Compounds for treating certain leukemias

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 TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 733,029, filed September 18, 2018, U.S. Provisional Application No. 62 / 816,637, filed March 11, 2019, and U.S. Provisional Application No. 62 / 889,929, filed August 21, 2019, the disclosures of each of which are incorporated herein by reference in their entirety for all purposes.

[0002] Technical field of the invention Provided herein are compounds, preferably compounds that inhibit the tyrosine kinase enzymatic activity of a protein selected from Abelson protein (ABL1), Abelson-associated protein (ABL2), or chimeric protein BCR-ABL1, compositions thereof, and methods for their production, as well as methods for inhibiting the tyrosine kinase enzymatic activity of a protein selected from Abelson protein (ABL1), Abelson-associated protein (ABL2), or chimeric protein BCR-ABL1, and methods for treating diseases in which the pathology and / or symptoms of the disease are prevented, suppressed, or ameliorated 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 and migrates to hematopoietic stem cells. This chromosome carries the BCR-ABL1 oncogene, encoding the chimeric BCR-ABL1 protein. Drugs 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 in treating 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, there is provided herein a compound of formula (I) or formula (Ia): [ka] [In the formula, L is -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-; R 1 is an optionally substituted C-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)NR 6 R 7 , N.R. 6 COR 7 , N.R. 6 SO2R 7 , or C(O)OR 6 and; R 2is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C 10 aryl or an optionally substituted 5-10 membered heteroaryl; R 3 is 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 therebetween form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 membered heterocycloalkyl; R 4 is an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl; X is O or S; Y is CH, C—(C1-C2 alkyl), or C-halo, or N; Z is CR 5 , or N; R 5 is H, or a halogen; R 6 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted C6-C 10aryl or an optionally substituted 5-10 membered heteroaryl; and R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted C6-C 10 aryl or an optionally substituted 5-10 membered heteroaryl; Alternatively, R 6 and R 7 together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heterocycle; 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-. or a tautomer or N-oxide thereof, or a pharmaceutically acceptable salt of either thereof.

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

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

[0007] In one aspect, provided is a method for treating a disease in a patient, whereby the pathology and / or symptoms of the disease are prevented, suppressed, or ameliorated by modulating BCR-ABL1 activity, the method comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein.

[0008] In one aspect, provided is a method of 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). DETAILED DESCRIPTION OF THE INVENTION

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

[0010] "Comprising" is intended to mean that the compositions and methods include the recited elements, but do not exclude others. "Consisting essentially of," when used to define compositions and methods, is intended to mean excluding other elements that are essential to the combination. For example, a composition consisting essentially of the elements defined herein does not exclude other elements that do not materially affect the basic and novel characteristics of the claimed invention. "Consisting of," is intended to mean, for example, excluding more than trace amounts of other ingredients and more than substantial method steps recited. Embodiments defined by each of these transitions are within the scope of the present invention.

[0011] An "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. Effective amounts can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, LD 50 (lethal dose for 50% of the population), and ED 50 (therapeutically effective dose in 50% of the population).

[0012] As used herein, the term "excipient" refers to an inert or inactive substance that can be used in the manufacture of a drug or pharmaceutical product, such as a tablet, that contains a compound of the invention as an active ingredient. A variety of substances can be encompassed by the term excipient, including, but not limited to, substances used as binders, disintegrants, coating agents, compression / encapsulation aids, creams or lotions, lubricants, solutions for parenteral administration, ingredients in chewable tablets, sweeteners or flavorings, suspending / gelling agents, or wet granulation agents. Binders include, for example, carbomer, povidone, xanthan gum, etc.; coatings include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression / encapsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrous or monohydrate; optionally combined with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, for example, maize starch, lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate; chewable tablet ingredients include, for example, dextrose, fructose dc, lactose (monohydrate, optionally combined with aspartame or cellulose); suspending / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc; and wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0013] "Patient" refers to mammals, 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, cows, and humans. In some embodiments, patient refers to a human.

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

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

[0016] A "prodrug" refers to a compound that, after administration, is metabolized or otherwise converted to become a compound (or drug) that is biologically active or more active in at least one property. With respect to a drug, a prodrug is chemically modified in a way that renders it 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. A prodrug may have altered metabolic stability or transport properties, reduced side effects or toxicity, or improved flavor compared to an active drug (see, e.g., 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 the corresponding drug. By way of example, and without limitation, prodrugs include carboxy esters, linear and cyclic phosphate esters, phosphoramides and phosphoramidates, carbamates, preferably phenolic carbamates (i.e., carbamates in which the hydroxy group is part of an aryl or heteroaryl moiety, the aryl and heteroaryl being optionally substituted), and the like.

[0017] "Salt" refers to an ionic compound formed between an acid and a base. When the compounds provided herein contain an acidic functional group, such salts include, but are not limited to, alkali metal, alkaline earth metal, and ammonium salts. As used herein, ammonium salts include salts containing protonated and alkylated nitrogen bases. Cations useful in pharmaceutically acceptable salts include, but are not limited to, Na, K, Rb, Cs, NH4, Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids. When 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, and salts of inorganic acids such as hydrogen halides, sulfuric acids, and phosphoric acids. Anions useful in pharmaceutically acceptable salts include, but are not limited to, for example, oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisulfate, monobasic, dibasic and tribasic phosphates, mesylate, tosylate, and the like.

[0018] A "therapeutically effective amount" or dose of a compound or composition means that amount of the compound or composition that results in the reduction or inhibition of symptoms or a prolongation of survival in a patient. As a result, multiple administrations of the compound or composition may be required.

[0019] "Treating" or "treatment" of a disease in a patient means 1) preventing the disease from occurring in a patient who has the predisposing factors for the disease or who does not yet show symptoms of the disease; 2) suppressing or inhibiting the onset of the disease; or 3) ameliorating or reversing the disease. As used herein, "treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. For purposes of this disclosure, beneficial or desired results include, but are not limited to, one or more of the following: reducing one or more symptoms attributable to a disease or disorder; reducing the severity of a disease or disorder; stabilizing a disease or disorder (e.g., preventing or delaying the worsening of a disease or disorder); delaying the onset or recurrence of a disease or disorder; slowing or slowing the progression of a disease or disorder; improving the symptoms of a disease or disorder; providing remission (partial or total) of a disease or disorder; reducing the dose of one or more other agents required to treat a disease or disorder; enhancing the effectiveness of other agents used to treat a disease or disorder; slowing the progression of a disease or disorder; improving quality of life; and / or prolonging the survival of a patient. "Treatment" also encompasses alleviation of the pathological consequences of a disease or disorder. The methods of the invention contemplate any one or more of these aspects of treatment.

[0020] An "isotopic isomer" of a compound is a compound in which one or more atoms of the compound are replaced by isotopes of those same atoms. For example, if H is replaced by D or T, or 12 C is 11 If replaced by C, or 14 N 15 Substitution of N with N may result in a slower metabolic rate and longer half-life. Substitution of H with T may provide a radioligand that may be useful for binding studies. 12 C as a short-lived isotope 11 Substitution with C can provide a useful ligand for positron emission tomography (PET) scans. 14 N 15Substituting for N, 15 It is possible to provide compounds that can be detected / monitored by N NMR spectroscopy. For example, an isotopic isomer of a compound containing -CH2CH3 is a compound that contains -CD2CD3 instead of -CH2CH3.

[0021] "Stereoisomer" or "stereoisomers" means compounds that differ in the stereogenicity of their constituent atoms, including, but not limited to, the chirality of one or more stereocenters or with respect to the cis or trans configuration at a carbon-carbon or carbon-nitrogen double bond. Stereoisomers include enantiomers and diastereomers.

[0022] "Tautomer" means an alternative form of a compound that differs in the location of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups that contain ring atoms that are 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, and more preferably 1 to 6 carbon atoms. This term includes straight-chain and branched hydrocarbyl groups, such as, for example, 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 means 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 having one or more, preferably one or two, sites of vinyl (>C=C<) unsaturation. Such groups include, for example, vinyl, allyl, and but-3-en-1-yl. The term includes cis and trans isomers or mixtures of these isomers. C x Alkenyl means an alkenyl group having 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 having one or more, preferably one to two, sites of acetylenic (C≡C-) unsaturation. Examples of such alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CHC≡CH). x Alkynyl means an alkynyl group having x carbon atoms.

[0026] The term "substituted alkyl" refers to an alkyl group having 1 to 5, preferably 1 to 3, and more preferably 1 to 2, substituents, and examples of 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, carboxyl ester, (carboxyl ester, ... and n is 0 or 1. The substituents are 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, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SOH, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0027] "Substituted alkenyl" means an alkenyl group having 1 to 3 substituents, 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, (carboxyl ester)amino ... and substituted alkylthio, substituted cycloalkyl, substituted cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein, with the proviso that no hydroxy or thiol substituent is attached to a vinyl (unsaturated) carbon atom.

[0028] "Substituted alkynyl" means an alkynyl group having 1 to 3 substituents, 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, (carboxyl ester)amino ... and substituted alkylthio, hydroxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein, with the proviso that no hydroxy or thiol substituent is attached to an acetylenic carbon atom.

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

[0030] "Substituted alkoxy" refers to 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 particularly halogenated methyl groups such as trifluoromethyl, difluoromethyl, and fluoromethyl.

[0031] "Acyl" refers to the group 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 alkynyl, alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Acyl includes the "acetyl" group, CHC(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 C(O)-substituted heterocyclic group, where R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl; and wherein 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" refers to the groups 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 a group represented by -NH2.

[0035] "Substituted amino" is -NR 31 R 32 where R 31 and R 32is 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 wherein R 31 and R 32 may optionally be taken together with the attached nitrogen to form a heterocyclic or substituted heterocyclic group, provided that R 31 and R 32 and R are not both hydrogen, 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. 31 is hydrogen and R 32 When R is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. 31 and R 32 When R is alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. 31 or R 32 is hydrogen, but not both. 31 and R 32 means that neither of the two is hydrogen.

[0036] "Aminocarbonyl" is -C(O)NR 33 R 34 where R 33 and R 34is 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 attached nitrogen to form a heterocyclic or substituted heterocyclic group, and in which 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 where R 33 and R 34 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 wherein R 33 and R 34 may optionally be taken together with the attached nitrogen to form a heterocyclic or substituted heterocyclic group, and in which 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 where R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 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 wherein R 33 and R 34 may optionally be taken together with the attached nitrogen to form a heterocyclic or substituted heterocyclic group, and in which 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" is -NR 30 C(S)NR 33 R 34 where R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 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 wherein R 33 and R 34may optionally be taken together with the attached nitrogen to form a heterocyclic or substituted heterocyclic group, and in which 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 where R 33 and R 34 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 wherein R 33 and R 34 may optionally be taken together with the attached nitrogen to form a heterocyclic or substituted heterocyclic group, and in which 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 where R 33 and R 34is 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 attached nitrogen to form a heterocyclic or substituted heterocyclic group, and in which 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 where R 33 and R 34 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 wherein R 33 and R 34 may optionally be taken together with the attached nitrogen to form a heterocyclic or substituted heterocyclic group, and in which 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 where R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 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 wherein R 33 and R 34 may optionally be taken together with the attached nitrogen to form a heterocyclic or substituted heterocyclic group, and in which 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 where R 33 , R 34 , and R 35 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 wherein R 33 and R 34may optionally be taken together with the attached nitrogen to form a heterocyclic or substituted heterocyclic group, and in which 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" means a monovalent aromatic carbocyclic group of 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-benzoxazin-3(4H)-on-7-yl, etc.), provided that the point of attachment is at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.

[0046] The term "substituted aryl" refers to an aryl group substituted with 1 to 5, preferably 1 to 3, and more preferably 1 to 2, substituents, and the 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. and is 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, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0047] "Aryloxy" means a radical represented by -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.

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

[0049] "Arylthio" refers to a radical of the formula -S-aryl, where aryl is as defined herein.

[0050] "Substituted arylthio" refers to a group represented by --S-(substituted aryl), where substituted aryl is as defined herein.

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

[0052] "Substituted arylamino" refers to -NR 37 (substituted aryl), wherein R 37 is hydrogen, alkyl, or substituted alkyl, where substituted aryl is as defined herein.

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

[0054] "Carboxy" or "carboxyl" means --COOH or a salt thereof.

[0055]

[0033] "Carboxyl ester" or "carboxy ester" refers to 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-substituted aryl, -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 -C(O)O-substituted heterocyclic group, wherein R 30is alkyl or hydrogen, 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.

[0057] "(Carboxyl ester)oxy" refers to the groups 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 the group -C≡N.

[0059] "Cycloalkyl" refers to a saturated or unsaturated, but non-aromatic, monocyclic or polycyclic, including fused, bridged, and spirocyclic ring systems, alkyl group of 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. xCycloalkyl refers to a cycloalkyl group having x ring carbon atoms. Suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more rings can be aryl, heteroaryl, or heterocyclic, provided that the attachment point is via a non-aromatic, non-heterocyclic, saturated carbocyclic ring. "Substituted cycloalkyl" refers to a cycloalkyl group having 1 to 5, preferably 1 to 3, substituents, including oxo, thione, 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, (carboxyl) cycloalkyl), cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0060] "Cycloalkyloxy" refers to -O-cycloalkyl.

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

[0062] "Cycloalkylamino" is -NR 37 (cycloalkyl), wherein R 37 is hydrogen, alkyl, or substituted alkyl.

[0063] "Substituted cycloalkylamino" refers to -NR 37 (substituted cycloalkyl), wherein R 37 is hydrogen, alkyl, or substituted alkyl, and substituted cycloalkyl is as defined herein.

[0064] "Cycloalkylthio" refers to -S-cycloalkyl.

[0065] "Substituted cycloalkylthio" refers to --S-(substituted cycloalkyl).

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

[0067] "Substituted guanidino" is -NR 36 C(=NR 36 )N(R 36 )2, where each R 36 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's attached to the common guanidino nitrogen atom are 36 The groups may optionally be taken together with the attached nitrogen to form a heterocyclic or substituted heterocyclic group, provided that at least one R 36 is not hydrogen, and wherein the above substituents are as defined herein.

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

[0069] "Hydroxy" or "hydroxyl" refers to a group designated -OH.

[0070] "Heteroalkylene" refers to a heteroalkyl group in which one or more carbons are -O-, -S-, SO2, -NR Q -, [ka] [In the formula, R Q is H or C1-C6 alkyl. "Substituted heteroalkylene" means a heteroalkynylene group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the substituents disclosed for substituted alkylene.

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

[0072] The term "substituted heteroaryl" refers to a heteroaryl group substituted with 1 to 5, preferably 1 to 3, and more preferably 1 to 2, substituents selected from the group consisting of the same substituents as defined for substituted aryl.

[0073] "Heteroaryloxy" refers to -O-heteroaryl.

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

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

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

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

[0078] "Substituted heteroarylamino" refers to -NR 37 (substituted heteroaryl), wherein R 37 is hydrogen, alkyl, or substituted alkyl, and substituted heteroaryl are as defined herein.

[0079] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" means a saturated or partially saturated, but not 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. xHeterocycloalkyl refers to a heterocycloalkyl group having x ring atoms, including the ring heteroatom. Heterocycles include monocyclic or fused polycyclic rings, including fused, bridged, and spiro ring systems. In fused ring systems, one or more rings can be cycloalkyl, aryl, or heteroaryl, provided that the attachment point is via a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group can be optionally oxidized to provide N-oxide, sulfinyl, or sulfonyl moieties.

[0080] "Heterocyclylene" means 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. "Substituted heterocyclylene" means a heterocyclylene group substituted with 1 to 5, preferably 1 to 3, of the same substituents as defined for substituted cycloalkyl.

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

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

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

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

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

[0086] "Heterocyclylamino" is -NR 37(heterocyclyl), wherein R 37 is hydrogen, alkyl, or substituted alkyl.

[0087] "Substituted heterocyclylamino" refers to -NR 37 (substituted heterocyclyl), wherein R 37 is hydrogen, alkyl, or substituted alkyl, and substituted heterocyclyl is as defined herein.

[0088] Examples of heterocyclyl and heteroaryl include, but are not limited to, azetidinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridazyl, indolizyl, indolyl, isoindolyl, indolyl, dihydroindolyl, indazolyl, purinyl, quinolidinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, isoindolyl, phenyl ... These include isothiazolyl, phenazinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, imidazolidinyl, imidazolinyl, piperidinyl, piperazinyl, indolinyl, phthalimidyl, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrobenzo[b]thiophenyl, thiazolyl, thiazolidinyl, thiophenyl, benzo[b]thiophenyl, morpholinyl, thiomorpholinyl (also called thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidinyl, and tetrahydrofuranyl.

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

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

[0091] "Spirocyclic ring system" means a bicyclic ring system having a single ring carbon atom shared by the two rings.

[0092] "Sulfinyl" refers to the divalent group -S(O)- or -S(=O)-.

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

[0094] "Substituted sulfonyl" refers to 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, or -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. Substituted sulfonyl includes groups such as methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-. Preferred substituted alkyl groups on the substituted alkyl-SO2- include halogenated alkyl groups, and particularly halogenated methyl groups such as trifluoromethyl, difluoromethyl, and fluoromethyl.

[0095] "Substituted sulfinyl" refers to 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, or -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. Substituted sulfinyl includes groups such as methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-. Preferred substituted alkyl groups on the 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, or -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 (substituted sulfonyl), wherein R 37 is hydrogen, alkyl, or substituted alkyl, and substituted sulfonyl is as defined herein.

[0098] "Thioacyl" refers to the group 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 the radical -SH.

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

[0101] "Thiocarbonyl" refers to the divalent group -C(S)-, which is equivalent to -C(=S)-.

[0102] "Thione" means the atom, (=S).

[0103] "Alkylthio" refers to a radical of the formula -S-alkyl, where alkyl is as defined herein.

[0104] "Substituted alkylthio" refers to 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 particularly halogenated methyl groups such as trifluoromethyl, difluoromethyl, and fluoromethyl.

[0105] "Vinyl" means an unsaturated hydrocarbon group derived from ethylene, -CH=CH2.

[0106] Throughout this specification, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes cases where the event or circumstance occurs and cases where it does not. For example, "the nitrogen atom is optionally oxidized to provide an N-oxide (N→O) moiety" means that the nitrogen atom may, but need not, be oxidized, and the description includes situations where the nitrogen atom is not oxidized and situations where the nitrogen atom is oxidized.

[0107] The term "optionally substituted" refers to a substituted or unsubstituted group. A substituted group can be substituted with one or more substituents, such as, for example, 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, NO, -COR. 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 heteroaryl, wherein each R 100 are independently hydrogen or C1-C8 alkyl; C3-C 12 Cycloalkyl; C4-C 10 Heterocyclyl; C6-C 14 aryl; or C2-C12 and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each 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 substituents are selected from the group consisting of chloro, fluoro, -OCH3, methyl, ethyl, isopropyl, cyclopropyl, -OCF3, -CF3, and -OCHF2.

[0108] R 101 and R 102 are independently hydrogen; C1-C8 alkyl, C1-C6 alkoxy, oxo, -CR optionally substituted with -COH or an ester thereof; 103 =C(R 103 )2, -CCR, C3-C 10 Cycloalkyl, C3-C 10 Heterocyclyl, C6-C 14 Aryl or C2-C 12 heteroaryl, where each R 103 are independently hydrogen or C1-C8 alkyl; C3-C 12 Cycloalkyl; C4-C 10 Heterocyclyl; C6-C 14 aryl; or C2-C 12 heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 3 alkyl groups, or 1 to 3 halo groups; or R 101 and R 102 may be taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered heterocycle.

[0109] Unless otherwise noted, the nomenclature of substituents not explicitly defined herein is accomplished by naming the terminal portion of the functional group followed by the adjacent functional group toward the point of attachment. For example, the substituent "alkoxycarbonylalkyl" refers to a group represented by (alkoxy)-C(O)-(alkyl)-.

[0110] It is understood that the present specification does not intend to include polymers defined by defining a substituent having an additional substituent (for example, a substituted aryl having a substituted aryl group as a substituent itself substituted with a substituted aryl group). In such cases, the maximum number of such substituents is three. In other words, each of the above definitions is interpreted restrictively, for example, a substituted aryl group is limited to -substituted aryl-(substituted aryl)-substituted aryl.

[0111] In some embodiments of substituted moieties, the moiety is substituted with a group that may be substituted with an additional group, but the additional group may not be further substituted. For example, in some embodiments of "substituted alkyl," the alkyl portion is substituted with an optionally further substituted group (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, substituted alkylthio), but the 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 of the alkyl portion is not itself substituted with a further substituted moiety. Although "substituted alkyl" is shown as an example, such an embodiment is contemplated for each substituted moiety described herein.

[0112] In some embodiments of substituted moieties, the moiety is substituted with a group that is not further substituted. Thus, in some embodiments, a "substituted alkyl" is an alkyl moiety substituted with one or more, and in some aspects 1 or 2 or 3 or 4 or 5, 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, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, guanidino, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, nitro, SO3H, sulfonyloxy, sulfonylamino, thioacyl, thiol, and alkylthio. Although "substituted alkyl" is shown as an example, such an embodiment is contemplated for each substituted moiety described herein.

[0113] It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with four fluoro groups), such impermissible substitution patterns being well known to those of ordinary skill in the art.

