LC / MS systems from Agilent were used (LC 1200 series / MS 6120 quadrupole LC / MS, LC 1260 infinity / MS 6120 quadrupole LC / MS, or LC 1260 Infinity II / MSD InfinityLab). Molecular weights are given in grams per mole [g / mol], and the detected mass is given in mass / charge [m / z].

[0154] LC / MS - Method A Gradient: 98% H2O (0.05% formic acid) / 2% acetonitrile (0.035% formic acid) for 0.2 min, then 98% H2O (0.05% formic acid) to 98% acetonitrile (0.035% formic acid) over 3.6 min, then 98% acetonitrile (0.035% formic acid) for 0.5 min. Flow rate: 1.0 ml / min. Column: 2.1 × 50 mm Waters ACQUITY UPLC BEH C18, 1.7 µm, 55ºC.

[0155] UV data: Retention time ad λ = 220 nm, given in min. MS data: ES+ ionization, m / z, unless otherwise specified, given as [M+H]+.

[0156] LC / MS - Method B Gradient: from 95% H2O (0.0375% TFA) / 5% acetonitrile (0.01875% TFA) to 5% H2O (0.0375% TFA) / 95% acetonitrile (0.01875% TFA) in 0.8 min; flow rate: 1.5 ml / min; column: Kinetex EVO C18 2.1 × 30 mm, 5 µm, 50ºC. UV data: Retention time ad λ = 220 nm, given in min. MS data: ES+ ionization, m / z, unless otherwise specified, given as [M+H]+.

[0157] LC / MS - Method C Gradient: from 100% H2O (0.0375% TFA) / 0% acetonitrile (0.01875% TFA) to 60% H2O (0.0375% TFA) / 40% acetonitrile (0.01875% TFA) in 0.8 min; flow rate: 1.5 ml / min; column: Kinetex EVO C18 2.1 × 30 mm, 5 µm, 50ºC. UV data: Retention time ad λ = 220 nm, given in min. MS data: ES+ ionization, m / z, unless otherwise specified, given as [M+H]+.

[0158] LC / MS method Q Gradient: from 95% H2O (0.0375% TFA) / 5% ACN (0.01875% TFA) to 5% H2O (0.0375% TFA) / 95% ACN (0.01875% TFA) over 1.05 min; flow rate: 2 ml / min; column: HALO C 18 3.0 x 30 mm, 5.0 μm, 50ºC UV data: Retention time ad λ = 220 nm, given in min. Detector: PDA MS data: ES+ ionization, m / z, unless otherwise specified, given as [M+H]+.

[0159] LC / MS method R Gradient: From 95% H2O (0.025% NH3·H2O) / 5% ACN to 5% H2O (0.025% NH3·H2O) / 5% ACN over 1.05 min; 5% A:95% B maintained for 0.4 min, then back to 95% A:5% B over 0.3 min; flow rate: 2 ml / min; column: Kinetex EVO C18 2.1 x 30 mm, 5 µm, 50ºC. UV data: Retention time ad λ = 220 nm, given in min. Detector: PDA MS data: ES+ ionization, m / z, unless otherwise specified, given as [M+H]+.

[0160] LC / MS method S Gradient: from 95% H2O (0.025% NH3·H2O) / 5% ACN to 5% H2O (0.025% NH3·H2O) / 5% ACN over 1.05 min; 5% A : 95% B maintained for 0.4 min, then back to 95% A : 5% B over 0.3 min; flow rate: 2 ml / min; column: Kinetex EVO C18 2.1 x 30 mm, 5 µm, 40ºC. UV data: Retention time ad λ = 220 nm, given in min. Detector: PDA MS data: ES+ ionization, m / z, unless otherwise specified, given as [M+H]+.

[0161] Chiral analysis methods: Method F Mobile phase: Phase A is CO2 and Phase B is MeOH (0.05% DEA); Gradient: MeOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3 mL / min; Column: Chiralcel OJ-3 50 × 4.6 mm ID, 3 µm, 35ºC; Back pressure: 100 bar; Detector: PDA UV data: Retention time ad λ = 220 nm, given in min. Method I Mobile phase: Phase A is CO2 and Phase B is MeOH (0.05% DEA); Gradient: MeOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3 mL / min; Column: Chiralpak AD-3 50 × 4.6 mm ID, 3 µm, 35ºC; Back pressure: 100 bar; Detector: PDA UV data: Retention time ad λ = 220 nm, given in min. Method M Mobile phase: Phase A is CO2 and Phase B is EtOH (0.05% DEA); Gradient: EtOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3 mL / min; Column: Chiralpak AD-3 50 × 4.6 mm ID, 3 µm, 35ºC; Back pressure: 100 bar; Detector: PDA UV data: Retention time ad λ = 220 nm, given in min. Method P Mobile phase: Phase A is CO2 and Phase B is MeOH (0.05% DEA); Gradient: EtOH (0.05% DEA) from 5% to 40% in CO2; Flow rate: 3 mL / min; Column: Chiralcel OD-3 50 × 4.6 mm, 3 µm, 35ºC; Back pressure: 100 bar; Detector: DAD UV data: Retention time ad λ = 220 nm, given in min. Method W Mobile phase: Phase A is CO2 and Phase B is MeOH (0.05% DEA); Gradient: MeOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3 mL / min; Column: Chiralcel OJ-3 50 × 4.6 mm ID, 3 µm, 35ºC; Back pressure: 100 bar; Detector: PDA UV data: Retention time ad λ = 220 nm, given in min. Method X Mobile phase: Phase A is CO2 and Phase B is EtOH (0.05% DEA); Gradient: EtOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3 mL / min; Column: Chiralcel OJ-3 50 × 4.6 mm ID, 3 µm, 35ºC; Back pressure: 100 bar; Detector: PDA UV data: Retention time ad λ = 220 nm, given in min. Method Z Mobile phase: Phase A is CO2 and Phase B is EtOH (0.05% DEA); Gradient: EtOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3 mL / min; Column: Chiralcel OD-3 50 × 4.6 mm, 3µm, 35ºC; Back pressure: 100 bar; Detector: PDA UV data: Retention time ad λ = 220 nm, given in min. Method AC Mobile phase: Phase A is CO2 and Phase B is iPrOH (0.05% DEA); Gradient: iPrOH (0.05% DEA) from 5% to 40% in CO2; Flow rate: 3 mL / min; Column: Chiralpak AD-3 50 × 4.6 mm ID, 3 µm, 35ºC; Back pressure: 100 bar; Detector: PDA UV data: Retention time ad λ = 220 nm, given in min. Method AE Mobile phase: Phase A is CO2 and Phase B is EtOH (0.05% DEA); Gradient: EtOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3 mL / min; Column: Chiralcel OJ-3 50 × 4.6 mm, 3µm, 35ºC; Back pressure: 100 bar; Detector: PDA UV data: Retention time ad λ = 220 nm, given in min. Method AF Mobile phase: Phase A is CO2 and Phase B is iPrOH + ACN (0.05% DEA); Gradient: iPrOH + ACN (0.05% DEA); (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3 mL / min; Column: Kromasil (S,S)Whelk-O1 50 × 4.6 mm ID, 3µm, 35ºC; Back pressure: 100 bar; Detector: PDA UV data: Retention time ad λ = 220 nm, given in min. Method AG Mobile phase: Phase A is CO2 and Phase B is EtOH (0.05% DEA); Gradient: EtOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3 mL / min; Column: Chiralpak AS-3 50 × 4.6 mm ID, 3 µm, 35ºC; Back pressure: 100 bar; Detector: PDA UV data: Retention time ad λ = 220 nm, given in min. Method AH Mobile phase: Phase A is CO2 and Phase B is EtOH (0.05% DEA); Gradient: EtOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3 mL / min; Column: Chiralpak AD-3 50 × 4.6 mm ID, 3 µm, 35ºC; Back pressure: 100 bar; Detector: PDA UV data: Retention time ad λ = 220 nm, given in min. Method AL Mobile phase: Phase A is CO2 and Phase B is iPrOH + ACN (0.05% DEA); Gradient: iPrOH + ACN (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3 mL / min; Column: Kromasil (S,S)Whelk-O1 50 × 4.6 mm I.D., 3µm, 35ºC; Back pressure: 100 bar; Detector: PDA UV data: Retention time ad λ = 220 nm, given in min. Method AR Mobile phase: Phase A is CO2 and Phase B is EtOH (0.05% DEA); Gradient: EtOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3 mL / min; Column: Chiralcel OD-3 50 × 4.6 mm ID, 3 µm, 35ºC; Back pressure: 100 bar; Detector: DAD UV data: Retention time ad λ = 220 nm, given in min. Method AS Mobile phase: Phase A is CO2 and Phase B is MeOH (0.05% DEA); Gradient: MeOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3 mL / min; Column: Chiralpak IC-3 50 × 4.6 mm ID, 3 µm, 3 µm, 35ºC; Back pressure: 100 bar; Detector: DAD UV data: Retention time ad λ = 220 nm, given in min. Salt In compounds described as HCl-, TFA-, or another salt, the exact amount of the corresponding salt is usually uncertain. Therefore, depending on the chemical structure (e.g., the number of basic centers), the amount of salt can range from as low as 0.01 equivalents to as high as 5.0 equivalents.

[0162] Chiral purity If the enantiomer ratio is greater than 90:10, the compound is plotted and named as a single enantiomer. For enantiomer ratios less than 90:10, the racemic form is used.

[0163] Example 1: Synthesis of compounds (5), (6), (7), (8), (9), (10), (11), (12), (13), (36), (37), (38), (39), (40), (48), (49), (50), (51), (64), (65), (92), (97), (98), (106), (107), (112), (113), (114), (115), and (116). Example 1.1: Synthesis of compounds (7), (8), and (9) Step 1: Synthesis of methyl trans-4-[(2-nitroaniline)methyl]cyclohexanecarboxylate (corresponding to the compound of formula (Va) as defined in Scheme 2) At room temperature, NET was added to a stirred solution of 1-fluoro-2-nitrobenzene (749 µl, 7.09 mmol) and methyl 4-(aminomethyl)cyclohexanecarboxylate hydrochloride (1.50 g, 7.09 mmol) in CH3CN (22 ml). i Pr2 (3.71 ml, 21.26 mmol). The solution was heated under reflux for 2 h. Volatile components were removed under reduced pressure, and the resulting residue was partitioned between EA and water. The aqueous layer was extracted with EA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated to give crude 4-[(2-nitroanilino)methyl]cyclohexane carboxylate, which was purified by column chromatography (SiO2; EA / heptane gradient) (860 mg, 2.95 mmol, 41% yield).

[0164] 1 H NMR (600 MHz, DMSO -d 6): δ ppm 8.18 (br t, J=5.41 Hz, 1 H), 8.06 (m,1 H), 7.52 (t, J=7.84 Hz, 1 H), 7.07 (d, J=8.44 Hz, 1 H), 6.67 (t, J=7.85 Hz,1 H), 3.58 (s, 3 H), 3.27 (m, 2 H), 2.27 (m, 1 H), 1.93 (m, 2 H), 1.82 (m, 2H), 1.63 (m, 1 H), 1.32 (m, 2 H), 1.06 (m, 2 H).

[0165] Step 2: Synthesis of methyl trans-4-[(2-aminoaniline)methyl]cyclohexanecarboxylate (corresponding to the compound of formula (VIa) as defined in Scheme 2) The stirred suspension of trans-4-(((2-nitrophenyl)amino)methyl)cyclohexane-1-carboxylate (862 mg, 2.95 mmol) in MeOH (70 ml) and Pd / C (10%, 54% water, 470 mg, 442 µmol) in a round-bottom flask was evacuated at 0ºC and backfilled with H2. This process was repeated 3 times. The suspension was vigorously stirred at room temperature under an H2 atmosphere (H2 balloon) for 2 h. The suspension was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure. The title compound was given as a yellow solid and used in the next reaction without further purification (695 mg, 2.65 mmol, 90% yield).

[0166] 1 H NMR (400 MHz, DMSO-d 6): δ ppm 6.49 (m, 2 H), 6.38 (m, 2 H), 4.47 (s, 2 H), 4.32 (t, J=5.62 Hz, 1 H), 3.58 (s, 3 H), 2.86 (t, J=6.11 Hz, 2 H), 2.27 (m, 1 H), 1.92 (m, 4 H), 1.55 (m, 1 H), 1.31 (m, 2 H), 1.00 (m, 2 H).

[0167] Step 3: Synthesis of methyl trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylate (corresponding to compound (IIIa) in Scheme 2) At room temperature, concentrated HCl (1.54 ml) was added to a stirred solution of trans-4-(((2-aminophenyl)amino)methyl)cyclohexane-1-carboxylate (694 mg, 2.65 mmol) and trimethyl orthoformate (15 ml, 137 mmol) in MeOH (15 ml). The solution was stirred at room temperature for 1 h. Volatile components were removed under reduced pressure and the resulting residue was partitioned between a saturated aqueous solution of NaHCO3 and EA. The aqueous layer was extracted with EA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated to give trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylate, which was used in the next reaction without further purification (700 mg, 2.57 mmol, 97% yield).

[0168] 1 H NMR (400 MHz, DMSO -d 6): δ ppm 8.18 (s, 1 H), 7.64 (m, 2 H), 7.22 (m, 2 H), 4.10 (d, J=7.09 Hz, 2 H), 3.56 (s, 3 H), 2.24 (m, 1 H), 1.85 (m, 3H), 1.58 (m, 2 H), 1.25 (m, 2 H), 1.07 (m, 2 H).

[0169] Step 4: Synthesis of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid - hydrolysis of step 2 in Scheme 1.

[0170] A solution of lithium hydroxide (185 mg, 7.71 mmol) in water (12 ml) was added to a solution of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylate (700 mg, 2.57 mmol) in MeOH (12 ml) and THF (12 ml). The resulting solution was stirred at room temperature for 3 h. Volatile components were removed under reduced pressure and the remaining aqueous solution was acidified with 1 N HCl (10.0 ml, 10.0 mmol). The resulting solution was lyophilized. The title compound (a mixture of 2xLiCl) was given as a white solid and used in the next reaction without further purification (1.05 g, quantified).

[0171] 1 H NMR (400 MHz, DMSO -d 6): δ ppm 12.04 (br s, 1 H), 9.14 (s, 1 H), 7.90 (d, J=7.21 Hz, 1 H), 7.80 (d, J=7.27 Hz, 1 H), 7.48 (m, 2 H), 4.27 (d, J=7.21 Hz, 2 H), 2.14 (m, 1 H), 1.91 (m, 3 H), 1.61 (m, 2 H), 1.24 (m, 2 H), 1.09 (m, 2 H).

[0172] Step 5a: As described in Step 5c of Example 1.4 below, but starting with trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, the synthesis of trans-3-((S)-2-(4-((1H-benzimidazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile (compound (7)) is carried out.

[0173] Step 5b: As described in Step 5a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-(4-((1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl)((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)methyl ketone (compound (8)) is carried out. Step 5c: As described in Step 5a above, but starting with (3S)-3-(5-fluoro-3-pyridyl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of trans-(4-((1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl)((S)-3-(5-fluoropyridyl-3-yl)isoxazolidine-2-yl)methyl ketone (compound (9)) is carried out.

[0174] Example 1.2: Synthesis of compounds (5) and (6) Step 1: As described in Step 1 of Example 1.1, but starting with 1-fluoro-2-nitro-4-benzonitrile, proceed with the synthesis of trans-4-[(4-cyano-2-nitro-aniline)methyl]cyclohexanecarboxylate (corresponding to the compound of formula (Va) as defined in Scheme 2).

[0175] Step 2: As described in Step 2 of Example 1.1, but starting with trans-4-[(4-cyano-2-nitro-aniline)methyl]cyclohexanecarboxylate, proceed with the synthesis of trans-4-[(2-amino-4-cyano-aniline)methyl]cyclohexanecarboxylate (corresponding to the compound of formula (VIa) as defined in Scheme 2).

[0176] Step 3: As described in Step 3 of Example 1.1, but starting with trans-4-[(2-amino-4-cyano-aniline)methyl]cyclohexanecarboxylate, proceed with the synthesis of trans-4-[(5-cyanobenzimidazol-1-yl)methyl]cyclohexanecarboxylate (corresponding to compound (IIIa) in Scheme 2).

[0177] Step 4: Synthesize trans-4-[(5-cyanobenzimidazol-1-yl)methyl]cyclohexanecarboxylic acid in a similar manner to that in Example 1.1, but by replacing trans-4-(benzimidazol-1-yl)cyclohexanecarboxylic acid with trans-4-[(5-cyanobenzimidazol-1-yl)methyl]cyclohexanecarboxylic acid. Step 5a: As described in Step 5c of Example 1.4 below, but starting with trans-4-[(5-cyanobenzimidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, the synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-benzi[d]imidazol-5-carboxynitrile (compound (5)) is carried out.

[0178] Step 5b: As described in Step 5a above, but starting with (3S)-3-(5-fluoro-3-pyridyl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-(((S)-3-(5-fluoropyridyl-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazol-5-carboxynitrile (compound (6)) is carried out.

[0179] Example 1.3: Synthesis of compounds (12), (13), (39), (64), and (98) Step 1: As described in Example 1.1, but starting with 5-cyano-1,4-difluoro-2-nitro-benzene, synthesize trans-4-[(5-cyano-4-fluoro-2-nitro-aniline)methyl]cyclohexanecarboxylate (corresponding to the compound of formula (Va) as defined in Scheme 2).

[0180] Step 2: As described in Example 1.1, but starting with trans-4-[(5-cyano-4-fluoro-2-nitro-aniline)methyl]cyclohexanecarboxylate, proceed with the synthesis of trans-4-[(2-amino-5-cyano-4-fluoro-aniline)methyl]cyclohexanecarboxylate (corresponding to the compound of formula (VIa) as defined in Scheme 2).

[0181] Step 3: As described in Example 1.1, but starting with trans-4-[(2-amino-5-cyano-4-fluoro-aniline)methyl]cyclohexanecarboxylate, proceed with the synthesis of trans-4-[(6-cyano-5-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylate (corresponding to compound (IIIa) in Scheme 2).

[0182] Step 4: Synthesize trans-4-[(6-cyano-5-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(6-cyano-5-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-(benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid. Step 5a: Synthesis of trans-1-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-benzo[d]imidazol-6-carboxynitrile (compound (64)).

[0183] Oxyma (37 mg, 0.25 mmol) and NaHCO3 (63 mg, 0.75 mmol) were added to a mixture of 4-[(6-cyano-5-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid (25 mg, 83.0 µmol) and DMF (1.5 ml). The mixture was stirred at room temperature for 1 h. 5-[(3S)-isooxazolidine-3-yl]pyridin-3-carboxynitrile (15 mg, 85.6 µmol) was added to DMF (1.5 ml). The mixture was heated to 40ºC for 2 h. At room temperature, the mixture was diluted with EA and washed with water. The organic layer was separated, washed with NH4Cl (saturated aqueous solution), NaHCO3 (saturated aqueous solution), and brine, dried (Na2SO4), filtered, and concentrated. The crude material was purified by preparative HPLC to give the title compound (17 mg, 37.1 µmol, 45% yield).

[0184] Step 5b: As described in Step 5a above, but starting with (3S)-3-pyrazin-2-ylisoxazolidine hydrochloride instead of 5-[(3S)-isoxazolidine-3-yl]pyridin-3-carboxylonitrile, the trans-5-fluoro-1-((4-(((S)-3-(pyrazin-2-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazol-6-carboxylonitrile (compound (98)) is synthesized.

[0185] Step 5c: As described in Step 5c of Example 1.4, but starting with trans-4-[(6-cyano-5-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid and (3S)-3-(3,5-difluorophenyl)isoxazolane, respectively, replacing trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid and 3-fluoro-5-[(3S)-isoxazolane-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-(((S)-3-(3,5-difluorophenyl)isoxazolane-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-benzi[d]imidazol-6-carboxylonitrile (compound (12)) is carried out.

[0186] Step 5d: As described in Step 5c of Example 1.4, but starting with trans-4-[(6-cyano-5-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-benzi[d]imidazol-6-carboxynitrile (compound (13)).

[0187] Step 5e: As described in Step 5d above, but starting with (3S)-3-(5-methyl-3-furanyl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of trans-5-fluoro-1-((4-(((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazolium-6-carboxynitrile (compound (39)) is carried out.

[0188] Example 1.4: Synthesis of compounds (10), (11), (40), (65), and (97) Step 1: As described in Example 1.1, but starting with 4-cyano-1,5-difluoro-2-nitrobenzene, synthesize trans-4-[(4-cyano-5-fluoro-2-nitro-aniline)methyl]cyclohexanecarboxylate (corresponding to the compound of formula (Va) as defined in Scheme 2). Step 2: As described in Example 1.1, but starting with trans-4-[(4-cyano-5-fluoro-2-nitro-aniline)methyl]cyclohexanecarboxylate, proceed with the synthesis of trans-4-[(2-amino-4-cyano-5-fluoro-aniline)methyl]cyclohexanecarboxylate (corresponding to the compound of formula (VIa) as defined in Scheme 2). Step 3: As described in Example 1.1, but starting with trans-4-[(2-amino-4-cyano-5-fluoro-aniline)methyl]cyclohexanecarboxylate, proceed with the synthesis of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylate (corresponding to compound (IIIa) in Scheme 2). Step 4: Synthesize trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid in a similar manner as in Example 1.1, but using trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid ester instead of trans-4-(benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid ester. Step 5a: As described in Step 5a of Example 1.3, but starting with trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid and 5-[(3S)-isoxazolidine-3-yl]pyridin-3-carboxylonite, respectively, the synthesis of trans-1-((4-(((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-benzimidazol-5-carboxylonite (compound (65)) is carried out.

[0189] Step 5b: As described in Step 5a above, but starting with (3S)-3-pyrazin-2-ylisoxazolidine hydrochloride instead of 5-[(3S)-isoxazolidine-3-yl]pyridin-3-carboxylonitrile, the trans-6-fluoro-1-((4-(((S)-3-(pyrazin-2-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazol-5-carboxylonitrile (compound (97)) is synthesized.

[0190] Step 5c: Synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-benzo[d]imidazolium-5-carboxynitrile (compound (11)) At room temperature, trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid (100 mg, 331 µmol), NEt i Pr2 (174 µl, 995 µmol) and 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride (98.7 mg, 431 µmol) were added to a stirred solution of DMF (2 ml) with HATU (151 mg, 398 µmol). Stirring was continued for 2 h at room temperature. The reaction mixture was filtered and subjected to preparative reversed-phase HPLC (70 mg, 147 µmol, 44% yield).

[0191] Step 5d: As described in Step 5c above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-(((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-benzo[d]imidazolium-5-carboxynitrile (compound (10)) is carried out.

[0192] Step 5e: As described in Step 5c above, but starting with (3S)-3-(5-methyl-3-furanyl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of trans-6-fluoro-1-((4-(((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazolium-5-carboxynitrile (compound (40)) is carried out.

