1-Isopropyl-3-methyl-8-(pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one as a selective modulator of ataxia-telangiectasia mutated (ATM) kinase and its use

Abstract

To provide novel compounds which selectively modulate ataxia telangiectasia mutated ("ATM") kinase.SOLUTION: The present application discloses specific substituted imidazo[4, 5-c]cinnolin-2-one compounds, illustrated by the compounds below, and pharmaceutically acceptable salts thereof. The present application also relates to pharmaceutical compositions comprising one or more of the compounds and salts thereof as an active ingredient, and to the use of the compounds and salts thereof in the treatment of ATM-associated diseases or conditions, including cancers.SELECTED DRAWING: None

Description

Technical Field

[0001] The present application relates to novel substituted imidazo[4,5-c]cinnolin-2-one compounds that selectively modulate ataxia-telangiectasia mutated (「ATM」) kinase and pharmaceutically acceptable salts thereof. The present application also relates to pharmaceutical compositions containing one or more of the above compounds and salts thereof as active ingredients, and the use of the above compounds and salts thereof in the treatment of ATM-related diseases or conditions including cancer.

Background Art

[0002] ATM kinase, a serine / threonine kinase, was named after the autosomal recessive genetic disease ataxia-telangiectasia (A-T) (Paul, T.T., Annu Rev Biochem, 2015, pp. 711-38). ATM plays a central role in the repair of DNA double-strand breaks (DSBs), which are highly toxic to cells if not repaired in a timely manner. DSBs can be repaired by two major pathways: non-homologous end joining (NHEJ) or homologous recombination (HR). NHEJ functions throughout the cell cycle and directly reseals the two broken ends with a minimal process. In contrast, HR occurs between the S and G2 phases of the cell cycle and requires extensive end processing (or resection). The resulting single-stranded DNA is used as a template for DNA synthesis after invading the homologous copy of the cleavage site (Clouaire, T. et al., DNA Repair (Amst), 2017, pp. 84-91). In comparison, NHEJ is a fast process but prone to errors; while HR is a slower process than NHEJ but error-free. ATM repairs DSBs via HR.

[0003] After DNA double-strand breaks (DSBs), ATM is recruited by the MRE11-RAD50-NBS1 (MRN) complex, which senses and initiates DNA repair. When ATM is transported to the DNA damage site, it dissociates from the inactive homodimer into active monomers and is catalytically activated by autophosphorylation at Ser1981 and other sites, as well as acetylation at Lys3016. Subsequently, ATM binds to the C-terminus of NBS1, a component of the MRN complex, and this functions as a transducer to phosphorylate and activate other protein kinases such as histone H2A.X (γH2A.X).

[0004] ATM is activated by DSBs, which can be induced by ionizing radiation, chemotherapeutic agents, and PARP inhibition. Topoisomerase I inhibitors (such as irinotecan and topotecan) and PARP inhibitors (such as olaparib) cause single-strand DNA breaks, which are converted to DSBs during replication (Choi M. et al., Mol Cancer Ther, 2016, pp. 1781-91). Other anticancer treatments such as ionizing radiation (IR), platinum agents (cisplatin), and topoisomerase II inhibitors (such as doxorubicin and etoposide) directly induce DSBs. By combining ATM inhibitors with chemotherapy, radiation, and PARP inhibitors, cancer cells are rendered almost unable to repair highly cytotoxic DSBs. Given the crucial role of ATM in DSBs, ATM kinase inhibitors are expected to have a synergistic effect with PARP inhibitors, topoisomerase inhibitors, or ionizing radiation in cancer treatment.

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

[0006] However, both compounds serve as substrates for aldehyde oxidase (AO), which has high activity. AO is highly expressed in humans and monkeys, not expressed in dogs, and has a low expression level in rodents. Compounds metabolized by AO have high clearance values, high pharmacokinetic variability (PK variability), and low oral bioavailability in humans (Garattini, E. et al., Expert Opin Drug Discovery, 2013, pp. 641-54; Zientek, M. et al., Drug Metab Dispos, 2010, pp. 1322-7). AO liability can be evaluated in the human liver cytosolic system. The PK of AZD0156 in humans was unexpectedly lower than the predicted value (Chen et al., AACR, 2018). For AZD1390, a Phase 0 clinical PK study was conducted before transitioning to Phase 1 clinical trials (NCT03215381 and NCT03423628), further suggesting that both AZD0156 and AZD1390 undergo metabolism via AO. Furthermore, AZD0156 is unable to penetrate the brain and has limited use for treating brain tumors. AZD1390 shows hERG liability, which has harmful effects on the heart.

[0007] In view of the above, there is a need to develop novel compounds that act on ATM kinase and preferably do not have AO liability and hEGR liability and are brain penetrant.

Summary of the Invention

[0008] Disclosed herein are novel substituted imidazo[4,5-c]cinnolin-2-one compounds that have potent ATM kinase inhibitory activity, do not exhibit AO vulnerability in human hepatic cytosol, thereby having good human pharmacokinetic properties (PK), low dose variability, and low PK variability. In addition, these compounds are neither human Pgp substrates nor human BCRP substrates, exhibit good brain permeability in animals, and have a favorable toxicity profile (e.g., reduced activity against hERG). As a result, the compounds of the present application are useful, in particular, in the treatment of ATM-related diseases or conditions, including cancers (not only extracranial cancers but also brain tumors).

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

Chemical formula

[0010] In another aspect, 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.

[0011] In a further aspect, there is provided a method of treating an ATM - related disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0012] In a further aspect, there is provided a method of treating Huntington's disease in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0013] 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 disorder or condition.

[0014] 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 disorder or condition.

[0015] 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 disorder or condition and administered concomitantly with, separately from, or sequentially to radiotherapy.

[0016] In a further aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in administration concomitantly with, separately from, or sequentially to at least one additional anti-tumor agent.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The following makes specific reference to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention is described in connection with the embodiments shown, it should be understood that these embodiments are not intended to limit the invention thereto. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined by the claims. Those skilled in the art will recognize many methods and materials that are the same as or equivalent to those described herein, and these can also be used in the practice of the invention. The invention is in no way limited to the methods and materials described. If one or more of the incorporated documents and similar materials, including but not limited to definitions of terms, usage of terms, descriptions of techniques, etc., are different from or conflict with this application, this application shall prevail.

[0018] It will be understood that certain features of the disclosure, which are, for clarity, described in connection with separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure that are, for brevity, described in connection with a single embodiment may also be provided separately or in any suitable sub-combination.

[0019] Definition The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of the present disclosure, chemical elements are specified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition, inside cover, and specific functional groups have the definitions as usually described therein. Further, organic chemistry, as well as general principles of specific functional groups and reactivity, are those described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987, the entire contents of each of which are hereby incorporated by reference.

[0020] Linking substituents are described in various parts of the present disclosure. When the structure clearly requires a linking group, the variable elements in Markush format listed in connection with that group are understood to be the linking group. For example, when the structure requires a linking group and the definition of the Markush group for the variable element lists "alkyl", "alkyl" is understood to represent the linking of an alkylene group.

[0021] As used herein, when the term "substituted" relates to a chemical group, it means that one or more hydrogen atoms of the chemical group have been removed and replaced by a substituent. The term "substituent", as used herein, has its ordinary meaning known in the art and refers to a chemical moiety that is covalently bonded to, or where appropriate, fused to, the parent group. As used herein, the terms "optionally substituted" or "optionally ~ substituted" mean that a chemical group may or may not have a substituent (i.e., unsubstituted form), or may have one or more substituents (i.e., substituted form). It should be understood that substitution at a given atom is subject to valence limitations.

[0022] As used herein, the term "C i-j " represents a range of carbon atom numbers, where i and j are integers, the range of carbon atom numbers includes both endpoints (i.e., i and j) and each integer point in between, and j is greater than i. For example, C 1-6 represents a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. In some embodiments, the term "C 1-12 " represents 1 to 12 carbon atoms, particularly 1 to 10 carbon atoms, particularly 1 to 8 carbon atoms, particularly 1 to 6 carbon atoms, particularly 1 to 5 carbon atoms, particularly 1 to 4 carbon atoms, particularly 1 to 3 carbon atoms, or particularly 1 to 2 carbon atoms.

[0023] As used herein, the term "alkyl", whether used as part of another term or independently, refers to a saturated straight-chain or branched-chain hydrocarbon chain, which may optionally be independently substituted with one or more of the following substituents. The term "C i-j"Alkyl" refers to an alkyl having from i to j carbon atoms. In some embodiments, the alkyl group contains from 1 to 12 carbon atoms. In some embodiments, the alkyl group contains from 1 to 11 carbon atoms. In some embodiments, the alkyl group contains from 1 to 11 carbon atoms, from 1 to 10 carbon atoms, from 1 to 9 carbon atoms, from 1 to 8 carbon atoms, from 1 to 7 carbon atoms, from 1 to 6 carbon atoms, from 1 to 5 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or from 1 to 2 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl-1-propyl (i-butyl), 2-butyl (s-butyl), 2-methyl-2-propyl (t-butyl), 1-pentyl (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, 1-heptyl, 1-octyl, etc. "C 1-12 Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl. "C 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, etc.

[0024] The above alkyl group can be further substituted by substituents that independently replace one or more hydrogen atoms on one or more carbons of the alkyl group. Examples of such substituents include acyl, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, haloalkyl, haloalkoxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, nitro, azide, heterocyclic group, alkylaryl, or aromatic ring moiety or heteroaromatic ring moiety, but are not limited thereto. The following alkenyl group, alkynyl group, saturated or partially unsaturated cycloalkyl group, heteroalkyl group, heterocyclic group, arylalkyl group, heteroarylalkyl group, heterocyclic alkyl group, cycloalkylalkyl group, aryl group, and heteroaryl group may be similarly substituted.

[0025] As used herein, the term "alkenyl", whether as part of another term or used independently, refers to a straight-chain or branched-chain hydrocarbon group having at least one carbon-carbon double bond, which may optionally be independently substituted with one or more substituents described herein, and includes radicals having "cis" and "trans" configurations, or "E" and "Z" configurations. In some embodiments, the alkenyl group contains from 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains from 2 to 11 carbon atoms. In some embodiments, the alkenyl group contains from 2 to 11 carbon atoms, from 2 to 10 carbon atoms, from 2 to 9 carbon atoms, from 2 to 8 carbon atoms, from 2 to 7 carbon atoms, from 2 to 6 carbon atoms, from 2 to 5 carbon atoms, from 2 to 4 carbon atoms, from 2 to 3 carbon atoms, and in some embodiments, the alkenyl group contains 2 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl (i.e., vinyl), propenyl, butenyl, pentenyl, 1-methyl-2-buten-1-yl, 5-hexenyl, and the like.

[0026] As used herein, the term "alkynyl", whether as part of another term or used independently, refers to a straight-chain or branched-chain hydrocarbon group having at least one carbon-carbon triple bond, which is optionally independently substituted with one or more substituents described herein. In some embodiments, the alkynyl group contains from 2 to 12 carbon atoms. In some embodiments, the alkynyl group contains from 2 to 11 carbon atoms. In some embodiments, the alkynyl group contains from 2 to 11 carbon atoms, from 2 to 10 carbon atoms, from 2 to 9 carbon atoms, from 2 to 8 carbon atoms, from 2 to 7 carbon atoms, from 2 to 6 carbon atoms, from 2 to 5 carbon atoms, from 2 to 4 carbon atoms, from 2 to 3 carbon atoms, and in some embodiments, the alkynyl group contains 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, etc.

[0027] As used herein, the term "alkoxy" or "alkoxyl", whether as part of another term or used independently, refers to an alkyl group as defined above that is attached to the parent molecule through an oxygen atom. The term "C i-j alkoxy" means that the alkyl portion of the alkoxy group has from i to j carbon atoms. In some embodiments, the alkoxy group contains from 1 to 12 carbon atoms. In some embodiments, the alkoxy group contains from 1 to 11 carbon atoms. In some embodiments, the alkoxy group contains from 1 to 11 carbon atoms, from 1 to 10 carbon atoms, from 1 to 9 carbon atoms, from 1 to 8 carbon atoms, from 1 to 7 carbon atoms, from 1 to 6 carbon atoms, from 1 to 5 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or from 1 to 2 carbon atoms. "C 1-12Examples of "alkoxyl" include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, neopentoxy, n-hexoxy, and the like.

[0028] As used herein, the term "acyl" refers to a functional group containing a carbonyl, e.g., -C(=O)R, where R is hydrogen or an optionally substituted aliphatic group, heteroaliphatic group, heterocyclic group, aryl group, heteroaryl group, or a functional group containing oxygen or nitrogen substituted (e.g., substituted with a hydrogen or an aliphatic moiety, heteroaliphatic moiety, aryl moiety, or heteroaryl moiety) to form a carboxylic acid functional group, ester functional group, or amide functional group. As used herein, the term "acyloxy" refers to an acyl group bonded to a parent molecule through an oxygen atom.

[0029] As used herein, the term "amino" or "amine" refers to a moiety in which a nitrogen atom is covalently bonded to at least one carbon atom or heteroatom. "Alkylamino" encompasses a group of a compound in which nitrogen is bonded to at least one alkyl group. Examples of alkylamino groups include benzylamino, methylamino, ethylamino, phenethylamino, and the like. "Dialkylamino" encompasses a group in which the nitrogen atom as described above is bonded to at least two additional alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino and diethylamino. "Arylamino" and "diarylamino" each encompass a group in which nitrogen is bonded to at least one or two aryl groups, respectively. "Alkylarylamino", "alkylaminoaryl", or "arylaminoalkyl" refers to a moiety in which an amino group is bonded to at least one alkyl group and at least one aryl group. "Alkaminolalkyl" refers to an alkyl group, alkenyl group, or alkynyl group bonded to a nitrogen atom, where the nitrogen atom is also bonded to an alkyl group. "Acylamino" encompasses a group in which nitrogen is bonded to an acyl group. Examples of acylamino include, but are not limited to, alkylcarbonylamino groups, arylcarbonylamino groups, carbamoyl groups, and ureido groups.

