Fluoroalkoxyalkylene-dihydroimidazo[5,1-D]tetradinone compounds and related compounds, and their use in the treatment of medical conditions

Abstract

The present invention provides fluoroalkoxyalkylenedihydroimidazo[5,1-d]tetradinone compounds and related compounds, pharmaceutical compositions, and their use in the treatment of cancer.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits and priority of U.S. Provisional Patent Application No. 63 / 517,715, filed on 4 August 2023, and U.S. Provisional Patent Application No. 63 / 544,054, filed on 13 October 2023, the respective applications whose entire contents are incorporated herein by reference.

[0002] Research and development funded by the federal government This invention was made with government support under grant number R44CA271994, granted by the National Cancer Institute, which is part of the National Institutes of Health. The government has certain rights to this invention.

[0003] The present invention provides fluoroalkoxyalkylenedihydroimidazo[5,1-d]tetradinone compounds and related compounds, pharmaceutical compositions, and their use in the treatment of cancer. [Background technology]

[0004] Cancer remains a significant health problem despite substantial research efforts and scientific advancements reported in the literature for treating the disease. Solid tumors such as prostate cancer, colon cancer, rectal cancer, skin cancer, breast cancer, and lung cancer remain very prevalent in the world population. Existing treatments for cancer include local therapies, such as surgery, radiation therapy, and cryotherapy, used alone or in combination, and systemic therapies (e.g., chemotherapy, hormone therapy, immunotherapy, and targeted therapy). Supportive care is also used in some situations; supportive care is additional treatment used to reduce side effects and address the patient's quality of life, rather than directly treating cancer. However, current cancer treatment options are not effective for all patients and / or may have substantially harmful side effects. New therapies are needed to address this unmet need in cancer treatment.

[0005] Certain imidazotetradinone compounds are described in the international patent applications International Publication No. 2023 / 049806 and International Publication No. 2009 / 077741, U.S. Patent No. 5,266,291, and Moody et al. Pharmaceuticals (2014) vol. 7, pages 797-838. Temozolomide, described in U.S. Patent No. 5,266,291, is marketed for the treatment of newly diagnosed glioblastoma multiforme and refractory anaplastic astrocytoma in patients who have experienced disease progression with drug regimens containing nitrosourea and procarbazine. Further novel compounds are needed to provide therapies with superior efficacy and / or reduced adverse side effects. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] International Publication No. 2023 / 049806 [Patent Document 2] International Publication No. 2009 / 077741 [Patent Document 3] U.S. Patent No. 5,266,291 [Non-patent literature]

[0007] [Non-Patent Document 1] This is described in Moody et al. Pharmaceuticals (2014) vol.7, pages 797-838. [Overview of the project] [Problems that the invention aims to solve]

[0008] Therefore, there is a need for new compounds and therapeutic methods to treat cancer. This invention addresses the aforementioned needs and also provides other relevant advantages. [Means for solving the problem]

[0009] The present invention provides fluoroalkoxyalkylenedihydroimidazo[5,1-d]tetradinone compounds and related compounds, pharmaceutical compositions, and their use in the treatment of cancer. In particular, one aspect of the present invention relates to a set of fluoroalkoxyalkylenedihydroimidazo[5,1-d]tetradinone compounds, for example, compounds represented by formula I: [ka] or provides a pharmaceutically acceptable salt thereof (wherein the formula, the variable elements are as defined in the detailed description). In a more specific embodiment, the compound of formula I is the compound represented by formula IA: [ka] or a pharmaceutically acceptable salt thereof (wherein the formula, the variable elements are as defined in the detailed description).

[0010] Another aspect of the present invention is a set of fluoroalkoxyalkylenedihydroimidazo[5,1-d]tetradinone compounds, for example, compounds represented by formula I-aa: [ka] The present invention provides either a pharmaceutically acceptable salt thereof (wherein the formula, the variable elements are as defined in the detailed description).

[0011] Another aspect of the present invention is a collection of fluoroalkoxyalkylenedihydroimidazo[5,1-d]tetradinone compounds, for example, compounds represented by formula II: [ka] The present invention provides either a pharmaceutically acceptable salt thereof (wherein the formula, the variable elements are as defined in the detailed description).

[0012] Another aspect of the present invention is a set of fluoroalkoxyalkylene imidazotriazene compounds, for example, compounds represented by formula IIIa or formula IIIb: [ka] The present invention provides either a pharmaceutically acceptable salt thereof (wherein the formula, the variable elements are as defined in the detailed description).

[0013] Another aspect of the present invention is a set of fluoroalkoxyalkylene nitrosourea compounds, for example, compounds represented by formula IV: [ka] The present invention provides either a pharmaceutically acceptable salt thereof (wherein the formula, the variable elements are as defined in the detailed description).

[0014] Another aspect of the present invention is a set of fluoroalkoxyalkylenehydrazine compounds, for example, compounds represented by formula V: [ka] The present invention provides either a pharmaceutically acceptable salt thereof (wherein the formula, the variable elements are as defined in the detailed description).

[0015] A further description of a further set of fluoroalkoxyalkylenedihydroimidazo[5,1-d]tetradinone and related compounds is provided in the detailed description. All of the aforementioned compounds may be part of a pharmaceutical composition containing a pharmaceutically acceptable carrier.

[0016] Another aspect of the present invention provides a method for treating cancer. The method, as further described in the detailed description, involves treating cancer by administering a therapeutically effective amount of a compound described herein, for example, a compound of formula I, IA, I-aa, II, III, IV, or V, to a subject in need. In a particular embodiment, the cancer is MGMT deficiency.

[0017] Another aspect of the present invention provides a method for inducing DNA damage in a subject. This method involves administering an effective amount of a compound described herein, for example, a compound of formula I, IA, I-aa, II, III, IV, or V, to a subject to induce DNA damage in the subject, as will be further described in the detailed description. In a particular embodiment, the subject has cancer.

[0018] Another aspect is a method for treating MGMT-deficient cancer in a patient, wherein the MGMT-deficient cancer cells of the patient in need are 2-(C 1~4 The present invention provides a method for treating MGMT-deficient cancer, comprising exposure to fluoroalkoxy)ethane-1-diazonium.

[0019] Another embodiment provides a method for treating MGMT-deficient cancer in a patient, comprising exposing the MGMT-deficient cancer cells of the patient in need of treatment to 2-(trifluoromethoxy)ethane-1-diazonium, thereby providing a method for treating MGMT-deficient cancer.

[0020] Another embodiment provides a method for treating MGMT-deficient cancer in a patient, comprising forming 2-(trifluoromethoxy)ethane-1-diazonium in MGMT-deficient cancer cells of a patient requiring treatment, thereby providing a method for treating MGMT-deficient cancer.

[0021] Another aspect is a method for treating MGMT-deficient cancer in a patient, wherein 2-(C) is used in the MGMT-deficient cancer cells of the patient in need. 1~4 The present invention provides a method for treating MGMT-deficient cancer, comprising forming a fluoroalkoxy)ethane-1-DNA adduct.

[0022] Another embodiment provides a method for treating MGMT-deficient cancer in a patient, comprising forming a 2-(trifluoromethoxy)ethane-1-DNA adduct in the MGMT-deficient cancer cells of the patient in need thereof, thereby providing a method for treating MGMT-deficient cancer.

[0023] Another embodiment provides a method for treating MGMT-deficient cancer in a patient, comprising exposing DNA to 2-(trifluoromethoxy)ethane-1-diazonium to form 2-(trifluoromethoxy)ethane-1-DNA adducts in the MGMT-deficient cancer cells of a patient requiring it, thereby providing a method for treating MGMT-deficient cancer.

[0024] Another embodiment provides a method for forming 2-(trifluoromethoxy)ethane-1-DNA adducts in cancer cells, comprising exposing DNA in cancer cells to 2-(trifluoromethoxy)ethane-1-diazonium.

[0025] Another embodiment provides a method for treating MGMT-deficient cancer in a patient, comprising administering a compound comprising a 2-(trifluoromethoxy)ethanyl group to a patient in need thereof, thereby providing a method for treating the patient, wherein the compound is converted in vivo to 2-(trifluoromethoxy)ethane-1-diazonium.

[0026] Another embodiment provides a method for forming a 2-(trifluoromethoxy)ethane-1-DNA adduct, comprising exposing DNA to a compound containing a 2-(trifluoromethoxy)ethanyl group, thereby providing a method for forming a 2-(trifluoromethoxy)ethane-1-DNA adduct, wherein the compound is converted in vivo to 2-(trifluoromethoxy)ethane-1-diazonium.

[0027] Another embodiment provides a method for forming a 2-(trifluoromethoxy)ethane-1-DNA adduct, comprising exposing DNA to 2-(trifluoromethoxy)ethane-1-diazonium, thereby providing a method for forming a 2-(trifluoromethoxy)ethane-1-DNA adduct. In a particular embodiment, the method comprises exposing the DNA of a cancer patient to 2-(trifluoromethoxy)ethane-1-diazonium. In a particular embodiment, the cancer patient has MGMT-deficient cancer.

[0028] Another embodiment is one or more [ka] The present invention provides a DNA adduct containing covalently bonded DNA in the presence of 1 to 10 [ka] The presence of covalently bonded DNA is included. [Modes for carrying out the invention]

[0029] This invention provides fluoroalkoxyalkylenedihydroimidazo[5,1-d]tetradinone compounds and related compounds, pharmaceutical compositions, and their use in the treatment of cancer. The compounds described herein offer advantages over compounds described in the literature. For example, the literature compound 3-(2-fluoroethyl)-N-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (referred to as compound A1; structure shown below) has been found to have lethal toxic adverse events in animal model studies. For example, compound A1 resulted in 100% death in rats when administered at a dose of 10 mg / kg. Compound A1 also resulted in 100% death in dogs when administered at a dose of 2 mg / kg. [ka]

[0030] While we do not wish to be bound by theory, it has been found that the fluoroethyl component of compound A1 causes lethal toxic adverse side effects. In contrast, compound I-1 described herein has been tested in rats and dogs, and no adverse clinical signs were observed at test doses exceeding the dose at which compound A1 caused the aforementioned 100% mortality.

[0031] Another exemplary advantage of the compounds described herein is their superior potency in inducing cancer cell death. For example, compound I-1 showed high potency in killing LN229 glioblastoma cells engineered to be MGMT-negative / MMR-positive, and high potency in killing LN229 glioblastoma cells engineered to be MGMT-negative / MMR-negative. In both cases, compound I-1 had an IC50 of less than 20 μM in the assay for inducing the death of the above LN229 glioblastoma cells. 50 This compound possessed the following properties. This high potency is in contrast to compound A2 (structure shown below), which did not exhibit detectable anticancer activity against the LN229 isogenic cell line set, even when used at concentrations up to 200 μM. This result demonstrates the superior anticancer effect of compound I-1 compared to compound A2. [ka]

[0032] The implementation of the present invention will utilize conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology, unless otherwise specified. Such techniques are described in the literature, for example, “Comprehensive Organic Synthesis” (BMTrost & I. Fleming, eds., 1991–1992); “Handbook of experimental immunology” (DMWeir & C.C. Blackwell, eds.); “Current protocols in molecular biology” (FMAusubel et al., eds., 1987, and periodic updates); and “Current protocols in immunology” (JEColigan et al., eds., 1991), each of which is incorporated herein by reference in its entirety.

[0033] Various aspects of the present invention are shown in the following sections, but an aspect of the present invention described in one particular section is not limited to any particular section. Furthermore, if a variable element is not accompanied by a definition, the definition preceding the variable element prevails.

[0034] definition The compounds of the present invention include those generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. Where used herein, unless otherwise specified, the following definitions shall apply. Unless otherwise specified, these definitions shall apply whether the terms are used alone or in combination with other terms. Accordingly, the definition of "alkyl" applies to "alkyl" and "alkyl" parts such as "-O-alkyl". For the purposes of the present invention, chemical elements are as defined in Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. th The general principles of organic chemistry are identified according to the ed. Furthermore, the entire content of which is incorporated herein by reference is "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5. th This is listed in Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001.

[0035] As used herein, the terms “aliphatic” or “aliphatic group” mean a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic (also referred to herein as “alicyclic”) and has a single bond with the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 4 aliphatic carbon atoms. In yet another embodiment, an aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet another embodiment, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, “alicyclic” refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic and has a single bond with the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0036] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e., a carbocyclic or heterocyclic structure having saturated or unsaturated units, with one or more atoms common between the two rings of the ring system. Thus, the term includes any acceptable ring condensation, such as ortho-condensations or spirocyclic structures. As used herein, the term “heterobicyclic” is a subset of “bicyclic” structures that require the presence of one or more heteroatoms in one or both rings of the bicyclic structure. Such heteroatoms may be present at the ring junction, may be substituted, and may be selected from nitrogen (including N-oxide), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, the bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system having at least one bridge, i.e., a carbocyclic or heterocyclic, saturated or partially unsaturated ring system. As defined by IUPAC, a “bridge” is an atom or valence bond connecting an unbranched chain of atoms or two bridgeheads, and a “bridgehead” is any skeletal atom of a ring system bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups shown below, each of which is bonded to the rest of the molecule with any substituteable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups may be substituted with one or more substituents shown for aliphatic groups. Additionally or alternatively, any substituteable nitrogen of a bridged bicyclic group may be substituted. Exemplary bicyclic rings include: [ka] These are some examples.

[0037] Examples of crosslinked bicyclic compounds include: [Chemical] include.

[0038] The term "lower alkyl" refers to a straight-chain or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. 1~4 The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon, any quaternized form of any basic nitrogen, or a replaceable nitrogen of a heterocyclic ring, such as, for example, N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR

[0039] (as in N-substituted pyrrolidinyl)). + include).

[0040] As used herein, the term "unsaturated" means that the moiety has one or more unsaturated units.

[0041] As used herein, the term "saturated or unsaturated, straight-chain or branched hydrocarbon chain of divalent C 1~8 (or C 1~6 )" refers to a divalent alkylene, alkenylene, and alkynylene chain that is straight-chain or branched as defined herein.

[0042] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -(where n is a positive integer, preferably 1-6, 1-4, 1-3, 1-2, or 2-3). A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are substituted with substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0043] The term deuteroalkylene refers to an alkylene group substituted with at least one deuterium (D). In certain embodiments, a deuteroalkylene contains one, two, three, or four deuterium (D). In certain embodiments, a deuteroalkylene contains two or three deuterium (D). In certain embodiments, a deuteroalkylene contains four deuterium (D). A deuterium-enriched compound is characterized by having a greater amount of deuterium than a naturally occurring compound or a synthetic compound prepared from a substrate having a naturally occurring isotopic distribution. A threshold amount for deuterium enrichment is specified in certain examples of this disclosure, and all percentages given for the amount of deuterium present are molar percentages. Deuterium ( 2 H) is, 1 Hydrogen is a stable, non-radioactive isotope of hydrogen, with an atomic weight of 2.014. 1 H hydrogen (i.e., protium), deuterium ( 2 H), and tritium ( 3 It exists naturally as a mixture of H. The natural abundance of deuterium is 0.015%. As those skilled in the art will know, in all chemical compounds containing H atoms, the H atoms are actually 1 H hydrogen, deuterium ( 2 H), and tritium ( 3 It is recognized that a mixture of H) contains approximately 0.015% deuterium. Therefore, compounds with deuterium levels concentrated to a greater extent than their natural abundance of 0.015% are considered unnatural and, consequently, novel to their unconcentrated counterparts.

[0044] Unless otherwise specified, where D is specifically listed or represented in an equation, D represents a mixture of hydrogen and deuterium in which the amount of deuterium is approximately 100% (i.e., the abundance of deuterium is in the range of at least 90% to a maximum of 100%). In certain embodiments, the abundance of deuterium in D is 95% to 100%, or 97% to 100%. In certain embodiments, the abundance of deuterium in D is at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.

[0045] The term "-(C0 alkylene)-" refers to a bond. Therefore, "-(C 0~3 The term "alkylene)-" refers to the bond (i.e., C0) and -(C 1~3 It includes an alkylene group.

[0046] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond, in which one or more hydrogen atoms are substituted by substituents. Suitable substituents include the substituted aliphatic groups listed below.

[0047] The term "halogen" refers to F, Cl, Br, or I.

[0048] The term “aryl,” used alone or as part of a larger phrase such as “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, where at least one ring in the ring system is aromatic, and each ring in the ring system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system, including but not limited to phenyl, biphenyl, naphthyl, anthracyl, which may have one or more substituents. Groups in which an aromatic ring is condensed with one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenantridinyl, or tetrahydronaphthyl, are also included in the scope of the term “aryl” as used herein.

[0049] The terms "heteroaryl" and "heteroaryl," used alone or as part of a larger term such as "heteroaryl" or "heteroarylcoxy," refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; sharing 6, 10, or 14 π electrons within the ring array; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, including any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthilidinyl, and pteridinyl. As used herein, the terms “heteroaryl” and “heteroar-” also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and unless otherwise specified, the bonding group or bond is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxadinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl groups may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which may include a substituted ring. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl moieties may be substituted independently.

[0050] As used herein, the terms “heterocyclic,” “heterocyclyl,” “heterocyclic group,” and “heterocyclic ring” are used interchangeably and refer to a stable 5-7 member monocyclic or 7-10 member bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has one or more, preferably 1-4, heteroatoms as defined above, in addition to carbon atoms. As used in relation to the ring atoms of a heterocyclic ring, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (as in the case of 3,4-dihydro-2H-pyrrolyl), NH (as in the case of pyrrolidinyl), or + It can be NR (as in the case of N-substituted pyrrolidinyl).

[0051] Heterocyclic rings can be bonded to their pendant group with any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms may be substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms “heterocyclic,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic group” are used interchangeably herein and also include groups in which the heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenantridinyl, or tetrahydroquinolinyl. The heterocyclyl group may be monocyclic or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted with a heterocyclyl, and the alkyl moiety and heterocyclyl moiety may be substituted independently. The term “oxo-heterocyclyl” refers to a heterocyclyl substituted with one or more oxo groups. The term “heterocyclylene” refers to a polyvalent heterocyclyl group having a number of empty valencies appropriate to describe the group bonded thereto. For example, a "heterocyclylene" is a divalent heterocyclyl group if it has two groups bonded to it; a "heterocyclylene" is a trivalent heterocyclyl group if it has three groups bonded to it. The term "oxo-heterocyclylene" refers to a polyvalent oxo-heterocyclyl group that has a number of empty valencies appropriate to describe the groups bonded to it.

[0052] As used herein, the term “partially unsaturated” refers to a ring moiety containing at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple unsaturated moies, but not to include aryl or heteroaryl moies as defined herein.

[0053] As described herein, the compounds of the present invention may contain “optionally substituted” moieties. Generally, the term “substituted” means that one or more hydrogens of a specified moiety are replaced with appropriate substituents, whether or not the term “optionally” precedes it. Unless otherwise specified, an “optionally substituted” group may have appropriate substituents at each substitutedable position of the group, and the substituents may be the same or different at all positions if two or more positions in any given structure can be replaced with two or more substituents selected from the specified group. The substituent combinations envisioned by the present invention preferably result in the formation of stable or chemically feasible compounds. As used herein, “stable” means a compound that does not substantially change when subjected to conditions that enable their generation, detection, and, in certain embodiments, their recovery, purification, and use for one or more purposes disclosed herein.

[0054] Each optional substituent on the substituted carbon is a halogen;-(CH2) 0~4 R°;-(CH2) 0~4 OR°;-O(CH2) 0~4 R o ;-O-(CH2) 0~4 C(O)OR°;-(CH2) 0~4 CH(OR°)2;-(CH2) 0~4 SR°;R° may be substituted -(CH2) 0~4 It may be substituted with Ph;R°-(CH2) 0~4 O(CH2) 0~1 It may be substituted with Ph;R° - CH=CHPh;R° - (CH2) 0~4O(CH2) 0~1 -Pyridyl;-NO2;-CN;-N3;-(CH2) 0~4 N(R°)2;-(CH2) 0~4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0~4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0~4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2) 0~4 C(O)R°;-C(S)R°;-(CH2) 0~4 C(O)OR°;-(CH2) 0~4 C(O)SR°;-(CH2) 0~4 C(O)OSiR°3;-(CH2) 0~4 OC(O)R°;-OC(O)(CH2) 0~4 SR-;SC(S)SR°;-(CH2) 0~4 SC(O)R°;-(CH2) 0~4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°;-(CH2) 0~4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0~4 SSR°;-(CH2) 0~4 S(O)2R°;-(CH2) 0~4 S(O)2OR°;-(CH2) 0~4 OS(O)2R°;-S(O)2NR°2;-S(O)(NR°)R°;-S(O)2N=C(NR°2)2;-(CH2) 0~4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;SiR°3;-(C 1~4 (Linear or branched alkylene) ON(R°)2; or -(C 1~4 It is a monovalent substituent independently selected from the linear or branched alkylene (C(O)ON(R°)2).

[0055] Each R° independently corresponds to hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (a 5-6 member heteroaryl ring), or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definition, two independent R°s together with their (one or more) intervening atoms to form a 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted with divalent substituents on the saturated carbon atoms of R° selected from =O and =S; or each R° may be a halogen, -(CH2) 0~2 R ● ,-(HaroR ● ), -(CH2) 0~2 OH, -(CH2) 0~2 Ure ● ,-(CH2) 0~2 CH(OR ● )2, -O(HaroR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● ,-(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● ,-(CH2) 0~2 SR ● ,-(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● ,-(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3, -C(O)SR ● ,-(C 1~4 (Straight-chain or branched alkylene) C(O)OR ● , or -SSR ● It may be substituted with a monovalent substituent selected independently of the given molecule.

[0056] Each R ● C1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or independently selected from 5- to 6-membered saturated, partially unsaturated, or aryl rings having from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each R ● is unsubstituted or, when halo precedes, substituted only with one or more halogens; alternatively, an optional substituent on a saturated carbon is =O, =S, =NNR * 2, =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR * 、-O(C(R * 2)) 2~3 O-, or -S(C(R * 2)) 2-3 S- is a divalent substituent independently selected from, or a divalent substituent bonded to an adjacent substitutable carbon of a "may be substituted" group is -O(CR * 2) 2~3 O-, and each independent occurrence of R* is selected from hydrogen, C 1~6 aliphatic, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​A 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from Ph, nitrogen, oxygen, or sulfur, and each R ● It is either unsubstituted, or, if preceded by a halo, substituted by only one or more halogens.

[0058] Any optional substituent on the substituted nitrogen is independently -R † , -NR † 2, -C(O)R † , -C(O)OR † ,-C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † and; each R † Hydrogen and C are independent of each other. 1~6 An aliphatic, unsubstituted-OPh, or unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or R † The two independent entities, together with their intervening atoms (one or more), form an unsubstituted 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R † C 1~6 If it is aliphatic, R † Halogen, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or may be substituted with -NO2, and each R ● C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1A 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from Ph, nitrogen, oxygen, or sulfur, and each R ● It is either unsubstituted, or, if preceded by a halo, substituted by only one or more halogens.

[0059] As used herein, the term “pharmaceutically acceptable salt” refers to a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and that has a reasonable benefit-risk ratio. pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. pharmaceutically acceptable salts of the compounds of the present invention include those derived from appropriate inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed by using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanesulfonate. Examples include nitrates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, and valersates.

[0060] Furthermore, acids generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, in P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC on their website). These disclosures are incorporated herein by reference.

[0061] Examples of salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1~4 Examples include alkyl)4 salts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate.

[0062] Unless otherwise specified, the structures shown herein mean all isomers (e.g., enantiomers, diastereomers, and geometric (or conformational) forms) of the structure; for example, the R and S configurations of each chiral center, the Z and E double bond isomers, and the Z and E conformational isomers. Thus, single stereochemical isomers of the compound, as well as enantiomers, diastereomers, and geometric (or conformational) mixtures, are within the scope of the invention. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention. The invention includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, substitution of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, including carbon substitution with 1C-enriched carbon, are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention.

[0063] A mixture of diastereomers can be separated into individual diastereomers based on their physicochemical differences by methods known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by the steps of converting the enantiomer mixture into a mixture of diastereomers by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or moscherate), separating the diastereomers, and converting the individual diastereomers into their corresponding pure enantiomers (e.g., by hydrolysis). Alternatively, specific enantiomers of the compounds of the present invention can be prepared by asymmetric synthesis. Furthermore, if the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxylic acid), a diastereomer salt can be formed using a suitable optically active acid or base, and the diastereomers thus formed can be separated by fractional crystallization or chromatographic means known in the art, after which the pure enantiomers can be recovered.

[0064] The individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers, for example, as a racemate or mixed with all other or other selected stereoisomers. The (one or more) chiral centers of the compounds of the present invention may have an S or R configuration as defined by the IUPAC 1974 recommendation. Furthermore, insofar as the compounds described herein may exist as atropisomers (e.g., substituted biaryls), all forms of such atropisomers are considered part of the present invention.

[0065] Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. When a chemical compound is referred to using both its chemical structure and chemical name, and there is ambiguity between the structure and the name, the structure takes precedence. It should also be noted that any carbon and heteroatoms with unsatisfactory valencies in the text, schemes, examples, and tables herein are assumed to have a sufficient number of hydrogen atoms to satisfy their valency.

[0066] As used herein, the terms "a" and "an" mean "one or more," and include the plural unless otherwise appropriate from the context.

[0067] The term "alkyl" is used herein to mean C1 to C1, respectively. 12 Alkyl, C1-C 10Alkyl and C1-C6 alkyl groups refer to saturated linear or branched hydrocarbons, such as linear or branched groups with 1-12, 1-10, or 1-6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. The term fluoroalkyl refers to an alkyl group substituted with at least one fluoropolymer. In certain embodiments, the fluoroalkyl group contains one, two, or three fluoro groups. In certain embodiments, the fluoroalkyl group contains two or three fluoro groups. In certain embodiments, the fluoroalkyl group contains three fluoro groups.

[0068] The term "cycloalkyl" as used herein refers to a monovalent saturated cyclic, bicyclic, or cross-linked (e.g., adamantyl) hydrocarbon group having 3 to 12, 3 to 8, 4 to 8, or 4 to 6 carbon atoms, called a "C3-C6 cycloalkyl," for example, derived from cycloalkanes. Examples of cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term "cycloalkylene" refers to a divalent cycloalkyl group.

[0069] The terms "alkenyl" and "alkynyl" are recognized in the art and refer to unsaturated aliphatic groups that are similar in length and possible substitutions to the alkyl groups described above, but each contains at least one double or triple bond.

[0070] The terms "alkoxyl" or "alkoxy" are recognized in the art and refer to the alkyl group defined above, to which an oxygen group is bonded. Typical alkoxyl groups include methoxy, ethoxy, propyloxy, and tert-butoxy. The term "haloalkoxyl" refers to an alkoxyl group substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, and -OCF2CF3.

[0071] The term "oxo" is recognized in this art and refers to an "=O" substituent. For example, cyclopentane substituted with an oxo group is cyclopentanone.

[0072] symbol [ka] This indicates a connection point.

[0073] If any substituent or variable element occurs two or more times in any component or compound of the present invention, unless otherwise indicated, the definition of each existence is independent of the definition of all other existences.

[0074] One or more compounds of the present invention can exist in a non-solvated form and a solvated form with a pharmaceutically acceptable solvent such as water or ethanol, and the present invention is intended to encompass both solvated and non-solvated forms. “Solvated form” means the physical association of the compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain examples, the solvated form can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. “Solvated form” encompasses both the solution phase and the isolateable solvated form. Non-limiting examples of suitable solvated forms include ethanolates and methanelates. “Hydrate” is a solvated form in which the solvent molecule is H2O.

[0075] As used herein, the terms “subject” and “patient” are interchangeable and refer to the organism treated by the method of the present invention. Such organisms include, but are not limited to, mammals (e.g., mice, monkeys, horses, cattle, pigs, dogs, cats, etc.), most preferably humans.

[0076] "I C 50 The term "50% inhibition of the target" is recognized in the art and refers to the concentration of a compound required to achieve 50% inhibition of the target.

[0077] The abbreviation "MGMT" is O 6 - stands for methylguanine-DNA methyltransferase.

[0078] As used herein, the term “effective dose” means an amount of a compound sufficient to produce a beneficial or desired result (e.g., a therapeutic, ameliorative, inhibitory, or prophylactic result). An effective dose may be administered in one or more doses, applications, or prescriptions and is not intended to be limited to a particular formulation or route of administration. As used herein, the term “treat” includes any effect that results in improvement of a condition, disease, disorder, etc., e.g., reduction, decrease, regulation, improvement or elimination, or improvement of its symptoms.

[0079] As used herein, the term “pharmaceutical composition” refers to a combination of an activator and an inert or active carrier that makes the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0080] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as phosphate-buffered saline, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. The composition may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] . Please refer to the following.

[0081] For therapeutic use, salts of the compounds of the present invention are intended to be pharmaceutically acceptable. However, salts of pharmaceutically unacceptable acids and bases may also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0082] Furthermore, if the compounds of the present invention contain both a basic moiety (but not limited to pyridine or imidazole) and an acidic moiety (but not limited to a carboxylic acid), a zwitterion ("intramolecular salt") may be formed. Salts of such acidic and basic moies used within the scope of the present invention are pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts. Such salts of the compounds of the present invention may be formed, for example, by reacting the compounds of the present invention with a fixed amount of acid or base, such as an equal amount, in a medium in which the salt precipitates or in an aqueous medium, followed by freeze-drying.

[0083] Throughout this specification, where a composition is described as having, including, or comprising, certain components, or where a process and method is described as having, including, or comprising, certain steps, it is intended that there exist compositions of the present invention that are essentially composed of or comprise the listed components, and processes and methods of the present invention that are essentially composed of or comprise the listed processing steps.

[0084] As a general rule, compositions that specify a percentage are based on weight unless otherwise specified.

[0085] I. Fluoroalkoxyalkylenedihydroimidazo[5,1-d]tetradinone and related compounds One aspect of the present invention provides fluoroalkoxyalkylenedihydroimidazo[5,1-d]tetradinone compounds and related compounds. These compounds may be used in pharmaceutical compositions and therapeutic methods described herein. Exemplary compounds, along with exemplary procedures for preparing the compounds, are described in the following sections.

