Compounds for treating specific leukemias

Abstract

The present application provides compounds for treating specific leukemias, in detail compounds, preferably compounds that inhibit the tyrosine kinase activity of a protein selected from Abesen protein (ABL1), Abesen-related protein (ABL2) or chimeric protein BCR-ABL1; compositions thereof, and methods for preparing the same; and methods for inhibiting the tyrosine kinase activity of a protein selected from Abesen protein (ABL1), Abesen-related protein (ABL2) or chimeric protein BCR-ABL1; and methods for treating diseases, wherein the regulation of BCR-ABL1 activity prevents, inhibits or improves the pathology and / or symptomology of the disease.

Description

[0001] This application is a divisional application of the PCT patent application entered into China with Chinese patent application number 2019800608963, invention name “Compounds for treating specific leukemias”, and application date September 17, 2019.

[0002] Cross-reference to related applications

[0003] This application claims priority to U.S. Provisional Application No. 62 / 733,029, filed on September 18, 2018, U.S. Provisional Application No. 62 / 816,637, filed on March 11, 2019, and U.S. Provisional Application No. 62 / 889,929, filed on August 21, 2019, the disclosure of each of which is incorporated herein by reference in its entirety for all purposes. Technical Field

[0004] Provided herein are compounds, preferably compounds that inhibit the tyrosine kinase activity of a protein selected from Abelson protein (ABL1), Abelson-related protein (ABL2), or chimeric protein BCR-ABL1; compositions thereof, and methods of preparing the same; methods of inhibiting the tyrosine kinase activity of a protein selected from Abelson protein (ABL1), Abelson-related protein (ABL2), or chimeric protein BCR-ABL1; and methods of treating a disease wherein modulation of BCR-ABL1 activity prevents, inhibits, or ameliorates the pathology and / or symptomology of the disease. Background Art

[0005] In chronic myeloid leukemia (CML), the Philadelphia chromosome (Ph) formed by the t(9,22) reciprocal chromosome translocation occurs in 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 through an ATP competitive mechanism (e.g. (imatinib), (nilotinib) and Dasatinib is an effective treatment for CML; however, some patients relapse due to the emergence of drug-resistant clones. For example, small molecules or combinations thereof can be used to inhibit the activity of BCR-ABL1 and BCR-ABL1 mutations through the ATP binding site, the myristoyl binding site, or a combination of both sites. Summary of the Invention

[0006] In one aspect, provided herein are compounds of Formula (I) or (Ia):

[0007]

[0008] or a tautomer or N-oxide thereof, or a pharmaceutically acceptable salt of any one of the foregoing, wherein:

[0009] L is -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-;

[0010] R 1 is an optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocycle, C(O)NR 6 R 7 、S(O)2NR 6 R 7 NR 6 COR 7 NR 6 SO2R 7 or C(O)OR 6 ;

[0011] 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 optionally substituted 5-10 membered heteroaryl;

[0012] 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 ;

[0013] or R 2 and R 3 Together with the intervening atoms, they form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 membered heterocycloalkyl;

[0014] R 4 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl;

[0015] X is O or S;

[0016] Y is CH, C-(C1-C2 alkyl) or C-halogen or N;

[0017] Z is CR 5 or N;

[0018] R 5 is H or halogen;

[0019] 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 optionally substituted 5-10 membered heteroaryl; and

[0020] 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 optionally substituted 5-10 membered heteroaryl;

[0021] or R 6 and R 7 together with the nitrogen to which it is attached, form an optionally substituted 4-7 membered heterocyclic ring,

[0022] with the proviso that the compound is not (i) 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid or (ii) 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid.

[0023] In some embodiments, the compound has Formula (IA-1):

[0024]

[0025] In one aspect, provided herein is a method of inhibiting tyrosine kinase enzyme activity of a protein selected from the group consisting of Abesin (ABL1), Abesin-related protein (ABL2), and chimeric protein BCR-ABL1, comprising contacting the protein with an effective amount of a compound or composition provided herein.

[0026] In one aspect, provided herein are methods of treating a disease in a patient wherein modulation of BCR-ABL1 activity prevents, inhibits, or ameliorates the pathology and / or symptomology of the disease, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein.

[0027] In one aspect, provided herein are methods 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

[0028] definition

[0029] Unless otherwise stated, as used herein, the following definitions shall apply. In addition, if any term or symbol used herein is not defined as described below, it shall have the ordinary meaning in the art.

[0030] "Comprising" is intended to mean that compositions and methods include the recited elements, but not to exclude other elements. When "consisting essentially of" is used to define compositions and methods, it is intended to exclude other elements that are of any essential significance to the combination. For example, a composition consisting essentially of the elements as defined herein will not exclude other elements that do not substantially affect the basic and novel characteristics of the claimed invention. "Consisting of" shall be intended to exclude more than trace amounts of, for example, the recited other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0031] An "effective amount" or dosage of a compound or composition is that amount of the compound or composition that is necessary to produce the desired result based on the disclosure herein. An effective amount can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example and not limited to, by measuring LD 50 (dose lethal to 50% of the population) and ED 50 (the dose that is therapeutically effective in 50% of the population).

[0032] As used herein, the term "excipient" refers to an inert or inactive substance that can be used to produce a drug or pharmaceutical, such as a tablet containing a compound of the present invention as an active ingredient. The term excipient can encompass a variety of substances, including but not limited to any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, parenteral solution, chewable tablet material, sweetener or flavoring agent, suspending / gelling agent, or wet granulation agent. Binders include, for example, carbomer, povidone, xanthan gum, and the like; coatings include, for example, cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, and the like; compression / encapsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, and the like; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, and the like. ; Creams or lotions include, for example, maltodextrin, carrageenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearoyl fumarate, etc.; materials for chewable tablets include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0033] "Patient" refers to a mammal and includes humans and non-human mammals. Examples of patients include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cattle, and humans. In some embodiments, the patient is a human.

