Compounds for treating specific types of leukemia

Abstract

To provide compounds that inhibit the activity of BCR-ABL1 and BCR-ABL1 mutants, or pharmaceutically acceptable salts thereof, as well as compositions comprising them and methods for treating leukemia with BCR-ABL1 and BCR-ABL1 mutations.SOLUTION: Provided are, for example, compound 2 represented by the following formula, or a pharmaceutically acceptable salt thereof, compositions comprising the same, and methods of treatment comprising administering the composition to a patient.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 62 / 733,029 filed on 18 September 2018, U.S. Provisional Application No. 62 / 816,637 filed on 11 March 2019, and U.S. Provisional Application No. 62 / 889,929 filed on 21 August 2019, the disclosures of which are incorporated herein by reference in their entirety for all purposes.

[0002] Technical field of inventions This specification provides compounds, preferably compounds that inhibit the tyrosine kinase enzyme activity of a protein selected from Avelson protein (ABL1), Avelson-related protein (ABL2), or chimeric protein BCR-ABL1, compositions thereof, and methods for producing the same; as well as methods for inhibiting the tyrosine kinase enzyme activity of a protein selected from Avelson protein (ABL1), Avelson-related protein (ABL2), or chimeric protein BCR-ABL1, and methods for treating a disease that prevent, suppress or improve the pathogenesis and / or symptoms of the disease by regulating BCR-ABL1 activity. [Background technology]

[0003] In chronic myeloid leukemia (CML), the Philadelphia chromosome (Ph) is formed by the t(9,22) reciprocal chromosome translocation and translocates to hematopoietic stem cells. This chromosome carries the BCR-ABL1 oncogene, which encodes the chimeric BCR-ABL1 protein. Agents that inhibit the tyrosine kinase activity of BCR-ABL1 via an ATP-competitive mechanism, such as Gleevec™ / Glivec™ (imatinib), Tasigna™ (nilotinib), and Sprycel™ (dasatinib), can be effective for the treatment of CML, however, some patients relapse due to the emergence of drug-resistant clones. For example, small molecules, or combinations thereof, can be useful for inhibiting the activity of BCR-ABL1 and BCR-ABL1 mutations via the ATP binding site, the myristoyl binding site, or a combination of both sites. [Summary of the Invention]

[0004] In one aspect, provided herein is a compound of formula (I) or formula (Ia): [Chemical Formula] wherein: L is -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-; R 1 is optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered heterocycle, C(O)NR 6 R 7 , S(O)2NR 6 R 7 , NR 6 COR 7 , NR 6 SO2R 7 , or C(O)OR 6 ; R 2This includes H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 member heterocycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C 10 An aryl, or a 5- to 10-membered heteroaryl, which may be optionally substituted; R 3 H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR 6 , or NR 6 R 7 and; Alternatively, R 2 and R 3 Together with the atoms in between, they form optionally substituted C3-C8 cycloalkyl groups, or optionally substituted 4- to 10-membered heterocycloalkyl groups; R 4 is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl; X is either O or S; Y is CH, C-(C1-C2 alkyl), C-halo, or N; Z is CR 5 , or N; R 5 is H, or halogen; R 6 This includes H, optionally substituted C1-C6 alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 4-10 member heterocycloalkyl groups, and optionally substituted C6-C 10An aryl, or a 5- to 10-membered heteroaryl which may be optionally substituted; and, R 7 This includes H, optionally substituted C1-C6 alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 4-10 member heterocycloalkyl groups, and optionally substituted C6-C 10 An aryl, or a 5- to 10-membered heteroaryl, which may be optionally substituted; Alternatively, R 6 and R 7 Together with the nitrogen atoms to which they bind, they form a 4-7 member heterocycle, which may be optionally substituted. However, the compound is other than (i) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl- or (ii) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-. A compound represented by, or its tautomer or N-oxide, or a pharmaceutically acceptable salt thereof is provided.

[0005] In some embodiments, the compound is of formula (IA-1): [ka] It is a compound represented by [the formula shown].

[0006] In one embodiment, a method is provided for inhibiting the tyrosine kinase enzyme activity of a protein selected from the group consisting of Abelson protein (ABL1), Abelson-associated protein (ABL2), and the chimeric protein BCR-ABL1, the method comprising contacting the protein with an effective amount of a compound or composition provided herein.

[0007] In one embodiment, a method is provided for treating a disease in a patient, for preventing, suppressing or improving the pathogenesis and / or symptoms of the disease by regulating BCR-ABL1 activity, the method comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein.

[0008] In one embodiment, a method is provided for treating leukemia in a patient, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein, wherein the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL). [Modes for carrying out the invention]

[0009] definition In this specification, unless otherwise specified, the following definitions shall apply. Furthermore, if a term or symbol used herein is not defined below, it shall have its ordinary meaning in the art.

[0010] "Contains" is intended to mean that compositions and methods include the elements described but do not exclude others. "Essentially consisting of" as used to define compositions and methods means excluding other elements that are essentially important to the combination. For example, a composition essentially consisting of the elements defined herein does not exclude other elements that do not substantially affect the basic and novel characteristics of the claimed invention. "Consists of" means excluding, for example, trace amounts of other components and steps beyond the substantial steps of the described method. Embodiments defined by each of these transitions are within the scope of the present invention.

[0011] The “effective amount” or dose of a compound or composition means the amount of the compound or composition that produces the desired intended result based on the disclosure herein. The effective amount can be determined by standard pharmaceutical methods using cell culture or experimental animals, for example, but is not limited to LD 50 (50% lethal dose in the population), and ED 50 (The effective dose for 50% of the population) is cited.

[0012] In this specification, the term “excipient” means an inert or inactive substance that may be used in the manufacture of a drug or pharmaceutical, such as a tablet, containing the compound of the present invention as an active ingredient. A variety of substances may be included in the term “excipient,” but are not limited to those used as binders, disintegrants, coatings, compression / encapsulation aids, creams or lotions, lubricants, parenteral solutions, ingredients for chewable tablets, sweeteners or flavorings, suspending / gelling agents, or wet granulation agents. Examples of binders include carbomer, povidone, and xanthan gum; examples of coating agents include cellulose phthalate acetate, ethylcellulose, gellan gum, maltodextrin, and enteric coating agents; examples of compression / encapsulation aids include calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrous or monohydrate; optionally combined with aspartame, cellulose, or microcrystalline cellulose), starch dc, and sucrose; examples of disintegrants include croscarmellose sodium, gellan gum, and sodium starch glycolate; examples of creams or lotions include... Examples of ingredients include maltodextrin and carrageenan; lubricants include, for example, magnesium stearate, stearic acid, and sodium stearyl fumarate; raw materials for chewable tablets include, for example, dextrose, fructose dc, and lactose (monohydrate, optionally combined with aspartame or cellulose); suspending / gelling agents include, for example, carrageenan, sodium starch glycolate, and xanthan gum; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, and sucrose dc; and wet granulating agents include, for example, calcium carbonate, maltodextrin, and microcrystalline cellulose.

[0013] "Patient" means mammal, including humans and non-human mammals. Examples of patients include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cattle, and humans. In some embodiments, "patient" means human.

[0014] "Pharmacologically acceptable" means safe and non-toxic, preferably in vivo, and more preferably in human administration.

[0015] "Pharmacologically acceptable salt" means a salt that is pharmaceutically acceptable. The compounds described herein may be administered as pharmaceutically acceptable salts.

[0016] A “prodrug” is a compound that, after administration, is metabolized or converted to become a biologically active or more active compound (or drug) with respect to at least one property. With respect to a drug, a prodrug is chemically modified in such a way that it becomes less active or inactive compared to the drug, but the chemical modification is such that the corresponding drug is produced by metabolism or other biological processes after the prodrug is administered. Compared to the active drug, a prodrug may result in altered metabolic stability or transport properties, reduced side effects or toxicity, or improved flavor (see, for example, Nogrady, 1985, Medicinal Chemistry: A Biochemical Approach, Oxford University Press, New York, pages 388–392, which is incorporated herein by reference). Prodrugs can be synthesized using reactants other than using the corresponding drug. Examples of prodrugs, though not limited to these, include carboxyesters, linear and cyclic phosphate esters, phosphoramides and phosphoramidates, carbamates, preferably phenolic carbamates (i.e., carbamates in which the hydroxyl group is part of an aryl or heteroaryl moiety, and the aryl and heteroaryl moieties may be optionally substituted).

[0017] "Salt" refers to an ionic compound formed between an acid and a base. Where the compounds provided herein contain an acidic functional group, such salts include, but are not limited to, salts of alkali metals, alkaline earth metals, and ammonium. In this specification, ammonium salts include salts containing protonated nitrogen bases and alkylated nitrogen bases. Useful cations in pharmaceutically acceptable salts include, but are not limited to, ammonium cations based on Na, K, Rb, Cs, NH4, Ca, Ba, imidazolium, and naturally occurring amino acids. Where the compounds provided herein contain a basic functional group, such salts include, but are not limited to, salts of organic acids such as carboxylic acids and sulfonic acids, as well as salts of inorganic acids such as hydrogen halides, sulfuric acid, and phosphoric acid. Useful anions in pharmaceutically acceptable salts include, but are not limited to, oxalates, maleates, acetates, propions, succinates, tartrates, chlorides, sulfates, bisulfates, monobasic phosphates, dibasic and tribasic phosphates, mesylates, and tosylates.

[0018] The "therapeutic dose" or dosage of a compound or composition refers to the amount of the compound or composition that results in the reduction or suppression of a patient's symptoms or an extension of their survival. As a result, multiple administrations of the compound or composition may be required.

[0019] In patients, “treating” or “treating” a disease means 1) preventing the onset of the disease in a patient who has a disease risk factor or who does not yet show symptoms of the disease, 2) suppressing or suppressing the onset of the disease, or 3) improving or regressing the disease. In this specification, “treating” or “treating” is an approach to obtain a beneficial or desirable outcome, including clinical outcomes. For the purposes of this disclosure, beneficial or desirable outcomes include, but are not limited to, one or more of the following: a reduction in one or more symptoms caused by the disease or disability; a reduction in the severity of the disease or disability; stabilization of the disease or disability (e.g., preventing or delaying the exacerbation of the disease or disability); a delay in the onset or recurrence of the disease or disability; a delay or slowing of the progression of the disease or disability; improvement of the condition of the disease or disability; providing (partial or overall) remission of the disease or disability; reducing the dose of one or more other drugs required to treat the disease or disability; enhancing the effects of other drugs used to treat the disease or disability; delaying the progression of the disease or disability; improving quality of life; and / or extending the patient’s survival. "Treatment" also includes the mitigation of the pathological consequences of a disease or disorder. The methods of the present invention aim to provide one or more of these therapeutic approaches.

[0020] An "isotopic isomer" of a compound is a compound in which one or more atoms of the compound are replaced by isotopes of the same atoms. For example, when H is replaced by D or T, or 12 C 11 If replaced by C, or 14 N 15 In some cases, N may be substituted. For example, but not limited to this, substituting with D may result in a decrease in metabolic rate and a longer half-life. Substituting H with T may provide a radioligand that could be useful for binding studies. 12 C is a short-lived isotope 11 Replacing it with C can provide a ligand useful for positron emission tomography (PET) scans. 14 N 15If we replace it with N, 15 We can provide compounds that can be detected / monitored by N NMR spectroscopy. For example, an isotopic isomer of a compound containing -CH2CH3 is a compound containing -CD2CD3 instead of -CH2CH3.

[0021] "Stereoisomers" or "multiple stereoisomers" refers to compounds that differ in the stereoforming properties of their constituent atoms, such as in the chirality of one or more stereocenters, or in the cis or trans configuration of carbon-carbon or carbon-nitrogen double bonds. Stereoiomers include enantiomers and diastereomers.

[0022] "Tautomer" refers to alternative forms of compounds with different proton positions, such as enol-keto and imine-enamine tautomers, or tautomer forms of heteroaryl groups that contain ring atoms bonded to both the ring-NH- and ring-N- moieties, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0023] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 12 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. This term includes linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-). x Alkyl refers to an alkyl group having x carbon atoms.

[0024] "Alkenyl" refers to a linear or branched monovalent hydrocarbyl group having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and one or more, preferably 1 to 2 vinyl (>C=C<) unsaturated moieties. Examples of such groups include vinyl, allyl, and buta-3-en-1-yl. This term includes cis and trans isomers, or mixtures of these isomers. x An alkenyl refers to an alkenyl group that has x carbon atoms.

[0025] "Alkynyl" refers to a linear or branched monovalent hydrocarbyl group having 2 to 6 carbon atoms, preferably 2 to 3 carbon atoms, and 1 or more, preferably 1 to 2 acetylene (C≡C-) unsaturated moieties. Examples of such alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CH2C≡CH). x Alkynyl refers to an alkynyl group having x carbon atoms.

[0026] "Substituting alkyl" means an alkyl group having 1 to 5 substituents, preferably 1 to 3, more preferably 1 to 2 substituents, and the substituents are alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylamino, carboxyl, carboxyl ester, ( Selected from the group consisting of (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, where the substituents are as defined herein.

[0027] "Substitutive alkenyl" means an alkenyl group having 1 to 3 substituents, preferably 1 to 2 substituents, and the substituents include alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylamino, carboxyl, carboxylester, (carboxylester)amino, (carboxylester) Selected from the group consisting of ter(oxy), cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein, except that the hydroxy or thiol substituent is not bonded to a vinyl (unsaturated) carbon atom.

[0028] "Substituting alkynyl" means an alkynyl group having 1 to 3 substituents, preferably 1 to 2 substituents, and the substituents include alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylamino, carboxyl, carboxylester, (carboxylester)amino, (carboxyl Selected from the group consisting of ster(oxy), cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein, except that the hydroxy or thiol substituent is not bonded to an acetylene carbon atom.

[0029] "Alkoxy" means a group represented by -O-alkyl, where alkyl is as defined herein. Examples of alkoxys include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

[0030] "Substituting alkoxy" means a group represented by -O-(substituted alkyl), where substituted alkyl is as defined herein. Preferred substituted alkyl groups in -O-(substituted alkyl) include halogenated alkyl groups, and in particular, halogenated methyl groups such as trifluoromethyl, difluoromethyl, and fluoromethyl.

[0031] "Acyl" means a group represented by HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Acyls include the "acetyl" group, CH3C(O)-.

[0032] "Acylamino" is -NR 30 C(O)alkyl, -NR 30 C(O) substituted alkyl, -NR 30 C(O) cycloalkyl, -NR 30 C(O) substituted cycloalkyl, -NR 30 C(O) alkenyl, -NR 30 C(O)-substituted alkenyl, alkoxy, substituted alkoxy-NR 30 C(O)alkynyl, -NR 30 C(O) substituted alkynyl, -NR 30 C(O)aryl, -NR 30 C(O) substituted aryl, -NR 30 C(O) heteroaryl, -NR 30 C(O) substituted heteroaryl, -NR 30C(O) heterocyclic and -NR 30 This refers to a group represented by a C(O) substituted heterocyclic group, where R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl; and where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0033] "Acyloxy" means a group represented by alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O-, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0034] "Amino" refers to the group represented by -NH2.

[0035] "Substituting amino acid" is -NR 31 R 32 This refers to the base shown by, where R 31 and R 32R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylamino, sulfonylamino, and substituted sulfonyl, and here, R 31 and R 32 R may optionally combine with the bonded nitrogen to form a heterocyclic or substituted heterocyclic group, however, 31 and R 32 Neither of them is hydrogen, and here alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 31 is hydrogen, R 32 When is alkyl, the substituted amino group may be referred to as alkylamino in this specification. 31 and R 32 When R is alkyl, the substituted amino group may be referred to as a dialkylamino in this specification. When referring to a monosubstituted amino, R 31 or R 32 This means that one of them is hydrogen, but not both are hydrogen. When we say disubstituted amino acid, R 31 and R 32 This means that neither of them is hydrogen.

[0036] "Aminocarbonyl" is -C(O)NR 33 R 34 This refers to the base shown by, where R 33 and R 34R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and here, R 33 and R 34 The nitrogen atoms may optionally combine with the bonded nitrogen to form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0037] "Aminothiocarbonyl" is -C(S)NR 33 R 34 This refers to the base shown by, where R 33 and R 34 R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and here, R 33 and R 34 The nitrogen atoms may optionally combine with the bonded nitrogen to form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0038] "Aminocarbonylamino" is -NR 30 C(O)NR 33R 34 represents a group represented by the formula, wherein R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R 33 and R 34 may optionally be taken together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0039] "Aminothiocarbonylamino" refers to -NR 30 C(S)NR 33 R 34 represents a group represented by the formula, wherein R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R 33 and R 34The nitrogen atoms may optionally combine with the bonded nitrogen to form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0040] "Aminocarbonyloxy" is -OC(O)NR 33 R 34 This refers to the base shown by, where R 33 and R 34 R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and here, R 33 and R 34 The nitrogen atoms may optionally combine with the bonded nitrogen to form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0041] "Aminosulfonyl" is -SO2NR 33 R 34 This refers to the base shown by, where R 33 and R 34R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and here, R 33 and R 34 The nitrogen atoms may optionally combine with the bonded nitrogen to form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0042] "Aminosulfonyloxy" is -O-SO2NR 33 R 34 This refers to the base shown by, where R 33 and R 34 R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and here, R 33 and R 34 The nitrogen atoms may optionally combine with the bonded nitrogen to form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0043] "Aminosulfonylamino" is -NR 30 -SO2NR33 R 34 This refers to the base shown by, where R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and here, R 33 and R 34 The nitrogen atoms may optionally combine with the bonded nitrogen to form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0044] "Amidino" is -C(=NR 35 )NR 33 R 34 This refers to the base shown by, where R 33 , R 34 , and R 35 R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and here, R 33 and R 34The nitrogen atoms may optionally combine with the bonded nitrogen to form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0045] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group having 6 to 14 carbon atoms, either monocyclic (e.g., phenyl (Ph)) or fused polycyclic (e.g., naphthyl or anthryl), where the fused ring may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-on-7-yl), but the bond is located on an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.

[0046] "Substituting aryl" means an aryl group substituted with 1 to 5 substituents, preferably 1 to 3, more preferably 1 to 2 substituents, where substituents include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, and substituted heterocyclyl Selected from the group consisting of aminocarboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, where the substituents are as defined herein.

[0047] "Aryloxy" means a group represented by -O-aryl, where aryl is as defined herein, for example, phenoxy and naphthoxy.

[0048] "Substituting aryloxy" means a group represented by -O-(substituted aryl), where substituted aryl is as defined herein.

[0049] "Arylthio" means a group denoted by -S-aryl, where aryl is as defined herein.

[0050] "Substituting arylthio" means a group denoted by -S-(substituting aryl), where the substituted aryl is as defined herein.

[0051] "Arylamino" is -NR 37 (aryl) means the group represented by (aryl), where aryl is as defined herein, and R 37 is hydrogen, alkyl, or substituted alkyl.

[0052] "Substituting arylamino" is -NR 37 This refers to the group represented by (substituted aryl), where R 37 is hydrogen, alkyl, or substituted alkyl, where substituted aryl is as defined herein.

[0053] "Carbonyl" means a divalent group, -C(O)-, which is equivalent to -C(=O)-.

[0054] "Carboxylate" or "carboxyl" means -COOH or its salt.

[0055] "Carboxyl ester" or "carboxyester" means a group represented by -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0056] "(Carboxyl ester)amino" is -NR 30 -C(O)O-alkyl, -NR 30 -C(O)O-substituted alkyl, -NR 30 -C(O)O-alkenyl, -NR 30 -C(O)O-substituted alkenyl, -NR 30 -C(O)O-alkynyl, -NR 30 -C(O)O-substituted alkynyl, -NR 30 -C(O)O-aryl, -NR 30 -C(O)O- Substitute Arial, -NR 30 -C(O)O-cycloalkyl, -NR 30 -C(O)O-substituted cycloalkyl, -NR 30 -C(O)O-heteroaryl, -NR 30 -C(O)O- substituted heteroaryl, -NR 30 -C(O)O-heterocyclic and -NR 30 This refers to a group represented by -C(O)O- substituted heterocyclic groups, where R 30is alkyl or hydrogen, and here alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0057] "(carboxyl ester)oxy" means a group represented by -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-alkenyl, -OC(O)O-substituted alkenyl, -OC(O)O-alkynyl, -OC(O)O-substituted alkynyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, OC(O)O-substituted cycloalkyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocyclic, and -OC(O)O-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0058] "Cyano" refers to a group represented by -C≡N.

[0059] "Cycloalkyl" means a monocyclic or polycyclic cyclic alkyl group, which is saturated or unsaturated but non-aromatic, comprising 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms, and includes condensed, cross-linked, and spirocyclic systems. xCycloalkyl means a cycloalkyl group having x ring carbon atoms. Suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more rings may be aryl, heteroaryl, or heterocyclic, provided the bonding is via a non-aromatic, non-heterocyclic ring, or saturated carbon ring. "Substitutive cycloalkyl" means a cycloalkyl group having 1 to 5, preferably 1 to 3, substituents, including oxo, thion, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxy Selected from the group consisting of silester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, where the substituents are as defined herein.

[0060] "Cycloalkyloxy" means -O-cycloalkyl.

[0061] "Substituting cycloalkyloxy" means -O- (substituted cycloalkyl).

[0062] "Cycloalkylamino" is -NR 37 This refers to a group represented by (cycloalkyl), where R 37 is hydrogen, alkyl, or substituted alkyl.

[0063] "Substituting cycloalkylamino" is -NR 37 This refers to a group represented by (substituted cycloalkyl), where R 37 is hydrogen, alkyl, or substituted alkyl, and substituted cycloalkyl is as defined herein.

[0064] "Cycloalkylthio" means -S-cycloalkyl.

[0065] "Substituting cycloalkylthio" means -S- (substituted cycloalkyl).

[0066] "Guanidino" refers to the group represented by -NHC(=NH)NH2.

[0067] "Substituting guanidino" is -NR 36 C(=NR 36 )N(R 36 ) means 2, where each R 36 These are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and two R atoms bonded to a common guanidino nitrogen atom. 36 The group may optionally combine with the bonded nitrogen to form a heterocyclic or substituted heterocyclic group, provided that at least one R 36 is not hydrogen, and here, the substituents are as defined herein.

[0068] "Halo" or "halogen" means fluoro, chloro, bromo, and iodine, and preferably fluoro or chloro.

[0069] "Hydroxy" or "hydroxyl" refers to the group represented by -OH.

[0070] "Heteroalkylenes" are compounds in which one or more carbon atoms are -O-, -S-, SO2, -NR Q -, [ka] [In the formula, R Q [It is H or C1-C6 alkyl.] This refers to the alkylene group that has been replaced in the part. "Substituted heteroalkylene" means a heteroalkylene group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the substituents disclosed in the substituted alkylene.

[0071] "Heteroaryl" means an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in its ring. Such heteroaryl groups can be monocyclic (e.g., pyridinyl or furyl) or fused polycyclic (e.g., indolidinyl or benzothienyl), where the fused ring may or may not be aromatic and / or may or may not contain heteroatoms, provided that the bonding portion is mediated by atoms of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atoms of the heteroaryl group may optionally be oxidized to supply an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Preferred heteroaryls include 5-membered or 6-membered heteroaryls such as pyridinyl, pyrrolyl, thiophenyl, and furanyl. Other preferred heteroaryls include 9-membered or 10-membered heteroaryls such as indolyl, quinolinyl, quinolonyl, isoquinolinyl, and isoquinolonyl.

[0072] "Substitutive heteroaryl" means a heteroaryl group substituted with 1 to 5 substituents, preferably 1 to 3, more preferably 1 to 2 substituents, selected from the group consisting of the same substituents as defined in substituted aryl.

[0073] "Heteroaryloxy" means -O-heteroaryl.

[0074] "Substituting heteroaryloxy" refers to a group represented by -O-(substituted heteroaryl).

[0075] "Heteroarylthio" refers to a group represented by -S-heteroaryl.

[0076] "Substituting heteroarylthio" refers to a group represented by -S-(substituted heteroaryl).

[0077] "Heteroarylamino" is -NR 37 This refers to a group represented by (heteroaryl), where R 37 is hydrogen, alkyl, or substituted alkyl.

[0078] "Substituting heteroarylamino" is -NR 37 This refers to a group represented by (substituted heteroaryl), where R 37 is hydrogen, alkyl, or substituted alkyl, and substituted heteroaryl is as defined herein.

[0079] "Heterocycle," "heterocyclic," "heterocycloalkyl," or "heterocyclyl" refers to a saturated or partially saturated but non-aromatic group having 1 to 10 ring carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and 1 to 4 ring heteroatoms, preferably 1 to 3 heteroatoms, more preferably 1 to 2 heteroatoms, selected from the group consisting of nitrogen, sulfur, or oxygen. xA heterocycloalkyl group refers to a heterocycloalkyl group having x ring atoms, each containing a ring heteroatom. Heterocycles include monocyclic groups or condensed polycyclic groups, which include condensation, bridging, and spirocyclic systems. In condensed ring systems, one or more rings may be cycloalkyl, aryl, or heteroaryl, provided that the bonding is via a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group may optionally be oxidized to supply an N-oxide, sulfinyl, or sulfonyl moiety.

[0080] "Heterocyclylene" refers to a saturated or partially saturated but non-aromatic divalent group having 1 to 10 ring carbon atoms and 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. "Substitutive heterocyclylene" refers to a heterocyclylene group substituted with 1 to 5, preferably 1 to 3, substituents, the same substituents defined for substituted cycloalkyl groups.

[0081] "Substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" means a heterocyclyl group substituted with 1 to 5, preferably 1 to 3, substituents, the same substituents defined for substituted cycloalkyl.

[0082] "Heterocyclyloxy" refers to a group represented by -O-heterocyclyl.

[0083] "Substituting heterocyclyloxy" refers to a group represented by -O-(substituted heterocyclyl).

[0084] "Heterocyclilthio" refers to a group represented by -S-heterocyclyl.

[0085] "Substituting heterocyclylthio" refers to a group represented by -S-(substituted heterocyclyl).

[0086] "Heterocyclylamino" is -NR 37This refers to the group represented by (heterocyclyl), where R 37 is hydrogen, alkyl, or substituted alkyl.

[0087] "Substituting heterocyclylamino" is -NR 37 This refers to the group represented by (substituted heterocyclyl), where R 37 is hydrogen, alkyl, or substituted alkyl, and substituted heterocyclyl is as defined herein.

[0088] Examples of heterocyclyls and heteroaryls include, but are not limited to, azetidinil, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridazyl, indolidyl, indolidyl, isoindolyl, indolyl, dihydroindolyl, indazolyl, purinyl, quinolidinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, carborinyl, phenanthridine, acridinyl, phenanthrolinyl, i Examples include sothiazolyl, phenazinil, isoxazolyl, phenoxazinil, phenothiazinil, imidazolidinil, imidazolinil, piperidinil, piperazinil, indolinil, phthalimidyl, 1,2,3,4-tetrahydroisoquinolinil, 4,5,6,7-tetrahydrobenzo[b]thiophenyl, thiazolyl, thiazolidinil, thiophenyl, benzo[b]thiophenyl, morpholinil, thiomorpholinil (also known as thiamorpholinil), 1,1-dioxothiomorpholinil, piperidinil, pyrrolidinil, and tetrahydrofuranil.

[0089] "Nitro" refers to the group represented by -NO2.

[0090] "Oxo" means atom, (=O) or (-O).

[0091] A "spiro ring system" refers to a bicyclic system that has a single ring carbon atom shared by two rings.

[0092] "Sulfinyl" means a divalent group, -S(O)- or -S(=O)-.

[0093] "Sulfonyl" refers to a divalent group, -S(O)2- or -S(=O)2-.

[0094] "Substituting sulfonyl" means a group represented by -SO2-alkyl, -SO2-substituted alkyl, -SO2-OH, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, and -SO2-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Examples of substituted sulfonyls include groups such as methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-. Preferred substituted alkyl groups on substituted alkyl-SO2- include halogenated alkyl groups, and in particular, halogenated methyl groups such as trifluoromethyl, difluoromethyl, and fluoromethyl.

[0095] "Substituting sulfinyl" means a group represented by -SO-alkyl, -SO-substituted alkyl, -SO-alkenyl, -SO-substituted alkenyl, -SO-cycloalkyl, -SO-substituted cycloalkyl, -SO-aryl, -SO-substituted aryl, -SO-heteroaryl, -SO-substituted heteroaryl, -SO-heterocyclic, and -SO-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Examples of substituted sulfinyls include methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-. Preferred substituted alkyl groups on substituted alkyl-SO- include halogenated alkyl groups, and in particular, halogenated methyl groups such as trifluoromethyl, difluoromethyl, and fluoromethyl.

[0096] "Sulfonyloxy" or "substituted sulfonyloxy" means a group represented by -OSO2-alkyl, -OSO2-substituted alkyl, -OSO2-OH, -OSO2-alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cycloalkyl, -OSO2-aryl, -OSO2-substituted aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, -OSO2-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0097] "Sulfonylamino" is -NR 37 This refers to the group represented by (substituted sulfonyl), where R 37 is hydrogen, alkyl, or substituted alkyl, and substituted sulfonyl is as defined herein.

[0098] "Thioacyl" means a group represented by HC(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted heterocyclic-C(S)-, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0099] "Mercapto" or "thiol" refers to a group denoted by -SH.

[0100] "Formyl" refers to the group represented by -C(O)H.

[0101] "Thiocaunal" means a divalent group, -C(S)-, which is equivalent to -C(=S)-.

[0102] "Thion" means atom (=S).

[0103] "Alkylthio" means a group represented by -S-alkyl, where alkyl is as defined herein.

[0104] "Substituting alkylthio" means a group represented by -S-(substituted alkyl), where substituted alkyl is as defined herein. Preferred substituted alkyl groups on -S-(substituted alkyl) include halogenated alkyl groups, and in particular, halogenated methyl groups such as trifluoromethyl, difluoromethyl, and fluoromethyl.

[0105] "Vinyl" refers to the unsaturated hydrocarbon group -CH=CH2, which is derived from ethylene.

[0106] Throughout this specification, the terms “optional” or “optionally” mean that the event or situation described thereafter may occur, but is not required to occur, and that the description includes both cases in which the event or situation occurs and cases in which it does not occur. For example, “The nitrogen atom is optionally oxidized to supply an N-oxide (N→O) moiety” means that the nitrogen atom may be oxidized, but is not required to be oxidized, and the description includes both cases in which the nitrogen atom is not oxidized and cases in which the nitrogen atom is oxidized.

[0107] The phrase "optionally substituted" means a substituted or unsubstituted group. The substituted group may be substituted by one or more substituents, such as 1, 2, 3, 4, or 5 substituents. Preferably, the substituents are selected from the functional groups provided herein. In certain more preferred embodiments, the substituents are oxo, halo, -CN, NO2, -CO2R 100 , -OR 100 , -SR 100 -SOR 100 , -SO2R 100 , -NR 101 R 102 ,-CONR 101 R 102 -SO2NR 101 R 102 , C1-C6 alkyl, C1-C6 alkoxy, -CR 100 =C(R 100 )2, -CCR 100 , C3-C 10 Cycloalkyl, C4-C 10 Heterocyclyl, C6-C 14 Aryl, and C5-C 12 Selected from heteroaryls, where each R 100 These are independently hydrogen, or C1-C8 alkyl; C3-C 12 Cycloalkyl; C4-C 10 Heterocycline; C6-C 14 Aryl; or C2-C12 The molecule is a heteroaryl group; where the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group may each be optionally substituted with 1 to 3 halo, 1 to 3 C1-C6 alkyl, 1 to 3 C1-C6 haloalkyl, or 1 to 3 C1-C6 alkoxy groups. More preferably, the substituent is selected from the group consisting of chloro, fluoro, -OCH3, methyl, ethyl, isopropyl, cyclopropyl, -OCF3, -CF3, and -OCHF2.

[0108] R 101 and R 102 These are independently C1-C8 alkyl, C1-C6 alkoxy, oxo, and -CR atoms, which may be optionally substituted with hydrogen;-CO2H or its esters. 103 =C(R 103 )2, -CCR, C3-C 10 Cycloalkyl, C3-C 10 Heterocyclyl, C6-C 14 Aryl, or C2-C 12 It is a heteroaryl, where each R 103 These are independently hydrogen, or C1-C8 alkyl; C3-C 12 Cycloalkyl; C4-C 10 Heterocycline; C6-C 14 Aryl; or C2-C 12 It is a heteroaryl group; where the cycloalkyl, heterocyclyl, aryl, or heteroaryl group may optionally be substituted with 1 to 3 alkyl groups or 1 to 3 halo groups, or R 101 and R 102 These may, together with the nitrogen atom to which they bond, form a 5-7 member heterocycle.

[0109] Unless otherwise specified, the nomenclature of substituents not explicitly defined herein is done by naming the terminal portion of the functional group, followed by the functional groups adjacent to the bonding site. For example, the substituent "alkoxycarbonylalkyl" means a group represented by (alkoxy)-C(O)-(alkyl)-.

[0110] It is understood that polymers formed by defining substituents having further substituents on themselves (e.g., substituted aryls having substituted aryl groups, such as substituents that themselves are substituted with substituted aryl groups) are not intended to be included herein. In such cases, the maximum number of such substituents is three. That is, each of the above definitions is to be interpreted restrictively, for example, a substituted aryl group is limited to -substituted aryl-(substituted aryl)-substituted aryl.

[0111] In some embodiments of the substitution portion, the portion is substituted with a group which may be substituted with a further group, but which cannot be additionally substituted. For example, in some embodiments of "substituted alkyl," the alkyl moiety is substituted by a group that may be further substituted (e.g., substituted alkoxy, substituted amino, substituted aryl, substituted aryloxy, substituted arylthio, substituted arylamino, substituted heteroarylamino, substituted cycloalkylamino, substituted heterocyclylamino, substituted cycloalkyl, substituted cycloalkyloxy, substituted cycloalkylthio, substituted guanidino, substituted heteroaryl, substituted heteroaryloxy, substituted heteroarylthio, substituted heterocyclic, substituted heterocyclyloxy, substituted heterocyclylthio, substituted sulfonyl, or substituted alkylthio), but the alkyl moiety, said substituted alkoxy, substituted amino, substituted aryl, substituted aryloxy, substituted arylthio, substituted arylamino, substituted heteroarylamino, substituted cycloalkylamino, substituted heterocyclylamino, substituted cycloalkyl, substituted cycloalkyloxy, substituted cycloalkylthio, substituted guanidino, substituted heteroaryl, substituted heteroaryloxy, substituted heteroarylthio, substituted heterocyclic, substituted heterocyclyloxy, substituted heterocyclylthio, substituted sulfonyl, or substituted alkylthio, is not substituted by a moiety that is itself further substituted. While "substituted alkyl" is given as an example, such embodiments are intended for each of the substituted parts described herein.

[0112] In some embodiments of the substitution portion, the portion is further substituted by a non-substituted group. Therefore, in some embodiments, the "substituted alkyl" is an alkyl moiety substituted by one or more, and in some embodiments, one or two or three or four or five moieties, the moieties independently selected from the group consisting of alkoxy, acyl, acylamino, acyloxy, amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, aryloxy, arylthio, arylamino, heteroarylamino, cycloalkylamino, heterocycloalkylamino, carboxyl, carboxylester, (carboxylester)amino, (carboxylester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, guanidino, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, nitro, SO3H, sulfonyloxy, sulfonylamino, thioacyl, thiol, and alkylthio. While "substituted alkyl" is given as an example, such embodiments are intended for each of the substituted parts described herein.

