Selective modulators of ataxia vasodilator mutations (ATM) kinases and their use

Abstract

This disclosure relates to imidazo[4,5-c]cinnolin-2-one compounds and pharma- ceutically acceptable salts thereof that selectively modulate ataxia telangiectasia mutated ("ATM") kinase. This disclosure also relates to pharmaceutical compositions comprising one or more of the compounds and their salts as active ingredients, and to the use of the compounds and their salts in the treatment of ATM-related diseases or conditions, including cancer.

Description

[Technical Field]

[0001]

[0001] This application relates to a novel substituted imidazo[4,5-c]sinnolin-2-one compound that selectively modulates ataxia vasodilator mutation ("ATM") kinase and pharmaceutically acceptable salts thereof. The application further relates to pharmaceutical compositions comprising one or more of the compound and its salts as active ingredients, and to the use of the compound and its salts in the treatment of ATM-related diseases or conditions, including cancer. [Background technology]

[0002]

[0002] ATM kinase is a serine / threonine kinase named after the autosomal recessive disorder ataxia vasodilator (AT) (Paul, TT, Annu Rev Biochem 2015, 711-38). ATM plays a central role in the repair of DNA double-strand breaks (DSBs), which are highly cytotoxic if not repaired in a timely manner. DSBs can be repaired by two main pathways: non-homologous end joining (NHEJ) or homologous recombination (HR). NHEJ functions throughout the cell cycle and directly reseals the two break ends with minimal processing. In contrast, HR occurs during the S and G2 phases of the cell cycle and requires extensive end processing (or excision). This generates single-stranded DNA that enters a homologous copy of the break locus, which is then used as a template for DNA synthesis (Clouaire, T. et al., DNA Repair (Amst) 2017, 84-91). In comparison, NHEJ is a fast but error-prone process; on the other hand, HR is a slower process than NHEJ but error-free. ATM repairs DSBs via HR.

[0003]

[0003] Following the DNA DSB, ATM is recruited by the MRE11-RAD50-NBS1 (MRN) complex, which senses and initiates DNA repair. When ATM is delivered to the site of DNA damage, it dissociates from an inactive homodimer to an active monomer and is catalytically activated by autophosphorylation at Ser1981 and other sites, as well as acetylation at Lys3016. ATM then binds to the C-terminus of NBS1, a component of the MRN complex, and acts as a transducer to phosphorylate and activate other protein kinases, such as histone H2A.X (γH2A.X).

[0004]

[0004] ATM is activated by DSBs, which can be induced by ionizing radiation, chemotherapeutic drugs, and PARP inhibitors. Topoisomerase-I inhibitors (irinotecan, topotecan, etc.) and PARP inhibitors (olaparib, etc.) cause single-strand DNA breaks that are converted into DSBs during replication (Choi M. et al., Mol Cancer Ther, 2016, 1781-91). Other anticancer treatments, such as ionizing radiation (IR), platinum drugs (cisplatin), and topoisomerase-II inhibitors (doxorubicin, etoposide), directly induce DSBs. The combination of ATM inhibitors with chemotherapy, radiation, and PARP inhibitors makes it nearly impossible for cancer cells to repair the highly cytotoxic DSBs. Given the important role that ATM plays in DSBs, ATM kinase inhibitors are expected to work in conjunction with PARP or topoisomerase inhibitors or ionizing radiation in the treatment of cancer.

[0005]

[0005] Numerous structurally different compounds have been reported to exhibit activity against ATM kinase. WO2015 / 170081, WO2017 / 046216 and WO2017 / 076895 (Astrazeneca AB) reported imidazo[4,5-c]quinoline-2-one compounds as selective modulators of ATM kinase, among which AZD0156 and AZD1390 are potent ATM inhibitors in Phase 1 clinical trials:

[0006] [Chem.]

[0007]

[0006] However, both compounds are aldehyde oxidase (AO) substrates with high activity. AO is highly expressed in humans and monkeys, not in dogs, and has low expression levels in rodents. Compounds metabolized by AO have shown high clearance, high PK variability, and low oral bioavailability in humans (Garattini, E. et al., Expert Opin Drug Discovery, 2013, 641 - 54; Zientek, M. et al., Drug Metab Dispos 2010, 1322 - 7). AO liability can be evaluated in human liver cytosolic systems. The human PK of AZD0156 was unexpectedly lower than predicted (Chen et al., AACR, 2018). Prior to involvement in Phase 1 clinical studies (NCT03215381 and NCT03423628), a Phase 0 clinical PK study was conducted for AZD1390, suggesting that both AZD0156 and AZD1390 undergo AO-mediated metabolism. [Summary of the Invention] [Problems to be Solved by the Invention]

[0008]

[0007] Therefore, there is still a need to develop new compounds that preferably act on ATM kinase without AO liability. [Means for Solving the Problems]

[0009]

[0008] Disclosed herein are novel substituted imidazo[4,5 - c]cinnolin - 2 - one compounds having potent ATM kinase inhibitory activity, showing no AO liability in human liver cytosol, and thus having good human pharmacokinetics (PK), low doses, and low PK variability. As a result, the compounds of the present application are particularly useful in the treatment of ATM - related diseases or conditions.

[0010]

[0009] In one aspect, the present disclosure provides a compound of formula (I):

[0011]

Chemical formula

[0012] or a pharmaceutically acceptable salt thereof, wherein: Ring A is aryl or heteroaryl; R 1 is hydrogen or methyl optionally substituted with one, two or three halogens; R 2 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 8 ; R 3 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, alkyl, alkenyl, alkynyl, haloalkyl and cycloalkyl; Each R 4 is independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, and cycloalkyl; R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl and cycloalkyl; or R 5 and R 6 together with the carbon atom to which they are attached form cycloalkyl or heterocyclyl; L is selected from a direct bond, alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more R 9 ; R7 -NR 10 R 11 , -OR 12 , -COOH, 1 or more R 13 Selected from a group consisting of saturated or unsaturated heterocyclyls that have been optionally substituted; R 8 This is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, and alkoxyl; R 9 This is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl; R 10 and R 11 each is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl and cycloalkyl; or R 10 and R 11 It optionally contains one or more additional heteroatoms selected from N, O, and S, along with the nitrogen atom to which they are attached, and one or more R 14 Forms heterocyclines that are optionally substituted; R 12 and R 13 Each is independently selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, and heterocyclyl; R 14 Halogen, cyano, sulfonyl, alkyl, alkenyl, alkynyl, haloalkyl, alkylalkoxyl, heterocyclyl, -NR 15 R 16 , and -OR 17 Selected from the group consisting of, R 15 and R 16 Each of these is independently a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group; R 17 This is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, and cycloalkyl. n is 0, 1, 2, or 3.

[0013]

[0010] In another embodiment, this disclosure is based on formula (II):

[0014] [ka]

[0015] The present invention provides compounds of or pharmaceutically acceptable salts thereof.

[0016]

[0011] In a further embodiment, the present disclosure relates to compounds selected from the group consisting of:

[0017] [ka]

[0018] or provide a pharmaceutically acceptable salt thereof.

[0019]

[0012] In another embodiment, a pharmaceutical composition is provided comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0020]

[0013] In a further embodiment, a method is provided for treating an ATM-related disease or condition in a subject requiring it, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0021]

[0014] In a further embodiment, compounds of formula (I) or pharmaceutically acceptable salts thereof are provided for use in the treatment of ATM-related diseases or conditions.

[0022]

[0015] In a further embodiment, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of ATM-related diseases or conditions is provided.

[0023]

[0016] In a further embodiment, compounds of formula (I) or pharmaceutically acceptable salts thereof are provided for use in the treatment of ATM-related diseases or conditions, wherein the compounds of formula (I) are administered concurrently with, separately from, or sequentially with radiotherapy.

[0024]

[0017] In a further embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, which is administered separately or sequentially with at least one additional antitumor agent.

[0025]

[0018] In a further embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, which is administered simultaneously with a PARP inhibitor, separately or sequentially. [Modes for carrying out the invention]

[0026]

[0019] Herein, certain embodiments of the present disclosure are mentioned in detail, and these examples are illustrated in the accompanying structures and formulas. While the present disclosure is described in conjunction with the listed embodiments, it is understood that they are not intended to limit the present disclosure to those embodiments. On the contrary, the present disclosure is intended to encompass all substitutes, modifications, and equivalents that fall within the scope of the present disclosure as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the present disclosure. The present disclosure is by no means limited to the methods and materials described herein. If one or more of the incorporated references and similar materials differ from or conflict with this application, including but not limited to defined terms, usage of terms, techniques described, etc., the present disclosure shall prevail. All references, patents, and patent applications cited herein are incorporated by reference in their entirety herein.

[0027]

[0020] For clarity, it should be understood that certain features of the present disclosure described in the context of separate embodiments may, moreover, be provided in combination in a single embodiment. Conversely, for simplicity, various features of the present disclosure described in the context of a single embodiment may, moreover, be provided separately or in any suitable secondary combination. It should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include their plural forms unless the context clearly indicates otherwise. Thus, for example, a reference to a compound includes multiple compounds. definition

[0021] Definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this disclosure, chemical elements are identified according to the Periodic Table, CAS versions, Handbook of Chemistry and Physics, 75th edition, inside front cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional parts and reactivity, are described in Organic Chemistry, Thomas Sorrell, 2nd edition, University Science Books, Sausalito, 2006; Smith and March March's Advanced Organic Chemistry, 6th edition, John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3rd edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4th edition, Cambridge University Press, Cambridge, 2004; the entire contents of each of these are incorporated herein by reference.

[0028]

[0022] Linked substituents are described in various places in this disclosure. Where a structure clearly requires a linking group, the Markush variable listed for that group is understood to be the linking group. For example, if a structure requires a linking group and the Markush group definition for that variable lists alkyl, then alkyl is understood to represent a linked alkylene group.

[0029]

[0023] If the bond to a substituent is indicated as crossing a bond that connects two atoms in the ring, such substituents can bond to any atom in the ring. If a substituent is listed without indicating the atom to which such substituent is bonded in the rest of the compound of a given formula, such substituents can bond to any atom in such formula. Combinations of substituents and / or variants are acceptable, but only if such combinations result in a stable compound.

[0030]

[0024] Any variable object (for example, R i If the group R appears more than once in any component or formula of a compound, its definition in each appearance is independent of its definition in any other appearance. For example, if the group R has 0 to 2 i If it is indicated that it is partially substituted, then the group may have up to two R i The parts may be replaced by arbitrary selection, and R in each occurrence i R i The selection is independent of the definition. Furthermore, combinations of substituents and / or variable compounds are acceptable, but only if such combinations result in a stable compound.

[0031]

[0025] When used herein, "C i~j The term "a" indicates a range of carbon atoms, where i and j are integers, and the range of carbon atoms includes the endpoints (i.e., i and j) and each integer point between them, where j is greater than i. For example, C 1~6This refers to a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. In some embodiments, "C 1~12 " % represents 1 to 12, especially 1 to 10, especially 1 to 8, especially 1 to 6, especially 1 to 5, especially 1 to 4, especially 1 to 3, or especially 1 to 2 carbon atoms.

[0032]

[0026] As used herein, the term “alkyl” refers to a saturated linear or branched hydrocarbon group which may be independently or optionally substituted with one or more substituents listed below, either as part of another term or independently. i~j The term "alkyl" refers to an alkyl group having i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms. In some embodiments, the alkyl group contains 1 to 9 carbon atoms. In some embodiments, the alkyl group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. 1~10 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 1~6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0033]

[0027] The alkyl group may be further substituted by substituents that independently replace one or more hydrogen atoms on one or more carbon atoms of the alkyl group. Examples of such substituents include, but are not limited to, acyl, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, haloalkyl, haloalkoxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfonyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, nitro, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may also be substituted as described below.

[0034]

[0028] As used herein, the term “alkenyl” means a linear or branched hydrocarbon group having at least one carbon-carbon double bond, which may be independently and optionally substituted with one or more substituents as described herein, and may include groups having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkenyl group contains 2 carbon atoms. Examples of alkenyl groups include, but are not limited to, etylene (or vinyl), propenyl, butenyl, pentenyl, 1-methyl-2-buten-1-yl, and 5-hexenyl.

[0035]

[0029] As used herein, the term “alkynyl” refers to a linear or branched hydrocarbon group having at least one carbon-carbon triple bond, which may be independently and optionally substituted with one or more substituents as described herein. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkynyl group contains 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, and 2-propynyl.

[0036]

[0030] As used herein, the term “alkoxy” refers to an alkyl group as already defined, which is attached to the parent molecule via an oxygen atom, whether used as part of another term or independently. i~j The term "alkoxy" means that the alkyl portion of the alkoxy group has i to j carbon atoms. In some embodiments, the alkoxy group contains 1 to 10 carbon atoms. In some embodiments, the alkoxy group contains 1 to 9 carbon atoms. In some embodiments, the alkoxy group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. 1~6 Examples of "alkoxyl" include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, neopentoxy, and n-hexoxy.

[0037]

[0031] As used herein, the term “alkylalkoxyl” refers to an alkyl moiety that is substituted with one or more alkoxyl moieties, whether used as part of another term or independently. “Alkylalkoxyl” can be bonded to the parent molecule structure via an alkyl group or an alkoxyl group.

[0038]

[0032] As used herein, the term “alkylcycloalkyl” refers to an alkyl moiety that is substituted with one or more cycloalkyl moieties, whether used as part of another term or independently. “Alkylcycloalkyl” can be bonded to the parent molecule structure via an alkyl group or a cycloalkyl group.

[0039]

[0033] As used herein, the term “aryl” refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, either as part of another term or independently, wherein at least one ring in the system is aromatic, and each ring in the system contains 3 to 12 ring members. Examples of “aryl” include, but are not limited to, phenyl, biphenyl, naphthyl, and anthracyl, which may support one or more substituents. Further included within the scope of the term “aryl” are groups in which an aromatic ring is fused to one or more additional rings, as used herein. In the case of polycyclic ring systems, only one of the rings needs to be aromatic (e.g., 2,3-dihydroindole), but all of the rings may be aromatic (e.g., quinoline). The second ring may be fused or crosslinked. Examples of polycyclic aryl groups include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenantridinyl, or tetrahydronaphthyl. The aryl group may be substituted with one or more substituents at the ring positions as described above.

[0040]

[0034] As used herein, the term “cycloalkyl” refers to monovalent, non-aromatic, saturated or partially unsaturated monocyclic and polycyclic ring systems in which all ring atoms are carbon and which contain at least three ring-forming carbon atoms. In some embodiments, cycloalkyls may contain 3 to 12 ring-forming carbon atoms, 3 to 10 ring-forming carbon atoms, 3 to 9 ring-forming carbon atoms, 3 to 8 ring-forming carbon atoms, 3 to 7 ring-forming carbon atoms, 3 to 6 ring-forming carbon atoms, 3 to 5 ring-forming carbon atoms, 4 to 12 ring-forming carbon atoms, 4 to 10 ring-forming carbon atoms, 4 to 9 ring-forming carbon atoms, 4 to 8 ring-forming carbon atoms, 4 to 7 ring-forming carbon atoms, 4 to 6 ring-forming carbon atoms, or 4 to 5 ring-forming carbon atoms. Cycloalkyls may be saturated or partially unsaturated. Cycloalkyls may be substituted. In some embodiments, cycloalkyls may be saturated cyclic alkyl groups. In some embodiments, the cycloalkyl group may be a partially unsaturated cyclic alkyl group containing at least one double or triple bond in its ring system.

[0041]

[0035] In some embodiments, the cycloalkyl group may be monocyclic or polycyclic. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, 1-cyclopenta-2-enyl, 1-cyclopenta-3-enyl, cyclohexyl, 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, 1-cyclohexa-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl.

[0042]

[0036] In some embodiments, the cycloalkyl group may be a saturated or partially unsaturated polycyclic (e.g., bicyclic and tricyclic) carbocyclic ring system, which may be configured as a condensed, spiro, or bridging ring system. As used herein, the term “condensed ring” refers to a ring system having two rings sharing two adjacent atoms, the term “spiro ring” refers to a ring system having two rings connected by one single common atom, and the term “bridging ring” refers to a ring system having two rings sharing three or more atoms. Examples of condensed carbocyclils include, but are not limited to, naphthyl, benzopyrenyl, anthracenyl, acenaphthenyl, and fluorenyl. Examples of spirocarbocyclils include, but are not limited to, spiro[5.5]undecanyl, spiro-pentadienyl, and spiro[3.6]-decanyl. Examples of cross-linked carbocyclils include, but are not limited to, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.1]nonanyl, and bicyclo[3.3.3]undecanyl.

[0043]

[0037] As used herein, the term "cyano" refers to -CN.

[0044]

[0038] As used herein, the term "halogen" refers to an atom selected from fluorine (or fluoro), chlorine (or chloro), bromine (or bromo), and iodine (or iod).

[0045]

[0039] As used herein, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl (-CF3), pentafluoroethyl (-C2F5), difluoromethyl (-CHF2), trichloromethyl (-CCl3), dichloromethyl (-CHCl2), and pentachloroethyl (-C2Cl5).

[0046]

[0040] As used herein, the term “heteroatom” means nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen (including N-oxide).

[0047]

[0041] As used herein, the term “heteroaryl” refers to an aryl group having one or more heteroatoms in addition to a carbon atom, whether used as part of another term or independently. Heteroaryl groups may be monocyclic. Examples of monocyclic heteroaryls include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthylidinyl, benzofuranyl, and pteridinyl. Heteroaryl groups also include polycyclic groups in which a heteroaromatic ring is fused to one or more aryl rings, heteroaryl rings, alicyclic rings, or heterocyclyl rings, wherein the group or attachment site is on the heteroaromatic ring. Examples of polycyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranil, benzo[1,3]dioxolyl, dibenzofuranil, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, sinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxadinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.

[0048]

[0042] As used herein, the term “heterocyclyl” means a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, etc., and the remaining ring atoms are carbon, where one or more ring atoms may be independently and optionally substituted with one or more substituents. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, the heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system. In some embodiments, the heterocyclyl may contain any oxidized form of carbon, nitrogen, or sulfur, and any quaternized form of basic nitrogen. The heterocyclyl group may be carbon-linked or nitrogen-linked where possible. In some embodiments, the heterocycle is carbon-linked. In some embodiments, the heterocycle is nitrogen-linked. For example, a group derived from pyrrole may be pyrrole-1-yl (nitrogen-linked) or pyrrole-3-yl (carbon-linked). Furthermore, the group derived from imidazole may be imidazole-1-yl (nitrogen-linked) or imidazole-3-yl (carbon-linked).

[0049]

[0043] The heterocyclyl group may be monocyclic. Examples of monocyclic heterocyclyls include, but are not limited to, oxetanyl, 1,1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, azetidinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, and triazinonyl.

[0050]

[0044] The heterocyclyl group may be polycyclic, including condensed, spiro, and bridging ring systems. A condensed heterocyclyl group includes a group in which the heterocyclyl group is fused with a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. Examples of condensed heterocyclyls include, but are not limited to, the phenyl condensed ring or pyridinyl condensed ring, such as quinolinyl, isoquinolinyl, quinoxalinyl, quinolidinyl, quinazolinyl, azaindridinyl, pteridinyl, clomenyl, isoclomenyl, indolyl, isoindolyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenadinyl, phenothiazinyl, phenanthiazinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, and [1,2,3]triazolo[4,3-a]pyridinyl groups. Examples of spiroheterocyclils include, but are not limited to, spiropyranil, spirooxazinil, 5-aza-spiro[2.4]heptanil, 6-aza-spiro[2.5]octanil, 6-aza-spiro[3.4]octanil, 2-oxa-6-aza-spiro[3.3]heptanil, 2-oxa-6-aza-spiro[3.4]octanil, 6-aza-spiro[3.5]nonanil, 7-aza-spiro[3.5]nonanil, and 1-oxa-7-aza-spiro[3.5]nonanil. Examples of cross-linked heterocyclils include, but are not limited to, 3-azabicyclo[3.1.0]hexanyl, 8-azabicyclo[3.2.1]octanyl, 1-azabicyclo[2.2.2]octanyl, 2-azabicyclo[2.2.1]heptanyl, and 1,4-diazabicyclo[2.2.2]octanyl.

[0051]

[0045] As used herein, the term "hydroxyl" refers to -OH.

[0052]

[0046] As used herein, the term "sulfonyl" refers to -SO2R', where R' is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0053]

[0047] As used herein, the term “partially unsaturated” refers to a group containing at least one double or triple bond. The term “partially unsaturated” is intended to include rings having multiple unsaturated moieties, but not to include aromatic (i.e., fully unsaturated) moieties.

[0054]

[0048] As used herein, the term “substituted” means that one or more hydrogens of the specified part are replaced with appropriate substituents, whether preceded or not by the term “optionally.” “Substituted” or “substituted with” is understood to include the implicit conditions that such substitutions are consistent with the allowable valence of the substituted atom and that the substitutions result in a stable or chemically feasible compound that does not spontaneously undergo transformations such as rearrangement, cyclization, or elimination. Unless otherwise indicated, a group “optionally substituted” may have appropriate substituents at each of its substituted positions, and if one or more positions in any given structure may be substituted with one or more substituents selected from the specified group, the substituents may be the same or different at all positions. It will be understood by those skilled in the art that substituents may be substituted themselves where appropriate. Unless specifically stated as “unsubstituted,” references to chemical parts herein are understood to include substituted variants. For example, references to "aryl" groups or parts implicitly include both substituted and unsubstituted variants. compound

[0049] The disclosure provides novel substituted imidazo[4,5-c]sinnolin-2-one compounds or pharmaceutically acceptable salts thereof, methods for synthesizing the compounds, pharmaceutical compositions containing them, and various uses of the disclosed compounds.

[0055]

[0050] In one embodiment, this disclosure is based on formula (I):

[0056] [ka]

[0057] We provide compounds or pharmaceutically acceptable salts thereof. During the ceremony: Ring A is either an aryl or heteroaryl ring; R 1 is a methyl molecule optionally substituted with hydrogen, or one, two, or three halogens; R 2 The group is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are one or more R 8 It is replaced by optional selection; R 3 This is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, alkyl, alkenyl, alkynyl, haloalkyl and cycloalkyl; Each R 4 This is independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, and cycloalkyl; R 5 and R 6 each is independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl and cycloalkyl; or R 5 and R 6They, together with the carbon atoms to which they are attached, form cycloalkyl or heterocyclines; L is selected from direct bond, alkyl, cycloalkyl or cycloalkylalkyl, where the alkyl, cycloalkyl and cycloalkylalkyl are one or more R 9 It is replaced by optional selection; R 7 -NR 10 R 11 , -OR 12 , -COOH, 1 or more R 13 Selected from a group consisting of saturated or unsaturated heterocyclyls that have been optionally substituted; R 8 This is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, and alkoxyl; R 9 This is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl; R 10 and R 11 each is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl and cycloalkyl; or R 10 and R 11 It optionally contains one or more additional heteroatoms selected from N, O, and S, along with the nitrogen atom to which they are attached, and one or more R 14 Forms heterocyclines that are optionally substituted; R 12 and R 13 Each is independently selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, and heterocyclyl; R 14 Halogen, cyano, sulfonyl, alkyl, alkenyl, alkynyl, haloalkyl, alkylalkoxyl, heterocyclyl, -NR 15 R 16 , and -OR17 Selected from the group consisting of, R 15 and R 16 Each of these is independently a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group; R 17 This is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, and cycloalkyl. n is 0, 1, 2, or 3.

[0058]

[0051] In some embodiments, ring A is an aryl ring.

[0059]

[0052] In some embodiments, ring A is a heteroaryl. In a particular embodiment, ring A is a 5- to 12-membered heteroaryl. In a particular embodiment, ring A is a 5- to 10-membered heteroaryl. In a particular embodiment, ring A is a 5- to 8-membered heteroaryl. In a particular embodiment, ring A is a 5- to 6-membered heteroaryl.

[0060]

[0053] In a particular embodiment, ring A is selected from the group consisting of thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridadinyl, pyrimidinyl, and pyrazinyl.

[0061]

[0054] In a particular embodiment, ring A is selected from pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In a particular embodiment, ring A is pyridyl.

[0062]

[0055] In some embodiments, R 1 It is hydrogen.

[0063]

[0056] In some embodiments, R 1 is a methyl molecule optionally substituted with one, two, or three halogens. In a particular embodiment, R 1is methyl optionally substituted with one, two or three fluoro. R 1 is methyl or trifluoromethyl.

[0064]

[0057] In some embodiments, R 2 is alkyl optionally substituted with one or more R 8 where R 8 is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, and alkoxyl. In certain embodiments, R 2 is C 8 alkyl, C 1~6 alkyl, C 1~5 alkyl, C 1~4 alkyl or C 1~3 alkyl optionally substituted with one or more R 8 where R

[0065]

[0058] In certain embodiments, R 2 is n-propyl or iso-propyl.

[0066]

[0059] In some embodiments, R 2 is cycloalkyl optionally substituted with one or more R 8 where R 8 is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl, and alkoxyl. In certain embodiments, R 2 is C 8 cycloalkyl, C 3~12 cycloalkyl, C 3~10 cycloalkyl, C 3~8 cycloalkyl, C 3~6 cycloalkyl or C 3~5 cycloalkyl optionally substituted with one or more R 8 where R 2 is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl, and alkoxyl.

[0067]

[0060] In a particular embodiment, R 2 The compound is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and each of these is one or more R 8 It is replaced by arbitrary selection in R 8 The compound is selected from hydroxyl, methyl, trifluoromethyl, or methoxy.

[0068]

[0061] In a particular embodiment, R 2 teeth,

[0069] [ka]

[0070] That is the case.

[0071]

[0062] In some embodiments, R 2 is one or more R 8 It is a heterocycline that is optionally substituted, R 8 R is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl and alkoxyl. In a particular embodiment, R 2 is one or more R 8 C is replaced by arbitrary selection. 3~12 Heterocyclyl, C 3~10 Heterocyclyl, C 3~8 Heterocyclyl, C 3~6 Heterocyclyl or C 3~5 It is a heterocycline, R 8 The element is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl, and alkoxyl.

[0072]

[0063] In a particular embodiment, R 2 The group consists of oxetanil, tetrahydrofuranil, and tetrahydropyranil, each of which contains one or more R8 It is replaced by arbitrary selection in R 8 The compound is selected from the group consisting of hydroxyl, methyl, trifluoromethyl, and methoxy.

[0073]

[0064] In a particular embodiment, R 2 teeth,

[0074] [ka]

[0075] That is the case.

[0076]

[0065] In some embodiments, R 2 is one or more R 8 It is a heteroaryl that is optionally substituted with R 8 R is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl and alkoxyl. In a particular embodiment, R 2 is one or more R 8 A heteroaryl molecule consisting of 5 to 12 members, 5 to 10 members, 5 to 8 members, 5 to 7 members, or 5 to 6 members, which is optionally substituted by R 8 The element is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl, and alkoxyl.

[0077]

[0066] In a particular embodiment, R 2 These are pyridine or pyrazole, each of which contains one or more R 8 It is replaced by arbitrary selection in R 8 The compound is selected from the group consisting of hydroxyl, methyl, trifluoromethyl, and methoxy.

[0078]

[0067] In some embodiments, R 3 It is hydrogen.

[0079]

[0068] In some embodiments, R 3 is a halogen. In a particular embodiment, R 3 is fluoro, chloro, or bromo. In a particular embodiment, R 3 It is fluoro.

[0080]

[0069] In some embodiments, R 4 It is hydrogen.

[0081]

[0070] In some embodiments, R 4 is alkyl. In a particular embodiment, R 4 C 1~6 It is alkyl. In a particular embodiment, R 4 C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl or C 1~2 It is alkyl.

[0082]

[0071] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0083]

[0072] In some embodiments, R 5 and R 6 One of them is hydrogen, and the other is alkyl. In a particular embodiment, R 5 and R 6 One of them is hydrogen, and the other is C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 It is alkyl. In a particular embodiment, R 5 and R 6 One of the atoms is hydrogen, and the other is selected from methyl, ethyl, n-propyl, i-propyl, or 3-methyl-1-butyl.

[0084]

[0073] In some embodiments, R 5and R 6 One of them is hydrogen, and the other is a haloalkyl. In a particular embodiment, R 5 and R 6 One of them is hydrogen, and the other is C 1~6 Haloalkyl, C 1~5 Haloalkyl, C 1~4 Haloalkyl, or C 1~3 It is a haloalkyl. In a particular embodiment, R 5 and R 6 One of them is hydrogen, and the other is methyl which is optionally substituted with one, two, or three halogens. In a particular embodiment, R 5 and R 6 One of them is hydrogen, and the other is methyl which is optionally substituted with one, two, or three fluoro atoms. In a particular embodiment, R 5 and R 6 One of them is hydrogen, and the other is trifluoromethyl.

[0085]

[0074] In some embodiments, R 5 and R 6 Both are hydrogen.

[0086]

[0075] In some embodiments, R 5 and R 6 Both are alkyl. In a particular embodiment, R 5 and R 6 Independently, C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 It is alkyl. In a particular embodiment, R 5 and R 6 Both are methyl.

[0087]

[0076] In some embodiments, R 5 and R 6 Along with the carbon atoms to which they are attached, one or more R 9This forms a cycloalkyl which is optionally substituted. In a particular embodiment, R 5 and R 6 C 3~12 Cycloalkyl, C 3~10 Cycloalkyl, C 3~8 Cycloalkyl, C 3~6 Cycloalkyl, or C 3~5 They form cycloalkyl groups, each of which consists of one or more R groups. 9 It is optionally replaced by R. In a particular embodiment, 5 and R 6 These, together with the carbon atoms to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0088]

[0077] In some embodiments, R 5 and R 6 Along with the carbon atoms to which they are attached, one or more R 9 This forms a heterocycline which is optionally substituted. In a particular embodiment, R 5 and R 6 Together with the carbon atoms to which they are attached, they form 3- to 12-membered heterocyclines, 3- to 10-membered heterocyclines, 3- to 8-membered heterocyclines, 3- to 6-membered heterocyclines, or 3- to 5-membered heterocyclines, each of which has one or more R 9 It is replaced by an optional choice.

[0089]

[0078] In a particular embodiment, R 5 and R 6 Together with the carbon atoms to which they are attached, they form a group selected from the following group:

[0090] [ka]

[0091]

[0079] In some embodiments, L is a direct bond.

[0092]

[0080] In some embodiments, L is one or more R 9 It is an alkyl which is optionally substituted. In a particular embodiment, L is C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 They are alkyl groups, and each of them is one or more R 9 It is optionally replaced by R. In a particular embodiment, L is one or more R 9 The methyl, ethyl, propyl, or butyl is optionally substituted. In some embodiments, each R 9 R is independently selected from the group consisting of hydrogen, halogens, and cycloalkyls. In a particular embodiment, R 9 is a halogen. In a particular embodiment, R 9 is fluoro. In a particular embodiment, R 9 C 3~12 Cycloalkyl, C 3~10 Cycloalkyl, C 3~8 Cycloalkyl, C 3~6 Cycloalkyl, or C 3~5 Selected from cycloalkyl. In a particular embodiment, R 9 It is cyclopropyl.

[0093]

[0081] In a particular embodiment, L is selected from methyl, ethyl, n-propyl, isopropyl, or isobutyl.

[0094]

[0082] In some embodiments, L is one or more R 9 It is a cycloalkyl that is optionally substituted. In a particular embodiment, L is C 3~12 Cycloalkyl, C 3~10 Cycloalkyl, C 3~8 Cycloalkyl, C 3~6 Cycloalkyl, or C3~5 They are cycloalkyl groups, and each of them is one or more R 9 It is optionally replaced by R. In some embodiments, each R 9 The element is selected from the group consisting of hydrogen, halogens, alkyl, haloalkyl, and cycloalkyl.

[0095]

[0083] In certain embodiments, L is cyclopropyl or cyclobutyl.

[0096]

[0084] In some embodiments, L is one or more R 9 It is a cycloalkylalkyl which is optionally substituted with (C 3~6 Cycloalkyl)(C 1~6 (Alkyl), (C 3~5 Cycloalkyl)(C 1~5 (alkyl), or (C 3~4 Cycloalkyl)(C 1~4 Selected from alkyl groups, each of which has one or more R 9 It is optionally replaced by R. In some embodiments, each R 9 The element is selected from the group consisting of hydrogen, halogens, alkyl, haloalkyl, and cycloalkyl.

[0097]

[0085] In a particular embodiment, L is cyclopropylmethyl. In a particular embodiment, L is

[0098] [ka]

[0099] That is the case.

[0100]

[0086] In some embodiments, R 7 -NR 10 R 11 That is the case.

[0101]

[0087] In a particular embodiment, R 10 and R 11 Each of them is an alkyl group independently. In a particular embodiment, R 10 and R 11 Each of them is independent of C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 It is alkyl. In a particular embodiment, R 10 and R 11 Both are C 1~3 It is alkyl. In a particular embodiment, R 10 and R 11 Both are methyl.

[0102]

[0088] In a particular embodiment, R 10 and R 11 One of them is hydrogen, and the other is alkyl. In a particular embodiment, R 10 and R 11 One of them is hydrogen, and the other is C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 It is alkyl. In a particular embodiment, R 10 and R 11 One of them is hydrogen, and the other is methyl.

[0103]

[0089] In some embodiments, R 10 and R 11 It optionally contains one or more additional heteroatoms selected from N, O, and S, along with the nitrogen atoms to which they are attached, and one or more R 14 It forms saturated heterocyclines that are substituted by arbitrary selection.

[0104]

[0090] In a particular embodiment, R 10 and R 11Together with the nitrogen atoms to which they are attached, they form saturated heterocyclines selected from the following group:

[0105] [ka]

[0106] Each of these is one or more R 14 It is replaced by an optional choice.

[0107]

[0091] In a particular embodiment, each R 14 These include halogens, cyano, sulfonyl, alkyl, haloalkyl, alkylalkoxyl, and -NR. 15 R 16 , and OR 17 It is independently selected from the group consisting of [the specified elements].

[0108]

[0092] In a particular embodiment, R 14 is a halogen. In a particular embodiment, R 14 It is fluoro.

[0109]

[0093] In a particular embodiment, R 14 It is cyano.

[0110]

[0094] In a particular embodiment, R 14 is sulfonyl. In a particular embodiment, R 14 It is -SO2(CH3).

[0111]

[0095] In a particular embodiment, R 14 is alkyl. In a particular embodiment, R 14 C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 It is alkyl. In a particular embodiment, R 14 It is methyl.

[0112]

[0096] In a particular embodiment, R 14 is a haloalkyl. In a particular embodiment, R 14 is a methyl molecule substituted with one, two, or three halogens. In a particular embodiment, R 14 It is trifluoromethyl.

[0113]

[0097] In a particular embodiment, R 14 is an alkylalkoxyl. In a particular embodiment, R 14 is, (C 1~6 Alkyl)(C 1~6 Alkoxyl), (C 1~5 Alkyl)(C 1~5 Alkoxyl), (C 1~4 Alkyl)(C 1~4 Alkoxyl), or (C 1~3 Alkyl)(C 1~3 Selected from alkoxyls. In a particular embodiment, R 14 It is methyl methoxyl.

[0114]

[0098] In a particular embodiment, R 14 -NR 15 R 16 That is the case.

[0115]

[0099] In a particular embodiment, R 15 and R 16 Each of them is an alkyl group independently. In a particular embodiment, R 15 and R 16 Each of them is independent of C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 It is alkyl. In a particular embodiment, R 15 and R 16 Both are C 1~3 It is alkyl. In a particular embodiment, R 15 and R 16 Both are methyl.

[0116]

[0100] In a particular embodiment, R 15 and R 16 One of them is hydrogen, and the other is alkyl. In a particular embodiment, R 15 and R 16 One of them is hydrogen, and the other is C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 It is alkyl. In a particular embodiment, R 15 and R 16 One of them is hydrogen, and the other is methyl.

[0117]

[0101] In some embodiments, R 7 は-OR 17 That is the case.

[0118]

[0102] In a particular embodiment, R 17 The alkyl or haloalkyl group is selected from the alkyl or haloalkyl group.

[0119]

[0103] In a particular embodiment, R 17 C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 It is an alkyl such as alkyl. In a particular embodiment, R 17 These are methyl, ethyl, or isopropyl.

[0120]

[0104] In a particular embodiment, R 17 is a haloalkyl. In a particular embodiment, R 17 is a methyl molecule substituted with one, two, or three halogens. In a particular embodiment, R 17 These are monofluoromethyl, difluoromethyl, or trifluoromethyl.

[0121]

[0105] In some embodiments, R 7 It is -COOH.

[0122]

[0106] In some embodiments, R 7 R 13 It is a heterocycline that has been replaced by arbitrary selection.

[0123]

[0107] In a particular embodiment, R 7 The group is selected from the following:

[0124] [ka]

[0125] Each of these is one or more R 13 It is replaced by an optional choice.

[0126]

[0108] In a particular embodiment, R 13 R is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, and heterocyclyl. In a particular embodiment, R 13 C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 It is an alkyl such as alkyl. In a particular embodiment, R 13 It is methyl.

[0127]

[0109] In a further embodiment, this disclosure relates to formula (II):

[0128] [ka]

[0129] We provide compounds of which, in the formula, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 And L are defined as described above.

[0130]

[0110] In some embodiments, in formula (II), R 5 and R 6 One of them is hydrogen, and the other is alkyl or haloalkyl.

[0131]

[0111] In a particular embodiment, R 5 and R 6 One of them is hydrogen, and the other is alkyl. In a particular embodiment, R 5 and R 6 One of them is hydrogen, and the other is C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 It is alkyl. In a particular embodiment, R 5 and R 6 One of the atoms is hydrogen, and the other is selected from methyl, ethyl, n-propyl, i-propyl, or 3-methyl-1-butyl.

[0132]

[0112] In a particular embodiment, R 5 and R 6 One of them is hydrogen, and the other is a haloalkyl. In a particular embodiment, R 5 and R 6 One of them is hydrogen, and the other is C 1~6 Haloalkyl, C 1~5 Haloalkyl, C 1~4 Haloalkyl, or C 1~3 It is a haloalkyl. In a particular embodiment, R 5 and R 6 One of them is hydrogen, and the other is methyl which is optionally substituted with one, two, or three halogens. In a particular embodiment, R 5 and R 6 One of them is hydrogen, and the other is methyl which is optionally substituted with one, two, or three fluoro atoms. In a particular embodiment, R 5 and R 6 One of them is hydrogen, and the other is trifluoromethyl.