[0193] Example 1.5: Synthesis of compounds (36), (37), and (38) Step 1: As described in Example 1.1, but starting with 5-cyano-1,3-difluoro-2-nitrobenzene, synthesize trans-4-[(5-cyano-3-fluoro-2-nitro-aniline)methyl]cyclohexanecarboxylate (corresponding to the compound of formula (Va) as defined in Scheme 2). Step 2: As described in Example 1.1, but starting with trans-4-[(5-cyano-3-fluoro-2-nitro-aniline)methyl]cyclohexanecarboxylate, proceed with the synthesis of trans-4-[(2-amino-5-cyano-3-fluoro-aniline)methyl]cyclohexanecarboxylate (corresponding to the compound of formula (VIa) as defined in Scheme 2). Step 3: As described in Example 1.1, but starting with trans-4-[(2-amino-5-cyano-3-fluoro-aniline)methyl]cyclohexanecarboxylate, proceed with the synthesis of trans-4-[(6-cyano-4-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylate (corresponding to compound (IIIa) in Scheme 2). Step 4: Synthesize trans-4-[(6-cyano-4-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(6-cyano-4-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-(benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid. Step 5a: As described in Step 5c of Example 1.4, but starting with trans-4-[(6-cyano-4-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, the synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-benzi[d]imidazol-6-carboxynitrile (compound (36)) is carried out.

[0194] Step 5b: As described in Step 5a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-(((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-benzo[d]imidazolium-6-carboxynitrile (compound (37)) is carried out.

[0195] Step 5c: As described in Step 5a above, but starting with (3S)-3-(5-methyl-3-furanyl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of trans-4-fluoro-1-((4-(((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazolium-6-carboxynitrile (compound (38)) is carried out.

[0196] Example 1.6: Synthesis of compounds (48), (49), (50), (51), (92), (106), (107), (112), and (113) Step 1: As described in Example 1.1, but starting with 1,4-difluoro-2-nitrobenzene, synthesize trans-4-[(4-fluoro-2-nitro-aniline)methyl]cyclohexanecarboxylate (corresponding to the compound of formula (Va) as defined in Scheme 2). Step 2: As described in Example 1.1, but starting with trans-4-[(4-fluoro-2-nitro-aniline)methyl]cyclohexanecarboxylate methyl ester, proceed with the synthesis of trans-4-[(2-amino-4-fluoro-aniline)methyl]cyclohexanecarboxylate methyl ester (corresponding to the compound of formula (VIa) as defined in Scheme 2). For compounds (48), (49), (92), and (107) Step 3: As described in Example 1.1, but starting with trans-4-[(4-fluoro-2-nitro-aniline)methyl]cyclohexanecarboxylate methyl ester, proceed with the synthesis of trans-4-[(5-fluorobenzimidazol-1-yl)methyl]cyclohexanecarboxylate methyl ester (corresponding to compound (IIIa) in Scheme 2). Step 4: Synthesize trans-4-[(5-fluorobenzimidazol-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(5-fluorobenzimidazol-1-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid ester. Step 5a: As described in Step 5a of Example 1.3, but starting with trans-4-[(5-fluorobenzimidazol-1-yl)methyl]cyclohexanecarboxylic acid and (3S)-3-pyrazin-2-ylisoxazolidine hydrochloride, respectively, to replace trans-4-[(6-cyano-5-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid and 5-[(3S)-isoxazolidine-3-yl]pyridin-3-carboxylonitrile, trans-(4-((5-fluoro-1H-benzimidazol-1-yl)methyl)cyclohexyl)((S)-3-(pyrazin-2-yl)isoxazolidine-2-yl)methyl ketone (compound (92)).

[0197] Step 5b: As described in Step 5a above, but starting with 5-[(3S)-isooxazolidine-3-yl]pyridin-3-carboxylonite instead of (3S)-3-pyrazin-2-ylisooxazolidine hydrochloride, the trans-5-((S)-2-(4-(((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexane-1-carbonyl)isooxazolidine-3-yl)nicotinonitrile (compound (107)) is synthesized.

[0198] Step 5c: As described in Step 5c of Example 1.4, but starting with trans-4-[(5-fluorobenzimidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, the synthesis of trans-3-fluoro-5-((S)-2-(4-(((5-fluoro-1H-benzi[d]imidazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)benzonitrile (compound (48)) is carried out.

[0199] Step 5d: As described in Step 5c above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl)methyl ketone (compound (49)) is carried out.

[0200] For compounds (106), (112), and (113) Step 3: As described in Example 1.1, but starting with trans-4-[(4-fluoro-2-nitro-aniline)methyl]cyclohexanecarboxylate methyl ester, proceed with the synthesis of trans-4-[(6-fluorobenzimidazol-1-yl)methyl]cyclohexanecarboxylate methyl ester (corresponding to compound (IIIa) in Scheme 2). Step 4: Synthesize trans-4-[(6-fluorobenzimidazol-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(6-fluorobenzimidazol-1-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid ester. Step 5a: As described in Step 5a of Example 1.3, but starting with trans-4-[(6-fluorobenzimidazol-1-yl)methyl]cyclohexanecarboxylic acid and 5-[(3S)-isooxazolidine-3-yl]pyridin-3-carboxylic acid, respectively, to synthesize trans-5-((S)-2-(4-(((6-fluoro-1H-benzimidazol-1-yl)methyl)cyclohexane-1-carbonyl)isooxazolidine-3-yl)nicotinonitrile (compound (106)).

[0201] Step 5b: As described in Step 5c of Example 1.4, but starting with trans-4-[(6-fluorobenzimidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-((S)-2-(4-(((6-fluoro-1H-benzi[d]imidazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)benzonitrile (compound (112)).

[0202] Step 5c: As described in Step 5b above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((6-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl)methyl ketone (compound (113)) is carried out.

[0203] For compounds (50) and (51) Step 3: Synthesis of trans-4-[(5-fluoro-2-methyl-benzimidazol-1-yl)methyl]cyclohexanecarboxylate (corresponding to compound (IIIa) in Scheme 2) Acetyl chloride (334 µl, 4.64 mmol, 2 equivalents) was added to a suspension of trans-4-(((2-amino-4-fluorophenyl)amino)methyl)cyclohexane-1-carboxylate (650 mg, 2.32 mmol, 1 equivalent) in dioxane (5 ml). The resulting solution was heated at 70ºC for 8 h. The resulting suspension was cooled to room temperature and filtered. The filter cake was suspended in EA and washed with a saturated NaHCO3 solution. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give 557 mg (79% yield) of the title compound as a brown oil.

[0204] Step 4: Synthesize trans-4-[(5-fluoro-2-methyl-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid in a similar manner as in Example 1.1, but using trans-4-[(5-fluoro-2-methyl-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid ester instead of trans-4-(benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid ester. Step 5a: As described in Step 5c of Example 1.4, but starting with trans-4-[(5-fluoro-2-methyl-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, the synthesis of trans-3-fluoro-5-((S)-2-(4-(((5-fluoro-2-methyl-1H-benzimidazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)benzonitrile (compound (50)) is carried out.

[0205] Step 5b: As described in Step 5a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((5-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl)methyl ketone (compound (51)) is carried out.

[0206] Example 1.7: Synthesis of compounds (114), (115), and (116) Step 1: As described in Example 1.1, but starting with 1,4-difluoro-2-nitrobenzene and trans-3-[(amino)methyl]cyclobutanecarboxylate, proceed with the synthesis of trans-3-[(4-fluoro-2-nitro-aniline)methyl]cyclobutanecarboxylate (corresponding to the compound of formula (Va) as defined in Scheme 2). Step 2: As described in Example 1.1, but starting with methyl trans-3-[(4-fluoro-2-nitro-aniline)methyl]cyclobutanecarboxylate, proceed with the synthesis of methyl trans-3-[(2-amino-4-fluoro-aniline)methyl]cyclobutanecarboxylate (corresponding to the compound of formula (VIa) as defined in Scheme 2). Step 3: As described in Example 1.1, but starting with trans-3-[(2-amino-4-fluoro-aniline)methyl]cyclobutanecarboxylate, proceed with the synthesis of trans-3-[(5-fluorobenzimidazol-1-yl)methyl]cyclobutanecarboxylate (corresponding to compound (IIIa) in Scheme 2). Step 4: Synthesize trans-3-[(5-fluorobenzimidazol-1-yl)methyl]cyclobutanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-3-[(5-fluorobenzimidazol-1-yl)methyl]cyclobutanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid ester. Step 5a: As described in Step 5c of Example 1.4, but starting with trans-3-fluoro-5-((S)-2-(3-(((5-fluoro-1H-benzimidazol-1-yl)methyl)cyclobutanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, the synthesis of trans-3-fluoro-5-((S)-2-(3-((5-fluoro-1H-benzimidazol-1-yl)methyl)cyclobutane-1-carbonyl)isoxazolidine-3-yl)benzonitrile (compound (116)) is carried out.

[0207] Step 5b: As described in Step 5a above, but starting with (3S)-3-(4-methylphenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-(3-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclobutyl)((S)-3-(p-tolyl)isoxazoline-2-yl)methyl ketone (compound (114)) is carried out.

[0208] Step 5c: As described in Step 5a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(3-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclobutyl) ketone (compound (115)) is carried out.

[0209] Example 2: Synthesis of compounds (66), (67), (68), (69), (84), (85), (86), (87), (100), and (101). Example 2.1: Synthesis of compounds (86) and (87) Step 1: Synthesis of 5-fluoro-1H-indazole-6-carboxynitrile (the nitrogen-containing heteroaromatic compound used in step 6a of scheme 3) Suspensions of ZnCN2 (521 mg, 4.39 mmol), 5-bromo-6-fluoro-1H-indazole (900 mg, 4.19 mmol), Pd2(dba)3 (200 mg, 209 µmol), and S-PHOS (175 mg, 418 µmol) in microwave-safe DMF (20 ml) and water (0.1 ml) were bubbled for 10 min at room temperature using a syringe. The mixture was then heated to 150ºC in the microwave for 30 min. The suspension was allowed to reach room temperature and diluted with EA. The resulting suspension was filtered and the filtrate was diluted with water. The aqueous layer was extracted with EA, and the combined organic layers were washed with water (3x), dried over Na2SO4, filtered, and concentrated to give a crude title compound as a pale yellow solid, which was then ground with CH2Cl2. The suspension was filtered, and the filter cake was washed with a small amount of CH2Cl2. 5-Fluoro-1H-indazole-6-carboxynitrile (370 mg, 2.30 mmol, 55% yield) was obtained as a pale yellow solid.

[0210] 1 H NMR (400 MHz, DMSO -d 6): δ ppm 13.7 (s, 1 H), 8.50 (d, J=6.21 Hz, 1H), 8.30 (s, 1 H) 7.65 (d, J=9.98 Hz, 1 H).

[0211] Step 2: The corresponding formate ester trans-4-[(6-cyano-5-fluoro-indazole-1-yl)methyl]cyclohexanecarboxylate methyl ester is synthesized in a similar manner to that performed in Step 1 of Example 3.1.

[0212] Step 3: Synthesize trans-4-[(6-cyano-5-fluoro-indazole-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(6-cyano-5-fluoro-indazole-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-(benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid. Step 4a: As described in Step 5c of Example 1.4, but starting with trans-4-[(6-cyano-5-fluoro-indazole-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-indazole-6-carboxynitrile (compound (87)).

[0213] Step 4b: As described in Step 4a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-indazole-6-carboxynitrile (compound (86)) is carried out.

[0214] Example 2.2: Synthesis of compounds (66) and (67) Step 1: In a similar manner to Step 1 of Example 2.1, but starting with 5-bromo-6-fluoro-1H-indazole, proceed with the synthesis of 6-fluoro-1H-indazole-5-carboxynitrile (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3).

[0215] Step 2: The corresponding formate ester trans-4-[(5-cyano-6-fluoro-indazole-1-yl)methyl]cyclohexanecarboxylate methyl ester is synthesized in a similar manner to that performed in Step 1 of Example 3.1.

[0216] Step 3: Synthesize trans-4-[(5-cyano-6-fluoro-indazole-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(5-cyano-6-fluoro-indazole-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-(benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid. Step 4a: As described in Step 5c of Example 1.4, but starting with trans-4-[(5-cyano-6-fluoro-indazole-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-indazole-5-carboxynitrile (compound (66)).

[0217] Step 4b: As described in Step 4a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-indazole-5-carboxynitrile (compound (67)) is carried out.

[0218] Example 2.3: Synthesis of compounds (68) and (69) Step 1: In a similar manner to Step 1 of Example 2.1, but starting with 5-bromo-6-fluoro-3-methyl-1H-indazole, proceed with the synthesis of 6-fluoro-3-methyl-1H-indazole-5-carboxynitrile (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: In a similar manner to Step 1 of Example 3.1, the corresponding formate ester trans-4-[(5-cyano-6-fluoro-3-methyl-indazole-1-yl)methyl]cyclohexane methyl ester is synthesized.

[0219] Step 3: Synthesize trans-4-[(5-cyano-6-fluoro-3-methyl-indazol-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(5-cyano-6-fluoro-3-methyl-indazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid. Step 4a: As described in Step 5c of Example 1.4, but starting with trans-4-[(5-cyano-6-fluoro-3-methyl-indazole-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-6-fluoro-3-methyl-1H-indazole-5-carboxynitrile (compound (69)).

[0220] Step 4b: As described in Step 4a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-(((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-6-fluoro-3-methyl-1H-indazole-5-carboxynitrile (compound (68)) is carried out.

[0221] Example 2.4: Synthesis of compounds (84) and (85) Step 1: In a similar manner to Step 1 of Example 2.1, but starting with 6-bromo-5-fluoro-3-methyl-1H-indazole, proceed with the synthesis of 5-fluoro-3-methyl-1H-indazole-6-carboxynitrile (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: In a similar manner to Step 1 of Example 3.1, the corresponding formate ester trans-4-[(6-cyano-5-fluoro-3-methyl-indazol-1-yl)methyl]cyclohexane methyl ester is synthesized.

[0222] Step 3: Synthesize trans-4-[(6-cyano-5-fluoro-3-methyl-indazole-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(6-cyano-5-fluoro-3-methyl-indazole-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid. Step 4a: As described in Step 5c of Example 1.4, but starting with trans-4-[(6-cyano-5-fluoro-3-methyl-indazole-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-5-fluoro-3-methyl-1H-indazole-6-carboxynitrile (compound (85)).

[0223] Step 4b: As described in Step 4a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-indazole-6-carboxynitrile (compound (84)) is carried out.

[0224] Example 2.5: Synthesis of compounds (100) and (101) Step 1: In a similar manner to Step 1 of Example 2.1, but starting with 6-bromo-4-fluoro-3-methyl-1H-indazole, synthesize 4-fluoro-3-methyl-1H-indazole-6-carboxynitrile (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3).

[0225] Step 2: In a similar manner to Step 1 of Example 3.1, the corresponding formate ester trans-4-[(6-cyano-4-fluoro-3-methyl-indazole-1-yl)methyl]cyclohexanecarboxylate methyl ester is synthesized.

[0226] Step 3: In a similar manner as in Example 1.1, but using trans-4-[(6-cyano-4-fluoro-3-methyl-indazol-1-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester, proceed with the synthesis of trans-4-[(6-cyano-4-fluoro-3-methyl-indazol-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1). Step 4a: As described in Step 5c of Example 1.4, but starting with trans-4-[(6-cyano-4-fluoro-3-methyl-indazole-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-4-fluoro-3-methyl-1H-indazole-6-carboxynitrile (compound (100)).

[0227] Step 4b: As described in Step 4a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-3-methyl-1H-indazole-6-carboxynitrile (compound (101)) is carried out.

[0228] Example 3: Compounds (2), (3), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (26), (27), (28), (29), (30), (31), (32), (33), (34), (35), (41), (42), (43), (44), (45), (46), (47), (52), (53), (54), (55), (56), (57), (58), (59), (60), (61), (62), (63), (82), (83), (88) Synthesis of (89), (90), (91), (93), (94), (95), (96), (104), (105), (108), (110), (111), (117), (118), (119), (120), (121), (123), (126), (127), (128), (130), (134), (137), (185), (186), (187), (188), (189), (190), (196), (198), (199), (200), (202), (203), (204), (215), (218) and (241) Synthesis of methyl trans-4-(iodomethyl)cyclohexanecarboxylate NaI (11.0 g, 73.2 mmol) was added to a stirred solution of trans-4-(methanesulfonyloxymethyl)cyclohexane-formate (6.43 g, 25.7 mmol) in acetone (100 ml) at room temperature. The solution was heated under reflux for 6 h. The suspension was cooled to room temperature and diluted with Et₂O. The suspension was filtered and the filtrate was concentrated under reduced pressure. The resulting crude yellow solid was ground again with Et₂O, filtered again, and the filtrate was concentrated under reduced pressure. The title compound was given as a pale yellow oil, which was used in the next reaction without further purification (6.08 g, 21.5 mmol, 84% yield).

[0229] 1 H NMR (400 MHz, CDCl3): δ ppm 3.67 (s, 3 H), 3.11 (d, J=7.21 Hz, 2H), 3.01 (s, 3 H) 2.23 (m, 1 H), 2.05 (m, 4 H), 1.45 (m, 3 H), 1.03 (m, 2 H).

[0230] Example 3.1: Synthesis of compounds (28), (29), (30), (31), (41), (43), (127), (189), (190), (196), (200), (203), (204), (215) Step 1: Synthesis of trans-4-[(6-cyanoydinazol-1-yl)methyl]cyclohexanecarboxylate and trans-4-[(6-cyanoydinazol-2-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in step 6a of scheme 3) To a stirred solution of 1H-indazole-6-carboxynitrile (200 mg, 1.40 mmol) in 1 mL DMF, NaH (33.5 mg, 1.40 mmol) was added and stirring was continued for 10 min at room temperature. A solution of trans-4-(iodomethyl)cyclohexanecarboxylate (1.11 g, 3.93 mmol) in 2 mL DMF was added, and the resulting suspension was stirred at room temperature for 1.5 h. Then, another portion of NaH (33.5 mg, 1.40 mmol) was added. The mixture was stirred again at room temperature for 1.5 h. The reaction was quenched with water at 0ºC, and the aqueous layer was extracted with MTBE. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to obtain the crude title compound, which was purified by column chromatography (SiO₂; EA / heptane gradient).

[0231] Methyl trans-4-[(6-cyanoindazole-1-yl)methyl]cyclohexanecarboxylate (196 mg, 660 µmol, 47% yield).

[0232] 1 H NMR (400 MHz, DMSO -d 6): δ ppm 8.45 (s, 1 H), 8.25 (s, 1 H), 7.97(d, J=8.31 ​​Hz, 1 H), 7.45 (d, J=8.31, 1 H), 4.34 (d, J=7.21 Hz, 2 H), 3.56(s, 3 H), 2.23 (m, 1 H), 1.89 (m, 3 H), 1.52 (m, 2 H), 1.25 (m, 2 H), 1.10 (m, 2 H).

[0233] Methyl trans-4-[(6-cyanoindazole-2-yl)methyl]cyclohexanecarboxylate (124 mg, 417 µmol, 30% yield).

[0234] 1 H NMR (400 MHz, DMSO -d 6): δ ppm 8.55 (s, 1 H), 8.30 (s, 1 H), 7.92(d, J=8.64 Hz, 1 H), 7.28 (d, J=8.62, 1 H), 4.36 (d, J=7.09 Hz, 2 H), 3.57(s, 3 H), 2.25 (m, 1 H), 1.92 (m, 3 H), 1.57 (m, 2 H), 1.28 (m, 2 H), 1.09 (m, 2 H).

[0235] Step 2: In a similar manner to that in Example 1.1, but using trans-4-[(6-cyanoydinazol-1-yl)methyl]cyclohexanecarboxylate and trans-4-[(6-cyanoydinazol-2-yl)methyl]cyclohexanecarboxylate instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylate, respectively, to synthesize trans-4-[(6-cyanoydinazol-1-yl)methyl]cyclohexanecarboxylic acid and trans-4-[(6-cyanoydinazol-2-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1). Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(6-cyanoindazole-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazole-1-yl)methyl]cyclohexanecarboxylic acid, the synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-indazole-6-carboxynitrile (compound (28)) is carried out.

[0236] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-indazole-6-carboxynitrile (compound (29)) is carried out.

[0237] Step 3c: As described in Step 5c of Example 1.4, but starting with trans-4-[(6-cyanoindazole-2-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazole-1-yl)methyl]cyclohexanecarboxylic acid, the synthesis of trans-2-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-2H-indazole-6-carboxynitrile (compound (30)) is carried out.

[0238] Step 3d: As described in Step 3c above, but starting with (3S)-3-(3-cyano-5-fluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-2-((4-(((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-2H-indazole-6-carboxynitrile (compound (31)) is carried out.

[0239] Step 3e: As described in Step 3c above, but starting with (3S)-3-(5-methylfuran-3-yl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of trans-2-((4-((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-2H-indazole-6-carboxynitrile (compound (41)) is carried out.

[0240] Step 3f: As described in step 3a above, but starting with (3S)-3-(5-methylfuran-3-yl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-1-((4-((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-indazole-6-carboxynitrile (compound (43)) is synthesized.

[0241] Step 3g: As described in step 3a above, but starting with (3S)-3-(5-cyanopyridin-3-yl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of trans-2-((4-(((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-2H-indazole-6-carboxynitrile (compound (127)) is carried out.

[0242] Step 3h: As described in Step 3a above, but starting with (3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-2-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxynitrile (compound (189)) is synthesized.

[0243] Step 3j: As described in Step 3a above, but starting with (3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-1-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxylonitrile (compound (190)) is synthesized.

[0244] Step 3k: As described in Step 3a above, but starting with (3S)-3-pyrazin-2-ylisoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-2-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxylonitrile (compound (196)) is synthesized.

[0245] Step 31: As described in Step 3a above, but starting with (3S)-3-pyrazin-2-ylisoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-1-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxylonitrile (compound (200)) is synthesized.

[0246] Step 3m: As described in Step 3a above, but starting with (3S)-3-(2-methylthiazol-4-yl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-2-[[4-[(3S)-3-(2-methylthiazol-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxynitrile (compound (203)) is synthesized.

[0247] Step 3n: As described in Step 3a above, but starting with (3S)-3-(2-methylthiazol-4-yl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-1-[[4-[(3S)-3-(2-methylthiazol-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxynitrile (compound (204)) is synthesized.

[0248] Step 3o: As described in Step 3a above, but starting with (3S)-3-(2-pyridyl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-[[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxylonitrile (compound (215)) is carried out.

[0249] Example 3.2: Synthesis of compounds (32), (33), and (44) Step 1: In a similar manner as in Step 1 of Example 3.1, but starting with 6-cyano-4-fluoro-1H-indazole, synthesize trans-4-[(6-cyano-4-fluoro-indazole-1-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3).

[0250] Step 2: Synthesize trans-4-[(6-cyano-4-fluoro-indazole-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(6-cyano-4-fluoro-indazole-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-(benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid. Step 3a: As described in step 5c of Example 1.4, but starting with trans-4-[(6-cyano-4-fluoro-indazole-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-indazole-6-carboxynitrile (compound (32)).

[0251] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-indazole-6-carboxynitrile (compound (33)) is carried out.

[0252] Step 3c: As described in Step 3a above, but starting with (3S)-3-(5-methylfuran-3-yl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of trans-4-fluoro-1-((4-(((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-indazole-6-carboxynitrile (compound (44)) is carried out.

[0253] Example 3.3: Synthesis of compounds (34), (35), and (42) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 6-cyano-4-fluoro-1H-indazole, synthesize trans-4-[(6-cyano-4-fluoro-indazole-2-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: Synthesize trans-4-[(6-cyano-4-fluoro-indazole-2-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(6-cyano-4-fluoro-indazole-2-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, the synthesis of trans-2-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-4-fluoro-2H-indazole-6-carboxynitrile (compound (34)) is carried out.

[0254] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-2-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-2H-indazole-6-carboxynitrile (compound (35)) is carried out.