[0113] It should be understood that the above definition is not intended to include unacceptable substitution patterns (e.g., methyl substituted with four fluoro groups). Such unacceptable substitution patterns are well known to those skilled in the art.

[0114] It is understood that certain features of the Invention described in the context of a different embodiment for clarification may also be provided in combination in one embodiment. Conversely, various features of the Invention described in the context of one embodiment for simplification may also be provided separately or in any suitable subcombination. All combinations of embodiments relating to chemical groups represented by variable groups are specifically covered by the Invention and are disclosed herein as all combinations have been individually and explicitly disclosed, to the extent that such combinations include compounds that are stable compounds (i.e., compounds that can be isolated, identified, and tested for biological activity). Furthermore, all subcombinations of chemical groups cited in embodiments describing such variable groups are also specifically covered by the Invention and are disclosed herein as each of such subcombinations of chemical groups has been individually and explicitly disclosed herein.

[0115] compound In one embodiment, formula (I): [ka] [In the formula, L is -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-; R 1 C6-C may be substituted as desired. 10 Aryl, optionally substituted 5-10 member heteroaryls, optionally substituted 4-10 member heterocycles, C(O)NR 6 R 7 , S(O)2NR 6 R 7 , NR 6 COR 7 , NR 6 SO2R 7 , or C(O)OR 6 and; R 2This includes H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 member heterocycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C 10 An aryl, or a 5- to 10-membered heteroaryl, which may be optionally substituted; R 3 H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR 6 , or NR 6 R 7 And; or, R 2 and R 3 Together with the atoms in between, they form a cycloalkyl or heterocycloalkyl group, preferably an optionally substituted C3-C8 cycloalkyl group, or an optionally substituted 4-10 member heterocycloalkyl group; R 4 This is an optionally substituted C1-C6 alkyl, preferably a C1-C3 haloalkyl such as CF3 or CF2Cl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl; X is either O or S; Y is CH, C-(C1-C2 alkyl), C-halo, or N; Z is CR 5 , or N; R 5 is H, or halogen; R 6This includes H, optionally substituted C1-C6 alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 4-10 member heterocycloalkyl groups, and optionally substituted C6-C 10 An aryl, or a 5- to 10-membered heteroaryl which may be optionally substituted; and, R 7 This includes H, optionally substituted C1-C6 alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 4-10 member heterocycloalkyl groups, and optionally substituted C6-C 10 An aryl, or a 5- to 10-membered heteroaryl which may be optionally substituted; or, R 6 and R 7 Together with the nitrogen atoms to which they bind, they form a 4-7 member heterocycle, which may be optionally substituted. However, the compound is other than (i) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl- or (ii) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-. The compounds represented by, or their tautomers or their N-oxides, or their respective isotopic isomers, or their respective prodrugs, or their stereoisomers, or their respective pharmaceutically acceptable salts, or their respective solvates are provided.

[0116] In some embodiments, formula (Ii): [ka] [In the formula, L is -NH-CO-, -CO-NH-, or -NH-SO2-; R 1 C6-C may be substituted as desired. 10Aryl, optionally substituted 5-10 member heteroaryls, optionally substituted 4-10 member heterocycles, C(O)NR 6 R 7 , S(O)2NR 6 R 7 , NR 6 COR 7 , NR 6 SO2R 7 , or C(O)OR 6 and; R 2 This includes H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 member heterocycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C 10 An aryl, or a 5- to 10-membered heteroaryl, which may be optionally substituted; R 3 H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR 6 , or NR 6 R 7 And; or, R 2 and R 3 Together with the atoms in between, they form a cycloalkyl or heterocycloalkyl group, preferably an optionally substituted C3-C8 cycloalkyl group, or an optionally substituted 4-10 member heterocycloalkyl group; R 4 This is an optionally substituted C1-C6 alkyl, preferably a C1-C3 haloalkyl such as CF3 or CF2Cl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl; X is either O or S; Y is CH, C-(C1-C2 alkyl), C-halo, or N; Z is CR 5 , or N; R 5 is H, or halogen; R 6 This includes H, optionally substituted C1-C6 alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 4-10 member heterocycloalkyl groups, and optionally substituted C6-C 10 An aryl, or a 5- to 10-membered heteroaryl which may be optionally substituted; and, R 7 This includes H, optionally substituted C1-C6 alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 4-10 member heterocycloalkyl groups, and optionally substituted C6-C 10 An aryl, or a 5- to 10-membered heteroaryl which may be optionally substituted; or, R 6 and R 7 These, together with the nitrogen atoms to which they bind, form a 4- to 7-member heterocycle, which may be optionally substituted. The compounds represented by, or their tautomers or their N-oxides, or their respective isotopic isomers, or their respective prodrugs, or their stereoisomers, or their respective pharmaceutically acceptable salts, or their respective solvates are provided.

[0117] This specification also includes formula (Ia): [ka] [In the formula, R 1 , R 2 , R 3 , R 4 X, Y, Z, and L are as defined in the compound of formula (I). A compound represented by is provided.

[0118] In some embodiments, the compound is of formula (IA): [ka] This is the compound shown by . When Z is N, R 5 It is understood that it does not exist. Similarly, R 5 If R 5 Z is bonded to the carbon atom of the aryl ring, and Z is CR 5 It is understood that this is the case.

[0119] In some embodiments, the compound is of formula (IA-1): [ka] It is a compound represented by [the formula shown].

[0120] In some embodiments, the compound is represented by formulas (IIA) to (IIH): [ka] [In the formula, R 10 This is a 5-6 member heteroaryl compound, which may be optionally substituted, preferably having up to two ring nitrogen atoms in the heteroaryl portion; R 20 is optionally substituted C1-C3 alkyl, optionally substituted C3-C4 cycloalkyl, or optionally substituted 4-6 member heterocycloalkyl, preferably R 20 is methyl, optionally substituted isopropyl, or cyclopropyl; R 30 is H, optionally substituted C1-C3 alkyl, optionally substituted C3-C4 cycloalkyl, or optionally substituted 5-6 member heterocycloalkyl, preferably optionally substituted cyclopropyl; Ring A is a 5-6 member heterocycloalkyl group which may be optionally substituted; and, The remaining variable groups are as defined herein. It is a compound selected from among them.

[0121] In some embodiments, the compound is of formula (IIA): [ka] It is a compound represented by [the formula shown].

[0122] In some embodiments, the compound is of formula (IIB): [ka] It is a compound represented by [the formula shown].

[0123] In some embodiments, the compound is of formula (IIC): [ka] It is a compound represented by [the formula shown].

[0124] In some embodiments, the compound is of formula (IID): [ka] It is a compound represented by [the formula shown].

[0125] In some embodiments, the compound is of formula (IIE): [ka] It is a compound represented by [the formula shown].

[0126] In some embodiments, the compounds provided herein are of formula (IIF): [ka] It is a compound represented by [the formula shown].

[0127] In some embodiments, the compounds provided herein are of formula (IIG): [ka] It is a compound represented by [the formula shown].

[0128] In some embodiments, the compounds provided herein are of formula (IIH): [ka] It is a compound represented by [the formula shown].

[0129] In some embodiments, the compounds provided herein are of formula (Ib): [ka] [In the formula, the remaining variable groups are as defined herein.] It is a compound represented by [the formula shown].

[0130] In some embodiments, the compounds provided herein are of formula (Ic): [ka] [In the formula, the remaining variable groups are as defined herein.] It is a compound represented by [the formula shown].

[0131] In some embodiments, the compounds provided herein are of formula (Id) or formula (Ie): [ka] [In the formula, the remaining variable groups are as defined herein.] It is a compound represented by [the formula shown].

[0132] In some embodiments, L is -NH-CO-. In some embodiments, L is -CO-NH-. In some embodiments, L is -NH-SO2-. In some embodiments, L is -SO2-NH-.

[0133] In some embodiments, R 1 C6-C may be substituted as desired. 10 It is an arrow. In some embodiments, R 1 R is a 5-10 member heteroaryl which may be optionally substituted. In some embodiments, R 1 R is a 4- to 10-member heterocycle, which may be optionally substituted. In some embodiments, R 1 C(O)NR 6 R 7 In some embodiments, R 1 S(O)2NR 6 R 7 In some embodiments, R 1 , NR 6 COR 7 In some embodiments, R 1 , NR 6 SO2R 7 In some embodiments, R 1 C(O)OR 6 That is the case.

[0134] In some embodiments, R 2 H is H. In some embodiments, R 2 is a C1-C6 alkyl which may be optionally substituted. In some embodiments, R 2 is a cycloalkylalkyl. In some embodiments, R 2 R is a heterocyclylalkyl. In some embodiments, R 2 is an arylalkyl. In some embodiments, R 2 is a heteroarylalkyl. In some embodiments, R 2is a C3-C8 cycloalkyl which may be optionally substituted. In some embodiments, R 2 R is a 4- to 10-membered heterocycloalkyl group which may be optionally substituted. In some embodiments, R 2 is a C2-C6 alkenyl which may be optionally substituted. In some embodiments, R 2 is a C2-C6 alkynyl which may be optionally substituted. In some embodiments, R 2 C6-C may be substituted as desired. 10 It is an arrow. In some embodiments, R 2 This is a 5- to 10-member heteroaryl compound, which may be optionally substituted.

[0135] In some embodiments, R 3 H is H. In some embodiments, R 3 is a C1-C6 alkyl which may be optionally substituted. In some embodiments, R 3 is a C2-C6 alkenyl which may be optionally substituted. In some embodiments, R 3 is a C2-C6 alkynyl which may be optionally substituted. In some embodiments, R 3 is a cycloalkyl which may be optionally substituted. In some embodiments, R 3 is a heterocycloalkyl which may be optionally substituted. In some embodiments, R 3 R is a 4-6 member heterocycloalkyl group which may be optionally substituted. In some embodiments, R 3 R is an aryl that may be optionally substituted. In some embodiments, R 3 C6-C may be substituted as desired. 10 It is an arrow. In some embodiments, R 3 is a heteroaryl which may be optionally substituted. In some embodiments, R 3 R is a 5-10 member heteroaryl which may be optionally substituted. In some embodiments, R3 These include C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 member heterocycloalkyl, and C6-C 10 The aryl or 5-10 membered heteroaryl is each optionally substituted with 1-3 substituents selected from the group consisting of halogens, hydroxyls, and C1-C6 alkyls. In some embodiments, R 3 is OR 6 In some embodiments, R 3 , NR 6 R 7 That is the case.

[0136] In some embodiments, R 2 and R 3 It forms a cycloalkyl ring A together with the atoms in between. 2 and R 3 R 2 It is understood that it does not contain the nitrogen atom to which it is bonded. Rather, R 2 It is understood that any further heteroatoms other than the nitrogen atom to which R is bonded do not form ring A. In some embodiments, R 2 and R 3 It forms a heterocycloalkyl ring A together with the atoms in between. 2 and R 3 R 2 It is understood that it contains a nitrogen atom to which it is bonded. 2 It is also understood that, in addition to the nitrogen atom to which is bonded, additional heteroatoms can form ring A. In some embodiments, R 2 and R 3 It combines with the atoms in between to form a heterocycloalkyl ring A, which is R 2 It does not contain heteroatoms other than the nitrogen atom to which it is bonded. In some embodiments, R 2 and R 3It combines with the atoms in between to form a heterocycloalkyl ring A, which is R 2 It includes a nitrogen atom to which it is bonded and additional heteroatoms. In some embodiments, R 2 and R 3 Together with the atoms in between, they form a C3-C8 cycloalkyl ring A, which may be optionally substituted. Preferred cycloalkyl substituents include, but are not limited to, C1-C6 alkyl, hydroxy C1-C6 alkyl, and C1-C6 alkyl substituted with 1 to 3 halos (preferably fluorine atoms). In some embodiments, R 2 and R 3 Together with the atoms in between, it forms a 4- to 10-membered heterocycloalkyl ring A, which may be optionally substituted. Preferred heterocycloalkyl substituents, but are not limited to, include C1-C6 alkyl, hydroxy C1-C6 alkyl, and C1-C6 alkyl substituted with 1 to 3 halos (preferably fluorine atoms).

[0137] In some embodiments, R 4 is a C1-C6 alkyl which may be optionally substituted. In some embodiments, R 4 is a C1-C3 haloalkyl. In some embodiments, R 4 is CF3. In some embodiments, R 4 is CF2Cl. In some embodiments, R 4 is a C2-C6 alkenyl which may be optionally substituted. In some embodiments, R 4 This is a C2-C6 alkynyl which may be optionally substituted.

[0138] In some embodiments, X is O. In some embodiments, X is S.

[0139] In some embodiments, Y is CH. In some embodiments, Y is C-(C1-C2 alkyl). In some embodiments, Y is C-halo. In some embodiments, Y is N.

[0140] In some embodiments, Z is CR 5 In some embodiments, Z is N.

[0141] In some embodiments, R 5 H is H. In some embodiments, R 5 It is a halogen.

[0142] In some embodiments, R 6 H is H. In some embodiments, R 6 is a C1-C6 alkyl which may be optionally substituted. In some embodiments, R 6 is a C3-C8 cycloalkyl which may be optionally substituted. In some embodiments, R 6 R is a 4- to 10-membered heterocycloalkyl group which may be optionally substituted. In some embodiments, R 6 C6-C may be substituted as desired. 10 It is an arrow. In some embodiments, R 6 R is a 5-10 member heteroaryl which may be optionally substituted. In some embodiments, R 6 These include C1-C6 alkyl, C3-C8 cycloalkyl, 4-10 member heterocycloalkyl, and C6-C 10 The compounds are aryl or 5-10 membered heteroaryls, each of which may optionally be substituted with 1-3 substituents selected from the group consisting of halogens, hydroxyls, and C1-C6 alkyls.

[0143] In some embodiments, R 7 H is H. In some embodiments, R 7is a C1-C6 alkyl which may be optionally substituted. In some embodiments, R 7 is a C3-C8 cycloalkyl which may be optionally substituted. In some embodiments, R 7 R is a 4- to 10-membered heterocycloalkyl group which may be optionally substituted. In some embodiments, R 7 C6-C may be substituted as desired. 10 It is an arrow. In some embodiments, R 7 R is a 5-10 member heteroaryl which may be optionally substituted. In some embodiments, R 7 These include C1-C6 alkyl, C3-C8 cycloalkyl, 4-10 member heterocycloalkyl, and C6-C 10 The compounds are aryl or 5-10 membered heteroaryls, each of which may optionally be substituted with 1-3 substituents selected from the group consisting of halogens, hydroxyls, and C1-C6 alkyls.

[0144] In some embodiments, R 6 H is; and R 7 This includes H, optionally substituted C1-C6 alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 4-10 member heterocycloalkyl groups, and optionally substituted C6-C 10 It is an aryl, or a 5- to 10-membered heteroaryl, which may be optionally substituted.

[0145] In some embodiments, R 6 and R 7 Together with the nitrogen atoms to which they bind, they form a 4- to 7-member heterocycle, which may be optionally substituted. In some embodiments, R 6 and R 7 These, together with the nitrogen to which they are bound, form a 4-7 member heterocycle, which may optionally be substituted with 1-3 substituents selected from the group consisting of halogens, hydroxyls, and C1-C6 alkyls.

[0146] In some embodiments, R 10 is a 5-6 member heteroaryl. In some embodiments, R 10 R is a 5-6 member heteroaryl group, and the heteroaryl portion has up to 2 ring nitrogen atoms. In some embodiments, 10 It is a 5-6 member heteroaryl compound that may optionally be substituted with 1-3 substituents selected from the group consisting of halogens, cyano, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, and C3-C6 cycloalkyl.

[0147] In some embodiments, R 20 is a C1-C3 alkyl which may be optionally substituted. In some embodiments, R 20 is a C3-C4 cycloalkyl which may be optionally substituted. In some embodiments, R 20 is methyl. In some embodiments, R 20 is an isopropyl which may be optionally substituted. In some embodiments, R 20 R is cyclopropyl. In some embodiments, 20 R is a C1-C3 alkyl, C3-C4 cycloalkyl, or 4-6 member heterocycloalkyl, each of which may be optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 member heterocyclyl, cyano, oxo, -C(O)NH(C1-C6 alkyl), and -C(O)NH(C3-C6 cycloalkyl). In some embodiments, R 30 H is H. In some embodiments, R 30 is a C1-C3 alkyl which may be optionally substituted. In some embodiments, R 30 is a C3-C4 cycloalkyl which may be optionally substituted. In some embodiments, R 30is a cyclopropyl which may be optionally substituted. In some embodiments, R 30 These are C1-C3 alkyl, C3-C4 cycloalkyl, or 5-6 member heterocycloalkyl groups, each of which may optionally be substituted with 1-3 substituents selected from the group consisting of halogens, hydroxyls, and C1-C6 alkyl groups.

[0148] In some embodiments, R 1 is a 5-6 member heteroaryl. In some embodiments, R 1 R is a 5-6 member heteroaryl containing up to two ring nitrogen atoms. In some embodiments, R 1 R is a 5-6 member heteroaryl containing two ring nitrogen atoms. In some embodiments, R 1 R is a 5-6 member heteroaryl containing one ring nitrogen atom. In some embodiments, R 1 R is a 5-6 member heteroaryl containing three ring nitrogen atoms. In some embodiments, R 1 is pyrimidinyl. In some embodiments, R 1 is pyrazolyl. In some embodiments, R 1 is pyridyl. In some embodiments, R 1 is triazolyl. In some embodiments, R 1 is imidazolyl. In some embodiments, R 1 is pyridazinyl. In some embodiments, R 1 R is a 5-6 member heteroaryl containing one ring nitrogen atom and one ring sulfur atom. In some embodiments, R 1 R is a 5-6 member heteroaryl containing one ring nitrogen atom and one ring oxygen atom. In some embodiments, R 1 is thiazolyl. In some embodiments, R 1 is oxazolyl. In some embodiments, R 1 is isothiazolyl. In some embodiments, R1 isoxazolyl. In some embodiments, R 1 R is a 4-5 membered heterocycline containing one ring nitrogen atom. In some embodiments, R 1 is a 4-5 member heterocycline which may be optionally substituted with 1-2 oxo groups. In some embodiments, R 1 is azetidinyl. In some embodiments, R 1 R is pyrrolidinyl. In any of these embodiments, R 1 R may optionally be substituted with 1 to 3 substituents selected from the group consisting of halogens, cyano, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, and C3-C6 cycloalkyl. In some modifications, R 1 R is substituted with one or two substituents selected from the group consisting of halogens, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 alkyl, and C3-C6 cycloalkyl. In some modifications, R 1 R is substituted with one substituent selected from the group consisting of halogens, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 alkyl, and C3-C6 cycloalkyl. In some modifications, R 1 It is substituted with one substituent selected from the group consisting of fluoro, chloro, bromo, cyano, hydroxyl, methoxy, ethoxy, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0149] In some embodiments, R 1 teeth, [ka] That is the case.

[0150] In some embodiments, R 1 teeth, [ka] That is the case.

[0151] In some embodiments, R 1 teeth, [ka] That is the case.

[0152] In some embodiments, R 1 teeth, [ka] That is the case.

[0153] In some embodiments, R 1 teeth, [ka] That is the case.

[0154] In some embodiments, R 1 teeth, [ka] That is the case.

[0155] In some embodiments, R 1 teeth, [ka] That is the case.

[0156] In some embodiments, R 1 teeth, [ka] That is the case.

[0157] In some embodiments, R 1 teeth, [ka] That is the case.

[0158] In some embodiments, R 1 teeth, [ka] That is the case.

[0159] In some embodiments, R 1 teeth, [ka] That is the case.

[0160] In some embodiments, R 1 teeth, [ka] That is the case.

[0161] In some embodiments, R 1 teeth, [ka] That is the case.

[0162] In some embodiments, R 1 teeth, [ka] That is the case.

[0163] In some embodiments, R 1 teeth, [ka] That is the case.

[0164] In some embodiments, R 1 teeth, [ka] That is the case.

[0165] In some embodiments, R 1 teeth, [ka] That is the case.

[0166] In some embodiments, R 1 teeth, [ka] That is the case.

[0167] In some embodiments, R 1 teeth, [ka] That is the case.

[0168] In some embodiments, R 1 teeth, [ka] That is the case.

[0169] In some embodiments, R 1 teeth, [ka] That is the case.

[0170] In some embodiments, R 1 teeth, [ka] That is the case.

[0171] In some embodiments, R 1 teeth, [ka] That is the case.

[0172] In some embodiments, R 1 teeth, [ka] That is the case.

[0173] In some embodiments, R 1 teeth, [ka] That is the case.

[0174] In some embodiments, R 1 teeth, [ka] That is the case.

[0175] In some embodiments, R 1 teeth, [ka] That is the case.

[0176] In some embodiments, R 1 teeth, [ka] That is the case.

[0177] In some embodiments, R 1 teeth, [ka] That is the case.

[0178] In some embodiments, R 1 teeth, [ka] That is the case.

[0179] In some embodiments, R 1 teeth, [ka] That is the case.

[0180] In some embodiments, R 1 teeth, [ka] That is the case.

[0181] In some embodiments, R 1 -CONHR 7 And here, R 7 This is H, C3-C6 cycloalkyl, or C1-C6 alkyl.

[0182] In some embodiments, R 1 is -CONH(C3-C6 cycloalkyl). In some embodiments, R 1 is -CONH(C3-C5 cycloalkyl). In some embodiments, R 1 It is -CONH (C3-C4 cycloalkyl).

[0183] In some embodiments, R 1 It is -CONH (cyclopropyl).

[0184] In some embodiments, R 1 This is -CONH2.

[0185] In some embodiments, R 1 is -CONH(C1-C6 alkyl). In some embodiments, R 1 is -CONH(C1-C3 alkyl). In some embodiments, R 1 This is -CON(H)(CH3) or -CON(H)(C2H5).

[0186] In some embodiments, R 2 is a C1-C3 alkyl which may be optionally substituted. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 R is propyl. In some embodiments, R 2 is an isopropyl which may be optionally substituted. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is butyl. In some embodiments, R 2 tertiary butyl is used in some embodiments. 2 is pentill. In some embodiments, R 2 is n-pentyl, sec-pentyl, 3-pentyl, or sec-isopentyl. In some embodiments, R 2 is a C3-C4 cycloalkyl which may be optionally substituted. In some embodiments, R 2 R is cyclopropyl. In some embodiments, 2 is cyclobutyl. In some embodiments, R 2 R is cyclopentyl. In some embodiments, R 2 R is a 4-6 member heterocyclyl. In some embodiments, R 2 R is a 4- to 6-membered heterocycline containing one or two heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen. In some embodiments, R 2 is tetrahydrofuranil. In some embodiments, R 2 is tetrahydropyranil. In some embodiments, R 2 is thietanyl. In some embodiments, R 2 R is pyrrolidinyl. In any of these embodiments, R 2R may optionally be substituted with 1 to 3 substituents selected from the group consisting of halogens, hydroxyls, C1-C6 alkoxys, C1-C6 alkyls, C3-C6 cycloalkyls, 4- to 6-membered heterocyclyls, cyanos, oxos, -C(O)NH(C1-C6 alkyls), and -C(O)NH(C3-C6 cycloalkyls). In some modifications, R 2 R is substituted with 1 to 3 substituents selected from the group consisting of halogens, hydroxyls, C1-C3 alkoxys, C1-C3 alkyls, C3-C5 cycloalkyls, 4-6 member heterocyclyls, cyanos, oxos, -C(O)NH(C1-C3 alkyls), and -C(O)NH(C3-C6 cycloalkyls). In some modifications, R 2 It is substituted with 1 to 3 substituents selected from the group consisting of fluoro, chloro, bromo, hydroxyl, methoxy, ethoxy, methyl, ethyl, cyclopropyl, cyclobutyl, oxetanyl, cyano, oxo, -C(O)NH(CH3), -C(O)NH(CH2CH3), -C(O)NH(cyclopropyl), -C(O)NH(cyclobutyl), -C(O)NH(cyclopentyl), and -C(O)NH(cyclohexyl). That is the case.

[0187] In some embodiments, R 2 H is H.

[0188] In some embodiments, R 2 teeth, [ka] That is the case.

[0189] In some embodiments, R 2 teeth, [ka] That is the case.

[0190] In some embodiments, R 2 teeth, [ka] That is the case.

[0191] In some embodiments, R 2 teeth, [ka] That is the case.

[0192] In some embodiments, R 2 teeth, [ka] That is the case.

[0193] In some embodiments, R 2 teeth, [ka] That is the case.

[0194] In some embodiments, R 2 teeth, [ka] That is the case.

[0195] In some embodiments, R 2 teeth, [ka] That is the case.

[0196] In some embodiments, R 2 teeth, [ka] That is the case.

[0197] In some embodiments, R 2 teeth, [ka] That is the case.

[0198] In some embodiments, R 2 teeth, [ka] That is the case.

[0199] In some embodiments, R 2 teeth, [ka] That is the case.

[0200] In some embodiments, R 2 teeth, [ka] That is the case.

[0201] In some embodiments, R 2 teeth, [ka] That is the case.

[0202] In some embodiments, R 2 teeth, [ka] That is the case.

[0203] In some embodiments, R 2 teeth, [ka] That is the case.

[0204] In some embodiments, R 2 teeth, [ka] That is the case.

[0205] In some embodiments, R 2 teeth, [ka] That is the case.

[0206] In some embodiments, R 2 teeth, [ka] That is the case.

[0207] In some embodiments, R 2 teeth, [ka] That is the case.

[0208] In some embodiments, R 2 teeth, [ka] That is the case.

[0209] In some embodiments, R 2 teeth, [ka] That is the case.

[0210] In some embodiments, R 2 teeth, [ka] That is the case.

[0211] In some embodiments, R 2 teeth, [ka] That is the case.

[0212] In some embodiments, R 2 teeth, [ka] That is the case.

[0213] In some embodiments, R 2 teeth, [ka] That is the case.

[0214] In some embodiments, R 2 teeth, [ka] That is the case.

[0215] In some embodiments, R 2 teeth, [ka] That is the case.

[0216] In some embodiments, R 2 teeth, [ka] That is the case.

[0217] In some embodiments, R 2 teeth, [ka] That is the case.

[0218] In some embodiments, R 2 teeth, [ka] That is the case.

[0219] In some embodiments, R 2 teeth, [ka] That is the case.

[0220] In some embodiments, R 2 teeth, [ka] That is the case.

[0221] In some embodiments, R 2 and R 3 Together with the atoms in between, they form a 5-6 member heterocycloalkyl ring A, which may be optionally substituted. In some embodiments, ring A may optionally be substituted with 1-3 substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkyl-OH, -C(O)(C1-C6 alkyl), and oxo. In some variations, ring A is substituted with 1-3 substituents selected from the group consisting of C1-C3 alkyl, hydroxyl, C1-C3 alkyl-OH, -C(O)(C1-C3 alkyl), and oxo. In some variations, ring A is substituted with 1-3 substituents selected from the group consisting of methyl, ethyl, hydroxyl, -CH2OH, -CH2CH2-OH, -C(O)CH3, -C(O)CH2CH3, and oxo.

[0222] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0223] In some embodiments, R 2 and R3 Together, [ka] It forms a structure.

[0224] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0225] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0226] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0227] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0228] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0229] In some embodiments, R 2 and R3 Together, [ka] It forms a structure.

[0230] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0231] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0232] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0233] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0234] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0235] In some embodiments, R 2 and R3 Together, [ka] It forms a structure.

[0236] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0237] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0238] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0239] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0240] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0241] In some embodiments, R 2 and R3 Together, [ka] It forms a structure.

[0242] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0243] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0244] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0245] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0246] In some embodiments, R 2 and R 3 Together, [ka] It forms a structure.

[0247] In some embodiments, R 2 and R3 Together, [ka] It forms a structure.

[0248] In some embodiments, R 3 H is H. In some embodiments, R 3 R is a C1-C6 alkyl group, which may optionally be substituted with 1 to 3 substituents selected from the group consisting of halogens, hydroxyls, and -O(C1-C6 alkyl). In some embodiments, R 3 is methyl. In some embodiments, R 3 is isopropyl. In some embodiments, R 3 R is difluoromethyl. In some embodiments, 3 R is hydroxyethyl. In some embodiments, 3 is -CH2CH2OH. In some embodiments, R 3 is -C(Me)2OH. In some embodiments, R 3 is -CH(Me)OH. In some embodiments, R 3 R is methoxymethyl. In some embodiments, R 3 R is hydroxymethyl. In some embodiments, 3 is a C3-C6 cycloalkyl group. In some embodiments, R 3 R is a C3-C6 cycloalkyl substituted with 1 to 3 substituents selected from the group consisting of halogens, C1-C6 alkyls, and hydroxyls. In some embodiments, R 3 R is cyclopropyl. In some embodiments, 3 is cyclobutyl. In some embodiments, R 3 is -OR 6 And here, R 6 is a C1-C6 alkyl group. In some embodiments, R 3is methoxy. In some embodiments, R 3 R is ethoxy. In some embodiments, 3 R is a 4-6 member heterocyclyl. In some embodiments, R 3 R is a 4-6 member heterocyclyl substituted with 1-3 substituents selected from the group consisting of halogens, C1-C6 alkyls, and hydroxyls. In some embodiments, R 3 It is tetrahydropyranyl.

[0249] In some embodiments, R 4 is a C1-C3 alkyl which may be optionally substituted. In some embodiments, R 4 is a C1-C3 alkyl group, and here, The alkyl group is substituted with one or more halo substituents. In some embodiments, R 4 is a C1-C3 alkyl group substituted with 1-3 halo substituents. In some embodiments, R 4 is CF3. In some embodiments, R 4 This is CF2Cl.

[0250] In one embodiment, a compound of formula (I) is provided, having one or more of the following characteristics: (I)R 1 teeth: (i) A 5-6 member heteroaryl compound, which may optionally be substituted with 1-3 substituents selected from the group consisting of halogens, cyano, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C1-C6 alkyl; or, (ii) A 4-5 member heterocycline which may optionally be substituted with 1-3 substituents selected from the group consisting of halogens, cyano, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkyl, and oxo; or, (iii)R 1 -CON editing 7 And here, R7 is H, C3-C6 cycloalkyl, or C1-C6 alkyl; (II)R 2 teeth: (iv) A C1-C6 alkyl group which may optionally be substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, cyano, -C(O)NH(C1-C6 alkyl), and -C(O)NH(C3-C6 cycloalkyl); or, (v)R 2 C3-C6 cycloalkyl, which may optionally be substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 member heterocyclyl, cyano, oxo, -C(O)NH(C1-C3 alkyl), and -C(O)NH(C3-C6 cycloalkyl); or, (vi) A 4-6 member heterocycline which may optionally be substituted with 1-3 substituents selected from the group consisting of halogen, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 member heterocycline, cyano, oxo, -C(O)NH(C1-C3 alkyl), and -C(O)NH(C3-C6 cycloalkyl); or, (vii)H is; (III)R 3 teeth: (viii) H; or, (ix) A C1-C6 alkyl group which may optionally be substituted with 1 to 3 substituents selected from the group consisting of halogens, hydroxyls, and -O(C1-C6 alkyl); or, (x)-OR 6 And here, R 6 is a C1-C6 alkyl group; or, (xi) A C3-C6 cycloalkyl group which may optionally be substituted with 1 to 3 substituents selected from the group consisting of halogens, C1-C6 alkyls, and hydroxyls; or, (xii) A 4-6 member heterocycline which may optionally be substituted with 1-3 substituents selected from the group consisting of halogens, C1-C6 alkyls, and hydroxyls; (IV)R 2 and R 3 The atoms in between form ring A, which is a 5-6 member heterocycloalkyl group that may optionally be substituted with 1-3 substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkyl-OH, -C(O)(C1-C6 alkyl), and oxo; (V)R 4 is a C1-C3 alkyl group which may be optionally substituted with 1 to 3 halogens; (VI)L is -NH-CO-; (VII)Z is CH, C-halo, or N; (VIII)X is O. In one variation, (I) applies. In one variation, (II) applies. In one variation, (III) applies. In one variation, (IV) applies. In one variation, (V) applies. In one variation, (VI) applies. In one variation, (VII) applies. In one variation, (VIII) applies. In one embodiment of this variation, (I), (II), (III), (V), (VI), (VII), and (VIII) apply. In another embodiment of this variation, (I), (IV), (V), (VI), (VII), and (VIII) apply. In one variation, (V), (VI), (VII), and (VIII) apply. In one variation, (i), (iv), and (viii) apply. In one variation, (i), (v), and (viii) apply. In one variation, (iv), (iv), and (ix) apply. In one variation, (iv), (iv), and (x) apply. In one variation, (i), (v), and (ix) apply. In one variation, (i), (vi), and (viii) apply. In one variation, (i), (iv), and (xi) apply. In one variation, (i), (vii), and (viii) apply. In one variation, (i), (iv), and (xii) apply. In one variation, (i), and (IV) apply. In one variation, (ii), (iv), and (viii) apply. In one variation, (ii), and (IV) apply. In one variation, (iii), (iv), and (viii) apply. In one variation, (iii), and (IV) apply.

[0251] In one embodiment, compounds of formula (I), their tautomers or N-oxides, or their respective isotopic isomers, or their respective prodrugs, or their stereoisomers, or their respective pharmaceutically acceptable salts, or their respective solvates, are provided, as shown in the following examples (e.g., Examples 1 to 49) and represented in Table 1 (Examples 50 to 232).

[0252] This disclosure also includes all salts of the compounds described herein, including pharmaceutically acceptable salts. This disclosure also includes any or all stereochemical forms of the described compounds, including enantiomers or diastereomers, tautomers, or other forms such as N-oxides, solvates, prodrugs, or isotopic isomers. Unless stereochemistry is expressly indicated by the chemical structure or name, the structure or name is intended to encompass all possible stereoisomers of the compound shown. Furthermore, if a particular stereochemical form is shown, it is understood that other stereochemical forms are also included in the invention. All forms of the compound, including crystalline or amorphous forms, are also included in the invention. Compositions containing the compounds of the invention, e.g., compositions of substantially pure compounds containing a particular stereochemical form thereof, are also intended. Compositions containing mixtures of the compounds of the invention in any ratio are also included in the invention, including mixtures of two or more stereochemical forms of the compounds of the invention in any ratio, and include racemic, non-racemic, enantiorich, and scalemic mixtures.

[0253] In this specification, all descriptions, modifications, embodiments, or aspects of a part may be combined with all descriptions, modifications, embodiments, or aspects of any other part, and it is understood that any combination of descriptions shall be as if they were described specifically and individually. For example, R of formula (I) 1 All descriptions, modifications, embodiments, or aspects provided herein in relation to R 2 , R 3 , R 4 , R 5 , R 6 , R 7All descriptions, variations, embodiments, or aspects of formula (I) can be combined with all descriptions, variations, embodiments, or aspects of X, L, Y, and / or Z, and all combinations shall be as if they were specifically and individually described. All descriptions, variations, embodiments, or aspects of formula (I) shall apply equally to other formulas described herein, where applicable, and all descriptions, variations, embodiments, or aspects shall be described equally, as if they were described separately and individually for all formulas. For example, all descriptions, variations, embodiments, or aspects of formula (I) shall apply equally to formulas (Ii), (Ia), (IA), (IA-1), (IIA), (IIB), (IIC), (IID), (IIE), (IIF), (IIG), (IIH), (Ib), (Ic), (Id), and (Ie) described herein, where applicable, and all descriptions, variations, embodiments, or aspects shall be described equally, as if they were described separately and individually for all formulas.

