Selective modulators of ataxia telangiectasia mutated (ATM) kinase and uses thereof - Patents.com

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] This application relates to novel substituted imidazo[4,5-c]cinnolin-2-one compounds and pharmaceutically acceptable salts thereof that selectively modulate ataxia telangiectasia mutated ("ATM") kinase. This application also relates to pharmaceutical compositions containing 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. [Background technology]

[0002] ATM kinase is a serine / threonine kinase named after the autosomal recessive disorder ataxia telangiectasia (AT) (Paul, T.T., 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 major pathways: nonhomologous end joining (NHEJ) or homologous recombination (HR). NHEJ operates throughout the cell cycle and directly reseals the two broken ends with minimal processing. In contrast, HR occurs during the S and G2 phases of the cell cycle and requires extensive end processing (or resection). This generates single-stranded DNA that invades 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 process but is error-prone; on the other hand, HR is a slower process than NHEJ but is error-free. ATM repairs DSBs via HR.

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

[0004] ATM is activated by DSBs, which can be induced by ionizing radiation, chemotherapy drugs, and PARP inhibitors. Topoisomerase I inhibitors (e.g., irinotecan, topotecan) and PARP inhibitors (e.g., olaparib) cause single-stranded DNA breaks that are converted to DSBs during replication (Choi M. et al., Mol Cancer Ther, 2016, 1781-91). Other anticancer treatments, such as ionizing radiation (IR), platinum-based drugs (cisplatin), and topoisomerase II inhibitors (doxorubicin, etoposide), directly induce DSBs. Combining ATM inhibitors with chemotherapy, radiation, and PARP inhibitors renders cancer cells nearly unable to repair DSBs, which are highly cytotoxic. Given the important role ATM plays in DSBs, ATM kinase inhibitors are expected to cooperate with PARP or topoisomerase inhibitors or ionizing radiation in cancer treatment.

[0005]

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

[0006] [ka]

[0007] However, both compounds are highly active aldehyde oxidase (AO) substrates. AO is highly expressed in humans and monkeys, but 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 assessed in the human liver cytosol system. The human PK of AZD0156 was unexpectedly lower than predicted (Chen et al., AACR, 2018), and phase 0 clinical PK studies were conducted for AZD1390 prior to its involvement in phase 1 clinical studies (NCT03215381 and NCT03423628), further suggesting that both AZD0156 and AZD1390 undergo AO-mediated metabolism. Summary of the Invention [Problem to be solved by the invention]

[0008]

[0007] Therefore, there remains a need to develop new compounds that act against ATM kinase, preferably without AO liability. [Means for solving the problem]

[0009] Disclosed herein are novel substituted imidazo[4,5-c]cinnolin-2-one compounds that have potent ATM kinase inhibitory activity, do not exhibit AO liability in human liver cytosol, and therefore have favorable human pharmacokinetics (PK), low doses, and low PK variability. As a result, the compounds of the present application are particularly useful in treating ATM-related diseases or conditions.

[0010] In one aspect, the present disclosure provides a compound of formula (I):

[0011] [ka]

[0012] or a pharmaceutically acceptable salt thereof, During the ceremony: Ring A is aryl or heteroaryl; R 1 is hydrogen or methyl optionally substituted with 1, 2 or 3 halogens; R 2 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are selected from the group consisting of one or more R 8 is optionally replaced by; R 3 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, alkyl, alkenyl, alkynyl, haloalkyl, and cycloalkyl; Each R 4 are 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 a cycloalkyl or heterocyclyl; L is selected from a direct bond, alkyl, or cycloalkyl, wherein said alkyl and cycloalkyl are selected from one or more R 9 is optionally replaced by; R7 is -NR 10 R 11 , -OR 12 , -COOH, one or more R 13 saturated or unsaturated heterocyclyl optionally substituted with; R 8 is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, and alkoxyl; R 9 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl; R 10 and R 11 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, and cycloalkyl; or R 10 and R 11 together with the nitrogen atom to which they are attached, optionally contain one or more additional heteroatoms selected from N, O and S and one or more R 14 forming an optionally substituted heterocyclyl; R 12 and R 13 are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, and heterocyclyl; R 14 is halogen, cyano, sulfonyl, alkyl, alkenyl, alkynyl, haloalkyl, alkylalkoxyl, heterocyclyl, -NR 15 R 16 , and -OR 17 is selected from the group consisting of R 15 and R 16 are each independently hydrogen, alkyl, alkenyl, or alkynyl; R 17 is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, and cycloalkyl; n is 0, 1, 2 or 3.

[0013] In another aspect, the present disclosure provides a compound of formula (II):

[0014] [ka]

[0015] or a pharmaceutically acceptable salt thereof.

[0016] In a further aspect, the present disclosure provides a compound selected from the group consisting of:

[0017] [ka]

[0018] or a pharmaceutically acceptable salt thereof.

[0019] In another embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0020]

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

[0021] In a further aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of an ATM-related disease or condition.

[0022] In a further aspect, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an ATM-related disease or condition.

[0023]

[0016] In a further aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of an ATM-related disease or condition, wherein the compound of formula (I) is administered simultaneously, separately or sequentially with radiation therapy.

[0024] In a further embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, administered simultaneously, separately or sequentially with at least one additional anti-tumor agent.

[0025] In a further embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, administered simultaneously, separately or sequentially with a PARP inhibitor. DETAILED DESCRIPTION OF THE INVENTION

[0026] Reference will now be made in detail to certain embodiments of the present disclosure, examples of which are illustrated in the accompanying structures and formulas. While the present disclosure will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the disclosure to those embodiments. On the contrary, the present disclosure is intended to encompass all alternatives, modifications, and equivalents falling within the scope of the present disclosure as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present disclosure. The present disclosure is in no way limited to the methods and materials described. In the event that one or more of the incorporated references and similar materials differs or contradicts this application, including, but not limited to, defined terminology, term usage, described techniques, etc., the present disclosure controls. All references, patents, and patent applications cited in this disclosure are hereby incorporated by reference in their entirety.

[0027] It will be understood that certain features of the present disclosure, which are described, for clarity, in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the present disclosure, which are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. It must be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include their plural forms unless the context clearly dictates otherwise. Thus, for example, reference to a compound includes a plurality of compounds. definition

[0021] The definitions of specific functional groups and chemical terms are described in more detail below.For the purpose of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein.In addition, the general principles of organic chemistry, as well as specific functional moieties 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] In various places in this disclosure, linking substituents are described. 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 the linking alkylene group.

[0029]

[0023] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, such substituent may be bonded to any atom in the ring. When substituents are listed without indicating the atom to which such substituent is bonded to the remainder of the compound of a given formula, such substituent may be bonded through any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0030] Any variable (e.g., R i When any group R occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, a group R i If a group is indicated as being substituted with a moiety, the group may be substituted with up to two R i and each occurrence of R i is R i Additionally, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0031] As used herein, "C i~j " denotes 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 therebetween, where j is greater than i. For example, C 1~6indicates a range of 1 to 6 carbon atoms, inclusive of 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 " denotes 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3 or particularly 1 to 2 carbon atoms.

[0032] As used herein, the term "alkyl," whether used as part of another term or independently, refers to a saturated, linear or branched chain hydrocarbon group that may be independently optionally substituted with one or more substituents described below. i~j The term "alkyl" refers to an alkyl having i to j carbon atoms. In some embodiments, an alkyl group contains 1 to 10 carbon atoms. In some embodiments, an alkyl group contains 1 to 9 carbon atoms. In some embodiments, an 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. "C 1~10 Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 1~6 Examples of "alkyl" 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, 3,3-dimethyl-2-butyl, and the like.

[0033] Alkyl groups may be further substituted with substituents that independently replace one or more hydrogen atoms on one or more carbons of the alkyl group. Examples of such substituents may 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, sulfonamido, nitro, trifluoromethyl, cyano, nitro, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, as described below, may also be similarly substituted.

[0034] As used herein, the term "alkenyl," whether used as part of another term or independently, refers to a linear or branched hydrocarbon group having at least one carbon-carbon double bond, which may be independently optionally substituted with one or more substituents described herein, and includes groups having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In some embodiments, alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms. In some embodiments, alkenyl groups contain 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, alkenyl groups contain 2 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethylenyl (or vinyl), propenyl, butenyl, pentenyl, 1-methyl-2 buten-1-yl, 5-hexenyl, and the like.

[0035] As used herein, the term "alkynyl," whether used as part of another term or independently, 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 described herein. In some embodiments, an alkenyl group contains 2 to 12 carbon atoms. In some embodiments, an alkynyl group contains 2 to 11 carbon atoms. In some embodiments, an 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, an alkynyl group contains 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

[0036]

[0030] As used herein, the term "alkoxy," whether used as part of another term or independently, refers to an alkyl group, as previously defined, attached to the parent molecule through an oxygen atom. i~j The term "alkoxy" means the alkyl portion of the alkoxy group has i to j carbon atoms. In some embodiments, an alkoxy group contains 1 to 10 carbon atoms. In some embodiments, an alkoxy group contains 1 to 9 carbon atoms. In some embodiments, an 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. "C 1~6 Examples of "alkoxyl" include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), t-butoxy, neopentoxy, n-hexoxy, and the like.

[0037] As used herein, the term "alkylalkoxyl," whether used as part of another term or independently, refers to an alkyl moiety substituted with one or more alkoxyl moieties. An "alkylalkoxyl" can be attached to the parent molecular structure through either an alkyl group or an alkoxyl group.

[0038]

[0032] As used herein, the term "alkylcycloalkyl," whether used as part of another term or independently, refers to an alkyl moiety substituted with one or more cycloalkyl moieties. An "alkylcycloalkyl" can be attached to the parent molecular structure through an alkyl group or a cycloalkyl group.

[0039] As used herein, the term "aryl," whether used as part of another term or independently, refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, 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, anthracyl, and the like, which may bear one or more substituents. Also included within the scope of the term "aryl," as it is used herein, are groups in which an aromatic ring is fused to one or more additional rings. In the case of polycyclic ring systems, only one of the rings need 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 bridged. Examples of polycyclic aryls include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl, etc. Aryl groups may be substituted at one or more ring positions with substituents as described above.

[0040] As used herein, the term "cycloalkyl," whether used as part of another term or independently, refers to monovalent non-aromatic saturated or partially unsaturated monocyclic and polycyclic ring systems in which all ring atoms are carbon and contain at least three ring-forming carbon atoms. In some embodiments, a cycloalkyl can 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. A cycloalkyl group can be saturated or partially unsaturated. A cycloalkyl group can be substituted. In some embodiments, a cycloalkyl group can be a saturated cyclic alkyl group. In some embodiments, a cycloalkyl group can be a partially unsaturated cyclic alkyl group that contains at least one double or triple bond in its ring system.

[0041] In some embodiments, a cycloalkyl group can be monocyclic or polycyclic. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl.

[0042] In some embodiments, cycloalkyl groups can be saturated or partially unsaturated polycyclic (e.g., bicyclic and tricyclic) carbocyclic ring systems, which can be arranged as fused, spiro, or bridged ring systems. As used herein, the term "fused ring" refers to a ring system having two rings that share two adjacent atoms, the term "spiro ring" refers to a ring system having two rings connected through a single common atom, and the term "bridged ring" refers to a ring system having two rings that share three or more atoms. Examples of fused carbocyclyls include, but are not limited to, naphthyl, benzopyrenyl, anthracenyl, acenaphthenyl, fluorenyl, and the like. Examples of spirocarbocyclyls include, but are not limited to, spiro[5.5]undecanyl, spiro-pentadienyl, spiro[3.6]-decanyl, and the like. Examples of bridged carbocyclyls 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, bicyclo[3.3.3]undecanyl, and the like.

[0043] As used herein, the term "cyano" refers to --CN.

[0044] As used herein, the term "halogen" refers to an atom selected from fluorine (or fluoro), chlorine (or chloro), bromine (or bromo) and iodine (or iodo).

[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), pentachloroethyl (-C2Cl5), and the like.

[0046] As used herein, the term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen (including N-oxide).

[0047] As used herein, the term "heteroaryl," whether used as part of another term or independently, refers to an aryl group having one or more heteroatoms in addition to carbon atoms. Heteroaryl groups can 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, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl, and pteridinyl. Heteroaryl groups also include polycyclic groups in which a heteroaromatic ring is fused to one or more aryl, heteroaryl, alicyclic, or heterocyclyl rings, where the group or point of attachment is on the heteroaromatic ring. Examples of polycyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo[1,3]dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0048] As used herein, the term "heterocyclyl" refers to 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, wherein one or more ring atoms can be independently optionally substituted with one or more substituents. In some embodiments, a heterocyclyl is a saturated heterocyclyl. In some embodiments, a heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system. In some embodiments, a heterocyclyl can contain any oxidized form of carbon, nitrogen, or sulfur, and any quaternized form of a basic nitrogen. Heterocyclyl groups can be carbon-linked or nitrogen-linked where possible. In some embodiments, heterocycles are carbon-linked. In some embodiments, heterocycles are nitrogen-linked. For example, a group derived from pyrrole can be pyrrol-1-yl (nitrogen-linked) or pyrrol-3-yl (carbon-linked). Additionally, groups derived from imidazole can be imidazol-1-yl (nitrogen-linked) or imidazol-3-yl (carbon-linked).

[0049] Heterocyclyl groups 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, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like.

[0050] Heterocyclyl groups may be polycyclic, including fused, spiro, and bridged ring systems. Fused heterocyclyl groups include groups in which a heterocyclyl group is fused with a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. Examples of fused heterocyclyls include, but are not limited to, phenyl- or pyridinyl-fused rings, such as quinolinyl, isoquinolinyl, quinoxalinyl, quinolidinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[4,3-a]pyridinyl groups, and the like. Examples of spiroheterocyclyl include, but are not limited to, spiropyranyl, spirooxazinyl, 5-aza-spiro[2.4]heptanyl, 6-aza-spiro[2.5]octanyl, 6-aza-spiro[3.4]octanyl, 2-oxa-6-aza-spiro[3.3]heptanyl, 2-oxa-6-aza-spiro[3.4]octanyl, 6-aza-spiro[3.5]nonanyl, 7-aza-spiro[3.5]nonanyl, 1-oxa-7-aza-spiro[3.5]nonanyl, and the like. Examples of bridged heterocyclyls include, but are not limited to, 3-aza-bicyclo[3.1.0]hexanyl, 8-aza-bicyclo[3.2.1]octanyl, 1-aza-bicyclo[2.2.2]octanyl, 2-aza-bicyclo[2.2.1]heptanyl, 1,4-diazabicyclo[2.2.2]octanyl, and the like.

[0051] As used herein, the term "hydroxyl" refers to --OH.

[0052] 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] As used herein, the term "partially unsaturated" refers to a group that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.

[0054] As used herein, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. "Substituted" or "substituted with" is understood to include the implicit proviso that such substitution is consistent with the allowed valence of the substituted atom and that the substitution results in a stable or chemically feasible compound that does not spontaneously undergo transformation, such as, for example, by rearrangement, cyclization, elimination, and the like. Unless otherwise indicated, an "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents can be either the same or different at every position. It will be understood by those of skill in the art that substituents may themselves be substituted, where appropriate. Unless specifically specified as "unsubstituted," reference to a chemical moiety herein is understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants. compound

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

[0055] In one aspect, the present disclosure provides a compound of formula (I):

[0056] [ka]

[0057] or a pharmaceutically acceptable salt thereof, During the ceremony: 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 said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are selected from the group consisting of one or more R 8 is optionally replaced by; R 3 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, alkyl, alkenyl, alkynyl, haloalkyl, and cycloalkyl; Each R 4 are 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 6together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; L is selected from a direct bond, alkyl, cycloalkyl, or cycloalkylalkyl, wherein said alkyl, cycloalkyl, and cycloalkylalkyl are selected from one or more R 9 is optionally replaced by; R 7 is -NR 10 R 11 , -OR 12 , -COOH, one or more R 13 saturated or unsaturated heterocyclyl optionally substituted with; R 8 is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, and alkoxyl; R 9 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl; R 10 and R 11 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, and cycloalkyl; or R 10 and R 11 together with the nitrogen atom to which they are attached, optionally contain one or more additional heteroatoms selected from N, O and S and one or more R 14 forming an optionally substituted heterocyclyl; R 12 and R 13 are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, and heterocyclyl; R 14 is halogen, cyano, sulfonyl, alkyl, alkenyl, alkynyl, haloalkyl, alkylalkoxyl, heterocyclyl, -NR 15 R 16 , and -OR17 is selected from the group consisting of R 15 and R 16 are each independently hydrogen, alkyl, alkenyl, or alkynyl; R 17 is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, and cycloalkyl; n is 0, 1, 2 or 3.

[0058] In some embodiments, ring A is aryl.

[0059] In some embodiments, ring A is heteroaryl. In certain embodiments, ring A is 5- to 12-membered heteroaryl. In certain embodiments, ring A is 5- to 10-membered heteroaryl. In certain embodiments, ring A is 5- to 8-membered heteroaryl. In certain embodiments, ring A is 5- to 6-membered heteroaryl.

[0060] In certain embodiments, Ring A is selected from the group consisting of thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0061] In certain embodiments, Ring A is selected from pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In certain embodiments, Ring A is pyridyl.

[0062] In some embodiments, R 1 is hydrogen.

[0063] In some embodiments, R 1 is methyl optionally substituted with one, two, or three halogens. In certain embodiments, R 1is methyl optionally substituted with one, two or three fluoro. 1 is methyl or trifluoromethyl.

[0064] In some embodiments, R 2 is one or more R 8 and R is alkyl optionally substituted with 8 is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, and alkoxyl. 2 is one or more R 8 C optionally replaced by 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl or C 1~3 alkyl, and R 8 is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, and alkoxyl.

[0065] In certain embodiments, R 2 is n-propyl or iso-propyl.

[0066] In some embodiments, R 2 is one or more R 8 is cycloalkyl optionally substituted with R 8 is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl, and alkoxyl. 2 is one or more R 8 C optionally replaced by 3~12 Cycloalkyl, C 3~10 Cycloalkyl, C 3~8 Cycloalkyl, C 3~6 Cycloalkyl or C 3~5 is cycloalkyl, and R 8 is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl, and alkoxyl.