[0034] "Pharmaceutically acceptable" means preferably safe and non-toxic for in vivo administration, more preferably to humans.

[0035] "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt. The compounds described herein can be administered in the form of a pharmaceutically acceptable salt.

[0036] "Prodrug" refers to a compound that is metabolized or otherwise converted into a biologically active or more active compound (or drug) with respect to at least one property after administration. Relative to the drug, the prodrug is chemically modified in a manner that makes it less active or inactive relative to the drug, but the chemical modification allows the corresponding drug to be produced by metabolism or other biological processes after the prodrug is administered. The prodrug may have altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or an improved flavor relative to the active drug (see, for example, Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pp. 388-392, which is incorporated herein by reference). Prodrugs can be synthesized using reactants other than the corresponding drug. For illustration and without limitation, prodrugs include carboxyl esters, linear and cyclic phosphates and phosphoramides and phosphoramidates, carbamates, preferably phenolic carbamates (i.e., carbamates in which the hydroxyl group is part of an aryl or heteroaryl moiety, wherein the aryl and heteroaryl groups are optionally substituted), and the like.

[0037] "Salt" refers to an ionic compound formed between an acid and a base. When the compounds provided herein contain acidic functional groups, 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 nitrogen bases and alkylated nitrogen bases. Exemplary and non-limiting cations that can be used in pharmaceutically acceptable salts include Na, K, Rb, Cs, NH4, Ca, Ba, imidazolium, and ammonium cations based on natural amino acids. When the compounds utilized herein contain basic functional groups, such salts include, but are not limited to, salts of organic acids (e.g., carboxylic acids and sulfonic acids) and inorganic acids (e.g., hydrogen halides, sulfuric acid, phosphoric acid, and the like). Exemplary and non-limiting anions that can be used in pharmaceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, sulfite, monobasic, dibasic, and tribasic phosphates, methanesulfonate, toluenesulfonate, and the like.

[0038] A "therapeutically effective amount" or dosage of a compound or composition is that amount of the compound or composition that results in a reduction or suppression of symptoms or a prolongation of survival in a patient. Multiple doses of the compound or composition may be required as a result.

[0039] "Treating" or "treatment" of a patient's disease refers to 1) preventing the disease from occurring in a patient who is susceptible to the disease or who has not yet shown symptoms of the disease; 2) inhibiting the disease or stopping its development; or 3) ameliorating the disease or causing the disease to regress. As used herein, "treatment" or "treating" is a method of obtaining beneficial or desired results (including clinical results). For the 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 caused by the disease or condition, alleviating the extent of the disease or condition, stabilizing the disease or condition (e.g., preventing or delaying the worsening of the disease or condition), delaying the occurrence or recurrence of the disease or condition, delaying or slowing the progression of the disease or condition, improving the disease or condition state, providing relief (partial or complete) of the disease or condition, reducing the dose of one or more other agents required to treat the disease or condition, enhancing the effect of another agent used to treat the disease or condition, delaying the progression of the disease or condition, improving the quality of life and / or prolonging the patient's survival. "Treatment" also encompasses the alleviation of the pathological consequences of the disease or condition. The methods of the present invention encompass any one or more of these therapeutic aspects.

[0040] An "isotopic variant" of a compound is one in which one or more atoms of the compound are replaced by isotopes of those same atoms. For example, where H is replaced by D or T, or 12 C Sutra 11 C substitution, or 14 N Sutra 15 By way of example and not limitation, substitution with D may in some cases result in a reduced metabolic rate and therefore a longer half-life. Substitution of H with T may provide a radioligand potentially useful for binding studies. 11 C substitution 12 C can provide ligands that can be used for positron emission tomography (PET) scanning. 15 N substitution 14 N is available through 15 Compounds detected / monitored by N NMR spectroscopy. For example, an isotopic variant of a compound containing -CH2CH3 is that compound but containing -CD2CD3 instead of -CH2CH3.

[0041] One or more "stereoisomers" refers to compounds that differ in the stereoselectivity of the constituent atoms, such as, but not limited to, the chirality of one or more stereocenters, or the cis or trans configuration about carbon-carbon or carbon-nitrogen double bonds. Stereoisomers include enantiomers and diastereomers.

[0042] "Tautomer" refers to alternative forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms attached to both the ring -NH- portion and the ring =N- portion, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0043] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 12 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms. This term includes, by way of example, straight-chain and branched hydrocarbon groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), tert-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-). x Alkyl refers to an alkyl group having x number of carbon atoms.

[0044] "Alkenyl" refers to a straight or branched monovalent hydrocarbon radical having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and having at least 1, and preferably 1 to 2, sites of vinyl (>C=C<) unsaturation. Such radicals are exemplified by vinyl, allyl, and but3-en1-yl. Included within this term are cis and trans isomers or mixtures of these isomers. x Alkenyl refers to an alkenyl group having x number of carbon atoms.

[0045] "Alkynyl" refers to a straight or branched monovalent hydrocarbon group having 2 to 6 carbon atoms, preferably 2 to 3 carbon atoms, and having at least 1, and preferably 1 to 2, sites of acetylenic (-C≡C-) unsaturation. Examples of such alkynyl groups include ethynyl (-C≡CH) and propargyl (-CH2C≡CH). x Alkynyl refers to an alkynyl group having x number of carbon atoms.