[0114] It is understood that certain features of the invention that are, for clarity, described in the context of a separate embodiment, may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of embodiments relating to chemical groups represented by variables are specifically embraced by the present invention and are disclosed herein as if all combinations were individually expressly disclosed, to the extent that such combinations encompass compounds that are stable compounds (i.e., compounds that can be isolated, identified, and tested for biological activity). Furthermore, all subcombinations of chemical groups listed in embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein as if each such subcombination of chemical groups were individually expressly disclosed herein.

[0115] compound In one embodiment, a compound of formula (I): [ka] [In the formula, L is -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-; R 1 is an optionally substituted C-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)NR 6 R 7 , N.R. 6 COR 7 , N.R. 6 SO2R 7 , or C(O)OR 6 and; R 2is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C 10 aryl or an optionally substituted 5-10 membered heteroaryl; R 3 is 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 or R 2 and R 3 together with the atoms therebetween form a cycloalkyl or heterocycloalkyl, preferably an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 membered heterocycloalkyl; R 4 is optionally substituted C1-C6 alkyl, preferably C1-C3 haloalkyl such as CF3 or CF2Cl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl; X is O or S; Y is CH, C—(C1-C2 alkyl), or C-halo, or N; Z is CR 5 , or N; R 5 is H, or a halogen; R 6is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted C6-C 10 aryl or an optionally substituted 5-10 membered heteroaryl; and R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted C6-C 10 aryl or an optionally substituted 5-10 membered heteroaryl; or R 6 and R 7 together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heterocycle; 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-. or a tautomer or an N-oxide thereof, or their respective isotopic isomers, or their respective prodrugs, or their stereoisomers, or their respective pharmaceutically acceptable salts, or their respective solvates.

[0116] In some embodiments, a compound of formula (Ii): [ka] [In the formula, L is -NH-CO-, -CO-NH-, or -NH-SO2-; R 1 is an optionally substituted C-C 10Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered heterocycle, C(O)NR 6 R 7 , S(O)NR 6 R 7 , N.R. 6 COR 7 , N.R. 6 SO2R 7 , or C(O)OR 6 and; R 2 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C 10 aryl or an optionally substituted 5-10 membered heteroaryl; R 3 is 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 or R 2 and R 3 together with the atoms therebetween form a cycloalkyl or heterocycloalkyl, preferably an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 membered heterocycloalkyl; R 4 is optionally substituted C1-C6 alkyl, preferably C1-C3 haloalkyl such as CF3 or CF2Cl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl; X is O or S; Y is CH, C—(C1-C2 alkyl), or C-halo, or N; Z is CR 5 , or N; R 5 is H, or a halogen; R 6 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted C6-C 10 aryl or an optionally substituted 5-10 membered heteroaryl; and R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted C6-C 10 aryl or an optionally substituted 5-10 membered heteroaryl; or R 6 and R 7 together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heterocycle. or a tautomer or an N-oxide thereof, or their respective isotopic isomers, or their respective prodrugs, or their stereoisomers, or their respective pharmaceutically acceptable salts, or their respective solvates.

[0117] Also provided herein are compounds of formula (Ia): [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , X, Y, Z, and L are as defined for compounds of formula (I). The compound is provided as follows:

[0118] In some embodiments, the compound has the formula (IA): [ka] When Z is N, R 5 Similarly, R 5 If there is R 5 is attached to a carbon atom of an aryl ring, and Z is CR 5 It is understood that.

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

[0120] In some embodiments, the compound has the formula (IIA)-(IIH): [ka] [In the formula, R 10 is an optionally substituted 5-6 membered heteroaryl, preferably the heteroaryl moiety has up to two ring nitrogen atoms; R 20 is an optionally substituted C1-C3 alkyl, an optionally substituted C3-C4 cycloalkyl, or an optionally substituted 4-6 membered 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 membered heterocycloalkyl, preferably optionally substituted cyclopropyl; Ring A is an optionally substituted 5-6 membered heterocycloalkyl; and The remaining variables are as defined herein. The compound is selected from

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

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

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

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

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

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

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

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

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

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

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

[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 is an optionally substituted C-C 10 In some embodiments, R 1 is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R 1 is an optionally substituted 4-10 membered heterocycle. In some embodiments, R 1 is C(O)NR 6 R 7 In some embodiments, R 1 is S(O)NR 6 R 7 In some embodiments, R 1 is NR 6 COR 7 In some embodiments, R 1 is NR 6 SO2R 7 In some embodiments, R 1 is C(O)OR 6 is.

[0134] In some embodiments, R 2 is H. In some embodiments, R 2 is an optionally substituted C1-C6 alkyl. In some embodiments, R 2 is cycloalkylalkyl. In some embodiments, R 2 is heterocyclylalkyl. In some embodiments, R 2 is arylalkyl. In some embodiments, R 2 is heteroarylalkyl. In some embodiments, R 2is an optionally substituted C-C cycloalkyl. In some embodiments, R 2 is an optionally substituted 4-10 membered heterocycloalkyl. In some embodiments, R 2 is an optionally substituted C-C alkenyl. In some embodiments, R 2 is an optionally substituted C2-C6 alkynyl. In some embodiments, R 2 is an optionally substituted C-C 10 In some embodiments, R 2 is an optionally substituted 5-10 membered heteroaryl.

[0135] In some embodiments, R 3 is H. In some embodiments, R 3 is an optionally substituted C1-C6 alkyl. In some embodiments, R 3 is an optionally substituted C-C alkenyl. In some embodiments, R 3 is an optionally substituted C2-C6 alkynyl. In some embodiments, R 3 is an optionally substituted cycloalkyl. In some embodiments, R 3 is an optionally substituted heterocycloalkyl. In some embodiments, R 3 is an optionally substituted 4-6 membered heterocycloalkyl. In some embodiments, R 3 is optionally substituted aryl. In some embodiments, R 3 is an optionally substituted C-C 10 In some embodiments, R 3 is an optionally substituted heteroaryl. In some embodiments, R 3 is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R3 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, each of which is optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxyl, and C1-C6 alkyl. 3 is OR 6 In some embodiments, R 3 is NR 6 R 7 is.

[0136] In some embodiments, R 2 and R 3 R, together with the atoms between them, form the cycloalkyl ring A. R, together with the atoms between them, form the cycloalkyl ring A. 2 and R 3 is R 2 It is understood that this does not include the nitrogen atom to which R is attached. 2 It is understood that no additional heteroatoms other than the nitrogen atom to which R is attached form ring A. In some embodiments, R 2 and R 3 R, together with the atoms between them, form the heterocycloalkyl ring A. R, together with the atoms between them, form the heterocycloalkyl ring A. 2 and R 3 is R 2 It is understood that R includes the nitrogen atom to which it is attached. 2 It is also understood that additional heteroatoms can form ring A in addition to the nitrogen atom to which R is attached. 2 and R 3 together with the atoms between them form a heterocycloalkyl ring A, which is 2 In some embodiments, R does not contain heteroatoms other than the nitrogen atom to which it is attached. 2 and R 3together with the atoms between them form a heterocycloalkyl ring A, which is 2 In some embodiments, R 2 and R 3 together with the atoms therebetween form an optionally substituted C3-C8 cycloalkyl ring A. Suitable cycloalkyl substituents include, but are not limited to, C1-C6 alkyl, hydroxyC1-C6 alkyl, and C1-C6 alkyl substituted with 1 to 3 halo (preferably fluorine atoms). In some embodiments, R 2 and R 3 together with the atoms therebetween form an optionally substituted 4-10 membered heterocycloalkyl ring A. Suitable heterocycloalkyl substituents include, but are not limited to, C1-C6 alkyl, hydroxyC1-C6 alkyl, and C1-C6 alkyl substituted with 1 to 3 halo (preferably fluorine atoms).

[0137] In some embodiments, R 4 is an optionally substituted C1-C6 alkyl. In some embodiments, R 4 is C1-C3 haloalkyl. In some embodiments, R 4 is CF. In some embodiments, R 4 is CF2Cl. In some embodiments, R 4 is an optionally substituted C-C alkenyl. In some embodiments, R 4 is an optionally substituted C2-C6 alkynyl.

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

[0142] In some embodiments, R 6 is H. In some embodiments, R 6 is an optionally substituted C1-C6 alkyl. In some embodiments, R 6 is an optionally substituted C-C cycloalkyl. In some embodiments, R 6 is an optionally substituted 4-10 membered heterocycloalkyl. In some embodiments, R 6 is an optionally substituted C-C 10 In some embodiments, R 6 is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R 6 is C1-C6 alkyl, C3-C8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, each of which may be optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, and C1-C6 alkyl.

[0143] In some embodiments, R 7 is H. In some embodiments, R 7is an optionally substituted C1-C6 alkyl. In some embodiments, R 7 is an optionally substituted C-C cycloalkyl. In some embodiments, R 7 is an optionally substituted 4-10 membered heterocycloalkyl. In some embodiments, R 7 is an optionally substituted C-C 10 In some embodiments, R 7 is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R 7 is C1-C6 alkyl, C3-C8 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, each of which may be optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, and C1-C6 alkyl.

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

[0145] In some embodiments, R 6 and R 7 are taken together with the nitrogen to which they are attached to form an optionally substituted 4- to 7-membered heterocycle. 6 and R 7 together with the nitrogen to which they are attached form a 4-7 membered heterocycle, optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxyl, and C1-C6 alkyl.

[0146] In some embodiments, R 10 is a 5-6 membered heteroaryl. In some embodiments, R 10 is a 5-6 membered heteroaryl, the heteroaryl moiety having up to two ring nitrogen atoms. 10 is a 5-6 membered heteroaryl optionally substituted with 1-3 substituents selected from the group consisting of halogen, cyano, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, and C3-C6 cycloalkyl.

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

[0148] In some embodiments, R 1 is a 5-6 membered heteroaryl. In some embodiments, R 1 is a 5-6 membered heteroaryl containing up to two ring nitrogen atoms. In some embodiments, R 1 is a 5-6 membered heteroaryl containing two ring nitrogen atoms. In some embodiments, R 1 is a 5-6 membered heteroaryl containing one ring nitrogen atom. In some embodiments, R 1 is a 5-6 membered heteroaryl containing 3 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 is a 5-6 membered heteroaryl containing one ring nitrogen atom and one ring sulfur atom. In some embodiments, R 1 is a 5-6 membered 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 is isoxazolyl. In some embodiments, R 1 is a 4-5 membered heterocyclyl containing one ring nitrogen atom. 1 is a 4-5 membered heterocyclyl optionally substituted with 1-2 oxo groups. 1 is azetidinyl. In some embodiments, R 1 is pyrrolidinyl. In any of these embodiments, R 1 is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, and C3-C6 cycloalkyl. 1 is substituted with 1 to 2 substituents selected from the group consisting of halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 alkyl, and C3-C6 cycloalkyl. 1 is substituted with one substituent selected from the group consisting of halogen, cyano, hydroxyl, C-C alkoxy, C-C alkyl, and C-C cycloalkyl. 1 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] is.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0182] In some embodiments, R 1 is -CONH(C-Ccycloalkyl). In some embodiments, R 1 is -CONH(C-C cycloalkyl). In some embodiments, R 1 is -CONH(C3-C4 cycloalkyl).

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

[0184] In some embodiments, R 1 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 is -CON(H)(CH3) or -CON(H)(C2H5).

[0186] In some embodiments, R 2 is an optionally substituted C1-C3 alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is propyl. In some embodiments, R 2 is optionally substituted isopropyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is butyl. In some embodiments, R 2 is tertiary butyl. In some embodiments, R 2 is pentyl. In some embodiments, R 2 is n-pentyl, sec-pentyl, 3-pentyl, or sec-isopentyl. 2 is an optionally substituted C-C cycloalkyl. In some embodiments, R 2 is cyclopropyl. In some embodiments, R 2 is cyclobutyl. In some embodiments, R 2 is cyclopentyl. In some embodiments, R 2 is a 4-6 membered heterocyclyl. In some embodiments, R 2 is a 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen. 2 is tetrahydrofuranyl. In some embodiments, R 2 is tetrahydropyranyl. In some embodiments, R 2 is thietanyl. In some embodiments, R 2 is pyrrolidinyl. In any of these embodiments, R 2is optionally 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 membered heterocyclyl, cyano, oxo, —C(O)NH(C1-C6 alkyl), and —C(O)NH(C3-C6 cycloalkyl). In some variations, R 2 is substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, C1-C3 alkoxy, C1-C3 alkyl, C3-C5 cycloalkyl, 4-6 membered heterocyclyl, cyano, oxo, —C(O)NH(C1-C3 alkyl), and —C(O)NH(C3-C6 cycloalkyl). 2 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(CH), —C(O)NH(CHCH), —C(O)NH(cyclopropyl), —C(O)NH(cyclobutyl), —C(O)NH(cyclopentyl), and —C(O)NH(cyclohexyl). is.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0221] In some embodiments, R 2 and R 3 together with the atoms therebetween form an optionally substituted 5-6-membered heterocycloalkyl ring A. In some embodiments, ring A is optionally substituted with 1-3 substituents selected from the group consisting of C-C alkyl, hydroxyl, C-C alkyl-OH, —C(O)(C-C alkyl), and oxo. In some variations, ring A is substituted with 1-3 substituents selected from the group consisting of C-C alkyl, hydroxyl, C-C alkyl-OH, —C(O)(C-C alkyl), and oxo. In some variations, ring A is substituted with 1-3 substituents selected from the group consisting of methyl, ethyl, hydroxyl, —CHOH, —CHCH—OH, —C(O)CH, —C(O)CHCH, and oxo.

[0222] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0223] In some embodiments, R 2 and R3 together, [ka] is formed.

[0224] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0225] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0226] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0227] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0228] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0229] In some embodiments, R 2 and R3 together, [ka] is formed.

[0230] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0231] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0232] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0233] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0234] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0235] In some embodiments, R 2 and R3 together, [ka] is formed.

[0236] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0237] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0238] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0239] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0240] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0241] In some embodiments, R 2 and R3 together, [ka] is formed.

[0242] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0243] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0244] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0245] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0246] In some embodiments, R 2 and R 3 together, [ka] is formed.

[0247] In some embodiments, R 2 and R3 together, [ka] is formed.

[0248] In some embodiments, R 3 is H. In some embodiments, R 3 is C1-C6 alkyl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, and —O(C1-C6 alkyl). In some embodiments, R 3 is methyl. In some embodiments, R 3 is isopropyl. In some embodiments, R 3 is difluoromethyl. In some embodiments, R 3 is hydroxyethyl. In some embodiments, R 3 is —CHCHOH. In some embodiments, R 3 is —C(Me)OH. In some embodiments, R 3 is —CH(Me)OH. In some embodiments, R 3 is methoxymethyl. In some embodiments, R 3 is hydroxymethyl. In some embodiments, R 3 is C-C cycloalkyl. In some embodiments, R 3 is C3-C6 cycloalkyl substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-C6 alkyl, and hydroxyl. 3 is cyclopropyl. In some embodiments, R 3 is cyclobutyl. In some embodiments, R 3 -OR 6 where R 6 is C1-C6 alkyl. In some embodiments, R 3is methoxy. In some embodiments, R 3 is ethoxy. In some embodiments, R 3 is a 4-6 membered heterocyclyl. In some embodiments, R 3 is a 4-6 membered heterocyclyl substituted with 1-3 substituents selected from the group consisting of halogen, C1-C6 alkyl, and hydroxyl. 3 is tetrahydropyranyl.

[0249] In some embodiments, R 4 is an optionally substituted C1-C3 alkyl. In some embodiments, R 4 is C1-C3 alkyl, The alkyl group is substituted with one or more halo substituents. In some embodiments, R 4 is C1-C3 alkyl substituted with 1 to 3 halo substituents. 4 is CF. In some embodiments, R 4 is CF2Cl.

[0250] In one embodiment, compounds of formula (I) are provided, wherein the compounds have any one or more of the following characteristics: (I)R 1 teeth: (i) a 5-6 membered heteroaryl optionally substituted with 1-3 substituents selected from the group consisting of halogen, cyano, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C1-C6 alkyl; or (ii) a 4- to 5-membered heterocyclyl optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxyl, C-C alkoxy, C-C cycloalkyl, C-C alkyl, and oxo; or (iii)R 1 -CONHR 7 where R7 is H, C3-C6 cycloalkyl, or C1-C6 alkyl; (II)R 2 teeth: (iv) C-C alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, C-C alkoxy, C-C alkyl, C-C cycloalkyl, 4- to 6-membered heterocyclyl, cyano, —C(O)NH(C-C alkyl), and —C(O)NH(C-C cycloalkyl); or (v)R 2 is a C-C cycloalkyl optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, C-C alkoxy, C-C alkyl, C-C cycloalkyl, 4- to 6-membered heterocyclyl, cyano, oxo, —C(O)NH(C-C alkyl), and —C(O)NH(C-C cycloalkyl); or (vi) a 4- to 6-membered heterocyclyl optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, C-C alkoxy, C-C alkyl, C-C cycloalkyl, a 4- to 6-membered heterocyclyl, cyano, oxo, —C(O)NH(C-C alkyl), and —C(O)NH(C-C cycloalkyl); or (vii) H; (III)R 3 teeth: (viii) H; or (ix) C1-C6 alkyl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, and —O(C1-C6 alkyl); or (x)-OR 6 where R 6 is C1-C6 alkyl; or (xi) C3-C6 cycloalkyl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-C6 alkyl, and hydroxyl; or (xii) a 4- to 6-membered heterocyclyl optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-C6 alkyl, and hydroxyl; (IV)R 2 and R 3 together with the atoms therebetween form ring A, which is a 5-6 membered heterocycloalkyl optionally substituted by 1-3 substituents selected from the group consisting of C-C alkyl, hydroxyl, C-C alkyl-OH, —C(O)(C-C alkyl), and oxo; (V)R 4 is C1-C3 alkyl 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 aspect of this variation, (I), (II), (III), (V), (VI), (VII), and (VIII) apply. In another aspect 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 aspect, provided are compounds of Formula (I), such as those provided in the following Examples (e.g., Examples 1-49) and depicted in Table 1 (Examples 50-232), or tautomers or N-oxides thereof, or their respective isotopic isomers, or their respective prodrugs, or their stereoisomers, or their respective pharmaceutically acceptable salts, or their respective solvates.

[0252] The present disclosure also includes all salts, such as pharmaceutically acceptable salts, of the compounds described herein. The present disclosure also includes any or all stereochemical forms, including enantiomeric or diastereomeric forms, tautomers, or other forms, such as N-oxides, solvates, prodrugs, or isotopic isomers, of the described compounds. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to encompass all possible stereoisomers of the depicted compound. Furthermore, when a specific stereochemical form is depicted, it is understood that other stereochemical forms are also encompassed by the present invention. All forms of the compounds, including crystalline or amorphous forms of the compounds, are also encompassed by the present invention. Compositions comprising compounds of the present invention, for example, compositions of substantially pure compounds comprising a specific stereochemical form, are also contemplated. Compositions comprising mixtures of compounds of the present invention in any ratio are also encompassed by the present invention, including mixtures of two or more stereochemical forms of compounds of the present invention in any ratio, and including racemic, non-racemic, enantioenriched, and scalemic mixtures.

[0253] In the description herein, it is understood that any description, variation, embodiment, or aspect of a moiety can be combined with any description, variation, embodiment, or aspect of any other moiety, and that all combinations of descriptions are equivalent to those specifically and individually set forth. For example, R 1 All descriptions, variations, embodiments, or aspects provided herein regarding 2 , R 3 , R 4 , R 5 , R 6 , R 7, X, L, Y, and / or Z, and all combinations are as if specifically and individually set forth. It is understood that all descriptions, variations, embodiments, or aspects of formula (I) apply equally to other formulas described herein, where applicable, and all descriptions, variations, embodiments, or aspects are as if separately and individually set forth for all formulas. For example, all descriptions, variations, embodiments, or aspects of formula (I) apply equally to formulas (Ii), (Ia), (IA), (IA-1), (IIA), (IIB), (IIC), (IID), (IIE), (IIF), (IIG), (IIH), (Ib), (Ic), (Id), and (Ie), where applicable, described herein, and all descriptions, variations, embodiments, or aspects are as if separately and individually set forth for all formulas.

[0254] The present invention also includes all salts, such as pharmaceutically acceptable salts, of the compounds described herein. The present invention also includes any or all stereochemical forms, including enantiomeric or diastereomeric forms, tautomers, or other forms, such as N-oxides, solvates, prodrugs, or isotopic isomers, of the described compounds. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to encompass all possible stereoisomers of the depicted compound. Furthermore, when a specific stereochemical form is depicted, it is understood that other stereochemical forms are also included in the present invention. All forms of the compounds, including crystalline or amorphous forms of the compounds, are also included in the present invention. Compositions containing the compounds of the present invention, for example, compositions of substantially pure compounds containing their specific stereochemical form, are also contemplated. 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 including racemic, non-racemic, enantioenriched, 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 a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In one aspect, 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, buccal, parenteral, nasal, topical, or rectal administration, or in a form suitable for administration by inhalation.