[0255] Step 3c: As described in Step 3a above, but starting with (3S)-3-(5-methylfuran-3-yl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of trans-4-fluoro-2-((4-(((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-2H-indazole-6-carboxynitrile (compound (42)) is carried out.

[0256] Example 3.4: Synthesis of compounds (45), (46), (47), and (130) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 6-cyano-4-fluoro-indole, synthesize trans-4-[(6-cyano-4-fluoro-indole-1-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: Synthesize trans-4-[(6-cyano-4-fluoro-indol-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(6-cyano-4-fluoro-indol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid. Step 3a: As described in Step 5a of Example 1.3, but starting with trans-4-[(6-cyano-4-fluoro-indole-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(6-cyano-5-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, the synthesis of trans-1-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-indole-6-carboxynitrile (compound (130)) is carried out.

[0257] Step 3b: As described in step 5c of Example 1.4, but starting with trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-indole-6-carboxynitrile (compound (46)).

[0258] Step 3c: As described in Step 3b above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-indole-6-carboxynitrile (compound (45)) is carried out.

[0259] Step 3d: As described in Step 3b above, but starting with (3S)-3-(5-methylfuran-3-yl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of trans-4-fluoro-1-((4-(((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-indole-6-carboxynitrile (compound (47)) is carried out.

[0260] Example 3.5: Synthesis of compounds (52), (53), (202), (217), and (218) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 5-cyano-1H-indazole, synthesize trans-4-[(5-cyanoydinazol-1-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: Synthesize trans-4-[(5-cyanoydinazol-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(5-cyanoydinazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-(benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid. Step 3a: As described in step 5a of Example 1.3, but starting with trans-4-[(5-cyanoindazole-1-yl)methyl]cyclohexanecarboxylic acid and (3S)-3-(2-methylthiazol-4-yl)isoxazolidine, respectively, to replace trans-4-[(6-cyano-5-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid and 5-[(3S)-isoxazolidine-3-yl]pyridin-3-carboxylonitrile, trans-1-[[4-[(3S)-3-(2-methylthiazol-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-5-carboxylonitrile (compound (202)).

[0261] Step 3b: As described in Step 3a above, but starting with (3S)-3-(2-methylthiazol-4-yl)isooxazolane instead of (3S)-3-(2-methylthiazol-4-yl)isooxazolane, proceed with the synthesis of trans-1-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isooxazolane-2-carbonyl]cyclohexyl]methyl]indazole-5-carboxynitrile (compound (217)).

[0262] Step 3c: As described in step 3a above, but starting with (3S)-3-(2-methylthiazolyl-4-yl)isooxazolidine, proceed with the synthesis of trans-1-[[4-[(3S)-3-pyrazin-2-ylisooxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-5-carboxylonitrile (compound (218)).

[0263] Step 3d: As described in step 5c of Example 1.4, but starting with trans-4-[(5-cyanoindazole-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazole-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-indazole-5-carboxynitrile (compound (53)).

[0264] Step 3e: As described in Step 3d above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-indazole-5-carboxynitrile (compound (52)) is carried out.

[0265] Example 3.6: Synthesis of compounds (54), (55), and (126) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 5-fluoro-1H-indazole, synthesize trans-4-[(5-fluoroindazole-1-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: Synthesize trans-4-[(5-fluoroindazole-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(5-fluoroindazole-1-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid methyl ester. Step 3a: As described in Step 5a of Example 1.3, but starting with trans-4-[(5-fluoroindazole-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(6-cyano-5-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, the synthesis of trans-5-((S)-2-(4-(((5-fluoro-1H-indazole-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile (compound (126)) is carried out.

[0266] Step 3b: As described in step 5c of Example 1.4, but starting with trans-4-[(5-fluoroindazole-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-((S)-2-(4-(((5-fluoro-1H-indazole-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)benzonitrile (compound (54)).

[0267] Step 3c: As described in Step 3b above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((5-fluoro-1H-indazol-1-yl)methyl)cyclohexyl)methyl ketone (compound (55)) is carried out.

[0268] Example 3.7: Synthesis of compounds (56) and (57) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 5-fluoro-1H-indazole, synthesize trans-4-[(5-fluoroindazole-2-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: Synthesize trans-4-[(5-fluoroindazole-2-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(5-fluoroindazole-2-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(5-fluoroindazole-2-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, the synthesis of trans-3-fluoro-5-((S)-2-(4-(((5-fluoro-2H-indazole-2-yl)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)benzonitrile (compound (56)) is carried out.

[0269] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((5-fluoro-2H-indazol-2-yl)methyl)cyclohexyl)methyl ketone (compound (57)) is carried out.

[0270] Example 3.8: Synthesis of compounds (58) and (59) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 5-cyano-1H-indazole, synthesize trans-4-[(5-cyanoydinazol-2-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: Synthesize trans-4-[(5-cyanoydinazol-2-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(5-cyanoydinazol-2-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in step 5c of Example 1.4, but starting with trans-4-[(5-cyanoindazole-2-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazole-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-2-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-2H-indazole-5-carboxynitrile (compound (59)).

[0271] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-2-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-2H-indazole-5-carboxynitrile (compound (58)) is carried out.

[0272] Example 3.9: Synthesis of compounds (60) and (61) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 3-methyl-1H-indazole, synthesize trans-4-[(3-methylindazole-1-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: Synthesize trans-4-[(3-methylindazole-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(3-methylindazole-1-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazole-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(3-methylindazole-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-((S)-2-(4-(((3-methyl-1H-indazole-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)benzonitrile (compound (61)).

[0273] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((3-methyl-1H-indazol-1-yl)methyl)cyclohexyl)methyl ketone (compound (60)) is carried out.

[0274] Example 3.10: Synthesis of compounds (62) and (63) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 3-methyl-1H-indazole, synthesize trans-4-[(3-methylindazole-2-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: Synthesize trans-4-[(3-methylindazole-2-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(3-methylindazole-2-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(3-methylindazole-2-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-((S)-2-(4-(((3-methyl-2H-indazole-2-yl)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)benzonitrile (compound (63)).

[0275] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((3-methyl-2H-indazol-2-yl)methyl)cyclohexyl)methyl ketone (compound (62)) is carried out.

[0276] Example 3.11: Synthesis of compounds (82) and (83) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 4,5-dimethylimidazole, synthesize trans-4-[(4,5-dimethylimidazole-1-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: Synthesize trans-4-[(4,5-dimethylimidazol-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(4,5-dimethylimidazol-1-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(4,5-dimethylimidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-((S)-2-(4-((4,5-dimethyl-1H-imidazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile (compound (82)).

[0277] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((4,5-dimethyl-1H-imidazol-1-yl)methyl)cyclohexyl)methyl ketone (compound (83)) is carried out.

[0278] Example 3.12: Synthesis of compounds (88) and (89) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 5-cyano-4-methyl-imidazolium, synthesize trans-4-[(5-cyano-4-methyl-imidazol-1-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: Synthesize trans-4-[(5-cyano-4-methyl-imidazol-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(5-cyano-4-methyl-imidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(5-cyano-4-methyl-imidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-4-methyl-1H-imidazol-5-carboxynitrile (compound (88)).

[0279] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-methyl-1H-imidazolium-5-carboxynitrile (compound (89)) is carried out.

[0280] Example 3.13: Synthesis of compounds (90) and (91) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 4-cyano-5-methyl-imidazolium, synthesize trans-4-[(4-cyano-5-methyl-imidazol-1-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: Synthesize trans-4-[(4-cyano-5-methyl-imidazol-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(4-cyano-5-methyl-imidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-(benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(4-cyano-5-methyl-imidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-5-methyl-1H-imidazol-4-carboxynitrile (compound (90)).

[0281] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-methyl-1H-imidazolium-4-carboxynitrile (compound (91)) is carried out.

[0282] Example 3.14: Synthesis of compounds (93), (94), and (123) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 6-fluoropyrrolo[3,2-b]pyridine, proceed with the synthesis of trans-4-[(6-fluoropyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: The synthesis of trans-4-[(6-fluoropyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) is carried out in a similar manner as in Example 1.1, but starting with trans-4-[(6-fluoropyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in Step 5a of Example 1.3, but starting with trans-4-[(6-fluoropyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(6-cyano-5-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, the synthesis of trans-5-((S)-2-(4-((6-fluoro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile (compound (123)) is carried out.

[0283] Step 3b: As described in Step 5c of Example 1.4, but starting with trans-4-[(6-fluoropyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-((S)-2-(4-(((6-fluoro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)benzonitrile (compound (93)).

[0284] Step 3c: As described in Step 3b above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((6-fluoro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexyl)methyl ketone (compound (94)) is carried out.

[0285] Example 3.15: Synthesis of compounds (95) and (96) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 5-fluoroindole, synthesize trans-4-[(5-fluoroindole-1-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: Synthesize trans-4-[(5-fluoroindol-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(5-fluoroindol-1-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(5-fluoroindol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-((S)-2-(4-(((5-fluoro-1H-indol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)benzonitrile (compound (95)).

[0286] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((5-fluoro-1H-indol-1-yl)methyl)cyclohexyl)methyl ketone (compound (96)) is carried out.

[0287] Example 3.16: Synthesis of compounds (104) and (105) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 6-carbamoylindole, synthesize trans-4-[(6-carbamoylindole-1-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: In a similar manner to that described in Example 1.1, synthesize the corresponding carboxylic acid from trans-4-[(6-carbamoylindol-1-yl)methyl]cyclohexanecarboxylic acid methyl ester (compound (IIa) in Scheme 1). Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(6-carbamoylindol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-indol-6-carboxamide (compound (104)).

[0288] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-indole-6-carboxamide (compound (105)) is synthesized.

[0289] Example 3.17: Synthesis of compounds (2), (3), (17), (108), (134), (185), (188), and (198). Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 6-cyanopyrrolo[3,2-b]pyridine, proceed with the synthesis of trans-4-[(6-cyanopyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: In a similar manner as in Example 1.1, but using trans-4-[(6-cyanopyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester, trans-4-[(6-cyanopyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1)) is synthesized.

[0290] Step 3a: As described in step 5c of Example 1.4, but starting with trans-4-[(6-cyanopyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, the synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridin-6-carboxylonitrile (compound (2)) is carried out.

[0291] Step 3b: As described in Step 3a above, but starting with (3S)-3-(5-fluoropyridin-3-yl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-(((S)-3-(5-fluoropyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxylonitrile (compound (3)) is carried out.

[0292] Step 3c: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-(((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxylonitrile (compound (17)) is carried out.

[0293] Step 3d: As described in Step 3a above, but starting with (3S)-3-(5-cyanopyridin-3-yl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-1-((4-(((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxylonitrile (compound (108)) was synthesized.

[0294] Step 3e: As described in Step 3a above, but starting with (3S)-3-pyrazin-2-ylisoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-1-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrrolo[3,2-b]pyridine-6-carboxylonitrile (compound (134)) is synthesized.

[0295] Step 3f: As described in Step 3a above, but starting with (3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-1-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrrolo[3,2-b]pyridine-6-carboxylonitrile (compound (185)) is synthesized.

[0296] Step 3g: As described in Step 3a above, but starting with (3S)-3-(2-pyridyl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-[[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrrolo[3,2-b]pyridine-6-carboxylonitrile (compound (188)) was carried out.

[0297] Step 3h: As described in Step 3a above, but starting with (3S)-3-(2-methylthiazol-4-yl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-[[4-[(3S)-3-(2-methylthiazol-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrrolo[3,2-b]pyridine-6-carboxynitrile (compound (198)) is carried out.

[0298] Example 3.18: Synthesis of compounds (110) and (111) Step 1: In a similar manner as in Step 1 of Example 3.1, but starting with 6-carbamoyl-3-methyl-indole, synthesize trans-4-[(6-carbamoyl-3-methyl-indole-1-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3).

[0299] Step 2: Synthesize trans-4-[(6-carbamoyl-3-methyl-indol-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(6-carbamoyl-3-methyl-indol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(6-carbamoyl-3-methyl-indole-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-3-methyl-1H-indole-6-carboxamide (compound (110)).

[0300] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-3-methyl-1H-indole-6-carboxamide (compound (111)) is carried out.

[0301] Example 3.19: Synthesis of compounds (117), (118), and (119) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 3,5-dimethylpyrazole, synthesize trans-4-[(3,5-dimethylpyrazole-1-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: Synthesize trans-4-[(3,5-dimethylpyrazol-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(3,5-dimethylpyrazol-1-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(3,5-dimethylpyrazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-((S)-2-(4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile (compound (119)).

[0302] Step 3b: As described in Step 3a above, but starting with (3S)-3-(p-tolyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the trans-(4-(((3,5-dimethyl-1H-pyrazol-1-yl)methyl)cyclohexyl)((S)-3-(p-tolyl)isoxazoline-2-yl)methyl ketone (compound (117)) is synthesized.

[0303] Step 3c: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)cyclohexyl)methyl ketone (compound (118)) is carried out.

[0304] Example 3.20: Synthesis of compounds (26), (27), (121), (137), (186), (187), and (199). Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 6-cyanopyrazolo[4,3-b]pyridine, proceed with the synthesis of trans-4-[(6-cyanopyrazolo[4,3-b]pyridin-1-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: In a similar manner as in Example 1.1, but using trans-4-[(6-cyanopyrazolo[4,3-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester, proceed with the synthesis of trans-4-[(6-cyanopyrazolo[4,3-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1). Step 3a: As described in step 5c of Example 1.4, but starting with trans-4-[(6-cyanopyrazolo[4,3-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, the synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-pyrazolo[4,3-b]pyridin-6-carboxylonitrile (compound (27)) is carried out.

[0305] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-(((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-pyrazolo[4,3-b]pyridine-6-carboxylonitrile (compound (26)) is carried out.

[0306] Step 3c: As described in Step 3a above, but starting with (3S)-3-pyrazin-2-ylisoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-1-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrazolo[4,3-b]pyridin-6-carboxylonitrile (compound (137)) is synthesized.

[0307] Step 3d: As described in Step 3a above, but starting with trans-4-[(5-cyanopyrazolo[4,3-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid and (S)-3-(5-cyanopyridin-3-yl)isooxazolidine instead of trans-4-[(6-cyanopyrazolo[4,3-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid and 3-fluoro-5-[(3S)-isooxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of trans-2-((4-(((S)-3-(5-cyanopyridin-3-yl)isooxazolidine-2-carbonyl)cyclohexyl)methyl)-2H-pyrazolo[3,4-b]pyridin-5-carboxylonitrile (compound (121)) is carried out.

[0308] Step 3e: As described in Step 3a above, but starting with (3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-1-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrazolo[4,3-b]pyridine-6-carboxylonitrile (compound (186)) is synthesized.

[0309] Step 3f: As described in Step 3a above, but starting with (3S)-3-(2-pyridyl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-[[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrazolo[4,3-b]pyridine-6-carboxynitrile (compound (187)) is carried out.

[0310] Step 3g: As described in Step 3a above, but starting with (3S)-3-(2-methylthiazol-4-yl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-1-[[4-[(3S)-3-(2-methylthiazol-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrazolo[4,3-b]pyridine-6-carboxynitrile (compound (199)) is synthesized.

[0311] Example 3.21: Synthesis of compound (14) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with pyrrolo[3,2-b]pyridine, synthesize trans-4-(pyrrolo[3,2-b]pyridin-1-ylmethyl)cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: Synthesize trans-4-(pyrrolo[3,2-b]pyridin-1-ylmethyl)cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-(pyrrolo[3,2-b]pyridin-1-ylmethyl)cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3: As described in step 5c of Example 1.4, but starting with trans-4-(pyrrolo[3,2-b]pyridin-1-ylmethyl)cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-((S)-2-(4-((1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile (compound (14)).

[0312] Example 3.22: Synthesis of compound (15) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with pyrrolo[3,2-c]pyridine, synthesize trans-4-(pyrrolo[3,2-c]pyridin-1-ylmethyl)cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: Synthesize trans-4-(pyrrolo[3,2-c]pyridin-1-ylmethyl)cyclohexanecarboxylic acid (compound (IIa) of Scheme 1) in a similar manner as in Example 1.1, but using trans-4-(pyrrolo[3,2-c]pyridin-1-ylmethyl)cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3: As described in step 5c of Example 1.4, but starting with trans-4-(pyrrolo[3,2-c]pyridin-1-ylmethyl)cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-((S)-2-(4-((1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile (compound (15)).

[0313] Example 3.23: Synthesis of compound (16) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with pyrrolo[2,3-c]pyridine, synthesize trans-4-(pyrrolo[2,3-c]pyridin-1-ylmethyl)cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: Synthesize trans-4-(pyrrolo[2,3-c]pyridin-1-ylmethyl)cyclohexanecarboxylic acid (compound (IIa) of Scheme 1) in a similar manner as in Example 1.1, but using trans-4-(pyrrolo[2,3-c]pyridin-1-ylmethyl)cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3: As described in step 5c of Example 1.4, but starting with trans-4-(pyrrolo[2,3-c]pyridin-1-ylmethyl)cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-((S)-2-(4-((1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile (compound (16)).

[0314] Example 3.24: Synthesis of compounds (18) and (20) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 2-oxo-1,3-benzoxazole, synthesize trans-4-[(2-oxo-1,3-benzoxazole-3-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: In a similar manner as in Example 1.1, but using trans-4-[(2-oxo-1,3-benzoxazol-3-yl)methyl]cyclohexanecarboxylate instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylate, trans-4-[(2-oxo-1,3-benzoxazol-3-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) is synthesized.

[0315] Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(2-oxo-1,3-benzoxazol-3-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, the synthesis of trans-3-fluoro-5-((S)-2-(4-(((2-oxobenzo[d]oxazol-3(2H)-yl)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)benzonitrile (compound (18)) is carried out.

[0316] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-3-((4-(((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)benzo[d]oxazol-2(3H)-one (compound (20)) is carried out.

[0317] Example 3.25: Synthesis of compounds (19) and (21) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 6-chloropyrrolo[3,2-b]pyridine, proceed with the synthesis of trans-4-[(6-chloropyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: In a similar manner as in Example 1.1, but using trans-4-[(6-chloropyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester, trans-4-[(6-chloropyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1)) is synthesized.

[0318] Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(6-chloropyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, the synthesis of trans-3-((S)-2-(4-(((6-chloro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile (compound (19)) is carried out.

[0319] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-(4-(((6-chloro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexyl)((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)methyl ketone (compound (21)) is carried out.

[0320] Example 3.26: Synthesis of compounds (22) and (23) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 6-cyano-5-fluoro-indole, synthesize trans-4-[(6-cyano-5-fluoro-indole-1-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: Synthesize trans-4-[(6-cyano-5-fluoro-indole-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(6-cyano-5-fluoro-indole-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid.

[0321] Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-indole-6-carboxynitrile (compound (22)). Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-indole-6-carboxynitrile (compound (23)) is carried out.

[0322] Example 3.27: Synthesis of compounds (24) and (25) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 6-cyanopyrazolo[4,3-b]pyridine, proceed with the synthesis of trans-4-[(6-cyanopyrazolo[4,3-b]pyridin-2-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: In a similar manner as in Example 1.1, but using trans-4-[(6-cyanopyrazolo[4,3-b]pyridin-2-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester, trans-4-[(6-cyanopyrazolo[4,3-b]pyridin-2-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1)) is synthesized.

[0323] Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(6-cyanopyrazolo[4,3-b]pyridin-2-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, the synthesis of trans-2-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-2H-pyrazolo[4,3-b]pyridin-6-carboxylonitrile (compound (24)) is carried out.

[0324] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-2-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-2H-pyrazolo[4,3-b]pyridine-6-carboxylonitrile (compound (25)) is carried out.

[0325] Example 3.28: Synthesis of compound (120) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 5-methyloxy-pyrrolo[3,2-b]pyridine, synthesize trans-4-[(5-methyloxy-pyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: Synthesis of trans-4-[(5-methyloxy-pyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid LiOH•H₂O (1 M, 6.61 ml, 2 equivalents) was added to a mixture of trans-4-[(5-methyloxy-pyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylate (1 g, 3.31 mmol, 1 equivalent) in THF (2 ml) and water (4 ml), and the mixture was stirred at 25ºC for 4 h. The reaction mixture was adjusted to pH 3 by adding 1 M HCl, then filtered and concentrated under reduced pressure. The crude product was milled with acetonitrile at 25ºC for 20 min to give the title compound as a white solid (700 mg, 2.43 mmol, 73% yield), which was used without further purification.

[0326] Step 3: As described in step 5c of Example 1.4, but starting with trans-4-[(5-methyloxy-pyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-[(3S)-2-[4-[(5-methoxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (120)).

[0327] Example 3.29: Synthesis of compound (128) Step 1: In a similar manner to Step 1 of Example 3.1, but starting with 6-methyloxy-pyrrolo[3,2-b]pyridine, synthesize trans-4-[(6-methyloxy-pyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylate (the nitrogen-containing heteroaromatic compound used in Step 6a of Scheme 3). Step 2: In a similar manner as in Example 3.28, but using trans-4-[(6-methyloxy-pyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-[(5-methyloxy-pyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid methyl ester, proceed with the synthesis of trans-4-[(6-methoxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1). Step 3: As described in step 5c of Example 1.4, but starting with trans-4-[(6-methoxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-[(3S)-2-[4-[(6-methoxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (128)).

[0328] Example 3.30: Synthesis of compound (241) Step 1: As described in Step 1 of Example 3.1, but starting from 6-cyanoindole and alkylating with trans-4-[(4-nitrophenyl)sulfonyloxymethyl]cyclohexanecarboxylate (Step 6a of Scheme 3), proceed to the synthesis of trans-4-[(6-cyanoindole-1-yl)methyl]cyclohexanecarboxylate. Step 2: Proceed as described in Step 2 of Example 3.1.

[0329] Step 3: As described in step 5c of Example 1.4, but starting with trans-4-[(6-cyanoindol-1-yl)methyl]cyclohexanecarboxylic acid and (3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine, proceed with the synthesis of trans-1-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indol-6-carboxynitrile (compound (241)).

[0330] Example 4: Synthesis of compounds (129), (146), (149), (152), and (153) Example 4.1: Synthesis of compound (129) Step 1: Synthesis of trans-4-[(6-hydroxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylate (compound (IIIb) in Scheme 3) Step a: Synthesis of methyl trans-4-(p-tolylsulfonyloxymethyl)cyclohexanecarboxylate DMAP (4.00 g, 32.75 mmol, 0.5 equivalent), TEA (7.29 g, 72.05 mmol, 1 equivalent), and TosCl (13.49 g, 70.74 mmol, 1.08 equivalent) were added to a solution of trans-4-(hydroxymethyl)cyclohexanecarboxylate (11.28 g, 65.50 mmol, 1 equivalent) in DCM (120 ml) at 25°C. The mixture was stirred at 25°C for 12 h. The reaction mixture was concentrated and the residue was purified by column chromatography (SiO2, petroleum ether / EA = 1 / 1 to 2 / 1) to give the title compound as a yellow solid (14 g, 41.08 mmol, 63% yield).

[0331] LC / MS: m / z 327.2 [M+H] + (Method B) Step b: Synthesis of methyl trans-4-[(6-bromopyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylate A mixture of 6-bromo-1H-pyrrolo[3,2-b]pyridine (2.85 g, 14.48 mmol, 1 equivalent), trans-4-(p-toluylsulfonyloxymethyl)cyclohexanecarboxylate (5.67 g, 17.37 mmol, 1.2 equivalent), and Cs₂CO₃ (9.43 g, 28.95 mmol, 2 equivalent) in DMF (20 ml) was degassed, purged with N₂, and stirred at 80ºC for 3 h. The residue was diluted with water (100 ml) and extracted with EA (100 ml × 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (ISCO®; 20 g SepaFlash® silica rapid column, mobile phase: petroleum ether and EA, gradient: 0-50% EA, flow rate: 80 ml / min) to give the title compound (4.43 g, 11.60 mmol, 80% yield) as a yellow oil.