[0254] The present invention also includes all salts of the compounds described herein, including pharmaceutically acceptable salts. The present invention also includes any or all stereochemical forms of the described compounds, including enantiomers or diastereomers, tautomers, or other forms such as N-oxides, solvates, prodrugs, or isotopic isomers. Unless stereochemistry is expressly indicated by the chemical structure or name, the structure or name is intended to encompass all possible stereoisomers of the compound shown. Furthermore, if a particular stereochemical form is shown, it is understood that other stereochemical forms are also included in the present invention. All forms of the compound, including crystalline or amorphous forms, are also included in the present invention. Compositions containing the compounds of the present invention, for example, compositions of substantially pure compounds containing a particular stereochemical form of that compound, are also intended. Compositions containing mixtures of the compounds of the present invention in any ratio are also included in the present invention, including mixtures of two or more stereochemical forms of the compounds of the present invention in any ratio, and include racemic, non-racemic, enantiorich, and scalemic mixtures.

[0255] Pharmaceutical compositions and formulations Pharmaceutical compositions of any of the compounds described herein are included in the present invention. Accordingly, the present invention includes pharmaceutical compositions comprising the compounds of the present invention, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers or excipients. In one embodiment, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions according to the present invention can be in a form suitable for oral, oral, parenteral, nasal, topical, or rectal administration, or in a form suitable for administration by inhalation.

[0256] The compounds described herein may, in one embodiment, be in a purified form, and compositions containing the purified form of the compounds are described herein. Compositions containing the compounds or salts thereof described herein are provided, such as substantially pure compositions of the compounds. In some embodiments, compositions containing the compounds or salts thereof described herein are in a substantially pure form. In one modification, “substantially pure” means a composition containing 35% or less impurities, where impurities are compounds other than the compound or salts thereof that constitute the majority of the composition. For example, a substantially pure composition of a compound selected from the compounds in Table 1 (A, B, etc.) is intended to contain 35% or less impurities, where impurities are compounds other than the compound or salts thereof. In one modification, a substantially pure composition of the compound or salt thereof is provided, in which the composition contains 25% or less impurities. In another modification, a substantially pure composition of the compound or salt thereof is provided, in which the composition contains 20% or less impurities. In yet another modification, a substantially pure composition of the compound or salt thereof is provided, in which the composition contains 10% or less impurities. In a further modification, a substantially pure composition of the compound or salt thereof is provided, in which the composition contains 5% or less impurities. In another variation, a composition of a substantially pure compound or a salt thereof is provided, in which the composition contains 3% or less impurities. In yet another variation, a composition of a substantially pure compound or a salt thereof is provided, in which the composition contains 1% or less impurities. In yet another variation, a composition of a substantially pure compound or a salt thereof is provided, in which the composition contains 0.5% or less impurities. In yet another variation, a substantially pure compound composition means that the composition contains 15% or less, preferably 10% or less, more preferably 5% or less, even more preferably 3% or less, and most preferably 1% or less impurities, where the impurities may be compounds in different stereochemical forms. For example, but not limited to, a substantially pure (S) compound composition means that the composition contains 15% or less, or 10% or less, or 5% or less, or 3% or less, or 1% or less of the (R) compound.

[0257] In one variation, the compounds described herein are synthetic compounds prepared for administration to an organism such as a human. In another variation, a composition comprising a substantially pure form of the compound is provided. In yet another variation, the present invention encompasses a pharmaceutical composition comprising the compounds described herein and a pharmaceutically acceptable carrier or excipient. In yet another variation, a method for administering the compound is provided. The purified forms, pharmaceutical compositions, and methods for administering the compound are suitable for any of the compounds or forms described herein.

[0258] The compound can be formulated for any available delivery route, including oral, mucosal (e.g., nasal, sublingual, vaginal, oral, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery forms. The compound can be formulated with a suitable carrier to provide delivery forms, including, but are not limited to, tablets, caplets, capsules (e.g., hard gelatin capsules or soft elastic gelatin capsules), cachets, lozenges, candies, gums, powders, suppositories, ointments, poultices (patches), pastes, powders, bandages, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalants), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs.

[0259] One or more of the compounds described herein can be used in the manufacture of pharmaceutical formulations, etc., by combining the compound or more compounds as active ingredients with a pharmaceutically acceptable carrier as described above. Depending on the therapeutic form of the system (e.g., transdermal patch versus oral tablet), the carrier may take various forms. Furthermore, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulsifiers, sweeteners, dyes, modifiers, and salts, buffers, coatings, or antioxidants for adjusting osmotic pressure. Formulations containing the compounds may also contain other substances having useful therapeutic properties. Pharmaceutical formulations can be manufactured by known pharmaceutical methods. Suitable formulations can be found, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st ed. (2005), which is incorporated herein by reference.

[0260] The compounds described herein can be administered to an individual (e.g., a human) in the form of generally acceptable oral compositions, such as tablets, coated tablets, hard-shell or soft-shell gel capsules, emulsions, or suspensions. Examples of carriers that can be used in the preparation of such compositions include lactose, corn starch or its derivatives, talc, stearic acid or its salts. Examples of carriers acceptable for soft-shell gel capsules include vegetable oils, waxes, fats, semi-solid and liquid polyols. Furthermore, pharmaceutical formulations may include preservatives, solubilizers, stabilizers, re-wetting agents, emulsifiers, sweeteners, dyes, modifiers, and salts, buffers, coatings, or antioxidants for adjusting osmotic pressure.

[0261] Any of the compounds described herein can be formulated into tablets in the dosage forms described.

[0262] Compositions containing the compounds provided herein are also described. In one variation, the composition comprises the compound and a pharmaceutically acceptable carrier or excipient. In another variation, a substantially pure composition of the compound is provided.

[0263] Instructions for use / treatment Compounds and compositions detailed herein, such as compounds or salts thereof, and pharmaceutical compositions comprising pharmaceutically acceptable carriers or excipients, may be used in the methods of administration and treatment provided herein. Compounds and compositions may also be used in in vitro methods, such as in vitro methods for administering the compound or composition to cells for screening purposes and / or for performing quality control assays.

[0264] In one embodiment, a method for inhibiting the tyrosine kinase enzyme activity of a protein selected from Avelson protein (ABL1), Avelson-related protein (ABL2), or chimeric protein BCR-ABL1 is provided herein, comprising contacting the protein with an effective amount of a compound or composition provided herein. In one embodiment, a method for inhibiting the tyrosine kinase enzyme activity of Avelson protein (ABL1) is provided herein, comprising contacting ABL1 with an effective amount of a compound or composition provided herein. In another embodiment, a method for inhibiting the tyrosine kinase enzyme activity of Avelson-related protein (ABL2) is provided herein, comprising contacting ABL2 with an effective amount of a compound or composition provided herein. In a further embodiment, a method for inhibiting the tyrosine kinase enzyme activity of chimeric protein BCR-ABL1 is provided herein, comprising contacting the chimeric protein with an effective amount of a compound or composition provided herein.

[0265] In one embodiment, a method for treating a disease in a patient in need thereof is provided herein, comprising administering to the patient a therapeutically effective amount of a compound or a salt thereof, or a composition thereof, provided herein. In some embodiments, the compound or a salt thereof or composition is administered according to the doses described herein.

[0266] The compounds or salts thereof provided herein and the compositions provided herein are considered effective in treating a variety of diseases and disorders. In some embodiments, the compounds or salts thereof provided herein, or the compositions provided herein, may be used in methods for treating diseases mediated by ABL1, ABL2, and / or BCR-ABL1.

[0267] In one embodiment, a method for treating a disease in a patient, comprising administering a therapeutically effective amount of a compound or composition provided herein to the patient, is provided, for preventing, suppressing or improving the pathophysiology and / or symptoms of the disease by regulating BCR-ABL1 activity. In one embodiment, a method for treating a disease in a patient, comprising administering a therapeutically effective amount of a compound or composition provided herein to the patient, is provided, for preventing the pathophysiology and / or symptoms of the disease by regulating BCR-ABL1 activity. In one embodiment, a method for treating a disease in a patient, comprising administering a therapeutically effective amount of a compound or composition provided herein to the patient, is provided, for suppressing the pathophysiology and / or symptoms of the disease by regulating BCR-ABL1 activity. In one embodiment, a method for treating a disease in a patient, comprising administering a therapeutically effective amount of a compound or composition provided herein to the patient, is provided, for improving the pathophysiology and / or symptoms of the disease by regulating BCR-ABL1 activity.

[0268] In some embodiments, the disease is leukemia. In some embodiments, the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL). In some embodiments, the leukemia is chronic myeloid leukemia (CML).

[0269] In one embodiment, a method for treating leukemia in a patient is provided herein, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In one embodiment, a method for treating leukemia in a patient is provided herein, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein, wherein the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL).

[0270] In some embodiments, the leukemia treated herein is CML or ALL, and the method further comprises administering a therapeutically effective amount of a compound selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.

[0271] In some embodiments, leukemia is resistant to treatment. In some embodiments, leukemia is resistant to treatment with imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and / or bafetinib. In some embodiments, CML is resistant to standard treatment, such as treatment with one or more of imatinib, nilotinib, and dasatinib. In some embodiments, leukemia has progressed during prior treatment. In some embodiments, prior treatment has included administration of imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and / or bafetinib.

[0272] In some embodiments, the method further comprises administering a therapeutically effective amount of a compound selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.

[0273] In some embodiments, AML is secondary AML that develops after myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN).

[0274] In one embodiment, a method for treating cancer in a patient is provided herein, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In some embodiments, the cancer is melanoma, hereditary leiomyomatosis, renal cell carcinoma (HLRCC), or other solid tumors.

[0275] In one embodiment, a method for treating a neurodegenerative disease in a patient is provided herein, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In some embodiments, the neurodegenerative disease is Alzheimer's disease or Parkinson's disease.

[0276] In another embodiment, a method is provided for delaying the onset and / or development of a BCR-ABL1 activity-mediated disease or disorder in a patient (such as a human) at risk of developing the disease or disorder. It is understood that delaying the onset may include prevention in cases where the individual or patient does not develop the disease or disorder. In one embodiment, an individual or patient at risk of developing a BCR-ABL1 activity-mediated disease or disorder has one or more risk factors for developing the disease or disorder, such as a family history of the individual or patient with the disease or disorder, or has underlying genetic conditions associated with an increased likelihood of developing the disease or disorder.

[0277] In one embodiment, a method for delaying the onset and / or development of leukemia in a patient in need is provided herein, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In one modification, a method for delaying the onset and / or development of CML in a patient in need is provided herein, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In one modification, a method for delaying the onset and / or development of AML in a patient in need is provided herein, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In one modification, a method for delaying the onset and / or development of ALL in a patient in need is provided herein, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein.

[0278] Methods for treating BCR-ABL1-mediated diseases, such as various types of leukemia, are well known to those skilled in the art, and such diseases can be treated with compounds or compositions provided herein.

[0279] In some embodiments, the patient is a mammal. In some embodiments, the patient is a primate, dog, cat, rabbit, or rodent. In some embodiments, the patient is a primate. In some embodiments, the patient is a human. In some embodiments, the human is about 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old, or any of these ages or older. In some embodiments, the human is a child. In some embodiments, the human is about 21, 18, 15, 10, 5, 4, 3, 2, or 1 year old, or any of these ages or younger. In some embodiments, the patient has a genetic condition associated with an increased likelihood of developing a disease such as leukemia. In some embodiments, the patient has mutations in the ABL1 and / or ABL2 genes. In some embodiments, the patient is Philadelphia chromosome positive.

[0280] The compounds or compositions provided herein may be administered to a patient for a desired time or period, e.g., about one month or longer, about two months or longer, about three months or longer, about six months or longer, or about twelve months or longer, according to an effective dosing regimen, which in some variations may extend to the patient's lifetime. In one variation, the compound is administered daily or on an intermittent schedule. The compound may be administered to a patient continuously over a period of time (e.g., once or more times a day). The frequency of administration may also be less than once a day, e.g., about once a week. The frequency of administration may be more than once a day, e.g., twice or three times a day. The frequency of administration may be intermittent (e.g., administering once a day for seven days, then not administering for seven days, repeating this 14-day cycle for about two months, about four months, about six months or longer). The frequency of administration may be achieved by using any compound provided herein in any dosage as described herein.

[0281] The compounds or salts thereof provided herein can be administered to patients via various routes, including, for example, intravenous, intramuscular, subcutaneous, oral, and transdermal.

[0282] The dose of a compound administered to a patient may vary depending on the specific compound or its salt, the method of administration, and the specific disease. In some embodiments, the amount of the compound or its salt is a therapeutically effective dose.

[0283] The effective amount of the compound may, in one embodiment, be a dose of about 0.01 to about 100 mg / kg. The effective amount or dose of the compound of this disclosure can be determined by predetermined methods such as modeling, dose escalation, or clinical trials, taking into account predetermined factors such as the method or route of administration or drug delivery, the pharmacokinetics of the drug, the severity and course of the disease being treated, the health status of the subject, the medical condition and weight. The dose is, for example, in the range of about 0.7 mg to 7 g per day, or about 7 mg to 350 mg per day, or about 350 mg to 1.75 g per day, or about 1.75 to 7 g per day.

[0284] This specification also provides for the use of compounds or salts thereof, or compositions thereof, in the manufacture of pharmaceuticals. In some embodiments, the manufacture of pharmaceuticals is for the treatment of diseases described herein. In some embodiments, the manufacture of pharmaceuticals is for the treatment of diseases mediated by ABL1, ABL2, and / or BCR-ABL1.

[0285] Products and Kits This disclosure further provides products comprising the compounds or salts thereof described herein, the compositions described herein, or one or more unit doses described herein, appropriately packaged. In certain embodiments, the product is intended for use in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, jars, flexible packaging, etc. The product may further be sterile and / or sealed.

[0286] This disclosure further provides a kit for carrying out the method of this disclosure, comprising one or more compounds described herein or a composition containing a compound described herein. The kit may use any of the compounds disclosed herein. In one variation, the kit may use a compound described herein or a salt thereof. The kit may be used for one or more of the uses described herein and may therefore include instructions relating to the treatment of a disease described herein, for example, the treatment of cancer.

[0287] The kit may be a unit dosage form, a bulk package (e.g., a multi-dose package), or a subunit dose. For example, a kit may be provided that contains sufficient doses of the compounds disclosed herein and / or additional pharmaceutically active compounds useful for the diseases detailed herein, and that effectively treats a patient over a long period, for example, one week, two weeks, three weeks, four weeks, six weeks, eight weeks, three months, four months, five months, seven months, eight months, nine months, or longer. The kit may include multiple unit doses of the compounds and instructions for use, and may be packaged in quantities sufficient for storage and use in a pharmacy (e.g., a hospital pharmacy or a compounding pharmacy).

[0288] The kit may optionally include an instruction set, a general instruction manual, but an electronic storage medium (e.g., a magnetic diskette or optical disk) containing the instructions is also acceptable in connection with the use of components of the method of this disclosure. The instructions included in the kit typically contain information about the ingredients and their administration to the patient.

[0289] Examples of Embodiments This disclosure will be further illustrated by the following embodiments. Features of each embodiment can be combined with other embodiments where appropriate and useful.

[0290] Embodiment 1 Equation (I) or Equation (Ia): [ka] [In the formula, L is -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-; R 1 C6-C may be substituted as desired. 10 Aryl, optionally substituted 5-10 member heteroaryls, optionally substituted 4-10 member heterocycles, C(O)NR 6 R 7 , S(O)2NR 6 R 7 , NR 6 COR 7 , NR6 SO2R 7 , or C(O)OR 6 and; R 2 This includes H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 member heterocycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C 10 An aryl, or a 5- to 10-membered heteroaryl, which may be optionally substituted; R 3 H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR 6 , or NR 6 R 7 And; or, R 2 and R 3 Together with the atoms in between, they form a cycloalkyl or heterocycloalkyl group, preferably an optionally substituted C3-C8 cycloalkyl group, or an optionally substituted 4-10 member heterocycloalkyl group; R 4 This is an optionally substituted C1-C6 alkyl, preferably a C1-C3 haloalkyl such as CF3 or CF2Cl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl; X is either O or S; Y is CH, C-(C1-C2 alkyl), C-halo, or N; Z is CR 5 , or N; R 5 If Z is CH, then H or a halogen; R 6This includes H, optionally substituted C1-C6 alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 4-10 member heterocycloalkyl groups, and optionally substituted C6-C 10 An aryl, or a 5- to 10-membered heteroaryl which may be optionally substituted; and, R 7 This includes H, optionally substituted C1-C6 alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted 4-10 member heterocycloalkyl groups, and optionally substituted C6-C 10 An aryl, or a 5- to 10-membered heteroaryl which may be optionally substituted; or R 6 and R 7 These, together with the nitrogen atoms to which they bind, form a 4- to 7-member heterocycle, which may be optionally substituted. The compounds indicated by, or their tautomers or their N-oxides, or their respective isotopic isomers, or their respective prodrugs, or their stereoisomers, or their respective pharmaceutically acceptable salts, or their respective solvates.

[0291] Embodiment 2 Equation (IA): [ka] [In the formula, the variable group is as defined in Embodiment 1.] The compound of Embodiment 1, as shown.

[0292] Embodiment 3 Formula (IIA) ~ Formula (IIE): [ka] [In the formula, R 10 This is a 5-6 member heteroaryl compound, preferably having up to 2 ring nitrogen atoms in the heteroaryl portion; R 20is an optionally substituted C1-C3 alkyl or optionally substituted C3-C4 cycloalkyl, preferably R 20 is methyl, optionally substituted isopropyl, or cyclopropyl; R 30 is H, optionally substituted C1-C3 alkyl, or optionally substituted C3-C4 cycloalkyl, preferably optionally substituted cyclopropyl; and, The remaining variable groups are as defined in Embodiment 1. A compound of Embodiment 2, selected from the above.

[0293] Embodiment 4 X is O, the compound of Embodiment 2 or 3.

[0294] Embodiment 5 R 1 This is a 5-10 member heteroaryl, preferably the heteroaryl portion containing up to 2 ring nitrogen atoms, or R 1 The compound is one of any one of Embodiments 2 to 4, wherein the heterocycle has 4 to 10 members, preferably the heterocyclyl portion contains up to 2 ring nitrogen atoms.

[0295] Embodiment 6 R 1 is: -CONH(cyclopropyl), -CONH2, -CONHMe, [ka] The compound is one of any two of the embodiments 2 to 5.

[0296] Embodiment 7 R 1 The compound is one of any two compounds from Embodiments 2 to 6, which is either pyrimidinyl or pyrazolyl.

[0297] Embodiment 8 R 2is an optionally substituted C1-C3 alkyl or optionally substituted C3-C4 cycloalkyl, preferably R 2 is one of the compounds from Embodiments 2 to 7, which is methyl, optionally substituted isopropyl, or cyclopropyl.

[0298] Embodiment 9 R 2 is: methyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl, [ka] The compound is one of any two of the embodiments 2 to 7.

[0299] Embodiment 10 R 3 A is any one of the compounds from Embodiments 2 to 9, wherein is: H, methyl, isopropyl, difluoromethyl, hydroxyethyl, cyclopropyl, cyclobutyl, -C(Me)2OH, methoxymethyl, hydroxymethyl, methoxy, hydroxyethyl, -CH2CH2OH, or tetrahydropyranyl.

[0300] Embodiment 11 R 2 and R 3 Together, [ka] A compound from any one of embodiments 2 to 6 that forms [the specified compound].

[0301] Embodiment 12 R 4 is a C1-C3 alkyl group which may be optionally substituted, preferably where the alkyl group is substituted with one or more halo substituents, more preferably R 4 The compound is one of the compounds from Embodiments 2 to 11, which is either CF3 or CF2Cl.

[0302] Embodiment 13 R 5 The compound is one of the embodiments 2 to 12, wherein H is present.

[0303] Embodiment 14 Y is a compound from any one of embodiments 2 to 13, where Y is CH.

[0304] Embodiment 15 Formula (Ib) or Formula (Ic): [ka] [In the formula, the remaining variable groups are as defined in Embodiment 1.] The compound of Embodiment 1, as shown.

[0305] Embodiment 16 Compounds selected from Examples 1-26 and the compounds of formula (I) in Table 1, or tautomers thereof or their N-oxides, or their respective isotopic isomers, or their respective prodrugs, or their stereoisomers, or their respective pharmaceutically acceptable salts, or their respective solvates.

[0306] Embodiment 17 A composition comprising one compound from any of Embodiments 2 to 16, and at least one pharmaceutically acceptable excipient.

[0307] Embodiment 18 A method for inhibiting the tyrosine kinase enzyme activity of a protein selected from the group consisting of Abelson protein (ABL1), Abelson-associated protein (ABL2), or the chimeric protein BCR-ABL1, comprising contacting the protein with an effective amount of one compound from any of Embodiments 2 to 16, or the composition of Embodiment 17.

[0308] Embodiment 19 A method for treating a disease in a patient, comprising administering to the patient a therapeutically effective amount of any one compound from Embodiments 2 to 16 or the composition of Embodiment 17, for preventing, suppressing or improving the pathophysiology and / or symptoms of the disease by modulating BCR-ABL1 activity.

[0309] Embodiment 20 A method for treating leukemia in a patient, comprising administering to the patient a therapeutically effective amount of any one compound from Embodiments 2 to 16 or the composition of Embodiment 17, wherein the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL).

[0310] Embodiment 21 The method of Embodiment 20, wherein the leukemia is CML or ALL, and the method further comprises administering a therapeutically effective amount of a compound selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.

[0311] Embodiment 22 The method of Embodiment 20 or 21, wherein the CML is resistant to standard treatment, such as treatment with one or more of imatinib, nilotinib, and dasatinib.

[0312] Embodiment 23 The method of Embodiment 20 or 21, wherein the AML is secondary AML that develops after myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN). [Examples]

[0313] The following abbreviations may be relevant to this application. Abbreviation Ac: Acetyl Bn: Benzyl Bu: Butyl Bz: Benzoyl CMC: Carboxymethylcellulose DCM: Dichloromethane DIPEA: Diisopropylethylamine DMF: Dimethylformamide DMEDA: N,N'-dimethylethylenediamine DSC: N,N'-disucineimimidyl carbonate, or bis(2,5-dioxopyrrolidine-1-yl) carbonate dppf:1,1'-bis(diphenylphosphin)ferrocene Et: Ethyl HATU:1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, NBS: N-bromosuccinimide PEG: Polyethylene glycol PMB: Paramethoxybenzyl Pr: Propyl Py: Pyridine rt: room temperature TEA: Triethylamine TBDPS: Tertiary butyldiphenylsilyl TBAF: Tetrabutylammonium fluoride THF: Tetrahydrofuran TMS: Trimethylsilyl TFA: Trifluoroacetic acid Ts: Tosil Xphos:2-Dicyclohexylphosphino-2',4',6'-Triisopropylbiphenyl

[0314] Synthesis example Preparation of the compound of formula (I): synthesis scheme In the examples of the compound of formula (I), as shown below, in the examples of certain embodiments, the compound of formula (I) is prepared by the following general method. Although the general method represents the synthesis of a particular compound of the present invention, it will be understood that the following general method, and other methods known to those skilled in the art, are applicable to all compounds and subclasses and species of those compounds described herein.

[0315] Scheme 1 [ka] [In the formula, R 1 and R 2 This is as defined in the compound of formula (I). The compound of formula (S7) can be prepared by the general synthesis method shown in Scheme 1. Nitroaniline (S2) can be easily prepared by treating 1a with various primary amines (S1) in a suitable solvent such as ethanol containing a base such as triethylamine, at a temperature from approximately room temperature to reflux, for 30 minutes to 8 hours, although this method is not limited to this method. Phenylenediamine (S3) can be formed by reduction of nitroaniline (S2) using a reducing agent such as iron, at a temperature from approximately room temperature to reflux, for about 1 hour, in a solvent such as acetic acid, although this method is not limited to this method. Cyclization from phenylenediamine (S3) to benzimidazole (S4) can be carried out in the presence of an acid such as p-TsOH, using a reagent such as trimethyl orthoformate, at a temperature from approximately room temperature to 100°C, for about 10 minutes to 1 hour, although this method is not limited to this method. The compound of formula (S5) can be produced from bromide (S4) by treating it with an aryl, heteroaryl, or heterocyclic boronic acid or boronic acid ester at high temperature in an organic solvent (such as 1,4-dioxane, but not limited to 1,4-dioxane) in the presence of water and an inorganic base (such as sodium carbonate, potassium carbonate, or potassium phosphate, but not limited to 1,1'-bis(diphenylphosphino)ferrocene) under palladium catalytic conditions, including but not limited to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The carboxylic acid of formula (S6) can be obtained by treating the ester (S5) with water and an organic solvent (such as methanol and / or tetrahydrofuran, but not limited to 1,1'-bis(diphenylphosphino)ferrocene) in the presence of a hydroxide source (such as lithium hydroxide, but not limited to 1,1'-bis(diphenylphosphino)ferrocene) under palladium catalytic conditions, including but not limited to 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). By reacting a carboxylic acid (S6) with a coupling reagent, but not limited to, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, a base, but not limited to, diisopropylethylamine, and an amine (1h), the amide of formula (S7) can be obtained.

[0316] Scheme 2 [ka] [In the formula, R 1 and R 2 [X is defined as in the compound of formula (I); X is a halogen; and Z is CH or N.] Compounds of formula (S10) can be prepared by the general synthesis method shown in Scheme 2. The carboxylic acid of formula (S8) is obtained by treating the ester (S5) in the presence of water and, but not limited to, an organic solvent such as methanol and / or tetrahydrofuran, with a hydroxide source such as, but not limited to, lithium hydroxide. The amide of formula (S9) is obtained by reacting the carboxylic acid (S8) with a coupling reagent such as, but not limited to, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, a base such as, but not limited to, diisopropylethylamine, and amine (1h). The compound of formula (S10) can be produced by treating a halide (S9) with an aryl, heteroaryl, or heterocyclic boronic acid or boronic acid ester at high temperature in an organic solvent (such as 1,4-dioxane, but not limited to 1,4-dioxane) in the presence of water and an inorganic salt (such as sodium carbonate, potassium carbonate, or potassium phosphate, but not limited to 1,1'-bis(diphenylphosphino)ferrocene) under palladium catalytic conditions, including but not limited to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).

[0317] Scheme 3 [ka] [In the formula, R 1 and R 3 This is as defined for the compound of formula (I). Compounds of formula (S15) can be prepared by the general synthesis method shown in Scheme 3. By treating compound (3a) with various carboxylic acids at a temperature of about 80°C to 130°C for about 1 to 2 hours, benzimidazole of formula (S11) can be obtained. By treating benzimidazole (S11) with methyl iodide at a temperature of about 50°C for about 3 hours in the presence of a base such as potassium carbonate (but not limited to potassium carbonate) and in an organic solvent such as N,N-dimethylformamide (but not limited to N,N-dimethylformamide), benzimidazole (S12) can be obtained. By treating ester (S12) with water and an organic solvent such as methanol and / or tetrahydrofuran (but not limited to methanol) and a hydroxide source such as lithium hydroxide (but not limited to lithium hydroxide), carboxylic acid of formula (S13) can be obtained. By reacting a carboxylic acid (S13) with an organic solvent such as N,N-dimethylformamide (but not limited to this) at approximately room temperature for approximately 30 minutes with a coupling reagent such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (but not limited to this), a base such as diisopropylethylamine (but not limited to this), and an amine (1h), the amide of formula (S14) can be obtained. The compound of formula (S15) can be produced from bromide (S14) by treating it with an aryl, heteroaryl, or heterocyclic boronic acid or boronic acid ester at high temperature in an organic solvent (such as 1,4-dioxane) in the presence of water and an inorganic salt (such as sodium carbonate, potassium carbonate, or potassium phosphate, but not limited to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) under palladium catalytic conditions, but not limited to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).

[0318] Scheme 4 [ka] [In the formula, R 1 , R 2and R 3 This is as defined in the compound of formula (I). The compound of formula (S20) can be prepared by the general synthesis method shown in Scheme 4. By treating the substituted phenylenediamine of formula (S16) with various carboxylic acids at a temperature of about 80°C to 130°C for about 1 to 2 hours, the benzimidazole of formula (S17) is obtained. By treating the ester (S17) with an organic solvent such as water, but not limited to methanol and / or tetrahydrofuran, and a hydroxide source such as lithium hydroxide, but not limited to these, the carboxylic acid of formula (S18) is obtained. The amide of (S19) is obtained by reacting the carboxylic acid (S18) with an organic solvent such as N,N-dimethylformamide, but not limited to this, at approximately room temperature for approximately 30 minutes, with a coupling reagent such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, but not limited to this, a base such as diisopropylethylamine, and an amine (1h). The compound of formula (S20) can be produced from bromide (S19) by treating it with an aryl, heteroaryl, or heterocyclic boronic acid or boronic acid ester at high temperature in an organic solvent (such as 1,4-dioxane) in the presence of water and an inorganic salt (such as sodium carbonate, potassium carbonate, or potassium phosphate, but not limited to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) under palladium catalytic conditions, but not limited to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).

[0319] Scheme 5 [ka] [In the formula, R 1 , R 2 and R 3 This is as defined in the compound of formula (I). Compounds of formula (S26) can be prepared by the general synthesis method shown in Scheme 5. The carboxylic acid of formula (S22) is obtained by treating the ester (S21) with water and, but not limited to, an organic solvent such as methanol and / or tetrahydrofuran, with a hydroxide source such as, but not limited to, lithium hydroxide. The carboxylic acid (S22) is reacted with, but not limited to, N,N-dimethylformamide, at a temperature of room temperature to 50°C for about 2 hours with a coupling reagent such as, but not limited to, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, a base such as, but not limited to, diisopropylethylamine, and amine (1h) to obtain the amide of formula (S23). Phenylenediamine (S24) can be formed by reduction of nitroaniline (S23) at a temperature of approximately 35°C for approximately 3 hours in a solvent such as acetic acid, using a reducing agent such as iron, although this is not limited to S24. The substituted phenylenediamine of formula (S24) can be formed by treatment with various carboxylic acids at a temperature of approximately 80°C to 130°C for approximately 1 to 2 hours, thereby forming formula ( S24-a )of Bromide Benzimidazole is obtained. The compound of formula (S26) is Benzimidazole bromide of formula (S24-a) Therefore, it can be produced by treating with an aryl, heteroaryl, or heterocyclic boronic acid or boronic acid ester at high temperature in an organic solvent (such as 1,4-dioxane) in the presence of water and an inorganic salt (such as sodium carbonate, potassium carbonate, or potassium phosphate, but not limited to this) under palladium catalytic conditions such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), but not limited to this, in the presence of an inorganic salt (such as sodium carbonate, potassium carbonate, or potassium phosphate, but not limited to this).

[0320] Scheme 6 [ka] [In the formula, R1 , R 2 and R 3 This is as defined in the compound of formula (I). The compound of formula (S29) can be prepared by the general synthesis method shown in Scheme 6. The compound of formula (S27) can be prepared by treating a bromide (S25) with an aryl, heteroaryl, or heterocyclic boronic acid or boronic acid ester at high temperature in an organic solvent (such as 1,4-dioxane, but not limited to 1,1'-bis(diphenylphosphino)ferrocene) under palladium catalytic conditions, including but not limited to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the presence of water and an inorganic salt (such as sodium carbonate, potassium carbonate, or potassium phosphate, but not limited to 1,1'-bis(diphenylphosphino)ferrocene), but not limited to 1,1'-bis(diphenylphosphino)ferrocene. The carboxylic acid of formula (S28) can be obtained by treating the ester (S27) with a hydroxide source such as lithium hydroxide, but not limited to 1,1'-bis(diphenylphosphino)ferrocene, in the presence of water and an organic solvent such as methanol and / or tetrahydrofuran, but not limited to 1,1'-bis(diphenylphosphino)ferrocene By reacting a carboxylic acid (S28) with an organic solvent such as N,N-dimethylformamide (but not limited to this) at a temperature of room temperature to 50°C for about 2 hours with a coupling reagent such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (but not limited to this), a base such as diisopropylethylamine (but not limited to this), and an amine (1h), the amide of formula (S29) can be obtained.

[0321] Scheme 7 [ka] [In the formula, R 1 is as defined in the compound of formula (I); X is a halide; and in this specification, R 15 and R 16 is any substituent. The compound of formula (S38) can be produced by the general synthesis method shown in Scheme 7. The compound of formula (S30) can be converted to the compound of formula (S31) in the presence of an acid such as hydrochloric acid, or in an organic solvent such as ethyl acetate, at a temperature of about 15°C for about 2 hours, although this method is not limited to this method. Nitroaniline (S32) can be easily obtained by treating the amine (S31) with a base such as triethylamine, or in (1a), at a temperature of about 15°C for about 1 hour, in a suitable solvent such as ethanol, or in (1a), although this method is not limited to this method. Phenylenediamine (S33) can be formed by the reduction of nitroaniline (S32) in a solvent such as acetic acid, or in (1a) at a temperature from room temperature to reflux, for about 1 hour, using a reducing agent such as iron, or in (1a) By reacting the carboxylic acid (S33) in an organic solvent such as N,N-dimethylformamide (but not limited to this) at approximately room temperature for 16 hours with a coupling reagent such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (but not limited to this) and a base such as diisopropylethylamine (but not limited to this), the benzimidazole of formula (S34) is obtained. By treating the ester (S34) in the presence of water and / or an organic solvent such as methanol and / or tetrahydrofuran (but not limited to this) with a hydroxide source such as lithium hydroxide (but not limited to this), the carboxylic acid of formula (S35) is obtained. By reacting a carboxylic acid (S35) with an organic solvent such as N,N-dimethylformamide (but not limited to this) at a temperature of approximately 40°C for approximately 6 hours with a coupling reagent such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (but not limited to this), a base such as pyridine (but not limited to this), and an amine (1h), the amide of formula (S36) can be obtained.The compound of formula (S37) can be produced by treating a bromide (S36) with an aryl, heteroaryl, or heterocyclic boronic acid or boronic acid ester at high temperature in an organic solvent (such as 1,4-dioxane, but not limited to this) in the presence of water and an inorganic salt (such as sodium carbonate, potassium carbonate, or potassium phosphate, but not limited to this) under palladium-catalyzed conditions, including but not limited to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). Alternatively, the compound of formula (S37) can be produced by Still coupling. The bromide (S36) is converted to a stannane compound (S38) at high temperature in an organic solvent (such as toluene, but not limited to this) under palladium-catalyzed conditions, including but not limited to palladiumtetrakistriphenylphosphine, under palladium-catalyzed conditions, including but not limited to this. The stannan compound (S38) can be treated with various aryl or heteroaryl halides at high temperatures under palladium-catalyzed conditions such as palladium tetrakithriphenylphosphine, or in organic solvents such as DMSO, although this is not limited to these conditions.