[0046] “Substituted alkyl” refers to an alkyl group having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of 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 heterocycloalkyl alkylthio, substituted alkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SOH, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein.

[0047] "Substituted alkenyl" refers to an alkenyl group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the group consisting of 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, (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, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SOH, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein and with the proviso that any hydroxy or thiol substitution is not attached to a vinyl (unsaturated) carbon atom.

[0048] "Substituted alkynyl" refers to an alkynyl group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the group consisting of 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, (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, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SOH, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein and with the proviso that any hydroxy or thiol substitution is not attached to an acetylenic carbon atom.

[0049] "Alkoxy" refers to the group -O-alkyl wherein alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, and n-pentoxy.

[0050] "Substituted alkoxy" refers to the group -O-(substituted alkyl) wherein the substituted alkyl is as defined herein. Preferred substituted alkyl groups in -O-(substituted alkyl) include halogenated alkyl groups and specifically halogenated methyl groups such as trifluoromethyl, difluoromethyl, fluoromethyl, and the like.

[0051] "Acyl" refers to the groups 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)-, heterocyclo-C(O)-, and substituted heterocyclo-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, and substituted heterocyclo are as defined herein. Acyl groups include "acetyl" CH3C(O)-.

[0052] "Acylamino" refers to the group -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 30 C(O)heterocycle and -NR 30 C(O)-substituted heterocycle, wherein 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, heterocycle, and substituted heterocycle are as defined herein.

[0053] "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-, heterocycle-C(O)O-, and substituted heterocycle-C(O)O-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0054] "Amino" refers to the group -NH2.

[0055] "Substituted amino" refers to the group -NR 31 R 32 , where R 31 and R 32 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylamino, sulfonylamino, and substituted sulfonyl, and wherein R 31 and R 32 optionally joined together with the nitrogen to which it is attached to form a heterocyclic or substituted heterocyclic group, provided that R 31 and R 32 are not all hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein. 31 is hydrogen and R 32 When R is an alkyl group, the substituted amino group is sometimes referred to herein as an alkylamino group. 31 and R 32 When R is an alkyl group, the substituted amino group is sometimes referred to herein as a dialkylamino group. When referring to a monosubstituted amino group, it means that R 31 or R 32 When referring to a disubstituted amino group, it means R 31 With R 32 Neither is hydrogen.

[0056] "Aminocarbonyl" refers to the group -C(O)NR 33 R 34 , where R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and wherein R 33 and R 34 The nitrogen to which they are attached are optionally joined together to form a heterocycle or a substituted heterocycle, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0057] "Aminothiocarbonyl" refers to the group -C(S)NR 33 R 34 , where R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and wherein R 33 and R 34 The nitrogen to which they are attached are optionally joined together to form a heterocycle or a substituted heterocycle, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0058] "Aminocarbonylamino" refers to the group -NR 30 C(O)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 34are 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, heterocycle, and substituted heterocycle, and wherein R 33 and R 34 and optionally joined together with the nitrogen to which they are bound to form a heterocycle or a substituted heterocycle, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0059] "Aminothiocarbonylamino" refers to the group -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 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and wherein R 33 and R 34 and optionally joined together with the nitrogen to which they are bound to form a heterocycle or a substituted heterocycle, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0060] "Aminocarbonyloxy" refers to the group -OC(O)NR 33 R 34 , where R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, and wherein R 33 and R 34and optionally the nitrogen to which it is bound join together to form a heterocyclyl or substituted heterocyclyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl are as defined herein.

[0061] "Aminosulfonyl" refers to the group -SO2NR 33 R 34 , where R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, and wherein R 33 and R 34 and optionally the nitrogen to which it is bound join together to form a heterocyclyl or substituted heterocyclyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl are as defined herein.

[0062] "Aminosulfonyloxy" refers to the group -O-SO2NR 33 R 34 , where R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, and wherein R 33 and R 34 and optionally the nitrogen to which it is bound join together to form a heterocyclyl or substituted heterocyclyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl are as defined herein.

[0063] "Aminosulfonylamino" refers to the group -NR 30 -SO2NR 33 R 34 , where R 30is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and wherein R 33 and R 34 and optionally joined together with the nitrogen to which they are bound to form a heterocycle or a substituted heterocycle, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0064] "Carbamimidoyl" refers to the group -C(=NR 35 )NR 33 R 34 , where R 33 、R 34 and R 35 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, and wherein R 33 and R 34 and optionally the nitrogen to which it is bound join together to form a heterocyclyl or substituted heterocyclyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl are as defined herein.

[0065] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl (Ph)) or multiple fused rings (e.g., naphthyl or anthracenyl), which may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like), provided that the point of attachment is at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.

[0066] “Substituted aryl” refers to an aryl group substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of 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, alkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SOH, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein.

[0067] "Aryloxy" refers to the group -O-aryl where aryl is as defined herein and includes, for example, phenoxy and naphthoxy.

[0068] "Substituted aryloxy" refers to the group -O-(substituted aryl) where substituted aryl is as defined herein.

[0069] "Arylthio" refers to the group -S-aryl where aryl is as defined herein.

[0070] "Substituted arylthio" refers to the group -S-(substituted aryl) where substituted aryl is as defined herein.

[0071] "Arylamino" refers to the group -NR 37 (aryl), wherein aryl is as defined herein and R 37 is hydrogen, alkyl or substituted alkyl.