[0332] LC / MS: m / z 351.0 / 353.0 [M+H] + (Method B) 1 H NMR (400 MHz, CDCl3): δ ppm 8.49 (d, J=1.8 Hz, 1 H), 7.76 (d, J=1.1Hz, 1 H), 7.27-7.26 (m, 1 H), 6.68 (d, J=2.8 Hz, 1 H), 3.93 (d, J=7.2 Hz, 2H), 3.66 (s, 3 H), 2.32-2.19 (m, 1 H), 2.04-1.96 (m, 2 H), 1.90-1.76 (m, 1H), 1.76-1.66 (m, 2 H), 1.40 (dq, J=3.3, 12.9 Hz, 2 H), 1.11-0.98 (m, 2H).

[0333] Step c: Synthesis of trans-4-[[6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylate A mixture of trans-4-[(6-bromopyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexane-formate (4.43 g, 12.61 mmol, 1 equivalent), BPD (3.52 g, 13.87 mmol, 1.1 equivalent), KOAc (3.71 g, 37.84 mmol, 3 equivalent) and Pd(dppf)Cl2·CH2Cl2 (1.03 g, 1.26 mmol, 0.1 equivalent) in dioxane (40 ml) was degassed and purged with N2 and stirred at 90ºC for 2 h under N2 atmosphere. The residue was diluted with water (60 ml) and extracted with EA (60 ml × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (ISCO®; 8 g SepaFlash® silica rapid column, mobile phase: petroleum ether and EA, gradient: 0-50% EA, flow rate: 40 ml / min) to give the title compound as a yellow oil (3.82 g, 9.56 mmol, 76% yield).

[0334] LC / MS: m / z 317.2 [M-81] + (Method B) 1 H NMR (400 MHz, CDCl3): δ ppm 8.78-8.41 (m, 1 H), 8.33-8.00 (m, 1 H), 7.20 (br s, 1 H), 4.13 (q, J=7.1 Hz, 2 H), 3.65-3.57 (m, 3 H), 2.24 (dt, J=4.4, 8.8 Hz, 1 H), 1.92-1.81 (m, 2 H), 1.80-1.70 (m, 2 H), 1.40 (s, 2 H), 1.27 (t, J=7.1 Hz, 3 H).

[0335] Step d: Synthesis of methyl trans-4-[(6-hydroxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylate Methyl trans-4-[[6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylate (3.62 g, 9.09 mmol, 1 equivalent) was added dropwise to a solution of trans-4-[[6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylate (3.62 g, 9.09 mmol, 1 equivalent) in THF (32 ml) and water (8 ml). After addition, the resulting mixture was stirred at 55ºC for 2 h. The residue was diluted with water (60 ml) and extracted with EA (60 ml × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was milled with petroleum ether / EA (3 / 1) at 25ºC for 60 min to give the title compound as a gray solid (2 g, 6.93 mmol, 76% yield).

[0336] LC / MS: m / z 289.2 [M+H] + (Method B) 1 H NMR (400 MHz, CDCl3): δ ppm 10.96-9.57 (m, 1 H), 8.43 (d, J=2.3 Hz, 1 H), 7.24 (d, J=1.6 Hz, 1 H), 7.16 (d, J=3.3 Hz, 1 H), 6.64 (d, J=2.8 Hz, 1H), 3.89 (d, J=7.1 Hz, 2 H), 3.66 (s, 3 H), 2.24 (tt, J=3.5, 12.2 Hz, 1 H), 2.05-1.93 (m, 2 H), 1.90-1.78 (m, 1 H), 1.76-1.67 (m, 2 H), 1.43-1.31 (m, 2H), 1.14-0.96 (m, 2 H).

[0337] Step 2: Synthesis of trans-4-[(6-benzyloxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid Step a: Synthesis of 1H-pyrrolo[3,2-b]pyridin-1-ylethyl ketone A mixture of 1H-pyrrolo[3,2-b]pyridine (22.7 g, 192.15 mmol, 1 equivalent), Ac₂O (58.85 g, 576.45 mmol, 53.99 mL, 3 equivalents), and DMAP (1.17 g, 9.61 mmol, 0.05 equivalents) in THF (230 mL) was stirred at 25ºC for 2 h. TLC indicated that compound 1 was consumed and a new spot was formed. The mixture was concentrated, diluted with water (500 mL), extracted with EtOAc (500 mL x 3), washed with saturated NaHCO₃ solution (300 mL), dried over Na₂SO₄, filtered, and concentrated to give 1H-pyrrolo[3,2-b]pyridin-1-yl ethyl ketone (30.7 g, 99.75% yield) as a yellow solid.

[0338] 1 H NMR (CDCl3400MHz): δ ppm 8.68 (1H, br d, J=8.3 Hz), 8.57 (1H, dd, J=1.5 and 4.8 Hz), 7.68 (1H, d, J=3.8 Hz), 7.27 (1H, s), 6.87 (1H, d, J=3.9Hz), 2.67 (3H, s) Step b: Synthesis of 1-(4-hydroxypyrrolo[3,2-b]pyridin-1-yl)acetone To a solution of 1H-pyrrolo[3,2-b]pyridin-1-yl ethyl ketone (28.7 g, 179.18 mmol, 1 equivalent) in DCM (300 mL), m-CPBA (43.65 g, 215.02 mmol, 85% purity, 1.2 equivalent) was added. The reaction mixture was stirred at 25ºC for 12 h. TLC indicated that the starting material was consumed and a new major spot was formed. The reaction was concentrated. The residue was purified by column chromatography (SiO2, DCM: MeOH = 10:1) to give 1(4-hydroxypyrrolo[3,2-b]pyridin-1-yl)ethyl ketone (36 g, crude) as a yellow solid.

[0339] 1 ¹H NMR (CDCl₃, 400MHz): δ ppm 8.25-8.45 (2H, m), 7.62 (1H, br s), 7.27(1H, s), 7.18 (1H, br s), 2.64-2.73 (3H, m).

[0340] Step c: Synthesis of 1H-pyrrolo[3,2-b]pyridine-6-ol A mixture of 1-(4-hydroxypyrrolo[3,2-b]pyridin-1-yl)acetone (31 g, 123.18 mmol, 70% purity, 1 equivalent) in Ac2O (240 mL) was stirred at 130ºC for 12 h. LCMS showed that sm was consumed and the desired MS was detected. The reaction mixture was concentrated. K2CO3 (28.50 g, 206.22 mmol, 1.5 equivalent) was added to the residue in MeOH (300 mL). The mixture was stirred at 25ºC for 1 h. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (SiO2, DCM: MeOH = 10:1) to give 1H-pyrrolo[3,2-b]pyridin-6-ol (16 g, crude) as a yellow oil.

[0341] 1 H NMR (MeOD, 400MHz): δ ppm7.97 (1H, d, J=2.4 Hz), 7.38 (1H, d, J=3.3Hz), 7.25 (1H, d, J=3.1 Hz), 6.48 (1H, d, J=2.8 Hz).

[0342] Step d: Synthesis of c-benzyloxy-1H-pyrrolo[3,2-b]pyridine CS₂CO₃ (32.79 g, 100.64 mmol, 1.5 equivalent) was added to a solution of 1H-pyrrolo[3,2-b]pyridin-6-ol (9 g, 67.10 mmol, 1 equivalent) and BnBr (11.48 g, 67.10 mmol, 7.97 mL, 1 equivalent) in 100 mL of DMF under N₂. The reaction mixture was stirred at 25ºC for 2 h. LC-MS (EW23468-84-P1A1) showed that reactant 1 was completely consumed. Several new peaks were observed on LC-MS and the desired mass of 29% was detected (Rt = 0.733 min). The reaction mixture was poured into H₂O (1000 mL) and extracted with EA (100 mL * 3). The combined organic layers were washed with brine (1000 mL), dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by reversed-phase HPLC (0.1% FA conditions). 6-Benzyloxy-1H-pyrrolo[3,2-b]pyridine (2 g, 8.92 mmol, 13.29% yield) was obtained as a white solid.

[0343] 1H NMR (400 MHz, chloroform-d) δ = 8.47 (br s, 1H), 8.39 (d, J = 2.6 Hz,1H), 7.50 – 7.46 (m, 2H), 7.45 – 7.39 (m, 2H), 7.38 – 7.33 (m, 2H), 7.25 (dd,J = 0.7, 2.4 Hz, 1H), 6.71 (ddd,J = 0.8, 2.1, 3.2 Hz, 1H), 5.16 (s, 2H).

[0344] Compound (IIa) in Scheme 1 - begins with 6-(benzyloxy)-1H-pyrrolo[2,3-b]pyridine in a similar manner as in Example 3.28.

[0345] Step 3: Synthesis of trans-4-[(6-hydroxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid Pd / C (100 mg, 2.74 mmol, 1 equivalent) was added to a solution of trans-4-[(6-benzyloxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexane-formic acid (1 g, 2.74 mmol, 1 equivalent) in MeOH (20 ml) under N2. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 25ºC under H2 (15 psi) for 3 h. The reaction mixture was filtered and concentrated. A crude product (750 mg, 2.73 mmol, 100% yield) as a white solid was obtained and used without further purification.

[0346] Step 4: As described in step 5c of Example 1.4, but starting with trans-4-[(6-hydroxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of formula -3-fluoro-5-[(3S)-2-[4-[(6-hydroxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (129)).

[0347] Example 4.2: Synthesis of compound (146) Methyl trans-4-[(6-hydroxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexane-formate can be synthesized as detailed in step 1 of Example 4.1 above.

[0348] Step 1: Synthesis of trans-4-[[6-(oxecyclobutane-3-yloxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylate (compound (IIIb) in Scheme 3) t-BuOK (116.75 mg, 1.04 mmol, 1.5 equivalent) was added to a solution of trans-4-[(6-hydroxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexane-formate (200 mg, 693.62 µmol, 1 equivalent) and 3-iodoxetane (191.41 mg, 1.04 mmol, 1.5 equivalent) in DMSO (2 ml). The mixture was stirred at 20ºC for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (500 mg, crude) as a black oil.

[0349] Step 2: In a similar manner as in Example 1.1, but using trans-4-[[6-(oxetane-3-yloxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester, trans-4-[[6-(oxetane-3-yloxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1)) is synthesized. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[[6-(oxecyclobutane-3-yloxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-[(3S)-2-[4-[[6-(oxecyclobutane-3-yloxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile (compound (146)).

[0350] Example 4.3: Synthesis of compound (149) Step 1: Synthesize methyl trans-4-[[6-(2-methoxyethoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylate (compound (IIIb) in Scheme 3) in a manner similar to that described in Example 4.1 above. Step 2: In a similar manner as in Example 3.28, but using trans-4-[[6-(2-methoxyethoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-[(5-methyloxy-pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylic acid methyl ester, proceed with the synthesis of trans-4-[[6-(2-methoxyethoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1). Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(3S)-2-[4-[[6-(2-methoxyethoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile (compound (149)).

[0351] Example 4.4: Synthesis of compound (152) Methyl trans-4-[(6-hydroxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexane-formate can be synthesized as detailed in step 1 of Example 4.1 above.

[0352] Step 1: Using iodomethylcyclopropyl, synthesize methyl trans-4-[[6-(cyclopropylmethoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylate (compound (IIIb) in Scheme 3) in a manner similar to that detailed in Example 4.1. Step 2: In a similar manner as in Example 3.28, but using trans-4-[[6-(cyclopropylmethoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-[(5-methyloxy-pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylic acid methyl ester, to synthesize trans-4-[[6-(cyclopropylmethoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1). Step 3: As described in step 5c of Example 1.4, but starting with trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-[(3S)-2-[4-[[6-(cyclopropylmethoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]-5-fluorobenzonitrile (compound (152)).

[0353] Example 4.5: Synthesis of compound (153) Methyl trans-4-[(6-hydroxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexane-formate can be synthesized as detailed in step 1 of Example 4.1 above.

[0354] Step 1: Synthesis of trans-4-[[6-(2-hydroxyethoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylate (compound (IIIb) in Scheme 3) Step a: Starting with methyl trans-4-[(6-hydroxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylate, as detailed in Example 4.2 above, proceed with the synthesis of methyl trans-4-[[6-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylate.

[0355] Step b: A mixture of trans-4-[[6-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylate (300 mg, 671.66 µmol, 1 equivalent) and TBAF (324.83 mg, 2.01 mmol, 328.45 µl, 3 equivalent) in THF (3 ml) was stirred at 25ºC for 1 h. The reaction mixture was diluted with water (10 ml) and extracted with EA (10 ml). The combined organic layers were washed with brine (10 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (234 mg, crude) as a yellow solid.

[0356] LC / MS: m / z 333.2 [M+H] + (Method B) Step 2: In a similar manner as in Example 3.28, but using trans-4-[[6-(2-hydroxyethoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-[(5-methyloxy-pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylic acid methyl ester, proceed with the synthesis of trans-4-[[6-(2-hydroxyethoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1). Step 3: As described in step 5c of Example 1.4, but starting with trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(3S)-2-[4-[[6-(2-hydroxyethoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile (compound (153)).

[0357] Example 5: Synthesis of compounds (302) and (398) Step 1: Synthesis of trans-4-[(6-methylpyridazin-4-yl)methyl]cyclohexanecarboxylate (compound (IIIb) in Scheme 3) The reaction mixture of trans-4-[(6-chloropyridazin-4-yl)methyl]cyclohexane-formate (300.0 mg, 1.12 mmol, 1.0 equivalent), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (91.2 mg, 0.11 mmol, 0.1 equivalent), Cs2CO3 (1.64 g, 5.02 mmol, 4.5 equivalent), water (2 ml) and trimethylcycloboroxane (50% in THF, 840.8 mg, 0.941 ml, 3.35 mmol, 3 equivalent) was degassed with argon for 5 min and stirred at 80ºC for 9 h. Trimethylcycloboroxane (50% in THF, 0.50 ml), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloromethane complex (50 mg), and a spatula tip of Cs₂CO₃ were added, and the reaction mixture was stirred again for 6.5 h. Trimethylcycloboroxane (50% in THF, 0.50 ml), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloromethane complex (50 mg), and a spatula tip of Cs₂CO₃ were added again, and the reaction mixture was stirred again for 3 h. The solvent was evaporated under reduced pressure, and the residue was quenched with EA and water (30 ml each). The aqueous phase was extracted with EA (20 ml). The combined organic layers were dried over MgSO4, evaporated, and purified by SiO2 chromatography (24 g SiO2, eluent: heptane / EA, gradient: 100% heptane for 5 min, 0-100% EA over 30 min, 100% EA for 10 min, flow rate: 40 ml / min) to give the title compound (125 mg, 0.50 mmol, 45% yield).

[0358] 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.90 (d, J=1.96 Hz, 1 H), 7.36 (d, J=1.83 Hz, 1 H), 3.57 (s, 3 H), 2.57 (s, 3 H), 2.25 (m, 1 H), 1.89 (m, 2 H), 1.59 (m, 3 H), 1.27 (m, 3 H), 1.00 (m, 2 H), 0.85 (br t, J=6.91, 6.91 Hz, 1H).

[0359] Step 2: Synthesize trans-4-[(6-methylpyridazin-4-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(6-methylpyridazin-4-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid methyl ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(6-methylpyridazin-4-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-[(3S)-2-[4-[(6-methylpyridazin-4-yl)methyl]cyclohexanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (302)).

[0360] Step 3b: As described in Step 3a above, but starting with (3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile, proceed with the synthesis of trans-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl]-[4-[(6-methylpyridazin-4-yl)methyl]cyclohexyl] ketone (compound (398)). Chiral SFC: RT 1.26 min (100%, Method X) Example 6: Synthesis of compound (184) Step 1: Synthesis of trans-4-[[6-(1-methylcyclopropoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylate (compound (IIIb) in Scheme 3) Step a: Synthesis of 1-(benzenesulfonyl)-6-bromo-pyrrolo[3,2-b]pyridine 6-Bromo-1H-pyrrolo[3,2-b]pyridine (1 g, 5.08 mmol, 1 equivalent) was added dropwise to a solution of NaH (223.29 mg, 5.58 mmol, 60% purity, 1.1 equivalent) in THF (6 ml) at 0ºC. After stirring at 0ºC for 15 min, a solution of benzenesulfonyl chloride (986.05 mg, 5.58 mmol, 714.53 µl, 1.1 equivalent) in THF (4 ml) was added dropwise at 0ºC. The resulting mixture was stirred at 25ºC for 18 h. The residue was diluted with water (30 ml) and extracted with EA (30 ml × 2). The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by rapid silica gel chromatography (ISCO®; 4 g SepaFlash® silica rapid column, eluent: petroleum ether and EA, gradient: 0-40% EA, flow rate 30 ml / min). The title compound was obtained as a white solid (1.65 g, 4.40 mmol, 87% yield).

[0361] LC / MS: m / z 337.0 [M+H] + (Method B) Step b: Synthesis of 1-(benzenesulfonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrrolo[3,2-b]pyridine 1-(benzenesulfonyl)-6-bromo-pyrrolo[3,2-b]pyridine (5 g, 14.83 mmol, 1 equivalent), BPD (4.90 g, 19.28 mmol, 1.3 equivalent), Pd(dppf)Cl2 (1.08 g, 1.48 mmol, 0.1 equivalent), and KOAc (2.91 g, 29.66 mmol, 2 equivalent) in dioxane (50 ml) were degassed and heated to 90ºC under N2 for 12 h. The reaction mixture was poured into saturated NH4Cl (300 ml), extracted with EA (100 ml × 3), and the combined organic layers were washed with brine (200 ml), dried over Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2, petroleum ether / EA = 5 / 1 to 1 / 1). The title compound was obtained as a white solid (4.2 g, 10.93 mmol, 74% yield).

[0362] LC / MS: m / z 385.3 [M+H] + (Method B) Step c: Synthesis of 1-(benzenesulfonyl)pyrrolo[3,2-b]pyridine-6-ol The reaction mixture was degassed in THF (40 ml) and water (10 ml) in 1-(benzenesulfonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrrolo[3,2-b]pyridine (4 g, 10.41 mmol, 1 equivalent) and sodium perborate tetrahydrate (6.41 g, 41.64 mmol, 8.01 ml, 4 equivalent), and then heated to 55ºC for 2 h under N2. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 (100 ml), extracted with EA (100 ml × 3), and the combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered, concentrated, and used directly for the next step. The title compound (2.8 g, 10.21 mmol, 98% yield) was given as a white solid.

[0363] LC / MS: m / z 275.1 [M+H] + (Method B) Step d: Synthesis of methyl 2-[1-(benzenesulfonyl)pyrrolo[3,2-b]pyridin-6-yl]oxy-4-bromo-butyrate 1-(benzenesulfonyl)pyrrolo[3,2-b]pyridin-6-ol (2.3 g, 8.39 mmol, 1 equivalent) was added in a single step to a mixture of K2CO3 (2.32 g, 16.77 mmol, 2 equivalents) and methyl 2,4-dibromobutyrate (3.27 g, 12.58 mmol, 1.5 equivalents) in DMF (15 ml) under N2 conditions and stirred at 25ºC for 2 h. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (100 ml), extracted with EA (50 ml × 3), the combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2, petroleum ether / EA = 10 / 1 to 1 / 1) to give the title compound (2.6 g, 5.74 mmol, 68% yield) as a yellow oil.

[0364] LC / MS: m / z 455.0 [M+H] + (Method B) Step e: Synthesis of methyl 1-[1-(benzenesulfonyl)pyrrolo[3,2-b]pyridin-6-yl]oxycyclopropanecarboxylate Methyl 2-[1-(benzenesulfonyl)pyrrolo[3,2-b]pyridin-6-yl]oxy-4-bromo-butyrate (2.6 g, 5.74 mmol, 1 equivalent) was added in a single dose to a mixture of t-BuOK (707.97 mg, 6.31 mmol, 1.1 equivalent) in THF (60 ml) under N2 conditions. The mixture was stirred at 25ºC for 2 h, poured into saturated NH4Cl (100 ml), and extracted with EA (50 ml × 3). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2, petroleum ether / EA = 10 / 1 to 0 / 1) to give the title compound (1.1 g, 2.95 mmol, 52% yield) as a yellow oil.

[0365] 1 H NMR (400 MHz, CDCl3): δ ppm 8.31 (d, J=2.4 Hz, 1 H), 7.90-7.80 (m,3 H), 7.71 (d, J=3.7 Hz, 1 H), 7.65-7.57 (m, 1 H), 7.55-7.46 (m, 2 H), 6.83 (d, J=3.8 Hz, 1 H), 3.76 (s, 3 H), 1.77-1.71 (m, 2 H), 1.42-1.36 (m, 2 H).

[0366] Step f: Synthesis of [1-[1-(benzenesulfonyl)pyrrolo[3,2-b]pyridin-6-yl]oxycyclopropyl]methanol LiAlH4 (110.07 mg, 2.90 mmol, 1 equivalent) was slowly added to a solution of methyl 1-[1-(benzenesulfonyl)pyrrolo[3,2-b]pyridin-6-yl]oxycyclopropane-formate (1.08 g, 2.90 mmol, 1 equivalent) in THF (22 ml) at 0°C and stirred at 0°C for 1 h. The reaction mixture was quenched by adding water at 0°C until no bubbles were observed (about 2 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (889 mg, crude) as a colorless oil.

[0367] LC / MS: m / z 345.0 [M+H] + (Method B) 1H NMR (400 MHz, CDCl3): δ ppm 8.32 (d, J=2.5 Hz, 1 H), 8.02 (dd, J=0.6, 2.5 Hz, 1 H), 7.90-7.86 (m, 2 H), 7.69 (d, J=3.8 Hz, 1 H), 7.62-7.57 (m,1 H), 7.52-7.46 (m, 2 H), 6.80 (dd, J=0.7, 3.8 Hz, 1 H), 3.92 (s, 2 H), 1.13-1.09 (m, 2 H), 1.07-1.02 (m, 2 H).

[0368] Step g: Synthesis of 1-(benzenesulfonyl)-6-[1-(iodomethyl)cyclopropoxy]pyrrolo[3,2-b]pyridine PPh3 (677.07 mg, 2.58 mmol, 1 equivalent) was added to a mixture of I2 (655.18 mg, 2.58 mmol, 1 equivalent) and imidazole (175.74 mg, 2.58 mmol, 1 equivalent) in DCM (8 ml) at 0ºC for 5 min. Then, a solution of [1-[1-(benzenesulfonyl)pyrrolo[3,2-b]pyridin-6-yl]oxycyclopropyl]methanol (889 mg, 2.58 mmol, 1 equivalent) in DCM (4 ml) was added dropwise to the reaction mixture at 0ºC and stirred at 20ºC for 2 h. The reaction mixture was quenched by adding Na2SO3 (5 ml), diluted with water (10 ml), extracted with DCM (10 ml × 2), the combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure and purified by rapid silica gel chromatography (eluent: petroleum ether and EA, gradient: 10%–40% EA) to give the title compound (829 mg, 1.82 mmol, 71% yield) as a yellow oil.