[0256] In one aspect, the compounds described herein can be in purified form, and compositions comprising the compounds in purified form are described herein. Compositions comprising the compounds described herein or salts thereof, such as compositions of substantially pure compounds, are provided. In some embodiments, compositions comprising the compounds described herein or salts thereof are in substantially pure form. In one variation, "substantially pure" refers to a composition containing 35% or less impurities, where impurities refer to compounds other than the compound or salts thereof that make up the majority of the composition. For example, a composition of a substantially pure compound selected from the compounds of Table 1 (A, B, etc.) refers to a composition containing 35% or less impurities, where impurities refer to compounds other than the compound or salts thereof. In one variation, a composition of a substantially pure compound or salt thereof containing 25% or less impurities is provided. In another variation, a composition of a substantially pure compound or salt thereof containing 20% ​​or less impurities is provided. In yet another variation, a composition of a substantially pure compound or salt thereof containing 10% or less impurities is provided. In a further variation, a composition of a substantially pure compound or salt thereof containing 5% or less impurities is provided. In another variation, a substantially pure composition of a compound or salt thereof is provided, the composition containing 3% or less of an impurity. In yet another variation, a substantially pure composition of a compound or salt thereof is provided, the composition containing 1% or less of an impurity. In a further variation, a substantially pure composition of a compound or salt thereof is provided, the composition containing 0.5% or less of an impurity. In yet another variation, a substantially pure composition of a compound means that the composition contains 15% or less of an impurity, preferably 10% or less, more preferably 5% or less, even more preferably 3% or less, and most preferably 1% or less of an impurity, which may be a compound of a different stereochemical form. For example, and without limitation, 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)-form of the compound.

[0257] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual, such as a human. In another variation, compositions containing the compounds in substantially pure form are provided. In another variation, the invention encompasses pharmaceutical compositions containing the compounds described herein and a pharmaceutically acceptable carrier or excipient. In another variation, methods of administering the compounds are provided. Purified forms, pharmaceutical compositions, and methods of administering the compounds are suitable for any of the compounds or forms thereof described herein.

[0258] The compounds can be formulated for any available delivery route, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery forms. The compounds can be formulated with a suitable carrier to provide delivery forms, including, but not limited to, tablets, caplets, capsules (e.g., hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, powders, suppositories, ointments, poultices (cataplasms), pastes, powders, dressings, 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 several compounds described herein can be used to manufacture preparations such as pharmaceutical preparations by combining a compound or compounds as an active ingredient with a pharmaceutically acceptable carrier as described above. Depending on the therapeutic form of the system (e.g., transdermal patch or oral tablet), the carrier can be in various forms. In addition, pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, modifiers, and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants. Preparations containing compounds can also contain other substances with useful therapeutic properties. Pharmaceutical preparations 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 individuals (e.g., humans) in the form of commonly accepted oral compositions, such as tablets, coated tablets, hard-shell or soft-shell gel capsules, emulsions, or suspensions. Carriers that can be used to prepare such compositions include, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. Acceptable carriers for soft-shell gel capsules include, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, adjusters, and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants.

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

[0262] Compositions comprising 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, compositions of substantially pure compounds are provided.

[0263] Methods of Use / Treatment The compounds and compositions detailed herein, such as pharmaceutical compositions comprising a compound provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, can be used in the methods of administration and treatment provided herein. The compounds and compositions can also be used in in vitro methods, such as in vitro methods in which the compound or composition is administered to cells for screening purposes and / or to perform quality control assays.

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

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

[0266] The compounds provided herein or their salts and the compositions provided herein are believed to be effective in treating various diseases and disorders. In some embodiments, the compounds provided herein or their salts, or the compositions provided herein, can be used in methods for treating diseases mediated by ABL1, ABL2, and / or BCR-ABL1.

[0267] In one aspect, provided herein is a method for treating a disease in a patient, wherein modulation of BCR-ABL1 activity prevents, suppresses, or ameliorates disease pathology and / or symptoms, the method comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In one embodiment, provided herein is a method for treating a disease in a patient, wherein modulation of BCR-ABL1 activity prevents disease pathology and / or symptoms, the method comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In one embodiment, provided herein is a method for treating a disease in a patient, wherein modulation of BCR-ABL1 activity suppresses disease pathology and / or symptoms, the method comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In one embodiment, provided herein is a method for treating a disease in a patient, wherein modulation of BCR-ABL1 activity ameliorates disease pathology and / or symptoms, the method comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein.

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

[0269] In one aspect, provided herein is a method of treating leukemia in a patient, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In one aspect, provided herein is a method of 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).

[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. In some embodiments, 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.

[0271] In some embodiments, the leukemia is resistant to treatment. In some embodiments, the leukemia is resistant to treatment with imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and / or bafetinib. In some embodiments, the CML is resistant to standard treatment, such as treatment with one or more of imatinib, nilotinib, and dasatinib. In some embodiments, the leukemia has progressed during previous treatment. In some embodiments, the previous treatment 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, the AML is secondary AML that develops after myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN).

[0274] In one aspect, provided herein is a method for treating cancer in a patient, 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 aspect, provided herein is a method for treating a neurodegenerative disease in a patient, 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 disease or disorder mediated by BCR-ABL1 activity 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 when an individual or patient does not develop the disease or disorder.In one embodiment, an individual or patient at risk of developing a disease or disorder mediated by BCR-ABL1 activity has one or more risk factors for developing the disease or disorder, such as a family history of an individual or patient with the disease or disorder, or has an underlying genetic condition associated with an increased likelihood of developing the disease or disorder.

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

[0278] Methods for treating diseases mediated by BCR-ABL1, such as various leukemias, are well known to those skilled in the art, and treatment of such diseases can be carried out with the 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 human. In some embodiments, the human is about 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years of age 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 of age 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 a mutation in the ABL1 and / or ABL2 gene. In some embodiments, the patient is Philadelphia chromosome positive.

[0280] The compounds or compositions provided herein can be administered to a patient for a desired time or period, for example, about 1 month or more, about 2 months or more, about 3 months or more, about 6 months or more, or about 12 months or more, or more, according to an effective dosing regimen, which in some variations may be for the patient's lifetime. In one variation, the compound is administered daily or on an intermittent schedule. The compound can be administered to a patient continuously (e.g., once a day or more) for a period of time. The dosing frequency can also be less than once a day, for example, about once a week. The dosing frequency can be more than once a day, for example, twice or three times a day. The dosing frequency can also be intermittent (e.g., once a day for 7 days, followed by 14 days of 7 days without dosing, repeated every about 2 months, about 4 months, about 6 months, or more). The dosing frequency can be achieved by using any of the compounds described herein at any dosage described herein.

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

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

[0283] In one embodiment, an effective amount of the compound may be a dose of about 0.01 to about 100 mg / kg. The effective amount or dose of the compound of the present disclosure can be determined by routine methods, such as modeling, dose escalation, or clinical trials, taking into account certain 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, and the subject's health, condition, and weight. Doses range, for example, from about 0.7 mg to 7 g per day, or from about 7 mg to 350 mg per day, or from about 350 mg to 1.75 g per day, or from about 1.75 to 7 g per day.

[0284] Also provided herein is the use of a compound described herein or a salt thereof, or a composition described herein, in the manufacture of a medicament. In some embodiments, the medicament is for the treatment of a disease described herein. In some embodiments, the medicament is for the treatment of a disease mediated by ABL1, ABL2, and / or BCR-ABL1.

[0285] Products and Kits The present disclosure further provides a product comprising a compound or salt thereof described herein, a composition described herein, or one or more unit doses described herein, suitably packaged. In certain embodiments, the product is for use in any of the methods described herein. Suitable packages are known in the art and include, for example, vials, containers, ampoules, bottles, jars, flexible packaging, etc. The product may also be sterilized and / or sealed.

[0286] The present disclosure further provides a kit for carrying out the method of the present disclosure, comprising one or more compounds described herein or a composition containing a compound described herein.The kit can use any of the compounds disclosed herein.In one variation, the kit uses a compound described herein or a salt thereof.The kit can be used for one or more of the purposes described herein, and therefore can include instructions for treating a disease described herein, such as treating cancer.

[0287] The kits may be in unit dosage form, bulk packages (e.g., multi-dose packages), or subunit doses. For example, kits may be provided that contain a sufficient dose of a compound disclosed herein and / or an additional pharmaceutically active compound useful for a disease detailed herein to effectively treat a patient for an extended period of time, such as 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. The kits may also include multiple unit doses of the compound and instructions for use, and may be packaged in an amount sufficient for storage and use in a pharmacy (e.g., a hospital pharmacy or a compounding pharmacy).

[0288] The kits can optionally include an instruction set, generally written instructions, although electronic storage media (e.g., magnetic diskettes or optical disks) containing instructions are also acceptable relating to the use of the components of the disclosed methods. Instructions included with the kits typically include information regarding the components and their administration to a patient.

[0289] Example of an embodiment The present disclosure is further illustrated by the following embodiments, the features of each embodiment may be combined with other embodiments where appropriate and useful.

[0290] Embodiment 1 Formula (I) or Formula (Ia): [ka] [In the formula, L is -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-; R 1 is an optionally substituted C-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)NR 6 R 7 , N.R. 6 COR 7 , N.R.6 SO2R 7 , or C(O)OR 6 and; R 2 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C 10 aryl or an optionally substituted 5-10 membered heteroaryl; R 3 is 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 or R 2 and R 3 together with the atoms therebetween form a cycloalkyl or heterocycloalkyl, preferably an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 membered heterocycloalkyl; R 4 is optionally substituted C1-C6 alkyl, preferably C1-C3 haloalkyl such as CF3 or CF2Cl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl; X is O or S; Y is CH, C—(C1-C2 alkyl), or C-halo, or N; Z is CR 5 , or N; R 5 is H, or halogen when Z is CH; R 6is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted C6-C 10 aryl or an optionally substituted 5-10 membered heteroaryl; and R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted C6-C 10 aryl, or an optionally substituted 5-10 membered heteroaryl; or R 6 and R 7 together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heterocycle. or a tautomer or an N-oxide thereof, 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 Formula (IA): [ka] wherein the variables are as defined in embodiment 1. 2. The compound of embodiment 1, wherein

[0292] Embodiment 3 Formula (IIA) ~ Formula (IIE): [ka] [In the formula, R 10 is a 5-6 membered heteroaryl, preferably the heteroaryl moiety has up to two ring nitrogen atoms; R 20is 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 variables are as defined in embodiment 1. The compound of embodiment 2, selected from:

[0293] Embodiment 4 The compound of embodiment 2 or 3, wherein X is O.

[0294] Embodiment 5 R 1 is a 5- to 10-membered heteroaryl, preferably the heteroaryl moiety contains up to two ring nitrogen atoms, or R 1 The compound of any one of embodiments 2-4, wherein is a 4-10 membered heterocycle, preferably wherein the heterocyclyl moiety contains up to two ring nitrogen atoms.

[0295] Embodiment 6 R 1 are: -CONH(cyclopropyl), -CONH2, -CONHMe, [ka] The compound of any one of embodiments 2-5, wherein

[0296] Embodiment 7 R 1 The compound of any one of embodiments 2-6, wherein is pyrimidinyl or pyrazolyl.

[0297] Embodiment 8 R 2is optionally substituted C1-C3 alkyl or optionally substituted C3-C4 cycloalkyl, preferably R 2 The compound of any one of embodiments 2-7, wherein is methyl, optionally substituted isopropyl, or cyclopropyl.

[0298] Embodiment 9 R 2 are: methyl, isopropyl, tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl, [ka] The compound of any one of embodiments 2-7, wherein

[0299] Embodiment 10 R 3 The compound of any one of embodiments 2-9, wherein is: H, methyl, isopropyl, difluoromethyl, hydroxyethyl, cyclopropyl, cyclobutyl, —C(Me) 2 OH, methoxymethyl, hydroxymethyl, methoxy, hydroxyethyl, —CH 2 CH 2 OH, or tetrahydropyranyl.

[0300] Embodiment 11 R 2 and R 3 together, [ka] The compound of any one of embodiments 2 to 6, wherein

[0301] Embodiment 12 R 4 is optionally substituted C1-C3 alkyl, preferably wherein the alkyl group is substituted by one or more halo substituents, more preferably R 4 The compound of any one of embodiments 2-11, wherein is CF3 or CF2Cl.

[0302] Embodiment 13 R 5 The compound of any one of embodiments 2-12, wherein is H.

[0303] Embodiment 14 The compound of any one of embodiments 2-13, wherein Y is CH.

[0304] Embodiment 15 Formula (Ib) or Formula (Ic): [ka] wherein the remaining variables are as defined in embodiment 1. 2. The compound of embodiment 1, wherein

[0305] Embodiment 16 A compound selected from the compounds of formula (I) in Examples 1 to 26 and Table 1, or a tautomer or an N-oxide thereof, 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 a compound of any one of embodiments 2-16 and at least one pharmaceutically acceptable excipient.

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

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

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

[0310] Embodiment 21 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 22. The method of embodiment 20 or 21, wherein the CML is resistant to standard therapy, such as treatment with one or more of imatinib, nilotinib, and dasatinib.

[0312] Embodiment 23 22. The method of embodiment 20 or 21, wherein the AML is secondary AML that develops after myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN). [Example]

[0313] The following abbreviations may be relevant to this application: Abbreviation Ac: Acetyl Bn: Benzyl Bu: butyl Bz: benzoyl CMC: Carboxymethyl cellulose DCM: dichloromethane DIPEA: Diisopropylethylamine DMF: dimethylformamide DMEDA: N,N'-dimethylethylenediamine DSC: N,N'-disuccinimidyl carbonate or bis(2,5-dioxopyrrolidin-1-yl) carbonate dppf: 1,1'-bis(diphenylphosphino)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: para-methoxybenzyl 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 Compounds of Formula (I): Synthetic Scheme As shown below in the examples of compounds of formula (I), in certain exemplary embodiments, compounds of formula (I) are prepared by the following general methods. While the general methods are representative of the synthesis of specific compounds of the present invention, it is understood that the following general methods, and other methods known to those of skill in the art, are applicable to all compounds and subclasses described herein, and species of each compound thereof.

[0315] Scheme 1 [ka] [In the formula, R 1 and R 2 is as defined in the compound of formula (I). Compounds of formula (S7) can be prepared by the general synthetic method shown in Scheme 1. Nitroanilines (S2) can be readily prepared by treating 1a with various primary amines (S1) in a suitable solvent, such as ethanol, containing a base, such as, but not limited to, triethylamine, at temperatures between about room temperature and reflux for 30 minutes to 8 hours. Phenylenediamines (S3) can be formed by reduction of nitroanilines (S2) using a reducing agent, such as, but not limited to, iron, in a solvent, such as, but not limited to, acetic acid, at temperatures between about room temperature and reflux for a period of about 1 hour. Cyclization of phenylenediamines (S3) to benzimidazoles (S4) can be carried out in the presence of an acid, such as, but not limited to, p-TsOH, using a reagent, such as, but not limited to, trimethyl orthoformate, at temperatures between about room temperature and 100°C for a period of about 10 minutes to 1 hour. Compounds of formula (S5) can be prepared from bromide (S4) by treatment with an aryl, heteroaryl, or heterocyclic boronic acid or boronic ester under palladium catalysis, such as, but not limited to, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the presence of water and an inorganic base, such as, but not limited to, sodium carbonate, potassium carbonate, or potassium phosphate, in an organic solvent, such as, but not limited to, 1,4-dioxane, at elevated temperature. Treatment of ester (S5) with a hydroxide source, such as, but not limited to, lithium hydroxide, in the presence of water and an organic solvent, such as, but not limited to, methanol and / or tetrahydrofuran, provides carboxylic acids of formula (S6). Reaction of carboxylic acid (S6) 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 an amine (1h) provides an amide of formula (S7).

[0316] Scheme 2 [ka] [In the formula, R 1 and R 2 is as defined in the compounds of formula (I); X is halogen; and Z is CH or N. Compounds of formula (S10) can be prepared by the general synthetic method shown in Scheme 2. Treatment of ester (S5) with a hydroxide source, such as, but not limited to, lithium hydroxide, in the presence of water and an organic solvent, such as, but not limited to, methanol and / or tetrahydrofuran, provides carboxylic acids of formula (S8). Reaction of 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 an amine (1h) provides amides of formula (S9). Compounds of formula (S10) can be prepared from the halide (S9) by treatment with an aryl, heteroaryl, or heterocyclic boronic acid or boronic ester under palladium catalyzed conditions, such as, but not limited to, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the presence of water and an inorganic salt, such as, but not limited to, sodium carbonate, potassium carbonate, or potassium phosphate, in an organic solvent, such as, but not limited to, 1,4-dioxane, at elevated temperature.

[0317] Scheme 3 [ka] [In the formula, R 1 and R 3 is as defined for compounds of formula (I). Compounds of formula (S15) can be prepared by the general synthetic method shown in Scheme 3. Treatment of compound (3a) with various carboxylic acids at temperatures between about 80°C and 130°C for about 1 to 2 hours provides benzimidazoles of formula (S11). Treatment of benzimidazole (S11) with methyl iodide in the presence of a base, such as, but not limited to, potassium carbonate, in an organic solvent, such as, but not limited to, N,N-dimethylformamide, at a temperature of about 50°C for about 3 hours provides benzimidazole (S12). Treatment of ester (S12) with a hydroxide source, such as, but not limited to, lithium hydroxide, in the presence of water and an organic solvent, such as, but not limited to, methanol and / or tetrahydrofuran, provides carboxylic acids of formula (S13). Reaction of carboxylic acid (S13) 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 an amine (1h) in an organic solvent, such as, but not limited to, N,N-dimethylformamide, at about room temperature for about 30 minutes provides an amide of formula (S14). Compounds of formula (S15) can be prepared from bromide (S14) by treatment with an aryl, heteroaryl, or heterocyclic boronic acid or boronic ester under palladium catalyzed conditions, such as, but not limited to, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the presence of water and an inorganic salt, such as, but not limited to, sodium carbonate, potassium carbonate, or potassium phosphate, in an organic solvent, such as, but not limited to, 1,4-dioxane, at elevated temperature.

[0318] Scheme 4 [ka] [In the formula, R 1 , R 2and R 3 is as defined in the compound of formula (I). Compounds of formula (S20) can be prepared by the general synthetic method shown in Scheme 4. Substituted phenylenediamines of formula (S16) are treated with various carboxylic acids at temperatures between about 80°C and 130°C for about 1 to 2 hours to provide benzimidazoles of formula (S17). Treatment of esters (S17) with a hydroxide source, such as, but not limited to, lithium hydroxide, in the presence of water and an organic solvent, such as, but not limited to, methanol and / or tetrahydrofuran, provides carboxylic acids of formula (S18). Reaction of carboxylic acid (S18) 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 an amine (1h) in an organic solvent, such as, but not limited to, N,N-dimethylformamide, at about room temperature for about 30 minutes provides the amide of (S19). Compounds of formula (S20) can be prepared from bromide (S19) by treatment with an aryl, heteroaryl, or heterocyclic boronic acid or boronic ester under palladium catalyzed conditions, such as, but not limited to, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the presence of water and an inorganic salt, such as, but not limited to, sodium carbonate, potassium carbonate, or potassium phosphate, in an organic solvent, such as, but not limited to, 1,4-dioxane, at elevated temperature.

[0319] Scheme 5 [ka] [In the formula, R 1 , R 2 and R 3 is as defined in the compound of formula (I). Compounds of formula (S26) can be prepared by the general synthetic method shown in Scheme 5. Treatment of ester (S21) with a hydroxide source, such as, but not limited to, lithium hydroxide, in the presence of water and an organic solvent, such as, but not limited to, methanol and / or tetrahydrofuran, provides carboxylic acids of formula (S22). Reaction of carboxylic acid (S22) 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 an amine (1h) in an organic solvent, such as, but not limited to, N,N-dimethylformamide, at a temperature between room temperature and 50° C. for about 2 hours provides amides of formula (S23). Phenylenediamines (S24) can be formed by reduction of nitroanilines (S23) using a reducing agent, such as, but not limited to, iron, in a solvent, such as, but not limited to, acetic acid, at a temperature of about 35°C for about 3 hours. Treatment of substituted phenylenediamines of formula (S24) with various carboxylic acids at temperatures of about 80°C-130°C for about 1 to 2 hours provides benzimidazoles of formula (S25). Compounds of formula (S26) can be prepared from bromides (S25) by treatment with aryl, heteroaryl, or heterocyclic boronic acids or boronic esters under palladium catalysis, such as, but not limited to, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the presence of water and an inorganic salt, such as, but not limited to, sodium carbonate, potassium carbonate, or potassium phosphate, in an organic solvent, such as, but not limited to, 1,4-dioxane, at elevated temperatures.

[0320] Scheme 6 [ka] [In the formula, R 1 , R 2 and R3 is as defined in the compound of formula (I). Compounds of formula (S29) can be prepared by the general synthetic method shown in Scheme 6. Compounds of formula (S27) can be prepared from bromide (S25) by treatment with an aryl, heteroaryl, or heterocyclic boronic acid or boronic ester under palladium catalysis, such as, but not limited to, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the presence of water and an inorganic salt, such as, but not limited to, sodium carbonate, potassium carbonate, or potassium phosphate, in an organic solvent, such as, but not limited to, 1,4-dioxane, at elevated temperature. Treatment of ester (S27) with a hydroxide source, such as, but not limited to, lithium hydroxide, in the presence of water and an organic solvent, such as, but not limited to, methanol and / or tetrahydrofuran, provides the carboxylic acid of formula (S28). Reaction of carboxylic acid (S28) 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 an amine (1h) in an organic solvent, such as, but not limited to, N,N-dimethylformamide, at a temperature between room temperature and 50° C. for about 2 hours provides an amide of formula (S29).