[0133]

[0113] In another embodiment, the present disclosure provides compounds selected from the group consisting of:

[0134] [ka]

[0135] In the formula, R 3 , R 5 , L, R 11 and R 12 This is defined as described above.

[0136]

[0114] In a particular embodiment, in any of formulas (III) to (VII), R 3 is hydrogen or fluorine; R 5 is hydrogen, alkyl, or haloalkyl; L is one or more R 9 It is an alkyl group that is optionally substituted; R 9 It is selected from the group consisting of hydrogen, halogens, and cycloalkyls; R 10 and R 11 Each of them is independently alkyl, or R 10 and R 11 One is hydrogen, and the other is alkyl; R 10 and R 11 It optionally contains one or more additional heteroatoms selected from N, O, and S, along with the nitrogen atoms to which they are attached, and one or more R 14 Forms saturated heterocyclines which are optionally substituted; R 14 These include halogens, cyano, sulfonyl, alkyl, haloalkyl, alkylalkoxyl, saturated or unsaturated heterocyclyl, -NR 15 R 16 , and -OR 17Selected from the group consisting of; R 15 and R 16 Each of them is independently alkyl, or R 15 and R 16 One of them is hydrogen, and the other is alkyl. R 17 The alkyl or haloalkyl group is selected from the alkyl or haloalkyl group.

[0137]

[0115] In certain embodiments, L is ethyl or propyl.

[0138]

[0116] In a particular embodiment, R 5 It is hydrogen, methyl, or trifluoromethyl.

[0139]

[0117] In a particular embodiment, R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form saturated heterocyclines selected from the following group:

[0140] [ka]

[0141] Each of these is one or more R 14 It is replaced by an optional choice.

[0142]

[0118] In a particular embodiment, each R 14 These include halogens, cyano, sulfonyl, alkyl, haloalkyl, alkylalkoxyl, and -NR. 15 R 16 , and OR 17 It is independently selected from the group consisting of [the specified elements].

[0143]

[0119] In a particular embodiment, R 15 and R 16 Each of them is an alkyl group independently. In a particular embodiment, R 15 and R 16Each of them is independent of C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 It is alkyl. In a particular embodiment, R 15 and R 16 Both are C 1~3 It is alkyl. In a particular embodiment, R 15 and R 16 Both are methyl.

[0144]

[0120] In a particular embodiment, R 15 and R 16 One of them is hydrogen, and the other is alkyl. In a particular embodiment, R 15 and R 16 One of them is hydrogen, and the other is C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 It is alkyl. In a particular embodiment, R 15 and R 16 One of them is hydrogen, and the other is methyl.

[0145]

[0121] In a particular embodiment, R 17 The alkyl or haloalkyl group is selected from the alkyl or haloalkyl group.

[0146]

[0122] In another embodiment, the present disclosure provides compounds selected from the group consisting of:

[0147] [ka]

[0148] In the formula, R 10 and R 11 This is defined as described above.

[0149]

[0123] In a particular embodiment, in any of formulas (IIIa) to (VIIa), R10 and R 11 Together with the nitrogen atoms to which they are attached, they form saturated heterocyclines selected from the following group:

[0150] [ka]

[0151] Each of these is one or more R 14 It is replaced by an optional choice.

[0152]

[0124] In a further embodiment, the present disclosure provides compounds selected from the group consisting of:

[0153] [ka]

[0154] In the formula, R 10 and R 11 This is defined as described above.

[0155]

[0125] In a particular embodiment, in any of formulas (IIIb), (IVb), and (VIIb), R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form saturated heterocyclines selected from the following group:

[0156] [ka]

[0157]

[0126] In one embodiment, the present disclosure provides compounds of formula (I) selected from the group consisting of the following, or pharmaceutically acceptable salts thereof: 8-(6-((2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(dimethylamino)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((2-(piperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((2-(pyrroridine-1-yl)ethoxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(4-fluoropiperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-8-(6-((2-methoxyethoxy)methyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(((1-methylpiperidine-4-yl)oxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((3-(dimethylamino)propoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(((1-methylpiperidine-4-yl)methoxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(((1-methylpyrrolidine-2-yl)methoxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(((1-methylpyrrolidine-3-yl)oxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((3-(3-azabicyclo[3.1.0]hexane-3-yl)propoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(((1-methylpiperidine-3-yl)oxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((3-(dimethylamino)cyclobutoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(((1-methylazetidine-3-yl)oxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexane-3-yl)propoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexane-3-yl)-2-methylpropoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-(((1-(3-azabicyclo[3.1.0]hexane-3-yl)cyclopropyl)methoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(((1-methylpiperidine-3-yl)methoxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(((1-methylpyrrolidine-3-yl)methoxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-(((1-(3-azabicyclo[3.1.0]hexane-3-yl)propan-2-yl)oxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-(((1-(3-azabicyclo[3.1.0]hexane-3-yl)-2-methylpropan-2-yl)oxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((1-(3-azabicyclo[3.1.0]hexane-3-ylmethyl)cyclopropoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-(2-((5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)methoxy)ethyl)piperidine-4-carbonitride 1-(2-((R)-1-(5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)ethyl)-3-methylpyrrolidine-3-carbonitrile 8-(6-((2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-8-(6-((2-(4-methoxypiperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-((2-(3-fluoropyrrolidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (S)-1-Isopropyl-3-methyl-8-(6-((2-(2-methylpyrrolidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(4,4-difluoropiperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(4,4-dimethylpiperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((2-(4-methylpiperazine-1-yl)ethoxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((2-morpholinoethoxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (S)-8-(6-((2-(3-fluoropyrrolidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-1-Isopropyl-3-methyl-8-(6-((2-(2-methylpyrrolidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(3,3-dimethylpyrrolidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(3-(dimethylamino)azetidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(3-fluoropiperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(2-azabicyclo[2.2.1]heptan-2-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(6-azaspiro[3,5]nonan-6-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-8-(6-((2-(3-methoxypiperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (S)-8-(6-((2-(3-(dimethylamino)pyrrolidin-1-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (S)-1-Isopropyl-8-(6-((2-(3-methoxypyrrolidine-1-yl)ethoxy)methyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-8-(6-((2-(4-methoxypiperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-((2R,5S)-2,5-dimethylpyrrolidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-((2-(3-(dimethylamino)pyrrolidin-1-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((2-(4-(trifluoromethoxy)piperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(7-azaspiro[3,5]nonan-7-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-((2-(3-(difluoromethoxy)pyrroridine-1-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (S)-8-(6-((2-(3-(difluoromethoxy)pyrroridine-1-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((2-(3-(trifluoromethoxy)pyrrolidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one (R)-8-(6-(1-(2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(6-Azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(6-Azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-1-Isopropyl-8-(6-(1-(2-(4-methoxypiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-8-(6-((R)-1-(2-((R)-3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-1-Isopropyl-3-methyl-8-(6-(1-(2-(4-(trifluoromethoxy)piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-8-(6-((R)-1-(2-((S)-3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(3,3-dimethylpyrrolidine-1-yl)ethoxy)methyl)pyridine-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(3,3-dimethylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-1-Isopropyl-3-methyl-8-(6-(1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-((R)-1-(2-((S)-3-(difluoromethoxy)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-8-(6-((S)-1-(2-((R)-3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-8-(6-((S)-1-(2-((S)-3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((1S)-1-(2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((1R)-1-(2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (S)-8-(6-(1-(2-(4-fluoropiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(4-fluoropiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((1S)-1-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((1R)-1-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (S)-8-(6-(1-(2-(4,4-dimethylpiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(4,4-dimethylpiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (S)-8-(6-(1-(2-(4,4-difluoropiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(4,4-difluoropiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((R)-3-cyclopropoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((R)-1-(2-((R)-3-methylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((R)-1-(2-((S)-3-methylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((R)-1-(2-((R)-3-(methylsulfonyl)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((R)-3-cyclopropoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(1-oxa-7-azaspiro[3.5]nonan-7-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-1-Isopropyl-3-methyl-8-(6-(1-(2-(4-(oxetan-3-yl)piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-1-Isopropyl-3-methyl-8-(6-(1-(2-(4-(trifluoromethyl)piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-8-(6-((R)-1-(2-((R)-3-(methoxymethyl)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(2-oxa-6-azaspiro[3.4]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-1-Isopropyl-3-methyl-8-(6-(1-(2-(piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((R)-1-(2-((R)-3-(trifluoromethoxy)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(6-Azaspiro[3,4]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-(2-((R)-1-(5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)ethyl)-3-methylpyrrolidine-3-carbonitrile (R)-1-(2-(1-(5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)ethyl)piperidine-4-carbonitride (R)-8-(6-(1-(2-(4-Isopropoxypiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((R)-3-Isopropoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(5-azaspiro[2,4]heptan-5-yl)ethoxy)methyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(4-fluoropiperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(4,4-dimethylpiperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(3,3-dimethylpyrrolidine-1-yl)ethoxy)methyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)methyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-((2-(3-(difluoromethoxy)pyrroridine-1-yl)ethoxy)methyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (S)-8-(6-((2-(3-(difluoromethoxy)pyrroridine-1-yl)ethoxy)methyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-((2-(4-(trifluoromethoxy)piperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(4,4-dimethylpiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((1R)-1-(2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((S)-3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-((1R)-1-(2-(3-(trifluoromethoxy)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-(4-fluoropiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3,3a,9b-tetrahydro-2H-imidazo[4,5-c]sinnolin-2-one (R)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(1-(2-(4-(trifluoromethoxy)piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(4-methoxypiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(3,3-dimethylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((R)-3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((R)-3-isopropoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-1-(2-(1-(5-(3-methyl-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-imidazo[4,5-c]sinnoline-8-yl)pyridine-2-yl)ethoxy)ethyl)piperidine-4-carbonil 8-(6-((R)-1-(2-((S)-3-(difluoromethoxy)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one (R)-8-(6-(1-(2-(2-oxa-6-azaspiro[3,4]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(1-(2-(4-(trifluoromethyl)piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[3,4]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((R)-3-(methoxymethyl)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-3-methyl-8-(6-(1-(2-(piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-3-methyl-8-(6-(1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((R)-3-cyclopropoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 3-Methyl-8-(6-((R)-1-(2-((R)-3-methylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(7-Azaspiro[3.5]nonan-7-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(1-oxa-7-azaspiro[3.5]nonan-7-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 3-methyl-8-(6-((R)-1-(2-((S)-3-methylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-3-methyl-8-(6-(1-(2-(4-(oxetan-3-yl)piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 3-Methyl-8-(6-((R)-1-(2-((R)-3-(methylsulfonyl)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 3-methyl-1-(2-((R)-1-(5-(3-methyl-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)ethyl)pyrrolidine-3-carbonitrile 8-(6-((2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)methyl)pyridine-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(3,3-dimethylpyrrolidine-1-yl)ethoxy)methyl)pyridine-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(4,4-dimethylpiperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 7-Fluoro-1-isopropyl-3-methyl-8-(6-((2-(3-(trifluoromethoxy)pyrrolidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one (R)-8-(6-(1-(2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-7-fluoro-8-(6-(1-(2-(4-fluoropiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one (R)-8-(6-(1-(2-(3,3-dimethylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 7-Fluoro-1-isopropyl-8-(6-((R)-1-(2-((S)-3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(4,4-dimethylpiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(6-Azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 7-Fluoro-1-isopropyl-3-methyl-8-(6-((1R)-1-(2-(3-(trifluoromethoxy)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-7-fluoro-1-isopropyl-8-(6-(1-(2-(4-methoxypiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((1R)-1-(2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-7-fluoro-1-isopropyl-3-methyl-8-(6-(1-(2-(4-(trifluoromethoxy)piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-1-(2-(1-(5-(7-Fluoro-1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)ethyl)piperidine-4-carbonil 8-(6-((R)-1-(2-((R)-3-(difluoromethoxy)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-(2-((R)-1-(5-(7-Fluoro-1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)ethyl)-3-methylpyrrolidine-3-carbonitrile (R)-8-(6-(1-(2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(4,4-dimethylpiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-7-fluoro-8-(6-(1-(2-(4-fluoropiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 7-Fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-((R)-1-(2-((R)-3-(trifluoromethoxy)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 7-Fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-((R)-1-(2-((S)-3-(trifluoromethoxy)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one (R)-8-(6-(1-(2-(3,3-dimethylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((R)-3-(difluoromethoxy)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(7-azaspiro[3.5]nonan-7-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(1-(2-(4-(trifluoromethoxy)piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((S)-3-(difluoromethoxy)pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-((2-(5-azaspiro[2,4]heptan-5-yl)ethoxy)methyl)pyridine-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]sinnolin-2(3H)-one 8-(6-((2-(3,3-dimethylpyrrolidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-(trans-3-methoxycyclobutyl)-3-methyl-8-(6-((R)-1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 1-(trans-3-methoxycyclobutyl)-8-(6-((R)-1-(2-((R)-3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(dimethylamino)ethoxy)methyl)pyridine-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-(trans-3-methoxycyclobutyl)-3-methyl-8-(6-((2-(pyrrolidin-1-yl)ethoxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-(trans-3-methoxycyclobutyl)-3-methyl-8-(6-((2-(piperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(4-fluoropiperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)methyl)pyridine-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-(6-Azaspiro[2.5]Octane-6-yl)Ethoxy)ethyl)pyridine-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-(cis-3-methoxycyclobutyl)-3-methyl-8-(6-((2-(pyrrolidin-1-yl)ethoxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-(cis-3-methoxycyclobutyl)-3-methyl-8-(6-((2-(piperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(4-fluoropiperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)methyl)pyridine-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(dimethylamino)ethoxy)methyl)pyridine-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(dimethylamino)ethoxy)methyl)pyridine-3-yl)-3-methyl-1-(oxetan-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 3-methyl-1-(oxetan-3-yl)-8-(6-((2-(piperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(4-fluoropiperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-3-methyl-1-(oxetan-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(4-fluoropiperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1-((1s,3s)-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 3-methyl-1-(oxetan-3-yl)-8-(6-((2-(pyrroridine-1-yl)ethoxy)methyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (S)-8-(6-((2-(4-fluoropiperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)methyl)pyridine-3-yl)-3-methyl-1-((S)-tetrahydro-2H-pyran-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (S)-1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one (R)-1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(3-methylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(3,3-dimethylpyrrolidine-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(5-azaspiro[2,4]heptan-5-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(4,4-dimethylpiperidine-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnoline-2-one 1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(4-methoxypiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnoline-2-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(3-methylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(3,3-dimethylpyrrolidine-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(5-azaspiro[2,4]heptan-5-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(4,4-dimethylpiperidine-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(4-methoxypiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 1-(3-methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 1-(3-methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(3-methylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnoline-2-one 1-(3-methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(3,3-dimethylpyrrolidine-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(5-azaspiro[2,4]heptan-5-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 1-(3-methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(4,4-dimethylpiperidine-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnoline-2-one 1-(3-methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(4-methoxypiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnoline-2-one 8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one (R)-2-(1-(5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)acetic acid 8-(6-(2-(2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)propan-2-yl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexane-3-yl)-1,1-difluoroethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(1-(2-(pyrroridine-1-yl)ethoxy)propyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(1-(2-(pyrroridine-1-yl)ethoxy)butyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(2-methyl-1-(2-(pyrroridine-1-yl)ethoxy)propyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one, and 1-Isopropyl-3-methyl-8-(6-(4-methyl-1-(2-(pyrroridine-1-yl)ethoxy)pentyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0127] Exemplary compounds of formula (I) are described in Table 1 below.

[0158] [Table 1-1]

[0159] Table 1-2

[0160] Table 1-3

[0161] Table 1-4

[0162] Table 1-5

[0163] Table 1-6

[0164] Table 1-7

[0165] Table 1-8

[0166] Table 1-9

[0167] Table 1-10

[0168] Table 1-11

[0169] Table 1-12

[0170] Table 1-13

[0171] Table 1-14

[0172] Table 1-15

[0173] Table 1-16

[0174] Table 1-17

[0175] Table 1-18

[0176] Table 1-19

[0177] Table 1-20

[0178] Table 1-21

[0179] Table 1-22

[0180] Table 1-23

[0181] Table 1-24

[0182] Table 1-25

[0183] Table 1-26

[0184] Table 1-27

[0185] Table 1-28

[0186] Table 1-29

[0187] Table 1-30

[0188] Table 1-31

[0189] Table 1-32

[0190] Table 1-33

[0191] Table 1-34

[0192] Table 1-35

[0193] Table 1-36

[0194] Table 1-37

[0195] Table 1-38

[0196] Table 1-39

[0197] Table 1-40

[0198] Table 1-41

[0199] Table 1-42

[0200] Table 1-43

[0201] Table 1-44

[0202] Table 1-45

[0203] Table 1-46

[0204] Table 1-47

[0205] Table 1-48

[0206] Table 1-49

[0207] Table 1-50

[0208] Table 1-51

[0209] Table 1-52

[0210] [Table 1-53]

[0211] [Table 1-54]

[0212] [Table 1-55]

[0213] [Table 1-56]

[0214]

[0128] The compounds provided herein are described by both general formulas and specific compounds. In addition, the compounds of this disclosure may exist in a number of different forms or derivatives, including, but are not limited to, stereoisomers, racemic mixtures, positional isomers, tautomers, salts, prodrugs, soft drugs, active metabolic derivatives (active metabolites), solvated forms, different crystalline forms or polymorphs, all of which are within the scope of this disclosure.

[0215]

[0129] The compounds of the present disclosure may contain one or more chiral centers and therefore may exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. Accordingly, the compounds and compositions of the present disclosure may be in the form of individual enantiomers, diastereomers or geometric isomers, or in the form of mixtures of stereoisomers. In certain embodiments, the compounds of the present disclosure are enantiopurine compounds. In certain embodiments, mixtures of enantiomers or diastereomers are provided.

[0216]

[0130] The term "enantiomer" refers to two stereoisomers of a compound that are mirror images of each other and cannot be superimposed. The term "diastereomer" refers to a pair of optical isomers that are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity.

[0217]

[0131] Furthermore, certain compounds may have one or more double bonds, which may exist as either Z or E isomers, as described herein, unless otherwise indicated. The disclosure further includes compounds as individual isomers substantially free of other isomers, and alternatively as mixtures of various isomers, e.g., as racemic mixtures of enantiomers. In addition to the compounds themselves described above, the disclosure also includes compositions comprising one or more compounds.

[0218]

[0132] As used herein, the term “isomer” includes any and all geometric isomers and stereoisomers. For example, “isomer” includes cis and trans isomers, E and Z isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures that fall within the scope of the present invention. For example, stereoisomers may be provided in some embodiments that substantially do not contain one or more corresponding stereoisomers and may be referred to as “stereochemically enriched.”

[0219]

[0133] Where a particular enantiomer is preferred, it can be provided in some embodiments substantially free of the reverse enantiomer and may be referred to as “optically enriched.” “Optically enriched,” as used herein, means that the compound is composed of a significantly large proportion of one enantiomer. In certain embodiments, the compound is composed of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound is composed of at least about 95% by weight, 98% by weight, or 99% by weight of the preferred enantiomer. The preferred enantiomer can be isolated from the racemic mixture by any method known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or can be prepared by asymmetric synthesis. For example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL. See Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH. Tables of Resolving Agents and Optical Resolutions, page 268 (ELEliel, editor, Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0220]

[0134] The compounds of this disclosure may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms “tautomer” or “tautomer form” refer to structural isomers of different energies that are interconvertible across a low-energy barrier. The presence and concentration of isomer forms may depend on the environment in which the compound is found, for example, whether the compound is a solid or in an organic solution or aqueous solution. As an example, proton tautomers (also known as prototropic tautomers) include interconversions via proton transfer, such as keto-enols, amide-imido acids, lactam-lactims, imine-enamine isomers, and cyclic forms, where the proton can occupy two or more positions in the heterocyclic system. Valence tautomers include interconversions by rearrangement of some of the bonding electrons. Tautomers may be in equilibrium or may be sterically fixed into one form by appropriate substitution. A compound of this disclosure identified by name or structure as a single specific tautomer form is intended to include other tautomer forms unless otherwise specified.

[0221]

[0135] As used herein, the term “prodrug” refers to a compound or a pharmaceutically acceptable salt thereof that yields a desired active compound when metabolized under physiological conditions or converted by solvolysis. Prodrugs include, but are not limited to, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of an active compound. Typically, prodrugs are inactive or less active than the active compound, but can provide one or more advantageous handling, administration, and / or metabolic properties. For example, some prodrugs are esters of an active compound; during metabolism, the ester group is cleaved to yield the active drug. In addition, some prodrugs are enzymatically activated to yield the active compound, or a compound that yields the active compound in a further chemical reaction. Prodrugs can progress from the prodrug form to the active form in a single step, or they may have one or more intermediate forms that may be active or inactive themselves. The preparation and use of prodrugs have been discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," ACSSymposium Series, in Bioreversible Carriers in Drug Design, Vol. 14, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; and in Prodrugs: Challenges and Rewards, edited by V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, and J. Tilley, Springer-Verlag New York, 2007, all of which are incorporated herein by reference in their entirety.

[0222]

[0136] As used herein, the term “soft drug” refers to a compound that exerts pharmacological effects but whose activity is limited to a short period of time due to degradation into inactive metabolites. See, for example, “Soft drugs: Principles and methods for the design of safe drugs,” Nicholas Bodor, Medicinal Research Reviews, vol. 4, no. 4, pp. 449–469, 1984, which is incorporated in its entirety by reference herein.

[0223]

[0137] As used herein, the term “metabolite,” for example, “active metabolite,” overlaps with “prodrug” as described above. Thus, such metabolites are compounds that are further metabolized into a pharmacologically active compound, or a pharmacologically active compound that is a derivative resulting from a metabolic process in the body of interest. For example, such metabolites may result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the administered compound or salt or prodrug. Of these, the active metabolite is the pharmacologically active derivative compound. With respect to prodrugs, the prodrug compound is generally inactive or has lower activity than the metabolite. With respect to active metabolites, the parent compound may be either the active compound or an inactive prodrug.

[0224]

[0138] Prodrugs and active metabolites can be identified using routine techniques known in the art. See, for example, Bertolini et al., 1997, J Med Chem 40:2011~2016; Shan et al., J Pharm Sci 86:756~757; Bagshawe, 1995, Drug Dev Res 34:220~230; Wermuth, see above.

[0225]

[0139] As used herein, the term “active intermediate” refers to an intermediate compound in a synthetic process that exhibits the same or essentially the same biological activity as the final synthetic compound.

[0226]

[0140] The compounds of this disclosure may be formulated in or in the form of pharmaceutically acceptable salts. Unless otherwise specified, the compounds provided herein include pharmaceutically acceptable salts of such compounds.

[0227]

[0141] As used herein, the term “pharmaceutically acceptable” means that a substance or composition is chemically and / or toxicologically compatible with other components of the formulation and / or the subject being treated therewith.

[0228]

[0142] As used herein, the term “pharmaceutically acceptable salt” includes, unless otherwise indicated, salts that retain the biological efficacy of the free acids and bases of the identified compound and are not biologically or otherwise undesirable. The intended pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, etc. pharmaceutically acceptable salts are nontoxic at the amounts and concentrations in which they are administered. Preparations of such salts can facilitate pharmacological use by altering the physical properties of the compound without preventing it from exerting its physiological effects. Useful alterations in physical properties include facilitating transmucosal administration by lowering the melting point and facilitating administration of higher concentrations of the drug by increasing solubility.

[0229]

[0143] Pharmaceutically acceptable salts include acid addition salts containing sulfates, chlorides, hydrochlorides, fumarates, maleates, phosphates, sulfamates, acetates, citrates, lactates, tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, and quinates. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.

[0230]

[0144] Pharmaceutically acceptable salts also include base addition salts containing acidic functional groups such as carboxylic acids or phenols, such as benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc. See, for example, Remington's Pharmaceutical Sciences, 19th edition, Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using appropriate corresponding bases.

[0231]

[0145] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of a compound can be isolated by dissolving it in a suitable solvent, such as an aqueous or aqueous alcohol solution containing a suitable acid, and then evaporating the solution. Thus, if the particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by treatment of the free base using any suitable method available in the art, for example, using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, or by using organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranocidylic acid, for example, glucuronic acid or galacturonic acid, alpha-hydroxy acids, for example, citric acid or tartaric acid, amino acids, for example, aspartic acid or glutamic acid, aromatic acids, for example, benzoic acid or cinnamic acid, sulfonic acids, for example, p-toluenesulfonic acid or ethanesulfonic acid.

[0232]

[0146] Similarly, if the special compound is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, by treatment of a free acid with an inorganic or organic base such as an amine (primary, secondary, or tertiary), alkali metal hydroxide, or alkaline earth metal hydroxide. Exemplary examples of suitable salts include organic salts derived from amino acids, e.g., L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, as well as cyclic amines, e.g., hydroxyethylpyrrolidine, piperidine, morpholine, or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0233]

[0147] It should also be understood that the compounds of this disclosure may exist in non-solvated forms, solvated forms (e.g., hydrated forms), and solid forms (e.g., crystalline or polymorphic forms), and this disclosure is intended to encompass all such forms.

[0234]

[0148] As used herein, the terms “solvate” or “solvated form” refer to a solubilated form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to capture a fixed molar ratio of solvent molecules in the crystalline solid state and thus form solvates. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by a combination of one or more molecules of water and one molecule of a substance in which water retains its molecular state as H2O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0235]

[0149] As used herein, the terms “crystalline form,” “crystalline form,” “polymorph,” and “polymorph” are interchangeable and refer to crystalline structures in which a compound (or its salt or solvate) can crystallize in different crystalline packing arrangements, all of which have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to be dominant. Crystalline polymorphs of the compound can be prepared by crystallization under different conditions.

[0236]

[0150] The disclosure is intended to include all isotopes of the atoms in the compounds. An isotope of an atom includes atoms that have the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the compounds of the disclosure are, but are not limited to, 1 H, 2 H, 3 H, 11 C, 12 C, 13 C, 14 C, 14 N,15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I, 127 I and 131 This means that it also includes those isotopes such as 1. In some embodiments, hydrogen includes protium, deuterium and tritium. In some embodiments, carbon is 12 C and 13 Includes C. Compound synthesis

[0151] The synthesis of the compounds provided herein, including their pharmaceutically acceptable salts, is illustrated in the synthesis schemes in the Examples. The compounds provided herein can be prepared using any known organic synthesis technique and can be synthesized according to any of a number of possible synthesis routes; therefore, these schemes are illustrative only and are not intended to limit other possible methods that can be used to prepare the compounds provided herein. In addition, the steps in the schemes are for better illustration and can be modified where appropriate. Embodiments of the compounds in the Examples were synthesized for research purposes and for potential submission to regulatory authorities.

[0237]

[0152] The reactions for preparing the compounds of this disclosure can be carried out in a suitable solvent that can be readily selected by those skilled in the art of organic synthesis. The suitable solvent may be substantially inactive with the starting materials (reactants), intermediates, or products at the temperature in which the reaction is carried out, for example, at a temperature ranging from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on a particular reaction step, a suitable solvent for that particular reaction step can be selected by those skilled in the art.

[0238]

[0153] The preparation of the compounds of this disclosure may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in TW Greene and PGMWuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley & Sons, Inc., New York (1999), which is incorporated herein in its entirety by reference.

[0239]

[0154] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C) The compounds can be monitored by spectroscopic means such as infrared spectroscopy, spectrophotometric methods (e.g., UV-Vis), and mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC). The compounds can be purified by those skilled in the art by various methods, including high-performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization," Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs, J. Combi. Chem. 2004, 6(6), 874-883, which is incorporated herein in its entirety by reference), and normal-phase silica chromatography.

[0240]

[0155] The structures of the compounds in the examples are characterized by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectroscopy (LC-MS). The NMR chemical shift (δ) is 10 -6 It is expressed in units of (ppm). 1 ¹H-NMR spectra are recorded in CDCl3, CD3OD, or DMSO-d6 solution using tetramethylsilane (TMS) as a reference standard (0.0 ppm) on a Varian instrument (400 MHz) or Brucker instrument (400 MHz) (reported in ppm).

[0241]

[0156] MS measurements are performed using a Shimadzu 2020 Mass Spectrometer, employing electrospray, chemical, and electron impulse ionization methods from a range of instruments.

[0242]

[0157] TLC measurements are performed using Shanghai Yu Cheng plates. The silica gel plates used for TLC are 0.15 mm to 0.2 mm. The silica gel plates used for separating and purifying the product by TLC are 0.4 mm to 0.5 mm.

[0243]

[0158] Column chromatography was performed on a Biotage system with a silica gel column (manufacturer: Dyax Corporation) or on a silica SepPak cartridge (Waters).

[0244]

[0159] The known starting materials of this disclosure can be synthesized by or in accordance with methods known in the art, or can be purchased from commercial suppliers such as Adamas-beta, Bidepharm, or Accela ChemBio Co., Ltd., and were used without further purification unless otherwise indicated. Tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dichloromethane (DCM), dichloroethane (DCE), dioxane, and 1,1,2,2-tetrachloroethane were purchased from Adamas-beta in sealed bottles and used as received.

[0245]

[0160] Unless otherwise specified, all reactions in this disclosure are carried out under positive pressure of nitrogen or argon or in dry tubing in anhydrous solvent, and the reaction flasks are typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware is oven-dried and / or heat-dried.

[0246]

[0161] For illustrative purposes, the following general synthetic routes for preparing the compounds and key intermediates of this disclosure are shown below. For a more detailed description of the individual reaction steps, please refer to the Examples section below. Those skilled in the art will understand that other synthetic routes may be used to synthesize the compounds of the present invention. While specific starting materials and reagents are illustrated in the scheme and discussed below, other starting materials and reagents may be readily substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art. General synthesis route

[0162] In some embodiments, the compound of formula (I) is of formula (II')

[0247] [ka]

[0248] (In the formula, X is a leaving group (for example, a halogen atom, for example, a chlorine, iodine, or bromine atom, or a triflate group)) The compound and formula (III'):

[0249] [ka]

[0250] (In the formula, Y is a boronic acid, a boronic acid ester (e.g., pinacol boronic acid ester), or a potassium trifluoroborate group.) It can be prepared by reaction with the compound. The reaction can be carried out under standard conditions well known to those skilled in the art, for example, at a suitable temperature in the presence of a palladium source (e.g., tetrakistriphenylphosphine palladium, palladium(II) acetate, or [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II)), optionally a phosphine ligand (e.g., X-phos, xanthophos, or S-phos), and a suitable base (e.g., cesium carbonate or triethylamine).

[0251]

[0163] In some embodiments, the compound of formula (II') can be obtained by conventional procedures. Scheme 1 illustrates the synthesis of the compound of formula (II').

[0252] [ka]

[0253]

[0164] Step 1:

[0165] The starting materials for formula (A1) are commercially available or can be prepared using conventional methods as described, for example, in WO2010 / 48582.

[0254]

[0166] The compound of formula (A2) can be prepared by the cinnoline-4-ol cyclization reaction of the compound of formula (A1) with a diazotizing reagent (e.g., NaNO2 or nitrite) under standard conditions.

[0255]

[0167] Step 2:

[0168] The compound of formula (A3) can be prepared by a nitration reaction of the compound of formula (A2) with a nitrating reagent (e.g., fuming nitric acid or concentrated nitric acid) under appropriate conditions.

[0256]

[0169] Step 3:

[0170] The compound of formula (A4) can be prepared by a halogenation reaction of the compound of formula (A3) with a halogenating reagent (e.g., POCl3 or SOCl2) in a suitable solvent (e.g., DMF) under standard conditions.

[0257]

[0171] Step 4:

[0172] The compound of formula (A5) can be prepared by a nucleophilic substitution reaction between the compound of formula (A4) and an amine (e.g., a primary or secondary amine) in a suitable solvent (e.g., THF or DMF) in the presence of an organic base (e.g., Et3N or di-isopropylethylamine) under standard conditions.

[0258]

[0173] Step 5:

[0174] The compound of formula (A6) can be prepared by a reduction reaction of the compound of formula (A5) with a reducing agent (e.g., SnCl2, or Fe / NH4Cl, or H2 / palladium) under appropriate reducing conditions.

[0259]

[0175] Step 6:

[0176] The compound of formula (A7) can be prepared by reacting the compound of formula (A6) with an acylation reagent (e.g., 1,1'-carbonyldiimidazole (CDI), ethyl carbonochloride, or bis(trichloromethyl) carbonate) under appropriate coupling conditions.

[0260]

[0177] Step 7:

[0178] The compound of formula (A7) can be reacted with a suitable alkylating reagent (e.g., iodomethane or DMF-DMA) and optionally a suitable base to provide the compound of formula (II').

[0261]

[0179] In some embodiments, the compound of formula (III') can be obtained by conventional procedures. Scheme 2 illustrates the synthesis of the compound of formula (III').

[0262] [ka]

[0263]

[0180] In Scheme 2, the compound of formula (III') can be prepared starting from B1, which is either commercially available or synthesized from heteroarylethanone with a Grignard reagent. Part of the compound of formula (III') was prepared via halogenation of B1 to obtain B2 with a halogenating agent, e.g., thionyl chloride, phosphoryl chloride, or a mixture of carbon tetrachloride and triphenylphosphine. After alkylation of B3 by a conventional procedure, the key intermediate B4 was finally reacted with a common boron source (e.g., bis(pinacolate)diborone (B2Pin2) or bis(catecholate)diborane (B2Cat2)) under suitable transition metal-catalyzed boration reaction conditions to obtain formula (III'). Alternatively, intermediate B1 can be coupled with a suitable halide B5 in which W is alkyl, followed by hydrolysis to obtain the free acid B6. Furthermore, the key intermediate B4 was synthesized by the amide reduction of B7, which was then prepared with the free acid B6 with R7 (amine) using an appropriate coupling reagent. Use of compounds

[0181] In one embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof that exhibits ATM kinase inhibitory activity.

[0264]

[0182] As used herein, the term “ATM kinase inhibitory activity” refers to a decrease in the activity of ATM kinase as a direct or indirect response to the presence of the compound of formula (I) or a pharmaceutically acceptable salt thereof, relative to the activity of ATM kinase in the absence of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Such a decrease in activity may be due to a direct interaction between the compound of formula (I) or a pharmaceutically acceptable salt thereof and ATM kinase, or to an interaction between the compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more other factors that subsequently affect ATM kinase activity. For example, the compound of formula (I) or a pharmaceutically acceptable salt thereof may reduce ATM kinase by directly binding to ATM kinase, thereby causing another factor to reduce ATM kinase activity (directly or indirectly), or by directly or indirectly reducing the amount of ATM kinase present in a cell or organism.

[0265]

[0183] In some embodiments, the compounds of the present disclosure are selective inhibitors of ATM kinase.

[0266]

[0184] As used herein, the terms “selective inhibitor” or “selectively inhibit” mean that the compound provided inhibits ATM kinase in at least one assay described herein (e.g., biochemical or cellular). In some embodiments, the terms “selective inhibitor” or “selectively inhibit” mean that the compound provided inhibits ATM kinase. 50IC for inhibiting enzymes in the PIKK family closely related to ATM kinases (PI3K, mTOR, and ATR, etc.) is at least 5000 times higher, at least 4000 times higher, at least 3000 times higher, at least 2000 times higher, at least 1000 times higher, at least 500 times higher, at least 400 times higher, at least 300 times higher, at least 200 times higher, at least 100 times higher, at least 90 times higher, at least 80 times higher, at least 70 times higher, at least 60 times higher, at least 50 times higher, at least 40 times higher, at least 30 times higher, at least 20 times higher, at least 10 times higher. 50 It means having

[0267]

[0185] In some embodiments, the compounds of this disclosure are not AO substrates as determined in human liver cytosol.

[0268]

[0186] As used herein, the term “AO substrate” means that a given compound is sensitive to oxidation by aldehyde oxidase (AO) and therefore highly sensitive to AO-mediated clearance. In some embodiments, the AO sensitivity of a compound is expressed in terms of its intrinsic clearance (CL) in the human liver cytosol system (Zientek M. et al., Drug MetabDispos, 2010, 1322-27), as described in detail in the Examples section below. intIt can be evaluated by [method]. A human liver cytosol system useful for evaluation is commercially available, for example, from Xenotech under catalog number H0606.C(AX) and lot number 1710130. Generally, human liver cytosol extracts can be prepared by ultracentrifugation of liver homogenates obtained from human donors. In certain embodiments, human liver cytosol extracts (e.g., H0606.C(AX) from Xenotech) can be specifically prepared from donors with high AO activity to minimize underestimation of AO-mediated clearance. PF-04217903 (2-[4-[3-(quinoline-6-ylmethyl)triazolo[4,5-b]pyrazine-5-yl]pyrazole-1-yl]ethanol, reported as a weak AO substrate) and zaleplon (N-[3-(3-cyanopyrazolo[1,5-a]pyrimidine-7-yl)phenyl]-N-ethylacetamide, considered a strong AO substrate) are both used as references in the human liver cytosolic system. Generally, compounds with lower CLs than PF-04217903 are used. int If it shows that, it cannot be considered as an AO substrate, but the compound has a higher CL than that of zaleplon. int If it shows this, it can be considered a strong AO substrate, and here, CL int This is determined by the AO assay described in the Examples section below.

[0269]

[0187] In some embodiments, the compounds of the present disclosure are found in lower levels of CL in human hepatocytes than PF-04217903. intIt exhibits low AO sensitivity. AOs are a group of proteins that require flavin adenine dinucleotide (FAD) and molybdopterin [molybdenum cofactor (MoCo)] for catalytic activity, and are cytosolic molybdoflavin enzymes. AOs oxidize aromatic aldehydes to their corresponding carboxylic acids and heterocycles to hydroxylated derivatives. The potential of AOs to oxidize heterocycles is particularly important in the context of drug design and development, as these chemical groups are popular synthetic blocks in medicinal chemistry. AO-mediated metabolism is often overlooked during the drug discovery phase, and high clearance challenges are not revealed until Phase 1 clinical trials. AOs are cytosolic enzymes, and therefore their potential contribution to the metabolic clearance of novel compounds has not been addressed in standard metabolic stability screens using liver microsomes. Hepatocytes are the entire cell system that contains both microsomes and cytosol. However, AO is an unstable protein with substantial loss of activity during hepatocyte preparation (Hutzler, J.M. et al., Drug MetabDispos, 2014, 1090-7). In vivo studies of AO-mediated metabolism in animal models are highly problematic because constituent liver AO differs between humans and popular experimental animals (Garattini, E. et al., Expert Opin Drug Discovery, 2013, 641-54). The human liver is characterized by a single, active AO isozyme, namely AOX1. The dominant AOX form expressed in many mouse and rat strains is AOX3. Two other experimental animals, cats and dogs, are characterized by the absence of AO enzyme activity. AO activity has been found to be much higher in higher primates (humans and monkeys) compared to rodents. AO is highly concentrated in the liver, where it oxidizes multiple aldehydes and nitrogenous heterocyclic compounds, such as anticancer drugs and immunosuppressants (e.g., Gordon AH, Green DE, Subrahmanyan, "Liver aldehyde oxidase," The Biochemical Journal).See 1940, 34(5):764-74. Human liver cytosolic extracts containing AO but not in amounts significant enough to contaminate CYP450 have been shown to be a valuable tool for predicting human AO-mediated in vivo clearance. Human liver cytosol purchased from Xenotech was used immediately after thawing and not reused, as AO is an unstable enzyme and rapidly inactivates upon freeze-thaw. In light of the highly variable AO activity, underestimation of clearance was minimized by selecting high-activity lots of human liver cytosol for the AO assay. Reference compounds zaleplon (high clearance by AO) and PF-04217903 (low clearance by AO) were used as controls in the AO assay.