[0086] One aspect of the present invention relates to a compound represented by formula I: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is hydrogen or C 1~4 It is alkyl; R 2 C 1~4 It is a fluoroalkyl group; R 3 is -C(O)N(R 4 )(R 5 ), -CO2R 5 -C(O)SR 4 ,-C(S)N(R 4 )(R 5 ), -C(=NR 7 )OR 4 -C(=NR 7 )SR 4 -C(=NR 7 )N(R 4 )(R 5 ), -C(O)-(halo), -C(O)-(C 1~4 Alkyl), -CN, halo, or C 1~4 It is alkyl; R 4 is hydrogen, C 1~4 Alkyl, or C 3~6It is a cycloalkyl; R 5 is hydrogen, C 1~4 Alkyl, C 1~4 Alkenil, C 1~4 Alkinyl, -(C 0~4 Alkylene)-R 6 ,-(C 1~4 Alkylene)-C(O)-R 6 ,-(C 1~4 Alkylene)-C(O)-(C 1~4 Alkyl), -(C 1~4 Alkilen)-OR 7 , or -(C 1~4 Alkylene)-N(R 7 )(R 8 ) and; or R 4 and R 5 These, together with the nitrogen atom to which they are bonded, form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatoms selected from nitrogen, oxygen, and sulfur, where the 3- to 7-membered heterocyclic ring contains 0, 1, 2, or 3 R 9 It is replaced by the presence of; R 6 C 3~6 They are cycloalkyl, phenyl, or 5-6 member heteroaryl groups; each having 0, 1, 2, or 3 R groups. 9 It is replaced by the presence of; R 7 and R 8 For each entity, independently, hydrogen, C 1~4 Alkyl, or C 3~6 It is cycloalkyl; or R 7 and R 8 These, together with the nitrogen atoms to which they are bonded, form a 3- to 7-membered heterocyclic ring containing nitrogen atoms; R 9 C is independent of each existence. 1~4 Alkyl, C 3~6 Cycloalkyl, halo, -OR 7 , or -N(R 7 )(R 8 ) represents; and X is C 1~3Alkylene or C 1~3 (It is a deuteroalkylene.) To provide.

[0087] The definition of a variable element in Formula I above encompasses multiple chemical groups. This application intends, for example, embodiments where i) the definition of a variable element is a single chemical group selected from the chemical groups shown above, ii) the definition of a variable element is a set of two or more chemical groups selected from the chemical groups shown above, and iii) the compound is defined by a combination of variable elements defined by (i) or (ii).

[0088] In certain embodiments, the compound is the compound of formula I.

[0089] As generally defined above, R 1 is hydrogen or C 1~4 It is alkyl. In a particular embodiment, R 1 is hydrogen or methyl. In a particular embodiment, R 1 is hydrogen. In a particular embodiment, R 1 is C 1~4 It is alkyl. In a particular embodiment, R 1 is methyl. In a particular embodiment, R 1 The group is selected from the groups shown in the compounds in Table 1 below.

[0090] As generally defined above, R 2 is C 1~4 It is a fluoroalkyl. In a particular embodiment, R 2 is C 1~2 It is a fluoroalkyl. In a particular embodiment, R 2 is a C1 fluoroalkyl. In certain embodiments, the fluoroalkyl contains at least three fluorine atoms. In certain embodiments, R 2 is C 1~2 It is a trifluoroalkyl. In a particular embodiment, R 2 is trifluoromethyl. In a particular embodiment, R 2The group is selected from the groups shown in the compounds in Table 1 below.

[0091] As generally defined above, R 3 is -C(O)N(R 4 )(R 5 ), -CO2R 5 -C(O)SR 4 ,-C(S)N(R 4 )(R 5 ), -C(=NR 7 )OR 4 -C(=NR 7 )SR 4 -C(=NR 7 )N(R 4 )(R 5 ), -C(O)-(halo), -C(O)-(C 1~4 Alkyl), -CN, halo, or C 1~4 It is alkyl. In a particular embodiment, R 3 is -C(O)N(R 4 )(R 5 ) In a particular embodiment, R 3 -CO2R 5 -C(O)SR 4 , or -C(S)N(R 4 )(R 5 ) In a particular embodiment, R 3 -C(=NR 7 )OR 4 -C(=NR 7 )SR 4 , or -C(=NR 7 )N(R 4 )(R 5 ) In a particular embodiment, R 3 is -C(O)-(halo), -C(O)-(C 1~4 Alkyl), -CN, halo, or C 1~4 It is alkyl. In a particular embodiment, R 3 These are -C(O)Cl, -C(O)CH3, -CN, chloro, fluoro, or -CH3.

[0092] In a particular embodiment, R 3 is -C(O)N(R4 )(R 5 ) In a particular embodiment, R 3 -CO2R 5 In a particular embodiment, R 3 -C(O)SR 4 In a particular embodiment, R 3 is -C(S)N(R 4 )(R 5 ) In a particular embodiment, R 3 is -C(=NR 7 )OR 4 In a particular embodiment, R 3 is -C(=NR 7 )SR 4 In a particular embodiment, R 3 is -C(=NR 7 )N(R 4 )(R 5 ) In a particular embodiment, R 3 is -C(O)-(halo). In a particular embodiment, R 3 is -C(O)Cl. In a particular embodiment, R 3 is -C(O)-(C 1~4 It is alkyl. In a particular embodiment, R 3 is -C(O)CH3. In a particular embodiment, R 3 is -CN. In a particular embodiment, R 3 is a halo. In a particular embodiment, R 3 is chloro or fluoro. In certain embodiments, R 3 is C 1~4 It is alkyl. In a particular embodiment, R 3 is -CH3. In a particular embodiment, R 3 The group is selected from the groups shown in the compounds in Table 1 below.

[0093] As generally defined above, R 4 is hydrogen, C 1~4 Alkyl, or C 3~6 It is cycloalkyl; or R 4 and R 5Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the 3- to 7-membered heterocyclic ring contains 0, 1, 2, or 3 R 9 It is replaced by the presence of R 4 is hydrogen, C 1~4 Alkyl, or C 3~6 It is a cycloalkyl. In a particular embodiment, R 4 is hydrogen or C 1~4 It is alkyl. In a particular embodiment, R 4 is hydrogen or methyl. In a particular embodiment, R 4 is C 1~4 Alkyl or C 3~6 It is a cycloalkyl group.

[0094] In a particular embodiment, R 4 is hydrogen. In a particular embodiment, R 4 is C 1~4 It is alkyl. In a particular embodiment, R 4 is methyl. In a particular embodiment, R 4 is C 3~6 It is a cycloalkyl. In a particular embodiment, R 4 The group is selected from the groups shown in the compounds in Table 1 below.

[0095] As generally defined above, R 5 is hydrogen, C 1~4 Alkyl, C 1~4 Alkenil, C 1~4 Alkinyl, -(C 0~4 Alkylene)-R 6 ,-(C 1~4 Alkylene)-C(O)-R 6 ,-(C 1~4 Alkylene)-C(O)-(C 1~4 Alkyl), -(C 1~4 Alkilen)-OR 7 , or -(C 1~4 Alkylene)-N(R 7 )(R 8) and; or, R 4 and R 5 Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the heterocyclic ring has 0, 1, 2, or 3 R 9 It is replaced by the presence of [something].

[0096] In a particular embodiment, R 5 is hydrogen, C 1~4 Alkyl, C 1~4 Alkenil, C 1~4 Alkinyl, -(C 0~4 Alkylene)-R 6 ,-(C 1~4 Alkylene)-C(O)-R 6 ,-(C 1~4 Alkylene)-C(O)-(C 1~4 Alkyl), -(C 1~4 Alkilen)-OR 7 , or -(C 1~4 Alkylene)-N(R 7 )(R 8 ) In a particular embodiment, R 5 is hydrogen, C 1~4 Alkyl, or -(C 0~4 Alkylene)-R 6 In a particular embodiment, R 5 is hydrogen, C 1~4 Alkyl, or -R 6 In a particular embodiment, R 5 is hydrogen, C 1~4 Alkyl, C 3~6 It is a cycloalkyl, phenyl, or 5-6 member heteroaryl; phenyl has 0 or 1 R 9 It is replaced by the presence of [something].

[0097] In a particular embodiment, R 5 is hydrogen, C 1~4 Alkyl, C 1~4 Alkenil, C 1~4 Alkinyl, -(C 1~4 Alkilen)-OR7 , or -(C 1~4 Alkylene)-N(R 7 )(R 8 ) In a particular embodiment, R 5 is hydrogen, C 1~4 Alkyl, C 1~4 Alkenyl, or C 1~4 In certain embodiments, R 5 is hydrogen or C 1~4 It is alkyl. In a particular embodiment, R 5 is C 1~4 Alkyl, C 1~4 Alkenyl, or C 1~4 It is alkinyl.

[0098] In a particular embodiment, R 5 is hydrogen. In a particular embodiment, R 5 is C 1~4 It is alkyl. In a particular embodiment, R 5 is C 1~4 It is an alkenyl. In a particular embodiment, R 5 is C 1~4 It is alkinyl.

[0099] In a particular embodiment, R 5 is, -(C 0~4 Alkylene)-R 6 ,-(C 1~4 Alkylene)-C(O)-R 6 , or -(C 1~4 Alkylene)-C(O)-(C 1~4 It is alkyl. In a particular embodiment, R 5 is, -(C 0~4 Alkylene)-R 6 or -(C 1~4 Alkylene)-C(O)-R 6 In a particular embodiment, R 5 is, -(C 0~4 Alkylene)-R 6 In a particular embodiment, R 5 ha-(C 1~4 Alkylene)-C(O)-R 6In a particular embodiment, R 5 ha-(C 1~4 Alkylene)-C(O)-(C 1~4 It is alkyl.

[0100] In a particular embodiment, R 5 is, -(C 1~4 Alkylene)-R 6 ,-(C 1~4 Alkilen)-OR 7 , or -(C 1~4 Alkylene)-N(R 7 )(R 8 ) In a particular embodiment, R 5 ha-(C 1~4 Alkylene)-R 6 That is the case.

[0101] In a particular embodiment, R 5 ha-R 6 In a particular embodiment, R 5 C 3~6 They are cycloalkyl, phenyl, or 5-6 member heteroaryl groups; each having 0, 1, 2, or 3 R groups. 9 It is replaced by the presence of R 5 C 3~6 It is a cycloalkyl, phenyl, or 5-6 member heteroaryl; phenyl has 0 or 1 R 9 It is replaced by the presence of R 5 C 3~6 It is a cycloalkyl, phenyl, or 6-membered heteroaryl; phenyl has 0 or 1 R 9 It is replaced by the presence of R 5 C 3~6 It is a cycloalkyl, phenyl, or 5-6 member heteroaryl. In certain embodiments, R 5 C 3~6 It is a cycloalkyl, phenyl, or 6-membered heteroaryl. In certain embodiments, R 5 is C 3~6 It is a cycloalkyl. In a particular embodiment, R5 This is 0 or 1 R 9 This is a phenyl compound substituted with the presence of R 5 is phenyl. In a particular embodiment, R 5 R is a 5-6 member heteroaryl. In a particular embodiment, R 5 It is a 6-membered heteroaryl.

[0102] In a particular embodiment, R 5 is, -(C 1~4 Alkilen)-OR 7 or -(C 1~4 Alkylene)-N(R 7 )(R 8 ) In a particular embodiment, R 5 is -(CH2)2-OR 7 or -(CH2)2-N(R 7 )(R 8 ) In a particular embodiment, R 5 ha-(C 1~4 Alkilen)-OR 7 In a particular embodiment, R 5 is -(CH2)2-OR 7 In a particular embodiment, R 5 ha-(C 1~4 Alkylene)-N(R 7 )(R 8 ) In a particular embodiment, R 5 -(CH2)2-N(R 7 )(R 8 )

[0103] In a particular embodiment, R 5 The group is selected from the groups shown in the compounds in Table 1 below.

[0104] In a particular embodiment, R 4 and R 5Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the 3- to 7-membered heterocyclic ring contains 0, 1, 2, or 3 R 9 It is replaced by the presence of R 4 and R 5 Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein the additional nitrogen atom is C 1~4 It may be substituted with alkyl. In a particular embodiment, R 4 and R 5 These, together with the nitrogen atoms to which they are bonded, form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and zero or one additional nitrogen atom; the additional nitrogen atom is C 1~4 It may be substituted with alkyl. In a particular embodiment, R 4 and R 5 These, together with the nitrogen atom to which they are bonded, form a 3- to 7-membered heterocyclic ring containing nitrogen atoms and no additional heteroatoms; the 3- to 7-membered heterocyclic ring may have 0, 1, 2, or 3 R atoms. 9 It is replaced by the presence of [something].

[0105] In a particular embodiment, R 4 and R 5 Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and zero or one additional heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 4 and R 5 These, together with the nitrogen atoms to which they are bonded, form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and zero or one additional nitrogen atom. In certain embodiments, R 4 and R 5 These, together with the nitrogen atom to which they are bonded, form a 3- to 7-membered heterocyclic ring containing nitrogen atoms but no additional heteroatoms.

[0106] In a particular embodiment, R 4 and R 5 The group is selected from the groups shown in the compounds in Table 1 below.

[0107] As generally defined above, R 6 C 3~6 They are cycloalkyl, phenyl, or 5-6 member heteroaryl groups; each having 0, 1, 2, or 3 R groups. 9 It is replaced by the presence of R 6 C 3~6 It is a cycloalkyl, phenyl, or 6-membered heteroaryl; each of which has 0, 1, 2, or 3 R 9 It is replaced by the presence of R 6 is a phenyl or 5-6 member heteroaryl, each having 0, 1, 2, or 3 R 9 It is replaced by the presence of R 6 is a phenyl or 6-membered heteroaryl, each having 0, 1, 2, or 3 R 9 It is replaced by the presence of [something].

[0108] In a particular embodiment, R 6 C 3~6 It is a cycloalkyl, phenyl, or 5-6 member heteroaryl; phenyl has 0 or 1 R 9 It is replaced by the presence of R 6 C 3~6 It is a cycloalkyl, phenyl, or 6-membered heteroaryl; phenyl has 0 or 1 R 9 It is replaced by the presence of R 6 R is phenyl or a 5-6 member heteroaryl, and phenyl has 0 or 1 R 9 It is replaced by the presence of R 6 is phenyl or a 6-membered heteroaryl, where phenyl has 0 or 1 R 9It is replaced by the presence of [something].

[0109] In a particular embodiment, R 6 C 3~6 It is a cycloalkyl, phenyl, or 5-6 member heteroaryl. In certain embodiments, R 6 C 3~6 It is a cycloalkyl, phenyl, or 6-membered heteroaryl. In certain embodiments, R 6 is phenyl or a 5-6 member heteroaryl. In certain embodiments, R 6 It is phenyl or a 6-membered heteroaryl.

[0110] In a particular embodiment, R 6 This can be 0, 1, 2, or 3 R 9 C replaced by the presence of 3~6 It is a cycloalkyl. In a particular embodiment, R 6 is C 3~6 It is a cycloalkyl. In a particular embodiment, R 6 This can be 0, 1, 2, or 3 R 9 This is a phenyl compound substituted with the presence of R 6 is phenyl. In a particular embodiment, R 6 This can be 0, 1, 2, or 3 R 9 It is a 5-6 member heteroaryl substituted with the presence of R 6 This can be 0, 1, 2, or 3 R 9 It is a 6-membered heteroaryl substituted with the presence of R 6 R is a 5-6 member heteroaryl. In a particular embodiment, R 6 It is a 6-membered heteroaryl.

[0111] As generally defined above, R 7 and R 8 For each entity, independently, hydrogen, C 1~4 Alkyl, or C 3~6 It is cycloalkyl; or R 7 and R8 These, together with the nitrogen atoms to which they are bonded, form a 3- to 7-membered heterocyclic ring containing nitrogen atoms. In certain embodiments, R 7 and R 8 For each entity, independently, hydrogen, C 1~4 Alkyl, or C 3~6 It is a cycloalkyl. In a particular embodiment, R 7 and R 8 For each entity, independently, hydrogen or C 1~4 It is alkyl. In a particular embodiment, R 7 and R 8 R is, independently of each other, hydrogen or methyl. In a particular embodiment, R 7 and R 8 C is independent of each existence. 1~4 Alkyl or C 3~6 It is a cycloalkyl group.

[0112] In a particular embodiment, R 7 and R 8 is hydrogen. In a particular embodiment, R 7 and R 8 C is independent of each existence. 1~4 It is alkyl. In a particular embodiment, R 7 and R 8 is methyl. In a particular embodiment, R 7 and R 8 C is independent of each existence. 3~6 It is a cycloalkyl. In a particular embodiment, R 7 and R 8 For each entity, the group is independently selected from the groups shown in the compounds in Table 1 below.

[0113] As generally defined above, R 9 C is independent of each existence. 1~4 Alkyl, C 3~6 Cycloalkyl, halo, -OR 7 , or -N(R 7 )(R 8 ) represents. In a particular embodiment, R9 C is independent of each existence. 1~4 Represents alkyl, fluoro, chloro, -OH, or -NH2. In certain embodiments, R 9 C 1~4 It is alkyl, fluoro, chloro, -OH, or -NH2. In certain embodiments, R 9 C is independent of each existence. 1~4 Alkyl, C 3~6 Represents a cycloalkyl or halo. In certain embodiments, R 9 C is independent of each existence. 1~4 Alkyl or C 3~6 Represents a cycloalkyl group. In certain embodiments, R 9 C is independent of each existence. 1~4 Represents alkyl or halo. In certain embodiments, R 9 R independently represents methyl or halo for each presence. In certain embodiments, R 9 This is independent for each existence, -OR 7 or -N(R 7 )(R 8 ) represents. In a particular embodiment, R 9 This represents either -OH or -NH2 independently for each entity.

[0114] In a particular embodiment, R 9 C is independent of each existence. 1~4 Represents an alkyl group. In a particular embodiment, R 9 is methyl. In a particular embodiment, R 9 C is independent of each existence. 3~6 Represents a cycloalkyl group. In certain embodiments, R 9 This represents a halo independently for each entity. In a particular embodiment, R 9 R represents fluoro or chloro independently for each entity. In certain embodiments, R 9 This is independent for each existence, -OR 7 This represents R 9 is -OH. In a particular embodiment, R9 For each existence independently, -N(R 7 )(R 8 ) represents. In a particular embodiment, R 9 is -NH2. In a particular embodiment, R 9 The group is selected from the groups shown in the compounds in Table 1 below.

[0115] As generally defined above, X is C 1~3 Alkylene or C 1~3 It is a deuteroalkylene. In certain embodiments, X is -CH2CH2- or -CH2CH(CH3)-. In certain embodiments, X is -CH2CH2-. In certain embodiments, X is -CH2CH2CH2-. In certain embodiments, X is -CH2CH(CH3)-. In certain embodiments, X is -CH2-. In certain embodiments, X is C 1~3 It is a deuteroalkylene.

[0116] In certain embodiments, X is -CZ2CZ2-, where each Z is hydrogen or deuterium, with at least 75% being deuterium in Z. In certain embodiments, the amount of deuterium in Z is at least 90%. In certain embodiments, the amount of deuterium in Z is at least 95%. In certain embodiments, X is -CD2CH2-. In certain embodiments, X is -CH2CD2-. In certain embodiments, X is -CD2CD2-.

[0117] In a particular embodiment, X is selected from the groups shown in the compounds in Table 1 below.

[0118] The above description outlines several embodiments relating to the compound of Formula I. This patent application specifically intends all combinations of these embodiments.

[0119] Another aspect of the present invention is formula IA: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is hydrogen or methyl; R 2 C 1~2 It is a fluoroalkyl group; R 4 is hydrogen or C 1~4 It is alkyl; R 5 is hydrogen, C 1~4 Alkyl, C 3~6 The compound is a cycloalkyl, phenyl, or 5-6 member heteroaryl; the phenyl compound may have 0 or 1 R 9 It is replaced by the presence of R 4 and R 5 These, together with the nitrogen atoms to which they are bonded, form a 3- to 7-membered saturated heterocyclic ring containing a nitrogen atom and 0 or 1 additional nitrogen atom; where the additional nitrogen atom is C 1~4 It may also be substituted with alkyl groups; R 9 C 1~4 It is alkyl, fluoro, chloro, -OH, or -NH2; and X is C 1~3 (It is alkylene) The present invention provides a compound represented by the following:

[0120] The definition of a variable element in formula IA above encompasses multiple chemical groups. This application intends, for example, embodiments where i) the definition of a variable element is a single chemical group selected from the chemical groups shown above, ii) the definition of a variable element is a set of two or more chemical groups selected from the chemical groups shown above, and iii) the compound is defined by a combination of variable elements defined by (i) or (ii).

[0121] In certain embodiments, the compound is a compound of formula IA.

[0122] As generally defined above, R 1is hydrogen or methyl. In a particular embodiment, R 1 is hydrogen. In a particular embodiment, R 1 It is methyl.

[0123] As generally defined above, R 2 is C 1~2 It is a fluoroalkyl. In a particular embodiment, R 2 is trifluoromethyl. In a particular embodiment, R 2 is a C1 fluoroalkyl. In certain embodiments, R 2 is C 1~2 It is a trifluoroalkyl group.

[0124] As generally defined above, R 4 is hydrogen or C 1~4 It is alkyl, or R 4 and R 5 These, together with the nitrogen atoms to which they are bonded, form a 3- to 7-membered saturated heterocyclic ring containing a nitrogen atom and zero or one additional nitrogen atom; the additional nitrogen atom is C 1~4 It may be substituted with alkyl. In a particular embodiment, R 4 is hydrogen or C 1~4 It is alkyl. In a particular embodiment, R 4 is hydrogen or methyl. In a particular embodiment, R 4 is hydrogen. In a particular embodiment, R 4 is C 1~4 It is alkyl. In a particular embodiment, R 4 It is methyl.

[0125] As generally defined above, R 5 is hydrogen, C 1~4 Alkyl, C 3~6 It is a cycloalkyl, phenyl, or 5-6 member heteroaryl; phenyl has 0 or 1 R 9 It is replaced by the presence of R 4 and R 5These, together with the nitrogen atoms to which they are bonded, form a 3- to 7-membered saturated heterocyclic ring containing a nitrogen atom and zero or one additional nitrogen atom; the additional nitrogen atom is C 1~4 It may be substituted with alkyl.

[0126] In a particular embodiment, R 5 is hydrogen, C 1~4 Alkyl, C 3~6 It is a cycloalkyl, phenyl, or 5-6 member heteroaryl; phenyl has 0 or 1 R 9 It is replaced by the presence of R 5 is hydrogen or C 1~4 It is alkyl. In a particular embodiment, R 5 is hydrogen. In a particular embodiment, R 5 is C 1~4 It is alkyl. In a particular embodiment, R 5 is hydrogen, C 1~4 Alkyl, C 3~6 It is cycloalkyl or phenyl.

[0127] In a particular embodiment, R 5 C 3~6 It is a cycloalkyl, phenyl, or 5-6 member heteroaryl; phenyl has 0 or 1 R 9 It is replaced by the presence of R 5 C 3~6 It is a cycloalkyl, phenyl, or 6-membered heteroaryl; phenyl has 0 or 1 R 9 It is replaced by the presence of R 5 C 3~6 It is a cycloalkyl, phenyl, or 5-6 member heteroaryl. In certain embodiments, R 5 C 3~6 It is a cycloalkyl, phenyl, or 6-membered heteroaryl. In certain embodiments, R 5 is C 3~6 It is a cycloalkyl. In a particular embodiment, R 5 This is 0 or 1 R9 This is a phenyl compound substituted with the presence of R 5 is phenyl. In a particular embodiment, R 5 R is a 5-6 member heteroaryl. In a particular embodiment, R 5 It is a 6-membered heteroaryl.

[0128] In a particular embodiment, R 4 and R 5 These, together with the nitrogen atoms to which they are bonded, form a 3- to 7-membered saturated heterocyclic ring containing a nitrogen atom and zero or one additional nitrogen atom; the additional nitrogen atom is C 1~4 It may be substituted with alkyl. In a particular embodiment, R 4 and R 5 These, together with the nitrogen atom to which they are bonded, form a 3- to 7-membered heterocyclic ring containing nitrogen atoms but no additional heteroatoms.

[0129] As generally defined above, R 9 C 1~4 It is alkyl, fluoro, chloro, -OH, or -NH2. In certain embodiments, R 9 is C 1~4 It is alkyl, fluoro, or chloro. In certain embodiments, R 9 is methyl, fluoro, or chloro. In certain embodiments, R 9 is -OH or -NH2. In certain embodiments, R 9 C 1~4 It is alkyl. In a particular embodiment, R 9 is methyl. In a particular embodiment, R 9 is fluoro or chloro. In certain embodiments, R 9 is -OH. In a particular embodiment, R 9 It is -NH2.

[0130] As generally defined above, X is C 1~3It is an alkylene. In certain embodiments, X is -CH2CH2- or -CH2CH(CH3)-. In certain embodiments, X is -CH2CH2-. In certain embodiments, X is -CH2CH2CH2-. In certain embodiments, X is -CH2CH(CH3)-. In certain embodiments, X is -CH2-.

[0131] The above description outlines several embodiments relating to the compound of formula IA. This patent application specifically intends all combinations of these embodiments.

[0132] Another aspect of the present invention is a compound represented by formula I-aa: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is hydrogen or methyl; R 2 C 1~2 It is a fluoroalkyl; and X is C 1~3 (It is alkylene) To provide.

[0133] The definition of a variable element in formula I-aa above encompasses multiple chemical groups. This application intends, for example, embodiments where i) the definition of a variable element is a single chemical group selected from the chemical groups shown above, ii) the definition of a variable element is a set of two or more chemical groups selected from the chemical groups shown above, and iii) the compound is defined by a combination of variable elements defined by (i) or (ii).

[0134] In certain embodiments, the compound is a compound of formula I-aa.

[0135] As generally defined above, R 1 is hydrogen or methyl. In a particular embodiment, R 1is hydrogen. In a particular embodiment, R 1 is methyl. In a particular embodiment, R 1 The group is selected from the groups shown in compounds I-1 and I-2 in Table 1 below.

[0136] As generally defined above, R 2 C 1~2 It is a fluoroalkyl. In a particular embodiment, R 2 is trifluoromethyl. In a particular embodiment, R 2 is a C1 fluoroalkyl. In certain embodiments, R 2 C 1~2 It is a trifluoroalkyl. In a particular embodiment, R 2 The group is selected from the groups shown in compounds I-1 and I-2 in Table 1 below.

[0137] As generally defined above, X is C 1~3 It is an alkylene. In certain embodiments, X is -CH2CH2-. In certain embodiments, X is -CH2CH2CH2-. In certain embodiments, X is -CH2-. In certain embodiments, X is selected from the groups shown in compounds I-1 and I-2 in Table 1 below.

[0138] The above description outlines several embodiments relating to the compound of formula I-aa. This patent application specifically intends all combinations of these embodiments.

[0139] In a particular embodiment, the compound [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a pharmaceutically acceptable salt thereof. [ka] That is the case.

[0140] Another aspect of the present invention relates to a compound represented by formula II: [ka] or a pharmaceutically acceptable salt thereof (In the formula, X is C 1~3 Alkylene or C 1~3 It is a deuteroalkylene; A 1 is a 5-10 member monocyclic or bicyclic heteroaryl containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur; or A 1 is phenyl; A 1 m R 3 The existence of n R 4 It is replaced by the presence of; R 1 is hydrogen or C 1~4 It is alkyl; R 2 C 1~4 It is a fluoroalkyl group; R 3 C is independent of each existence. 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, halogen, cyano, C 1~4 Alkoxyl, or C 1~4 Represents a haloalkoxyl; R 4 C 1~6 Alkyl, C 1~6 Haloalkyl, cyano, halogen, -(C 1~6 Alkylene)-R 5 ,-(C 1~6 Alkylene)-N(R 6 )(R 7 ), -C(O)-R 5 ,-C(O)N(R 6 )(R 7 ), -C(O)-(saturated C 1~6 aliphatic), -(C 1~6 Alkylene)-C(O)-R 5 ,-(C 1~6 Alkylene)-C(O)N(R)6 )(R 7 ), C 1~4 Alkoxyl, C 1~4 Haloalkoxyl, or R 5 and; R 5 is phenyl; C 3~7 Cycloalkyl; a 3-7 member saturated heterocycline containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; or a 5-10 member monocyclic or bicyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; where phenyl, cycloalkyl, heterocycline, and heteroaryl contain one, two, or three R 8 It may be replaced by the presence of; R 6 and R 7 Hydrogen and C are independent of each other. 1~6 Alkyl, C 2~6 Hydroxylalkyl, -(C 1~6 Alkylene)-C 3~6 Cycloalkyl, -(C 2~6 Alkylene)-N(R 9 )(R 10 ), or R 5 and; R 8 For each entity, independently, halogens, cyanos, and saturated C 1~6 Aliphatic, or C 1~4 Represents alkoxyl; or two R 8 The presence of these intervening atoms, together with them, forms a ring; R 9 and R 10 Each of these independently exists as either hydrogen or C. 1~6 Represents alkyl; m is 0, 1, or 2; and n is either 0 or 1. To provide.

[0141] The definition of a variable element in Formula II above encompasses multiple chemical groups. This application intends, for example, embodiments where i) the definition of a variable element is a single chemical group selected from the chemical groups shown above, ii) the definition of a variable element is a set of two or more chemical groups selected from the chemical groups shown above, and iii) the compound is defined by a combination of variable elements defined by (i) or (ii).

[0142] In certain embodiments, the compound is the compound of formula II.

[0143] As generally defined above, X is C 1~3 Alkylene or C 1~3 It is a deuteroalkylene. In certain embodiments, X is -CH2CH2- or -CH2CH(CH3)-. In certain embodiments, X is -CH2CH2-. In certain embodiments, X is -CH2CH2CH2-. In certain embodiments, X is -CH2CH(CH3)-. In certain embodiments, X is -CH2-. In certain embodiments, X is C 1~3 It is a deuteroalkylene.

[0144] In certain embodiments, X is -CZ2CZ2-, where each Z is hydrogen or deuterium, with at least 75% being deuterium in Z. In certain embodiments, the amount of deuterium in Z is at least 90%. In certain embodiments, the amount of deuterium in Z is at least 95%. In certain embodiments, X is -CD2CH2-. In certain embodiments, X is -CH2CD2-. In certain embodiments, X is -CD2CD2-.

[0145] In a particular embodiment, X is selected from the groups shown in the compounds in Table 2 below.

[0146] As generally defined above, A 1is a 5-10 member monocyclic or bicyclic heteroaryl containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur; or A 1 is phenyl; A 1 m R 3 The existence of n R 4 It is replaced by the presence of [something].

[0147] In a particular embodiment, A 1 This is a 5-10 member monocyclic or bicyclic heteroaryl containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heteroaryl has m R 3 The existence of n R 4 It is replaced by the presence of A. 1 This is a 5-6 membered monocyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl has m R 3 The existence of n R 4 It is replaced by the presence of A. 1 It is a six-membered monocyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl has m R 3 The existence of n R 4 It is replaced by the presence of A. 1 m R 3 The existence of n R 4 This is pyridyl replaced by the presence of [another compound].

[0148] In a particular embodiment, A 1 It is a five-membered monocyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl has m R 3 The existence of n R 4 It is replaced by the presence of A. 1It is a five-membered monocyclic heteroaryl containing two or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, where at least one of the heteroatoms is nitrogen; the heteroaryl contains m R 3 The existence of n R 4 It is replaced by the presence of A. 1 These are thiazolyl, thiadiazolyl, oxadiazolyl, oxazolyl, or imidazolyl; each of them contains m R 3 The existence of n R 4 It is replaced by the presence of A. 1 These are thiazole-2-yl, 1,2,4-thiadiazole-5-yl, 1,2,4-oxadiazole-5-yl, oxazole-2-yl, or imidazole-2-yl; each of these contains m R 3 The existence of n R 4 It is replaced by the presence of [something].