[0321] Scheme 7 [ka] [In the formula, R 1 is as defined in compounds of formula (I); X is a halide; and, as used herein, R 15 and R 16 is an optional substituent. Compounds of formula (S38) can be prepared by the general synthetic method shown in Scheme 7. Compounds of formula (S30) can be converted to compounds of formula (S31) in the presence of an acid, such as, but not limited to, hydrochloric acid, in an organic solvent, such as, but not limited to, ethyl acetate, at a temperature of about 15° C. for about 2 hours. Nitroanilines (S32) can be readily obtained by treating amines (S31) with (1a) and a base, such as, but not limited to, triethylamine, in a suitable solvent, such as ethanol, at a temperature of about 15° C. for about 1 hour. Phenylenediamines (S33) can be formed by reduction of nitroanilines (S32) with a reducing agent, such as, but not limited to, iron, in a solvent, such as, but not limited to, acetic acid, at a temperature of about room temperature to reflux for a time period ranging from about 1 hour. Reaction of carboxylic acid (S33) 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, in an organic solvent, such as, but not limited to, N,N-dimethylformamide, at about room temperature for 16 hours, along with a base, such as, but not limited to, diisopropylethylamine, provides benzimidazoles of formula (S34). Treatment of ester (S34) with a hydroxide source, such as, but not limited to, lithium hydroxide, in the presence of water and an organic solvent, such as, but not limited to, methanol and / or tetrahydrofuran, provides carboxylic acids of formula (S35). Reaction of carboxylic acid (S35) 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, pyridine, and an amine (1h) in an organic solvent, such as, but not limited to, N,N-dimethylformamide, at a temperature of about 40° C. for about 6 hours provides an amide of formula (S36).Compounds of formula (S37) can be prepared from bromide (S36) by treatment with an aryl, heteroaryl, or heterocyclic boronic acid or boronic acid ester under palladium catalysis, such as, but not limited to, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the presence of water and an inorganic salt, such as, but not limited to, sodium carbonate, potassium carbonate, or potassium phosphate, in an organic solvent, such as, but not limited to, 1,4-dioxane, at elevated temperature. Alternatively, compounds of formula (S37) can be prepared by Stille coupling. Bromide (S36) is converted to stannane compound (S38) under palladium catalysis, such as, but not limited to, palladium tetrakistriphenylphosphine, in an organic solvent, such as, but not limited to, toluene, at elevated temperature. The stannane compound (S38) can be treated with various aryl or heteroaryl halides under palladium catalyzed conditions, such as, but not limited to, palladium tetrakistriphenylphosphine, in an organic solvent, such as, but not limited to, DMSO, at elevated temperatures.

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

[0323] Scheme 9 [ka] [In the formula, R 1 and R 2 is as defined in the compounds of formula (I); and R 15 and R 16 is an optional substituent. Compounds of formula (S37 and S41) can be prepared by the general synthetic method shown in Scheme 9. Compound (S36) can be treated with various aryl and heteroaryl stannane compounds under palladium catalysis, such as, but not limited to, palladium tetrakistriphenylphosphine, in an organic solvent, such as, but not limited to, toluene, at elevated temperatures to provide compound (S37). Additionally, bromide (S36) can be treated with various amines under palladium catalysis or copper catalysis, such as, but not limited to, [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate or (BuNCuI) in an organic solvent, such as, but not limited to, tetrahydrofuran or 1,4-dioxane, at elevated temperatures to provide compound (S41).

[0324] Scheme 10 [ka] [In the formula, R 1 and R 2 is as defined in the compound of formula (I). Compounds of formula (S46) can be prepared by the general synthetic method shown in Scheme 10. In the presence of iron and acetic acid, compound (S42) undergoes cyclization to give compounds of formula (S43). Treatment of ester (S43) with a hydroxide source, such as, but not limited to, lithium hydroxide, in the presence of water and an organic solvent, such as, but not limited to, methanol and / or tetrahydrofuran, gives carboxylic acids of formula (S44). Reaction of carboxylic acid (S44) 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, pyridine, and an amine (1h) in an organic solvent, such as, but not limited to, N,N-dimethylformamide, at a temperature of about 40° C. for about 6 hours gives amides of formula (S45). Compounds of formula (S46) can be prepared from bromide (S45) by treatment with an aryl, heteroaryl, or heterocyclic boronic acid or boronic ester under palladium catalyzed conditions, such as, but not limited to, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the presence of water and an inorganic salt, such as, but not limited to, sodium carbonate, potassium carbonate, or potassium phosphate, in an organic solvent, such as, but not limited to, 1,4-dioxane, at elevated temperature.

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

[0326] Methyl 3-bromo-4-(methylamino)-5-nitrobenzoate (1c) To a solution of methyl 3-bromo-4-fluoro-5-nitrobenzoate (1a, 3 g, 10.79 mmol, 1 eq) and methylamine hydrochloride (1b, 874.23 mg, 12.95 mmol, 1.2 eq) in EtOH (50 mL) was added TEA (3.28 g, 32.37 mmol, 4.51 mL, 3 eq). The mixture was stirred at 15 °C for 12 h. TLC (petroleum ether:ethyl acetate = 5:1, R f =0.50). The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 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, 1.5 g, 5.19 mmol, 1 eq) in AcOH (20 mL) was added Fe (2.90 g, 51.89 mmol, 10 eq) in one portion at 15° C. The mixture was stirred at 15° C. for 1 h. Another batch of Fe (869.31 mg, 15.57 mmol, 3 eq) was added in one portion at 15° C., and the mixture was stirred at 35° C. for 1 h. TLC (petroleum ether:ethyl acetate=3:1, R f=0.30), indicating that 1c was completely consumed, and one major new spot with 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 brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. 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) was added p-TsOH (6.65 mg, 0.039 mmol, 0.1 eq). The mixture was stirred at 100 °C for 1 h. LCMS 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 NaHCO (5 mL) and brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 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-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylate (1f) To a mixture of methyl 7-bromo-1-methyl-1H-benzo[d]imidazole-5-carboxylate (1e, 0.1 g, 0.372 mmol, 1 eq) and pyrimidin-5-ylboronic acid (92.09 mg, 0.743 mmol, 2 eq) in dioxane (5 mL) and HO (0.3 mL) under N was added Pd(dppf)Cl (19.03 mg, 0.026 mmol, 0.07 eq) and NaCO (78.77 mg, 0.743 mmol, 2 eq). The mixture was stirred at 100 °C for 12 h. LCMS showed the presence of 1e and one major peak with the desired mass. The mixture was filtered and concentrated to give the crude residue. The residue was purified by preparative TLC (SiO, 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-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid (1g) To a solution of methyl 1-methyl-7-(pyrimidin-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 HO (1 mL) was added LiOH·HO (14.08 mg, 0.335 mmol, 2 eq) under N at 15 °C. The mixture was stirred at 15 °C for 12 h. LCMS showed that 1f was completely consumed, and one major peak with the desired mass was detected. The mixture was adjusted to pH = 5 with aqueous HCl (1 M) and concentrated to give the crude product 1 g as a brown solid. The product was used in the next step without further purification.

[0331] N-(4-(chlorodifluoromethoxy)phenyl)-1-methyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (1) To a solution of 1-methyl-7-(pyrimidin-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) in DMF (1 mL) was added DIEA (61.00 mg, 0.472 mmol, 82.21 μL, 3 eq) at 15° C. The mixture was stirred at 15° C. for 12 hours. LCMS showed that 1 g was completely consumed, and the desired 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 give the title compound 1 as a yellow solid. 1 H 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-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide The title compound was prepared according to Scheme 2. This General Method B illustrates Scheme 2 and provides specific synthetic details applicable to the title compound. [ka]

[0333] 7-Bromo-1-((1s,3s)-3-hydroxycyclobutyl)-1H-benzo[d]imidazole-5-carboxylic acid (2b) To a solution of methyl 7-bromo-1-((1s,3s)-3-hydroxycyclobutyl)-1H-benzo[d]imidazole-5-carboxylate (synthesized in a similar manner to 1e; 2a, 140 mg, 0.431 mmol, 1 eq) in THF (2 mL), MeOH (2 mL), and HO (1 mL) was added LiOH·HO (27.10 mg, 0.646 mmol, 1.5 eq). The mixture was stirred at 15 °C for 12 h. LCMS showed complete consumption of 2a, and the desired MS was detected. The aqueous phase was acidified to pH = 5 by the addition of aqueous HCl. The mixture was filtered and concentrated in vacuo to give 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) To a solution of 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) in DMF (2 mL) was added HATU (146.65 mg, 0.386 mmol, 1.2 eq) and DIEA (83.08 mg, 0.643 mmol, 111.97 μL, 2 eq). The mixture was stirred at 15 °C for 12 h. LCMS showed complete consumption of 2b, and the desired MS was detected. The mixture was diluted with water (3 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (3 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative TLC (SiO, ethyl acetate:methanol=10:1) to give 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-(pyrimidin-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 pyrimidin-5-ylboronic acid (20.37 mg, 0.164 mmol, 2 eq) in dioxane (3 mL) and HO (0.3 mL) was added Pd(dppf)Cl (6.01 mg, 8.22 μmol, 0.1 eq) and KPO (52.34 mg, 0.247 mmol, 3 eq). The mixture was stirred at 100 °C for 12 h. LCMS showed complete consumption of 2c, and the desired product was detected. The aqueous phase was extracted with HO (5 mL) and ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The mixture was purified by preparative HPLC (NHHCO condition, column: Waters Xbridge Prep OBD C18 150*30 10u; mobile phase: [water (10 mM NHHCO)-ACN]; B%: 25%-45%, 10 min) to give the title compound 2 as a white solid. Calculated MS mass [M+H] + (C 23 H 18 O3N5ClF2) m / z 486.1, LCMS detected 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-(pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carboxamide The title compound was prepared according to Scheme 3. This General Method C illustrates Scheme 3 and provides specific synthetic details applicable to the title compound. [ka]

[0337] Methyl 4-bromo-2-(difluoromethyl)-1H-benzo[d]imidazole-6-carboxylate (3b) Methyl 3,4-diamino-5-bromobenzoate (synthesized in a similar manner to 1d; 3a, 0.2 g, 0.816 mmol, 1 eq) was dissolved in CHFCOOH (3 mL). The mixture was stirred at 130 °C for 1 h. TLC (petroleum ether:ethyl acetate = 3:1) showed that the starting material was consumed, and LCMS showed the desired MS. The mixture was concentrated, and the residue was dissolved in EtOAc (10 mL). The organic layer was washed with aqueous NaHCO (5 mL × 3) and then concentrated to give 3b 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) was added KCO (271.82 mg, 1.97 mmol, 3 eq) and MeI (930.52 mg, 6.56 mmol, 408.12 uL, 10 eq). The mixture was stirred at 50 °C for 10 h. TLC (petroleum ether:ethyl acetate = 2:1) showed that the starting material was consumed. The mixture was concentrated, and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 2:1) to give 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 HO (1 mL) was added LiOH·HO (30.24 mg, 0.721 mmol, 2 eq) at 25 °C. The mixture was stirred at 50 °C for 2 h. TLC (petroleum ether:ethyl acetate = 2:1) showed that the starting material was consumed. The mixture was concentrated, and aqueous HCl (1 M) was added until the pH reached 3–4. The suspension was filtered, and the solid was washed with HO (1 mL) and dried to give 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) was added DIPEA (93.20 mg, 0.721 mmol, 125.61 μL, 3 eq) and HATU (205.65 mg, 0.541 mmol, 1.2 eq). The mixture was stirred at 25° C. for 0.5 h, after which 4-(chlorodifluoromethoxy)aniline (1h, 83.76 mg, 0.433 mmol, 1.2 eq) was added. The reaction mixture was stirred at 25° C. for 3.5 h. TLC (petroleum ether:ethyl acetate=3:1) showed the starting material was consumed, and LCMS showed the desired MS. The mixture was concentrated and the residue was purified by column chromatography by preparative TLC (SiO 2 , petroleum ether:ethyl acetate=1:1) to give 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-(pyrimidin-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 pyrimidin-5-ylboronic acid (51.56 mg, 0.416 mmol, 2 eq) in dioxane (4 mL) and HO (1 mL) was added KPO (132.49 mg, 0.624 mmol, 3 eq) and Pd(dppf)Cl (15.22 mg, 0.021 mmol, 0.1 eq) under N. The mixture was stirred at 100 °C under N for 4 h. LCMS showed that the starting material was consumed and the desired product was detected. The mixture was poured into water and extracted with EtOAc. The organic layer was concentrated and the resulting residue was purified by preparative HPLC (NH4HCO3 condition, column: Waters Xbridge Prep OBD C18 150*30 10u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 30%-50%, 10 min) to give the title compound 3 as a white solid. Calculated MS mass [M+H] + (C 21 H 14 ClF4N5O2) m / z 480.1, LCMS detected 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-(pyrimidin-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 a similar manner to 1d; 3a, 0.16 g, 0.653 mmol, 1 eq) in CHCOOH (3 mL) at 20 °C was added 4-methylbenzenesulfonic acid (11.24 mg, 0.065 mmol, 0.1 eq). The mixture was stirred at 100 °C for 3 h. LCMS showed the desired MS. The mixture was poured into water (20 mL) and then extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 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) was added CHCl (158.24 mg, 1.11 mmol, 69.40 uL, 2 eq). The mixture was stirred at 15° C. for 16 h. LCMS showed the desired MS. The mixture was poured into water (20 mL) and then extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the product. The residue was analyzed by preparative TLC (petroleum ether:ethyl acetate=0:1, R f =0.40) to give 4b as a brown oil.

[0345] Methyl 1,2-dimethyl-4-(pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carboxylate (4c) To a mixture of methyl 4-bromo-1,2-dimethyl-1H-benzo[d]imidazole-6-carboxylate (4b, 0.02 g, 0.071 mmol, 1 eq), pyrimidin-5-ylboronic acid (26.26 mg, 0.212 mmol, 3 eq), and KPO (44.98 mg, 0.212 mmol, 3 eq) in dioxane (2 mL) and HO (0.2 mL) was added Pd(dppf)Cl (5.17 mg, 7.06 μmol, 0.1 eq) under N. The mixture was stirred at 110 °C for 16 h. LCMS showed the desired MS. The mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=0:1, R f =0.37) to give 4c as a yellow oil.

[0346] 1,2-Dimethyl-4-(pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carboxylic acid (4d) To a mixture of 4c (0.015 g, 0.053 mmol, 1 eq) in HO (0.5 mL), THF (1 mL), and MeOH (1 mL) was added LiOH HO (4.46 mg, 0.106 mmol, 2 eq). The mixture was stirred at 15 °C for 16 h. LCMS showed the desired MS. The mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 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-(pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carboxamide (4) To a mixture of 1,2-dimethyl-4-(pyrimidin-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), DIPEA (14.45 mg, 0.112 mmol, 19.48 uL, 2 eq) in DMF (1 mL) was added 4-[chloro(difluoro)methoxy]aniline (1h, 16.24 mg, 0.084 mmol, 1.5 eq) at 20 °C. The mixture was stirred at 20 °C for 16 h. The mixture was concentrated in vacuo. LCMS showed the desired MS. The mixture was poured into water and extracted with EtOAc, and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product. The residue was purified by preparative HPLC (TFA condition, column: Nano-Micro UniSil 5-100 C18 ULTRA 100*250mm 5um; mobile phase: [water (0.1% TFA)-ACN]; B%: 25%-50%, 11 min) to give the title compound 4 as a white solid. Calculated MS mass [M+1] + (C 21 H 16 ClF2N5O2) m / z 444.1, LCMS detected 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-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0349] The title compound was prepared according to Scheme 4. This General Method D illustrates Scheme 4 and provides specific synthetic details applicable to the title compound. [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 in a similar manner to 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 h. LCMS showed that 5a was completely consumed, and the desired MS was detected. The mixture was filtered and concentrated under reduced pressure to give the crude residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=0:1) to give 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) To a solution of (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) in THF (1 mL), MeOH (1 mL), and HO (0.5 mL) was added LiOH·HO (30.04 mg, 0.716 mmol, 2 eq). The mixture was stirred at 15 °C for 2 h. LCMS showed that 5b was completely consumed, and the desired MS was detected. The aqueous phase was acidified to pH = 5 with aqueous HCl, and the mixture was filtered and concentrated in vacuo. 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) To a solution of (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) in DMF (2 mL) was added HATU (130.69 mg, 0.344 mmol, 1.2 eq) and DIEA (148.08 mg, 1.15 mmol, 199.56 µL, 4 eq). The mixture was stirred at 15 °C for 12 h. LCMS showed complete consumption of 5c, and the desired MS was detected. The mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by preparative TLC (SiO, ethyl acetate:methanol=10:1) to give 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-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (5) To a solution of (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 pyrimidin-5-ylboronic acid (28.34 mg, 0.229 mmol, 2 eq) in dioxane (1 mL) and HO (0.1 mL) was added Pd(dppf)Cl (8.37 mg, 11.44 μmol, 0.1 eq) and KPO (72.82 mg, 0.343 mmol, 3 eq). The mixture was stirred at 100° C. for 16 h. LCMS showed complete consumption of 5e, and the desired MS was detected. The mixture was filtered and concentrated under reduced pressure to give the crude residue. The residue was purified by preparative TLC (SiO 2 , ethyl acetate:methanol=10:1) to give the title compound 5 as a white solid. Calculated MS mass [M+H] + (C 23 H 18 O3N5ClF4) m / z 524.1, LCMS detected 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-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide The title compound was prepared according to Scheme 5. This General Method E illustrates Scheme 5 and provides specific synthetic details applicable to the title compound. [ka]

[0355] 3-Bromo-4-(methylamino)-5-nitrobenzoic acid (6a) To a mixture of methyl 3-bromo-4-(methylamino)-5-nitrobenzoate (1c, 1.7 g, 5.88 mmol, 1 eq) in THF (20 mL) and HO (4 mL) was added LiOH HO (493.55 mg, 11.76 mmol, 2 eq) in one portion. The mixture was stirred at 60 °C for 12 h. TLC (petroleum ether:ethyl acetate = 3:1, R f = 0.0), indicating that 1c was completely consumed, and one major new spot with high polarity was detected. The mixture was adjusted to pH = 3 with aqueous HCl (1 M). The mixture was filtered, and the yellow solid was washed with HO (10 mL) to give 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) was added HATU (2.28 g, 6.00 mmol, 1.1 eq) and DIEA (775.28 mg, 6.00 mmol, 1.04 mL, 1.1 eq) in one portion. The mixture was heated to 30 °C and stirred for 12 h. LC-MS showed the detection of one 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 to 5:1) to give 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) at 20 °C, Fe (2.60 g, 46.60 mmol, 10 eq) was added in one portion. The mixture was stirred at 35 °C for 3 h. TLC (petroleum ether:ethyl acetate = 1:1, R f =0.6), which indicated that 6b was completely consumed, with one new spot forming. Ethyl acetate (40 mL) was added, and the mixture was filtered through a Celite™ pad. The filtrate was washed with HO (30 mL), saturated NaHCO solution (20 mL × 3), and brine (20 mL), then dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 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 uL, 20 eq) was stirred at 130 °C for 12 h. The mixture turned 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 (SiO, petroleum ether:ethyl acetate=1:1) to give 6d as a yellow oil.

[0359] N-(4-(chlorodifluoromethoxy)phenyl)-2-isopropyl-1-methyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (6) To a mixture of 3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(methylamino)benzamide (6d, 0.03 g, 0.063 mmol, 1 eq) and pyrimidin-5-ylboronic acid (15.73 mg, 0.127 mmol, 2 eq) in dioxane (4 mL) and HO (0.3 mL) was added Pd(dppf)Cl (4.64 mg, 6.35 μmol, 0.1 eq) and KPO (40.41 mg, 0.190 mmol, 3 eq) in one portion at 15 °C under N. The mixture was stirred at 110 °C for 12 h. LC-MS showed complete consumption of the starting material, with one major peak having the desired mass. The mixture was filtered through a Celite™ pad, and the filtrate was concentrated to give a 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 give the title compound 6 as a white solid. Calculated MS mass [M+H] + (C 23 H 20O2N5ClF2) m / z 472.1, LCMS detected 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-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide The title compound was prepared according to Scheme 6. This General Method F illustrates Scheme 6 and provides specific synthetic details applicable to the title compound. [ka]

[0361] Methyl 1,2-dimethyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylate (7b) To a mixture of methyl 7-bromo-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxylate (synthesized in a similar manner to 1e; 7a, 0.15 g, 0.53 mmol, 1 eq) and pyrimidin-5-ylboronic acid (65.65 mg, 0.53 mmol, 1 eq) in dioxane (5 mL) and HO (0.5 mL) was added Pd(dppf)Cl (38.77 mg, 0.53 mmol, 0.1 eq) and KPO.3HO (423.28 mg, 1.59 mmol, 3 eq) under N. The mixture was stirred at 110 °C for 16 h. TLC (ethyl acetate:methanol = 8:1, R f=0.20) showed complete consumption of 7a, with one major new, more polar spot detected. LC-MS showed complete consumption of 7a, with one major peak of the desired mass detected. The mixture was filtered and concentrated to give a residue that was purified by preparative TLC (SiO, ethyl acetate:methanol=8:1) to give 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-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid (7c) To a solution of methyl 1,2-dimethyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylate (7b, 0.06 g, 0.213 mmol, 1 eq) in THF (2 mL), MeOH (2 mL), and HO (1 mL) was added LiOH·HO (17.84 mg, 0.425 mmol, 2 eq). The mixture was stirred at 50 °C for 3 h. LC-MS showed that 7b was completely consumed, with one major peak having the desired mass. The mixture was adjusted to pH 5 with aqueous HCl (1 M) and concentrated to give 7c as a brown solid. The product was used in the next step without further purification.