[0030] As used herein, the terms "amide" or "aminocarboxy" refer to a compound or moiety containing a nitrogen atom bonded to the carbon of a carbonyl or thiocarbonyl group. The term encompasses "alkaminocarboxy" groups that include an alkyl, alkenyl, or alkynyl group bonded to the amino group that is bonded to the carbon of the carbonyl or thiocarbonyl group. The term also encompasses "arylaminocarboxy" groups that include an aryl or heteroaryl moiety bonded to the amino group that is bonded to the carbon of the carbonyl or thiocarbonyl group. The terms "alkylaminocarboxy", "alkenylaminocarboxy", "alkynylaminocarboxy", and "arylaminocarboxy" each include a moiety in which the alkyl, alkenyl, alkynyl, and aryl moieties are bonded to a nitrogen atom, and the nitrogen atom is bonded to the carbon of the carbonyl group. Amides can be substituted with substituents such as straight-chain alkyl, branched-chain alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic. The substituents on the amide group may be further substituted.

[0031] As used herein, the term "aryl", whether as part of another term or used independently, refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, wherein at least one ring within the system is aromatic and each ring within the system contains 3 to 12 ring members. Examples of "aryl" include, but are not limited to, phenyl, biphenyl, naphthyl, anthracyl, etc., which may optionally have one or more substituents. Also, as used herein, included within the scope of the term "aryl" are groups in which an aromatic ring is fused to one or more additional rings. In the case of a polycyclic ring system, only one of the rings need be aromatic (e.g., 2,3-dihydroindole), although all of the rings may be aromatic (e.g., quinoline). The second ring described above can be fused or bridged. Examples of polycyclic aryl include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl. An aryl group can be substituted at one or more ring positions with substituents as described above.

[0032] As used herein, the terms "cycloalkyl group", "carbocyclic group", and "carbocycle" are interchangeable and, whether used as part of another term or independently, refer to monocyclic and polycyclic ring systems that are monovalent, non-aromatic, saturated or partially unsaturated, in which all ring atoms are carbon and that contain at least 3 ring-forming carbon atoms. In some embodiments, the cycloalkyl can contain from 3 to 12 ring-forming carbon atoms, from 3 to 10 ring-forming carbon atoms, from 3 to 9 ring-forming carbon atoms, from 3 to 8 ring-forming carbon atoms, from 3 to 7 ring-forming carbon atoms, from 3 to 6 ring-forming carbon atoms, from 3 to 5 ring-forming carbon atoms, from 4 to 12 ring-forming carbon atoms, from 4 to 10 ring-forming carbon atoms, from 4 to 9 ring-forming carbon atoms, from 4 to 8 ring-forming carbon atoms, from 4 to 7 ring-forming carbon atoms, from 4 to 6 ring-forming carbon atoms, or from 4 to 5 ring-forming carbon atoms. The cycloalkyl group can be saturated or partially unsaturated. The cycloalkyl group can be substituted. In some embodiments, the cycloalkyl group can be a saturated cycloalkyl group. In some embodiments, the cycloalkyl group can be a partially unsaturated cycloalkyl group containing at least one double bond or triple bond in its ring system.

[0033] In some embodiments, the cycloalkyl group can be a saturated or partially unsaturated monocyclic carbocyclic ring system, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, 1-cyclopenta-2-enyl, 1-cyclopenta-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl.

[0034] In some embodiments, the cycloalkyl group may be a saturated or partially unsaturated polycyclic (e.g., bicyclic and tricyclic) carbocyclic ring system, which can be arranged as a fused ring system, a spiro ring system, or a bridged ring system. 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 via one common atom, and the term "bridged ring" refers to a ring system having two rings that share three or more atoms. Examples of fused carbocyclic groups include, but are not limited to, naphthyl, benzopyrenyl, anthracenyl, acenaphthenyl, fluorenyl, etc. Examples of spiro carbocyclic groups include, but are not limited to, spiro[5.5]undecanyl, spiropentadienyl, spiro[3.6]decanyl, etc. Examples of bridged carbocyclic groups 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, etc.

[0035] As used herein, the term "cyano" refers to -CN.

[0036] As used herein, the term "halo" or "halogen" refers to an atom selected from fluorine (or fluoro), chlorine (or chloro), bromine (or bromo), and iodine (or iodo).

[0037] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

[0038] As used herein, the term "haloalkoxy" or "haloalkoxyl" refers to an alkoxyl group substituted with one or more halogen atoms.

[0039] As used herein, the term "heteroaryl", whether as part of another term or used independently, refers to an aryl group having one or more heteroatoms in addition to carbon atoms. 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 basic nitrogen. Examples of heteroaryl 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 also includes groups in which the aromatic heterocyclic ring is fused to one or more aryl rings, cycloaliphatic rings, or heterocyclic rings, and the free radical or point of attachment is on the aromatic heterocyclic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. In some embodiments, the term "5- to 10-membered heteroaryl" refers to a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the term "5- to 12-membered heteroaryl" refers to a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 12-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0040] As used herein, the terms "heterocyclic ring" or "heterocyclic group" refer to a saturated or unsaturated carbocyclic group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, etc., the remaining ring atoms are carbon, and one or more ring atoms may be optionally substituted with one or more substituents. In some embodiments, the heterocyclic group is a saturated heterocyclic group. In some embodiments, the heterocyclic group is a partially unsaturated heterocyclic group having one or more double bonds in its ring system. In some embodiments, the heterocyclic group may include any oxidized form of carbon, nitrogen, or sulfur, and any quaternized form of basic nitrogen. The "heterocyclic group" is a free radical and also includes a heterocyclic free radical condensed with a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. The heterocyclic free radical may be carbon-bonded or nitrogen-bonded if possible. In some embodiments, the heterocyclic ring is carbon-bonded. In some embodiments, the heterocyclic ring is nitrogen-bonded. For example, a group derived from pyrrole can be pyrrol-1-yl (nitrogen-bonded) or pyrrol-3-yl (carbon-bonded). Further, a group derived from an imidazole group can be imidazol-1-yl (nitrogen-bonded) or imidazol-3-yl (carbon-bonded).

[0041] In some embodiments, the term "3- to 12-membered heterocyclic group" refers to a 3- to 12-membered, saturated or partially unsaturated, monocyclic or polycyclic, heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Condensed ring systems, spiro ring systems, and bridged ring systems are also included within the scope of this definition. Examples of monocyclic heterocyclic groups include, but are not limited to, oxetanyl, 1,1-dioxothietanyl pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, triazinonyl, etc. Examples of condensed heterocyclic groups include, but are not limited to, phenyl-condensed rings or pyridinyl-condensed rings such as quinolinyl group, isoquinolinyl group, quinoxalinyl group, quinolidinyl group, quinazolinyl group, azaindolidinyl group, pteridinyl group, chromenyl group, isochromenyl group, indolyl group, isoindolyl group, indolidinyl group, indazolyl group, purinyl group, benzofuranyl group, isobenzofuranyl group, benzimidazolyl group, benzothienyl group, benzothiazolyl group, carbazolyl group, phenazinyl group, phenothiazinyl group, phenanthridinyl group, imidazo[1,2-a]pyridinyl group, [1,2,4]triazolo[4,3-a]pyridinyl group, [1,2,3]triazolo[4,3-a]pyridinyl group, etc. Examples of spiro heterocyclic groups include, but are not limited to, spiropyranyl, spirooxazinyl, etc. Examples of bridged heterocyclic groups include, but are not limited to, morphanyl, hexamethylenetetraminyl, 3-aza-bicyclo[3.1.0]hexane, 8-aza-bicyclo[3.2.1]octane, 1-aza-bicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane (DABCO), etc.

[0042] As used herein, the term "partially unsaturated" refers to a radical containing at least one double bond or triple bond. The term "partially unsaturated" is intended to include rings having multiple unsaturated sites, but is not intended to include aromatic (i.e., fully unsaturated) moieties.

[0043] As used herein, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the designated moiety have been replaced with a suitable substituent. "Substitution" or "substituted with" is understood to include the implicit condition that such substitution is in accordance with the allowable valence of the atom being substituted and results in a stable or chemically feasible compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, etc. Unless otherwise specified, an "optionally substituted" group has a suitable substituent at each substitutable position, and when two or more positions in any structure are substituted with two or more substituents selected from a particular group, those substituents may be the same or different at any position. It will be understood by those skilled in the art that the substituents themselves may be substituted where appropriate. Unless specifically described as "unsubstituted", references to chemical moieties herein include substituted variants. For example, references to an "aryl" group or aryl moiety implicitly include both substituted and unsubstituted variants.

[0044] When a bond to a substituent is shown to cross a bond connecting two atoms within a ring, such substituent may be bonded to any atom within that ring. When a substituent is described without indicating the atom through which it is bonded to the remainder of a compound of a given formula, such substituent may be bonded through any atom within such formula. Combinations of substituents and / or variable portions are possible, but only if such combinations result in a stable compound.

[0045] Any variable portion (e.g., R i) If it appears two or more times in any constituent or formula of the compound, its definition in each occurrence is independent of that in any other occurrence. That is, for example, if a group is shown as being substituted by 0 to 2 R i moieties, the group may optionally be substituted by up to two R i moieties, and each occurrence of R i is independently selected from the definition of R i . Combinations of substituents and / or variable moieties are also possible, but only if such combinations result in stable compounds.

[0046] Compound The present disclosure provides novel substituted imidazo[4,5-c]cinnolin-2-one compounds and pharmaceutically acceptable salts thereof, synthetic methods for preparing the compounds, pharmaceutical compositions containing the compounds, and various uses of the compounds of the present disclosure.

[0047] In one aspect, the present disclosure provides a compound of formula (I):

Chemical formula

[0048]

[0049] In some embodiments, R

[0049]

[0050] In some embodiments, R

[0051] In some embodiments, R2 is isopropyl.

[0051] In some embodiments, R 2 is tetrahydropyranyl.

[0052] In some embodiments, R 2 is tetrahydropyran-3-yl.

[0053] In some embodiments, R 3 is hydrogen.

[0054] In some embodiments, R 3 is fluoro.

[0055] In some embodiments, R 2 is tetrahydropyran-3-yl and, when R 3 is hydrogen, R 7 is not -O(CH2)3N(CH3)2.

[0056] In some embodiments, R 4 R 5 and R 6 are hydrogen.

[0057] In some embodiments, R 4 is fluoro and R 5 and R 6 are hydrogen.

[0058] In some embodiments, R 7 is -L-NR 8 R 9 where L is optionally -(CH2) 11 optionally substituted by one or more R m O(CH2) n -, m is 0, 1, or 2, n is an integer in the range of 2 to 4, and R 11 is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, alkoxyl, and saturated or unsaturated heterocyclic groups.

[0059] In some embodiments, R 7 is -L-NR 8 R 9 where L is -(CH2) m O(CH2) n -, and R 8 and R 9 are each independently selected from optionally substituted C 12 alkyl by one or more R 1-6 where the combination of m and n is selected from m being 0 and n being 3, or m being 1 and n being 2; R 12 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, alkyl, alkenyl, alkynyl, and alkoxy.

[0060] In some embodiments, R 7 is -L-NR 8 R 9 where L is -(CH2) m O(CH2) n -, and R 8 and R 9 are independently selected from methyl, ethyl, propyl, or butyl, and the combination of m and n is selected from m being 0 and n being 3, or m being 1 and n being 2.

[0061] In certain embodiments, R 7 is -L-NR 8 R 9 where L is -(CH2) m O(CH2) n -, and R 8 and R 9 are methyl, and the combination of m and n is selected from m being 0 and n being 3, or m being 1 and n being 2.

[0062] In some embodiments, R 7 is -L-NR 8 R 9 where L is -(CH2) m O(CH2) n -, and R 8and R 9 together with the nitrogen atom to which they are attached form

Chemical formula

[0063] In some embodiments, R 7 is -L-NR 8 R 9 where L is -(CH2) m O(CH2) n -, and the combination of m and n is selected from m being 0 and n being 3, or m being 1 and n being 2; and R 8 and R 9 together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, or azabicyclo[3.1.0]hexan-3-yl, and the above azetidinyl, pyrrolidinyl, piperidinyl, or azabicyclo[3.1.0]hexan-3-yl may optionally be substituted by one or more Rs 13 where R 13 is halogen. In certain embodiments, R 13 is fluoro.

[0064] In certain embodiments, R 7 is -L-NR 8 R 9 where L is -(CH2) m O(CH2) n- wherein the combination of m and n is selected from m being 0 and n being 3, or m being 1 and n being 2; and R 8 and R 9 together with the nitrogen atom to which they are attached form a pyrrolidinyl which may optionally be substituted by one or more fluorines.

[0065] In certain embodiments, R 7 is -L-NR 8 R 9 where L is -(CH2) m O(CH2) n - wherein the combination of m and n is selected from m being 0 and n being 3, or m being 1 and n being 2; and R 8 and R 9 together with the nitrogen atom to which they are attached form a piperidinyl which may optionally be substituted by one or more fluorines.

[0066] In certain embodiments, R 7 is -L-NR 8 R 9 where L is -(CH2) m O(CH2) n - wherein the combination of m and n is selected from m being 0 and n being 3, or m being 1 and n being 2; and R 8 and R 9 together with the nitrogen atom to which they are attached form an azabicyclo[3.1.0]hexan-3-yl which may optionally be substituted by fluorine. In some embodiments, when m is 0 and n is 3, R13 is not a halogen. In some embodiments, when m is 0 and n is 3, R13 is not an azabicyclo[3.1.0]hexan-3-yl.

[0067] In some embodiments, R 7 is -L-NR 8 R 9 where L is a direct bond, and R8 and R 9 together with the nitrogen atom to which they are attached form [Chemical formula] and any of these may optionally be substituted by one or more R 13 where x is 1, 2, 3, or 4; y is 0, 1, or 2; z is 0, 1, or 2; R 13 is selected from the group consisting of acyl, alkyl, alkenyl, alkynyl, alkoxy, amide, amino, alkylamino, aryl, cyano, cycloalkyl, halogen, haloalkyl, haloalkoxy, heteroaryl, hydroxy, nitro, and -(CH2) q NR 14 R 15 and q is 0, 1, or 2; R 14 and R 15 are each independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached may optionally contain one or more additional heteroatoms selected from N, O, and S and may optionally form a saturated or unsaturated heterocyclic group substituted by one or more R 16 ; R 16 is selected from the group consisting of acyl, alkyl, alkenyl, alkynyl, alkoxy, amide, amino, aryl, cyano, cycloalkyl, halogen, haloalkyl, haloalkoxy, heteroaryl, hydroxy, and nitro.