[0072] "Substituted arylamino" refers to the group -NR 37 (substituted aryl), wherein R 37 is hydrogen, alkyl or substituted alkyl, wherein substituted aryl is as defined herein.

[0073] "Carbonyl" refers to a divalent group -C(O)- which is equivalent to -C(=O)-.

[0074] "Carboxy" or "carboxyl" refers to -COOH or a salt thereof.

[0075] "Carboxyl ester or carboxy "ester)" refers to the groups -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-heterocycle, and -C(O)O-substituted heterocycle, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0076] "(Carboxyester)amino" refers to the group -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-heterocycle and -NR 30 -C(O)O-substituted heterocycle, wherein R 30 is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0077] "(Carboxyester)oxy" refers to the groups -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-heterocycle, and -OC(O)O-substituted heterocycle, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0078] "Cyano" refers to the group -C≡N.

[0079] "Cycloalkyl" refers to a saturated or unsaturated, but non-aromatic, cyclic alkyl group having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms, having single or multiple rings (including fused, bridged, and spiro ring systems). x Cycloalkyl refers to a cycloalkyl group having x number of carbon atoms. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more rings may be aryl, heteroaryl, or heterocyclic, provided that the point of attachment is through a non-aromatic, non-heterocyclic ring or a saturated carbocyclic ring. "Substituted cycloalkyl" refers to a cycloalkyl group having 1 to 5, or preferably 1 to 3, substituents selected from the group consisting of oxo, thioketo, 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)

[00145] The present invention also includes, but is not limited to, (alkyl 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, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SOH, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio and substituted alkylthio, wherein the substituents are as defined herein.

[0080] "Cycloalkyloxy" refers to an -O-cycloalkyl group.

[0081] "Substituted cycloalkyloxy" refers to -O-(substituted cycloalkyl).

[0082] "Cycloalkylamino" refers to the group -NR 37 (cycloalkyl), where R 37 is hydrogen, alkyl or substituted alkyl.

[0083] "Substituted cycloalkylamino" refers to the group -NR 37 (substituted cycloalkyl), wherein R 37 is hydrogen, alkyl or substituted alkyl, and substituted cycloalkyl is as defined herein.

[0084] "Cycloalkylthio" refers to an -S-cycloalkyl group.

[0085] "Substituted cycloalkylthio" refers to -S-(substituted cycloalkyl).

[0086] "Guanidino" refers to the group -NHC(=NH)NH2.

[0087] "Substituted guanidino" refers to -NR 36 C(=NR 36 )N(R 36 )2, where each R 36 R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocyclyl and the two Rs attached to the common guanidinium nitrogen atom 36 The groups are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic ring, provided that at least one R 36 is not hydrogen, and wherein the substituents are as defined herein.

[0088] "Halo" or "halogen" refers to fluorine, chlorine, bromine and iodine and is preferably fluorine or chlorine.

[0089] "Hydroxy" or "hydroxyl" refers to the group -OH.

[0090] "Heteroalkylene" refers to an alkylene group in which one or more carbon atoms are replaced by -O-, -S-, SO2, -NR Q -、

[0091]

[0092] Partial replacement, where R Qis H or C1-C6 alkyl. "Substituted heteroalkylene" refers to a heteroalkynylene group having 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the substituents disclosed for substituted alkylene.

[0093] "Heteroaryl" refers to an aromatic group having 1 to 10 carbon atoms in the ring and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The heteroaryl group may have a single ring (e.g., pyridyl or furyl) or multiple fused rings (e.g., indolizinyl or benzothienyl), wherein the fused rings may or may not be aromatic and / or 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 are optionally oxidized to provide an N-oxide (N→O), sulfinyl, and / or sulfonyl moiety. Preferred heteroaryl groups include 5- or 6-membered heteroaryl groups, such as pyridyl, pyrrolyl, thienyl, and furanyl. Other preferred heteroaryl groups include 9- or 10-membered heteroaryl groups, such as indolyl, quinolyl, quinolinonyl, isoquinolyl, and isoquinolinonyl.

[0094] "Substituted heteroaryl" refers to a heteroaryl group substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same substituent groups defined for substituted aryl.

[0095] "Heteroaryloxy" refers to an -O-heteroaryl group.

[0096] "Substituted heteroaryloxy" refers to the group -O-(substituted heteroaryl).

[0097] "Heteroarylthio" refers to the group -S-heteroaryl.

[0098] "Substituted heteroarylthio" refers to the group -S-(substituted heteroaryl).

[0099] "Heteroarylamino" refers to the group -NR 37 (heteroaryl), wherein R 37 is hydrogen, alkyl or substituted alkyl.

[0100] "Substituted heteroarylamino" refers to the group -NR 37 (substituted heteroaryl), wherein R 37 is hydrogen, alkyl or substituted alkyl, and substituted heteroaryl is as defined herein.

[0101] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated, but non-aromatic, group having 1 to 10 ring carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms, and 1 to 4 ring heteroatoms, preferably 1 to 3 heteroatoms, and more preferably 1 to 2 heteroatoms, selected from the group consisting of nitrogen, sulfur, or oxygen. x Heterocycloalkyl refers to a heterocycloalkyl group having x number of ring atoms (including ring heteroatoms). Heterocycle encompasses monocyclic or multiple fused rings, including fused, bridged, and spirocyclic ring systems. In a fused ring system, one or more rings may be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclyl group are optionally oxidized to provide an N-oxide, sulfinyl, or sulfonyl moiety.