[0149] In a particular embodiment, A 1 This is a 9-10 membered bicyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl has m R 3 The existence of n R 4 It is replaced by the presence of A. 1 It is a nine-membered bicyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl has m R 3 The existence of n R 4 It is replaced by the presence of A. 1 It is a nine-membered bicyclic heteroaryl compound containing two or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, where at least one of the heteroatoms is nitrogen; the heteroaryl compound contains m R 3 The existence of n R 4 It is replaced by the presence of A. 1These are benzo[d]oxazolyl, oxazolo[4,5-b]pyridinyl, or benzo[d]imidazolyl; each of these contains m R 3 The existence of n R 4 It is replaced by the presence of A. 1 is benzo[d]oxazole-2-yl, benzo[d]imidazole-2-yl, or benzo[d]thiazole-2-yl; each of them contains m R 3 The existence of n R 4 It is replaced by the presence of [something].

[0150] In a particular embodiment, A 1 A is a 5-10 member monocyclic or bicyclic heteroaryl containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, A 1 This is a 5-6 membered monocyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, A 1 A is a five-membered monocyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur. In a particular embodiment, A 1 is thiazolyl, thiadiazolyl, oxadiazolyl, oxazolyl, or imidazolyl. In certain embodiments, A 1 is thiazole-2-yl, 1,2,4-thiadiazole-5-yl, 1,2,4-oxadiazole-5-yl, oxazole-2-yl, or imidazole-2-yl. In certain embodiments, A 1 A is a six-membered monocyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, A 1 It is pyridyl.

[0151] In a particular embodiment, A 1This is a 9-10 membered bicyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, A 1 A is a nine-membered bicyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur. In a particular embodiment, A 1 is benzo[d]oxazolyl, oxazolo[4,5-b]pyridinyl, or benzo[d]imidazolyl. In certain embodiments, A 1 These are benzo[d]oxazole-2-yl, benzo[d]imidazole-2-yl, or benzo[d]thiazole-2-yl.

[0152] In a particular embodiment, A 1 m R 3 The existence of n R 4 It is a phenyl substituted with the presence of A. In a particular embodiment, A 1 is phenyl. In a particular embodiment, A 1 The group is selected from the groups shown in the compounds in Table 2 below.

[0153] As generally defined above, R 1 is hydrogen or C 1~4 It is alkyl. In a particular embodiment, R 1 is hydrogen or methyl. In a particular embodiment, R 1 is hydrogen. In a particular embodiment, R 1 C 1~4 It is alkyl. In a particular embodiment, R 1 is methyl. In a particular embodiment, R 1 The group is selected from the groups shown in the compounds in Table 2 below.

[0154] As generally defined above, R 2 C 1~4 It is a fluoroalkyl. In a particular embodiment, R 2 C 1~2 It is a fluoroalkyl. In a particular embodiment, R2 is a C1 fluoroalkyl. In certain embodiments, R 2 C 1~2 It is a trifluoroalkyl. In certain embodiments, the fluoroalkyl contains at least three fluorine atoms. In certain embodiments, R 2 is trifluoromethyl. In a particular embodiment, R 2 The group is selected from the groups shown in the compounds in Table 2 below.

[0155] As generally defined above, R 3 C is independent of each existence. 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, halogen, cyano, C 1~4 Alkoxyl, or C 1~4 Represents a haloalkoxyl. In a particular embodiment, R 3 C is independent of each existence. 1~6 Alkyl, C 1~6 Haloalkyl, or C 3~6 Represents a cycloalkyl group. In certain embodiments, R 3 For each entity, independently, halogen, cyano, C 1~4 Alkoxyl, or C 1~4 Represents a haloalkoxyl. In a particular embodiment, R 3 C is independent of each existence. 1~6 Alkyl, C 1~6 Represents a haloalkyl or halogen. In certain embodiments, R 3 This independently represents methyl, ethyl, or halogen for each entity.

[0156] In a particular embodiment, R 3 C is independent of each existence. 1~6 Represents an alkyl group. In a particular embodiment, R 3 R independently represents methyl or ethyl for each presence. In certain embodiments, R 3 is methyl. In a particular embodiment, R 3is ethyl. In certain embodiments, R 3 C is independent of each existence. 1~6 Represents a haloalkyl group. In a particular embodiment, R 3 C is independent of each existence. 3~6 Represents a cycloalkyl group. In certain embodiments, R 3 R represents a halogen independently for each entity. In a particular embodiment, R 3 is cyano. In a particular embodiment, R 3 C is independent of each existence. 1~4 Represents alkoxyl. In certain embodiments, R 3 C is independent of each existence. 1~4 Represents a haloalkoxyl. In a particular embodiment, R 3 The group is selected from the groups shown in the compounds in Table 2 below.

[0157] As generally defined above, R 4 C 1~6 Alkyl, C 1~6 Haloalkyl, cyano, halogen, -(C 1~6 Alkylene)-R 5 ,-(C 1~6 Alkylene)-N(R 6 )(R 7 ), -C(O)-R 5 ,-C(O)N(R 6 )(R 7 ), -C(O)-(saturated C 1~6 aliphatic), -(C 1~6 Alkylene)-C(O)-R 5 ,-(C 1~6 Alkylene)-C(O)N(R) 6 )(R 7 ), C 1~4 Alkoxyl, C 1~4 Haloalkoxyl, or R 5 That is the case.

[0158] In a particular embodiment, R 4 C 1~6 Alkyl, C 1~6is haloalkyl, cyano, or halogen. In certain embodiments, R 4 is -(C 1~6 alkylene)-R 5 ,-(C 1~6 alkylene)-N(R 6 )(R 7 ),-C(O)-R 5 ,-C(O)N(R 6 )(R 7 ),-C(O)-(saturated C 1~6 aliphatic),-(C 1~6 alkylene)-C(O)-R 5 ,-(C 1~6 alkylene)-C(O)N(R 6 )(R 7 ),C 1~4 alkoxyl, or C 1~4 haloalkoxyl. In certain embodiments, R 4 is -(C 1~6 alkylene)-R 5 ,-C(O)-R 5 ,-(C 1~6 alkylene)-C(O)-R 5 , or R 5 . In certain embodiments, R 4 is -C(O)-R 5 or -(C 1~6 alkylene)-C(O)-R 5 . In certain embodiments, R 4 is -(C 1~6 alkylene)-N(R 6 )(R 7 ),-C(O)N(R 6 )(R 7 ), or -(C 1~6 alkylene)-C(O)N(R 6 )(R​​​​​​​​​​​​​​​​​is haloalkyl, cyano, halogen, or C 1~4 haloalkoxyl. In certain embodiments, R 4 is C 1~6 alkyl, cyano, or R 5 .

[0159] In certain embodiments, R 4 is C 1~6 alkyl. In certain embodiments, R 4 is methyl. In certain embodiments, R 4 is C 1~6 haloalkyl. In certain embodiments, R 4 is cyano. In certain embodiments, R 4 is halogen. In certain embodiments, R 4 is -(C 1~6 alkylene)-R 5 . In certain embodiments, R 4 is -(C 1~6 alkylene)-N(R 6 )(R 7 ). In certain embodiments, R 4 is -C(O)-R 5 . In certain embodiments, R 4 is -C(O)N(R 6 )(R 7 !>). In certain embodiments, R 4 is -C(O)-(saturated C 1~6 aliphatic). In certain embodiments, R 4 is -(C 1~6 alkylene)-C(O)-R 5 . In certain embodiments, R 4 is -(C 1~6 alkylene)-C(O)N(R 6 )(R 7 ). In certain embodiments, R 4 is C 1~4 alkoxyl. In certain embodiments, R 4 is C 1~4 haloalkoxyl. In certain embodiments, R 4R 5 In a particular embodiment, R 4 The group is selected from the groups shown in the compounds in Table 2 below.

[0160] As generally defined above, R 5 is phenyl; C 3~7 Cycloalkyls; 3-7 member saturated heterocyclines containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; or 5-10 member monocyclic or bicyclic heteroaryls containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; phenyl, cycloalkyl, heterocyclil, and heteroaryl contain one, two, or three R 8 It may be replaced by the presence of [another element].

[0161] In a particular embodiment, R 5 A is a 5-10 member monocyclic or bicyclic heteroaryl containing one, two, or three heteroatoms independently selected from phenyl or oxygen, nitrogen, and sulfur; phenyl and heteroaryls contain one, two, or three R 8 It may be replaced by the presence of R 5 R is a 5-10 member monocyclic or bicyclic heteroaryl containing one, two, or three heteroatoms independently selected from phenyl or oxygen, nitrogen, and sulfur. In certain embodiments, R 5 phenyl is a 5-6 membered monocyclic heteroaryl containing one, two, or three heteroatoms independently selected from phenyl or oxygen, nitrogen, and sulfur; phenyl and heteroaryl contain one, two, or three R 8 It may be replaced by the presence of R 5 It is a 5-6 membered monocyclic heteroaryl compound containing one, two, or three heteroatoms independently selected from phenyl or oxygen, nitrogen, and sulfur.

[0162] In a particular embodiment, R5 This is 1, 2, or 3 R 8 It is a phenyl which may be substituted with the presence of R 5 is phenyl, 4-fluorophenyl, 4-cyanophenyl, 3-cyanophenyl, 2-cyanophenyl, 4-methylphenyl, 3-methylphenyl, or 2-methylphenyl. In certain embodiments, R 5 It is phenyl.

[0163] In a particular embodiment, R 5 This is 1, 2, or 3 R 8 C may be replaced by the presence of 3~7 It is a cycloalkyl. In a particular embodiment, R 5 is C 3~7 It is a cycloalkyl. In a particular embodiment, R 5 These are cyclopropyl, cyclobutyl, or cyclopentyl.

[0164] In a particular embodiment, R 5 A is a 3- to 7-membered saturated heterocycline containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; a heterocycline contains one, two, or three R 8 It may be replaced by the presence of R 3 These are azetidinil, pyrrolidinil, piperidinil, morpholinil, or piperazinil; each of them contains one, two, or three R 8 It may be replaced by the presence of R 5 It is a 3- to 7-membered saturated heterocycline containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0165] In a particular embodiment, R 5 A heteroaryl is a 5-10 member monocyclic or bicyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; the heteroaryl contains one, two, or three R 8It may be replaced by the presence of R 5 This is a 5- to 10-membered monocyclic or bicyclic heteroaryl compound containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0166] In a particular embodiment, R 5 A heteroaryl compound is a 5-6 membered monocyclic heteroaryl compound containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; the heteroaryl compound contains one, two, or three R 8 It may be replaced by the presence of R 5 R is a 5-6 membered monocyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 5 These are thiazolyl, imidazolinyl, oxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl; each of them contains one, two, or three R 8 It may be replaced by the presence of R 5 These are thiazolyl, imidazolinil, oxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.

[0167] In a particular embodiment, R 5 A heteroaryl compound is a five-membered monocyclic heteroaryl compound containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; the heteroaryl compound contains one, two, or three R 8 It may be replaced by the presence of R 5 It is a five-membered monocyclic heteroaryl compound containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0168] In a particular embodiment, R 5 A heteroaryl compound is a six-membered monocyclic heteroaryl compound containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; the heteroaryl compound contains one, two, or three R8 It may be replaced by the presence of R 5 It is a six-membered monocyclic heteroaryl compound containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0169] In a particular embodiment, R 5 A heteroaryl compound is an 8-10 membered bicyclic heteroaryl compound containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; the heteroaryl compound contains one, two, or three R 8 It may be replaced by the presence of R 5 R is an 8- to 10-membered bicyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 5 The group is selected from the groups shown in the compounds in Table 2 below.

[0170] As generally defined above, R 6 and R 7 Hydrogen and C are independent of each other. 1~6 Alkyl, C 2~6 Hydroxylalkyl, -(C 1~6 Alkylene)-C 3~6 Cycloalkyl, -(C 2~6 Alkylene)-N(R 9 )(R 10 ), or R 5 In a particular embodiment, R 6 and R 7 These are independently hydrogen or C 1~6 It is alkyl. In a particular embodiment, R 6 is hydrogen or C 1~6 It is alkyl, R 7 C 2~6 Hydroxylalkyl, -(C 1~6 Alkylene)-C 3~6 Cycloalkyl, -(C 2~6 Alkylene)-N(R 9 )(R 10 ), or R 5In a particular embodiment, R 6 is hydrogen or C 1~6 It is alkyl, R 7 C 2~6 Hydroxylalkyl or -(C 2~6 Alkylene)-N(R 9 )(R 10 ) In a particular embodiment, R 6 and R 7 The group is selected from the groups shown in the compounds in Table 2 below.

[0171] As generally defined above, R 8 For each entity, independently, halogens, cyanos, and saturated C 1~6 Aliphatic, or C 1~4 Represents alkoxyl; or two R 8 The presence of these intervening atoms, together with the intervening atoms, forms a ring. In a particular embodiment, R 8 For each entity, independently, halogens, cyanos, and saturated C 1~6 Aliphatic, or C 1~4 Represents alkoxyl. In certain embodiments, R 8 Each element independently represents a halogen or cyano. In certain embodiments, two R 8 The presence of these intervening atoms, together with the intervening atoms, forms a ring. In a particular embodiment, R 8 The group is selected from the groups shown in the compounds in Table 2 below.

[0172] As generally defined above, R 9 and R 10 Each of these independently exists as either hydrogen or C. 1~6 Represents an alkyl group. In a particular embodiment, R 9 and R 10 is hydrogen. In a particular embodiment, R 9 and R 10 Each of these is independent of each existence, C 1~6 Represents an alkyl group. In a particular embodiment, R 9 and R 10The group is selected from the groups shown in the compounds in Table 2 below.

[0173] As generally defined above, m is 0, 1, or 2. In certain embodiments, m is 0 or 1. In certain embodiments, m is 1 or 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is selected from the values ​​represented in the compounds in Table 2 below.

[0174] As generally defined above, n is either 0 or 1. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, m is selected from the values ​​represented in the compounds in Table 2 below.

[0175] In a particular embodiment, the compound of formula II is the compound of formula IIa or formula IIb: [ka] or a pharmaceutically acceptable salt thereof (wherein R 4 (as defined in the embodiments herein). In certain embodiments, the compound is a compound of formula IIa or formula IIb.

[0176] In a particular embodiment, the compound of formula II is a compound of formula IIc or formula IId: [ka] or a pharmaceutically acceptable salt thereof (wherein R 4 (as defined in the embodiments herein). In certain embodiments, the compound is a compound of formula IIc or formula IId.

[0177] In a particular embodiment, the compound of formula II is the compound of formula IIe or formula IIf: [ka] or a pharmaceutically acceptable salt thereof (wherein R 4 (as defined in the embodiments herein). In certain embodiments, the compound is a compound of formula IIe or formula IIf.

[0178] The above description outlines several embodiments relating to the compound of Formula II. This patent application specifically intends all combinations of these embodiments.

[0179] Another aspect of the present invention relates to a compound represented by formula IIIa or formula IIIb: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is hydrogen or C 1~4 It is alkyl; R 2 is hydrogen, C 1~4 Alkyl, C 1~4 Alkenil, C 1~4 Alkinyl, C 1~4 Haloalkyl, -(C 0~4 Alkylene)-(C 3~7 Cycloalkyl), or -(C 1~4 Alkilen)-OR 6 It is; or R 1 and R 2 These, together with the nitrogen atom to which they are bonded, form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatoms selected from nitrogen, oxygen, and sulfur, where the 3- to 7-membered heterocyclic ring contains 0, 1, 2, or 3 R 7 It is replaced by the presence of; R 3 C 1~4 It is a fluoroalkyl group; R 4 C 1~4 Alkyl, hydrogen, C 1~4 Haloalkyl, -(C 0~4 Alkylene)-(C 3~7 Cycloalkyl, or -C(O)-(C1~4 Alkyl) is; R 5 and R 6 Each of them is independently of hydrogen or C 1~4 Represents alkyl; R 7 C is independent of each existence. 1~4 Alkyl, C 3~6 Represents cycloalkyl or halo; and X is C 1~3 Alkylene or C 1~3 (It is a deuteroalkylene.) To provide.

[0180] The definitions of variable elements in formulas IIIa and IIIb above encompass multiple chemical groups. This application intends, for example, embodiments where i) the definition of a variable element is a single chemical group selected from the chemical groups shown above, ii) the definition of a variable element is a set of two or more chemical groups selected from the chemical groups shown above, and iii) the compound is defined by a combination of variable elements defined by (i) or (ii).

[0181] In certain embodiments, the compound is the compound of formula IIIa or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is the compound of formula IIIa. In certain embodiments, the compound is the compound of formula IIIb or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is the compound of formula IIIb. In certain embodiments, the compound is the compound of formula IIIa of formula IIIb.

[0182] As generally defined above, R 1 is hydrogen or C 1~4 Alkyl; or R 1 and R 2 Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the 3- to 7-membered heterocyclic ring contains 0, 1, 2, or 3 R 7It is replaced by the presence of [something].

[0183] In a particular embodiment, R 1 is hydrogen or C 1~4 It is alkyl. In a particular embodiment, R 1 is hydrogen or methyl. In a particular embodiment, R 1 is hydrogen. In a particular embodiment, R 1 C 1~4 It is alkyl. In a particular embodiment, R 1 is methyl. In a particular embodiment, R 1 The group is selected from the groups shown in the compounds in Table 3 below.

[0184] As generally defined above, R 2 is hydrogen, C 1~4 Alkyl, C 1~4 Alkenil, C 1~4 Alkinyl, C 1~4 Haloalkyl, -(C 0~4 Alkylene)-(C 3~7 Cycloalkyl), or -(C 1~4 Alkilen)-OR 6 It is; or R 1 and R 2 Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the 3- to 7-membered heterocyclic ring contains 0, 1, 2, or 3 R 7 It is replaced by the presence of [something].

[0185] In a particular embodiment, R 2 is hydrogen, C 1~4 Alkyl, C 1~4 Alkenil, C 1~4 Alkinyl, C 1~4 Haloalkyl, -(C 0~4 Alkylene)-(C 3~7 Cycloalkyl), or -(C 1~4 Alkilen)-OR 6 In a particular embodiment, R 2C 1~4 Alkenil, C 1~4 Alkinyl, C 1~4 Haloalkyl, -(C 0~4 Alkylene)-(C 3~7 Cycloalkyl), or -(C 1~4 Alkilen)-OR 6 That is the case.

[0186] In a particular embodiment, R 2 is hydrogen, C 1~4 Alkyl, C 1~4 Alkenil, C 1~4 Alkinyl, or C 1~4 It is a haloalkyl. In a particular embodiment, R 2 is hydrogen or C 1~4 It is alkyl. In a particular embodiment, R 2 is hydrogen or methyl. In a particular embodiment, R 2 C 1~4 Alkyl, C 1~4 Alkenil, C 1~4 Alkinyl, or C 1~4 It is a haloalkyl. In a particular embodiment, R 2 is hydrogen. In a particular embodiment, R 2 is C 1~4 It is alkyl. In a particular embodiment, R 2 is methyl. In a particular embodiment, R 2 is C 1~4 It is an alkenyl. In a particular embodiment, R 2 is C 1~4 In certain embodiments, R 2 is C 1~4 It is a haloalkyl group.

[0187] In a particular embodiment, R 2 is, -(C 0~4 Alkylene)-(C 3~7 Cycloalkyl) or -(C 1~4 Alkilen)-OR 6 In a particular embodiment, R 2 is, -(C 0~4 Alkylene)-(C3~7 It is a cycloalkyl. In a particular embodiment, R 2 is, -(C 1~4 Alkilen)-OR 6 In a particular embodiment, R 2 The group is selected from the groups shown in the compounds in Table 3 below.

[0188] In a particular embodiment, R 1 and R 2 Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the 3- to 7-membered heterocyclic ring contains 0, 1, 2, or 3 R 7 It is replaced by the presence of R 1 and R 2 Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein the additional nitrogen atom is C 1~4 It may be substituted with alkyl. In a particular embodiment, R 1 and R 2 These, together with the nitrogen atoms to which they are bonded, form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and zero or one additional nitrogen atom; the additional nitrogen atom is C 1~4 It may be substituted with alkyl. In a particular embodiment, R 1 and R 2 These, together with the nitrogen atom to which they are bonded, form a 3- to 7-membered heterocyclic ring containing nitrogen atoms and no additional heteroatoms; the 3- to 7-membered heterocyclic ring may have 0, 1, 2, or 3 R atoms. 7 It is replaced by the presence of [something].

[0189] In a particular embodiment, R 1 and R 2Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and zero or one additional heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 1 and R 2 These, together with the nitrogen atoms to which they are bonded, form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and zero or one additional nitrogen atom. In certain embodiments, R 1 and R 2 These, together with the nitrogen atoms to which they are bonded, form a 3- to 7-membered heterocyclic ring containing nitrogen atoms but no additional heteroatoms. In certain embodiments, R 1 and R 2 The group is selected from the groups shown in the compounds in Table 3 below.

[0190] As generally defined above, R 3 C 1~4 It is a fluoroalkyl. In a particular embodiment, R 3 C 1~2 It is a fluoroalkyl. In a particular embodiment, R 3 is a C1 fluoroalkyl. In certain embodiments, the fluoroalkyl contains at least three fluorine atoms. In certain embodiments, R 3 C 1~2 It is a trifluoroalkyl. In a particular embodiment, R 3 is trifluoromethyl. In a particular embodiment, R 3 The group is selected from the groups shown in the compounds in Table 3 below.

[0191] As generally defined above, R 4 C 1~4 Alkyl, hydrogen, C 1~4 Haloalkyl, -(C 0~4 Alkylene)-(C 3~7 Cycloalkyl, or -C(O)-(C 1~4 It is alkyl. In a particular embodiment, R 4 C 1~4 Alkyl, C1~4 Haloalkyl, -(C 0~4 Alkylene)-(C 3~7 Cycloalkyl, or -C(O)-(C 1~4 It is alkyl. In a particular embodiment, R 4 C 1~4 Alkyl, hydrogen, C 1~4 Haloalkyl, -(C 0~4 Alkylene)-(C 3~7 It is a cycloalkyl. In a particular embodiment, R 4 C 1~4 Haloalkyl, -(C 0~4 Alkylene)-(C 3~7 Cycloalkyl, or -C(O)-(C 1~4 It is alkyl.

[0192] In a particular embodiment, R 4 C 1~4 It is alkyl. In a particular embodiment, R 4 is methyl. In a particular embodiment, R 4 is hydrogen. In a particular embodiment, R 4 C 1~4 It is a haloalkyl. In a particular embodiment, R 4 is, -(C 0~4 Alkylene)-(C 3~7 It is a cycloalkyl. In a particular embodiment, R 4 C 3~7 It is a cycloalkyl. In a particular embodiment, R 4 is, -(C 1~4 Alkylene)-(C 3~7 It is a cycloalkyl. In a particular embodiment, R 4 is -C(O)-(C 1~4 It is alkyl. In a particular embodiment, R 4 The group is selected from the groups shown in the compounds in Table 3 below.

[0193] As generally defined above, R 5 and R 6 Each of them independently represents hydrogen or C 1~4Represents an alkyl group. In a particular embodiment, R 5 and R 6 is hydrogen. In a particular embodiment, R 5 and R 6 Each of them is independent of C 1~4 Represents an alkyl group. In a particular embodiment, R 5 is hydrogen. In a particular embodiment, R 5 C 1~4 It is alkyl. In a particular embodiment, R 6 is hydrogen. In a particular embodiment, R 6 is C 1~4 It is alkyl. In a particular embodiment, R 5 and R 6 The group is selected from the groups shown in the compounds in Table 3 below.

[0194] As generally defined above, R 7 C is independent of each existence. 1~4 Alkyl, C 3~6 Represents a cycloalkyl or halo. In certain embodiments, R 7 C is independent of each existence. 1~4 Alkyl or C 3~6 Represents a cycloalkyl group. In certain embodiments, R 7 C is independent of each existence. 1~4 Represents alkyl or halo. In certain embodiments, R 7 C is independent of each existence. 3~6 Represents cycloalkyl or halo.

[0195] In a particular embodiment, R 7 C is independent of each existence. 1~4 Represents an alkyl group. In a particular embodiment, R 7 C is independent of each existence. 3~6 Represents a cycloalkyl group. In certain embodiments, R 7 This represents a halo independently for each entity. In a particular embodiment, R 7 The group is selected from the groups shown in the compounds in Table 3 below.

[0196] As generally defined above, X is C 1~3 Alkylene or C 1~3 It is a deuteroalkylene. In certain embodiments, X is -CH2CH2- or -CH2CH(CH3)-. In certain embodiments, X is -CH2CH2-. In certain embodiments, X is -CH2CH2CH2-. In certain embodiments, X is -CH2CH(CH3)-. In certain embodiments, X is -CH2-. In certain embodiments, X is C 1~3 It is a deuteroalkylene.

[0197] In certain embodiments, X is -CZ2CZ2-, where each Z is hydrogen or deuterium, with at least 75% being deuterium in Z. In certain embodiments, the amount of deuterium in Z is at least 90%. In certain embodiments, the amount of deuterium in Z is at least 95%. In certain embodiments, X is -CD2CH2-. In certain embodiments, X is -CH2CD2-. In certain embodiments, X is -CD2CD2-.

[0198] In a particular embodiment, X is selected from the groups shown in the compounds in Table 3 below.

[0199] The above description outlines several embodiments relating to the compounds of formulas IIIa and IIIb. This patent application specifically intends all combinations of these embodiments.

[0200] Another aspect of the present invention relates to a compound represented by formula IV: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is hydrogen or C 1~4 It is alkyl; R 2 is hydrogen, C 1~4Alkyl, C 1~4 Alkenil, C 1~4 Alkinyl, C 1~4 Haloalkyl, -(C 0~4 Alkylene)-(C 3~7 Cycloalkyl), -(C 1~4 Alkilen)-OR 5 ,-(C 1~4 Alkylene)-N(R 5 )(R 6 ), -(C 1~4 Alkylene)-P(O)(OR 5 )(OR 6 ), -(C 0~4 Alkylene)-phenyl,-(C 0~4 Alkylene)-(a 5-10 member monocyclic or bicyclic heteroaryl containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur), or-(C 0~4 Alkylene)-(a 3-10 member monocyclic or bicyclic saturated or partially unsaturated heterocycline containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur); cycloalkyl, phenyl, heteroaryl, and heterocyclines are n R 4 It is replaced by the presence of; Or R 1 and R 2 These, together with the nitrogen atom to which they are bonded, form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatoms selected from nitrogen, oxygen, and sulfur, where the 3- to 7-membered heterocyclic ring contains 0, 1, 2, or 3 R 4 It is replaced by the presence of; R 3 C 1~4 It is a fluoroalkyl group; R 4 C is independent of each existence. 1~4 Alkyl, C 1~4 Haloalkyl, Halo, -(C 0~4 Alkilen)-OR 5 , or -(C 0~4 Alkylene)-N(R 5 )(R 6 ) represents; R 5 and R 6 These are, independently of each other, hydrogen and C. 1~4 Alkyl, or C 1~4 Represents a haloalkyl group; X is C 1~3 Alkylene or C 1~3 It is a deuteroalkylene; and n is 0, 1, 2, 3, or 4. To provide.

[0201] The definition of a variable element in Formula IV above encompasses multiple chemical groups. This application intends, for example, embodiments in which i) the definition of a variable element is a single chemical group selected from the chemical groups shown above, ii) the definition of a variable element is a set of two or more chemical groups selected from the chemical groups shown above, and iii) the compound is defined by a combination of variable elements defined by (i) or (ii).

[0202] In certain embodiments, the compound is the compound of formula IV.

[0203] As generally defined above, R 1 is hydrogen or C 1~4 Alkyl; or R 1 and R 2 Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the 3- to 7-membered heterocyclic ring contains 0, 1, 2, or 3 R 4 It is replaced by the presence of [something].

[0204] In a particular embodiment, R 1 is hydrogen or C 1~4 It is alkyl. In a particular embodiment, R 1 is hydrogen or methyl. In a particular embodiment, R 1 is hydrogen. In a particular embodiment, R 1 C 1~4It is alkyl. In a particular embodiment, R 1 is methyl. In a particular embodiment, R 1 The group is selected from the groups shown in the compounds in Table 4 below.

[0205] As generally defined above, R 2 is hydrogen, C 1~4 Alkyl, C 1~4 Alkenil, C 1~4 Alkinyl, C 1~4 Haloalkyl, -(C 0~4 Alkylene)-(C 3~7 Cycloalkyl), -(C 1~4 Alkilen)-OR 5 ,-(C 1~4 Alkylene)-N(R 5 )(R 6 ), -(C 1~4 Alkylene)-P(O)(OR 5 )(OR 6 ), -(C 0~4 Alkylene)-phenyl,-(C 0~4 Alkylene)-(a 5-10 member monocyclic or bicyclic heteroaryl containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur), or-(C 0~4 Alkylene)-(a 3-10 member monocyclic or bicyclic saturated or partially unsaturated heterocycline containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur); cycloalkyl, phenyl, heteroaryl, and heterocyclines are n R 4 It is replaced by the presence of R 1 and R 2 Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the 3- to 7-membered heterocyclic ring contains 0, 1, 2, or 3 R 4 It is replaced by the presence of [something].

[0206] In a particular embodiment, R 2 is hydrogen, C 1~4Alkyl, C 1~4 Alkenil, C 1~4 Alkinyl, C 1~4 Haloalkyl, -(C 0~4 Alkylene)-(C 3~7 Cycloalkyl), -(C 1~4 Alkilen)-OR 5 ,-(C 1~4 Alkylene)-N(R 5 )(R 6 ), -(C 1~4 Alkylene)-P(O)(OR 5 )(OR 6 ), -(C 0~4 Alkylene)-phenyl,-(C 0~4 Alkylene)-(a 5-10 member monocyclic or bicyclic heteroaryl containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur), or-(C 0~4 Alkylene)-(a 3-10 member monocyclic or bicyclic saturated or partially unsaturated heterocycline containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur); cycloalkyl, phenyl, heteroaryl, and heterocyclines are n R 4 It is replaced by the presence of [something].

[0207] In a particular embodiment, R 2 is hydrogen, C 1~4 Alkyl, C 1~4 Alkenil, C 1~4 Alkinyl, or C 1~4 It is a haloalkyl. In a particular embodiment, R 2 is hydrogen or C 1~4 It is alkyl. In a particular embodiment, R 2 is hydrogen or methyl. In a particular embodiment, R 2 C 1~4 Alkyl, C 1~4 Alkenil, C 1~4 Alkinyl, or C 1~4 It is a haloalkyl. In a particular embodiment, R 2 is hydrogen. In a particular embodiment, R 2 C1~4 It is alkyl. In a particular embodiment, R 2 is methyl. In a particular embodiment, R 2 C 1~4 It is an alkenyl. In a particular embodiment, R 2 is C 1~4 In certain embodiments, R 2 is C 1~4 It is a haloalkyl group.