[0067] In certain embodiments, R 2 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is selected from the group consisting of one or more R 8 and optionally substituted with R 8 is selected from hydroxyl, methyl, trifluoromethyl or methoxy.

[0068] In certain embodiments, R 2 teeth,

[0069] [ka]

[0070] is.

[0071] In some embodiments, R 2 is one or more R 8 heterocyclyl optionally substituted with R 8 is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl, and alkoxyl. 2 is one or more R 8 C optionally replaced by 3~12 Heterocyclyl, C 3~10 Heterocyclyl, C 3~8 Heterocyclyl, C 3~6 Heterocyclyl or C 3~5 heterocyclyl, and R 8 is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl, and alkoxyl.

[0072] In certain embodiments, R 2 is selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, each of which is selected from the group consisting of one or more R8 and optionally substituted with R 8 is selected from the group consisting of hydroxyl, methyl, trifluoromethyl and methoxy.

[0073] In certain embodiments, R 2 teeth,

[0074] [ka]

[0075] is.

[0076] In some embodiments, R 2 is one or more R 8 and R is heteroaryl optionally substituted with 8 is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl, and alkoxyl. 2 is one or more R 8 and R is a 5- to 12-membered heteroaryl, a 5- to 10-membered heteroaryl, a 5- to 8-membered heteroaryl, a 5- to 7-membered heteroaryl, or a 5- to 6-membered heteroaryl optionally substituted with 8 is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl, and alkoxyl.

[0077] In certain embodiments, R 2 is pyridine or pyrazole, each of which may be one or more R 8 and optionally substituted with R 8 is selected from the group consisting of hydroxyl, methyl, trifluoromethyl and methoxy.

[0078] In some embodiments, R 3 is hydrogen.

[0079] In some embodiments, R 3 is halogen. In certain embodiments, R 3 is fluoro, chloro, or bromo. 3 is fluoro.

[0080] In some embodiments, R 4 is hydrogen.

[0081] In some embodiments, R 4 is alkyl. In certain embodiments, R 4 is C 1~6 In certain embodiments, R 4 is C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl or C 1~2 It is alkyl.

[0082] 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] In some embodiments, R 5 and R 6 One of R is hydrogen and the other is alkyl. 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 In certain embodiments, R 5 and R 6 is hydrogen and the other is selected from methyl, ethyl, n-propyl, i-propyl, or 3-methyl-1-butyl.

[0084] In some embodiments, R 5and R 6 One of R is hydrogen and the other is haloalkyl. 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 In certain embodiments, R 5 and R 6 is hydrogen and the other is methyl optionally substituted with one, two, or three halogens. 5 and R 6 is hydrogen and the other is methyl optionally substituted with 1, 2, or 3 fluoro atoms. 5 and R 6 One of the groups is hydrogen and the other is trifluoromethyl.

[0085] In some embodiments, R 5 and R 6 are both hydrogen.

[0086] In some embodiments, R 5 and R 6 and R are alkyl. 5 and R 6 independently, C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 In certain embodiments, R 5 and R 6 Both of the are methyl.

[0087] In some embodiments, R 5 and R 6 consists of one or more R groups, along with the carbon atoms to which they are attached. 9In certain embodiments, R 5 and R 6 C, along with the carbon atoms to which they are attached. 3~12 Cycloalkyl, C 3~10 Cycloalkyl, C 3~8 Cycloalkyl, C 3~6 Cycloalkyl, or C 3~5 cycloalkyl, each of which may be one or more R 9 In certain embodiments, R 5 and R 6 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0088] In some embodiments, R 5 and R 6 consists of one or more R groups, along with the carbon atoms to which they are attached. 9 In certain embodiments, R 5 and R 6 together with the carbon atoms to which they are attached form a 3- to 12-membered heterocyclyl, a 3- to 10-membered heterocyclyl, a 3- to 8-membered heterocyclyl, a 3- to 6-membered heterocyclyl, or a 3- to 5-membered heterocyclyl, each of which may be selected from one or more R 9 is optionally replaced by

[0089] In certain embodiments, R 5 and R 6 together with the carbon atom to which they are attached form a group selected from the group consisting of:

[0090] [ka]

[0091] In some embodiments, L is a direct bond.

[0092] In some embodiments, L is one or more R 9 In certain embodiments, L is alkyl optionally substituted with C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 alkyl, each of which may be one or more R 9 In certain embodiments, L is optionally substituted with one or more R 9 In some embodiments, each R 9 is independently selected from the group consisting of hydrogen, halogen, and cycloalkyl. 9 is halogen. In certain embodiments, R 9 is fluoro. In certain embodiments, R 9 is C 3~12 Cycloalkyl, C 3~10 Cycloalkyl, C 3~8 Cycloalkyl, C 3~6 Cycloalkyl, or C 3~5 In certain embodiments, R 9 is cyclopropyl.

[0093] In certain embodiments, L is chosen from methyl, ethyl, n-propyl, isopropyl, or isobutyl.

[0094] In some embodiments, L is one or more R 9 In certain embodiments, L is cycloalkyl optionally substituted with C 3~12 Cycloalkyl, C 3~10 Cycloalkyl, C 3~8 Cycloalkyl, C 3~6 Cycloalkyl, or C3~5 cycloalkyl, each of which may be one or more R 9 In some embodiments, each R 9 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, and cycloalkyl.

[0095] In certain embodiments, L is cyclopropyl or cyclobutyl.

[0096] In some embodiments, L is one or more R 9 In certain embodiments, L is cycloalkylalkyl 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 alkyl), each of which is selected from one or more R 9 In some embodiments, each R 9 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, and cycloalkyl.

[0097] In certain embodiments, L is cyclopropylmethyl.

[0098] [ka]

[0099] is.

[0100] In some embodiments, R 7 Ha-NR 10 R 11 is.

[0101] In certain embodiments, R 10 and R 11 are each independently alkyl. In certain embodiments, R 10 and R 11 are each independently C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 In certain embodiments, R 10 and R 11 are both C 1~3 In certain embodiments, R 10 and R 11 are both methyl.

[0102] In certain embodiments, R 10 and R 11 One of R is hydrogen and the other is alkyl. 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 In certain embodiments, R 10 and R 11 One of the groups is hydrogen and the other is methyl.

[0103] In some embodiments, R 10 and R 11 together with the nitrogen atom to which they are attached optionally contain one or more additional heteroatoms selected from N, O and S and one or more R 14 to form an optionally substituted saturated heterocyclyl.

[0104] In certain embodiments, R 10 and R 11together with the nitrogen atom to which they are attached form a saturated heterocyclyl selected from the group consisting of:

[0105] [ka]

[0106] Each of these can be one or more R 14 is optionally replaced by

[0107] In certain embodiments, each R 14 is halogen, cyano, sulfonyl, alkyl, haloalkyl, alkylalkoxyl, -NR 15 R 16 , and OR 17 are independently selected from the group consisting of:

[0108] In certain embodiments, R 14 is halogen. In certain embodiments, R 14 is fluoro.

[0109] In certain embodiments, R 14 is cyano.

[0110] In certain embodiments, R 14 is sulfonyl. In certain embodiments, R 14 is -SO2(CH3).

[0111] In certain embodiments, R 14 is alkyl. In certain embodiments, R 14 is C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 In certain embodiments, R 14 is methyl.

[0112] In certain embodiments, R 14 is haloalkyl. In certain embodiments, R 14 is methyl substituted with one, two, or three halogens. In certain embodiments, R 14 is trifluoromethyl.

[0113] In certain embodiments, R 14 is alkylalkoxyl. In certain embodiments, 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 In certain embodiments, R 14 is methyl methoxyl.

[0114] In certain embodiments, R 14 Ha-NR 15 R 16 is.

[0115] In certain embodiments, R 15 and R 16 are each independently alkyl. In certain embodiments, R 15 and R 16 are each independently C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 In certain embodiments, R 15 and R 16 are both C 1~3 In certain embodiments, R 15 and R 16 are both methyl.

[0116] In certain embodiments, R 15 and R 16 One of R is hydrogen and the other is alkyl. 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 In certain embodiments, R 15 and R 16 One of the groups is hydrogen and the other is methyl.

[0117] In some embodiments, R 7 HA-OR 17 is.

[0118] In certain embodiments, R 17 is selected from alkyl or haloalkyl.

[0119] In certain embodiments, R 17 is C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 In certain embodiments, R 17 is methyl, ethyl, or isopropyl.

[0120] In certain embodiments, R 17 is haloalkyl. In certain embodiments, R 17 is methyl substituted with one, two, or three halogens. In certain embodiments, R 17 is monofluoromethyl, difluoromethyl or trifluoromethyl.

[0121] In some embodiments, R 7 is -COOH.

[0122] In some embodiments, R 7 is R 13 is heterocyclyl optionally substituted by

[0123] In certain embodiments, R 7 is selected from the group consisting of:

[0124] [ka]

[0125] Each of these can be one or more R 13 is optionally replaced by

[0126] In certain embodiments, R 13 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, and heterocyclyl. 13 is C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 In certain embodiments, R 13 is methyl.

[0127] In a further aspect, the present disclosure provides a compound of formula (II):

[0128] [ka]

[0129] wherein R 1 , R 2 , R 3 , R 5 , R 6 , R 7 and L is as defined above.

[0130] In some embodiments, in Formula (II), R 5 and R 6 One of the groups is hydrogen and the other is alkyl or haloalkyl.

[0131] In certain embodiments, R 5 and R 6 One of R is hydrogen and the other is alkyl. 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 In certain embodiments, R 5 and R 6 is hydrogen and the other is selected from methyl, ethyl, n-propyl, i-propyl, or 3-methyl-1-butyl.

[0132] In certain embodiments, R 5 and R 6 One of R is hydrogen and the other is haloalkyl. 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 In certain embodiments, R 5 and R 6 is hydrogen and the other is methyl optionally substituted with one, two, or three halogens. 5 and R 6 is hydrogen and the other is methyl optionally substituted with 1, 2, or 3 fluoro atoms. 5 and R 6 One of the groups is hydrogen and the other is trifluoromethyl.

[0133] In another aspect, the present disclosure provides a compound selected from the group consisting of:

[0134] [ka]

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

[0136] In certain embodiments, in any of formulas (III) to (VII), R 3 is hydrogen or fluoro; R 5 is hydrogen, alkyl, or haloalkyl; L is one or more R 9 is alkyl optionally substituted with; R 9 is selected from the group consisting of hydrogen, halogen, and cycloalkyl; R 10 and R 11 are each independently alkyl, or R 10 and R 11 one of which is hydrogen and the other is alkyl; R 10 and R 11 together with the nitrogen atom to which they are attached optionally contain one or more additional heteroatoms selected from N, O and S and one or more R 14 forming an optionally substituted saturated heterocyclyl; R 14 is halogen, 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 are each independently alkyl, or R 15 and R 16 one of which is hydrogen and the other is alkyl; R 17 is selected from alkyl or haloalkyl.

[0137] In certain embodiments, L is ethyl or propyl.

[0138] In certain embodiments, R 5 is hydrogen, methyl or trifluoromethyl.

[0139] In certain embodiments, R 10 and R 11 together with the nitrogen atom to which they are attached form a saturated heterocyclyl selected from the group consisting of:

[0140] [ka]

[0141] Each of these can be one or more R 14 is optionally replaced by

[0142] In certain embodiments, each R 14 is halogen, cyano, sulfonyl, alkyl, haloalkyl, alkylalkoxyl, -NR 15 R 16 , and OR 17 are independently selected from the group consisting of:

[0143] In certain embodiments, R 15 and R 16 are each independently alkyl. In certain embodiments, R 15 and R 16are each independently C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 In certain embodiments, R 15 and R 16 are both C 1~3 In certain embodiments, R 15 and R 16 are both methyl.

[0144] In certain embodiments, R 15 and R 16 One of R is hydrogen and the other is alkyl. 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 In certain embodiments, R 15 and R 16 One of the groups is hydrogen and the other is methyl.

[0145] In certain embodiments, R 17 is selected from alkyl or haloalkyl.

[0146] In another aspect, the present disclosure provides a compound selected from the group consisting of:

[0147] [ka]

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

[0149] In certain embodiments, in any of formulas (IIIa) to (VIIa), R10 and R 11 together with the nitrogen atom to which they are attached form a saturated heterocyclyl selected from the group consisting of:

[0150] [ka]

[0151] Each of these can be one or more R 14 is optionally replaced by

[0152] In a further aspect, the present disclosure provides a compound selected from the group consisting of:

[0153] [ka]

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

[0155] In certain embodiments, in any of formulas (IIIb), (IVb), and (VIIb), R 10 and R 11 together with the nitrogen atom to which they are attached form a saturated heterocyclyl selected from the group consisting of:

[0156] [ka]

[0157]

[0126] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof selected from the group consisting of: 8-(6-((2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(dimethylamino)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((2-(piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((2-(pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4-fluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-8-(6-((2-methoxyethoxy)methyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(((1-methylpiperidin-4-yl)oxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((3-(dimethylamino)propoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(((1-methylpiperidin-4-yl)methoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(((1-methylpyrrolidin-2-yl)methoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(((1-methylpyrrolidin-3-yl)oxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((3-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(((1-methylpiperidin-3-yl)oxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((3-(dimethylamino)cyclobutoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(((1-methylazetidin-3-yl)oxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-methylpropoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-(((1-(3-azabicyclo[3.1.0]hexan-3-yl)cyclopropyl)methoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(((1-methylpiperidin-3-yl)methoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(((1-methylpyrrolidin-3-yl)methoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-(((1-(3-azabicyclo[3.1.0]hexan-3-yl)propan-2-yl)oxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-(((1-(3-azabicyclo[3.1.0]hexan-3-yl)-2-methylpropan-2-yl)oxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((1-(3-azabicyclo[3.1.0]hexan-3-ylmethyl)cyclopropoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-(2-((5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-8-yl)pyridin-2-yl)methoxy)ethyl)piperidine-4-carbonitrile 1-(2-((R)-1-(5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-8-yl)pyridin-2-yl)ethoxy)ethyl)-3-methylpyrrolidine-3-carbonitrile 8-(6-((2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-8-(6-((2-(4-methoxypiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-((2-(3-fluoropyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-1-Isopropyl-3-methyl-8-(6-((2-(2-methylpyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4,4-difluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4,4-dimethylpiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((2-(4-methylpiperazin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((2-morpholinoethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-8-(6-((2-(3-fluoropyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-1-Isopropyl-3-methyl-8-(6-((2-(2-methylpyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3-(dimethylamino)azetidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3-fluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(2-azabicyclo[2.2.1]heptan-2-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(6-azaspiro[3.5]nonan-6-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-8-(6-((2-(3-methoxypiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-8-(6-((2-(3-(dimethylamino)pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-1-Isopropyl-8-(6-((2-(3-methoxypyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-8-(6-((2-(4-methoxypiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-((2-(3-(dimethylamino)pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((2-(4-(trifluoromethoxy)piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(7-azaspiro[3.5]nonan-7-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-((2-(3-(difluoromethoxy)pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-8-(6-((2-(3-(difluoromethoxy)pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((2-(3-(trifluoromethoxy)pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one (R)-8-(6-(1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-1-Isopropyl-8-(6-(1-(2-(4-methoxypiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-8-(6-((R)-1-(2-((R)-3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-1-Isopropyl-3-methyl-8-(6-(1-(2-(4-(trifluoromethoxy)piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-8-(6-((R)-1-(2-((S)-3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-1-Isopropyl-3-methyl-8-(6-(1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-((R)-1-(2-((S)-3-(difluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-8-(6-((S)-1-(2-((R)-3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-8-(6-((S)-1-(2-((S)-3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((1S)-1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((1R)-1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-8-(6-(1-(2-(4-fluoropiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(4-fluoropiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((1S)-1-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((1R)-1-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-8-(6-(1-(2-(4,4-dimethylpiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(4,4-dimethylpiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-8-(6-(1-(2-(4,4-difluoropiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(4,4-difluoropiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((R)-3-cyclopropoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((R)-1-(2-((R)-3-methylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((R)-1-(2-((S)-3-methylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((R)-1-(2-((R)-3-(methylsulfonyl)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((R)-3-cyclopropoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(1-oxa-7-azaspiro[3.5]nonan-7-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-1-Isopropyl-3-methyl-8-(6-(1-(2-(4-(oxetan-3-yl)piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-1-Isopropyl-3-methyl-8-(6-(1-(2-(4-(trifluoromethyl)piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-8-(6-((R)-1-(2-((R)-3-(methoxymethyl)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(2-oxa-6-azaspiro[3.4]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-1-Isopropyl-3-methyl-8-(6-(1-(2-(piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((R)-1-(2-((R)-3-(trifluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[3.4]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-(2-((R)-1-(5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-8-yl)pyridin-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]cinnolin-8-yl)pyridin-2-yl)ethoxy)ethyl)piperidine-4-carbonitrile (R)-8-(6-(1-(2-(4-isopropoxypiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((R)-3-isopropoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4-fluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4,4-dimethylpiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-((2-(3-(difluoromethoxy)pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-8-(6-((2-(3-(difluoromethoxy)pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-((2-(4-(trifluoromethoxy)piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(4,4-dimethylpiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((1R)-1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((S)-3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-((1R)-1-(2-(3-(trifluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-(4-fluoropiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3,3a,9b-tetrahydro-2H-imidazo[4,5-c]cinnolin-2-one (R)-3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(1-(2-(4-(trifluoromethoxy)piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(4-methoxypiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((R)-3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((R)-3-isopropoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-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]cinnolin-8-yl)pyridin-2-yl)ethoxy)ethyl)piperidine-4-carbonitrile 8-(6-((R)-1-(2-((S)-3-(difluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one (R)-8-(6-(1-(2-(2-oxa-6-azaspiro[3.4]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(1-(2-(4-(trifluoromethyl)piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[3.4]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((R)-3-(methoxymethyl)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-3-Methyl-8-(6-(1-(2-(piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-3-Methyl-8-(6-(1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((R)-3-cyclopropoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 3-methyl-8-(6-((R)-1-(2-((R)-3-methylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(7-azaspiro[3.5]nonan-7-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(1-oxa-7-azaspiro[3.5]nonan-7-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 3-methyl-8-(6-((R)-1-(2-((S)-3-methylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-3-Methyl-8-(6-(1-(2-(4-(oxetan-3-yl)piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 3-methyl-8-(6-((R)-1-(2-((R)-3-(methylsulfonyl)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-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]cinnolin-8-yl)pyridin-2-yl)ethoxy)ethyl)pyrrolidine-3-carbonitrile 8-(6-((2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4,4-dimethylpiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 7-Fluoro-1-isopropyl-3-methyl-8-(6-((2-(3-(trifluoromethoxy)pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one (R)-8-(6-(1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-7-Fluoro-8-(6-(1-(2-(4-fluoropiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one (R)-8-(6-(1-(2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 7-Fluoro-1-isopropyl-8-(6-((R)-1-(2-((S)-3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(4,4-dimethylpiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 7-Fluoro-1-isopropyl-3-methyl-8-(6-((1R)-1-(2-(3-(trifluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-7-Fluoro-1-isopropyl-8-(6-(1-(2-(4-methoxypiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((1R)-1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-7-Fluoro-1-isopropyl-3-methyl-8-(6-(1-(2-(4-(trifluoromethoxy)piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-1-(2-(1-(5-(7-fluoro-1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-8-yl)pyridin-2-yl)ethoxy)ethyl)piperidine-4-carbonitrile 8-(6-((R)-1-(2-((R)-3-(difluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-(2-((R)-1-(5-(7-fluoro-1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-8-yl)pyridin-2-yl)ethoxy)ethyl)-3-methylpyrrolidine-3-carbonitrile (R)-8-(6-(1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(4,4-dimethylpiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-7-Fluoro-8-(6-(1-(2-(4-fluoropiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 7-Fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-((R)-1-(2-((R)-3-(trifluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 7-Fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-((R)-1-(2-((S)-3-(trifluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one (R)-8-(6-(1-(2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((R)-3-(difluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(7-azaspiro[3.5]nonan-7-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-7-Fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(1-(2-(4-(trifluoromethoxy)piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((S)-3-(difluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-((2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)methyl)pyridin-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)ethyl)pyridin-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-(trans-3-Methoxycyclobutyl)-3-methyl-8-(6-((R)-1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-(trans-3-Methoxycyclobutyl)-8-(6-((R)-1-(2-((R)-3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(dimethylamino)ethoxy)methyl)pyridin-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-(trans-3-Methoxycyclobutyl)-3-methyl-8-(6-((2-(pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-(trans-3-Methoxycyclobutyl)-3-methyl-8-(6-((2-(piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4-fluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)methyl)pyridin-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)ethyl)pyridin-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-(cis-3-Methoxycyclobutyl)-3-methyl-8-(6-((2-(pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-(cis-3-Methoxycyclobutyl)-3-methyl-8-(6-((2-(piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4-fluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)methyl)pyridin-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(dimethylamino)ethoxy)methyl)pyridin-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(dimethylamino)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(oxetan-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 3-Methyl-1-(oxetan-3-yl)-8-(6-((2-(piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4-fluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(oxetan-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4-fluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-((1s,3s)-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 3-Methyl-1-(oxetan-3-yl)-8-(6-((2-(pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-8-(6-((2-(4-fluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-((S)-tetrahydro-2H-pyran-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one (R)-1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(3-methylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(4,4-dimethylpiperidin-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(4-methoxypiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(3-methylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(4,4-dimethylpiperidin-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(4-methoxypiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-(3-Methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-(3-Methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(3-methylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-(3-Methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-(3-Methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(4,4-dimethylpiperidin-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-(3-Methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(4-methoxypiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one (R)-2-(1-(5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-8-yl)pyridin-2-yl)ethoxy)acetic acid 8-(6-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)propan-2-yl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexan-3-yl)-1,1-difluoroethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(1-(2-(pyrrolidin-1-yl)ethoxy)propyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(1-(2-(pyrrolidin-1-yl)ethoxy)butyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-(2-methyl-1-(2-(pyrrolidin-1-yl)ethoxy)propyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one, and 1-Isopropyl-3-methyl-8-(6-(4-methyl-1-(2-(pyrrolidin-1-yl)ethoxy)pentyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one Illustrative compounds of formula (I) are set forth 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] The compounds provided herein are described with reference to both generic formulas and specific compounds. In addition, the compounds of the present disclosure can exist in many different forms or derivatives, including, but 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 within the scope of this disclosure.