[0102] "Heterocyclylene" refers to a divalent saturated or partially saturated, but non-aromatic, 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" refers to a heterocyclylene substituted with 1 to 5, or preferably 1 to 3, substituents as defined for substituted cycloalkyl.

[0103] "Substituted heterocycle" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to heterocyclyl substituted with 1 to 5, or preferably 1 to 3, of the same substituents as defined for substituted cycloalkyl.

[0104] "Heterocyclyloxy" refers to the group -O-heterocyclyl.

[0105] "Substituted heterocyclyloxy" refers to the group -O-(substituted heterocyclyl).

[0106] "Heterocyclylthio" refers to the group -S-heterocyclyl.

[0107] "Substituted heterocyclylthio" refers to the group -S-(substituted heterocyclyl).

[0108] "Heterocyclylamino" refers to the group -NR 37 (heterocyclic group), wherein R 37 is hydrogen, alkyl or substituted alkyl.

[0109] "Substituted heterocyclylamino" refers to the group -NR 37 (substituted heterocyclic group), wherein R 37 is hydrogen, alkyl or substituted alkyl, and substituted heterocyclyl is as defined herein.

[0110] Examples of heterocyclic and heteroaryl groups include, but are not limited to, azetidinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazolyl, pyrimidinyl, pyridazinyl, indolizyl, isoindolyl, indolyl, indolinyl, indazolyl, purinyl, quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, phenanthroline, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, thiazolyl, thiazolidinyl, thienyl, benzo[b]thienyl, morpholinyl, thiomorpholinyl (also known as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidinyl, and tetrahydrofuranyl.

[0111] "Nitro" refers to the radical -NO2.

[0112] "Oxo" refers to the atom (=O) or (O).

[0113] "Spirocyclic system" refers to a bicyclic ring system having a single ring carbon atom common to both rings.

[0114] "Sulfinyl" refers to the divalent radical -S(O)- or -S(=O)-.

[0115] "Sulfonyl" refers to the divalent radical -S(O)2- or -S(=O)2-.

[0116] "Substituted sulfonyl" refers to the groups -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-heterocycle, -SO2-substituted heterocycle, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein. Substituted sulfonyl includes groups such as methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-. Preferred substituted alkyl groups on substituted alkyl-SO2- include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluoromethyl, fluoromethyl and the like.

[0117] "Substituted sulfinyl" refers to the groups -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-heterocycle, -SO-substituted heterocycle, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein. Substituted sulfinyl includes groups such as methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-. Preferred substituted alkyl groups on substituted alkyl-SO- include halogenated alkyl groups and specifically halogenated methyl groups, such as trifluoromethyl, difluoromethyl, fluoromethyl, and the like.

[0118] "Sulfonyloxy" or "substituted sulfonyloxy" refers to the group -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-heterocycle, -OSO2-substituted heterocycle, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0119] "Sulfonylamino" refers to the group -NR 37 (substituted sulfonyl), wherein R 37 is hydrogen, alkyl or substituted alkyl, and substituted sulfonyl is as defined herein.

[0120] "Thioacyl" refers to the groups 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)-, heterocyclyl-C(S)-, and substituted heterocyclyl-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl are as defined herein.

[0121] "Mercapto" or "thiol" refers to the group -SH.

[0122] "Formyl" refers to the group -C(O)H.

[0123] "Thiocarbonyl" refers to a divalent group -C(S)- which is equivalent to -C(=S)-.

[0124] "Thione" refers to the atom (=S).

[0125] "Alkylthio" refers to the group -S-alkyl where alkyl is as defined herein.

[0126] "Substituted alkylthio" refers to the group -S-(substituted alkyl), where substituted alkyl is as defined herein. Preferred alkyl substituted on -S-(substituted alkyl) include halogenated alkyl, and specifically halogenated methyl, such as trifluoromethyl, difluoromethyl, fluoromethyl, and the like.

[0127] "Vinyl" refers to an unsaturated hydrocarbon radical -CH=CH2 derived from ethylene.

[0128] The terms "optional" or "optionally" as used throughout the specification mean that the subsequently described event or circumstance may occur, but need not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. 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 that the description includes instances where the nitrogen atom is not oxidized and instances where the nitrogen atom is oxidized.

[0129] The term "optionally substituted" refers to a substituted or unsubstituted group. A substituted group may be substituted with one or more substituents (e.g., 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 selected from oxo, halo, -CN, NO2, -CO2R 100 、-OR 100 、-SR 100 、-SOR 100 、-SO2R 100 、-NR 101 R 102 、-CONR 101 R 102 、-SO2NR 101 R 102 , C1-C6 alkyl, C1-C6 alkoxy, -CR 100 =C(R 100 2. -CCR 100 、C3-C 10 Cycloalkyl, C4-C10 Heterocyclic group, 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 Heterocyclic group; C6-C 14 Aryl; or C2-C 12 Heteroaryl; wherein each alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted with 1-3 halo, 1-3 C1-C6 alkyl, 1-3 C1-C6 haloalkyl or 1-3 C1-C6 alkoxy groups. More preferably, the substituent is selected from the group consisting of chloro, fluoro, -OCH3, methyl, ethyl, isopropyl, cyclopropyl, -OCF3, -CF3 and -OCHF2.