[0270]

[0188] Without wishing to link it to any particular theory, it appears to have a significant effect on pharmacokinetics. Due to its broad substrate specificity, AO can oxidize many drugs in the liver (Strelevitz TJ, Orozco CC, Obach RS. "Hydralazine as a selective probe inactivator of aldehyde oxidase in human hepatocytes: estimation of the contribution of aldehyde oxidase to metabolic clearance" Drug Metabolism and Disposition. 2012, 40(7):1441~8). AO contributes significantly to the hepatic clearance of drugs and other compounds (Hartmann T, Terao M, Garattini E, Teutloff C, Alfaro JF, Jones JP, Leimkuhler S. "The impact of single nucleotide polymorphisms on human aldehyde oxidase" Drug Metabolism and Disposition. 2012, 40(5):856~64). AO-mediated metabolism tends to reach high clearance in humans. For high-clearance compounds, small variations in intrinsic clearance due to different enzyme expression levels among patients lead to large variations in bioavailability. Human AOX1 is highly polymorphic, and some inactivating missense and nonsense polymorphic sites have been described in the human population (Garattini, E. et al., Expert Opin Drug Discovery, 2012, 487-503; Hartmann, T. et al., Drug MetabDispos, 2012, 856-864). This polymorphism results in a reduction in the level of encoded AOX1 protein, explaining the reported inter-individual variability in AOX activity. In addition, many factors, including sex, age, smoking, drug use, and disease status, can influence AO activity.Therefore, compounds with high AO-mediated clearance exhibit large inter-patient PK variability, which can lead to unexpected toxicity in some individuals while the efficacy is not achieved in others (Garattini, E. et al., Expert Opin Drug Discovery, 2013, 641-54; Hutzler, JM et al., Drug MetabDispos 2014, 1090-7).

[0271]

[0189] In contrast to the previously reported ATM inhibitors AZD0156 and AZD1390, which are strong AO substrates, the compounds of this disclosure have remarkably low sensitivity to AO oxidation. Thus, in one embodiment, the compounds provided herein and their pharmaceutically acceptable salts are not AO substrates and, as a result, exhibit a better PK profile than compounds that are AO substrates. For example, the compounds provided herein exhibit low PK variability among humans with different levels of AO activity.

[0272]

[0190] In some embodiments, the compounds of the present disclosure exhibit good solubility in water. In some embodiments, the compounds of the present disclosure exhibit solubility in water of over 90 μM, over 100 μM, over 200 μM, over 300 μM, over 400 μM, over 500 μM, over 600 μM, over 700 μM, over 800 μM, over 900 μM, or over 1000 μM.

[0273]

[0191] As a result of their ATM kinase inhibitory activity (or, optionally, selective ATM kinase inhibitory activity), the compounds of formula (I) and their pharmaceutically acceptable salts are useful in the treatment of diseases or medical conditions that are at least partially mediated by ATM kinases, for example, cancer.

[0274]

[0192] As used herein, the term “cancer” is intended to encompass both non-metastatic and metastatic cancers. In this context, treating cancer involves treating both the primary tumor and tumor metastases.

[0275]

[0193] As used herein, the term “treatment” is intended to have its normal meaning in order to address a disease, thereby alleviating one, some or all of its symptoms, whole or in part, or correcting or compensating for an underlying condition. The term “treatment” also includes “prevention” unless otherwise specifically indicated. The terms “therapeutic” and “therapeutically” should be interpreted in their corresponding ways.

[0276]

[0194] As used herein, the term “prevention” is intended to have its normal meaning and includes primary prevention, which is to prevent the onset of a disease, and secondary prevention, which is to protect a patient temporarily or permanently from the onset or exacerbation of the disease or new symptoms associated with the disease, once the disease has already developed.

[0277]

[0195] The term “procedure” is used synonymously with “treatment.” Similarly, the term “to treat” can be considered as “to administer treatment,” where “treatment” is as defined herein.

[0278]

[0196] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for therapeutic use.

[0279]

[0197] In some embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof are provided for use as pharmaceuticals.

[0280]

[0198] In some embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof are provided for use in the treatment of ATM-related diseases or conditions. In some embodiments, the ATM-related disease or condition is cancer. In some embodiments, cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma (including, but not limited to, lip carcinoma, oral carcinoma, oropharyngeal carcinoma, hypopharyngeal carcinoma, glottal laryngeal carcinoma, supraglottal laryngeal carcinoma, ethmoid sinus carcinoma, maxillary sinus carcinoma, and occult primary carcinoma), breast cancer, hepatocellular carcinoma, small cell lung cancer, and non-small cell lung cancer.

[0281]

[0199] In some embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof are provided for use in the manufacture of pharmaceuticals for the treatment of ATM-related diseases or conditions.

[0282]

[0200] In some embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof are provided for use in the manufacture of pharmaceuticals for the treatment of cancer. Pharmaceutical composition

[0201] This disclosure provides pharmaceutical compositions comprising one or more compounds of this disclosure or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition comprises one or more compounds of this disclosure or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0283]

[0202] When used herein, “pharmaceutical composition” is a formulation containing the compound of the Disclosure in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is a bulk or unit dosage form. The unit dosage form is any of a variety of forms, including, for example, tablets, capsules, pills, powders, granules, sachets, caches, lozenges, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), sprays, ointments, pastes, creams, lotions, gels, patches, inhalants, or suppositories. The amount of the active ingredient (e.g., a formulation of the disclosed compound or its salt, hydrate, solvate, or isomer) in a unit dose of the composition is a therapeutically effective dose and will vary according to any special treatments that may be involved. Those skilled in the art will understand that it is sometimes necessary to make routine adjustments to the dosage depending on the patient’s age and condition. The dosage will also depend on the route of administration. Various routes are intended, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, subarachnoid, and nasal. Dosage forms for topical or transdermal administration of the compounds of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In some embodiments, the compounds of this disclosure are mixed with pharmaceutically acceptable excipients and any required preservatives, buffers, or sprays under sterile conditions.

[0284]

[0203] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is generally safe, non-toxic, and useful in preparing a pharmaceutical composition that is not biologically or otherwise undesirable, and includes excipients that are acceptable for veterinary and human medicinal use. As used herein and in claims, “pharmaceutically acceptable excipient” includes both one and more such excipients.

[0285]

[0204] As used herein, the term “therapeutic effective dose” means the amount of a medicinal agent necessary to treat, improve or prevent an identified disease or condition, or to produce a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective dose for a subject depends on the subject’s weight, size, and health; the nature and severity of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutic effective dose for a given situation can be determined by routine experimental methods, which are within the skill and judgment of the clinician.

[0286]

[0205] In some embodiments, the pharmaceutical composition can be formulated so that a dose of 0.01 to 500 mg / kg body weight / day of the compound or a pharmaceutically acceptable salt

[0287]

[0206] In some embodiments, the pharmaceutical composition comprises one or more compounds of the Disclosure or pharmaceutically acceptable salts thereof as a first active ingredient, and further comprises a second active ingredient. The second active ingredient may be any antitumor agent known in the Art, such as an antineoplastic agent, an anti-angiogenic agent, an immunotherapy approach, or a potency enhancer.

[0288]

[0207] Examples of antineoplastic agents include, but are not limited to, DNA alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, nitrogen mustards such as cyclophosphamide and ifosfamide, bendamustine, melphalan, chlorambucil, busulfan, temozolomide, and nitrosourea such as carmustine); antimetabolites (e.g., gemcitabine and folate antimetabolites, fluoropyrimidines such as 5-fluorouracil and tegafur, larcitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); and antitumor antibiotics (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, liposomal doxorubicin, pirarubicin, daunomycin, barurubicin, epirubicin, idarubicin, mitomycin, dactinomycin, amrubicin, and mitramycin). Examples include antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, as well as taxoids such as taxol and taxotere, and polokinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrin, irinotecan, topotecan, and camptothecin); inhibitors of DNA repair mechanisms, e.g., CHK kinase; DNA-dependent protein kinase inhibitors; poly(ADP-ribose) polymerase inhibitors (PARP inhibitors, including olaparib, lucaparib, niraparib, thalazoparib, pamiparib, and fluzoparib); as well as Hsp90 inhibitors such as tanespimycin and letaspimycin; ATR kinase inhibitors (e.g., AZD6738); and WEE1 kinase inhibitors (e.g., AZD1775 / MK-1775).

[0289]

[0208] Examples of anti-angiogenic agents include those that inhibit the effects of vascular endothelial growth factor, such as, but are not limited to, the anti-vascular endothelial growth factor antibody bevacizumab, and VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD6474), sorafenib, batalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW786034), and cediranib (AZD2171); Examples include compounds disclosed in previous patent applications WO97 / 22596, WO97 / 30035, WO97 / 32856 and WO98 / 13354; as well as compounds that function by other mechanisms (e.g., linamides, inhibitors of integrin ανβ3 function and angiostatins), or inhibitors of angiopoietin and their receptors (Tie-1 and Tie-2), inhibitors of PLGF, and inhibitors of delta-like ligands (DLL-4).

[0290]

[0209] Examples of immunotherapy approaches include, but are not limited to, ex vivo and in vivo approaches to increase the immunogenicity of patient tumor cells, e.g., transfection using cytokines such as interleukin-2, interleukin-4, or granulocyte-macrophage colony-stimulating factor; approaches to reduce T cell anergy or regulatory T cell function; and approaches to enhance the T cell response to tumors, e.g., blocking antibodies and CD against CTLA4 (e.g., ipilimumab and tremelimumab), B7H1, PD-1 (e.g., BMS-936558 or AMP-514), PD-L1 (e.g., MEDI4736). Examples include agonist antibodies against 137; approaches using transfected immune cells such as cytokine-transfected dendritic cells; approaches using cytokine-transfected tumor cell lines, antibodies against tumor-associated antigens, and antibodies that deplete target cell types (e.g., conjugated anti-CD20 antibodies, e.g., rituximab, radiolabeled anti-CD20 antibodies Bexal and Zevalin, and anti-CD54 antibody Canvas); approaches using anti-idiotype antibodies; approaches that enhance natural killer cell function; and approaches that utilize antibody-toxin conjugates (e.g., anti-CD33 antibody Mylotarg); immunotoxins such as moxetumomab Pasdotox; and agonists of Toll-like receptor 7 or Toll-like receptor 9.

[0291]

[0210] An example of a potency enhancer is leucovorin.

[0292]

[0211] In some embodiments, a pharmaceutical composition is provided comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one additional antitumor agent. In some embodiments, there is one additional antitumor agent. In some embodiments, there are two additional antitumor agents. In some embodiments, there are three or more additional antitumor agents.

[0293]

[0212] In some embodiments, the amount of additional antitumor agents present in the compositions of the Disclosure may be less than or equal to the amount typically administered in a composition containing the antitumor agent as the sole active agent. In certain embodiments, the amount of additional antitumor agents present in the compositions of the Disclosure ranges from about 50% to 100% of the amount typically present in a composition containing the antitumor agent as the sole therapeutically active agent.

[0294]

[0213] In another embodiment, compounds of formula (I) or pharmaceutically acceptable salts thereof are provided in combination with one or more antitumor agents listed above.

[0295]

[0214] In some embodiments, additional antitumor agents are selected from the group consisting of doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, and bleomycin.

[0296]

[0215] As used herein, the term “combination” refers to simultaneous, separate, or sequential administration. In some embodiments, “combination” refers to simultaneous administration. In some embodiments, “combination” refers to separate administration. In some embodiments, “combination” refers to sequential administration. When administration is sequential or separate, delays in administering the second component should not result in loss of the beneficial effect of the combination.

[0297]

[0216] In a further embodiment, pharmaceutical compositions are provided comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more antitumor agents listed above, in association with a pharmaceutically acceptable excipient.

[0298]

[0217] In a further embodiment, a kit is provided comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more antitumor agents listed above.

[0299]

[0218] In a further embodiment, a kit is provided which includes the following: (a) The compound of formula (I) or a pharmaceutically acceptable salt thereof in a first unit dosage form; (b) an antitumor agent selected from those listed above in a second unit dosage form; and (c) A container containing the first and second unit dosage forms. Methods for treatment

[0219] In a further embodiment, due to the selective ATM kinase inhibitory activity and non-AO liability of the compounds of the Disclosure, a method is provided for treating an ATM-related disease or condition in a subject requiring such treatment, comprising administering a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the Disclosure to the subject.

[0300]

[0220] In some embodiments, the ATM-related disease or condition is cancer. In some embodiments, cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer, and non-small cell lung cancer. In some embodiments, cancer is head and neck squamous cell carcinoma, including, but not limited to, lip carcinoma, oral carcinoma, oropharyngeal carcinoma, hypopharyngeal carcinoma, glottal laryngeal carcinoma, supraglottal laryngeal carcinoma, ethmoid sinus carcinoma, maxillary sinus carcinoma, and occult primary carcinoma. In some embodiments, cancer is metastatic cancer. In some embodiments, metastatic cancer includes central nervous system metastases. In some embodiments, central nervous system metastases include brain metastases. In some embodiments, central nervous system metastases include leptomeningeal metastases. "Lesser meningeal metastases" occur when cancer spreads to the meninges, the layers of tissue that cover the brain and spinal cord. Metastases can spread to the meninges via the bloodstream, or they can migrate from brain metastases, carried by cerebrospinal fluid (CSF) that flows through the meninges.

[0301]

[0221] As used herein, the term “subjects requiring it” means subjects having an ATM-related disease or condition (e.g., cancer) or subjects having an increased risk of developing an ATM-related disease or condition (e.g., cancer) relative to the general population. In the case of cancer, subjects requiring it may have a precancerous condition. “Subjects” include warm-blooded animals. In some embodiments, warm-blooded animals are humans.

[0302]

[0222] In this context, the term “therapeutic dose” refers to the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof that is effective in providing “treatment” in a subject or in treating an ATM-related disease or disorder in a subject. In the case of cancer, a therapeutic dose may cause any of the observable or measurable changes in a subject as described above in the definitions of “treatment,” “treatment,” and “prevention.” For example, an effective dose may reduce the number of cancer or tumor cells; reduce the overall tumor size; inhibit or halt tumor cell infiltration into peripheral organs, including soft tissue and bone, for example; inhibit and halt tumor metastasis; inhibit and halt tumor growth; alleviate to some extent one or more of the symptoms associated with cancer; reduce morbidity and mortality; improve quality of life; or a combination of these effects. An effective dose may be sufficient to reduce the symptoms of a disease that responds to inhibition of ATM kinase activity. With regard to cancer treatment, in vivo efficacy can be measured, for example, by determining the duration of survival, time to disease progression (TTP) response rate (RR), duration of response, and / or quality of life. As will be recognized by those skilled in the art, the effective dose can vary depending on the route of administration, the use of excipients, and the use in combination with other agents. For example, when combination therapy is used, the amount of the compound of formula (I) described in this specification or a pharmaceutically acceptable salt, and the amount of other pharmaceutically active agents (one or more), when combined, are jointly effective in treating targeting disorders in animal patients. In this context, the combined dose is a “therapeutic effective dose” if, when combined, they are sufficient to reduce the symptoms of a disease responsive to inhibition of ATM activity as described above.

[0303]

[0223] Generally, a “therapeutic dose” can be determined by those skilled in the art by starting with, for example, the dosage ranges described in this specification for the compound of formula (I) or any pharmaceutically acceptable salt thereof, and the approved or otherwise published dosage ranges for other pharmaceutically active compounds(s)(s)(s).

[0304]

[0224] The methods for treating ATM-related diseases or conditions described herein may be used as monotherapy. As used herein, the term “monotherapy” means the administration of a single activity or therapeutic compound to a subject in need of it. In some embodiments, monotherapy involves the administration of a therapeutically effective amount of one of the compounds of this disclosure or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.

[0305]

[0225] Depending on the specific disease or condition to be treated, the methods for treating ATM-related diseases or conditions described in this specification may involve, in addition to the administration of the compound of formula (I), one or more additional treatments, such as conventional surgery, radiotherapy, chemotherapy, or a combination of such additional treatments. As used herein, the term “combination therapy” refers to the administration of a combination of multiple active compounds.

[0306]

[0226] Additional treatments, such as additional antitumor agents, may be administered separately from the compounds of this disclosure as part of a multi-dosage regimen. Alternatively, these additional treatments may be part of a single dosage form that is mixed with the compounds of this disclosure in a single composition.

[0307]

[0227] In some embodiments, the compounds of the present disclosure may be administered sequentially or separately, concurrently with, conventional surgical procedures, radiotherapy, or chemotherapy.

[0308]

[0228] Radiation therapy can include one or more of the following categories of treatment: (i) external radiation therapy using electromagnetic radiation, and intraoperative radiation therapy using electromagnetic radiation; (ii) internal radiation therapy or brachytherapy; including interstitial radiation therapy or intraluminal radiation therapy; or (iii) whole-body radiation therapy, including but not limited to iodine-131 and strontium-89.

[0309]

[0229] Chemotherapy may include antitumor agents known in the art, such as the antineoplastic agents, anti-angiogenic agents, immunotherapy approaches, and potency enhancers described in this specification.

[0310]

[0230] In one embodiment, a method is provided for treating an ATM-related disease or condition in a subject requiring treatment of an ATM-related disease or condition, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered concurrently with, separately from, or sequentially with radiotherapy.

[0311]

[0231] In some embodiments, the radiation therapy is cerebral radiation.

[0312]

[0232] In some embodiments, the ATM-related disease or condition is cancer. In some embodiments, the cancer is selected from glioblastoma, lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), breast cancer (e.g., triple-negative breast cancer), head and neck squamous cell carcinoma (e.g., lip carcinoma, oral carcinoma, oropharyngeal carcinoma, hypopharyngeal carcinoma, glottal laryngeal carcinoma, supraglottal laryngeal carcinoma, ethmoid sinus carcinoma, maxillary sinus carcinoma, or occult primary carcinoma), esophageal cancer, cervical cancer, and endometrial cancer. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is metastatic cancer. In some embodiments, the metastatic cancer is metastasis of the central nervous system. In some embodiments, the metastasis of the central nervous system is brain metastasis.

[0313]

[0233] In some embodiments, a method is provided for treating glioblastoma in subjects requiring treatment of glioblastoma, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered concurrently with, separately from, or sequentially with cerebral radiation.

[0314]

[0234] In another embodiment, a method is provided for treating an ATM-related disease or condition in a subject requiring treatment of an ATM-related disease or condition, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered separately or sequentially, concurrently with one or more additional antitumor agents.

[0315]

[0235] In some embodiments, the ATM-related disease or condition is cancer. In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the amount of one or more additional antitumor agents are effective together in producing an anticancer effect.

[0316]

[0236] In some embodiments, additional antitumor agents include antineoplastic agents, anti-angiogenic agents, immunotherapy approaches, and potency enhancers.

[0317]

[0237] In some embodiments, additional antitumor agents are selected from the group consisting of doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, and bleomycin.

[0318]

[0238] In some embodiments, the compounds of the present disclosure may be administered simultaneously with, sequentially with, or separately from, an antineoplastic agent.

[0319]

[0239] In a particular embodiment, the antineoplastic agent is a PARP inhibitor. In a particular embodiment, the PARP inhibitor is selected from the group consisting of olaparib, rucaparib, niraparib, talazoparib, pamiparib, and fluzoparib. [Examples]

[0320]

[0240] For illustrative purposes, the following examples are included. However, these examples should be understood to be intended only to suggest ways of practicing the present disclosure and not to limit the present invention. Those skilled in the art will recognize that the chemical reactions described can be readily adapted to prepare many other compounds of the present disclosure, and that alternative methods for preparing the compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, the synthesis of non-exemplary compounds according to the present disclosure can be successfully carried out by modifications obvious to those skilled in the art, for example, by appropriately protecting interfering groups, by using other suitable reagents known in the art other than those described, and / or by routine modifications of the reaction conditions. Alternatively, other reactions disclosed herein or known in the art are recognized to be applicable for preparing other compounds of the present disclosure.

[0321]

[0241] The following abbreviations are used in the examples:

[0322] [Table 2-1]

[0323] [Table 2-2]

[0324] Example 1 8-(6-((2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0325] [ka]

[0326] Step 1: 6-Bromosine Noline-4-Oll

[0327] [ka]

[0328]

[0242] 1-(2-amino-5-bromophenyl)ethenone (200 g, 935 mmol) was slowly dissolved in concentrated HCl (2 L) and water (440 mL) at a temperature below 10°C, and the mixture was stirred at 0°C for 1 hour. Next, a solution of NaNO2 (71.0 g, 1.03 mol) in water (360 mL) was added dropwise to the mixture at a temperature below 0°C, and the resulting reaction mixture was stirred at 0°C for a further 1 hour. The reaction mixture was then stirred at 65°C for 16 hours. After cooling to room temperature, the mixture was poured into ice water (1 L) and filtered. The filtered residue was dried in an oven at 55°C for 24 hours to obtain the desired product (174 g, 82.7% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 14.09 (s, 1H), 8.12 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H).LC-MS(ESI)m / z:225[M+H] + . Step 2: 6-Bromo-3-Nitrosinnoline-4-ol

[0329] [ka]

[0330]

[0243] 6-bromosinnolin-4-ol (50.0 g) was slowly dissolved in fuming HNO3 (200 mL) at 20°C to 35°C, and the reaction mixture was stirred at 28°C to 33°C for 5 hours. The mixture was poured into ice water (500 mL) and filtered. The filtered residue in EtOH (500 mL) was heated at 85°C for approximately 2 hours until the solution became clear. After cooling to 10°C, the mixture was filtered, and the filter cake was dried in an oven at 50°C for 16 hours to obtain the desired product (35.0 g, 58.3% yield) as a yellow solid. LC-MS(ESI) m / z: 270[M+H] + . Step 3: 6-Bromo-4-chloro-3-nitrosinnoline

[0331] [ka]

[0332]

[0244] To a solution of 6-bromo-3-nitrosinnolin-4-ol (100 g, 372 mmol) in dry DMF (1 L), POCl3 (51.0 mL, 558 mmol) was added dropwise under N2 at 0°C, and the reaction mixture was stirred at 10°C-15°C for 12 hours. The mixture was poured into ice water (1.5 L) and filtered. The filtered residue was tritulated in MTBE (500 mL) at room temperature for 1 hour and filtered. The filtered cake was dried in an oven at 40°C for 16 hours to obtain the desired product (90.0 g, 84.3% yield) as a yellow solid. LC-MS(ESI) m / z: 288[M+H] + . Step 4: 6-Bromo-N-isopropyl-3-nitrosinnoline-4-amine

[0333] [ka]

[0334]

[0245] A mixture of 6-bromo-4-chloro-3-nitrosinnoline (50.0 g, 174 mmol) and propan-2-amine (15.4 g, 261 mmol) in DCM (500 mL) was mixed with TEA (77.4 mL, 522 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into 1 L of 1 M HCl solution on ice and extracted with DCM (500 mL x 2). The combined organic layer was washed with brine (800 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the desired product (50.0 g, 79.8% yield) as a brown solid. LC-MS(ESI) m / z: 311[M+H] + . Step 5: 6-Bromo-N4-isopropylcinnoline-3,4-diamine

[0335] [ka]

[0336]

[0246] A solution of 6-bromo-N-isopropyl-3-nitrosinnoline-4-amine (75.0g, 242 mmol) in MeOH (400mL) is dissolved in SnCl2 . H2O (164 g, 726 mmol) was added at 0°C, and the reaction mixture was stirred at 60°C for 2 hours. The mixture was adjusted to pH approximately 8 with 50% NaOH solution at less than 45°C, and stirred at 55°C for 45 minutes. The mixture was filtered, and the filtered residue was tritulated in THF (300 mL) at room temperature for 1 hour. This was filtered, and the combined filtrate was evaporated under reduced pressure. The residue was tritulated in THF (300 mL) at room temperature for 1 hour and filtered again. By evaporating the filtrate under reduced pressure, the desired product (50.0 g, 73.8% yield) was obtained as a dark brown solid. LC-MS(ESI) m / z: 281[M+H] + . Step 6: 8-bromo-1-isopropyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one(8)

[0337] [ka]

[0338]

[0247] To a solution of 6-bromo-N4-isopropylsinnoline-3,4-diamine (49.0 g, 175 mmol) in dry THF (500 mL), CDI (85.0 g, 525 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was evaporated under reduced pressure, and the residue was dissolved in water (250 mL). The pH was adjusted to approximately 7 with 1 M HCl solution, and the mixture was filtered. The filtered residue was dried in an oven at 55°C for 16 hours to obtain the desired product (40.0 g, 74.6% yield). LC-MS(ESI) m / z: 307[M+H] + . Step 7: 8-Bromo-1-isopropyl-3-methyl-1H-imidazo[4,5-c]synnoline-2(3H)-one

[0339] [ka]

[0340]

[0248] To a solution of 8-bromo-1-isopropyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (40.0 g, 131 mmol) in dry DMF (300 mL), t-BuONa (15.0 g, 157 mmol) was added at 0°C and the mixture was stirred under N2 at 0°C for 30 minutes. MeI (37.2 g, 262 mmol) was added dropwise to the reaction mixture at 10°C-15°C and the reaction mixture was stirred at 10°C-15°C for 2 hours. The mixture was poured into ice water (600 mL) and filtered. The filtered residue was tritulated with MeOH (200 mL) for 1 hour and filtered. The filtered cake was dried under vacuum to obtain the desired product (20.0 g, 47.8% yield). 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 9.2 Hz, 1H), 8.28 (d, J = 1.4 Hz, 1H), 7.73 (dd, J = 9.2, 1.8 Hz, 1H), 5.21-5.02 (m, 1H), 3.75 (s, 3H), 1.77 (d, J = 6.9 Hz, 6H).LC-MS(ESI)m / z:321[M+H] + . Step 8: 5-Bromo-2-(chloromethyl)pyridine

[0341] [ka]

[0342]

[0249] To a solution of (5-bromopyridine-2-yl)methanol (5.00 g, 26.7 mmol) in DCM (50 mL), SOCl2 (3.87 mL, 53.4 mmol) was slowly added, and the resulting reaction mixture was stirred at room temperature for 2 hours. The mixture was evaporated under reduced pressure. The residue was dissolved in DCM (50 mL) and washed with saturated NaHCO3 solution (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (5.30 g) as a brown oil. LC-MS(ESI) m / z: 206[M+H] + . Step 9: 2-(3-azabicyclo[3.1.0]hexane-3-yl)ethanol

[0343] [ka]

[0344]

[0250] A mixture of 3-azabicyclo[3.1.0]hexane (900 mg, 10.8 mmol) and 2-bromoethanol (1.61 g, 13.0 mmol) in MeCN (20 mL) was mixed with K2CO3 (4.47 g, 32.4 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product (1.20 g) as a yellow oil. LC-MS(ESI) m / z: 128 [M+H] + . Step 10: 3-(2-((5-bromopyridine-2-yl)methoxy)ethyl)-3-azabicyclo[3.1.0]hexane

[0345] [ka]

[0346]

[0251] To a solution of 2-(3-azabicyclo[3.1.0]hexane-3-yl)ethanol (1.20 g, 9.45 mmol) in dry THF (15 mL), NaH (756 mg, 18.9 mmol) was slowly added at 0°C, and the reaction mixture was stirred at 0°C for 30 minutes. Next, a solution of 5-bromo-2-(chloromethyl)pyridine (1.94 g, 9.45 mmol) in THF (10 mL) was added dropwise to the mixture, and the resulting reaction mixture was slowly warmed to room temperature and stirred at 0°C for 2 hours. The mixture was poured into ice water (70 mL) and extracted with ELISA (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried on anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (DCM:MeOH = 100:1 to 20:1) to obtain the desired product (950 mg, 26.7% yield in two steps) as a brown oil. LC-MS(ESI) m / z: 297[M+H] + . Step 11: 8-(6-((2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0347] [ka]

[0348]

[0252] A mixture of 3-(2-((5-bromopyridine-2-yl)methoxy)ethyl)-3-azabicyclo[3.1.0]hexane (100 mg, 0.338 mmol), bis(pinacolate)diborone (112 mg, 0.439 mmol), AcOK (99.4 mg, 1.01 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (27.6 mg, 0.0338 mmol) in 1,4-dioxane (5 mL) was stirred at 100°C for 2 hours. After cooling to room temperature, water (1 mL), 8-bromo-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (108 mg, 0.338 mmol), K2CO3 (93.3 mg, 0.676 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (27.6 mg, 0.0338 mmol) were added to the reaction mixture, and the resulting reaction mixture was stirred at 100°C for 2 hours. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography (DCM:MeOH=9:1) to obtain the desired product (20.0 mg, 12.9% yield in two steps) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 2.3 Hz, 1H), 8.48-8.41 (m, 2H), 8.32 (dd, J = 8.2, 2.4 Hz, 1H), 8.10 (dd, J = 9.0, 1.8 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 5.38-5.25 (m, 1H), 4.65 (s, 2H), 3.65-3.57 (m, 5H), 2.99 (d, J = 8.6 Hz, 2H), 2.67 (t, J = 5.8 Hz, 2H), 2.37-2.31 (m, 2H), 1.67 (d, J = 6.6 Hz, 6H), 1.37-1.32 (m, 2H), 0.61-0.55 (m, 1H), 0.33-0.27 (m, 1H).LC-MS(ESI)m / z:459[M+H] + .

[0349]

[0253] The following compounds were prepared using different starting materials according to the method described above.

[0350] [Table 3-1]

[0351] [Table 3-2]

[0352] [Table 3-3]

[0353] [Table 3-4]

[0354] [Table 3-5]

[0355] Table 3-6

[0356] Example 2

[0254] 1 H NMR (600 MHz, DMSO-d6) δ 9.05 (d, J = 2.3 Hz, 1H), 8.47-8.41 (m, 2H), 8.33 (dd, J = 8.1, 2.4 Hz, 1H), 8.10 (dd, J = 9.0, 1.8 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 5.36-5.27 (m, 1H), 4.66 (s, 2H), 3.66 (t, J = 5.8 Hz, 2H), 3.60 (s, 3H), 2.53-2.52 (m, 2H), 2.20 (s, 6H), 1.67 (d, J = 6.7 Hz, 6H). Example 3

[0255] 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 2.4 Hz, 1H), 8.48-8.40 (m, 2H), 8.33 (dd, J = 8.1, 2.4 Hz, 1H), 8.10 (dd, J = 9.1, 1.7 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 5.38-5.26 (m, 1H), 4.66 (s, 2H), 3.67 (t, J = 5.9 Hz, 2H), 3.60 (s, 3H), 2.59 (t, J = 5.8 Hz, 2H), 2.48-2.37 (m, 4H), 1.67 (d, J = 6.7 Hz, 6H), 1.55-1.46 (m, 4H), 1.43-1.33 (m, 2H). Example 4

[0256] 11H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 2.3 Hz, 1H), 8.47-8.40 (m, 2H), 8.33 (dd, J = 8.1, 2.4 Hz, 1H), 8.10 (dd, J = 9.1, 1.7 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 5.36-5.26 (m, 1H), 4.66 (s, 2H), 3.67 (t, J = 5.9 Hz, 2H), 3.60 (s, 3H), 3.43-3.41 (m, 4H), 2.69 (t, J = 5.9 Hz, 2H), 1.73-1.61 (m, 10H). Example 5

[0257] 1 1H NMR (600 MHz, DMSO-d6) δ 9.05 (d, J = 2.4 Hz, 1H), 8.48-8.43 (m, 2H), 8.33 (dd, J = 8.1, 2.4 Hz, 1H), 8.11 (dd, J = 9.1, 1.8 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 5.35-5.27 (m, 1H), 4.73-4.60 (m, 3H), 3.67 (t, J = 5.8 Hz, 2H), 3.61 (s, 3H), 2.64-2.55 (m, 4H), 2.41-2.32 (m, 2H), 1.91-1.79 (m, 2H), 1.74-1.65 (m, 8H). Example 6

[0258] 1 1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 2.4 Hz, 1H), 8.45-8.35 (m, 2H), 8.30 (dd, J = 8.2, 2.4 Hz, 1H), 8.07 (dd, J = 9.0, 1.7 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 5.35-5.21 (m, 1H), 4.65 (s, 2H), 3.71-3.63 (m, 2H), 3.57 (s, 3H), 3.55-3.50 (m, 2H), 3.27 (s, 3H), 1.65 (d, J = 6.7 Hz, 6H). Example 7

[0259] 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 2.3 Hz, 1H), 8.50-8.41 (m, 2H), 8.32 (dd, J = 8.1, 2.4 Hz, 1H), 8.10 (dd, J = 9.1, 1.8 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 5.36-5.26 (m, 1H), 4.67 (s, 2H), 3.60 (s, 3H), 3.09-3.00 (m, 1H), 2.72-2.63 (m, 2H), 2.20 (s, 3H), 2.17-2.09 (m, 2H), 1.96-1.88 (m, 2H), 1.67 (d, J = 6.7 Hz, 6H), 1.63-1.53 ​​(m, 2H). Example 8

[0260] 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 2.4 Hz, 1H), 8.48-8.41 (m, 2H), 8.33 (dd, J = 8.2, 2.5 Hz, 1H), 8.11 (dd, J = 9.1, 1.8 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 5.37-5.27 (m, 1H), 4.63 (s, 2H), 3.60 (s, 3H), 3.58-3.56 (m, 2H), 2.32 (t, J = 7.3 Hz, 2H), 2.13 (s, 6H), 1.78-1.70 (m, 2H), 1.66 (d, J = 5.5 Hz, 6H). Example 9

[0261] 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 2.4 Hz, 1H), 8.45 (dd, J = 7.3, 5.4 Hz, 2H), 8.33 (dd, J = 8.1, 2.4 Hz, 1H), 8.11 (dd, J = 9.1, 1.8 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 5.37-5.26 (m, 1H), 4.64 (s, 2H), 3.60 (s, 3H), 2.87-2.79 (m, 2H), 2.21 (s, 3H), 2.03-1.92 (m, 2H), 1.75-1.55 (m, 10H), 1.34–1.13 (m, 3H). Example 10

[0262] 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 2.4 Hz, 1H), 8.46-8.38 (m, 2H), 8.31 (dd, J = 8.1, 2.4 Hz, 1H), 8.08 (dd, J = 9.1, 1.7 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 5.35-5.22 (m, 1H), 4.64 (s, 2H), 3.59-3.56 (m, 4H), 3.47-3.43 (m, 1H), 2.96-2.88 (m, 1H), 2.44-2.39 (m, 1H), 2.32 (s, 3H), 2.17-2.09 (m, 1H), 1.93-1.83 (m, 1H), 1.69-1.58 (m, 8H), 1.56-1.47 (m, 1H). Example 11

[0263] 11H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 2.4 Hz, 1H), 8.46 - 8.36 (m, 2H), 8.28 (dd, J = 8.1, 2.4 Hz, 1H), 8.06 (dd, J = 9.0, 1.7 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 5.33 - 5.23 (m, 1H), 4.56 (s, 2H), 4.24 - 4.15 (m, 1H), 3.57 (s, 3H), 2.72 - 2.66 (m, 1H), 2.64 - 2.55 (m, 2H), 2.44 - 2.35 (m, 1H), 2.26 (s, 3H), 2.13 - 2.02 (m, 1H), 1.84 - 1.73 (m, 1H), 1.64 (d, J = 6.7 Hz, 6H). Example 12

[0264] 1 1H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 2.3 Hz, 1H), 8.43-8.35 (m, 2H), 8.26 (dd, J = 8.1, 2.4 Hz, 1H), 8.05 (dd, J = 9.0, 1.7 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 5.33-5.20 (m, 1H), 4.57 (s, 2H), 3.55 (s, 3H), 3.50 (t, J = 7.8, 4.8 Hz, 2H), 2.88 (d, J = 8.5 Hz, 2H), 2.45-2.38 (m, 2H), 2.18 (d, J = 8.5 Hz, 2H), 1.74-1.54 (m, 8H), 1.33-1.24 (m, 2H), 0.51 (m, J = 3.8 Hz, 1H), 0.28-0.18 (m, 1H). Example 13

[0265] 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 2.4 Hz, 1H), 8.50-8.41 (m, 2H), 8.32 (dd, J = 8.2, 2.4 Hz, 1H), 8.11 (dd, J = 9.1, 1.8 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 5.40-5.25 (m, 1H), 4.70 (s, 2H), 3.60 (s, 3H), 3.58-3.52 (m, 1H), 3.00-2.91 (m, 1H), 2.61-2.55 (m, 1H), 2.22 (s, 3H), 2.04-1.88 (m, 3H), 1.74-1.58 (m, 7H), 1.50-1.39 (m, 1H), 1.29-1.18 (m, 1H). Example 14

[0266] 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 2.4 Hz, 1H), 8.46-8.38 (m, 2H), 8.29 (dd, J = 8.2, 2.4 Hz, 1H), 8.07 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 5.34-5.22 (m, 1H), 4.52 (s, 2H), 3.86-3.77 (m, 1H), 3.58 (s, 3H), 2.44-2.33 (m, 2H), 2.23-2.14 (m, 1H), 2.00 (s, 6H), 1.74-1.58 (m, 8H). Example 15