[0068] In some embodiments, R 7 is -L-NR 8 R 9 where L is a direct bond and R 8 and R 9together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, or piperidinyl, and said azetidinyl, pyrrolidinyl, or piperidinyl may optionally be substituted by one or more R 13 ; R 13 is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, amide, amino, alkylamino, aryl, cyano, cycloalkyl, halogen, haloalkyl, haloalkoxy, heteroaryl, hydroxy, nitro, and -(CH2) q NR 14 R 15 ; q is 0, 1, or 2; R 14 and R 15 are each independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.

[0069] In some embodiments, R 7 is -L-NR 8 R 9 where L is a direct bond, and R 8 and R 9 together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, or piperidinyl, and said azetidinyl, pyrrolidinyl, or piperidinyl may optionally be substituted by one or more R 13 ; R 13 is -(CH2) q NR 14 R 15 ; q is 0, 1, or 2; R 14 and R 15 are each independently selected from C 1-6 alkyl. In certain embodiments, R 14 and R 15 are methyl.

[0070] In certain embodiments, R 7 is -L-NR 8 R 9 where L is a direct bond, and R 8 and R 9Together with the nitrogen atom to which they are attached, they may form a pyrrolidinyl optionally substituted by one or more -N(CH3)2 groups or -(CH2)N(CH3)2 groups.

[0071] In certain embodiments, R 7 is -L-NR 8 R 9 where L is a direct bond, and R 8 and R 9 Together with the nitrogen atom to which they are attached, they may form a piperidinyl optionally substituted by one or more -N(CH3)2 groups or -(CH2)N(CH3)2 groups.

[0072] In some embodiments, R 7 is -L-NR 8 R 9 where L is -CONR 10 (CH2) p -, R 8 and R 9 are each independently selected from C 12 alkyl optionally substituted by one or more R 1-6 , p is an integer in the range of 2 to 4, R 10 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and carbon-bonded saturated or unsaturated heterocyclic groups, and R 12 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, alkyl, alkenyl, alkynyl, and alkoxy.

[0073] In some embodiments, R 7 is -L-NR 8 R 9 where L is -CONR 10 (CH2) p -, R 8 and R 9 are selected from methyl, ethyl, propyl, or butyl; p is 2; and R 10 is hydrogen.

[0074] In certain embodiments, R 7 is -L-NR 8 R 9 where L is -CONH(CH2)2- and R 8 and R 9 are methyl.

[0075] In one aspect, the disclosure provides a compound of formula (I),

Chemical formula

[0076] In certain embodiments, L may optionally be substituted by one or more R 11 to be -(CH2) m O(CH2) n -; R 8 and R 9 are each independently selected from C 12 alkyl, which may optionally be substituted by one or more R 1-6 ; or R 8 and R 9 together with the nitrogen atom to which they are attached form

Chemical formula

[0077] In certain embodiments, L may optionally be one or more R 11 substituted -CONR 10 (CH2) p -; R 8 and R 9 may each independently be selected from C 12 alkyl optionally substituted by one or more R 1-6 ; R 10 is hydrogen; R 12 is hydrogen; and p is an integer in the range of 2 - 4.

[0078] In certain embodiments, L is a direct bond; and R 8 and R 9 together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl optionally substituted by one or more R 13 ; R 13 is -(CH2) q NR 14 R 15 ; R 14 and R 15 are each independently selected from C 1-6 alkyl; and q is 0, 1, or 2.

[0079] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof selected from the group consisting of: 7-Fluoro-1-isopropyl-3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-(3-(Dimethylamino)propoxy)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 7-Fluoro-1-isopropyl-3-methyl-8-(6-(3-(pyrrolidin-1-yl)propoxy)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-(4-(Dimethylamino)piperidin-1-yl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-(3-((Dimethylamino)methyl)pyrrolidin-1-yl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-((2-(Dimethylamino)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 7-Fluoro-1-isopropyl-3-methyl-8-(6-((2-(piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 7-Fluoro-1-isopropyl-3-methyl-8-(6-((2-(pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; (R)-7-Fluoro-8-(6-((2-(3-fluoropyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 7-Fluoro-8-(6-((2-(4-fluoropiperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-((2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; N-(2-(Dimethylamino)ethyl)-5-(7-fluoro-1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-8-yl)picolylamide; 7-Fluoro-8-(6-(3-(4-fluoropiperidin-1-yl)propoxy)pyridin-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; (S)-7-Fluoro-8-(6-(3-(3-fluoropyrrolidin-1-yl)propoxy)pyridin-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; (R)-7-Fluoro-8-(6-(3-(3-fluoropyrrolidin-1-yl)propoxy)pyridin-3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-(3-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-(3-(Dimethylamino)propoxy)-2-fluoropyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 7-Fluoro-3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-(3-(Dimethylamino)propoxy)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 7-Fluoro-3-methyl-8-(6-(3-(pyrrolidin-1-yl)propoxy)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-(3-((Dimethylamino)methyl)pyrrolidin-1-yl)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-(4-(Dimethylamino)piperidin-1-yl)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-(Dimethylamino)ethoxy)methyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 7-Fluoro-8-(6-(3-(4-fluoropiperidin-1-yl)propoxy)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; (R)-7-Fluoro-8-(6-(3-(3-fluoropyrrolidin-1-yl)propoxy)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-((2-(diethylamino)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-((2-(ethyl(methyl)amino)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 7-Fluoro-1-isopropyl-3-methyl-8-(6-((2-morpholinoethoxy)methyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 7-Fluoro-1-isopropyl-3-methyl-8-(6-((2-(piperazin-1-yl)ethoxy)methyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 7-Fluoro-1-isopropyl-3-methyl-8-(6-((2-(4-methylpiperazin-1-yl)ethoxy)methyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-((2-(4-cyclopropylpiperazin-1-yl)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-((2-(2-azaspiro[3.3]heptan-2-yl)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-((2-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-((2-(2-Azaspiro[3.4]octan-2-yl)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-((2-(6-Azabicyclo[3.2.0]heptan-6-yl)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-(3-(Diethylamino)propoxy)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-(3-(Ethyl(methyl)amino)propoxy)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 7-Fluoro-1-isopropyl-3-methyl-8-(6-(3-morpholinopropoxy)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 7-Fluoro-1-isopropyl-3-methyl-8-(6-(3-(piperazin-1-yl)propoxy)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 7-Fluoro-1-isopropyl-3-methyl-8-(6-(3-(4-methylpiperazin-1-yl)propoxy)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-(3-(4-Cyclopropylpiperazin-1-yl)propoxy)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-(3-(2-Azaspiro[3.3]heptan-2-yl)propoxy)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-(3-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)propoxy)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-(3-(2-Azaspiro[3.4]octan-2-yl)propoxy)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; and 8-(6-(3-(6-Azabicyclo[3.2.0]heptan-6-yl)propoxy)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one.

[0080] Exemplary compounds of formula (I) are set forth in Table 1 below. [Table 1] TIFF0007706585000009.tif229165TIFF0007706585000010.tif234167TIFF0007706585000011.tif242168TIFF0007706585000012.tif205168TIFF0007706585000013.tif203166TIFF0007706585000014.tif203165TIFF0007706585000015.tif202168TIFF0007706585000016.tif240168TIFF0007706585000017.tif197169

[0081] The compounds provided herein are described with reference to both general formulas and specific compounds. In addition, the compounds of the present disclosure may exist in several different forms or derivatives, all of which are within the scope of the present disclosure. These include, for example, tautomers, stereoisomers, racemic mixtures, positional isomers, salts, prodrugs, solvated forms, various crystalline forms or polymorphs, and active metabolites.

[0082] The compounds of the present disclosure may contain one or more asymmetric centers and, thus, may exist as various stereoisomers, for example, as enantiomers and / or diastereomers. Thus, the compounds of the present invention and their compositions may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the present disclosure are enantiopure compounds. In certain embodiments, a mixture of enantiomers or diastereomers is provided.

[0083] The term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. The term "diastereomers" refers to pairs of optical isomers that are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectroscopic properties, and reactivity.

[0084] Furthermore, certain compounds described herein may have one or more double bonds that can exist as either the Z isomer or the E isomer, unless otherwise specified. The present disclosure further encompasses the compounds as individual isomers substantially free of other isomers, or as mixtures of various isomers, for example, as a racemic mixture of enantiomers. In addition to the compounds themselves, the present disclosure also encompasses compositions containing one or more compounds.

[0085] As used herein, the term "isomer" encompasses all geometric 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 mixtures thereof as being within the scope of the present invention. For example, stereoisomers may in some embodiments be provided substantially free of one or more corresponding stereoisomers and may be referred to as "stereochemically enriched."

[0086] When a particular enantiomer is preferred, in some embodiments, that enantiomer may be provided substantially free of the opposite enantiomer and may be referred to as "optically enriched." As used herein, "optically enriched" means that the compound is composed of one enantiomer in a significantly greater proportion. In certain embodiments, the compound is composed of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound is composed of at least about 95% by weight, at least about 98% by weight, or at least about 99% by weight of the preferred enantiomer. The preferred enantiomer may be isolated from the racemic mixture by any method known to those skilled in the art, including chiral high performance liquid chromatography (HPLC), as well as the formation and crystallization of chiral salts, or may be produced by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H. et al., Tetrahedron, 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, New York, 1962); Wilen, S.H., Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel (ed.), Univ. of Notre Dame Press, Notre Dame, Indiana, 1972).

[0087] The compounds of the present disclosure may exist in various tautomeric forms, and all such forms are included within the scope of the present disclosure. The terms "tautomer" or "tautomeric form" refer to structurally isomeric forms of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include keto-enol isomerization, amide-imidic acid isomerization, lactam-lactim isomerization, imine-enamine isomerization, and cyclic forms in which a hydrogen ion can occupy two or more positions in a heterocyclic system (e.g., 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole, and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole), etc., including interconversion via the movement of a hydrogen ion. Valence tautomers include interconversion by partial rearrangement of bonding electrons. Tautomers can be in an equilibrium state or can be stereochemically fixed in one form by appropriate substitution. Compounds of the present disclosure that are specified as one particular tautomeric form by name or structure are intended to include other tautomeric forms unless otherwise stated.

[0088] The compounds of the present disclosure also include prodrugs, active metabolite derivatives (active metabolites), active intermediates, and pharmaceutically acceptable salts thereof.

[0089] As used herein, the term "prodrug" refers to a compound or a pharmaceutically acceptable salt thereof that yields the desired active compound when metabolized under physiological conditions or when converted by solvolysis. Prodrugs include, but are not limited to, esters, amides, carbamates, carbonates, ureas, solvates, or hydrates of the active compound. Typically, prodrugs are inactive or less active than their active compounds but can confer one or more advantageous handling, administration, and / or metabolic properties. For example, some prodrugs are esters of the active compound; during metabolic cleavage, the ester group is cleaved to afford the active agent. Also, some prodrugs yield the active compound or a compound that yields the active compound after further chemical reaction upon enzymatic activation. Prodrugs may proceed from the prodrug form to the active form in one step or may have one or more intermediate forms that themselves may be active, inactive, or have some degree of activity. The preparation and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche (ed.), American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.

[0090] As used herein, the term "metabolite" (e.g., active metabolite) overlaps with the above-mentioned prodrug. That is, such a metabolite is a pharmacologically active compound or a compound that becomes a pharmacologically active compound through further metabolism, and is a derivative resulting from the metabolic process in the body of a subject. For example, such a metabolite can be obtained from the administered compound or salt or prodrug by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, ester hydrolysis, enzymatic cleavage, etc. Naturally, an active metabolite is such a pharmacologically active derivative compound. In the case of a prodrug, the prodrug compound is usually inactive or less active than the metabolite. In the case of an active metabolite, the parent compound may be an active compound or an inactive prodrug.

[0091] Prodrugs and active metabolites may be identified using conventional methods known in the art. See, for example, Bertolini et al., 1997, J Med Chem, 40: pp 2011-2016; Shan et al., J Pharm Sci, 86: pp 756-757; Bagshawe, 1995, DrugDev Res, 34: pp 220-230; Wermuth, supra note.

[0092] As used herein, the term "active intermediate" refers to an intermediate compound in a synthesis process that exhibits the same or essentially the same biological activity as the final synthetic compound.

[0093] The compounds of the present disclosure can also be formulated as pharmaceutically acceptable salts or can be in the form of pharmaceutically acceptable salts. Unless otherwise stated, the compounds provided herein include pharmaceutically acceptable salts of the compound.

[0094] As used herein, the term "pharmaceutically acceptable" indicates that a substance or composition is chemically and / or toxicologically compatible with the other components constituting the formulation and / or the subject being treated therewith.

[0095] As used herein, the term "pharmaceutically acceptable salt" includes salts that retain the biological effects of the free acids and free bases of the particular compounds and are not biologically or otherwise undesirable, unless otherwise specified. Intended pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, etc. Pharmaceutically acceptable salts are non-toxic at the amounts and concentrations at which they are administered. The preparation of such salts can facilitate pharmacological use by changing the physical properties of the compound without interfering with the expression of the physiological action of the compound. Useful changes in physical properties include a decrease in melting point to facilitate transmucosal administration and an increase in solubility to facilitate administration of higher concentrations of the agent.

[0096] 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.

[0097] Pharmaceutically acceptable salts also include base addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc when acid functional groups such as carboxylic acid or phenol are present. See, for example, Remington’s Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, Pennsylvania, Volume 2, page 1457, 1995; “Handbook of Pharmaceutical Salts: Properties, Selection, and Use”, Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using an appropriate corresponding base.