[0322] Scheme 8 [ka] [In the formula, R 1 and R 6 This is as defined for the compound of formula (I). The compound of formula (S40) can be prepared by the general synthesis method shown in Scheme 8. The compound of formula (S39) can be obtained by treating compound (S38) with tetramethoxyalkane at a temperature of about 50°C for about 16 hours. The compound of formula (S40) can be prepared by treating bromide (S39) with an aryl, heteroaryl, or heterocyclic boronic acid or boronic acid ester at high temperature in an organic solvent (not limited to 1,4-dioxane) in the presence of water and an inorganic salt (not limited to sodium carbonate, potassium carbonate, or potassium phosphate) under palladium catalytic conditions such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).

[0323] Scheme 9 [ka] [In the formula, R 1 and R 2 R is defined as in the compound of formula (I); and 15 and R 16 is any substituent. Compounds of formula (S37 and S41) can be prepared by the general synthesis method shown in Scheme 9. Compound (S37) is obtained by treating compound (S36) with various aryl and heteroaryl stannane compounds at high temperature in an organic solvent such as toluene, but not limited to this, under palladium-catalyzed conditions such as palladium tetrakistriphenylphosphine, but not limited to this. In addition, compound (S41) is obtained by treating bromide (S36) at high temperature in an organic solvent such as tetrahydrofuran or 1,4-dioxane, but not limited to this, with various amines under palladium-catalyzed or copper conditions such as [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate or (Bu4NCuI2)2, but not limited to this.

[0324] Scheme 10 [ka] [In the formula, R 1 and R 2 This is as defined in the compound of formula (I). Compound (S46) can be prepared by the general synthesis method shown in Scheme 10. In the presence of iron and acetic acid, compound (S42) is cyclized to obtain compound (S43). The carboxylic acid of formula (S44) is obtained by treating ester (S43) in the presence of an organic solvent, but not limited to methanol and / or tetrahydrofuran, with a hydroxide source, but not limited to lithium hydroxide. The carboxylic acid (S44) is reacted with a coupling reagent, but not limited to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, a base, but not limited to pyridine, and amine (1h) in an organic solvent, but not limited to N,N-dimethylformamide, at a temperature of about 40°C for about 6 hours to obtain amide (S45). The compound of formula (S46) can be produced from bromide (S45) by treating it with an aryl, heteroaryl, or heterocyclic boronic acid or boronic acid ester at high temperature in an organic solvent (such as 1,4-dioxane, but not limited to 1,1'-bis(diphenylphosphino)ferrocene) under palladium catalytic conditions, including but not limited to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the presence of water and an inorganic salt (such as sodium carbonate, potassium carbonate, or potassium phosphate, but not limited to 1,1'-bis(diphenylphosphino)ferrocene).

[0325] Example 1 (General Method A) N-(4-(chlorodifluoromethoxy)phenyl)-1-methyl-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide The compound in the title was prepared according to Scheme 1. This general method A illustrates Scheme 1 and provides specific synthetic details applicable to the compound in the title. [ka]

[0326] Methyl 3-bromo-4-(methylamino)-5-nitrobenzoate (1c) To a solution of methyl 3-bromo-4-fluoro-5-nitrobenzoate (1a, 3g, 10.79 mmol, 1eq) and methylamine hydrochloride (1b, 874.23 mg, 12.95 mmol, 1.2eq) in EtOH (50 mL), TEA (3.28 g, 32.37 mmol, 4.51 mL, 3eq) was added. The mixture was stirred at 15°C for 12 hours. TLC (petroleum ether:ethyl acetate = 5:1, R) f A single major new spot with high polarity was detected at (=0.50). The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water and extracted with toluene. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 1c as a yellow solid. 1 H NMR (400 MHz, CDCl3-d) δ 8.52 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 6.54 (br s, 1H), 3.91 (s, 3H), 3.09 (d, J = 5.5 Hz, 3H).

[0327] Methyl 3-amino-5-bromo-4-(methylamino)benzoate (1d) To a solution of methyl 3-bromo-4-(methylamino)-5-nitrobenzoate (1c, 1.5g, 5.19 mmol, 1eq) in AcOH (20 mL), Fe (2.90 g, 51.89 mmol, 10 eqs) was added all at once at 15°C. The mixture was stirred at 15°C for 1 hour. Another batch of Fe (869.31 mg, 15.57 mmol, 3 eqs) was added all at once at 15°C, and the mixture was stirred at 35°C for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1, R) fA value of 0.30 indicated that 1c was completely consumed, and one major new spot of high polarity was detected. Ethyl acetate (100 mL) was added. The organic layer was washed with H2O (50 mL × 2), saturated NaHCO3 (30 mL × 4) and saline solution (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The product was used in the next step without further purification. Compound 1d was obtained as a brown oil. 1 H NMR (400 MHz, CDCl3-d) δ 7.63 (d, J = 1.8 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 4.05-3.93 (m, 2H), 3.89-3.84 (m, 3H), 3.61 (br s, 1H), 2.81-2.72 (m, 3H).

[0328] Methyl 7-bromo-1-methyl-1H-benzo[d]imidazole-5-carboxylate (1e) To a solution of methyl 3-amino-5-bromo-4-(methylamino)benzoate (1d, 0.1 g, 0.386 mmol, 1 eq) in trimethoxymethane (15 mL), p-TsOH (6.65 mg, 0.039 mmol, 0.1 eq) was added. The mixture was stirred at 100°C for 1 hour. LC-MS showed that 1d was completely consumed, and one major peak with the desired mass was detected. The mixture was concentrated, and ethyl acetate (20 mL) was added. The organic layer was washed with saturated NaHCO3 (5 mL) and saline solution (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 1e as a white solid. The product was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3-d) δ 8.43 (d, J = 1.5 Hz, 1H), 8.16 (d, J = 1.3 Hz, 1H), 7.91 (s, 1H), 4.18 (s, 3H), 4.00-3.92 (m, 3H).

[0329] Methyl 1-methyl-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxylate (1f) Dioxane (5 mL) and H2O (0.3 mL) containing a mixture of methyl 7-bromo-1-methyl-1H-benzo[d]imidazole-5-carboxylate (1e, 0.1 g, 0.372 mmol, 1 eq) and pyrimidine-5-ylboronic acid (92.09 mg, 0.743 mmol, 2 eq) were added under N2, along with Pd(dppf)Cl2 (19.03 mg, 0.026 mmol, 0.07 eq) and Na2CO3 (78.77 mg, 0.743 mmol, 2 eq). The mixture was stirred at 100°C for 12 hours. LC-MS showed a residual of 1e and detected one major peak with the desired mass. The mixture was filtered and concentrated to obtain a crude residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:methanol = 9:1). Compound 1f was obtained as a brown solid. 1 H NMR (400 MHz, CDCl3-d) δ 9.35 (s, 1H), 8.90 (s, 2H), 8.62 (d, J = 1.5 Hz, 1H), 7.97-7.88 (m, 2H), 3.98 (s, 3H), 3.51 (s, 3H).

[0330] 1-Methyl-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid (1g) To a solution of methyl 1-methyl-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxylate (1f, 0.045 g, 0.168 mmol, 1 eq) in THF (2 mL), MeOH (2 mL), and H2O (1 mL), LiOH·H2O (14.08 mg, 0.335 mmol, 2 eq) was added under N2 at 15°C. The mixture was stirred at 15°C for 12 hours. LC-MS showed that 1f was completely consumed and one major peak with the desired mass was detected. The mixture was adjusted to pH=5 with HCl water (1 M), concentrated to obtain 1 g of the crude product as a brown solid. The product was used in the next step without further purification.

[0331] N-(4-(chlorodifluoromethoxy)phenyl)-1-methyl-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide (1) 1-methyl-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid (1 g, 0.04 g, 0.157 mmol, 1 eq), 4-(chlorodifluoromethoxy)aniline (33.50 mg, 0.173 mmol, 1.1 eq), and HATU (71.79 mg, 0.189 mmol, 1.2 eq) were mixed in DMF (1 mL) at 15°C with DIEA (61.00 mg, 0.472 mmol, 82.21 μL, 3 eq). The mixture was stirred at 15°C for 12 hours. LC-MS showed that 1 g was completely consumed and the target mass was detected. The mixture was concentrated, and the resulting residue was purified by preparative HPLC (FA conditions, column: Luna C18 100*30 5u; mobile phase: [water (0.225% FA)-ACN]; B%: 35%-50%, 14 min) to obtain compound 1 of the title as a yellow solid. 1 1H NMR (400 MHz, MeOD-d4) δ 1 H NMR (400 MHz, MeOD-d4) δ 9.31 (s, 1H), 9.06 (s, 2H), 8.45 (d, J = 1.5 Hz, 1H), 8.39 (s, 1H), 7.91 (d, J = 1.5 Hz, 1H), 7.84 (d, J = 9.0 Hz, 2H), 7.31 (d, J = 9.0 Hz, 2H), 3.60 (s, 3H).

[0332] Example 2 (General Method B) N-(4-(chlorodifluoromethoxy)phenyl)-1-((1s,3s)-3-hydroxycyclobutyl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide The compound in question was prepared according to Scheme 2. This general method B illustrates Scheme 2 and provides specific synthetic details applicable to the compound in question. [ka]

[0333] 7-Bromo-1-((1s,3s)-3-hydroxycyclobutyl)-1H-benzo[d]imidazole-5-carboxylic acid (2b) To a solution of THF (2 mL), MeOH (2 mL), and H2O (1 mL) containing methyl 7-bromo-1-((1s,3s)-3-hydroxycyclobutyl)-1H-benzo[d]imidazole-5-carboxylate (synthesized by the same method as 1e; 2a, 140 mg, 0.431 mmol, 1 eq), LiOH·H2O (27.10 mg, 0.646 mmol, 1.5 eq) was added. The mixture was stirred at 15°C for 12 hours. LC-MS showed that 2a was completely consumed and the MS of the desired compound was detected. The aqueous phase was acidified to pH=5 by the addition of HCl water. The mixture was filtered and concentrated under vacuum to obtain compound 2b as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.10 (br s, 1 H) 8.72 (s, 1 H) 8.19 (d, J = 1.1 Hz, 1 H) 7.96 (s, 1 H) 5.37 (br d, J = 6.2 Hz, 1 H) 4.94-5.07 (m, 1 H) 4.01-4.11 (m, 1 H) 2.86-2.95 (m, 2 H) 2.37-2.44 (m, 2 H).

[0334] 7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-benzo[d]imidazole-5-carboxamide (2c) 7-Bromo-1-((1s,3s)-3-hydroxycyclobutyl)-1H-benzo[d]imidazole-5-carboxylic acid (2b, 100 mg, 0.321 mmol, 1 eq) and 4-[chloro(difluoro)methoxy]aniline (74.66 mg, 0.386 mmol, 1.2 eq) were dissolved in DMF (2 mL), to which HATU (146.65 mg, 0.386 mmol, 1.2 eq) and DIEA (83.08 mg, 0.643 mmol, 111.97 μL, 2 eq) were added. The mixture was stirred at 15 °C for 12 hours. LC-MS showed that 2b was completely consumed and the desired MS was detected. The mixture was diluted with water (3 mL) and extracted with SiO2 (10 mL x 3). The combined organic layers were washed with saline solution (3 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO₂, ethyl acetate:methanol = 10:1) to obtain 2c as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1 H) 8.72 (s, 1 H) 8.40 (d, J = 1.3 Hz, 1 H) 8.05 (d, J = 1.3 Hz, 1 H) 7.92 (d, J = 9.0 Hz, 2 H) 7.36 (d, J = 9.0 Hz, 2 H) 5.37 (d, J = 6.4 Hz, 1 H) 4.96-5.08 (m, 1 H) 4.01-4.13 (m, 1 H) 2.89-2.98 (m, 2 H) 2.36-2.43 (m, 2 H).

[0335] N-(4-(chlorodifluoromethoxy)phenyl)-1-((1s,3s)-3-hydroxycyclobutyl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide (2) To a solution of 7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-benzo[d]imidazole-5-carboxamide (2c, 40 mg, 0.082 mmol, 1 eq) and pyrimidine-5-ylboronic acid (20.37 mg, 0.164 mmol, 2 eq) in dioxane (3 mL) and H2O (0.3 mL), Pd(dppf)Cl2 (6.01 mg, 8.22 mmol, 0.1 eq) and K3PO4 (52.34 mg, 0.247 mmol, 3 eq) was added. The mixture was stirred at 100°C for 12 hours. LC-MS showed that 2c was completely consumed and the desired MS was detected. The aqueous phase was extracted with H2O (5 mL) and ethyl acetate (5 mL x 3). The combined organic layers were washed with saline solution (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The mixture was purified by preparative HPLC (NH4HCO3 conditions, column: Waters Xbridge Prep OBD C18 150*30 10u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 25%-45%, 10 min) to obtain compound 2 of the title as a white solid. Calculated MSmas [M+H] + (C 23 H 18 (O3N5ClF2) with a m / z of 486.1, and LCMS detection value of m / z 486.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1 H) 9.36 (s, 1 H) 9.06 (s, 2 H) 8.62 (s, 1 H) 8.51 (d, J = 1.5 Hz, 1 H) 7.94 (d, J = 9.0 Hz, 2 H) 7.81 (d, J = 1.5 Hz, 1 H) 7.37 (d, J = 8.8 Hz, 2 H) 5.21 (d, J = 6.6 Hz, 1 H) 3.97 (quin, J = 8.0 Hz, 1 H) 3.66 (sxt, J = 7.1 Hz, 1 H) 2.06-2.16 (m, 4 H).

[0336] Example 3 (General Method C) N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-methyl-4-(pyrimidine-5-yl)-1H-benzo[d]imidazole-6-carboxamide The compound in the title was prepared according to Scheme 3. This general method C illustrates Scheme 3 and provides specific synthetic details applicable to the compound in the title. [ka]

[0337] Methyl 4-bromo-2-(difluoromethyl)-1H-benzo[d]imidazole-6-carboxylate (3b) Methyl 3,4-diamino-5-bromobenzoate (synthesized by the same method as in 1d; 3a, 0.2 g, 0.816 mmol, 1 eq) was dissolved in CHF2COOH (3 mL). The mixture was stirred at 130°C for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1) showed that the starting material had been consumed, and LCMS showed the desired MS. The mixture was concentrated, and the residue was dissolved in HCl (10 mL). The organic layer was washed with NaHCO3 water (5 mL x 3), then concentrated, and 3b was obtained as a brown solid. The crude product was used in the next step without further purification.

[0338] Methyl 4-bromo-2-(difluoromethyl)-1-methyl-1H-benzo[d]imidazole-6-carboxylate (3c) To a solution of methyl 4-bromo-2-(difluoromethyl)-1H-benzo[d]imidazole-6-carboxylate (3b, 200 mg, 0.656 mmol, 1 eq) in DMF (2 mL), K2CO3 (271.82 mg, 1.97 mmol, 3 eq) and MeI (930.52 mg, 6.56 mmol, 408.12 μL, 10 eq) were added. The mixture was stirred at 50°C for 10 hours. TLC (petroleum ether:ethyl acetate = 2:1) showed that the starting materials had been consumed. The mixture was concentrated, and the residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 2:1) to obtain 3c as a yellow solid. 1 H NMR (400 MHz, CDCl3-d) δ 8.24 (d, J = 1.1 Hz, 1H), 8.17 (d, J = 1.1 Hz, 1H), 7.17-6.85 (m, 1H), 4.04 (s, 3H), 3.98 (s, 3H).

[0339] 4-Bromo-2-(difluoromethyl)-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid (3d) To a solution of methyl 4-bromo-2-(difluoromethyl)-1-methyl-1H-benzo[d]imidazole-6-carboxylate (3c, 115 mg, 0.36 mmol, 1 eq) in THF (3 mL), MeOH (2 mL), and H2O (1 mL), LiOH·H2O (30.24 mg, 0.721 mmol, 2 eq) was added at 25°C. The mixture was stirred at 50°C for 2 hours. TLC (petroleum ether:ethyl acetate = 2:1) showed that the starting material had been consumed. The mixture was concentrated and HCl water (1 M) was added until the pH was 3-4. The suspension was filtered, the solid was washed with H2O (1 mL), and dried to obtain 3d as a yellow solid. The crude product was used in the next step without further purification. 1 H NMR (400 MHz, MeOD-d4) δ 8.35 (s, 1H), 8.07 (s, 1H), 7.70-7.32 (m, 1H), 4.02 (s, 3H).

[0340] 4-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-methyl-1H-benzo[d]imidazole-6-carboxamide (3e) To a solution of 4-bromo-2-(difluoromethyl)-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid (3d, 110 mg, 0.361 mmol, 1 eq) in DMF (3 mL), DIPEA (93.20 mg, 0.721 mmol, 125.61 μL, 3 eq) and HATU (205.65 mg, 0.541 mmol, 1.2 eq) were added. The mixture was stirred at 25°C for 0.5 hours, after which 4-(chlorodifluoromethoxy)aniline (1 h, 83.76 mg, 0.433 mmol, 1.2 eq) was added. The reaction mixture was stirred at 25°C for 3.5 hours. TLC (petroleum ether:ethyl acetate = 3:1) showed that the starting material had been consumed, and LC-MS showed the desired MS. The mixture was concentrated, and the residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) column chromatography to obtain 3e as a yellow solid. 1 H NMR (400 MHz, CDCl3-d) δ 8.10 (d, J = 1.2 Hz, 1H), 7.98-7.91 (m, 2H), 7.74 (d, J = 8.9 Hz, 2H), 7.30 (d, J = 8.9 Hz, 2H), 7.18-6.88 (m, 1H), 4.07 (s, 3H).

[0341] N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-methyl-4-(pyrimidine-5-yl)-1H-benzo[d]imidazole-6-carboxamide (3) To a solution of 4-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-methyl-1H-benzo[d]imidazole-6-carboxamide (3e, 100 mg, 0.208 mmol, 1 eq) and pyrimidine-5-ylboronic acid (51.56 mg, 0.416 mmol, 2 eq) in dioxane (4 mL) and H2O (1 mL), K3PO4 (132.49 mg, 0.624 mmol, 3 eq) and Pd(dppf)Cl2 (15.22 mg, 0.021 mmol, 0.1 eq) were added under N2. The mixture was stirred under N2 at 100°C for 4 hours. LCMS showed that the starting materials had been consumed and the desired product was detected. The mixture was poured into water and extracted with ELISA. The organic layer was concentrated, and the resulting residue was purified by preparative HPLC (NH4HCO3 conditions, column: Waters Xbridge Prep OBD C18 150*30 10u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 30%-50%, 10 min) to obtain compound 3 of the title as a white solid. Calculated MSmas [M+H] + (C 21 H 14 (ClF4N5O2) m / z 480.1, LCMS detection value m / z 480.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.55 (s, 2H), 9.26 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 7.93 (d, J = 9.2 Hz, 2H), 7.69-7.37 (m, 3H), 4.08 (s, 3H).

[0342] Example 4 N-(4-(chlorodifluoromethoxy)phenyl)-1,2-dimethyl-4-(pyrimidine-5-yl)-1H-benzo[d]imidazole-6-carboxamide [ka]

[0343] Methyl 7-bromo-2-methyl-1H-benzo[d]imidazole-5-carboxylate (4a) To a mixture of methyl 3,4-diamino-5-bromobenzoate (synthesized in the same manner as 1d; 3a, 0.16 g, 0.653 mmol, 1 eq) in CH3COOH (3 mL), 4-methylbenzenesulfonic acid (11.24 mg, 0.065 mmol, 0.1 eq) was added at 20 °C. The mixture was stirred at 100 °C for 3 hours. LC-MS revealed the desired MS. The mixture was poured into water (20 mL) and then extracted with RINKAN (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 4a as a brown oil.

[0344] Methyl 4-bromo-1,2-dimethyl-1H-benzo[d]imidazole-6-carboxylate (4b) To a mixture of methyl 7-bromo-2-methyl-1H-benzo[d]imidazole-5-carboxylate (4a, 0.15 g, 0.557 mmol, 1 eq) and NaH (44.59 mg, 1.11 mmol, 60% purity, 2 eq) in DMF (1 mL), CH3I (158.24 mg, 1.11 mmol, 69.40 μL, 2 eq) was added. The mixture was stirred at 15°C for 16 hours. The desired MS was shown by LC-MS. The mixture was poured into water (20 mL) and then extracted with siRNA (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the product. The residue was subjected to preparative TLC (petroleum ether:ethyl acetate = 0:1, R f By refining it using a solution of 0.40, 4b was obtained as a brown oil.

[0345] Methyl 1,2-dimethyl-4-(pyrimidine-5-yl)-1H-benzo[d]imidazole-6-carboxylate (4c) Methyl 4-bromo-1,2-dimethyl-1H-benzo[d]imidazole-6-carboxylate (4b, 0.02 g, 0.071 mmol, 1 eq), pyrimidine-5-ylboronic acid (26.26 mg, 0.212 mmol, 3 eq), and K3PO4 (44.98 mg, 0.212 mmol, 3 eq) were mixed in dioxane (2 mL) and H2O (0.2 mL) under N2, to which Pd(dppf)Cl2 (5.17 mg, 7.06 mmol, 0.1 eq) was added. The mixture was stirred at 110 °C for 16 hours. The desired MS was shown by LC-MS. The mixture was poured into water and extracted with siRNA. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. Residue, preparative TLC (petroleum ether:ethyl acetate = 0:1, R f It was refined using a method (=0.37) to obtain 4c as a yellow oil.

[0346] 1,2-dimethyl-4-(pyrimidine-5-yl)-1H-benzo[d]imidazole-6-carboxylic acid (4d) To a mixture of 4c (0.015 g, 0.053 mmol, 1 eq) of H2O (0.5 mL), THF (1 mL), and MeOH (1 mL), LiOH·H2O (4.46 mg, 0.106 mmol, 2 eqs) was added. The mixture was stirred at 15°C for 16 hours. LC-MS revealed the desired MS. The mixture was poured into water and extracted with siRNA. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 4d as a red solid. The crude product was used in the next step without further purification.

[0347] N-(4-(chlorodifluoromethoxy)phenyl)-1,2-dimethyl-4-(pyrimidine-5-yl)-1H-benzo[d]imidazole-6-carboxamide (4) 1,2-dimethyl-4-(pyrimidine-5-yl)-1H-benzo[d]imidazole-6-carboxylic acid (4d, 15 mg, 0.056 mmol, 1 eq), HATU (25.51 mg, 0.067 mmol, 1.2 eq), and DIPEA (14.45 mg, 0.112 mmol, 19.48 μL, 2 eq) were mixed in DMF (1 mL) and 4-[chloro(difluoro)methoxy]aniline (1 h, 16.24 mg, 0.084 mmol, 1.5 eq) at 20°C. The mixture was stirred at 20°C for 16 hours. The mixture was concentrated under vacuum. The desired MS was shown by LC-MS. The mixture was poured into water and extracted with siRNA. The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain the crude product. The residue was purified by preparative HPLC (TFA conditions, column: Nano-Micro UniSil 5-100 C18 ULTRA 100*250mm 5um; mobile phase: [water (0.1% TFA)-ACN]; B%: 25%-50%, 11 min) to obtain compound 4, the subject of the title, as a white solid. Calculated value of MSmas [M+1] + (C 21 H 16 (ClF2N5O2) m / z 444.1, LCMS detection value m / z 444.1. 1 H NMR (400 MHz, MeOD-d4) δ 9.33-9.25 (m, 3H), 8.48 (s, 1H), 8.25 (s, 1H), 7.88 (d, J = 9.0 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 4.07 (s, 3H), 2.85 (s, 3H).

[0348] Example 5 (General Method D) (R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0349] The compound in the title was prepared according to Scheme 4. This general method D illustrates Scheme 4 and provides specific synthetic details applicable to the compound in the title. [ka]

[0350] (R)-Methyl 7-bromo-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-1H-benzo[d]imidazole-5-carboxylate (5b) A solution of (R)-methyl 3-amino-5-bromo-4-((1-hydroxypropan-2-yl)amino)benzoate (synthesized by the same method as 1d; 5a, 230 mg, 0.759 mmol, 1 eq) in 2,2-difluoroacetic acid (4.59 g, 0.048 mmol, 3 mL, 63 eq) was stirred at 110°C for 3 hours. LC-MS showed that 5a was completely consumed and the MS of the choice was detected. The mixture was filtered and concentrated under reduced pressure to obtain the crude residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1) to obtain 5b as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1 H) 8.11 (s, 1 H), 7.37-7.75 (m, 1 H), 5.95-6.10 (m, 1 H), 5.31 (t, J = 5.2 Hz, 1 H), 3.90 (s, 3 H), 3.74-3.87 (m, 2 H), 1.59 (br d, J = 7.3 Hz, 3 H).

[0351] (R)-7-bromo-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-1H-benzo[d]imidazole-5-carboxylic acid (5c) (R)-methyl 7-bromo-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-1H-benzo[d]imidazole-5-carboxylate (5b, 130 mg, 0.358 mmol, 1 eq) was dissolved in THF (1 mL), MeOH (1 mL), and H2O (0.5 mL), to which LiOH·H2O (30.04 mg, 0.716 mmol, 2 eq) was added. The mixture was stirred at 15°C for 2 hours. LC-MS showed that 5b had been completely consumed, and the MS of the desired compound was detected. The aqueous phase was acidified to pH=5 with HCl water, and the mixture was filtered and concentrated under vacuum. The product was used in the next step without further purification. Compound 5c was obtained as a white solid.

[0352] (R)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-1H-benzo[d]imidazole-5-carboxamide (5e) (R)-7-bromo-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-1H-benzo[d]imidazole-5-carboxylic acid (5c, 100 mg, 0.286 mmol, 1 eq) and 4-(chlorodifluoromethoxy)aniline (1h, 66.54 mg, 0.344 mmol, 1.2 eq) were dissolved in DMF (2 mL), to which HATU (130.69 mg, 0.344 mmol, 1.2 eq) and DIEA (148.08 mg, 1.15 mmol, 199.56 μL, 4 eq) were added. The mixture was stirred at 15°C for 12 hours. LC-MS showed that 5c was completely consumed and the MS of interest was detected. The mixture was diluted with water (5 mL) and extracted with SiO2 (10 mL × 3). The combined organic layers were washed with saline solution (5 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude residue. The residue was purified by preparative TLC (SiO₂, ethyl acetate:methanol = 10:1) to obtain 5e as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1 H), 8.49 (s, 1 H), 8.21 (s, 1 H), 7.93 (d, J = 9.3 Hz, 2 H), 7.43-7.71 (m, 1 H), 7.38 (br d, J = 9.0 Hz, 2 H), 6.02 (br d, J = 6.2 Hz, 1 H), 5.23-5.45 (m, 1 H), 3.72-3.93 (m, 2 H), 1.60 (br d, J = 6.8 Hz, 3 H).

[0353] (R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide (5) (R)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-1H-benzo[d]imidazole-5-carboxamide (5e, 60 mg, 0.114 mmol, 1 eq) and pyrimidine-5-ylboronic acid (28.34 mg, 0.229 mmol, 2 eq) were dissolved in dioxane (1 mL) and H2O (0.1 mL) with Pd(dppf)Cl2 (8.37 mg, 11.44 mmol, 0.1 eq) and K3PO4 (72.82 mg, 0.343 mmol, 3 eq). The mixture was stirred at 100°C for 16 hours. LC-MS showed that 5e was completely consumed and the MS of the desired compound was detected. The mixture was filtered and concentrated under reduced pressure to obtain the crude residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:methanol = 10:1) to obtain compound 5, the title compound, as a white solid. Calculated MSmas [M+H] + (C 23 H 18 (O3N5ClF4) with a m / z of 524.1, and LCMS detection value at m / z 524.1. 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1 H) 9.35 (s, 1 H) 9.07 (s, 2 H) 8.58 (d, J = 1.5 Hz, 1 H) 7.93 (d, J = 9.3 Hz, 2 H) 7.84 (d, J = 1.8 Hz, 1 H) 7.42-7.70 (m, 1 H) 7.38 (d, J = 9.0 Hz, 2 H) 5.11 (t, J = 5.1 Hz, 1 H) 4.25-4.45 (m, 1 H) 3.41-3.63 (m, 2 H) 1.37 (br d, J = 7.1 Hz, 3 H).

[0354] Example 6 (General Method E) N-(4-(chlorodifluoromethoxy)phenyl)-2-isopropyl-1-methyl-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide The compound in question was prepared according to Scheme 5. This general method E illustrates Scheme 5 and provides specific synthetic details applicable to the compound in question. [ka]

[0355] 3-Bromo-4-(methylamino)-5-nitrobenzoic acid (6a) Methyl 3-bromo-4-(methylamino)-5-nitrobenzoate (1c, 1.7g, 5.88 mmol, 1eq) was added all at once to a mixture of THF (20 mL) and H2O (4 mL) with LiOH·H2O (493.55 mg, 11.76 mmol, 2eq). The mixture was stirred at 60°C for 12 hours. TLC (petroleum ether:ethyl acetate = 3:1, R) f The presence of 0.0 indicated that 1c was completely consumed, and one major new spot of high polarity was detected. The mixture was adjusted to pH=3 with HCl water (1M). The mixture was filtered, and the yellow solid was washed with H2O (10 mL) to obtain 6b as a yellow solid. The product was used in the next step without further purification.

[0356] 3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(methylamino)-5-nitrobenzamide (6b) To a mixture of 3-bromo-4-(methylamino)-5-nitrobenzoic acid (6a, 1.27 g, 6.54 mmol, 1.2 eq) and 4-(chlorodifluoromethoxy)aniline (1h, 1.50 g, 5.45 mmol, 1 eq) in DMF (10 mL), HATU (2.28 g, 6.00 mmol, 1.1 eq) and DIEA (775.28 mg, 6.00 mmol, 1.04 mL, 1.1 eq) were added in one addition. The mixture was heated to 30°C and stirred for 12 hours. LC-MS revealed the detection of a single major peak with the desired mass. The mixture was concentrated, and the reaction residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 20:1-5:1) to obtain 6b as a yellow solid.

[0357] 3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(methylamino)benzamide (6c) To a solution of 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(methylamino)-5-nitrobenzamide (6b, 2.1 g, 4.66 mmol, 1 eq) in AcOH (15 mL), Fe (2.60 g, 46.60 mmol, 10 eq) was added all at once at 20 °C. The mixture was stirred at 35 °C for 3 hours. TLC (petroleum ether:ethyl acetate = 1:1, R) f A reading of 0.6 indicated that 6b was completely consumed, and a new spot was formed. Ethyl acetate (40 mL) was added, and the mixture was filtered through a Celite® pad. The filtrate was washed with H2O (30 mL), saturated NaHCO3 solution (20 mL x 3), and saline solution (20 mL), then dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 6c as a yellow solid. The crude product was used in the next step without further purification.

[0358] 3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(methylamino)benzamide (6d) A mixture of 3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(methylamino)benzamide (6c, 0.075 g, 0.178 mmol, 1 eq) and 2-methylpropanoic acid (314.18 mg, 3.57 mmol, 330.72 μL, 20 eq) was stirred at 130°C for 12 hours. The mixture changed from brown to dark. LC-MS showed that 6e was completely consumed and the desired mass was detected. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to obtain 6d as a yellow oil.

[0359] N-(4-(chlorodifluoromethoxy)phenyl)-2-isopropyl-1-methyl-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide (6) 3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(methylamino)benzamide (6d, 0.03g, 0.063 mmol, 1eq) and pyrimidine-5-ylboronic acid (15.73mg, 0.127 mmol, 2eq) were added in a mixture of dioxane (4mL) and H2O (0.3mL) at 15°C under N2, along with Pd(dppf)Cl2 (4.64mg, 6.35µmol, 0.1eq) and K3PO4 (40.41mg, 0.190 mmol, 3eq). The mixture was stirred at 110°C for 12 hours. LC-MS showed that the starting materials were completely consumed, and one major peak with the desired mass was detected. The mixture was filtered through a Celite® pad, and the filtrate was concentrated to obtain the crude residue. The residue was purified by preparative HPLC (TFA conditions: column: Luna C18 100*30 5u; mobile phase: [water (0.1% TFA)-ACN]; B%: 15%-45%, 14 min) to obtain compound 6, the title compound, as a white solid. Calculated MSmas [M+H] + (C 23 H 20(O2N5ClF2) m / z 472.1, LCMS detection value m / z 472.1. 1 H NMR (400 MHz, MeOD-d4) δ 9.34 (s, 1H), 9.07 (s, 2H), 8.43 (d, J = 1.5 Hz, 1H), 8.01 (d, J = 1.5 Hz, 1H), 7.84 (d, J = 9.0 Hz, 2H), 7.31 (d, J = 9.0 Hz, 2H), 3.64-3.55 (m, 4H), 1.52 (d, J = 6.8 Hz, 6H).

[0360] Example 7 (General Method F) N-(4-(chlorodifluoromethoxy)phenyl)-1,2-dimethyl-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide The compound in the title was prepared according to Scheme 6. This general method F illustrates Scheme 6 and provides specific synthetic details applicable to the compound in the title. [ka]

[0361] Methyl 1,2-dimethyl-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxylate (7b) Methyl 7-bromo-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxylate (synthesized by the same method as 1e; 7a, 0.15 g, 0.53 mmol, 1 eq) and pyrimidine-5-ylboronic acid (65.65 mg, 0.53 mmol, 1 eq) were added to a mixture of dioxane (5 mL) and H2O (0.5 mL) under N2, with Pd(dppf)Cl2 (38.77 mg, 0.53 mmol, 0.1 eq) and K3PO4.3H2O (423.28 mg, 1.59 mmol, 3 eq). The mixture was stirred at 110°C for 16 hours. TLC (ethyl acetate:methanol = 8:1, R) fA reading of 0.20 indicated that 7a was completely consumed, and one major new spot of high polarity was detected. LC-MS also indicated that 7a was completely consumed, and one major peak with the desired mass was detected. The mixture was filtered and concentrated to obtain the residue, which was purified by preparative TLC (SiO2, ethyl acetate:methanol = 8:1) to obtain 7b as a light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 9.01 (s, 2H), 8.21 (d, J = 1.3 Hz, 1H), 7.67 (d, J = 1.3 Hz, 1H), 3.87 (s, 3H), 3.32-3.31 (m, 3H), 2.55 (s, 3H).

[0362] 1,2-dimethyl-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid (7c) Methyl 1,2-dimethyl-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxylate (7b, 0.06 g, 0.213 mmol, 1 eq) was dissolved in THF (2 mL), MeOH (2 mL), and H2O (1 mL), to which LiOH·H2O (17.84 mg, 0.425 mmol, 2 eq) was added. The mixture was stirred at 50°C for 3 hours. LC-MS showed that 7b was completely consumed, and one major peak with the desired mass was detected. The mixture was adjusted to pH=5 with HCl water (1 M), concentrated, and 7c was obtained as a brown solid. The product was used in the next step without further purification.