[0363] N-(4-(chlorodifluoromethoxy)phenyl)-1,2-dimethyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (7) To a mixture of 1,2-dimethyl-7-(pyrimidin-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) was added DIEA (82.38 mg, 0.637 mmol, 111.03 µL, 3 eq). The mixture was stirred at 15 °C for 12 h. LC-MS showed complete consumption of 7c, with one major peak of the expected mass being detected. The mixture was concentrated to give 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 give the title compound 7 as a white solid. Calculated MS mass [M+H] + (C 21 H 16 ClF2N5O2) m / z 444.1, LCMS detected 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-pyrimidin-5-yl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxamide The title compound was prepared according to Scheme 7. This General Method G illustrates Scheme 7 and provides specific synthetic details applicable to the title compound. [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 / EtOAc (5 mL) was stirred at 15° C. for 2 h. LCMS showed that 8) was completely consumed, and the desired MS was detected. The mixture was filtered and concentrated under reduced pressure to give 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) was added TEA (454.94 mg, 4.50 mmol, 625.78 μL, 2.5 eq). The mixture was stirred at 15 °C for 1 h. LCMS showed complete consumption of 1a, 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 EtOAc (20 mL × 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 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 give 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) was added Fe (621.91 mg, 11.14 mmol, 10 eq). The reaction mixture was stirred at 35° C. for 1 hour. LCMS showed that 8c was completely consumed, and the target MS was detected. The mixture was filtered through a Celite™ pad and washed with ethyl acetate. The mixture was concentrated under reduced pressure to give a crude residue, which was purified by preparative HPLC (HCl condition, column: Phenomenex Luna C18 200*40 mm*10 um; mobile phase: [water (0.05% HCl)-ACN]; B%: 15%-45%, 10 min) to give 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) was added HATU (109.03 mg, 0.287 mmol, 1.1 eq) and DIEA (101.07 mg, 0.782 mmol, 136.21 uL, 3 eq). The mixture was stirred at 20 °C for 16 h. LCMS showed that 8d 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 the crude residue. The residue was purified by preparative TLC (SiO.sub.2, petroleum ether:ethyl acetate=0:1) to give 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 HO (0.5 mL) was added LiOH·HO (13.49 mg, 0.321 mmol, 2 eq). The mixture was stirred at 40 °C for 6 h. TLC (petroleum ether:ethyl acetate = 0:1, R f = 0), 8e was completely consumed, and one major new spot, which was more polar, was detected. The mixture was concentrated in vacuo. The mixture was added to HO (3 mL), and the aqueous phase was acidified to pH = 5 with aqueous HCl. The mixture was concentrated in vacuo to give 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) To a solution of 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) in pyridine (2 mL) was added HATU (69.11 mg, 0.182 mmol, 1.2 eq). The mixture was stirred at 40 °C for 6 h. LCMS showed that 8f 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 the crude residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate=0:1) to give 8 g as 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-pyrimidin-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 pyrimidin-5-ylboronic acid (20.97 mg, 0.169 mmol, 2 eq) in dioxane (1 mL) and HO (0.1 mL) was added Pd(dppf)Cl (6.19 mg, 8.46 μmol, 0.1 eq) and KPO (53.89 mg, 0.254 mmol, 3 eq). The mixture was stirred at 110 °C for 16 h. LCMS showed complete consumption of 8 g, and the desired product was detected. The mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a crude residue. The residue was purified by preparative TLC (SiO, ethyl acetate:methanol = 10:1) to give the title compound 8 as a yellow solid. Calculated MS mass [M+H] + (C 22 H 16 O3N5ClF2) m / z 472.1, LCMS detected 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-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide The title compound was prepared according to Scheme 8. This General Method H illustrates Scheme 8 and provides specific synthetic details applicable to the title compound. [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 in a similar manner to 6c; 9a, 100 mg, 0.223 mmol, 1 eq) in AcOH (2 mL) was added tetramethoxymethane (197.23 mg, 1.45 mmol, 6.5 eq). The mixture was stirred at 50° C. for 16 h. LCMS showed that 9a was completely consumed, and the desired MS was detected. TLC (petroleum ether:ethyl acetate=3:1, R f =0.4) indicated that 9a was completely consumed, and one major new, less polar spot was detected. The reaction mixture was concentrated under reduced pressure. The mixture was washed with saturated aqueous NaHCO3, dried over Na2SO4, and evaporated to dryness. The crude residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 3:1) to give 9b as a white solid.

[0374] N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-2-methoxy-7-(pyrimidin-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), pyrimidin-5-ylboronic acid (30.42 mg, 0.246 mmol, 3 eq), Pd(dppf)Cl (5.99 mg, 8.18 µmol, 0.1 eq), and KPO (52.12 mg, 0.246 mmol, 3 eq) in dioxane (4 mL) and HO (0.4 mL) was degassed and purged with N three times. The mixture was stirred at 110 °C under N for 16 h. LCMS showed complete consumption of 9b, and the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO 2 , petroleum ether:ethyl acetate=1:1) to give the title compound 9 as a white solid. Calculated MS mass [M+1] + (C 23 H 20 ClF2N5O3) m / z 488.1, LCMS detected 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-imidazol-1-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide [ka]

[0376] N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-cyclopropyl-1H-imidazol-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 in a similar manner to 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), KCO (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 and purged with N three times, after which the mixture was stirred at 140 °C under N atmosphere for 16 h. The reaction mixture was concentrated and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was identified by preparative TLC (ethyl acetate:methanol = 10:1, R f =0.2) to give the crude product, which was 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 give the title compound 10 as a white solid. Calculated MS mass [M+1] + (C 24 H 22 ClF2N5O2) m / z 486.1, LCMS detected 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-imidazol-1-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide [ka]

[0378] N-(4-(chlorodifluoromethoxy)phenyl)-7-(1H-imidazol-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) was added KCO (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). The mixture was stirred at 120 °C for 12 h. The mixture was dissolved in EtOAc (20 mL), washed with water (10 mL × 5), and the organic layer was concentrated. The residue was purified by preparative HPLC (NH4HCO3 condition, column: Waters Xbridge Prep OBD C18 150*30 10u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 35%-55%, 10 min) to give the title 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-(pyrimidin-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-oxo-propanoate (107.11 mg, 0.784 mmol, 83.68 uL, 1.1 eq) in DCM was added TEA (72.17 mg, 0.713 mmol, 99.27 uL, 1 eq) dropwise. The mixture was heated to 30 °C and stirred for 0.5 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=1:1) to give 12a as a brown solid.

[0381] Methyl 2-(7-bromo-5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-1-methyl-1H-benzo[d]imidazol-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 h. LC-MS showed complete consumption of the reactant, with one major peak having the desired mass detected. The mixture was poured into EtOAc, and the mixture was washed with water, saturated NaHCO and brine. The combined organic layers were dried over NaSO and concentrated. The residue was purified by preparative TLC to give 12b as a yellow solid.

[0382] 7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide (12c) To a solution of methyl 2-(7-bromo-5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-1-methyl-1H-benzo[d]imidazol-2-yl)acetate (12b, 50 mg, 0.099 mmol, 1 eq) in THF at 20 °C under N was added LiBH (10.83 mg, 0.497 mmol, 5 eq) slowly in one portion. The mixture was heated to 30 °C and stirred for 50 min. LC-MS showed complete consumption of the reactant, with one major peak having the desired mass detected. After cooling the reaction mixture to 0 °C, the reaction mixture was quenched by the addition of HO and acidified to pH = 6 with 1 N HCl. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative TLC (SiO, ethyl acetate:methanol = 10:1) to give 12c as a yellow solid.

[0383] N-(4-(chlorodifluoromethoxy)phenyl)-2-(2-hydroxyethyl)-1-methyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (12) To a mixture of 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 pyrimidin-5-ylboronic acid (12e, 20.88 mg, 0.169 mmol, 2 eq) in dioxane (3 mL) and HO (0.3 mL) was added Pd(dppf)Cl (6.17 mg, 8.43 μmol, 0.1 eq) and KPO (53.66 mg, 0.253 mmol, 3 eq) in one portion at 20 °C under N. The mixture was heated to 110 °C and stirred for 12 h. LC-MS showed complete consumption of the reactant, with one major peak of the desired mass being detected. The mixture was filtered through a Celite™ pad, and the filtrate was concentrated to give 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 give the title compound 12 as a white solid. Calculated MS mass [M+1] + (C 22 H 18 ClF2N5O3) m / z 474.1, LCMS detected m / z 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) To a mixture of 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) in MeOH (20 mL) at 20 °C under N was added Pd(PPh3)4 (50.39 mg, 0.044 mmol, 0.1 eq) in one portion. The mixture was heated to 100 °C and stirred under CO (0.436 mmol, 3 MPa) for 24 h. LC-MS indicated ∼60% of the reaction mixture remained. LC-MS showed one new peak, with ∼30% of the desired compound. HPLC indicated 60% of the reaction mixture remained. The mixture was filtered through a Celite pad, and the filtrate was concentrated to give 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 give 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) To a mixture of methyl 5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-1-isopropyl-1H-benzo[d]imidazole-7-carboxylate (13b, 10 mg, 0.023 mmol, 1 eq) in THF (1 mL), HO (1 mL), and MeOH (0.5 mL) at 20 °C, LiOH·HO (1.92 mg, 0.046 mmol, 2 eq) was added in one portion. The mixture was heated to 45 °C and stirred for 2 h. LC-MS showed complete consumption of the reactant, with one major peak having the desired mass. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was poured into HO (0.5 mL) and acidified to pH = 5 with 1 N HCl. The mixture was filtered, and the filter cake was washed with 0.5 mL of HO and dried under vacuum to give the crude product. The crude residue 13c was obtained as a white solid and was 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 uL, 1.2 eq) in DMF (2 mL) at 20 °C, HATU (39.48 mg, 0.104 mmol, 1.1 eq) and DIEA (24.40 mg, 0.189 mmol, 32.88 uL, 2 eq) were added in one portion. The mixture was stirred at 20 °C for 12 h. LC-MS showed 40% of the reaction mixture remained. LC-MS showed one new peak and 60% of the desired compound. The reaction mixture was concentrated under reduced pressure to remove the solvent. To the residue was added EtOAc (15 mL). The organic layer was washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The residue was purified by preparative TLC (SiO2, EtOAc:MeOH = 10:1) to give the title compound 13 as a white solid. Calculated MS mass [M+1] + (C 22 H 21 ClF2N4O3) m / z 463.1, LCMS detected 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-(pyrimidin-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 in a similar manner to 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 DCM (5 mL) at 25 °C was stirred for 16 h. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL × 3). The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude residue was purified by column chromatography to give 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 h. EtOAc (20 mL) was added and the mixture was filtered. The filtrate was washed with water (20 mL × 3), the organic layer was dried over Na2SO4, and the mixture was concentrated. Compound 14c was obtained as a yellow oil, which did not require 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, 0.6 g, 1.08 mmol, 1 eq) and TsOH (18.66 mg, 0.108 mmol, 0.1 eq) in CH(OMe) (10 mL) was stirred at 100 °C for 1 h. 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-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxylate (14f) To a solution of 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) in dioxane (5 mL) and HO (1 mL) was added KPO (497.19 mg, 2.34 mmol, 3 eq) and Pd(dppf)Cl (28.56 mg, 0.039 mmol, 0.05 eq) under N. The mixture was stirred at 100 °C for 4 h. 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-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxylic acid (14g) To a solution of methyl 1-((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)-7-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxylate (14f, 360 mg, 0.64 mmol, 1 eq) in THF (3 mL), MeOH, and HO (2 mL) at 25 °C was added LiOH·HO (40.26 mg, 0.96 mmol, 1.5 eq). The reaction was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure. Water (5 mL) was added, and the mixture was extracted with EtOAc (10 mL). Aqueous HCl (1 M) was added until the aqueous phase reached pH = 3-4. The aqueous phase was extracted again with EtOAc (10 mL × 3), and the organic layer was dried over NaSO, filtered, and concentrated to give the crude product. No further purification was required. Compound 14g was obtained as a red solid.

[0394] 1-((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)-N-(4-(chlorodifluoromethoxy)phenyl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (14i) To a solution of 1-((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)-7-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxylic acid (14g, 90mg, 0.164mmol, 1eq) and 1h (38.10mg, 0.197mmol, 1.2eq) in DMF (3mL) was added DIPEA (63.59mg, 0.492mmol, 85.71uL, 3eq) and HATU (93.55mg, 0.246mmol, 1.5eq) at 25°C. The mixture was stirred at 25°C for 12 hours. EtOAc (10mL) was added, and the mixture was washed with water (10mL x 5). The organic layer was dried over Na2SO4 and concentrated to give 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-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (14) To a solution of 1-((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)-N-(4-(chlorodifluoromethoxy)phenyl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (14i, 0.03 g, 0.041 mmol, 1 eq) in dry THF (3 mL) was added TBAF (1 M, 41.42 uL, 1 eq) at 25 °C under N. The mixture was stirred at 25 °C for 2 h and concentrated. The residue was purified by preparative HPLC (NHHCO condition, column: Waters Xbridge Prep OBD C18 150*30 10 u; mobile phase: [water (10 mM NHHCO)-ACN]; B%: 35%-55%, 10 min) to give the title compound 14 as a yellow solid. Calculated MS mass [M+1] + (C 23 H 18 ClF2N5O3) m / z 486.1, LCMS detected 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-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide [ka]

[0397] Methyl 3-bromo-4-(cyclopropylamino)-5-(2,2-difluoroacetamido)benzoate (15c) To a solution of methyl 3-amino-5-bromo-4-(cyclopropylamino)benzoate (synthesized in a similar manner to 1d; 15a, 200 mg, 0.701 mmol, 1 eq) in DCM (8 mL) was added TEA (212.93 mg, 2.10 mmol, 3 eq) and 2,2-difluoroacetic anhydride (15b) (122.08 mg, 0.701 mmol, 1 eq) at 0 °C. The mixture was stirred at 15 °C under a N atmosphere for 2 h. LCMS showed the detection of a peak with the desired MS. The reaction mixture was concentrated. The crude product was isolated by preparative TLC (petroleum ether:ethyl acetate = 3:1, R f =0.4) to give 15c as a yellow solid.

[0398] Methyl 7-bromo-1-cyclopropyl-2-(difluoromethyl)-1H-benzo[d]imidazole-5-carboxylate (1d) To a solution of 15d (80 mg, 0.220 mmol, 1 eq) in toluene (3 mL) was added AcOH (1.32 mg, 0.022 mmol, 10 eq). The mixture was stirred at 60° C. for 16 h. LCMS showed a peak with the desired MS. The reaction mixture was concentrated and the crude product was isolated by preparative TLC (petroleum ether:ethyl acetate=1:1, R f =0.4) to give 15d 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 HO (0.5 mL) was added LiOH HO (4.86 mg, 0.116 mmol, 2 eq). The mixture was stirred at 50 °C for 2 h. LCMS showed a peak with the desired MS. The mixture was concentrated and poured into HO (1 mL), and the pH was adjusted to 5 with HCl (1 M in HO). The mixture was concentrated to give 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 h. LCMS showed a peak with the desired MS. The reaction mixture was concentrated, and the crude product was isolated by preparative TLC (petroleum ether:ethyl acetate = 2:1, R f =0.5) to give 15 g as a yellow solid. 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-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (15) A mixture of 15g (35 mg, 0.069 mmol, 1 eq), pyrimidin-5-ylboronic acid (25.68 mg, 0.207 mmol, 3 eq), Pd(dppf)Cl (5.05 mg, 6.91 umol, 0.01 eq), KPO (43.99 mg, 0.207 mmol, 3 eq), dioxane (2 mL) and HO (0.2 mL) was degassed and purged with N three times. The reaction mixture was stirred under N at 100 °C for 8 h. LCMS showed a peak with the desired MS. The reaction mixture was concentrated, and the crude product was isolated by preparative TLC (petroleum ether:ethyl acetate = 0:1, R f =0.45) to give the title compound 15 as a white solid. Calculated MS mass [M+H] + (C 23 H 16 ClF4N5O2) m / z 506.1, LCMS detected 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-(pyrimidin-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-methyl-propan-1-ol (115.41 mg, 1.29 mmol), TEA (131.02 mg, 1.29 mmol) and EtOH (5 mL) was stirred at 15° C. for 3 hours. The reaction mixture was concentrated and the crude product was isolated by preparative TLC (petroleum ether:ethyl acetate=3:1, R f =0.5) to give 16b 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-(pyrimidin-5-yl)benzoate (16d) A mixture of 16b (200 mg, 0.576 mmol), 16c (142.76 mg, 1.15 mmol), Pd(dppf)Cl (21.08 mg, 0.029 mmol), KPO (366.86 mg, 1.73 mmol) in dioxane (4 mL) and HO (0.4 mL) was degassed and purged with N three times. The mixture was stirred under N at 110 °C for 6 h. LCMS showed a peak with the desired MS. The reaction mixture was concentrated, and the crude product was isolated by preparative TLC (petroleum ether:ethyl acetate = 0:1, R f =0.4) to give 16d 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-(pyrimidin-5-yl)benzoate (16e) To a solution of 16d (70 mg, 0.202 mmol) in EtOH (4 mL) was added Fe (112.87 mg, 2.02 mmol) and NH4Cl (108.11 mg, 2.02 mmol). The mixture was stirred at 80°C for 0.5 h. LCMS showed a peak with the desired MS. The mixture was filtered through a Celite™ pad, and the filtrate was concentrated. The crude product was isolated by preparative TLC (petroleum ether:ethyl acetate = 10:1, R f =0.3) to give 16e 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-(pyrimidin-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) was added PTSA (1.09 mg, 6.32 mmol). The mixture was stirred at 80° C. for 1 hour. LCMS showed a peak with the desired MS. The reaction mixture was concentrated, and the crude residue was purified by preparative TLC (ethyl acetate:methanol=10:1, R f =0.4) to give 16f 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-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylate (16g) To a solution of 16f (10 mg, 0.025 mmol) in MeOH (2 mL) was added HCl (0.1 M, 499.47 μL). The mixture was stirred at 15° C. for 3 hours. LCMS showed a peak with the desired MS. The reaction mixture was concentrated to give 16g as a yellow oil. The product was used in the next step without purification.