[0208] In a particular embodiment, R 2 is, -(C 1~4 Alkilen)-OR 5 ,-(C 1~4 Alkylene)-N(R 5 )(R 6 ), or -(C 1~4 Alkylene)-P(O)(OR 5 )(OR 6 ) In a particular embodiment, R 2 is, -(C 1~4 Alkilen)-OR 5 In a particular embodiment, R 2 is, -(C 1~4 Alkylene)-N(R 5 )(R 6 ) In a particular embodiment, R 2 is, -(C 1~4 Alkylene)-P(O)(OR 5 )(OR 6 )

[0209] In a particular embodiment, R 2 is, -(C 0~4 Alkylene)-(C 3~7 Cycloalkyl), -(C 0~4 Alkylene)-phenyl,-(C 0~4 Alkylene)-(a 5-10 member monocyclic or bicyclic heteroaryl containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur), or-(C 0~4Alkylene)-(a 3-10 member monocyclic or bicyclic saturated or partially unsaturated heterocycline containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur); cycloalkyl, phenyl, heteroaryl, and heterocyclines are n R 4 It is replaced by the presence of [something].

[0210] In a particular embodiment, R 2 is, -(C 0~4 Alkylene)-(C 3~7 Cycloalkyl) or -(C 0~4 Alkylene)-phenyl; cycloalkyl and phenyl have n R 4 It is replaced by the presence of R 2 is, -(C 0~4 Alkylene)-(C 3~7 It is a cycloalkyl group; the cycloalkyl group consists of n R 4 It is replaced by the presence of R 2 is, -(C 1~4 Alkylene)-(C 3~7 It is a cycloalkyl group; the cycloalkyl group consists of n R 4 It is replaced by the presence of R 2 This is n R 4 C replaced by the presence of 3~7 It is a cycloalkyl. In a particular embodiment, R 2 This is n R 4 C replaced by the presence of 5~6 It is a cycloalkyl. In a particular embodiment, R 2 ha-(C 0~4 Alkylene)-phenyl is; phenyl has n R 4 It is replaced by the presence of R 2 is, -(C 1~4 Alkylene)-phenyl is; phenyl has n R 4 It is replaced by the presence of R 2 This is n R 4 This is a phenyl compound substituted with the presence of [substance name].

[0211] In a particular embodiment, R 2 is, -(C 0~4 Alkylene)-(5-10 membered monocyclic or bicyclic heteroaryl containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur) or-(C 0~4 Alkylene)-(a 3-10 member monocyclic or bicyclic saturated or partially unsaturated heterocycline containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur); heteroaryls and heterocyclines are n R 4 It is replaced by the presence of [something].

[0212] In a particular embodiment, R 2 is, -(C 0~4 Alkylene)-(a 5-10 member monocyclic or bicyclic heteroaryl containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur); the heteroaryl has n R 4 It is replaced by the presence of [something].

[0213] In a particular embodiment, R 2 is, -(C 0~4 Alkylene)-(a 5-6 membered monocyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur); the heteroaryl has n R 4 It is replaced by the presence of R 2 ha-(C 1~4 Alkylene)-(a 5-6 membered monocyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur); the heteroaryl has n R 4 It is replaced by the presence of R 2 A heteroaryl compound is a 5-6 membered monocyclic heteroaryl compound containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; the heteroaryl compound contains n R 4 It is replaced by the presence of [something].

[0214] In a particular embodiment, R 2 is, -(C 0~4 Alkylene)-(a five-membered monocyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur); the heteroaryl has n R 4 It is replaced by the presence of R 2 is, -(C 1~4 Alkylene)-(a five-membered monocyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur); the heteroaryl has n R 4 It is replaced by the presence of R 2 It is a five-membered monocyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; the heteroaryl has n R 4 It is replaced by the presence of [something].

[0215] In a particular embodiment, R 2 is, -(C 0~4 Alkylene is a six-membered monocyclic heteroaryl containing one or two heteroatoms selected from nitrogen; the heteroaryl has n R 4 It is replaced by the presence of R 2 is, -(C 1~4 Alkylene is a six-membered monocyclic heteroaryl containing one or two heteroatoms selected from nitrogen; the heteroaryl has n R 4 It is replaced by the presence of R 2 It is a six-membered monocyclic heteroaryl containing one or two heteroatoms selected from nitrogen; the heteroaryl has n R 4 It is replaced by the presence of [something].

[0216] In a particular embodiment, R 2 is, -(C 0~4Alkylene)-(an 8-10 membered bicyclic heteroaryl containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur); the heteroaryl has n R 4 It is replaced by the presence of R 2 is, -(C 1~4 Alkylene)-(an 8-10 membered bicyclic heteroaryl containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur); the heteroaryl has n R 4 It is replaced by the presence of R 2 It is an 8-10 membered bicyclic heteroaryl containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur; the heteroaryl contains n R 4 It is replaced by the presence of [something].

[0217] In a particular embodiment, R 2 is, -(C 0~4 Alkylene)-(a 3-10 member monocyclic or bicyclic saturated or partially unsaturated heterocycline containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur); the heterocycline is a polycyclic polycycline with n R 4 It is replaced by the presence of [something].

[0218] In a particular embodiment, R 2 is, -(C 0~4 Alkylene)-(a 3-7 member monocyclic saturated or partially unsaturated heterocycline containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur); the heterocycline is a heterocycline with n R 4 It is replaced by the presence of R 2 is, -(C 0~4 Alkylene)-(a 5-6 member monocyclic saturated heterocycline containing one or two heteroatoms independently selected from oxygen and nitrogen); the heterocycline is a 5-6 member monocyclic saturated heterocycline containing n R 4 It is replaced by the presence of R 2 is, -(C1~4 Alkylene)-(a 5-6 member monocyclic saturated heterocycline containing one or two heteroatoms independently selected from oxygen and nitrogen); the heterocycline is a 5-6 member monocyclic saturated heterocycline containing n R 4 It is replaced by the presence of R 2 A heterocycline is a 5-6 member monocyclic saturated heterocycline containing one or two heteroatoms independently selected from oxygen and nitrogen; a heterocycline contains n R 4 It is replaced by the presence of [something].

[0219] In a particular embodiment, R 2 is, -(C 0~4 Alkylene)-(a 7-10 membered bicyclic saturated or partially unsaturated heterocycline containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur); the heterocycline is a group of n R 4 It is replaced by the presence of R 2 is, -(C 1~4 Alkylene)-(a 7-10 membered bicyclic saturated or partially unsaturated heterocycline containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur); the heterocycline is a group of n R 4 It is replaced by the presence of R 2 A is a 7-10 membered bicyclic saturated or partially unsaturated heterocycline containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; a heterocycline is a polycyclic polycycline containing n R 4 It is replaced by the presence of [something].

[0220] In a particular embodiment, R 2 The group is selected from the groups shown in the compounds in Table 4 below.

[0221] In a particular embodiment, R 1 and R 2Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the 3- to 7-membered heterocyclic ring contains 0, 1, 2, or 3 R 4 It is replaced by the presence of R 1 and R 2 Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein the additional nitrogen atom is C 1~4 It may be substituted with alkyl. In a particular embodiment, R 1 and R 2 These, together with the nitrogen atoms to which they are bonded, form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and zero or one additional nitrogen atom; the additional nitrogen atom is C 1~4 It may be substituted with alkyl. In a particular embodiment, R 1 and R 2 These, together with the nitrogen atom to which they are bonded, form a 3- to 7-membered heterocyclic ring containing nitrogen atoms and no additional heteroatoms; the 3- to 7-membered heterocyclic ring may have 0, 1, 2, or 3 R atoms. 4 It is replaced by the presence of [something].

[0222] In a particular embodiment, R 1 and R 2 Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and zero or one additional heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 1 and R 2 These, together with the nitrogen atoms to which they are bonded, form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and zero or one additional nitrogen atom. In certain embodiments, R 1 and R 2These, together with the nitrogen atoms to which they are bonded, form a 3- to 7-membered heterocyclic ring containing nitrogen atoms but no additional heteroatoms. In certain embodiments, R 1 and R 2 The group is selected from the groups shown in the compounds in Table 4 below.

[0223] As generally defined above, R 3 C 1~4 It is a fluoroalkyl. In a particular embodiment, R 3 C 1~2 It is a fluoroalkyl. In a particular embodiment, R 3 is a C1 fluoroalkyl. In certain embodiments, the fluoroalkyl contains at least three fluorine atoms. In certain embodiments, R 3 C 1~2 It is a trifluoroalkyl. In a particular embodiment, R 3 is trifluoromethyl. In a particular embodiment, R 3 The group is selected from the groups shown in the compounds in Table 4 below.

[0224] As generally defined above, R 4 C is independent of each existence. 1~4 Alkyl, C 1~4 Haloalkyl, Halo, -(C 0~4 Alkilen)-OR 5 , or -(C 0~4 Alkylene)-N(R 5 )(R 6 ) represents. In a particular embodiment, R 4 C is independent of each existence. 1~4 Alkyl, C 1~4 Represents haloalkyl or halo. In certain embodiments, R 4 This is independent for each existence, -(C 0~4 Alkilen)-OR 5 or -(C 0~4 Alkylene)-N(R 5 )(R 6 ) represents. In a particular embodiment, R 4These independently represent methyl, fluoro, -OH, -CH2-OH, and -NH2 for each entity.

[0225] In a particular embodiment, R 4 C is independent of each existence. 1~4 Represents an alkyl group. In a particular embodiment, R 4 C is independent of each existence. 1~4 Represents a haloalkyl group. In a particular embodiment, R 4 This represents a halo independently for each entity. In a particular embodiment, R 4 This is independent for each existence, -(C 0~4 Alkilen)-OR 5 This represents R 4 This is independent for each existence, -(C 0~4 Alkylene)-N(R 5 )(R 6 ) represents. In a particular embodiment, R 4 The group is selected from the groups shown in the compounds in Table 4 below.

[0226] As generally defined above, R 5 and R 6 Each of these independently exists as hydrogen, C 1~4 Alkyl, or C 1~4 Represents a haloalkyl group. In a particular embodiment, R 5 and R 6 is hydrogen. In a particular embodiment, R 5 and R 6 Each of these is independent of each existence, C 1~4 Represents an alkyl group. In a particular embodiment, R 5 and R 6 Each of these is independent of each existence, C 1~4 Represents a haloalkyl group. In a particular embodiment, R 5 and R 6 The group is selected from the groups shown in the compounds in Table 4 below.

[0227] As generally defined above, X is C 1~3Alkylene or C 1~3 It is a deuteroalkylene. In certain embodiments, X is -CH2CH2- or -CH2CH(CH3)-. In certain embodiments, X is -CH2CH2-. In certain embodiments, X is -CH2CH2CH2-. In certain embodiments, X is -CH2CH(CH3)-. In certain embodiments, X is -CH2-. In certain embodiments, X is C 1~3 It is a deuteroalkylene.

[0228] In certain embodiments, X is -CZ2CZ2-, where each Z is hydrogen or deuterium, with at least 75% being deuterium in Z. In certain embodiments, the amount of deuterium in Z is at least 90%. In certain embodiments, the amount of deuterium in Z is at least 95%. In certain embodiments, X is -CD2CH2-. In certain embodiments, X is -CH2CD2-. In certain embodiments, X is -CD2CD2-.

[0229] In a particular embodiment, X is selected from the groups shown in the compounds in Table 4 below.

[0230] As generally defined above, n is 0, 1, 2, 3, or 4. In certain embodiments, n is 0, 1, or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is selected from the values ​​represented in the compounds in Table 4 below.

[0231] The above description outlines several embodiments relating to the compound of formula IV. This patent application specifically intends all combinations of these embodiments.

[0232] Another aspect of the present invention relates to a compound represented by formula V: [ka] or a pharmaceutically acceptable salt thereof (In the formula, A 1 These are phenyl, pyridinyl, thiazolyl, dihydroisoquinolinyl, or quinazolinol; each of them contains one R 2 It is replaced by the presence of; R 1 C 1~4 It is a fluoroalkyl group; R 2 is -C(O)N(R 3 )(R 4 );-CO2R 3 ;C 1~4 Alkyl; C 1~4 Haloalkyl;-C(O)-(C 1~4 Alkyl; a 5-membered or 6-membered monocyclic heteroaryl containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur; or a 3- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur; R 2 -C(O)N(R 3 )(R 4 ) unless R 2 This is one -N(R 6 )(R 7 It may be replaced by the presence of; R 3 is hydrogen or C 1~4 It is alkyl; R 4 is hydrogen, C 1~4 Alkyl, C 1~4 Alkenil, C 1~4 Alkinyl, C 1~4 Haloalkyl, -(C 0~4 Alkylene)-(C 3~7 Cycloalkyl), or one -C(O)N(R 6 )(R 7 ) may be replaced by the presence of -(C 1~4 Alkilen)-OR 6 And; or, R 3 and R 4These, together with the nitrogen atom to which they are bonded, form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatoms selected from nitrogen, oxygen, and sulfur, where the 3- to 7-membered heterocyclic ring contains 0, 1, 2, or 3 R 6 It is replaced by the presence of; R 6 and R 7 Each of these independently exists as either hydrogen or C. 1~4 Represents alkyl; R 8 C is independent of each existence. 1~4 Alkyl, C 3~6 Represents cycloalkyl or halo; and X 1 and X 2 Each of them is independent of C 1~3 (Represents alkylene) To provide.

[0233] The definition of a variable element in formula V above encompasses multiple chemical groups. This application intends, for example, embodiments where i) the definition of a variable element is a single chemical group selected from the chemical groups shown above, ii) the definition of a variable element is a set of two or more chemical groups selected from the chemical groups shown above, and iii) the compound is defined by a combination of variable elements defined by (i) or (ii).

[0234] In a particular embodiment, the compound is the compound of formula V.

[0235] As generally defined above, A 1 These are phenyl, pyridinyl, thiazolyl, dihydroisoquinolinyl, or quinazolinol; each of them contains one R 2 It is replaced by the presence of A. 1 is phenyl or pyridinyl, each of which has one R 2 It is replaced by the presence of A. 1These are pyridinyl, thiazolyl, dihydroisoquinolinyl, or quinazolinonyl; each of them contains one R 2 It is replaced by the presence of [something].

[0236] In a particular embodiment, A 1 This is one R 2 It is a phenyl substituted with the presence of A. In a particular embodiment, A 1 This is one R 2 It is a pyridinyl substituted with the presence of A 1 This is one R 2 It is thiazolyl substituted with the presence of A 1 This is one R 2 It is a dihydroisoquinolinyl substituted with the presence of A. In certain embodiments, A 1 This is one R 2 This is quinazolinyl replaced by the presence of [another element].

[0237] In a particular embodiment, A 1 teeth [ka] or [ka] In a particular embodiment, A 1 teeth [ka] In a particular embodiment, A 1 teeth [ka] or [ka] In a particular embodiment, A 1 teeth [ka] In a particular embodiment, A 1 teeth [ka] In a particular embodiment, A 1 teeth [ka] In a particular embodiment, A 1 teeth [ka] That is the case.

[0238] In a particular embodiment, A 1 teeth [ka] or [ka] In a particular embodiment, A 1 teeth [ka] In a particular embodiment, A 1 teeth [ka] or [ka] In a particular embodiment, A 1 teeth [ka] In a particular embodiment, A 1 teeth [ka] In a particular embodiment, A1 teeth [ka] In a particular embodiment, A 1 teeth [ka] That is the case.

[0239] In a particular embodiment, R 1 The group is selected from the groups shown in the compounds in Table 5 below.

[0240] As generally defined above, R 1 C 1~4 It is a fluoroalkyl. In a particular embodiment, R 1 C 1~2 It is a fluoroalkyl. In a particular embodiment, R 1 is a C1 fluoroalkyl. In certain embodiments, the fluoroalkyl contains at least three fluorine atoms. In certain embodiments, R 1 C 1~2 It is a trifluoroalkyl. In a particular embodiment, R 1 is trifluoromethyl. In a particular embodiment, R 1 The group is selected from the groups shown in the compounds in Table 5 below.

[0241] As generally defined above, R 2 is -C(O)N(R 3 )(R 4 );-CO2R 3 ;C 1~4 Alkyl; C 1~4 Haloalkyl;-C(O)-(C 1~4 Alkyl; a 5-membered or 6-membered monocyclic heteroaryl containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur; or a 3- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur; R 2-C(O)N(R 3 )(R 4 ) unless R 2 This is one -N(R 6 )(R 7 ) may be replaced by the presence of R 2 is -C(O)N(R 3 )(R 4 )

[0242] In a particular embodiment, R 2 -CO2R 3 , C 1~4 Alkyl, C 1~4 Haloalkyl, -C(O)-(C 1~4 A 3- to 7-membered monocyclic saturated heterocycline containing an alkyl group, or one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur; R 2 This is one -N(R 6 )(R 7 ) may be replaced by the presence of R 2 -CO2R 3 , C 1~4 Haloalkyl, -C(O)-(C 1~4 A 3- to 7-membered monocyclic saturated heterocycline containing an alkyl group, or one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur; R 2 This is one -N(R 6 )(R 7 ) may be replaced by the presence of R 2 C 1~4 Alkyl or C 1~4 It is a haloalkyl, and each of them has one -N(R 6 )(R 7 ) may be replaced by the presence of R 2 This is one -N(R 6 )(R 7 C may be replaced by the presence of ) 1~4 It is alkyl. In a particular embodiment, R 2 This is one -N(R 6 )(R 7C may be replaced by the presence of ) 1~4 It is a haloalkyl. In a particular embodiment, R 2 This is one -N(R 6 )(R 7 -CO2R may be substituted by the presence of ) 3 In a particular embodiment, R 2 This is one -N(R 6 )(R 7 -C(O)-(C 1~4 It is alkyl. In a particular embodiment, R 2 R is a 3- to 7-membered monocyclic saturated heterocycline containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur; 2 This is one -N(R 6 )(R 7 It may be replaced by the presence of )

[0243] In a particular embodiment, R 2 -CO2R 3 , C 1~4 Alkyl, C 1~4 Haloalkyl, -C(O)-(C 1~4 A 3- to 7-membered monocyclic saturated heterocycline containing an alkyl group, or one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur; R 2 This is one -N(R 6 )(R 7 ) is replaced by the presence of R 2 -CO2R 3 , C 1~4 Haloalkyl, -C(O)-(C 1~4 A 3- to 7-membered monocyclic saturated heterocycline containing an alkyl group, or one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur; R 2 This is one -N(R 6 )(R 7 ) is replaced by the presence of R 2 C 1~4 Alkyl or C 1~4 It is a haloalkyl, and each of them has one -N(R6 )(R 7 ) is replaced by the presence of R 2 This is one -N(R 6 )(R 7 C replaced by the presence of ) 1~4 It is alkyl. In a particular embodiment, R 2 This is one -N(R 6 )(R 7 C replaced by the presence of ) 1~4 It is a haloalkyl. In a particular embodiment, R 2 This is one -N(R 6 )(R 7 -CO2R replaced by the presence of ) 3 In a particular embodiment, R 2 This is one -N(R 6 )(R 7 -C(O)-(C) substituted by the presence of ) 1~4 It is alkyl. In a particular embodiment, R 2 R is a 3- to 7-membered monocyclic saturated heterocycline containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur; 2 This is one -N(R 6 )(R 7 It is replaced by the presence of ).

[0244] In a particular embodiment, R 2 -CO2R 3 , C 1~4 Alkyl, C 1~4 Haloalkyl, -C(O)-(C 1~4 A 3- to 7-membered monocyclic saturated heterocycline containing an alkyl group, or one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 2 -CO2R 3 , C 1~4 Haloalkyl, -C(O)-(C 1~4 A 3- to 7-membered monocyclic saturated heterocycline containing an alkyl group, or one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 2 C1~4 Alkyl or C 1~4 It is a haloalkyl. In a particular embodiment, R 2 C 1~4 It is alkyl. In a particular embodiment, R 2 C 1~4 It is a haloalkyl. In a particular embodiment, R 2 -CO2R 3 In a particular embodiment, R 2 is -C(O)-(C 1~4 It is alkyl. In a particular embodiment, R 2 It is a 3- to 7-membered monocyclic saturated heterocycline containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0245] In a particular embodiment, R 2 R is a 5-membered or 6-membered monocyclic heteroaryl containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur; 2 This is one -N(R 6 )(R 7 ) may be replaced by the presence of R 2 R is a five-membered monocyclic heteroaryl compound containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; 2 This is one -N(R 6 )(R 7 ) may be replaced by the presence of R 2 R is a six-membered monocyclic heteroaryl compound containing one, two, or three nitrogen heteroatoms; 2 This is one -N(R 6 )(R 7 It may be replaced by the presence of )

[0246] In a particular embodiment, R 2 R is a five-membered or six-membered monocyclic heteroaryl containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 2R is a five-membered monocyclic heteroaryl containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 2 is imidazolyl, oxazolyl, or thiazolyl. In certain embodiments, R 2 is imidazole-2-yl, oxazole-2-yl, or thiazole-2-yl. In certain embodiments, R 2 R is a six-membered monocyclic heteroaryl containing one, two, or three nitrogen heteroatoms. In certain embodiments, R 2 The group is selected from the groups shown in the compounds in Table 5 below.

[0247] As generally defined above, R 3 is hydrogen or C 1~4 Alkyl; or R 3 and R 4 Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the 3- to 7-membered heterocyclic ring contains 0, 1, 2, or 3 R 8 It is replaced by the presence of [something].

[0248] In a particular embodiment, R 3 is hydrogen or C 1~4 It is alkyl. In a particular embodiment, R 3 is hydrogen or methyl. In a particular embodiment, R 3 is hydrogen. In a particular embodiment, R 3 is C 1~4 It is alkyl. In a particular embodiment, R 3 is methyl. In a particular embodiment, R 3 The group is selected from the groups shown in the compounds in Table 5 below.

[0249] As generally defined above, R 4 is hydrogen, C 1~4 Alkyl, C 1~4 Alkenil, C1~4 Alkinyl, C 1~4 Haloalkyl, or one -C(O)N(R) 6 )(R 7 ) may be replaced by the presence of -(C 1~4 Alkilen)-OR 6 And; or, R 3 and R 4 Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the 3- to 7-membered heterocyclic ring contains 0, 1, 2, or 3 R 8 It is replaced by the presence of [something].

[0250] In a particular embodiment, R 4 is hydrogen, C 1~4 Alkyl, C 1~4 Alkenil, C 1~4 Alkinyl, C 1~4 Haloalkyl, or one -C(O)N(R) 6 )(R 7 ) may be replaced by the presence of -(C 1~4 Alkilen)-OR 6 In a particular embodiment, R 4 is hydrogen, C 1~4 Alkyl, C 1~4 Alkenil, C 1~4 Alkinyl, or C 1~4 It is a haloalkyl. In a particular embodiment, R 4 is hydrogen or C 1~4 It is alkyl. In a particular embodiment, R 4 is hydrogen or methyl. In a particular embodiment, R 4 C 1~4 Alkyl, C 1~4 Alkenil, C 1~4 Alkinyl, or C 1~4 It is a haloalkyl. In a particular embodiment, R 4 is hydrogen. In a particular embodiment, R 4 C 1~4 It is alkyl. In a particular embodiment, R 4is methyl. In a particular embodiment, R 4 C 1~4 It is an alkenyl. In a particular embodiment, R 4 C 1~4 In certain embodiments, R 4 C 1~4 It is a haloalkyl group.

[0251] In a particular embodiment, R 4 This is one -C(O)N(R 6 )(R 7 ) may be replaced by the presence of -(C 1~4 Alkilen)-OR 6 In a particular embodiment, R 4 is, -(C 1~4 Alkilen)-OR 6 In a particular embodiment, R 4 This is one -C(O)N(R 6 )(R 7 (C) is replaced by the presence of -(C) 1~4 Alkilen)-OR 6 In a particular embodiment, R 4 is, -(C 1~4 It is alkylene)-OH. In a particular embodiment, R 4 -(C) is substituted with the presence of one -C(O)NH2. 1~4 It is alkylene)-OH. In a particular embodiment, R 4 The group is selected from the groups shown in the compounds in Table 5 below.

[0252] In a particular embodiment, R 3 and R 4 Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the 3- to 7-membered heterocyclic ring contains 0, 1, 2, or 3 R 8 It is replaced by the presence of R 3 and R 4Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and 0 or 1 additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein the additional nitrogen atom is C 1~4 It may be substituted with alkyl. In a particular embodiment, R 3 and R 4 These, together with the nitrogen atoms to which they are bonded, form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and zero or one additional nitrogen atom; the additional nitrogen atom is C 1~4 It may be substituted with alkyl. In a particular embodiment, R 3 and R 4 These, together with the nitrogen atom to which they are bonded, form a 3- to 7-membered heterocyclic ring containing nitrogen atoms and no additional heteroatoms; the 3- to 7-membered heterocyclic ring may have 0, 1, 2, or 3 R atoms. 8 It is replaced by the presence of [something].

[0253] In a particular embodiment, R 3 and R 4 Together with the nitrogen atom to which they are bonded, they form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and zero or one additional heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 3 and R 4 These, together with the nitrogen atoms to which they are bonded, form a 3- to 7-membered heterocyclic ring containing a nitrogen atom and zero or one additional nitrogen atom. In certain embodiments, R 3 and R 4 These, together with the nitrogen atoms to which they are bonded, form a 3- to 7-membered heterocyclic ring containing nitrogen atoms but no additional heteroatoms. In certain embodiments, R 3 and R 4 The group is selected from the groups shown in the compounds in Table 5 below.

[0254] As generally defined above, R 6 and R 7 Each of these independently exists as either hydrogen or C. 1~4Represents an alkyl group. In a particular embodiment, R 6 and R 7 is hydrogen. In a particular embodiment, R 6 and R 7 Each of these is independent of each existence, C 1~4 Represents an alkyl group. In a particular embodiment, R 6 and R 7 is methyl. In a particular embodiment, R 6 is hydrogen. In a particular embodiment, R 6 is C 1~4 It is alkyl. In a particular embodiment, R 6 is methyl. In a particular embodiment, R 7 is hydrogen. In a particular embodiment, R 7 is C 1~4 It is alkyl. In a particular embodiment, R 7 is methyl. In a particular embodiment, R 6 and R 7 The group is selected from the groups shown in the compounds in Table 5 below.

[0255] As generally defined above, R 8 C is independent of each existence. 1~4 Alkyl, C 3~6 Represents a cycloalkyl or halo. In certain embodiments, R 8 C is independent of each existence. 1~4 Alkyl or C 3~6 Represents a cycloalkyl group. In certain embodiments, R 8 C is independent of each existence. 1~4 Represents alkyl or halo. In certain embodiments, R 8 C is independent of each existence. 3~6 Represents cycloalkyl or halo.

[0256] In a particular embodiment, R 8 C is independent of each existence. 1~4 Represents an alkyl group. In a particular embodiment, R 8 C is independent of each existence.3~6 Represents a cycloalkyl group. In certain embodiments, R 8 This represents a halo independently for each entity. In a particular embodiment, R 8 The group is selected from the groups shown in the compounds in Table 5 below.

[0257] As generally defined above, X 1 and X 2 Each of them is independent of C 1~3 Alkilen C 1~3 Represents a deuteroalkylene. In a particular embodiment, X 1 C 1~3 It is an alkylene. In a particular embodiment, X 1 is -CH2CH2- or -CH2CH(CH3)-. In a particular embodiment, X 1 is -CH2CH2-. In a particular embodiment, X 1 is -CH2CH2CH2-. In a particular embodiment, X 1 is -CH2CH(CH3)-. In a particular embodiment, X 1 is -CH2-. In a particular embodiment, X 1 C 1~3 It is a deuteroalkylene.

[0258] In a particular embodiment, X 1 X is -CZ2CZ2-, where each Z is hydrogen or deuterium, with the abundance of deuterium in Z being at least 75%. In certain embodiments, the abundance of deuterium in Z is at least 90%. In certain embodiments, the abundance of deuterium in Z is at least 95%. In certain embodiments, X is -CD2CH2-. In certain embodiments, X 1 is -CH2CD2-. In a particular embodiment, X 1 It is -CD2CD2-.

[0259] In a particular embodiment, X 1 The group is selected from the groups shown in the compounds in Table 5 below.

[0260] In a particular embodiment, X 2 C 1~3 It is an alkylene. In a particular embodiment, X 2 is -CH2CH2- or -CH2CH(CH3)-. In a particular embodiment, X 2 is -CH2CH2-. In a particular embodiment, X 2 is -CH2CH2CH2-. In a particular embodiment, X 2 is -CH2CH(CH3)-. In a particular embodiment, X 2 It is -CH2-.

[0261] In a particular embodiment, X 2 C 1~3 It is a deuteroalkylene. In a particular embodiment, X 2 X is -CZ2CZ2-, where each Z is hydrogen or deuterium, with the abundance of deuterium in Z being at least 75%. In certain embodiments, the abundance of deuterium in Z is at least 90%. In certain embodiments, the abundance of deuterium in Z is at least 95%. In certain embodiments, X is -CD2CH2-. In certain embodiments, X 2 is -CH2CD2-. In a particular embodiment, X 2 It is -CD2CD2-.

[0262] In a particular embodiment, X 2 The group is selected from the groups shown in the compounds in Table 5 below.

[0263] The above description outlines several embodiments relating to the compound of formula V. This patent application specifically intends all combinations of these embodiments.

[0264] Exemplary specific compounds In certain embodiments, the compound is one of the compounds in Table 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is one of the compounds in Table 1. In certain embodiments, the compound is one of the compounds I-1, I-3 to I-12, or I-24 to I-40 in Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is one of the compounds I-1, I-3 to I-12, or I-24 to I-40 in Table 1. In certain embodiments, the compound is one of the compounds in Table 1 or a pharmaceutically acceptable salt thereof, and the compound has the biological activity listed in Table 6. In certain embodiments, the compound is one of the compounds in Table 1, and the compound has the biological activity listed in Table 6. In certain embodiments, the compound is one of the compounds I-1 or I-2 in Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is one of the compounds I-1 or I-2 in Table 1.

[0265] [Table 1] TIFF0007863272000046.tif237160 TIFF0007863272000047.tif247161 TIFF0007863272000048.tif174107 TIFF0007863272000049.tif221161 TIFF0007863272000050.tif171107 TIFF0007863272000051.tif237160 TIFF0007863272000052.tif133160

[0266] In certain embodiments, the compound is one of the compounds in Table 2 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is one of the compounds in Table 2. In certain embodiments, the compound is one of the compounds II-1 to II-6 in Table 2 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is one of the compounds II-1 to II-6 in Table 2.

[0267] [Table 2] TIFF0007863272000054.tif232161 TIFF0007863272000055.tif225161 TIFF0007863272000056.tif156161

[0268] In certain embodiments, the compound is one of the compounds listed in Table 3 or a pharmaceutically acceptable salt thereof.

[0269] [Table 3] TIFF0007863272000058.tif241161 TIFF0007863272000059.tif193164

[0270] In certain embodiments, the compound is a compound from Table 4 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound from Table 4. In certain embodiments, the compound is compound IV-1 or IV-2 from Table 4, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound IV-1 or IV-2 from Table 4.