[0130] R 101 and R 102 are independently hydrogen; C1-C8 alkyl, optionally -CO2H or an ester thereof, C1-C6 alkoxy, oxo, -CR 103 =C(R 103 )2, -CCR, C3-C 10 Cycloalkyl, C3-C 10 Heterocyclic group, C6-C 14 Aryl or C2-C 12 Heteroaryl substituted, wherein each R 103 are independently hydrogen or C1-C8 alkyl; C3-C 12 Cycloalkyl; C4-C 10 Heterocyclic group; C6-C 14 Aryl; or C2-C 12 wherein each cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with 1-3 alkyl or 1-3 halo groups, or R 101 and R 102 Together with the nitrogen atom to which it is attached, it forms a 5-7 membered heterocyclic ring.

[0131] Unless otherwise indicated, nomenclature of substituents not specifically defined herein is achieved by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "alkoxycarbonylalkyl" refers to the group (alkoxy)-C(O)-(alkyl)-.

[0132] It should be understood that in all of the substituted groups defined above, polymers obtained by limiting a substituent having other substituents to itself (e.g., a substituted aryl having a substituted aryl as a substituent, which itself is substituted with a substituted aryl, etc.) are not intended to be included herein. In such cases, the maximum number of substituents is 3. That is, each of the above definitions is subject to the following limitations, for example: substituted aryl is limited to -substituted aryl-(substituted aryl)-substituted aryl.

[0133] In some embodiments of a substituted moiety, the moiety is substituted with a group that is further substituted with another group, but the other group cannot be additionally substituted. For example, in some embodiments of "substituted alkyl", the alkyl moiety is substituted with a group that can be further substituted, such as a substituted alkoxy, a substituted amino, a substituted aryl, a substituted aryloxy, a substituted arylthio, a substituted arylamino, a substituted heteroarylamino, a substituted cycloalkylamino, a substituted heterocyclylamino, a substituted cycloalkyl, a substituted cycloalkyloxy, a substituted cycloalkylthio, a substituted guanidino, a substituted heteroaryl, a substituted heteroaryloxy, a substituted heteroarylthio, a substituted heterocycle, a substituted heterocyclyloxy, a substituted heterocyclylthio, a substituted sulfonyl, In some embodiments, the alkyl group is substituted with a substituted alkylthio group, 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 heterocycle, substituted heterocyclyloxy, substituted heterocyclylthio, substituted sulfonyl, or substituted alkylthio group on the alkyl portion is not itself substituted with a further substituted moiety. Although "substituted alkyl" is provided as an example, the embodiments are intended for every substituted moiety described herein.

[0134] 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, heterocyclo, heterocyclyloxy, heterocyclylthio, nitro, SOH, sulfonyloxy, sulfonylamino, thioacyl, thiol, and alkylthio. Although "substituted alkyl" is provided as an example, the embodiments are intended for every substituted moiety described herein.

[0135] It is to be understood that the above definition is not intended to include impermissible substitution patterns (eg, a methyl group substituted with four fluoro groups), which are well known to those skilled in the art.

[0136] It should be understood that certain features of the present invention described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the present invention described in the context of a single embodiment for simplicity may also be provided individually or in any suitable subcombination. All combinations of embodiments for chemical groups represented by variables are specifically encompassed by the present invention and disclosed herein to the extent that the combinations encompass compounds that produce stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity) as each and every combination is individually and explicitly disclosed. In addition, all subcombinations of chemical groups listed in the embodiments describing the variables are also specifically encompassed by the present invention and disclosed herein as each and every subcombination of chemical groups is individually and explicitly disclosed herein.

[0137] Compound

[0138] In one aspect, the present invention provides a compound of formula (I):

[0139]

[0140] or its tautomer or N-oxide, or an isotopic variant of each thereof, or a prodrug of each thereof, or a stereoisomer of the foregoing, or a pharmaceutically acceptable salt of each thereof, or a solvate of each thereof, wherein:

[0141] L is -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-;

[0142] R 1 is an optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocycle, C(O)NR 6 R 7 、S(O)2NR 6 R 7 NR 6 COR 7 or NR 6 SO2R 7 or C(O)OR 6 ;

[0143] 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 optionally substituted 5-10 membered heteroaryl;

[0144] 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

[0145] R 2 and R 3 Together with the intervening atoms, they form a cycloalkyl or heterocycloalkyl, preferably an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 membered heterocycloalkyl;

[0146] R 4 is optionally substituted C1-C6 alkyl, preferably C1-C3 haloalkyl, such as CF3 or CF2Cl; optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl;

[0147] X is O or S;

[0148] Y is CH, C-(C1-C2 alkyl) or C-halogen or N;

[0149] Z is CR 5 or N;

[0150] R 5 is H or halogen;

[0151] 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 optionally substituted 5-10 membered heteroaryl; and

[0152] 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 optionally substituted 5-10 membered heteroaryl; or

[0153] R 6 and R 7 together with the nitrogen to which it is attached, form an optionally substituted 4-7 membered heterocyclic ring,

[0154] with the proviso that the compound is not (i) 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid or (ii) 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid.

[0155] In some embodiments, compounds of formula (Ii) are provided:

[0156]

[0157] or its tautomer or N-oxide, or an isotopic variant of each thereof, or a prodrug of each thereof, or a stereoisomer of the foregoing, or a pharmaceutically acceptable salt of each thereof, or a solvate of each thereof, wherein:

[0158] L is -NH-CO-, -CO-NH- or -NH-SO2-;

[0159] R 1 is an optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocycle, C(O)NR 6 R 7 、S(O)2NR 6 R 7 NR 6 COR 7 or NR 6 SO2R 7 or C(O)OR 6 ;

[0160] 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 optionally substituted 5-10 membered heteroaryl;

[0161] 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

[0162] R 2 and R 3 Together with the intervening atoms, they form a cycloalkyl or heterocycloalkyl, preferably an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 membered heterocycloalkyl;

[0163] R 4 is optionally substituted C1-C6 alkyl, preferably C1-C3 haloalkyl, such as CF3 or CF2Cl; optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl;

[0164] X is O or S;

[0165] Y is CH, C-(C1-C2 alkyl) or C-halogen or N;

[0166] Z is CR 5 or N;

[0167] R 5 is H or halogen;

[0168] 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 optionally substituted 5-10 membered heteroaryl; and

[0169] R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted C6-C 10aryl or optionally substituted 5-10 membered heteroaryl; or

[0170] R 6 and R 7 Together with the nitrogen to which it is attached, it forms an optionally substituted 4-7 membered heterocyclic ring.