[0267] 11H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 2.3 Hz, 1H), 8.44 - 8.35 (m, 2H), 8.27 (dd, J = 8.3, 2.4 Hz, 1H), 8.05 (dd, J = 9.1, 1.7 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 5.34 - 5.20 (m, 1H), 4.52 (s, 2H), 4.21 - 4.11 (m, 1H), 3.56 (s, 3H), 3.28 - 3.24 (m, 2H), 2.84 - 2.76 (m, 2H), 2.20 (s, 3H), 1.63 (d, J = 6.7 Hz, 6H). Example 16

[0268] 1 1H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 2.3 Hz, 1H), 8.45 - 8.34 (m, 2H), 8.28 (dd, J = 8.2, 2.3 Hz, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 5.32 - 5.20 (m, 1H), 4.57 (s, 2H), 3.55 (s, 3H), 3.44 - 3.41 (m, 2H), 2.95 - 2.82 (m, 2H), 2.71 - 2.57 (m, 1H), 2.45 - 2.38 (m, 2H), 1.63 (d, J = 6.7 Hz, 6H), 1.35 - 1.25 (m, 2H), 1.01 (d, J = 6.5 Hz, 3H), 0.55 - 0.47 (m, 1H), 0.29 - 0.19 (m, 1H). Example 17

[0269] 11H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 2.3 Hz, 1H), 8.46-8.38 (m, 2H), 8.32 (dd, J = 8.1, 2.4 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 5.35-5.23 (m, 1H), 4.63 (s, 2H), 3.58 (s, 3H), 3.49-3.42 (m, 2H), 2.79 (d, J = 8.2 Hz, 2H), 2.65 (d, J = 8.1 Hz, 2H), 1.65 (d, J = 6.7 Hz, 6H), 1.35-1.24 (m, 2H), 1.01 (s, 6H), 0.53-0.46 (m, 1H), 0.29-0.19 (m, 1H). Example 18

[0270] 1 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.49-8.39 (m, 2H), 8.34 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 5.38-5.24 (m, 1H), 4.63 (s, 2H), 3.64-3.54 (m, 5H), 2.94 (d, J = 7.9 Hz, 2H), 2.77 (d, J = 8.2 Hz, 2H), 1.66 (d, J = 6.4 Hz, 6H), 1.33-1.18 (m, 4H), 0.58-0.48 (m, 2H), 0.44-0.38 (m, 1H), 0.32-0.21 (m, 1H). Example 19

[0271] 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.47-8.37 (m, 2H), 8.31 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 5.36-5.20 (m, 1H), 4.60 (s, 2H), 3.58 (s, 3H), 2.82-2.72 (m, 1H), 2.65-2.55 (m, 1H), 2.12 (s, 3H), 1.96-1.76 (m, 3H), 1.73-1.53 ​​(m, 8H), 1.52-1.35 (m, 2H), 1.02-0.85 (m, 2H). Example 20

[0272] 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (dd, J = 2.5, 0.8 Hz, 1H), 8.48-8.40 (m, 2H), 8.32 (dd, J = 8.2, 2.4 Hz, 1H), 8.10 (dd, J = 9.1, 1.7 Hz, 1H), 5.38-5.24 (m, 1H), 4.64 (s, 2H), 3.60 (s, 3H), 3.47-3.44 (m, 2H), 2.59-2.53 (m, 1H), 2.48-2.38 (m, 2H), 2.35-2.28 (m, 1H), 2.24 (s, 3H), 1.93-1.83 (m, 1H), 1.73-1.60 (m, 7H), 1.48-1.37 (m, 1H). Example 21

[0273] 11H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.46 - 8.35 (m, 2H), 8.27 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 5.34 - 5.22 (m, 1H), 4.66 (q, J = 13.8 Hz, 2H), 3.69 - 3.61 (m, 1H), 3.57 (s, 3H), 3.01 - 2.87 (m, 2H), 2.63 - 2.51 (m, 1H), 2.44 - 2.37 (m, 1H), 2.36 - 2.21 (m, 2H), 1.64 (d, J = 6.7 Hz, 6H), 1.34 - 1.24 (m, 2H), 1.12 (d, J = 6.1 Hz, 3H), 0.59 - 0.52 (m, 1H), 0.34 - 0.19 (m, IH). Example 22

[0274] 1 1H NMR (400 MHz, DMSO) δ 9.01 (d, J = 2.4 Hz, 1H), 8.48 - 8.37 (m, 2H), 8.30 (dd, J = 8.2, 2.5 Hz, 1H), 8.08 (dd, J = 9.0, 1.7 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 5.38 - 5.24 (m, 1H), 4.58 (s, 2H), 3.59 (s, 3H), 3.06 (d, J = 8.6 Hz, 2H), 2.53 (s, 2H), 2.43 (d, J = 8.7 Hz, 2H), 1.67 (d, J = 6.7 Hz, 6H), 1.38 - 1.25 (m, 2H), 1.19 (s, 6H), 0.62 - (m, 1H), 0.34 - 0.23 (m, 1H). Example 23

[0275] 11H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.42 - 8.34 (m, 2H), 8.23 (dd, J = 8.1, 2.3 Hz, 1H), 8.04 (d, J = 9.1 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 5.32 - 5.17 (m, 1H), 4.67 (s, 2H), 3.56 (s, 3H), 3.03 (d, J = 8.6 Hz, 2H), 2.63 (s, 2H), 2.37 - 2.25 (m, 2H), 1.63 (d, J = 6.7 Hz, 6H), 1.35 - 1.24 (m, 2H), 0.85 - 0.75 (m, 2H), 0.56 - 0.44 (m, 3H), 0.30 - 0.21 (m, 1H). Example 24

[0276] 1 ​​​​​​H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 2.1 Hz, 1H), 8.49-8.40 (m, 2H), 8.32 (dd, J = 8.1, 2.3 Hz, 1H), 8.09 (dd, J = 9.1, 1.5 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 5.36-5.26 (m, 1H), 4.67 (s, 2H), 3.68 (t, J = 5.6 Hz, 2H), 3.60 (s, 3H), 3.30-3.20 (m, 1H), 2.85-2.66 (m, 5H), 2.56-2.52 (m, 1H), 2.25-2.12 (m, 1H), 1.99-1.88 (m, 1H), 1.67 (d, J = 6.7 Hz, 6H). Example 26 8-(6-((2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0357] [ka]

[0358] Step 1: 2-((5-bromopyridine-2-yl)methoxy)acetic acid

[0359] [ka]

[0360]

[0278] To a solution of (5-bromopyridine-2-yl)methanol (5.00 g, 27.0 mmol) in dry DMF (50 mL), NaH was slowly added at 0°C, and the reaction mixture was stirred at 0°C for 30 minutes. Methyl 2-bromoacetate (3.60 mL, 35.0 mmol) was then added dropwise to the mixture, and the resulting reaction mixture was slowly warmed to room temperature and stirred at room temperature for 3 hours. The mixture was poured into a 1 M NaOH solution (70 mL) on ice and stirred at room temperature for 1 hour. The mixture was extracted with Depositphotos (10 mL × 2), and the aqueous layer was adjusted to pH approximately 4 with a 1 M HCl solution. This was extracted with Depositphotos (100 mL × 3), the organic layer was washed with a 5% LiCl solution (20 mL) and brine (20 mL), dried on anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product, which was triturated in MTBE (50 mL) at room temperature for 20 minutes and filtered. The filtered cake was dried under vacuum for 3 hours to obtain the desired product (4.30 g, 65% yield) as a white solid. Step 2: 2-((5-bromopyridine-2-yl)methoxy)-1-(5-azaspiro[2.4]heptan-5-yl)ethane-1-one

[0361] [ka]

[0362]

[0279] A mixture of 2-((5-bromopyridine-2-yl)methoxy)acetic acid (500 mg, 2.04 mmol) and 5-azaspiro[2.4]heptane hydrochloride (271 mg, 2.04 mmol) in DCM (10 mL) was mixed with 50% T3P in siRNA (2.60 g, 4.08 mmol), followed by DIEA (1.0 mL, 6.12 mol) at 0°C. After stirring at room temperature for 16 hours, the mixture was poured into ice-saturated NaHCO3 solution (20 mL) and extracted with DCM (20 mL × 2). The organic layer was washed with saturated NH4Cl solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product (600 mg) as a brown oil. LC-MS (ESI) m / z: 325 [M + H] + . Step 3: 5-(2-((5-bromopyridine-2-yl)methoxy)ethyl)-5-azaspiro[2.4]heptane

[0363] [ka]

[0364]

[0280] A solution of 2-((5-bromopyridine-2-yl)methoxy)-1-(5-azaspiro[2.4]heptan-5-yl)ethane-1-one (600 mg, 1.85 mmol) in dry THF, with 1 M BH3 . THF solution (9.25 mL, 9.25 mmol) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with MeOH (10 mL) and evaporated under reduced pressure. The residue was dissolved in EtOH (20 mL) and stirred at 90°C for 3 hours. The mixture was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel (DCM:MeOH = 100:1 to 10:1) to obtain the desired product (329 mg, 52.0% yield in two steps) as a light brown oil. LC-MS(ESI) m / z: 311[M+H] + . Step 4: 8-(6-((2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0365] [ka]

[0366]

[0281] The crude product was prepared in the same manner as in Example 1 and purified by flash chromatography (DCM:MeOH=9:1) to obtain the desired product (50.0 mg, 21.9% yield in two steps) as a light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 2.0 Hz, 1H), 8.49-8.41 (m, 2H), 8.33 (dd, J = 8.1, 2.3 Hz, 1H), 8.11 (dd, J = 9.1, 1.5 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 5.37-5.27 (m, 1H), 4.67 (s, 2H), 3.67 (t, J = 5.9 Hz, 2H), 3.60 (s, 3H), 2.77-2.67 (m, 4H), 2.53 (s, 2H), 1.73 (t, J = 6.9 Hz, 2H), 1.67 (d, J = 6.7 Hz, 6H), 0.56-0.45 (m, 4H).LC-MS(ESI)m / z:473[M+H] + .

[0367]

[0282] The following compounds were prepared using different starting materials according to the method described above.

[0368] [Table 4-1]

[0369] [Table 4-2]

[0370] Table 4-3

[0371] Table 4-4

[0372] Table 4-5

[0373] Table 4-6

[0374] Example 27

[0283] 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.48-8.39 (m, 2H), 8.32 (d, J = 8.1 Hz, 1H), 8.09 (d, J = 9.1 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 5.36-5.26 (m, 1H), 4.65 (s, 2H), 3.90-3.80 (m, 1H), 3.66 (t, J = 5.5 Hz, 2H), 3.60 (s, 3H), 3.16 (s, 3H), 2.77-2.52 (m, 6H), 2.01-1.90 (m, 1H), 1.73-1.59 (m, 7H). Example 28

[0284] 11H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 2.3 Hz, 1H), 8.47-8.39 (m, 2H), 8.32 (dd, J = 8.2, 2.4 Hz, 1H), 8.09 (dd, J = 9.1, 1.8 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 5.37-5.29 (m, 1H), 5.28-5.07 (m, 1H), 4.66 (s, 2H), 3.67 (t, J = 5.8 Hz, 2H), 3.59 (s, 3H), 2.94-2.81 (m, 2H), 2.75-2.57 (m, 3H), 2.40-2.30 (m, 1H), 2.19-2.01 (m, 1H), 1.94-1.75 (m, 1H), 1.66 (d, J = 6.8 Hz, 6H). Example 29

[0285] 1 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 2.2 Hz, 1H), 8.47-8.38 (m, 2H), 8.31 (dd, J = 8.1, 2.3 Hz, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 5.35-5.24 (m, 1H), 4.65 (s, 2H), 3.65 (t, J = 6.0 Hz, 2H), 3.59 (s, 3H), 3.13-3.06 (m, 1H), 3.04-2.95 (m, 1H), 2.36-2.26 (m, 2H), 2.19-2.09 (m, 1H), 1.89-1.79 (m, 1H), 1.73-1.57 (m, 8H), 1.33-1.19 (m, 1H), 1.02 (d, J = 6.0 Hz, 3H). Example 30

[0286] 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.48-8.38 (m, 2H), 8.31 (d, J = 7.6 Hz, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 5.35-5.23 (m, 1H), 4.65 (s, 2H), 3.73-3.62 (m, 2H), 3.58 (s, 3H), 2.69-2.61 (m, 2H), 2.61-2.52 (m, 4H), 2.01-1.85 (m, 4H), 1.65 (d, J = 6.3 Hz, 6H). Example 31

[0287] 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 2.0 Hz, 1H), 8.46-8.38 (m, 2H), 8.31 (dd, J = 8.1, 2.3 Hz, 1H), 8.08 (dd, J = 9.1, 1.6 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 5.38-5.25 (m, 1H), 4.65 (s, 2H), 3.66 (t, J = 5.9 Hz, 2H), 3.59 (s, 3H), 2.57 (t, J = 5.9 Hz, 2H), 2.46-2.34 (m, 4H), 1.67 (d, J = 6.8 Hz, 6H), 1.35-1.27 (m, 4H), 0.88 (s, 6H). Example 32

[0288] 1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 2.1 Hz, 1H), 8.48-8.40 (m, 2H), 8.32 (dd, J = 8.1, 2.4 Hz, 1H), 8.09 (dd, J = 9.1, 1.6 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 5.37-5.23 (m, 1H), 4.65 (s, 2H), 3.66 (t, J = 5.8 Hz, 2H), 3.59 (s, 3H), 2.56 (t, J = 5.8 Hz, 2H), 2.48-2.18 (m, 8H), 2.14 (s, 3H), 1.67 (d, J = 6.8 Hz, 6H). Example 33

[0289] 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 2.3 Hz, 1H), 8.47-8.39 (m, 2H), 8.32 (dd, J = 8.1, 2.4 Hz, 1H), 8.09 (dd, J = 9.1, 1.7 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 5.37-5.26 (m, 1H), 4.66 (s, 2H), 3.69 (t, J = 5.7 Hz, 2H), 3.62-3.51 (m, 7H), 2.58 (t, J = 5.8 Hz, 2H), 2.47-2.39 (m, 4H), 1.67 (d, J = 6.7 Hz, 6H). Example 34

[0290] 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.48-8.38 (m, 2H), 8.31 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 5.36-5.19 (m, 1H), 5.25-5.05 (m, 1H), 4.65 (s, 2H), 3.66 (t, J = 5.9 Hz, 2H), 3.58 (s, 3H), 2.94-2.80 (m, 2H), 2.70 (t, J = 5.9 Hz, 2H), 2.64-2.53 (m, 1H), 2.40-2.31 (m, 1H), 2.18-2.03 (m, 1H), 1.92-1.76 (m, 1H), 1.65 (d, J = 6.7 Hz, 6H). Example 35

[0291] 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.48-8.40 (m, 2H), 8.32 (d, J = 7.9 Hz, 1H), 8.09 (d, J = 8.9 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 5.36-5.26 (m, 1H), 4.66 (s, 2H), 3.67 (t, J = 5.5 Hz, 2H), 3.59 (s, 3H), 3.17-2.99 (m, 1H), 2.65-2.53 (m, 1H), 2.42-2.14 (m, 2H), 1.93-1.82 (m, 1H), 1.71-1.57 (m, 9H), 1.33-1.20 (m, 1H), 1.05 (d, J = 5.6 Hz, 3H). Example 36

[0292] 11H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.45 - 8.37 (m, 2H), 8.29 (d, J = 8.2 Hz, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 5.35 - 5.23 (m, 1H), 4.64 (s, 2H), 3.62 (t, J = 5.9 Hz, 2H), 3.58 (s, 3H), 2.67 - 2.56 (m, 4H), 2.31 (s, 2H), 1.65 (d, J = 6.7 Hz, 6H), 1.48 (t, J = 7.0 Hz, 2H), 1.02 (s, 6H). Example 37

[0293] 1 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 2.3 Hz, 1H), 8.47 - 8.40 (m, 2H), 8.32 (dd, J = 8.2, 2.3 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 5.36 - 5.24 (m, 1H), 4.62 (s, 2H), 3.59 (s, 3H), 3.52 (t, J = 5.7 Hz, 2H), 3.46 - 3.42 (m, 2H), 2.83 - 2.71 (m, 3H), 2.62 (t, J = 5.7 Hz, 2H), 1.98 (s, 5H), 1.66 (d, J = 6.9, 1.8 Hz, 6H). Example 38

[0294] 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.46-8.38 (m, 2H), 8.30 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 9.3 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 5.36-5.23 (m, 1H), 4.70-4.49 (m, 3H), 3.66 (t, J = 5.6 Hz, 2H), 3.59 (s, 3H), 2.86-2.73 (m, 1H), 2.61 (t, J = 5.6 Hz, 2H), 2.45-2.36 (m, 1H), 2.34-2.24 (m, 1H), 1.89-1.69 (m, 2H), 1.66 (d, J = 6.7 Hz, 6H), 1.54-1.34 (m, 3H). Example 39

[0295] 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.46-8.39 (m, 2H), 8.31 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 5.36-5.25 (m, 1H), 4.64 (s, 2H), 3.64-3.52 (m, 5H), 3.22-3.17 (m, 1H), 2.80-2.59 (m, 3H), 2.28-2.22 (m, 1H), 2.17-2.12 (m, 1H), 1.70-1.61 (m, 7H), 1.55-1.42 (m, 2H), 1.40-1.29 (m, 1H), 1.24-1.14 (m, 2H). Example 40

[0296] 11H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 2.2 Hz, 1H), 8.45 - 8.38 (m, 2H), 8.30 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 5.35 - 5.23 (m, 1H), 4.66 (s, 2H), 3.66 (t, J = 5.9 Hz, 2H), 3.59 (s, 3H), 2.53 (t, J = 5.8 Hz, 2H), 2.38 - 2.20 (m, 4H), 1.85 - 1.76 (m, 2H), 1.74 - 1.58 (m, 10H), 1.44 - 1.32 (m, 4H). Example 41

[0297] 1 1H NMR (以400MHz測定,溶媒為DMSO-d6) δ 9.02 (s, 1H), 8.46 - 8.37 (m, 2H), 8.30 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 5.36 - 5.23 (m, 1H), 4.64 (s, 2H), 3.65 (t, J = 5.7 Hz, 2H), 3.58 (s, 3H), 3.22 (s, 3H), 3.20 - 3.12 (m, 1H), 3.00 - 2.93 (m, 1H), 2.71 - 2.64 (m, 1H), 2.58 (t, J = 5.7 Hz, 2H), 2.03 - 1.94 (m, 1H), 1.92 - 1.84 (m, 2H), 1.65 (d, J = 6.7 Hz, 6H), 1.62 - 1.57 (m, 1H), 1.45 - 1.31 (m, 1H), 1.11 - 1.00 (m, 1H). Example 42

[0298] 11H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.50 - 8.40 (m, 2H), 8.33 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 5.38 - 5.27 (m, 1H), 4.66 (s, 2H), 3.65 (t, J = 5.8 Hz, 2H), 3.61 (s, 3H), 2.78 - 2.56 (m, 6H), 2.34 - 2.26 (m, 1H), 2.08 (s, 6H), 1.88 - 1.76 (m, 1H), 1.67 (d, J = 6.6 Hz, 6H), 1.61 - 1.52 (m, 1H). Example 43

[0299] 1 1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 2.1 Hz, 1H), 8.48 - 8.40 (m, 2H), 8.32 (dd, J = 8.1, 2.4 Hz, 1H), 8.09 (dd, J = 9.1, 1.6 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 5.37 - 5.25 (m, 1H), 4.66 (s, 2H), 3.90 - 3.81 (m, 1H), 3.66 (t, J = 5.9 Hz, 2H), 3.60 (s, 3H), 3.17 (s, 3H), 2.79 - 2.53 (m, 5H), 2.49 - 2.41 (m, 1H), 2.01 - 1.91 (m, 1H), 1.66 (d, J = 7.1 Hz, 6H), 1.64 - 1.59 (m, 1H). Example 44

[0300] 11H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.38 (d, J = 10.9 Hz, 2H), 8.27 (s, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.59 (s, 1H), 5.33 - 5.21 (m, 1H), 4.62 (s, 2H), 3.70 - 3.48 (m, 5H), 3.22 - 3.04 (m, 4H), 2.79 - 2.62 (m, 2H), 2.58 - 2.50 (m, 2H), 2.18 - 2.00 (m, 2H), 1.86 - 1.72 (m, 2H), 1.64 (d, J = 3.9 Hz, 6H), 1.43 - 1.30 (m, 2H). Example 45

[0301] 1 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.47 - 8.40 (m, 2H), 8.32 (d, J = 7.7 Hz, 1H), 8.09 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 5.35 - 5.26 (m, 1H), 4.65 (s, 2H), 3.65 - 3.56 (m, 4H), 3.46 - 3.39 (m, 1H), 2.77 (t, J = 6.2 Hz, 2H), 2.70 - 2.61 (m, 2H), 1.84 - 1.73 (m, 2H), 1.66 (d, J = 6.6 Hz, 6H), 1.30 - 1.20 (m, 2H), 1.03 (d, J = 6.0 Hz, 6H). Example 46

[0302] 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.47-8.39 (m, 2H), 8.33-8.28 (m, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 5.36-5.25 (m, 1H), 4.64 (s, 2H), 3.64 (t, J = 5.8 Hz, 2H), 3.59 (s, 3H), 2.75-2.54 (m, 5H), 2.46-2.39 (m, 1H), 2.33-2.26 (m, 1H), 2.07 (s, 6H), 1.84-1.75 (m, 1H), 1.66 (d, J = 6.7 Hz, 6H), 1.60-1.50 (m, 1H). Example 47

[0303] 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 2.0 Hz, 1H), 8.48-8.40 (m, 2H), 8.32 (dd, J = 8.1, 2.3 Hz, 1H), 8.10 (dd, J = 9.1, 1.4 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 5.37-5.26 (m, 1H), 4.66 (s, 2H), 4.47-4.36 (m, 1H), 3.67 (t, J = 5.7 Hz, 2H), 3.60 (s, 3H), 2.77-2.69 (m, 2H), 2.59 (t, J = 5.7 Hz, 2H), 2.32 (t, J = 9.4 Hz, 2H), 1.96-1.87 (m, 2H), 1.76-1.63 (m, 8H). Example 48

[0304] 11H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.46-8.38 (m, 2H), 8.30 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 5.35-5.23 (m, 1H), 4.64 (s, 2H), 3.70-3.52 (m, 5H), 3.08-2.99 (m, 2H), 2.88-2.79 (m, 2H), 2.68 (t, J = 5.8 Hz, 2H), 2.35-2.22 (m, 2H), 1.66 (d, J = 6.7 Hz, 6H). Example 49

[0305] 1 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.56 (d, J = 9.0 Hz, 1H), 8.47 (s, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.87 (d, J = 8.9 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 5.72-5.45 (m, 2H), 5.30-5.17 (m, 1H), 4.75 (s, 2H), 4.08-3.95 (m, 2H), 3.78 (s, 3H), 3.22-3.12 (m, 2H), 3.12-2.91 (m, 2H), 1.96-1.86 (m, 6H), 1.85-1.76 (m, 10H). Example 50

[0306] 1H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 1.9 Hz, 1H), 8.50-8.41 (m, 2H), 8.36-8.30 (m, 1H), 8.11 (dd, J = 9.1, 1.7 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 6.68 (t, J = 76.0 Hz, 1H), 5.36-5.27 (m, 1H), 4.73-4.62 (m, 3H), 3.67 (t, J = 5.8 Hz, 2H), 3.61 (s, 3H), 2.80-2.65 (m, 5H), 2.48-2.40 (m, 1H), 2.22-2.09 (m, 1H), 1.81-1.72 (m, 1H), 1.67 (d, J = 6.8 Hz, 6H). Example 51

[0307] 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 2.0 Hz, 1H), 8.49 - 8.42 (m, 2H), 8.36 - 8.31 (m, 1H), 8.11 (dd, J = 9.1, 1.7 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 6.67 (t, J = 76.0 Hz, 1H), 5.38 - 5.26 (m, 1H), 4.72 - 4.63 (m, 3H), 3.67 (t, J = 5.8 Hz, 2H), 3.61 (s, 3H), 2.78 - 2.66 (m, 5H), 2.47 - 2.40 (m, 1H), 2.20 - 2.10 (m, 1H), 1.81 - 1.73 (m, 1H), 1.67 (d, J = 6.8 Hz, 6H). Example 52

[0308] 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.56 (d, J = 8.9 Hz, 1H), 8.44 (s, 1H), 8.07 (d, J = 7.3 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 8.1 Hz, 1H), 5.14 - 5.01 (m, 1H), 4.85 - 4.70 (m, 4H), 4.30 - 4.18 (m, 2H), 3.83 - 3.69 (m, 5H), 3.61 (t, J = 11.8 Hz, 2H), 3.01 - 2.92 (m, 1H), 2.90 - 2.73 (m, 6H), 2.68 - 2.56 (m, 1H), 2.32 - 2.21 (m, 1H), 2.10 - 1.99 (m, 2H). Example 53 (R)-8-(6-(1-(2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0375] [ka]

[0376] Step 1: 5-Bromopicolinoyl Chloride

[0377] [ka]

[0378]

[0309] To a solution of 5-bromopicolinic acid (80.0 g, 398 mmol) in DCM (600 mL), SOCl2 (144 mL, 1.99 mol) was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. The mixture was evaporated under reduced pressure to obtain a crude product (82.0 g) as a white solid, which was used for the next step without further purification. Step 2: 5-Bromo-N-methoxy-N-methylpicoramide

[0379] [ka]

[0380]

[0310] To a solution of N,O-dimethylhydroxylamine hydrochloride (46.6 g, 478 mmol) in DCM (800 mL), TEA (283 mL, 1.91 mol), followed by 5-bromopicolinoyl chloride (82.0 g), was added gradually at 0°C. After stirring at room temperature for 3 hours, the mixture was poured into ice-saturated NaHCO3 solution (800 mL) and extracted with DCM (400 mL x 2). The combined organic layer was washed with 1 M HCl solution (800 mL x 2) and brine (800 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (67.0 g) as a brown oil, which was used for the next step without further purification. LC-MS (ESI) m / z: 245 [M + H] + . Step 3: 5-Bromo-N-methoxy-N-methylpicorinamide

[0381] [ka]

[0382]

[0311] To a solution of 5-bromo-N-methoxy-N-methylpicolinamide (67.0 g, 275 mmol) in dry THF (550 mL), MeMgBr (3 M in THF) (137 mL, 413 mmol) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into ice-saturated NH4Cl solution (800 mL) and extracted with siRNA (400 mL x 2). The combined organic layer was washed with brine (800 mL), dried on anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product, which was tritulated with MeOH (200 mL) at room temperature for 1 hour and filtered. The filtered cake was dried under vacuum for 3 hours to obtain the desired product (41.5 g, 52.4% yield in three steps) as an off-white solid. LC-MS(ESI) m / z:200[M+H] + . Step 4: (R)-1-(5-bromopyridine-2-yl)ethanol

[0383] [ka]

[0384]

[0312] A solution of (S)-2-methyl-CBS-oxazaboloridine (42.8g, 155 mmol) in dry THF (400mL) is mixed with 1M BH3 .A THF solution (309 mL, 309 mmol) was added dropwise at 0°C for approximately 1 hour, and the reaction mixture was stirred at 0°C for 1 hour. Next, a solution of 5-bromo-N-methoxy-N-methylpicolinamide (41.5 g, 206 mmol) in dry THF (400 mL) was added dropwise at -40°C for approximately 1.5 hours, and the resulting mixture was stirred at -40°C for 1 hour. The mixture was poured into a 1 M HCl solution (800 mL) and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, the solid precipitated, and the mixture was filtered. The residue was adjusted to pH approximately 8 with a 1 M NaOH solution and extracted with MTBE (400 mL × 2). The organic layer was washed with brine (500 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was evaporated under reduced pressure to obtain the desired product (32.0 g, 99.60% ee, 77.3% yield) as a pale yellow oil. LC-MS(ESI)m / z:202[M+H] + . Step 5: (R)-2-(1-(5-bromopyridine-2-yl)ethoxy)acetic acid

[0385] [ka]

[0386]

[0313] To a solution of (R)-1-(5-bromopyridine-2-yl)ethanol (32.0 g, 159 mmol) in dry DMF (500 mL), NaH was slowly added at 0°C, and the reaction mixture was stirred at 0°C for 30 minutes. Next, methyl 2-bromoacetate (21 mL, 207 mmol) was added dropwise to the mixture, and the resulting reaction mixture was slowly warmed to room temperature and stirred at room temperature for 3 hours. The mixture was poured into a 1 M NaOH solution (420 mL) on ice and stirred at room temperature for 1 hour. The mixture was extracted with ELISA (200 mL x 2), and the aqueous layer was adjusted to pH approximately 4 with a 1 M HCl solution. The mixture was extracted with RINKAN (200 mL x 3), the organic layer was washed with 5% LiCl solution (200 mL) and brine (200 mL), dried on anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. This was triturated with MTBE (100 mL) at room temperature for 20 minutes and filtered. The filtered cake was dried under vacuum for 3 hours to obtain the desired product (26 g, 63.1% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.71-8.54 (m, 1H), 8.08 (dd, J = 8.4, 2.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 4.60 (q, J = 6.5 Hz, 1H), 3.99 (q, J = 37.5, 16.6 Hz, 2H), 1.40 (d, J = 6.5 Hz, 3H).LC-MS(ESI)m / z:611.0[M+H] + . Step 6: (R)-2-(1-(5-bromopyridine-2-yl)ethoxy)-1-(5-azaspiro[2.4]heptan-5-yl)ethenone

[0387] [ka]

[0388]

[0314] A mixture of (R)-2-(1-(5-bromopyridine-2-yl)ethoxy)acetic acid (19.4 g, 74.9 mmol) and 5-azaspiro[2.4]heptane hydrochloride (10.0 g, 74.9 mmol) in DCM (250 mL) was mixed with 50% T3P in siRNA (95.4 g, 150 mmol), followed by DIEA (49.4 mL, 300 mmol) at 0°C. After stirring at room temperature for 16 hours, the mixture was poured into ice-saturated NaHCO3 solution (500 mL) and extracted with DCM (150 mL x 2). The organic layer was washed with saturated NH4Cl solution (200 mL) and brine (200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (28.0 g) as a brown oil, which was used for the next step without further purification. LC-MS(ESI)m / z:339[M+H] + . Step 7: (R)-5-(2-(1-(5-bromopyridine-2-yl)ethoxy)ethyl)-5-azaspiro[2.4]heptane

[0389] [ka]

[0390]

[0315] A solution of (R)-2-(1-(5-bromopyridine-2-yl)ethoxy)-1-(5-azaspiro[2.4]heptan-5-yl)ethanone (28.0 g, 82.8 mmol) in dry THF, with 1 M BH3 . A THF solution (414 mL, 414 mmol) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with MeOH (500 mL) and evaporated under reduced pressure. The residue was dissolved in EtOH (300 mL) and stirred at 90°C for 3 hours. The mixture was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel (DCM:MeOH = 100:1 to 10:1) to obtain the desired product (12.0 g, 49.0% yield in two steps) as a light brown oil. LC-MS(ESI) m / z: 325[M+H] + . Step 8: (R)-8-(6-(1-(2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0391] [ka]

[0392]

[0316] The crude product was prepared in the same manner as in Example 1 and purified by chromatography on silica gel (DCM:MeOH = 100:1 to 10:1) to obtain the desired product (3.50 g, 23.3% yield in two steps) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.55 (d, J = 9.0 Hz, 1H), 8.28 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 9.1 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 5.30-5.13 (m, 1H), 4.79-4.64 (m, 1H), 4.02-3.87 (m, 2H), 3.77 (s, 3H), 3.57-3.12 (m, 6H), 2.15-1.93 (m, 2H), 1.79 (d, J = 6.9 Hz, 6H), 1.57 (d, J = 6.4 Hz, 3H), 0.82-0.62 (m, 4H).LC-MS(ESI)m / z:487[M+H] + .

[0393]

[0317] The following compounds were prepared using different starting materials according to the method described above.

[0394] [Table 5-1]

[0395] [Table 5-2]

[0396] Table 5-3

[0397] Table 5-4

[0398] Table 5-5

[0399] Example 54

[0318] 1 H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 1.9 Hz, 1H), 8.56 (d, J = 9.0 Hz, 1H), 8.28 (s, 2H), 8.05 (dd, J = 8.1, 2.3 Hz, 1H), 7.88 (dd, J = 9.0, 1.7 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 6.24 (t, J = 73.6 Hz, 1H), 5.27-5.17 (m, 1H), 4.92-4.85 (m, 1H), 4.68 (q, J = 6.5 Hz, 1H), 3.80-3.69 (m, 5H), 3.48-3.40 (m, 1H), 3.21-2.99 (m, 5H), 2.39-2.28 (m, 1H), 1.79 (d, J = 7.0 Hz, 6H), 1.57 (d, J = 6.5 Hz, 3H), 0.90-0.79 (m, 1H). Example 55

[0319] 11H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 1.9 Hz, 1H), 8.51 - 8.42 (m, 2H), 8.33 (dd, J = 8.2, 2.4 Hz, 1H), 8.10 (dd, J = 9.1, 1.6 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 5.40 - 5.28 (m, 1H), 4.62 (q, J = 6.5 Hz, 1H), 3.62 - 3.57 (m, 4H), 3.54 - 3.44 (m, 1H), 2.70 - 2.58 (m, 2H), 2.55 - 2.52 (m, 4H), 1.67 (d, J = 6.7 Hz, 6H), 1.45 (d, J = 6.5 Hz, 3H), 1.35 (s, 4H), 0.25 (s, 4H). Example 56

[0320] 1 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 1.9 Hz, 1H), 8.51 - 8.40 (m, 2H), 8.32 (dd, J = 8.2, 2.3 Hz, 1H), 8.10 (dd, J = 9., 1.4 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 5.38 - 5.25 (m, 1H), 4.60 (q, J = 6.5 Hz, 1H), 3.60 (s, 3H), 3.57 - 3.53 (m, 1H), 3.49 - 3.44 (m, 1H), 3.21 (s, 3H), 3.18 - 3.12 (m, 1H), 2.78 - 2.70 (m, 2H), 2., 2.53 (m, 2H), 2.24 - 2.13 (m, 2H), 1.86 - 1.77 (m, 2H), 1.67 (d, J = 6.7 Hz, 6H), 1.48 - 1.37 (m, 5H). Example 57

[0321] 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.49-8.38 (m, 2H), 8.30 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 5.36-5.26 (m, 1H), 4.63-4.54 (m, 1H), 3.88-3.81 (m, 1H), 3.61-3.55 (m, 5H), 3.15 (s, 3H), 2.77-2.52 (m, 6H), 2.00-1.90 (m, 1H), 1.72-1.55 (m, 7H), 1.43 (d, J = 6.3 Hz, 3H). Example 58

[0322] 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.48-8.38 (m, 2H), 8.31 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 5.36-5.25 (m, 1H), 4.58 (q, J = 6.3 Hz, 1H), 4.45-4.35 (m, 1H), 3.59 (s, 3H), 3.56-3.49 (m, 1H), 3.47-3.39 (m, 1H), 2.73-2.63 (m, 2H), 2.58-2.51 (m, 2H), 2.32-2.21 (m, 2H), 1.95-1.84 (m, 2H), 1.73-1.58 (m, 8H), 1.42 (d, J = 6.5 Hz, 3H). Example 59

[0323] 11H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 2.0 Hz, 1H), 8.50 - 8.41 (m, 2H), 8.33 (dd, J = 8.2, 2.3 Hz, 1H), 8.10 (dd, J = 9.1, 1.6 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 5.39 - 5.27 (m, 1H), 4.60 (q, J = 6.5 Hz, 1H), 3.94 - 3.81 (m, 1H), 3.60 (s, 3H), 3.58 - 3.53 (m, 1H), 3.48 - 3.43 (m, 1H), 3.16 (s, 3H), 2.76 - 2.52 (m, 6H), 2.01 - 1.91 (m, 1H), 1.72 - 1.59 (m, 7H), 1.44 (d, J = 6.5 Hz, 3H). Example 60

[0324] 1 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 1.8 Hz, 1H), 8.51 - 8.40 (m, 2H), 8.35 - 8.27 (m, 1H), 8.10 (d, J = 9.1 Hz, 1H), 7.63 (dd, J = 8.1, 2.1 Hz, 1H), 5.37 - 5.27 (m, 1H), 4.93 (s, 1H), 4.61 (q, J = 6.4 Hz, 1H), 3.64 - 3.53 (m, 4H), 3.50 - 3.43 (m, 1H), 2.87 - 2.56 (m, 5H), 2.42 - 2.32 (m, 1H), 2.28 - 2.15 (m, 1H), 1.90 - 1.79 (m, 1H), 1.67 (d, J = 6.7 Hz, 6H), 1.44 (d, J = 6.5 Hz, 3H). Example 61

[0325] 11H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 1.9 Hz, 1H), 8.50 - 8.41 (m, 2H), 8.32 (dd, J = 8.2, 2.4 Hz, 1H), 8.10 (dd, J = 9.1, 1.6 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 5.33 (dt, J = 13.5, 6.7 Hz, 1H), 4.61 (q, J = 6.5 Hz, 1H), 3.60 (s, 3H), 3.57 - 3.53 (m, 1H), 3.49 - 3.42 (m, 1H), 2.75 - 2.60 (m, 4H), 2.37 (s, 2H), 1.67 (d, J = 6.7 Hz, 6H), 1.52 (t, J = 7.1 Hz, 2H), 1.44 (d, J = 6.5 Hz, 3H), 1.04 (d, J = 2.4 Hz, 6H). Example 62

[0326] 1 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.53 (d, J = 9.0 Hz, 1H), 8.25 (s, 1H), 8.01 (dd, J = 8.1, 1.4 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.65 (d, J = 8.1 Hz, 1H), 5.28 - 5.11 (m, 1H), 4.64 (q, J = 6.5 Hz, 1H), 3.76 (s, 3H), 3.67 - 3.52 (m, 2H), 2.82 - 2.67 (m, 2H), 2.63 - 2.50 (m, 4H), 1.87 - 1.69 (m, 10H), 1.55 (d, J = 6.5 Hz, 3H). Example 63

[0327] 11H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 2.0 Hz, 1H), 8.45 (dd, J = 11.9, 5.2 Hz, 2H), 8.32 (dd, J = 8.2, 2.4 Hz, 1H), 8.10 (dd, J = 9.1, 1.6 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 6.66 (t, J = 76.0 Hz, 1H), 5.36 - 5.26 (m, 1H), 4.70 - 4.64 (m, 1H), 4.60 (q, J = 6.5 Hz, 1H), 3.60 (s, 3H), 3.58 - 3.52 (m, 2H), 2.77 - 2.59 (m, 5H), 2.44 - 2.36 (m, 1H), 2.19 - 2.07 (m, 1H), 1.80 - 1.70 (m, 1H), 1.67 (d, J = 6.7 Hz, 6H), 1.44 (d, J = 6.5 Hz, 3H). Example 64