[0098] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of a compound can be dissolved in a suitable solvent such as an aqueous solution or an aqueous alcohol solution containing an appropriate acid and then isolated by evaporation of the solution. That is, when a particular compound is a base, the desired pharmaceutically acceptable salt may 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, phosphoric acid, or 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, pyranosidyl acid (such as glucuronic acid or galacturonic acid), α-hydroxy acid (such as citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic acid (such as benzoic acid or cinnamic acid), sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid).

[0099] Similarly, when a particular compound is an acid, the desired pharmaceutically acceptable salts may be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine (primary amine, secondary amine, or tertiary amine), an alkali metal hydroxide or an alkaline earth metal hydroxide. Exemplary suitable salts include amino acids such as L-glycine, L-lysine, and L-arginine, ammonia, primary amines, secondary amines, and tertiary amines, and organic acid salts derived from cyclic amines (such as hydroxyethylpyrrolidine, piperidine, morpholine, or piperazine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0100] Also, the compounds of the present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms), and as solids (e.g., crystalline forms or polymorphs), and it is understood that the present disclosure is intended to encompass all such forms.

[0101] As used herein, the terms "solvate" or "solvated form" mean a solvate addition form containing a stoichiometric or non-stoichiometric amount of a solvent. Some compounds have a tendency to capture a fixed molar ratio of solvent molecules in the crystalline solid state to form solvates. When the solvent is water, the solvate formed is a hydrate; when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with one molecule of a substance, where water retains its molecular state as H2O.

[0102] As used herein, the terms "crystalline form", "crystal form", "polymorphic form", and "polymorph" can be used interchangeably and refer to the crystal structure of a compound (or its salt or solvate) when it can crystallize in different crystal packing arrangements with the same elemental composition. When the crystal forms are different, the X-ray diffraction pattern, infrared spectrum, melting point, density, hardness, crystal shape, optical properties, electrical properties, stability, and solubility are usually different. Depending on the recrystallization solvent, the rate of crystallization, the storage temperature, and other factors, one crystal form may be dominant. The crystal polymorphs of the above compounds can be prepared by crystallization under different conditions.

[0103] The present disclosure is also intended to encompass all isotopes of atoms within a compound. 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 within the compounds of the present disclosure include, but are not limited to, 1 H, 2 H, 3 H, 11 C, 12 C, 13 C, 14 C, 14 N, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 127 I, and 131 I and the like, and are also intended to encompass their isotopes. In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes 12 C and 13 C.

[0104] Synthesis of compound The synthesis of the compounds provided herein, including their pharmaceutically acceptable salts, is illustrated in the synthesis schemes of the examples. The compounds provided herein can be prepared using any known organic synthesis method and can be synthesized according to any of a number of possible synthetic routes. These schemes are for illustrative purposes only and are not intended to limit other possible methods that can be used to prepare the compounds provided herein. In addition, each step of each scheme is for better illustration purposes and can be changed as needed. Each embodiment of each compound in the examples was synthesized for research purposes and, in some cases, for the purpose of submission to regulatory authorities.

[0105] The reactions for preparing the compounds of the present disclosure can be carried out in a suitable solvent, which can be readily selected by those 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, e.g., temperatures ranging from the freezing point temperature to the boiling point temperature of the solvent. A given reaction can be carried out in one solvent or in a mixture of two or more solvents. Based on a particular reaction step, those skilled in the art can select a solvent suitable for that particular reaction step.

[0106] The preparation of the compounds of the present disclosure can 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 those skilled in the art. The chemical nature of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, Inc., New York (1999), which is hereby incorporated by reference in its entirety.

[0107] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., ultraviolet-visible spectrophotometry), 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 those skilled in the art by various methods, for example, 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), pp. 874-883, which is hereby incorporated by reference in its entirety), and normal phase silica chromatography.

[0108] The structures of the compounds in the examples are characterized by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are reported in -6 (ppm) units. 1 1H-NMR spectra are recorded on a Varian instrument (400 MHz) using tetramethylsilane (TMS) as the standard sample (0.0 ppm) in CDCl3 solution, CD3OD solution, or DMSO-d6 solution (reported in ppm units).

[0109] MS measurements are performed on a series of instruments using electrospray ionization, chemical ionization, and electron impact ionization on a Shimadzu 2010 mass spectrometer or an Agilent 6110A mass selective detector (MSD) or a 1969A time-of-flight (TOF) mass spectrometer.

[0110] TLC measurements were performed using a Yantai Huanghai HSGF254 silica gel plate or an Anhui Liang Chen Gui Yuan plate. The silica gel plate used for TLC is 0.15 mm - 0.2 mm. The silica gel plate used for the separation and purification of products by TLC is 0.4 mm - 0.5 mm.

[0111] Column chromatography was performed on a Biotage system (manufacturer: Dyax Corporation) with a silica gel column or on a silica SepPak cartridge (Waters).

[0112] The known starting materials of the present disclosure can also be synthesized by using or according to methods known in the art, or alternatively, can be purchased from commercial supply companies such as Aldrich Chemical Company, Adamas-beta, Tokyo Chemical Industry (TCI), or Accela ChemBio, and were used without further purification unless otherwise specified. Tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dichloromethane (DCM), dichloroethane (DCE), dioxane, and 1,1,2,2-tetrachloroethane were purchased from Aldrich in Sure / Seal bottles and used as received.

[0113] Unless otherwise specified, all reactions of the present disclosure were carried out under positive pressure nitrogen or argon or in an anhydrous solvent using a drying tube, and the reaction flask was usually equipped with a rubber septum for introducing substrates and reagents via a syringe. Glassware was oven-dried and / or heat-dried.

[0114] For purposes of illustration, the following shows the general synthetic routes for preparing the compounds and important intermediates of the present disclosure. For a more detailed description of the individual reaction steps, please refer to the Examples section below. It will be understood by those skilled in the art that other synthetic routes may be used to synthesize the compounds of the present invention. Specific starting materials and reagents are shown in each scheme and discussed below, but other starting materials and reagents can be readily substituted to achieve various derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods below can be further modified using conventional chemical reactions well known to those skilled in the art in light of the present disclosure.

[0115] General Synthetic Route In some embodiments, the compound of formula (I) is a compound of formula (IIa) or formula (IIb):

Chemical Formula

Chemical Formula

[0116] In some embodiments, the compound of formula (I) may be prepared by reaction of a compound of formula IIa with a compound of formula IIIc,

Chemical Formula

[0117] The compound of formula (IIa) and the compound of formula (IIb) are compounds of formula (IV):

Chemical formula

Chemical formula

[0118] The compound of formula (IV) can be prepared by a method similar to the method shown in the Examples section.

[0119] In some embodiments, the compound of formula (I) is a compound of formula (VIa) or formula (VIb) of the compound of formula (IV):

Chemical formula

[0120] The compound of formula (VIa) or formula (VIb) can be prepared by a method similar to the method shown in the Examples section.

[0121] Use of compound In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof that exhibits ATM kinase inhibitory activity.

[0122] As used herein, the term "ATM kinase inhibitory activity" refers to a decrease in the activity of ATM kinase as a direct or indirect response to the presence of a compound of formula (I) or a pharmaceutically acceptable salt thereof, compared to the activity of ATM kinase in the absence of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Such a decrease in activity may be due to a direct interaction between the compound of formula (I) or a pharmaceutically acceptable salt thereof and ATM kinase, or alternatively, may be due to an interaction between the compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more other factors that affect ATM kinase activity. For example, the compound of formula (I) or a pharmaceutically acceptable salt thereof may decrease ATM kinase by directly binding to ATM kinase, or may decrease ATM kinase by (directly or indirectly) decreasing ATM kinase activity in another factor, or may decrease ATM kinase by (directly or indirectly) decreasing the amount of ATM kinase present in a cell or organism.

[0123] In some embodiments, the compounds of the present disclosure are selective inhibitors of ATM kinase.

[0124] As used herein, the term "selective inhibitor" or "selectively inhibits" means that the provided compound inhibits ATM kinase in at least one assay described herein (e.g., a biochemical assay or a cellular assay). In some embodiments, the term "selective inhibitor" or "selectively inhibits" refers to the IC when the provided compound inhibits an enzyme within the PIKK family (such as PI3K, mTOR, and ATR) that is closely related to ATM kinase 50 However, when inhibiting ATM kinase, the IC 50 Is at least 5000 times higher, at least 4000 times higher, at least 3000 times higher, at least 2000 times higher, at least 1000 times higher, at least 500 times higher, at least 400 times higher, at least 300 times higher, at least 200 times higher, at least 100 times higher, at least 90 times higher, at least 80 times higher, at least 70 times higher, at least 60 times higher, at least 50 times higher, at least 40 times higher, at least 30 times higher, at least 20 times higher, at least 10 times higher, than that when inhibiting ATM kinase.

[0125] In some embodiments, the compounds of the present disclosure do not serve as AO substrates when measured in human liver cytosol.

[0126] As used herein, the term "AO substrate" means that a given compound is susceptible to oxidation by aldehyde oxidase ("AO") and thus highly sensitive to clearance via AO. In some embodiments, the AO sensitivity of a compound is the intrinsic clearance (CL in a human liver cytosolic system, as detailed in the Examples section below int) can be evaluated (Zientek M. et al., Drug MetabDispos, 2010, pp. 1322-27). Human liver cytosol systems useful in this evaluation are commercially available, for example, from Xenotech, catalog number H0606.C(AX), lot number 1710130. Typically, 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 specially prepared from donors with high AO activity to minimize underestimation of AO-mediated clearance. In some embodiments, 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, regarded as a strong AO substrate) are both used as standards in the human liver cytosol system. In certain embodiments, CL int The compound has a CL of PF-04217903 as determined by the AO assay described in the Examples section below. int CL lower than (1.8 μL / min / mg protein) int If the compound exhibits the CL of zaleplon, the compound is not considered an AO substrate and int (3.1 μL / min / mg protein) int If the compound exhibits the following properties, it will be considered a strong AO substrate.

[0127] In some embodiments, compounds of the present disclosure exhibit low AO sensitivity and inhibit CL in human hepatocytes. intis less than about 1.8 μL / min / mg protein, less than about 1.7 μL / min / mg protein, less than about 1.6 μL / min / mg protein, less than about 1.5 μL / min / mg protein, less than about 1.4 μL / min / mg protein, less than about 1.3 μL / min / mg protein, less than about 1.2 μL / min / mg protein, less than 1.1 μL / min / mg protein, less than about 1 μL / min / mg protein, less than about 0.9 μL / min / mg protein, less than about 0.8 μL / min / mg protein, less than about 0.7 μL / min / mg protein, less than about 0.6 μL / min / mg protein, less than about 0.5 μL / min / mg protein, less than about 0.4 μL / min / mg protein, less than about 0.3 μL / min / mg protein, less than about 0.2 μL / min / mg protein, or less than about 0.1 μL / min / mg protein.

[0128] AO is a molybdenum-flavin enzyme in the cytosol, a group of proteins that require flavin adenine dinucleotide (FAD) and molybdopterin [molybdenum cofactor (MoCo)] for their catalytic activity. AO oxidizes aromatic aldehydes to the corresponding carboxylic acids and oxidizes heterocycles to hydroxylated derivatives. Since these chemical groups are popular synthetic building blocks in pharmaceutical chemistry, the potential of AO to oxidize heterocycles is particularly important in drug design and development. AO-mediated metabolism is often overlooked at the drug discovery stage, and it is not until Phase 1 clinical trials that the problem of high clearance values becomes apparent. Since AO is a cytosolic enzyme, its potential contribution to the metabolic clearance of new compounds is not considered in standard metabolic stability screening using liver microsomes. Hepatocytes are a whole cell system containing both microsomes and cytosol. However, AO is an unstable protein and its activity is considerably lost during the preparation of hepatocytes (Hutzler, J.M. et al., Drug Metab Dispos, 2014, pp. 1090-7). In vivo studies on AO-mediated metabolism in animal models also have major problems because the AO in the liver, which is a component of it, differs between humans and commonly used experimental animals (Garattini, E. et al., Expert Opin Drug Discovery, 2013, pp. 641-54). The human liver is characterized by a single active AO isozyme, namely AOX1. The main AOX type expressed in many mouse and rat strains is AOX3. Two other experimental animals, cats and dogs, are characterized by the absence of AO enzyme activity. AO activity has been found to be even higher in higher primates (humans and monkeys) compared to rodents. AO is present at high concentrations in the liver, and in the liver, AO oxidizes multiple aldehydes and nitrogen-containing heterocyclic compounds such as anticancer agents and immunosuppressive agents (see, for example, Gordon AH, Green DE, Subrahmanyan, "Liver aldehyde oxidase", The Biochemical Journal., 1940, 34(5): pp. 764-74).Human liver cytosol extract contains AO, but has little contamination of CYP450, and has been found to be a useful tool for predicting in vivo clearance mediated by human AO. Since AO is an unstable enzyme and rapidly inactivates upon freeze-thawing, the human liver cytosol produced by Xenotech was used immediately after thawing and not reused. Given the significant variability in AO activity, a high-activity lot of human liver cytosol was selected for the AO assay to minimize the underestimation of clearance as much as possible. As controls in the AO assay, the reference compounds zaleplon (high clearance value by AO) and PF-04217903 (low clearance by AO) were used.

[0129] While not wishing to be bound by any particular theory, AO is thought to have a significant impact on pharmacokinetics. Due to its broad substrate specificity, AO is capable of oxidizing 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): pp1441 - 8). The contribution of AO to the hepatic clearance of drugs and other compounds is significant (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): pp856 - 64). AO-mediated metabolism is likely to lead to high clearance values in humans. In the case of compounds with high clearance values, even small changes in intrinsic clearance due to differences in enzyme expression levels among patients can cause significant changes in bioavailability. Human AOX1 is highly polymorphic, and several missense and even nonsense polymorphic sites that cause inactivation have been reported in the human population (Garattini, E. et al., Expert Opin Drug Discovery, 2012, pp487 - 503; Hartmann, T. et al., Drug MetabDispos, 2012, pp856 - 64). Such polymorphisms result in a decrease in the level of the encoded AOX1 protein and explain the reported inter-individual variation in AOX activity. In addition, many factors, such as gender, age, smoking, drug use, and disease status, may affect AO activity.Therefore, compounds with high AO-mediated clearance values have large PK variability among patients, which may lead to unexpected toxicity in some individuals, while efficacy may not be achieved in other patients (Garattini, E. et al., Expert Opin Drug Discovery, 2013, pages 641-54; Hutzler, J.M. et al., Drug Metab Dispos, 2014, pages 1090-7).