[0171] Also provided herein are compounds of formula (Ia):

[0172]

[0173] where R 1 、R 2 、R 3 、R 4 , X, Y, Z and L are as defined for the compound of formula (I).

[0174] In some embodiments, the compound has Formula (IA):

[0175]

[0176] It will be understood that when Z is N, then R 5 does not exist. Similarly, it should be understood that when R 5 If exists, then R 5 bonded to a carbon atom in an aryl ring such that Z is CR 5 .

[0177] In some embodiments, the compound has Formula (IA-1):

[0178]

[0179] In some embodiments, the compound is selected from Formula (IIA)-(IIH):

[0180]

[0181] where R 10 is an optionally substituted 5-6 membered heteroaryl, preferably the heteroaryl moiety has a maximum of 2 ring nitrogen atoms;

[0182] 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;

[0183] 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;

[0184] Ring A is optionally substituted 5-6 membered heterocycloalkyl; and

[0185] The remaining variables are as defined herein.

[0186] In some embodiments, the compound has Formula (IIA):

[0187]

[0188] In some embodiments, the compound has Formula (IIB):

[0189]

[0190] In some embodiments, the compound has Formula (IIC):

[0191]

[0192] In some embodiments, the compound has Formula (IID):

[0193]

[0194] In some embodiments, the compound has Formula (IIE):

[0195]

[0196] In some embodiments, compounds provided herein have Formula (IIF):

[0197] In some embodiments, the compounds provided herein have Formula (IIG):

[0198]

[0199] In some embodiments, the compounds provided herein have Formula (IIH):

[0200]

[0201] In some embodiments, compounds provided herein have Formula (Ib):

[0202]

[0203] The remaining variables are as defined herein.

[0204] In some embodiments, compounds provided herein have Formula (Ic):

[0205]

[0206] The remaining variables are as defined herein.

[0207] In some embodiments, compounds provided herein have Formula (Id) or (Ie):

[0208]

[0209] The remaining variables are as defined herein.

[0210] 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-.

[0211] In some embodiments, R 1 is an optionally substituted C6-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 It is C(O)NR 6 R 7 In some embodiments, R 1 It is S(O)2NR 6 R 7 In some embodiments, R 1 It is NR 6 COR 7 In some embodiments, R 1 Yes or NR 6 SO2R 7 In some embodiments, R 1 It is C(O)OR 6 .

[0212] In some embodiments, R 2 is H. In some embodiments, R 2 is an optionally substituted C1-C6 alkyl. In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 is an optionally substituted C3-C8 cycloalkyl. 2 is an optionally substituted 4-10 membered heterocycloalkyl. 2 is an optionally substituted C2-C6 alkenyl. In some embodiments, R 2is an optionally substituted C2-C6 alkynyl. In some embodiments, R 2 is an optionally substituted C6-C 10 In some embodiments, R 2 is an optionally substituted 5-10 membered heteroaryl.

[0213] 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 C2-C6 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. 3 is an optionally substituted 4-6 membered heterocycloalkyl. 3 is an optionally substituted aryl group. In some embodiments, R 3 is an optionally substituted C6-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, R 3 It is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4 to 6 membered heterocycloalkyl, C6-C 10 aryl or 5 to 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 It is NR 6 R 7 .

[0214] In some embodiments, R 2 and R 3 Together with the intervening atoms, they form Ring A, which is a cycloalkyl group. 2 and R 3 Together with the intervening atoms, they form Ring A, which is a cycloalkyl group, excluding R 2 In contrast, it is understood that there is no nitrogen atom other than R 2 Other heteroatoms other than the nitrogen atom to which it is attached constitute Ring A. In some embodiments, R 2 and R 3Together with the intervening atoms, they form Ring A, which is a heterocycloalkyl group. 2 and R 3 Together with the intervening atoms, they form Ring A, which is a heterocycloalkyl group comprising R 2 It is also understood that additional heteroatoms, further 2 The nitrogen atom to which it is attached may constitute Ring A. In some embodiments, R 2 and R 3 Together with the intervening atoms, they form Ring A, which is a heterocycloalkyl group and does not include any of the following: 2 In some embodiments, R 2 and R 3 Together with the intervening atoms, they form Ring A, which is a heterocycloalkyl group and includes R 2 In some embodiments, R 2 and R 3 Together with the intervening atoms, they form Ring A, which is an optionally substituted C3-C8 cycloalkyl group. Suitable cycloalkyl substituents include, but are not limited to, C1-C6 alkyl, hydroxy C1-C6 alkyl, and C1-C6 alkyl substituted with 1-3 halogen groups, preferably fluorine atoms. In some embodiments, R 2 and R 3 Together with the intervening atoms, they form Ring A, which is an optionally substituted 4-10 membered heterocycloalkyl. Suitable heterocycloalkyl substituents include, but are not limited to, C1-C6 alkyl, hydroxy C1-C6 alkyl, and C1-C6 alkyl substituted with 1-3 halo groups, preferably fluorine atoms.