[0363] N-(4-(chlorodifluoromethoxy)phenyl)-1,2-dimethyl-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide (7) DIEA (82.38 mg, 0.637 mmol, 111.03 μL, 3 eq) was added to a mixture of 1,2-dimethyl-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid (7c, 0.057 g, 0.212 mmol, 1 eq), 4-(chlorodifluoromethoxy)aniline (1h, 45.24 mg, 0.234 mmol, 1.1 eq), and HATU (96.95 mg, 0.255 mmol, 1.2 eq) in DMF (2 mL). The mixture was stirred at 15°C for 12 hours. LC-MS showed that 7c was completely consumed, and one major peak with the desired mass was detected. The mixture was concentrated to obtain a crude residue, which was purified by preparative HPLC (FA conditions: column: Nano-micro Kromasil C18 100*30mm 5um; mobile phase: [water (0.225% FA)-ACN]; B%: 1%-50%, 15 min) to obtain compound 7 of the title as a white solid. Calculated MSmas [M+H] + (C 21 H 16 (ClF2N5O2) was detected at m / z 444.1, and the LCMS detection value was m / z 444.2. 1 H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.32 (s, 1H), 9.06 (s, 2H), 8.35 (d, J = 1.3 Hz, 1H), 7.92 (d, J = 9.0 Hz, 2H), 7.76 (d, J = 1.5 Hz, 1H), 7.36 (d, J = 9.0 Hz, 2H), 3.37 (s, 3H), 2.57 (s, 3H).

[0364] Example 8 (General Method G) N-[4-[chloro(difluoro)methoxy]phenyl]-6-pyrimidine-5-yl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxamide The compound in the title was prepared according to Scheme 7. This general method G illustrates Scheme 7 and provides specific synthetic details applicable to the compound in the title. [ka]

[0365] 2-(2-aminoethoxy)acetic acid (8b) A solution of 2-[2-(tert-butoxycarbonylamino)ethoxy]acetic acid (8a, 800 mg, 3.65 mmol, 1 eq) in HCl / siRNA (5 mL) was stirred at 15°C for 2 hours. LC-MS showed that 8) was completely consumed and the desired MS was detected. The mixture was filtered and concentrated under reduced pressure to obtain 8b as a white solid. The product was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 12.76 (br s, 1 H) 8.09 (br s, 3 H) 4.06 (s, 2 H) 3.66 (t, J = 5.2 Hz, 2 H) 2.87-3.02 (m, 2 H).

[0366] 2-[2-(2-bromo-4-methoxycarbonyl-6-nitro-anilino)ethoxy]acetic acid (8c) To a solution of methyl 3-bromo-4-fluoro-5-nitrobenzoate (1a, 500 mg, 1.80 mmol, 1 eq) and 2-(2-aminoethoxy)acetic acid (8b, 335.75 mg, 2.16 mmol, 1.2 eq, HCl) in EtOH (10 mL), TEA (454.94 mg, 4.50 mmol, 625.78 μL, 2.5 eq) was added. The mixture was stirred at 15 °C for 1 hour. LC-MS showed that 1a was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (25 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 to obtain the crude residue. The residue was purified by silica gel chromatography (column length: 250 mm, diameter: 100 mm, 200-300 mesh, silica gel, petroleum ether / ethyl acetate = 5 / 1, ethyl acetate / methanol / CH3COOH = 5 / 1 / 0.1%) to obtain 8c as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 1.7 Hz, 1 H) 8.18 (d, J = 1.7 Hz, 1 H) 7.09 (br s, 1 H) 3.89 (s, 2 H) 3.83 (s, 3 H) 3.65 (br t, J = 5.0 Hz, 2 H) 3.19-3.28 (m, 2 H).

[0367] 2-[2-(2-amino-6-bromo-4-methoxycarbonyl-anilino)ethoxy]acetic acid (8d) To a solution of 2-[2-(2-bromo-4-methoxycarbonyl-6-nitro-anilino)ethoxy]acetic acid (8c, 420 mg, 1.11 mmol, 1 eq) in AcOH (5 mL), Fe (621.91 mg, 11.14 mmol, 10 eq) was added. The reaction mixture was stirred at 35°C for 1 hour. LC-MS showed that 8c was completely consumed and the desired MS was detected. The mixture was filtered through a Celite® pad and washed with ethyl acetate. The mixture was concentrated under reduced pressure to obtain a crude residue, which was purified by preparative HPLC (HCl conditions, column: Phenomenex Luna C18 200*40 mm*10 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 15%-45%, 10 min) to obtain 8d as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.53 (s, 1 H) 7.49 (s, 1 H) 4.16 (br s, 2 H) 4.05 (s, 3 H) 3.60 (br t, J = 4.9 Hz, 2 H) 3.26-3.35 (m, 2 H).

[0368] Methyl 6-bromo-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxylate (8e) To a solution of 2-[2-(2-amino-6-bromo-4-methoxycarbonyl-anilino)ethoxy]acetic acid (8d, 100 mg, 0.261 mmol, 1 eq, HCl) in DMF (20 mL), HATU (109.03 mg, 0.287 mmol, 1.1 eq) and DIEA (101.07 mg, 0.782 mmol, 136.21 μL, 3 eq) were added. The mixture was stirred at 20°C for 16 hours. LC-MS showed that 8d was completely consumed and the MS of interest was detected. The mixture was diluted with water (5 mL) and extracted with RINKAN (5 mL × 3). The combined organic layers were washed with saline (5 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1) to obtain 8e as a white solid. 1 H NMR (400 MHz, CDCl3-d) δ 8.34 (d, J = 1.3 Hz, 1 H) 8.11 (d, J = 1.3 Hz, 1 H) 5.05 (s, 2 H) 4.71 (t, J = 5.3 Hz, 2 H) 4.15-4.26 (m, 2 H) 3.95 (s, 3 H).

[0369] 6-Bromo-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxylic acid (8f) To a solution of methyl 6-bromo-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxylate (8e, 50 mg, 0.161 mmol, 1 eq) in MeOH (1 mL), THF (1 mL), and H2O (0.5 mL), LiOH·H2O (13.49 mg, 0.321 mmol, 2 eq) was added. The mixture was stirred at 40°C for 6 hours. TLC (petroleum ether:ethyl acetate = 0:1, R) f The presence of 0) indicated that 8e was completely consumed, and one major new, more polar spot was detected. The mixture was concentrated under vacuum. The mixture was added to H2O (3 mL), and the aqueous phase was acidified to pH=5 with HCl water. The mixture was concentrated under vacuum to obtain 8f as a white solid. The product was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 1.2 Hz, 1 H) 7.94 (d, J = 1.3 Hz, 1 H) 5.00 (s, 2 H) 4.63 (t, J = 5.3 Hz, 2 H) 4.16 (t, J=5.3 Hz, 2 H).

[0370] 6-Bromo-N-[4-[chloro(difluoro)methoxy]phenyl]-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxamide (8g) 6-bromo-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxylic acid (8f, 45 mg, 0.151 mmol, 1 eq) and 4-(chlorodifluoromethoxy)aniline (1h, 35.18 mg, 0.182 mmol, 1.2 eq) were dissolved in pyridine (2 mL) and HATU (69.11 mg, 0.182 mmol, 1.2 eq) was added. The mixture was stirred at 40°C for 6 hours. LC-MS showed that 8f was completely consumed and the MS of the choice was detected. The mixture was diluted with water (5 mL) and extracted with toluene (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1) to obtain 8 g of a white solid. 1 H NMR (400 MHz, CDCl3-d) δ 8.11 (s, 1 H) 8.00 (s, 1 H) 7.96 (br s, 1 H) 7.73 (d, J = 8.9 Hz, 2 H) 7.29 (br s, 2 H) 5.06 (s, 2 H) 4.73 (t, J = 5.3 Hz, 2 H) 4.22 (t, J = 5.1 Hz, 2 H).

[0371] N-[4-[chloro(difluoro)methoxy]phenyl]-6-pyrimidine-5-yl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxamide (8) To a solution of 6-bromo-N-[4-[chloro(difluoro)methoxy]phenyl]-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxamide (8 g, 40 mg, 0.085 mmol, 1 eq) and pyrimidine-5-ylboronic acid (20.97 mg, 0.169 mmol, 2 eq) in dioxane (1 mL) and H2O (0.1 mL), Pd(dppf)Cl2 (6.19 mg, 8.46 mmol, 0.1 eq) and K3PO4 (53.89 mg, 0.254 mmol, 3 eq) was added. The mixture was stirred at 110°C for 16 hours. LC-MS showed that 8 g was completely consumed, and the desired MS was detected. The mixture was diluted with water (15 mL) and extracted with toluene (15 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude residue. The residue was purified by preparative TLC (SiO₂, ethyl acetate:methanol = 10:1) to obtain compound 8, the title compound, as a yellow solid. Calculated MSmas [M+H] + (C 22 H 16 O3N5ClF2) with m / z 472.1, LCMS detection value m / z 472.1 1 H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1 H) 9.32 (s, 1 H) 9.10 (s, 2 H) 8.42 (s, 1 H) 7.93 (d, J = 9.0 Hz, 2 H) 7.82 (s, 1 H) 7.26-7.45 (m, 1 H) 7.36 (br d, J = 8.8 Hz, 1 H) 5.03 (s, 2 H) 3.98 (br t, J = 4.9 Hz, 2 H) 3.70-3.83 (m, 2 H).

[0372] Example 9 (General Method H) N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-2-methoxy-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide The compound in the title was prepared according to Scheme 8. This general method H illustrates Scheme 8 and provides specific synthetic details applicable to the compound in the title. [ka]

[0373] 7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-2-methoxy-1H-benzo[d]imidazole-5-carboxamide (9b) To a solution of 3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(isopropylamino)benzamide (synthesized by the same method as 6c; 9a, 100 mg, 0.223 mmol, 1 eq) in AcOH (2 mL), tetramethoxymethane (197.23 mg, 1.45 mmol, 6.5 eq) was added. The mixture was stirred at 50°C for 16 hours. LC-MS showed that 9a was completely consumed, and the MS of the target was detected. TLC (petroleum ether:ethyl acetate = 3:1, R) f A value of 0.4 indicated that 9a was completely consumed, and one major new spot of lower polarity was detected. The reaction mixture was concentrated under reduced pressure. The mixture was washed with saturated aqueous NaHCO3 solution, dried over Na2SO4, and evaporated to dry. The crude residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 3:1) to obtain 9b as a white solid.

[0374] N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-2-methoxy-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide (9) A mixture of 7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-2-methoxy-1H-benzo[d]imidazole-5-carboxamide (9b, 40 mg, 0.082 mmol, 1 eq), pyrimidine-5-ylboronic acid (30.42 mg, 0.246 mmol, 3 eq), Pd(dppf)Cl2 (5.99 mg, 8.18 mmol, 0.1 eq), and K3PO4 (52.12 mg, 0.246 mmol, 3 eq) in dioxane (4 mL) and H2O (0.4 mL) was degassed and purged three times with N2. The mixture was stirred under an N2 atmosphere at 110°C for 16 hours. LC-MS showed that 9b was completely consumed and the MS of the target was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to obtain compound 9, the title compound, as a white solid. Calculated value of MSmas [M+1] + (C 23 H 20 The detection value for ClF2N5O3 was m / z 488.1, and the LCMS detection value was m / z 488.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.33 (s, 1H), 9.06 (s, 2H), 8.21 (d, J = 1.5 Hz, 1H), 7.94-7.89 (m, 2H), 7.64 (d, J = 1.5 Hz, 1H), 7.35 (d, J = 9.0 Hz, 2H), 4.18 (s, 3H), 3.99-3.91 (m, 1H), 1.29 (d, J = 6.8 Hz, 6H).

[0375] Example 10 N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-cyclopropyl-1H-imidazole-1-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide [ka]

[0376] N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-cyclopropyl-1H-imidazole-1-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (10) A mixture of 7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (synthesized by the same method as 2c; 10a, 50 mg, 0.109 mmol, 1 eq), 4-cyclopropyl-1H-imidazole (10b, 23.58 mg, 0.218 mmol, 2 eq), CuI (20.76 mg, 0.109 mmol, 1 eq), K2CO3 (150.65 mg, 1.09 mmol, 10 eq), and DMEDA (19.22 mg, 0.218 mmol, 23.47 μL, 2 eq) in DMF (2 mL) was degassed, purged three times with N2, and then stirred under an N2 atmosphere at 140°C for 16 hours. The reaction mixture was concentrated, and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic layers were washed with saline solution (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was subjected to preparative TLC (ethyl acetate:methanol = 10:1, R₂). f The crude product was purified by (=0.2) and further purified by preparative HPLC (NH4HCO3, column: Waters Xbridge Prep OBD C18 150*30 10u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 35%-55%, 10 min) to obtain compound 10 of the title as a white solid. Calculated value of MSmas [M+1] + (C 24 H 22 ClF2N5O2) with a m / z of 486.1, and LCMS detection value of m / z 486.1; 1H NMR (400 MHz, MeOD-d4) δ 8.61 (s, 1H), 8.49 (d, J = 1.5 Hz, 1H), 7.92 (s, 2H), 7.87-7.81 (m, 2H), 7.33-7.24 (m, 3H), 3.78 (td, J = 6.7, 13.4 Hz, 1H), 2.01-1.89 (m, 1H), 1.46 (br s, 6H), 0.93 (dd, J = 2.0, 8.4 Hz, 2H), 0.77 (br s, 2H).

[0377] Example 11 N-(4-(chlorodifluoromethoxy)phenyl)-7-(1H-imidazole-1-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide [ka]

[0378] N-(4-(chlorodifluoromethoxy)phenyl)-7-(1H-imidazole-1-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (11) To a solution of 7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (10a, 200 mg, 0.436 mmol, 1 eq) and imidazole (148.42 mg, 2.18 mmol, 5 eq) in DMF (2 mL), K2CO3 (602.64 mg, 4.36 mmol, 10 eq), CuI (83.04 mg, 0.436 mmol, 1 eq), and DMEDA (115.31 mg, 1.31 mmol, 140.79 μL, 3 eq) were added. The mixture was stirred at 120 °C for 12 hours. The mixture was dissolved in SiO2 (20 mL), washed with water (10 mL x 5), and the organic layer was concentrated. The residue was purified by preparative HPLC (NH4HCO3 conditions, column: Waters Xbridge Prep OBD C18 150*30 10u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 35%-55%, 10 min) to obtain compound 11 as a white solid. 1 H NMR (400 MHz, MeOD-d4) δ 8.63 (s, 1H), 8.51 (d, J = 1.5 Hz, 1H), 8.11 (s, 1H), 7.95 (d, J = 1.5 Hz, 1H), 7.89-7.78 (m, 2H), 7.58 (d, J = 1.3 Hz, 1H), 7.35-7.21 (m, 3H), 3.70 (quin, J = 6.7 Hz, 1H), 1.43 (br s, 6H).

[0379] Example 12 N-(4-(chlorodifluoromethoxy)phenyl)-2-(2-hydroxyethyl)-1-methyl-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide [ka]

[0380] Methyl 3-((3-bromo-5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(methylamino)phenyl)amino)-3-oxopropanoate (12a) To a solution of 3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(methylamino)benzamide (6c, 300 mg, 0.713 mmol) and methyl 3-chloro-3-oxopropanoate (107.11 mg, 0.784 mmol, 83.68 μL, 1.1 eq) in DCM, TEA (72.17 mg, 0.713 mmol, 99.27 μL, 1 eq) was added dropwise. The mixture was heated to 30°C and stirred for 0.5 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to obtain 12a as a brown solid.

[0381] Methyl 2-(7-bromo-5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-1-methyl-1H-benzo[d]imidazole-2-yl)acetate (12b) A solution of methyl 3-((3-bromo-5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(methylamino)phenyl)amino)-3-oxopropanoate (12a, 130 mg, 0.25 mmol) in AcOH was heated to 60°C and stirred for 6 hours. LC-MS showed that the reactants were completely consumed, and one major peak with the desired mass was detected. The mixture was poured into RINKAN, and the mixture was washed with water, saturated NaHCO3, and brine. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by preparative TLC to obtain 12b as a yellow solid.

[0382] 7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide (12c) Methyl 2-(7-bromo-5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-1-methyl-1H-benzo[d]imidazole-2-yl) acetate (12b, 50 mg, 0.099 mmol, 1 eq) was slowly added in one go to a solution of THF with LiBH4 (10.83 mg, 0.497 mmol, 5 eq) at 20°C under N2. The mixture was heated to 30°C and stirred for 50 minutes. LC-MS showed that the reactants were completely consumed, and one major peak with the desired mass was detected. After cooling the reaction mixture to 0°C, the reaction mixture was quenched by the addition of H2O and acidified to pH=6 with 1N HCl. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative TLC (SiO2, ethyl acetate:methanol = 10:1) to obtain 12c as a yellow solid.

[0383] N-(4-(chlorodifluoromethoxy)phenyl)-2-(2-hydroxyethyl)-1-methyl-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide (12) 7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide (12c, 40 mg, 0.084 mmol, 1 eq) and pyrimidine-5-ylboronic acid (12e, 20.88 mg, 0.169 mmol, 2 eq) were added in a mixture of dioxane (3 mL) and H2O (0.3 mL) at 20°C under N2, along with Pd(dppf)Cl2 (6.17 mg, 8.43 mmol, 0.1 eq) and K3PO4 (53.66 mg, 0.253 mmol, 3 eq). The mixture was heated to 110°C and stirred for 12 hours. LC-MS showed that the reactants were completely consumed, and one major peak with the desired mass was detected. The mixture was filtered through a Celite® pad, and the filtrate was concentrated to obtain the crude product, which was purified by preparative HPLC (FA conditions, column: Waters Atlantis T3 150*30*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 10%-50%, 13 min) to obtain compound 12 of the title as a white solid. Calculated value of MSmas [M+1] + (C 22 H 18 ClF2N5O3) has a m / z of 474.1 and an LCMS detection value of m / z of 474.0; 1 H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 9.33 (s, 1H), 9.07 (s, 2H), 8.40 (s, 1H), 7.94 (d, J = 9.2 Hz, 2H), 7.77 (s, 1H), 7.37 (d, J = 9.0 Hz, 2H), 4.89 (t, J = 5.6 Hz, 1H), 3.96-3.86 (m, 2H), 3.41 (s, 3H), 3.07 (t, J = 6.9 Hz, 2H).

[0384] Example 13 N 5 -(4-(chlorodifluoromethoxy)phenyl)-N 7-Cyclopropyl-1-isopropyl-1H-benzo[d]imidazole-5,7-dicarboxamide [ka]

[0385] Methyl 5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-1-isopropyl-1H-benzo[d]imidazole-7-carboxylate (13b) 7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (10a, 200 mg, 0.436 mmol, 1 eq) and TEA (176.49 mg, 1.74 mmol, 242.76 μL, 4 eq) were added in a mixture of MeOH (20 mL) to a mixture of Pd(PPh3)4 (50.39 mg, 0.044 mmol, 0.1 eq) under N2 at 20°C. The mixture was heated to 100°C and stirred under CO (0.436 mmol, 3 MPa) for 24 hours. LC-MS showed that approximately 60% of the reaction product remained. LC-MS revealed one new peak, detecting approximately 30% of the target compound. HPLC showed that approximately 60% of the reaction product remained. The mixture was filtered through a Celite® pad, and the filtrate was concentrated to obtain the crude product. The residue was purified by preparative HPLC (NH4HCO3, column: YMC-Actus Triart C18 100*30mm*5um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 45%-65%, 12 min) to obtain 13b as a white solid. 1 H NMR (400 MHz, MeOD-d4) δ 8.64 (s, 1H), 8.54 (d, J = 1.7 Hz, 1H), 8.45 (d, J = 1.7 Hz, 1H), 7.90-7.84 (m, 2H), 7.33 (d, J = 9.0 Hz, 2H), 5.40 (td, J = 6.6, 13.3 Hz, 1H), 4.06 (s, 3H), 1.62 (d, J = 6.7 Hz, 6H).

[0386] 5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-1-isopropyl-1H-benzo[d]imidazole-7-carboxylic acid (13c) Methyl 5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-1-isopropyl-1H-benzo[d]imidazole-7-carboxylate (13b, 10 mg, 0.023 mmol, 1 eq) was added in a single batch to a mixture of THF (1 mL), H2O (1 mL), and MeOH (0.5 mL) at 20 °C, with LiOH·H2O (1.92 mg, 0.046 mmol, 2 eq). The mixture was heated to 45 °C and stirred for 2 hours. LC-MS showed that the reactants were completely consumed, and one major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was poured into H2O (0.5 mL) and acidified to pH=5 with 1N HCl. The mixture was filtered, the filter cake was washed with 0.5 mL of H2O, and dried under vacuum to obtain the crude product. A crude residue 13c was obtained as a white solid and used in the next step without further purification.

[0387] N 5 -(4-(chlorodifluoromethoxy)phenyl)-N 7 -Cyclopropyl-1-isopropyl-1H-benzo[d]imidazole-5,7-dicarboxamide (13) To a mixture of 5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-1-isopropyl-1H-benzo[d]imidazole-7-carboxylic acid (13c, 40 mg, 0.094 mmol, 1 eq) and cyclopropanamine (6.47 mg, 0.113 mmol, 7.85 μL, 1.2 eq) in DMF (2 mL), HATU (39.48 mg, 0.104 mmol, 1.1 eq) and DIEA (24.40 mg, 0.189 mmol, 32.88 μL, 2 eq) were added in one batch at 20°C. The mixture was stirred at 20°C for 12 hours. LC-MS showed a residual 40% of the reaction product. LC-MS revealed one new peak, indicating 60% of the target compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. siRNA (15 mL) was added to the residue. The organic layer was washed with H2O (10 mL) and saline solution (10 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product. The residue was purified by preparative TLC (SiO2, siRNA:MeOH = 10:1) to obtain compound 13 as a white solid. Calculated value of MSmas [M+1] + (C 22 H 21 ClF2N4O3) with m / z 463.1, LCMS detection value m / z 463.1; 1 H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.88 (d, J = 4.3 Hz, 1H), 8.61 (s, 1H), 8.48 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 9.0 Hz, 2H), 7.89 (d, J = 1.6 Hz, 1H), 7.37 (d, J = 9.0 Hz, 2H), 4.96 (quin, J = 6.7 Hz, 1H), 3.02-2.87 (m, 1H), 1.50 (d, J = 6.7 Hz, 6H), 0.85-0.70 (m, 2H), 0.65-0.56 (m, 2H).

[0388] Example 14 N-(4-(chlorodifluoromethoxy)phenyl)-1-((1-hydroxycyclopropyl)methyl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide [ka]

[0389] Methyl 3-bromo-4-(((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)amino)-5-nitrobenzoate (14b) A mixture of methyl 3-bromo-4-(((1-hydroxycyclopropyl)methyl)amino)-5-nitrobenzoate (synthesized by the same method as 1c; 14a, 0.48 g, 1.39 mmol, 1 eq), imidazole (142.02 mg, 2.09 mmol, 1.5 eq), and TBDPSCl (458.70 mg, 1.67 mmol, 428.69 uL, 1.2 eq) in 5 mL of DCM at 25°C was stirred for 16 hours at 25°C. 10 mL of water was added, and the mixture was extracted with 3 x 20 mL of DCM. The organic layer was dried over Na2SO4 and concentrated to obtain the crude product. The crude residue was purified by column chromatography to obtain 1c as a yellow oil. 1 H NMR (400 MHz, CDCl3-d) δ 8.43 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.55-7.48 (m, 4H), 7.39-7.28 (m, 6H), 6.94-6.84 (m, 1H), 3.85 (s, 3H), 2.92 (d, J = 4.4 Hz, 2H), 0.89 (s, 9H), 0.84-0.79 (m, 2H), 0.39-0.29 (m, 2H).

[0390] Methyl 3-amino-5-bromo-4-(((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)amino)benzoate (14c) A solution of methyl 3-bromo-4-(((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)amino)-5-nitrobenzoate (14b, 634 mg, 1.09 mmol, 1 eq) and Fe (606.79 mg, 10.86 mmol, 10 eq) in AcOH (7 mL) was stirred at 35°C for 1 hour. SiO (20 mL) was added, and the mixture was filtered. The filtrate was washed with water (20 mL x 3), the organic layer was dried over Na₂SO₄, and the mixture was concentrated. Compound 14c was obtained as a yellow oil and required no further purification. 1 H NMR (400 MHz, chloroform-d) δ 7.67-7.63 (m, 4H), 7.54 (d, J = 1.7 Hz, 1H), 7.37-7.30 (m, 6H), 7.17 (d, J = 1.8 Hz, 1H), 3.79 (s, 3H), 2.84 (s, 2H), 1.00-0.98 (m, 9H), 0.76-0.67 (m, 2H), 0.33-0.21 (m, 2H).

[0391] Methyl 7-bromo-1-((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)-1H-benzo[d]imidazole-5-carboxylate (14d) A solution of methyl 3-amino-5-bromo-4-(((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)amino)benzoate (14c, 0.6g, 1.08 mmol, 1eq) and TsOH (18.66 mg, 0.108 mmol, 0.1eq) in CH(OMe)3 (10 mL) was stirred at 100°C for 1 hour. The crude product was washed with TMBE / PE, the mixture was filtered, and the solid was concentrated. No further purification was required. Compound 14d was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3-d) δ 8.46 (s, 1H), 8.38 (s, 1H), 8.12 (s, 1H), 7.61 (d, J = 7.1 Hz, 4H), 7.48-7.41 (m, 2H), 7.39-7.33 (m, 4H), 4.52 (s, 2H), 3.98 (s, 3H), 1.05-0.93 (m, 11H), 0.67-0.54 (m, 2H).

[0392] Methyl 1-((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)-7-(pyridine-3-yl)-1H-benzo[d]imidazole-5-carboxylate (14f) Methyl 7-bromo-1-((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)-1H-benzo[d]imidazole-5-carboxylate (14d, 440 mg, 0.781 mmol, 1 eq) and 12e (116.09 mg, 0.934 mmol, 1.2 eq) were dissolved in dioxane (5 mL) and H2O (1 mL). K3PO4 (497.19 mg, 2.34 mmol, 3 eq) and Pd(dppf)Cl2 (28.56 mg, 0.039 mmol, 0.05 eq) were added under N2. The mixture was stirred at 100°C for 4 hours. The mixture was concentrated, and the residue was purified by column chromatography. Compound 14f was obtained as a yellow solid. 1 H NMR (400 MHz, CDCl3-d) δ 9.20 (s, 1H), 8.60-8.52 (m, 2H), 8.39 (s, 2H), 7.70 (d, J = 1.5 Hz, 1H), 7.34-7.23 (m, 6H), 7.16-7.09 (m, 4H), 3.92 (s, 3H), 3.36 (s, 2H), 0.87-0.76 (m, 11H), 0.30-0.23 (m, 2H).

[0393] 1-((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)-7-(pyridine-3-yl)-1H-benzo[d]imidazole-5-carboxylic acid (14g) Methyl 1-((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)-7-(pyridine-3-yl)-1H-benzo[d]imidazole-5-carboxylate (14f, 360 mg, 0.64 mmol, 1 eq) was added to a solution of THF (3 mL), MeOH, and H2O (2 mL) at 25°C with LiOH·H2O (40.26 mg, 0.96 mmol, 1.5 eq). The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure. Water (5 mL) was added, and the mixture was extracted with HCl (10 mL). Aqueous HCl (1 M) solution was added until the aqueous phase reached pH = 3-4. The aqueous phase was extracted again with HCl (10 mL x 3), and the organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude product. No further purification was required. A red solid, 14 g of the compound was obtained.

[0394] 1-((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)-N-(4-(chlorodifluoromethoxy)phenyl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide (14i) To a solution of 1-((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)-7-(pyridine-3-yl)-1H-benzo[d]imidazole-5-carboxylic acid (14 g, 90 mg, 0.164 mmol, 1 eq) and 1 h (38.10 mg, 0.197 mmol, 1.2 eq) in DMF (3 mL), DIPEA (63.59 mg, 0.492 mmol, 85.71 μL, 3 eq) and HATU (93.55 mg, 0.246 mmol, 1.5 eq) were added at 25 °C. The mixture was stirred at 25 °C for 12 hours. RINKAN (10 mL) was added, and the mixture was washed with water (10 mL x 5). The organic layer was dried over Na₂SO₄ and concentrated to obtain the crude product. The residue was purified by column chromatography. Compound 14i was obtained as a pale yellow solid.

[0395] N-(4-(chlorodifluoromethoxy)phenyl)-1-((1-hydroxycyclopropyl)methyl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide (14) 1-((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)-N-(4-(chlorodifluoromethoxy)phenyl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide (14i, 0.03g, 0.041 mmol, 1eq) was dissolved in 3 mL of dry THF, and TBAF (1M, 41.42 μL, 1eq) was added under N2 conditions at 25°C. The mixture was stirred and concentrated at 25°C for 2 hours. The residue was purified by preparative HPLC (NH4HCO3 conditions, column: Waters Xbridge Prep OBD C18 150*30 10u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 35%-55%, 10 min) to obtain compound 14 as a yellow solid. Calculated value of MSmas [M+1] + (C 23 H 18 ClF2N5O3) with a m / z of 486.1, and LCMS detection value of m / z 486.1; 1 H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.33 (s, 1H), 9.04 (s, 2H), 8.53 (s, 2H), 7.98-7.93 (m, J = 9.2 Hz, 2H), 7.81 (s, 1H), 7.42-7.33 (m, J = 9.0 Hz, 2H), 5.46 (s, 1H), 3.94 (s, 2H), 0.61-0.52 (m, 2H), 0.49-0.41 (m, 2H).

[0396] Example 15 N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-2-(difluoromethyl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide [ka]

[0397] Methyl 3-bromo-4-(cyclopropylamino)-5-(2,2-difluoroacetamide)benzoate (15c) To a solution of methyl 3-amino-5-bromo-4-(cyclopropylamino)benzoate (synthesized by the same method as 1d; 15a, 200 mg, 0.701 mmol, 1 eq) in DCM (8 mL), TEA (212.93 mg, 2.10 mmol, 3 eq) and 2,2-difluoroacetic anhydride (15b) (122.08 mg, 0.701 mmol, 1 eq) were added at 0°C. The mixture was stirred at 15°C for 2 hours under an N2 atmosphere. Detection of the peak with the desired MS was shown by LC-MS. The reaction mixture was concentrated. The crude product was subjected to preparative TLC (petroleum ether:ethyl acetate = 3:1, R f Purified using (=0.4), 15c was obtained as a yellow solid.

[0398] Methyl 7-bromo-1-cyclopropyl-2-(difluoromethyl)-1H-benzo[d]imidazole-5-carboxylate (1d) AcOH (1.32 mg, 0.022 mmol, 10 eq) was added to a solution of 15d (80 mg, 0.220 mmol, 1 eq) in toluene (3 mL). The mixture was stirred at 60°C for 16 hours. LC-MS showed a peak with the desired MS. The reaction mixture was concentrated, and the crude product was subjected to preparative TLC (petroleum ether:ethyl acetate = 1:1, R). f Purified using (=0.4), 15d was obtained as a yellow solid. 1 H NMR (400 MHz, CDCl3-d) δ 8.43 (d, J = 1.3 Hz, 1H), 8.29 (d, J = 1.3 Hz, 1H), 7.18-6.85 (m, 1H), 3.97 (s, 3H), 3.70-3.60 (m, 1H), 1.46-1.39 (m, 2H), 1.39-1.34 (m, 2H)

[0399] 7-Bromo-1-cyclopropyl-2-(difluoromethyl)-1H-benzo[d]imidazole-5-carboxylic acid (15e) To a solution of 15d (1520 mg, 0.058 mmol, 1 eq) in THF (1 mL), MeOH (1 mL), and H2O (0.5 mL), LiOH·H2O (4.86 mg, 0.116 mmol, 2 eqs) was added. The mixture was stirred at 50°C for 2 hours. LC-MS showed a peak with the desired MS. The mixture was concentrated and poured into H2O (1 mL), and the pH was adjusted to 5 with HCl (1 M, in H2O). The mixture was concentrated again to obtain 15e as a yellow solid. 1 H NMR (400 MHz, CDCl3-d) δ 8.49 (s, 1H), 8.32 (d, J = 1.3 Hz, 1H), 7.04-6.89 (m, 1H), 3.65 (br dd, J = 3.4, 7.2 Hz, 1H), 1.46-1.41 (m, 2H), 1.37 (br s, 2H).

[0400] 7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-2-(difluoromethyl)-1H-benzo[d]imidazole-5-carboxamide (15g) A mixture of 15e (18 mg, 0.054 mmol, 1 eq), 1h (15.79 mg, 0.082 mmol, 1.5 eq), HATU (31.01 mg, 0.082 mmol, 1.5 eq), and DIEA (21.08 mg, 0.163 mmol, 3 eq) in DMF (1 mL) was stirred at 15°C for 2 hours. LC-MS showed peaks with the desired MS. The reaction mixture was concentrated, and the crude product was subjected to preparative TLC (petroleum ether:ethyl acetate = 2:1, R). f Purified using (=0.5), 15 g of a yellow solid was obtained. 1H NMR (400 MHz, CDCl3-d) δ 8.20 (d, J = 1.5 Hz, 1H), 8.16 (d, J = 1.5 Hz, 1H), 7.85 (s, 1H), 7.72 (d, J = 9.0 Hz, 2H), 7.30 (br s, 2H), 7.04 (s, 1H), 3.72 (br s, 1H), 1.47-1.42 (m, 2H), 1.37 (br d, J = 4.4 Hz, 2H).

[0401] N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-2-(difluoromethyl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide (15) A mixture of 15 g (35 mg, 0.069 mmol, 1 eq) of pyrimidine-5-ylboronic acid (25.68 mg, 0.207 mmol, 3 eq), Pd(dppf)Cl2 (5.05 mg, 6.91 mmol, 0.01 eq), and K3PO4 (43.99 mg, 0.207 mmol, 3 eq) in dioxane (2 mL) and H2O (0.2 mL) was degassed and purged three times with N2. The reaction mixture was stirred at 100°C for 8 hours under an N2 atmosphere. LC-MS showed peaks with the desired MS. The reaction mixture was concentrated, and the crude product was subjected to preparative TLC (petroleum ether:ethyl acetate = 0:1, R). f The compound 15, as indicated in the title, was purified using a solution of 0.45 (=0.45) and obtained as a white solid. Calculated MSmas [M+H] + (C 23 H 16 ClF4N5O2) was detected at m / z 506.1, and the LCMS detection value was also m / z 506.1. 1H NMR (400 MHz, CH3OD-d4) δ 9.29 (s, 1H), 9.15 (s, 2H), 8.50 (d, J = 1.5 Hz, 1H), 8.02 (d, J = 1.5 Hz, 1H), 7.86 (d, J = 9.0 Hz, 2H), 7.48-7.21 (m, 3H), 3.45 (td, J = 3.3, 7.1 Hz, 1H), 0.80 (br s, 2H), 0.60 (br d, J = 6.6 Hz, 2H).