[0130] Unlike the previously reported ATM inhibitors AZD0156 and AZD1390, which are strong AO substrates, the compounds of the present disclosure are surprisingly less sensitive to AO oxidation. Thus, in one aspect, the compounds provided herein and pharmaceutically acceptable salts thereof are not AO substrates and, as a result, exhibit a better PK profile than compounds that are AO substrates. For example, the compounds provided herein have low PK variability among humans with different AO activity levels.

[0131] In some embodiments, the compounds of the present disclosure are not substrates of P-glycoprotein (Pgp) nor substrates of ATP-binding cassette subfamily G member 2 (ABCG2, or BCRP). As used herein, the term "Pgp substrate" means that a given compound is likely to be transported back by Pgp into the intestinal lumen (in the case of Pgp distributed in intestinal epithelium), bile duct (in the case of Pgp distributed in hepatocytes), urinary filtrate (in the case of Pgp distributed in cells of the proximal renal tubule of the kidney), capillary (in the case of Pgp distributed in capillary endothelial cells that constitute the blood-brain barrier and blood-testis barrier), etc. As used herein, the term "BCRP substrate" means that the absorption of a given compound by BCRP is hindered at the apical membrane of the intestine, blood-testis barrier, blood-brain barrier, and the membranes of hematopoietic progenitor cells and other stem cells, particularly at the blood-brain barrier. Thus, compounds or pharmaceutically acceptable salts thereof are provided that can be applied to the treatment of both extracranial cancers and metastatic cancers such as brain metastases by exhibiting good brain permeability in a subject.

[0132] In some embodiments, the Pgp sensitivity and BCRP sensitivity of the compounds can be evaluated by the MDCK-MDR1·Pgp·permeability assay and the Caco-2·BCRP·permeability assay detailed in the Examples section below, respectively. In some embodiments, the compounds of the present disclosure do not exhibit Pgp sensitivity, and the MDCK-Pgp efflux ratio (MDCK-Pgp ER) is less than 2.5.

[0133] In some embodiments, the compounds of the present disclosure can cross the blood-brain barrier (BBB) without the need for a drug that promotes blood-brain barrier (BBB) translocation.

[0134] In some embodiments, the compounds of the present disclosure exhibit low hERG inhibition when measured by the hEGR inhibition assay detailed in the Examples section below. In some embodiments, the compounds of the present disclosure exhibit hERG inhibition of less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, or less than 20% at 10 μM.

[0135] In some embodiments, the compounds of the present disclosure exhibit good water solubility. In some embodiments, the compounds of the present disclosure exhibit water solubility 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.

[0136] The compounds of formula (I) and pharmaceutically acceptable salts thereof are useful in therapy as a result of their ATM kinase inhibitory activity (optionally selective ATM kinase inhibitory activity), for example, in the treatment of diseases or medical conditions mediated at least in part by ATM kinase, including but not limited to cancer.

[0137] As used herein, the term "cancer" is intended to include both non-metastatic and metastatic cancers. In this regard, treating cancer includes treating both the primary tumor and tumor metastases.

[0138] As used herein, the term "therapy" is intended to have its ordinary meaning of addressing a disease in order to completely or partially remove one, several, or all of the symptoms of the disease, or to correct or compensate for the underlying pathological condition. The term "therapy" includes "prevention" unless specifically indicated otherwise. The terms "therapeutic" and "therapeutically" should be construed accordingly.

[0139] As used herein, the term "prevention" is intended to have its ordinary meaning and includes primary prevention to prevent the onset of a disease and secondary prevention, where the disease has already occurred and the patient is protected from progression, i.e., worsening of the disease, or the development of new symptoms associated with the disease, either temporarily or permanently.

[0140] The term "treatment" is used synonymously with "therapy". Similarly, the term "treat" can be regarded as "applying a therapy", where "therapy" is as defined herein.

[0141] Thus, in one aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

[0142] In some embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0143] In some embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of ATM-related diseases or conditions. In some embodiments, the above ATM-related diseases or conditions are cancer. In some embodiments, the above 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 above cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, head and neck squamous cell carcinoma, and lung cancer.

[0144] In some embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Huntington's disease.

[0145] 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 ATM-related diseases or conditions.

[0146] 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.

[0147] 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 Huntington's disease.

[0148] Pharmaceutical composition The present disclosure provides a pharmaceutical composition comprising one or more compounds of the present disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the above pharmaceutical composition comprises one or more compounds of the present disclosure or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0149] As used herein, the term "pharmaceutical composition" refers to a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition described above is in bulk form or unit dosage form. The unit dosage forms described above include tablets, capsules, pills, powders, granules, sachets, cachets, confectionery tablets, suspensions, emulsions, aqueous solutions, syrups, aerosols (as solids or in liquid media), sprays, ointments, pastes, creams, lotions, gels, patches, inhalants, or suppositories, etc., and can be in any of various forms. The content of the active ingredient (e.g., a formulation of a compound of the present disclosure, or a salt, hydrate, solvate, or isomer thereof) in the unit dosage composition is a therapeutically effective amount and varies depending on the specific treatment involved. It will be understood by those skilled in the art that it may be necessary to routinely vary the dosage depending on the age and condition of the patient. The dosage will also depend 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 the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, aqueous solutions, patches, and inhalants. In some embodiments, the compounds of the present disclosure are mixed under aseptic conditions with pharmaceutically acceptable excipients and any preservatives, buffers, or propellants that may be required.

[0150] As used herein, the term "pharmaceutically acceptable excipient" means an excipient useful in the preparation of pharmaceutical compositions that is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes excipients acceptable for animal use and for human pharmaceutical use. "Pharmaceutically acceptable excipient" as used herein and in the claims includes both the case of comprising one such excipient and the case of comprising two or more such excipients.

[0151] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical that treats, ameliorates, or prevents a confirmed disease or condition, or an amount of a pharmaceutical that exhibits a detectable therapeutic or inhibitory effect. This effect can be detected by any measurement method known in the art. The exact effective amount for a subject depends 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. It will depend on. The therapeutically effective amount in a given situation can be determined by conventional experimental methods within the skill and judgment of a clinician. It can be determined by routine experimental methods within the scope of the clinician's skill and judgment.

[0152] In some embodiments, the pharmaceutical composition can be formulated such that the compound of the present disclosure or a pharmaceutically acceptable salt thereof can be administered at a dose of 0.01 to 500 mg / kg body weight / day, for example, 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.

[0153] In some embodiments, the pharmaceutical composition contains one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof as a first active ingredient, and further contains a second active ingredient. The second active ingredient can be any antitumor drug known in the art, for example, an anti-cancer drug, an anti-angiogenic drug, an immunotherapy approach, an efficacy enhancer, etc.

[0154] Examples of anti-cancer drugs include DNA alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, e.g., ifosfamide, bendamustine, melphalan, chlorambucil, busulfan, temozolomide, and nitrosourea, e.g., carmustine); antimetabolites (e.g., gemcitabine, and folic acid antimetabolites, e.g., fluoropyrimidine, e.g., 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumor antibiotics (e.g., anthracycline, e.g., doxorubicin, bleomycin, doxorubicin, liposomal doxorubicin, pirarubicin, daunomycin, valrubicin, epirubicin, idarubicin, mitomycin C, dactinomycin, amrubicin, and mitramycin); mitosis inhibitors (e.g., vinca alkaloids, e.g., vincristine, vinblastine, vindesine, and vinorelbine, and taxoids, e.g., paclitaxel and docetaxel, and polokinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxin, e.g., etoposide and teniposide, amsacrine, irinotecan, topotecan, and camptothecin); inhibitors of DNA repair mechanisms, e.g., CHK kinase; DNA-dependent protein kinase inhibitors; inhibitors of poly ADP ribose polymerase (PARP inhibitors, e.g., olaparib); and Hsp90 inhibitors, e.g., tanespimycin and retaspimycin, inhibitors of ATR kinase (e.g., AZD6738); and inhibitors of WEE1 kinase (e.g., AZD1775 / MK-1775), but are not limited thereto.

[0155] Examples of anti-angiogenic agents include those that inhibit the action of vascular endothelial growth factor, such as bevacizumab, an anti-vascular endothelial growth factor antibody, VEGF receptor tyrosine kinase inhibitors such as vandetanib (ZD6474), sorafenib, batatinib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW786034), and cediranib (AZD2171); compounds such as those disclosed in International Publications Nos. WO 97 / 22596, WO 97 / 30035, WO 97 / 32856, and WO 98 / 13354; and compounds that act through other mechanisms (e.g., linomide, inhibitors of integrin ανβ3 function, and angiostatin), or inhibitors of angiopoietin and its receptors (Tie-1 and Tie-2), inhibitors of PLGF, inhibitors of delta-like ligand (DLL-4), etc., but are not limited thereto.

[0156] Examples of immunotherapy approaches include ex vivo and in vivo approaches to increase the immunogenicity of a patient's tumor cells, such as 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 the T cell response to a tumor, such as CTLA4 blocking antibodies (e.g., ipilimumab and tremelimumab), B7H1 blocking antibodies, PD-1 blocking antibodies (e.g., BMS-936558 or AMP-514), PD-L1 blocking antibodies (e.g., MEDI4736), and agonist antibodies to CD137; approaches using transfected immune cells such as cytokine transfected dendritic cells; approaches using cytokine transfected cancer cell lines, approaches using antibodies against tumor associated antigens, approaches using antibodies that deplete target cell populations (e.g., unbound anti-CD20 antibodies such as rituximab, radio-labeled anti-CD20 antibodies such as bexarotene and zevalin, and anti-CD54 antibody such as campath); approaches using anti-idiotype antibodies; approaches to enhance natural killer cell function; and approaches utilizing antibody-toxin conjugates (e.g., mylotarg, an anti-CD33 antibody); approaches utilizing immunotoxins such as moxetumomab pasudotox; and approaches utilizing agonists of Toll-like receptor 7 or Toll-like receptor 9, but are not limited thereto.

[0157] Examples of potency enhancers include leucovorin.

[0158] 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.

[0159] In some embodiments, the amount of additional anti-tumor agent present in the compositions of the present disclosure can be less than the amount that would typically be administered in a composition containing the anti-tumor agent as the sole active agent. In certain embodiments, the amount of additional anti-tumor agent in the compositions of the present disclosure will range from about 50% to 100% of the amount normally present in a composition containing the anti-tumor agent as the sole therapeutically active agent.

[0160] Thus, in another aspect, provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with one or more of the above anti-tumor agents.

[0161] As used herein, the term "combination" refers to simultaneous administration, separate administration, 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 the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effects of the combination.

[0162] In a further aspect, provided is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with one or more of the above anti-tumor agents, and a pharmaceutically acceptable excipient.

[0163] In a further aspect, provided is a kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with one or more of the above anti-tumor agents. In a further aspect, provided is a kit comprising: (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 the above in a second unit dosage form; and (c) a container for containing the first unit dosage form and the second unit dosage form.

[0164] Treatment method In a further aspect, there is provided a method of 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) of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, based on the selective ATM kinase inhibitory activity, non-AO vulnerability, non-Pgp vulnerability, non-BCRP vulnerability, and brain permeability of the compounds of the present disclosure.

[0165] In some embodiments, the ATM-related disease or condition described above is cancer. In some embodiments, the cancer described above 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 described above is metastatic cancer. In some embodiments, the metastatic cancer described above includes central nervous system metastases. In some embodiments, the central nervous system metastases described above include brain metastases. In some embodiments, the central nervous system metastases described above include leptomeningeal metastases. "Leptomeningeal metastases" occur when cancer spreads to the meninges, the tissue layer that covers the brain and spinal cord. Metastases can spread to the meninges through the blood, or metastases can be carried by cerebrospinal fluid (CSF) flowing in the meninges and move from brain metastases.

[0166] In a further aspect, there is provided a method of treating Huntington's disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0167] As used herein, the term "subject in need thereof" is a subject having a disease or condition related to ATM (e.g., cancer), or a subject having an increased risk of developing a disease or condition related to ATM (e.g., cancer) relative to the general population. In the case of cancer, the subject in need thereof can be a subject having a pre-cancerous condition. "Subject" includes warm-blooded animals. In some embodiments, the warm-blooded animal is a human.

[0168] In this regard, 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 "treatment" to a subject or to "treat" a disease or disorder associated with ATM in a subject. In the case of cancer, a therapeutically effective amount may be an amount that causes any observable or measurable change in a subject as described in the definitions of "treatment methods", "treatment", and "prevention" above. For example, an effective amount may be to reduce the number of cancer cells or tumor cells; reduce the overall tumor size; inhibit or stop the infiltration of tumor cells into peripheral organs such as soft tissues and bones; inhibit or stop tumor metastasis; inhibit or stop tumor growth; reduce to some extent one or more of the symptoms associated with cancer; reduce morbidity and mortality; improve the quality of life; or a combination of these effects. An effective amount may also be an amount sufficient to reduce the symptoms of a disease that responds to inhibition of ATM kinase activity. In the case of cancer treatment, the in vivo efficacy can be measured, for example, by evaluating survival time, time to progression (TTP), response rate (RR), duration of effect, and / or quality of life. As will be appreciated by those skilled in the art, the effective amount may vary depending on the route of administration, the use of excipients, and the co-administration of other agents. For example, when combination therapy is used, the amount of the compound of formula (I) or the pharmaceutically acceptable salt described herein and the amount of other pharmaceutically active agents, when combined, together are effective to treat the target disorder in an animal patient. In this regard, the combined amounts are "therapeutically effective amounts" when those amounts are sufficient, when combined, to reduce the symptoms of a disease that responds to inhibition of ATM activity as described above.

[0169] Generally, a "therapeutically effective amount" may be determined by one of ordinary skill in the art, such as starting from the dosage ranges described herein for a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the approved or published dosage ranges of other pharmaceutically active compounds.