[0369] LC / MS: m / z 454.9 [M+H] + (Method B) 1H NMR (400 MHz, CDCl3): δ ppm 8.40 (d, J=2.3 Hz, 1 H), 8.00 (d, J=2.3Hz, 1 H), 7.88 (d, J=7.5 Hz, 2 H), 7.73 (d, J=3.8 Hz, 1 H), 7.64-7.57 (m, 1H), 7.54-7.47 (m, 2 H), 6.85 (d, J=3.7 Hz, 1 H), 3.53 (s, 2 H), 1.52-1.46 (m, 2 H), 1.14-1.09 (m, 2 H).

[0370] Step h: Synthesis of 1-(benzenesulfonyl)-6-(1-methylcyclopropoxy)pyrrolo[3,2-b]pyridine To a mixture of 1-(benzenesulfonyl)-6-[1-(iodomethyl)cyclopropoxy]pyrrolo[3,2-b]pyridine (829 mg, 1.82 mmol, 1 equivalent) in DMSO (9 ml), NaBH4 (69.03 mg, 1.82 mmol, 1 equivalent) was added and the mixture was stirred at 90ºC for 1 h. The reaction mixture was cooled, quenched by adding NH4Cl (10 ml), diluted with water (60 ml), and extracted with EA (50 ml × 3). The combined organic layers were washed with brine (80 ml × 2), dried over Na2SO4, filtered, and concentrated to give the title compound (650 mg, crude) as a yellow oil.

[0371] Step i: Synthesis of 6-(1-methylcyclopropoxy)-1H-pyrrolo[3,2-b]pyridine To a solution of 1-(benzenesulfonyl)-6-(1-methylcyclopropoxy)pyrrolo[3,2-b]pyridine (600.00 mg, 1.83 mmol, 1 equivalent) in MeOH (6 ml) and THF (3 ml), NaOH (2.5 M, 7.31 ml, 10 equivalents) was added and stirred at 20ºC for 1 h. The reaction mixture was diluted with water (40 ml), extracted with EA (20 ml × 3), the combined organic layers were washed with brine (30 ml), dried over Na2SO4, filtered, concentrated, and purified by rapid silica gel chromatography (eluent: petroleum ether and EA, gradient: 10%–35% EA) to give the title compound (200 mg, 1.06 mmol, 58% yield) as a yellow oil.

[0372] LC / MS: m / z 189.1 [M+H] + (Method B) 1 H NMR (400 MHz, CDCl3): δ ppm 8.29 (d, J=2.3 Hz, 2 H), 7.39 (dd, J=0.9, 2.4 Hz, 1 H), 7.35-7.32 (m, 1 H), 6.69 (dt, J=1.0, 2.1 Hz, 1 H), 1.59 (s, 3 H), 1.08-1.05 (m, 2 H), 0.77-0.73 (m, 2 H).

[0373] Step j: Synthesis of methyl trans-4-[[6-(1-methylcyclopropoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylate A mixture of 6-(1-methylcyclopropoxy)-1H-pyrrolo[3,2-b]pyridine (200 mg, 1.06 mmol, 1 equivalent), trans-4-(p-tolylsulfonyloxymethyl)cyclohexanecarboxylate (518.99 mg, 1.59 mmol, 1.5 equivalent) and Cs2CO3 (690.74 mg, 2.12 mmol, 2 equivalent) in DMF (2 ml) was stirred at 80ºC for 12 h. The reaction mixture was filtered, diluted with water (10 ml), extracted with EA (10 ml × 3), the combined organic layers were washed with brine (20 ml × 2), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by rapid silica gel chromatography (eluent: petroleum ether and EA, gradient: 0-35% EA) and preparative TLC (SiO2, petroleum ether / EA = 1 / 2) to give the title compound as a yellow oil (250 mg, 730.07 µmol, 69% yield).

[0374] 1H NMR (400 MHz, CDCl3): δ ppm 8.31 (d, J=2.4 Hz, 1 H), 7.22 (d, J=1.8Hz, 1 H), 7.17 (d, J=3.1 Hz, 1 H), 6.63 (d, J=2.8 Hz, 1 H), 3.96-3.85 (m, 3H), 3.66 (s, 2 H), 3.50 (s, 2 H), 2.28-2.21 (m, 1 H), 2.00 (br d, J=11.0 Hz, 3 H), 1.92-1.78 (m, 2 H), 1.77-1.69 (m, 2 H), 1.47-1.35 (m, 3 H), 1.08-1.05(m, 2 H), 0.79-0.73 (m, 2 H).

[0375] Step 2: In a similar manner as in Example 3.28, but using trans-4-[[6-(1-methylcyclopropoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-[(5-methyloxy-pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylic acid methyl ester, to synthesize trans-4-[[6-(1-methylcyclopropoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1)). Step 3: As described in step 5c of Example 1.4, but starting with trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(3S)-2-[4-[[6-(1-methylcyclopropoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (184)).

[0376] Example 7: Synthesis of compounds (272), (273), (274), (267), (268), (269), (270), (271), (275), (276), (277), (278), (286), and (287). Example 7.1: Synthesis of compounds (272), (273) and (274) Step 1: Synthesis of methyl 4-[(3-carbamoyl-4-methyl-phenyl)methyl]bicyclo[2.2.2]octane-1-carboxylate (compound (IIIb) in Scheme 3) Step a: Synthesis of methyl 4-(hydroxymethyl)bicyclo[2.2.2]octane-1-carboxylate BH3•Me2S (10 M, 2.83 ml, 3 equivalents) was added to a stirred solution of 4-methoxycarbonylbicyclo[2.2.2]octane-1-carboxylic acid (2 g, 9.42 mmol, 1 equivalent) in THF (20 ml) under a N2 atmosphere at 0°C. The reaction mixture was warmed to 20°C and stirred for 4 h. The reaction mixture was quenched with MeOH (30 ml) at 20°C, stirred at 20°C for 2 h, concentrated under reduced pressure, and purified by column chromatography (SiO2, petroleum ether / EA = 10 / 1 to 5 / 1) to give the title compound (1.52 g, 7.67 mmol, 81% yield) as a colorless oil.

[0377] 1 H NMR (400 MHz, DMSO-d6): δ ppm 4.36 (t, J=5.4 Hz, 1 H), 3.55 (s, 3H), 3.02 (d, J=5.4 Hz, 2 H), 1.75-1.61 (m, 6 H), 1.38-1.30 (m, 6 H).

[0378] Step b: Synthesis of methyl 4-(bromomethyl)bicyclo[2.2.2]octane-1-carboxylate CBr4 (2.09 g, 6.30 mmol, 2.5 equivalent) and NEt3 (637.99 mg, 6.30 mmol, 877.56 µl, 2.5 equivalent) were added to a solution of methyl 4-(hydroxymethyl)bicyclo[2.2.2]octane-1-carboxylate (500 mg, 2.52 mmol, 1 equivalent) in DCM (3 ml) at 0°C. Then, PPh3 (1.59 g, 6.05 mmol, 2.4 equivalent) in DCM (3 ml) was added at 0°C. The mixture was stirred at 45°C for 12 h, concentrated under reduced pressure, and purified by column chromatography (SiO2, petroleum ether / EA = 10 / 1 to 5 / 1) to give the title compound (453 mg, 1.73 mmol, 69% yield) as a yellow oil.

[0379] 1 H NMR (400 MHz, CDCl3): δ ppm 3.65 (s, 3 H), 3.21 (s, 2 H), 1.88-1.75 (m, 6 H), 1.58-1.47 (m, 6 H).

[0380] Step c: Synthesis of 5-bromo-2-methyl-benzamide DIPEA (3.61 g, 27.90 mmol, 4.86 ml, 2 equivalents) was added to a mixture of 5-bromo-2-methylbenzoic acid (3 g, 13.95 mmol, 1 equivalent) and HATU (7.96 g, 20.93 mmol, 1.5 equivalents) in DMF (30 ml), stirred for 10 min, NH3•H2O (9.75 g, 77.90 mmol, 10.71 ml, 28% purity, 5.58 equivalents) was added, and stirred at 25ºC for 16 h. The mixture was poured into water (200 ml), cooled to 0°C for 20 minutes, washed with 1 N HCl (150 ml × 2), saturated sodium bicarbonate solution (150 ml × 2), and EA (200 ml × 3), dried over Na2SO4, filtered, concentrated under reduced pressure, and ground at 20°C with petroleum ether / EA = 5 / 1 (20 ml) for 10 minutes to give the title compound as a white solid (2.4 g, 11.19 mmol, 80% yield).

[0381] LC / MS: m / z 214.3 [M+H] + (Method B) 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.95 (s, 1 H), 7.83 (br s, 1 H), 7.54-7.41 (m, 3 H), 7.26-7.12 (m, 1 H), 2.31 (s, 3 H).

[0382] Step d: Synthesis of methyl 4-[(3-carbamoyl-4-methyl-phenyl)methyl]bicyclo[2.2.2]octane-1-carboxylate Add the following to a 40 ml vial equipped with a stir bar: methyl 4-(bromomethyl)bicyclo-[2.2.2]octane-1-carboxylate (500 mg, 1.91 mmol, 1 equivalent), 5-bromo-2-methylbenzamide (532.78 mg, 2.49 mmol, 1.3 equivalent), TTMSS (476.08 mg, 1.91 mmol, 590.67 µl, 1 equivalent), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (21.48 mg, 19.15 µmol, 0.01 equivalent), NiCl2.dtbbpy (3.81 mg, 9.57 µmol, 0.005 equivalent), and Na2CO3 (405.85 mg, 3.83 mmol, 2 equivalent) from DME (20 ml). The vials were placed under nitrogen and sealed (two batches using the same amount of reagent in parallel). The reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm distance) while maintaining a reaction temperature of 20ºC for 14 h with a cooling fan. The reaction mixture was filtered, concentrated under reduced pressure, and purified by reversed-phase HPLC (column: 80 g fast column Welch Ultimate XB C18 20–40 μm, 120 Å; mobile phase: water (0.1% formic acid) and ACN; gradient: 5%–50% ACN over 20 min, 50% ACN for 5 min; flow rate: 85 ml / min) to give two batches of the title compound as a white solid (252 mg, 798.89 µmol, 21% yield).

[0383] LC / MS: m / z 316.4 [M+H] + (Method B) 1 H NMR (400 MHz, CDCl3): δ ppm 7.62 (s, 1 H), 7.31 (s, 1 H), 7.10 (d,J=7.8 Hz, 1 H), 7.05-6.95 (m, 2 H), 3.53 (s, 3 H), 2.37 (s, 2 H), 2.33-2.28 (m, 3 H), 1.71-1.57 (m, 6 H), 1.43-1.28 (m, 6 H).

[0384] Step 2: The synthesis of 4-[(3-carbamoyl-4-methyl-phenyl)methyl]bicyclo[2.2.2]octane-1-carboxylic acid (compound (IIa) in Scheme 1) was carried out in a similar manner as in Example 3.28, but using methyl 4-[(3-carbamoyl-4-methyl-phenyl)methyl]bicyclo[2.2.2]octane-1-carboxylic acid instead of trans-4-[(5-methyloxy-pyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylic acid. Step 3a: As described in step 5c of Example 1.4, but starting with 4-[(3-carbamoyl-4-methyl-phenyl)methyl]bicyclo[2.2.2]octane-1-carboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of 5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]-1-bicyclo[2.2.2]octyl]methyl]-2-methyl-benzamide (compound (274)).

[0385] Step 3b: As described in Step 3a above, but starting with (3S)-3-(6-methyl-3-pyridyl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of 2-methyl-5-[[4-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-bicyclo[2.2.2]octyl]methyl]benzamide (compound (272)) is carried out.

[0386] Step 3c: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)-isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of 5-[[4-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]-1-bicyclo[2.2.2]octyl]methyl]-2-methylbenzamide (compound (273)) is carried out.

[0387] Example 7.2: Synthesis of compounds (269), (270) and (271) Step 1: Starting with 5-bromo-2-methylbenzamide, proceed with the synthesis of methyl 4-[(3-carbamoyl-4-methyl-phenyl)methyl]norbornene-1-carboxylate (compound (IIIb) in Scheme 3) in a manner similar to that described in Example 7.1. Step 2: The synthesis of 4-[(3-carbamoyl-4-methyl-phenyl)methyl]norbornane-1-carboxylic acid (compound (IIa) in Scheme 1) is carried out in a similar manner as in Example 1.1, but with methyl 4-[(3-carbamoyl-4-methyl-phenyl)methyl]norbornane-1-carboxylic acid instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid and saponification is performed with NaOH instead of LiOH.

[0388] Step 3a: As described in Step 5c of Example 1.4, but starting with 4-[(3-carbamoyl-4-methyl-phenyl)methyl]norbornene-1-carboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of 5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]norbornene-1-yl]methyl]-2-methylbenzamide (compound (270)).

[0389] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine instead of 3-fluoro-5-[(3S)-isooxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of 5-[[4-[(3S)-3-(3,5-difluorophenyl)isooxazolidine-2-carbonyl]norbornen-1-yl]methyl]-2-methyl-benzamide (compound (269)) is carried out.

[0390] Step 3c: As described in Step 3a above, but starting with (3S)-3-(6-methyl-3-pyridyl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of 2-methyl-5-[[4-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]norbornene-1-yl]methyl]benzamide (compound (271)) is carried out.

[0391] Example 7.3: Synthesis of compounds (267), (268), and (286) Step 1: Synthesis of 5-bromo-2-methylpyridine-3-carboxylonitrile Step a: Synthesis of 5-bromo-N-tert-butyl-2-methylpyridine-3-carboxamide Under a N2 atmosphere, 5-bromo-2-methylpyridin-3-carboxylic acid (2 g, 9.26 mmol, 1 equivalent), HATU (5.28 g, 13.89 mmol, 1.5 equivalent), and NET were reacted. iPr2 (3.59 g, 27.77 mmol, 4.84 ml, 3 equivalents) was added to a solution of 2-methyl-2-propylamine (812.51 mg, 11.11 mmol, 1.17 ml, 1.2 equivalents) in DMF (20 ml) and stirred at 25ºC for 12 h. The reaction mixture was poured into water (200 ml), extracted with EA (100 ml × 3), the combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2, petroleum ether / EA = 1 / 0 to 1 / 1) to give the title compound as a white solid (2.5 g, 9.22 mmol, 100% yield).

[0392] 1 H NMR (400 MHz, CDCl3): δ ppm 8.58 (s, 1 H), 7.75 (s, 1 H), 5.65 (brs, 1 H), 2.60 (s, 3 H), 1.49 (s, 10 H).

[0393] Step b: Synthesis of 5-bromo-2-methylpyridine-3-carboxylon POCl3 (13.57 g, 88.51 mmol, 8.23 ​​ml, 10 equivalents) was added to a solution of 5-bromo-N-tert-butyl-2-methylpyridine-3-carboxamide (2.4 g, 8.85 mmol, 1 equivalent) in toluene (20 ml) under a nitrogen atmosphere. The reaction mixture was stirred at 110ºC for 2 h, poured into a saturated aqueous solution of NaHCO3 (200 ml), extracted with EA (50 ml × 3), and the combined organic layers were washed with brine (50 ml), dried over Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2, petroleum ether / EA = 1 / 0 to 1 / 1) to give the title compound as a white solid (1.2 g, 6.09 mmol, 69% yield).

[0394] 1 H NMR (400 MHz, CDCl3): δ ppm 8.67 (d, J=2.3 Hz, 1 H), 7.94 (d, J=2.3Hz, 1 H), 2.67 (s, 3 H).

[0395] Step 2: Synthesize trans-4-[(5-cyano-6-methyl-3-pyridyl)methyl]cyclohexanecarboxylate (compound (IIIb) in Scheme 3) in a similar manner as in step d of Example 7.1, but using 5-cyano-6-methyl-3-bromopyridine. Step 3: In a similar manner as in Example 3.28, but using trans-4-[(5-cyano-6-methyl-3-pyridyl)methyl]cyclohexanecarboxylate instead of trans-4-[(5-methyloxy-pyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylate, proceed with the synthesis of trans-4-[(5-cyano-6-methyl-3-pyridyl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1). Step 4a: As described in Step 5c of Example 1.4, but starting with trans-4-[(5-cyano-6-methyl-3-pyridyl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-2-methyl-pyridin-3-carboxylonitrile (compound (268)).

[0396] Step 4b: As described in Step 4a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-5-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-2-methyl-pyridine-3-carboxylonitrile (compound (267)) is carried out.

[0397] Step 4c: As described in Step 4a above, but starting with (3S)-3-(3-cyano-5-fluoro-4-methyl-phenyl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-4-methyl-phenyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-2-methyl-pyridine-3-carboxynitrile (compound (286)) is synthesized.

[0398] Example 7.4: Synthesis of compounds (275), (276), and (287) Step 1: Synthesis of 5-bromo-4-methylpyridine-3-carboxylon CuCN (3.57 g, 39.85 mmol, 1 equivalent) was added to a solution of 3,5-dibromo-4-methylpyridine (10 g, 39.85 mmol, 1 equivalent) in DMF (300 ml), and the mixture was stirred at 140ºC for 5 h. The reaction mixture was filtered, diluted with water (1000 ml), extracted with EA (200 ml × 3), the combined organic layers were washed with brine (200 ml), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, petroleum ether / EA = 4 / 1 to 3 / 1) to give the title compound as a white solid (2.96 g, 14.87 mmol, 37% yield).

[0399] LC / MS: m / z 197.0 [M+H] + (Method B) 1 H NMR (400 MHz, CDCl3): δ ppm 8.85 (s, 1 H), 8.73 (s, 1 H), 2.67 (s, 3H).

[0400] Step 2: Synthesize trans-4-[(5-cyano-4-methyl-3-pyridyl)methyl]cyclohexanecarboxylate (compound (IIIb) in Scheme 3) in a similar manner as in step d of Example 7.1, but using 5-cyano-4-methyl-3-bromopyridine. Step 3: In a similar manner as in Example 3.28, but using trans-4-[(5-cyano-4-methyl-3-pyridyl)methyl]cyclohexanecarboxylate instead of trans-4-[(5-methyloxy-pyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylate, proceed with the synthesis of trans-4-[(5-cyano-4-methyl-3-pyridyl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1). Step 4a: As described in Step 5c of Example 1.4, but starting with trans-4-[(5-cyano-4-methyl-3-pyridyl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-4-methyl-pyridin-3-carboxylonitrile (compound (276)).

[0401] Step 4b: As described in Step 4a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-5-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-4-methyl-pyridine-3-carboxylonitrile (compound (275)) is carried out.

[0402] Step 4c: As described in Step 4a above, but starting with (3S)-3-(3-cyano-5-fluoro-4-methyl-phenyl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-4-methyl-phenyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-4-methyl-pyridine-3-carboxylonitrile (compound (287)) is synthesized.

[0403] Example 7.5: Synthesis of compounds (277) and (278) Step 1: Synthesize 5-bromo-6-methylpyridine-3-carboxylonite in a similar manner as in Example 7.4, but using 3,5-dibromo-6-methylpyridine. Step 2: Synthesize trans-4-[(5-cyano-2-methyl-3-pyridyl)methyl]cyclohexanecarboxylate (compound (IIIb) in Scheme 3) in a similar manner as in step d of Example 7.1, but using 5-cyano-2-methyl-3-bromopyridine. Step 3: In a similar manner as in Example 3.28, but using trans-4-[(5-cyano-2-methyl-3-pyridyl)methyl]cyclohexanecarboxylate instead of trans-4-[(5-methyloxy-pyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylate, proceed with the synthesis of trans-4-[(5-cyano-2-methyl-3-pyridyl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1). Step 4a: As described in Step 5c of Example 1.4, but starting with trans-4-[(5-cyano-2-methyl-3-pyridyl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-6-methyl-pyridin-3-carboxylonitrile (compound (277)).

[0404] Step 4b: As described in Step 4a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-5-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-6-methyl-pyridine-3-carboxynitrile carboxylate (compound (278)) is carried out.

[0405] Example 7.6: Synthesis of compounds (310) and (315) Step 1: Synthesis of 6-chloro-2-methyl-[1,2,4]triazolo[1,5-b]pyridazine Step a: Synthesis of N'-(6-chloropyridazin-3-yl)-N,N-dimethyl-acetamidine To a solution of 6-chloropyridazine-3-amine (5 g, 38.60 mmol, 1 equivalent) in DMF (50 mL), 1,1-dimethoxy-N,N-dimethyl-ethylamine (10.28 g, 77.19 mmol, 11.29 mL, 2 equivalents) was added. The mixture was stirred at 130ºC for 3 h. The residue was concentrated under reduced pressure to give 7.67 g (38.61 mmol, quantitative yield) of the title compound as a white solid.

[0406] LC / MS: m / z 199.2 [M+H] + Rt = 0.123 min (LC / MS method C).

[0407] Step b: Synthesis of N'-(6-chloropyridazine-3-yl)-N-hydroxyacetamidine NH₂OHˑHCl (3.18 g, 45.81 mmol, 1.3 equivalent) was added to a solution of N'-(6-chloropyridazin-3-yl)-N,N-dimethyl-acetamidine (7.67 g, 38.61 mmol, 1 equivalent) in i-PrOH (80 ml). The mixture was stirred at 50ºC for 3 h. The residue was concentrated under reduced pressure to give 6.58 g (35.26 mmol, 91% yield) of the title compound as a white solid.

[0408] LC / MS: m / z 187.2 [M+H] + Rt = 0.181 min (LC / MS method C) 1 H NMR (CDCl3, 400 MHz) δ ppm 7.38 (d, J=9.3 Hz, 1H), 6.97 (d, J=9.3Hz, 1H), 2.44 (s, 3H).

[0409] Step c: Synthesis of 6-chloro-2-methyl-[1,2,4]triazolo[1,5-b]pyridazine TFAA (8.15 g, 38.79 mmol, 5.40 ml, 1.1 equivalent) was added to a solution of N'-(6-chloropyridazine-3-yl)-N-hydroxy-acetamidine (6.58 g, 35.26 mmol, 1 equivalent) in THF (70 ml) at 0°C. The mixture was stirred at 25°C for 3 h. The residue was diluted with water (100 ml) and extracted with EA (100 ml × 2). The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by rapid silica gel chromatography (ISCO®; 8 g SepaFlash® silica rapid column, eluent: EA and petroleum ether, gradient: 0–60% EA; flow rate: 80 ml / min) to give 5.1 g (30.25 mmol, 86% yield) of the title compound as a white solid.

[0410] LC / MS: m / z 169.1 [M+H] + Rt = 0.266 min (LC / MS method B) 1 H NMR (CDCl 3, 400 MHz): δ ppm 7.99 (d, J=9.3 Hz, 1H), 7.39 (d, J=9.3Hz, 1H), 2.66 (s, 3H).

[0411] Step 2: Synthesis of trans-4-[(2-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)methyl]cyclohexanecarboxylate (compound (IIIb) in Scheme 3) Add the following to a 40 mL vial equipped with a stir bar: 6-chloro-2-methyl-[1,2,4]triazolo[1,5-b]pyridazine (500 mg, 2.97 mmol, 1 equivalent), (1r,4r)-4-(bromomethyl)cyclohexane-1-carboxylate (906.53 mg, 3.86 mmol, 1.3 equivalent), NiCl2.dtbbpy (5.90 mg, 14.83 µmol, 0.005 equivalent), TTMSS (737.50 mg, 2.97 mmol, 915.01 uL, 1 equivalent), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (33.27 mg, 29.66 µmol, 0.01 equivalent), and Na2CO3 (628.71 mg, 5.93 mmol, 2 equivalent) from DME (30 mL). Seal the vial and add it under nitrogen. Stir the reaction and irradiate it with a 34 W blue LED lamp (7 cm distance), while maintaining the reaction temperature at 25ºC for 14 h with a cooling fan. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (0.1% FA conditions: flow rate: 100 mL / min; gradient: 100% H2O (0.1% FA) / 0% ACN to 50% H2O (0.1% FA) / 50% ACN over 20 min; 50% H2O (0.1% FA) / 50% ACN over 20 min; column: Welch Ultimate XB_C18, 20–40 μm, 120 A) to give trans-4-[(2-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)methyl]cyclohexanecarboxylate (0.2 g, 547.96 µmol, 4.62% yield, 79% purity) as a white solid.