[0215]

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

[0216] The term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. The term "diastereomers" refers to a pair of optical isomers that are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities.

[0217]

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

[0218] 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 thereof, as falling within the scope of the present invention. For example, a stereoisomer can, in some embodiments, be provided substantially free of one or more corresponding stereoisomers and can also be referred to as "stereochemically enriched."

[0219] When a particular enantiomer is preferred, it can, in some embodiments, be provided substantially free of the opposite enantiomer and can be referred to as "optically enriched." "Optically enriched," as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments, the compound is made up of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound is made up of at least about 95%, 98%, or 99% by weight of the preferred enantiomer. The preferred enantiomer can be isolated from a racemic mixture by any method known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and chiral salt formation and crystallization, or can be prepared by asymmetric synthesis. See, e.g., 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, p. 268 (E.L. Eliel, ed., University of Notre Dame Press, Notre Dame, IN 1972).

[0220] The compounds of the present disclosure may also exist in different tautomeric forms, and all such forms are encompassed within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. The presence and concentration of isomeric forms may vary depending on the environment in which the compound is found, for example, whether the compound is a solid or in an organic or aqueous solution. By way of example, proton tautomers (also known as prototropic tautomers) include interconversions via the migration of a proton, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerizations, and cyclic forms, where the proton can occupy more than one position in a heterocyclic ring system. Valence tautomers include interconversions via reorganization of some of the bonding electrons. Tautomers may be in equilibrium or sterically locked into one form by appropriate substitution. Compounds of the present disclosure identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0221] As used herein, the term "prodrug" refers to a compound or a pharmaceutically acceptable salt thereof that, when metabolized under physiological conditions or converted by solvolysis, yields the desired active compound. Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of an active compound. Typically, prodrugs are inactive or less active than the active compound, but may offer one or more advantageous handling, administration, and / or metabolic properties. For example, some prodrugs are esters of the active compound; during metabolism, the ester group is cleaved to yield the active drug. Moreover, some prodrugs are enzymatically activated to yield the active compound, or a compound from which further chemical reaction yields the active compound. Prodrugs can progress from the prodrug form to the active form in a single step, or can have one or more intermediate forms that may themselves be active or inactive. The preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, in Bioreversible Carriers in Drug Design, Vol. 14, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; in Prodrugs: Challenges and Rewards, edited by V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley, Springer-Verlag New York, 2007, all of which are hereby incorporated by reference in their entireties.

[0222] As used herein, the term "soft drug" refers to a compound that exerts a pharmacological effect but has a limited duration of activity due to degradation to inactive metabolites. See, e.g., "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 hereby incorporated by reference in its entirety.

[0223]

[0137] As used herein, the term "metabolite," e.g., active metabolite, overlaps with prodrugs as described above. Thus, such metabolites are compounds that are further metabolized to pharmacologically active compounds or derivatives resulting from metabolic processes in the subject's body. 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, active metabolites are such pharmacologically active derivative compounds. For prodrugs, the prodrug compound is generally inactive or less active than the metabolic product. For active metabolites, the parent compound may be either an active compound or an inactive prodrug.

[0224]

[0138] Prodrugs and active metabolites can be identified using routine techniques known in the art. See, e.g., 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, supra.

[0225] 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 the present disclosure can be formulated as or may be in the form of a pharmaceutically acceptable salt. Unless specified to the contrary, the compounds provided herein include pharmaceutically acceptable salts of such compounds.

[0227]

[0141] As used herein, the term "pharmaceutically acceptable" indicates that a substance or composition is chemically and / or toxicologically compatible with other ingredients comprising the formulation and / or the subject being treated therewith.

[0228]

[0142] As used herein, the term "pharmaceutically acceptable salts," unless otherwise indicated, includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable. Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono-, bis-, tris-, tetrakis-, and the like. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effects. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate the administration of higher drug concentrations.

[0229] Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, and quinate. 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] Pharmaceutically acceptable salts also include base addition salts containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines, and zinc when an acidic functional group, such as a carboxylic acid or phenol, is present. See, for example, Remington's Pharmaceutical Sciences, 19th ed., 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 the appropriate corresponding base.

[0231] 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 alcoholic solution containing an appropriate acid, and then evaporating the solution. Thus, if a particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, e.g., glucuronic acid or galacturonic acid, an alpha-hydroxy acid, e.g., citric acid or tartaric acid, an amino acid, e.g., aspartic acid or glutamic acid, an aromatic acid, e.g., benzoic acid or cinnamic acid, or a sulfonic acid, e.g., p-toluenesulfonic acid or ethanesulfonic acid.

[0232] Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, or an alkaline earth metal hydroxide. Illustrative 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, and 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 the present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms), and solid forms (e.g., crystalline or polymorphic forms), and the present disclosure is intended to encompass all such forms.

[0234] As used herein, the term "solvate" or "solvate form" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of a substance in which the water retains its molecular state as HO. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0235] As used herein, the terms "crystalline form," "crystalline form," "polymorphic form," and "polymorph" can be used interchangeably and refer to crystalline structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors can cause one crystalline form to predominate. Crystalline polymorphs of the compound can be prepared by crystallization under different conditions.

[0236]

[0150] The present disclosure is further intended to include all isotopes of atoms in the compounds. Isotopes of an atom include atoms having 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 present disclosure include, but are not limited to, the following: 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 In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes: 12 C and 13 Contains C. Compound synthesis

[0151] The synthesis of the compounds provided herein, including their pharmaceutically acceptable salts, is illustrated in the synthetic 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 synthetic 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. Additionally, the steps in the schemes are for better illustration and can be varied where appropriate. The compound embodiments in the Examples were synthesized for research purposes and for potential regulatory submissions.

[0237]

[0152] The reactions for preparing the compounds of the present disclosure can be carried out in a suitable solvent, which can be readily selected by one skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, which can range, for example, 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 the particular reaction step, a suitable solvent for a particular reaction step can be selected by one skilled in the art.

[0238] Preparation of the compounds of the present disclosure may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one of ordinary skill in the art. Protecting group chemistry can be found, for example, in T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 3rd ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[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 13The concentration of the compound can be monitored by spectroscopic means such as infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC). Compounds can be purified by one skilled in the art by a variety of 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 by reference in its entirety), and normal-phase silica chromatography.

[0240] The structures of the compounds in the examples are characterized by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectroscopy (LC-MS). The NMR chemical shifts (δ) are -6 It is expressed in units of (ppm). 1 H-NMR spectra were recorded in CDCl, CDOD, or DMSO-d solutions (reported in ppm) on a Varian instrument (400 MHz) or a Brucker instrument (400 MHz) using tetramethylsilane (TMS) as the reference standard (0.0 ppm).

[0241]

[0156] MS measurements are performed using a Shimadzu 2020 Mass Spectrometer using electrospray, chemical and electron impact 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 products by TLC are 0.4 mm to 0.5 mm.

[0243] Column chromatography was performed on a Biotage system (manufacturer: Dyax Corporation) with a silica gel column or on a silica SepPak cartridge (Waters).

[0244] Known starting materials of this disclosure can be synthesized by or according to methods known in the art or purchased from commercial sources 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] Unless otherwise specified, all reactions in this disclosure were carried out under a positive pressure of nitrogen or argon or using dry tubes in anhydrous solvents; reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven-dried and / or heat-dried.

[0246] For illustrative purposes, the following sets forth general synthetic routes for preparing the compounds of the present disclosure as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those of skill in the art will appreciate that other synthetic routes can be used to synthesize the compounds of the present invention. While specific starting materials and reagents are illustrated in the schemes and discussed below, other starting materials and reagents can 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 synthetic route In some embodiments, the compound of formula (I) has the formula (II'):

[0247] [ka]

[0248] wherein X is a leaving group (e.g., a halogen atom, such as a chlorine, iodine, or bromine atom, or a triflate group). and a compound of formula (III'):

[0249] [ka]

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

[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] Step 1:

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

[0254] Compounds of formula (A2) can be prepared by the cinnoline-4-ol cyclization reaction of compounds of formula (A1) with a diazotization reagent (eg, NaNO2 or nitrite) under standard conditions.

[0255] Step 2:

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

[0256] Step 3: Compounds of formula (A4) may be prepared by the halogenation reaction of compounds of formula (A3) with a halogenating reagent (eg POCl3 or SOCl2) in a suitable solvent (eg DMF) under standard conditions.

[0257] Step 4: Compounds of formula (A5) can be prepared by nucleophilic substitution reaction of compounds of formula (A4) with an amine (e.g., a primary or secondary amine) in the presence of an organic base (e.g., Et3N or di-isopropylethylamine) in a suitable solvent (e.g., THF or DMF) under standard conditions.

[0258] Step 5:

[0174] Compounds of formula (A6) can be prepared by the reduction reaction of compounds of formula (A5) with a reducing agent (eg, SnCl2, or Fe / NH4Cl, or H2 / palladium) under suitable reducing conditions.

[0259] Step 6:

[0176] Compounds of formula (A7) can be prepared by reaction of compounds of formula (A6) with an acylating reagent (e.g., 1,1'-carbonyldiimidazole (CDI), ethyl carbonochloridate, or bis(trichloromethyl)carbonate) under suitable coupling conditions.

[0260] Step 7:

[0178] Compounds of formula (A7) can be reacted with a suitable alkylating reagent (e.g., iodomethane or DMF-DMA) optionally in the presence of a suitable base to provide compounds 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] In Scheme 2, compounds of formula (III') can be prepared starting from B1, which is either commercially available or synthesized from heteroaryl ethanone with a Grignard reagent. Some compounds of formula (III') were prepared via halogenation of B1 with a halogenating agent, such as thionyl chloride, phosphoryl chloride, or a mixture of carbon tetrachloride and triphenylphosphine, to give B2. After alkylation of B3 by conventional procedures, key intermediate B4 was finally reacted with a common boron source (e.g., bis(pinacolato)diboron (B2Pin2) or bis(catecholate)diborane (B2Cat2)) under suitable transition metal-catalyzed boronation reaction conditions to give formula (III'). Alternatively, intermediate B1 can be coupled with an appropriate halide B5, where W is alkyl, followed by hydrolysis to give the free acid B6. Furthermore, key intermediate B4 was synthesized by amide reduction of B7, which was prepared by the free acid B6 with R7 (amine) with an appropriate coupling reagent. Use of the compound In one aspect, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof, which exhibit ATM kinase inhibitory activity.

[0264] As used herein, the term "ATM kinase inhibitory activity" refers to a decrease in ATM kinase activity as a direct or indirect response to the presence of a 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 can be due to the direct interaction of the compound of Formula (I) or a pharmaceutically acceptable salt thereof with ATM kinase, or due to the interaction of the compound of Formula (I) or a pharmaceutically acceptable salt thereof with one or more other factors that in turn affect ATM kinase activity. For example, a compound of Formula (I) or a pharmaceutically acceptable salt thereof can decrease ATM kinase activity by directly binding to ATM kinase, by causing (directly or indirectly) another factor to decrease ATM kinase activity, or by decreasing (directly or indirectly) the amount of ATM kinase present in a cell or organism.

[0265] In some embodiments, compounds of the present disclosure are selective inhibitors of ATM kinase.

[0266] As used herein, the term "selective inhibitor" or "selectively inhibits" means that a provided compound inhibits ATM kinase in at least one assay described herein (e.g., biochemical or cellular). In some embodiments, the term "selective inhibitor" or "selectively inhibits" refers to a compound that exhibits an IC50 value for inhibiting ATM kinase. 50at least 5000-fold higher, at least 4000-fold higher, at least 3000-fold higher, at least 2000-fold higher, at least 1000-fold higher, at least 500-fold higher, at least 400-fold higher, at least 300-fold higher, at least 200-fold higher, at least 100-fold higher, at least 90-fold higher, at least 80-fold higher, at least 70-fold higher, at least 60-fold higher, at least 50-fold higher, at least 40-fold higher, at least 30-fold higher, at least 20-fold higher, at least 10-fold higher, for inhibiting enzymes in the PIKK family closely related to ATM kinases (such as PI3K, mTOR, and ATR). 50 It means having.

[0267]

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

[0268] As used herein, the term "AO substrate" means that a given compound is susceptible to oxidation by aldehyde oxidase (AO) and is therefore highly susceptible to AO-mediated clearance. In some embodiments, the AO susceptibility of a compound is measured by measuring the intrinsic clearance (CL) in the human liver cytosol system (Zientek M. et al., Drug Metab Dispos, 2010, 1322-27), as described in detail in the Examples section below. int) can be evaluated. A human liver cytosol system useful in the 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-(quinolin-6-ylmethyl)triazolo[4,5-b]pyrazin-5-yl]pyrazol-1-yl]ethanol, reported as a weak AO substrate) and zaleplon (N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide, considered as a strong AO substrate) are both used as references in the human liver cytosol system. In general, compounds show lower CL than those of PF-04217903. int If a compound exhibits a higher CL than that of zaleplon, it is not considered an AO substrate. int If the CL int is determined by the AO assay described in the Examples section below.

[0269] In some embodiments, compounds of the present disclosure have a lower CL in human hepatocytes than that of PF-04217903. intAO exhibits low AO susceptibility. AO is a group of cytosolic molybdo-flavoenzymes, proteins that require flavin adenine dinucleotide (FAD) and molybdopterin [molybdenum cofactor (MoCo)] for catalytic activity. AO oxidizes aromatic aldehydes to their corresponding carboxylic acids and heterocycles to hydroxylated derivatives. The potential of AO to oxidize heterocycles is particularly important in the context of drug design and development, as these chemical groups are popular building blocks in medicinal chemistry. AO-mediated metabolism is often overlooked during the drug discovery stage, and high clearance issues are not revealed until phase 1 clinical trials. AO is a cytosolic enzyme; therefore, its potential contribution to the metabolic clearance of new compounds is not addressed in standard metabolic stability screens using liver microsomes. Hepatocytes are a whole cell system containing both microsomes and cytosol. However, AO is an unstable protein with substantial loss of activity in hepatocyte preparations (Hutzler, J.M. et al., Drug MetabDispos, 2014, 1090-7). In vivo studies of AO-mediated metabolism in animal models are highly problematic because the constituent hepatic AO in humans and popular experimental animals differ (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 predominant 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 enzymatic activity. AO activity has been found to be much more active 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 (see, e.g., Gordon AH, Green DE, Subrahmanyan, "Liver aldehyde oxidase," The Biochemical Journal).1940, 34(5):764-74). Human liver cytosol extracts containing AO but without significant amounts of contaminating CYP450s have been shown to be a valuable tool for predicting in vivo clearance mediated by human AO. Human liver cytosol purchased from Xenotech was used immediately after thawing and not reused because AO is a labile enzyme that is rapidly inactivated by freeze-thawing. In light of highly variable AO activity, high-activity lots of human liver cytosol were selected for the AO assay to minimize underprediction of clearance. The reference compounds zaleplon (high clearance by AO) and PF-04217903 (low clearance by AO) were used as controls in the AO assay.