[0170] The method for treating ATM-related diseases or symptoms described herein may be used as a monotherapy. As used herein, the term "monotherapy" refers to the administration of a single active compound or therapeutic compound to a subject in need of treatment. In some embodiments, the monotherapy will involve 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.

[0171] Depending on the particular disease or symptom being treated, the method for treating ATM-related diseases or symptoms described herein may, in addition to administration of a compound of formula (I), include one or more additional therapies, such as conventional surgery, radiation therapy, chemotherapy, or combinations of such additional therapies. As used herein, the term "combination therapy" refers to the administration of a combination of multiple active compounds.

[0172] Additional therapies, such as additional anti-tumor agents, may be administered separately from the compounds of the present disclosure as part of multiple dosing regimens. Alternatively, these additional therapies may be part of a single dosage form, mixed with the compounds of the present disclosure in a single composition.

[0173] In some embodiments, the compounds of the present disclosure may be administered simultaneously with, sequentially with, or separately from treatment by conventional surgery, radiation therapy, or chemotherapy.

[0174] Radiation therapy may include one or more of the following therapy categories: (i) external beam radiation therapy using electromagnetic radiation, and intraoperative radiation therapy using electromagnetic radiation; (ii) brachytherapy or intracavitary radiation therapy, including interstitial radiation therapy or intracavitary radiation therapy; or (iii) systemic radiation therapy, including but not limited to iodine 131 and strontium 89.

[0175] Chemotherapy may include anti-tumor agents known in the art, such as anti-cancer drugs, anti-angiogenic drugs, immunotherapy approaches, potency enhancers, etc., as described herein.

[0176] Thus, in one aspect, there is provided a method of treating an ATM - related disease or condition in a subject in need of treatment, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered concomitantly with, separately from, or sequentially to radiation therapy.

[0177] In some embodiments, the radiation therapy described above is brain irradiation.

[0178] In some embodiments, the ATM - related disease or condition described above 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, 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 central nervous system metastasis. In some embodiments, the central nervous system metastasis is brain metastasis.

[0179] In some embodiments, there is provided a method of treating glioblastoma in a subject in need of treatment, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered concomitantly with, separately from, or sequentially to brain irradiation.

[0180] In another aspect, there is provided a method of treating an ATM - related disease or condition in a subject in need of treatment, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered concomitantly with, separately from, or sequentially to one or more additional anti - tumor agents.

[0181] In some embodiments, the ATM - related disease or condition described above is cancer. In certain embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the amount of the one or more additional anti - tumor agents described above together are an amount effective to produce an anti - cancer effect.

[0182] In some embodiments, the additional anti-tumor agents described above include anti-cancer drugs, anti-angiogenic drugs, immunotherapy approaches, potency enhancers, and the like.

[0183] In some embodiments, the additional anti-tumor agents described above are selected from the group consisting of doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, and bleomycin.

Examples

[0184] For illustrative purposes, the following examples are included. However, it should be understood that these examples do not limit the present invention and are intended only to present ways of practicing the present disclosure. It will be understood by those skilled in the art that the chemical reactions described can be readily adapted to prepare some other compounds of the present disclosure and that other methods for preparing the compounds of the present disclosure are also considered to be within the scope of the present disclosure. For example, the synthesis of compounds not exemplified in the present disclosure can be carried out by obvious modifications by those skilled in the art, such as appropriately protecting interfering groups, using other suitable reagents known in the art other than those described, and / or by making customary modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art are recognized as applicable for preparing other compounds of the present disclosure.

[0185] The following abbreviations were used in the examples.

Table 2

[0186] Example 1 7-Fluoro-1-isopropyl-3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one The compound of Example 1 was prepared according to the synthetic route shown in Scheme 1.

Chem.

[0187] Step 1: 1-(2-Amino-5-bromo-4-fluorophenyl)ethanone (A2)

Chem.

[0188] Step 2: 6-Bromo-7-fluorocinnolin-4-ol (A3)

Chem.

[0189] To a stirred solution of 1-(2-amino-5-bromo-4-fluorophenyl)ethan-1-one (40 g, 172 mmol) in concentrated HCl (325 mL) and H2O (56 mL), NaNO2 (12 g, 172 mmol) in H2O (12 mL) was added dropwise at 0 °C. The resulting mixture was stirred at this temperature for 1 h and then heated at 65 °C for 16 h. The crude mixture was poured into ice water and the precipitate was collected by filtration. The solid was washed with water and dried under reduced pressure to give the desired product (33 g, 79% yield) as a yellow solid. MS: m / z 243 [M+H] + 。

[0190] Step 3: 6-Bromo-7-fluoro-3-nitrosinolin-4-ol (A4)

Chem.

[0191] Step 4: 6-Bromo-4-chloro-7-fluoro-3-nitrosinolin (A5)

Chem.

[0192] Step 5: 6-Bromo-7-fluoro-N-isopropyl-3-nitroquinolin-4-amine (A6)

Chemical formula

[0193] Step 6: 6-Bromo-7-fluoro-N4-isopropylquinoline-3,4-diamine (A7)

Chemical formula

[0194] Step 7: 8-Bromo-7-fluoro-1-isopropyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (A8)

Chemical formula

[0195] Step 8: 8-Bromo-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (A9)

Chemical formula

[0196] Step 9: 7-Fluoro-8-(6-fluoropyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (A10)

Chemical Structure

[0197] Project 10: 7-Fluoro-1-isopropyl-3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

Chem.

[0198] Also, the compound of Example 1 was prepared according to the synthetic route shown in Scheme 2.

Chem.

[0199] Step 1: 5-Bromo-2-(3-(piperidin-1-yl)propoxy)pyridine (B2)

Chem.

[0200] Steps 2 and 3: 7-Fluoro-1-isopropyl-3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

Chem.

[0201] Example 2 8-(6-(3-(Dimethylamino)propoxy)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one [Chemical formula] The title compound was directly synthesized from 8-bromo-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one according to Scheme 2 of Example 1 to give the desired product (17% yield) as a yellow solid. MS: m / z 439 [M+H] + . 11H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 5.16 - 5.10 (m, 2H), 7.91 (dt, J = 8.6, 2.3 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 5.20 - 5.07 (m, 1H), 4.52 (t, J = 5.8 Hz, 2H), 3.75 (s, 3H), 3.20 - 3.14 (m, 2H), 2.81 (s, 6H), 2.43 - 2.36 (m, 2H), 1.76 (d, J = 6.9 Hz, 6H).

[0202] Example 3 7-Fluoro-1-isopropyl-3-methyl-8-(6-(3-(pyrrolidin-1-yl)propoxy)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

Chemical Structure

[0203] Also, the title compound was synthesized according to Scheme 2 of Example 1 to obtain the desired product (yield 53%) as a white solid. The analytical data were the same as those obtained above.

[0204] Example 4 8-(6-(4-(Dimethylamino)piperidin-1-yl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

Chem.

[0205] Example 5 8-(6-(3-((Dimethylamino)methyl)pyrrolidin-1-yl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

Chem.

[0206] Example 6 8-(6-((2-(dimethylamino)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one The compound of Example 6 was prepared according to the synthetic route depicted in Scheme 3. [ka]

[0207] Step 1: 2-((5-bromopyridin-2-yl)methoxy)-N,N-dimethylethanamine (C2) [ka] To a stirred solution of 2-(dimethylamino)ethanol (267 mg, 3.0 mmol) in DMF (20 mL) at 0 °C under nitrogen was added NaH (60%, 120 mg, 3.0 mmol). The resulting mixture was stirred at 0 °C for an additional 30 minutes, then 5-bromo-2-(chloromethyl)pyridine (300 mg, 1.5 mmol) was added thereto. After stirring at room temperature for 2 hours, the crude mixture was poured into ice water and extracted with EtOAc (10 mL × 2 times). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and then concentrated to give the crude product (350 mg) as a brown oily substance, which was used in the next step without further purification. MS: m / z 259 [M+H] + .

[0208] Steps 2 and 3: 8-(6-((2-(dimethylamino)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one [Chemical formula] Under nitrogen, to a stirred solution of 2-((5-bromopyridin-2-yl)methoxy)-N,N-dimethylethane-1-amine (350 mg, 1.4 mmol), KOAc (392 mg, 4.0 mmol), and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (343 mg, 1.4 mmol) in 1,4-dioxane (20 mL) at room temperature was added Pd(dppf)Cl2 (100 mg, 0.1 mmol). The resulting mixture was stirred under nitrogen at 90 °C for 16 h. After cooling the reaction, 8-bromo-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one (475 mg, 1.4 mmol), K2CO3 (276 mg, 2 mmol), and H2O (1 mL) were added, followed by Pd(dppf)Cl2 (100 mg, 0.1 mmol). After stirring at 100 °C under nitrogen for 4 h, the crude mixture was cooled, diluted with EtOAc (20 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1 to 10:1) to afford the crude product, which was further purified by preparative TLC (DCM:MeOH = 10:1) to give the desired product (30 mg, 5% yield) as a pale yellow solid. MS: m / z 439 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.18 (d, J = 11.1 Hz, 3H), 7.62 (s, 1H), 5.15 (s, 1H), 4.83 (s, 2H), 4.05 (t, J = 5.0 Hz, 2H), 3.76 (s, 3H), 3.15 (s, 2H), 2.77 (s, 6H), 1.76 (s, 6H).

[0209] Example 7 7-Fluoro-1-isopropyl-3-methyl-8-(6-((2-(piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

Chem.

[0210] Example 8 7-Fluoro-1-isopropyl-3-methyl-8-(6-((2-(pyrrolidin-1-yl)ethoxy)methyl)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

Chem.

[0211] Example 9 (R)-7-Fluoro-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

Chemical Structure

[0212] Example 10 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

Chem.

[0213] Example 11 8-(6-((2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)methyl)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

Chem.

[0214] Example 12 N-(2-(Dimethylamino)ethyl)-5-(7-fluoro-1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-8-yl)picolinamide The compound of Example 12 was prepared according to the synthetic route shown in Scheme 4. [Chemical formula]

[0215] Step 1: 5-Bromo-N-(2-(dimethylamino)ethyl)picolinamide (D2) [Chemical formula] To a solution of 5-bromopicolinic acid (250 mg, 1.2 mmol) in DMF (20 mL) were added HOBt (140 mg, 1.2 mmol), EDCI (400 mg, 2 mmol) and DIPEA (330 mg, 3 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. Next, N’,N’-dimethylethane-1,2-diamine (170 mg, 2 mmol) was added to this mixture. After the reaction mixture was stirred at room temperature for 12 hours, it was poured into ice water. The resulting mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product (250 mg) as a brown oily substance, which was used in the next step without further purification. MS: m / z 272 [M+H] + 。

[0216] Steps 2 and 3: N-(2-(dimethylamino)ethyl)-5-(7-fluoro-1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-8-yl)picolinamide

Chemical formula

[0217] Example 13 7-Fluoro-8-(6-(3-(4-fluoropiperidin-1-yl)propoxy)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one The compound of Example 13 was prepared according to the synthetic route shown in Scheme 5.

Chem.

[0218] Step 1: 3-((Tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (E2)

Chem.

[0219] Steps 2 and 3: 7-Fluoro-1-isopropyl-3-methyl-8-(6-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (E4)

Chem.

[0220] Step 4: 7-Fluoro-8-(6-(3-hydroxypropoxy)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one (E5)

Chem.

[0221] Step 4: 3-((5-(7-Fluoro-1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-8-yl)pyridin-2-yl)oxy)propyl methanesulfonate (E6)

Chemical Structure

[0222] Step 5: 7-Fluoro-8-(6-(3-(4-fluoropiperidin-1-yl)propoxy)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

Chem.

[0223] To a stirred solution of 3-((5-(7-fluoro-1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-8-yl)pyridin-2-yl)oxy)propyl methanesulfonate (170 mg, 0.32 mmol) and DIEA (206 mg, 1.6 mmol) in MeCN (5 mL) at room temperature was added 4-fluoropiperidine (180 mg, 1.28 mmol) all at once. The resulting mixture was stirred at room temperature for 16 h and then diluted with DCM (20 mL). The organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to give the desired product (10 mg, 6% yield) as a yellow solid. MS: 497 [M+H] + . 1 1H NMR (400 MHz, CD3OD) δ 8.31 (d, J = 7.7 Hz, 1H), 8.21 (d, J = 2.6 Hz, 1H), 8.00 (d, J = 11.5 Hz, 1H), 7.91 (dt, J = 9.4, 2.3 Hz, 1H), 6.71 (d, J = 9.4 Hz, 1H), 5.37 - 5.21 (m, 1H), 4.79 - 4.65 (m, 1H), 4.21 (t, J = 7.0 Hz, 2H), 3.66 (s, 3H), 2.95 - 2.62 (m, 6H), 2.14 (t, J = 7.2 Hz, 2H), 2.08 - 1.85 (m, 5H), 1.75 (d, J = 6.8 Hz, 6H).

[0224] Example 14 (S)-7-Fluoro-8-(6-(3-(3-fluoropyrrolidin-1-yl)propoxy)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

Chem.

[0225] Example 15 (R)-7-Fluoro-8-(6-(3-(3-fluoropyrrolidin-1-yl)propoxy)pyridin-3-yl)-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

Chem.

[0226] Example 16 8-(6-(3-(3-Azabicyclo[3.1.0]hexan-3-yl)propoxy)pyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1H-imidazo[4,5-c]cinnolin-2(3H)-one

Chem.

Table 4

[0227] Example 17 8-(6-(3-(Dimethylamino)propoxy)-2-fluoropyridin-3-yl)-7-fluoro-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one

Chemical formula

[0228] Example 18 7-Fluoro-3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one The compound of Example 18 was prepared according to the synthetic route shown in Scheme 6. [Chemical formula]

[0229] Step 1: 6-Bromo-7-fluoro-3-nitro-N-(tetrahydro-2H-pyran-4-yl)cinnolin-4-amine (F1) [Chemical formula] To a stirred solution of 6-bromo-4-chloro-7-fluoro-3-nitro cinnoline (1 g, 3.28 mmol) and triethylamine (1.4 mL, 9.8 mmol) in DCM (15 mL) at room temperature was added tetrahydro-2H-pyran-4-amine (497 mg, 4.9 mmol). The resulting mixture was stirred at room temperature for 16 hours and concentrated. The residue was purified by silica gel chromatography to give the desired product (800 mg, 65% yield) as a yellow solid. MS: m / z 371 [M+H] + .