[0408] 1-(1-Hydroxy-2-methylpropan-2-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid (16h) To a solution of 16g ​​(10 mg, 0.031 mmol) in MeOH (1 mL), THF (1 mL), and HO (0.5 mL) was added LiOH HO (3.86 mg, 0.092 mmol). The mixture was stirred at 50 °C for 3 h. LCMS showed a peak with the desired MS. The mixture was concentrated, and the residue was poured into HO (1 mL). The pH of the solution was adjusted to 4, and addition of HCl (1 M in HO) gave 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-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (16) A mixture of 16h (10 mg, 0.032 mmol), 4-(chlorodifluoromethoxy)aniline (1h), 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 h. LCMS showed a peak with the desired MS. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (NHHCO, column: Agela Durashell C18 150*25 5u; mobile phase: [water (10 mM NHHCO)-ACN]; B%: 35%-65%, 10 min) to give the title compound 16 as a white solid. Calculated MS mass [M+1] + (C 23 H 20 ClF2N5O3) m / z 488.1, LCMS detected 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-pyrazol-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, 1 g, 11.62 mmol) in THF (15 mL) was added NaH (697.06 mg, 17.43 mmol, 60% purity) at 0° C. After stirring for 10 min, 1-(chloromethyl)-4-methoxy-benzene (2.18 g, 13.94 mmol) was slowly added to the reaction mixture. The resulting solution was stirred at 15° C. for 16 h. TLC (petroleum ether:ethyl acetate=5:1, R f =0.4) showed the formation of a new spot. LCMS showed a peak with the desired MS. The reaction mixture was concentrated. To the residue, HO (20 mL) was added, and the aqueous phase was extracted with ethyl acetate (60 mL). The organic layer was washed with brine (5 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1 to 30:1) to give 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 solution of 17b (850 mg, 4.12 mmol) in THF (15 mL) was slowly added a solution of n-BuLi (2.5 M, 2.47 mL, 1.5 eq) at -70 °C. The mixture was stirred for 15 min while maintaining the temperature below -60 °C. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (17c, 1.61 g, 4.95 mmol) in THF (1 mL) was added to the reaction mixture, and the resulting solution was subsequently stirred for an additional 2 h. TLC (petroleum ether:ethyl acetate = 3:1, R f =0.6) showed the formation of a new spot. LCMS showed a peak with the desired MS. The reaction mixture was quenched by the addition of water, HO (20 mL), and then ethyl acetate (80 mL) was added. After the reaction was quenched, 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 to 10:1) to give 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)stannane (413.68 mg, 1.26 mmol), and Pd(PPh) (121.59 mg, 0.105 mmol) in toluene (5 mL) was degassed and purged with N three times. The mixture was stirred under N at 130 °C for 16 h. TLC (petroleum ether:ethyl acetate = 3:1, R f =0.7) showed the formation of a new spot. LCMS showed the detection of a peak with the desired MS. The reaction mixture was quenched by the addition of KF (5 mL), followed by the addition of ethyl acetate (40 mL). After the reaction was quenched, the reaction mixture was poured into a separatory funnel and separated. The organic layer was concentrated, and the residue was analyzed by preparative TLC (petroleum ether:ethyl acetate=3:1, R f =0.7) to give 17e 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-pyrazol-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(PPh) (37.58 mg, 0.033 mmol) in DMSO (3 mL) was degassed and purged with N three times. The mixture was stirred under a N atmosphere at 100 °C for 16 h. LCMS showed the 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 × 3). The combined organic layers were dried over NaSO, filtered, and concentrated to give the crude product. The crude residue was purified by preparative TLC (ethyl acetate:methanol=10:1, R f =0.6) to give 17 g as a yellow oil. 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-pyrazol-5-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (17) A solution of 17g (80 mg, 0.137 mmol) in TFA (2 mL) was stirred at 15° C. for 16 hours. LCMS showed the detection of a peak with the desired MS. The reaction mixture was concentrated. The crude residue was purified by preparative TLC (ethyl acetate:methanol=10:1, R f =0.4) to give the title compound 17 as a white solid. Calculated MS mass [M+H] + (C 21 H 17 ClF3N5O2) m / z 464.1, LCMS detected 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-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide [ka]

[0417] N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-7-(4-fluoro-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide (18b) To a mixture of 7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-1H-benzo[d]imidazole-5-carboxamide (synthesized in a similar manner to 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) was added Pd(PPh) (12.65 mg, 0.011 mmol, 0.05 eq). The reaction mixture was stirred at 100 °C for 16 h. LCMS showed the detection of a peak with the desired MS. The mixture was poured into water (10 mL), and the mixture was extracted with EtOAc (10 mL × 2). The combined organic layer was concentrated and purified by preparative TLC (EtOAc:MeOH=10:1, R f =0.6) to give 18b as a yellow oil.

[0418] N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-7-(4-fluoro-1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide (18) N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-7-(4-fluoro-1-(4-methoxybenzyl)-1H-pyrazol-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 h. LCMS showed the detection of a peak with the desired MS. The solvent was evaporated in vacuo, and the residue was dissolved in EtOAc (5 mL). The organic layer was washed with saturated NaHCO (2 mL), brine (2 mL), and concentrated to give a crude residue, which was purified by preparative TLC (EtOAc:MeOH=10:1, R f =0.3) to give the title compound 18 as a white solid. Calculated MS mass [M+H] + (C 21 H 15ClF3N5O2) m / z 462.1, LCMS detected 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-dioxidothietan-3-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide [ka]

[0420] N-(4-(chlorodifluoromethoxy)phenyl)-7-(pyrimidin-5-yl)-1-(thietan-3-yl)-1H-benzo[d]imidazole-5-carboxamide (19c) To a mixture of 7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(thietan-3-yl)-1H-benzo[d]imidazole-5-carboxamide (19a, 130 mg, 0.266 mmol, 1 eq), pyrimidin-5-ylboronic acid (synthesized in a similar manner to 2c; 19b, 98.87 mg, 0.798 mmol, 3 eq), KPO (169.38 mg, 0.798 mmol, 3 eq) in dioxane (2 mL) and HO (0.2 mL) was added Pd(dppf)Cl (19.46 mg, 0.27 mmol, 0.1 eq) under N. The mixture was stirred at 100 °C for 16 h. LCMS showed acceptable MS. The mixture was poured into water and then extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product. The residue was analyzed by preparative TLC (ethyl acetate:methanol=10:1, R f =0.30) to give 19c 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-dioxidothietan-3-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (19) To a mixture of N-(4-(chlorodifluoromethoxy)phenyl)-7-(pyrimidin-5-yl)-1-(thietan-3-yl)-1H-benzo[d]imidazole-5-carboxamide (19c, 40 mg, 0.082 mmol, 1 eq) in DCM (2 mL) was added saturated aqueous sodium bicarbonate and mCPBA (70.74 mg, 0.328 mmol, 80% purity, 4 eq) at 0 °C. The reaction mixture was stirred at 15 °C for 16 h. LCMS showed the desired MS. The mixture was poured into water and then extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the desired product. The residue was analyzed by preparative TLC (ethyl acetate:methanol=10:1, R f =0.37) to give the title compound 19 as a white solid. Calculated MS mass [M+1] + (C 22 H 16 ClF2N5O4S) m / z 520.1, LCMS detected 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-(pyrimidin-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, 2 g, 9.21 mmol, 1 eq) in THF (10 mL) was added dropwise TEA (2.80 g, 27.63 mmol, 3.85 mL, 3 eq) at 15 °C, followed by the dropwise addition of propan-2-amine (653.37 mg, 11.05 mmol, 949.67 uL, 1.2 eq). The resulting mixture was stirred at 0 °C for 1 h. TLC (petroleum ether: EtOAc = 5:1, R f =0.50), indicated that 20a was completely consumed, and one major new spot was detected. The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. 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, 2 g, 7.81 mmol, 1 eq) in DCM (5 mL) was added Br2 (2.00 g, 12.51 mmol, 645.16 uL, 1.60 eq). The mixture was stirred at 0 °C for 1 h. TLC (petroleum ether: EtOAc = 5:1, R f=0.50), which indicated that 20b was completely consumed. The reaction mixture was quenched by the addition of saturated NaSO (5 mL). The residue was diluted with HO (20 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by silica gel column chromatography (SiO, petroleum ether:ethyl acetate = 10:1) to give 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, 1 g, 2.98 mmol, 1 eq) in EtOH (20 mL) was added Fe (1.67 g, 29.84 mmol, 10 eq) and NH4Cl (1.60 g, 29.84 mmol, 1.04 mL, 10 eq). The mixture was stirred at 80 °C for 6 h. TLC (petroleum ether: EtOAc = 3:1) showed that 20c was completely consumed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 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) (2 mL) was added p-TsOH (10.16 mg, 0.059 mmol, 0.1 eq). The mixture was stirred at 100 °C for 1.5 h. 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 H O (20 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na SO , filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by preparative TLC (SiO, 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) To a solution of methyl 7-bromo-6-fluoro-1-isopropyl-1H-benzo[d]imidazole-5-carboxylate (20e, 140 mg, 0.444 mmol, 1 eq) in THF (5 mL), MeOH (5 mL), and HO (2 mL) was added LiOH·HO (46.60 mg, 1.11 mmol, 2.5 eq). The mixture was stirred at 50 °C for 12 h. TLC (petroleum ether:ethyl acetate = 1:1) showed that 20e was completely consumed. The mixture was adjusted to pH = 5 with aqueous HCl (1 M) and concentrated to give 20f as a white solid, which was 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) was added 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). The mixture was stirred at 50 °C for 3 h. TLC (petroleum ether:ethyl acetate = 1:1) showed complete consumption of 20f. The reaction mixture was concentrated under reduced pressure. The residue was diluted with HO (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1:1). Compound 20 g 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-(pyrimidin-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 HO (0.5 mL) was added Pd(dppf)Cl (7.68 mg, 0.01 mmol, 0.1 eq), pyrimidin-5-ylboronic acid (38.99 mg, 0.315 mmol, 3 eq), and KPO (66.80 mg, 0.315 mmol, 3 eq). The mixture was stirred at 100 °C for 6 h. LC-MS showed complete consumption of 20 g, with one major peak having the desired MS. The mixture was concentrated to give the crude product. The residue was purified by preparative HPLC (NH4HCO3 condition, column: Waters Xbridge 150*50 10u; mobile phase: [water (10 mM NH4HCO3)-MeOH]; B%: 55%-75%, 12 min) to give the title compound 20 as a white solid. Calculated MS mass [M+H] + (C 22 H 17 ClF3N5O2) m / z 476.1, LCMS detected 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-(pyrimidin-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) To a mixture of 7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1H-benzo[d]imidazole-5-carboxamide (synthesized in a similar manner to 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 added KCO (18.58 mg, 0.134 mmol, 0.7 eq) under N. The mixture was stirred at 80 °C for 4 h. TLC (ethyl acetate:methanol = 10:1, R f =0.32) indicated the completion of the reaction. The mixture was poured into water (20 mL) and then extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product. The residue was analyzed by preparative TLC (ethyl acetate:methanol = 10:1, Rf =0.32) to give 21c 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-(pyrimidin-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 pyrimidin-5-ylboronic acid (21d, 4.82 mg, 0.039 mmol, 2 eq) in dioxane (2 mL) and HO (0.4 mL) was added Pd(dppf)Cl (1.42 mg, 1.95 μmol, 0.1 eq) and KPO (12.40 mg, 0.058 mmol, 3 eq). The reaction mixture was stirred at 100 °C for 6 h. LCMS showed the detection of a peak with the expected MS. The reaction mixture was concentrated, and the residue was dissolved in EtOAc (5 mL) and washed with HO (2 mL) and brine (5 mL). The organic layer was concentrated and purified by preparative TLC (EtOAc:MeOH=5:1) to give the title compound 21 as a white solid. Calculated MS mass [M+H] + (C 24 H 19 ClF2N6O3) m / z 513.1, LCMS detected 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-(thiazol-4-yl)-1H-benzo[d]imidazole-5-carboxamide The title compound was prepared using the analogous coupling reaction outlined in Scheme 9. This General Method I is illustrated in Scheme 9 and provides specific synthetic details applicable to the title compound. [ka]

[0434] N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(thiazol-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(thiazol-4-yl)stannane (22b, 97.89 mg, 0.262 mmol, 1.2 eq), and Pd(PPh) (25.19 mg, 0.022 mmol, 0.1 eq) were added to a microwave tube containing dioxane (4 mL). The sealed tube was heated at 150 °C for 3 h under microwave irradiation. Water (5 mL) was added to the reaction mixture, which was then extracted with EtOAc (10 mL × 2). The combined organic layers were concentrated, and the crude residue was purified by preparative HPLC (TFA condition, column: Luna C18 100*30 5u; mobile phase: [water (0.1% TFA)-ACN]; B%: 15%-50%, 10 min) to give the title compound 22 as a yellow solid. Calculated MS mass [M+1] + (C 21 H 17 ClF2N4O2S) m / z 463.1, LCMS detected m / z 463.0. 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-triazol-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) in DME (15 mL) was added PMBNH (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 Pd(dba) (179.68 mg, 0.196 mmol). The mixture was stirred at 100 °C under a N atmosphere for 12 hours. LCMS showed the 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 EtOAc (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=3 / 1, 1 / 3) to give 23b as a yellow solid. Calculated MS mass [M+1] + (C 26 H 25 ClF2N4O3) m / z 515.2, LCMS detected 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 h. LCMS showed detection of the desired MS. The reaction mixture was concentrated under reduced pressure. The mixture was purified by preparative HPLC (NHHCO condition, column: Agela Durashell C18 150*25 5u; mobile phase: [water (10 mM NHHCO)-ACN]; B%: 35%-65%, 10 min) to give 23c as a yellow solid. Calculated MS mass [M+1] + (C 18 H 17 ClF2N4O2) m / z 395.1, LCMS detected 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-formamide (9.37 mg, 0.106 mmol) in pyridine (1.5 mL) was added chlorotrimethylsilane (57.79 mg, 0.532 mmol, 67.51 μL) and TEA (25.12 mg, 0.248 mmol, 34.55 μL). The mixture was stirred at 100° C. for 18 hours. LCMS showed complete consumption of 23c, with one major peak having the desired mass. 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 give the title compound 23 as a white solid. Calculated MS mass [M+1] + (C 20 H 17 ClF2N6O2) m / z 447.1, LCMS detected 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-oxopyrrolidin-3-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide This General Method J provides specific synthetic details applicable to the title compound. By varying the coupling reagents, additional compounds can be prepared analogously to this method. [ka]

[0440] 3-Bromo-4-fluoro-5-nitrobenzoic acid (24b) To a solution of 4-fluoro-3-nitrobenzoic acid (24a, 5 g, 27.01 mmol) in HSO (30 mL) was added NBS (5.77 g, 32.41 mmol). The mixture was stirred at 60 °C for 6 h. The mixture was added to ice-cold water (2 L) with vigorous stirring. The precipitate was filtered to give 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 SOCl (2 mL) was stirred at 60 °C for 3 h. The mixture was concentrated to give 3-bromo-4-fluoro-5-nitrobenzoyl chloride (214 mg, crude) as a white solid. To a mixture of 4-(chlorodifluoromethoxy)aniline (1h, 146.64 mg, 0.758 mmol) and pyridine (89.89 mg, 1.13 mmol, 91.72 μL) in THF (2 mL) was added 3-bromo-4-fluoro-5-nitrobenzoyl chloride (213.97 mg, 0.758 mmol) under N. The mixture was stirred at 20 °C for 3 h. LCMS showed the desired elution. The mixture was extracted with ethyl acetate (2 mL × 3), and the combined organic layers were washed with brine (5 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was analyzed by preparative TLC (SiO, petroleum ether:ethyl acetate = 1:1, R f =0.3) to give compound 24c as a white solid.

[0442] (S)-3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-5-nitro-4-((5-oxopyrrolidin-3-yl)amino)benzamide (24e) To a mixture of 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluoro-5-nitrobenzamide (24c, 100 mg, 0.228 mmol) and (4S)-4-aminopyrrolidin-2-one (24d, 22.78 mg, 0.228 mmol) in EtOH (2 mL) was added TEA (69.06 mg, 0.682 mmol, 94.99 μL). The mixture was stirred at 50 °C for 3 h. LCMS showed the desired MS. The mixture was concentrated and analyzed by preparative TLC (SiO, petroleum ether:ethyl acetate = 3:1, R f =0.1) to give 24e 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-oxopyrrolidin-3-yl)amino)benzamide (24f) To a mixture of (S)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-5-nitro-4-((5-oxopyrrolidin-3-yl)amino)benzamide (24e, 0.053 g, 0.102 mmol) in AcOH (1 mL) at 20 °C under N was added Fe (56.95 mg, 1.02 mmol) in one portion. The mixture was stirred at 35 °C for 2 h. LCMS showed the desired MS. The mixture was poured into saturated NaHCO and extracted with ethyl acetate (5 mL × 2). The combined organic layers were washed with brine (5 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 24f as a yellow solid.

[0444] (S)-7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(5-oxopyrrolidin-3-yl)-1H-benzo[d]imidazole-5-carboxamide (24g) To a mixture of (S)-3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((5-oxopyrrolidin-3-yl)amino)benzamide (24f, 0.0358 g, 73.11 mmol) in CH(OMe) (2 mL) at 20 °C under N was added TsOH (1.26 mg, 7.31 μmol) in one portion, and the mixture was stirred at 20 °C for 30 min. LCMS showed the desired MS. The mixture was extracted with ethyl acetate (3 mL × 2), and the combined organic layers were washed with brine (5 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 24g as a yellow solid.

[0445] (S)-N-(4-(chlorodifluoromethoxy)phenyl)-1-(5-oxopyrrolidin-3-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (24) To a mixture of (S)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(5-oxopyrrolidin-3-yl)-1H-benzo[d]imidazole-5-carboxamide (24 g, 35.3 mg, 0.071 mmol) and pyrimidin-5-ylboronic acid (17.51 ​​mg, 0.141 mmol) in HO (0.1 mL) and dioxane (1 mL) under N was added Pd(dppf)Cl (5.17 mg, 7.06 mmol) and KPO (29.99 mg, 0.141 mmol) in one portion. The mixture was stirred at 100 °C for 12 h. LCMS showed the desired product. The mixture was extracted with ethyl acetate (3 mL × 3), and the combined organic layers were washed with brine (5 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was analyzed by preparative TLC (SiO, petroleum ether:ethyl acetate = 1:5, R f =0.1) to give the title compound 24 as a brown solid. Calculated MS mass [M+1]+ (C 23 H 17 ClF2N6O3) m / z 499.1, LCMS detected 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-oxadiazol-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) (57.60 mg, 0.491 mmol, 31.14 uL), and Pd(PPh) (18.89 mg, 0.016 mmol) in DMF (3 mL) was placed in a microwave tube. The sealed tube was heated at 150 °C under microwave irradiation for 2 h. LCMS showed the desired MS. The mixture was extracted with ethyl acetate (2 mL × 3), and the combined organic layer was washed with brine (5 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was analyzed by preparative TLC (SiO, petroleum ether:ethyl acetate = 0:1, R f =0.67) to give 1b 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) To a solution of N-(4-(chlorodifluoromethoxy)phenyl)-7-cyano-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (25b, 20 mg, 0.049 mmol) in DMF (3 mL) was added NH2OH.HCl (34.33 mg, 0.494 mmol) and TEA (49.99 mg, 0.49 mmol, 68.76 uL). The mixture was stirred at 75 °C for 12 h. LCMS showed the desired MS. The aqueous phase was extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was analyzed by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f =0.5) to give 25c as a white solid. Calculated MS mass [M+1] + (C 19 H 18 ClF2N5O3) m / z 438.1, LCMS detected m / z 438.3.

[0449] N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1H-benzo[d]imidazole-5-carboxamide (25) To a solution of (Z)-N-(4-(chlorodifluoromethoxy)phenyl)-7-(N'-hydroxycarbamimidoyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (25c, 0.02 g, 0.046 mmol) in THF (2 mL) under N was added bis(2,5-dioxopyrrolidin-1-yl)carbonate (15.21 mg, 0.059 mmol) and TEA (9.24 mg, 0.091 mmol, 12.72 μL). The mixture was stirred at 60 °C for 12 h. LCMS showed acceptable MS. The aqueous phase was extracted with ethyl acetate (3 mL × 3), and the combined organic layers were washed with brine (5 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (SiO2, ethyl acetate:methanol = 10:1, R f =0.1) to give the title compound 25 as a yellow solid. Calculated MS mass [M+1] + (C 20 H 16 ClF2N5O4) m / z 464.1, LCMS detected 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) To a solution of N-(4-(chlorodifluoromethoxy)phenyl)-7-cyano-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (25b, 30 mg, 0.074 mmol) in DMSO (3 mL) was added NHOH.HCl (41.20 mg, 0.593 mmol) and TEA (13.86 mg, 0.137 mmol). The mixture was stirred at 80 °C for 12 h. LCMS showed the desired MS. The aqueous phase was extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was analyzed by preparative TLC (SiO, petroleum ether:ethyl acetate = 0:1, R f =0.5) to give the title compound 26 as a white solid. Calculated MS mass [M+1] + (C 19 H 17 ClF2N4O3) m / z 423.1, LCMS detected 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-(pyrimidin-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 μL) in DMF (3 mL) was added KCO (391.88 mg, 2.84 mmol). The mixture was stirred at 30 °C for 16 h. LCMS showed complete consumption of 27a, 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 NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, 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) To a solution of methyl 4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-carboxylate (27b, 70 mg, 0.276 mmol) and pyrimidin-5-ylboronic acid (68.38 mg, 0.552 mmol) in dioxane (1 mL) and HO (0.1 mL) was added Pd(dppf)Cl (20.19 mg, 27.59 mmol) and KPO (175.71 mg, 0.828 mmol). The mixture was stirred at 110 °C under N for 16 h. LCMS showed complete consumption of 27b, 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 NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO 2 , ethyl acetate:methanol=10:1) to give 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-(pyrimidin-5-yl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (27d) To a solution of methyl 3-isopropyl-4-(pyrimidin-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 HO (0.25 mL) was added LiOH·HO (9.88 mg, 0.235 mmol). The mixture was stirred at 20 °C for 2 h. TLC (ethyl acetate:methanol = 10:1, R f= 0.0), which indicated that 27c was completely consumed, and one major new spot, which was more polar, was detected. The mixture was concentrated in vacuo. The mixture was then added to HO (3 mL) and the aqueous phase was acidified to pH = 5 with aqueous HCl. The mixture was concentrated in vacuo. The product was used in the next step without further purification. Compound 27d was obtained as a white solid. 1 H 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 μL) and HATU (51.54 mg, 0.136 mmol). The mixture was stirred at 25 °C for 4 h. LCMS showed complete consumption of 27d, 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 NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO 2 , 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, LCMS detected m / z 459.0. 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-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide This General Method K provides specific synthetic details applicable to the title compound. By varying the coupling reagents, additional compounds can be prepared analogously 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-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide (28b) To a solution of (R)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-fluoropropan-2-yl)-1H-benzo[d]imidazole-5-carboxamide (synthesized in a manner similar to that for 15g; 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) in DME (1.5 mL), EtOH (1.5 mL), and HO (0.3 mL) was added Pd(PPh)Cl (4.00 mg, 5.70 mmol) and NaCO (12.07 mg, 0.114 mmol). The mixture was stirred at 80° C. for 2 hours. LCMS showed that 28a 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=2:1) ​​to give 28b as a yellow solid.