[0271] [Table 4] TIFF0007863272000061.tif216160

[0272] In certain embodiments, the compound is a compound from Table 5 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound from Table 5. In certain embodiments, the compound is compound V-1 from Table 5 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound V-1 from Table 5.

[0273] [Table 5] TIFF0007863272000063.tif237162 TIFF0007863272000064.tif254162 TIFF0007863272000065.tif69161

[0274] Synthesis method Methods for preparing the compounds described herein are illustrated in the following synthesis schemes. These schemes are provided for illustrative purposes only and are not intended to limit the scope or spirit of the invention. The starting materials shown in the schemes can be obtained from commercial sources or prepared according to procedures described in the literature.

[0275] Scheme 1 shows a general method for preparing (trifluoromethoxy)ethyl-imidazo[5,1-d]tetrazinecarboxamide B. The reaction of 2-(trifluoromethoxy)ethane-1-amine with diphosgene yields 1-isocyanato-2-(trifluoromethoxy)ethane. The reaction of imidazolyl A with 1-isocyanato-2-(trifluoromethoxy)ethane yields (trifluoromethoxy)ethyl-imidazo[5,1-d]tetrazinecarboxamide B.

[0276] Scheme 1. [ka]

[0277] Scheme 2 is (fluoroalkoxy)alkylenedihydroimidazo[5,1-d]tetradinecarboxamide D, for example R 3 -C(O)N(R 4 )(R 5 This describes the compounds defined by formula I and general methods for preparing certain compounds shown in Table 1. For example, hydrolysis of carboxamide A (prepared in the same manner as shown in Scheme 1 above) using TFA and NaNO2 in water yields carboxylic acid B. Amide coupling of carboxylic acid B and amine C using a known amide coupling reagent such as T3P or HATU and a base such as Et3N or NMM in a polar aprotic solvent such as DMF yields (fluoroalkoxy)alkylenedihydroimidazo[5,1-d]tetrazinecarboxamide D. Variable element R 1 , R 2 , R 4 , R 5 , and X may be, for example, as defined above in relation to formula I.

[0278] Scheme 2. [ka]

[0279] Further dihydroimidazo[5,1-d]tetrazine compounds of formula I (e.g., R 3 -CO2R 5 -C(O)SR 4 ,-C(S)N(R 4 )(R 5 ), -C(=NR 7 )OR 4 -C(=NR 7 )SR 4 -C(=NR 7 )N(R 4 )(R 5 ), -C(O)-(halo), -C(O)-(C 1~4Those defined by formula I, which are alkyl, -CN, or halo, and certain compounds shown in Table 1, can be prepared by functional group transformations of compounds A, B, and D shown in Scheme 2, as described in detail for certain compounds in the Examples (e.g., Examples 14, 16-20, and 28). Furthermore, acid chlorides of carboxylic acid B from Scheme 2 (prepared by treatment with reagents such as SOCl2, for example) can be condensed with various nucleophiles such as alcohols, phenols, and thiols to form R 3 -CO2R 5 or -C(O)SR 4 A compound of formula I can be obtained. References describing additional functional group transformations are provided below.

[0280] Scheme 3 uses (fluoroalkoxy)alkylenedihydroimidazo[5,1-d]tetrazine D, for example R 3 C 1~4 Alkyl is defined by formula I, A 1 This describes compounds defined by formula II, where is phenyl, and general methods for preparing certain compounds shown in Tables 1 and 2. For example, diazo-imidazole B is obtained by diazotization of amino-imidazole A using NaNO2 in an acid such as hydrochloric acid. (Fluoroalkoxy)alkylenedihydroimidazo[5,1-d]tetrazine D is obtained by condensation of diazo-imidazole B and isocyanate C in a solvent such as DMSO. Variable element R 1 , R 2 , and X may be, for example, as defined above in relation to formula I or formula II.

[0281] Scheme 3. [ka]

[0282] Heteroaryl compounds, such as those defined by formula II and those shown in Table 2, can be prepared by coupling and cyclocondensation of compounds A, B, and D shown in Scheme 2 with thioamide analogs of carboxamide A (e.g., prepared by treating carboxamide A with Lawson's reagent). Exemplary strategies and procedures for heteroaryl synthesis can be found, for example, in Svec, RL, et al. "Tunable Stability of Imidazotetrazines Leads to a Potent Compound for Glioblastoma," ACS Chemical Biology, 2018, 13, pp. 3206-3216, and International Publication No. 2020 / 033880. Schemes 3 and 4 show exemplary general methods for heteroaryl synthesis.

[0283] Scheme 4 is a (fluoroalkoxy)alkylenedihydroimidazo[5,1-d]tetrazine monocyclic heteroaryl B, E, and H, e.g., A 1This describes compounds defined by formula II, where oxazolyl, thiazolyl, oxadiazolyl, and thiadiazolyl, and provides exemplary general methods for preparing certain compounds shown in Table 2. Oxazole B is obtained by cyclization condensation of carboxamide A (prepared as described for carboxamide B in Scheme 2) using a dehydrating reagent such as POCl3. Thiazole E is obtained by tandem coupling and cyclization condensation of thioamide C (prepared, for example, by treating carboxamide A in Scheme 2 with Lawson's reagent) and carbonyl-containing compound D (where LG is a leaving group such as bromo). Using procedures such as those described in Lin, Y. et al., "New Synthesis of 1,2,4-Thiadiazoles," J. Org. Chem., 1980, 45, pp. 3750-3753, 1,2,4-oxadiazole or 1,2,4-thiadiazole H can be obtained by tandem coupling and cyclocondensation of carboxamide or thioamide F (compound A in scheme 2 or compound C in scheme 3, respectively) with N,N-dimethylformamide dimethylacetal G. Variable element R 1 , R 2 , R 3 , R 4 , and X may be, for example, as defined above in relation to Equation II.

[0284] Scheme 4. [ka]

[0285] Scheme 5 is a (fluoroalkoxy)alkylenedihydroimidazo[5,1-d]tetrazine bicyclic heteroaryl D, for example A 1Formula II is defined by benzimidazol, benzoxazol, and benzothiazolyl, and exemplary general methods for preparing certain compounds shown in Table 2 are described. For example, coupling carboxylic acid A (compound B in scheme 2) with aniline B using HBTU or HATU yields carboxamide C. For example, cyclization condensation of carboxamide C using POCl3 or PPh3 and DIAD yields benzimidazole, benzoxazole, or benzothiazole D. Variable element R 1 , R 2 , R 3 , R 4 X, m, and n may be as defined above, for example, in relation to Equation II.

[0286] Scheme 5. [ka]

[0287] Scheme 6 shows exemplary general methods for preparing (fluoroalkoxy)alkyleneimidazotriazenes D and G, for example, those defined by formulas IIIa and IIIb, and those shown in Table 3. For example, diazotization of aminoimidazole A or E using NaNO2 in an acid such as hydrochloric acid yields diazoimidazole B or F. Condensation of diazoimidazole B or F with amine C in the presence of a base such as Et3N or DIPEA yields (fluoroalkoxy)alkylenetriazenyli-imidazole-carboxamide D or G. Variable element R 1 , R 2 , R 3 , R 4 , R 5 , and X may be as defined above, for example, in relation to equations IIIa and IIIb.

[0288] Scheme 6. [ka]

[0289] Scheme 7 shows a general method for preparing (fluoroalkoxy)alkylene nitrosourea D, for example, those defined by formula IV and those shown in Table 4. The condensation of isocyanate A and (fluoroalkoxy)alkylamine B in a solvent such as Et2O or THF, in the presence of a base such as Et3N or DIPEA, yields R 1 Urea C, which is hydrogen, is obtained. 1 C 1~4 The preparation of alkyl urea C can be achieved by alkylation using alkylating agents such as alkyl halides and bases such as Et3N. For example, nitrosylation of urea C using NaNO2 in formic acid yields nitrosourea D. Variable element R 1 , R 2 , R 3 , and X may be, for example, as defined above in relation to Equation IV.

[0290] Scheme 7. [ka]

[0291] Scheme 8 shows exemplary general methods for preparing (fluoroalkoxy)alkylene hydrazines F, for example, those defined by formula V and shown in Table 5. Protected alcohol B is obtained by protecting the nitrogen atom of hydrazino alcohol A (when the protecting group PG is Boc) using solvents such as Boc2O and dioxane. Fluoroalkylation (R) of alcohol B is performed using solvents such as RINKAN, for example, TMSCF3, AgOTf, Selectfluor, and 2-fluoropyridine. 1Fluoroalkoxy-protected hydrazine C is obtained by (when is CF3). Protected disubstituted hydrazine E is obtained by alkylation of hydrazine C with alkylating agent D using a base such as NaH and a solvent such as DMF or THF (when LG is a leaving group such as bromide). (Fluoroalkoxy)alkylene hydrazine F is obtained by deprotection of hydrazine E using an acid such as hydrochloric acid in a solvent such as Depositphotos (when PG is Boc). Ring A 1 The upper R 2 The substituent may be included in the alkylating agent D in its final form (for example, R 2 -C(O)N(R 3 )(R 4 ), C 1~4 Alkyl, C 1~4 Haloalkyl, or -C(O)-(C 1~4 If it is alkyl, or ring A 1 The upper R 2 The substituents may be synthesized to their final form either before or after the deprotection step (for example, as with the functional group transformations described for Scheme 3, A 1 The above carboxamide or carboxylic acid substituent is heteroaryl R 2 (By converting to the base). Variable element A 1 , R 1 , X 1 , and X 2 This could be, for example, as defined above in relation to equation V.

[0292] Scheme 8. [ka]

[0293] In these schemes, it will be understood by those skilled in the art that functional groups present in various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents that are incompatible with the reaction conditions will be obvious to those skilled in the art, and therefore alternative methods will be shown (e.g., the use of protecting groups or alternative reactions). The chemistry and strategies of protecting groups are, for example, incorporated herein by reference in their entirety, "Protecting Groups in Organic Synthesis," TW Greene and PGMWuts, 3. rd This is well known in the art, as detailed in edition, John Wiley & Sons, 1999.

[0294] The modular synthetic routes shown in schemes 1-8 can be easily modified to provide additional compounds by performing functional group transformations on intermediates and / or final compounds. Such functional group transformations are well known in the art, as described, for example, in Comprehensive Organic Synthesis (BMTrost & I. Fleming, eds., 1991-1992); Organic Synthesis, 3rd Ed. (Michael B. Smith, Wavefunction, Inc., Irvine: 2010); Modern Methods of Organic Synthesis, 4th Ed. (William Carruthers and Iain Coldham, Cambridge University Press, Cambridge: 2004); March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8th Ed. (Michael B. Smith, John Wiley & Sons, New York: 2020); and Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Ed. (Richard C. Larock, ed., John Wiley & Sons, New York: 2018).

[0295] II. Treatment application Another aspect of the present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound described herein, for example, a compound of formula I, IA, I-aa, II, III, IV, or V, to a subject in need thereof. In certain embodiments, the particular compound of formula I, IA, I-aa, II, III, IV, or V is a compound defined by one of the embodiments described in Section I above.

[0296] In certain embodiments, the present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound described herein, for example, a compound of formula I, to a subject in need. In certain embodiments, the specific compound of formula I is a compound defined by one of the embodiments described in Section I above. In certain embodiments, the present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound described herein, for example, a compound of formula IA, to a subject in need. In certain embodiments, the specific compound of formula IA is a compound defined by one of the embodiments described in Section I above. In certain embodiments, the present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound described herein, for example, a compound of formula I-aa, to a subject in need. In certain embodiments, the specific compound of formula I-aa is a compound defined by one of the embodiments described in Section I above. In certain embodiments, the present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound described herein, for example, a compound of formula II, to a subject in need. In certain embodiments, the specific compound of formula II is the compound defined by one of the embodiments described in Section I above. In certain embodiments, the present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound described herein, for example, a compound of formula III, to a subject in need. In certain embodiments, the specific compound of formula III is the compound defined by one of the embodiments described in Section I above. In certain embodiments, the present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound described herein, for example, a compound of formula IV, to a subject in need. In certain embodiments, the specific compound of formula IV is the compound defined by one of the embodiments described in Section I above.In certain embodiments, the present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound described herein, for example, a compound of formula V, to a subject in need thereof. In certain embodiments, the specific compound of formula V is a compound defined by one of the embodiments described in Section I above.

[0297] Another aspect of the present invention provides a method for inducing DNA damage in a subject, comprising administering an effective amount of a compound described herein, for example, a compound of formula I, IA, I-aa, II, III, IV, or V, to the subject. In a particular embodiment, the subject has cancer. In a particular embodiment, the compound is a compound of formula I. In a particular embodiment, the particular compound of formula I is a compound defined by one of the embodiments described in Section I above. In a particular embodiment, the compound is a compound of formula IA. In a particular embodiment, the particular compound of formula IA is a compound defined by one of the embodiments described in Section I above. In a particular embodiment, the compound is a compound of formula I-aa. In a particular embodiment, the particular compound of formula I-aa is a compound defined by one of the embodiments described in Section I above. In a particular embodiment, the compound is a compound of formula II. In a particular embodiment, the particular compound of formula II is a compound defined by one of the embodiments described in Section I above. In a particular embodiment, the compound is a compound of formula III. In certain embodiments, a particular compound of formula III is a compound defined by one of the embodiments described in Section I above. In certain embodiments, the compound is a compound of formula IV. In certain embodiments, a particular compound of formula IV is a compound defined by one of the embodiments described in Section I above. In certain embodiments, the compound is a compound of formula V. In certain embodiments, a particular compound of formula V is a compound defined by one of the embodiments described in Section I above. While not bound by any particular theory, it is understood that compounds of formula I, IA, I-aa, II, III, IV, or V as described herein generate reactive alkylating agents in vivo that react with the target DNA to cause DNA damage. The DNA damage may be alkylated DNA.

[0298] Further features The methods described herein may be further defined according to further characteristics such as cancer and / or the nature of the subject.

[0299] In certain embodiments, cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous carcinoma, bile duct cancer, gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, leukemia, urothelial carcinoma, colorectal cancer, or glioblastoma multiforme.

[0300] In certain embodiments, the cancer is invasive breast cancer, colon adenocarcinoma, head and neck cancer, lung adenocarcinoma, rectal adenocarcinoma, acute myeloid leukemia, glioblastoma multiforme, low-grade brain glioma, colorectal cancer, or metastatic melanoma. In certain embodiments, the cancer is melanoma. In certain embodiments, the cancer is glioblastoma multiforme.

[0301] In certain embodiments, the disorder is a cancer selected from the group consisting of ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous carcinoma, bile duct cancer, gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, and leukemia.

[0302] In certain embodiments, cancer is a solid tumor. In certain embodiments, cancer is a sarcoma or carcinoma. In certain embodiments, cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous carcinoma, bile duct cancer, gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia.

[0303] In certain embodiments, cancer is prostate cancer, breast cancer, lung cancer, liver cancer, bladder cancer, urinary tract cancer, or eye cancer. In certain embodiments, cancer is prostate cancer. In certain embodiments, cancer is breast cancer. In certain embodiments, cancer is lung cancer. In certain embodiments, cancer is liver cancer. In certain embodiments, cancer is bladder cancer. In certain embodiments, cancer is urinary tract cancer. In certain embodiments, cancer is eye cancer.

[0304] In certain embodiments, cancers include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, and stomach cancer; leukemia; benign and malignant lymphomas (e.g., Burkitt lymphoma and non-Hodgkin lymphoma); benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, and myosarcoma. , peripheral neuroepithelioma, sarcomas including synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, gangliomas, gangliogliomas, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, and Schwann cell tumor; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratoma.

[0305] In certain embodiments, cancer includes neuroblastoma, craniopharyngioma, glioma, glioblastoma, Schwann cell tumor, astrocytoma, oligodendroglioma, medulloblastoma, pineal gland tumor, hemangioblastoma, retinoblastoma, ependymoma, chordoma, meningioma, medullary carcinoma, small cell lung cancer, papillary carcinoma, papillary carcinoma, mesothelioma, nasopharyngeal carcinoma, acoustic neuroma, oral cancer, esophageal cancer, head and neck cancer, gastric cancer, colon cancer, rectal cancer, skin cancer, melanoma, sweat gland carcinoma, sebaceous gland carcinoma, squamous cell carcinoma, and basal cell carcinoma. These include basal cell carcinoma, bile duct cancer, gallbladder cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, bladder cancer, renal cell carcinoma, kidney cancer, Wilms' tumor, thyroid cancer, parathyroid tumor, synovial tumor, soft tissue sarcoma (e.g., rhabdomyosarcoma (RMS)), Kaposi's sarcoma, synovial sarcoma, osteosarcoma, Ewing's sarcoma, malignant rhabdoid tumor, leiomyosarcoma, liposarcoma, intralymphatic sarcoma, lymphangiosarcoma, myxosarcoma, osteosarcoma, fibrosarcoma, chondrosarcoma, or endosarcoma.

[0306] In certain embodiments, cancer is lymphoma. In certain embodiments, cancer is Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, non-Hodgkin lymphoma, lymphoid malignancies of T-cell or B-cell origin, peripheral T-cell lymphoma, adult T-cell leukemia-lymphoma, or Waldenström macroglobulinemia.

[0307] In certain embodiments, cancer is leukemia. In certain embodiments, cancer is acute leukemia, lymphoblastic leukemia, acute lymphoblastic leukemia, myeloid leukemia, acute myeloid leukemia, acute T-cell leukemia, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, polycythemia vera, multiple myeloma, or erythroleukemia.

[0308] In certain embodiments, cancer is myelodysplastic syndrome and / or myeloproliferative syndrome. In certain embodiments, cancer is myelodysplastic syndrome. In certain embodiments, cancer is myeloproliferative syndrome.

[0309] In certain embodiments, cancer is a cancer or associated myeloproliferative disorder selected from histiocytosis, essential thrombocythemia, myelofibrosis, heavy chain disease, and other malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus.

[0310] In certain embodiments, cancer is B-cell non-Hodgkin lymphoma, progressive solid tumor, soft tissue sarcoma, INI1-deficient cancer, BAP1-deficient cancer, follicular lymphoma, relapsed / refractory follicular lymphoma, diffuse large B-cell lymphoma, relapsed / refractory diffuse large B-cell lymphoma, non-Hodgkin lymphoma, pediatric non-Hodgkin lymphoma, pediatric non-Hodgkin lymphoma with EZH2, SMARCB1, or SMARCA4 mutations, histiocytic disorder, pediatric histiocytic disorder, pediatric histiocytic disorder with EZH2, SMARCB1, or SMARCA4 mutations, solid tumor with EZH2, SMARCB1, or SMARCA4 mutations, resistant prostate cancer, relapsed / refractory small cell lung cancer, B-cell lymphoma, relapsed / refractory B-cell lymphoma, adult T-cell leukemia-lymphoma, or progressive diffuse large cell lymphoma.

[0311] In certain embodiments, the cancer is a malignant rhabdoid tumor, an atypical teratomatous rhabdoid tumor, an epithelioid sarcoma, a renal medullary carcinoma, an undifferentiated pancreatic rhabdoid carcinoma, a Schwann cell tumor, an epithelioid malignant peripheral nerve sheath tumor, or a diffuse endogenous glioma.

[0312] In certain embodiments, the cancer is retinoblastoma pleomorphism, metastatic castration-resistant prostate cancer, small cell neuroendocrine carcinoma of the prostate, small cell lung cancer, triple-negative breast cancer, hepatocellular carcinoma, bladder cancer, or urinary tract cancer.

[0313] In certain embodiments, cancers include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endosarcoma, lymphangiosarcoma, lymphangiosarcoma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, primary bronchial carcinoma, renal cell carcinoma, liver carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, and angioblastoma. In certain embodiments, cancers include neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma pleomorphic, glioblastoma, brainstem glioma, malignant brain tumors with poor prognosis, malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumors, rectal adenocarcinoma, Dukes C&D colorectal cancer, unresectable colorectal cancer, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karyotype acute myeloblastic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, low-grade follicular lymphoma, metastatic melanoma, focal melanoma, malignant mesothelioma, and malignant pleural dehydrothelioma. Syndrome, peritoneal cancer, serous papillary carcinoma, gynecological sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans, hormone-resistant prostate cancer, resected high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, Waldenström macroglobulinemia, smoldering myeloma, slow-acting myeloma, fallopian tube cancer, androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid cancer, medullary thyroid carcinoma, or leiomyoma.

[0314] In certain embodiments, the cancer is metastatic cancer. In certain embodiments, the cancer is recurrent cancer and / or refractory cancer.

[0315] In certain embodiments, cancers include ovarian cancer, uterine cancer, gestational trophoblastic disease, endometrial cancer, cervical cancer, fetal cancer, choriocarcinoma, prostate cancer (including hormone-insensitive prostate cancer and castration-resistant prostate cancer), testicular tumors (including germ cell testicular cancer / seminoma), cystadenocarcinoma, breast cancer (including estrogen-receptor-positive breast cancer), brain tumors (including neuroblastoma, craniopharyngioma, glioma, glioblastoma, Schwann cell tumor, astrocytoma, oligodendroglioma, medulloblastoma, and pinealoma), hemangioblastoma, retinoblastoma, ependymoma, chordoma, meningioma, medullary carcinoma, lung cancer (small cell lung cancer, papillary adenocarcinoma, and These include papillary carcinoma, mesothelioma, nasopharyngeal carcinoma, acoustic neuroma, oral cancer, esophageal cancer, head and neck cancer, gastric cancer, colon cancer, rectal cancer, skin cancer, melanoma, sweat gland carcinoma, sebaceous gland carcinoma, squamous cell carcinoma, basal cell carcinoma, bile duct cancer, gallbladder cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, bladder cancer, renal cell carcinoma, kidney cancer, Wilms' tumor, thyroid cancer, parathyroid tumor, synoviomas, soft tissue sarcomas (e.g., rhabdomyosarcoma (RMS)), Kaposi's sarcoma, synovial sarcoma, osteosarcoma, Ewing's sarcoma, malignant rhabdoid tumor, leiomyosarcoma, liposarcoma, intralymphatic sarcoma, lymphangiosarcoma, myxosarcoma, osteosarcoma, fibrosarcoma, chondrosarcoma, or endosarcoma.

[0316] In certain embodiments, cancer is MGMT deficiency. - ) Cancer refers to cancer in which the abundance of the mRNA transcript of the MGMT gene is more than one standard deviation lower than that of the associated healthy control tissue, or in which the abundance of the associated functional protein itself is more than one standard deviation lower. This deficiency can be caused by promoter methylation, gene mutation, or other means that result in downregulation of the gene. MGMT expression levels have been determined in various cancer cell lines. Exemplary MGMT expression data are provided, for example, in Tables 7-11 of Examples 36 and 37 below.

[0317] In certain embodiments, cancer is MMR deficiency. -MMR deficiency refers to cancer in which the abundance of any mRNA transcript of any of the MMR genes (MSH2, MSH6, MLH1, MLH3, PMS2, PMS1), or the abundance of each (one or more) functional protein, is more than one standard deviation lower than that of the associated healthy control tissue. Alternatively, cancers exhibiting microsatellite instability hyperphenotype (MSI-H) are also considered to be MMR deficiency. See, for example, Li et al. - Microsatellite instability: a review of what the oncologist should know - Cancer Cell International, Article Number 16 (2020).

[0318] In certain embodiments, cancer is resistant to treatment using temozolomide.

[0319] subject In certain embodiments, the subject is human. In certain embodiments, the subject is adult human. In certain embodiments, the subject is child human.

[0320] Medical use Another aspect of the present invention provides the use of compounds described herein (e.g., compounds of formulas I, IA, I-aa, II, III, IV, or V, or other compounds in Section I) in the manufacture of pharmaceuticals. In certain embodiments, the pharmaceuticals are for the treatment of disorders described herein, such as cancer.

[0321] Another aspect of the present invention provides the use of the compounds described herein (e.g., compounds of formula I, IA, I-aa, II, III, IV, or V, or other compounds in Section I) for treating medical disorders such as cancer and other medical disorders described herein.

[0322] Bioactivity Test Compounds may be evaluated for their ability to kill cancer cells by following assay procedures described in the literature to assess the ability of test compounds to kill cancer cells. Furthermore, compounds may be evaluated for their ability to kill cancer cells by following the assay procedures described below.

[0323] The cytotoxicity of the compound can be measured by a short-term cell viability assay against four isogenic LN229 glioblastoma cell lines engineered to have or lack MGMT and / or MMR activity, using MSH2-targeting short hairpin RNA (shRNA). This approach allows for the determination of the relationship between MGMT status, MMR status, and compound activity. LN229 cells are maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum, 1% penicillin / streptomycin, and 0.1% fungin. Day 0: Cells are seeded into sterile 96-well plates (Corning Costar 96-well) at a concentration of 500 cells / well using a multichannel pipette. The assay plates are then incubated overnight in a 37°C 5% CO2 incubator. Day 1: The compound is prepared as a 50 mM stock in dimethyl sulfoxide (DMSO) and stored at room temperature (RT) protected from light until use. Before compound addition, the compound stock solution is serially diluted 2-fold in DMSO at concentrations of 30 mM to 0.117 mM in a 96-well master plate. The vehicle control wells contain DMSO. 97 μL of culture medium is added to each well of a new 96-well plate (daughter plate), and 3 μL of the drug solution from the master plate is added to the corresponding wells of the daughter plate to obtain a 3× plate. Three repeated dilution curves for each compound are performed on each assay plate. The final concentration of the compound ranges from 300 μM to 1.171 μM (9 points, 2-fold dilution dose-response curve), and the final DMSO concentration is 1%.

[0324] Assay plates are incubated in a humidified 5% CO2 incubator at 37°C for 120 hours. Day 5: After incubation, cells are fixed with 4% paraformaldehyde and stained with Hoechst dye to visualize the nuclei. Fixation, staining, and washing are performed using Thermo Scientific Multidrop Combi. Images are acquired with BioTek Cytation 5 Cell Imaging Multimode Reader and quantified using Cell Profiler image analysis software. Raw cell count data for the test compound are normalized to viability percentages relative to the DMSO vehicle control.

[0325] Formation of 2-(trifluoromethoxy)ethane-1-diazonium and DNA adducts While not wishing to be bound by theory, another aspect relates to the use of the compounds described herein to produce 2-(trifluoromethoxy)ethane-1-diazonium in vivo, a potent alkylating agent that can react with DNA to yield a 2-(trifluoromethoxy)ethane-1-DNA adduct. 2-(trifluoromethoxy)ethane-1-diazonium has the following chemical structure: [ka]

[0326] The formation of 2-(trifluoromethoxy)ethane-1-DNA adducts is due to DNA repair protein O 6Cells with low levels of methylguanine-DNA methyltransferase (MGMT) ultimately lead to cell death containing 2-(trifluoromethoxy)ethane-1-DNA adducts. Numerous cancer cell types have low levels of MGMT, and cancer cells die after administration of compounds containing the 3-(2-(trifluoromethoxy)ethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one skeleton. Healthy cells have sufficient levels of MGMT, and therefore healthy cells do not succumb to the effects of compounds containing the 3-(2-(trifluoromethoxy)ethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one skeleton (i.e., do not die).

[0327] Therefore, although we do not wish to be bound by theory, compounds containing the 3-(2-(trifluoromethoxy)ethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one skeleton described herein are converted in vivo to 2-(trifluoromethoxy)ethane-1-diazonium. 2-(trifluoromethoxy)ethane-1-diazonium reacts with intracellular DNA to produce 2-(trifluoromethoxy)ethane-1-DNA adducts. Cancer cells with low levels of MGMT die as a result of 2-(trifluoromethoxy)ethane-1-DNA adducts.

[0328] Therefore, one embodiment is a method for treating MGMT-deficient cancer in a patient, wherein the MGMT-deficient cancer cells of the patient in need are 2-(C 1~4 The present invention provides a method for treating MGMT-deficient cancer, comprising exposure to fluoroalkoxy)ethane-1-diazonium.

[0329] Another embodiment provides a method for treating MGMT-deficient cancer in a patient, comprising exposing the MGMT-deficient cancer cells of the patient in need of treatment to 2-(trifluoromethoxy)ethane-1-diazonium, thereby providing a method for treating MGMT-deficient cancer.

[0330] Another embodiment provides a method for treating MGMT-deficient cancer in a patient, comprising forming 2-(trifluoromethoxy)ethane-1-diazonium in MGMT-deficient cancer cells of a patient requiring treatment, thereby providing a method for treating MGMT-deficient cancer.

[0331] Another aspect is a method for treating MGMT-deficient cancer in a patient, wherein 2-(C) is used in the MGMT-deficient cancer cells of the patient in need. 1~4 The present invention provides a method for treating MGMT-deficient cancer, comprising forming a fluoroalkoxy)ethane-1-DNA adduct.

[0332] Another embodiment provides a method for treating MGMT-deficient cancer in a patient, comprising forming a 2-(trifluoromethoxy)ethane-1-DNA adduct in the MGMT-deficient cancer cells of the patient in need thereof, thereby providing a method for treating MGMT-deficient cancer.

[0333] Another embodiment provides a method for treating MGMT-deficient cancer in a patient, comprising exposing DNA to 2-(trifluoromethoxy)ethane-1-diazonium to form 2-(trifluoromethoxy)ethane-1-DNA adducts in the MGMT-deficient cancer cells of a patient requiring it, thereby providing a method for treating MGMT-deficient cancer.

[0334] Another embodiment provides a method for forming 2-(trifluoromethoxy)ethane-1-DNA adducts in cancer cells, comprising exposing DNA in cancer cells to 2-(trifluoromethoxy)ethane-1-diazonium.

[0335] Another embodiment provides a method for treating MGMT-deficient cancer in a patient, comprising administering a compound comprising a 2-(trifluoromethoxy)ethanyl group to a patient in need, thereby treating the patient, wherein the compound is converted in vivo to 2-(trifluoromethoxy)ethane-1-diazonium.

[0336] Another aspect provides a method for forming a 2-(trifluoromethoxy)ethane-1-DNA adduct, comprising exposing DNA to a compound containing a 2-(trifluoromethoxy)ethanyl group, thereby forming a 2-(trifluoromethoxy)ethane-1-DNA adduct, wherein the compound is converted to 2-(trifluoromethoxy)ethane-1-diazonium in vivo.

[0337] Another embodiment provides a method for forming a 2-(trifluoromethoxy)ethane-1-DNA adduct, comprising exposing DNA to 2-(trifluoromethoxy)ethane-1-diazonium, thereby providing a method for forming a 2-(trifluoromethoxy)ethane-1-DNA adduct. In a particular embodiment, the method comprises exposing the DNA of a cancer patient to 2-(trifluoromethoxy)ethane-1-diazonium. In a particular embodiment, the cancer patient has MGMT-deficient cancer.

[0338] Another embodiment is one or more [ka] The present invention provides a DNA adduct containing covalently bonded DNA in the presence of 1 to 10 [ka] The presence of covalently bonded DNA is present. In certain embodiments, the DNA adduct contains 1 to 5 DNA molecules. [ka] It contains covalently bonded DNA in the presence of [something]. In certain embodiments, the DNA adduct contains 1 to 2 [something]. [ka] It contains covalently bonded DNA in the presence of a DNA adduct. In a particular embodiment, the DNA adduct is one [ka] The presence of covalently bonded DNA is included.