[0328] 1 1H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 2.0 Hz, 1H), 8.56 (d, J = 9.0 Hz, 1H), 8.28 (s, 1H), 8.05 (dd, J = 8.1, 2.3 Hz, 1H), 7.88 (dd, J = 9.0, 1.7 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 5.28 - 5.18 (m, 1H), 4.69 (q, J = 6.4 Hz, 1H), 4.06 - 3.99 (m, 1H), 3.86 - 3.68 (m, 5H), 3.49 - 3.39 (m, 2H), 3.35 - 3.23 (m, 4H), 3.14 - 2.96 (m, 4H), 2.20 - 2.11 (m, 1H), 1.80 (d, J = 7.0 Hz, 6H), 1.58 (d, J = 6.5 Hz, 3H). Example 65

[0329] 11H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.55 (d, J = 9.0 Hz, 1H), 8.29 (s, 1H), 8.07 (d, J = 7.7 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 5.29 - 5.17 (m, 1H), 4.78 - 4.64 (m, 1H), 4.13 - 4.03 (m, 1H), 3.92 - 3.83 (m, 2H), 3.78 (s, 3H), 3.33 (s, 3H), 3.27 - 3.05 (m, 4H), 2.30 - 1.99 (m, 4H), 1.80 (d, J = 6.8 Hz, 6H), 1.59 (d, J = 5.8 Hz, 3H). Example 66 【033D】<L 1 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.52 - 8.35 (m, 2H), 8.30 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 5.38 - 5.18 (m, 1H), 4.64 - 4.44 (m, 1H), 3.59 (s, 3H), 3.51 - 3.44 (m, 1H), 3.42 - 3.36 (m, 1H), 2.92 (t, J = 8.1 Hz, 2H), 2.65 - 2.53 (m, 2H), 2.28 (t, J = 6.9 Hz, 2H), 1.66 (d, J = 6.5 Hz, 6H), 1.41 (d, J = 6.4 Hz, 3H), 1.35 - 1.26 (m, 2H), 0.59 - 0.52 (m, 1H), 0.32 - 0.22 (m, 1H). Example 67

[0331] 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.49-8.36 (m, 2H), 8.30 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 5.35-5.23 (m, 1H), 4.63-4.46 (m, 1H), 3.59 (s, 3H), 3.52-3.45 (m, 1H), 3.43-3.36 (m, 1H), 2.92 (t, J = 8.1 Hz, 2H), 2.65-2.53 (m, 2H), 2.28 (t, J = 6.8 Hz, 2H), 1.66 (d, J = 6.5 Hz, 6H), 1.41 (d, J = 6.4 Hz, 3H), 1.35-1.28 (m, 2H), 0.59-0.52 (m, 1H), 0.31-0.22 (m, 1H). Example 68

[0332] 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.47-8.37 (m, 2H), 8.30 (d, J = 7.5 Hz, 1H), 8.07 (d, J = 9.1 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 5.37-5.24 (m, 1H), 4.74-4.50 (m, 2H), 3.62-3.39 (m, 5H), 2.60-2.50 (m, 4H), 2.35-2.24 (m, 2H), 1.88-1.74 (m, 2H), 1.71-1.57 (m, 8H), 1.42 (d, J = 6.1 Hz, 3H). Example 69

[0333] 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.46-8.38 (m, 2H), 8.30 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 9.3 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 5.37-5.24 (m, 1H), 4.73-4.52 (m, 2H), 3.58 (s, 3H), 3.56-3.49 (m, 1H), 3.48-3.40 (m, 1H), 2.60-2.51 (m, 4H), 2.35-2.26 (m, 2H), 1.89-1.74 (m, 2H), 1.72-1.59 (m, 8H), 1.42 (d, J = 6.1 Hz, 3H). Example 70

[0334] 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.48-8.37 (m, 2H), 8.29 (d, J = 7.3 Hz, 1H), 8.08 (d, J = 8.7 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 5.37-5.21 (m, 1H), 4.65-4.52 (m, 1H), 3.58 (s, 3H), 3.54-3.42 (m, 2H), 3.00 (t, J = 10.5 Hz, 2H), 2.85-2.73 (m, 2H), 2.69-2.56 (m, 2H), 2.34-2.23 (m, 2H), 1.66 (d, J = 6.6 Hz, 6H), 1.42 (d, J = 6.5 Hz, 3H). Example 71

[0335] 11H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.49-8.39 (m, 2H), 8.30 (d, J = 8.1 Hz, 1H), 8.09 (d, J = 9.0 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 5.38-5.25 (m, 1H), 4.68-4.53 (m, 1H), 3.59 (s, 3H), 3.53-3.42 (m, 2H), 3.01 (t, J = 10.1 Hz, 2H), 2.84-2.75 (m, 2H), 2.69-2.57 (m, 2H), 2.33-2.25 (m, 2H), 1.67 (d, J = 6.6 Hz, 6H), 1.43 (d, J = 6.4 Hz, 3H). Example 72

[0336] 1 1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 2.3 Hz, 1H), 8.55-8.39 (m, 2H), 8.32 (dd, J = 8.2, 2.4 Hz, 1H), 8.09 (dd, J = 9.1, 1.7 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 5.38-5.24 (m, 1H), 4.67-4.49 (m, 1H), 3.60 (s, 3H), 3.56-3.50 (m, 1H), 3.48-3.41 (m, 1H), 2.59-2.52 (m, 2H), 2.41-2.28 (m, 4H), 1.67 (d, J = 6.7 Hz, 6H), 1.43 (d, J = 6.5 Hz, 3H), 1.29 (t, J = 5.6 Hz, 4H), 0.87 (s, 6H). Example 73

[0337] 11H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.48-8.38 (m, 2H), 8.31 (dd, J = 8.2, 2.2 Hz, 1H), 8.08 (dd, J = 9.1, 1.8 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 5.40-5.24 (m, 1H), 4.62-4.49 (m, 1H), 3.59 (s, 3H), 3.57-3.51 (m, 1H), 3.47-3.40 (m, 1H), 2.55-2.51 (m, 2H), 2.35 (t, J = 5.7 Hz, 4H), 1.67 (d, J = 6.7 Hz, 6H), 1.43 (d, J = 6.6 Hz, 3H), 1.29 (t, J = 5.6 Hz, 4H), 0.87 (s, 6H). Example 74

[0338] 1 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.49-8.39 (m, 2H), 8.31 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 5.37-5.25 (m, 1H), 4.62-4.51 (m, 1H), 3.63-3.52 (m, 4H), 3.50-3.42 (m, 1H), 2.68-2.51 (m, 6H), 1.99-1.84 (m, 4H), 1.66 (d, J = 6.6 Hz, 6H), 1.43 (d, J = 6.5 Hz, 3H). Example 75

[0339] 1H NMR (400 MHz, DMSO) δ 9.04 (d, J = 2.4, 0.8 Hz, 1H), 8.49-8.40 (m, 2H), 8.33 (dd, J = 8.2, 2.4 Hz, 1H), 8.09 (dd, J = 9.0, 1.7 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 5.38-5.27 (m, 1H), 4.64-4.54 (m, 1H), 3.59 (s, 3H), 3.58-3.54 (m, 1H), 3.50-3.43 (m, 1H), 2.67-2.57 (m, 2H), 2.57-2.52 (m, 4H), 2.01-1.85 (m, 4H), 1.67 (d, J = 6.7 Hz, 6H), 1.43 (d, J = 6.5 Hz, 2H). Example 76 8-(6-((R)-1-(2-((R)-3-cyclopropoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0400] [ka]

[0401] Step 1: (3R)-Benzyl 3-(1-ethoxyethoxy)pyrrolidine-1-carboxylate

[0402] [ka]

[0403]

[0340] Two drops of TFA were added at 0°C to a solution of (R)-benzyl 3-hydroxypyrrolidine-1-carboxylate (3.00 g, 13.6 mmol) in ethoxyethane (15 mL) and DCM (5 mL), and the reaction mixture was stirred at room temperature for 48 hours. The mixture was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (PE:siRNA = 1:0 to 10:1) to obtain the desired product (2.70 g, 67.8% yield) as diesel fuel. Step 2: (R)-Benzyl 3-(vinyloxy)pyrrolidine-1-carboxylate

[0404] [ka]

[0405]

[0341] To a solution of (3R)-benzyl 3-(1-ethoxyethoxy)pyrrolidine-1-carboxylate (2.70 g, 9.22 mmol) in anhydrous DCM (30 mL), TEA (0.684 mL, 4.61 mmol), followed by TMSOTF (0.833 mL, 4.61 mmol), was added dropwise at 0°C under N2. The reaction mixture was then warmed to room temperature and stirred for 2 hours. The mixture was cooled again to 0°C, and another TEA (0.684 mL, 4.61 mmol) and TMSOTF (0.833 mL, 4.61 mmol) were added dropwise. The reaction mixture was then slowly warmed to room temperature and stirred overnight. The mixture was poured into a 1 M NaOH solution on ice (50 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine, dried on anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (PE:HCl = 1:0 to 10:1) to obtain the desired product (319 mg, 14.0% yield) as diesel fuel. LC-MS(ESI) m / z: 248[M+H] + . Step 3: (R)-Benzyl 3-cyclopropoxypyrrolidine-1-carboxylate

[0406] [ka]

[0407]

[0342] A 1 M diethylzinc solution in hexane (3.23 mL, 3.23 mmol) was added to dry DCM (15 mL), and a solution of diiodomethane (0.260 mL, 3.23 mmol) in dry DCM (3 mL) was added dropwise under N2 at 0°C. The resulting reaction mixture was then stirred at 0°C for 30 minutes. A solution of (R)-benzyl 3-(vinyloxy)pyrrolidine-1-carboxylate (319 mg, 1.29 mmol) was added dropwise at 0°C. The reaction mixture was slowly warmed to room temperature and stirred overnight. The mixture was poured into ice-saturated NH4Cl solution (30 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with saturated NaHCO3 solution (40 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (PE:SiO = 1:0 to 10:1) to obtain the desired product (182 mg, 54.1% yield) as diesel fuel. LC-MS(ESI) m / z: 262[M+H] + . Step 4: (R)-3-Cyclopropoxypyrrolidine

[0408] [ka]

[0409]

[0343] To a solution of (R)-benzyl 3-cyclopropoxypyrrolidine-1-carboxylate (150 mg, 0.575 mmol) in MeOH (3 mL) and 6 M HCl solution (0.5 mL), Pd / C (15.0 mg) was added, and the reaction mixture was stirred overnight at room temperature. The mixture was filtered, and the filtrate was evaporated under reduced pressure to obtain the crude desired product (104 mg) as a light brown oil. LC-MS (ESI) m / z: 128 [M + H] + . Step 5: (R)-2-(1-(5-bromopyridine-2-yl)ethoxy)ethanol

[0410] [ka]

[0411]

[0344] A solution of (R)-2-(1-(5-bromopyridine-2-yl)ethoxy)acetic acid (9.50 g, 36.7 mmol) in THF (100 mL) is mixed with 1 M BH3 . A THF solution (73.4 mL, 73.4 mmol) was added dropwise under N2 at 0°C. The reaction mixture was then stirred at room temperature for 1 hour. The mixture was quenched with MeOH (100 mL) at 0°C and stirred at 80°C for 1 hour. The mixture was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (DCM:MeOH = 100:1 to 20:1) to obtain the desired product (6.20 g, 69.0% yield) as a pale yellow oil. LC-MS(ESI) m / z: 246[M+H] + . Step 6: (R)-8-(6-(1-(2-hydroxyethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0412] [ka]

[0413]

[0345] The crude product was prepared in the same manner as in Example 1, and purified by chromatography on silica gel (DCM:MeOH = 100:1 to 10:1) to obtain the desired product (1.10 g, 66.3% yield) as a brown solid. LC-MS(ESI) m / z: 408[M+H] + . Step 7: (R)-2-(1-(5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)acetaldehyde

[0414] [ka]

[0415]

[0346] To a solution of oxalyl chloride (0.343 mL, 4.05 mmol) in dry DCM (5 mL), DMSO (0.574 mL, 8.10 mmol) was added dropwise under N2 at -78°C, and the resulting reaction mixture was stirred at -78°C for 15 minutes. Next, a solution of (R)-8-(6-(1-(2-hydroxyethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (1.10 g, 2.70 mmol) in dry DCM (10 mL) was added dropwise at -78°C. After stirring at -78°C for 20 minutes, TEA (1.87 mL, 13.5 mmol) was added. The resulting mixture was slowly warmed to room temperature. The mixture was quenched with water (30 mL) and extracted with HCl (20 mL x 2). The combined organic layer was washed with brine (40 mL), dried on anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude desired product (1.10 g) as a brown solid. LC-MS(ESI) m / z: 406[M+H] + . Step 8: 8-(6-((R)-1-(2-((R)-3-cyclopropoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0416] [ka]

[0417]

[0347] A mixture of (R)-3-cyclopropoxypyrrolidine (50.0 mg, 0.394 mmol) and (R)-2-(1-(5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)acetaldehyde (159 mg, 0.394 mmol) in DCE (4 mL) was slowly added with sodium triacetoxyborohydride (251 mg, 1.18 mmol) at 0°C, and the reaction mixture was stirred overnight at room temperature. The mixture was poured into ice-saturated NaHCO3 solution (20 mL) and extracted with DCM (15 mL x 2). The organic layer was washed with brine (30 mL), dried on anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM:MeOH=9:1) to obtain the desired product (40.0 mg, 19.7% yield) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.55 (d, J = 9.0 Hz, 1H), 8.28 (s, 1H), 8.05 (dd, J = 8.1, 2.1 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 5.28-5.16 (m, 1H), 4.68 (q, J = 6.5 Hz, 1H), 4.30-4.20 (m, 1H), 3.83-3.70 (m, 5H), 3.55-3.41 (m, 1H), 3.31-3.23 (m, 1H), 3.17-2.96 (m, 4H), 2.27-2.05 (m, 3H), 1.79 (d, J = 6.9 Hz, 6H), 1.57 (d, J = 6.5 Hz, 3H), 0.65-0.41 (m, 4H).LC-MS(ESI)m / z:517[M+H] + .

[0418]

[0348] The following compounds were prepared using different starting materials according to the method described above.

[0419] [Table 6-1]

[0420] Table 6-2

[0421] Table 6-3

[0422] Table 6-4

[0423] Table 6-5

[0424] Example 77

[0349] 1 H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.54 (d, J = 9.0 Hz, 1H), 8.28 (s, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.87 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 5.30-5.14 (m, 1H), 4.75-4.68 (m, 1H), 4.04-3.86 (m, 3H), 3.77 (s, 3H), 3.35-3.26 (m, 2H), 3.22-2.90 (m, 2H), 2.72-2.15 (m, 4H), 1.79 (d, J = 6.9 Hz, 6H), 1.58 (d, J = 6.4 Hz, 3H), 1.14 (d, J = 6.1 Hz, 3H). Example 78

[0350] 11H NMR (600 MHz, DMSO-d6) δ 9.10 (d, J = 2.0 Hz, 1H), 8.51 (s, 1H), 8.45 (d, J = 9.1 Hz, 1H), 8.38 (dd, J = 8.1, 2.3 Hz, 1H), 8.17 (dd, J = 9.1, 1.4 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 5.40 - 5.32 (m, 1H), 4.74 - 4.70 (m, 1H), 3.78 - 3.71 (m, 1H), 3.67 - 3.62 (m, 2H), 3.60 (s, 3H), 3.45 - 3.22 (m, 3H), 3.18 - 3.07 (m, 1H), 2.73 - 2.63 (m, 1H), 2.37 - 2.29 (m, ...... Example 79

[0351] 1 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 1.8 Hz, 1H), 8.51 (s, 1H), 8.44 (d, J = 9.1 Hz, 1H), 8.37 (dd, J = 8.2, 2.1 Hz, 1H), 8.17 (d, J = 9.1 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 5.44 - 5.25 (m, 1H), 4.73 (q, J = 6.4 Hz, 1H), 4.26 - 4.13 (m, 1H), 3.80 - 3.74 (m, 4H), 3.69 - 3.63 (m, 2H), 3.59 (s, 3H), 3.52 - 3.46 (m, 2H), 3.15 (s, 3H), 2....... Example 80

[0352] 11H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 2.0 Hz, 1H), 8.56 (d, J = 9.0 Hz, 1H), 8.29 (s, 1H), 8.05 (dd, J = 8.1, 2.3 Hz, 1H), 7.88 (dd, J = 9.0, 1.7 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 5.29 - 5.18 (m, 1H), 4.69 (q, J = 6.3 Hz, 1H), 3.93 - 3.59 (m, 7H), 3.34 - 3.24 (m, 1H), 3.16 - 2.88 (m, 4H), 2.22 (2, 2H), 1.98 - 1.83 (m, 3H), 1.80 (d, J = 7.0 Hz, 6H), 1.57 (d, J = 6.5 Hz, 3H), 0.62 - 0.47 (m, 4H). Example 81

[0353] 1 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.56 (d, J = 8.9 Hz, 1H), 8.27 (s, 1H), 8.03 (d, J = 6.1 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 5.29 - 5.16 (m, 1H), 4.80 - 4.70 (m, 4H), 4.61 (q, J = 6.6 Hz, 1H), 3.78 (s, 3H), 3.54 - 3.38 (m, 6H), 2.71 - 2.58 (m, 2H), 1.80 (d, J = 6.9 Hz, 6H), 1.54 (d, J = 6.5 Hz, 3H). Example 82

[0354] 11H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 2.0 Hz, 1H), 8.49 - 8.40 (m, 2H), 8.33 (dd, J = 8.2, 2.3 Hz, 1H), 8.10 (dd, J = 9.1, 1.4 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 5.38 - 5.26 (m, 1H), 4.59 (q, J = 6.4 Hz, 1H), 4.35 (t, J = 7.7 Hz, 2H), 3.60 (s, 3H), 3.56 - 3.53 (m, 1H), 3.47 - 3.41 (m, 1H), 2.58 - 2.52 (m, 2H), 2.49 - 2.44 (m, 2H), 2.33 - 2.19 (m, 4H), 1.83 - 1.60 (m, 10H), 1.43 (d, J = 6.5 Hz, 3H). Example 83

[0355] 1 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 1.9 Hz, 1H), 8.50 - 8.41 (m, 2H), 8.33 (dd, J = 8.2, 2.4 Hz, 1H), 8.11 (dd, J = 9.1, 1.7 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 5.38 - 5.29 (m, 1H), 4.62 - 4.53 (m, 3H), 4.31 (t, J = 6.2 Hz, 2H), 3.60 (s, 3H), 3.56 - 3.53 (m, 1H), 3.49 - 3.46 (m, 1H), 2.90 - 2.83 (m, 2H), 2.71 - 2.63 (m, 1H), 2.59 - 2.52 (m, 2H), 2.03 - 1.92 (m, 2H), 1.67 (d, J = 6.7 Hz, 6H), 1.59 - 1.49 (m, 3H), 1.43 (d, J = 6.5 Hz, 3H), 1.08 - 0.96 (m, 2H). Example 84

[0356] 1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 2.3 Hz, 1H), 8.49-8.40 (m, 2H), 8.34-8.28 (m, 1H), 8.13-8.05 (m, 1H), 7.63 (d, J = 8.1 Hz, 1H), 5.35-5.26 (m, 1H), 4.59 (q, J = 6.4 Hz, 1H), 3.60 (s, 3H), 3.57-3.52 (m, 1H), 3.49-3.44 (m, 1H), 3.01-2.89 (m, 2H), 2.60-2.51 (m, 2H), 2.30-2.15 (m, 1H), 2.06-1.94 (m, 2H), 1.79-1.71 (m, 2H), 1.66 (d, J = 6.7 Hz, 6H), 1.49-1.39 (m, 5H). Example 85

[0357] 1 H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.54 (d, J = 9.0 Hz, 1H), 8.27 (s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.62 (d, J = 7.4 Hz, 1H), 5.28-5.16 (m, 1H), 4.72 (d, J = 6.0 Hz, 1H), 3.99-3.83 (m, 2H), 3.76 (s, 3H), 3.73-3.47 (m, 2H), 3.46-3.40 (m, 2H), 3.35 (s, 3H), 3.31-3.17 (m, 3H), 2.83-2.69 (m, 1H), 2.33-2.21 (m, 1H), 1.99-1.73 (m, 8H), 1.58 (d, J = 5.9 Hz, 3H). Example 86

[0358] 11H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.55 (d, J = 9.0 Hz, 1H), 8.28 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 5.29 - 5.17 (m, 1H), 5.14 - 4.98 (m, 1H), 4.72 - 4.62 (m, 4H), 3.83 - 3.64 (m, 5H), 3.39 - 3.26 (m, 2H), 3.10 - 2.96 (m, 4H), 2.31 (t, J = 7.0 Hz, 2H), 1.79 (d, J = 6.9 Hz, 6H), 1.57 (d, J = 6.4 Hz, 3H). Example 87

[0359] 1 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.56 (d, J = 8.9 Hz, 1H), 8.28 (s, 1H), 8.04 (d, J = 6.5 Hz, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 5.28 - 5.15 (m, 1H), 4.68 (q, J = 6.5 Hz, 1H), 3.93 - 3.75 (m, 5H), 3.10 - 2.85 (m, 6H), 1.93 - 1.84 (m, 4H), 1.79 (d, J = 6.9 Hz, 6H), 1.63 - 1.52 (m, 5H). Example 88

[0360] 11H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 2.1 Hz, 1H), 8.50 - 8.42 (m, 2H), 8.31 (dd, J = 8.1, 2.3 Hz, 1H), 8.10 (d, J = 9.1 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 5.38 - 5.28 (m, 1H), 4.96 - 4.89 (m, 1H), 4.65 - 4.56 (m, 1H), 3.61 (s, 3H), 3.59 - 3.53 (m, 1H), 3.49 - 3.45 (m, 1H), 2.81 - 2.60 (m, 5H), 2.39 - 2.32 (m, 1H), 2.27 - 2.19 (m, 1H), 1.90 - 1.79 (m, 1H), 1.67 (d, J = 6.7 Hz, 6H), 1.44 (d, J = 6.5 Hz, 3H). Example 89

[0361] 1 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.56 (d, J = 9.0 Hz, 1H), 8.47 (s, 1H), 8.04 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 5.31 - 5.14 (m, 1H), 4.74 - 4.65 (m, 1H), 3.91 - 3.72 (m, 5H), 3.37 - 3.11 (m, 6H), 2.25 - 1.84 (m, 8H), 1.79 (d, J = 6.9 Hz, 6H), 1.57 (d, J = 6.4 Hz, 3H). Example 90

[0362] 11H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 2.1 Hz, 1H), 8.51 - 8.40 (m, 2H), 8.36 - 8.29 (m, 1H), 8.10 (dd, J = 9.1, 1.5 Hz, 1H), 7.66 (dd, J = 8.1, 4.8 Hz, 1H), 5.37 - 5.26 (m, 1H), 4.61 (q, J = 6.5 Hz, 1H), 3.60 (s, 3H), 3.58 - 3.55 (m, 1H), 3.48 - 3.43 (m, 1H), 3.10 - 3.02 (m, 1H), 2.86 - 2.76 (m, 1H), 2.74 - 2.53 (m, 3H), 2.46 - 2.37 (m, 1H), 2.28 - 2.17 (m, 1H), 1.86 - 1.76 (m, 1H), 1.67 (d, J = 6.7 Hz, 6H), 1.45 (d, J = 6.5 Hz, 3H), 1.40 (d, J = 2.2 Hz, 3H). Example 91

[0363] 1 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.47 - 8.39 (m, 2H), 8.31 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 5.38 - 5.24 (m, 1H), 4.57 (q, J = 6.4 Hz, 1H), 3.58 (s, 3H), 3.56 - 3.50 (m, 2H), 2.86 - 2.79 (m, 1H), 2.62 - 2.51 (m, 4H), 2.37 - 2.26 (m, 2H), 1.86 - 1.77 (m, 2H), 1.72 - 1.60 (m, 8H), 1.42 (d, J = 6.5 Hz, 3H). Example 92

[0364] 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.55 (d, J = 9.1 Hz, 1H), 8.28 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 5.27-5.18 (m, 1H), 4.72-4.61 (m, 1H), 4.45-4.26 (m, 1H), 3.85-3.62 (m, 7H), 3.58-3.49 (m, 1H), 3.08-2.79 (m, 4H), 2.15-1.96 (m, 4H), 1.79 (d, J = 6.7 Hz, 6H), 1.56 (d, J = 6.0 Hz, 3H), 1.15 (d, J = 5.6 Hz, 6H). Example 93

[0365] 1 H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 8.55 (d, J = 9.2 Hz, 1H), 8.31 (s, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.72 (s, 1H), 5.28-5.15 (m, 1H), 4.92-4.77 (m, 1H), 4.41-4.27 (m, 1H), 4.17-3.90 (m, 4H), 3.77 (s, 3H), 3.70-3.59 (m, 1H), 3.54-3.34 (m, 2H), 3.27-3.10 (m, 2H), 2.40-2.22 (m, 1H), 2.18-2.05 (m, 1H), 1.80 (d, J = 6.4 Hz, 6H), 1.62 (d, J = 6.1 Hz, 3H), 1.16 (d, J = 5.8 Hz, 6H). Example 94 8-(6-((2-(5-azaspiro[2,4]heptan-5-yl)ethoxy)methyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0425] [ka]

[0426] Step 1: 6-Bromo-3-nitro-N-(tetrahydro-2H-pyran-4-yl)cinnoline-4-amine

[0427] [ka]

[0428]

[0366] A mixture of 6-bromo-4-chloro-3-nitrosinnoline (60.0 g, 170 mmol) and tetrahydro-2H-pyran-4-amine (25.8 g, 255 mmol) in DCM (500 mL) was mixed with TEA (75.4 mL, 510 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into 1 L of 1 M HCl solution on ice and extracted with DCM (500 mL x 2). The combined organic layer was washed with brine (800 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the desired product (75.0 g, 100.0% yield) as a brown solid. LC-MS(ESI) m / z: 353[M+H] + . Step 2: 6-Bromo-N4-(tetrahydro-2H-pyran-4-yl)cinnoline-3,4-diamine

[0429] [ka]

[0430]

[0367] A solution of 6-bromo-3-nitro-N-(tetrahydro-2H-pyran-4-yl)cinolin-4-amine (75.0 g, 212 mmol) in MeOH (200 mL) is mixed with SnCl2 .H2O (144 g, 636 mmol) was added at 0°C, and the reaction mixture was stirred at 60°C for 2 hours. The mixture was adjusted to pH approximately 8 with 50% NaOH solution at less than 45°C, and stirred at 55°C for 45 minutes. The mixture was filtered, and the filtered residue was tritulated in THF (300 mL) at room temperature for 1 hour. This was filtered, and the combined filtrate was evaporated under reduced pressure. The residue was tritulated in THF (300 mL) at room temperature for 1 hour and filtered. By evaporating the filtrate under reduced pressure, the desired product (54.0 g, 78.7% yield) was obtained as a dark brown solid. LC-MS(ESI) m / z: 323[M+H] + . Step 3: 8-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0431] [ka]

[0432]

[0368] To a solution of 6-bromo-N4-(tetrahydro-2H-pyran-4-yl)cinnoline-3,4-diamine (54.0 g, 154 mmol) in dry THF (500 mL), CDI (75.0 g, 462 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was evaporated under reduced pressure, and the residue was dissolved in water (250 mL). The pH was adjusted to approximately 7 with 1 M HCl solution, and the mixture was filtered. The filtered residue was dried in an oven at 55°C for 16 hours to obtain the desired product (42.0 g, 72.0% yield). LC-MS(ESI) m / z: 349[M+H] + . Step 4: 8-bromo-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0433] [ka]

[0434]

[0369] To a solution of 8-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (42.0 g, 120 mmol) in dry DMF (300 mL), t-BuONa (14.0 g, 144 mmol) was added at 0°C and the mixture was stirred under N2 at 0°C for 30 minutes. Then, MeI (34.1 g, 240 mmol) was added dropwise to the reaction mixture at 10°C-15°C and the reaction mixture was stirred at 10°C-15°C for 2 hours. The mixture was poured into ice water (600 mL) and filtered. The filtered residue was tritulated with MeOH (200 mL) for 1 hour and filtered. The filter cake was dried under vacuum to obtain the desired product (35.0 g, 80.0% yield). LC-MS(ESI)m / z:363[M+H] + . Step 5: 8-(6-((2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)methyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0435] [ka]

[0436]

[0370] The crude product was prepared in the same manner as in Example 1 and purified by flash chromatography (DCM:MeOH=9:1) to obtain the desired product (40.0 mg, 24.1% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 1.9 Hz, 1H), 8.53-8.43 (m, 2H), 8.35 (dd, J = 8.2, 2.4 Hz, 1H), 8.14 (dd, J = 9.1, 1.6 Hz, 1H), 7.65 (d, J = 8.1 Hz, 1H), 5.18-5.04 (m, 1H), 4.68 (s, 2H), 4.11-4.01 (m, 2H), 3.70 (t, J = 5.8 Hz, 2H), 3.65-3.60 (m, 5H), 2.85-2.77 (m, 4H), 2.72-2.59 (m, 4H), 2.00-1.92 (m, 2H), 1.76 (t, J = 6.9 Hz, 2H), 0.59-0.48 (m, 4H).LC-MS(ESI)m / z:515[M+H] + .

[0437]

[0371] The following compounds were prepared using different starting materials according to the method described above.

[0438] [Table 7-1]

[0439] [Table 7-2]

[0440] Example 95

[0372] 11H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.50 (s, 1H), 8.45 (d, J = 9.2 Hz, 1H), 8.33 (d, J = 8.1 Hz, 1H), 8.13 (d, J = 9.1 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 5.16 - 5.05 (m, 1H), 4.77 - 4.55 (m, 3H), 4.10 - 3.99 (m, 2H), 3.70 - 3.56 (m, 7H), 2.71 - 2.55 (m, 6H), 2.41 - 2.31 (m, 2H), 2.00 - 1.92 (m, 2H), 1.92 - 1.78 (m, 2H), 1.75 - 1.64 (m, 2H). Example 96

[0373] 1 1H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 2.0 Hz, 1H), 8.51 (s, 1H), 8.46 (d, J = 9.1 Hz, 1H), 8.34 (dd, J = 8.2, 2.4 Hz, 1H), 8.14 (dd, J = 9.1, 1.6 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 5.17 - 5.07 (m, 1H), 4.66 (s, 2H), 4.06 (dd, J = 11.2, 4.4 Hz, 2H), 3.69 - 3.58 (m, 7H), 2.72 - 2.62 (m, 2H), 2.58 (t, J = 5.9 Hz, 2H), 2.44 - 2.37 (m, 4H), 2.00 - 1.93 (m, 2H), 1.34 - 1.30 (m, 4H), 0.89 (s, 6H). Example 97

[0374] 11H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.59 (d, J = 8.9 Hz, 1H), 8.47 (s, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 5.17 - 5.03 (m, 1H), 4.80 (s, 2H), 4.33 - 4.18 (m, 2H), 3.98 - 3.86 (m, 2H), 3.82 (s, 3H), 3.65 (t, J = 11.9 Hz, 2H), 3.17 - 3.01 (m, 4H), 2.94 - 2.72 (m, 4H), 2.04 - 1.94 (m, 2H), 1.79 (t, J = 6.5 Hz, 2H), 1.20 (s, 6H). Example 98

[0375] 1 1H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 2.3 Hz, 1H), 8.50 (s, 1H), 8.45 (d, J = 9.1 Hz, 1H), 8.33 (dd, J = 8.1, 2.3 Hz, 1H), 8.13 (d, J = 9.1 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 5.16 - 5.05 (m, 1H), 4.65 (s, 2H), 4.09 - 3.99 (m, 2H), 3.66 - 3.53 (m, 7H), 3.02 - 2.94 (m, 2H), 2.72 - 2.60 (m, 4H), 2.37 - 2.30 (m, 2H), 2.00 - 1.92 (m, 2H), 1.40 - 1.25 (m, 2H), 0.61 - 0.56 (m, 1H), 0.34 - 0.25 (m, 1H). Example 99

[0376] 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.53-8.38 (m, 2H), 8.32 (d, J = 8.1 Hz, 1H), 8.13 (s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 6.65 (t, J = 76.0 Hz, 1H), 5.14-5.04 (m, 1H), 4.72-4.62 (m, 3H), 4.08-3.98 (m, 2H), 3.70-3.55 (m, 7H), 2.82-2.57 (m, 7H), 2.45-2.40 (m, 1H), 2.18-2.08 (m, 1H), 1.99-1.89 (m, 2H), 1.81-1.70 (m, 1H). Example 100

[0377] 1 H NMR (400 MHz, DMSO-d6)) δ 9.04 (s, 1H), 8.51-8.40 (m, 2H), 8.31 (d, J = 8.2 Hz, 1H), 8.13 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 6.64 (t, J = 75.9 Hz, 1H), 5.13-5.03 (m, 1H), 4.71-4.60 (m, 3H), 4.08-3.99 (m, 2H), 3.68-3.53 (m, 7H), 2.79-2.55 (m, 7H), 2.45-2.38 (m, 1H), 2.18-2.07 (m, 1H), 1.98-1.89 (m, 2H), 1.79-1.69 (m, 1H). Example 101

[0378] 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.53-8.41 (m, 2H), 8.33 (d, J = 7.4 Hz, 1H), 8.14 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 5.17-5.03 (m, 1H), 4.65 (s, 2H), 4.47-4.35 (m, 1H), 4.10-3.99 (m, 2H), 3.69-3.55 (m, 7H), 2.77-2.55 (m, 6H), 2.35-2.26 (m, 2H), 2.00-1.84 (m, 4H), 1.74-1.62 (m, 2H). Example 102 (R)-8-(6-(1-(2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0441] [ka]

[0442] Step 1: (R)-8-(6-(1-(2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0443] [ka]

[0444]

[0379] The crude product was prepared in the same manner as in Example 1, and purified by chromatography on silica gel (DCM:MeOH = 100:1 to 10:1) to obtain the desired product (4.6 g, 28.3% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.56 (d, J = 8.8 Hz, 1H), 8.45 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 5.08 (s, 1H), 4.73-4.48 (m, 5H), 4.26 (d, J = 8.0 Hz, 2H), 3.90-3.75 (m, 5H), 3.63 (t, J = 11.8 Hz, 2H), 3.50-3.37 (m, 2H), 3.31-3.08 (m, 4H), 2.75-2.95 (m, 2H), 1.55 (d, J = 6.2 Hz, 3H), 0.70 (d, J = 10.4 Hz, 4H).LC-MS(ESI)m / z:529[M+H] + .

[0445]

[0380] The following compounds were prepared using different starting materials according to the method described above.