[0230] 6-Bromo-7-fluoro-N4-(tetrahydro-2H-pyran-4-yl)cinnoline-3,4-diamine (F2) [Chemical formula] To a stirred solution of 6-bromo-7-fluoro-3-nitro-N-(tetrahydro-2H-pyran-4-yl)cinnolin-4-amine (900 mg, 2.43 mmol) in EtOAc (20 mL) at room temperature was added SnCl2·2H2O (2.2 g, 9.7 mmol). The resulting mixture was stirred at 80 °C for 2 hours. The crude mixture was basified to pH 9 by adding an aqueous NaHCO3 solution, and the precipitate was then filtered off. The filtrate was diluted with EtOAc (20 mL), and the organic phase was washed with water and brine, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the desired product (750 mg, 90% yield) as a yellow solid. MS: m / z 341 [M+H] + .

[0231] Step 3: 8-Bromo-7-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (F3) [Chemical formula] To a stirred solution of 6-bromo-7-fluoro-N4-(tetrahydro-2H-pyran-4-yl)cinnoline-3,4-diamine (900 mg, 2.65 mmol) in THF (20 mL) at room temperature was added CDI (2.2 g, 13.3 mmol). The resulting mixture was stirred at 70 °C for 16 h and then concentrated. The residue was poured into ice water and the precipitate was collected by filtration. The solid was washed with water and dried under reduced pressure to give the desired product (800 mg, 82% yield) as a yellow solid. MS: m / z 367 [M+H] + .

[0232] Step 4: 8-Bromo-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (F4) [Chemical formula] To a stirred solution of 8-bromo-7-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (800 mg, 2.18 mmol) in DMF (3 mL) at room temperature was added K2CO3 (905 mg, 6.56 mmol) and the resulting mixture was stirred at 40 °C for 2 h. The reaction mixture was cooled to 0 °C and MeI (774 mg, 5.45 mmol) was added dropwise. The resulting mixture was stirred at room temperature for a further 2 h and then poured into ice water. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give the desired product (500 mg, 60% yield) as a yellow solid. MS: m / z 381 [M+H] + .

[0233] Step 5: 7-Fluoro-1-isopropyl-3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

Chem.

[0234] Example 19 8-(6-(3-(Dimethylamino)propoxy)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

Chem.

[0235] The title compound was prepared using the same procedure as in Example 18. MS: 481 [M+H] + . 1 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 8.27 (d, J = 7.4 Hz, 1H), 8.18 (d, J = 11.2 Hz, 1H), 7.93 (dt, J = 8.7, 2.3 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 5.02 (s, 1H), 4.52 (t, J = 5.9 Hz, 2H), 4.24 (dd, J = 11.9, 4.9 Hz, 2H), 3.78 (s, 3H), 3.60 (dd, J = 12.9, 10.8 Hz, 2H), 3.13 (s, 2H), 2.77 (m, 8H), 2.38 (s, 2H), 1.98 - 1.91 (m, 2H).

[0236] Example 20 7-Fluoro-3-methyl-8-(6-(3-(pyrrolidin-1-yl)propoxy)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

Chem.

[0237] Example 21 8-(6-(3-((Dimethylamino)methyl)pyrrolidin-1-yl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

Chem.

[0238] The title compound was prepared using the same procedure as in Example 18. MS: m / z 506 [M + H] + . 11H NMR (400 MHz, CDCl3) δ 8.49 (t, J = 1.8 Hz, 1H), 8.19 (d, J = 7.5 Hz, 1H), 8.11 (d, J = 11.4 Hz, 1H), 7.80 (dt, J = 8.9, 2.4 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H), 4.99 (s, 1H), 4.24 (dd, J = 11.8, 4.8 Hz, 2H), 3.76 (s, 5H), 3.63 - 3.50 (m, 3H), 3.27 (dd, J = 10.4, 7.2 Hz, 1H), 2.83 (d, J = 14.1 Hz, 2H), 2.61 (p, J = 7.4 Hz, 1H), 2.46 (s, 1H), 2.35 (s, 6H), 2.29 - 2.18 (m, 1H), 1.94 - 1.89 (m, 2H), 1.85 - 1.80 (m, 2H).

[0239] Example 22 8-(6-(4-(Dimethylamino)piperidin-1-yl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

Chem.

[0240] Example 23 8-(6-((2-(Dimethylamino)ethoxy)methyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

Chem.

[0241] Example 24 7-Fluoro-8-(6-(3-(4-fluoropiperidin-1-yl)propoxy)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one The compound of Example 24 was prepared according to the synthetic route shown in Scheme 7.

Chemical formula

[0242] Step 1: 7-Fluoro-3-methyl-8-(6-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (G1) To a stirred solution of 5-bromo-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridine (200 mg, 0.635 mmol), B2Pin2 (194 mg, 0.76 mmol), and KOAc (187 mg, 1.9 mmol) in dioxane (5 mL) at room temperature under nitrogen, Pd(dppf)Cl2·CH2Cl2 (52 mg, 0.064 mmol) was added. The resulting mixture was stirred at 100 °C under N2 protection for 16 h. After cooling the reaction, 8-bromo-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one (241 mg, 0.635 mmol), Pd(dppf)Cl2·CH2Cl2 (52 mg, 0.064 mmol), Na2CO3 (200 mg, 1.9 mmol), and H2O (1 mL) were added. The resulting mixture was stirred at 100 °C under N2 protection for an additional 4 h and concentrated to dryness. The residue was purified by silica gel column chromatography to give the desired product (320 mg, 94% yield) as a dark solid. MS: 538 [M+H] + 。

[0243] Step 2: 7-Fluoro-8-(6-(3-hydroxypropoxy)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (G2) [Chemical formula] To a stirred solution of 7-fluoro-3-methyl-8-(6-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (360 mg, 0.67 mmol) in DCM / MeOH (3 mL / 3 mL) at room temperature was added PTSA (255 mg, 1.34 mmol). The resulting mixture was stirred at room temperature for 4 h and diluted with DCM (20 mL). The mixture was washed with aqueous NaHCO3, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the desired product (220 mg, 72% yield), which was used in the next step without further purification. MS: 454 [M+H] + .

[0244] Step 3: 3-((5-(7-Fluoro-3-methyl-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-8-yl)pyridin-2-yl)oxy)propyl methanesulfonate (G3) [Chemical formula] To a solution of 7-fluoro-8-(6-(3-hydroxypropoxy)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (220 mg, 0.49 mmol) and triethylamine (150 mg, 1.47 mmol) in DCM (3 mL) was added MsCl (112 mg, 0.97 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h and diluted with DCM (15 mL). The organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product (340 mg, yield 100%), which was used in the next step without further purification. MS: 532 [M+H] + 。

[0245] Step 4: 7-Fluoro-8-(6-(3-(4-fluoropiperidin-1-yl)propoxy)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one

Chemical formula

[0246] Example 25 (R)-7-Fluoro-8-(6-(3-(3-fluoropyrrolidin-1-yl)propoxy)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one [Chemical Structure] This substance was synthesized from (R)-3-fluoropyrrolidine using the same procedure as in Example 24, and the desired product (yield 14%) was obtained as a yellow solid. MS: 525 [M + H] + . 1 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.14 (d, J = 11.8 Hz, 1H), 7.98 (s, 1H), 7.74 (d, J = 9.6 Hz, 1H), 6.72 (d, J = 9.6 Hz, 1H), 5.21 - 5.07 (m, 2H), 4.29 - 4.14 (m, 4H), 3.78 (s, 3H), 3.63 (t, J = 12.0 Hz, 2H), 2.98 - 2.89 (m, 2H), 2.78 - 2.62 (m, 4H), 2.18 - 1.87 (m, 8H).

[0247] Example 26 Biological assay The potency of the compounds of the present disclosure can be measured by several pharmacological assays known in the art. The pharmacological assays exemplified below were performed using the compounds of the present disclosure and the reference compound 8-[6-(3-dimethylamino-propoxy)-pyridin-3-yl]-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]cinnolin-2(3H)-one (Reference Compound 1): a) ATM biochemical potency assay; b) PI3K biochemical potency assay; c) mTOR biochemical potency assay; d) ATR biochemical potency assay, and e) ATM SN-38 HT-29 cell potency assay. In the description of these assays, the following is usually the case: i. The following abbreviations were used: 4NQO = 4-nitroquinoline N-oxide; Ab = antibody; BSA = bovine serum albumin; CO2 = 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; HRP = horseradish peroxidase; i.p. = 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 the electron coupling reagent (phenazine methosulfate) PMS; s.c. = subcutaneous. ii. IC 50 values were calculated using the Smart Fitting Model from GeneData. This IC 50 value was defined as the concentration of the test compound that inhibited 50% of the biological activity.

[0248] Measurement method a): ATM biochemical potency The ATM (Millipore, catalog number 14 - 933) enzyme solution was prepared in 1× kinase-based buffer. 10 μl of the 2× enzyme solution was transferred to each well of a 384-well assay plate containing 100 nl of the compound added by Echo. The plate was incubated at room temperature for 10 minutes. A 2× peptide solution was prepared using a peptide labeled with FAM and ATP in 1× kinase-based buffer (final concentration: 1.5 nM). 10 μl of the 2× peptide solution was added to each well of the 384-well assay plate, and after incubating the plate at 37 °C for 210 minutes, 40 μl of stop buffer was added to stop the reaction. Data was collected using calipers.

[0249] Measurement method b): ATR biochemical potency The ATR enzyme was manufactured by ChemPartner (batch: CP-ATR-20161102-M2). A 2× enzyme solution was prepared in 1× kinase-based buffer. 10 μl of the 2× enzyme solution (final concentration: 2.5 nM) was added to each well of a 384-well assay plate containing 60 nl of the compound in each well. This plate was incubated at room temperature for 10 minutes. A 2× peptide solution was prepared using a peptide labeled with FAM and ATP in 1× kinase-based buffer. 10 μl of the 2× peptide solution was added to each well of the 384-well assay plate, and this plate was incubated at 28 °C for 240 minutes. 40 μl of stop buffer was added to stop the reaction. Data was collected using calipers.

[0250] Measurement method c): PI3K biochemical potency PI3Kα enzyme (Invitrogen, catalog number PV4788), PIK3Cδ enzyme (Invitrogen, catalog number PV6452), PIK3Cβ enzyme (Millipore, catalog number 14-603-K), PIK3Cγ enzyme (Invitrogen, catalog number PR8641C), PI3Kα (p110α / p85a) kinase reaction solution, PIK3Cδ kinase reaction solution, PIK3Cβ (p110β) kinase reaction solution, and PIK3Cγ (pp110γ) kinase reaction solution were prepared in 1× kinase buffer at 4 times the final concentration of each reagent in the assay method (final concentration: PI3Kα: 0.7 nM, PIK3Cδ: 3 nM, PIK3Cβ: 4.8 nM, PIK3Cγ: 11 nM). 2.5 μl of the kinase solution was added to each well of a 384-well assay plate, and each well contained 2.5 μl of the compound at serially diluted concentrations. A 2× substrate solution was prepared using PIP2 substrate and ATP in 1× kinase reaction buffer so that the final concentration of each reagent in the assay method was doubled. 5 μl of the substrate solution was added to each well of the assay plate to initiate the reaction. The assay plate was incubated at room temperature for 1 hour. 5 μl of the reaction mixture was transferred to a new 384-well plate. 5 μl of the ADP-Glo reagent (Promega, catalog number v9102 / 3, lot number 0000176563) was added to each well of the new assay plate to stop the reaction. The plate was gently shaken for 40 minutes for equilibration. 10 μl of the kinase detection reagent was added to each well, and after equilibration for 60 minutes, the luminescence was read using a plate reader (Envision).

[0251] Measurement method d): mTOR biochemical potency A solution of mTOR enzyme (Millipore, catalog number 14 - 770, lot number 2052551) was prepared in 1× kinase buffer at 4 times the final concentration (final concentration: 6 nM) in the assay. 2.5 μl of the kinase solution was added to each well of a 384 - well assay plate, and each well was made to contain 2.5 μl of the compound at serially diluted concentrations. A 2× substrate solution was prepared using ULight - 4E - BP1 (Thr37 / 46) peptide (PE, catalog number TRF0128 - M, lot number 1695274) and ATP in 1× kinase reaction buffer such that it was 2 times the final concentration of each reagent in the assay. 5 μl of the substrate solution was added to each well of the assay plate to initiate the reaction. The assay plate was incubated at room temperature for 30 minutes. A detection solution of kinase - stopping buffer (EDTA) and Eu - anti - phospho - 4E - BP1 antibody (Thr37 / 46) (PE, catalog number TRF0216 - M, lot number 1571838) was prepared in Lance detection buffer at 2 times the desired final concentration of each reagent. 10 μl of the detection buffer solution was added to each well of the assay plate. After equilibrating the assay plate at room temperature for 60 minutes, it was read using a plate reader (Lance signal (665 nm) of the Envision program).

[0252] Measurement method e): ATM SN-38 BT-29 cell potency Principle: SN38 is an active metabolite of irinotecan and acts as a topoisomerase I inhibitor. SN38 causes single - strand DNA breaks (SSBs), which are converted to double - strand breaks (DSBs) during replication. ATM is responsible for repairing DSBs. The inhibition of ATM was evaluated by a high - content imaging system in HT - 29 cells (ATCC, catalog number HTB - 38) treated with SN38.