[0339] In a particular embodiment, the DNA adduct is the following [ka] Includes.

[0340] Another embodiment provides a method for treating MGMT-deficient cancer in a patient, comprising administering a compound containing a 2-(trifluoromethoxy)ethanyl group to a patient in need, thereby treating the patient, wherein the compound is converted in vivo to 2-(trifluoromethoxy)ethane-1-diazonium. In certain embodiments, the compound is a small molecule organic compound having a molecular weight of less than 2000 g / mol. In certain embodiments, the compound is a small molecule organic compound having a molecular weight of less than 1000 g / mol. In certain embodiments, the compound is a small molecule organic compound having a molecular weight of less than 900, 800, 700, 600, 500, 400, or 300 g / mol.

[0341] III. Combination Therapy Another aspect of the present invention provides combination therapy. Compounds described herein (e.g., compounds of formulas I, IA, I-aa, II, III, IV, or V, or other compounds in Section I) or pharmaceutically acceptable salts thereof may be used in combination with further therapeutic agents for treating medical disorders such as autoimmune disorders or cancer.

[0342] In some embodiments, the present invention provides a method for treating a disclosed disease or condition, comprising administering an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof to a patient in need, and co-administering an effective amount of one or more additional therapeutic agents, for example, the therapeutic agents described herein, simultaneously or sequentially. In some embodiments, the method comprises co-administering one further therapeutic agent. In some embodiments, the method comprises co-administering two further therapeutic agents. In some embodiments, the combination of the disclosed compound and one or more further therapeutic agents acts synergistically.

[0343] One or more other therapeutic agents may be administered separately from the compound or composition of the present invention as part of a multi-dose regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form mixed with the compound of the present invention in a single composition. When administered as a multi-dose plan, one or more other therapeutic agents and the compound or composition of the present invention may be administered simultaneously, sequentially, or within a certain period of time from each other, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours from each other. In some embodiments, one or more other therapeutic agents and the compound or composition of the present invention may be administered more than 24 hours apart as a multi-dose regimen.

[0344] anticancer drugs Examples of therapeutic drugs that may be used as part of combination therapy in cancer treatment include, for example, mitomycin, tretinoin, ribomustine, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carbocon, pentostatin, nitracrine, dinostatin, cetrorelix, letrozole, larcitrexed, daunorubicin, fadrozol, fotemustine, thymalfacin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, eriptinium acetate, ketanserine, doxifluridine, etretinate, isotretinoin. Examples include streptozocin, nimustine, vindesine, flutamide, drogenil, butosine, carmofur, razoxan, schizophyllan, carboplatin, mitractol, tegafur, ifosfamide, prednimustine, picibanil, levamisol, teniposide, improsulfan, enocitabine, lislide, oxymetholone, tamoxifen, progesterone, mepitiostane, epithiostanol, formestan, interferon-alpha, interferon-2-alpha, interferon-beta, interferon-gamma, colony-stimulating factor-1, colony-stimulating factor-2, denileukin difuticox, interleukin-2, and luteinizing hormone-releasing factor.

[0345] Radiation therapy may also be used as part of combination therapy.

[0346] A further class of drugs that may be used as part of combination therapy in the treatment of cancer is immune checkpoint inhibitors (also called immune checkpoint blockers). Immune checkpoint inhibitors are a class of therapeutic drugs that have the effect of blocking immune checkpoints. See, for example, Pardoll in Nature Reviews Cancer (2012) vol. 12, pages 252-264. Exemplary immune checkpoint inhibitors include drugs that inhibit one or more of the following: (i) cytotoxic T lymphocyte antigen 4 (CTLA4), (ii) programmed cell death protein 1 (PD1), (iii) PDL1, (iv) LAB3, (v) B7-H3, (vi) B7-H4, and (vii) TIM3. The CTLA4 inhibitor ipilimumab is approved by the U.S. Food and Drug Administration for the treatment of melanoma. In certain embodiments, immune checkpoint inhibitors include pembrolizumab.

[0347] Other drugs that may be used as part of combination therapy in cancer treatment include monoclonal antibody drugs that target non-checkpoint targets (e.g., Herceptin) and non-cytotoxic drugs (e.g., tyrosine kinase inhibitors).

[0348] Accordingly, another aspect of the present invention provides a method for treating cancer in a patient, comprising administering (i) a therapeutically effective amount of a compound described herein and (ii) a second anticancer agent to a patient in need, wherein the second therapeutic agent may be one of the further therapeutic agents described above (e.g., mitomycin, tretinoin, ribomustine, gemcitabine, immune checkpoint inhibitors, or monoclonal antibody agents targeting non-checkpoint targets) or one of the following: Inhibitors selected from ALK inhibitors, ATR inhibitors, A2A antagonists, base excision repair inhibitors, Bcr-Abl tyrosine kinase inhibitors, Bruton's tyrosine kinase inhibitors, CDC7 inhibitors, CHK1 inhibitors, cyclin-dependent kinase inhibitors, DNA-PK inhibitors, inhibitors of both DNA-PK and mTOR, DNMT1 inhibitors, DNMT1 inhibitors + 2-chlorodeoxyadenosine, HDAC inhibitors, Hedgehog signaling pathway inhibitors, IDO inhibitors, JAK inhibitors, mTOR inhibitors, MEK inhibitors, MELK inhibitors, MTH1 inhibitors, PARP inhibitors, phosphoinositide 3-kinase inhibitors, inhibitors of both PARP1 and DHODH, proteasome inhibitors, topoisomerase II inhibitors, tyrosine kinase inhibitors, VEGFR inhibitors, WEE1 inhibitors, and ubiquitin-specific protease 1 (USP1) inhibitors; • Agonists for OX40, CD137, CD40, GITR, CD27, HVEM, TNFRSF25, or ICOS; Therapeutic antibodies targeting one of the following: CD20, CD30, CD33, CD52, EpCAM, CEA, gpA33, mucin, TAG-72, CAIX, PSMA, folate-binding protein, ganglioside, Le, VEGF, VEGFR, VEGFR2, integrin αVβ3, integrin α5β1, EGFR, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP, tenascin, CD19, KIR, NKG2A, CD47, CEACAM1, c-MET, VISTA, CD73, CD38, BAFF, interleukin-1 beta, B4GALNT1, interleukin-6, and interleukin-6 receptor; • Cytokines selected from IL-12, IL-15, GM-CSF, and G-CSF; • A therapeutic agent selected from ciproisel-T, aldesleukin (a human recombinant interleukin-2 product having the chemical name des-alanil-1,serine-125 human interleukin-2), dabrafenib (a kinase inhibitor having the chemical name N-{3-[5-(2-aminopyrimidine-4-yl)-2-tert-butyl-1,3-thiazole-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide), vemurafenib (a kinase inhibitor having the chemical name propane-1-sulfonic acid{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl}amide), and 2-chloro-deoxyadenosine; or • Placental growth factor, antibody-drug conjugates, oncolytic viruses, or anti-cancer vaccines.

[0349] In certain embodiments, the second anticancer agent is an ALK inhibitor. In certain embodiments, the second anticancer agent is an ALK inhibitor comprising ceritinib or crizotinib. In certain embodiments, the second anticancer agent is an ATR inhibitor. In certain embodiments, the second anticancer agent is an ATR inhibitor comprising AZD6738 or VX-970. In certain embodiments, the second anticancer agent is an A2A antagonist. In certain embodiments, the second anticancer agent is a base excision repair inhibitor comprising methoxyamine. In certain embodiments, the second anticancer agent is a base excision repair inhibitor such as methoxyamine. In certain embodiments, the second anticancer agent is a Bcr-Abl tyrosine kinase inhibitor. In certain embodiments, the second anticancer agent is a Bcr-Abl tyrosine kinase inhibitor comprising dasatinib or nilotinib. In certain embodiments, the second anticancer agent is a Bruton's tyrosine kinase inhibitor. In certain embodiments, the second anticancer agent is a Bruton's tyrosine kinase inhibitor, including ibrutinib. In certain embodiments, the second anticancer agent is a CDC7 inhibitor. In certain embodiments, the second anticancer agent is a CDC7 inhibitor, including RXDX-103 or AS-141.

[0350] In certain embodiments, the second anticancer agent is a CHK1 inhibitor. In certain embodiments, the second anticancer agent is a CHK1 inhibitor comprising MK-8776, ARRY-575, or SAR-020106. In certain embodiments, the second anticancer agent is a cyclin-dependent kinase inhibitor. In certain embodiments, the second anticancer agent is a cyclin-dependent kinase inhibitor comprising palbociclib. In certain embodiments, the second anticancer agent is a DNA-PK inhibitor. In certain embodiments, the second anticancer agent is a DNA-PK inhibitor comprising MSC2490484A. In certain embodiments, the second anticancer agent is an inhibitor of both DNA-PK and mTOR. In certain embodiments, the second anticancer agent comprises CC-115.

[0351] In certain embodiments, the second anticancer agent is a DNMT1 inhibitor. In certain embodiments, the second anticancer agent is a DNMT1 inhibitor comprising decitabine, RX-3117, guadecitabine, NUC-8000, or azacitidine. In certain embodiments, the second anticancer agent comprises a DNMT1 inhibitor and 2-chlorodeoxyadenosine. In certain embodiments, the second anticancer agent comprises ASTX-727.

[0352] In certain embodiments, the second anticancer agent is an HDAC inhibitor. In certain embodiments, the second anticancer agent is an HDAC inhibitor including OBP-801, CHR-3996, etinostate, resminostate, prasinostat, CG-200745, panobinostat, romidepsin, mosetinostat, bellinostat, AR-42, licorinostat, KA-3000, or ACY-241.

[0353] In certain embodiments, the second anticancer agent is a Hedgehog signaling pathway inhibitor. In certain embodiments, the second anticancer agent is a Hedgehog signaling pathway inhibitor comprising soni-degib or bismodegib. In certain embodiments, the second anticancer agent is an IDO inhibitor. In certain embodiments, the second anticancer agent is an IDO inhibitor comprising INCB024360. In certain embodiments, the second anticancer agent is a JAK inhibitor. In certain embodiments, the second anticancer agent is a JAK inhibitor comprising ruxolitinib or tofacitinib. In certain embodiments, the second anticancer agent is an mTOR inhibitor. In certain embodiments, the second anticancer agent is an mTOR inhibitor comprising everolimus or temsirolimus. In certain embodiments, the second anticancer agent is a MEK inhibitor. In certain embodiments, the second anticancer agent is a MEK inhibitor comprising cobimetinib or trametinib. In certain embodiments, the second anticancer agent is a MELK inhibitor. In certain embodiments, the second anticancer agent is a MELK inhibitor, including ARN-7016, APTO-500, or OTS-167. In certain embodiments, the second anticancer agent is an MTH1 inhibitor. In certain embodiments, the second anticancer agent is an MTH1 inhibitor, including (S)-crizotinib, TH287, or TH588.

[0354] In certain embodiments, the second anticancer agent is a PARP inhibitor. In certain embodiments, the second anticancer agent is a PARP inhibitor including MP-124, olaparib, BGB-290, talazoparib, veliparib, niraparib, E7449, rucaparib, or ABT-767. In certain embodiments, the second anticancer agent is a phosphoinositide 3-kinase inhibitor. In certain embodiments, the second anticancer agent is a phosphoinositide 3-kinase inhibitor including idelalisib. In certain embodiments, the second anticancer agent is an inhibitor of both PARP1 and DHODH (i.e., an agent that inhibits both poly-ADP-ribose polymerase 1 and dihydroorotate dehydrogenase).

[0355] In certain embodiments, the second anticancer agent is a proteasome inhibitor. In certain embodiments, the second anticancer agent is a proteasome inhibitor comprising bortezomib or carfilzomib. In certain embodiments, the second anticancer agent is a topoisomerase-II inhibitor. In certain embodiments, the second anticancer agent is a topoisomerase-II inhibitor comprising vosaroxine.

[0356] In certain embodiments, the second anticancer agent is a tyrosine kinase inhibitor. In certain embodiments, the second anticancer agent is a tyrosine kinase inhibitor comprising bosutinib, cabozantinib, imatinib, or ponatinib. In certain embodiments, the second anticancer agent is a VEGFR inhibitor. In certain embodiments, the second anticancer agent is a VEGFR inhibitor comprising regorafenib. In certain embodiments, the second anticancer agent is a WEE1 inhibitor. In certain embodiments, the second anticancer agent is a WEE1 inhibitor comprising AZD1775. In certain embodiments, the second anticancer agent is a USP1 inhibitor comprising TNG-348 or KSQ-4279.

[0357] In certain embodiments, the second anticancer agent is an agonist of OX40, CD137, CD40, GITR, CD27, HVEM, TNFRSF25, or ICOS. In certain embodiments, the second anticancer agent is rituximab, ibritumomab tiuxetan, tocitumomab, obinutuzumab, ofatumumab, brentuximab vedotin, gemtuzumab ozogamicin, alemtuzumab, IGN101, adekatumumab, rabetuzumab, huA33, pemtumomab, olegovomab, minetumomab, cG250, J591, Mov18, farletuzumab, 3F8, ch14.18, KW-2 871, hu3S193, lgN311, bevacizumab, IM-2C6, pazopanib, sorafenib, axitinib, CDP791, lenvatinib, ramucirumab, etaracizumab, voroximab, cetuximab, panitumumab, nimotuzumab, 806, afatinib, erlotinib, gefitinib, osimertinib, vandetanib, trastuzumab, pertuzumab, MM-121, AMG The therapeutic antibody is selected from the group consisting of 102, METMAB, SCH 900105, AVE1642, IMC-A12, MK-0646, R1507, CP 751871, KB004, IIIA-4, mapatumumab, HGS-ETR2, CS-1008, denosumab, cibrotuzumab, F19, 81C6, MEDI551, lirirumab, MEDI9447, daratumumab, belimumab, canakinumab, dinutuximab, siltuximab, and tocilizumab.

[0358] In certain embodiments, the second anticancer agent is a placental growth factor. In certain embodiments, the second anticancer agent is a placental growth factor containing ziv-aflibercept. In certain embodiments, the second anticancer agent is an antibody-drug conjugate. In certain embodiments, the second anticancer agent is an antibody-drug conjugate selected from the group consisting of brentuximab vedotin and trastuzumab emtansine. In certain embodiments, the second anticancer agent is an antibody-drug conjugate selected from the group consisting of brentuximab vedotin, trastuzumab emtansine, and trastuzumab deruxtecan.

[0359] In certain embodiments, the second anticancer agent is an oncolytic virus. In certain embodiments, the second anticancer agent is the oncolytic virus tarimodine laherparepbec. In certain embodiments, the second anticancer agent is an anticancer vaccine. In certain embodiments, the second anticancer agent is an anticancer vaccine selected from the group consisting of GM-CSF tumor vaccine, STING / GM-CSF tumor vaccine, and NY-ESO-1. In certain embodiments, the second anticancer agent is a cytokine selected from IL-12, IL-15, GM-CSF, and G-CSF.

[0360] In certain embodiments, the second anticancer agent is a therapeutic agent selected from ciproisel-T, aldesleukin (a human recombinant interleukin-2 product having the chemical name des-alanil-1,serine-125 human interleukin-2), dabrafenib (a kinase inhibitor having the chemical name N-{3-[5-(2-aminopyrimidine-4-yl)-2-tert-butyl-1,3-thiazole-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide), vemurafenib (a kinase inhibitor having the chemical name propane-1-sulfonic acid{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl}amide), and 2-chlorodeoxyadenosine.

[0361] Further consideration The doses and administration regimens of the active ingredients used in combination therapy may be determined by the attending physician. In certain embodiments, the compounds described herein (e.g., compounds of formula I, IA, I-aa, II, III, IV, or V, or other compounds in Section I) and (one or more) further therapeutic agents are administered at doses commonly used when such agents are used as monotherapy to treat a disorder. In other embodiments, the compounds described herein (e.g., compounds of formula I, IA, I-aa, II, III, IV, or V, or other compounds in Section I) and (one or more) further therapeutic agents are administered at doses lower than commonly used when such agents are used as monotherapy to treat a disorder. In certain embodiments, the compounds described herein (e.g., compounds of formula I, IA, I-aa, II, III, IV, or V, or other compounds in Section I) and (one or more) further therapeutic agents are present in the same composition suitable for oral administration.

[0362] In certain embodiments, the compounds described herein (e.g., compounds of formulas I, IA, I-aa, II, III, IV, or V, or other compounds in Section I) and (one or more) additional therapeutic agents may act additively or synergistically. Synergistic combinations may enable the use of low doses of one or more agents and / or the low-frequency administration of one or more agents in combination therapy. Administration of low doses or low-frequency one or more agents may reduce the toxicity of the therapy without reducing the efficacy of the therapy.

[0363] Another aspect of the present invention is a kit comprising a therapeutically effective amount of a compound described herein (e.g., compounds of formula I, IA, I-aa, II, III, IV, or V, or other compounds in Section I), a pharmaceutically acceptable carrier, vehicle, or diluent, and optionally at least one further therapeutic agent listed above.

[0364] IV. Considerations for Pharmaceutical Composition and Administration As described above, the present invention provides pharmaceutical compositions comprising one or more of the above compounds in a therapeutically effective amount, formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The pharmaceutical compositions may be specifically formulated for administration in solid or liquid forms, including: (1) oral administration, e.g., oral tablets (aqueous or nonaqueous solutions or suspensions), tablets, e.g., those targeting buccal, sublingual, and systemic absorption, boluses, powders, granules, and pastes for application to the tongue; (2) parenteral administration, e.g., sterile solutions or suspensions, or as sustained-release formulations, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection; (3) topical administration, e.g., as creams, ointments, or controlled-release patches or sprays applied to the skin; (4) intravaginal or rectal administration, e.g., as pessaries, creams, or foams; (5) sublingual; (6) ocular; (7) transdermal; or (8) transnasal. In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound described herein (e.g., compounds of formula I, IA, I-aa, II, III, IV, or V, or other compounds in Section I) and a pharmaceutically acceptable carrier.

[0365] As used herein, the phrase “therapeutic dose” means an amount of a compound, material, or composition containing the compound of the present invention that is effective in producing some desired therapeutic effect in at least a cellular subpopulation of animals with a reasonable benefit / risk ratio applicable to any medical treatment.

[0366] The phrase "pharmaceutically acceptable" is used herein to mean a compound, material, composition, and / or dosage form that is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that is commensurate with a reasonable benefit-risk ratio, within the bounds of sound medical judgment.

[0367] Wetting agents such as sodium lauryl sulfate and magnesium stearate, emulsifiers and lubricants, as well as colorants, release agents, coating agents, sweeteners, flavoring agents and fragrances, preservatives and antioxidants may also be present in the composition.

[0368] Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bicarbonate, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0369] The formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may be conveniently provided in unit dosage forms and may be prepared by any method well known in the field of pharmacy. The amount of active ingredient that can be combined with a carrier material to yield a single dosage form varies depending on the host being treated and the specific mode of administration. The amount of active ingredient that can be combined with a carrier material to yield a single dosage form is generally the amount of the compound that produces the therapeutic effect. Generally, out of 100%, this amount is in the range of about 0.1% to about 99% of the active ingredient, preferably about 5% to about 70%, and most preferably about 10% to about 30%.

[0370] In certain embodiments, the formulation of the present invention comprises the compound of the present invention and an excipient selected from the group consisting of cyclodextrin, cellulose, liposomes, micellar-forming agents such as bile acids, and polymer carriers such as polyesters and polyanhydrides. In certain embodiments, the aforementioned formulation makes the compound of the present invention orally bioavailable.

[0371] Methods for preparing these formulations or compositions include the step of associating the compounds of the present invention with a carrier and optionally one or more auxiliary components. Generally, formulations are prepared by homogeneously and closely associating the compounds of the present invention with a liquid carrier or a fine solid carrier or both, and then, if necessary, shaping the product.

[0372] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (flavor-based, usually using sucrose and acacia or tragacanth), powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as flavored tablets (using gelatin and glycerin, or an inert base such as sucrose and acacia), and / or as mouthwashes, each containing a predetermined amount of the compound of the present invention as an active ingredient. The compound of the present invention may also be administered as a bolus, lick, or paste.

[0373] In the solid dosage forms of the present invention for oral administration (capsules, tablets, pills, sugar-coated tablets, powders, granules, lozenges, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) water-retaining agents such as glycerol; (4) agar, calcium carbonate, potato or tapioca starch, alginic acid, and certain silicic acids. (5) Disintegrants such as salts and sodium carbonate; (6) Dissolution retarders such as paraffin; (7) Absorption enhancers such as quaternary ammonium compounds and surfactants such as poloxamer and sodium lauryl sulfate; (8) Wetting agents such as cetyl alcohol, glycerol monostearate, and nonionic surfactants; (9) Absorbents such as kaolin and bentonite clay; (10) Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (11) Colorants; and (12) Controlled release agents such as crospovidone or ethylcellulose. In the case of capsules, tablets and pills, the pharmaceutical composition may also contain buffers. Similar types of solid compositions may also be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0374] Tablets may be prepared by compression or molding, sometimes with one or more auxiliary components. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked carboxymethylcellulose sodium), surfactants, or dispersants. Molded tablets may be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent using appropriate machinery.

[0375] Tablets, as well as other solid dosage forms of the pharmaceutical compositions of the present invention, such as sugar-coated tablets, capsules, pills, and granules, may be notched or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation field. They may also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using hydroxypropyl methylcellulose, other polymer matrices, liposomes, and / or microspheres in varying proportions to provide a desired release profile. They may be formulated for rapid release, for example, by lyophilization. They may be sterilized, for example, by filtration with a bacterial-retaining filter or by incorporating a sterilizer in the form of a sterile solid composition that can be dissolved in sterile water or any other sterile injection medium immediately before use. These compositions may also contain an opaque agent and may be compositions that release the active ingredient only in specific parts of the gastrointestinal tract, or preferentially, and optionally in a delayed manner. Examples of embedding compositions that can be used include polymer substances and waxes. The active ingredient may also be in microencapsulated form, optionally containing one or more of the above excipients.

[0376] Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, as well as mixtures thereof.

[0377] In addition to inert diluents, oral compositions may also contain adjuvants such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, colorants, fragrances and preservatives.

[0378] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, or mixtures thereof.

[0379] Formulations of the pharmaceutical compositions of the present invention for rectal or vaginal administration may be provided as suppositories, which may be prepared by mixing one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylate, which are solid at room temperature but liquid at body temperature, and therefore melt in the rectum or vaginal cavity, releasing the active compound.

[0380] Formulations of the present invention suitable for vaginal administration include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing carriers known to be suitable in the art.

[0381] Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound can be mixed with a pharmaceutically acceptable carrier under sterile conditions and with any preservatives, buffers, or propellants as needed.

[0382] The ointments, pastes, creams, and gels may contain, in addition to the active compounds of the present invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0383] The powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof, in addition to the compounds of the present invention. The sprays may further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0384] Transdermal patches offer the further advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be prepared by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flow rate of the compounds across the skin. The rate of such flow can be controlled by providing a rate-controlled membrane or by dispersing the compounds in a polymer matrix or gel.

[0385] Ophthalmic preparations, eye ointments, powders, and solutions are also intended to fall within the scope of this invention.

[0386] The pharmaceutical compositions of the present invention, suitable for parenteral administration, comprise one or more compounds of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injection solutions or dispersions immediately before use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostatic agents, solutes that are isotonic with the blood of the recipient to whom the formulation is intended, or suspending agents or thickeners.

[0387] Suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by the use of coating materials such as lecithin, maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0388] These compositions may also contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action on the target compound can be ensured by including various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, and sorbic acid. It may also be desirable to include isotonic agents such as sugars and sodium chloride in the composition. Furthermore, the inclusion of absorption-delaying agents, such as aluminum monostearate and gelatin, can lead to longer absorption of the injectable pharmaceutical form.

[0389] In some cases, it is desirable to delay the absorption of a drug from subcutaneous or intramuscular injection in order to prolong its effects. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low water solubility. The rate of drug absorption depends on its dissolution rate, which may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oily vehicle.

[0390] Injectable depot formulations are prepared by forming a microcapsule matrix of the target compound in a biodegradable polymer such as polylactide-polyglycolide. The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Depot injection formulations are also prepared by encapsulating the drug in liposomes or microemulsions compatible with body tissues.

[0391] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they can be administered either on their own or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably 10 to 30%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0392] The formulations of the present invention can be administered orally, parenterally, topically, or rectally. They are, of course, administered in a form suitable for each route of administration. For example, they can be administered in the form of tablets or capsules, by injection, inhalation, eye drops, ointments, suppositories, etc., topically by injection, infusion, or inhalation, by lotion or ointment; and rectally by suppositories. Oral administration is preferred.

[0393] As used herein, the phrases “parenteral administration” and “administered parenterally” mean, but are not limited to, injections, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0394] As used herein, the phrases “systemic administration,” “administered systemically,” “peripheral administration,” and “administered peripherally” mean the administration of a compound, drug, or other substance other than direct administration to the central nervous system, such as subcutaneous administration, so that the compound, drug, or other substance enters the patient’s system and is therefore susceptible to metabolism and other similar processes.

[0395] These compounds may be administered to humans and other animals for therapeutic purposes by any suitable route of administration, including orally, nasally (e.g., by spray), rectally, vaginally, parenterally, intracisional, and topically (by powder, ointment, or drops) (including buccal and sublingual).

[0396] Regardless of the selected route of administration, the compounds of the present invention, and / or the pharmaceutical compositions of the present invention, which can be used in an appropriate hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0397] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be varied to obtain an amount of the active ingredient that is effective in achieving a desired therapeutic response for a particular patient, composition, and mode of administration without causing toxicity to the patient.

[0398] The selected dosage level depends on a variety of factors, including the activity of the specific compound of the present invention used, or its ester, salt, or amide; the route of administration; the time of administration; the rate of excretion or metabolism of the specific compound used; the rate and extent of absorption; the duration of treatment; other drugs, compounds, and / or materials used in combination with the specific compound used; the age, sex, weight, condition, overall health, and prior medical history of the patient being treated; and similar factors well known in the medical field.

[0399] A physician or veterinarian with ordinary skills in the art can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian could start with a dose of the compound of the present invention used in the pharmaceutical composition at a level lower than the level required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[0400] Generally, the appropriate daily dose of the compound of the present invention is the amount of the compound that is the minimum effective dose to produce a therapeutic effect. Such an effective dose generally depends on the factors mentioned above. Preferably, the compound is administered at about 0.01 mg / kg to about 200 mg / kg, more preferably about 0.1 mg / kg to about 100 mg / kg, and even more preferably about 0.5 mg / kg to about 50 mg / kg. When the compounds described herein are co-administered with another agent (e.g., as a sensitizer), the effective dose may be less than when the agent is used alone.

[0401] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more subdoses, administered separately at appropriate intervals throughout the day, and possibly in unit dosage form. The preferred administration is once daily.

[0402] The present invention further provides a unit dosage form (such as a tablet or capsule) containing a therapeutically effective amount of the compound described herein for treating the medical disorders described herein.

[0403] [Examples] The present invention, as generally described herein, is included solely for illustrative purposes of certain aspects and embodiments of the invention and is not intended to limit the invention, and will be more readily understood by referring to the following examples.

[0404] [Example 1] Preparation of 4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (I-1) [ka] Part I: Synthesis of 1-Isocyanato-2-(trifluoromethoxy)ethane [ka] A mixture of 2-(trifluoromethoxy)ethanamine (1.50 g, 9.06 mmol, 1.00 equivalent, HCl salt) and DIEA (2.46 g, 19.0 mmol, 3.31 mL, 2.10 equivalents) in DCM (15.0 mL) was added dropwise to a solution of diphosgene (1.13 g, 5.71 mmol, 689 μL, 0.63 equivalents) in DCM (15.0 mL) over 10 minutes at 0°C via a syringe pump. After the addition was complete, the cooling bath was removed and the reaction mixture was heated to 25°C and stirred for 1 hour. The reaction mixture was transferred to a separatory funnel. The organic layer was sequentially washed with 1N hydrochloric acid aqueous solution (30 mL, pre-cooled to 0°C) and saturated sodium chloride aqueous solution (30 mL, pre-cooled to 0°C). The washed organic layer was dried on magnesium sulfate. The dried solution was filtered, and the filtrate was concentrated at approximately 10°C to 15°C. Compound 1-isocyanato-2-(trifluoromethoxy)ethane (1.40 g, 9.03 mmol, 99.6% yield) was obtained as a yellow oil and used directly in the next step without further purification.

[0405] Part II synthesis of 4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide [ka] To a solution of 4-carbamoyl-1H-imidazole-5-diazonium (500 mg, 3.62 mmol, 1.00 equivalent) in DMSO (3.00 mL), 1-isocyanato-2-(trifluoromethoxy)ethane (1.40 g, 9.03 mmol, 2.50 equivalents) was added, and the resulting mixture was stirred at 25°C for 12 hours. The reaction mixture was then filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 250*50 mm*10 μm; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 10%~40%B over 10.0 minutes), and the marked compound was obtained as a pink solid (804.9 mg, 2.75 mmol, yield 76.1%). 1 H NMR(400 MHz,DMSO-d6)δ 8.88(s,1H),7.84(s,1H),7.71(s,1H),4.67-4.62(m,2H),4.51-4.46(m,2H).MS(ESI): Calculated mass of C8H7F3N6O3 292.05, m / z actual value 293.0 [M+H] + .

[0406] [Example 2] Preparation of 4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (I-33) [ka] To a solution of 4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (1.2 g, 4.11 mmol, 1 equivalent) in TFA (8.57 g, 75.1 mmol, 5.58 mL, 18.3 equivalents), NaNO2 (652 mg, 9.45 mmol, 2.3 equivalents) in H2O (3 mL) was added at 0°C. The mixture was stirred at 35°C for 12 hours. The desired solid product precipitated from the reaction mixture and was isolated by filtration to obtain 4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (0.66 g, 2.25 mmol, yield 54.8%) as a yellow solid.

[0407] [Example 3] Preparation of N-ethyl-4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide(I-3) [ka] A mixture of 4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (100 mg, 341 μmol, 1.0 equivalent) and ethylamine-HCl (27.8 mg, 341 μmol, 1.0 equivalent) in DMF (3 mL) was mixed with triethylamine (138 mg, 1.36 mmol, 190 μL, 4.0 equivalents) and T3P (propylphosphonic anhydride solution, 492 mg, 682 μmol, 50% purity, 2.0 equivalents) at 0°C, and the mixture was then stirred at 25°C for 0.5 hours. LC-MS indicated that the reaction was complete. The mixture was filtered, and the filtrate was separated and purified by HPLC (column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 10%~40%B over 8.0 minutes) to obtain the marked compound as a purple solid (52 mg, 156 μmol, yield 45.8%, purity 96.16%). 1H NMR(400 MHz,DMSO-d6)δ 8.90(s,1H),8.56(br t,J=6.0 Hz,1H),4.73-4.63(m,2H),4.57-4.41(m,2H),3.33-3.28(m,2H),1.14(t,J=7.2 Hz,3H).LC / MS [M+H] + 321.08 (calculated value); LC / MS [M+H] + 321.08 (measured value).