[0446] [Table 8-1]

[0447] [Table 8-2]

[0448] [Table 8-3]

[0449] [Table 8-4]

[0450] Example 103

[0381] 11H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 2.0 Hz, 1H), 8.52 (s, 1H), 8.45 (d, J = 9.1 Hz, 1H), 8.35 (dd, J = 8.2, 2.4 Hz, 1H), 8.14 (dd, J = 9.1, 1.6 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 5.18 - 5.05 (m, 1H), 4.61 (q, J = 6.5 Hz, 1H), 4.10 - 3.99 (m, 2H), 3.62 (s, 3H), 3.60 - 3.56 (m, 2H), 3.52 - 3.45 (m, 2H), 2.72 - 2.57 (m, 4H), 2.49 - 2.42 (m, 4H), 2.01 - 1.91 (m, 2H), 1.44 (d, J = 6.5 Hz, 3H), 1.36 - 1.29 (m, 4H), 0.89 (s, 6H). Example 104

[0382] 1 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 2.3 Hz, 1H), 8.53 (s, 1H), 8.45 (d, J = 9.1 Hz, 1H), 8.34 (dd, J = 8.2, 2.4 Hz, 1H), 8.15 (dd, J = 9.1, 1.7 Hz, 1H), 7.6(d, J = 8.2 Hz, 1H), 5.18 - 5.07 (m, 1H), 4.59 (q, J = (6.5 Hz, 1H), 4.11 - 4.00 (m, 2H), 3.67 - 3.58 (m, 5H), 3.55 - 3.48 (m, 1H), 3.45 - 3.39 (m, 1H), 3.00 - 2.91 (m, 2H), 2.74 - 2.58 (m, 4H), 2.40 - 2.26 (m, 2H), 2.02 - 1.91 (m, 2H), 1.43 (d, J = 6.5 Hz, 3H), 1.38 - 1.32 (m, 2H), 0.63 - 0.56 (m, 1H), 0.35 - 0.25 (m, 1H). Example 105

[0383] 1 It should be noted that there seems to be a minor error in the transcription of "7.6(d, J = 8.2 Hz, 1H)" in the translation of , it should probably be "7.66 (d, J = 8.2 Hz, 1H)" as in the original text of . But I translated it as it was provided to maintain consistency with the input.1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 1.9 Hz, 1H), 8.53 (s, 1H), 8.46 (d, J = 9.1 Hz, 1H), 8.39 - 8.31 (m, 1H), 8.15 (dd, J = 9.1, 1.6 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 5.19 - 5.06 (m, 1H), 4.60 (q, J = 6.5 Hz, 1H), 4.09 - 4.01 (m, 2H), 3.91 - 3.80 (m, 1H), 3.68 - 3.59 (m, 5H), 3.58 - 3.52 (m, 2H), 3.15 (s, 3H), 2.75 - 2.55 (m, 6H), 2.45 - 2.37 (m, 2H), 2.01 - 1.87 (m, 3H), 1.66 - 1.58 (m, 1H), 1.44 (d, J = 6.5 Hz, 3H). Example 106

[0384] 1 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 1.9 Hz, 1H), 8.53 (s, 1H), 8.46 (d, J = 9.1 Hz, 1H), 8.38 - 8.30 (m, 1H), 8.18 - 8.10 (m, 1H), 7.65 (d, J = 8.2 Hz, 1H), 5.18 - 5.06 (m, 1H), 4.98 - 4.89 (m, 1H), 4.61 (q, J = 6.5 Hz, 1H), 4.13 - 3.99 (m, 2H), 3.68 - 3.53 (m, 7H), 2.84 - 2.59 (m, 7H), 2.41 - 2.31 (m, 1H), 2.28 - 2.18 (m, 1H), 2.00 - 1.92 (m, 2H), 1.89 - 1.79 (m, 1H), 1.45 (d, J = 6.5 Hz, 3H). Example 107

[0385] 11H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.57 (d, J = 9.1 Hz, 1H), 8.43 (s, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 5.11 - 5.00 (m, 1H), 4.72 - 4.57 (m, 1H), 4.33 - 4.18 (m, 2H), 3.81 - 3.57 (m, 7H), 2.94 - 2.59 (m, 9H), 2.02 - 1.92 (m, 2H), 1.60 - 1.38 (m, 7H), 0.29 (s, 4H). Example 108

[0386] 1 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.50 (s, 1H), 8.43 (d, J = 9.0 Hz, 1H), 8.33 (d, J = 8.1 Hz, 1H), 8.12 (d, J = 9.0 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 5.17 - 5.04 (m, 1H), 4.75 - 4.53 (m, 2H), 4.08 - 3.97 (m, 2H), 3.68 - 3.51 (m, 6H), 3.49 - 3.40 (m, 1H), 2.71 - 2.61 (m, 2H), 2.59 - 2.52 (m, 4H), 2.37 - 2.26 (m, 2H), 2.00 - 1.91 (m, 2H), 1.89 - 1.75 (m, 2H), 1.72 - 1.61 (m, 2H), 1.42 (d, J = 6.5 Hz, 3H). Example 109

[0387] 11H NMR (400 MHz, CDCl3) δ 8.89 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 9.1 Hz, 1H), 8.39 (s, 1H), 8.03 (dd, J = 8.2, 2.3 Hz, 1H), 7.87 (dd, J = 9.1, 1.6 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 5.07 - 4.95 (m, 1H), 4.59 (q, J = 6.5 Hz, 1H), 4.33 - 4.13 (m, 3H), 3.73 (s, 3H), 3.68 - 3.51 (m, 4H), 2.88 - 2.36 (m, 8H), 2.07 - 1.79 (m, 6H), 1.49 (d, J = 6.6 Hz, 3H). Example 110

[0388] 1 1H NMR (400 MHz, CDCl3) δ 8.8 (s, 1H), 8.51 (d, J = 9.0 Hz, 1H), 8.38 (s, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 5.09 - 4.95 (m, 1H), 4.64 - 4.53 (m, 1H), 4.24 - 4.11 (m, 2H), 3.73 (s, 3H), 3.68 - 3.49 (m, 4H), 3.29 - 3.19 (m, 4H), 2.87 - 2.66 (m, 6H), 2.56 - 2.29 (m, 2H), 2.03 - 1.84 (m, 6H), 1.49 (d, J = 6.5 Hz, 3H). Example 111

[0389] 11H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J = 2.1 Hz, 1H), 8.53 (s, 1H), 8.46 (d, J = 9.1 Hz, 1H), 8.37-8.28 (m, 1H), 8.16 (d, J = 9.1 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 5.20-5.05 (m, 1H), 4.63-4.56 (m, 1H), 4.08-3.99 (m, 2H), 3.67-3.59 (m, 5H), 3.57-3.52 (m, 1H), 2.73-2.56 (m, 7H), 2.35-2.28 (m, 2H), 2.01-1.92 (m, 2H), 1.50 (t, J = 7.1 Hz, 2H), 1.44 (d, J = 6.5 Hz, 3H), 1.04 (d, J = 2.1 Hz, 6H). Example 112

[0390] 1 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.56 (d, J = 9.1 Hz, 1H), 8.43 (s, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 5.14-4.99 (m, 1H), 4.71-4.59 (m, 1H), 4.32-4.20 (m, 2H), 4.00-3.90 (m, 1H), 3.79 (s, 3H), 3.73-3.57 (m, 4H), 3.29 (s, 3H), 3.07-2.71 (m, 8H), 2.13-2.04 (m, 1H), 2.00-1.84 (m, 3H), 1.56 (d, J = 6.4 Hz, 3H). Example 113

[0391] 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.52 (s, 1H), 8.45 (d, J = 9.1 Hz, 1H), 8.33 (d, J = 9.0 Hz, 1H), 8.14 (d, J = 9.1 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 5.18-5.04 (m, 1H), 4.62-4.55 (m, 1H), 4.09-3.97 (m, 3H), 3.66-3.50 (m, 8H), 3.47-3.41 (m, 1H), 2.84-2.52 (m, 7H), 2.01-1.91 (m, 3H), 1.61-1.50 (m, 1H), 1.44 (d, J = 6.5 Hz, 3H), 1.07-1.00 (m, 6H). Example 114

[0392] 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 1.9 Hz, 1H), 8.53 (s, 1H), 8.46 (d, J = 9.1 Hz, 1H), 8.35 (dd, J = 8.2, 2.3 Hz, 1H), 8.15 (dd, J = 9.1, 1.5 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 5.20-5.05 (m, 1H), 4.60 (q, J = 6.5 Hz, 1H), 4.11-3.99 (m, 2H), 3.67-3.60 (m, 5H), 3.57-3.54 (m, 2H), 2.89-2.80 (m, 1H), 2.74-2.52 (m, 6H), 2.39-2.26 (m, 2H), 2.02-1.92 (m, 2H), 1.90-1.78 (m, 2H), 1.75-1.63 (m, 2H), 1.44 (d, J = 6.5 Hz, 3H). Example 116 (R)-8-(6-(1-(2-(2-oxa-6-azaspiro[3,4]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0451] [ka]

[0452] Step 1: (R)-8-(6-(1-(2-hydroxyethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0453] [ka]

[0454]

[0393] The crude product was prepared in the same manner as in Example 1 and purified by chromatography on silica gel (DCM:MeOH = 100:1 to 10:1) to obtain the desired product (1.20 g, 65.6% yield in two steps) as a brown solid. LC-MS(ESI) m / z:450[M+H] + . Step 2: (R)-2-(1-(5-(3-methyl-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)acetaldehyde

[0455] [ka]

[0456]

[0394] To a solution of oxalyl chloride (0.343 mL, 4.05 mmol) in dry DCM (5 mL), DMSO (0.574 mL, 8.10 mmol) was added dropwise under N2 at -78°C, and the resulting reaction mixture was stirred at -78°C for 15 minutes. Next, a solution of (R)-8-(6-(1-(2-hydroxyethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (1.20 g, 2.70 mmol) in dry DCM (10 mL) was added dropwise at -78°C. After stirring at -78°C for 20 minutes, TEA (1.87 mL, 13.5 mmol) was added. The resulting mixture was then slowly warmed to room temperature. The mixture was quenched with water (30 mL) and extracted with SiO2 (20 mL x 2). The combined organic layer was washed with brine (40 mL), dried on anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude desired product (1.10 g) as a brown solid. LC-MS(ESI) m / z: 448[M+H] + . Step 3: (R)-8-(6-(1-(2-(2-oxa-6-azapiro[3,4]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0457] [ka]

[0458]

[0395] A mixture of 2-oxa-6-azaspiro[3.4]octane (45.0 mg, 0.394 mmol) and (R)-2-(1-(5-(3-methyl-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)acetaldehyde (176 mg, 0.394 mmol) in DCE (4 mL) was slowly added with sodium triacetoxyborohydride (251 mg, 1.18 mmol) at 0°C, and the reaction mixture was stirred overnight at room temperature. The mixture was poured into ice-saturated NaHCO3 solution (20 mL) and extracted with DCM (15 mL x 2). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (DCM:MeOH=9:1) to obtain the desired product (40.0 mg, 18.7% yield) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ 8.96 (d, J = 2.0 Hz, 1H), 8.58 (d, J = 9.0 Hz, 1H), 8.47 (s, 1H), 8.10 (dd, J = 8.1, 2.3 Hz, 1H), 7.94 (dd, J = 9.0, 1.5 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 5.16-4.95 (m, 1H), 4.75-4.57 (m, 5H), 4.31-4.16 (m, 2H), 3.80 (s, 3H), 3.75-3.60 (m, 4H), 3.23-2.74 (m, 8H), 2.29-2.16 (m, 2H), 2.02-1.90 (m, 2H), 1.58 (d, J = 6.5 Hz, 3H).LC-MS(ESI)m / z:545[M+H] + .

[0459]

[0396] The following compounds were prepared using different starting materials according to the method described above.

[0460] [Table 9-1]

[0461] Table 9-2

[0462] Table 9-3

[0463] Table 9-4

[0464] Example 117

[0397] 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 2.2 Hz, 1H), 8.53 (s, 1H), 8.46 (d, J = 9.1 Hz, 1H), 8.35 (dd, J = 8.2, 2.4 Hz, 1H), 8.15 (dd, J = 9.1, 1.5 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 5.18 - 5.07 (m, 1H), 4.60 (q, J = 6.4 Hz, 1H), 4.11 - 3.99 (m, 2H), 3.67 - 3.59 (m, 5H), 3.58 - 3.53 (m, 1H), 3.50 - 3.45 (m, 1H), 2.99 - 2.91 (m, 2H), 2.74 - 2.53 (m, 4H), 2.29 - 2.17 (m, 1H), 2.06 - 2.00 (m, 2H), 1.98 - 1.91 (m, 2H), 1.79 - 1.71 (m, 2H), 1.50 - 1.37 (m, 5H). Example 118

[0398] 11H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.58 (d, J = 9.2 Hz, 1H), 8.46 (s, 1H), 8.11 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 5.14 - 5.02 (m, 1H), 4.77 - 4.66 (m, 1H), 4.34 - 4.21 (m, 2H), 3.96 - 3.75 (m, 6H), 3.69 - 3.55 (m, 3H), 3.21 - 3.09 (m, 2H), 2.93 - 2.77 (m, 2H), 2.27 - 1.87 (m, 12H), 1.58 (d, J = 6.6 Hz, 3H). Example 119

[0399] 1 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 2.0 Hz, 1H), 8.53 (s, 1H), 8.46 (d, J = 9.1 Hz, 1H), 8.35 (dd, J = 8.2, 2.4 Hz, 1H), 8.15 (dd, J = 9.1, 1.5 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 5.19 - 5.06 (m, 1H), 4.61 (q, J = 6.5 Hz, 1H), 4.12 - 4.01 (m, 2H), 3.68 - 3.51 (m, 7H), 3.48 - 3.42 (m, 1H), 3.23 - 3.18 (m, 5H), 2.74 - 2.56 (m, 6H), 2.36 - 2.24 (m, 2H), 1.99 - 1.92 (m, 2H), 1.87 - 1.76 (m, 1H), 1.44 (d, J = 6.5 Hz, 3H), 1.38 - 1.30 (m, 1H). Example 120

[0400] 11H NMR (400 MHz, CDCl3) δ 8.96 (d, J = 1.8 Hz, 1H), 8.57 (d, J = 9.0 Hz, 1H), 8.46 (s, 1H), 8.09 (dd, J = 8.1, 2.1 Hz, 1H), 7.93 (d, J = 9.1 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 5.17 - 5.01 (m, 1H), 4.67 (q, J = 6.5 Hz, 1H), 4.29 - 4.20 (m, 2H), 3.90 - 3.73 (m, 5H), 3.65 (t, J = 11.4 Hz, 2H), 3.00 - 2.74 (m, 8H), 2.02 - 1.93 (m, 2H), 1.90 - 1.79 (m, 4H), 1.63 - 1.50 (m, 5H). Example 121

[0401] 1 1H NMR (400 MHz, CDCl3) δ 8.98 (d, J = 2.1 Hz, 1H), 8.57 (d, J = 9.1 Hz, 1H), 8.47 (s, 1H), 8.11 (dd, J = 8.2, 2.3 Hz, 1H), 7.93 (dd, J = 9.1, 1.6 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 5.16 - 5.02 (m, 1H), 4.72 (q, J = 6.5 Hz, 1H), 4.34 - 4.20 (m, 2H), 4.03 - 3.88 (m, 2H), 3.79 (s, 3H), 3.72 - 3.63 (m, 2H), 3.49 - 3.36 (m, 4H), 3.30 (t, J = 4.8 Hz, 2H), 2.93 - 2.79 (m, 2H), 2.19 - 2.11 (m, 4H), 2.01 - 1.91 (m, 2H), 1.59 (d, J = 6.5 Hz, 3H). Example 122

[0402] 11H NMR (400 MHz, CDCl3) δ 8.96 (d, J = 1.9 Hz, 1H), 8.57 (d, J = 9.0 Hz, 1H), 8.47 (s, 1H), 8.12 (dd, J = 8.1, 2.3 Hz, 1H), 7.93 (dd, J = 9.0, 1.5 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 5.11 (s, 1H), 4.77 - 4.63 (m, 1H), 4.36 - 4.19 (m, 3H), 3.90 - 3.82 (m, 2H), 3.80 (s, 3H), 3.72 - 3.60 (m, 4H), 3.34 - 3.09 (m, 5H), 2.93 - 2.80 (m, 2H), 2.28 - 2.14 (m, 2H), 2.03 - 1.91 (m, 3H), 1.59 (d, J = 6.5 Hz, 3H), 0.68 - 0.47 (m, 4H). Example 123

[0403] 1 1H NMR (600 MHz, DMSO-d6) δ 9.12 (d, J = 2.0 Hz, 1H), 8.54 (s, 1H), 8.48 (d, J = 9.0 Hz, 1H), 8.39 (dd, J = 8.2, 2.4 Hz, 1H), 8.17 (dd, J = 9.1, 1.6 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 5.19 - 5.07 (m, 1H), 4.72 (q, J = 6.5 Hz, 1H), 4.11 - 4.00 (m, 2H), 3.66 - 3.63 (m, 2H), 3.62 (s, 3H), 3.61 - 3.59 (m, 2H), 3.44 - 3.06 (m, 5H), 2.72 - 2.60 (m, 3H), 2.37 - 2.29 (m, 1H), 2.22 - 2.08 (m, 1H), 2.01 - 1.93 (m, 2H), 1.66 - 1.48 (m, 4H), 1.08 (d, J = 6.7 Hz, 3H). Example 124

[0404] 11H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 2.1 Hz, 1H), 8.53 (s, 1H), 8.46 (d, J = 9.1 Hz, 1H), 8.35 (dd, J = 8.2, 2.4 Hz, 1H), 8.15 (dd, J = 9.1, 1.6 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 5.19 - 5.07 (m, 1H), 4.59 (q, J = 6.5 Hz, 1H), 4.09 - 4.00 (m, 2H), 3.67 - 3.59 (m, 5H), 3.57 - 3.52 (m, 1H), 3.49 - 3.43 (m, 1H), 2.74 - 2.59 (m, 2H), 2.57 - 2.52 (m, 1H), 2.48 - 2.43 (m, 1H), 2.38 - 2.23 (m, 4H), 2.01 - 1.93 (m, 2H), 1.85 - 1.77 (m, 2H), 1.72 - 1.64 (m, 4H), 1.52 (t, J = 5.4 Hz, 4H), 1.43 (d, J = 6.5 Hz, 3H). Example 125

[0405] 1 1H NMR (400 MHz, CDCl3) δ 8.94 (d, J = 2.0 Hz, 1H), 8.57 (d, J = 9.1 Hz, 1H), 8.45 (s, 1H), 8.08 (dd, J = 8.2, 2.3 Hz, 1H), 7.93 (dd, J = 9.1, 1.6 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 5.19 - 4.99 (m, 1H), 4.66 (q, J = 6.6 Hz, 1H), 4.52 (t, J = 7.8 Hz, 2H), 4.30 - 4.19 (m, 2H), 3.80 (s, 3H), 3.75 - 3.59 (m, 4H), 2.94 - 2.61 (m, 8H), 2.40 (t, J = 7.8 Hz, 2H), 2.11 - 1.93 (m, 6H), 1.55 (d, J = 6.6 Hz, 3H). Example 126

[0406] 11H NMR (400 MHz, DMSO-d6) δ 9.12 (d, J = 1.9 Hz, 1H), 8.54 (s, 1H), 8.48 (d, J = 9.1 Hz, 1H), 8.39 (dd, J = 8.2, 2.4 Hz, 1H), 8.16 (dd, J = 9.1, 1.6 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 5.20 - 5.08 (m, 1H), 4.72 (q, J = 6.5 Hz, 1H), 4.10 - 4.00 (m, 2H), 3.81 - 3.70 (m, 1H), 3.67 - 3.60 (m, 6H), 3.16 - 3.06 (m, 2H), 2.73 - 2.59 (m, 4H), 2.39 - 2.27 (m, 2H), 2.23 - 2.07 (m, 2H), 2.01 - 1.93 (m, 2H), 1.68 - 1.58 (m, 1H), 1.52 (d, J = 6.5 Hz, 3H), 1.07 (d, J = 6.7 Hz, 3H). Example 127

[0407] 1 1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.57 (d, J = 9.0 Hz, 1H), 8.48 (s, 1H), 8.11 (d, J = 6.0 Hz, 1H), 7.93 (d, J = 9.3 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 5.16 - 5.02 (m, 1H), 4.81 (s, 3H), 4.71 - 4.55 (m, 1H), 4.31 - 4.20 (m, 2H), 4.12 - 3.94 (m, 2H), 3.82 - 3.74 (m, 4H), 3.71 - 3.52 (m, 6H), 3.05 - 2.79 (m, 4H), 2.04 - 1.91 (m, 2H), 1.56 (d, J = 6.6 Hz, 3H). Example 128

[0408] 11H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.57 (d, J = 9.0 Hz, 1H), 8.46 (s, 1H), 8.09 (d, J = 6.3 Hz, 1H), 7.93 (d, J = 9.3 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 5.16 - 5.02 (m, 1H), 4.76 (t, J = 6.9 Hz, 2H), 4.67 (q, J = 6.5 Hz, 1H), 4.44 (t, J = 6.1 Hz, 2H), 4.26 (dd, J = 11.5, 4.4 Hz, 2H), 3.85 - 3.71 (m, 5H), 3.64 (t, J = 11.5 Hz, 2H), 3.43 - 3.22 (m, 2H), 3.00 - 2.74 (m, 5H), 2.51 - 2.34 (m, 2H), 1.97 (d, J = 9.5 Hz, 3H), 1.84 - 1.65 (m, 4H), 1.56 (d, J = 6.5 Hz, 3H). Example 129

[0409] 1 1H NMR (600 MHz, DMSO-d6) δ 9.11 (d, J = 2.2 Hz, 1H), 8.54 (s, 1H), 8.47 (d, J = 9.1 Hz, 1H), 8.38 (dd, J = 8.2, 2.4 Hz, 1H), 8.18 (dd, J = 9.1, 1.6 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 5.18 - 5.09 (m, 1H), 4.74 (q, J = 6.5 Hz, 1H), 4.25 - 4.15 (m, 1H), 4.10 - 4.02 (m, 2H), 3.82 - 3.75 (m, 2H), 3.69 - 3.66 (m, 4H), 3.61 (s, 3H), 3.50 - 3.48 (m, 4H), 3.13 (s, 3H), 2.69 - 2.60 (m, 2H), 2.44 - 2.35 (m, 2H), 2.00 - 1.93 (m, 2H), 1.51 (d, J = 6.5 Hz, 3H). Example 130

[0410] 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.55 - 8.40 (m, 2H), 8.33 (d, J = 4.4 Hz, 1H), 8.12 (d, J = 9.1 Hz, 1H), 7.69 (s, 1H), 5.20 - 5.01 (m, 1H), 4.68 - 4.52 (m, 1H), 4.14 - 3.97 (m, 2H), 3.70 - 3.53 (m, 7H), 3.12 - 2.52 (m, 8H), 2.44 - 2.31 (m, 1H), 2.26 - 2.10 (m, 1H), 2.03 - 1.90 (m, 2H), 1.89 - 1.68 (m, 1H), 1.52 - 1.34 (m, 5H). Example 131 8-(6-((2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)methyl)pyridine-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0465] [ka]

[0466] Step 1: 1-(2-amino-5-bromo-4-fluorophenyl)ethenone

[0467] [ka]

[0468]

[0411] To a solution of BCl3 (1.5 L, 1 M, 1.5 mol in DCM) stirred at 0°C, 4-bromo-3-fluoroaniline (250 g, 1.32 mol) in DCE (2.5 L) was added dropwise. MeCN (210 mL) and AlCl3 (210 g, 1.58 mol) were added to the solution little by little. The resulting mixture was stirred at 120°C for 16 hours. After the reaction had cooled, 2N HCl aqueous solution (3.1 L) was added dropwise to the mixture at 0°C, and the resulting mixture was stirred at 100°C for 2 hours. The reaction mixture was poured into ice water and extracted with DCM (2 L x 2). The combined organic phases were washed with brine, dried on anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (EA:PE=1:5) to obtain the desired product, 1-(2-amino-5-bromo-4-fluorophenyl)ethenone (60 g, 20% yield), as a white solid. MS:m / z232[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.8 Hz, 1H), 6.52-6.39 (m, 3H), 2.54 (s, 6H). Step 2: 6-bromo-7-fluorosinnoline-4-ol

[0469] [ka]

[0470]

[0412] A stirring solution of 1-(2-amino-5-bromo-4-fluorophenyl)ethane-1-one (120 g, 519.5 mmol) in concentrated HCl (1.7 L) and H2O (380 mL) was to be mixed with a solution of NaNO2 (40 g, 580 mmol) in H2O (100 mL) added dropwise at 0°C. After stirring for 0-1 hour, the resulting mixture was heated to 65°C for 16 hours. The reaction mixture was poured into ice water, and the precipitate was collected by filtration. The solid was washed with water and dried under vacuum to obtain the desired product (100 g, 80% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.62 (s, 1H), 8.25 (d, J = 7.4 Hz, 1H), 7.79 (s, 1H), 7.46 (d, J = 9.3 Hz, 1H).LC-MS:m / z243[M+H] + . Step 3: 6-bromo-7-fluoro-3-nitrosinnoline-4-ol

[0471] [ka]

[0472]

[0413] To a solution of 6-bromo-7-fluorosinnolin-4-ol (200 g, 826.4 mmol) in fuming HNO3 (600 mL) stirred at 0°C, concentrated H2SO4 (200 mL) was carefully added dropwise over 10 minutes. The resulting mixture was stirred at 60°C for 3 hours. After cooling to room temperature, the reaction mixture was poured into ice water. The precipitate was collected by filtration, washed with water, filtered again, and dried under vacuum to obtain the desired product (180 g, 76% yield) as a yellow solid. MS:m / z288[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 14.46 (s, 1H), 8.46 (d, J = 7.1 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H). Step 4: 6-Bromo-4-chloro-7-fluoro-3-nitrosinnoline

[0473] [ka]

[0474]

[0414] To a solution of 6-bromo-7-fluoro-3-nitrosinnoline-4-ol (180 g, 627 mmol) in DMF (900 mL) stirred at 0°C, POCl3 (125 g, 815 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water, the solid was filtered, washed with water, filtered again, and dried to obtain the crude product 6-bromo-4-chloro-7-fluoro-3-nitrosinnoline (145 g, 76% yield) as a yellow solid, which was used for the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 6.6 Hz, 1H), 8.38 (d, J = 7.7 Hz, 1H). Step 5: 6-Bromo-7-fluoro-N-isopropyl-3-nitrosinnoline-4-amine

[0475] [ka]

[0476]

[0415] To a solution of 6-bromo-4-chloro-7-fluoro-3-nitrosinnoline (145 g, 475 mmol) and Et3N (96 g, 951 mmol) in DCM (1.5 L) stirred at room temperature, isopropylamine (42 g, 715 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The crude mixture was washed with water (1 L), concentrated to dryness, and the residue was purified by column chromatography (EA:PE=1:1) on silica gel to obtain the desired product (102 g, 65% yield) as a yellow solid. MS:m / z329[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.54 (d, J = 6.5 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 4.46 (dp, J = 8.3, 6.2 Hz, 1H), 1.55 (d, J = 6.3 Hz, 6H). Step 6: 6-Bromo-7-fluoro-N4-isopropylcinnoline-3,4-diamine

[0477] [ka]

[0478]

[0416] To a solution of 6-bromo-7-fluoro-N-isopropyl-3-nitrosinnoline-4-amine (102 g, 311 mmol) in siRNA (1 L) stirred at room temperature, SnCl2·2H2O (281 g, 1244 mmol) was added. The resulting mixture was stirred at 80°C for 2 hours. The crude mixture was basicized with an aqueous solution of NaHCO3 to adjust the pH to 9 and filtered. The filtrate was extracted with siRNA (1 L). The organic phase was washed with water and brine, filtered, and the filtrate was concentrated to obtain the desired product (85 g, 88% yield) as a yellow solid. MS:m / z299[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 7.2 Hz, 1H), 7.80 (d, J = 9.7 Hz, 1H), 5.95 (s, 2H), 5.34 (d, J = 9.8 Hz, 1H), 4.05-3.90 (m, 1H), 1.16 (d, J = 6.3 Hz, 6H). Step 7: 8-Bromo-7-fluoro-1-isopropyl-1H-imidazo[4,5-c]synnoline-2(3H)-one

[0479] [ka]

[0480]

[0417] To a solution of 6-bromo-7-fluoro-N4-isopropylsinnoline-3,4-diamine (85 g, 285 mmol) in THF (1 L) stirred at room temperature, CDI (184 g, 1140 mmol) was added. The resulting mixture was stirred at 70°C for 16 hours. The reaction mixture was concentrated, the residue was poured into ice water, the solid was filtered, washed with water, and dried to obtain the desired product (81 g, 88% yield) as a yellow solid. MS:m / z325[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 6.7 Hz, 1H), 8.11 (d, J = 8.9 Hz, 1H), 5.06 (s, 1H), 3.74 (s, 3H), 1.77 (d, J = 6.9 Hz, 6H). Step 8: 8-Bromo-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0481] [ka]

[0482]

[0418] To a solution of 8-bromo-7-fluoro-1-isopropyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (55 g, 170 mmol) in DMF (500 mL), K2CO3 (70 g, 510 mmol) was added at room temperature, followed by MeI (60 g, 425 mmol). After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water, and the precipitate was collected by filtration. The residue was purified by chromatography on silica gel (DCM:MeOH = 30:1) to obtain the desired product (48 g, 84% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.66 (d, J = 6.9 Hz, 1H), 8.17 (d, J = 9.6 Hz, 1H), 5.10 (p, J = 6.8 Hz, 1H), 1.59 (d, J = 6.7 Hz, 6H).LC-MS:m / z339[M+H] + . Step 9: 8-(6-((2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)methyl)pyridine-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0483] [ka]

[0484]

[0419] The crude product was prepared in the same manner as in Example 1, and purified by flash chromatography (DCM:MeOH=9:1) to obtain the desired product (30.0 mg, 19.0% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.42 (d, J = 7.7 Hz, 1H), 8.28 (s, 1H), 8.24 (d, J = 11.5 Hz, 1H), 8.21-8.16 (m, 1H), 7.65 (d, J = 8.1 Hz, 1H), 5.30-5.21 (m, 1H), 4.67 (s, 2H), 3.68 (t, J = 5.9 Hz, 2H), 3.59 (s, 3H), 2.77-2.68 (m, 4H), 2.52 (s, 2H), 1.73 (t, J = 6.9 Hz, 2H), 1.63 (d, J = 6.7 Hz, 6H), 0.57-0.46 (m, 4H).LC-MS(ESI)m / z:491[M+H] + .

[0485]

[0420] The following compounds were prepared using different starting materials according to the method described above.

[0486] Table 10

[0487] Example 132

[0421] 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.41 (d, J = 7.7 Hz, 1H), 8.22 (d, J = 11.5 Hz, 1H), 8.20-8.15 (m, 1H), 7.65 (d, J = 8.1 Hz, 1H), 5.31-5.21 (m, 1H), 4.68 (s, 2H), 3.68 (t, J = 5.9 Hz, 2H), 3.59 (s, 3H), 2.78-2.67 (m, 4H), 2.42 (s, 2H), 1.63 (d, J = 6.7 Hz, 6H), 1.54 (t, J = 7.1 Hz, 2H), 1.06 (s, 6H). Example 133

[0422] 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.40 (d, J = 7.5 Hz, 1H), 8.21 (d, J = 11.4 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 5.32-5.16 (m, 1H), 4.65 (s, 2H), 3.65 (t, J = 5.7 Hz, 2H), 3.58 (s, 3H), 2.56 (t, J = 5.7 Hz, 2H), 2.43-2.30 (m, 4H), 1.62 (d, J = 6.6 Hz, 6H), 1.36-1.25 (m, 4H), 0.87 (s, 6H). Example 134

[0423] 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.20-8.13 (m, 2H), 8.01 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 5.12 (s, 1H), 4.86 (d, J = 16.1 Hz, 2H), 3.82 (s, 1H), 3.74 (s, 3H), 3.21 (s, 1H), 3.03-2.61 (m, 8H), 2.33 (d, J = 6.9 Hz, 1H), 2.10 (s, 1H), 1.74 (d, J = 6.9Hz, 6H). Example 135 (R)-8-(6-(1-(2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0488] [ka]

[0489] Step 1: (R)-8-(6-(1-(2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0490] [ka]

[0491]

[0424] The crude product was prepared in the same manner as in Example 1 and purified by flash chromatography (DCM:MeOH=9:1) to obtain the desired product (30.0 mg, 18.4% yield in two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.44 (d, J = 7.7 Hz, 1H), 8.29-8.17 (m, 2H), 7.68 (d, J = 8.1 Hz, 1H), 5.33-5.22 (m, 1H), 4.66 (q, J = 6.5 Hz, 1H), 3.70-3.64 (m, 1H), 3.60 (s, 3H), 3.58-3.54 (m, 1H), 3.12-3.00 (m, 4H), 2.87 (s, 2H), 1.84 (t, J = 7.1 Hz, 2H), 1.64 (d, J = 6.7 Hz, 6H), 1.48 (d, J = 6.5 Hz, 3H), 0.68-0.53 (m, 4H).LC-MS(ESI)m / z:505[M+H] + .

[0492]

[0425] The following compounds were prepared using different starting materials according to the method described above.

[0493] [Table 11-1]

[0494] [Table 11-2]

[0495] [Table 11-3]

[0496] Example 136

[0426] 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.43 (d, J = 7.7 Hz, 1H), 8.26-8.15 (m, 2H), 7.66 (d, J = 8.1 Hz, 1H), 5.32-5.21 (m, 1H), 4.75-4.54 (m, 2H), 3.65-3.53 (m, 4H), 3.51-3.42 (m, 1H), 2.62-2.53 (m, 4H), 2.37-2.28 (m, 2H), 1.91-1.77 (m, 2H), 1.74-1.60 (m, 8H), 1.44 (d, J = 6.5 Hz, 3H). Example 137

[0427] 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.43 (d, J = 7.7 Hz, 1H), 8.23-8.14 (m, 2H), 7.66 (d, J = 8.1 Hz, 1H), 5.32-5.22 (m, 1H), 4.61 (q, J = 6.5 Hz, 1H), 3.59 (s, 3H), 3.57-3.53 (m, 1H), 3.49-3.45 (m, 1H), 2.75-2.61 (m, 4H), 2.37 (s, 2H), 1.64 (d, J = 6.7 Hz, 6H), 1.52 (t, J = 7.1 Hz, 2H), 1.45 (d, J = 6.5 Hz, 3H), 1.04 (d, J = 2.2 Hz, 6H). Example 138

[0428] 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.44 (d, J = 7.7 Hz, 1H), 8.23 ​​(d, J = 11.5 Hz, 1H), 8.21 - 8.15 (m, 2H), 7.65 (d, J = 8.1 Hz, 1H), 5.32 - 5.22 (m, 1H), 4.61 (q, J = 6.5 Hz, 1H), 3.90 - 3.83 (m, 1H), 3.59 (s, 3H), 3.57 - 3.54 (m, 2H), 3.50 - 3.45 (m, 2H), 2.76 - 2.53 (m, 6H), 2.50 - 2.45 (m, 1H), 2.01 - 1.91 (m, 1H), 1.69 - 1.59 (m, 7H), 1.45 (d, J = 6.5 Hz, 3H). Example 139

[0429] 1 H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.42 (d, J = 7.5 Hz, 1H), 8.24-8.13 (m, 2H), 7.65 (d, J = 8.1 Hz, 1H), 5.31-5.17 (m, 1H), 4.64-4.54 (m, 1H), 3.61-3.52 (m, 4H), 3.49-3.44 (m, 1H), 2.59-2.51 (m, 2H), 2.42-2.31 (m, 4H), 1.62 (d, J=6.5 Hz, 6H), 1.43 (d, J = 6.3 Hz, 3H), 1.33-1.25 (m, 4H), 0.87 (s, 6H). Example 140

[0430] 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.44 (d, J = 7.7 Hz, 1H), 8.22-8.14 (m, 2H), 7.68 (d, J = 8.1 Hz, 1H), 5.33-5.22 (m, 1H), 4.62 (q, J = 6.5 Hz, 1H), 3.64-3.61 (m, 1H), 3.60 (s, 3H), 3.54-3.51 (m, 1H), 2.71-2.60 (m, 2H), 2.56-2.52 (m, 4H), 1.64 (d, J = 6.7 Hz, 6H), 1.46 (d, J = 6.5 Hz, 3H), 1.35 (s, 4H), 0.26 (s, 4H). Example 141

[0431] 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.44 (d, J = 7.7 Hz, 1H), 8.25 - 8.12 (m, 2H), 7.69 - 7.62 (m, 1H), 5.31 - 5.23 (m, 1H), 4.97 - 4.88 (m, 1H), 4.61 (q, J = 6.3 Hz, 1H), 3.62 - 3.54 (m, 4H), 3.51 - 3.44 (m, 1H), 2.85 - 2.57 (m, 5H), 2.41 - 2.32 (m, 1H), 2.28 - 2.18 (m, 1H), 1.89 - 1.80 (m, 1H), 1.63 (d, J = 6.7 Hz, 6H), 1.45 (d, J = 6.5 Hz, 3H). Example 142

[0432] 11H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.42 (d, J = 7.4 Hz, 1H), 8.21-8.13 (m, 2H), 7.65 (d, J = 8.0 Hz, 1H), 5.30-5.20 (m, 1H), 4.64-4.55 (m, 1H), 3.58 (s, 3H), 3.54-3.49 (m, 1H), 3.22-3.10 (m, 5H), 2.78-2.69 (m, 2H), 2.62-2.54 (m, 2H), 2.25-2.12 (m, 2H), 1.85-1.77 (m, 2H), 1.62 (d, J = 6.4 Hz, 6H), 1.48-1.35 (m, 5H). Example 143

[0433] 1 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.42 (d, J = 7.6 Hz, 1H), 8.21 (d, J = 11.5 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 5.30-5.20 (m, 1H), 4.57 (q, J = 6.4 Hz, 1H), 3.58 (s, 3H), 3.53-3.43 (m, 2H), 2.93 (t, J = 8.1 Hz, 2H), 2.67-2.55 (m, 2H), 2.36-2.24 (m, 2H), 1.62 (d, J = 6.6 Hz, 6H), 1.42 (d, J = 6.5 Hz, 3H), 1.36-1.27 (m, 2H), 0.60-0.53 (m, 1H), 0.32-0.22 (m, 1H). Example 144

[0434] 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.16-8.08 (m, 2H), 7.99-7.92 (m, 1H), 7.55 (d, J = 8.2 Hz, 1H), 5.13-5.02 (m, 1H), 4.65-4.55 (m, 1H), 4.38-4.22 (m, 1H), 3.75-3.54 (m, 5H), 2.96-2.59 (m, 4H), 1.93-1.78 (m, 2H), 1.70 (d, J = 6.9 Hz, 6H), 1.50 (d, J = 6.6 Hz, 3H), 1.23-1.14 (m, 2H), 0.86–0.71 (m, 2H). Example 145

[0435] 1 H NMR (400 MHz, DMSO) δ 8.87 (s, 1H), 8.44 (d, J = 7.7 Hz, 1H), 8.30 (s, 1H), 8.26-8.15 (m, 2H), 7.66 (d, J = 8.1 Hz, 1H), 5.30-5.20 (m, 1H), 4.60 (q, J = 6.5 Hz, 1H), 3.59 (s, 3H), 3.58-3.53 (m, 1H), 3.50-3.46 (m, 1H), 2.90-2.81 (m, 1H), 2. 63-2.52 (m, 4H), 2.38-2.27 (m, 2H), 1.91-1.79 (m, 2H), 1.74-1.59 (m, 8H), 1.44 (d, J = 6.5 Hz, 3H). Example 146

[0436] 11H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.44 (d, J = 7.7 Hz, 1H), 8.30 - 8.21 (m, 1H), 8.20 - 8.16 (m, 1H), 7.66 (d, J = 8.1 Hz, 1H), 6.66 (t, J = 76.0 Hz, 1H), 5.33 - 5.20 (m, 1H), 4.71 - 4.55 (m, 2H), 3.60 (s, 3H), 3.58 - 3.53 (m, 2H), 2.76 - 2.64 (m, 4H), 2.62 - 2.55 (m, 1H), 2.42 - 2.36 (m, 1H), 2.19 - 2.10 (m, 1H), 1.80 - 1.70 (m, 1H), 1.63 (d, J = 6.7 Hz, 6H), 1.45 (d, J = 6.5 Hz, 3H). Example 147

[0437] 1 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.44 (d, J = 7.7 Hz, 1H), 8.26 - 8.15 (m, 2H), 7.68 (dd, J = 8.2, 2.1 Hz, 1H), 5.32 - 5.20 (m, 1H), 4.61 (q, J = 6.3 Hz, 1H), 3.59 (s, 3H), 3.58 - 3.54 (m, 1H), 3.50 - 3.44 (m, 1H), 3.11 - 3.01 (m, 1H), 2.85 - 2.56 (m, 4H), 2.44 - 2.39 (m, 1H), 2.28 - 2.18 (m, 1H), 1.85 - 1.75 (m, 1H), 1.64 (d, J = 6.7 Hz, 6H), 1.46 (d, J = 6.5 Hz, 3H), 1.40 (d, J = 2.2 Hz, 3H). Example 148 (R)-8-(6-(1-(2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0497] [ka]

[0498] Step 1: 6-Bromo-7-fluoro-3-nitro-N-(tetrahydro-2H-pyran-4-yl)cinnoline-4-amine

[0499] [ka]

[0500]

[0438] To a solution of 6-bromo-4-chloro-7-fluoro-3-nitrosinnoline (90.0 g, 295 mmol) and Et3N (63.7 g, 590 mmol) in DCM (1 L) stirred at room temperature, tetrahydro-2H-pyran-4-amine (44.8 g, 444 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The mixture was poured into a 1 M HCl solution on ice (1 L), and the DCM was evaporated under reduced pressure to precipitate a yellow solid, which was then filtered. The filter residue was tritulated in MTBE (300 mL) at room temperature for 1 hour and filtered. The filter cake was dried in an oven at 55°C for 16 hours to obtain the desired product (80.0 g, 73.4% yield) as a yellow solid. LC-MS(ESI) m / z: 371[M+H] + . Step 2: 6-Bromo-7-fluoro-N4-(tetrahydro-2H-pyran-4-yl)sinnoline-3,4-diamine

[0501] [ka]

[0502]

[0439] In a solution of 6-bromo-7-fluoro-3-nitro-N-(tetrahydro-2H-pyran-4-yl)sinnoline-4-amine (80.0g, 216 mmol) in MeOH (400 mL), add SnCl2 . H2O (146 g, 648 mmol) was added at 0°C, and the reaction mixture was stirred at 60°C for 2 hours. The mixture was adjusted to pH approximately 8 with 50% NaOH solution at less than 45°C, and stirred at 55°C for 45 minutes. The mixture was filtered, and the filtered residue was tritulated in MeOH (300 mL) at room temperature for 1 hour. After filtration, the combined filtrate was evaporated under reduced pressure. The residue was tritulated in MTBE (300 mL) at room temperature for 1 hour and filtered. The filter cake was dried in an oven at 55°C for 16 hours to obtain the desired product (65.0 g, 88.6% yield) as a yellow solid. LC-MS(ESI) m / z: 341[M+H] + . Step 3: 8-Bromo-7-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0503] [ka]

[0504]

[0440] To a solution of 6-bromo-7-fluoro-N4-(tetrahydro-2H-pyran-4-yl)cinnoline-3,4-diamine (35.0 g, 103 mmol) in THF (350 mL) stirred at room temperature, CDI (50.1 g, 309 mmol) was added. The resulting mixture was stirred at 65 °C for 2 hours. The mixture was evaporated under reduced pressure, and the residue was dissolved in water (250 mL). The pH was adjusted to approximately 7 with 1 M HCl solution, and the mixture was filtered. The filtered residue was dried in an oven at 55 °C for 16 hours to obtain the desired product (31.0 g, 82.4% yield). LC-MS(ESI) m / z: 367[M+H] + . Step 4: 8-Bromo-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0505] [ka]

[0506]

[0441] To a solution of 8-bromo-7-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (31.0 g, 84.7 mmol) in dry DMF (250 mL), t-BuONa (9.76 g, 102 mmol) was added at 0°C. After stirring under N2 at 0°C for 30 minutes, MeI (14.5 g, 102 mmol) was added dropwise to the reaction mixture at 10°C-15°C, and the reaction mixture was stirred at 10°C-15°C for 2 hours. The mixture was poured into ice water (600 mL) and filtered. The filtered residue was tritulated with MeOH (200 mL) at 80°C for 1 hour and filtered. The desired product (25.0 g, 76.8% yield) was obtained by drying the filter cake under vacuum. LC-MS(ESI) m / z:381[M+H] + . Step 5: (R)-8-(6-(1-(2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0507] [ka]

[0508]

[0442] The crude product was prepared in the same manner as in Example 1 and purified by flash chromatography (DCM:MeOH=9:1) to obtain the desired product (40.0 mg, 22.7% yield in two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.47 (d, J = 7.8 Hz, 1H), 8.29-8.20 (m, 2H), 7.68 (d, J = 8.2 Hz, 1H), 5.14-5.01 (m, 1H), 4.61 (q, J = 6.6 Hz, 1H), 4.05-3.96 (m, 2H), 3.61 (s, 3H), 3.59-3.56 (m, 2H), 3.51-3.48 (m, 1H), 2.74-2.56 (m, 7H), 2.47 (s, 2H), 1.98-1.90 (m, 2H), 1.71 (t, J = 6.8 Hz, 2H), 1.45 (d, J = 6.5 Hz, 3H), 0.56-0.44 (m, 4H).LC-MS(ESI)m / z:547[M+H] + .