[0459] (R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-fluoropropan-2-yl)-7-(1H-pyrazol-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-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide (28b, 25 mg, 0.042 mmol) in DCM (1 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL). The mixture was stirred at 20 °C for 1 h. LCMS showed that 28b 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=1:1) to give 28 as a white solid. Calculated MS mass [M+H] + (C 22 H 17 O2N5ClF5) m / z 514.1, LCMS detected 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-(pyrimidin-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]thiazine-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) 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 (synthesized in a similar manner to 8g; 29a, 2 mg, 4.09 μmol) in acetone (0.5 mL) and HO (0.1 mL) was added oxone (5.03 mg, 8.18 μmol). The mixture was stirred at 20° C. for 24 h. TLC (petroleum ether:ethyl acetate=0:1, R f =0.77), indicating complete consumption of 29a, and one major new spot with high polarity was detected. The reaction was quenched with sodium sulfide. The reaction mixture was concentrated under reduced pressure to remove acetone. The residue was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 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 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-(pyrimidin-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]thiazine-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), pyrimidin-5-ylboronic acid (4.28 mg, 0.035 mmol), Pd(dppf)Cl (843.09 μg, 1.15 μmol), KPO (7.34 mg, 0.035 mmol) in dioxane (1 mL) and HO (0.1 mL) was degassed and purged with N three times, and then the mixture was stirred under N at 110 °C for 16 h. TLC (petroleum ether:ethyl acetate = 0:1, R f =0.3), which indicated that 29b was completely consumed, and one major new spot with high polarity was detected. The reaction mixture was concentrated to remove dioxane under reduced pressure. The residue was diluted with HO (1 mL) and extracted with ethyl acetate (1 mL × 3). The combined organic layers were washed with brine (1 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 0:1) to give 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 title compound. Additional compounds can be prepared analogously to this method by varying the coupling 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 ethynyl(trimethyl)silane (85.65 mg, 0.872 mmol, 120.81 μL) in TEA (1 mL) was added CuI (3.32 mg, 0.017 mmol) and Pd(PPh)Cl (12.24 mg, 0.017 mmol) under N, and the mixture was stirred at 80 °C for 2 h. LCMS showed the desired MS. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate=1:1, R f =0.4) to give 30a 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) To a mixture of N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazole-5-carboxamide (30a, 70 mg, 0.147 mmol) in MeOH (2 mL) was added K2CO3 (40.65 mg, 0.294 mmol, 2 eq). The mixture was stirred at 20 °C for 0.5 h. TLC (petroleum ether:ethyl acetate = 1:1, R f =0.5) indicated that 30a was consumed, and one major new spot with high polarity was detected. The mixture was concentrated and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was analyzed by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f =0.5) to give 30b 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-triazol-4-yl)-1H-benzo[d]imidazole-5-carboxamide (30c) To a mixture of N-(4-(chlorodifluoromethoxy)phenyl)-7-ethynyl-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (30b, 50 mg, 0.124 mmol) and 1-(azidomethyl)-4-methoxy-benzene (22.23 mg, 0.136 mmol) in THF (1 mL) and HO (1 mL) was added CuSO 5HO (1.55 mg, 6.19 mmol) and sodium (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (2.45 mg, 0.012 mmol) under N. The mixture was stirred at 20 °C for 3 h. LCMS showed acceptable MS. The mixture was extracted with ethyl acetate (3 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was analyzed by preparative TLC (SiO, petroleum ether:ethyl acetate = 0:1, R f =0.4) to give 30c 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-triazol-4-yl)-1H-benzo[d]imidazole-5-carboxamide (30c, 40 mg, 0.071 mmol) in TFA (3 mL) was stirred at 60° C. for 12 hours. LCMS showed the desired MS. The mixture was concentrated and extracted with ethyl acetate (5 mL×3). The combined organic layers were washed with brine (10 mL×2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was analyzed by preparative TLC (SiO2, petroleum ether:ethyl acetate=0:1, R f =0.3) to give 30 as an off-white solid. Calculated MS mass [M+1] + (C 20 H 17 ClF2N6O2) m / z 447.1, LCMS detected m / z 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-pyrazol-3-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide This general method M provides specific synthetic details applicable to the title compound. Additional compounds can be prepared analogously to this method by varying the coupling and / or deprotection reagents. [ka]

[0469] N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(trimethylstannyl)-1H-benzo[d]imidazole-5-carboxamide (31a) To a mixture of 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) in toluene (3 mL) was added Pd(PPh3)4 (23.86 mg, 0.021 mmol) under N2. The mixture was stirred at 130 °C for 12 h. LCMS showed the correct MS. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 2). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was analyzed by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, R f =0.4) to give 31a as a colorless oil.

[0470] N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (31b) To a mixture of 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) in DMSO (3 mL) was added Pd(PPh) (10.65 mg, 9.22 µmol) under N. The mixture was stirred at 100 °C for 12 hours. LCMS showed the desired MS. The mixture was filtered and extracted with ethyl acetate (3 mL × 3) and water. The combined organic layer was washed with brine (5 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 0:1, R f =0.6) to give 31b as a yellow oil. Calculated MS mass [M+1] + (C 28 H 31 ClF2N6O3Si) m / z 601.2, LCMS detected m / z 601.2.

[0471] N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-cyano-1H-pyrazol-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-pyrazol-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 h. LCMS showed acceptable MS. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=0:1, R f =0.4) to give 31 as a yellow solid. Calculated MS mass [M+1] + (C 22H 17 ClF2N6O2) m / z 471.1, LCMS detected m / z 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) A solution of (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 in a similar manner to 8g; 32a, 50 mg, 0.103 mmol) in MeOH (1 mL) and DMF (3 mL) was heated under N2 with 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), Xantphos (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 in vacuo and purged with CO several times. The mixture was stirred under CO (2 MPa) at 120 °C for 12 h. LCMS showed detection of the desired MS. The reaction mixture was concentrated under reduced pressure. The residue was diluted with HO (10 mL), and the mixture was extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was analyzed by preparative TLC (SiO, ethyl acetate:petroleum ether=3:1, R f =0.3) to afford the title compound 32b 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) To a solution of (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) in MeOH (1 mL), THF (1 mL), and HO (1 mL) was added LiOH·HO (7.93 mg, 0.189 mmol). The mixture was stirred at 50 °C for 5 h. LCMS showed detection of the desired MS. The reaction mixture was concentrated under reduced pressure to remove the solvent. HO was added, and 1 M HCl was added dropwise to the mixture until pH = 5. The mixture was concentrated to give 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) To a solution of (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) in DMF (2 mL) was added HATU (53.02 mg, 0.139 μmol) and DIEA (48.06 mg, 0.372 mmol, 64.77 μL). The mixture was stirred at 20° C. for 24 hours. LCMS showed detection of the desired product. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with HO (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was analyzed by preparative TLC (SiO, petroleum ether:ethyl acetate=0:1, R f =0.60) to give the title compound 32 as a white solid. Calculated MS mass [M+1] + (C 21 H 19 ClF2N4O4) m / z 465.1, LCMS detected 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-pyrazol-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 title compound. By varying the coupling reagents, additional compounds can be prepared analogously 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) A solution of (R)-1-(3-amino-5-bromo-4-((1-hydroxypropan-2-yl)amino)phenyl)-2-(4-(chlorodifluoromethoxy)phenyl)ethanone (synthesized in a similar manner to 6c; 33a, 330 mg, 0.71 mmol) and di(imidazol-1-yl)methanethione (379.68 mg, 2.13 mmol) in THF (15 mL) was stirred at 15° C. for 16 hours. TLC (petroleum ether:ethyl acetate=0:1, R f =0.6) showed the formation of two new spots. LCMS showed the detection of two peaks with MS 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 give 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 crude product batch was further purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1 to 0:1) to give 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-pyrazol-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), KPO (26.94 mg, 0.127 mmol), Pd(dppf)Cl (6.19 mg, 8.46 µmol), and BocO (4.62 mg, 0.021 µmol, 4.86 µL) in dioxane (2 mL) and HO (0.2 mL) was degassed and purged with N three times. The mixture was stirred at 110° C. under a N atmosphere for 16 hours. LCMS showed that 33c remained. To this mixture was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (24.63 mg, 0.127 mmol), KPO (17.96 mg, 0.085 mmol), and Pd(dppf)Cl (6.19 mg, 8.46 mmol). The mixture was stirred at 110° C. under a N atmosphere for 4 hours. LCMS showed the detection of a peak with the desired MS. TLC (ethyl acetate:methanol=10:1, R f =0.48) indicated the formation of a new spot. The reaction mixture was concentrated and H2O (10 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC (ethyl acetate:methanol = 10:1, R f =0.48) to give the crude product, which was purified by preparative TLC (DCM:methanol = 10:1, R f =0.5) to give 33 as a white solid. Calculated MS mass [M+1] + (C 21 H 16 ClF2N5O3) m / z 460.1, LCMS detected 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-pyrazol-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 title compound. Additional compounds can be prepared analogously to this method by varying the coupling 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 in a similar manner to 8e; 34a, 1.2 g, 2.78 mmol) in TFA (10 mL) was stirred at 75° C. for 16 h. LCMS showed acceptable MS. The mixture was concentrated to give 34b as a yellow oil. Calculated MS mass [M+1] + (C 13 H 13 BrN2O4) m / z 341.0, LCMS detected 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) To a solution of (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) in THF (5 mL), MeOH (5 mL), and HO (1 mL) was added LiOH·HO (233.71 mg, 5.57 mmol). The mixture was stirred at 50 °C for 1 h. LCMS showed the desired MS. The mixture was concentrated, and the residue was dissolved in water (5 mL). The suspension was extracted with ethyl acetate (10 mL × 2), and HCl (1 M) was added dropwise to the aqueous phase until pH = 3. The precipitated solid was collected by filtration and dried to give 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) To a mixture of (R)-6-bromo-4-(hydroxymethyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxylic acid (34c, 0.85 g, 2.60 mmol) and 4-(chlorodifluoromethoxy)aniline (1h, 528.13 mg, 2.73 mmol) in pyridine (10 mL) was added HATU (1.48 g, 3.90 mmol). The mixture was stirred at 40 °C for 6 h. LCMS showed a desired MS. The reaction mixture was poured into water (30 mL), and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layer was washed with brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1 to 0:1, R f =0.4) to give 34d as a white solid. Calculated Mass [M+1] + (C 19 H 15 BrClF2N3O4) m / z 502.0, LCMS detected 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-pyrazol-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide (34) To a mixture of (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) in dioxane (5 mL) and HO (0.5 mL) was added KPO (422.27 mg, 1.99 mmol), Pd(dppf)Cl (72.78 mg, 0.099 mmol), and (Boc)O (217.08 mg, 0.995 mmol, 228.51 µL) under N. The mixture was stirred at 110 °C for 16 h. LCMS showed the desired MS. The mixture was filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=100:1 to 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 detected 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 [ka] (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) To a mixture of (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, 0.03 g, 0.06 mmol) in DCM (2 mL) was added DAST (19.24 mg, 0.119 mmol, 15.77 uL) at 0 °C under N. The mixture was stirred at 25 °C for 8 h. LCMS showed the desired MS. The crude product was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 0:1, R f =0.6) to give 35a as a white solid. Calculated MS mass [M+1] + (C 19 H 14 BrClF3N3O3) m / z 504.0, LCMS detected m / z 504.0.

[0485] (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 (35) To a mixture of (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) in dioxane (2 mL) and HO (0.2 mL) was added (Boc)O (4.32 mg, 0.02 mmol, 4.55 µL), Pd(dppf)Cl (1.45 mg, 1.98 µmol), and KPO (12.62 mg, 0.059 mmol). The mixture was stirred at 110° C. for 12 hours. LCMS showed the desired 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 give 35 as a white solid. Calculated MS mass [M+1] + (C 22 H 17 ClF3N5O3) m / z 492.1, LCMS detected 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-hydroxyazetidin-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-hydroxyazetidin-1-yl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide (36) To a mixture of (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), azetidin-3-ol (36a, 15.02 mg, 0.205 mmol) in THF (0.8 mL) was added BrettPhos Pd G3 (3.73 mg, 4.11 μmol), and t-BuONa (2 M, 41.09 μL) under N2. The mixture was stirred at 100 °C in a sealed tube for 16 h. LCMS showed a peak with the desired MS. TLC (ethyl acetate:methanol = 10:1, R f =0.47) showed the formation of a new spot. The reaction mixture was concentrated. The crude product was purified by preparative TLC (ethyl acetate:methanol=10:1, R f =0.47), which was further purified by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 25%-55%, 7 min) to give 36 as a white solid. Calculated MS mass [M+1] + (C 22 H 21 ClF2N4O4) m / z 479.1, LCMS detected 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-pyrazol-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) To a solution of methyl 3-amino-5-bromo-4-(piperidin-1-yl)benzoate (synthesized in a similar manner to 1d; 37a, 160 mg, 0.511 mmol) in formic acid (3 mL) was added HO (521.32 mg, 4.60 mmol, 441.79 μL, 30% purity). The mixture was heated at reflux for 40 minutes. LCMS showed complete consumption of 37a, with one major peak having the desired mass. TLC (petroleum ether:ethyl acetate = 2:1, R f=0.20) indicated that the reaction was completely consumed, with one new spot forming. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL). The organic layer was washed with saturated aqueous NaHCO3 (10 mL x 3), dried over Na2SO4, filtered, and concentrated. The crude product was identified by preparative TLC (petroleum ether:ethyl acetate = 2:1, R f =0.20) to give 37b 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), HO (1 mL), and THF (1 mL) was added LiOH·HO (13.57 mg, 0.323 mmol). The mixture was stirred at 50 °C for 2 h. LCMS showed that 37b was completely consumed, with one major peak having the desired mass. The mixture was concentrated to remove the THF and MeOH. 1 M aqueous HCl was then added dropwise to the reaction mixture until pH = 5. The suspension was filtered, and the filter cake was washed with HO (1 mL) and dried to give 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) was added HATU (72.66 mg, 0.191 mmol), DIEA (61.75 mg, 0.478 mmol, 83.22 μL), and 4-(chlorodifluoromethoxy)aniline (1h, 61.66 mg, 0.319 μmol). The mixture was stirred at 15° C. for 16 h. LCMS showed complete consumption of 37c, with one major peak having the desired mass. TLC (ethyl acetate:methanol=10:1, R f =0.36) indicated that 37c was completely consumed, and one new spot was formed. To the mixture was added HO (20 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC (ethyl acetate:methanol = 10:1, R f =0.36) to give 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-pyrazol-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)Cl (3.11 mg, 4.25 mmol), and KPO (27.06 mg, 0.127 mmol) in dioxane (1 mL) and HO (0.1 mL) was degassed and purged with N three times. The mixture was stirred at 110 °C under N for 16 h. LCMS showed that 37d was completely consumed, and one major peak with the desired mass was detected. TLC (dichloromethane:methanol=10:1, R f =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 brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC (dichloromethane:methanol = 10:1, R f =0.30) to give 37 as a white solid. Calculated MS mass [M+1] + (C 22 H 18 ClF2N5O2) m / z 458.1, LCMS detected 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-pyrazol-5-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide The title compound was prepared according to Scheme 10. This General Method P illustrates Scheme 10 and provides specific synthetic details applicable to the title compound. [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-hydroxypiperidin-1-yl)-5-nitrobenzoate (synthesized in a similar manner to 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 added slowly in portions to the reaction mixture over 32 hours. TLC (ethyl acetate:methanol=10:1, R f=0.37) showed the formation of two new spots. LCMS 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 x 3), then with saturated aqueous NaHCO3 (30 mL x 3), dried over Na2SO4, and evaporated to dryness. The crude product was purified by preparative TLC (ethyl acetate:methanol = 10:1, R f =0.3) to give 38b 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 purified by preparative TLC (ethyl acetate:methanol=10:1, R f =0.37) to give 38c 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) To a solution of (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) in MeOH (1 mL), HO (1 mL), and THF (1 mL) was added LiOH·HO (6.45 mg, 0.154 mmol). The mixture was stirred at 50 °C for 2 h. TLC (ethyl acetate:methanol = 10:1, R f =0.0) indicated the formation of a new spot. The mixture was concentrated to remove the solvent. To the mixture was added 1 M HCl dropwise until the reaction mixture reached pH=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) To a solution of (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) in DMF (2 mL) was added HATU (54.99 mg, 0.145 mmol), DIEA (124.62 mg, 0.964 mmol, 167.95 μL), and 4-[chloro(difluoro)methoxy]aniline (1h, 28.00 mg, 0.145 mmol). The mixture was stirred at 15° C. for 16 hours. TLC (ethyl acetate:methanol=10:1, R f =0.3) showed the formation of a new spot. LCMS showed the detection of a peak with the desired MS. The mixture was quenched with water (20 mL), and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC (ethyl acetate:methanol = 10:1, R f =0.3) to give 38e as a yellow solid.

[0497] (R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-hydroxy-9-(1H-pyrazol-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)Cl (4.51 mg, 6.16 mmol), and KPO (19.63 mg, 0.092 mmol) in dioxane (2 mL) and HO (0.2 mL) was degassed and purged with N three times. The mixture was stirred at 120 °C under N for 16 h. TLC (ethyl acetate:methanol = 5:1, R f =0.2) showed the formation of a new spot. LCMS showed the detection of a peak with the desired 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 give 38 as a white solid. Calculated Mass [M+1] + (C 22 H 18 ClF2N5O2) m / z 474.1, LCMS detected 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-hydroxypyridin-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 title compound. By varying the coupling reagents, additional compounds can be prepared analogously 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-dioxabo A mixture of (loran-2-yl)-1,3,2-dioxaborolane (939.17 mg, 3.70 mmol), Pd(OAc) (9.23 mg, 0.041 mmol), XPhos (48.97 mg, 0.103 mmol), and KPO (261.68 mg, 1.23 mmol) in dioxane (6.2 mL) was degassed and purged with N three times. The mixture was stirred under N atmosphere in a microwave at 60 °C for 16 h. LCMS showed detection of the desired MS. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 0:1) to give 39a as a white solid.

[0500] (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(4-hydroxypyridin-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 μmol), 2-bromopyridin-4-ol (2.44 mg, 0.014 mmol), Pd(dppf)Cl (685.43 μg, 9.37 μmol), NaCO (2.98 mg, 0.028 mmol) in DME (0.5 mL) and HO (0.1 mL) was degassed and purged with N three times. The mixture was stirred under N atmosphere in a microwave reactor at 120 °C for 1 h. LCMS showed that 39a was completely consumed, and the desired 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 give 39 as a white solid. Calculated MS mass [M+1] + (C 24 H 19 ClF2N4O4) m / z 501.1, LCMS detected m / z 501.1; 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-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide This general method R provides specific synthetic details applicable to the title compound. Additional compounds can be prepared analogously to this method by varying the coupling reagents. [ka]

[0502] (S)-3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-5-(2-hydroxypropanamido)-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) was added 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). The mixture was stirred at 15° C. for 4 hours. TLC (petroleum ether:ethyl acetate=1:1, R f =0.45) indicated complete consumption of 9a, with one major new, more polar spot detected. LCMS showed the desired MS. The reaction mixture was diluted with HO (20 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 1:1) to give 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) To a solution of (S)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-5-(2-hydroxypropanamido)-4-(isopropylamino)benzamide (40a, 40 mg, 0.077 mmol) in toluene (1 mL) was added 4-methylbenzenesulfonic acid (2.65 mg, 0.015 mmol). The mixture was stirred at 100° C. for 4 hours. TLC (petroleum ether:ethyl acetate=1:1, R f =0.15) indicated complete consumption of 40a, with one major new, more polar spot detected. LCMS showed the desired MS. The residue was diluted with HO (20 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 1:1) to give 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-pyrazol-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, 10 mg, 0.02 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11.58 mg, 0.06 mmol) A mixture of KPO (12.67 mg, 0.06 mmol), Pd(dppf)Cl (1.46 mg, 1.99 mmol), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11.58 mg, 0.06 mmol) in dioxane (1 mL) and HO (0.1 mL) was degassed and purged with N three times. The mixture was stirred at 115 °C under N atmosphere for 4 h. TLC (ethyl acetate:methanol = 20:1, R f =0.24) indicated complete consumption of 40b, with one major new, more polar spot detected. LCMS showed the desired MS. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (ethyl acetate:methanol = 20:1) to give 40 as a white solid. Calculated Mass [M+1] + (C 23 H 22 ClF2N5O3) m / z 490.1, LCMS detected m / z 490.1; 1 H NMR (400 MHz, MeOD-d4) δ 8.34 (br s, 1H), 7.92-7.79 (m, 4H), 7.29 (d, J = 9.3 Hz, 2H), 6.61 (d, J = 2.0 Hz, 1H), 5.29 (q, J = 6.0 Hz, 1H), 4.76 (br s, 1H), 1.73 (d, J = 6.4 Hz, 3H), 1.45 (dd, J = 7.1, 12.0 Hz, 6H).