[0270] Without wishing to be bound by any particular theory, AO appears to have a significant impact 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):1441-1448). 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):856-856). AO-mediated metabolism tends to lead to high clearance in humans. For high-clearance compounds, small variations in intrinsic clearance due to different enzyme expression levels between patients can lead to large variations in bioavailability. Human AOX1 is highly polymorphic, and several 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, 856-64). These polymorphisms result in reduced levels of the encoded AOX1 protein, explaining the reported inter-individual variability in AOX activity. Additionally, many factors can affect AO activity, such as gender, age, smoking, drug use, and disease status.Therefore, compounds with high AO-mediated clearance have large inter-patient PK variability, which leads to unexpected toxicity in some individuals, while efficacy is not achieved in others (Garattini, E. et al., Expert Opin Drug Discovery, 2013, 641-54; Hutzler, JM et al., Drug Metab Dispos 2014, 1090-7).

[0271] In contrast to the previously reported ATM inhibitors AZD0156 and AZD1390, which are strong AO substrates, the compounds of the present disclosure have surprisingly low susceptibility to AO oxidation. Thus, in one aspect, the compounds provided herein and their pharmaceutically acceptable salts are not AO substrates, and as a result, exhibit better PK profiles than compounds that are AO substrates. For example, the compounds provided herein have low PK variability among people with different levels of AO activity.

[0272] In some embodiments, the compounds of the present disclosure exhibit good solubility in water, ie, a solubility in water of greater than 90 μM, greater than 100 μM, greater than 200 μM, greater than 300 μM, greater than 400 μM, greater than 500 μM, greater than 600 μM, greater than 700 μM, greater than 800 μM, greater than 900 μM, or greater than 1000 μM.

[0273]

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

[0274]

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

[0275] As used herein, the term "treatment" is intended to have its normal meaning, to address a disease, to alleviate in whole or in part one, some, or all of its symptoms, or to correct or compensate for an underlying pathology. The term "treatment" also includes "prophylaxis," unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be interpreted in a corresponding manner.

[0276]

[0194] As used herein, the term "prevention" is intended to have its normal meaning and includes primary prevention, to prevent the onset of disease, and secondary prevention, where the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the onset of new symptoms associated with the disease.

[0277] The term "treatment" is used synonymously with "therapy." Similarly, the term "treating" can be considered as "administering therapy," as "treatment" is defined herein.

[0278]

[0196] Thus, in one aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

[0279] In some embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[0280] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is provided for use in treating an ATM-related disease or condition. In some embodiments, the ATM-related disease or condition is cancer. In some embodiments, 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 (including but not limited to lip carcinoma, oral carcinoma, oropharyngeal carcinoma, hypopharyngeal carcinoma, glottic laryngeal carcinoma, supraglottic 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] In some embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of an ATM-related disease or condition.

[0282]

[0200] In some embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of cancer. Pharmaceutical Composition

[0201] The present disclosure provides pharmaceutical compositions comprising one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions comprise one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient.

[0283]

[0202] As used herein, a "pharmaceutical composition" is a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form may be any of a variety of forms, including, for example, tablets, capsules, pills, powders, granules, sachets, cachets, lozenges, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), sprays, ointments, pastes, creams, lotions, gels, patches, inhalants, or suppositories. The quantity of active ingredient (e.g., a disclosed compound or a formulation thereof, a salt, hydrate, solvate, or isomer thereof) in a unit dose of composition is a therapeutically effective amount and will vary according to the particular treatment involved. Those skilled in the art will recognize that it is sometimes necessary to make routine variations in dosage depending on the age and condition of the patient. The dosage also depends on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. 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 the present disclosure are mixed under sterile conditions with pharmaceutically acceptable excipients and any required preservatives, buffers, or propellants.

[0284]

[0203] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. "Pharmaceutically acceptable excipient," as used in the specification and claims, includes both one and more than one such excipient.

[0285]

[0204] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation, which is within the skill and judgment of the clinician.

[0286]

[0205] In some embodiments, the pharmaceutical composition can be formulated to administer a dose of between 0.01 and 500 mg / kg body weight / day, e.g., 0.05 to 500 mg / kg body weight / day, 0.1 to 500 mg / kg body weight / day, 0.1 to 400 mg / kg body weight / day, 0.1 to 300 mg / kg body weight / day, 0.1 to 200 mg / kg body weight / day, 0.1 to 100 mg / kg body weight / day, 0.1 to 80 mg / kg body weight / day, 1 to 100 mg / kg body weight / day, or 1 to 80 mg / kg body weight / day, of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0287] In some embodiments, the pharmaceutical composition comprises one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof as a first active ingredient and further comprises a second active ingredient, which may be any anti-tumor agent known in the art, such as an anti-neoplastic agent, an anti-angiogenic agent, an immunotherapeutic approach, an efficacy enhancer, etc.

[0288] Examples of antineoplastic agents include, but are not limited to, DNA alkylating agents (e.g., nitrogen mustards such as cisplatin, oxaliplatin, carboplatin, cyclophosphamide, ifosfamide, nitrosoureas such as bendamustine, melphalan, chlorambucil, busulfan, temozolomide, and carmustine); antimetabolites (e.g., gemcitabine and antifolates, fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumor antibiotics (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, liposomal doxorubicin, pirarubicin, daunomycin, valrubicin, epirubicin, idarubicin, mitomycin, dactinomycin, amrubicin, and mithramycin). antimitotic drugs (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids such as taxol and taxotere, and polo kinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, irinotecan, topotecan, and camptothecin); inhibitors of DNA repair mechanisms, such as CHK kinase; DNA-dependent protein kinase inhibitors; inhibitors of poly(ADP-ribose) polymerase (PARP inhibitors, including olaparib, rucaparib, niraparib, talazoparib, pamiparib, and fluzoparib); and Hsp90 inhibitors such as tanespimycin and retaspimycin, inhibitors of ATR kinase (such as AZD6738); and inhibitors of WEE1 kinase (such as AZD1775 / MK-1775).

[0289] Examples of anti-angiogenic agents include those that inhibit the effects of vascular endothelial growth factor, such as, but not limited to, the anti-vascular endothelial growth factor antibody bevacizumab, VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD6474), sorafenib, vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW786034), and cediranib (AZD2171); compounds such as those disclosed in International Patent Applications WO97 / 22596, WO97 / 30035, WO97 / 32856 and WO98 / 13354; as well as compounds that act by other mechanisms (e.g., linomide, an inhibitor of integrin ανβ3 function and angiostatin), or inhibitors of angiopoietins and their receptors (Tie-1 and Tie-2), inhibitors of PLGF, inhibitors of delta-like ligand (DLL-4).

[0290] Examples of immunotherapeutic approaches include, but are not limited to, ex vivo and in vivo approaches to increase the immunogenicity of patient tumor cells, e.g., transfection with cytokines such as interleukin-2, interleukin-4, or granulocyte-macrophage colony-stimulating factor; approaches to reduce T cell anergy or regulatory T cell function; approaches to enhance T cell responses to tumors, e.g., blocking antibodies against CTLA4 (e.g., ipilimumab and tremelimumab), B7H1, PD-1 (e.g., BMS-936558 or AMP-514), PD-L1 (e.g., MEDI4736), and CD4+. These 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, such as rituximab, radiolabeled anti-CD20 antibodies Bexar and Zevalin, and the anti-CD54 antibody Cambus); approaches using anti-idiotypic antibodies; approaches that enhance natural killer cell function; and approaches that utilize antibody-toxin conjugates (e.g., the anti-CD33 antibody Mylotarg); immunotoxins such as moxetumomab pasudotox; and agonists of Toll-like receptor 7 or Toll-like receptor 9.

[0291]

[0210] An example of an efficacy enhancer is leucovorin.

[0292]

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

[0293] In some embodiments, the amount of additional anti-tumor agent present in the compositions of the present disclosure can be less than or equal to the amount normally administered in a composition comprising that anti-tumor agent as the only active agent. In certain embodiments, the amount of additional anti-tumor agent in the compositions of the present disclosure ranges from about 50% to 100% of the amount normally present in a composition comprising that anti-tumor agent as the only therapeutically active agent.

[0294]

[0213] Thus, in another aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more anti-tumor agents listed above.

[0295]

[0214] In some embodiments, the additional anti-tumor agent is selected from the group consisting of doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, and bleomycin.

[0296] 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, the delay in administering the second component should be such that the beneficial effect of the combination is not lost.

[0297]

[0216] In a further aspect, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more of the anti-tumor agents listed above, in association with a pharmaceutically acceptable excipient.

[0298] In a further aspect, there is provided a kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more anti-tumor agents listed above.

[0299]

[0218] In a further aspect, a kit is provided that includes: (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof in a first unit dosage form; (b) an anti-tumor 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 aspect, due to the selective ATM kinase inhibitory activity and non-AO liability of the compounds disclosed herein, there is provided a method for treating an ATM-related disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the disclosure.

[0300] In some embodiments, the ATM-related disease or condition is cancer. In some embodiments, 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. In some embodiments, the cancer is head and neck squamous cell carcinoma, including, but not limited to, lip carcinoma, oral carcinoma, oropharyngeal carcinoma, hypopharyngeal carcinoma, glottic laryngeal carcinoma, supraglottic laryngeal carcinoma, ethmoid sinus carcinoma, maxillary sinus carcinoma, and occult primary carcinoma. In some embodiments, the cancer is metastatic cancer. In some embodiments, the metastatic cancer comprises central nervous system metastases. In some embodiments, central nervous system metastases comprise brain metastases. In some embodiments, central nervous system metastases comprise leptomeningeal metastases. "Lepmeningeal metastasis" occurs 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 blood, or they travel from brain metastases carried by cerebrospinal fluid (CSF) that flows through the meninges.

[0301] As used herein, the term "subject in need thereof" is a subject having an ATM-related disease or condition (e.g., cancer) or a subject at increased risk of developing an ATM-related disease or condition (e.g., cancer) relative to the general population. In the case of cancer, the subject in need thereof may have a precancerous condition. "Subject" includes warm-blooded animals. In some embodiments, the warm-blooded animal is a human.

[0302] In this context, the term "therapeutically effective amount" refers to an amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof that is effective to provide "therapy" in a subject or to treat an ATM-related disease or disorder in a subject. In the case of cancer, a therapeutically effective amount may cause any of the observable or measurable changes in a subject as described above in the definitions of "therapy," "treatment," and "prevention." For example, an effective amount may reduce the number of cancer or tumor cells; reduce overall tumor size; inhibit or stop tumor cell invasion into peripheral organs, including, for example, soft tissue and bone; inhibit and stop tumor metastasis; inhibit and stop tumor growth; alleviate to some extent one or more symptoms associated with cancer; reduce morbidity and mortality; improve quality of life; or a combination of such effects. An effective amount may be an amount sufficient to reduce the symptoms of a disease responsive to inhibition of ATM kinase activity. For 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 amount can vary depending on the route of administration, excipient usage, and co-use with other drugs. For example, when a combination therapy is used, the amount of the compound of formula (I) or pharmaceutically acceptable salt described herein and the amount of other pharmaceutically active drug(s) when combined are jointly effective for treating the targeted disorder in an animal patient. In this context, the combined amount is a "therapeutically effective amount" if, when combined, they are sufficient to reduce the symptoms of a disease responsive to the inhibition of ATM activity as described above.

[0303]

[0223] In general, a "therapeutically effective amount" can be determined by one of ordinary skill in the art by starting, for example, with the dosage ranges set forth herein for the compound of formula (I) or a pharmaceutically acceptable salt thereof, and with the approved or otherwise published dosage range(s) for the other pharmaceutically active compound(s).

[0304] The methods for treating ATM-related diseases or conditions described herein can be used as monotherapy. As used herein, the term "monotherapy" refers to the administration of a single active or therapeutic compound to a subject in need thereof. In some embodiments, monotherapy involves the administration of a therapeutically effective amount of one of the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

[0305] Depending on the particular disease or condition to be treated, the methods of treating ATM-associated diseases or conditions described herein may involve, in addition to the administration of a compound of formula (I), one or more additional treatments, such as conventional surgery, radiation therapy, chemotherapy, or a combination of such additional treatments. As used herein, the term "combination therapy" refers to the administration of a combination of two or more active compounds.

[0306]

[0226] Additional treatments, such as additional anti-tumor agents, can be administered separately from the compounds of the present disclosure, as part of a multiple dose regimen. Alternatively, these additional treatments may be part of a single dosage form, mixed together with the compounds of the present disclosure in a single composition.

[0307]

[0227] In some embodiments, compounds of the present disclosure can be administered simultaneously, sequentially or separately with conventional surgical, radiotherapy or chemotherapy treatment.

[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 or intraluminal radiation therapy; or (iii) systemic radiation therapy, including, but not limited to, iodine-131 and strontium-89.

[0309]

[0229] Chemotherapy may include anti-tumor agents known in the art, such as anti-neoplastic agents, anti-angiogenic agents, immunotherapeutic approaches, efficacy enhancers, etc., as described in this specification.

[0310]

[0230] Thus, in one aspect, there is provided a method of treating an ATM-related disease or condition in a subject in need thereof, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially with radiation therapy.

[0311]

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

[0312] 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, glottic laryngeal carcinoma, supraglottic 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 a central nervous system metastasis. In some embodiments, the central nervous system metastasis is a brain metastasis.

[0313]

[0233] In some embodiments, a method of treating glioblastoma in a subject in need thereof is provided, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially with brain radiation.

[0314]

[0234] In another aspect, a method of treating an ATM-related disease or condition in a subject in need thereof is provided, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially with one or more additional anti-tumor agents.

[0315] In some embodiments, the ATM-related disease or condition is cancer. In certain embodiments, the amounts of the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the one or more additional anti-tumor agents are synergistically effective in producing an anti-cancer effect.

[0316]

[0236] In some embodiments, additional anti-tumor agents include anti-neoplastic agents, anti-angiogenic agents, immunotherapeutic approaches, efficacy enhancers, and the like.

[0317]

[0237] In some embodiments, the additional anti-tumor agent is 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 can be administered simultaneously, sequentially or separately from the anti-neoplastic agent.

[0319] In certain embodiments, the anti-neoplastic agent is a PARP inhibitor. In certain embodiments, the PARP inhibitor is selected from the group consisting of olaparib, rucaparib, niraparib, talazoparib, pamiparib, and fluzoparib. [Example]

[0320] The following examples are included for illustrative purposes. However, it should be understood that these examples do not limit the invention, but are meant only to suggest a method of practicing the present disclosure. 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 compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, the synthesis of non-exemplified compounds according to the present disclosure can be successfully carried out by modifications apparent to those skilled in the art, such as by appropriate protection of interfering groups, by utilizing other suitable reagents known in the art other than those described, and / or by routine modification of reaction conditions. Alternatively, it will be recognized that other reactions disclosed herein or known in the art have applicability for preparing other compounds of the present disclosure.