[0402] Example 16 N-(4-(chlorodifluoromethoxy)phenyl)-1-(1-hydroxy-2-methylpropan-2-yl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide [ka]

[0403] Methyl 3-bromo-4-((1-hydroxy-2-methylpropan-2-yl)amino)-5-nitrobenzoate (16b) A mixture of methyl 3-bromo-4-fluoro-5-nitrobenzoate (1a, 300 mg, 1.08 mmol), 2-amino-2-methylpropan-1-ol (115.41 mg, 1.29 mmol), and TEA (131.02 mg, 1.29 mmol) in EtOH (5 mL) was stirred at 15°C for 3 hours. The reaction mixture was concentrated, and the crude product was subjected to preparative TLC (petroleum ether:ethyl acetate = 3:1, R). f By refining using the method (=0.5), 16b was obtained as a yellow oil. 1 H NMR (400 MHz, CDCl3-d) δ 8.41 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 5.06 (br s, 1H), 3.95 (s, 3H), 3.48 (s, 2H), 1.19 (s, 6H).

[0404] Methyl 4-((1-hydroxy-2-methylpropan-2-yl)amino)-3-nitro-5-(pyrimidine-5-yl)benzoate (16d) A mixture of dioxane (4 mL) and H2O (0.4 mL) containing 16b (200 mg, 0.576 mmol), 16c (142.76 mg, 1.15 mmol), Pd(dppf)Cl2 (21.08 mg, 0.029 mmol), and K3PO4 (366.86 mg, 1.73 mmol) was degassed and purged three times with N2. The mixture was stirred at 110°C for 6 hours under an N2 atmosphere. LC-MS showed peaks with the desired MS. The reaction mixture was concentrated, and the crude product was subjected to preparative TLC (petroleum ether:ethyl acetate = 0:1, R). f Purified using (=0.4), 16d was obtained as a yellow solid. 1 H NMR (400 MHz, CDCl3-d) δ 9.25 (s, 1H), 9.02 (s, 2H), 8.63 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 5.79 (s, 1H), 4.02-3.93 (m, 3H), 3.15 (br s, 2H), 0.76 (s, 6H).

[0405] Methyl 3-amino-4-((1-hydroxy-2-methylpropan-2-yl)amino)-5-(pyrimidine-5-yl)benzoate (16e) To a solution of 16d (70 mg, 0.202 mmol) in EtOH (4 mL), Fe (112.87 mg, 2.02 mmol) and NH4Cl (108.11 mg, 2.02 mmol) were added. The mixture was stirred at 80°C for 0.5 hours. LC-MS showed peaks with the desired MS. The mixture was filtered through a Celite® pad, and the filtrate was concentrated. The crude product was subjected to preparative TLC (petroleum ether:ethyl acetate = 10:1, R). f Purified using (=0.3), 16e was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3-d) δ 9.19 (s, 1H), 8.90 (s, 2H), 7.48 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 3.91 (s, 3H), 3.50 (s, 2H), 3.25 (s, 2H), 0.76 (s, 6H).

[0406] Methyl 1-(1-(dimethoxymethoxy)-2-methylpropan-2-yl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxylate (16f) To a solution of 16e (20 mg, 0.063 mmol) in trimethoxymethane (1.94 g, 18.24 mmol), PTSA (1.09 mg, 6.32 mmol) was added. The mixture was stirred at 80°C for 1 hour. LC-MS showed a peak with the desired MS. The reaction mixture was concentrated, and the crude residue was separated and subjected to preparative TLC (ethyl acetate:methanol = 10:1, R). f By refining it using the method (=0.4), 16f was obtained as a yellow oil. 1 H NMR (400 MHz, CDCl3-d) δ 9.33 (s, 1H), 8.84 (s, 2H), 8.60 (s, 1H), 8.31 (s, 1H), 7.70 (s, 1H), 4.85 (s, 1H), 3.96 (s, 3H), 3.58 (s, 2H), 3.09 (s, 6H), 1.44 (s, 5H), 1.42 (br s, 1H).

[0407] Methyl 1-(1-hydroxy-2-methylpropan-2-yl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxylate (16g) To a 16f (10 mg, 0.025 mmol) solution in MeOH (2 mL), HCl (0.1 M, 499.47 μL) was added. The mixture was stirred at 15°C for 3 hours. LC-MS revealed a peak with the desired MS. The reaction mixture was concentrated to obtain 16 g of yellow oil. The product was used in the next step without purification.

[0408] 1-(1-hydroxy-2-methylpropan-2-yl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid (16h) LiOH·H2O (3.86 mg, 0.092 mmol) was added to a 16 g (10 mg, 0.031 mmol) solution of MeOH (1 mL), THF (1 mL), and H2O (0.5 mL). The mixture was stirred at 50°C for 3 hours. LC-MS showed a peak with the desired MS. The mixture was concentrated, and the residue was poured into H2O (1 mL). The pH of the solution was adjusted to 4, and HCl (1 M, in H2O) was added to obtain 16H as a white solid. The product was used in the next step without further purification.

[0409] N-(4-(chlorodifluoromethoxy)phenyl)-1-(1-hydroxy-2-methylpropan-2-yl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide (16) A mixture of 16h (10 mg, 0.032 mmol), 4-(chlorodifluoromethoxy)aniline (1 h), HATU (18.26 mg, 0.048 mmol), and DIEA (12.41 mg, 0.096 mmol) in DMF (1 mL) was stirred at 15°C for 3 hours. LC-MS showed a peak with the desired MS. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (NH4HCO3, column: Agela Durashell C18 150*25 5u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 35%-65%, 10 min) to obtain compound 16 as a white solid. Calculated value of MSmas [M+1] + (C 23 H 20 ClF2N5O3) has a m / z of 488.1, and the LCMS detection value is also m / z 488.1. 1H NMR (400 MHz, MeOD-d4) δ 9.31 (s, 1H), 8.98 (s, 2H), 8.55 (s, 1H), 8.47 (d, J = 1.8 Hz, 1H), 7.83 (d, J = 9.0 Hz, 2H), 7.71 (d, J = 1.8 Hz, 1H), 7.29 (d, J = 9.0 Hz, 2H), 3.56 (s, 2H), 1.41 (s, 6H).

[0410] Example 17 N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-fluoro-1H-pyrazole-5-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide [ka]

[0411] 4-Fluoro-1-(4-methoxybenzyl)-1H-pyrazole (17b) To a solution of 4-fluoro-1H-pyrazole (17a, 1g, 11.62 mmol) in THF (15 mL), NaH (697.06 mg, 17.43 mmol, 60% purity) was added at 0°C. After stirring for 10 minutes, 1-(chloromethyl)-4-methoxybenzene (2.18 g, 13.94 mmol) was slowly added to the reaction mixture. The resulting solution was stirred at 15°C for 16 hours. TLC (petroleum ether:ethyl acetate = 5:1, R) f The formation of new spots was indicated by (=0.4). LC-MS showed a peak with the desired MS. The reaction mixture was concentrated. H2O (20 mL) was added to the residue, and the aqueous phase was extracted with ethyl acetate (60 mL). The organic layer was washed with brine (5 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1~30:1) to obtain 17b as a yellow oil. 1H NMR (400 MHz, CDCl3-d) δ 7.35 (d, J = 4.0 Hz, 1H), 7.21-7.17 (m, 3H), 6.91-6.87 (m, 2H), 5.14 (s, 2H), 3.81 (s, 3H).

[0412] 5-Bromo-4-fluoro-1-(4-methoxybenzyl)-1H-pyrazole (17d) To a 15 mL solution of 17b (850 mg, 4.12 mmol) in THF, a solution of n-BuLi (2.5 M, 2.47 mL, 1.5 eq) was slowly added at -70°C. The mixture was stirred for 15 minutes, maintaining a temperature below -60°C. A 1 mL solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (17c, 1.61 g, 4.95 mmol) in THF was added to the reaction mixture, and the resulting solution was subsequently stirred for a further 2 hours. TLC (petroleum ether:ethyl acetate = 3:1, R) f The formation of new spots was indicated by (0.6). LC-MS showed a peak with the desired MS. The reaction mixture was quenched by adding water, H2O (20 mL), and then ethyl acetate (80 mL) was added. After quenching the reaction, the reaction mixture was poured into a separatory funnel and separated. The organic layer was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 45:1~10:1) to obtain 17d as a yellow solid. 1 H NMR (400 MHz, CDCl3-d) δ 7.43 (d, J = 4.8 Hz, 1H), 7.20 (d, J = 8.8 Hz, 2H), 6.89-6.85 (m, 2H), 5.23 (s, 2H), 3.80 (s, 3H).

[0413] 4-Fluoro-1-(4-methoxybenzyl)-5-(trimethylstannyl)-1H-pyrazole (17e) A mixture of 17d (300 mg, 1.05 mmol), trimethyl(trimethylstannyl)stannan (413.68 mg, 1.26 mmol), and Pd(PPh3)4 (121.59 mg, 0.105 mmol) in toluene (5 mL) was degassed and purged three times with N2. The mixture was stirred at 130°C for 16 hours under an N2 atmosphere. TLC (petroleum ether:ethyl acetate = 3:1, R f The formation of new spots was shown by (=0.7). Detection of the peak with the desired MS was shown by LC-MS. The reaction mixture was quenched by adding KF (5 mL), and then ethyl acetate (40 mL) was added. After quenching the reaction, the reaction mixture was poured into a separatory funnel and separated. The organic layer was concentrated, and the residue was separated by preparative TLC (petroleum ether:ethyl acetate = 3:1, R f By refining it using the method (=0.7), 17e was obtained as a yellow oil. 1 H NMR (400 MHz, CDCl3-d) δ 7.40 (d, J = 4.8 Hz, 1H), 6.92 (t, J = 8.4 Hz, 2H), 6.88-6.83 (m, 2H), 5.21 (s, 2H), 3.79 (s, 3H), 0.25 (s, 9H).

[0414] N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-fluoro-1-(4-methoxybenzyl)-1H-pyrazole-5-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (17g) A mixture of 7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (10a, 74.58 mg, 0.163 mmol), 17e (120.00 mg, 0.325 mmol), and Pd(PPh3)4 (37.58 mg, 0.033 mmol) in DMSO (3 mL) was degassed and purged three times with N2. The mixture was stirred at 100°C for 16 hours under an N2 atmosphere. LC-MS showed detection of a peak with the desired MS. The mixture was quenched by the addition of water (40 mL), and the mixture was extracted with ethyl acetate (60 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain the crude product. Crude residue, preparative TLC (ethyl acetate:methanol = 10:1, R f After purification using a solution of 0.6, 17 g of yellow oil was obtained. 1 H NMR (400 MHz, CDCl3-d) δ 8.49 (d, J = 1.5 Hz, 1H), 8.13-8.08 (m, 1H), 7.87 (s, 1H), 7.72 (s, 2H), 7.61-7.56 (m, 2H), 7.49 (s, 2H), 7.28 (br s, 1H), 6.77 (d, J = 8.6 Hz, 2H), 6.70-6.65 (m, 2H), 5.70-5.57 (m, 1H), 5.10-4.92 (m, 3H), 3.91-3.78 (m, 2H), 3.66 (s, 3H), 1.67 (d, J = 6.6 Hz, 2H), 1.34 (d, J = 6.6 Hz, 3H), 1.15 (d, J = 6.6 Hz, 3H).

[0415] N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-fluoro-1H-pyrazole-5-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (17) A 17g (80mg, 0.137 mmol) TFA (2mL) solution was stirred at 15°C for 16 hours. LC-MS revealed the presence of the peak with the desired MS. The reaction mixture was concentrated. The crude residue was separated and subjected to preparative TLC (ethyl acetate:methanol = 10:1, R). f The compound 17, as indicated in the title, was obtained as a white solid by purification using a solution of 0.4. Calculated MSmas [M+H] + (C 21 H 17 (ClF3N5O2) m / z 464.1, LCMS detection value m / z 464.0. 1 H NMR (400 MHz, MeOD-d4) δ 8.56 (br s, 1H), 8.43 (br s, 1H), 7.93 (d, J = 1.8 Hz, 1H), 7.87-7.80 (m, 3H), 7.29 (d, J = 9.0 Hz, 2H), 4.67 (br s, 1H), 1.43 (d, J = 6.6 Hz, 6H).

[0416] Example 18 N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-7-(4-fluoro-1H-pyrazole-5-yl)-1H-benzo[d]imidazole-5-carboxamide [ka]

[0417] N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-7-(4-fluoro-1-(4-methoxybenzyl)-1H-pyrazole-5-yl)-1H-benzo[d]imidazole-5-carboxamide (18b) Pd(PPh3)4 (12.65 mg, 0.011 mmol, 0.05 eq) was added to a mixture of 7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-1H-benzo[d]imidazole-5-carboxamide (synthesized by the same method as 10a; 18a, 100 mg, 0.219 mmol, 1 eq) and 4-fluoro-1-(4-methoxybenzyl)-5-(trimethylstannyl)-1H-pyrazole (17e, 80.81 mg, 0.219 mmol, 1 eq) in DMSO (1.5 mL). The reaction mixture was stirred at 100 °C for 16 hours. LC-MS showed detection of a peak with the desired MS. The mixture was poured into water (10 mL) and extracted with ELISA (10 mL x 2). The combined organic layers are concentrated and preparatively separated into TLC (Â1:MeOH = 10:1, R2). f By refining it using a solution of 0.6, 18b was obtained as a yellow oil.

[0418] N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-7-(4-fluoro-1H-pyrazole-5-yl)-1H-benzo[d]imidazole-5-carboxamide (18) N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-7-(4-fluoro-1-(4-methoxybenzyl)-1H-pyrazole-5-yl)-1H-benzo[d]imidazole-5-carboxamide (18b, 120 mg, 0.206 mmol, 1 eq) was dissolved in TFA (3 mL). The reaction mixture was stirred at 20°C for 2 hours. LC-MS revealed the detection of a peak with the desired MS. The solvent was evaporated under vacuum, and the residue was dissolved in HCl (5 mL). The organic layer was washed with saturated NaHCO3 (2 mL) and saline (2 mL), concentrated to obtain a crude residue, which was then separated by preparative TLC (HCl:MeOH = 10:1, R) f The compound 18, as indicated in the title, was obtained as a white solid by purification using a solution of 0.3. Calculated MSmas [M+H] + (C 21 H 15(ClF3N5O2) m / z 462.1, LCMS detection value m / z 462.0. 1 H NMR (400 MHz, CDCl3-d) δ9.55 (br s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.92 (s, 1H), 7.82-7.75 (m, 2H), 7.50 (d, J = 4.6 Hz, 1H), 7.22 (br d, J = 8.8 Hz, 2H), 3.42 (br d, J = 3.3 Hz, 1H), 0.80-0.63 (m, 4H).

[0419] Example 19 N-(4-(chlorodifluoromethoxy)phenyl)-1-(1,1-dioxidethiethane-3-yl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide [ka]

[0420] N-(4-(chlorodifluoromethoxy)phenyl)-7-(pyrimidine-5-yl)-1-(thietan-3-yl)-1H-benzo[d]imidazole-5-carboxamide (19c) 7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(thietan-3-yl)-1H-benzo[d]imidazole-5-carboxamide (19a, 130 mg, 0.266 mmol, 1 eq), pyrimidine-5-ylboronic acid (synthesized by the same method as in 2c; 19b, 98.87 mg, 0.798 mmol, 3 eq), and K3PO4 (169.38 mg, 0.798 mmol, 3 eq) were mixed in dioxane (2 mL) and H2O (0.2 mL) with N2, to which Pd(dppf)Cl2 (19.46 mg, 0.27 mmol, 0.1 eq) was added. The mixture was stirred at 100°C for 16 hours. The desired MS was shown by LC-MS. The mixture was poured into water and then extracted with RINKAN. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The residue was separated by preparative TLC (ethyl acetate:methanol = 10:1, R f Purified using (=0.30), 19c was obtained as a white solid. 1 H NMR (400 MHz, CDCl3-d) δ 9.36 (s, 1H), 8.82 (s, 2H), 8.43 (s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.71 (s, 1H), 7.66 (br d, J = 8.8 Hz, 2H), 7.22 (br s, 2H), 5.06 (quin, J = 8.2 Hz, 1H), 3.63 (t, J = 9.0 Hz, 2H), 3.14 (t, J = 9.0 Hz, 2H).

[0421] N-(4-(chlorodifluoromethoxy)phenyl)-1-(1,1-dioxidethiethane-3-yl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide (19) N-(4-(chlorodifluoromethoxy)phenyl)-7-(pyrimidine-5-yl)-1-(thietan-3-yl)-1H-benzo[d]imidazole-5-carboxamide (19c, 40 mg, 0.082 mmol, 1 eq) was dissolved in DCM (2 mL) and a saturated sodium bicarbonate aqueous solution and mCPBA (70.74 mg, 0.328 mmol, 80% purity, 4 eq) were added at 0°C. The reaction mixture was stirred at 15°C for 16 hours. The desired MS was shown by LC-MS. The mixture was poured into water and then extracted with EtOAC. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the desired product. The residue was separated by preparative TLC (ethyl acetate:methanol = 10:1, R f The compound 19, as indicated in the title, was purified using a solution of 0.37 (=0.37) and obtained as a white solid. Calculated value of MSmas [M+1] + (C 22 H 16 The detection value for ClF2N5O4S was m / z 520.1, and the LCMS detection value was m / z 520.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 9.38 (s, 1H), 9.03 (s, 2H), 8.83 (s, 1H), 8.55 (s, 1H), 7.95 (br d, J = 8.8 Hz, 2H), 7.88-7.77 (m, 1H), 7.38 (br d, J = 8.6 Hz, 2H), 4.94-4.83 (m, 1H), 4.74 (br d, J = 13.2 Hz, 2H), 4.41-4.26 (m, 2H).

[0422] Example 20 N-(4-(chlorodifluoromethoxy)phenyl)-6-fluoro-1-isopropyl-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide [ka]

[0423] Methyl 2-fluoro-4-(isopropylamino)-5-nitrobenzoate (20b) To a solution of methyl 2,4-difluoro-5-nitrobenzoate (20a, 2g, 9.21 mmol, 1eq) in THF (10 mL), TEA (2.80 g, 27.63 mmol, 3.85 mL, 3eq) was added dropwise at 15°C, followed by the addition of propan-2-amine (653.37 mg, 11.05 mmol, 949.67 μL, 1.2 eq). The resulting mixture was stirred at 0°C for 1 hour. TLC (petroleum ether: siRNA = 5:1, R f A value of 0.50 indicated that 20a was completely consumed, and one major new spot was detected. The aqueous phase was extracted with siRNA (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The product was used in the next step without further purification. Compound 20b was obtained as a yellow solid. 1 H NMR (400 MHz, CDCl3-d) δ 8.91 (d, J = 7.8 Hz, 1H), 8.29 (br d, J = 4.9 Hz, 1H), 6.52 (d, J = 13.7 Hz, 1H), 3.90 (s, 3H), 3.83-3.70 (m, 1H), 1.36 (d, J = 6.4 Hz, 6H).

[0424] Methyl 3-bromo-2-fluoro-4-(isopropylamino)-5-nitrobenzoate (20c) To a solution of methyl 2-fluoro-4-(isopropylamino)-5-nitrobenzoate (20b, 2g, 7.81 mmol, 1eq) in DCM (5mL), Br2 (2.00g, 12.51 mmol, 645.16uL, 1.60eq) was added. The mixture was stirred at 0°C for 1 hour. TLC (petroleum ether:ethyl = 5:1, R) fA reaction (0.50) indicated that 20b was completely consumed. The reaction mixture was quenched by adding saturated Na2SO3 (5 mL). The residue was diluted with H2O (20 mL) and extracted by DCM (10 mL x 3). The combined organic layers were washed with saline (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1) to obtain 20c as a yellow solid. 1 H NMR (400 MHz, CDCl3-d) δ8.72 (d, J = 7.3 Hz, 1H), 4.49-4.34 (m, 1H), 3.93 (s, 3H), 1.29-1.27 (m, 6H).

[0425] Methyl 5-amino-3-bromo-2-fluoro-4-(isopropylamino)benzoate (20d) To a solution of methyl 3-bromo-2-fluoro-4-(isopropylamino)-5-nitrobenzoate (20c, 1g, 2.98 mmol, 1eq) in EtOH (20 mL), Fe (1.67 g, 29.84 mmol, 10 eq) and NH4Cl (1.60 g, 29.84 mmol, 1.04 mL, 10 eq) were added. The mixture was stirred at 80°C for 6 hours. TLC (petroleum ether:ethyl acetate = 3:1) showed that the 20c had been completely consumed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saline solution (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1~1:1). Compound 20d was obtained as a brown oil. 1 H NMR (400 MHz, CDCl3-d) δ 7.21 (d, J = 6.8 Hz, 1H), 3.90 (s, 3H), 3.80-3.71 (m, 1H), 1.17 (d, J = 6.4 Hz, 6H).

[0426] Methyl 7-bromo-6-fluoro-1-isopropyl-1H-benzo[d]imidazole-5-carboxylate (20e) To a solution of methyl 5-amino-3-bromo-2-fluoro-4-(isopropylamino)benzoate (20d, 180 mg, 0.590 mmol, 1 eq) in CH(OMe)3 (2 mL), p-TsOH (10.16 mg, 0.059 mmol, 0.1 eq) was added. The mixture was stirred at 100 °C for 1.5 hours. TLC (petroleum ether:ethyl acetate = 1:1) showed that 20d was completely consumed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (20 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with saline solution (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1:1). Compound 20e was obtained as a white solid. 1 H NMR (400 MHz, CDCl3-d) δ 8.34 (d, J = 5.9 Hz, 1H), 8.15 (s, 1H), 5.64 (quind, J = 6.7, 13.4 Hz, 1H), 3.97 (s, 3H), 1.65 (d, J = 6.4 Hz, 6H).

[0427] 7-Bromo-6-fluoro-1-isopropyl-1H-benzo[d]imidazole-5-carboxylic acid (20f) Methyl 7-bromo-6-fluoro-1-isopropyl-1H-benzo[d]imidazole-5-carboxylate (20e, 140 mg, 0.444 mmol, 1 eq) was dissolved in THF (5 mL), MeOH (5 mL), and H2O (2 mL), to which LiOH·H2O (46.60 mg, 1.11 mmol, 2.5 eq) was added. The mixture was stirred at 50°C for 12 hours. TLC (petroleum ether:ethyl acetate = 1:1) showed that 20e was completely consumed. The mixture was adjusted to pH=5 with HCl water (1 M), concentrated to obtain 20f as a white solid, and used in the next step without further purification.

[0428] 7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-fluoro-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (20g) To a solution of 7-bromo-6-fluoro-1-isopropyl-1H-benzo[d]imidazole-5-carboxylic acid (20f, 70 mg, 0.232 mmol, 1 eq) in DMF (2 mL), HATU (106.07 mg, 0.279 mmol, 1.2 eq), 4-[chloro(difluoro)methoxy]aniline (1h, 49.50 mg, 0.256 mmol, 1.1 eq), and DIEA (90.13 mg, 0.697 mmol, 121.47 μL, 3 eq) were added. The mixture was stirred at 50°C for 3 hours. TLC (petroleum ether:ethyl acetate = 1:1) showed that the 20f had been completely consumed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (10 mL) and extracted with siRNA (10 mL × 3). The combined organic layers were washed with saline solution (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 10 / 1 to 1:1). 20 g of the compound was obtained as a white solid. 1H NMR (400 MHz, MeOD-d4) δ 8.57 (s, 1H), 8.01 (d, J = 6.4 Hz, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 9.3 Hz, 2H), 5.70 (td, J = 6.7, 13.6 Hz, 1H), 1.67 (d, J = 6.8 Hz, 6H).

[0429] N-(4-(chlorodifluoromethoxy)phenyl)-6-fluoro-1-isopropyl-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide (20) To a solution of 7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-fluoro-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (20 g, 50 mg, 0.105 mmol, 1 eq) in dioxane (2.5 mL) and H2O (0.5 mL), Pd(dppf)Cl2 (7.68 mg, 0.01 mmol, 0.1 eq), pyrimidine-5-ylboronic acid (38.99 mg, 0.315 mmol, 3 eq), and K3PO4 (66.80 mg, 0.315 mmol, 3 eq) were added. The mixture was stirred at 100°C for 6 hours. LC-MS showed that 20 g was completely consumed, and one major peak with the desired MS was detected. The mixture was concentrated to obtain the crude product. The residue was purified by preparative HPLC (NH4HCO3 conditions, column: Waters Xbridge 150*50 10u; mobile phase: [water (10mM NH4HCO3)-MeOH]; B%: 55%-75%, 12 min) to obtain compound 20 as a white solid. Calculated MSmas [M+H] + (C 22 H 17 ClF3N5O2) with a m / z of 476.1, and LCMS detection value of m / z 476.1; 1H NMR (400 MHz, CDCl3-d) δ 9.42 (s, 1H), 8.93 (s, 2H), 8.74 (d, J = 7.3 Hz, 1H), 8.44 (br d, J = 15.7 Hz, 1H), 8.18 (s, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H), 3.96 (td, J = 6.8, 13.3 Hz, 1H), 1.38 (d, J = 6.8 Hz, 6H).

[0430] Example 21 N-(4-(chlorodifluoromethoxy)phenyl)-1-(2-(cyclopropylamino)-2-oxoethyl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide [ka]

[0431] 7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(2-(cyclopropylamino)-2-oxoethyl)-1H-benzo[d]imidazole-5-carboxamide (21c) A mixture of 7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1H-benzo[d]imidazole-5-carboxamide (synthesized by the same method as in 2c; 21a, 80 mg, 0.192 mmol, 1 eq) and 2-chloro-N-cyclopropylacetamide (21b, 30.78 mg, 0.230 mmol, 1.2 eq) in DMF (1 mL) was mixed with K2CO3 (18.58 mg, 0.134 mmol, 0.7 eq) under N2. The mixture was stirred at 80°C for 4 hours. TLC (ethyl acetate:methanol = 10:1, R) f The reaction was terminated by a reaction of 0.32. The mixture was poured into water (20 mL) and then extracted with siRNA (20 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain the crude product. The residue was separated by preparative TLC (ethyl acetate:methanol = 10:1, R₂f Purified using (=0.32), 21c was obtained as a white solid. 1 H NMR (400 MHz, MeOD-d4) δ 8.21 (d, J = 6.2 Hz, 2H), 8.01 (s, 1H), 7.74 (d, J = 8.9 Hz, 2H), 7.20 (br d, J = 8.9 Hz, 2H), 5.19 (s, 2H), 2.61 (dt, J = 3.7, 7.5 Hz, 1H), 0.65 (br d, J = 5.1 Hz, 2H), 0.46 (br d, J = 2.4 Hz, 2H).

[0432] N-(4-(chlorodifluoromethoxy)phenyl)-1-(2-(cyclopropylamino)-2-oxoethyl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide (21) To a solution of 7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(2-(cyclopropylamino)-2-oxoethyl)-1H-benzo[d]imidazole-5-carboxamide (21c, 10 mg, 0.019 mmol, 1 eq) and pyrimidine-5-ylboronic acid (21d, 4.82 mg, 0.039 mmol, 2 eq) in dioxane (2 mL) and H2O (0.4 mL), Pd(dppf)Cl2 (1.42 mg, 1.95 mmol, 0.1 eq) and K3PO4 (12.40 mg, 0.058 mmol, 3 eq) was added. The reaction mixture was stirred at 100°C for 6 hours. LC-MS showed detection of peaks with the desired MS. The reaction mixture was concentrated, and the residue was dissolved in toluene (5 mL) and washed with H₂O (2 mL) and saline solution (5 mL). The organic layer was concentrated and purified by preparative TLC (toluene:MeOH = 5:1) to obtain compound 21 as a white solid. Calculated MSmas [M+H] + (C 24 H 19 ClF2N6O3) with a m / z of 513.1, and LCMS detection value of m / z 513.1. 1H NMR (400 MHz, MeOD-d4) δ 8.91 (s, 1H), 8.54 (s, 2H), 8.08 (d, J = 1.5 Hz, 1H), 7.91 (s, 1H), 7.50-7.41 (m, 3H), 6.92 (d, J = 9.0 Hz, 2H), 4.32 (s, 2H), 2.05 (tt, J = 3.9, 7.2 Hz, 1H), 0.31-0.21 (m, 2H), 0.01-0.00 (m, 2H).

[0433] Example 22 (General Method I) N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(thiazole-4-yl)-1H-benzo[d]imidazole-5-carboxamide The title compound was prepared using a similar coupling reaction outlined in Scheme 9. This general method I illustrates Scheme 9 and provides specific synthetic details applicable to the title compound. [ka]

[0434] N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(thiazole-4-yl)-1H-benzo[d]imidazole-5-carboxamide (22) 7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (10a, 100 mg, 0.218 mmol, 1 eq), tributyl(thiazole-4-yl)stannan (22b, 97.89 mg, 0.262 mmol, 1.2 eq), and Pd(PPh3)4 (25.19 mg, 0.022 mmol, 0.1 eq) were added to a microwave tube containing dioxane (4 mL). The sealed tube was heated under microwave irradiation at 150°C for 3 hours. Water (5 mL) was added to the reaction mixture and extracted with SiO2 (10 mL x 2). The combined organic layers were concentrated, and the crude residue was purified by preparative HPLC (TFA conditions, column: Luna C18 100*30 5u; mobile phase: [water (0.1% TFA)-ACN]; B%: 15%-50%, 10 min) to obtain compound 22 as a yellow solid. Calculated value of MSmas [M+1] + (C 21 H 17 The molecular weight (ClF2N4O2S) is 463.1 m / z, and the LCMS detection value is 463.0 m / z. 1 H NMR (400 MHz, CDCl3-d) δ 8.95-8.91 (m, 1H), 8.86 (d, J = 1.6 Hz, 1H), 8.40 (s, 1H), 8.03 (s, 1H), 7.84 (s, 1H), 7.74 (br d, J = 8.8 Hz, 2H), 7.50 (d, J = 1.6 Hz, 1H), 7.24-7.15 (m, 2H), 4.53 (td, J = 6.6, 13.3 Hz, 1H), 1.26 (d, J = 6.6 Hz, 6H).

[0435] Example 23 N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(4H-1,2,4-triazole-4-yl)-1H-benzo[d]imidazole-5-carboxamide [ka]

[0436] N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-((4-methoxybenzyl)amino)-1H-benzo[d]imidazole-5-carboxamide (23b) To a mixture of 7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (10a, 900 mg, 1.96 mmol) and DME (15 mL), PMBNH2 (323.00 mg, 2.35 mmol, 304.71 μL), NaOBu-t (565.70 mg, 5.89 mmol), XPhos (93.54 mg, 0.196 mmol), and Pd2(dba)3 (179.68 mg, 0.196 mmol) were added. The mixture was stirred at 100°C for 12 hours under an N2 atmosphere. LC-MS showed detection of a peak with the desired MS. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (5 mL) and extracted with  (5 mL × 3). The combined organic layers were washed with saline solution (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1, 1 / 3) to obtain 23b as a yellow solid. Calculated value of MSmas [M+1] + (C 26 H 25 ClF2N4O3) with a m / z of 515.2, and LCMS detection value of m / z 515.2. 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.38-8.36 (m, 1H), 7.93-7.89 (m, 2H), 7.78 (d, J = 1.2 Hz, 1H), 7.38 (d, J = 8.6 Hz, 2H), 7.33 (br d, J = 9.0 Hz, 2H), 7.04 (s, 1H), 6.91 (d, J = 8.7 Hz, 2H), 6.01-5.94 (m, 1H), 5.32-5.23 (m, 1H), 4.40 (br d, J = 5.3 Hz, 2H), 3.72 (s, 3H), 1.57 (d, J = 6.5 Hz (6H).

[0437] 7-amino-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (23c) A solution of N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-((4-methoxybenzyl)amino)-1H-benzo[d]imidazole-5-carboxamide (23b, 100 mg, 0.194 mmol) in HCl / dioxane (40 mL) was stirred at 20°C for 12 hours. LC-MS detected the desired MS. The reaction mixture was concentrated under reduced pressure. The mixture was purified by preparative HPLC (NH4HCO3 conditions, column: Agela Durashell C18 150*25 5u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 35%-65%, 10 min) to obtain 23c as a yellow solid. Calculated value of MSmas [M+1] + (C 18 H 17 (ClF2N4O2) m / z 395.1, LCMS detection value m / z 395.1. 1H NMR (400 MHz, MeOD-d4) δ 8.34 (br s, 1H), 7.82 (d, J = 9.0 Hz, 2H), 7.69 (d, J = 1.6 Hz, 1H), 7.29 (d, J = 9.2 Hz, 2H), 7.23 (d, J = 1.6 Hz, 1H), 5.25-5.12 (m, 1H), 1.66 (d, J = 6.7 Hz, 6H).

[0438] N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(4H-1,2,4-triazol-4-yl)-1H-benzo[d]imidazole-5-carboxamide (23) To a solution of 7-amino-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (23c, 14 mg, 0.035 mmol) and N-formamideformamide (9.37 mg, 0.106 mmol) in pyridine (1.5 mL), chloro-trimethyl-silane (57.79 mg, 0.532 mmol, 67.51 μL) and TEA (25.12 mg, 0.248 mmol, 34.55 μL) were added. The mixture was stirred at 100 °C for 18 hours. LC-MS showed that 23c was completely consumed, and one major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Atlantis T3 150*30*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 20%-60%, 13 min) to obtain compound 23 as a white solid. Calculated value of MSmas [M+1] + (C 20 H 17 (ClF2N6O2) m / z 447.1, LCMS detection value m / z 447.1. 1H NMR (400 MHz, CDCl3-d) δ 8.50-8.45 (m, 3H), 8.23 ​​(s, 2H), 7.91 (d, J = 1.0 Hz, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.29 (br d, J = 9.3 Hz, 2H), 3.74-3.61 (m, 1H), 1.45 (d, J = 6.4 Hz, 6H).

[0439] Example 24 (General Method J) (S)-N-(4-(chlorodifluoromethoxy)phenyl)-1-(5-oxopyrrolidine-3-yl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide This general method J provides specific synthetic details applicable to the compound in the title. By changing the coupling reagent, additional compounds can be prepared according to this method. [ka]

[0440] 3-Bromo-4-fluoro-5-nitrobenzoic acid (24b) To a solution of 4-fluoro-3-nitrobenzoic acid (24a, 5g, 27.01 mmol) in H2SO4 (30 mL), NBS (5.77 g, 32.41 mmol) was added. The mixture was stirred at 60°C for 6 hours. The mixture was then added to ice-cold water (2 L) with vigorous stirring. The precipitate was filtered to obtain 24b as a white solid. 1 H NMR (400 MHz, CDCl3-d) δ 8.72 (dd, J = 2.2, 6.4 Hz, 1H), 8.58 (dd, J = 2.2, 5.5 Hz, 1H).

[0441] 3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluoro-5-nitrobenzamide (24c) A suspension of 3-bromo-4-fluoro-5-nitrobenzoic acid (24b, 150 mg, 0.568 mmol) in SOCl2 (2 mL) was stirred at 60°C for 3 hours. The mixture was concentrated to obtain 3-bromo-4-fluoro-5-nitrobenzoyl chloride (214 mg, crude) as a white solid. 3-bromo-4-fluoro-5-nitrobenzoyl chloride (213.97 mg, 0.758 mmol) was added to a mixture of 4-(chlorodifluoromethoxy)aniline (1 h, 146.64 mg, 0.758 mmol) and pyridine (89.89 mg, 1.13 mmol, 91.72 μL) in THF (2 mL) under N2. The mixture was stirred at 20°C for 3 hours. The desired MS was shown by LC-MS. The mixture was extracted with ethyl acetate (2 mL x 3), the combined organic layer was washed with saline solution (5 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was then separated into preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, R f The compound was purified using a solution of 0.3. Compound 24c was obtained as a white solid.