[0505] Example 41 (R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-methyl-6-(pyrrolidin-1-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide [ka]

[0506] (R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-methyl-6-(pyrrolidin-1-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide (41) A mixture of (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, 50 mg, 0.103 mmol), pyrrolidine (438.39 mg, 6.16 mmol, 514.54 µL), (BuNCuI) (23.00 mg, 0.021 mmol), CsCO (66.95 mg, 0.205 mmol), and 3,4,7,8-tetramethyl-1,10-phenanthroline (2.43 mg, 0.01 mmol) in dioxane (2 mL) was degassed and purged with N three times. The mixture was stirred at 120 °C under N for 16 h. LCMS showed the detection of the desired mass. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:methanol=20:1) to give 41 as a white solid. Calculated Mass [M+1] + (C 23 H 23 ClF2N4O3) m / z 477.1, LCMS detected m / z 477.1. 1H NMR (400 MHz, CDCl3-d) 8.61 (s, 1H), 7.74 (d, J = 9.0 Hz, 2H), 7.25 (s, 1H), 7.22 (d, J = 6.6 Hz, 2H), 5.16-4.92 (m, 2H), 4.47 (br s, 1H), 4.15-4.00 (m, 2H), 3.26 (br s, 4H), 2.12 (br s, 4H), 1.63 (d, J = 6.6 Hz, 3H).

[0507] Example 42 (General Method S) (R)-N-(4-(chlorodifluoromethoxy)phenyl)-3-methyl-5-(pyridazin-3-yl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide This General Method S provides specific synthetic details applicable to the title compound. By varying the coupling reagents, additional compounds can be prepared analogously to this method. [ka]

[0508] (R)-3-amino-5-bromo-4-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)amino)-N-(4-(chlorodifluoromethoxy)phenyl)benzamide (42a) A mixture of (R)-3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((1-hydroxypropan-2-yl)amino)benzamide (33a, 2 g, 4.30 mmol), imidazole (439.50 mg, 6.46 mmol), TBSCl (973.05 mg, 6.46 mmol, 791.10 uL), and DMAP (52.58 mg, 430.40 umol) in DCM (30 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 15 °C for 2 h. TLC (petroleum ether:ethyl acetate = 3:1, R f=0.5) indicated the formation of a new spot. LCMS showed the detection of a peak with the desired MS. The reaction mixture was concentrated, and H2O (20 mL) was added. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to give 42a as a yellow oil. 1 H NMR (400MHz, CDCl3-d) δ 7.69 (br s, 1H), 7.66 (d, J = 9.0 Hz, 2H), 7.37 (d, J = 1.8 Hz, 1H), 7.25 (br d, J = 8.8 Hz, 2H), 7.14 (d, J = 1.8 Hz, 1H), 4.31 (br s, 2H), 3.78-3.66 (m, 2H), 3.62-3.50 (m, 2H), 1.15 (d, J = 6.2 Hz, 3H), 0.94 (s, 9H), 0.11 (s, 6H).

[0509] (R)-7-Bromo-1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (42b) A mixture of (R)-3-amino-5-bromo-4-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)amino)-N-(4-(chlorodifluoromethoxy)phenyl)benzamide (42a, 2.4 g, 4.15 mmol), di(imidazol-1-yl)methanethione (2.22 g, 12.44 mmol), DIEA (1.07 g, 8.29 mmol, 1.44 mL) in THF (20 mL) was degassed and purged with N three times. The mixture was stirred under N atmosphere at 60 °C for 16 h. TLC (petroleum ether:ethyl acetate = 2:1, R f=0.54) indicated the formation of a new spot. LCMS showed the detection of a peak with the desired MS. The mixture was concentrated, and H2O (50 mL) was added. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1 to 2:1) to give 42b as a yellow solid. 1 H NMR (400MHz, CDCl3-d) δ 11.21 (s, 1H), 7.96 (s, 1H), 7.86 (d, J = 1.1 Hz, 1H), 7.75-7.67 (m, 3H), 7.28 (s, 1H), 7.26 (s, 1H), 6.11-5.97 (m, 1H), 4.99 (t, J = 9.6 Hz, 1H), 3.95 (dd, J = 5.1, 10.4 Hz, 1H), 1.86 (d, J = 7.1 Hz, 3H), 0.68 (s, 9H), 0.00 (s, 3H),-0.12 (s, 3H).

[0510] (R)-7-Bromo-1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(methylthio)-1H-benzo[d]imidazole-5-carboxamide (42c) To a solution of (R)-7-bromo-1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (42b, 2.4 g, 3.86 mmol) in DMF (20 mL) was added MeI (822.82 mg, 5.80 mmol, 360.89 μL) and KCO (1.07 g, 7.73 mmol). The mixture was stirred at 15 °C for 2 h. TLC (petroleum ether:ethyl acetate = 2:1, R f=0.72) indicated the formation of a new spot. LCMS showed the detection of a peak with the desired MS. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 2:1) to give 42c as a yellow oil. 1 H NMR (400MHz, CDCl3-d) δ 8.03 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.89 (s, 1H), 7.74-7.67 (m, 2H), 7.28 (s, 1H), 7.25 (s, 1H), 6.21-6.05 (m, 1H), 4.28 (dd, J = 9.2, 10.4 Hz, 1H), 3.89 (dd, J = 5.7, 10.6 Hz, 1H), 2.83 (s, 3H), 1.67 (d, J = 7.3 Hz, 3H), 0.67 (s, 9H), -0.04 (s, 3H), -0.18 (s, 3H)

[0511] (R)-7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(1-hydroxypropan-2-yl)-2-(methylthio)-1H-benzo[d]imidazole-5-carboxamide (42d) To a solution of (R)-7-bromo-1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(methylthio)-1H-benzo[d]imidazole-5-carboxamide (42c, 1 g, 1.57 mmol) in THF (20 mL) was added TBAF (1 M, 1.73 mL). The mixture was stirred at 15° C. for 3 h. TLC (petroleum ether:ethyl acetate=0:1, R f=0.65) indicated the formation of a new spot. LCMS showed the detection of a peak with the desired MS. The mixture was quenched with AcONH4 (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 0:1) to give 42d as a yellow solid. 1 H NMR (400MHz, CDCl3-d) δ 8.63 (s, 1H), 7.87 (d, J = 9.0 Hz, 2H), 7.62 (d, J = 1.7 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H), 6.14 (ddd, J = 4.6, 7.4, 10.0 Hz, 1H), 4.59 (dd, J = 10.0, 12.7 Hz, 1H), 3.91 (dd, J = 4.4, 12.8 Hz, 1H), 2.84 (s, 3H), 1.59 (d, J = 7.3 Hz, 3H).

[0512] (R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3-methyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide (42e) A solution of (R)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(1-hydroxypropan-2-yl)-2-(methylthio)-1H-benzo[d]imidazole-5-carboxamide (42d, 500 mg, 960.11 μmol) in DMF (6 mL) was degassed and purged with O2 three times, and the mixture was cooled to 0 °C. NaH (46.08 mg, 1.15 mmol, 60% purity, 1.2 eq) was added. The mixture was stirred under O2 at 0-15 °C for 6 h. TLC (petroleum ether:ethyl acetate = 1:2, R f=0.5) showed the formation of a new spot. LCMS showed the detection of a peak with the desired MS. The mixture was quenched with NH4Cl (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 0:1) to give 42e as a white solid. 1 H NMR (400MHz, CDCl3-d) δ 8.24 (s, 1H), 7.90 (dd, J = 1.3, 15.9 Hz, 2H), 7.74 (d, J = 9.0 Hz, 2H), 7.25 (s, 1H), 5.29-5.19 (m, 1H), 5.09-4.98 (m, 1H), 4.78 (dd, J = 2.2, 8.6 Hz, 1H), 1.69 (d, J = 6.4 Hz, 3H)

[0513] (R)-N-(4-(chlorodifluoromethoxy)phenyl)-3-methyl-5-(pyridazin-3-yl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide (42) A mixture of (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3-methyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide (42e, 25 mg, 52.89 μmol), tributyl(pyridazin-3-yl)stannane (39.05 mg, 105.78 μmol, 2 eq), palladium; tritert-butylphosphane (2.70 mg, 5.29 μmol, 0.1 eq) in dioxane (2 mL) was degassed and purged with N2 three times, and then the mixture was stirred under N2 at 110 °C for 16 h. TLC (ethyl acetate:methanol = 10:1, R f=0.31) showed the formation of a new spot. LCMS showed the detection of a peak with the desired MS. The reaction mixture was concentrated and H2O (20 mL) was added. The aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC (ethyl acetate:methanol = 10:1, R f =0.31) to give the crude product, which was further purified by preparative HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.225% FA)-ACN]; B%: 20%-70%, 12 min) to give 42 as a pale yellow solid. Calculated MS mass [M+1] + (C 22 H 16 ClF2N5O3) m / z 472.1, LCMS detected m / z 472.0; 1 H NMR (400MHz, MeOD-d4) δ 9.28 (dd, J = 1.5, 4.9 Hz, 1H), 8.33 (dd, J = 1.5, 8.6 Hz, 1H), 8.21-8.17 (m, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.95 (dd, J = 5.0, 8.6 Hz, 1H), 7.88-7.84 (m, 2H), 7.31 (d, J = 9.0 Hz, 2H), 5.39-5.26 (m, 2H), 4.83 (dd, J = 2.8, 8.4 Hz, 1H), 0.94 (d, J = 6.4Hz, 3H).

[0514] Example 43 (General Law T) (S)-N-(4-(chlorodifluoromethoxy)phenyl)-2-hydroxy-9-(pyrimidin-5-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide This General Method T provides specific synthetic details applicable to the title compound. By varying the coupling reagents, additional compounds can be prepared analogously to this method. [ka]

[0515] (S)-Methyl 3-amino-5-bromo-4-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)benzoate (43b) To a mixture of (S)-methyl 3-amino-5-bromo-4-(3-hydroxypiperidin-1-yl)benzoate (synthesized in a similar manner to 1d; 43a, 970 mg, 2.95 mmol) and imidazole (501.52 mg, 7.37 mmol) in DCM (20 mL) at 20 °C under N2, TBSCl (666.18 mg, 4.42 mmol) and DMAP (36.00 mg, 0.295 mmol) were added in one portion. The mixture was stirred at 20 °C for 12 h. TLC (petroleum ether:ethyl acetate = 3:1, R f =0.7), which indicated that 43a was completely consumed, and one new spot formed. The mixture was washed with water (8 mL × 3) and brine (8 mL), dried over Na2SO4, filtered, and concentrated to give 43b as a yellow oil, which was used in the next step without further purification.

[0516] (S)-Methyl 9-bromo-2-((tert-butyldimethylsilyl)oxy)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate (43c) To a solution of (S)-methyl 3-amino-5-bromo-4-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)benzoate (43b, 1.18 g, 2.66 mmol) in 2,2,2-trifluoroethanol (10 mL) at 20 °C under N was added chloroiridium; (1Z,5Z)-cycloocta-1,5-diene (268.11 mg, 0.399 mmol) in one portion. The mixture was heated to 85 °C and stirred for 72 h. LCMS showed complete consumption of 43b, with one major peak having the desired mass. TLC (petroleum ether:ethyl acetate=1:1, R f=0.4), which indicated th...

Claims

1. Formula (I) or Formula (Ia): 【Chemistry 1】 [In the formula, L is -NH-CO-, -CO-NH-, -NH-SO ２ - or -SO ２ -NH-; R １ is an optionally substituted C ６ -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) ２ N.R. ６ R ７ , N.R. ６ C.O.R. ７ , N.R. ６ SO ２ R ７ , or C(O)OR ６ and R ２ is H, optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ８ Cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted C ２ -C ６ alkenyl, optionally substituted C ２ -C ６ alkynyl, optionally substituted C ６ -C １０ aryl or optionally substituted 5-10 membered heteroaryl; R ３ is H, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ alkenyl, optionally substituted C ２ -C ６ alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR ６ , or N.R. ６ R ７ and Or, R ２ and R ３ together with the atoms therebetween, optionally substituted C ３ -C ８ forming a cycloalkyl or an optionally substituted 4-10 membered heterocycloalkyl; R ４ is an optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ alkenyl or optionally substituted C ２ -C ６ alkynyl; X is O or S; Y is CH, C-(C １ -C ２ alkyl), C-halo, or N; Z is CR ５ or N; R ５ is H or a halogen; R ６ is H, optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ８ Cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted C ６ -C １０ aryl or an optionally substituted 5-10 membered heteroaryl; and R ７ is H, optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ８ Cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted C ６ -C １０ aryl or optionally substituted 5-10 membered heteroaryl; Or, R ６ and R ７ together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heterocycle; 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-. or a tautomer thereof, or a pharma- ceutically acceptable salt of either of them.

2. R １ But, C ６ -C １０ aryl, 5-10 membered heteroaryl, or 4-10 membered heterocycle, each of which is optionally selected from halogen, cyano, hydroxyl, C １ -C ６ Alkoxy, C １ -C ６ Alkyl and C ３ -C ６ optionally substituted with 1 to 3 substituents selected from the group consisting of cycloalkyl; R ２ But, C １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl, 4-10 membered heterocycloalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ６ -C １０ aryl, or 5-10 membered heteroaryl, each of which is optionally selected from halogen, hydroxyl, C １ -C ６ Alkoxy, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, 4-6 membered heterocyclyl, cyano, oxo, -C(O)NH(C １ -C ６ alkyl), and -C(O)NH(C ３ -C ６ cycloalkyl); R ３ But, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, 4-6 membered heterocycloalkyl, C ６ -C １０ aryl or 5-10 membered heteroaryl, each of which is optionally selected from halogen, hydroxyl, and C １ -C ６ optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl; Or, R ２ and R ３ together with the atoms in between, C ３ -C ８ cycloalkyl or 4-10 membered heterocycloalkyl, each of which is optionally １ -C ６ Alkyl, Hydroxyl, C １ -C ６ Alkyl-OH, -C(O)(C １ -C ６ alkyl), and oxo; R ４ But, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ alkynyl, each of which is optionally substituted with 1 to 3 halogens; R ６ But, C １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl, 4-10 membered heterocycloalkyl, C ６ -C １０ aryl or 5-10 membered heteroaryl, each of which is optionally selected from halogen, hydroxyl, and C １ -C ６ and, R ７ But, C １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl, 4-10 membered heterocycloalkyl, C ６ -C １０ aryl or 5-10 membered heteroaryl, each of which is optionally selected from halogen, hydroxyl, and C １ -C ６ optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl; Or, R ６ and R ７ together with the nitrogen to which they are attached, optionally halogen, hydroxyl, and C １ -C ６ forming a 4-7 membered heterocycle, optionally substituted by 1 to 3 substituents selected from the group consisting of alkyl; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

3. Formula (IA-1): 【Chemistry 2】 3. The compound according to claim 1 or 2, which is a compound represented by the formula: or a pharma- ceutically acceptable salt thereof.

4. Formula (IIA) to formula (IIH): 【Chemistry 3】 [In the formula, R １０ is an optionally substituted 5-6 membered heteroaryl; R ２０ is an optionally substituted C １ -C ３ Alkyl, optionally substituted C ３ -C ４ cycloalkyl or an optionally substituted 4-6 membered heterocycloalkyl; R ３０ is H, optionally substituted C １ -C ３ Alkyl, optionally substituted C ３ -C ４ cycloalkyl or an optionally substituted 5-6 membered heterocycloalkyl; and Ring A is an optionally substituted 5- to 6-membered heterocycloalkyl.

4. The compound of claim 3, which is a compound selected from the group consisting of:

5. R １０ optionally halogen, cyano, hydroxyl, C １ -C ６ Alkoxy, C １ -C ６ Alkyl and C ３ -C ６ is a 5-6 membered heteroaryl optionally substituted by 1-3 substituents selected from the group consisting of cycloalkyl; R ２０ But, C １ -C ３ Alkyl, C ３ -C ４ cycloalkyl, or 4-6 membered heterocycloalkyl, each of which is optionally selected from halogen, hydroxyl, C １ -C ６ Alkoxy, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, 4-6 membered heterocyclyl, cyano, oxo, -C(O)NH(C １ -C ６ alkyl), and -C(O)NH(C ３ -C ６ cycloalkyl); R ３０ But, C １ -C ３ Alkyl, C ３ -C ４ cycloalkyl, or 5-6 membered heterocycloalkyl, each of which is optionally selected from halogen, hydroxyl, and C １ -C ６ optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl; Ring A is optionally C １ -C ６ Alkyl, Hydroxyl, C １ -C ６ Alkyl-OH, -C(O)(C １ -C ６ alkyl), and oxo; 5. The compound of claim 4, or a pharma- ceutically acceptable salt thereof.

6. 6. The compound according to any one of claims 3 to 5, wherein X is O, or a pharma- ceutically acceptable salt thereof.

7. R １ is a 5- to 10-membered heteroaryl or a 4- to 10-membered heterocycle, each of which is optionally selected from halogen, cyano, hydroxyl, C １ -C ６ Alkoxy, C １ -C ６ Alkyl and C ３ -C ６ The compound according to any one of claims 3 to 6, or a pharma- ceutically acceptable salt thereof, optionally substituted by 1 to 3 substituents selected from the group consisting of cycloalkyl.

8. R １ -CONH (cyclopropyl), -CONH ２ , -CONHMe, 【Chemistry 4】 7. The compound according to any one of claims 3 to 6, which is: or a pharma- ceutically acceptable salt thereof.

9. R １ is pyrimidinyl or pyrazolyl, each of which is optionally selected from halogen, cyano, hydroxyl, C １ -C ６ Alkoxy, C １ -C ６ Alkyl and C ３ -C ６ The compound according to any one of claims 3 to 7, or a pharma- ceutically acceptable salt thereof, optionally substituted by 1 to 3 substituents selected from the group consisting of cycloalkyl.

10. R ２ But, C １ -C ３ Alkyl or C ３ -C ４ cycloalkyl, each of which is optionally selected from halogen, hydroxyl, C １ -C ６ Alkoxy, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, 4-6 membered heterocyclyl, cyano, oxo, -C(O)NH(C １ -C ６ alkyl), and -C(O)NH(C ３ -C ６ 10. The compound according to any one of claims 3 to 9, or a pharma- ceutically acceptable salt thereof, optionally substituted by 1 to 3 substituents selected from the group consisting of: aryl, aryloxy ...

11. R ２ methyl, ethyl, isopropyl, tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl, 【Chemistry 5】 10. The compound according to any one of claims 3 to 9, which is: or a pharma- ceutically acceptable salt thereof.

12. R ３ is H, methyl, isopropyl, difluoromethyl, hydroxyethyl, cyclopropyl, cyclobutyl, -C(Me) ２ OH, -CH(Me)OH, methoxymethyl, hydroxymethyl, methoxy, ethoxy, -CH ２ CH ２ 12. The compound according to any one of claims 3 to 11, which is OH or tetrahydropyranyl, or a pharma- ceutically acceptable salt thereof.

13. R ２ and R ３ But together, 【Chemistry 6】 10. The compound according to any one of claims 3 to 9, or a pharma- ceutically acceptable salt thereof, which is formed.

14. R ４ C optionally substituted with 1 to 3 halo substituents １ -C ３ The compound according to any one of claims 3 to 13, or a pharma- ceutically acceptable salt thereof, which is alkyl.

15. R ４ But, CF ３ , or C.F. ２ 15. The compound according to any one of claims 3 to 14, wherein R is C1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R2

16. R ５ The compound according to any one of claims 3 to 15, wherein is H, or a pharma- ceutically acceptable salt thereof.

17. 17. The compound according to any one of claims 3 to 16, or a pharma- ceutically acceptable salt thereof, wherein Y is CH.

18. Formula (Id) or Formula (Ie): 【Chemistry 7】 4. The compound according to claim 3, which is a compound represented by the formula: or a pharma- ceutically acceptable salt thereof.

19. A compound selected from Examples 1-232, or a pharma- ceutically acceptable salt thereof.

20. A composition comprising a compound according to any one of claims 3 to 19 or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

21. A method for inhibiting the tyrosine kinase enzyme activity of a protein selected from the group consisting of Abelson protein (ABL1), Abelson-related protein (ABL2), and the chimeric protein BCR-ABL1, comprising contacting the protein with an effective amount of a compound according to any one of claims 3 to 19, or a pharma- ceutically acceptable salt thereof, or a composition according to claim 20.

22. A method for treating a disease in a patient, preventing, suppressing or ameliorating disease pathology and / or symptoms by regulating BCR-ABL1 activity, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 3 to 19, or a pharma- ceutically acceptable salt thereof, or a composition according to claim 20.

23. 20. A method of treating leukemia in a patient comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 3 to 19, or a pharma- ceutically acceptable salt thereof, or a composition of claim 20, wherein the leukemia is chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), or acute lymphoblastic leukemia (ALL).

24. 24. The method of claim 23, wherein the leukemia is CML or ALL, and the method further comprises administering a therapeutically effective amount of a compound selected from the group consisting of imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.

25. 25. The method of claim 23 or 24, wherein the CML is resistant to standard therapy.

26. 26. The method of claim 25, wherein the CML is resistant to treatment with one or more of imatinib, nilotinib, and dasatinib.

27. 24. The method of claim 23, wherein the AML is secondary AML that develops after myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN).

Images