[0321] 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]hexan-3-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0325] [ka]

[0326] Step 1: 6-Bromocinnolin-4-ol

[0327] [ka]

[0328] 1-(2-Amino-5-bromophenyl)ethenone (200 g, 935 mmol) was slowly dissolved in concentrated HCl (2 L) and water (440 mL) below 10° C., and the mixture was stirred at 0° C. for 1 h. Then, a solution of NaNO (71.0 g, 1.03 mol) in water (360 mL) was added dropwise below 0° C., and the resulting reaction mixture was stirred at 0° C. for another 1 h. The reaction mixture was then stirred at 65° C. for 16 h. 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 h to give 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-nitrocinnolin-4-ol

[0329] [ka]

[0330] 6-Bromocinnoline-4-ol (50.0 g) was slowly dissolved in fuming HNO3 (200 mL) at 20°C-35°C, and the reaction mixture was stirred at 28°C-33°C for 5 h. 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 h 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 h to give 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-nitrocinnoline

[0331] [ka]

[0332] To a solution of 6-bromo-3-nitrocinnolin-4-ol (100 g, 372 mmol) in dry DMF (1 L) was added POCl (51.0 mL, 558 mmol) dropwise at 0 °C under N, and the reaction mixture was stirred at 10-15 °C for 12 h. The mixture was poured into ice water (1.5 L) and filtered. The filtered residue was triturated with MTBE (500 mL) at room temperature for 1 h and filtered. The filtered cake was dried in an oven at 40 °C for 16 h to give 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-nitrocinnoline-4-amine

[0333] [ka]

[0334] To a mixture of 6-bromo-4-chloro-3-nitrocinnoline (50.0 g, 174 mmol) and propan-2-amine (15.4 g, 261 mmol) in DCM (500 mL), TEA (77.4 mL, 522 mmol) was added, and the reaction mixture was stirred at room temperature for 3 h. The mixture was poured into ice 1 M HCl solution (1 L) and extracted with DCM (500 mL × 2). The combined organic layers were washed with brine (800 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give 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] To a solution of 6-bromo-N-isopropyl-3-nitrocinnoline-4-amine (75.0 g, 242 mmol) in MeOH (400 mL) was added SnCl . HO (164 g, 726 mmol) was added at 0° C., and the reaction mixture was stirred at 60° C. for 2 h. The mixture was adjusted to pH 8 with 50% NaOH solution at below 45° C. and stirred at 55° C. for 45 min. The mixture was filtered, and the filtered residue was triturated with THF (300 mL) at room temperature for 1 h. It was filtered, and the combined filtrate was evaporated under reduced pressure. The residue was triturated with THF (300 mL) at room temperature for 1 h and filtered again. The filtrate was evaporated under reduced pressure to give the desired product (50.0 g, 73.8% yield) as a dark brown solid. LC-MS (ESI) m / z: 281 [M+H] + . Step 6: 8-Bromo-1-isopropyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (8)

[0337] [ka]

[0338] To a solution of 6-bromo-N4-isopropylcinnoline-3,4-diamine (49.0 g, 175 mmol) in dry THF (500 mL) was added CDI (85.0 g, 525 mmol), 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). It was adjusted to pH 7 with 1 M HCl solution and filtered. The filtered residue was dried in an oven at 55° C. for 16 hours to give 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]cinnolin-2(3H)-one

[0339] [ka]

[0340] To a solution of 8-bromo-1-isopropyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (40.0 g, 131 mmol) in dry DMF (300 mL) was added t-BuONa (15.0 g, 157 mmol) at 0° C. and stirred at 0° C. for 30 min under N2. To the reaction mixture, MeI (37.2 g, 262 mmol) was added dropwise at 10° C.-15° C., and the reaction mixture was stirred at 10° C.-15° C. for 2 h. The mixture was poured into ice water (600 mL) and filtered. The filtered residue was triturated with MeOH (200 mL) for 1 h and filtered. The filter cake was dried under vacuum to give 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] To a solution of (5-bromopyridin-2-yl)methanol (5.00 g, 26.7 mmol) in DCM (50 mL) was slowly added SOCl (3.87 mL, 53.4 mmol), and the resulting reaction mixture was stirred at room temperature for 2 h. The mixture was evaporated under reduced pressure. The residue was dissolved in DCM (50 mL) and washed with saturated NaHCO solution (50 mL). The organic layer was dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give 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]hexan-3-yl)ethanol

[0343] [ka]

[0344] To 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 added K2CO3 (4.47 g, 32.4 mmol), and the reaction mixture was stirred at room temperature for 16 h. The mixture was filtered, and the filtrate was evaporated under reduced pressure to give the crude product (1.20 g) as a yellow oil. LC-MS (ESI) m / z: 128 [M+H] + . Step 10: 3-(2-((5-bromopyridin-2-yl)methoxy)ethyl)-3-azabicyclo[3.1.0]hexane

[0345] [ka]

[0346] To a solution of 2-(3-azabicyclo[3.1.0]hexan-3-yl)ethanol (1.20 g, 9.45 mmol) in dry THF (15 mL) was slowly added NaH (756 mg, 18.9 mmol) at 0° C., and the reaction mixture was stirred at 0° C. for 30 minutes. Then, to the mixture was added a solution of 5-bromo-2-(chloromethyl)pyridine (1.94 g, 9.45 mmol) in THF (10 mL) dropwise, and the resulting reaction mixture was slowly warmed to room temperature and stirred at that temperature for 2 hours. The mixture was poured into ice-water (70 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM:MeOH = 100:1 to 20:1) to give the desired product (950 mg, 26.7% yield over two steps) as a brown oil. LC-MS (ESI) m / z: 297 [M+H] + . Step 11: 8-(6-((2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0347] [ka]

[0348] A mixture of 3-(2-((5-bromopyridin-2-yl)methoxy)ethyl)-3-azabicyclo[3.1.0]hexane (100 mg, 0.338 mmol), bis(pinacolato)diboron (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, the reaction mixture was added with water (1 mL), 8-bromo-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-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), and the resulting reaction mixture was stirred at 100 °C for 2 h. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography (DCM:MeOH = 9:1) to give the desired product (20.0 mg, 12.9% yield for 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 according to the methods described above using different starting materials.

[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 [[ID= 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,​​​​​H 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 【026۸】 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 【026۹】 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, 1H). Example 22

[0274] 1 1H NMR (4 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 - 0.53 (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 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 2.1 Hz, 1H), 8.48-8.40 (m, 2H), 8.33 (dd, J = 8.1, 2.4 Hz, 1H), 8.10 (dd, J = 9.1, 1.6 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 5.39-5.25 (m, 1H), 4.66 (s, 2H), 3.66 (t, J = 5.7 Hz, 2H), 3.60 (s, 3H), 2.90-2.80 (m, 1H), 2.69-2.56 (m, 4H), 2.43-2.29 (m, 2H), 1.90-1.81 (m, 2H), 1.75-1.69 (m, 2H), 1.67 (d, J = 6.7 Hz, 6H). Example 25

[0277] 1H 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)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0357] [ka]

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

[0359] [ka]

[0360] To a solution of (5-bromopyridin-2-yl)methanol (5.00 g, 27.0 mmol) in dry DMF (50 mL) was slowly added NaH at 0° C., and the reaction mixture was stirred at 0° C. for 30 minutes. Then, methyl 2-bromoacetate (3.60 mL, 35.0 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 ice-cold 1 M NaOH solution (70 mL) and stirred at room temperature for 1 hour. The mixture was extracted with EtOAc (10 mL × 2), and the aqueous layer was adjusted to pH 4 with 1 M HCl solution. It was extracted with EtOAc (100 mL × 3), and the organic layer was washed with 5% LiCl solution (20 mL) and brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was triturated with MTBE (50 mL) at room temperature for 20 minutes and filtered. The filtered cake was dried under vacuum for 3 hours to give the desired product (4.30 g, 65% yield) as a white solid. Step 2: 2-((5-bromopyridin-2-yl)methoxy)-1-(5-azaspiro[2.4]heptan-5-yl)ethan-1-one

[0361] [ka]

[0362] To a mixture of 2-((5-bromopyridin-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 added 50% T3P in EtOAc (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 h, 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 give the crude product (600 mg) as a brown oil. LC-MS (ESI) m / z: 325 [M+H] + . Step 3: 5-(2-((5-bromopyridin-2-yl)methoxy)ethyl)-5-azaspiro[2.4]heptane

[0363] [ka]

[0364] To a solution of 2-((5-bromopyridin-2-yl)methoxy)-1-(5-azaspiro[2.4]heptan-5-yl)ethan-1-one (600 mg, 1.85 mmol) in dry THF was added 1 M BH . The 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 h. 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 h. 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 give the desired product (329 mg, 52.0% yield for 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)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0365] [ka]

[0366] The crude product was prepared in a similar manner to Example 1 and purified by flash chromatography (DCM:MeOH=9:1) to give the desired product (50.0 mg, 21.9% yield over 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 according to the methods described above using different starting materials.

[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 (400 MHz, 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] <0000�46>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 - ∞.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)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0375] [ka]

[0376] Step 1: 5-Bromopicolinoyl chloride

[0377] [ka]

[0378] To a solution of 5-bromopicolinic acid (80.0 g, 398 mmol) in DCM (600 mL) was added SOCl (144 mL, 1.99 mol) dropwise at room temperature, and the reaction mixture was stirred at room temperature for 3 h. The mixture was evaporated under reduced pressure to give the 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-methylpicolinamide

[0379] [ka]

[0380] To a solution of N,O-dimethylhydroxylamine hydrochloride (46.6 g, 478 mmol) in DCM (800 mL) was added TEA (283 mL, 1.91 mol) followed by 5-bromopicolinoyl chloride (82.0 g) in portions at 0° C. After stirring at room temperature for 3 h, the mixture was poured into ice-saturated NaHCO solution (800 mL) and extracted with DCM (400 mL × 2). The combined organic layers were washed with 1 M HCl solution (800 mL × 2) and brine (800 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give 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-methylpicolinamide

[0381] [ka]

[0382] 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 h. The mixture was poured into ice-saturated NH4Cl solution (800 mL) and extracted with EtOAc (400 mL × 2). The combined organic layers were washed with brine (800 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was triturated with MeOH (200 mL) at room temperature for 1 h and filtered. The filtered cake was dried under vacuum for 3 h to give the desired product (41.5 g, 52.4% yield for three steps) as an off-white solid. LC-MS (ESI) m / z: 200 [M+H] + . Step 4: (R)-1-(5-bromopyridin-2-yl)ethanol

[0383] [ka]

[0384] To a solution of (S)-2-methyl-CBS-oxazaborolidine (42.8 g, 155 mmol) in dry THF (400 mL) was added 1 M BH .A THF solution (309 mL, 309 mmol) was added dropwise at 0° C. for about 1 hour, and the reaction mixture was stirred at 0° C. for 1 hour. A solution of 5-bromo-N-methoxy-N-methylpicolinamide (41.5 g, 206 mmol) in dry THF (400 mL) was then added dropwise at −40° C. for about 1.5 hours, and the resulting mixture was stirred at −40° C. for 1 hour. The mixture was poured into ice-cold 1 M HCl solution (800 mL) and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the solid precipitated and filtered. The residue was adjusted to pH 8 with 1 M NaOH solution and extracted with MTBE (400 mL × 2). The organic layer was washed with brine (500 mL), dried over anhydrous NaSO, filtered, and the filtrate was evaporated under reduced pressure to give 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-bromopyridin-2-yl)ethoxy)acetic acid

[0385] [ka]

[0386] To a solution of (R)-1-(5-bromopyridin-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. Then, 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 ice 1 M NaOH solution (420 mL) and stirred at room temperature for 1 hour. The mixture was extracted with EtOAc (200 mL×2), and the aqueous layer was adjusted to pH 4 with 1 M HCl solution. It was extracted with EtOAc (200 mL × 3), the organic layer was washed with 5% LiCl solution (200 mL) and brine (200 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which 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 give 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-bromopyridin-2-yl)ethoxy)-1-(5-azaspiro[2.4]heptan-5-yl)ethenone

[0387] [ka]

[0388] To a mixture of (R)-2-(1-(5-bromopyridin-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 added 50% T3P in EtOAc (95.4 g, 150 mmol) followed by DIEA (49.4 mL, 300 mmol) at 0° C. After stirring at room temperature for 16 h, the mixture was poured into ice-saturated NaHCO3 solution (500 mL) and extracted with DCM (150 mL × 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 give 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-bromopyridin-2-yl)ethoxy)ethyl)-5-azaspiro[2.4]heptane

[0389] [ka]

[0390] To a solution of (R)-2-(1-(5-bromopyridin-2-yl)ethoxy)-1-(5-azaspiro[2.4]heptan-5-yl)ethanone (28.0 g, 82.8 mmol) in dry THF was added 1 M BH . The THF solution (414 mL, 414 mmol) was added dropwise at 0° C., and the reaction mixture was stirred at room temperature for 2 h. 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 h. 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 give the desired product (12.0 g, 49.0% yield for 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)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0391] [ka]

[0392] The crude product was prepared in a similar manner as in Example 1 and purified by chromatography on silica gel (DCM:MeOH=100:1 to 10:1) to give the desired product (3.50 g, 23.3% yield over 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 according to the methods described above using different starting materials.

[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, 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), 2.62 - 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 【03^24】 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 【03^25】 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

[0330] 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-cyclopropoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0400] [ka]

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

[0402] [ka]

[0403] To a solution of (R)-benzyl 3-hydroxypyrrolidine-1-carboxylate (3.00 g, 13.6 mmol) in ethoxyethane (15 mL) and DCM (5 mL) was added 2 drops of TFA at 0° C., and the reaction mixture was stirred at room temperature for 48 h. The mixture was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (PE:EtOAc = 1:0 to 10:1) to give the desired product (2.70 g, 67.8% yield) as a light oil. Step 2: (R)-Benzyl 3-(vinyloxy)pyrrolidine-1-carboxylate

[0404] [ka]

[0405] 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 h. The mixture was once again cooled to 0° C., and another portion of TEA (0.684 mL, 4.61 mmol) and TMSOTF (0.833 mL, 4.61 mmol) was added dropwise. The reaction mixture was then slowly warmed to room temperature and stirred overnight. The mixture was poured into ice 1 M NaOH solution (50 mL) and extracted with DCM (20 mL × 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: EtOAc = 1:0 to 10:1) to give the desired product (319 mg, 14.0% yield) as a light oil. LC-MS (ESI) m / z: 248 [M+H] + . Step 3: (R)-Benzyl 3-cyclopropoxypyrrolidine-1-carboxylate

[0406] [ka]

[0407] A 1 M solution of diethylzinc 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 at 0 °C under N2. The resulting reaction mixture was then stirred at 0 °C for 30 min. To the mixture was added a solution of (R)-benzyl 3-(vinyloxy)pyrrolidine-1-carboxylate (319 mg, 1.29 mmol) dropwise at 0 °C. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The mixture was poured into ice-saturated NH4Cl solution (30 mL) and extracted with DCM (20 mL × 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: EtOAc = 1:0 to 10:1) to give the desired product (182 mg, 54.1% yield) as a light oil. LC-MS (ESI) m / z: 262 [M+H] + . Step 4: (R)-3-Cyclopropoxypyrrolidine

[0408] [ka]

[0409] 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) was added Pd / C (15.0 mg), and the reaction mixture was stirred at room temperature overnight. The mixture was filtered, and the filtrate was evaporated under reduced pressure to give 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-bromopyridin-2-yl)ethoxy)ethanol

[0410] [ka]

[0411] To a solution of (R)-2-(1-(5-bromopyridin-2-yl)ethoxy)acetic acid (9.50 g, 36.7 mmol) in THF (100 mL) was added 1 M BH . The THF solution (73.4 mL, 73.4 mmol) was added dropwise at 0° C. under N2. The reaction mixture was then stirred at room temperature for 1 h. The mixture was quenched with MeOH (100 mL) at 0° C. and stirred at 80° C. for 1 h. The mixture was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (DCM:MeOH = 100:1 to 20:1) to give 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)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0412] [ka]

[0413] The crude product was prepared in a similar manner as in Example 1 and purified by chromatography on silica gel (DCM:MeOH = 100:1 to 10:1) to give 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]cinnolin-8-yl)pyridin-2-yl)ethoxy)acetaldehyde

[0414] [ka]

[0415] To a solution of oxalyl chloride (0.343 mL, 4.05 mmol) in dry DCM (5 mL) was added DMSO (0.574 mL, 8.10 mmol) dropwise at −78° C. under N2, and the resulting reaction mixture was stirred at −78° C. for 15 min. Then, to the reaction mixture was added a solution of (R)-8-(6-(1-(2-hydroxyethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (1.10 g, 2.70 mmol) in dry DCM (10 mL) dropwise at −78° C. After stirring for 20 min at −78° C., TEA (1.87 mL, 13.5 mmol) was added. The resulting mixture was allowed to warm slowly to room temperature. The mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 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-cyclopropoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0416] [ka]

[0417] To 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]cinnolin-8-yl)pyridin-2-yl)ethoxy)acetaldehyde (159 mg, 0.394 mmol) in DCE (4 mL) was added sodium triacetoxyborohydride (251 mg, 1.18 mmol) slowly at 0° C., and the reaction mixture was stirred at room temperature overnight. The mixture was poured into ice-saturated NaHCO solution (20 mL) and extracted with DCM (15 mL × 2). The organic layer was washed with brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM:MeOH=9:1) to give 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 according to the methods described above using different starting materials.

[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, 1H), 2.23 - 2.07 (m, 1H), 1.68 (d, J = 6.7 Hz, 6H), 1.66 - 1.58 (m, 1H), 1.51 (d, J = 6.5 Hz, 3H), 1.07 (d, J = 6.7 Hz, 3H). Example 79

[0351] 1 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 1.8 Hz, (此处原文有误,推测为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), 2.46 - 2.36 (m, 2H), 1.67 (d, J = 6.7 Hz, 6H), 1.50 (d, J = 6.5 Hz, 3H). Example 80

[0352] 1 Note: There seems to be an error in the "1H" in the "1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 1.8 Hz, 1H)" part of the original text numbered . It is likely a misprint. The translation is done based on the best understanding of the overall context.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), 8.05 (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), 2.49-2.4​​​​​​​​​​​H 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).<00XXX106>Example 87<00XXX107>

[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).<00XXX108>Example 88<00XXX109>

[0360] 1 Remark: The 7 - digit tags , , , are kept as they are because the specific content they represent is not clear from the context. If there is more information about their meaning, a more accurate translation might be possible. Also, the "XXX" in the translated tags is used to indicate that the original 7 - digit number is retained as is.1H 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)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0425] [ka]

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

[0427] [ka]

[0428] To a mixture of 6-bromo-4-chloro-3-nitrocinnoline (60.0 g, 170 mmol) and tetrahydro-2H-pyran-4-amine (25.8 g, 255 mmol) in DCM (500 mL), TEA (75.4 mL, 510 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into ice 1 M HCl solution (1 L) and extracted with DCM (500 mL × 2). The combined organic layer was washed with brine (800 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give 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] To a solution of 6-bromo-3-nitro-N-(tetrahydro-2H-pyran-4-yl)cinnolin-4-amine (75.0 g, 212 mmol) in MeOH (200 mL) was added SnCl .HO (144 g, 636 mmol) was added at 0° C., and the reaction mixture was stirred at 60° C. for 2 h. The mixture was adjusted to pH 8 with 50% NaOH solution at below 45° C. and stirred at 55° C. for 45 min. The mixture was filtered, and the filtered residue was triturated with THF (300 mL) at room temperature for 1 h. It was filtered, and the combined filtrate was evaporated under reduced pressure. The residue was triturated with THF (300 mL) at room temperature for 1 h and filtered. The filtrate was evaporated under reduced pressure to give the desired product (54.0 g, 78.7% yield) 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]cinnolin-2(3H)-one

[0431] [ka]

[0432] 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) was added CDI (75.0 g, 462 mmol), 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). It was adjusted to pH 7 with 1 M HCl solution and filtered. The filtered residue was dried in an oven at 55° C. for 16 hours to give 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]cinnolin-2(3H)-one

[0433] [ka]

[0434] To a solution of 8-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (42.0 g, 120 mmol) in dry DMF (300 mL) was added t-BuONa (14.0 g, 144 mmol) at 0° C. and stirred at 0° C. for 30 minutes under N2. 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 triturated with MeOH (200 mL) for 1 hour and filtered. The filter cake was dried under vacuum to give 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)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0435] [ka]

[0436] The crude product was prepared in a similar manner to Example 1 and purified by flash chromatography (DCM:MeOH=9:1) to give 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 according to the methods described above using different starting materials.