[0253] Details of the experiment: HT-29 cells were trypsinized, and approximately 10,000 cells per well were seeded into 96-well microplates and incubated overnight at 37°C in 5% CO2. The test compound was added to the 96-well plates and incubated at 37°C in 5% CO2 for 1 hour. Then, SN38 (MCE, catalog number HY-13704) was added to this 96-well plate at a final concentration of 30 nM and incubated at 37°C in 5% CO2 for 1 hour. After removing the medium, the cells were fixed by the addition of 50 μl of 3.7% formaldehyde / PBSA and incubated at room temperature for 20 minutes. After rinsing the plates three times with PBSA, 50 μl of permeabilization buffer (0.1% Triton-X100 / PBSA) was added and the plates were incubated at room temperature for 20 minutes. After rinsing the plates once with PBSA, 50 μl of primary antibody solution was added and the plates were incubated overnight at 4°C. The primary antibody solution was prepared by diluting the anti-phosphorylated ATM (Ser1981) antibody (Merck Millipore, catalog number 05-740) 1 / 10,000 with antibody buffer (3% BSA, 0.05% Tween / PBSA). The plates were rinsed three times with PBST (0.05% Tween / PBSA). 50 μl of secondary antibody solution was added to the plates and incubated at room temperature for 1 hour in the dark. This secondary antibody solution was prepared by diluting the secondary antibody (goat anti-mouse IgG (H+L) cross-adsorbed secondary antibody, Alexa Fluor 488, Invitrogen, catalog number A11001) 1 / 500 and Hoechst 1 / 10,000 with antibody buffer. After rinsing the plates three times with PBST, 100 μl of PBSA was added to each well. The plates were sealed with black plate seals.

[0254]

Table 5

[0255]

Table 6

[0256] After image analysis, further statistics were performed using Excel 2013 (Microsoft). Subsequently, a graphical view was created using Prism 7.0 (GraphPad).

[0257] The compounds synthesized in Examples 1 to 45 and Reference Compound 1 were tested by the above-described measurement methods a) to e). For some representative compounds, the IC 50 results are shown in Table 2. From Table 2, it can be seen that the compounds of the present disclosure not only exhibit very good ATM kinase inhibition, but also have very high ATM kinase selectivity compared to other kinases of the PIKK family (PI3Kα, PI3Kβ, PI3Kγ, PI3Kδ, mTor, and ATR). For other example compounds for which the results are not shown, the IC 50 against ATM kinase was 1000 nM or less. For some of these compounds, the IC 50 against ATM kinase was 500 nM or less, some were 400 nM or less, some were 300 nM or less, some were 200 nM or less, or 100 nM or less, or 50 nM or less. In addition, for some of the example compounds for which the results are not shown, the IC 50 against other kinases of the PIKK family (PI3Kα, PI3Kβ, PI3Kγ, PI3Kδ, mTor, and ATR) was greater than 1 μM, and some were greater than 3 μM, greater than 5 μM, greater than 7 μM, or greater than 10 μM.

[0258]

Table 7

[0259] Example 27 DMPK Inhibition Test and hERG Inhibition Test The DMPK inhibition test and hERG inhibition test were performed using the compounds of the present disclosure, as well as Reference Compound 1, Reference Compound 2 (AZD0156), and Reference Compound 3 (AZD1390), using the following measurement methods: f) MDCK-MDR1 Pgp evaluation, g) Caco-2 BCRP evaluation, and h) hERG inhibition evaluation.

[0260] Measurement method f): MDCK-MDR1 Pgp evaluation Using MDCK-MDR1 cells, efflux transport via P-glycoprotein (Pgp) was evaluated. The final concentrations of the test compound and the control compound were 1 μM. The multiwell insert plates were incubated at 37 °C for 2 hours.

[0261] Measurement method g): Caco-2 BCRP evaluation Using Caco-2 cells, a test for efflux transport via BCRP was conducted. The ratio of drug transport by BCRP was determined in the presence and absence of novobiocin, a potent BCRP inhibitor, and novobiocin was added at a final concentration of 30 μM to both the apical and basolateral sides. The final concentrations of the test compound and the control compound were 1 μM. The multiwell insert plates were incubated at 37 °C for 2 hours. When the efflux ratio (-inhibitor / +inhibitor) was greater than 2, it was considered a BCRP substrate.

[0262] Measurement method h): hERG safety evaluation Inhibition of the hERG channel was performed in a HEK293 cell line stably expressing the hERG channel by the manual patch-clamp method.

[0263] The results of representative compounds of the present disclosure and reference compounds 1 to 3 in measurement methods f), g), and h) are shown in Table 3.

[0264]

Table 8

[0265] As can be seen from Table 3, reference compound 2 was found to be a Pgp substrate. Reference compound 3 is not a Pgp substrate but shows significant hERG inhibition. In comparison, the representative compounds of Examples 1 and 3 to 5 are neither Pgp substrates nor BCRP substrates and have been shown to have brain permeability. Furthermore, the compounds of Examples 1 and 3 show a significant improvement in hERG vulnerability compared to reference compound 3.

[0266] For all other example compounds for which results are not shown, they all show DMPK and hERG results similar to those of the exemplary compounds of Example 1 and Examples 3 to 5.

[0267] Example 28 AO activity assay The AO activity assay was performed using the compounds of the present disclosure, as well as reference compounds 2, 3, 4 (zaleplon, a positive control for the AO assay), and 5 (PF-04217903, a weak AO substrate), using the following measurement method i) aldehyde oxidase measurement method.

[0268] Measurement method i): Aldehyde oxidase measurement method The AO activity in human liver cytosol was evaluated. The incubation system included 25 mM phosphate buffer, 1 mg / mL human liver cytosol, and 0.5 μM of the test compound or positive control. The reaction was stopped by adding 5 volumes of cold acetonitrile with the internal standard at the time points of 0.5 minute, 5 minutes, 10 minutes, 20 minutes, 30 minutes, and 60 minutes. The samples were centrifuged at 3,220 g for 30 minutes. The supernatant aliquoted to 100 μL was mixed with 100 μL of ultrapure water and then used for LC / MS / MS analysis.

[0269] All calculations were performed using Microsoft Excel. The peak area was determined from the extracted ion chromatogram. The gradient value k was determined by linear regression of the curve of the natural logarithm of the parent drug residue rate versus the incubation time. The in vitro half-life (in vitro t 1 / 2 ) was determined from the above gradient value using the following formula:

Equation

Equation

[0270] The compounds synthesized in Examples 1 to 25 and Reference Compounds 2 to 4 were tested by measurement method i) as described above. The results of representative compounds of the present disclosure and Reference Compounds 2 to 5 are shown in Table 4.

[0271] [Table 9]

[0272] Reference Compound 2 and Reference Compound 3 are potent AO substrates with intrinsic clearance values of 4.65 and 7.2 μL / min / mg protein, respectively, and have been shown to be higher than the intrinsic clearance value of Reference Compound 4 (3.1 μL / min / mg protein). Reference Compound 4 showed a high clearance value in humans at 16 mL / min / kg, which corresponds to approximately 80% of hepatic blood flow (Zientek, M. et al., Drug Metab Dispos, 2010, pages 1322 - 7). In contrast, the compounds of the present disclosure showed lower intrinsic clearance values than the intrinsic clearance value of Reference Compound 5 (1.8 μL / min / mg protein). Reference Compound 5 showed low to moderate clearance values in humans at 6 mL / min / kg, which corresponds to approximately 30% of hepatic blood flow. This indicates that the compounds of the present disclosure are not AO substrates.

[0273] For the other Example compounds for which results are not shown, all showed intrinsic clearances of 2 μL / min / mg protein or less, 1.8 μL / min / mg protein or less, 1.6 μL / min / mg protein or less, 1.4 μL / min / mg protein or less, 1.2 μL / min / mg protein or less, 1 μL / min / mg protein or less, 0.9 μL / min / mg protein or less, 0.8 μL / min / mg protein or less, 0.7 μL / min / mg protein or less, 0.6 μL / min / mg protein or less, or 0.5 μL / min / mg protein or less.

[0274] The above description should be regarded as merely illustrative of the principles of the present disclosure. Further, since many modifications and variations will be readily apparent to those skilled in the art, it is not desired to limit the invention to the exact construction and methods shown above. Accordingly, all suitable modifications and equivalents can be considered to be included within the scope of the invention as defined by the following claims.

[0275] The words "comprise", "comprising", "include", "including", and "includes", as used in this specification and the following claims, are intended to specify the presence of the stated features, integers, components, or steps, but do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

Claims

1. A compound of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof (wherein R １ is hydrogen or methyl; R ２ is tetrahydropyranyl; R ３ is fluoro; R ４ , R ５ and R ６ is independently selected from hydrogen or fluoro, respectively; R ７ is -L-NR ８ R ９ wherein L is a direct bond, -(CH ２ ) ｍ O(CH ２ ) ｎ -, or -CONR １０ (CH ２ ) ｐ -, and the -(CH ２ ) ｍ O(CH ２ ) ｎ - and the -CONR １０ (CH ２ ) ｐ - may be optionally substituted by one or more R １１ ; R ８ and R ９ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, saturated or unsaturated cycloalkyl, and saturated or unsaturated heterocyclic groups, and said alkyl, alkenyl, alkynyl, saturated or unsaturated cycloalkyl, and saturated or unsaturated heterocyclic groups may optionally be substituted by one or more R １２ ; or, R ８ and R ９ may, together with the nitrogen atom to which they are attached, contain one or more additional heteroatoms selected from N, O, and S, and, optionally, one or more R １３ may form a saturated or unsaturated heterocyclic group which may be substituted by; R １０ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and a carbon-bonded saturated or unsaturated heterocyclic group, said heterocyclic group may optionally contain one or more additional heteroatoms selected from N, O, and S, and optionally one or more R １３ may be substituted by; R １１ is selected from the group consisting of saturated or unsaturated heterocyclic groups which may contain hydrogen, halogen, alkyl, cycloalkyl, alkoxyl, and optionally one or more additional heteroatoms selected from N, O, and S, and which may optionally be substituted by one or more R １３ ; R １２ is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, alkyl, alkenyl, alkynyl, and alkoxy; R １３ is selected from the group consisting of acyl, alkyl, alkenyl, alkynyl, alkoxy, amide, amino, aryl, cyano, cycloalkyl, halogen, haloalkyl, haloalkoxy, heteroaryl, hydroxy, nitro, and -(CH ２ ), ｑ NR １４ R １５ ; R １４ and R １５ are each independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl; or R １４ and R １５ may, together with the nitrogen atom to which they are attached, contain one or more additional heteroatoms selected from N, O, and S, and, in some cases, one or more R １６ form a saturated or unsaturated heterocyclic group which may be substituted by; R １６ is selected from the group consisting of acyl, alkyl, alkenyl, alkynyl, alkoxy, amide, amino, aryl, cyano, cycloalkyl, halogen, haloalkyl, haloalkoxy, heteroaryl, hydroxy, and nitro; m is 0, 1, or 2; n is an integer in the range of 2 to 4; p is an integer in the range of 2 to 4; and q is 0, 1, or 2).

2. R １ The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is methyl.

3. R ４ 、R ５ 、and R ６ is hydrogen, a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R ７ is -L-NR ８ R ９ The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is -L-NR and L is a direct bond.

5. R ８ and R ９ are each independently selected from C １２ alkyl which may optionally be substituted by one or more R １－６ groups, a compound of formula (I) according to claim 4 or a pharmaceutically acceptable salt thereof.

6. R ８ and R ９ together with the nitrogen atom to which they are attached: 【Chemical 2】 is formed, and any of these may optionally be substituted by one or more R １３ wherein x is 1, 2, 3 or 4; y is 0, 1 or 2; and z is 0, 1 or 2, a compound of formula (I) according to claim 4 or a pharmaceutically acceptable salt thereof.

7. R １３ The compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt thereof, wherein R is halogen.

8. R ７ is - L - NR ８ R ９ wherein, L is a direct bond, and R ８ and R ９ together with the nitrogen atom to which they are attached [Chemical Formula 3] is formed, and any of these may optionally be substituted by one or more R １３ wherein x is 1, 2, 3 or 4; y is 0, 1 or 2; and z is 0, 1 or 2, a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

9. R １３ is -(CH ２ ) ｑ NR １４ R １５ and R １４ and R １５ are each independently selected from C １－６ alkyl, a compound of formula (I) according to claim 8 or a pharmaceutically acceptable salt thereof.

10. R ７ is - L - NR ８ R ９ where L is - CONR １０ (CH ２ ) ｐ - and R ８ and R ９ may in some cases be independently selected from C １２ alkyl optionally substituted by one or more R １－６ and R １０ is hydrogen, a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

11. 7-Fluoro-3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 7-Fluoro-3-methyl-8-(6-(3-(pyrrolidin-1-yl)propoxy)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 8-(6-(3-((dimethylamino)methyl)pyrrolidin-1-yl)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-(4-(dimethylamino)piperidin-1-yl)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-(dimethylamino)ethoxy)methyl)pyridin-3-yl)-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; 7-Fluoro-8-(6-(3-(4-fluoropiperidin-1-yl)propoxy)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one; and (R)-7-Fluoro-8-(6-(3-(3-fluoropyrrolidin-1-yl)propoxy)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of

12. The compound of formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, having an AO intrinsic clearance value of less than 1.8 μL / min per mg of protein in human hepatic cytosolic system.

13. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

14. The pharmaceutical composition according to claim 13, which does not contain an agent for promoting blood-brain barrier (BBB) translocation.

15. The pharmaceutical composition according to claim 13 or 14, further comprising at least one additional anti-tumor drug selected from the group consisting of doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, and bleomycin.

16. Use of the compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of an ATM-related disease or condition in a subject in need thereof.

17. The use according to claim 16, wherein the ATM-related disease or condition is cancer.

18. The use according to claim 17, wherein 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.

19. The use according to claim 17, wherein the cancer is metastatic cancer such as brain metastasis.

20. The use according to claim 16, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject simultaneously with, individually, or sequentially to radiotherapy.

21. The use according to claim 20, wherein the radiotherapy is brain irradiation.

22. Use according to claim 20 or 21, wherein the ATM-related disease or symptom is cancer, preferably glioblastoma. **Claim 23** Use according to claim 16, wherein the compound of formula (I) is administered to the subject simultaneously, individually, 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. **Claim 24** Use of a compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of Huntington's disease in a subject in need thereof. **Claim 25** Use according to claim 16 or 24, wherein the compound is capable of crossing the blood-brain barrier (BBB) in the absence of an agent for promoting blood-brain barrier (BBB) crossing.

Images