[0412] Step 3: In a similar manner as in Example 3.28, but using trans-4-[(2-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)methyl]cyclohexanecarboxylate instead of trans-4-[(5-methyloxy-pyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarboxylate, proceed with the synthesis of trans-4-[(2-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1). LiOHˑH₂O (553.03 mg, 13.18 mmol, 2 equivalents) and H₂O (10 mL) were added to a solution of trans-4-[(2-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)methyl]cyclohexanecarboxylic acid (1.61 g, 5.75 mmol, 87.29% yield, 98% purity) in THF (10 mL). The mixture was stirred at 25 °C for 2 h. The pH was adjusted to 3 with 1 M HCl. Trans-4-[(2-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)methyl]cyclohexanecarboxylic acid (1.61 g, 5.75 mmol, 87.29% yield, 98% purity) was obtained as a white solid.

[0413] LCMS: m / z 275.3 [M+1]+ 1 H NMR: (DMSO-d 6, 400 MHz) δ ppm 8.20 (d, J = 9.1 Hz, 1H), 7.52 (d, J =9.3 Hz, 1H), 2.75 (d, J = 6.9 Hz, 2H), 2.49 – 2.49 (m, 3H), 2.13 (tt, J =3.3, 12.0 Hz, 1H), 1.94 – 1.83 (m, 2H), 1.78 – 1.72 (m, 1H), 1.68 (br d, J =12.9 Hz, 2H), 1.33 – 1.23 (m, 2H), 1.12 – 0.99 (m, 2H) Step 4a: As described in Step 5c of Example 1.4, but starting with trans-4-[(2-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)methyl]cyclohexanecarboxylic acid and (3S)-3-(3,4-difluorophenyl)isoxazolidine, replacing trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid and 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of trans-[(3S)-3-(3,4-difluorophenyl)isoxazolidine-2-yl]-[4-[(2-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)methyl]cyclohexyl]methyl ketone (compound (310)) is carried out.

[0414] Step 4b: Synthesis of [(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-yl]-[4-[(2-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)methyl]cyclohexyl] methyl ketone (compound (315)).

[0415] DIEA (235.57 mg, 1.82 mmol, 317.48 μL, 5 equivalents) and HATU (207.91 mg, 546.81 µmol, 1.5 equivalents), and (3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine (82.08 mg, 437.45 µmol, 1.2 equivalents, HCl) were added to a solution of trans-4-[(2-methyl-[1,2,4]triazolo[1,5-b]pyridazine-6-yl)methyl]cyclohexanecarboxylic acid (100 mg, 364.54 µmol, 1 equivalent) in DMF (1 mL). The mixture was stirred at 25 °C for 12 h. The residue was diluted with 10 mL of H2O and extracted with 10 mL of ethyl acetate (10 mL * 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex C18 75 * 30 mm * 3 µm; mobile phase: [water (0.225% FA)-ACN]; B%: 25%-55%, 7 min) to give compound (315) as a white solid (86 mg, 208.95 µmol, 57.32% yield, 99% purity).

[0416] Example 8: Compounds (1), (109), (124), (125), (135), (136), (139), (140), (141), (142), (143), (147), (148), (160), (161), (162), (163), (164), (165), (167), (168), (169), (170), (171), (172) (173), (174), (175), (176), (177), (178), (179), (180), (181), (182), (183), (197), (205), (206), (207), (208), (209), (210), (212), (213), (216), (219), (220), (221), (222), (223) (225), (226), (227), (237), (238), (239), (240), (242), (243), (244), (245), (246), (247), (248), (249), (250), (256), (257), (256), (260), (261), (262), (263), (264), (265), (266) Synthesis of (279), (280), (281), (282), (283), (284), (285), (289), (292), (293), (294), (295), (296), (297), (303), (304), (306), (307), (311), (316), (321), 372, 373, and 374 via photoredox catalysis or cross-electrophilic coupling Synthesis of methyl trans-4-(bromomethyl)cyclohexanecarboxylate (compound (IVb) of Scheme 3) NBS (8.30 g, 46.0 mmol) was added fractionally to a stirred solution of methyl 4-(hydroxymethyl)cyclohexanecarboxylate (4.0 g, 23.0 mmol) and triphenylphosphine (9.10 g, 35.0 mmol) in CH2Cl2 (172 ml) at 0ºC. The black solution was stirred at room temperature for 10 min, volatile components were removed under reduced pressure, and the resulting dark residue was ground with heptane / EA (1 / 1; 200 ml) for 1 h. The suspension was decanted, and the solution was evaporated to give a yellow solid, which was ground with heptane (200 ml). The solution was evaporated. The resulting crude product (5 g) was purified by column chromatography (80 g, SiO2; EA / heptane gradient 0–30% EA) to give the title compound (3.86 g, 16.4 mmol, 71% yield).

[0417] 1 H NMR (400 MHz, DMSO-d6): δ ppm 3.58 (s, 3 H), 3.42 (d, 2 H), 2.23 (m, 1 H), 1.88 (m, 4 H), 1.57 (m, 1 H), 1.33 (m, 2 H), 1.05 (m, 2 H).

[0418] Example 8.1: Synthesis of compounds (109) and (139) Step 1: Synthesis of trans-4-[(3-cyano-4-methyl-phenyl)methyl]cyclohexanecarboxylate (a typical example of photoredox catalysis) (the compound of formula (IIIb) in Scheme 3). In an Ar atmosphere vial, NiCl2 ethylene glycol dimethyl ether complex (11.2 mg, 51 µmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (13.7 mg, 51 µmol) were suspended in 1.6 ml THF. The suspension was sonicated in an ultrasonic bath at 50ºC for 10 min. Volatile components were removed under reduced pressure, and [Ir(dF(Me)ppy)2(dtbbpy)]PF6 (10.3 mg, 10.2 µmol) was added and suspended in DME (10 ml) to form a catalyst suspension.

[0419] 5-Bromo-2-methylbenzonitrile (200 mg, 1.02 mmol), methyl trans-4-(bromomethyl)cyclohexanecarbamate (360 mg, 1.50 mmol), LiOH (48.9 mg, 2.04 mmol), and tris(trimethylsilyl)silane (254 mg, 1.00 mmol, 0.315 ml) were placed in a vial under an Ar atmosphere. The catalyst suspension was added, and Ar was bubbled through the resulting suspension for 10 min. The vial was sealed and irradiated for 24 h in a PennOC photoreactor M1 (100% light intensity).

[0420] The reaction mixture was diluted with EA and water, and the aqueous layer was extracted with EA. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude title compound, which was purified by column chromatography (SiO2; EA / heptane gradient) (120 mg, 450 µmol, 44% yield).

[0421] 1H NMR (400 MHz, DMSO-d6): δ ppm 7.40 (s, 1 H), 7.23 (m, 2 H), 3.42 (s, 3 H), 2.36 (m, 2 H), 2.34 (s, 3 H), 2.07 (m, 1 H), 1.73 (m, 3 H), 1.47 (m, 2 H), 1.33 (m, 1 H), 1.11 (m, 2 H), 0.81 (m, 2 H).

[0422] Step 2: Synthesize trans-4-[(3-cyano-4-methyl-phenyl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(3-cyano-4-methyl-phenyl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(3-cyano-4-methyl-phenyl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-5-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-2-methylbenzonitrile (compound (109)).

[0423] Step 3b: As described in Step 3a above, but starting with (3S)-3-pyrazin-2-ylisoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-2-methyl-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]benzonitrile (compound (139)) is synthesized.

[0424] Example 8.2: Synthesis of compounds (225), (226), and (227) Step 1: Synthesis of methyl trans-4-[(2-methylimidazo[1,2-a]pyridin-6-yl)methyl]cyclohexanecarboxylate (a typical example of photoredox catalysis as detailed in JACS 2016, 138, 8084-8087) (the compound of formula (IIIb) in Scheme 3). In an Ar atmosphere, NiBr2 ethylene glycol dimethyl ether complex (15.0 mg, 50 µmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (13.0 mg, 50 µmol) were suspended in 9 mL of dioxane. The suspension was sonicated in an ultrasonic bath at 50ºC for 10 min to form a catalyst suspension.

[0425] 6-Bromo-2-methylimidazo[1,2-a]pyridine (210 mg, 1.00 mmol), methyl trans-4-(bromo-methyl)cyclohexanecarboxylate (350 mg, 1.50 mmol), LiOH (48.0 mg, 2.00 mmol), tris(trimethylsilyl)silane (300 mg, 1.20 mmol, 0.37 ml), and [Ir(dF(Me)ppy)2(dtbbpy)]PF6 (20 mg, 20.0 µmol) were placed in a vial under an Ar atmosphere. The catalyst suspension was added, and Ar was bubbled through the resulting suspension for 10 min. The vial was sealed and irradiated for 24 h in a PennOC photoreactor M1 (100% light intensity). Volatile components were removed under reduced pressure, and the resulting residue was partitioned between EA and water. The aqueous layer was extracted with EA and the combined organic layer was dried over Na2SO4, filtered and concentrated to obtain the crude title compound, which was purified by column chromatography (SiO2; EA / MeOH gradient; 0-20% MeOH) (60 mg, 210 µmol, 21% yield).

[0426] Step 2: Synthesize trans-4-[(2-methylimidazo[1,2-a]pyridin-6-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(2-methylimidazo[1,2-a]pyridin-6-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(2-methylimidazo[1,2-a]pyridin-6-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-[(3S)-2-[4-[(2-methylimidazo[1,2-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (225)).

[0427] Step 3b: As described in Step 3a above, but starting with (3S)-3-pyrazin-2-ylisoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-[4-[(2-methylimidazo[1,2-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone (compound (226)) is synthesized.

[0428] Step 3c: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(2-methylimidazo[1,2-a]pyridin-6-yl)methyl]cyclohexyl] ketone (compound (227)) is synthesized.

[0429] Example 8.3: Synthesis of compounds (140) and (141) Step 1: Synthesize trans-4-[(5-cyano-3-pyridyl)methyl]cyclohexanecarboxylate (the compound of formula (IIIb) in Scheme 3) as described in Example 8.2 above. Step 2: Synthesize trans-4-[(5-cyano-3-pyridyl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(5-cyano-3-pyridyl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(5-cyano-3-pyridyl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]pyridine-3-carboxylonitrile (compound (141)).

[0430] Step 3b: As described in Step 3a above, but starting with (3S)-3-pyrazin-2-ylisoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]pyridine-3-carboxylonitrile (compound (140)) is synthesized.

[0431] Example 8.4: Synthesis of compounds (135) and (136) Step 1: Synthesize trans-4-[[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]methyl]cyclohexanecarboxylate (the compound of formula (IIIb) in Scheme 3) in a manner similar to that in Example 8.2 above. Step 2: In a similar manner as in Example 1.1, but using trans-4-[[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]methyl]cyclohexanecarboxylate instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylate, proceed with the synthesis of trans-4-[[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1). Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-[(3S)-2-[4-[[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]methyl]cyclohexanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (135)).

[0432] Step 3b: As described in Step 3a above, but starting with (3S)-3-(p-tolyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the trans-[4-[[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]methyl]cyclohexyl]-[(3S)-3-(p-tolyl)isoxazoline-2-yl]methyl ketone (compound (136)) is synthesized.

[0433] Example 8.5: Synthesis of compounds (124) and (125) Step 1: Synthesize trans-4-[[6-(3,5-dimethylpyrazol-1-yl)pyrimidin-4-yl]methyl]cyclohexanecarboxylate (the compound of formula (IIIb) in Scheme 3) in a manner similar to that in Example 8.2 above. Step 2: In a similar manner as in Example 1.1, but using trans-4-[[6-(3,5-dimethylpyrazol-1-yl)pyrimidin-4-yl]methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester, proceed with the synthesis of trans-4-[[6-(3,5-dimethylpyrazol-1-yl)pyrimidin-4-yl]methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1). Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[[6-(3,5-dimethylpyrazol-1-yl)pyrimidin-4-yl]methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-[(3S)-2-[4-[[6-(3,5-dimethylpyrazol-1-yl)pyrimidin-4-yl]methyl]cyclohexanecarbonyl]isoxazolidine-3-yl]-5-fluorobenzonitrile (compound (124)).

[0434] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, proceed with the synthesis of trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[[6-(3,5-dimethylpyrazol-1-yl)pyrimidin-4-yl]methyl]cyclohexyl]methyl ketone (125)).

[0435] Example 8.6: Synthesis of compounds (142), (143), (337) and 338.

[0436] Step 1: Synthesize trans-4-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)cyclohexanecarboxylate (the compound of formula (IIIb) in Scheme 3) in a manner similar to that in Example 8.2 above. Step 2: Synthesize trans-4-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-[(3S)-2-[4-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)cyclohexanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (142)).

[0437] Step 3b: As described in Step 3a above, but starting with (3S)-3-pyrazin-2-ylisoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]-[4-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)cyclohexyl] ketone (compound (143)) is synthesized.

[0438] Step 3c: As described in Step 3a above, but starting with (3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl]-[4-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)cyclohexyl] ketone (compound (337)) is synthesized.

[0439] Chiral SFC: RT 1.31 min (100%, Method X) Step 3c: As described in Step 3a above, but starting with 3-(5-fluoro-3-pyridyl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, proceed with the synthesis of trans-[(3S)-3-(5-fluoropyridin-3-yl)-1,2-oxazolidine-2-yl]-[4-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)cyclohexyl] ketone (compound (338)). Chiral SFC: RT 1.32 min (100%, Method X) Example 8.7: Synthesis of compounds (147) and (148) Step 1: Synthesize trans-4-[(5-fluoro-3-pyridyl)methyl]cyclohexanecarboxylate (the compound of formula (IIIb) in Scheme 3) in a manner similar to that in Example 8.2 above. Step 2: Synthesize trans-4-[(5-fluoro-3-pyridinyl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(5-fluoro-3-pyridinyl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in step 5c of Example 1.4, but starting with trans-4-[(5-fluoro-3-pyridyl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-[(3S)-2-[4-[(5-fluoro-3-pyridyl)methyl]cyclohexanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (148)).

[0440] Step 3b: As described in Step 3a above, but starting with (3S)-3-pyrazin-2-ylisoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-[4-[(5-fluoro-3-pyridinyl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone (compound (147)) is synthesized.

[0441] Example 8.8: Synthesis of compounds (256), (257), and (259) Step 1: Synthesize trans-4-[[3-fluoro-5-(hydroxymethyl)phenyl]methyl]cyclohexanecarboxylate (the compound of formula (IIIb) in Scheme 3) in a manner similar to that in Example 8.2 above. Step 2: Synthesize trans-4-[[3-fluoro-5-(hydroxymethyl)phenyl]methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[[3-fluoro-5-(hydroxymethyl)phenyl]methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(3S)-2-[4-[[3-fluoro-5-(hydroxymethyl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile (compound (256)).

[0442] Step 3b: As described in Step 3a above, but starting with 5-[(3S)-2-isoxazolin-3-yl]pyridin-3-carboxylonite instead of 3-fluoro-5-[(3S)-isoxazolin-3-yl]benzonitrile hydrochloride, the synthesis of trans-5-[(3S)-2-[4-[[[3-fluoro-5-(hydroxymethyl)phenyl]methyl]cyclohexanecarbonyl]isoxazolin-3-yl]pyridin-3-carboxylonite (compound (257)) is carried out.

[0443] Step 3c: As described in Step 3a above, but starting with (3S)-3-pyrazin-2-ylisoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-[4-[[3-fluoro-5-(hydroxymethyl)phenyl]methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone (compound (259)) is synthesized.

[0444] Example 8.9: Synthesis of compounds (279) and (280) Step 1: Synthesize trans-4-[[3-fluoro-4-(2-hydroxyethyl)phenyl]methyl]cyclohexanecarboxylate (the compound of formula (IIIb) in Scheme 3) in a manner similar to that described in Example 8.2 above. Step 2: Synthesize trans-4-[[3-fluoro-4-(2-hydroxyethyl)phenyl]methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[[3-fluoro-4-(2-hydroxyethyl)phenyl]methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-[(3S)-2-[4-[[3-fluoro-4-(2-hydroxyethyl)phenyl]methyl]cyclohexanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (279)).

[0445] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[[3-fluoro-4-(2-hydroxyethyl)phenyl]methyl]cyclohexyl]methyl ketone (compound (280)) is carried out.

[0446] Example 8.10: Synthesis of compounds (282) and (283) Step 1: As described in Example 8.2 above, synthesize trans-4-[[3-fluoro-5-(2-hydroxyethyl)phenyl]methyl]cyclohexanecarboxylate (the compound of formula (IIIb) in Scheme 3). Step 2: Synthesize trans-4-[[3-fluoro-5-(2-hydroxyethyl)phenyl]methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[[3-fluoro-5-(2-hydroxyethyl)phenyl]methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-[(3S)-2-[4-[[3-fluoro-5-(2-hydroxyethyl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile (compound (282)).

[0447] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[[3-fluoro-5-(2-hydroxyethyl)phenyl]methyl]cyclohexyl]methyl ketone (compound (283)) is carried out.

[0448] Example 8.11: Synthesis of compounds (265) and (266) Step 1: As described in Example 8.2 above, synthesize methyl trans-4-[[3-fluoro-4-(hydroxymethyl)phenyl]methyl]cyclohexanecarboxylate (the compound of formula (IIIb) in Scheme 3). Step 2: Synthesize trans-4-[[3-fluoro-4-(hydroxymethyl)phenyl]methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[[3-fluoro-4-(hydroxymethyl)phenyl]methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[[3-fluoro-4-(hydroxymethyl)phenyl]methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-[(3S)-2-[4-[[3-fluoro-4-(hydroxymethyl)phenyl]methyl]cyclohexanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (266)).

[0449] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[[3-fluoro-4-(hydroxymethyl)phenyl]methyl]cyclohexyl]methyl ketone (compound (265)) is carried out.

[0450] Example 8.12: Synthesis of compounds (245) and (246) Step 1: Synthesize methyl trans-4-(pyrazin-2-ylmethyl)cyclohexanecarboxylate (the compound of formula (IIIb) in Scheme 3) in a manner similar to that in Example 8.2 above. Step 2: Synthesize trans-4-(pyrazin-2-ylmethyl)cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using methyl trans-4-(pyrazin-2-ylmethyl)cyclohexanecarboxylate instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylate. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-(pyrazin-2-ylmethyl)cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-[(3S)-2-[4-(pyrazin-2-ylmethyl)cyclohexanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (245)).

[0451] Step 3b: As described in Step 3a above, but starting with (3S)-3-pyrazin-2-ylisoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]-[4-(pyrazin-2-ylmethyl)cyclohexyl] ketone (compound (246)) is synthesized.

[0452] Example 8.13: Synthesis of compounds (247) and (248) Step 1: Synthesize methyl trans-4-(pyrimidin-5-ylmethyl)cyclohexanecarboxylate (the compound of formula (IIIb) in Scheme 3) in a manner similar to that in Example 8.2 above. Step 2: Synthesize trans-4-(pyrimidin-5-ylmethyl)cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-(pyrimidin-5-ylmethyl)cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-(pyrimidin-5-ylmethyl)cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-[(3S)-2-[4-(pyrimidin-5-ylmethyl)cyclohexanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (247)).

[0453] Step 3b: As described in Step 3a above, but starting with (3S)-3-pyrazin-2-ylisoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]-[4-(pyrimidin-5-ylmethyl)cyclohexyl] ketone (compound (248)) is synthesized.

[0454] Example 8.14: Synthesis of compounds (167) and (168) Step 1: Synthesize trans-4-[(3-methylimidazol-4-yl)methyl]cyclohexanecarboxylate (the compound of formula (IIIb) in Scheme 3) in a manner similar to that in Example 8.2 above. Step 2: Synthesize trans-4-[(3-methylimidazol-4-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(3-methylimidazol-4-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(3-methylimidazol-4-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-[(3S)-2-[4-[(3-methylimidazol-4-yl)methyl]cyclohexanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (167)).

[0455] Step 3b: As described in Step 3a above, but starting with 5-[(3S)-2-isoxazolin-3-yl]pyridin-3-carboxylonite instead of 3-fluoro-5-[(3S)-isoxazolin-3-yl]benzonitrile hydrochloride, the trans-5-[(3S)-2-[4-[(3-methylimidazol-4-yl)methyl]cyclohexanecarbonyl]isoxazolin-3-yl]pyridin-3-carboxylonite (compound (168)) is synthesized.

[0456] Example 8.15: Synthesis of compounds (239), (240) and (360) Step 1: Synthesize trans-4-[(2-methylthiazolyl-4-yl)methyl]cyclohexanecarboxylate (the compound of formula (IIIb) in Scheme 3) in a manner similar to that in Example 8.2 above. Step 2: Synthesize trans-4-[(2-methylthiazol-4-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(2-methylthiazol-4-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(2-methylthiazol-4-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-[(3S)-2-[4-[(2-methylthiazol-4-yl)methyl]cyclohexanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (239)).

[0457] Step 3b: As described in Step 3a above, but starting with (3S)-3-pyrazin-2-ylisoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-[4-[(2-methylthiazolyl-4-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone (compound (240)) is synthesized.

[0458] Step 3c: As described in Step 3a above, but starting with (3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the synthesis of trans-(S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl]-[4-[(2-methyl-1,3-thiazolyl-4-yl)methyl]cyclohexyl]methyl ketone (compound (360)) is carried out. Chiral SFC: RT 1.03 min (100%, Method X) Example 8.16: Synthesis of compounds (263), (264), (309), (343), (344), and (346) Step 1: Synthesize trans-4-[(2-methylpyrimidin-5-yl)methyl]cyclohexanecarboxylate (the compound of formula (IIIb) in Scheme 3) in a manner similar to that in Example 8.2 above. Step 2: Synthesize trans-4-[(2-methylpyrimidin-5-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(2-methylpyrimidin-5-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid methyl ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(2-methylpyrimidin-5-yl)methyl]cyclohexanecarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl]cyclohexanecarboxylic acid, proceed with the synthesis of trans-3-fluoro-5-[(3S)-2-[4-[(2-methylpyrimidin-5-yl)methyl]cyclohexanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (263)).

[0459] Step 3b: As described in Step 3a above, but starting with (3S)-3-(3,5-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the synthesis of trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(2-methylpyrimidin-5-yl)methyl]cyclohexyl] ketone (compound (264)) is carried out.

[0460] Step 3c: As described in Step 3a above, but starting with (3S)-3-(3,4-difluorophenyl)isoxazoline instead of 3-fluoro-5-[(3S)-isoxazoline-3-yl]benzonitrile hydrochloride, the trans-[(3S)-3-(3,4-difluorophenyl)isoxazoline-2-yl]-[4-[(2-methylpyrimidin-5-yl)methyl]cyclohexyl] ketone (compound (309)) is synthesized.

[0461] Step 3c: As described in step 3a above, but starting with (3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl]-[4-[(2-methylpyrimidin-5-yl)methyl]cyclohexyl] ketone (compound (343)) is synthesized.