[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), 8.3 (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)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0441] [ka]

[0442] Step 1: (R)-8-(6-(1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0443] [ka]

[0444] The crude product was prepared in a similar manner as in Example 1 and purified by chromatography on silica gel (DCM:MeOH=100:1 to 10:1) to give 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 according to the methods described above using different starting materials.

[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), 7.64 (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] 11H 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 8.88 (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)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0451] [ka]

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

[0453] [ka]

[0454] The crude product was prepared in a similar manner as in Example 1 and purified by chromatography on silica gel (DCM:MeOH = 100:1 to 10:1) to give the desired product (1.20 g, 65.6% yield over 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]cinnolin-8-yl)pyridin-2-yl)ethoxy)acetaldehyde

[0455] [ka]

[0456] To a solution of oxalyl chloride (0.343 mL, 4.05 mmol) in dry DCM (5 mL) was added DMSO (0.574 mL, 8.10 mmol) dropwise at −78° C. under N2, and the resulting reaction mixture was stirred at −78° C. for 15 min. Then, to the reaction mixture was added a solution of (R)-8-(6-(1-(2-hydroxyethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (1.20 g, 2.70 mmol) in dry DCM (10 mL) dropwise at −78° C. After stirring for 20 min at −78° C., TEA (1.87 mL, 13.5 mmol) was added. The resulting mixture was then allowed to warm slowly to room temperature. The mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give 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-azaspiro[3.4]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0457] [ka]

[0458] To 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]cinnolin-8-yl)pyridin-2-yl)ethoxy)acetaldehyde (176 mg, 0.394 mmol) in DCE (4 mL) was added sodium triacetoxyborohydride (251 mg, 1.18 mmol) slowly at 0° C., and the reaction mixture was stirred at room temperature overnight. The mixture was poured into ice-saturated NaHCO solution (20 mL) and extracted with DCM (15 mL × 2). The organic layer was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (DCM:MeOH=9:1) to give 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 according to the methods described above using different starting materials.

[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)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0465] [ka]

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

[0467] [ka]

[0468] To a solution of BCl3 (1.5 L, 1 M in DCM, 1.5 mol) 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 portionwise to the solution. The resulting mixture was stirred at 120 °C for 16 h. After cooling the reaction, 2 N aqueous HCl (3.1 L) was added dropwise to the mixture at 0 °C, and the resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was poured into ice water and extracted with DCM (2 L × 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (EA:PE=1:5) to give the desired product 1-(2-amino-5-bromo-4-fluorophenyl)ethenone (60 g, 20% yield) as a white solid. MS: m / z 232 [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-fluorocinnolin-4-ol

[0469] [ka]

[0470] To a stirred solution of 1-(2-amino-5-bromo-4-fluorophenyl)ethan-1-one (120 g, 519.5 mmol) in concentrated HCl (1.7 L) and HO (380 mL) was added a solution of NaNO (40 g, 580 mmol) in HO (100 mL) dropwise at 0 °C. After stirring for 0-1 h, the resulting mixture was heated to 65 °C for 16 h. 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 give 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-nitrocinnolin-4-ol

[0471] [ka]

[0472] To a solution of 6-bromo-7-fluorocinnolin-4-ol (200 g, 826.4 mmol) in fuming HNO (600 mL) stirred at 0° C., concentrated HSO (200 mL) was carefully added dropwise over 10 min. The resulting mixture was stirred at 60° C. for 3 h. After cooling to room temperature, the reaction mixture was poured into ice water. The precipitate was collected by filtration, washed with water, filtered, and dried under vacuum to give the desired product (180 g, 76% yield) as a yellow solid. MS: m / z 288 [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-nitrocinnoline

[0473] [ka]

[0474] To a solution of 6-bromo-7-fluoro-3-nitrocinnoline-4-ol (180 g, 627 mmol) in DMF (900 mL) stirred at 0° C., POCl (125 g, 815 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was poured into ice water, and the solid was filtered, washed with water, filtered, and dried to give the crude product 6-bromo-4-chloro-7-fluoro-3-nitrocinnoline (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-nitrocinnoline-4-amine

[0475] [ka]

[0476] To a solution of 6-bromo-4-chloro-7-fluoro-3-nitrocinnoline (145 g, 475 mmol) and EtN (96 g, 951 mmol) in DCM (1.5 L) stirred at room temperature, was added isopropylamine (42 g, 715 mmol). The resulting mixture was stirred at room temperature for 2 h. The crude mixture was washed with water (1 L) and concentrated to dryness, and the residue was purified by column chromatography on silica gel (EA:PE=1:1) to give the desired product (102 g, 65% yield) as a yellow solid. MS: m / z 329 [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] To a solution of 6-bromo-7-fluoro-N-isopropyl-3-nitrocinnolin-4-amine (102 g, 311 mmol) in EtOAc (1 L) stirred at room temperature was added SnCl2·2H2O (281 g, 1244 mmol). The resulting mixture was stirred at 80 °C for 2 h. The crude mixture was basified with aqueous NaHCO3 to adjust the pH to 9 and filtered. The filtrate was extracted with EtOAc (1 L). The organic phase was washed with water and brine, filtered, and the filtrate was concentrated to give the desired product (85 g, 88% yield) as a yellow solid. MS: m / z 299 [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]cinnolin-2(3H)-one

[0479] [ka]

[0480] To a solution of 6-bromo-7-fluoro-N4-isopropylcinnoline-3,4-diamine (85 g, 285 mmol) in THF (1 L) stirred at room temperature was added CDI (184 g, 1140 mmol). The resulting mixture was stirred at 70° C. for 16 h. The reaction mixture was concentrated, the residue poured into ice water, and the solid was filtered, washed with water, and dried to give the desired product (81 g, 88% yield) as a yellow solid. MS: m / z 325 [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]cinnolin-2(3H)-one

[0481] [ka]

[0482] To a solution of 8-bromo-7-fluoro-1-isopropyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (55 g, 170 mmol) in DMF (500 mL) was added KCO (70 g, 510 mmol) 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 silica gel chromatography (DCM:MeOH=30:1) to give 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)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0483] [ka]

[0484] The crude product was prepared in a similar manner to Example 1 and purified by flash chromatography (DCM:MeOH=9:1) to give 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 according to the methods described above using different starting materials.

[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)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0488] [ka]

[0489] Step 1: (R)-8-(6-(1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0490] [ka]

[0491] The crude product was prepared in a similar manner to Example 1 and purified by flash chromatography (DCM:MeOH=9:1) to give the desired product (30.0 mg, 18.4% yield over 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 according to the methods described above using different starting materials.

[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)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0497] [ka]

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

[0499] [ka]

[0500] To a solution of 6-bromo-4-chloro-7-fluoro-3-nitrocinnoline (90.0 g, 295 mmol) and EtN (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 ice 1 M HCl solution (1 L), and the DCM was evaporated under reduced pressure to precipitate a yellow solid, which was filtered. The filter residue was triturated with 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 give 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)cinnoline-3,4-diamine

[0501] [ka]

[0502] To a solution of 6-bromo-7-fluoro-3-nitro-N-(tetrahydro-2H-pyran-4-yl)cinnolin-4-amine (80.0 g, 216 mmol) in MeOH (400 mL) was added SnCl . HO (146 g, 648 mmol) was added at 0° C., and the reaction mixture was stirred at 60° C. for 2 h. The mixture was adjusted to pH 8 with 50% NaOH solution at below 45° C. and stirred at 55° C. for 45 min. The mixture was filtered, and the filtered residue was triturated with MeOH (300 mL) at room temperature for 1 h. After filtration, the combined filtrate was evaporated under reduced pressure. The residue was triturated with MTBE (300 mL) at room temperature for 1 h and filtered. The filter cake was dried in an oven at 55° C. for 16 h to give 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]cinnolin-2(3H)-one

[0503] [ka]

[0504] 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). It was adjusted to pH 7 with 1 M HCl solution and filtered. The filtered residue was dried in an oven at 55° C. for 16 hours to give 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]cinnolin-2(3H)-one

[0505] [ka]

[0506] To a solution of 8-bromo-7-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (31.0 g, 84.7 mmol) in dry DMF (250 mL) was added t-BuONa (9.76 g, 102 mmol) at 0° C. After stirring at 0° C. for 30 minutes under N2, 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 triturated with MeOH (200 mL) at 80° C. for 1 hour and filtered. The filter cake was dried under vacuum to give the desired product (25.0 g, 76.8% yield). LC-MS (ESI) m / z: 381 [M+H] + . Step 5: (R)-8-(6-(1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0507] [ka]

[0508] The crude product was prepared in a similar manner to Example 1 and purified by flash chromatography (DCM:MeOH=9:1) to give the desired product (40.0 mg, 22.7% yield over 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 according to the methods described above using different starting materials.

[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)pyridin-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0514] [ka]

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

[0516] [ka]

[0517] A solution of tert-butyl (3-oxocyclobutyl)carbamate (10.0 g, 54.0 mmol) in dry tetrahydrofuran (200 mL) was stirred at −78° C. for 10 minutes under N 2 . To the reaction mixture, 1N lithium triisobutylhydroborate (81.0 mL, 81.0 mmol) was added dropwise at −78° C., and the reaction mixture was stirred at −78° C. for 2 hours. To the reaction mixture, 2N NaOH solution (40 mL) was added dropwise at −45° C., followed by HO (30 mL) at −45° C. The resulting mixture was warmed to room temperature and extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with sodium bisulfite solution (50 mL) and brine (200 mL), dried over anhydrous Na 2 SO 4 , 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 give the desired product (8.50 g, 84.1% yield) as a light oil. Step 2: (trans)-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-nitrobenzoate

[0518] [ka]

[0519] To 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 dry tetrahydrofuran (150 mL) was added triphenylphosphine (15.0 g, 57.0 mmol) followed by diisopropyl azodicarboxylate (14.6 g, 72.0 mmol) at 0° C. under N. The resulting mixture was allowed to warm slowly 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 give the crude product (20.0 g) as a white solid. Step 3: tert-Butyl (trans-3-hydroxycyclobutyl)carbamate

[0520] [ka]

[0521] To a solution of trans-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-nitrobenzoate (20.0 g, 60.0 mmol) in HO (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 h. MeOH was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (150 mL × 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous NaSO, 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 give the crude product (9.00 g) as a white solid. Step 4: tert-Butyl (trans-3-methoxycyclobutyl)carbamate

[0522] [ka]

[0523] To a solution of tert-butyl (trans-3-hydroxycyclobutyl)carbamate (9.00 g, 48.0 mmol) in DCM (90 mL) was added N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (10.3 g, 48.0 mmol) followed by trimethyloxonium tetrafluoroborate (7.60 g, 51.0 mmol), and the reaction mixture was stirred at 40° C. for 72 h under N2. 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 give the desired product (2.50 g, 27.4% yield for three steps) as a white solid. Step 5: trans-3-Methoxycyclobutan-1-amine

[0524] [ka]

[0525] To a solution of tert-butyl (trans-3-methoxycyclobutyl)carbamate (2.50 g) in 1,4-dioxane (20 mL) was added 4 M hydrochloric acid in 1,4-dioxane (20 mL) 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 give the crude product (1.50 g) as an off-white solid. Step 6: 6-Bromo-N-(trans-3-methoxycyclobutyl)-3-nitrocinnolin-4-amine

[0526] [ka]

[0527] To a mixture of 6-bromo-4-chloro-3-nitrocinnoline (2.8 g, 9.9 mmol) and propan-2-amine (1.5 g, 15 mmol) in DCM (30 mL), TEA (2.8 mL, 20 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into ice 1 M HCl solution (19 mL) and extracted with DCM (50 mL × 2). The combined organic layer was washed with brine (80 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give the desired product (3.70 g, 86.1% purity) as a brown solid. Step 7: 6-Bromo-N 4 -(trans-3-Methoxycyclobutyl)cinnoline-3,4-diamine

[0528] [ka]

[0529] To a solution of 6-bromo-N-(trans-3-methoxycyclobutyl)-3-nitrocinnolin-4-amine (3.7 g, 10.5 mmol) in MeOH (40 mL) was added SnCl . HO (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 pH 8 with 50% NaOH solution at below 45° C. and stirred at 55° C. for 45 minutes. The mixture was filtered, and the filtered residue was triturated with THF (30 mL) at room temperature for 1 hour. After filtration, the combined filtrate was evaporated under reduced pressure. The residue was triturated with THF (30 mL) at room temperature for 1 hour and filtered. The filtrate was evaporated under reduced pressure to give the desired product (2.00 g, 58.8% yield) as a dark brown solid. Step 8: 8-Bromo-1-(trans-3-methoxycyclobutyl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one

[0530] [ka]

[0531] 6-Bromo-N in dry THF (20 mL) 4 To a solution of -(trans-3-methoxycyclobutyl)cinnoline-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). It was adjusted to pH 7 with 1 M HCl solution and filtered. The filtered residue was dried in an oven at 55° C. for 16 hours to give 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]cinnolin-2-one

[0532] [ka]

[0533] To a solution of 8-bromo-1-(trans-3-methoxycyclobutyl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one (1.20 g, 3.50 mmol) in dry DMF (10 mL) was added t-BuONa (404 mg, 4.20 mmol) at 0°C and stirred at 0°C for 30 min under N2. Then, MeI (1.00 g, 7.00 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 h. The mixture was poured into ice water (60 mL) and filtered. The filtered residue was triturated with MeOH (20 mL) for 1 h and filtered. The filter cake was dried under vacuum to give 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)pyridin-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one

[0534] [ka]

[0535] The crude product was prepared in a manner similar to that of Example 1 and purified by chromatography on silica gel (DCM:MeOH=100:1 to 10:1) to give a crude product, which was purified three times by flash chromatography (DCM:MeOH=9:1) to give the desired product (50.0 mg, 20% yield for 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 according to the methods described above using different starting materials.

[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 - 8.23 (m, 2H), 8.04 (dd, J = 9.1, ¼ 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), 第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] 1 It should be noted that there seems to be an error in the original text where "第2.66" appears in the NMR data of Example 176. This might be a typo. The translation is done based on the provided text as accurately as possible while keeping the tags intact.H 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 according to the methods described above using different starting materials.

[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 according to the methods described above using different starting materials.

[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-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one and (R)-1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one

[0548] [ka]

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

[0550] [ka]

[0551] To a solution of 5-bromopicolinaldehyde (770 mg, 4.16 mmol) in dry THF (15 mL) was added TMSCF (885 mg, 6.23 mmol) dropwise at 0 °C, followed by a solution of TBAF in THF (10.4 mL, 10.4 mmol, 1 M), and the reaction mixture was stirred at room temperature for 16 h. The mixture was poured into water (40 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (PE: EtOAc = 25: 1 to 10: 1) to give the desired product (645 mg, 60.8% yield). LC-MS (ESI) m / z: 256 [M+H] + . Step 2: 2-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethoxy)acetic acid

[0552] [ka]

[0553] To a solution of 1-(5-bromopyridin-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 ice 1M NaOH solution (15 mL) and stirred at room temperature for 1 hour. The mixture was extracted with EtOAc (10 mL×2), and the aqueous layer was adjusted to pH 4 with 1M HCl solution. It was extracted with EtOAc (20 mL × 3), and the organic layer was washed with 5% LiCl solution (30 mL) and brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product (620 mg) as a brown oil. LC-MS (ESI) m / z: 314 [M+H] + . Step 3: 2-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethoxy)-1-(pyrrolidin-1-yl)ethenone

[0554] [ka]

[0555] To a mixture of 2-(1-(5-bromopyridin-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 added 50% T3P in EtOAc (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 h. The mixture was poured into ice-saturated NaHCO3 solution (30 mL) and extracted with DCM (15 mL × 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 give 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-(pyrrolidin-1-yl)ethoxy)ethyl)pyridine

[0556] [ka]

[0557] To a solution of 2-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethoxy)-1-(pyrrolidin-1-yl)ethanone (820 mg, 2.24 mmol) in dry THF (10 mL) was added 1 M BH . The 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 h. 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 h. 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 give the desired product (380 mg, 60.6% yield for three 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-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0558] [ka]

[0559] The crude product was prepared in a similar manner as in Example 1 and purified by chromatography on silica gel (DCM:MeOH=100:1 to 10:1) to give the desired product (160 mg, 60.9% yield over 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-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one and (R)-1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one Subsequent separation of 1-isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one by chiral SFC gave two isomers.