[0408] [Example 4] Preparation of 4-oxo-N-phenyl-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide(I-9) [ka] To a solution of 4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (0.1 g, 341 μmol, 1 equivalent) and aniline (63.5 mg, 682 μmol, 2 equivalents) in DMF (1 mL), triethylamine (103 mg, 1.02 mmol, 142 μL, 3 equivalents) and T3P (propylphosphonic anhydride solution, 245 mg, 682 μmol, 2 equivalents) were added. The mixture was stirred at 20°C for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was quenched at 0°C by adding TFA (0.1 mL). Next, the mixture was filtered, and the filtrate was separated and purified by HPLC (column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 25%~65%B over 8.0 minutes) to obtain the marked compound as a pink solid (19.6 mg, 53.2 μmol, yield 15.6%). 1 H NMR(400 MHz,DMSO-d6)δ 10.41(s,1H),9.04(s,1H),7.91-7.83(m,2H),7.42-7.32(m,2H),7.17-7.08(m,1H),4.70-4.64(m,2H),4.54-4.49(m,2H).LC / MS [M+H] +369.1 (calculated value); LC / MS [M+H] + 369.1 (measured value).

[0409] [Example 5] Preparation of N-(2-(dimethylamino)ethyl)-N-methyl-4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (I-11) [ka] To a solution of 4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (0.1 g, 341 μmol, 1 equivalent) in DMF (1 mL), HATU (130 mg, 341 μmol, 1 equivalent), N-methylmorpholine (34.5 mg, 341 μmol, 1 equivalent), and N1,N1,N2-trimethylethane-1,2-diamine (34.7 mg, 341 μmol, 1 equivalent) were added, and the mixture was then stirred at 20°C for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was quenched at 0°C by adding TFA (0.1 mL). Next, the mixture was filtered, and the filtrate was separated and purified by HPLC (column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 1%~35%B over 8.0 minutes) to obtain the marked compound as a pink oily substance (0.083g, 168.92μmol, yield 49.52%, TFA). 1 H NMR(400 MHz,DMSO-d6)δ 8.84(s,1H),4.74-4.62(m,2H),4.57-4.50(m,2H),3.92-3.85(m,2H),3.48-3.40(m,2H),3.17(s,3H),2.85(s,6H).LC / MS [M+H] + 378.14 (calculated value); LC / MS [M+H] + 377.8 (measured value).

[0410] [Example 6] Preparation of 8-(4-methylpiperazine-1-carbonyl)-3-(2-(trifluoromethoxy)ethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one(I-10) [ka] To a solution of 4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (100 mg, 343 μmol, 1.0 equivalent) and 1-methylpiperazine (68.8 mg, 686 μmol, 2 equivalents) in DMF (1 mL), Et3N (104 mg, 1.03 mmol, 143 μL, 3 equivalents), followed by T3P (propylphosphonic anhydride solution, 495 mg, 686 μmol, 50% purity, 2 equivalents) was added at 0°C, and the mixture was then stirred at 20°C for 1 hour. LC-MS showed that the starting materials were consumed and the desired MS was observed. The mixture was filtered, and the filtrate was separated and purified by HPLC (column: Phenomenex Gemini-NX 150*30mm*5μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 5%~35%B over 20.0 minutes) to obtain the marked compound as a purple oily substance (18.3 mg, 45.35 μmol, yield 13.20%). 1 H NMR(400 MHz,DMSO-d6)δ 8.96(s,1H),4.68-4.62(m,2H),4.53-4.42(m,2H),3.66-3.43(m,4H),3.30-3.05(m,4H),2.85(s,3H).LC / MS [M+H] + 376.1 (calculated value); LC / MS [M+H] + 376.1 (measured value).

[0411] [Example 7] Preparation of 8-(pyrrolidine-1-carbonyl)-3-(2-(trifluoromethoxy)ethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one(I-7) [ka] To a solution of 4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (0.11 g, 375 μmol, 1 equivalent) and pyrrolidine (53.4 mg, 750 μmol, 2 equivalents) in DMF (1 mL), Et3N (114 mg, 1.13 mmol, 157 μL, 3 equivalents) and T3P (propylphosphonic anhydride solution, 540 mg, 750 μmol, 50% purity, 2 equivalents) were added at 0°C, and the mixture was then stirred at 25°C for 1 hour. LC-MS showed that the starting materials were completely consumed and the desired MS was observed. The reaction mixture was filtered, and the filtrate was separated and purified by HPLC (column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 20%~60%B over 8.0 minutes) to obtain the marked compound as a white solid (16.3 mg, 46.3 μmol, yield 12.3%). 1 H NMR(400 MHz,DMSO-d6)δ 8.88(s,1H),4.68-4.57(m,2H),4.54-4.44(m,2H),3.64(br t,J=6.8 Hz,2H),3.54(br t,J=6.8 Hz,2H),1.92-1.83(m,4H).LC / MS [M+H] + 347.1 (calculated value); LC / MS [M+H] + 347.1 (measured value).

[0412] [Example 8] Preparation of N,N-dimethyl-4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide(I-4) [ka] To a solution of 4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (100 mg, 341 μmol, 1 equivalent) and N,N-dimethylamine hydrochloride (55.6 mg, 682 μmol, 2 equivalents) in DMF (1 mL), triethylamine (172 mg, 1.71 mmol, 237 μL, 5 equivalents) and T3P (propylphosphonic anhydride solution, 491 mg, 682 μmol, 50% purity, 2 equivalents) were added at 0°C, and the mixture was then stirred at 25°C for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (column: Phenomenex Luna C18 80*30mm*3μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 10%~40%B over 8.0 minutes) to obtain the marked compound as a purple solid (76 mg, 230.5 μmol, yield 67.6%). 1 H NMR(400 MHz,DMSO-d6)δ 8.88(s,1H),4.62(t,J=5.2 Hz,2H),4.48(t,J=5.2 Hz,2H),3.06(s,6H).LC / MS [M+H] + 321.1 (calculated value); LC / MS [M+H] + 321.2 (measured value).

[0413] [Example 9] Preparation of N-cyclopropyl-4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (I-6) [ka] To a mixture of 4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (80.0 mg, 273 μmol, 1.0 equivalent) and cyclopropanamine (31.2 mg, 546 μmol, 2.0 equivalents) in DMF (3 mL), Et3N (110 mg, 1.09 mmol, 152 μL, 4.0 equivalents) and T3P (propylphosphonic anhydride solution, 393 mg, 546 μmol, 50% purity, 2.0 equivalents) were added at 0°C, and the mixture was then stirred at 25°C for 0.5 hours. LC-MS indicated that the reaction was complete. The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40mm*3μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 10%~40%B over 20.0 minutes) to obtain the marked compound as a purple solid (10.1 mg, 29.7 μmol, yield 10.8%). 1 LC / MS [M+H] + 333.2 (calculated value); LC / MS [M+H] + 333.2 (measured value).

[0414] [Example 10] Preparation of hydrochloride salt of N-(2-aminoethyl)-4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide(I-12) [ka] Synthesis of part-I-tert-butyl(2-(4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazin-8-carboxamide)ethyl)carbamate [ka] To a solution of 4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (150 mg, 512 μmol, 1.00 equivalent) in DMF (3.00 mL), tert-butyl N-(2-aminoethyl)carbamate (123 mg, 767 μmol, 121 μL, 1.50 equivalent), Et3N (155 mg, 1.54 mmol, 214 μL, 3.00 equivalent), and T3P (propylphosphonic anhydride solution, 737 mg, 1.02 mmol, 50% purity, 2.00 equivalent) were added at 0°C, and the mixture was then stirred at 25°C for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was diluted with H2O (16.0 mL) and extracted with ELISA (10.0 mL × 3). The combined organic layers were washed with brine (15.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was triturated with MTBE (5.00 mL) at 15°C for 5 minutes to obtain the labeled compound as a white solid (143 mg, 328 μmol, yield 64.2%).

[0415] Synthesis of hydrochloride salt of Part II-N-(2-aminoethyl)-4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide(I-12) [ka] To a solution of tert-butyl N-[2-[[4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazin-8-carbonyl]amino]ethyl]carbamate (143 mg, 328 μmol, 1.00 equivalent) in HCl (3.00 mL), HCl / HCl (4.00 M, 5.00 mL) was added, and the mixture was stirred at 25°C for 20 minutes. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was triturated with HCl (5 mL) at 15°C for 5 minutes to obtain the marked compound as a white solid (67.8 mg, 182.3 μmol, yield 55.5%).1 H NMR(400 MHz,DMSO-d6)δ 8.96(s,1H),8.77(t,J=5.6 Hz,1H),7.96(br s,3H),4.75-4.60(m,2H),4.57-4.44(m,2H),3.59-3.54(m,2H),3.06-2.93(m,2H).LC / MS [M+H] + 336.1 (calculated value); LC / MS [M] + 336.1 (measured value).

[0416] [Example 11] Preparation of N-cyclopentyl-4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (I-5) [ka] To a solution of 4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (90 mg, 307 μmol, 1 equivalent) and cyclopentanamine (39.2 mg, 460 μmol, 1.5 equivalents) in DMF (1 mL), triethylamine (93.2 mg, 921 μmol, 128 μL, 3 equivalents), followed by T3P (propylphosphonic anhydride solution, 442 mg, 614 μmol, 50% purity, 2 equivalents) was added at 0°C, and the mixture was then stirred at 20°C for 1 hour. LC-MS showed that the starting materials were consumed and the desired MS was observed. The mixture was filtered, and the filtrate was separated and purified by HPLC (column: Phenomenex luna C18 100*40mm*3μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 20%~55%B over 8.0 minutes) to obtain the marked compound as a white solid (49.6 mg, 132.9 μmol, yield 43.3%). 1H NMR(400 MHz,DMSO-d6)δ 8.90(s,1H)8.31(d,J=7.6 Hz,1H),4.68-4.63(m,2H)4.53-4.47(m,2H),4.32-4.23(m,1H),1.93-1.86(m,2H),1.73-1.66(m,2H)1.64-1.51(m,4H).LC / MS [M+H] + 361.1 (calculated value); LC / MS [M+H] + 361.1 (measured value).

[0417] [Example 12] Preparation of 4-oxo-N-(2-pyridyl)-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (I-8) [ka] To a solution of 4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (0.1 g, 341 μmol, 1 equivalent) in DMF (2 mL), HATU (156 mg, 409 μmol, 1.2 equivalents), N-methylmorpholine (69.0 mg, 682 μmol, 75.0 μL, 2 equivalents) and pyridine-2-amine (64.2 mg, 682 μmol, 2 equivalents) were added, and the mixture was stirred at 20°C for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (column: Xselect CSH C18 100*30mm*5μm; mobile phase: [H2O(0.04% HCl)-ACN]; gradient: 20%~50%B over 15.0 minutes) to obtain the marked compound as a white solid (34 mg, 92.1 μmol, yield 27.0%). 1 H NMR(400 MHz,DMSO-d6)δ 10.38(s,1H),9.04(s,1H),8.52-8.37(m,1H),8.25(d,J=8.4 Hz,1H),8.02(br t,J=7.2 Hz,1H),7.35-7.25(m,1H),4.77-4.64(m,2H),4.57-4.47(m,2H).LC / MS [M+H] +370.08 (calculated value); LC / MS [M+H] + 370.2 (measured value).

[0418] [Example 13] Preparation of 4-oxo-3-(2-(trifluoromethoxy)ethyl-1,1,2,2-d4)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (I-29) [ka] The indicated compound was prepared. 1 H NMR(400 MHz,DMSO-d6)δ 8.88(s,1H),7.85(s,1H),7.71(s,1H).LC / MS [M+H] + 297.1 (calculated value); LC / MS [M+H] + 297.1 (measured value).

[0419] [Example 14] Preparation of 4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazin-8-carbothioamide (I-31) [ka] To a solution of 4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (0.5 g, 1.71 mmol, 1 equivalent) in DCM (5 mL), P2S5 (304 mg, 1.37 mmol, 146 μL, 0.8 equivalents) and trimethyl(trimethylsilyloxy)silane (611 mg, 3.76 mmol, 800 μL, 2.2 equivalents) were added. The mixture was stirred at 45°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a solid, which was then triturated with MTBE (20 mL) at 25°C for 10 minutes to obtain the marked compound as a yellow solid (0.48 g, 1.56 mmol, yield 91.0%). 1H NMR(400 MHz,DMSO-d6)δ 9.98(br s,1H),9.51(br s,1H),8.86(s,1H),4.67-4.63(m,2H),4.53-4.49(m,2H).LC / MS [M+H] + 309.0 (calculated value); LC / MS [M+H] + 309.0 (measured value).

[0420] [Example 15] Preparation of 8-(5-methylthiazole-2-yl)-3-(2-(trifluoromethoxy)ethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one(II-6) [ka] 4-Oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbothioamide (0.38 g, 1.23 mmol, 1 equivalent) was dissolved in acetone (10 mL), to which 2-bromopropanal (507 mg, 3.70 mmol, 3 equivalents) was added, and the mixture was stirred at 70°C for 16 hours. The mixture was filtered and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 100*40 mm*5 μm; mobile phase: [H2O(0.2% FA)-ACN]; gradient: 30%~60%B over 8.0 minutes) to obtain the marked compound as a yellow solid (50.9 mg, 144 μmol, yield 11.71%). 1 H NMR(400 MHz,DMSO-d6)δ 8.91(s,1H),7.76(d,J=1.2 Hz,1H),4.62(t,J=5.2 Hz,2H),4.49(t,J=5.2 Hz,2H),2.54(s,3H).LC / MS [M+H] + 347.1 (calculated value); LC / MS [M+H] + 347.1 (measured value).

[0421] [Example 16] Preparation of methyl-4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxyimidothioate (I-32) [ka] 4-Oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazin-8-carbothioamide (0.48 g, 1.56 mmol, 1 equivalent) was dissolved in MeCN (6 mL) and CH3I (2.21 g, 15.57 mmol, 10 equivalents) was added. The mixture was stirred at 25°C for 16 hours. The reaction mixture was filtered and then concentrated under reduced pressure. The crude product was triturated with MTBE (10 mL) at 25°C for 10 minutes to obtain the marked compound as a yellow solid (0.5 g, 1.55 mmol, 99.6% yield). 1 H NMR(400 MHz,DMSO-d6)δ 9.22(s,1 H)4.72(t,J=4.8 Hz,2 H)4.51(t,J=5.0 Hz,2 H)2.84(s,3 H).

[0422] [Example 17] Preparation of 4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazin-8-carboxyimidoamide (I-34) [ka] To a solution of methyl 4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxyimidothioate (0.22 g, 683 μmol, 1 equivalent) in MeCN (5 mL), ammonium acetate (158 mg, 2.05 mmol, 3 equivalents) was added. The mixture was stirred at 40°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude solid. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 1%~30%B over 8.0 minutes) to obtain the marked compound as a white solid (17.6 mg, 60.44 μmol, yield 8.85%). 1 H NMR(400 MHz,DMSO-d6)δ 9.25(d,J=12.88 Hz,3 H)9.22(s,1 H)4.75-4.70(m,2 H)4.53(t,J=4.88 Hz,2 H).LC / MS [M+H] + 292.1 (calculated value); LC / MS [M+H] + 292.1 (measured value).

[0423] [Example 18] Preparation of 4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonitrile (I-40) [ka] 4-Oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (1 g, 3.42 mmol, 1 equivalent) was dissolved in DMF (10 mL) and PCl5 (713 mg, 3.42 mmol, 1 equivalent) was added at 0°C. The mixture was heated to 25°C and stirred for 10 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250*50 mm*15 μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 30%~60%B over 10.0 minutes) to obtain the marked compound as a black oil (485 mg, 1.77 mmol, yield 51.7%). 1 H NMR(400 MHz,DMSO-d6)δ 9.12(s,1 H)4.71(t,J=5.00 Hz,2 H)4.56-4.45(m,2 H).LC / MS [M+H] + 275.0 (calculated value); LC / MS [M+H] + 275.1 (measured value).

[0424] [Example 19] Preparation of ethyl-4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylate (I-30) [ka] To a solution of 4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (80 mg, 273 μmol, 1 equivalent) in DMF (1 mL), iodoethane (63.8 mg, 409 μmol, 1.5 equivalents), N,N-diisopropylethylamine (70.5 mg, 546 μmol, 2 equivalents) and 4-dimethylaminopyridine (6.67 mg, 54.6 μmol, 0.2 equivalents) were added. The mixture was stirred at 25°C for 16 hours. The mixture was filtered, and the filtrate was separated and purified by HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 25%~55%B over 8.0 minutes) to obtain the marked compound as a white solid (69 mg, 215 μmol, yield 78.7%). 1 H NMR(400 MHz,DMSO-d6)δ 8.91(s,1H),4.69-4.64(m,2H),4.53-4.48(m,2H),4.45-4.37(m,2H),1.35(t,J=7.2 Hz,3H).LC / MS [M+H] + 322.1 (calculated value); LC / MS [M+H] + 322.1 (measured value).

[0425] [Example 20] Preparation of 8-chloro-3-(2-(trifluoromethoxy)ethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one (I-39) [ka] To a solution of 4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (100 mg, 341 μmol, 1 equivalent) in acetone (2 mL), dess-martin periodinane (579 mg, 1.36 mmol, 4 equivalents) and tetramethylammonium chloride (97.2 mg, 887 μmol, 2.6 equivalents) were added under N2 conditions. The mixture was stirred at 60°C for 4 hours. The reaction mixture was filtered and purified by preparative HPLC (column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 25%~65%B over 8.0 minutes) to obtain the marked compound as a white solid (13.2 mg, 46.6 μmol, yield 13.7%). 1 H NMR(400 MHz,DMSO-d6)δ 8.90(s,1H),4.60(t,J=5.2 Hz,2H),4.47(t,J=5.6 Hz,2H).LC / MS [M+H] + 284.0 (calculated value); LC / MS [M+H] + 284.2 (measured value).

[0426] [Example 21] Preparation of 8-acetyl-3-(2-(trifluoromethoxy)ethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one (I-38) [ka] The indicated compound was prepared. 1 H NMR(400 MHz,DMSO-d6)δ 8.92(s,1H),4.67(t,J=5.2 Hz,2H),4.53-4.48(m,2H),2.70(s,3H).LC / MS [M+H] + 292.1 (calculated value); LC / MS [M+H] + 292.1 (measured value).

[0427] [Example 22] Preparation of N-(2-aminophenyl)-4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (I-24) [ka] A solution of benzene-1,2-diamine (166 mg, 1.54 mmol, 1.5 equivalents) in DMF (0.5 mL) was added to a solution of HBTU (427 mg, 1.13 mmol, 1.1 equivalent) and 4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (300 mg, 1.02 mmol, 1 equivalent) in DMF (5 mL). The mixture was stirred at 20°C for 12 hours. The reaction mixture was quenched at 25°C by adding H2O (20 mL) and extracted with RINKAN (20 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® silica flash column, eluent with a 0-50% ethyl acetate / petroleum ether gradient at 90 mL / min), yielding the marked compound as a yellow solid (300 mg, 783 μmol, yield 76.49%). 1 H NMR(400 MHz,DMSO-d6)δ 9.79(s,1H),9.02(s,1H),7.43(dd,J=7.75,1.13 Hz,1H),7.05-6.94(m,1H),6.84(dd,J=8.00,1.25 Hz,1H),6.74-6.56(m,1H),5.06-4.80(m,2H),4.74-4.64(m,2H),4.58-4.46(m,2H).

[0428] [Example 23] Alternative preparation of 8-(1H-benzo[d]imidazole-2-yl)-3-(2-(trifluoromethoxy)ethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one(II-1) The indicated compound was prepared according to the following procedure.

[0429] Step 1: Preparation of N-(2-aminophenyl)-4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide [ka] A solution of HBTU (427 mg, 1.13 mmol, 1.1 equivalent) and 4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (300 mg, 1.02 mmol, 1 equivalent) in DMF (5 mL) was mixed with a solution of benzene-1,2-diamine (166 mg, 1.54 mmol, 1.5 equivalent) in DMF (0.5 mL). The mixture was stirred at 20°C for 12 hours. The reaction mixture was quenched at 25°C by adding 20 mL of H₂O and extracted with ₹ (20 mL × 3). The combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® silica flash column, eluent with a 0-50% ethyl acetate / petroleum ether gradient at 90 mL / min), yielding the marked compound as a yellow solid (300 mg, 783 μmol, yield 76.49%). 1 H NMR(400 MHz,DMSO-d6)δ 9.79(s,1 H),9.02(s,1 H),7.43(dd,J=7.75,1.13 Hz,1 H),7.05-6.94(m,1 H),6.84(dd,J=8.00,1.25 Hz,1 H),6.74-6.56(m,1 H),5.06-4.80(m,2 H),4.74-4.64(m,2 H),4.58-4.46(m,2 H).

[0430] Step 2: Preparation of 8-(1H-benzo[d]imidazole-2-yl)-3-(2-(trifluoromethoxy)ethyl)imidazol[5,1-d][1,2,3,5]tetrazin-4(3H)-one [ka] A solution of N-(2-aminophenyl)-4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazin-8-carboxamide (270 mg, 704 μmol, 1 equivalent) in POCl3 (5 mL) was stirred at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 15%~40% B over 8.0 minutes) to obtain the marked compound as a yellow solid (161.1 mg, 422 μmol, yield 59.85%, purity 95.59%). 1 H NMR(400 MHz,DMSO-d6)δ 9.14(s,1 H),7.83-7.64(m,2 H),7.40-7.35(m,2 H),4.72-4.66(m,2 H),4.57-4.51(m,2 H).MS(ESI):C 14 H 10 The calculated mass of F3N7O2 is 365.08, and the measured m / z value is 366.1[M+H]+.

[0431] [Example 24] Preparation of N-(2-hydroxyphenyl)-4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (I-27) [ka] To a solution of 4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (0.3 g, 1.02 mmol, 1 equivalent), isobutyl chloroformate (147 mg, 1.07 mmol, 141 μL, 1.05 equivalents), followed by Et3N in THF (10 mL) (109 mg, 1.07 mmol, 150 μL, 1.05 equivalents). The mixture was then stirred at 20°C for 2 hours. The precipitate was removed by vacuum filtration, and then 2-aminophenol (117 mg, 1.07 mmol, 1.05 equivalents) was added to the filtrate. The resulting mixture was stirred under nitrogen at 20°C for 12 hours. The reaction mixture was filtered and concentrated to dryness. The crude product was triturated with toluene (10 mL) at 0°C for 5 minutes, yielding the marked compound as a yellow solid (0.3 g, 781 μmol, yield 76.3%).

[0432] [Example 25] Preparation of 8-(benzo[d]oxazol-2-yl)-3-(2-(trifluoromethoxy)ethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one(II-4) [ka] N-(2-hydroxyphenyl)-4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (0.2 g, 520 μmol, 1 equivalent) was dissolved in THF (10 mL) and PPh3 (683 mg, 2.60 mmol, 5 equivalents) and DIAD (526 mg, 2.60 mmol, 504 μL, 5 equivalents) were added. The mixture was stirred at 20°C for 12 hours. The reaction mixture was filtered and concentrated. The crude product was triturated with MTBE (10 mL) and SiO (2 mL) at 20°C for 5 minutes to obtain the marked compound as a pale green solid (43.1 mg, 117.7 μmol, yield 22.6%). 1H NMR(400 MHz,DMSO-d6)δ 9.15(s,1H),7.99-7.86(m,2H),7.55-7.467(m,2H),4.75-4.67(m,2H),4.57-4.48(m,2H).LC / MS [M+H] + 367.1 (calculated value); LC / MS [M+H] + 367.2 (measured value).

[0433] [Example 26] Preparation of 4-oxo-N-(2-oxo-2-phenylethyl)--3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (I-25) [ka] To a solution of 4-oxo-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (0.2 g, 682 μmol, 1 equivalent) in DMF (2 mL), HBTU (271.66 mg, 716.33 μmol, 1.05 equivalent) was added, and the mixture was stirred at 25°C for 20 minutes. Next, 2-amino-1-phenyl-ethanone (128.79 mg, 750.45 μmol, 1.1 equivalent, HCl) was added, followed by DIPEA (352.69 mg, 2.73 mmol, 475.32 μL, 4 equivalents), and the reaction mixture was stirred at 25°C for 2 hours. The mixture was poured into H2O (10 mL) and extracted with RINKAN (5 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® silica flash column, eluent with a 0-30% ethyl acetate / petroleum ether gradient at 75 mL / min), yielding the marked compound as a yellow oily substance (156 mg, 380 μmol, yield 55.7%).

[0434] [Example 27] Preparation of 8-(5-phenyloxazol-2-yl)-3-(2-(trifluoromethoxy)ethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one(II-2) [ka] A mixture of 4-oxo-N-phenacyl-3-[2-(trifluoromethoxy)ethyl]imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (0.13 g, 317 μmol, 1 equivalent) in POCl3 (1 mL) was stirred at 80°C for 0.5 hours. After completion, the reaction mixture was concentrated, quenched with H2O (2 mL), and then extracted with RINKAN (2 mL × 3). The combined organic layer was dried over Na2SO4 and then concentrated. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 35%~65%B over 8.0 minutes) to obtain the marked compound as a yellow solid (21.7 mg, 55.3 μmol, yield 17.5%). 1 H NMR(400 MHz,DMSO-d6)δ 9.01(s,1H),8.01(s,1H),7.85(d,J=7.38 Hz,2H),7.55(t,J=7.69 Hz,2H),7.48-7.40(m,1H),4.67(t,J=4.8 Hz,2H),4.53(t,J=4.8 Hz,2H).MS(ESI): Mass calculation value 392.08, m / z actual value 393.1 [M+H] + .

[0435] [Example 28] Preparation of 4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl chloride (I-37) [ka] To a mixture of 4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (150 mg, 512 μmol, 1 equivalent) and DMF (3.74 mg, 0.1 equivalent) in THF (5 mL), SOCl2 (73.1 mg, 614 μmol, 1.2 equivalents) was added under N2 at 25 °C. The reaction mixture was heated to 70 °C and stirred for 2 hours. The reaction mixture was concentrated under vacuum to obtain the marked compound as a yellow oily substance (0.15 g, crude product).

[0436] [Example 29] Preparation of 4-oxo-N-(2-oxopropyl)-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (I-28) [ka] A mixture of 4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazin-8-carbonyl chloride (0.15 g, 481 μmol, 1 equivalent) and 1-aminopropan-2-one (52.7 mg, 481 μmol, 1 equivalent, HCl) in DMF (3 mL) was mixed with pyridine (76.1 mg, 963 μmol, 2 equivalents) under N2 at 25 °C, and the mixture was stirred for 12 hours. The mixture was quenched with H2O (4 mL), and the aqueous phase was extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (Biotage®; 4g SepaFlash® silica flash column, eluent with a 0-100% ethyl acetate / petroleum ether gradient at 50 mL / min), yielding the marked compound as a yellow solid (0.15 g, 431 μmol, yield 89.5%). 1H NMR(400 MHz,DMSO-d6)δ 8.92(s,1H),8.63(t,J=5.6 Hz,1H),4.64(t,J=5.2 Hz,2H),4.49(t,J=5.2 Hz,2H),4.16(d,J=5.6 Hz,2H),2.14(s,3H).

[0437] [Example 30] Preparation of 8-(5-methyloxazol-2-yl)-3-(2-(trifluoromethoxy)ethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one(II-3) [ka] A solution of 4-oxo-N-(2-oxopropyl)-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (0.1 g, 287 μmol, 1 equivalent) in POCl3 (3 mL) was stirred at 60°C for 12 hours. The reaction mixture was concentrated under vacuum. The residue was poured into ice water (w / w=1 / 1; 30 mL) and stirred for 5 minutes. The aqueous phase was extracted with DCM (15 mL x 3). The combined organic phase was washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 100×40mm×5μm; mobile phase: [H2O(0.2% FA)-ACN]; gradient: 30%~65%B over 8.0 minutes), yielding the marked compound as a yellow solid (21.0 mg, 62.6 μmol, yield 21.8%). 1 H NMR(400 MHz,DMSO-d6)δ 8.94(s,1H),7.14(s,1H),4.64(t,J=4.8 Hz,2H),4.50(t,J=5.2 Hz,2H),2.44(s,3H).LC / MS [M+H] + 331.1 (calculated value); LC / MS [M+H] + 331.1 (measured value).

[0438] [Example 31] Preparation of 8-phenyl-3-(2-(trifluoromethoxy)ethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one(II-5) [ka]

[0439] Synthesis of Part I-5-nitro-4-phenyl-1H-imidazole [ka] A mixture of 4-bromo-5-nitro-1H-imidazole (5 g, 26.1 mmol, 1 equivalent), phenylboronic acid (6.35 g, 52.1 mmol, 2 equivalents), [2-(2-aminoethyl)phenyl]-chloropalladium; dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (1.92 g, 2.60 mmol, 0.1 equivalent), and K3PO4 (16.59 g, 78.14 mmol, 3 equivalents) in dioxane (50 mL) and H2O (50 mL) was degassed, purged three times with N2, and then stirred at 110°C for 16 hours under an N2 atmosphere. The reaction mixture was extracted with RINKAN (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluent with a 0-50% ethyl acetate / petroleum ether gradient at 66 mL / min), yielding the marked compound as a yellow solid (3.2 g, 16.9 mmol, yield 65.0%). 1 H NMR(400 MHz,DMSO-d6)δ 7.90(s,1H),7.70-7.63(m,2H),7.56-7.46(m,3H).

[0440] Part II: Synthesis of 4-phenyl-1H-imidazole-5-amine [ka] To a solution of 5-nitro-4-phenyl-1H-imidazole (3.2 g, 16.9 mmol, 1 equivalent) in MeOH (30 mL), Pd / C (1.80 g, 1.69 mmol, 10% purity, 0.1 equivalent) was added. The suspension was degassed under vacuum and purged several times with H2. The reaction mixture was stirred under H2 (15 psi) at 20°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent with a 0-100% ethyl acetate / petroleum ether gradient at 80 mL / min), and the marked compound was obtained as a reddish-brown oily substance (1.2 g, 7.54 mmol, yield 44.6%). 1 H NMR(400 MHz,DMSO-d6)δ 11.76(s,1H),7.54(br s,2H),7.35-7.30(m,3H),7.05(t,J=7.4 Hz,1H),4.61(br s,2 h).

[0441] Part III - Synthetic 4-phenyl-1H-imidazole-5-diazonium [ka] To a solution of 4-phenyl-1H-imidazole-5-amine (0.27 g, 1.70 mmol, 1 equivalent) in HCl (2 M, 1.70 mL, 2 equivalents), NaNO2 (176 mg, 2.54 mmol, 1.5 equivalents) in H2O (0.9 mL) was added dropwise at 0°C, and the mixture was stirred for 1 hour. The reaction mixture was filtered, and the filtrate was freeze-dried to obtain a crude pink solid, which was used without further purification (0.29 g, 1.69 mmol, yield 99.9%).