[0462] Chiral SFC: RT 2.056 min (100%, method AH) Step 3c: As described in Step 3a above, but starting with (3S)-3-(6-methyl-3-pyridyl)isoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl]-[4-[(2-methylpyrimidin-5-yl)methyl]cyclohexyl] ketone (compound (344)) is synthesized.

[0463] Chiral SFC: RT 1.13 min (100%, Method X) Step 3c: As described in step 3a above, but starting with (3S)-3-pyrazin-2-ylisoxazolidine instead of 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride, the trans-[4-[(2-methylpyrimidin-5-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidine-2-yl]methyl ketone (compound (346)) is synthesized.

[0464] Chiral SFC: RT 1.08 min (100%, Method X) Example 8.17: Synthesis of compounds (303), (304), (357), (387) and (388) Step 1: Synthesize trans-4-[(6-methylpyridazin-3-yl)methyl]cyclohexanecarboxylate (the compound of formula (IIIb) in Scheme 3) in a manner similar to that in Example 8.2 above. Step 2: Synthesize trans-4-[(6-methylpyridazin-3-yl)methyl]cyclohexanecarboxylic acid (compound (IIa) in Scheme 1) in a similar manner as in Example 1.1, but using trans-4-[(6-methylpyridazin-3-yl)methyl]cyclohexanecarboxylic acid methyl ester instead of trans-4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylic acid ester. Step 3a: As described in Step 5c of Example 1.4, but starting with trans-4-[(6-methylpyridazin-3-yl)methyl]cyclohexanecar...

Claims

1. A compound of formula (I) (I) in R1 represents a phenyl or monocyclic heteroaryl group optionally substituted with one, two, or three R3 groups; R2 represents an aryl or heteroaryl group that is optionally replaced by one, two, or three R6 groups; Each R3 is independently selected from halogen, cyano, (C1-C4)alkyl, or (C1-C4)alkoxy; R4 and R5 are independently selected from halogens, (C1-C4)alkyl groups, (C1-C4)alkoxy groups, or R4 and R5 together form a (C1-C4)alkylene bridge; m and s are independently 0 or 1; p, q, r, and t are independently 0 or 1; Each R6 is independently selected from halogen, cyano, -OH, -NH2 group, (C1-C4)alkyl, -CF3, -C(O)NH2, -C(O)NH-(C1-C4)alkyl, -C(O)OH, -C(O)O-(C1-C4)alkyl, -SO2NH2, (C1-C4)alkoxy, -O-(C1-C4)alkylene-(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -O-(C3-C6)heterocyclic alkyl, (C3-C6)heterocyclic alkyl, heteroaryl, and lateral oxy, wherein the (C1-C4)alkyl, (C1-C4)alkoxy, -O-(C3-C6)cycloalkyl, (C1-C4)alkyl, (C3-C6)heterocyclic alkyl, or heteroaryl is optionally substituted by one, two, three, or four R7s; Each R7 is independently a halogen, side radical, -OH, (C1-C4)alkyl, or (C1-C4)alkoxy. Or its pharmaceutically acceptable salt, solvate or stereoisomer.

2. The compound of formula (I) as described in claim 1, wherein: R1 represents a phenyl or a 5- or 6-membered monocyclic heteroaryl group optionally substituted with one, two or three R3s; R2 represents a phenyl group, a 5- or 6-membered monocyclic heteroaryl group, or a 9- or 10-membered bicyclic heteroaryl group optionally substituted with one, two, or three R6 groups; Each R3 is independently selected from halogen, cyano, (C1-C4)alkyl, and (C1-C4)alkoxy; R4 and R5 together form a (C1-C4) alkylene bridge; m and s are independently 0 or 1; p, q, r, and t are independently 0 or 1; Each R6 is independently selected from halogen, cyano, -NH2 group, -OH, (C1-C4)alkyl, -C(O)NH2, -C(O)NH-(C1-C4)alkyl, (C1-C4)alkoxy, -O-(C1-C4)alkylene-(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -O-(C3-C6)heterocyclic alkyl, 4- or 5-membered heterocyclic alkyl, 5- or 6-membered heteroaryl and oxy group, wherein the (C1-C4)alkyl, (C1-C4)alkoxy, -O-(C3-C6)cycloalkyl, heterocyclic alkyl, heteroaryl are optionally substituted by one or two R7s; Each R7 is independently -OH, (C1-C4)alkyl, or (C1-C4)alkoxy. Or its pharmaceutically acceptable salt, solvate or stereoisomer.

3. The compound of formula (I) as described in claim 1 or 2, wherein the compound has the following formula (Ig): (Ig) in R1, R2, R4, R5, r, q, p, t, m, and s are as defined in claim 1 or 2, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

4. The compound of formula (I) as claimed in claim 1 or 2, wherein the compound has the following formula (Ia): (him) in: R1, R2, R4, R5, m, and s are as defined in claim 1 or 2, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

5. The compound of formula (Ia) as described in the preceding claim, wherein R1 is a phenyl group that is optionally substituted with one or two R3s; R2 is a 9-membered bicyclic heteroaryl group optionally substituted with one or two R6 groups, particularly benzimidazolyl; Each R3 is independently selected from halogen, cyano, or (C1-C4) alkyl; m and s are 0; Each R6 is a halogen, especially fluorine. Or its pharmaceutically acceptable salt, solvate or stereoisomer.

6. The compound of formula (Ia) as claimed in claim 4 or 5, wherein the compound has the following formula (If): (If) in R1, R2, R4, R5, m, and s are as defined in claim 4 or 5, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

7. The compound of formula (I) as claimed in claim 1 or 2, wherein the compound has the following formula (Ib): (One) Wherein R1, R2, R4, R5, m, and s are as defined in claim 1 or 2. Or its pharmaceutically acceptable salt, solvate or stereoisomer.

8. The compound of formula (I) as claimed in claim 1 or 2, wherein the compound has the following formula (Ic): (Ic) Wherein R1, R2, R4, R5, m, and s are as defined in claim 1 or 2. Or its pharmaceutically acceptable salt, solvate or stereoisomer.

9. A compound of formula (Ic) as claimed in the preceding claim, wherein R1 is a phenyl or a 6-membered monocyclic heteroaryl group optionally substituted with one or two R3 groups, and in particular, R1 is a phenyl, pyrazinyl, pyridinyl, thiazolyl, oxazolyl, or pyrimidinyl group optionally substituted with one or two R3 groups. R2 is a 5- or 6-membered monocyclic heteroaryl or a 9-membered bicyclic heteroaryl, optionally substituted with one or two R6, particularly R2 is an imidazopyridinyl, indazole, pyrazolyl, pyridinyl, pyrimidinyl, triazolpyridinyl, triazolpyridinyl, pyrazolpyridinyl, imidazopyridinyl, phenyl, pyridinyl, or thiazolyl. Each R3 is independently selected from halogen, cyano, (C1-C4)alkyl or (C1-C4)alkoxy, and in particular each R3 is independently selected from fluorine, cyano, methoxy or methyl; m and s are 0 or m is 0 and s is 1, and R4 is a methyl group; Each R6 is independently selected from halogen, cyano, -NH2 group, (C1-C4)alkyl, (C1-C4)alkoxy, -CF3, and (C3-C6) heterocyclic alkyl optionally substituted with one, two, three, or four R7s, particularly each R6 is independently selected from fluorine, cyano, methyl, methoxy, or hydroxyoxetane. R7 can be a halogen, side group, -OH, methyl or methoxy group independently. Or its pharmaceutically acceptable salt, solvate or stereoisomer.

10. The compound of formula (Ic) as claimed in claim 8 or 9, wherein the compound has the following formula (Ie): (Ie) in R1, R2, R4, R5, m, and s are as defined in claim 8 or 9, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

11. The compound of formula (I) as claimed in claim 1 or 2, wherein the compound has the following formula (Id): (Id) Wherein R1, R2, R4, R5, m, and s are as defined in claim 1 or 2. Or its pharmaceutically acceptable salt, solvate or stereoisomer.

12. The compound of formula (I) as claimed in claim 1, wherein the compound has the following formula (Ib), (Ic), particularly formula (Ie) or (Id): (One) (Ic) (Ie) (Id) Wherein R1, R2, R4, R5, m, and s are as defined in claim 1 or 2. Or its pharmaceutically acceptable salts, solvates or stereoisomers; In particular, it has: As in formula (Ib) of claim 7, As in claim 8 or 9, formula (Ic), and more particularly as in claim 10, formula (Ie), or As in claim 11, formula (Id), Or its pharmaceutically acceptable salts, solvates or stereoisomers; More particularly: As in formula (Ib) of claim 7, As in formula (Ic) of claim 8 or 9, and more particularly as in formula (Ie) of claim 10, Or its pharmaceutically acceptable salt, solvate or stereoisomer.

13. The compound of formula (I) as claimed in claim 1, wherein when the group When the cyclobutyl group is optionally substituted, R4 and R5 are independently selected from halogens, (C1-C4)alkyl groups, or (C1-C4)alkoxy groups.