[0560] (S)-1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-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). (R)-1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-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). SFC conditions: Instrument: MGII Preparative SFC (SFC-14) Column: Cellulose-2, 250 x 30 mm I.D., 5 μm Mobile phase: A for CO2 and B for isopropanol (0.1% NH3H2O) Gradient: B40%, Flow rate: 60 mL / min, Back pressure: 100 bar, Column temperature: 38°C, Wavelength: 220 nm, Cycle time: approximately 22 minutes

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

[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]cinnolin-8-yl)pyridin-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]cinnolin-8-yl)pyridin-2-yl)ethoxy)acetic acid

[0576] [ka]

[0577]

[0501] The crude product was prepared in a similar manner to Example 1 and purified by prep-TLC (DCM:MeOH=10:1) to give the crude product, which was purified by prep-HPLC to give the desired product (100 mg, 38.0% yield for 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]hexan-3-yl)ethoxy)propan-2-yl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0579] [ka]

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

[0581] [ka]

[0582] To a solution of 1-(5-bromopyridin-2-yl)ethanone (3.00 g, 15.1 mmol) in dry THF (30 mL) was added MeMgBr (3 M) in THF (7.54 mL, 22.6 mmol) dropwise at 0° C., and the reaction mixture was stirred at room temperature for 16 h. The mixture was poured into ice-saturated NH4Cl solution (50 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (PE:EtOAc = 25:1 to 5:1) to give 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-bromopyridin-2-yl)propan-2-yl)oxy)acetic acid

[0583] [ka]

[0584] To a solution of 2-(5-bromopyridin-2-yl)propan-2-ol (1.00 g, 4.65 mmol) in dry THF (10 mL) was slowly added NaH (372 mg, 9.30 mmol) at 0° C., and the reaction mixture was stirred at 0° C. for 30 minutes. To the mixture, 2-bromoacetic acid (834 mg, 6.05 mmol) was added dropwise, 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), adjusted to pH 4 with 1 M HCl solution, and extracted with EtOAc (15 mL×3). The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure to give 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]hexan-3-yl)-2-((2-(5-bromopyridin-2-yl)propan-2-yl)oxy)ethenone

[0585] [ka]

[0586] To a mixture of 1-((5-bromopyridin-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 added 50% T3P in EtOAc (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 h. The mixture was poured into ice-saturated NaHCO3 solution (50 mL) and extracted with DCM (20 mL × 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 give the crude product (980 mg) as a brown oil. LC-MS (ESI) m / z: 339 [M+H] + . Step 4: 3-(2-((2-(5-bromopyridin-2-yl)propan-2-yl)oxy)ethyl)-3-azabicyclo[3.1.0]hexane

[0587] [ka]

[0588] To a solution of 1-(3-azabicyclo[3.1.0]hexan-3-yl)-2-((2-(5-bromopyridin-2-yl)propan-2-yl)oxy)ethanone (980 mg, 2.90 mmol) in dry THF (10 mL) was added 1 M BH .The 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 h. 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 h. 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 give the desired product (450 mg, 29.9% yield for three 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]hexan-3-yl)ethoxy)propan-2-yl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0589] [ka]

[0590] The crude product was prepared in a manner similar to that in Example 1 and purified by chromatography on silica gel (DCM:MeOH=100:1 to 10:1) to give 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]hexan-3-yl)-1,1-difluoroethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0592] [ka]

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

[0594] [ka]

[0595] To a solution of 2-(5-bromopyridin-2-yl)propan-2-ol (2.00 g, 10.7 mmol) in dry THF (20 mL) was slowly added NaH (856 mg, 21.4 mmol) at 0° C., and the reaction mixture was stirred at 0° C. for 30 minutes. 2-Bromo-2,2-difluoroacetic acid (2.23 g, 12.8 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 2 hours. The mixture was poured into ice water (10 mL), adjusted to pH 4 with 1 M HCl solution, and extracted with EtOAc (15 mL×3). The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure to give 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]hexan-3-yl)-2-((5-bromopyridin-2-yl)methoxy)-2,2-difluoroethanone

[0596] [ka]

[0597] To a mixture of 2-((5-bromopyridin-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 added 50% T3P in EtOAc (3.08 g, 4.84 mmol) followed by DIEA (937 mg, 7.26 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. The mixture was poured into ice-saturated NaHCO3 solution (50 mL) and extracted with DCM (20 mL × 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 give the crude product (730 mg) as a brown oil. LC-MS(ESI)m / z:347[M+H] + . Step 3: 3-(2-((5-bromopyridin-2-yl)methoxy)-2,2-difluoroethyl)-3-azabicyclo[3.1.0]hexane

[0598] [ka]

[0599] To a solution of 1-(3-azabicyclo[3.1.0]hexan-3-yl)-2-((5-bromopyridin-2-yl)methoxy)-2,2-difluoroethanone (730 mg, 2.11 mmol) in dry THF (10 mL) was added 1 M BH . The 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 h. 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 h. 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 give the desired product (470 mg, 13.2% yield for 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]hexan-3-yl)-1,1-difluoroethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0600] [ka]

[0601] The crude product was prepared in a manner similar to that in Example 1 and purified by chromatography on silica gel (DCM:MeOH=100:1 to 10:1) to give the desired product (30.0 mg, 10.1% yield for 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-(pyrrolidin-1-yl)ethoxy)propyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0603] [ka]

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

[0605] [ka]

[0606] To a solution of 5-bromopicolinaldehyde (1.00 g, 5.41 mmol) in dry THF (10 mL) was added dropwise ethylmagnesium bromide (1 M) in THF (8.12 mL, 8.12 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 16 h. The mixture was poured into ice-saturated NH4Cl solution (50 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the crude product (1.20 g) as a brown oil. LC-MS (ESI) m / z: 216 [M+H] + . Step 2: 2-(1-(5-bromopyridin-2-yl)propoxy)acetic acid

[0607] [ka]

[0608] To a solution of 2-(5-bromopyridin-2-yl)propan-2-ol (1.20 g, 4.65 mmol) in dry THF (10 mL) was slowly added NaH (372 mg, 9.30 mmol) at 0° C., and the reaction mixture was stirred at 0° C. for 30 minutes. Ethyl 2-bromoacetate (1.00 g, 6.05 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 2 hours. 1M NaOH solution (5 mL) was then added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The mixture was adjusted to pH 4 with 1M HCl solution and extracted with EtOAc (15 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give the crude product (820 mg) as a brown oil. LC-MS (ESI) m / z: 274 [M+H] + . Step 3: 2-(1-(5-bromopyridin-2-yl)propoxy)-1-(pyrrolidin-1-yl)ethenone

[0609] [ka]

[0610] To a mixture of 2-(1-(5-bromopyridin-2-yl)propoxy)acetic acid (820 mg, 3.00 mmol) and pyrrolidine (277 mg, 3.90 mmol) in DCM (10 mL) was added 50% T3P in EtOAc (3.82 g, 6.00 mmol) followed by DIEA (1.47 mL, 9.00 mmol) at 0° C. The reaction mixture was then stirred at room temperature for 16 h. The mixture was poured into ice-saturated NaHCO3 solution (50 mL) and extracted with DCM (20 mL × 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 give the crude product (452 ​​mg) as a brown oil. LC-MS (ESI) m / z: 339 [M+H] + . Step 4: 5-Bromo-2-(1-(2-(pyrrolidin-1-yl)ethoxy)propyl)pyridine

[0611] [ka]

[0612] To a solution of 2-(1-(5-bromopyridin-2-yl)propoxy)-1-(pyrrolidin-1-yl)ethanone (452 ​​mg, 1.34 mmol) in dry THF (5 mL) was added 1 M BH . The 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 h. 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 h. 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 give the desired product (111 mg, 6.33% yield for four steps) as a light brown oil. LC-MS (ESI) m / z: 325 [M+H] + . Step 5: 1-Isopropyl-3-methyl-8-(6-(1-(2-(pyrrolidin-1-yl)ethoxy)propyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

[0613] [ka]

[0614] The crude product was prepared in a manner similar to that in Example 1 and purified by chromatography on silica gel (DCM:MeOH=100:1 to 10:1) to give 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 according to the methods described above using different starting materials.

[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 The potency of the compounds of the present disclosure can be determined by a number of pharmacological assays known in the art. The exemplary pharmacological assays that follow herein were carried out on the compounds of the present disclosure, as well as on the control compound 7-fluoro-8-(6-((2-(4-fluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-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 potency assay, and g) ATM SN-38 HT-29 cell potency assay. In describing the assays, generally: i. The following abbreviations have been used: 4NQO = 4-nitroquinoline N-oxide; Ab = antibody; BSA = bovine serum albumin; CO = carbon dioxide; DMEM = Dulbecco's modified Eagle's medium; DMSO = dimethyl sulfoxide; EDTA = ethylenediaminetetraacetic acid; EGTA = ethylene glycol tetraacetic acid; ELISA = enzyme-linked immunosorbent assay; EMEM = Eagle's minimum essential medium; FBS = fetal bovine serum; h = hour(s); HRP = horseradish peroxidase; ip = intraperitoneal; PBS = phosphate-buffered saline; PBST = phosphate-buffered saline / Tween; Tris = tris(hydroxymethyl)aminomethane; MTS reagent: [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt, and electron coupling reagent (phenazine methosulfate) PMS; sc = subcutaneous.

[0618] ii. IC using smart fitting models in Genedata 50 The IC value was calculated. 50 Values ​​were the concentrations of test compounds that inhibited 50% of the biological activity.

[0619] Assay a): ATM Biochemical Potency ATM (Millipore, Cat. No. 14-933) enzyme solution was prepared in 1x kinase base buffer. 10 μl of 2x 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. 2x peptide solution was prepared with FAM-labeled peptide and ATP in 1x kinase base buffer (final concentration: 1.5 nM). 10 μl of the 2x peptide solution was added to each well of the 384-well assay plate, which was 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] Assay b): ATR Biochemical Potency ATR enzyme (batch: Eurofins Cat. No. 14-953) solution was prepared in 1x kinase base buffer. 10 μl of 2x enzyme solution (final concentration: 2.5 nM) was added to each well of a 384-well assay plate containing 60 nl of compound per well. The plate was incubated at room temperature for 10 minutes. A 2x peptide solution was prepared with FAM-labeled peptide and ATP in 1x kinase base buffer. 10 μl of the 2x peptide solution was added to each well of the 384-well assay plate, which was incubated at 28°C for 240 minutes. The reaction was stopped by adding 40 μl of stop buffer. Data were collected using a caliper.

[0621] Assay c): PI3K Biochemical Potency

[0526] PI3Kα (p110α / p85a), PIK3Cδ, PIK3Cβ (p110β), and PIK3Cγ (pp110γ) kinase reaction solutions for PI3Kα (Invitrogen, Cat. No. PV4788), PIK3Cδ (Millipore, Cat. No. 14-604-M), PIK3Cβ (Eurofins, Cat. No. 14-603-K), and PIK3Cγ (Invitrogen, Cat. No. PR8641C) enzymes were prepared in 1x kinase buffer at 4x the final concentrations of each reagent in the assay (final concentrations: PI3Kα 0.7 nM, PIK3Cδ 3 nM, PIK3Cβ 4.8 nM, PIK3Cγ 11 nM). 2.5 μl of kinase solution was added to each well of a 384-well assay plate containing 2.5 μl of compound at serially diluted concentrations. A 2× substrate solution was prepared with 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. No. 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, which was then equilibrated for 60 minutes before being read for luminescence on a plate reader (Envision).

[0622] Assay d): mTOR Biochemical Potency A solution of mTOR enzyme (Millipore, Cat. No. 14-770) was prepared in 1x kinase buffer at 4x the final concentration in the assay (final concentration: 6 nM). 2.5 μl of kinase solution was added to each well of a 384-well assay plate containing 2.5 μl of compound at serially diluted concentrations. A 2x substrate solution was prepared with ULight-4E-BP1 (Thr37 / 46) peptide (PE, Cat. No. TRF0128-M) and ATP in 1x 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 30 minutes. Detection solutions of kinase quench buffer (EDTA) and Eu-anti-phospho-4E-BP1 antibody (Thr37 / 46) (PE, Cat. No. TRF0216-M) were prepared at twice the desired final concentration of each reagent in Lance detection buffer. 10 μl of detection solution buffer was added to each well of the assay plate. The assay plate was equilibrated at room temperature for 60 minutes before being read on a plate reader (Lance signal (665 nm) from the Envision program).

[0623] Assay e): DNA-PK Biochemical Assay A DNA-PK kinase reaction solution of DNA-PK enzyme (Promega, Cat. No. V4106, Lot. No. 0000224016) was prepared in 1x kinase buffer at twice the final concentration of each reagent in the assay (final concentrations: DNA-PK 1 U / µl, activator 6 µg / ml). 2.5 µl of kinase solution was added to each well of a 384-well assay plate containing 2.5 µl of compound at serially diluted concentrations. A substrate solution was prepared with ATP in 1x kinase reaction buffer at twice the final concentration of each reagent in the assay. Final concentrations: substrate 0.2 µg / ml and ATP 20 µM. The reaction was initiated by adding 2.5 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 ​​MAX Reagent 1 (Promega, Cat. No. v9102 / 3, Lot. No. 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, which was equilibrated for 30 minutes before being read for luminescence on a plate reader (Envision).

[0624] Assay f): phosp-KAP1 MCF-7 cell potency MCF-7 cells were seeded into 384-well cell culture plates at 25 μl / well and incubated at 37° C. and 5% CO for 24 hours. Test compounds were added to the 384-well plates. Etoposide at a final concentration of 100 μM was then added to each well, except for vehicle control wells, which were incubated at 37° C. and 5% CO 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 was 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, followed by incubation 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 antibody solution (anti-pKAP1 antibody (Bethyl Laboratories, A300-767A)) was added, and the plate was incubated overnight at 4° C. The plate was rinsed five times with PBST (0.1% Tween-20 in PBS). 20 ul / well of secondary antibody (IRDye 800CW goat anti-rabbit IgG, LI-COR, 926-32211 / (IRDye 800CW goat anti-mouse IgG, LI-COR, 926-32210) solution containing DNA stain DRAQ5 was added to the plate, which was incubated at room temperature for 1 hour away from light. The plate was rinsed five times with PBST (0.1% Tween-20 in PBS). After the final wash, the wash solution was removed and the plate was centrifuged upside down at 1000 rpm for 1 minute using paper to absorb all the wash buffer. The bottom of the plate was cleaned with moist lint-free paper. The plate was immediately scanned for results using ODYSSEY CLX (LI-COR). Data Analysis: 1) Fluorescence intensity (FI) was detected for each well.

[0625] 2) % Inhibition is calculated as follows:

[0626]

number

[0627]

number

[0628] : Mean FI for positive controls across the plate.

[0629]

number

[0630] : Mean FI for negative controls across the plate.

[0631] 3) Calculate IC50 and plot the effect-dose curve of the compound: IC50s are calculated by fitting the % inhibition values ​​and the logarithm of the compound concentration to a non-linear regression (dose response - variable slope) using GraphPad Prism 6.0.

[0632] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)) X: logarithm of compound concentration; Y: % inhibition Assay g): ATM SN-38 HT-29 Cell Potency

[0534] Rationale: SN38 is the active metabolite of irinotecan and a topoisomerase-I inhibitor. SN38 induces single-strand DNA breaks (SSBs) that are converted to double-strand breaks (DSBs) during replication. ATM plays a role in repairing DSBs. Inhibition of ATM was assessed in SN38-treated HT-29 cells (ATCC, Cat. No. HTB-38) by a high-content imaging system.

[0633]

[0536] Experiment details: HT-29 cells were trypsinized and approximately 10,000 cells per well were seeded into a 96-well microplate, which was then incubated overnight at 37°C and 5% CO2. Test compounds were added to the 96-well plate, which was then incubated for 1 hour at 37°C and 5% CO2. SN38 (MCE, Cat. No. HY-13704) at a final concentration of 30 nM was then added to the 96-well plate, which was then incubated for 1 hour at 37°C and 5% CO2. After removing the medium, the cells were fixed by adding 50 μl of 3.7% formaldehyde in PBSA and incubated for 20 minutes at room temperature. After rinsing the plate three times with PBSA, 50 μl of permeabilization buffer (0.1% Triton-X 100 in PBSA) was added, and the plate was incubated for 20 minutes at room temperature. After rinsing the plates once with PBSA, 50 μl of primary antibody solution was added and the plates were incubated at 4° C. overnight. A primary antibody solution was prepared by diluting the primary antibody (anti-phospho-ATM (Ser1981) antibody, (Merck Millipore, Cat. No. 05-740) at 1 / 10,000 in antibody buffer (3% BSA, 0.05% Tween in PBSA). The plate was rinsed three times with PBST (0.05% Tween in PBSA). 50 μl of secondary antibody solution was added to the plate, which was incubated at room temperature for 1 hour away from light. A secondary antibody solution was prepared by diluting the secondary antibody (goat anti-mouse IgG (H+L) Cross-Adsorbed Secondary Antibody, Alexa Fluor 488, Invitrogen, Cat. No. A11001) at 1 / 500 and Hoechst at 1 / 10,000 in antibody buffer. The plate was rinsed three times with PBST, and then 100 μl of PBSA was added per well. The plate was sealed with a black plate seal.

[0634]

[0538] Data capture

[0635] [Table 18]

[0636]

[0539] Data Analysis

[0637] [Table 19]

[0638] After image analysis, further statistics were performed with Excel 2013 (Microsoft). Graphical views were then generated using Prism 7.0 (Graphpad).

[0639] The compounds synthesized in Examples 1-222 and Reference Compound 1 were tested in assays a)-g) as described above. For some representative compounds, the IC 50 The results are provided in Tables 2-3.

[0640] [Table 20-1]

[0641] [Table 20-2]

[0642] [Table 21-1]

[0643] [Table 21-2]

[0644]

[0542] From Tables 2-3, it can be seen that the compounds of the present disclosure not only have good inhibition of ATM kinase, but are also selective for ATM kinase over other kinases in the PIKK family (PI3Kα, PI3Kβ, PI3Kγ, PI3Kδ, mTor, DNA-PK and ATR).

[0645]

[0543] For the other example compounds for which results are not shown, all had IC values ​​of 1000 nM or less against ATM kinase. 50 Some of these compounds have an IC50 against ATM kinase of 500 nM or less, some of 400 nM or less, some of 300 nM or less, some of 200 nM or less, or 100 nM or less, or even 50 nM or less. 50 In addition, some of the example compounds for which results are not shown have IC values ​​of greater than 1 μM, some greater than 3 μM, 5 μM, 7 μM, or even greater than 10 μM, against other kinases in the PIKK family (PI3Kα, PI3Kβ, PI3Kγ, PI3Kδ, mTor, and ATR). 50 Shows.

[0646] Example...

Claims

1. Formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof (In the formula: 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 said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are selected from the group consisting of one or more R ８ optionally substituted with; 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 a cycloalkyl or heterocyclyl, said cycloalkyl or heterocyclyl being selected from one or more R ９ optionally substituted with; L is selected from a direct bond, alkyl, cycloalkyl, or cycloalkylalkyl, wherein said alkyl, cycloalkyl, and cycloalkylalkyl are selected from one or more R ９ optionally substituted with; R ７ is -NR １０ R １１ , -OR １２ , —COOH, one or more R １３ saturated or unsaturated heterocyclyl optionally substituted with; R ８ is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, and alkoxyl; R ９ is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl; R １０ and R １１ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, and cycloalkyl; or R １０ and R １１ together with the nitrogen atom to which they are attached, optionally contain one or more additional heteroatoms selected from N, O and S and one or more R １４ forming an optionally substituted heterocyclyl; R １２ and R １３ are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, and heterocyclyl; R １４ is halogen, cyano, sulfonyl, alkyl, alkenyl, alkynyl, haloalkyl, alkylalkoxyl, heterocyclyl, -NR １５ R １６ and -OR １７ is selected from the group consisting of R １５ and R １６ are each independently hydrogen, alkyl, alkenyl, or alkynyl; R １７ 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 heteroaryl, optionally selected from the group consisting of thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl; or R １ is methyl optionally substituted with one, two or three halogens; 2. A compound of formula (I) according to claim 1 or a pharma- ceutically acceptable salt thereof.