[0509]

[0443] The following compounds were prepared using different starting materials according to the method described above.

[0510] [Table 12-1]

[0511] [Table 12-2]

[0512] [Table 12-3]

[0513] Example 149

[0444] 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.53-8.43 (m, 2H), 8.29-8.23 (m, 1H), 7.69 (d, J = 8.2 Hz, 1H), 5.13-5.01 (m, 1H), 4.61 (q, J = 6.3 Hz, 1H), 4.07-3.96 (m, 2H), 3.65-3.54 (m, 6H), 3.49-3.45 (m, 1H), 2.70-2.53 (m, 4H), 2.40-2.32 (m, 4H), 1.99-1.90 (m, 2H), 1.45 (d, J = 6.5 Hz, 3H), 1.34-1.27 (m, 4H), 0.88 (s, 6H). Example 150

[0445] 1 H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.47 (d, J = 7.7 Hz, 1H), 8.30-8.19 (m, 2H), 7.69 (d, J = 8.2 Hz, 1H), 5.13-5.01 (m, 1H), 4.74-4.56 (m, 2H), 4.05-3.97 (m, 2H), 3.62-3.55 (m, 6H), 3.51-3.46 (m, 1H), 2.71-2.53 (m, 7H), 2.38-2.29 (m, 2H), 1.99-1.63 (m, 7H), 1.45 (d, J = 6.5 Hz, 3H). Example 153

[0446] 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.45 (d, J = 7.6 Hz, 1H), 8.27-8.16 (m, 2H), 7.68 (d, J = 8.1 Hz, 1H), 5.12-5.00 (m, 1H), 4.67-4.53 (m, 1H), 4.08-3.95 (m, 2H), 3.59 (s, 3H), 3.58-3.52 (m, 4H), 2.76-2.56 (m, 6H), 2.36 (s, 2H), 1.99-1.88 (m, 2H), 1.51 (t, J = 6.9 Hz, 2H), 1.44 (d, J = 6.4 Hz, 3H), 1.03 (s, 6H). Example 154

[0447] 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.23 ​​(d, J = 7.7 Hz, 1H), 8.02-7.94 (m, 2H), 7.46 (d, J = 8.2 Hz, 1H), 4.89-4.77 (m, 1H), 4.43-4.32 (m, 1H), 3.81-3.69 (m, 2H), 3.40-3.31 (m, 7H), 3.29-3.23 (m, 1H), 2.47-2.30 (m, 7H), 2.24-2.17 (m, 4H), 1.75-1.66 (m, 2H), 1.21 (d, J = 6.5 Hz, 3H), 1.09 (s, 4H). Example 155

[0448] 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.45 (d, J = 7.9 Hz, 1H), 8.27-8.16 (m, 2H), 7.66 (d, J = 8.6 Hz, 1H), 6.64 (t, J = 76.0 Hz, 1H), 5.09-5.00 (m, 1H), 4.70-4.55 (m, 2H), 4.03-3.94 (m, 2H), 3.64-3.44 (m, 7H), 2.76-2.56 (m, 7H), 2.43-2.33 (m, 1H), 2.17-2.07 (m, 1H), 1.96-1.88 (m, 2H), 1.77-1.68 (m, 1H), 1.44 (d, J = 6.4 Hz, 3H). Example 156

[0449] 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.44 (d, J = 7.8 Hz, 1H), 8.27-8.17 (m, 2H), 7.67 (d, J = 8.3 Hz, 1H), 5.11-5.00 (m, 1H), 4.59 (q, J = 6.5 Hz, 1H), 4.07-3.94 (m, 2H), 3.63-3.52 (m, 6H), 3.49-3.42 (m, 2H), 2.69-2.57 (m, 2H), 2.47-2.40 (m, 1H), 2.36-2.18 (m, 4H), 1.98-1.89 (m, 2H), 1.84-1.75 (m, 2H), 1.71-1.63 (m, 4H), 1.54-1.46 (m, 4H), 1.43 (d, J = 6.5 Hz, 3H). Example 157

[0450] 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.47 (d, J = 7.7 Hz, 1H), 8.29-8.21 (m, 2H), 7.69 (d, J = 8.2 Hz, 1H), 5.11-5.01 (m, 1H), 4.61 (q, J = 6.5 Hz, 1H), 4.46-4.36 (m, 1H), 4.04-3.95 (m, 2H), 3.61 (s, 3H), 3.60-3.54 (m, 2H), 3.50-3.44 (m, 1H), 2.74-2.53 (m, 7H), 2.33-2.23 (m, 2H), 1.98-1.87 (m, 4H), 1.75-1.63 (m, 2H), 1.45 (d, J = 6.5 Hz, 3H). Example 158

[0451] 1 H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.46 (d, J = 7.6 Hz, 1H), 8.28-8.20 (m, 2H), 7.67 (d, J = 8.1 Hz, 1H), 6.65 (t, J = 76.0 Hz, 1H), 5.11-5.00 (m, 1H), 4.71-4.56 (m, 2H), 4.04-3.93 (m, 2H), 3.63-3.54 (m, 8H), 2.77-2.57 (m, 6H), 2.42-2.30 (m, 1H), 2.22-2.07 (m, 1H), 1.99-1.89 (m, 2H), 1.78-1.70 (m, 1H), 1.45 (d, J = 6.5 Hz, 3H). Example 159 8-(6-((2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)methyl)pyridine-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0514] [ka]

[0515] Step 1: tert-butyl(cis-3-hydroxycyclobutyl)carbamate

[0516] [ka]

[0517]

[0452] A solution of tert-butyl (3-oxocyclobutyl) carbamate (10.0 g, 54.0 mmol) in dry tetrahydrofuran (200 mL) was stirred under N2 at -78°C for 10 minutes. 1N lithium triisobutyl hydroborate (81.0 mL, 81.0 mmol) was added dropwise to the reaction mixture at -78°C, and the reaction mixture was stirred at -78°C for 2 hours. 2N NaOH solution (40 mL) was added dropwise to the reaction mixture at -45°C, followed by H2O2 (30 mL) at -45°C. The resulting mixture was warmed to room temperature and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with sodium bisulfite solution (50 mL) and brine (200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (PE:EA = 5:1 to 1:1) to obtain the desired product (8.50 g, 84.1% yield) as diesel fuel. Step 2: (trans)-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-nitrobenzoate

[0518] [ka]

[0519]

[0453] A mixture of tert-butyl (trans-3-hydroxycyclobutyl) carbamate (7.00 g, 38.0 mmol) and 4-nitrobenzoic acid (7.00 g, 42.0 mmol) in 150 mL of dry tetrahydrofuran was mixed with triphenylphosphine (15.0 g, 57.0 mmol), followed by diisopropyl azodicarboxylic acid (14.6 g, 72.0 mmol) at 0°C under N2. The resulting mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel (PE:EA = 20:1 to 5:1) to obtain a crude product (20.0 g) as a white solid. Step 3: tert-butyl(trans-3-hydroxycyclobutyl)carbamate

[0520] [ka]

[0521]

[0454] To a solution of trans-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-nitrobenzoate (20.0 g, 60.0 mmol) in H2O (90 mL) and MeOH (400 mL), potassium carbonate (12.5 g, 90.0 mmol) was added, and the reaction mixture was stirred at 70°C for 1 hour. The MeOH was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (150 mL x 3). The combined organic layer was washed with brine (150 mL), dried on anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (PE:EA = 5:1 to 1:1) to obtain the crude product (9.00 g) as a white solid. Step 4: tert-butyl(trans-3-methoxycyclobutyl)carbamate

[0522] [ka]

[0523]

[0455] To a solution of tert-butyl (trans-3-hydroxycyclobutyl) carbamate (9.00 g, 48.0 mmol) in DCM (90 mL), N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (10.3 g, 48.0 mmol), followed by trimethyloxonium tetrafluoroborate (7.60 g, 51.0 mmol), the reaction mixture was stirred under N2 at 40°C for 72 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel (PE:EA = 15:1 to 3:1) to obtain the desired product (2.50 g, 27.4% yield in three steps) as a white solid. Step 5: trans-3-methoxycyclobutan-1-amine

[0524] [ka]

[0525]

[0456] To a solution of tert-butyl (trans-3-methoxycyclobutyl)carbamate (2.50 g) in 1,4-dioxane (20 mL), 4 M hydrochloric acid in 1,4-dioxane (20 mL) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure to obtain the crude product (1.50 g) as an off-white solid. Step 6: 6-Bromo-N-(trans-3-methoxycyclobutyl)-3-nitrosinnoline-4-amine

[0526] [ka]

[0527]

[0457] A mixture of 6-bromo-4-chloro-3-nitrosinnoline (2.8 g, 9.9 mmol) and propan-2-amine (1.5 g, 15 mmol) in DCM (30 mL) was mixed with TEA (2.8 mL, 20 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into a 1 M HCl solution on ice (19 mL) and extracted with DCM (50 mL x 2). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the desired product (3.70 g, 86.1% purity) as a brown solid. Step 7: 6-Bromo-N 4 -(trans-3-methoxycyclobutyl)sinnoline-3,4-diamine

[0528] [ka]

[0529]

[0458] In a solution of 6-bromo-N-(trans-3-methoxycyclobutyl)-3-nitrosinnoline-4-amine (3.7g, 10.5 mmol) in MeOH (40 mL), add SnCl2 . H2O (7 g, 31.5 mmol) was added at 0°C, and the reaction mixture was stirred at 60°C for 2 hours. The mixture was adjusted to a pH of approximately 8 with 50% NaOH solution at less than 45°C, and stirred at 55°C for 45 minutes. The mixture was filtered, and the filtered residue was tritulated in THF (30 mL) at room temperature for 1 hour. After filtration, the combined filtrate was evaporated under reduced pressure. The residue was tritulated in THF (30 mL) at room temperature for 1 hour and filtered. By evaporating the filtrate under reduced pressure, the desired product (2.00 g, 58.8% yield) was obtained as a dark brown solid. Step 8: 8-Bromo-1-(trans-3-methoxycyclobutyl)-1,3-dihydro-2H-imidazo[4,5-c]sinnoline-2one

[0530] [ka]

[0531]

[0459] 6-bromo-N in dried THF (20 mL) 4 To a solution of -(trans-3-methoxycyclobutyl)sinnoline-3,4-diamine (2.00 g, 6.20 mmol), CDI (3.10 g, 18.6 mmol) was added, and the reaction mixture was stirred at 65°C for 2 hours. The mixture was evaporated under reduced pressure, and the residue was dissolved in water (20 mL). The pH was adjusted to approximately 7 with 1 M HCl solution, and the mixture was filtered. The filtered residue was dried in an oven at 55°C for 16 hours to obtain the desired product (1.20 g, 54.5% yield) as a brown solid. Step 9: 8-Bromo-1-(trans-3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one

[0532] [ka]

[0533]

[0460] To a solution of 8-bromo-1-(trans-3-methoxycyclobutyl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one (1.20 g, 3.50 mmol) in dry DMF (10 mL), t-BuONa (404 mg, 4.20 mmol) was added at 0°C and the mixture was stirred under N2 at 0°C for 30 minutes. Then, MeI (1.00 g, 7.00 mmol) was added dropwise to the reaction mixture at 10°C to 15°C and the reaction mixture was stirred at 10°C to 15°C for 2 hours. The mixture was poured into ice water (60 mL) and filtered. The filtered residue was tritulated with MeOH (20 mL) for 1 hour and filtered. The filter cake was dried under vacuum to obtain the desired product (950 mg, 74.9% yield) as a light brown solid. Step 10: 8-(6-((2-(5-Azaspiro[2,4]heptan-5-yl)ethoxy)methyl)pyridine-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one

[0534] [ka]

[0535]

[0461] The crude product was prepared in the same manner as in Example 1 and purified by chromatography on silica gel (DCM:MeOH = 100:1 to 10:1) to obtain the crude product. This was purified three times by flash chromatography (DCM:MeOH = 9:1) to obtain the desired product (50.0 mg, 20% yield in two steps) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 9.1 Hz, 1H), 8.37-8.29 (m, 2H), 8.10 (dd, J = 9.1, 1.7 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 5.63-5.52 (m, 1H), 4.67 (s, 2H), 4.32-4.23 (m, 1H), 3.66 (t, J = 5.9 Hz, 2H), 3.61 (s, 3H), 3.24-3.13 (m, 5H), 2.72-2.57 (m, 6H), 2.48 (s, 2H), 1.72 (t, J = 6.8 Hz, 2H), 0.56-0.44 (m, 4H).LC-MS(ESI)m / z:515[M+H] + .

[0536]

[0462] The following compounds were prepared using different starting materials according to the method described above.

[0537] [Table 13-1]

[0538] [Table 13-2]

[0539] Table 13-3

[0540] Table 13-4

[0541] Table 13-5

[0542] Example 160

[0463] 1 H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.55 (d, J = 9.0 Hz, 1H), 8.21 (s, 1H), 8.06 (d, J = 7.5 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 5.58-5.44 (m, 1H), 4.84-4.65 (m, 2H), 4.40-4.29 (m, 1H), 4.25-4.09 (m, 2H), 3.78 (s, 3H), 3.47-3.31 (m, 9H), 2.69-2.59 (m, 2H), 2.10-1.88 (m, 4H), 1.29 (s, 6H). Example 161

[0464] 11H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 1.9 Hz, 1H), 8.42 (d, J = 9.1 Hz, 1H), 8.38 - 8.30 (m, 2H), 8.10 (dd, J = 9.1, 1.7 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 5.65 - 5.53 (m, 1H), 4.61 (q, J = 6.5 Hz, 1H), 4.33 - 4.24 (m, 1H), 3.60 (s, 3H), 3.59 - 3.54 (m, 1H), 3.50 - 3.46 (m, 1H), 3.22 (s, 3H), 3.21 - 3.14 (m, 2H), 2.78 - 2.58 (m, 6H), 2.54 (s, 2H), 1.73 (t, J = 6.9 Hz, 2H), 1.45 (d, J = 6.5 Hz, 3H), 0.57 - 0.45 (m, 4H). Example 163

[0465] 1 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.55 (d, J = 9.0 Hz, 1H), 8.19 (s, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 5.54 - 5.45 (m, 1H), 4.71 - 4.63 (m, 1H), 4.36 - 4.31 (m, 1H), 4.03 - 3.96 (m, 1H), 3.81 - 3.66 (m, 6H), 3.47 - 3.36 (m, 3H), 3.35 (s, 3H), 3.31 (s, 3H), 3.02 - 2.79 (m, 4H), 2.71 - 2.59 (m, 2H), 2.19 - 2.07 (m, 1H), 2.00 - 1.88 (m, 1H), 1.57 (d, J = 6.5 Hz, 3H). Example 164

[0466] 11H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 9.1 Hz, 1H), 8.37 (d, J = 1.4 Hz, 1H), 8.33 (dd, J = 8.2, 2.4 Hz, 1H), 8.10 (dd, J = 9.1, 1.7 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 5.63-5.54 (m, 1H), 4.61 (q, J = 6.5 Hz, 1H), 4.32-4.22 (m, 1H), 3.63-3.54 (m, 4H), 3.52-3.44 (m, 1H), 3.22 (s, 3H), 3.20-3.13 (m, 2H), 2.68-2.53 (m, 4H), 2.47-2.33 (m, 4H), 1.44 (d, J = 6.5 Hz, 3H), 1.37-1.24 (m, 4H), 0.23 (s, 4H). Example 165

[0467] 1 1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 2.3 Hz, 1H), 8.35 (d, J = 9.1 Hz, 1H), 8.31-8.2三 (m, 2H), 8.04 (dd, J = 9.1, 1.7 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 5.57-5.45 (m, 1H), 4.63 (s, 2H), 4.29-4.20 (m, 1H), 3.64 (t, J = 5.8 Hz, 2H), 3.57 (s, 3H), 3.24-3.08 (m, 5H), 2.65-2.50 (m, 4H), 2.20 (s, 6H). Example 166

[0468] 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.39 (d, J = 9.1 Hz, 1H), 8.35 - 8.26 (m, 2H), 8.07 (d, J = 9.1 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 5.59 - 5.50 (m, 1H), 4.65 (s, 2H), 4.31 - 4.20 (m, 1H), 3.66 (t, J = 6.0 Hz, 2H), 3.59 (s, 3H), 3.23 - 3.10 (m, 5H), 2.76 - 2.67 (m, 2H), 2.65 - 2.50 (m, 6H), 1.74 - 1.58 (m, 4H). Example 167

[0469] 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 2.3 Hz, 1H), 8.39 (d, J = 9.0 Hz, 1H), 8.35-8.25 (m, 2H), 8.07 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 5.61-5.48 (m, 1H), 4.64 (s, 2H), 4.31-4.19 (m, 1H), 3.64 (t, J = 5.9 Hz, 2H), 3.58 (s, 3H), 3.23-3.10 (m, 5H), 2.65-2.51 (m, 4H), 2.44-2.27 (m, 4H), 1.54-1.42 (m, 4H), 1.41-1.29 (m, 2H). Example 168

[0470] 1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 2.3 Hz, 1H), 8.36 (d, J = 9.1 Hz, 1H), 8.31-8.23 (m, 2H), 8.05 (dd, J = 9.1, 1.7 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 5.59-5.45 (m, 1H), 4.75-4.53 (m, 3H), 4.30-4.18 (m, 1H), 3.65 (t, J = 5.8 Hz, 2H), 3.57 (s, 3H), 3.25-3.09 (m, 5H), 2.68-2.51 (m, 6H), 2.42-2.29 (m, 2H), 1.92-1.75 (m, 2H), 1.75-1.60 (m, 2H). Example 169

[0471] 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 2.3 Hz, 1H), 8.35 (d, J = 9.1 Hz, 1H), 8.31-8.22 (m, 2H), 8.04 (dd, J = 9.1, 1.7 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 5.56-5.46 (m, 1H), 4.61 (s, 2H), 4.31-4.18 (m, 1H), 3.63-3.52 (m, 5H), 3.26-3.05 (m, 5H), 2.96 (d, J = 8.6 Hz, 2H), 2.71-2.53 (m, 4H), 2.31 (d, J = 8.4 Hz, 2H), 1.37-1.28 (m, 2H), 0.60-0.54 (m, 1H), 0.31-0.24 (m, 1H). Example 170

[0472] 11H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 2.0 Hz, 1H), 8.54 (d, J = 1.3 Hz, 1H), 8.42 (d, J = 9.1 Hz, 1H), 8.34 (dd, J = 8.2, 2.4 Hz, 1H), 8.09 (dd, J = 9.1, 1.6 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 5.19 - 5.06 (m, 1H), 4.61 (q, J = 6.5 Hz, 1H), 3.91 - 3.82 (m, 1H), 3.62 - 3.56 (m, 5H), 3.52 - 3.46 (m, 4H), 3.20 (s, 3H), 3.03 - 2.95 (m, 2H), 2.87 - 2.78 (m, 2H), 2.67 - 2.56 (m, 2H), 1.44 (d, J = 6.5 Hz, 3H), 1.38 - 1.26 (m, 4H), 0.24 (s, 4H). Example 171

[0473] 1 1H NMR (400 MHz, DMSO) δ 9.07 (d, J = 1.9 Hz, 1H), 8.55 (d, J = 1.3 Hz, 1H), 8.43 (d, J = 9.1 Hz, 1H), 8.34 (dd, J = 8.2, 2.4 Hz, 1H), 8.10 (dd, J = 9.1, 1.7 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 5.19 - 5.08 (m, 1H), 4.61 (q, J = 6.5 Hz, 1H), 3.93 - 3.83 (m, 1H), 3.60 (s, 3H), 3.59 - 3.54 (m, 1H), 3.48 - 3.44 (m, 1H), 3.20 (s, 3H), 3.05 - 2.95 (m, 2H), 2.88 - 2.80 (m, 2H), 2.77 - 2.64 (m, 4H), 2.53 (s, 2H), 1.73 (t, J = 6.9 Hz, 2H), 1.45 (d, J = 6.5 Hz, 3H), 0.57 - 0.46 (m, 4H). Example 172

[0474] 11H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 2.4 Hz, 1H), 8.50 (d, J = 1.8 Hz, 1H), 8.40 (d, J = 9.0 Hz, 1H), 8.31 (dd, J = 8.1, 2.5 Hz, 1H), 8.07 (dd, J = 9.1, 1.7 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 5.15 - 5.03 (m, 1H), 4.64 (s, 2H), 3.90 - 3.80 (m, 1H), 3.66 (t, J = 5.9 Hz, 2H), 3.57 (s, 3H), 3.18 (s, 3H), 3.01 - 2.91 (m, 2H), 2.86 - 2.77 (m, 2H), 2.70 (t, J = 5.9 Hz, 2H), 2.56 - 2.50 (m, 4H), 1.73 - 1.60 (m, 4H). Example 173

[0475] 1 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.51 (s, 1H), 8.41 (d, J = 9.1 Hz, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 5.15 - 5.04 (m, 1H), 4.64 (s, 2H), 3.92 - 3.80 (m, 1H), 3.65 (t, J = 5.9 Hz, 2H), 3.58 (s, 3H), 3.18 (s, 3H), 3.01 - 2.92 (m, 2H), 2.86 - 2.76 (m, 2H), 2.60 - 2.52 (m, 2H), 2.44 - 2.32 (m, 4H), 1.57 - 1.29 (m, 6H). Example 174

[0476] 11H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 2.9 Hz, 1H), 8.48 (s, 1H), 8.39 (dd, J = 9.1, 2.8 Hz, 1H), 8.30 (dd, J = 8.0, 2.7 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 5.16 - 5.03 (m, 1H), 4.74 - 4.53 (m, 3H), 3.91 - 3.81 (m, 1H), 3.65 (t, J = 5.6 Hz, 2H), 3.57 (s, 3H), 3.18 (s, 3H), 3.02 - 2.91 (m, 2H), 2.87 - 2.74 (m, 2H), 2.65 - 2.53 (m, 4H), 2.43 - 2.29 (m, 2H), 1.89 - 1.76 (m, 2H), 1.74 - 1.59 (m, 2H). Example 175

[0477] 1 1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 2.3 Hz, 1H), 8.50 (s, 1H), 8.40 (d, J = 9.1 Hz, 1H), 8.31 (dd, J = 8.1, 2.4 Hz, 1H), 8.07 (d, J = 9.1 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 5.17 - 5.02 (m, 1H), 4.63 (s, 2H), 3.91 - 3.81 (m, 1H), 3.63 - 3.54 (m, 5H), 3.18 (s, 3H), 3.04 - 2.91 (m, 4H), 2.87 - 2.76 (m, 2H), 2.66 (t, J = 5.8 Hz, 2H), 2.40 - 2.29 (m, 2H), 1.36 - 1.30 (m, 2H), 0.61 - 0.53 (m, 1H), 0.32 - 0.24 (m, 1H). Example 176

[0478] 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.51 (s, 1H), 8.41 (d, J = 9.1 Hz, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 5.16-5.05 (m, 1H), 4.64 (s, 2H), 3.90-3.81 (m, 1H), 3.64 (t, J = 5.8 Hz, 2H), 3.58 (s, 3H), 3.18 (s, 3H), 3.01-2.91 (m, 2H), 2.86-2.77 (m, 2H), 2.54-2.51 (m, 2H), 2.18 (s, 6H).

[0479] The following compounds were prepared using different starting materials according to the method described above.

[0543] [Table 14-1]

[0544] [Table 14-2]

[0545] Example 177

[0480] 1 H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.27-8.14 (m, 2H), 8.10 (s, 1H), 7.86 (d, J = 9.0, 2.0 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 4.82-4.71 (m, 1H), 4.61 (s, 2H), 4.45-4.36 (m, 1H), 4.14-4.04 (m, 1H), 3.79-3.69 (m, 1H), 3.61 (t, J = 5.9 Hz, 2H), 3.49-3.44 (m, 1H), 3.41 (s, 3H), 2.47-2.45 (m, 2H), 2.16 (s, 6H). Example 178

[0481] 1 H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J = 1.9 Hz, 1H), 8.29-8.19 (m, 2H), 8.13 (d, J = 1.9 Hz, 1H), 7.89 (dd, J = 9.0, 1.9 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 4.81-4.74 (m, 1H), 4.64 (s, 2H), 4.46-4.39 (m, 1H), 4.15-4.07 (m, 1H), 3.79-3.71 (m, 1H), 3.64 (t, J = 5.9 Hz, 2H), 3.52-3.47 (m, 1H), 3.43 (s, 3H), 2.56-2.52 (m, 2H), 2.44-2.32 (m, 4H), 1.53-1.44 (m, 4H), 1.42-1.31 (m, 2H) Example 179

[0482] 1 H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.27-8.15 (m, 2H), 8.10 (s, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 4.81-4.53 (m, 4H), 4.41 (d, J = 9.2 Hz, 1H), 4.15-4.03 (m, 1H), 3.78-3.68 (m, 1H), 3.63 (t, J = 5.8 Hz, 2H), 3.50-3.44 (m, 1H), 3.41 (s, 3H), 2.68-2.52 (m, 4H), 2.42-2.27 (m, 2H), 1.92-1.75 (m, 2H), 1.74-1.59 (m, 2H). Example 180

[0483] 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 2.9 Hz, 1H), 8.48 (s, 1H), 8.39 (dd, J = 9.1, 2.8 Hz, 1H), 8.30 (dd, J = 8.0, 2.7 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 5.16-5.03 (m, 1H), 4.74-4.53 (m, 3H), 3.91-3.81 (m, 1H), 3.65 (t, J = 5.6 Hz, 2H), 3.57 (s, 3H), 3.18 (s, 3H), 3.02-2.91 (m, 2H), 2.87-2.74 (m, 2H), 2.65-2.53 (m, 4H), 2.43-2.29 (m, 2H), 1.89-1.76 (m, 2H), 1.74-1.59 (m, 2H). Example 181

[0484] 1 H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J = 2.3 Hz, 1H), 8.27-8.15 (m, 2H), 8.09 (d, J = 1.8 Hz, 1H), 7.84 (dd, J = 9.0, 1.9 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 4.76 (t, J = 8.4 Hz, 1H), 4.61 (s, 2H), 4.45-4.36 (m, 1H), 4.14-4.03 (m, 1H), 3.76-3.69 (m, 1H), 3.63 (t, J = 5.9 Hz, 2H), 3.48-3.45 (m, 1H), 3.40 (s, 3H), 2.72-2.64 (m, 2H), 2.50-2.45 (m, 4H), 1.71-1.59 (m, 4H).

[0485] The following compounds were prepared using different starting materials according to the method described above.

[0546] [Table 15]

[0547] Example 182

[0486] 1 H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.56 (d, J = 9.0 Hz, 1H), 8.27 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 4.91 - 4.82 (m, 1H), 4.79 - 4.60 (m, 3H), 4.48 - 4.37 (m, 1H), 4.21 - 4.12 (m, 1H), 4.07 - 3.98 (m, 1H), 3.80 - 3.71 (m, 5H), 3.63 - 3.52 (m, 1H), 2.88 - 2.75 (m, 1H), 2.75 - 2.63 (m, 4H), 2.57 - 2.44 (m, 2H), 2.28 - 2.15 (m, 1H), 2.03 - 1.87 (m, 6H). Example 183

[0487] 1 H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.53 (d, J = 9.0 Hz, 1H), 8.25 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 4.93 - 4.79 (m, 1H), 4.72 (s, 2H), 4.46 - 4.36 (m, 1H), 4.18 - 4.10 (m, 1H), 4.07 - 3.95 (m, 1H), 3.78 - 3.64 (m, 5H), 3.60 - 3.48 (m, 1H), 3.14 - 3.02 (m, 2H), 2.84 - 2.70 (m, 3H), 2.50 - 2.36 (m, 2H), 2.25 - 2.15 (m, 1H), 1.95 - 1.86 (m, 2H), 1.40 - 1.31 (m, 2H), 0.79 - 0.67 (m, 1H), 0.41 - 0.30 (m, 1H). Examples 184 and 185 (S)-1-isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one and (R)-1-isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one

[0548] [ka]

[0549] Step 1: 1-(5-bromopyridine-2-yl)-2,2,2-trifluoroethanol

[0550] [ka]

[0551]

[0488] To a solution of 5-bromopicolinealdehyde (770 mg, 4.16 mmol) in dry THF (15 mL), TMSCF3 (885 mg, 6.23 mmol) was added dropwise, followed by a solution of TBAF in THF (10.4 mL, 10.4 mmol, 1 M). The reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into water (40 mL) and extracted with siRNA (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (PE:siRNA = 25:1 to 10:1) to obtain the desired product (645 mg, 60.8% yield). LC-MS(ESI) m / z: 256[M+H] + . Step 2: 2-(1-(5-bromopyridine-2-yl)-2,2,2-trifluoroethoxy)acetic acid

[0552] [ka]

[0553]

[0489] To a solution of 1-(5-bromopyridine-2-yl)-2,2,2-trifluoroethanol (455 mg, 1.78 mmol) in dry DMF (5 mL), NaH (143 mg, 3.57 mmol) was slowly added at 0°C, and the reaction mixture was stirred at 0°C for 30 minutes. Methyl 2-bromoacetate (0.257 mL, 2.31 mmol) was added dropwise, and the resulting reaction mixture was slowly warmed to room temperature and stirred at room temperature for 3 hours. The mixture was poured into a 1 M NaOH solution (15 mL) on ice and stirred at room temperature for 1 hour. The mixture was extracted with ELISA (10 mL x 2), and the aqueous layer was adjusted to pH approximately 4 with a 1 M HCl solution. The mixture was extracted with HCl (20 mL x 3), the organic layer was washed with 5% LiCl solution (30 mL) and brine (30 mL), dried on anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product (620 mg) as a brown oil. LC-MS(ESI) m / z: 314[M+H] + . Step 3: 2-(1-(5-bromopyridine-2-yl)-2,2,2-trifluoroethoxy)-1-(pyrrolidine-1-yl)ethenone

[0554] [ka]

[0555]

[0490] A mixture of 2-(1-(5-bromopyridine-2-yl)-2,2,2-trifluoroethoxy)acetic acid (620 mg, 1.98 mmol) and pyrrolidine (155 mg, 2.18 mmol) in DCM (10 mL) was mixed with 50% T3P in Depositphotos (2.52 g, 3.96 mmol), followed by DIEA (1.00 mL, 5.94 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into ice-saturated NaHCO3 solution (30 mL) and extracted with DCM (15 mL x 2). The organic layer was washed with saturated NH4Cl solution (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (820 mg) as a brown oil, which was used for the next step without further purification. LC-MS(ESI)m / z:367[M+H] + . Step 4: 5-Bromo-2-(2,2,2-trifluoro-1-(2-(pyrrolidine-1-yl)ethoxy)ethyl)pyridine

[0556] [ka]

[0557]

[0491] A solution of 2-(1-(5-bromopyridine-2-yl)-2,2,2-trifluoroethoxy)-1-(pyrrolidine-1-yl)ethanone (820 mg, 2.24 mmol) in dried THF (10 mL) is mixed with 1 M BH3 . THF solution (11.2 mL, 11.2 mmol) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with MeOH (20 mL) and evaporated under reduced pressure. The residue was dissolved in EtOH (20 mL) and stirred at 90°C for 3 hours. The mixture was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel (DCM:MeOH = 100:1 to 10:1) to obtain the desired product (380 mg, 60.6% yield in 3 steps) as a light brown oil. LC-MS(ESI) m / z: 353[M+H] + . Step 5: 1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0558] [ka]

[0559]

[0492] The crude product was prepared in the same manner as in Example 1 and purified by chromatography on silica gel (DCM:MeOH = 100:1 to 10:1) to obtain the desired product (160 mg, 60.9% yield in two steps) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 9.00 (d, J = 2.0 Hz, 1H), 8.58 (d, J = 9.0 Hz, 1H), 8.32 (s, 1H), 8.14 (dd, J = 8.1, 2.3 Hz, 1H), 7.89 (dd, J = 9.0, 1.7 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 5.29 - 5.17 (m, 1H), 5.06 (q, J = 6.4 Hz, 1H), 4.21 - 4.05 (m, 2H), 3.78 (s, 3H), 3.43 - 3.14 (m, 6H), 2.12 (s, 4H), 1.81 (dd, J = 6.9, 1.0 Hz, 6H).LC-MS(ESI)m / z:515[M+H] + . Step 6: (S)-1-isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one and (R)-1-isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one

[0493] 1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one was subsequently separated by chiral SFC to obtain two isomers.

[0560]

[0494] (S)-1-isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one as a white solid.

[0561]

[0495] 1 H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 8.57 (d, J = 9.0 Hz, 1H), 8.29 (s, 1H), 8.09 (dd, J = 8.1, 2.1 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 5.27-5.16 (m, 1H), 4.97 (q, J = 6.5 Hz, 1H), 3.86 (ddt, J = 13.1, 9.9, 5.1 Hz, 2H), 3.77 (s, 3H), 2.89 (h, J = 7.0 Hz, 2H), 2.72 (s, 4H), 1.84 (s, 4H), 1.79 (d, J = 6.9 Hz, 6H).

[0496] (R)-1-isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one as a white solid.

[0562]

[0497] 1H NMR (400 MHz, CDCl3) δ 8.99 (d, J = 2.1 Hz, 1H), 8.56 (d, J = 9.0 Hz, 1H), 8.30 (s, 1H), 8.12 (dd, J = 8.1, 2.2 Hz, 1H), 7.87 (d, J = 9.1 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 5.27-5.15 (m, 1H), 5.05 (q, J = 6.3 Hz, 1H), 4.14 (ddd, J = 34.3, 11.1, 6.0 Hz, 2H), 3.77 (s, 3H), 3.32 (d, J = 4.5 Hz, 6H), 2.12 (s, 4H), 1.79 (d, J = 6.9 Hz, 6H).

[0498] SFC conditions: Instrument: MGII preparative SFC (SFC-14) Column: Cellulose-2, 250×30mm I.D., 5μm Mobile phase: CO2 (A) and isopropanol (0.1% NH3H2O) (B)

[0499] Gradient: B40%, Flow rate: 60 mL / min, Back pressure: 100 bar, Column temperature: 38°C, Wavelength: 220 nm, Cycle time: Approx. 22 min

[0500] The following compounds were prepared using different starting materials according to the method described above.