14. The compound of formula (I) according to any one of claims 1 to 13, wherein the compound is selected from: (1) trans-3-[(3S)-2-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile; (2) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxynitrile, (3) trans-1-((4-((S)-3-(5-fluoropyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxynitrile, (4) trans-1-((4-((S)-3-(5-fluoropyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-4-methyl-1H-imidazol-5-carboxynitrile, (5) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazolium-5-carboxynitrile, (6) trans-1-((4-((S)-3-(5-fluoropyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazol-5-carboxynitrile, (7) trans-3-((S)-2-(4-((1H-benzo[d]imidazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)-5-fluorobenzonitrile, (8) trans-(4-((1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl)((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)methyl ketone, (9) trans-(4-((1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl)((S)-3-(5-fluoropyridin-3-yl)isoxazolidine-2-yl)methyl ketone, (10) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-benzo[d]imidazolium-5-carboxynitrile, (11) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-benzo[d]imidazolium-5-carboxynitrile, (12) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-benzo[d]imidazolium-6-carboxynitrile, (13) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-benzo[d]imidazolium-6-carboxynitrile, (14) trans-3-((S)-2-(4-((1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolide-3-yl)-5-fluorobenzonitrile, (15) trans-3-((S)-2-(4-((1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolide-3-yl)-5-fluorobenzonitrile, (16) Inverse - 3-((S)-2-(4-((1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)-5-fluorobenzonitrile, (17) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxynitrile, (18) trans-3-fluoro-5-((S)-2-(4-((2-oxobenzo[d]oxazol-3(2H)-yl)methyl)cyclohexane-1-carbonyl)isooxazolidine-3-yl)benzonitrile, (19) trans-3-((S)-2-(4-((6-chloro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)-5-fluorobenzonitrile, (20) trans-3-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)benzo[d]oxazol-2(3H)-one, (21) trans-(4-((6-chloro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexyl)((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)methyl ketone, (22) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-indole-6-carboxynitrile, (23) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-indole-6-carboxynitrile, (24) trans-2-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-2H-pyrazolo[4,3-b]pyridine-6-carboxynitrile, (25) trans-2-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-2H-pyrazolo[4,3-b]pyridine-6-carboxynitrile, (26) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-pyrazolo[4,3-b]pyridine-6-carboxynitrile, (27) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-pyrazolo[4,3-b]pyridine-6-carboxynitrile, (28) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-indazole-6-carboxynitrile, (29) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-indazole-6-carboxynitrile, (30) trans-2-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-2H-indazole-6-carboxynitrile, (31) trans-2-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-2H-indazole-6-carboxynitrile, (32) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-indazole-6-carboxynitrile, (33) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-indazole-6-carboxynitrile, (34) trans-2-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-2H-indazole-6-carboxynitrile, (35) trans-2-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-2H-indazole-6-carboxynitrile, (36) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-benzo[d]imidazolium-6-carboxynitrile, (37) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-benzo[d]imidazolium-6-carboxynitrile, (38) trans-4-fluoro-1-((4-((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazol-6-carboxynitrile, (39) trans-5-fluoro-1-((4-((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazol-6-carboxynitrile, (40) trans-6-fluoro-1-((4-((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazol-5-carboxynitrile, (41) trans-2-((4-((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-2H-indazole-6-carboxynitrile, (42) trans-4-fluoro-2-((4-((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-2H-indazole-6-carboxynitrile, (43) trans-1-((4-((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-indazole-6-carboxynitrile, (44) trans-4-fluoro-1-((4-((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-indazole-6-carboxynitrile, (45) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-indole-6-carboxynitrile, (46) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-indole-6-carboxynitrile, (47) trans-4-fluoro-1-((4-((S)-3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-indole-6-carboxynitrile, (48) trans-3-fluoro-5-((S)-2-(4-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)benzonitrile, (49) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl) ketone, (50) trans-3-fluoro-5-((S)-2-(4-((5-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)benzonitrile, (51) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((5-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl) ketone, (52) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-indazole-5-carboxynitrile, (53) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-indazole-5-carboxynitrile, (54) trans-3-fluoro-5-((S)-2-(4-((5-fluoro-1H-indazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)benzonitrile, (55) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((5-fluoro-1H-indazol-1-yl)methyl)cyclohexyl) ketone, (56) trans-3-fluoro-5-((S)-2-(4-(((5-fluoro-2H-indazol-2-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)benzonitrile, (57) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((5-fluoro-2H-indazol-2-yl)methyl)cyclohexyl) ketone, (58) trans-2-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-2H-indazole-5-carboxynitrile, (59) trans-2-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-2H-indazole-5-carboxynitrile, (60) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((3-methyl-1H-indazol-1-yl)methyl)cyclohexyl) ketone, (61) trans-3-fluoro-5-((S)-2-(4-((3-methyl-1H-indazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)benzonitrile, (62) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((3-methyl-2H-indazol-2-yl)methyl)cyclohexyl) ketone, (63) trans-3-fluoro-5-((S)-2-(4-((3-methyl-2H-indazol-2-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)benzonitrile, (64) trans-1-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-benzo[d]imidazol-6-carboxynitrile, (65) trans-1-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-benzo[d]imidazol-5-carboxynitrile, (66) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-indazole-5-carboxynitrile, (67) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-indazole-5-carboxynitrile, (68) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-6-fluoro-3-methyl-1H-indazole-5-carboxynitrile, (69) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-6-fluoro-3-methyl-1H-indazole-5-carboxynitrile, (70) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-benzo[d]imidazolium-6-carboxamide, (71) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-benzo[d]imidazolium-6-carboxamide, (72) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-indazole-5-carboxamide, (73) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-indazole-5-carboxamide, (74) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-benzo[d]imidazol-5-carboxamide, (75) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-benzo[d]imidazol-5-carboxamide, (76) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-indole-6-carboxamide, (77) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-indole-6-carboxamide, (78) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-pyrazolo[4,3-b]pyridine-6-carboxamide, (79) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-pyrazolo[4,3-b]pyridine-6-carboxamide, (80) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-benzo[d]imidazolium-6-carboxamide, (81) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-benzo[d]imidazolium-6-carboxamide, (82) trans-3-((S)-2-(4-((4,5-dimethyl-1H-imidazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)-5-fluorobenzonitrile, (83) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((4,5-dimethyl-1H-imidazol-1-yl)methyl)cyclohexyl) ketone, (84) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-3-methyl-1H-indazole-6-carboxynitrile, (85) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-3-methyl-1H-indazole-6-carboxynitrile, (86) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-indazole-6-carboxynitrile, (87) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-fluoro-1H-indazole-6-carboxynitrile, (88) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-methyl-1H-imidazolium-5-carboxynitrile, (89) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-methyl-1H-imidazolium-5-carboxynitrile, (90) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-methyl-1H-imidazolium-4-carboxynitrile, (91) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-5-methyl-1H-imidazolium-4-carboxynitrile, (92) trans-(4-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl)((S)-3-(pyrazin-2-yl)isoxazolidine-2-yl)methyl ketone, (93) trans-3-fluoro-5-((S)-2-(4-((6-fluoro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)benzonitrile, (94) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((6-fluoro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexyl) ketone, (95) trans-3-fluoro-5-((S)-2-(4-(((5-fluoro-1H-indol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazolide-3-yl)benzonitrile, (96) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((5-fluoro-1H-indol-1-yl)methyl)cyclohexyl) ketone, (97) trans-6-fluoro-1-((4-((S)-3-(pyrazin-2-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazol-5-carboxynitrile, (98) trans-5-fluoro-1-((4-((S)-3-(pyrazin-2-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-benzo[d]imidazol-6-carboxynitrile, (99) trans-1-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]pyrrolo[3,2-b]pyridine-5-carboxynitrile, (100) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-3-methyl-1H-indazole-6-carboxynitrile, (101) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-3-methyl-1H-indazole-6-carboxynitrile, (102) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-4-fluoro-3-methyl-1H-indazole-6-carboxamide, (103) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-4-fluoro-3-methyl-1H-indazole-6-carboxamide, (104) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-indole-6-carboxamide, (105) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-1H-indole-6-carboxamide, (106) trans-5-((S)-2-(4-((6-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)nicotinonitrile, (107) trans-5-((S)-2-(4-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)nicotinonitrile, (108) trans-1-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxynitrile, (109) trans-5-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-2-methylbenzonitrile, (110) trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-3-methyl-1H-indole-6-carboxamide, (111) trans-1-((4-((S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl)cyclohexyl)methyl)-3-methyl-1H-indole-6-carboxamide, (112) trans-3-fluoro-5-((S)-2-(4-((6-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)benzonitrile, (113) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((6-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl) ketone, (114) trans-(3-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclobutyl)((S)-3-(p-tolyl)isoxazoline-2-yl)methyl ketone, (115) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(3-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclobutyl) ketone, (116) trans-3-fluoro-5-((S)-2-(3-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)cyclobutane-1-carbonyl)isoxazoline-3-yl)benzonitrile, (117) trans-(4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)cyclohexyl)((S)-3-(p-tolyl)isoxazoline-2-yl)methyl ketone, (118) trans-((S)-3-(3,5-difluorophenyl)isoxazoline-2-yl)(4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)cyclohexyl) ketone, (119) trans-3-((S)-2-(4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)-5-fluorobenzonitrile, (120) trans-3-fluoro-5-[(3S)-2-[4-[(5-methoxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (121) trans-2-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxynitrile, (122) trans-1-[[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-6-oxo-pyridin-3-carboxynitrile, (123) trans-5-((S)-2-(4-((6-fluoro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)nicotinonitrile, (124) trans-3-[(3S)-2-[4-[[6-(3,5-dimethylpyrazol-1-yl)pyrimidin-4-yl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]-5-fluorobenzonitrile, (125) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[[6-(3,5-dimethylpyrazol-1-yl)pyrimidin-4-yl]methyl]cyclohexyl] ketone, (126) trans-5-((S)-2-(4-((5-fluoro-1H-indazol-1-yl)methyl)cyclohexane-1-carbonyl)isoxazoline-3-yl)nicotinonitrile, (127) trans-2-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-2H-indazole-6-carboxynitrile, (128) trans-3-fluoro-5-[(3S)-2-[4-[(6-methoxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (129) trans-3-fluoro-5-[(3S)-2-[4-[(6-hydroxypyrrolo[3,2-b]pyridin-1-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (130) trans-1-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-4-fluoro-1H-indole-6-carboxynitrile, (131) trans-2-methyl-5-[[4-[(3S)-3-(p-tolyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]benzamide, (132) trans-5-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-2-methylbenzamide, (133) trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-2-methyl-benzamide, (134) trans-1-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrrolo[3,2-b]pyridine-6-carboxynitrile, (135) trans-3-fluoro-5-[(3S)-2-[4-[[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (136) trans-[4-[[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]methyl]cyclohexyl]-[(3S)-3-(p-tolyl)isoxazoline-2-yl] ketone, (137) trans-1-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrazolo[4,3-b]pyridine-6-carboxynitrile, (138) trans-2-methyl-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]benzamide, (139) trans-2-methyl-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]benzonitrile, (140) trans-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]pyridine-3-carboxynitrile, (141) trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]pyridine-3-carboxynitrile, (142) trans-3-fluoro-5-[(3S)-2-[4-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (143) trans-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]-[4-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)cyclohexyl] ketone, (144) trans-3-fluoro-5-[(3S)-2-[4-[(3-oxoisoindololin-5-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (145) trans-6-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]isoindololin-1-one, (146) trans-3-fluoro-5-[(3S)-2-[4-[[6-(oxecyclobutane-3-yloxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (147) trans-[4-[(5-fluoro-3-pyridinyl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (148) trans-3-fluoro-5-[(3S)-2-[4-[(5-fluoro-3-pyridyl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (149) trans-3-fluoro-5-[(3S)-2-[4-[[6-(2-methoxyethoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (150) trans-3-fluoro-5-[(3S)-2-[4-[(1-methylpyrazol-4-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (151) trans-[4-[(1-methylpyrazol-4-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (152) trans-3-[(3S)-2-[4-[[6-(cyclopropylmethoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]-5-fluorobenzonitrile, (153) trans-3-fluoro-5-[(3S)-2-[4-[[6-(2-hydroxyethoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (154) trans-6-[[4-[(3S)-3-(4-fluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]isoindololin-1-one, (155) trans-6-[[4-[(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]isoindololin-1-one, (156) trans-6-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]isoindololin-1-one, (157) trans-6-[[4-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]isoindololin-1-one, (158) trans-5-[[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-2-methylbenzamide, (159) trans-2-methyl-5-[[4-[(3S)-3-(2-methylthiazolyl-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]benzamide, (160) trans-3-fluoro-5-[[4-[(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-N-methyl-benzamide, (161) trans-3-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-5-fluoro-N-methylbenzamide, (162) trans-3-fluoro-N-methyl-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]benzamide, (163) trans-3-[[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-5-fluoro-N-methylbenzamide, (164) trans-3-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-5-fluoro-N-methyl-benzamide, (165) trans-3-fluoro-5-[[4-[(3S)-3-(4-fluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-N-methyl-benzamide, (166) trans-5-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-2-methylbenzamide, (167) trans-3-fluoro-5-[(3S)-2-[4-[(3-methylimidazol-4-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (168) trans-5-[(3S)-2-[4-[(3-methylimidazol-4-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]pyridin-3-carboxynitrile, (169) trans-3-fluoro-5-[(3S)-2-[4-[[4-(3-hydroxyoxetane-3-yl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (170) trans-[(3S)-3-(4-fluorophenyl)isoxazoline-2-yl]-[4-[[4-(3-hydroxyoxetane-3-yl)phenyl]methyl]cyclohexyl] ketone, (171) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[[4-(3-hydroxyoxetane-3-yl)phenyl]methyl]cyclohexyl] ketone, (172) trans-4-fluoro-3-[[4-[(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-N-methyl-benzamide, (173) trans-4-fluoro-3-[[4-[(3S)-3-(4-fluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-N-methyl-benzamide, (174) trans-3-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-4-fluoro-N-methylbenzamide, (175) trans-4-fluoro-N-methyl-3-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]benzamide, (176) trans-3-[[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-4-fluoro-N-methyl-benzamide, (177) trans-3-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-4-fluoro-N-methyl-benzamide, (178) trans-[4-[(5-fluoro-2-methyl-3-pyridyl)methyl]cyclohexyl]-[(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-yl] methyl ketone, (179) trans-[4-[(5-fluoro-2-methyl-3-pyridyl)methyl]cyclohexyl]-[(3S)-3-(4-fluorophenyl)isoxazoline-2-yl] methyl ketone, (180) trans-[4-[(5-fluoro-2-methyl-3-pyridinyl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (181) trans-3-fluoro-5-[(3S)-2-[4-[(5-fluoro-2-methyl-3-pyridyl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (182) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(5-fluoro-2-methyl-3-pyridyl)methyl]cyclohexyl] ketone, (183) trans-5-[(3S)-2-[4-[[4-(3-hydroxyoxetane-3-yl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]pyridine-3-carboxynitrile, (184) trans-3-fluoro-5-[(3S)-2-[4-[[6-(1-methylcyclopropoxy)pyrrolo[3,2-b]pyridin-1-yl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (185) trans-1-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrrolo[3,2-b]pyridine-6-carboxynitrile, (186) trans-1-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrazolo[4,3-b]pyridine-6-carboxynitrile, (187) trans-1-[[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrazolo[4,3-b]pyridine-6-carboxynitrile, (188) trans-1-[[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrrolo[3,2-b]pyridine-6-carboxynitrile, (189) trans-2-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxynitrile, (190) trans-1-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxynitrile, (191) trans-2-fluoro-5-[[4-[(3S)-3-(4-fluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]benzamide, (192) trans-5-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-2-fluoro-benzamide, (193) trans-2-fluoro-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]benzamide, (194) trans-5-[[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]-2-fluoro-benzamide, (195) trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-2-fluoro-benzamide, (196) trans-2-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxynitrile, (197) trans-5-[(3S)-2-[4-[(5-fluoro-2-methyl-3-pyridinyl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]pyridin-3-carboxynitrile, (198) trans-1-[[4-[(3S)-3-(2-methylthiazolyl-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrrolo[3,2-b]pyridine-6-carboxynitrile, (199) trans-1-[[4-[(3S)-3-(2-methylthiazolyl-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]pyrazolo[4,3-b]pyridine-6-carboxynitrile, (200) trans-1-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxynitrile, (201) trans-1-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxamide, (202) trans-1-[[4-[(3S)-3-(2-methylthiazolyl-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-5-carboxynitrile, (203) trans-2-[[4-[(3S)-3-(2-methylthiazolyl-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxynitrile, (204) trans-1-[[4-[(3S)-3-(2-methylthiazolyl-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxynitrile, (205) trans-[4-[(8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (206) trans-3-fluoro-5-[(3S)-2-[4-[(8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (207) trans-[4-[[3-fluoro-5-(2-methylimidazol-1-yl)phenyl]methyl]cyclohexyl]-[(3S)-3-(4-fluorophenyl)isoxazoline-2-yl] ketone, (208) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[[3-fluoro-5-(2-methylimidazol-1-yl)phenyl]methyl]cyclohexyl] ketone, (209) trans-[4-[[3-fluoro-5-(2-methylimidazol-1-yl)phenyl]methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (210) trans-5-[(3S)-2-[4-[[3-fluoro-5-(2-methylimidazol-1-yl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]pyridin-3-carboxynitrile, (211) trans-[4-[[3-fluoro-5-(2-methylpyrazol-3-yl)phenyl]methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (212) trans-4-fluoro-6-[[4-[(3S)-3-(4-fluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]isoindololin-1-one, (213) trans-4-fluoro-6-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]isoindoline-1-one, (214) trans-3-fluoro-5-[(3S)-2-[4-[[3-fluoro-5-(2-methylpyrazol-3-yl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (215) trans-1-[[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxynitrile, (216) trans-3-fluoro-5-[(3S)-2-[4-[[3-fluoro-5-(2-methylimidazol-1-yl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (217) trans-1-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-5-carboxynitrile, (218) trans-1-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-5-carboxynitrile, (219) trans-3-fluoro-5-[(3S)-2-[4-[(7-fluoro-3-oxo-isoindololin-5-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (220) trans-[4-[[3-fluoro-5-(2-methylimidazol-1-yl)phenyl]methyl]cyclohexyl]-[(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-yl] ketone, (221) trans-3-fluoro-5-[(3S)-2-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (222) trans-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (223) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (224) trans-3-fluoro-5-[(3S)-2-[4-[(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (225) trans-3-fluoro-5-[(3S)-2-[4-[(2-methylimidazo[1,2-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (226) trans-[4-[(2-methylimidazo[1,2-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl] ketone, (227) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(2-methylimidazo[1,2-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (228) trans-2-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxamide, (229) trans-1-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxamide, (230) trans-1-[[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxamide, (231) trans-1-[[4-[(3S)-3-(4-cyano-2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxamide, (232) trans-2-[[4-[(3S)-3-(4-cyano-2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxamide, (233) trans-2-[[4-[(3S)-3-(2-methylthiazolyl-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxamide, (234) trans-1-[[4-[(3S)-3-(2-methylthiazolyl-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-6-carboxamide, (235) trans-5-[(3S)-2-[4-[(1-methylpyrazol-4-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]pyridin-3-carboxynitrile, (236) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(1-methylpyrazol-4-yl)methyl]cyclohexyl] ketone, (237) trans-3-fluoro-5-[(3S)-2-[4-[(2-methylpyrazol-3-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (238) trans-[4-[(2-methylpyrazol-3-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (239) trans-3-fluoro-5-[(3S)-2-[4-[(2-methylthiazolyl-4-yl)methyl]cyclohexanecarbonyl]isoxazolyl-3-yl]benzonitrile, (240) trans-[4-[(2-methylthiazolyl-4-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (241) trans-1-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indole-6-carboxynitrile, (242) trans-2-fluoro-5-[[4-[(3S)-3-(4-fluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]benzonitrile, (243) trans-2-fluoro-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]benzonitrile, (244) trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-2-fluorobenzonitrile, (245) trans-3-fluoro-5-[(3S)-2-[4-(pyrazin-2-ylmethyl)cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (246) trans-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]-[4-(pyrazin-2-ylmethyl)cyclohexyl] ketone, (247) trans-3-fluoro-5-[(3S)-2-[4-(pyrimidin-5-ylmethyl)cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (248) trans-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]-[4-(pyrimidin-5-ylmethyl)cyclohexyl] ketone, (249) trans-3-fluoro-5-[(3S)-2-[4-[(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]-1,2-oxazolidine-3-yl]benzonitrile, (250) trans-[4-[(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidine-2-yl] ketone, (251) trans-1-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl]indole-5-carboxamide, (252) trans-1-[[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indole-5-carboxamide, (253) trans-1-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indole-5-carboxamide, (254) trans-1-[[4-[(3S)-3-(2-methylthiazolyl-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indole-5-carboxamide, (255) trans-1-[[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indole-5-carboxamide, (256) trans-3-fluoro-5-[(3S)-2-[4-[[3-fluoro-5-(hydroxymethyl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (257) trans-5-[(3S)-2-[4-[[3-fluoro-5-(hydroxymethyl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]pyridin-3-carboxynitrile, (258) trans-3-fluoro-5-[(3S)-2-[4-[(1-methyltriazol-4-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (259) trans-[4-[[3-fluoro-5-(hydroxymethyl)phenyl]methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (260) trans-[(3S)-3-(4-fluorophenyl)isoxazoline-2-yl]-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (261) trans-[(3S)-3-(3,4-difluorophenyl)isoxazoline-2-yl]-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (262) trans-5-[(3S)-2-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]pyridin-3-carboxynitrile, (263) trans-3-fluoro-5-[(3S)-2-[4-[(2-methylpyrimidin-5-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (264) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(2-methylpyrimidin-5-yl)methyl]cyclohexyl] ketone, (265) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[[3-fluoro-4-(hydroxymethyl)phenyl]methyl]cyclohexyl] ketone, (266) trans-3-fluoro-5-[(3S)-2-[4-[[3-fluoro-4-(hydroxymethyl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (267) trans-5-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-2-methylpyridine-3-carboxylonitrile, (268) trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-2-methylpyridine-3-carboxylonitrile, (269) 5-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]norbornene-1-yl]methyl]-2-methylbenzamide, (270) 5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]norbornene-1-yl]methyl]-2-methylbenzamide, (271) 2-Methyl-5-[[4-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]norbornen-1-yl]methyl]benzamide, (272) 2-Methyl-5-[[4-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-bicyclo[2.2.2]octyl]methyl]benzamide, (273) 5-[[4-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]-1-bicyclo[2.2.2]octyl]methyl]-2-methylbenzamide, (274) 5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]-1-bicyclo[2.2.2]octyl]methyl]-2-methyl-benzamide, (275) trans-5-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-4-methylpyridine-3-carboxylonitrile, (276) trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-4-methylpyridine-3-carboxylonitrile, (277) trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-6-methylpyridine-3-carboxylonitrile, (278) trans-5-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-6-methylpyridine-3-carboxynitrile carboxylate, (279) trans-3-fluoro-5-[(3S)-2-[4-[[3-fluoro-4-(2-hydroxyethyl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (280) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[[3-fluoro-4-(2-hydroxyethyl)phenyl]methyl]cyclohexyl] ketone, (281) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (282) trans-3-fluoro-5-[(3S)-2-[4-[[3-fluoro-5-(2-hydroxyethyl)phenyl]methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (283) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[[3-fluoro-5-(2-hydroxyethyl)phenyl]methyl]cyclohexyl] ketone, (284) trans-3-fluoro-5-[(3S)-2-[4-[(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (285) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (286) trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-4-methyl-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-2-methyl-pyridine-3-carboxylonitrile, (287) trans-5-[[4-[(3S)-3-(3-cyano-5-fluoro-4-methyl-phenyl)isoxazoline-2-carbonyl]cyclohexyl]methyl]-4-methyl-pyridine-3-carboxylonitrile, (288) trans-3-[(3S)-2-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]-5-fluorobenzonitrile, (289) trans-4-fluoro-3-[(3S)-2-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (290) trans-3-[(3S)-2-[4-[(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]-5-fluorobenzonitrile, (291) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)methyl]cyclohexyl] ketone, (292) trans-3-[(3S)-2-[4-[(2,7-dimethylimidazo[1,2-b]pyridazin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]-5-fluorobenzonitrile, (293) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(2,7-dimethylimidazo[1,2-b]pyridazin-6-yl)methyl]cyclohexyl] ketone, (294) trans-3-fluoro-5-[(3S)-2-[4-[(1-methylindazol-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (295) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(1-methylindazole-6-yl)methyl]cyclohexyl] ketone, (296) trans-3-fluoro-5-[(3S)-2-[4-[(1-methylpyrazolo[4,3-b]pyridin-6-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (297) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(1-methylpyrazolo[4,3-b]pyridin-6-yl)methyl]cyclohexyl] ketone, (298) 6-Fluoro-1-[[trans-4-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]indazole-5-carboxynitrile, (299) trans-2-fluoro-5-[[4-[(3S)-3-(6-methylpyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl]benzamide, (300) trans-3-[(3S)-2-[4-[(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]cyclohexanecarbonyl]-1,2-oxazolidine-3-yl]-5-fluorobenzonitrile, (301) trans-[4-[(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidine-2-yl]methyl ketone, (302) trans-3-fluoro-5-[(3S)-2-[4-[(6-methylpyridazin-4-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (303) trans-3-fluoro-5-[(3S)-2-[4-[(6-methylpyridazin-3-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]benzonitrile, (304) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(6-methylpyridazin-3-yl)methyl]cyclohexyl] ketone, (305) trans-[4-[[5-(2,5-dimethylpyrazol-3-yl)-3-pyridinyl]methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (306) trans-[(3S)-3-(4-fluorophenyl)isoxazoline-2-yl]-[4-[(2-methylpyrazol-3-yl)methyl]cyclohexyl] ketone, (307) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(2-methylpyrazol-3-yl)methyl]cyclohexyl] ketone, (308) trans-[4-[[5-(1,3-dimethylpyrazol-4-yl)-3-pyridinyl]methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (309) trans-[(3S)-3-(3,4-difluorophenyl)isoxazoline-2-yl]-[4-[(2-methylpyrimidin-5-yl)methyl]cyclohexyl] ketone, (310) trans-[(3S)-3-(3,4-difluorophenyl)isoxazoline-2-yl]-[4-[(2-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)methyl]cyclohexyl] ketone, (311) trans-[(3S)-3-(3,4-difluorophenyl)isoxazoline-2-yl]-[4-[(2-methylpyrazol-3-yl)methyl]cyclohexyl] ketone, (312) trans-3-[(3S)-2-[4-[(2,6-dimethylpyrimidin-4-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]-5-fluorobenzonitrile, (313) trans-[(3S)-3-(3,5-difluorophenyl)isoxazoline-2-yl]-[4-[(6-methylpyrimidin-4-yl)methyl]cyclohexyl] ketone, (314) trans-[4-[(8-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidine-2-yl] ketone, (315) trans-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidin-2-yl]-[4-[(2-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)methyl]cyclohexyl] ketone, (316) trans-[4-[(5-fluoro-2-methyl-3-pyridinyl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyrazin-2-yl)isoxazolidine-2-yl]methyl ketone, (317) trans-[4-[(3,7-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(3-fluorophenyl)isoxazoline-2-yl] methyl ketone, (318) trans-[(3S)-3-(3,4-difluorophenyl)isoxazoline-2-yl]-[4-[(3,7-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (319) trans-[4-[(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(4-fluorophenyl)isoxazoline-2-yl] ketone, (320) trans-[4-[(8-fluoro-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(4-fluorophenyl)isoxazoline-2-yl] ketone, (321) trans-[(3S)-3-(4-fluorophenyl)isoxazoline-2-yl]-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)methyl]cyclohexyl] ketone, (322) trans-[2-cyano-4-[(3S)-2-[4-[(2-methylimidazo[1,2-b]pyridazin-7-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]phenyl], (323) trans-[2-fluoro-4-[(3S)-2-[4-[(2-methylimidazo[1,2-b]pyridazin-7-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]phenyl], (324) trans-[4-[(3S)-2-[4-[(2-methylimidazo[1,2-b]pyridazin-7-yl)methyl]cyclohexanecarbonyl]isoxazoline-3-yl]phenyl], (325) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazoline-2-yl] ketone, (326) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (327) trans-[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-yl]-[4-[(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (328) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyrazin-2-yl)isoxazolidin-2-yl] methyl ketone, (329) trans-[4-[(1-methylpyrazolo[4,3-b]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (330) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (331) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-fluoropyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (332) trans-[4-[(2,5-dimethylpyridin-4-yl)methyl]cyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl] ketone, (333) trans-[4-[(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (334) trans-[(3S)-3-(5-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (335) trans-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (336) trans-[(3S)-3-(5-fluoropyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (337) trans-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl]-[4-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)cyclohexyl] ketone, (338) trans-[(3S)-3-(5-fluoropyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)cyclohexyl] ketone, (339) trans-[4-[(2,5-dimethylpyridin-4-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyrazin-2-yl)-1,2-oxazolidin-2-yl] methyl ketone, (340) trans-[4-[(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidine-2-yl] ketone, (341) trans-[4-[(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (342) trans-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl]-[4-[(8-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (343) trans-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(2-methylpyrimidin-5-yl)methyl]cyclohexyl] ketone, (344) trans-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(2-methylpyrimidin-5-yl)methyl]cyclohexyl] ketone, (345) trans-[(3S)-3-(5-fluoropyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(8-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (346) trans-[4-[(2-methylpyrimidin-5-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidin-2-yl]methyl ketone, (347) trans-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (348) trans-[4-[[4-(3-hydroxyoxetane-3-yl)phenyl]methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl] ketone, (349) trans-[4-[(2-methylimidazo[1,2-b]pyridazin-7-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidin-2-yl]methyl ketone, (350) trans-[4-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-ylmethyl)-cyclohexyl]-((S)-3-pyrazin-2-yl-isoxazolidine-2-yl)-methyl ketone, (351) trans-[4-[(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (352) trans-[4-[[4-(3-hydroxyoxetane-3-yl)phenyl]methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidin-2-yl]methyl ketone, (353) trans-[4-[(2-methylimidazo[1,2-b]pyridazin-7-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl] ketone, (354) trans-[4-(2,5-dimethyl-pyridin-4-ylmethyl)-cyclohexyl]-[(S)-3-(6-methyl-pyridin-3-yl)-isoxazolidine-2-yl]-methyl ketone, (355) trans-[4-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)methyl]cyclohexyl]-[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazoline-2-yl]-methyl ketone (356) trans-[4-(2,5-dimethyl-pyridin-4-ylmethyl)-cyclohexyl]-((S)-3-pyrazin-2-yl-isoxazolidine-2-yl)-methyl ketone, (357) trans-[4-[(6-methylpyridazin-3-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidine-2-yl]methyl ketone, (358) trans-[4-[(3,5-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidine-2-yl] ketone, (359) trans-[4-[(8-fluoro-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidine-2-yl] ketone, (360) trans-(S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(2-methyl-1,3-thiazolyl-4-yl)methyl]cyclohexyl] ketone, (361) trans-[4-(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)-cyclohexyl]-[(S)-3-(2-methyl-thiazolyl-4-yl)isoxazolidine-2-yl]-methyl ketone, (362) trans-[(S)-3-(2-methyl-thiazolyl-4-yl)-isoxazolidine-2-yl]-[4-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)cyclohexyl]-methyl ketone, (363) trans-[4-(8-fluoro-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylmethyl)-cyclohexyl]-[(S)-3-(2-methyl-thiazolyl-4-yl)isoxazolidine-2-yl]-methyl ketone, (364) trans-[4-(8-fluoro-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylmethyl)-cyclohexyl]-[(S)-3-(6-methyl-pyridin-3-yl)-isoxazolidine-2-yl]-methyl ketone, (365) trans-[4-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylmethyl)-cyclohexyl]-[(S)-3-(6-methyl-pyridin-3-yl)-isoxazoline-2-yl]-methyl ketone, (366) trans-[4-(2,5-dimethyl-pyridin-4-ylmethyl)-cyclohexyl]-[(S)-3-(2-methyl-thiazolyl-4-yl)-isoxazolidine-2-yl]-methyl ketone, (367) trans-[4-(8-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)-cyclohexyl]-[(S)-3-(2-methyl-thiazolyl-4-yl)isoxazoline-2-yl]-methyl ketone, (368) trans-[4-(8-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)-cyclohexyl]-[(S)-3-(6-methyl-pyridin-3-yl)-isoxazolidine-2-yl]-methyl ketone, (369) trans-{4-[4-(3-hydroxy-oxacyclobutane-3-yl)-benzyl]-cyclohexyl}-[(S)-3-(2-methyl-thiazolyl-4-yl)-isoxazolyl-2-yl]-methyl ketone, (370) trans-[4-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-ylmethyl)-cyclohexyl]-[(S)-3-(2-methyl-thiazo-4-yl)-isoxazolidine-2-yl]-methyl ketone, (371) trans-[4-(2-methyl-imidazo[1,2-b]pyridazin-7-ylmethyl)-cyclohexyl]-[(S)-3-(2-methyl-thiazo-4-yl)-isoxazolidine-2-yl]-methyl ketone, (372) trans-[(S)-3-(2-methyl-thiazolyl-4-yl)-isoxazolidine-2-yl]-[4-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)cyclohexyl]-methyl ketone, (373) trans-[(S)-3-(6-methyl-pyridin-3-yl)-isoxazolidine-2-yl]-[4-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)cyclohexyl]-methyl ketone, (374) trans-[4-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-cyclohexyl]-((S)-3-pyrazin-2-yl-isoxazolidine-2-yl)-methyl ketone, (375) trans-[4-(3,5-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylmethyl)-cyclohexyl]-[(S)-3-(2-methyl-thiazolyl-4-yl)isoxazoline-2-yl]-methyl ketone, (376) trans-[4-(3,5-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylmethyl)-cyclohexyl]-[(S)-3-(6-methyl-pyridin-3-yl)-isoxazoline-2-yl]-methyl ketone, (377) trans-[4-[(2,5-dimethylpyridin-4-yl)methyl]cyclohexyl]-[(3S)-3-(2-methyl-1,3-oxazol-4-yl)-1,2-oxazolidine-2-yl] ketone, (378) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (379) trans-[4-[(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyrazin-2-yl)-1,2-oxazolidine-2-yl] ketone, (380) trans-[4-[(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-fluoropyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (381) trans-[4-[(8-chloro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (382) trans-[4-[(8-chloro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-fluoropyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (383) trans-[4-[(8-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (384) trans-[4-[(5-fluoro-2-methylpyridin-4-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyrazin-2-yl)-1,2-oxazolidin-2-yl] methyl ketone, (385) trans-[4-[(5-chloro-2-methylpyridin-4-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyrazin-2-yl)-1,2-oxazolidin-2-yl] methyl ketone, (386) trans-[4-[(5-fluoro-2-methylpyridin-4-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl] ketone, (387) trans-[4-[(6-methylpyridazin-3-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl] methyl ketone, (388) trans-[4-[(6-methylpyridazin-3-yl)methyl]cyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl] ketone, (389) trans-[4-[(5-chloro-2-methylpyridin-4-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl] ketone, (390) trans-[4-[(8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (391) trans-[4-[(2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (392) trans-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (393) trans-[4-[(2,4-dimethylpyrimidin-5-yl)methyl]cyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl] methyl ketone, (394) trans-[4-[(5-fluoro-2-methylpyridin-4-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidin-2-yl] ketone, (395) trans-[(3S)-3-(5-methylpyrazin-2-yl)-1,2-oxazolidin-2-yl]-[4-[(2-methylpyrazin-3-yl)methyl]cyclohexyl] ketone, (396) trans-[4-[(5-chloro-2-methylpyridin-4-yl)methyl]cyclohexyl]-[(3S)-3-pyrazin-2-yl-1,2-oxazolidin-2-yl] methyl ketone, (397) trans-[4-[(2-methylpyrazol-3-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] methyl ketone, (398) trans-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(6-methylpyridazin-4-yl)methyl]cyclohexyl] ketone, (399) trans-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[[2-methyl-4-(trifluoromethyl)pyrimidin-5-yl]methyl]cyclohexyl] ketone, (400) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]-1-methylcyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (401) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]-1-methylcyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (402) cis-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]-1-methylcyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (403) cis-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]-1-methylcyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (404) trans-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidin-2-yl]-[4-[(2-methylpyrazol-3-yl)methyl]cyclohexyl] ketone, (405) cis-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]-4-methylcyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (406) cis-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]-4-methylcyclohexyl]-[(3S)-3-(5-fluoro-6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (407) cis-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]-4-methylcyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (408) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]-4-methylcyclohexyl]-[(3S)-3-(6-methylpyridin-3-yl)-1,2-oxazolidine-2-yl] ketone, (409) trans-[(3S)-3-(5-methylpyrazin-2-yl)-1,2-oxazolidin-2-yl]-[4-[(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl] ketone, (410) trans-[4-[(1,3-dimethylpyrazolo[4,3-b]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(5-methylpyrazin-2-yl)-1,2-oxazolidine-2-yl] methyl ketone, and (411) trans-[4-[(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl]cyclohexyl]-[(3S)-3-(6-methylpyrazin-2-yl)isoxazolidin-2-yl] ketone; Or its pharmaceutically acceptable salt, solvate or stereoisomer.

15. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 13, or a compound as claimed in claim 14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

16. A pharmaceutical agent comprising a compound of formula (I) as claimed in any one of claims 1 to 13, or a compound as claimed in claim 14, or a pharmaceutically acceptable salt thereof.

17. A compound of formula (I) according to any one of claims 1 to 13, or a compound according to claim 14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, used as a pharmaceutical agent.

18. A compound of formula (I) according to any one of claims 1 to 13, or a compound according to claim 14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the treatment and / or prevention of diseases, disorders, or conditions at least partially mediated by receptor-interacting protein kinase 1.

19. A compound of formula (I) according to any one of claims 1 to 13 or a compound according to claim 14 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, for the treatment and / or prevention of diseases selected from: Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS).

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