3. R ２ is one or more R ８ is alkyl optionally substituted with ８ is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, and alkoxyl, and optionally R ２ is n-propyl or iso-propyl; or R ２ is one or more R ８ cycloalkyl optionally substituted with R ８ is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl, and alkoxyl, and optionally R ２ is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is selected from the group consisting of one or more R ８ and optionally substituted with R ８ is selected from hydroxyl, methyl, trifluoromethyl or methoxy, and further optionally, R ２ but, 【Chemistry 2】 or R ２ is one or more R ８ and R is heterocyclyl optionally substituted with ８ is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl, and alkoxyl, and optionally R ２ is selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, each of which is selected from the group consisting of one or more R ８ and optionally substituted with R ８ is selected from the group consisting of hydroxyl, methyl, trifluoromethyl and methoxy, and further optionally, R ２ but, 【Chemistry 3】 or R ２ is one or more R ８ and R is a heteroaryl optionally substituted with ８ is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl, and alkoxyl, and optionally R ２ is pyridine or pyrazole, each of which is represented by one or more R ８ and optionally substituted with R ８ is selected from the group consisting of hydroxyl, methyl, trifluoromethyl and methoxy; 2. A compound of formula (I) according to claim 1 or a pharma- ceutically acceptable salt thereof.

4. R ３ is hydrogen or fluoro; or R ４ is hydrogen; 2. A compound of formula (I) according to claim 1 or a pharma- ceutically acceptable salt thereof.

5. R ５ and R ６ is hydrogen and the other is alkyl or haloalkyl, and optionally R ５ and R ６ One of them is hydrogen and the other is C １～６ Alkyl or C １～６ haloalkyl, and optionally R ５ and R ６ is hydrogen and the other is methyl optionally substituted with one, two or three halogens, and optionally R ５ and R ６ is hydrogen and the other is methyl or trifluoromethyl; or R ５ and R ６ are hydrogen; or R ５ and R ６ are both alkyl; or R ５ and R ６ together with the carbon atom to which they are attached form a cycloalkyl; or R ５ and R ６ together with the carbon atom to which they are attached form a heterocyclyl; 2. A compound of formula (I) according to claim 1 or a pharma- ceutically acceptable salt thereof.

6. L, is a direct bond or cycloalkylalkyl; or One or more R ９ and each R ９ is independently selected from the group consisting of hydrogen, halogen, and cycloalkyl; or One or more R ９ and each R ９ is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, and cycloalkyl; 2. A compound of formula (I) according to claim 1 or a pharma- ceutically acceptable salt thereof.

7. R ７ -NR １０ R １１ and, in some cases, R １０ and R １１ are each independently alkyl, or R １０ and R １１ one of is hydrogen and the other is alkyl; or R １０ and R １１ together with the nitrogen atom to which they are attached, optionally contain one or more additional heteroatoms selected from N, O and S and one or more R １４ and optionally R １０ and R １１ together with the nitrogen atom to which they are attached form a saturated heterocyclyl selected from the group consisting of: 【Chemistry 4】 Each of these may be one or more R １４ and optionally substituted with R １４ is halogen, cyano, sulfonyl, alkyl, haloalkyl, alkylalkoxyl, -NR １５ R １６ , and OR １７ and optionally, R １５ and R １６ are each independently alkyl; or R １５ and R １６ one of is hydrogen and the other is alkyl; or R １７ is selected from alkyl or haloalkyl; 2. A compound of formula (I) according to claim 1 or a pharma- ceutically acceptable salt thereof.

8. R ７ is -COOH; or R ７ But, R １３ and R is heterocyclyl optionally substituted with １３ is alkyl, and optionally R ７ is selected from the group consisting of: 【Chemistry 5】 Each of these may be one or more R １３ is optionally replaced by; 2. A compound of formula (I) according to claim 1 or a pharma- ceutically acceptable salt thereof.

9. The compound has the formula (II): 【Chemistry 6】 (In the formula, R １ , R ２ , R ３ , R ５ , R ６ , R ７ and L is as defined in claim 1. and optionally R ５ and R ６ is hydrogen and the other is alkyl or haloalkyl, and further optionally, R ５ and R ６ 2. The compound of formula (I) according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein one of is hydrogen and the other is methyl or trifluoromethyl.

10. The compound has a formula selected from the group consisting of: 【Chemistry 7】 (In the formula, R ３ , R ５ , L, R １１ and R １２ is as defined in claim 1) In some cases, R ３ is hydrogen or fluoro; R ５ is hydrogen, alkyl or haloalkyl; L is one or more R ９ is alkyl optionally substituted with R ９ is selected from the group consisting of hydrogen, halogen, and cycloalkyl; R １０ and R １１ are each independently alkyl, or R １０ and R １１ one of which is hydrogen and the other is alkyl; R １０ and R １１ together with the nitrogen atom to which they are attached, optionally contain one or more additional heteroatoms selected from N, O and S and one or more R １４ forming a saturated heterocyclyl optionally substituted with R １４ is halogen, 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 are each independently alkyl, or R １５ and R １６ one of which is hydrogen and the other is alkyl; R １７ is selected from alkyl or haloalkyl; Furthermore, in some cases, L is ethyl or propyl; and / or R ５ is hydrogen, methyl or trifluoromethyl; or R １０ and R １１ together with the nitrogen atom to which they are attached form a saturated heterocyclyl selected from the group consisting of: 【Chemistry 8】 Each of these may be one or more R １４ is optionally replaced by; 2. A compound of formula (I) according to claim 1 or a pharma- ceutically acceptable salt thereof.

11. The compound has a formula selected from the group consisting of: 【Chemistry 9】 (In the formula, R １０ and R １１ is as defined in claim 1) In some cases, R １０ and R １１ together with the nitrogen atom to which they are attached form a saturated heterocyclyl selected from the group consisting of: 【Chemistry 10】 Each of these may be one or more R １４ 2. The compound of formula (I) according to claim 1, optionally substituted with:

12. The compound has a formula selected from the group consisting of: 【Chemistry 11】 (In the formula, R １０ and R １１ is as defined in claim 1) In some cases, R １０ and R １１ together with the nitrogen atom to which they are attached form a saturated heterocyclyl selected from the group consisting of: 【Chemistry 12】 2. A compound of formula (I) according to claim 1 or a pharma- ceutically acceptable salt thereof.

13. The compound is selected from the group consisting of: 8-(6-((2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(dimethylamino)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((2-(piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-3-methyl-8-(6-((2-(pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4-fluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-8-(6-((2-methoxyethoxy)methyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-3-methyl-8-(6-(((1-methylpiperidin-4-yl)oxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((3-(dimethylamino)propoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-3-methyl-8-(6-(((1-methylpiperidin-4-yl)methoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-3-methyl-8-(6-(((1-methylpyrrolidin-2-yl)methoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-3-methyl-8-(6-(((1-methylpyrrolidin-3-yl)oxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((3-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-3-methyl-8-(6-(((1-methylpiperidin-3-yl)oxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((3-(dimethylamino)cyclobutoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-3-methyl-8-(6-(((1-methylazetidin-3-yl)oxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-methylpropoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-(((1-(3-azabicyclo[3.1.0]hexan-3-yl)cyclopropyl)methoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-3-methyl-8-(6-(((1-methylpiperidin-3-yl)methoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-3-methyl-8-(6-(((1-methylpyrrolidin-3-yl)methoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-(((1-(3-azabicyclo[3.1.0]hexan-3-yl)propan-2-yl)oxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-(((1-(3-azabicyclo[3.1.0]hexan-3-yl)-2-methylpropan-2-yl)oxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((1-(3-azabicyclo[3.1.0]hexan-3-ylmethyl)cyclopropoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-(2-((5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-8-yl)pyridin-2-yl)methoxy)ethyl)piperidine-4-carbonitrile 1-(2-((R)-1-(5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-8-yl)pyridin-2-yl)ethoxy)ethyl)-3-methylpyrrolidine-3-carbonitrile 8-(6-((2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-8-(6-((2-(4-methoxypiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-((2-(3-fluoropyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-1-Isopropyl-3-methyl-8-(6-((2-(2-methylpyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4,4-difluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4,4-dimethylpiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-3-methyl-8-(6-((2-(4-methylpiperazin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-3-methyl-8-(6-((2-morpholinoethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-8-(6-((2-(3-fluoropyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-1-Isopropyl-3-methyl-8-(6-((2-(2-methylpyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3-(dimethylamino)azetidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3-fluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(2-azabicyclo[2.2.1]heptan-2-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(6-azaspiro[3.5]nonan-6-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-8-(6-((2-(3-methoxypiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-8-(6-((2-(3-(dimethylamino)pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-1-Isopropyl-8-(6-((2-(3-methoxypyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-Isopropyl-8-(6-((2-(4-methoxypiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-((2-(3-(dimethylamino)pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-3-methyl-8-(6-((2-(4-(trifluoromethoxy)piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(7-azaspiro[3.5]nonan-7-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-((2-(3-(difluoromethoxy)pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-8-(6-((2-(3-(difluoromethoxy)pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-3-methyl-8-(6-((2-(3-(trifluoromethoxy)pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one (R)-8-(6-(1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-1-Isopropyl-8-(6-(1-(2-(4-methoxypiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-8-(6-((R)-1-(2-((R)-3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-1-Isopropyl-3-methyl-8-(6-(1-(2-(4-(trifluoromethoxy)piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-8-(6-((R)-1-(2-((S)-3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-1-Isopropyl-3-methyl-8-(6-(1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-((R)-1-(2-((S)-3-(difluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-8-(6-((S)-1-(2-((R)-3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-8-(6-((S)-1-(2-((S)-3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((1S)-1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((1R)-1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-8-(6-(1-(2-(4-fluoropiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(4-fluoropiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((1S)-1-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((1R)-1-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-8-(6-(1-(2-(4,4-dimethylpiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(4,4-dimethylpiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-8-(6-(1-(2-(4,4-difluoropiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(4,4-difluoropiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((R)-3-cyclopropoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-3-methyl-8-(6-((R)-1-(2-((R)-3-methylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-3-methyl-8-(6-((R)-1-(2-((S)-3-methylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-3-methyl-8-(6-((R)-1-(2-((R)-3-(methylsulfonyl)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((R)-3-cyclopropoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(1-oxa-7-azaspiro[3.5]nonan-7-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-1-Isopropyl-3-methyl-8-(6-(1-(2-(4-(oxetan-3-yl)piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-1-Isopropyl-3-methyl-8-(6-(1-(2-(4-(trifluoromethyl)piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-8-(6-((R)-1-(2-((R)-3-(methoxymethyl)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(2-oxa-6-azaspiro[3.4]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-1-Isopropyl-3-methyl-8-(6-(1-(2-(piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-3-methyl-8-(6-((R)-1-(2-((R)-3-(trifluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[3.4]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-(2-((R)-1-(5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-8-yl)pyridin-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]cinnolin-8-yl)pyridin-2-yl)ethoxy)ethyl)piperidine-4-carbonitrile (R)-8-(6-(1-(2-(4-isopropoxypiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((R)-3-isopropoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4-fluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4,4-dimethylpiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-((2-(3-(difluoromethoxy)pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-8-(6-((2-(3-(difluoromethoxy)pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-((2-(4-(trifluoromethoxy)piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(4,4-dimethylpiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((1R)-1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((S)-3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-((1R)-1-(2-(3-(trifluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-(4-fluoropiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3,3a,9b-tetrahydro-2H-imidazo[4,5-c]cinnolin-2-one (R)-3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(1-(2-(4-(trifluoromethoxy)piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(4-methoxypiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((R)-3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((R)-3-isopropoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-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]cinnolin-8-yl)pyridin-2-yl)ethoxy)ethyl)piperidine-4-carbonitrile 8-(6-((R)-1-(2-((S)-3-(difluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one (R)-8-(6-(1-(2-(2-oxa-6-azaspiro[3.4]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(1-(2-(4-(trifluoromethyl)piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[3.4]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((R)-3-(methoxymethyl)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-3-Methyl-8-(6-(1-(2-(piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-3-Methyl-8-(6-(1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((R)-3-cyclopropoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 3-Methyl-8-(6-((R)-1-(2-((R)-3-methylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(7-azaspiro[3.5]nonan-7-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(1-oxa-7-azaspiro[3.5]nonan-7-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 3-Methyl-8-(6-((R)-1-(2-((S)-3-methylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-3-Methyl-8-(6-(1-(2-(4-(oxetan-3-yl)piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 3-Methyl-8-(6-((R)-1-(2-((R)-3-(methylsulfonyl)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-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]cinnolin-8-yl)pyridin-2-yl)ethoxy)ethyl)pyrrolidine-3-carbonitrile 8-(6-((2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4,4-dimethylpiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 7-Fluoro-1-isopropyl-3-methyl-8-(6-((2-(3-(trifluoromethoxy)pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one (R)-8-(6-(1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-7-Fluoro-8-(6-(1-(2-(4-fluoropiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one (R)-8-(6-(1-(2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 7-Fluoro-1-isopropyl-8-(6-((R)-1-(2-((S)-3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(4,4-dimethylpiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 7-Fluoro-1-isopropyl-3-methyl-8-(6-((1R)-1-(2-(3-(trifluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-7-Fluoro-1-isopropyl-8-(6-(1-(2-(4-methoxypiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((1R)-1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-7-Fluoro-1-isopropyl-3-methyl-8-(6-(1-(2-(4-(trifluoromethoxy)piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-1-(2-(1-(5-(7-fluoro-1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-8-yl)pyridin-2-yl)ethoxy)ethyl)piperidine-4-carbonitrile 8-(6-((R)-1-(2-((R)-3-(difluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-(2-((R)-1-(5-(7-fluoro-1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-8-yl)pyridin-2-yl)ethoxy)ethyl)-3-methylpyrrolidine-3-carbonitrile (R)-8-(6-(1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(4,4-dimethylpiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-7-Fluoro-8-(6-(1-(2-(4-fluoropiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 7-Fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-((R)-1-(2-((R)-3-(trifluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 7-Fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-((R)-1-(2-((S)-3-(trifluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one (R)-8-(6-(1-(2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((R)-3-(difluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-8-(6-(1-(2-(7-azaspiro[3.5]nonan-7-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (R)-7-Fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(1-(2-(4-(trifluoromethoxy)piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-((S)-3-(difluoromethoxy)pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-((2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)methyl)pyridin-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)ethyl)pyridin-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-(trans-3-methoxycyclobutyl)-3-methyl-8-(6-((R)-1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-(trans-3-methoxycyclobutyl)-8-(6-((R)-1-(2-((R)-3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(dimethylamino)ethoxy)methyl)pyridin-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-(trans-3-methoxycyclobutyl)-3-methyl-8-(6-((2-(pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-(trans-3-methoxycyclobutyl)-3-methyl-8-(6-((2-(piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4-fluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)methyl)pyridin-3-yl)-1-(trans-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)ethyl)pyridin-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((R)-1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)ethyl)pyridin-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-(cis-3-methoxycyclobutyl)-3-methyl-8-(6-((2-(pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-(cis-3-methoxycyclobutyl)-3-methyl-8-(6-((2-(piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4-fluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)methyl)pyridin-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(dimethylamino)ethoxy)methyl)pyridin-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(dimethylamino)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(oxetan-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 3-Methyl-1-(oxetan-3-yl)-8-(6-((2-(piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4-fluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(oxetan-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(4-fluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-((1s,3s)-3-methoxycyclobutyl)-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 3-Methyl-1-(oxetan-3-yl)-8-(6-((2-(pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-8-(6-((2-(4-fluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)methyl)pyridin-3-yl)-3-methyl-1-((S)-tetrahydro-2H-pyran-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (S)-1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one (R)-1-Isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(3-methylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(4,4-dimethylpiperidin-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-isopropyl-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(4-methoxypiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(3-methylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(4,4-dimethylpiperidin-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-8-(6-(2,2,2-trifluoro-1-(2-(4-methoxypiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-(3-Methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(pyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-(3-Methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(3-methylpyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-(3-Methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(3-methoxypyrrolidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(3,3-dimethylpyrrolidin-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(5-azaspiro[2.4]heptan-5-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-(3-Methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(piperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(4,4-dimethylpiperidin-1-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 1-(3-methoxycyclobutyl)-3-methyl-8-(6-(2,2,2-trifluoro-1-(2-(4-methoxypiperidin-1-yl)ethoxy)ethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one 8-(6-(1-(2-(6-azaspiro[2.5]octan-6-yl)ethoxy)-2,2,2-trifluoroethyl)pyridin-3-yl)-1-(3-methoxycyclobutyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one (R)-2-(1-(5-(1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-8-yl)pyridin-2-yl)ethoxy)acetic acid 8-(6-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)propan-2-yl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 8-(6-((2-(3-azabicyclo[3.1.0]hexan-3-yl)-1,1-difluoroethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-3-methyl-8-(6-(1-(2-(pyrrolidin-1-yl)ethoxy)propyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-3-methyl-8-(6-(1-(2-(pyrrolidin-1-yl)ethoxy)butyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 1-isopropyl-3-methyl-8-(6-(2-methyl-1-(2-(pyrrolidin-1-yl)ethoxy)propyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one, and 1-isopropyl-3-methyl-8-(6-(4-methyl-1-(2-(pyrrolidin-1-yl)ethoxy)pentyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one 2. A compound of formula (I) according to claim 1 or a pharma- ceutically acceptable salt thereof.

14. 10. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

15. A pharmaceutical composition for treating an ATM-related disease or condition in a subject, comprising a compound of formula (I) according to any one of claims 1 to 14 or a pharma- ceutically acceptable salt thereof, wherein preferably, 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, more preferably, the ATM-related disease or condition is head and neck squamous cell carcinoma.

16. The pharmaceutical composition is administered simultaneously, separately or sequentially to a subject with radiation therapy; or said pharmaceutical composition is administered simultaneously, separately or sequentially with at least one additional anti-tumor 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, separately or sequentially with a PARP inhibitor, preferably the PARP inhibitor is selected from the group consisting of olaparib, rucaparib, niraparib, talazoparib, pamiparib and fluzoparib; 16. The pharmaceutical composition of claim 15.

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