[0442] Synthesis of Part IV-8-phenyl-3-(2-(trifluoromethoxy)ethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one(II-5) [ka] A mixture of 4-phenyl-1H-imidazole-5-diazonium (276 mg, 1.61 mmol, 1 equivalent) and 1-isocyanato-2-(trifluoromethoxy)ethane (0.25 g, 1.61 mmol, 1 equivalent) in DMSO (5 mL) was degassed, purged three times with N2, and then the mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 40%~75%B over 8.0 minutes) to obtain the marked compound as a brown solid (24.5 mg, 75.3 μmol, yield 4.67%). 1 LC / MS [M+H] + 326.1 (calculated value); LC / MS [M+H] + 326.1 (measured value).

[0443] [Example 32] Preparation of 3-cyclohexyl-1-nitroso-1-(2-(trifluoromethoxy)ethyl)urea(IV-1) [ka] Part I: Synthesis of 1-Cyclohexyl-3-(2-(trifluoromethoxy)ethyl)urea [ka] To a solution of cyclohexyl isocyanate (0.3 g, 2.40 mmol, 306 μL, 1 equivalent) and 2-(trifluoromethoxy)ethanamine (396.77 mg, 2.40 mmol, 1 equivalent, HCl) in CHCl3 (30 mL), Et3N (242.53 mg, 2.40 mmol, 333.60 μL, 1 equivalent) was added dropwise at 0°C. After stirring at 0°C for 2 hours, the reaction mixture was heated to 25°C and stirred for a further 2 hours. The mixture was concentrated to remove CHCl3, and the residue was washed with H2O (5 mL) to remove the hydrochloride. The remaining solid was filtered, the filtrate was redissolved in CHCl3 (5 mL), dried over Na2SO4, and reconcentrated. The crude product was triturated with MTBE (5 mL × 2) at 0°C to obtain the marked compound as a white solid (0.6 g). 1 H NMR(400 MHz,CDCl3)δ 4.73-4.58(m,1H),4.34(s,1H)3.97(t,J=5.00 Hz,2H)3.43(d,J=4.00 Hz,3H)1.90-1.82(m,2H),1.63-1.58(m,2H),1.57-1.47(m,1H),1.22-1.36(m,2H),1.15-0.98(m,3H).

[0444] Synthesis of Part II-3-Cyclohexyl-1-Nitroso-1-(2-(trifluoromethoxy)ethyl)urea(IV-1) [ka] To a solution of 1-cyclohexyl-3-[2-(trifluoromethoxy)ethyl]urea (0.4 g, 1.57 mmol, 1 equivalent) in HCOOH (2 mL), NaNO2 (379.94 mg, 5.51 mmol, 3.5 equivalents) was added in divided portions at 0°C. After addition, the reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with H2O (10 mL), and the aqueous layer was extracted with CHCl3 (5 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated to obtain the marked compound as a yellow oily substance (0.15 g, 34%). 1H NMR(400 MHz,CDCl3)δ 6.77-6.66(m,1H),4.13-4.05(m,2H),3.94-3.88(m,2H),3.86-3.77(m,1H),2.05-1.9 5(m,2H),1.75-1.65(m,2H),1.63-1.53(m,1H),1.41-1.29(m,2H),1.29-1.12(m,3H).

[0445] [Example 33] Preparation of 1-nitroso-1,3-bis(2-(trifluoromethoxy)ethyl)urea(IV-2) [ka] Part I: Synthesis of 1,3-bis(2-(trifluoromethoxy)ethyl)urea [ka] To a solution of 1-isocyanato-2-(trifluoromethoxy)ethane (0.9 g, 5.80 mmol, 1 equivalent) and 2-(trifluoromethoxy)ethaneamine (960 mg, 5.80 mmol, 1 equivalent, HCl) in CHCl3 (10 mL), Et3N (587 mg, 5.80 mmol, 808 μL, 1 equivalent) was added dropwise at 0°C. After stirring at 0°C for 2 hours, the reaction mixture was heated to 25°C and stirred for a further 2 hours. The mixture was concentrated, and the residue was purified by flash silica gel chromatography (ISCO®; 2 g SepaFlash® silica flash column, eluent with a 0-X% ethyl acetate / petroleum ether gradient at 70 mL / min) to obtain the marked compound as a white solid (0.72 g, 2.53 mmol, yield 43.7%). 1 H NMR(400 MHz,CDCl3)δ 4.93(br s,2H),3.97(t,J=5.2 Hz,4H),3.44(br t,J=4.8 Hz,4H).

[0446] Synthesis of Part II-1-nitroso-1,3-bis(2-(trifluoromethoxy)ethyl)urea(IV-21) [ka] To a solution of 1,3-bis[2-(trifluoromethoxy)ethyl]urea (0.36 g, 1.27 mmol, 1 equivalent) in formic acid (2 mL), NaNO2 (306 mg, 4.43 mmol, 3.5 equivalents) was added in fractions at 0°C. After addition, the reaction mixture was stirred at 0°C for 2 hours. Water (10 mL) was added, and the aqueous layer was extracted with CHCl3 (5 mL x 2). The combined organic layers were dried over Na2SO4 and then concentrated to obtain the marked compound as a yellow oily substance (0.3 g, crude product). 1 H NMR(400 MHz,CDCl3)δ 7.28(br s,1 H),4.21(q,J=5.3 Hz,4 H)4.04-3.99(m,2 H)3.84(q,J=5.4 Hz,2 H).

[0447] [Example 34] Preparation of N,N-dimethyl-4-((2-(2-(trifluoromethoxy)ethyl)hydrazinyl)methyl)benzamide (V-1) [ka] Synthesis of part I-di-tert-butyl 1-(2-hydroxyethyl)hydrazine-1,2-dicarboxylate [ka] To a solution of 2-hydrazinoethanol (5 g, 65.7 mmol, 4.46 mL, 1 equivalent) in dioxane (100 mL), Boc₂O (31.55 g, 144.55 mmol, 33.21 mL, 2.2 equivalents) was added at 0°C. The mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water (30 mL), and the resulting mixture was extracted with RINKAN (30 mL x 3). The organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent with a 0-15% ethyl acetate / petroleum ether gradient at 80 mL / min), yielding the marked compound as a white solid (11 g, 39.8 mmol, yield 60.6%). 1 H NMR(400 MHz,CDCl3)δ 6.40(s,1H),3.71(br s,2H),3.58(br s,2H),1.52-1.45(br s,18H).

[0448] Synthesis of part II-di-tert-butyl 1-(2-(trifluoromethoxy)ethyl)hydrazine-1,2-dicarboxylate [ka] To a solution of KF (4.20 g, 72.4 mmol, 4 equivalents), AgOTf (13.95 g, 54.28 mmol, 3 equivalents), Selectfluor (9.62 g, 27.14 mmol, 1.5 equivalents), and di-tert-butyl 1-(2-hydroxyethyl)hydrazine-1,2-dicarboxylate (5 g, 18.09 mmol, 1 equivalent) in SiO2 (100 mL), 2-fluoropyridine (5.27 g, 54.3 mmol, 4.66 mL, 3 equivalents) and TMSCF3 (7.72 g, 54.28 mmol, 3 equivalents) were added at 30°C. The resulting mixture was stirred under an N2 atmosphere at 30°C for 16 hours. The reaction mixture was poured into water (30 mL), and the resulting mixture was then extracted with SiO2 (3 × 30 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent with a 0-10% ethyl acetate / petroleum ether gradient at 80 mL / min) to obtain the marked compound as a white solid (0.69 g, 2.00 mmol, yield 11.1%). 1 H NMR(400 MHz,CDCl3)δ 6.33(br s,1H),4.05-4.00(m,2H),3.69(br s,2H),1.52-1.41(br s,18H).

[0449] Synthesis of Part III-di-tert-butyl 1-(4-(dimethylcarbamoyl)benzyl)-2-(2-(trifluoromethoxy)ethyl)hydrazine-1,2-dicarboxylate [ka] To a solution of di-tert-butyl 1-(2-(trifluoromethoxy)ethyl)hydrazine-1,2-dicarboxylate (0.1 g, 290 μmol, 1 equivalent) in DMF (2 mL), NaH (14.0 mg, 348 μmol, 60% purity, 1.2 equivalents) was added at 0°C. After stirring at 0°C for 5 minutes, 4-(bromomethyl)-N,N-dimethylbenzamide (105.5 mg, 435.6 μmol, 1.5 equivalents) was added, and the resulting mixture was stirred at 25°C for 30 minutes. The reaction mixture was quenched with H2O (1 mL) and then extracted with RINKAN (5 mL x 3). The organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® silica flash column, eluent with a 0-20% ethyl acetate / petroleum ether gradient at 45 mL / min), yielding the marked compound as a white oily substance (0.07 g, 138 μmol, yield 47.7%).

[0450] Synthesis of Part IV - N,N-dimethyl-4-((2-(2-(trifluoromethoxy)ethyl)hydrazinyl)methyl)benzamide (V-1) [ka] A solution of di-tert-butyl 1-(4-(dimethylcarbamoyl)benzyl)-2-(2-(trifluoromethoxy)ethyl)hydrazine-1,2-dicarboxylate (0.07 g, 138 μmol, 1 equivalent) in HCl / siRNA (3 mL) was stirred at 25°C for 16 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 1%~30%B over 8.0 minutes) to obtain the marked compound as a yellow oil (14 mg, 46 μmol, yield 33%). 1H NMR(400 MHz,D2O)δ 7.48-7.37(m,4H),4.18-4.13(m,2H),4.10(s,2H),3.21-3.17(m,2H),3.03(s,3H),2.92(s,3H).LC / MS [M+H] + 306.1 (calculated value); LC / MS [M+H] + 306.1 (measured value).

[0451] [Example 35] General procedure for preparing nitrosourea compounds The following provides a general procedure that may be used to prepare nitrosourea compounds.

[0452] Step 1: Preparation of 1-(2-(trifluoromethoxy)ethyl)urea [ka] A solution of 1-isocyanato-2-(trifluoromethoxy)ethane (1.0 equivalent) in diethyl ether is added dropwise to a solution of ammonia in THF (1.0 equivalent), and the reaction mixture is stirred at room temperature for 6 to 12 hours. The reaction mixture is then concentrated to dryness using a rotary evaporator to obtain the marked compound.

[0453] Step 2: Preparation of 1-nitroso-1-(2-(trifluoromethoxy)ethyl)urea [ka] To a 0.3 M solution of 1-(2-(trifluoromethoxy)ethyl)urea (1 equivalent) in HCOOH, 3.5 equivalents of NaNO2 were added in divided portions at 0°C. After addition, the reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with H2O (10 times the volume), the aqueous layer was extracted with CHCl3 (5 times the volume x 2), and the combined organic layers were dried over Na2SO4 and concentrated to obtain the marked compound.

[0454] [Example 36] Further general procedures for preparing nitrosourea compounds The following reaction scheme outlines further exemplary methods for preparing nitrosourea compounds, based in part on the general procedure described in Example 35.

[0455] Scheme 1 is a general procedure for preparing 3-((4-amino-2-methylpyrimidine-5-yl)methyl)-1-nitroso-1-(2-(trifluoromethoxy)ethyl)urea.

[0456] Scheme 1. [ka] Scheme 2 is a general procedure for preparing 3-(4-methylcyclohexyl)-1-nitroso-1-(2-(trifluoromethoxy)ethyl)urea.

[0457] Scheme 2. [ka]

[0458] Scheme 3 is a general procedure for preparing diethyl(1-(3-nitroso-3-(2-(trifluoromethoxy)ethyl)ureido)ethyl)phosphonate.

[0459] Scheme 3. [ka]

[0460] [Example 37] General procedure for preparing N-cyclopropyl-4-((2-(2-(trifluoromethoxy)ethyl)hydrazinyl)methyl)benzamide The compound can be prepared using the following general procedure.

[0461] Step 1: Preparation of 4-((1,2-bis(tert-butoxycarbonyl)-2-(2-(trifluoromethoxy)ethyl)hydrazinyl)methyl)benzoic acid [ka] To a 0.2 M solution of di-tert-butyl 1-(2-(trifluoromethoxy)ethyl)hydrazine-1,2-dicarboxylate (1 equivalent) in DMF, NaH (60% purity, 1.2 equivalents) was added at 0°C. The reaction mixture was stirred at 0°C for 5 minutes, then 4-(bromomethyl)benzoic acid (1.5 equivalents) was added, and the resulting mixture was stirred at 25°C for 30 minutes. The reaction mixture was quenched with H2O (1x volume), and then extracted with ELISA (5x volume x 3). The organic layer was washed with brine (5x volume), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to obtain the labeled compound.

[0462] Step 2: Preparation of 4-((2-(2-(trifluoromethoxy)ethyl)hydrazinyl)methyl)benzoic acid [ka] A 0.3 M solution of 4-((1,2-bis(tert-butoxycarbonyl)-2-(2-(trifluoromethoxy)ethyl)hydrazinyl)methyl)benzoic acid (1 equivalent) in HCl / siRNA is stirred at 25°C for 16 hours. The mixture is filtered and concentrated under reduced pressure. The residue is purified by preparative HPLC to obtain the marked compound.

[0463] Step 3: Preparation of N-cyclopropyl-4-((2-(2-(trifluoromethoxy)ethyl)hydrazinyl)methyl)benzamide [ka] To a 0.1 M solution (1 equivalent) of 4-((2-(2-(trifluoromethoxy)ethyl)hydrazinyl)methyl)benzoic acid in DMF, EDCI (1.2 equivalents) and triethylamine (2.5 equivalents) are added. N-cyclopropylamine (1 equivalent) is added, and the reaction mixture is stirred at room temperature for 24 hours. The solvent is removed by rotary evaporation, and the crude residue is purified (e.g., by preparative HPLC) to obtain the marked compound.

[0464] [Example 38] Further general procedures for preparing procarbazine compounds The following reaction scheme outlines further exemplary methods for preparing nitrosourea compounds, based in part on the general procedure described in Example 35.

[0465] Scheme 1 is a general procedure for preparing N-(sec-butyl)-4-((2-(2-(trifluoromethoxy)ethyl)hydrazinyl)methyl)benzamide.

[0466] Scheme 1. [ka]

[0467] Scheme 2 is a general procedure for preparing N-(1-hydroxybutan-2-yl)-4-((2-(2-(trifluoromethoxy)ethyl)hydrazinyl)methyl)benzamide.

[0468] Scheme 2. [ka]

[0469] Scheme 3 is a general procedure for preparing N-(1-hydroxy-2-methylpropan-2-yl)-4-((2-(2-(trifluoromethoxy)ethyl)hydrazinyl)methyl)benzamide.

[0470] Scheme 3. [ka]

[0471] Scheme 4 is a general procedure for preparing N-ethyl-4-((2-(2-(trifluoromethoxy)ethyl)hydrazinyl)methyl)benzamide.

[0472] Scheme 4. [ka]

[0473] Scheme 5 is a general procedure for preparing N-(tert-butyl)-4-((2-(2-(trifluoromethoxy)ethyl)hydrazinyl)methyl)benzamide.

[0474] Scheme 5. [ka]

[0475] Scheme 6 is a general procedure for preparing N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-4-((2-(2-(trifluoromethoxy)ethyl)hydrazinyl)methyl)benzamide.

[0476] Scheme 6. [ka]

[0477] [Example 39] General procedure for preparing phenyl 4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylate [ka]

[0478] The compound can be prepared using the following general procedure.

[0479] To a 0.2 M solution of 4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (1 equivalent) in THF, DMF (0.05 equivalents) is added, and the reaction mixture is cooled in an ice bath. Then, SOCl2 (1.1 equivalents) is added, and the reaction mixture is stirred at 0°C for 1 hour. Next, phenol (1.5 equivalents) is added, and the reaction mixture is heated to room temperature and stirred for 24 hours. The reaction mixture is concentrated to dryness using a rotary evaporator, and the residue is purified (e.g., by preparative HPLC) to obtain the marked compound.

[0480] [Example 40] General procedure for preparing S-ethyl 4-oxo-3-(2-(trifluoromethoxy)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbothioate The following reaction scheme outlines an exemplary synthetic route for preparing the indicated compound. [ka]

[0481] [Example 41] General procedure for preparing 8-methyl-3-(2-(trifluoromethoxy)ethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one The following reaction scheme outlines an exemplary synthetic route for preparing the indicated compound. [ka]

[0482] [Example 42] General procedure for preparing (E)-5-(3-methyl-3-(2-(trifluoromethoxy)ethyl)triaza-1-en-1-yl)-1H-imidazole-4-carboxamide [ka]

[0483] The compound can be prepared using the following general procedure. Step 1: Preparation of 4-carbamoyl-1H-imidazole-5-diazonium [ka] To a 0.2M stirred solution (0.2M) of 5-amino-1H-imidazole-4-carboxamide HCl salt (1 equivalent) in 1M HCl, add a 0.5M NaNO2 solution (1.1 equivalents) at 0°C and stir for 10 minutes. After the reaction is complete, filter the precipitated solid, wash with cold water (2x volume) and heptane (3x volume), and dry under vacuum to obtain the marked compound.

[0484] Step 2: Preparation of (E)-5-(3-methyl-3-(2-(trifluoromethoxy)ethyl)triaza-1-en-1-yl)-1H-imidazole-4-carboxamide [ka] To a 0.2 M stirred solution (1 equivalent) of 4-carbamoyl-1H-imidazole-5-diazonium salt in THF, N-methyl-2-(trifluoromethoxy)ethane-1-amine hydrochloride (1.09 equivalents) and Et3N (1.09 equivalents) were added at room temperature, and the mixture was stirred for 6 hours. After the reaction was complete, the precipitated solid was filtered, washed with ethyl acetate (2 × 5 times volume), and dried under vacuum to obtain the marked compound.

[0485] [Example 43] Anti-cancer bioactivity assay Exemplary compounds were evaluated for their anticancer activity using the assays described below in this specification.

[0486] Part I - Experimental Procedure Isogenic LN229 glioblastoma cells were maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum, 1% penicillin / streptomycin, and 0.1% fungin. Day 0: Cells were seeded at a concentration of 500 cells / well into sterile 96-well plates (Corning Costar 96-well) using a multichannel pipette. The assay plates were then incubated overnight in a 37°C 5% CO2 incubator. Day 1: The compound was prepared as a 50 mM stock in dimethyl sulfoxide (DMSO) and stored at room temperature (RT) protected from light until use. Before compound addition, the compound stock solution was serially diluted 2-fold in DMSO from 30 mM to 0.117 mM in a 96-well master plate. The vehicle control well contained DMSO. 97 μL of culture medium was added to each well of a new 96-well plate (daughter plate), and 3 μL of drug solution from the master plate was added to the corresponding wells of the daughter plate to obtain a 3× plate. Three repeated dilution curves for each compound were performed on each assay plate. The final concentrations of the compounds ranged from 300 μM to 1.171 μM (9 points, 2x dilution dose-response curve), and the final DMSO concentration was 1%.

[0487] Assay plates were incubated in a humidified 5% CO2 incubator at 37°C for 120 hours. Day 5: After incubation, cells were fixed with 4% paraformaldehyde and stained with Hoechst dye to visualize the nuclei. Fixation, staining, and washing were performed using Thermo Scientific Multidrop Combi. Images were acquired with BioTek Cytation 5 Cell Imaging Multimode Reader and quantified using Cell Profiler image analysis software. Raw cell count data for the test compound were normalized to viability percentages relative to the DMSO vehicle control.

[0488] Part II - Results The inhibition data for the compounds tested in the assay are shown in the table below. The symbol "++++" indicates an IC of 20 μM or less. 50 This indicates that the IC has a range of over 20 μM to 50 μM. 50 This indicates that the IC has a range of over 50 μM to 100 μM. The symbol "++" indicates an IC with a range of over 50 μM to 100 μM. 50 This indicates that the IC has a thickness of over 100 μM. The symbol "+" indicates an IC with a thickness of over 100 μM. 50 This indicates that the cells expressed a normal amount of MGMT, and that the cells expressed a normal amount of MMR.

[0489] [Table 6]

[0490] [Example 44] Cell panel anti-cancer bioactivity assay using nuclear dyes Compound I-1 was evaluated for its anticancer activity against a panel of cancer cell lines using the assay described below in this specification.

[0491] Part I - Experimental Procedure Cells were grown in RPMI1640, 10% FBS, 2 mM L-alanyl-L-glutamine, 1 mM sodium pyruvate, or a special medium. Cells were seeded in 384-well plates and incubated at 37°C in a humidified atmosphere of 5% CO2. Compounds were added the day after cell seeding. Simultaneously, untreated cell plates (time 0) were prepared. After a 5-day incubation period, cells were fixed and stained to enable nuclear fluorescence imaging.

[0492] The compound was serially diluted in 2-fold steps from the specified maximum test concentration and assayed at 10 different concentrations using the maximum assay concentration of 0.1% DMSO. Automated fluorescence microscopy was performed using a Molecular Devices ImageXpress Micro XL high-content imager, and images were acquired with a 4x objective lens. 16-bit TIFF images were acquired and analyzed with MetaXpress 5.1.0.41 software.

[0493] Data Analysis Cell proliferation was measured by the fluorescence intensity of an integrated nuclear dye. The output is called the relative cell number, and the measured nuclear intensity is converted to a percentage (POC) relative to the control using the following formula:

number

[0494] Cellular response parameters were calculated using nonlinear regression against a single-site dose-response sigmoid model:

number

[0495] Using the untreated plate at time 0, the number of doubling cycles during the assay period was determined using the following formula:

number

[0496] Cell count IC 50 This is the concentration of the test compound at 50% of the maximum possible reaction. EC 50 is the concentration of the test compound at the curve inflection point or half of the effective reaction (parameter C of the fitted curve solution). GI 50is the concentration required to reduce observed growth by half (midway between the curve's maximum value and the time 0 value). The active area is an estimate of the integral area on the curve. The active area values ​​range from 0 to 10, where a value of 0 indicates no inhibition of growth at all concentrations, and a value of 10 indicates complete inhibition of growth at all concentrations. In rare cases, values ​​less than 0 or greater than 10 may be observed. In these cases, values ​​less than 0 should be considered equivalent to 0, and values ​​greater than 10 should be considered equivalent to 10.

[0497] Curve fitting, calculations, and reporting were performed using a custom data organization engine and MathIQ-based software (AIM).

[0498] Part II - Results The data for compound I-1 and cell lines tested in this assay are shown in Table 7 below. The symbol "++++" indicates an EC of 30 μM or less. 50 or IC 50 This indicates an EC in the range of over 30 μM to 70 μM. The symbol "+++" indicates an EC in the range of over 30 μM to 70 μM. 50 or IC 50 This indicates that the EC is in the range of over 70 μM to 150 μM. The symbol "++" indicates an EC of over 70 μM to 150 μM. 50 or IC 50 This indicates that the EC is greater than 150 μM. The symbol "+" indicates an EC of more than 150 μM. 50 or IC 50 This indicates.

[0499] The relative MGMT mRNA expression (Log2 scale) in cancer cell lines is also shown in Table 7 below, with the mean gene value being 6.53. The symbol "#" indicates low expression, with a Log2 value in the range of greater than 2.00 to 4.00. The symbol "##" indicates moderate expression, with a Log2 value in the range of greater than 4.00 to 6.00. The symbol "###" indicates high expression, with a Log2 value in the range of greater than 6.00 to 10.00.

[0500] [Table 7] TIFF0007863272000157.tif196163

[0501] [Example 45] PRISM assay for cell panel anti-cancer bioactivity assay Compound I-1 was evaluated for its anticancer activity against a panel of cancer cell lines using the PRISM assay described below in this specification.

[0502] Part I - Experimental Procedure The PRISM multiplexed cell viability platform (which simultaneously profiles relative inhibition in mixtures) enabled multiplexed screening of compound I-1 across 900 barcoded cell lines representing more than 45 strains. Details of the assay technique are described in Yu, C., et al., "High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines," Nat. Biotechnol. 2016, Vol. 34, pp. 419-423; and Corsello, SM, et al., "Discovering the anti-cancer potential of non-oncology drugs by systematic viability profiling," Nat. Cancer, 2020, Vol. 1, pp. 235-248, each of which is incorporated herein by reference in its entirety.

[0503] In short, a unique oligonucleotide barcode is stably transduced into individual cancer cell lines. After barcode transduction, the individual cell lines are pooled together in groups of 20-25 based on similarity in growth rate, then thawed in 384-well assay preparation plates and treated with the test compound. After 5 days of incubation, the amount of transcribed barcode in each individual cancer cell line is quantified using isolated mRNA to calculate relative viability (Log2 factor change, "LFC").

[0504] Compound I-1 was screened in the PRISM assay at 8 point doses (3-fold dilution) by 5 days of treatment with 885 QC-certified cancer cell lines. Two PRISM cell line collections were used in the assay: PR500 (containing only adherent cell lines) and PR300+ (containing adherent and suspension cell lines). To ensure high data quality, benchmark compounds (included in the validation compounds) were also tested at doses. All compounds were run in triplicate, with each plate containing a positive control (bortezomib, 20 μM) and a negative control (DMSO).

[0505] Part II - Results Compound I-1 was tested at a concentration of 66.7 μM. Table 8 shows the cell lines in which compound I-1 produced the most significant anticancer effect, characterized by a change in cell abundance characterized by a Log2 ratio change in the range of -3.5 to -2.0. Table 9 shows the cell lines in which compound I-1 produced a significant anticancer effect, characterized by a change in cell abundance characterized by a Log2 ratio change in the range of greater than -2.0 to -1.0. Table 10 shows the cell lines in which compound I-1 produced an anticancer effect, characterized by a change in cell abundance characterized by a range of greater than -1.0 to -0.5. Table 11 shows the cell lines in which compound I-1 produced an anticancer effect, characterized by a change in cell abundance characterized by a range of greater than -0.5 to -0.001. Table 12 shows cell lines in which compound I-1 did not appear to produce an anticancer effect at the concentration tested under the conditions of this experiment.

[0506] Tables 8-11 below also show the Log2 expression of MGMT in cell lines. The symbol "#" indicates low expression, with a Log2 value of 2.00 or less. The symbol "##" indicates moderate expression, with a Log2 value in the range of greater than 2.00 to 4.00. The symbol "###" indicates high expression, with a Log2 value in the range of greater than 4.00 to 7.50.

[0507] [Table 8]

[0508] [Table 9] TIFF0007863272000160.tif222165

[0509] Table 10 TIFF0007863272000162.tif251165 TIFF0007863272000163.tif252165 TIFF0007863272000164.tif248165 TIFF0007863272000165.tif89166

[0510] Table 11 TIFF0007863272000167.tif246165 TIFF0007863272000168.tif248165 TIFF0007863272000169.tif247165 TIFF0007863272000170.tif248165 TIFF0007863272000171.tif247165 TIFF0007863272000172.tif246165 TIFF0007863272000173.tif246165 TIFF0007863272000174.tif85166

[0511] Table 12 TIFF0007863272000176.tif171110 TIFF0007863272000177.tif255163 TIFF0007863272000178.tif173110 TIFF0007863272000179.tif255164 TIFF0007863272000180.tif253165 TIFF0007863272000181.tif84165

[0512] [Example 46] Anti-cancer bioactivity assay The activity of compounds I-1 and A1 was evaluated using the anti-cancer assays described below in this specification.

[0513] Part I - Experimental Procedure Compounds I-1 and A1 were tested for their anticancer activity against isogenic LN229 glioblastoma cells using a procedure based on the steps described in Example 43 above, except that the maximum concentration of the compounds tested was 200 μM. [Table 13]

[0514] Part II - Results Compound A1 did not exhibit detectable anticancer activity in this assay. In contrast, compound I-1 was able to induce the death of MGMT-negative / MMR-positive LN229 cells. Compound I-1 required less than 20 μM IC50 in the assay to induce the death of MGMT-negative / MMR-positive LN229 cells. 50 Compound I-1 had the following properties. Furthermore, compound I-1 was able to induce the death of MGMT-negative / MMR-negative LN229 cells. Compound I-1 required less than 20 μM IC in the assay to induce the death of MGMT-negative / MMR-negative LN229 cells. 50 It possessed this characteristic. This demonstrates the superior anti-cancer effect of compound I-1 compared to compound A1.

[0515] Embedding by reference The entirety of each disclosure of the patent documents and scientific papers referenced herein is incorporated by reference for all purposes.

[0516] Equivalents The present invention may be embodied in other specific forms without departing from its spirit or essential features. Therefore, the embodiments described herein should be considered illustrative in all respects and not limiting the invention described herein. Accordingly, the scope of the invention is indicated not by the foregoing description but by the appended claims, and all modifications that fall within the equivalent meaning and scope of the claims are intended to be encompassed therein.

Claims

1. Compound represented by formula I-aa: 【Transformation 3】 or a pharmaceutically acceptable salt thereof (In the formula, R １ is hydrogen or methyl; R ２ C １～２ It is fluoroalkyl; and X is C １～３ (It is alkylene).

2. The compound according to claim 1, which is a compound of formula I-aa.

3. X is -CH ２ CH ２ - The compound according to claim 1.

4. R １ The compound according to claim 1, wherein the compound is hydrogen.

5. R １ The compound according to claim 1, wherein is methyl.

6. R ２ The compound according to claim 1, wherein R is trifluoromethyl.

7. R ２ C １ The compound according to claim 1, wherein it is a fluoroalkyl compound.

8. R ２ C １～２ The compound according to claim 1, wherein it is a trifluoroalkyl group.

9. The compound, 【Chemistry 4】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. The compound, 【Transformation 5】 The compound according to claim 1.

11. A pharmaceutical composition comprising the compound described in claim 1 and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising the compound described in claim 9 and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 for the treatment of cancer in a target area.

14. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 9 for the treatment of cancer in a target area.

15. A pharmaceutical composition comprising an effective amount of the compound according to claim 1 for causing DNA damage in a target.

16. A pharmaceutical composition comprising an effective amount of the compound according to claim 9 for causing DNA damage in a target.

17. The pharmaceutical composition according to claim 15, wherein the subject has cancer.

18. The pharmaceutical composition according to any one of claims 13, 14, or 17, wherein the cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland cancer, bile duct cancer, gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, leukemia, urothelial carcinoma, colorectal cancer, or glioblastoma multiforme.

19. The pharmaceutical composition according to any one of claims 13, 14, or 17, wherein the cancer is invasive breast cancer, colon adenocarcinoma, head and neck cancer, lung adenocarcinoma, rectal adenocarcinoma, acute myeloid leukemia, glioblastoma multiforme, low-grade cerebral glioma, colorectal cancer, or metastatic melanoma.

20. The pharmaceutical composition according to any one of claims 13, 14, or 17, wherein the cancer is glioblastoma multiforme.

21. The pharmaceutical composition according to any one of claims 13, 14, or 17, wherein the cancer is MGMT deficient.

22. The pharmaceutical composition according to any one of claims 13, 14, or 17, wherein the cancer is MMR deficiency.

23. The pharmaceutical composition according to any one of claims 13, 14, or 17, wherein the cancer is resistant to treatment using temozolomide.

24. The pharmaceutical composition according to any one of claims 13, 14, or 17, wherein the subject is a human.

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