[0442] (S)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-5-nitro-4-((5-oxopyrrolidine-3-yl)amino)benzamide (24e) A mixture of 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluoro-5-nitrobenzamide (24c, 100 mg, 0.228 mmol) and (4S)-4-aminopyrrolidine-2-one (24d, 22.78 mg, 0.228 mmol) in EtOH (2 mL) was mixed with TEA (69.06 mg, 0.682 mmol, 94.99 μL). The mixture was stirred at 50°C for 3 hours. The desired MS was shown by LC-MS. The mixture was concentrated and preparative TLC (SiO2, petroleum ether:ethyl acetate = 3:1, R) was performed. f Purified using (=0.1), 24e was obtained as a yellow solid. 1H NMR (400 MHz, MeOD-d4) δ 8.62 (d, J = 2.2 Hz, 1H), 8.45 (d, J = 2.2 Hz, 1H), 7.84-7.80 (m, 2H), 7.30 (d, J = 8.8 Hz, 2H), 4.64 (br s, 1H), 3.80 (dd, J = 6.8, 10.7 Hz, 1H), 3.39 (dd, J = 4.2, 10.7 Hz, 1H), 2.80 (dd, J = 7.9, 17.1 Hz, 1H), 2.41 (dd, J = 4.8, 17.1 Hz, 1H).

[0443] (S)-3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((5-oxopyrrolidine-3-yl)amino)benzamide (24f) (S)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-5-nitro-4-((5-oxopyrrolidine-3-yl)amino)benzamide (24e, 0.053 g, 0.102 mmol) was mixed with AcOH (1 mL), and Fe (56.95 mg, 1.02 mmol) was added all at once under N2 at 20 °C. The mixture was stirred at 35 °C for 2 hours. The desired MS was shown by LC-MS. The mixture was poured into saturated NaHCO3 and extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with saline solution (5 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 24f as a yellow solid.

[0444] (S)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(5-oxopyrrolidine-3-yl)-1H-benzo[d]imidazole-5-carboxamide (24g) To a mixture of (S)-3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((5-oxopyrrolidine-3-yl)amino)benzamide (24 f, 0.0358 g, 73.11 mmol) and CH(OMe)3 (2 mL), TsOH (1.26 mg, 7.31 ml) was added all at once under N2 at 20°C, and the mixture was stirred at 20°C for 30 minutes. The desired MS was shown by LC-MS. The mixture was extracted with ethyl acetate (3 mL x 2), the combined organic layers were washed with saline solution (5 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 24 g of a yellow solid.

[0445] (S)-N-(4-(chlorodifluoromethoxy)phenyl)-1-(5-oxopyrrolidine-3-yl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide (24) (S)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(5-oxopyrrolidine-3-yl)-1H-benzo[d]imidazole-5-carboxamide (24 g, 35.3 mg, 0.071 mmol) and pyrimidine-5-ylboronic acid (17.51 ​​mg, 0.141 mmol) were mixed with H2O (0.1 mL) and dioxane (1 mL). Under N2, Pd(dppf)Cl2 (5.17 mg, 7.06 mmol) and K3PO4 (29.99 mg, 0.141 mmol) were added all at once. The mixture was stirred at 100°C for 12 hours. The desired MS was shown by LC-MS. The mixture was extracted with ethyl acetate (3 mL x 3), the combined organic layers were washed with saline solution (5 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was then separated into preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:5, R f By purification using (=0.1), the compound 24 described in the title was obtained as a brown solid. Calculated value of MS mass [M+1]+ (C 23 H 17 ClF2N6O3) has a m / z of 499.1, and the LCMS detection value is also m / z 499.1. 1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.90 (br s, 2H), 8.49 (s, 1H), 8.40 (s, 1H), 8.10 (s, 1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.28 (br s, 2H), 6.12 (br s, 1H), 4.69 (br s, 1H), 3.65 (dd, J = 6.5, 11.1 Hz, 1H), 3.51 (br d, J = 11.7 Hz, 1H), 2.82-2.60 (m, 2H).

[0446] Example 25 N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)-1H-benzo[d]imidazole-5-carboxamide [ka]

[0447] N-(4-(chlorodifluoromethoxy)phenyl)-7-cyano-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (25b) A solution of 7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (10a, 0.15 g, 0.327 mmol), Zn(CN)2 (57.60 mg, 0.491 mmol, 31.14 μL), and Pd(PPh3)4 (18.89 mg, 0.016 mmol) in DMF (3 mL) was placed in a microwave tube. The sealed tube was heated under microwave irradiation at 150 °C for 2 hours. The desired MS was shown by LC-MS. The mixture was extracted with ethyl acetate (2 mL x 3), the combined organic layers were washed with saline solution (5 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f Purified using (=0.67), 1b was obtained as a white solid. 1 H NMR (400 MHz, CDCl3-d) δ 8.52 (s, 1H), 8.30-8.21 (m, 2H), 8.09 (s, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H), 5.32 (spt, J = 6.7 Hz, 1H), 1.72 (d, J = 6.6 Hz, 6H).

[0448] (Z)-N-(4-(chlorodifluoromethoxy)phenyl)-7-(N'-hydroxycarbamimidoyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (25c) N-(4-(chlorodifluoromethoxy)phenyl)-7-cyano-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (25b, 20 mg, 0.049 mmol) was dissolved in DMF (3 mL), to which NH2OH.HCl (34.33 mg, 0.494 mmol) and TEA (49.99 mg, 0.49 mmol, 68.76 μL) were added. The mixture was stirred at 75°C for 12 hours. The desired MS was shown by LC-MS. The aqueous phase was extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saline solution (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was separated by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f Purified using (=0.5), 25c was obtained as a white solid. Calculated value of MSmas [M+1] + (C 19 H 18 The detection value for ClF2N5O3 was m / z 438.1, and the LCMS detection value was m / z 438.3.

[0449] N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)-1H-benzo[d]imidazole-5-carboxamide (25) (Z)-N-(4-(chlorodifluoromethoxy)phenyl)-7-(N'-hydroxycarbamimidoyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (25c, 0.02g, 0.046 mmol) was dissolved in THF (2 mL) and bis(2,5-dioxopyrrolidine-1-yl) carbonate (15.21 mg, 0.059 mmol) and TEA (9.24 mg, 0.091 mmol, 12.72 μL) were added under N2 conditions. The mixture was stirred at 60°C for 12 hours. The desired MS was shown by LC-MS. The aqueous phase was extracted with ethyl acetate (3 mL x 3), and the combined organic layers were washed with saline solution (5 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Residue, preparative TLC (SiO2, ethyl acetate:methanol = 10:1, R f By purification using (=0.1), the compound 25 described in the title was obtained as a yellow solid. Calculated value of MSmas [M+1] + (C 20 H 16 ClF2N5O4) with a m / z of 464.1, LCMS detection value m / z 464.1; 1 H NMR (400 MHz, MeOD-d4) δ 8.55 (s, 1H), 8.43 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.85 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 8.9 Hz, 2H), 5.25 (td, J = 6.6, 13.3 Hz, 1H), 1.53 (d, J = 6.7 Hz, 6H).

[0450] Example 26 N 5 -(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5,7-dicarboxamide [ka]

[0451] N 5-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5,7-dicarboxamide (26) N-(4-(chlorodifluoromethoxy)phenyl)-7-cyano-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (25b, 30 mg, 0.074 mmol) was dissolved in DMSO (3 mL), to which NH2OH.HCl (41.20 mg, 0.593 mmol) and TEA (13.86 mg, 0.137 mmol) were added. The mixture was stirred at 80°C for 12 hours. The desired MS was shown by LC-MS. The aqueous phase was extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saline solution (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was separated by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f The compound 26, as indicated in the title, was obtained as a white solid by purification using a solution of 0.5. Calculated value of MSmas [M+1] + (C 19 H 17 The measured value for ClF2N4O3 was m / z 423.1, and the LCMS detection value was m / z 423.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.62 (s, 1H), 8.48 (d, J = 1.6 Hz, 1H), 8.27 (s, 1H), 7.98 (d, J = 1.7 Hz, 1H), 7.97-7.94 (m, 2H), 7.78 (s, 1H), 7.37 (d, J = 9.0 Hz, 2H), 5.09 (quin, J = 6.6 Hz, 1H), 1.52 (s, 3H), 1.50 (s, 3H).

[0452] Example 27 N-(4-(chlorodifluoromethoxy)phenyl)-3-isopropyl-4-(pyrimidine-5-yl)-3H-imidazo[4,5-c]pyridine-6-carboxamide [ka]

[0453] Methyl 4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-carboxylate (27b) To a solution of methyl 4-chloro-3H-imidazo[4,5-c]pyridine-6-carboxylate (27a, 200 mg, 0.945 mmol) and 2-iodopropane (482.01 mg, 2.84 mmol, 283.53 uL) in DMF (3 mL) was added K2CO3 (391.88 mg, 2.84 mmol). The mixture was stirred at 30°C for 16 hours. LCMS indicated that 27a was completely consumed, and the target MS was detected. The mixture was diluted with water (5 mL), and extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate=1:2) to give 27c as a white solid. 1 H NMR (400 MHz, CDCl3-d) δ 8.54 (s, 1H), 8.30 (s, 1H), 5.60-5.42 (m, 1H), 4.04 (s, 3H), 1.70 (d, J = 6.7 Hz, 6H).

[0454] Methyl 3-isopropyl-4-(pyrimidin-5-yl)-3H-imidazo[4,5-c]pyridine-6-carboxylate (27c) Methyl 4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-carboxylate (27b, 70 mg, 0.276 mmol) and pyrimidine-5-ylboronic acid (68.38 mg, 0.552 mmol) were dissolved in dioxane (1 mL) and H2O (0.1 mL). Pd(dppf)Cl2 (20.19 mg, 27.59 mmol) and K3PO4 (175.71 mg, 0.828 mmol) were added to the solution. The mixture was stirred under N2 at 110°C for 16 hours. LC-MS showed that 27b was completely consumed and the MS of the desired component was detected. The mixture was diluted with water (5 mL) and extracted with RINKAN (5 mL x 3). The combined organic layers were washed with saline (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:methanol = 10:1) to obtain 27c as a white solid. 1 H NMR (400 MHz, MeOD-d4) δ 9.36 (s, 1H), 9.13 (s, 2H), 8.82 (s, 1H), 8.56 (s, 1H), 4.36-4.23 (m, 1H), 4.01 (s, 3H), 1.45 (d, J = 6.6 Hz, 6H).

[0455] 3-Isopropyl-4-(pyrimidine-5-yl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (27d) To a solution of methyl 3-isopropyl-4-(pyrimidine-5-yl)-3H-imidazo[4,5-c]pyridine-6-carboxylate (27c, 35 mg, 0.118 mmol) in THF (0.5 mL), MeOH (0.5 mL), and H2O (0.25 mL), LiOH·H2O (9.88 mg, 0.235 mmol) was added. The mixture was stirred at 20°C for 2 hours. TLC (ethyl acetate:methanol = 10:1, R) f= 0.0) indicated that 27c was completely consumed, and one major new spot with higher polarity was detected. The mixture was concentrated under vacuum. The mixture was then added to H2O (3 mL), and the aqueous phase was acidified to pH = 5 with aqueous HCl. The mixture was concentrated under vacuum. The product was used in the next step without further purification. Compound 27d was obtained as a white solid. 1 1H NMR (400 MHz, MeOD-d4) δ 9.69 (s, 1H), 9.46 (s, 1H), 9.22 (s, 2H), 8.80-8.67 (m, 1H), 4.42 (s, 1H), 1.50 (d, J = 6.6 Hz, 6H).

[0456] N-(4-(chlorodifluoromethoxy)phenyl)-3-isopropyl-4-(pyrimidin-5-yl)-3H-imidazo[4,5-c]pyridine-6-carboxamide (27) To a solution of 3-isopropyl-4-(pyrimidin-5-yl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (27d, 32 mg, 0.113 mmol) and 1h (32.80 mg, 0.169 mmol) in DMF (2 mL) was added DIEA (43.80 mg, 0.339 mmol, 59.03 uL) and HATU (51.54 mg, 0.136 mmol). The mixture was stirred at 25°C for 4 hours. LCMS indicated that 27d was completely consumed, and the desired MS was detected. The mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1) to give 27 as a white solid. Calculated MS mass [M+H] + (C 21 H 17 O2N6ClF2) m / z 459.1, found m / z 459.0 by LCMS. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.42 (s, 1H), 9.30 (s, 2H), 8.94 (s, 1H), 8.50 (s, 1H), 8.05-7.95 (m, 2H), 7.37 (d, J = 9.0 Hz, 2H), 4.38-4.09 (m, 1H), 1.38 (d, J = 6.7 Hz, 6H).

[0457] Example 28 (General Method K) (R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-fluoropropan-2-yl)-7-(1H-pyrazole-5-yl)-1H-benzo[d]imidazole-5-carboxamide This general method K provides specific synthetic details applicable to the compound in the title. By changing the coupling reagent, additional compounds can be prepared according to this method. [ka]

[0458] N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-((R)-1-fluoropropan-2-yl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-yl)-1H-benzo[d]imidazole-5-carboxamide (28b) (R)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-fluoropropan-2-yl)-1H-benzo[d]imidazole-5-carboxamide (synthesized by the same method as 15 g; 28a, 30 mg, 0.057 mmol) and 1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (63.38 mg, 0.228 mmol) were dissolved in DME (1.5 mL), EtOH (1.5 mL), and H2O (0.3 mL), to which Pd(PPh3)2Cl2 (4.00 mg, 5.70 ml) and Na2CO3 (12.07 mg, 0.114 mmol) were added. The mixture was stirred at 80°C for 2 hours. LC-MS showed that 28a was completely consumed, and the desired MS was detected. The mixture was diluted with water (5 mL) and extracted with toluene (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO₂, petroleum ether:ethyl acetate = 2:1) to obtain 28b as a yellow solid.

[0459] (R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-fluoropropan-2-yl)-7-(1H-pyrazole-5-yl)-1H-benzo[d]imidazole-5-carboxamide (28) To a solution of N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-((R)-1-fluoropropan-2-yl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-yl)-1H-benzo[d]imidazole-5-carboxamide (28b, 25 mg, 0.042 mmol) in DCM (1 mL), TFA (1.54 g, 13.51 mmol, 1 mL) was added. The mixture was stirred at 20°C for 1 hour. LC-MS showed that 28b was completely consumed and the MS of the target was detected. The mixture was diluted with water (5 mL) and extracted with RINKAN (5 mL x 3). The combined organic layers were washed with saline (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to obtain 28 as a white solid. Calculated MSmas [M+H] + (C 22 H 17 (O2N5ClF5) m / z 514.1, LCMS detection value m / z 514.1. 1 H NMR (400 MHz, MeOD-d4) δ 8.47 (d, J = 1.3 Hz, 1H), 7.98 (d, J = 1.7 Hz, 1H), 7.88 (br s, 1H), 7.87-7.81 (m, 2H), 7.44-7.15 (m, 3H), 6.66 (d, J = 2.2 Hz, 1H), 4.70-4.67 (m, 1H), 4.63-4.45 (m, 2H), 1.52 (br d, J = 7.2 Hz, 3H).

[0460] Example 29 N-(4-(chlorodifluoromethoxy)phenyl)-6-(pyrimidine-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]thiadin-8-carboxamide 2,2-dioxide [ka]

[0461] 6-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]thiazine-8-carboxamide 2,2-dioxide (29b) Oxone (5.03 mg, 8.18 mg) was added to a solution of 6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]thiazine-8-carboxamide (8 g synthesized by the same method as 29a, 2 mg, 4.09 umol) in acetone (0.5 mL) and H2O (0.1 mL). The mixture was stirred at 20°C for 24 hours. TLC (petroleum ether:ethyl acetate = 0:1, R) f A reaction (=0.77) indicated that 29a was completely consumed, and one major new spot of high polarity was detected. The reaction was quenched with sodium sulfide. The reaction mixture was concentrated under reduced pressure and acetone was removed. The residue was diluted with H2O (10 mL) and extracted with siRNA (10 mL × 3). The combined organic layers were washed with saline (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1) to obtain 29b as a brown solid. 1 H NMR (400 MHz, MeOD-d4) δ 8.18 (d, J = 1.5 Hz, 1H), 8.05 (d, J = 1.5 Hz, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.20 (br d, J = 8.8 Hz, 2H), 5.17-5.12 (m, 2H), 5.08 (s, 2H), 3.81-3.75 (m, 2H).

[0462] N-(4-(chlorodifluoromethoxy)phenyl)-6-(pyrimidine-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]thiadin-8-carboxamide 2,2-dioxide (29) A mixture of 6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]thiazine-8-carboxamide 2,2-dioxide (29b, 6 mg, 0.012 mmol), pyrimidine-5-ylboronic acid (4.28 mg, 0.035 mmol), Pd(dppf)Cl2 (843.09 ug, 1.15 umol), and K3PO4 (7.34 mg, 0.035 mmol) with dioxane (1 mL) and H2O (0.1 mL) was degassed, purged three times with N2, and then stirred under an N2 atmosphere at 110°C for 16 hours. TLC (petroleum ether:ethyl acetate = 0:1, R f A reaction of 0.3 indicated that 29b was completely consumed, and one major new spot of high polarity was detected. The reaction mixture was concentrated and the dioxane was removed under reduced pressure. The residue was diluted with H2O (1 mL) and extracted with ethyl acetate (1 mL × 3). The combined organic layers were washed with saline (1 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 0:1) to obtain 29 as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 9.33 (s, 1H), 9.09 (s, 2H), 8.45 (d, J = 1.0 Hz, 1H), 7.91 (d, J = 9.3 Hz, 2H), 7.83 (d, J = 1.5 Hz, 1H), 7.36 (d, J = 8.8 Hz, 2H), 5.09 (s, 2H), 4.12 (br t, J = 5.9 Hz, 2H), 3.75 (br t, J = 5.6 Hz, 2H).

[0463] Example 30 (General Method L) N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide This general method L provides specific synthetic details applicable to the compound in the title. Additional compounds can be prepared according to this method by changing the coupling reagents and / or deprotection reagents. [ka]

[0464] N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazole-5-carboxamide (30a) To a mixture of 7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (10a, 80 mg, 0.174 mmol) and ethinyl(trimethyl)silane (85.65 mg, 0.872 mmol, 120.81 uL) in TEA (1 mL), CuI (3.32 mg, 0.017 mmol) and Pd(PPh3)2Cl2 (12.24 mg, 0.017 mmol) were added under N2, and the mixture was stirred at 80°C for 2 hours. The desired MS was shown by LC-MS. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saline solution (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Residue, preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, R f Purified using the method described by (=0.4), 30a was obtained as a white solid. 1 H NMR (400 MHz, CDCl3-d) δ 8.31 (s, 1H), 8.15 (br d, J = 7.2 Hz, 2H), 8.00 (s, 1H), 7.75 (br d, J = 8.9 Hz, 2H), 7.30-7.27 (m, 2H), 5.65 (td, J = 6.8, 13.4 Hz, 1H), 1.66 (d, J = 6.7 Hz, 6H), 0.31 (s, 9H).

[0465] N-(4-(chlorodifluoromethoxy)phenyl)-7-ethynyl-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (30b) N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazole-5-carboxamide (30a, 70 mg, 0.147 mmol) was mixed with MeOH (2 mL) and K2CO3 (40.65 mg, 0.294 mmol, 2 eq). The mixture was stirred at 20°C for 0.5 hours. TLC (petroleum ether:ethyl acetate = 1:1, R) f A ratio of 0.5 indicated that 30a had been consumed, and one major new spot of high polarity was detected. The mixture was concentrated and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saline solution (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was separated into preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f Purified using (=0.5), 30b was obtained as a yellow solid. 1 H NMR (400 MHz, CDCl3-d) δ 8.33 (d, J = 1.6 Hz, 1H), 8.22-8.13 (m, 2H), 8.06 (d, J = 1.5 Hz, 1H), 7.78-7.72 (m, 2H), 7.29 (s, 2H), 5.68-5.49 (m, 1H), 3.44 (s, 1H), 1.66 (d, J = 6.7 Hz, 6H).

[0466] N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-yl)-1H-benzo[d]imidazole-5-carboxamide (30c) N-(4-(chlorodifluoromethoxy)phenyl)-7-ethynyl-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (30b, 50 mg, 0.124 mmol) and 1-(azidomethyl)-4-methoxybenzene (22.23 mg, 0.136 mmol) were added to a mixture of THF (1 mL) and H2O (1 mL) under N2, with CuSO4·5H2O (1.55 mg, 6.19 mmol) and sodium (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-oleate (2.45 mg, 0.012 mmol). The mixture was stirred at 20°C for 3 hours. The desired MS was shown by LC-MS. The mixture was extracted with ethyl acetate (3 mL × 3). The combined organic layers were washed with saline solution (5 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was then separated into preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f Purified using (=0.4), 30c was obtained as a yellow solid. 1 H NMR (400 MHz, CDCl3-d) δ 8.28 (s, 1H), 8.20 (s, 1H), 8.09 (br s, 1H), 7.79-7.66 (m, 4H), 7.32 (br d, J = 8.4 Hz, 2H), 7.26-7.25 (m, 1H), 6.95 (d, J = 8.4 Hz, 2H), 5.59 (s, 2H), 5.11-5.02 (m, 1H), 3.84 (s, 3H), 1.36 (d, J = 6.7 Hz, 6H).

[0467] N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide (30) A mixture of N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-yl)-1H-benzo[d]imidazole-5-carboxamide (30c, 40mg, 0.071 mmol) and TFA (3 mL) was stirred at 60°C for 12 hours. The desired MS was shown by LC-MS. The mixture was concentrated and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saline solution (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was separated by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f Purified using (=0.3), 30 was obtained as an off-white solid. Calculated value of MSmas [M+1] + (C 20 H 17 ClF2N6O2) has a m / z of 447.1 and an LCMS detection value of m / z of 447.0; 1 H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.62 (s, 1H), 8.48 (d, J = 1.3 Hz, 1H), 8.31 (br s, 1H), 7.95 (d, J = 9.0 Hz, 2H), 7.85 (d, J = 1.3 Hz, 1H), 7.36 (d, J = 9.0 Hz, 2H), 4.63 (br s, 1H), 1.32 (d, J = 6.6 Hz, 6H).

[0468] Example 31 (General Method M) N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-cyano-1H-pyrazole-3-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide This general method M provides specific synthetic details applicable to the compound in the title. Additional compounds can be prepared according to this method by changing the coupling reagents and / or deprotection reagents. [ka]

[0469] N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(trimethylstannyl)-1H-benzo[d]imidazole-5-carboxamide (31a) 7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (10a, 94.7 mg, 0.206 mmol) and trimethyl(trimethylstannyl)stannane (270.57 mg, 0.826 mmol, 171.25 μL) were mixed in toluene (3 mL) and Pd(PPh3)4 (23.86 mg, 0.021 mmol) under N2. The mixture was stirred at 130 °C for 12 hours. The desired MS was shown by LC-MS. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with saline solution (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was separated by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, R f By refining it using the method described by (=0.4), 31a was obtained as a colorless oil.

[0470] N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (31b) N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(trimethylstannyl)-1H-benzo[d]imidazole-5-carboxamide (31a, 50 mg, 0.92 mmol) and 3-iodo-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carbonitrile (64.37 mg, 0.184 mmol) were mixed in DMSO (3 mL) and Pd(PPh3)4 (10.65 mg, 9.22 mmol) under N2. The mixture was stirred at 100°C for 12 hours. The desired MS was shown by LC-MS. The mixture was filtered and extracted with ethyl acetate (3 mL x 3) and water. The combined organic layers were washed with saline solution (5 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Residue, preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f By refining it using a solution of 0.6, 31b was obtained as a yellow oil. Calculated value of MSmas [M+1] + (C 28 H 31 (ClF2N6O3Si) m / z 601.2, LCMS detection value m / z 601.2.

[0471] N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-cyano-1H-pyrazole-3-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (31) A mixture of N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (31b, 20 mg, 33.27 mmol) in TFA (0.5 mL) and DCM (0.5 mL) was stirred at 20°C for 2 hours. The desired MS was shown by LC-MS. The mixture was concentrated under reduced pressure. The residue was separated by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f Purified using (=0.4), 31 was obtained as a yellow solid. Calculated value of MSmas [M+1] + (C 22H 17 ClF2N6O2) with a m / z of 471.1 and an LCMS detection value of 471.0; 1 H NMR (400 MHz, DMSO-d6) δ 14.16 (br s, 1H), 10.52 (s, 1H), 8.90-8.78 (m, 1H), 8.68 (br s, 1H), 8.59 (br s, 1H), 7.96 (d, J = 9.0 Hz, 2H), 7.91 (s, 1H), 7.37 (br d, J = 8.8 Hz, 2H), 4.39 (br s, 1H), 1.36 (br d, J = 6.7 Hz, 6H).

[0472] Example 32 (R)-N 8 -(4-(chlorodifluoromethoxy)phenyl)-N 6 ,4-dimethyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-6,8-dicarboxamide [ka]

[0473] (R)-Methyl 8-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-6-carboxylate (32b) (R)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide (synthesized by the same method as 8g; 32a, 50mg, 0.103 mmol) is dissolved in MeOH (1 mL) and DMF (3 mL) under N2 and Pd(d ppf)Cl2 (15.03 mg, 0.021 mmol), TEA (51.98 mg, 0.514 mmol, 71.50 μL), Pd(OAc)2 (4.61 mg, 0.021 mmol), xanthophos (11.89 mg, 0.021 mmol), PPh3 (5.39 mg, 0.021 mmol), and DPPP (8.47 mg, 0.021 mmol) were added. The suspension was degassed under vacuum and purged several times with CO. The mixture was stirred at 120°C under CO (2 MPa) for 12 hours. Detection of the target MS was shown by LC-MS. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (10 mL), and the mixture was extracted with SiO (10 mL x 3). The combined organic layers were washed with saline solution (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was then separated into preparative TLC (SiO2, ethyl acetate:petroleum ether = 3:1, R f By purification using (=0.3), the compound 32b described in the title was obtained as a brown solid. 1 H NMR (400 MHz, MeOD-d4) δ 8.53-8.42 (m, 2H), 7.88-7.81 (m, 2H), 7.30 (d, J = 9.0 Hz, 2H), 5.41 (br dd, J = 1.8, 6.5 Hz, 1H), 5.18-4.95 (m, 2H), 4.24-4.18 (m, 1H), 4.12-4.08 (m, 1H), 4.04 (s, 3H), 1.40 (d, J = 6.5 Hz, 3H).

[0474] (R)-8-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-6-carboxylic acid (32c) (R)-methyl 8-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-6-carboxylate (32b, 22 mg, 0.047 mmol) was dissolved in MeOH (1 mL), THF (1 mL), and H2O (1 mL), to which LiOH·H2O (7.93 mg, 0.189 mmol) was added. The mixture was stirred at 50°C for 5 hours. Detection of the desired MS was shown by LC-MS. The reaction mixture was concentrated under reduced pressure to remove the solvent. H2O was added, and 1 M HCl was added dropwise to the mixture until the pH was 5. The mixture was concentrated to obtain the crude product, which was used in the next step without purification. 1 H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.55 (d, J = 1.7 Hz, 1H), 8.38 (d, J = 1.7 Hz, 1H), 7.96 (d, J = 9.2 Hz, 2H), 7.38 (d, J = 9.0 Hz, 2H), 5.38-5.26 (m, 1H), 5.16-4.90 (m, 2H), 4.29-3.98 (m, 2H), 1.31 (d, J = 6.5 Hz, 3H).

[0475] (R)-N 8 -(4-(chlorodifluoromethoxy)phenyl)-N 6 ,4-dimethyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-6,8-dicarboxamide (32) (R)-8-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-6-carboxylic acid (32c, 21 mg, 0.046 mmol) and methanamine hydrochloride (31.38 mg, 0.465 mmol) were dissolved in DMF (2 mL) and HATU (53.02 mg, 0.139 µl) and DIEA (48.06 mg, 0.372 mmol, 64.77 µL) were added. The mixture was stirred at 20°C for 24 hours. Detection of the target MS was shown by LC-MS. The reaction mixture was concentrated under reduced pressure and the solvent was removed. The residue was diluted with H2O (5 mL) and extracted with RINKAN (5 mL × 3). The combined organic layers were washed with saline solution (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was then separated into preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f The compound 32, as indicated in the title, was obtained as a white solid by purification using a solution of 0.60. Calculated value of MSmas [M+1] + (C 21 H 19 ClF2N4O4) was detected at m / z 465.1, and the LCMS detection value was also m / z 465.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.85-8.73 (m, 1H), 8.42 (d, J = 1.6 Hz, 1H), 8.04-7.90 (m, 3H), 7.37 (d, J = 9.0 Hz, 2H), 5.13-4.89 (m, 3H), 4.18-3.95 (m, 2H), 2.87 (d, J = 4.6 Hz, 3H), 1.28 (d, J = 6.5 Hz, 3H).

[0476] Example 33 (General Method N) (R)-N-(4-(chlorodifluoromethoxy)phenyl)-3-methyl-5-(1H-pyrazole-5-yl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide This general method N provides specific synthetic details applicable to the compound in the title. By changing the coupling reagent, additional compounds can be prepared according to this method. [ka]

[0477] (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3-methyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole-7-carboxamide (33b), and, (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3-methyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide (33c) (R)-1-(3-amino-5-bromo-4-((1-hydroxypropan-2-yl)amino)phenyl)-2-(4-(chlorodifluoromethoxy)phenyl)ethanone (synthesized by the same method as 6c; 33a, 330 mg, 0.71 mmol) and di(imidazole-1-yl)methanethion (379.68 mg, 2.13 mmol) were mixed in THF (15 mL) and stirred at 15°C for 16 hours. TLC (petroleum ether:ethyl acetate = 0:1, R f The formation of two new spots was shown by (0.6). LC-MS showed the detection of two peaks with MS values ​​of 33b and 33c. The mixture was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 0:1) to obtain 33b as a yellow solid. 1H NMR (400 MHz, CDCl3-d) δ 8.14 (s, 1H), 7.99 (d, J = 1.5 Hz, 1H), 7.93 (d, J = 1.5 Hz, 1H), 7.77-7.69 (m, 2H), 7.28 (br s, 1H), 7.26 (br s, 1H), 5.39 (quin, J = 6.5 Hz, 1H), 4.35-4.24 (m, 1H), 3.48 (d, J = 11.1 Hz, 1H), 1.57 (d, J = 6.4 Hz, 3H). The batch of crude product was further purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 0:1) to obtain 33c as a colorless solid. 1 H NMR (400 MHz, CDCl3-d) δ 8.49 (s, 1H), 8.02 (d, J = 1.3 Hz, 1H), 7.92 (d, J = 1.5 Hz, 1H), 7.79-7.72 (m, 2H), 7.28 (br s, 1H), 7.26 (s, 1H), 5.37 (quin, J = 6.6 Hz, 1H), 4.26 (dd, J = 7.2, 11.1 Hz, 1H), 4.13 (q, J = 7.2 Hz, 1H), 3.46 (d, J = 11.0 Hz, 1H), 1.56 (d, J = 6.4 Hz, 3H).

[0478] (R)-N-(4-(chlorodifluoromethoxy)phenyl)-3-methyl-5-(1H-pyrazole-5-yl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide (33) A mixture of (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3-methyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide (33c, 20 mg, 0.042 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (32.84 mg, 0.169 mmol), K3PO4 (26.94 mg, 0.127 mmol), Pd(dppf)Cl2 (6.19 mg, 8.46 µl), and Boc2O (4.62 mg, 0.021 µl, 4.86 µL) in dioxane (2 mL) and H2O (0.2 mL) was degassed and purged three times with N2. The mixture was stirred at 110°C for 16 hours under an N2 atmosphere. LC-MS showed the presence of residual 33c. To this mixture, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (24.63 mg, 0.127 mmol), K3PO4 (17.96 mg, 0.085 mmol), and Pd(dppf)Cl2 (6.19 mg, 8.46 mmol) were added. The mixture was stirred at 110°C for 4 hours under an N2 atmosphere. LC-MS showed the detection of a peak with the desired MS. TLC (ethyl acetate:methanol = 10:1, R f The formation of new spots was shown by (=0.48). The reaction mixture was concentrated and H2O (10 mL) was added. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saline solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was subjected to preparative TLC (ethyl acetate:methanol = 10:1, R f The product is purified by (=0.48) to obtain a crude product, which is then separated by preparative TLC (DCM:methanol=10:1, R f Further purification using (=0.5) yielded 33 as a white solid. Calculated value of MSmas [M+1] + (C 21 H 16 ClF2N5O3) was detected at m / z 460.1, and the LCMS detection value was also m / z 460.1. 1H NMR (400 MHz, MeOD-d4) δ 8.00 (br d, J = 9.7 Hz, 2H), 7.88-7.81 (m, 3H), 7.29 (d, J = 8.8 Hz, 2H), 6.79 (br s, 1H), 5.29 (br d, J = 7.9 Hz, 2H), 4.79 (br d, J = 5.7 Hz, 1H), 1.00 (br d, J = 4.9 Hz, 3H).

[0479] Example 34 (General Method O) (R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-(hydroxymethyl)-6-(1H-pyrazole-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide This general method O provides specific synthetic details applicable to the compound in the title. Additional compounds can be prepared according to this method by changing the coupling reagents and / or deprotection reagents. [ka]

[0480] (R)-Methyl 6-bromo-4-(hydroxymethyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxylate (34b) A solution of (R)-methyl 4-((benzyloxy)methyl)-6-bromo-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxylate (synthesized by the same method as 8e; 34a, 1.2 g, 2.78 mmol) in TFA (10 mL) was stirred at 75°C for 16 hours. The desired MS was shown by LC-MS. The mixture was concentrated to obtain 34b as a yellow oil. Calculated value of MSmas [M+1] + (C 13 H 13 The BrN2O4 sample showed a m / z of 341.0, and the LCMS detection value was also m / z 341.0.

[0481] (R)-6-bromo-4-(hydroxymethyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxylic acid (34c) (R)-methyl 6-bromo-4-(hydroxymethyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxylate (34b, 0.95 g, 2.78 mmol) was dissolved in THF (5 mL), MeOH (5 mL), and H2O (1 mL), to which LiOH·H2O (233.71 mg, 5.57 mmol) was added. The mixture was stirred at 50°C for 1 hour. The desired MS was shown by LC-MS. The mixture was concentrated, and the residue was dissolved in water (5 mL). The suspension was extracted with ethyl acetate (10 mL x 2), and HCl (1 M) was added dropwise to the aqueous phase until the pH was 3. The precipitated solid was collected by filtration and dried to obtain 34c as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.95 (d, J = 1.2 Hz, 1H), 5.45-5.36 (m, 1H), 5.13-5.05 (m, 1H), 4.97-4.88 (m, 1H), 4.38 (d, J = 12.1 Hz, 1H), 4.02 (br d, J = 11.9 Hz, 1H), 3.90 (br d, J = 10.1 Hz, 1H), 3.67 (dt, J = 5.9, 10.1 Hz, 1H).