[0563] [Table 16-1]

[0564] [Table 16-2]

[0565] [Table 16-3]

[0566] [Table 16-4]

[0567] [Table 16-5]

[0568] [Table 16-6]

[0569] [Table 16-7]

[0570] [Table 16-8]

[0571] [Table 16-9]

[0572] [Table 16-10]

[0573] Example 216 (R)-2-(1-(5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)acetic acid

[0574] [ka]

[0575] Step 1: (R)-2-(1-(5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)acetic acid

[0576] [ka]

[0577]

[0501] A crude product was prepared in the same manner as in Example 1, and purified by prep-TLC (DCM:MeOH=10:1) to obtain the crude product, which was then purified by prep-HPLC to obtain the desired product (100 mg, 38.0% yield in two steps) as a yellow syrup. 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.56 (s, 1H), 8.46-8.38 (m, 2H), 8.24 (d, J = 9.1 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 5.45-5.35 (m, 1H), 4.79-4.71 (m, 1H), 4.06 (q, J = 38.5, 16.6 Hz, 2H), 3.59 (s, 3H), 1.68 (d, J = 6.7 Hz, 6H), 1.50 (d, J = 6.6 Hz, 3H).LC-MS(ESI)m / z:422[M+H] + .

[0578] Example 217 8-(6-(2-(2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)propan-2-yl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0579] [ka]

[0580] Step 1: 2-(5-bromopyridine-2-yl)propan-2-ol

[0581] [ka]

[0582]

[0502] To a solution of 1-(5-bromopyridine-2-yl)ethanone (3.00 g, 15.1 mmol) in dry THF (30 mL), MeMgBr (3 M) in THF (7.54 mL, 22.6 mmol) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into ice-saturated NH4Cl solution (50 mL) and extracted with  (30 mL × 2). The combined organic layer was washed with brine (50 mL), dried on anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (PE: = 25:1 to 5:1) to obtain the desired product (1.60 g, 49.3%) as an off-white solid. LC-MS (ESI) m / z: 216 [M + H] + . Step 2: 2-((2-(5-bromopyridine-2-yl)propan-2-yl)oxy)acetic acid

[0583] [ka]

[0584]

[0503] To a solution of 2-(5-bromopyridine-2-yl)propan-2-ol (1.00 g, 4.65 mmol) in dry THF (10 mL), NaH (372 mg, 9.30 mmol) was slowly added at 0°C, and the reaction mixture was stirred at 0°C for 30 minutes. 2-bromoacetic acid (834 mg, 6.05 mmol) was added dropwise to the mixture, and the resulting reaction mixture was slowly warmed to room temperature and stirred at room temperature for 2 hours. The mixture was poured into ice water (10 mL), the pH was adjusted to approximately 4 with 1 M HCl solution, and extracted with siRNA (15 mL x 3). The organic layer was dried on anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product (1.00 g) as a brown oil. LC-MS(ESI) m / z: 274[M+H] + . Step 3: 1-(3-azabicyclo[3.1.0]hexane-3-yl)-2-((2-(5-bromopyridine-2-yl)propan-2-yl)oxy)ethenone

[0585] [ka]

[0586]

[0504] A mixture of 1-((5-bromopyridine-2-yl)methoxy)cyclopropanecarboxylic acid (1.00 g, 3.66 mmol) and 3-azabicyclo[3.1.0]hexane (334 mg, 4.03 mmol) in DCM (10 mL) was mixed with 50% T3P in Depositphotos (4.66 g, 7.32 mmol), followed by DIEA (1.80 mL, 11.0 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into ice-saturated NaHCO3 solution (50 mL) and extracted with DCM (20 mL x 2). The organic layer was washed with saturated NH4Cl solution (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product (980 mg) as a brown oil. LC-MS(ESI) m / z: 339 [M+H] + . Step 4: 3-(2-((2-(5-bromopyridine-2-yl)propan-2-yl)oxy)ethyl)-3-azabicyclo[3.1.0]hexane

[0587] [ka]

[0588]

[0505] A solution of 1-(3-azabicyclo[3.1.0]hexane-3-yl)-2-((2-(5-bromopyridine-2-yl)propan-2-yl)oxy)ethanone (980 mg, 2.90 mmol) in dried THF (10 mL) is mixed with 1 M BH3 .THF solution (14.5 mL, 14.5 mmol) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with MeOH (20 mL) and evaporated under reduced pressure. The residue was dissolved in EtOH (30 mL) and stirred at 90°C for 3 hours. The mixture was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel (DCM:MeOH = 100:1 to 10:1) to obtain the desired product (450 mg, 29.9% yield in 3 steps) as a light brown oil. LC-MS(ESI) m / z: 325[M+H] + . Step 5: 8-(6-(2-(2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)propan-2-yl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0589] [ka]

[0590]

[0506] The crude product was prepared in the same manner as in Example 1, and purified by chromatography on silica gel (DCM:MeOH = 100:1 to 10:1) to obtain the desired product (60.0 mg, 20.0% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.50-8.36 (m, 2H), 8.27 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 5.38-5.26 (m, 1H), 3.59 (s, 3H), 3.40-3.34 (m, 2H), 2.93 (d, J = 8.6 Hz, 2H), 2.60 (t, J = 6.2 Hz, 2H), 2.28 (d, J = 8.7 Hz, 2H), 1.66 (d, J = 6.7 Hz, 6H), 1.51 (s, 6H), 1.35-1.24 (m, 2H), 0.64-0.53 (m, 1H), 0.33-0.23 (m, 1H).LC-MS(ESI)m / z:487[M+H] + .

[0591] Example 218 8-(6-((2-(3-azabicyclo[3.1.0]hexane-3-yl)-1,1-difluoroethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0592] [ka]

[0593] Step 1: 2-((5-bromopyridine-2-yl)methoxy)-2,2-difluoroacetic acid

[0594] [ka]

[0595]

[0507] To a solution of 2-(5-bromopyridine-2-yl)propan-2-ol (2.00 g, 10.7 mmol) in dry THF (20 mL), NaH (856 mg, 21.4 mmol) was slowly added at 0°C, and the reaction mixture was stirred at 0°C for 30 minutes. Next, 2-bromo-2,2-difluoroacetic acid (2.23 g, 12.8 mmol) was added dropwise to the mixture, and the resulting reaction mixture was slowly warmed to room temperature and stirred at room temperature for 2 hours. The mixture was poured into ice water (10 mL), the pH was adjusted to approximately 4 with 1 M HCl solution, and extracted with siRNA (15 mL x 3). The organic layer was dried on anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product (680 mg) as a brown oil. LC-MS(ESI) m / z: 282[M+H] + . Step 2: 1-(3-azabicyclo[3.1.0]hexane-3-yl)-2-((5-bromopyridine-2-yl)methoxy)-2,2-difluoroethanone

[0596] [ka]

[0597]

[0508] A mixture of 2-((5-bromopyridine-2-yl)methoxy)-2,2-difluoroacetic acid (680 mg, 2.42 mmol) and 3-azabicyclo[3.1.0]hexane (201 mg, 2.42 mmol) in DCM (10 mL) was mixed with 50% T3P in siRNA (3.08 g, 4.84 mmol), followed by DIEA (937 mg, 7.26 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into ice-saturated NaHCO3 solution (50 mL) and extracted with DCM (20 mL x 2). The organic layer was washed with saturated NH4Cl solution (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (730 mg) as a brown oil. LC-MS(ESI)m / z:347[M+H] + . Step 3: 3-(2-((5-bromopyridine-2-yl)methoxy)-2,2-difluoroethyl)-3-azabicyclo[3.1.0]hexane

[0598] [ka]

[0599]

[0509] A solution of 1-(3-azabicyclo[3.1.0]hexane-3-yl)-2-((5-bromopyridine-2-yl)methoxy)-2,2-difluoroethanone (730 mg, 2.11 mmol) in dried THF (10 mL) is mixed with 1 M BH3 . THF solution (10.6 mL, 10.6 mmol) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with MeOH (20 mL) and evaporated under reduced pressure. The residue was dissolved in EtOH (30 mL) and stirred at 90°C for 2 hours. The mixture was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel (DCM:MeOH = 100:1 to 20:1) to obtain the desired product (470 mg, 13.2% yield in three steps) as a light brown oil. LC-MS(ESI) m / z: 333[M+H] + . Step 4: 8-(6-((2-(3-azabicyclo[3.1.0]hexane-3-yl)-1,1-difluoroethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0600] [ka]

[0601]

[0510] The crude product was prepared in the same manner as in Example 1, and purified by chromatography on silica gel (DCM:MeOH = 100:1 to 10:1) to obtain the desired product (30.0 mg, 10.1% yield in two steps). 1H NMR (400 MHz, dmso) δ 9.08 (s, 1H), 8.51-8.39 (m, 2H), 8.35 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 9.1 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 5.37-5.25 (m, 1H), 5.05 (s, 2H), 3.59 (s, 3H), 3.12-2.93 (m, 4H), 2.58 (d, J = 8.6 Hz, 2H), 1.66 (d, J = 6.7 Hz, 6H), 1.40-1.31 (m, 2H), 0.57-0.49 (m, 1H), 0.37-0.28 (m, 1H).LC-MS(ESI)m / z:495[M+H] + .

[0602] Example 219 1-Isopropyl-3-methyl-8-(6-(1-(2-(pyrroridine-1-yl)ethoxy)propyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0603] [ka]

[0604] Step 1: 1-(5-bromopyridine-2-yl)propan-1-ol

[0605] [ka]

[0606]

[0511] To a solution of 5-bromopicoline aldehyde (1.00 g, 5.41 mmol) in dry THF (10 mL), ethylmagnesium bromide (1 M) in THF (8.12 mL, 8.12 mmol) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into ice-saturated NH4Cl solution (50 mL) and extracted with SiO2 (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried on anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (1.20 g) as a brown oil. LC-MS(ESI) m / z: 216[M+H] + . Step 2: 2-(1-(5-bromopyridine-2-yl)propoxy)acetic acid

[0607] [ka]

[0608]

[0512] To a solution of 2-(5-bromopyridine-2-yl)propan-2-ol (1.20 g, 4.65 mmol) in dry THF (10 mL), NaH (372 mg, 9.30 mmol) was slowly added at 0°C, and the reaction mixture was stirred at 0°C for 30 minutes. Next, ethyl 2-bromoacetate (1.00 g, 6.05 mmol) was added dropwise to the mixture, and the resulting reaction mixture was slowly warmed to room temperature and stirred at room temperature for 2 hours. Next, 1 M NaOH solution (5 mL) was added to the reaction mixture and stirred at room temperature for 1 hour. The mixture was adjusted to pH approximately 4 with 1 M HCl solution and extracted with siRNA (15 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (820 mg) as a brown oil. LC-MS(ESI) m / z: 274 [M + H] + . Step 3: 2-(1-(5-bromopyridine-2-yl)propoxy)-1-(pyrrolidine-1-yl)ethenone

[0609] [ka]

[0610]

[0513] A mixture of 2-(1-(5-bromopyridine-2-yl)propoxy)acetic acid (820 mg, 3.00 mmol) and pyrrolidine (277 mg, 3.90 mmol) in DCM (10 mL) was mixed with 50% T3P in  (3.82 g, 6.00 mmol), followed by DIEA (1.47 mL, 9.00 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into ice-saturated NaHCO3 solution (50 mL) and extracted with DCM (20 mL x 2). The organic layer was washed with saturated NH4Cl solution (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (452 ​​mg) as a brown oil. LC-MS (ESI) m / z: 339 [M + H] + . Step 4: 5-Bromo-2-(1-(2-(pyrrolidine-1-yl)ethoxy)propyl)pyridine

[0611] [ka]

[0612]

[0514] A solution of 2-(1-(5-bromopyridine-2-yl)propoxy)-1-(pyrrolidine-1-yl)ethanone (452 ​​mg, 1.34 mmol) in dried THF (5 mL) is mixed with 1 M BH3 . THF solution (6.70 mL, 6.70 mmol) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with MeOH (20 mL) and evaporated under reduced pressure. The residue was dissolved in EtOH (30 mL) and stirred at 90°C for 3 hours. The mixture was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel (DCM:MeOH = 100:1 to 20:1) to obtain the desired product (111 mg, 6.33% yield in 4 steps) as a light brown oil. LC-MS(ESI) m / z: 325[M+H] + . Step 5: 1-Isopropyl-3-methyl-8-(6-(1-(2-(pyrroridine-1-yl)ethoxy)propyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one

[0613] [ka]

[0614]

[0515] The crude product was prepared in the same manner as in Example 1, and purified by chromatography on silica gel (DCM:MeOH = 100:1 to 10:1) to obtain the desired product (20.0 mg, 12.0% yield) as a pale solid. 1 H NMR (400 MHz, CD3OD) δ 8.98 (d, J = 1.9 Hz, 1H), 8.49 (d, J = 1.4 Hz, 1H), 8.44 (d, J = 9.1 Hz, 1H), 8.33 (dd, J = 8.2, 2.4 Hz, 1H), 8.09 (dd, J = 9.1, 1.7 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 5.41-5.30 (m, 1H), 4.47 (t, J = 6.4 Hz, 1H), 3.72-3.54 (m, 5H), 3.04-2.81 (m, 6H), 1.96-1.84 (m, 6H), 1.77 (d, J = 6.9 Hz, 6H), 0.98 (t, J = 7.4 Hz, 3H).LC-MS(ESI)m / z:475[M+H] + .

[0615]

[0516] The following compounds were prepared using different starting materials according to the method described above.

[0616] [Table 17]

[0617] Example 220

[0517] 11H NMR (400 MHz, CD3OD) δ 9.09 (d, J = 1.9 Hz, 1H), 8.69 (s, 1H), 8.42 (dd, J = 8.2, 2.2 Hz, 1H), 8.39 (s, 2H), 7.73 (d, J = 8.2 Hz, 1H), 5.53 - 5.44 (m, 1H), 4.33 (d, J = 7.0 Hz, 1H), 3.81 - 3.72 (m, 2H), 3.70 - 3.60 (m, 5H), 3.53 - 3.40 (m, 2H), 3.25 - 3.09 (m, 2H), 2.25 - 2.00 (m, 5H), 1.81 (d, J = 6.8 Hz, 6H), 1.10 (d, J = 6.7 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H). Example 221

[0518] 1 1H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 2.0 Hz, 1H), 8.56 (d, J = 9.0 Hz, 1H), 8.29 (s, 1H), 8.02 (dd, J = 8.1, 2.3 Hz, 1H), 7.90 (dd, J = 9.0, 1.7 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 5.28 - 5.18 (m, 1H), 4.19 (d, J = 6.5 Hz, 1H), 3.78 (s, 3H), 3.62 - 3.52 (m, 2H), 2.86 - 2.73 (m, 2H), 2.63 (s, 4H), 2.21 - 2.07 (m, 1H), 1.88 - 1.70 (m, 10H), 1.03 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H). Example 222

[0519] 1H NMR (400 MHz, CD3OD) δ 9.00 (d, J = 1.9 Hz, 1H), 8.50 (d, J = 1.4 Hz, 1H), 8.44 (d, J = 9.1 Hz, 1H), 8.34 (dd, J = 8.2, 2.3 Hz, 1H), 8.09 (dd, J = 9.1, 1.7 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 5.40-5.28 (m, 1H), 4.55-4.51 (m, 1H), 3.75-3.66 (m, 4H), 3.64-3.57 (m, 1H), 3.22-2.97 (m, 6H), 2.03-1.82 (m, 6H), 1.77 (d, J = 6.9 Hz, 6H), 1.62-1.52 (m, 1H), 1.45-1.36 (m, 1H), 1.26-1.15 (m, 1H), 0.90 (d, J = 6.5 Hz, 6H). Example 223 Biological assays

[0520] The potency of the compounds of this disclosure can be determined by a number of pharmacological assays known in the art. The illustrative pharmacological assays described herein are performed with the compounds of this disclosure and the control compound 7-fluoro-8-(6-((2-(4-fluoropiperidine-1-yl)ethoxy)methyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (reference compound 1, identified in WO2020052688A1 as a potent inhibitor of ATM kinase): a) ATM biochemical potency assay; b) ATR biochemical potency assay; c) PI3K biochemical potency assay; d) mTOR biochemical potency assay; e) DNA-PK biochemical potency assay; f) phosp-KAP1 MCF-7 cell fertility assay; and g) ATM SN-38 HT-29 cell fertility assay. In the description of the assays, generally: i. The following abbreviations are used: 4NQO = 4-nitroquinoline N-oxide; Ab = antibody; BSA = bovine serum albumin; CO2 = carbon dioxide; DMEM = Dulbecco's modified Eagle medium; DMSO = dimethyl sulfoxide; EDTA = ethylenediaminetetraacetic acid; EGTA = ethylene glycol tetraacetic acid; ELISA = enzyme-coupled immunosorbent assay; EMEM = Eagle minimum essential medium; FBS = fetal bovine serum; h = time (singular or plural); HRP = horseradish peroxidase; ip = intraperitoneal; PBS = phosphate-buffered saline; PBST = phosphate-buffered saline / Tween; Tris = tris(hydroxymethyl)aminomethane; MTS reagent: [3-(4,5-dimethylthiazole-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, internal salt, and electron coupling reagent (phenazine methosulfate) PMS; sc = subcutaneous.

[0618] ii. Using the smart fitting model in Geneda, IC 50 The value was calculated. IC 50 The value represented the concentration of the test compound that inhibited 50% of the biological activity.

[0619]

[0521] Assay a): ATM biochemical efficacy

[0522] ATM (Millipore, Cat No. 14-933) enzyme solution was prepared in 1× kinase base buffer. 10 μl of 2× enzyme solution was transferred to each well of a 384-well assay plate containing 100 nl of compound added by Echo. The plate was incubated at room temperature for 10 minutes. 2× peptide solution was prepared with FAM-labeled peptide and ATP in 1× kinase base buffer (final concentration: 1.5 nM). 10 μl of 2× peptide solution was added to each well of a 384-well assay plate and incubated at 37°C for 210 minutes, after which the reaction was stopped by adding 40 μl of stop buffer. Data were collected by caliper.

[0620]

[0523] Assay b): ATR biochemical efficacy

[0524] An ATR enzyme (batch: Eurofins Cat No. 14-953) solution was prepared in 1× kinase base buffer. 10 μl of 2× enzyme solution (final concentration: 2.5 nM) was added to each well of a 384-well assay plate containing 60 nl of the compound in each well. The plate was incubated at room temperature for 10 minutes. A 2× peptide solution was prepared with FAM-labeled peptide and ATP in 1× kinase base buffer. 10 μl of 2× peptide solution was added to each well of a 384-well assay plate and incubated at 28°C for 240 minutes. The reaction was stopped by adding 40 μl of stop buffer. Data were collected using calipers.

[0621]

[0525] Assay c): PI3K biochemical efficacy

[0526] Reaction solutions of the PI3Kα (p110α / p85a), PIK3Cδ (Millipore, Cat No. 14-604-M), PIK3Cβ (Eurofins, Cat No. 14-603-K), and PIK3Cγ (Invitrogen, Cat No. PR8641C) enzymes with PI3Kα (p110α / p85a), PIK3Cδ, PIK3Cβ (p110β), and PIK3Cγ (pp110γ) kinases were prepared in 1× kinase buffer at four times the final concentrations of each reagent used in the assay (final concentrations: PI3Kα 0.7nM, PIK3Cδ 3nM, PIK3Cβ 4.8nM, PIK3Cγ 11nM). 2.5 μl of kinase solution was added to each well of a 384-well assay plate containing 2.5 μl of the compound at the serial dilution concentration. A 2× substrate solution was prepared using PIP2 substrate and ATP in 1× kinase reaction buffer at twice the final concentration of each reagent in the assay. The reaction was initiated by adding 5 μl of substrate solution to each well of the assay plate. The assay plate was incubated at room temperature for 1 hour. 5 μl of the reaction mix was transferred to a new 384-well plate. The reaction was stopped by adding 5 μl of ADP-Glo ​​reagent (Promega, Cat number v9102 / 3) to each well of the new assay plate. The plate was gently shaken and equilibrated for 40 minutes. 10 μl of kinase detection reagent was added to each well and equilibrated for 60 minutes, after which luminescence was read using a plate reader (Envision).

[0622]

[0527] Assay d): mTOR biochemical efficacy

[0528] A solution of mTOR enzyme (Millipore, Cat No. 14-770) was prepared in 1× kinase buffer at four times the final concentration (final concentration: 6 nM) used in the assay. 2.5 μl of the kinase solution was added to each well of a 384-well assay plate containing 2.5 μl of the compound at the serial dilution concentration. A 2× substrate solution was prepared with ULight-4E-BP1 (Thr37 / 46) peptide (PE, Cat No. TRF0128-M) and ATP in 1× kinase reaction buffer at twice the final concentration of each reagent used in the assay. The reaction was initiated by adding 5 μl of the substrate solution to each well of the assay plate. The assay plate was incubated at room temperature for 30 minutes. Detection solutions in kinase quench buffer (EDTA) and Eu-antiphospho-4E-BP1 antibody (Thr37 / 46) (PE, Cat No. TRF0216-M) were prepared in Lance detection buffer at twice the desired final concentration of each reagent. 10 μl of detection buffer solution was added to each well of the assay plate. After equilibrating the assay plate at room temperature for 60 minutes, the results were read using a plate reader (Lance signal (665 nm) from the Envision program).

[0623]

[0529] Assay e): DNA-PK biochemical assay

[0530] A DNA-PK kinase reaction solution of the DNA-PK enzyme (Promega, Cat No. V4106, Lot No. 0000224016) was prepared in 1× kinase buffer at twice the final concentration of each reagent in the assay (final concentration: DNA-PK 1U / μl, activator 6μg / ml). 2.5 μl of the kinase solution was added to each well of a 384-well assay plate containing 2.5 μl of the compound at the serial dilution concentration. A substrate solution was prepared with ATP in 1× kinase reaction buffer at twice the final concentration of each reagent in the assay. Final concentration: substrate 0.2 ug / ml and ATP 20 uM. The reaction was initiated by adding 2.5 μl of the substrate solution to each well of the assay plate. The assay plate was incubated at room temperature for 1 hour. 5 μl of the reaction mix was transferred to a new 384-well plate. The reaction was stopped by adding 5 μl of ADP-Glo ​​MAX reagent 1 (Promega, Cat number v9102 / 3, Lot number 0000176563) to each well of the assay plate. The plate was equilibrated at room temperature for 2 hours. 10 μl of ADP-Glo ​​MAX reagent 2 was added to each well and equilibrated for 30 minutes, after which the luminescence was read using a plate reader (Envision).

[0624]

[0531] Assay f): phosp-KAP1 MCF-7 cell capacity

[0532] MCF-7 cells were seeded at 25 μl / well in a 384-well cell culture plate and incubated at 37°C and 5% CO2 for 24 hours. The test compound was added to the 384-well plate. A final concentration of 100 μM etoposide was then added to each well except the vehicle control well and incubated at 37°C and 5% CO2 for 1 hour. After removing the medium, the cells were fixed by adding 25 μl / well of 8% paraformaldehyde in PBSA and incubated at room temperature for 20 minutes. After rinsing the plate three times with PBSA, 50 μl of permeabilization buffer (0.1% Triton X-100 in PBS) was added and the plate incubated at room temperature for 20 minutes. After rinsing the plate with PBSA, the cells were blocked in the 384-well plate by adding 50 μl of Odyssey blocking buffer and incubated at room temperature for 1.5 hours. The blocking buffer was removed using a plate washer (BioTek ELx405 select CW). 20 μl / well of primary antibod...

Claims

1. Equation (I): 【Chemistry 1】 Compounds or pharmaceutically acceptable salts thereof (In the formula: Ring A is aryl or heteroaryl; R １ is a methyl molecule optionally substituted with hydrogen, or one, two, or three halogens; R ２ R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are one or more R ８ It is replaced by optional selection; R ３ This is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, alkyl, alkenyl, alkynyl, haloalkyl and cycloalkyl; Each R ４ This is independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, and cycloalkyl; One of R5 and R6 is hydrogen, and the other is an alkyl or haloalkyl group; L is selected from direct bond, alkyl, cycloalkyl or cycloalkylalkyl, where the alkyl, cycloalkyl and cycloalkylalkyl are one or more R ９ It is replaced by optional selection; R ７ is selected from the group consisting of -NR １０ R １１ , -OR １２ , -COOH, one or more R １３ which is optionally substituted with and consists of a saturated or unsaturated heterocyclyl; R ８ This is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, and alkoxyl; R ９ This is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl; R １０ and R １１ each is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl and cycloalkyl; or R １０ and R １１ It optionally contains one or more additional heteroatoms selected from N, O, and S, along with the nitrogen atoms to which they are attached, and one or more R １４ Forms heterocyclines which are optionally substituted; R １２ and R １３ Each is independently selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, and heterocyclyl; R １４ Halogen, cyano, sulfonyl, alkyl, alkenyl, alkynyl, haloalkyl, alkylalkoxyl, heterocyclyl, -NR １５ R １６ , and -OR １７ Selected from the group consisting of, R １５ and R １６ Each of these is independently a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group; R １７ This is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, and cycloalkyl. n is 0, 1, 2, or 3.

2. Ring A is aryl; or Ring A is a heteroaryl, and may be selected from the group consisting of thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridadinyl, pyrimidinyl, and pyrazinyl; or R １ However, it is a methyl molecule that is optionally substituted with one, two, or three halogens; A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R ２ However, 1 or more R ８ The alkyl group is optionally substituted, R ８ However, R is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, and alkoxyl, and optionally R ２ However, it is n-propyl or iso-propyl; or R ２ However, 1 or more R ８ It is a cycloalkyl group that is optionally substituted with R ８ However, R is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl, and alkoxyl, and optionally R ２ However, it is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and each of these is one or more R ８ It is replaced by arbitrary selection in R ８ However, R is selected from hydroxyl, methyl, trifluoromethyl or methoxy, and may also be used. ２ but, 【Chemistry 2】 is; or R ２ However, 1 or more R ８ It is a heterocycline that has been optionally substituted, R ８ However, R is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl and alkoxyl, and optionally R ２ However, it is selected from the group consisting of oxetanil, tetrahydrofuranil, and tetrahydropyranil, and each of these is one or more R ８ It is replaced by arbitrary selection in R ８ However, R is selected from the group consisting of hydroxyl, methyl, trifluoromethyl, and methoxy, and may also be selected. ２ but, 【Transformation 3】 is; or R ２ However, 1 or more R ８ It is a heteroaryl that is optionally substituted with R ８ However, R is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl and alkoxyl, and optionally R ２ However, these are pyridine or pyrazole, and each of these is one or more R ８ It is replaced by arbitrary selection in R ８ However, the group consisting of hydroxyl, methyl, trifluoromethyl, and methoxy is selected; A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R ３ is hydrogen or fluoro; or R ４ is hydrogen; A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

5. R ５ and R ６ One of them is hydrogen, and the other is C １～６ Alkyl or C １～６ It is a haloalkyl, and in some cases, R ５ and R ６ One of them is hydrogen, and the other is methyl which is optionally substituted with one, two or three halogens, and further, R ５ and R ６ One of them is hydrogen, and the other is methyl or trifluoromethyl; A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

6. L, Directly bonded or cycloalkylalkyl; or 1 ELR ９ The alkyl group is optionally substituted, and each R ９ but independently selected from the group consisting of hydrogen, halogens, and cycloalkyls; or 1 ELR ９ A cycloalkyl group that is optionally substituted, and each R ９ However, it is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl and cycloalkyl; A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

7. R ７ ga-NR １０ R １１ And, depending on the circumstances, R １０ and R １１ However, each is independently alkyl, or R １０ and R １１ One of them is hydrogen and the other is alkyl; or R １０ and R １１ However, along with the nitrogen atoms to which they are attached, they optionally contain one or more additional heteroatoms selected from N, O, and S, and one or more R １４ It forms a saturated heterocycline which is optionally substituted, and in some cases, R １０ and R １１ However, together with the nitrogen atoms to which they are attached, they form saturated heterocyclines selected from the following group: 【Chemistry 4】 Each of these is one or more R １４ It is replaced by arbitrary selection, and in some cases, R １４ However, halogen, cyano, sulfonyl, alkyl, haloalkyl, alkylalkoxyl, -NR １５ R １６ , and OR １７ Independently selected from the group consisting of, R １５ and R １６ However, each is independently alkyl, or R １５ and R １６ One of them is hydrogen and the other is alkyl; or R １７ However, it is selected from alkyl or haloalkyl; A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

8. R ７ is -COOH; or R ７ is a heterocyclyl optionally substituted by R １３ where R １３ is alkyl, and optionally, R ７ is selected from the group consisting of: 【Transformation 5】 Each of these is one or more R １３ It is replaced by optional selection; A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

9. The compound is given by formula (II): 【Transformation 6】 (wherein, R １ , R ２ , R ３ , R ５ , R ６ , R ７ and L are as defined in claim 1) And in some cases, R ５ and R ６ A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein one of the atoms is hydrogen and the other is methyl or trifluoromethyl.

10. The compound has a formula selected from the following group: 【Transformation 7】 (In the formula, R ３ , R ５ , L, R １１ and R １２ (As defined in claim 1) Depending on the circumstances, R ３ However, it is hydrogen or fluoro; R ５ However, it is alkyl or haloalkyl; L is 1 Terr R ９ It is an alkyl group that is optionally substituted; R ９ However, it is selected from the group consisting of hydrogen, halogens, and cycloalkyls; R １０ and R １１ However, each is independently alkyl, or R １０ and R １１ One of them is hydrogen, and the other is an alkyl group; R １０ and R １１ However, along with the nitrogen atoms to which they are attached, they optionally contain one or more additional heteroatoms selected from N, O, and S, and one or more R １４ Forms saturated heterocyclines which are optionally substituted; R １４ However, halogens, cyano, sulfonyl, alkyl, haloalkyl, alkylalkoxyl, saturated or unsaturated heterocyclyl, -NR １５ R １６ , and -OR １７ Selected from the group consisting of; R １５ and R １６ However, each is independently alkyl, or R １５ and R １６ One of them is hydrogen, and the other is alkyl. R １７ However, it is selected from alkyl or haloalkyl; Furthermore, in some cases, L is ethyl or propyl; and / or R ５ but is methyl or trifluoromethyl; or R １０ and R １１ However, together with the nitrogen atoms to which they are attached, they form saturated heterocyclines selected from the following group: 【Transformation 8】 Each of these is one or more R １４ It is replaced by optional selection; A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

11. The compound has a formula selected from the following group: 【Chemistry 9】 (In the formula, R １０ and R １１ (As defined in claim 1) Depending on the case, R １０ and R １１ However, together with the nitrogen atoms to which they are attached, they form saturated heterocyclines selected from the following group: 【Chemistry 10】 Each of these is one or more R １４ A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, which is optionally substituted by [a specific compound].

12. The compound has a formula selected from the following group: 【Chemistry 11】 (In the formula, R １０ and R １１ (As defined in claim 1) Depending on the case, R １０ and R １１ However, together with the nitrogen atoms to which they are attached, they form saturated heterocyclines selected from the following group: 【Chemistry 12】 A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

13. The compound is selected from the following group: (R)-8-(6-(1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-1-isopropyl-8-(6-(1-(2-(4-methoxypiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-8-(6-((R)-1-(2-((R)-3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-1-isopropyl-3-methyl-8-(6-(1-(2-(4-(trifluoromethoxy)piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-8-(6-((R)-1-(2-((S)-3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((1R)-1-(2-(3-(trifluoromethoxy)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one (R)-8-(6-(1-(2-(3,3-dimethylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-1-isopropyl-3-methyl-8-(6-(1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-((R)-1-(2-((S)-3-(difluoromethoxy)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-8-(6-((S)-1-(2-((R)-3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-8-(6-((S)-1-(2-((S)-3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((1S)-1-(2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((1R)-1-(2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (S)-8-(6-(1-(2-(4-fluoropiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(4-fluoropiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((1S)-1-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((1R)-1-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (S)-8-(6-(1-(2-(4,4-dimethylpiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(4,4-dimethylpiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (S)-8-(6-(1-(2-(4,4-difluoropiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(4,4-difluoropiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((R)-3-cyclopropoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((R)-1-(2-((R)-3-methylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((R)-1-(2-((S)-3-methylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((R)-1-(2-((R)-3-(methylsulfonyl)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((R)-3-cyclopropoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(1-oxa-7-azaspiro[3.5]nonan-7-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-1-isopropyl-3-methyl-8-(6-(1-(2-(4-(oxetan-3-yl)piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-1-isopropyl-3-methyl-8-(6-(1-(2-(4-(trifluoromethyl)piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-8-(6-((R)-1-(2-((R)-3-(methoxymethyl)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(2-oxa-6-azaspiro[3.4]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-1-isopropyl-3-methyl-8-(6-(1-(2-(piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((R)-1-(2-((R)-3-(trifluoromethoxy)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[3.4]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-(2-((R)-1-(5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)ethyl)-3-methylpyrrolidine-3-carbonitrile (R)-1-(2-(1-(5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)ethyl)piperidine-4-carbonitride (R)-8-(6-(1-(2-(4-isopropoxypiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((R)-3-isopropoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(5-azaspiro[2,4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(4,4-dimethylpiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((1R)-1-(2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((S)-3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-((1R)-1-(2-(3-(trifluoromethoxy)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-(4-fluoropiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3,3a,9b-tetrahydro-2H-imidazo[4,5-c]sinnolin-2-one (R)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(1-(2-(4-(trifluoromethoxy)piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(4-methoxypiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(3,3-dimethylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((R)-3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((R)-3-isopropoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-1-(2-(1-(5-(3-methyl-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)ethyl)piperidine-4-carbonitrile 8-(6-((R)-1-(2-((S)-3-(difluoromethoxy)pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one (R)-8-(6-(1-(2-(2-oxa-6-azaspiro[3,4]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(1-(2-(4-(trifluoromethyl)piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[3,4]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((R)-3-(methoxymethyl)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-3-methyl-8-(6-(1-(2-(piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-3-methyl-8-(6-(1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((R)-3-cyclopropoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 3-methyl-8-(6-((R)-1-(2-((R)-3-methylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(7-azaspiro[3.5]nonan-7-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(1-oxa-7-azaspiro[3.5]nonan-7-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 3-methyl-8-(6-((R)-1-(2-((S)-3-methylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-3-methyl-8-(6-(1-(2-(4-(oxetan-3-yl)piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 3-methyl-8-(6-((R)-1-(2-((R)-3-(methylsulfonyl)pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 3-Methyl-1-(2-((R)-1-(5-(3-methyl-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)ethyl)pyrrolidine-3-carbonilicate (R)-8-(6-(1-(2-(5-azaspiro[2,4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-7-fluoro-8-(6-(1-(2-(4-fluoropiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one (R)-8-(6-(1-(2-(3,3-dimethylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 7-Fluoro-1-isopropyl-8-(6-((R)-1-(2-((S)-3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(4,4-dimethylpiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 7-Fluoro-1-isopropyl-3-methyl-8-(6-((1R)-1-(2-(3-(trifluoromethoxy)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-7-fluoro-1-isopropyl-8-(6-(1-(2-(4-methoxypiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((1R)-1-(2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-7-fluoro-1-isopropyl-3-methyl-8-(6-(1-(2-(4-(trifluoromethoxy)piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-1-(2-(1-(5-(7-fluoro-1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)ethyl)piperidine-4-carbonitride 8-(6-((R)-1-(2-((R)-3-(difluoromethoxy)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-(2-((R)-1-(5-(7-fluoro-1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)ethyl)-3-methylpyrrolidine-3-carbonitrile (R)-8-(6-(1-(2-(5-azaspiro[2,4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(4,4-dimethylpiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-7-fluoro-8-(6-(1-(2-(4-fluoropiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 7-Fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-((R)-1-(2-((R)-3-(trifluoromethoxy)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 7-Fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-((R)-1-(2-((S)-3-(trifluoromethoxy)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one (R)-8-(6-(1-(2-(3,3-dimethylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((R)-3-(difluoromethoxy)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-8-(6-(1-(2-(7-azaspiro[3.5]nonan-7-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one (R)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(1-(2-(4-(trifluoromethoxy)piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-((S)-3-(difluoromethoxy)pyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-((R)-1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-(trans-3-methoxycyclobutyl)-3-methyl-8-(6-((R)-1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 1-(trans-3-methoxycyclobutyl)-8-(6-((R)-1-(2-((R)-3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridine-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one 8-(6-((R)-1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)ethyl)pyridine-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]sinnoline-2(3H)-one (S)-1-isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one (R)-1-isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(3-methylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(3,3-dimethylpyrrolidine-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(5-azaspiro[2,4]heptan-5-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(4,4-dimethylpiperidine-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(4-methoxypiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(3-methylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(3,3-dimethylpyrrolidine-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(5-azaspiro[2,4]heptan-5-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(4,4-dimethylpiperidine-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(4-methoxypiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 1-(3-methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrroridine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 1-(3-methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(3-methylpyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 1-(3-methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(3-methoxypyrrolidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(3,3-dimethylpyrrolidine-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(5-azaspiro[2,4]heptan-5-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(3-azabicyclo[3.1.0]hexane-3-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 1-(3-methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(piperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(4,4-dimethylpiperidine-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 1-(3-methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(4-methoxypiperidine-1-yl)ethoxy)ethyl)pyridine-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one 8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)-2,2,2-trifluoroethyl)pyridine-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one (R)-2-(1-(5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]sinnolin-8-yl)pyridine-2-yl)ethoxy)acetic acid 1-Isopropyl-3-methyl-8-(6-(1-(2-(pyrroridine-1-yl)ethoxy)propyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(1-(2-(pyrroridine-1-yl)ethoxy)butyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(2-methyl-1-(2-(pyrroridine-1-yl)ethoxy)propyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one, and 1-Isopropyl-3-methyl-8-(6-(4-methyl-1-(2-(pyrroridine-1-yl)ethoxy)pentyl)pyridine-3-yl)-1H-imidazo[4,5-c]sinnoline-2(3H)-one A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound of formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

15. A pharmaceutical composition for treating ATM-related diseases or conditions in a subject, comprising a compound of formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein the ATM-related disease or condition is cancer, more preferably the cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer and non-small cell lung cancer, and more preferably the ATM-related disease or condition is head and neck squamous cell carcinoma.

16. Radiotherapy is administered to the target simultaneously with, separately or sequentially, the pharmaceutical composition; or the pharmaceutical composition is administered simultaneously with, separately or sequentially, at least one additional antitumor agent selected from the group consisting of doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, and bleomycin; or The pharmaceutical composition is administered simultaneously with, separately from, or sequentially with the PARP inhibitor, preferably the PARP inhibitor is selected from the group consisting of olaparib, lucaparib, niraparib, talazoparib, pamiparib, and fluzoparib; The pharmaceutical composition according to claim 15.

Images