[0482] (R)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(hydroxymethyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide (34d) (R)-6-bromo-4-(hydroxymethyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxylic acid (34c, 0.85g, 2.60 mmol) and 4-(chlorodifluoromethoxy)aniline (1h, 528.13mg, 2.73 mmol) were mixed with pyridine (10 mL) and HATU (1.48 g, 3.90 mmol). The mixture was stirred at 40°C for 6 hours. The desired MS was shown by LC-MS. The reaction mixture was poured into water (30 mL) and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saline solution (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1~0:1, R f Purified using (=0.4), 34d was obtained as a white solid. Calculated value of Mass [M+1] + (C 19 H 15 (BrClF2N3O4) m / z 502.0, LCMS detection value m / z 502.0; 1 H NMR (400 MHz, CDCl3-d) δ 8.10 (brs, 1H), 8.04 (d, J = 1.3 Hz, 1H), 7.98 (d, J = 1.3 Hz, 1H), 7.72 (d, J = 9.0 Hz, 2H), 7.28 (s, 2H), 5.16 (d, J = 16.5 Hz, 1H), 5.12-5.06 (m, 1H), 4.94 (d, J = 16.3 Hz, 1H), 4.57 (d, J = 12.3 Hz, 1H), 4.22 (dd, J = 2.8, 10.5 Hz, 1H), 4.15-4.08 (m, 2H), 2.27 (br s, 1H).

[0483] (R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-(hydroxymethyl)-6-(1H-pyrazole-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide (34) (R)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(hydroxymethyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide (34d, 0.5 g, 0.995 mmol) and pyrimidin-5-ylboronic acid (369.72 mg, 2.98 mmol) were added to a mixture of dioxane (5 mL) and H2O (0.5 mL), followed by addition of K3PO4 (422.27 mg, 1.99 mmol), Pd(dppf)Cl2 (72.78 mg, 0.099 mmol) and (Boc)2O (217.08 mg, 0.995 mmol, 228.51 uL) under N2 atmosphere. The mixture was stirred at 110°C for 16 hours. LCMS showed the target MS. The mixture was filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=100:1~0:1, R f =0.3) to give 34 as a yellow solid. Calculated Mass [M+1] + (C 22 H 18 ClF2N5O4) m / z 490.1, LCMS found m / z 490.1; 1 H NMR (400 MHz, MeOD-d4) δ 8.29 (br s, 1H), 7.95 (s, 1H), 7.84 (br d, J = 8.6 Hz, 3H), 7.30 (br d, J = 8.8 Hz, 2H), 6.71 (br s, 1H), 5.17-4.93 (m, 2H), 4.37 (br d, J = 12.2 Hz, 1H), 4.08 (br d, J = 11.0 Hz, 1H), 3.60 (s, 1H), 3.53-3.40 (m, 2H).

[0484] Example 35 (S)-N-(4-(chlorodifluoromethoxy)phenyl)-4-(fluoromethyl)-6-(1H-pyrazol-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide

Chemical Formula

[0485] (S)-N-(4-(chlorodifluoromethoxy)phenyl)-4-(fluoromethyl)-6-(1H-pyrazole-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide (35) (S)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(fluoromethyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide (35a, 10 mg, 0.02 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11.53 mg, 0.059 mmol) were mixed with dioxane (2 mL) and H2O (0.2 mL), to which (Boc)2O (4.32 mg, 0.02 mmol, 4.55 μL), Pd(dppf)Cl2 (1.45 mg, 1.98 μL), and K3PO4 (12.62 mg, 0.059 mmol) were added. The mixture was stirred at 110°C for 12 hours. The desired MS was shown by LC-MS. The mixture was filtered and concentrated. The residue was purified by preparative HPLC (column: Nano-micro Kromasil C18 100*30mm 5um; mobile phase: [water (0.1% TFA)-ACN]; B%: 36%-53%, 10 min) to obtain 35 as a white solid. Calculated value of MSmas [M+1] + (C 22 H 17 ClF3N5O3) with m / z 492.1, LCMS detection value m / z 492.1; 1 H NMR (400 MHz, CDCl3-d) δ 8.21 (br s, 1H), 8.11 (br s, 1H), 7.92 (s, 1H), 7.80-7.73 (m, 3H), 7.29 (s, 2H), 6.68 (br s, 1H), 5.33 (br s, 1H), 5.18 (br d, J = 16.1 Hz, 1H), 5.05-4.92 (m, 1H), 4.49-4.27 (m, 2H), 4.17-3.98 (m, 2H).

[0486] Example 36 (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxyazetidine-1-yl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide [ka]

[0487] (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxyazetidine-1-yl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide (36) (R)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide (32a, 20 mg, 0.041 mmol) and azetidine-3-ol (36a, 15.02 mg, 0.205 mmol) were mixed in THF (0.8 mL) and BrettPhos Pd G3 (3.73 mg, 4.11 µl) and t-BuONa (2 M, 41.09 µL) were added under N2. The mixture was stirred in a sealed tube at 100 °C for 16 hours. LC-MS showed peaks with the desired MS. TLC (ethyl acetate:methanol = 10:1, R f The formation of new spots was shown by (=0.47). The reaction mixture was concentrated. The crude product was separated by preparative TLC (ethyl acetate:methanol = 10:1, R f The sample was purified by (=0.47), and further purified by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 25%-55%, 7 min) to obtain 36 as a white solid. Calculated value of MSmas [M+1] + (C 22 H 21 ClF2N4O4) with a m / z of 479.1, and LCMS detection value of m / z 479.1; 1H NMR (400 MHz, MeOD-d4) δ 7.91 (d, J = 1.3 Hz, 1H), 7.86-7.81 (m, 2H), 7.54 (d, J = 1.3 Hz, 1H), 7.30 (d, J = 9.0 Hz, 2H), 5.05-4.99 (m, 2H), 4.95 (s, 1H), 4.72-4.65 (m, 1H), 4.36 (br t, J = 6.5 Hz, 1H), 4.22 (dd, J = 3.3, 12.0 Hz, 1H), 4.10-4.04 (m, 2H), 4.02-3.96 (m, 1H), 3.54 (t, J = 6.3 Hz, 1H), 1.56 (d, J = 6.4 Hz, 3H).

[0488] Example 37 N-(4-(chlorodifluoromethoxy)phenyl)-9-(1H-pyrazole-5-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide [ka]

[0489] Methyl 9-bromo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate (37b) Methyl 3-amino-5-bromo-4-(piperidine-1-yl)benzoate (synthesized by the same method as 1d; 37a, 160 mg, 0.511 mmol) was added to a solution of formic acid (3 mL) with H2O2 (521.32 mg, 4.60 mmol, 441.79 μL, 30% purity). The mixture was heated at reflux temperature for 40 minutes. LC-MS showed that 37a was completely consumed, and one major peak with the desired mass was detected. TLC (petroleum ether:ethyl acetate = 2:1, R) fA reaction (=0.20) indicated that the reactants were completely consumed, and a new spot was formed. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL). The organic layer was washed with saturated NaHCO3 (10 mL x 3) water, dried over Na2SO4, filtered, and concentrated. The crude product was subjected to preparative TLC (petroleum ether:ethyl acetate = 2:1, R f Purified using (=0.20), 37b was obtained as a white solid. 1 H NMR (400 MHz, CDCl3-d) δ 8.24-8.18 (m, 1H), 8.00 (d, J = 1.3 Hz, 1H), 4.61-4.55 (m, 2H), 3.87 (s, 3H), 3.09-3.01 (m, 2H), 2.10-2.03 (m, 2H), 1.99-1.89 (m, 2H).

[0490] 9-Bromo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylic acid (37c) To a solution of methyl 9-bromo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate (37b, 50 mg, 0.162 mmol) in MeOH (1 mL), H2O (1 mL), and THF (1 mL), LiOH·H2O (13.57 mg, 0.323 mmol) was added. The mixture was stirred at 50°C for 2 hours. LC-MS showed that 37b was completely consumed, and one major peak with the desired mass was detected. The mixture was concentrated to remove THF and MeOH. Then, 1 M HCl water was added dropwise to the reaction mixture until the pH was 5. The suspension was filtered, the filter cake was washed with H2O (1 mL), and dried to obtain 37 as a white solid. 1 H NMR (400 MHz, CDCl3-d) δ 8.34 (d, J = 1.3 Hz, 1H), 8.31 (d, J = 1.2 Hz, 1H), 4.87-4.84 (m, 2H), 3.32-3.32 (m, 2H), 2.28-2.06 (m, 4H).

[0491] 9-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide (37d) To a solution of 9-bromo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylic acid (37c, 47 mg, 0.159 mmol) in DMF (4 mL), HATU (72.66 mg, 0.191 mmol), DIEA (61.75 mg, 0.478 mmol, 83.22 μL), and 4-(chlorodifluoromethoxy)aniline (1 h, 61.66 mg, 0.319 μL) were added. The mixture was stirred at 15°C for 16 hours. LC-MS showed that 37c was completely consumed, and one major peak with the desired mass was detected. TLC (ethyl acetate:methanol = 10:1, R) f (=0.36) indicated that 37c was completely consumed and one new spot was formed. H2O (20 mL) was added to the mixture. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saline solution (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was subjected to preparative TLC (ethyl acetate:methanol = 10:1, R f It was refined using (=0.36) to obtain 37d as a white oil. 1 H NMR (400 MHz, CDCl3-d) δ 8.01 (d, J = 1.5 Hz, 1H), 7.96 (d, J = 1.5 Hz, 1H), 7.75-7.67 (m, 2H), 7.15 (d, J = 8.8 Hz, 2H), 4.60 (t, J = 6.2 Hz, 2H), 3.02 (t, J = 6.5 Hz, 2H), 2.09-2.04 (m, 2H), 1.97-1.88 (m, 2H).

[0492] N-(4-(chlorodifluoromethoxy)phenyl)-9-(1H-pyrazole-5-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide (37) A mixture of 9-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide (37d, 20 mg, 0.042 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (24.73 mg, 0.127 mmol), Pd(dppf)Cl2 (3.11 mg, 4.25 mmol), and K3PO4 (27.06 mg, 0.127 mmol) in dioxane (1 mL) and H2O (0.1 mL) was degassed and purged three times with N2. The mixture was stirred under an N2 atmosphere at 110°C for 16 hours. LC-MS showed that 37d was completely consumed, and one major peak with the desired mass was detected. TLC (dichloromethane:methanol = 10:1, R f A ratio of 0.44 indicated that 37d was completely consumed, and one new spot was formed. The mixture was concentrated and H2O (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saline solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was subjected to preparative TLC (dichloromethane:methanol = 10:1, R f Purified using (=0.30), 37 was obtained as a white solid. Calculated value of MSmas [M+1] + (C 22 H 18 ClF2N5O2) with a m / z of 458.1, and LCMS detection value of m / z 458.1; 1H NMR (400 MHz, MeOD-d4) δ 8.26-8.23 (m, 1H), 7.86-7.81 (m, 4H), 7.29 (d, 2H, J = 9.0 Hz), 6.62 (s, 1H), 3.86 (br s, 2H), 3.12 (br t, 2H, J = 6.1 Hz), 1.99 (br s, 4H).

[0493] Example 38 (General Method P) (R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-hydroxy-9-(1H-pyrazole-5-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide The compound in the title was prepared according to Scheme 10. This general method P illustrates Scheme 10 and provides specific synthetic details applicable to the compound in the title. [ka]

[0494] (R)-methyl 9-bromo-2-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate (39b), and, (R)-Methyl 9-bromo-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate (38c) A solution of methyl(R)-methyl 3-bromo-4-(3-hydroxypiperidine-1-yl)-5-nitrobenzoate (synthesized by the same method as in 1d; 38a, 100 mg, 0.278 mmol) in AcOH (3 mL) was stirred at 30°C. Iron powder (155.48 mg, 2.78 mmol) was slowly added to the reaction mixture over 32 hours. TLC (ethyl acetate:methanol = 10:1, R fThe formation of two new spots was shown by (=0.37). LC-MS showed the detection of two peaks with the desired MS. The reaction mixture was filtered, and the filtrate was partitioned with ethyl acetate (50 mL) and H2O (50 mL). The separated organic layer was washed with water (50 mL × 3), then with saturated NaHCO3 water (30 mL × 3), dried over Na2SO4, and evaporated to dry. The crude product was subjected to preparative TLC (ethyl acetate:methanol = 10:1, R f Purified using (=0.3), 38b was obtained as a yellow solid. 1 H NMR (400 MHz, MeOD-d4) δ 8.16 (d, J = 1.1 Hz, 1H), 8.02 (d, J = 1.3 Hz, 1H), 4.82-4.74 (m, 1H), 4.69-4.61 (m, 1H), 4.50-4.42 (m, 1H), 3.93 (s, 3H), 3.25 (dd, J = 6.7, 9.8 Hz, 1H), 3.13-3.04 (m, 1H), 2.20-2.09 (m, 2H). The crude product was subjected to preparative TLC (ethyl acetate:methanol = 10:1, R f Purified using (=0.37), 38c was obtained as a yellow solid. 1 H NMR (400 MHz, MeOD-d4) δ 8.27 (d, J = 0.9 Hz, 1H), 8.07 (d, J = 1.1 Hz, 1H), 4.97 (t, J = 5.4 Hz, 1H), 4.79-4.70 (m, 1H), 4.65-4.52 (m, 1H), 3.94 (s, 3H), 2.38 (br dd, J = 6.8, 13.5 Hz, 1H), 2.26-2.04 (m, 3H).

[0495] (R)-9-bromo-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylic acid (38d) (R)-methyl 9-bromo-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate (38c, 25 mg, 0.077 mmol) was dissolved in MeOH (1 mL), H2O (1 mL), and THF (1 mL), to which LiOH·H2O (6.45 mg, 0.154 mmol) was added. The mixture was stirred at 50°C for 2 hours. TLC (ethyl acetate:methanol = 10:1, R f The formation of new spots was indicated by (=0.0). The mixture was concentrated and the solvent was removed. 1 M HCl was added dropwise to the mixture until the pH reached 5. The mixture was concentrated, and the crude product was used in the next step without further purification.

[0496] (R)-9-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide (38e) (R)-9-bromo-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylic acid (38d, 30 mg, 0.096 mmol) was dissolved in DMF (2 mL) and HATU (54.99 mg, 0.145 mmol), DIEA (124.62 mg, 0.964 mmol, 167.95 μL), and 4-[chloro(difluoro)methoxy]aniline (1 h, 28.00 mg, 0.145 mmol) were added. The mixture was stirred at 15°C for 16 hours. TLC (ethyl acetate:methanol = 10:1, R f The formation of new spots was shown by (=0.3). Detection of the peak with the desired MS was shown by LC-MS. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saline (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was subjected to preparative TLC (ethyl acetate:methanol = 10:1, R f Purified using the method (=0.3), 38e was obtained as a yellow solid.

[0497] (R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-hydroxy-9-(1H-pyrazole-5-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide (38) A mixture of (R)-9-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide (38e, 15 mg, 0.031 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (17.94 mg, 0.092 mmol), Pd(dppf)Cl2 (4.51 mg, 6.16 mmol), and K3PO4 (19.63 mg, 0.092 mmol) with dioxane (2 mL) and H2O (0.2 mL) was degassed and purged three times with N2. The mixture was stirred at 120°C under an N2 atmosphere for 16 hours. TLC (ethyl acetate:methanol = 5:1, R f The formation of new spots was shown by (=0.2). Detection of the peak with the desired MS was shown by LC-MS. The mixture was concentrated. The crude product was purified by preparative HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.225% FA)-ACN]; B%: 1%-50%, 12 min) to obtain 38 as a white solid. Calculated value of Mass [M+1] + (C 22 H 18 ClF2N5O2) with a m / z of 474.1, and LCMS detection value of m / z 474.1; 1 H NMR (400 MHz, MeOD-d4) δ 8.34 (s, 1H), 7.88 (d, J = 1.6 Hz, 1H), 7.87-7.82 (m, 3H), 7.29 (d, J = 8.9 Hz, 2H), 6.62 (d, J = 2.1 Hz, 1H), 5.01 (t, J = 5.1 Hz, 1H), 3.95-3.76 (m, 2H), 2.19 (br d, J = 6.7 Hz, 2H), 2.07-1.88 (m, 2H).

[0498] Example 39 (General Method Q) (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(4-hydroxypyridine-2-yl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide This general method Q provides specific synthetic details applicable to the compound in the title. By changing the coupling reagent, additional compounds can be prepared according to this method. [ka]

[0499] (R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide (39a) (R)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide (32a, 200 mg, 0.411 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxabond A mixture of dioxane (6.2 mL) containing loran-2-yl)-1,3,2-dioxaborolane (939.17 mg, 3.70 mmol), Pd(OAc)2 (9.23 mg, 0.041 mmol), XPhos (48.97 mg, 0.103 mmol), and K3PO4 (261.68 mg, 1.23 mmol) was degassed and purged three times with N2. The mixture was stirred under an N2 atmosphere and microwave at 60°C for 16 hours. Detection of the target MS was shown by LC-MS. The reaction mixture was concentrated under reduced pressure and the solvent was removed. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1) to obtain 39a as a white solid.

[0500] (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(4-hydroxypyridine-2-yl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide (39) A mixture of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide (39a, 5 mg, 9.37 ml), 2-bromopyridine-4-ol (2.44 mg, 0.014 mmol), Pd(dppf)Cl2 (685.43 ug, 9.37 ml), and Na2CO3 (2.98 mg, 0.028 mmol) in DME (0.5 mL) and H2O (0.1 mL) was degassed and purged three times with N2. The mixture was stirred in a microwave reactor at 120°C for 1 hour under an N2 atmosphere. LC-MS indicated that 39a was completely consumed, and the target MS was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (column: Xtimate C18 150*25mm*5um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 25%-55%, 10 min) to obtain 39 as a white solid. Calculated value of MSmas [M+1] + (C 24 H 19 ClF2N4O4) with a frequency of 501.1 m / z, LCMS detection value of 501.1 m / z; 1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 1.5 Hz, 1H), 8.03 (br d, J = 6.8 Hz, 1H), 7.96 (d, J = 1.5 Hz, 1H), 7.88-7.81 (m, 2H), 7.29 (d, J = 8.8 Hz, 2H), 6.79 (br s, 1H), 6.68 (br d, J = 6.8 Hz, 1H), 5.15-4.96 (m, 2H), 4.46 (br s, 1H), 4.13 (br d, J = 3.1 Hz, 1H), 3.99 (d, J = 12.3 Hz, 1H), 1.14 (d, J = 6.6 Hz, 3H).

[0501] Example 40 (General Method R) (S)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(1-hydroxyethyl)-1-isopropyl-7-(1H-pyrazole-5-yl)-1H-benzo[d]imidazole-5-carboxamide This general method R provides specific synthetic details applicable to the compound in the title. By changing the coupling reagent, additional compounds can be prepared according to this method. [ka]

[0502] (S)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-5-(2-hydroxypropanamide)-4-(isopropylamino)benzamide (40a) To a solution of 3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(isopropylamino)benzamide (9a, 350 mg, 0.78 mmol) in DCM (1 mL), DIEA (302.44 mg, 2.34 mmol, 407.60 μL), (2S)-2-hydroxypropanoic acid (140.53 mg, 1.56 mmol, 116.14 μL), and 2-chloro-1,3-dimethylimidazolinium chloride (158.24 mg, 0.936 mmol) were added. The mixture was stirred at 15°C for 4 hours. TLC (petroleum ether:ethyl acetate = 1:1, R) f A value of 0.45 indicated that 9a was completely consumed, and one major new spot of high polarity was detected. The desired MS was detected by LC-MS. The reaction mixture was diluted with H2O (20 mL) and extracted by DCM (10 mL x 3). The combined organic layers were washed with saline (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to obtain 40b as a white solid. 1 H NMR (400 MHz, MeOD-d4) δ 8.53 (d, J = 2.4 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.83-7.80 (m, 2H), 7.30 (br d, J = 9.3 Hz, 2H), 4.34 (q, J = 6.8 Hz, 1H), 3.56 (td, J = 6.4, 12.7 Hz, 1H), 1.49 (d, J = 6.8 Hz, 3H), 1.24 (d, J = 6.4 Hz, 6H).

[0503] (S)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(1-hydroxyethyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (40b) (S)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-5-(2-hydroxypropanamide)-4-(isopropylamino)benzamide (40a, 40 mg, 0.077 mmol) was dissolved in toluene (1 mL), to which 4-methylbenzenesulfonic acid (2.65 mg, 0.015 mmol) was added. The mixture was stirred at 100°C for 4 hours. TLC (petroleum ether:ethyl acetate = 1:1, R f A reaction (=0.15) indicated that 40a was completely consumed, and one major new spot of high polarity was detected. The desired MS was detected by LC-MS. The residue was diluted with H2O (20 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with saline (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to obtain 40b as a white solid. 1 H NMR (400 MHz, MeOD-d4) δ 8.29 (s, 1H), 8.14 (br s, 1H), 7.86 (d, J = 9.3 Hz, 2H), 7.32 (br d, J = 9.3 Hz, 2H), 4.92-4.92 (m, 1H), 4.87-4.86 (m, 1H), 1.91 (br s, 3H), 1.76 (br d, J = 6.4 Hz, 6H).

[0504] (S)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(1-hydroxyethyl)-1-isopropyl-7-(1H-pyrazole-5-yl)-1H-benzo[d]imidazole-5-carboxamide (40) (S)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(1-hydroxyethyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (40b, 10mg, 0.02mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11.58mg, 0.06mmol) A mixture of dioxane (1 mL) and H2O (0.1 mL) containing K3PO4 (12.67 mg, 0.06 ...

Claims

1. Formula (S20): 【Chemistry 1】 Formula (S20) [In the formula, R １ is 4- to 10-membered heterocyclyl, C ６ -C １０ aryl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, CN, C １ -C ６ alkyl, OH, OC １ -C ６ alkyl, and C ３ -C ６ cycloalkyl; R ２ C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ８ Cycloalkyl, 4-10 member heterocycloalkyl, C ６ -C １０ It is an aryl or a 5- to 10-membered heteroaryl, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ８ Cycloalkyl, 4-10 member heterocycloalkyl, C ６ -C １０ Aryls and 5- to 10-membered heteroaryls can be any of the following: oxo, halo, CN, and C. １ -C ６ Alkyl, C(O)NHC １ -C ６ Alkyl, C(O)NHC ３ -C ６ Cycloalkyl, OH, OC １ -C ６ Alkyl, C ３ -C ６ It may be substituted with one, two, or three substituents independently selected from the group consisting of cycloalkyls and 4- to 6-membered heterocyclines; and R ３ C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ６ Cycloalkyl, 4-6 member heterocycloalkyl, C ６ -C １０ It is an aryl or a 5- to 10-membered heteroaryl, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ６ Cycloalkyl, 4-6 member heterocycloalkyl, C ６ -C １０ Aryls and 5- to 10-membered heteroaryls can be optionally, halo, C １ -C ６ Alkyl, OH, and OC １ -C ６ [May be substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups.] A method for synthesizing the compound shown, Formula (S24-a): 【Chemistry 2】 Formula (S24-a) [In the formula, R2 and R3 are the same as defined in formula (S20)] A method comprising contacting a compound represented by formula (S20) with a boronic acid or boronic acid ester in the presence of a catalyst to form a compound represented by formula (S20).

2. The method according to claim 1, wherein the catalyst is a palladium catalyst.

3. The palladium catalyst is Pd(dppf)Cl ２ The method according to claim 2.

4. Boronic acid or boronic acid ester, 【Transformation 3】 [In the formula, R1 is the same as the definition in formula (S20) of claim 1.] The method according to any one of claims 1 to 3.

5. The method according to any one of claims 1 to 4, wherein the contact between the compound represented by formula (S24-a) and a boronic acid or boronic acid ester occurs in the presence of an inorganic base.

6. The method according to claim 5, wherein the inorganic base is potassium phosphate.

7. Formula (S18): 【Chemistry 4】 Formula (S18) [In the formula, R2 and R3 are the same as defined in formula (S20) of claim 1.] The compound shown is, in the presence of a coupling reagent, compound: 【Transformation 5】 The method according to any one of claims 1 to 6, further comprising contacting with to form a compound represented by formula (S24-a).

8. Formula (S24): 【Transformation 6】 Formula (S24) [In the formula, R2 is the same as the definition in formula (S20) of claim 1.] The compound shown is, compound: 【Transformation 7】 [In the formula, R3 is the same as the definition in formula (S20) of claim 1.] The method according to any one of claims 1 to 6, further comprising contacting with to form a compound represented by formula (S24-a).

9. Formula (S20): 【Transformation 8】 Formula (S20) [In the formula, R １ These are heterocyclyl groups with 4 to 10 members, C ６ -C １０ These are aryls, or 5- to 10-membered heteroaryls, which can be any halo, CN, or C. １ -C ６ Alkyl, OH, OC1-C6 alkyl, and C ３ -C ６ It may be substituted with one, two, or three substituents independently selected from the group consisting of cycloalkyl groups; R ２ is C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ８ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６ -C １０ aryl, or 5- to 10-membered heteroaryl, and C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ８ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６ -C １０ aryl, and 5- to 10-membered heteroaryl are each optionally independently oxo, halo, CN, C １ -C ６ alkyl, C(O)NHC １ -C ６ alkyl, C(O)NHC ３ -C ６ cycloalkyl, OH, OC １ -C ６ alkyl, C ３ -C ６ cycloalkyl, and 4- to 6-membered heterocyclyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of; and R ３ C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ６ Cycloalkyl, 4-6 member heterocycloalkyl, C ６ -C １０ It is an aryl or a 5- to 10-membered heteroaryl, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ６ Cycloalkyl, 4-6 member heterocycloalkyl, C ６ -C １０ Aryls and 5- to 10-membered heteroaryls can be optionally, halo, C １ -C ６ Alkyl, OH, and OC １ -C ６ [May be substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups.] A method for synthesizing the compound shown, Formula (S28): 【Chemistry 9】 Formula (S28) [In the formula, R1, R2, and R3 are the same as defined in formula (S20)] The compound shown is, in the presence of a coupling reagent, compound: 【Chemistry 10】 A method comprising contacting with to form a compound represented by formula (S20).

10. R １ However, halo, CN, OH, OC １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, and C １ -C ６ The method according to any one of claims 1 to 9, wherein the heteroaryl molecule is a 5-6 member that may be optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl groups.

11. R １ but, 【Chemistry 11】 The method according to claim 10.

12. R ２ However, halo, OH, OC １ -C ６ Alkyl, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, 4-6 membered heterocyclyl, CN, C(O)NHC １ -C ６ Alkyl and C(O)NHC ３ -C ６ C may be optionally substituted with 1 to 3 substituents selected from the group consisting of cycloalkyl groups. １ -C ６ The method according to any one of claims 1 to 11, wherein the alkyl group is alkyl.

13. R ２ but, 【Chemistry 12】 The method according to claim 12.

14. R ３ However, halo, OH, and OC １ -C ６ C may be optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl groups. １ -C ６ The method according to any one of claims 1 to 13, wherein the alkyl group is alkyl.

15. R ３ but, 【Chemistry 13】 The method according to claim 14.

16. The method according to any one of claims 1 to 15, further comprising contacting a compound represented by formula (S20) with an acid to form a pharmaceutically acceptable acid addition salt or a tautomer thereof.

17. The method according to claim 16, wherein the pharmaceutically acceptable acid addition salt is a tosylate or a tautomer thereof.

18. Formula (S24-a): 【Chemistry 14】 Formula (S24-a) [In the formula, R ２ C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ８ Cycloalkyl, 4-10 member heterocycloalkyl, C ６ -C １０ It is an aryl or a 5- to 10-membered heteroaryl, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ８ Cycloalkyl, 4-10 member heterocycloalkyl, C ６ -C １０ Aryls and 5- to 10-membered heteroaryls can be any of the following: oxo, halo, CN, and C. １ -C ６ Alkyl, C(O)NHC １ -C ６ Alkyl, C(O)NHC ３ -C ６ Cycloalkyl, OH, OC １ -C ６ Alkyl, C ３ -C ６ It may be substituted with one, two, or three substituents independently selected from the group consisting of cycloalkyls and 4- to 6-membered heterocyclines; and R ３ C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ６ Cycloalkyl, 4-6 member heterocycloalkyl, C ６ -C １０ It is an aryl or a 5- to 10-membered heteroaryl, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ６ Cycloalkyl, 4-6 member heterocycloalkyl, C ６ -C １０ Aryls and 5- to 10-membered heteroaryls can be optionally, halo, C １ -C ６ Alkyl, OH, and OC １ -C ６ [May be substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups.] The compound shown by [this symbol].

19. Formula (S28): 【Chemistry 15】 Formula (S28) [In the formula, R １ These are heterocyclyl groups with 4 to 10 members, C ６ -C １０ These are aryls, or 5- to 10-membered heteroaryls, which can be any halo, CN, or C. １ -C ６ Alkyl, OH, OC1-C6 alkyl, and C ３ -C ６ It may be substituted with one, two, or three substituents independently selected from the group consisting of cycloalkyl groups; R ２ C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ８ Cycloalkyl, 4-10 member heterocycloalkyl, C ６ -C １０ It is an aryl or a 5- to 10-membered heteroaryl, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ８ Cycloalkyl, 4-10 member heterocycloalkyl, C ６ -C １０ Aryls and 5- to 10-membered heteroaryls can be any of the following: oxo, halo, CN, and C. １ -C ６ Alkyl, C(O)NHC １ -C ６ Alkyl, C(O)NHC ３ -C ６ Cycloalkyl, OH, OC １ -C ６ Alkyl, C ３ -C ６ It may be substituted with one, two, or three substituents independently selected from the group consisting of cycloalkyls and 4- to 6-membered heterocyclines; and R ３ C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ６ Cycloalkyl, 4-6 member heterocycloalkyl, C ６ -C １０ It is an aryl or a 5- to 10-membered heteroaryl, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ６ Cycloalkyl, 4-6 member heterocycloalkyl, C ６ -C １０ Aryls and 5- to 10-membered heteroaryls can be optionally, halo, C １ -C ６ Alkyl, OH, and OC １ -C ６ [May be substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups.] The compound shown by [this symbol].

20. Formula (S24): 【Chemistry 16】 Formula (S24) [In the formula, R ２ C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ８ Cycloalkyl, 4-10 member heterocycloalkyl, C ６ -C １０ It is an aryl or a 5- to 10-membered heteroaryl, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ８ Cycloalkyl, 4-10 member heterocycloalkyl, C ６ -C １０ Aryls and 5- to 10-membered heteroaryls can be any of the following: oxo, halo, CN, and C. １ -C ６ Alkyl, C(O)NHC １ -C ６ Alkyl, C(O)NHC ３ -C ６ Cycloalkyl, OH, OC １ -C ６ Alkyl, C ３ -C ６ It may be substituted with one, two, or three substituents independently selected from the group consisting of cycloalkyls and 4- to 6-membered heterocyclines. The compound shown by [this symbol].

21. R １ However, halo, CN, OH, OC １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, and C １ -C ６ The compound according to claim 19, which is a 5-6 member heteroaryl that may be optionally substituted with 1-3 substituents selected from the group consisting of alkyl groups.

22. R １ but, 【Chemistry 17】 The compound according to claim 21.

23. R ２ However, halo, OH, OC １ -C ６ Alkyl, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, 4-6 membered heterocyclyl, CN, C(O)NHC １ -C ６ Alkyl and C(O)NHC ３ -C ６ C may be optionally substituted with 1 to 3 substituents selected from the group consisting of cycloalkyl groups. １ -C ６ The compound according to any one of claims 18 to 20, wherein it is alkyl.

24. R ２ but, [Chemistry 18] The compound according to claim 23.

25. R ３ However, halo, OH, and OC １ -C ６ C may be optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl groups. １ -C ６ The compound according to any one of claims 18 to 19, wherein it is alkyl.

26. R ３ but, 【Chemistry 19】 The compound according to claim 25.

27. Compound: 【Chemistry 20】 or its tautomers, or its pharmaceutically acceptable salts.

28. Compound: 【Chemistry 21】 or a pharmaceutically acceptable salt thereof.

29. Compound: 【Chemistry 22】 An acid addition salt thereof, or a tautomer thereof.

30. The acid addition salt according to claim 29, or a tautomer thereof, wherein the acid addition salt is a tosylate.

31. A pharmaceutical composition comprising a compound according to any one of claims 27 to 28, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or an acid addition salt according to any one of claims 29 to 30, or a tautomer thereof, and at least one pharmaceutically acceptable excipient.

32. The pharmaceutical composition according to claim 31, in the form of an oral composition.

33. The pharmaceutical composition according to claim 32, wherein the oral composition is a tablet, a coated tablet, a hard-shell gel capsule, a soft-shell gel capsule, an emulsion, or a suspension.

34. A pharmaceutical composition according to any one of claims 31 to 33, for use in treatment.

35. A pharmaceutical composition according to any one of claims 31 to 33 for treating leukemia in a patient.

36. The pharmaceutical composition according to claim 35, wherein the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL).

37. The pharmaceutical composition according to claim 36, wherein leukemia is ALL.

38. The pharmaceutical composition according to claim 36, wherein leukemia is AML.

39. The pharmaceutical composition according to claim 36, wherein leukemia is CML.

40. A pharmaceutical composition according to any one of claims 35 to 39, wherein the leukemia is resistant to standard treatment.

41. The pharmaceutical composition according to claim 40, wherein the standard treatment is treatment with another tyrosine kinase inhibitor.

42. The pharmaceutical composition according to claim 40, wherein the standard treatment is treatment with one or more of imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.

43. A pharmaceutical composition according to any one of claims 31 to 42, for treating CML or ALL in a patient, in combination with one or more of imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.

44. The pharmaceutical composition according to claim 35 for use in a method comprising contacting BCR-ABL1 in a patient with a compound according to any one of claims 27 to 28, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or an acid addition salt according to any one of claims 29 to 30, or a tautomer thereof.

45. The pharmaceutical composition according to claim 44, wherein the leukemia is chronic myeloid leukemia.

46. A pharmaceutical composition according to claim 31 for use in a method for inhibiting the tyrosine kinase enzyme activity of a protein selected from the group consisting of Avelson protein (ABL1), Avelson-related protein (ABL2), and chimeric protein BCR-ABL1, wherein the method comprises contacting a protein with a compound according to any one of claims 27 to 28, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or an acid addition salt according to any one of claims 29 to 30, or a tautomer thereof.

47. The pharmaceutical composition according to claim 31, for treating a disease in a patient, wherein the modulation of BCR-ABL1 activity prevents, suppresses, or improves the pathophysiology and / or symptoms of the disease.

48. The pharmaceutical composition according to claim 36, wherein the AML is secondary AML that develops after myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN).

49. A method for producing a pharmaceutically acceptable acid addition salt or a tautomer thereof, comprising contacting the compound according to claim 27 or 28 with an acid to form a pharmaceutically acceptable acid addition salt or a tautomer thereof.

50. The method according to claim 49, wherein the pharmaceutically acceptable acid addition salt or tautomer thereof is a tosylate.

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