[0215] 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 CF3. In some embodiments, R 4 is CF2Cl. In some embodiments, R 4 is an optionally substituted C2-C6 alkenyl. In some embodiments, R 4 is an optionally substituted C2-C6 alkynyl group.

[0216] In some embodiments, X is O. In some embodiments, X is S.

[0217] 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.

[0218] In some embodiments, Z is CR5 In some embodiments, Z is N.

[0219] In one embodiment, R 5 is H. In another embodiment, R 5 It's a halogen.

[0220] 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 C3-C8 cycloalkyl. 6 is an optionally substituted 4-10 membered heterocycloalkyl. 6 is an optionally substituted C6-C 10 In some embodiments, R 6 is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R 6 It is C1-C6 alkyl, C3-C8 cycloalkyl, 4-10 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.

[0221] In some embodiments, R 7 is H. In some embodiments, R 7 is an optionally substituted C1-C6 alkyl. In some embodiments, R 7 is an optionally substituted C3-C8 cycloalkyl. 7 is an optionally substituted 4-10 membered heterocycloalkyl. 7 is an optionally substituted C6-C 10 In some embodiments, R 7 is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R 7 It is C1-C6 alkyl, C3-C8 cycloalkyl, 4-10 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.

[0222] 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 10aryl or optionally substituted 5-10 membered heteroaryl.

[0223] In some embodiments, R 6 and R 7 Together with the nitrogen to which it is attached, it forms an optionally substituted 4-7 membered heterocyclic ring. 6 and R 7 Together with the nitrogen to which it is attached, it forms a 4-7 membered heterocyclic ring optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy and C1-C6 alkyl.

[0224] In some embodiments, R 10 is a 5-6 membered heteroaryl. In some embodiments, R 10 is a 5-6 membered heteroaryl group, wherein the heteroaryl moiety has up to 2 ring nitrogen atoms. In some embodiments, R 10 is a 5-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkyl and C3-C6 cycloalkyl.

[0225] In some embodiments, R 20 is an optionally substituted C1-C3 alkyl. In some embodiments, R 20 is an optionally substituted C3-C4 cycloalkyl. In some embodiments, R 20 In some embodiments, R 20 is an optionally substituted isopropyl group. In some embodiments, R 20 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, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, 4 to 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 C3-C4 cycloalkyl. In some embodiments, R 30 is an 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 1-3 substituents selected from the group consisting of halogen, hydroxy and C1-C6 alkyl.

[0226] In some embodiments, R1 is a 5-6 membered heteroaryl. In some embodiments, R 1 is a 5-6 membered heteroaryl group containing up to 2 ring nitrogen atoms. In some embodiments, R 1 is a 5-6 membered heteroaryl group containing 2 ring nitrogen atoms. In some embodiments, R 1 is a 5-6 membered heteroaryl group containing 1 ring nitrogen atom. In some embodiments, R 1 is a 5-6 membered heteroaryl group containing 3 ring nitrogen atoms. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is a 5-6 membered heteroaryl group containing one ring nitrogen atom and one ring sulfur atom. 1 is a 5-6 membered heteroaryl group containing 1 ring nitrogen atom and 1 ring oxygen atom. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is a 4-5 membered heterocyclic group containing 1 ring nitrogen atom. In some embodiments, R 1 is a 4-5 membered heterocyclyl optionally substituted by 1-2 oxo groups. In some embodiments, R 1 In some embodiments, R 1 In any of these embodiments, R 1 is optionally substituted with 1-3 substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, and C3-C6 cycloalkyl. 1 is substituted with 1-2 substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, and C3-C6 cycloalkyl. In some variations, R 1 is substituted with one substituent selected from the group consisting of halogen, cyano, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, and C3-C6 cycloalkyl. In some variations, R 1Substituted with 1 substituent selected from the group consisting of fluoro, chloro, bromo, cyano, hydroxy, methoxy, ethoxy, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0227] In some embodiments, R 1 yes

[0228]

[0229] In some embodiments, R 1 yes

[0230]

[0231] In some embodiments, R 1 yes

[0232]

[0233] In some embodiments, R 1 yes

[0234]

[0235] In some embodiments, R 1 yes

[0236]

[0237] In some embodiments, R 1 yes

[0238]

[0239] In some embodiments, R 1 yes

[0240]

[0241] In some embodiments, R 1 yes

[0242]

[0243] In some embodiments, R 1 yes

[0244]

[0245] In some embodiments, R 1 yes

[0246]

[0247] In some embodiments, R 1 yes

[0248]

[0249] In some embodiments, R 1 yes

[0250]

[0251] In some embodiments, R 1 yes

[0252]

[0253] In some embodiments, R 1 yes

[0254]

[0255] In some embodiments, R 1 yes

[0256]

[0257] In some embodiments, R 1 yes

[0258]

[0259] In some embodiments, R 1 yes

[0260]

[0261] In some embodiments, R 1 yes

[0262]

[0263] In some embodiments, R 1 yes

[0264]

[0265] In some embodiments, R 1 yes

[0266]

[0267] In some embodiments, R 1 yes

[0268]

[0269] In some embodiments, R 1 yes

[0270]

[0271] In some embodiments, R 1 yes

[0272]

[0273] In some embodiments, R 1 yes

[0274]

[0275] In some embodiments, R 1 yes

[0276]

[0277] In some embodiments, R 1 yes

[0278]

[0279] In some embodiments, R 1 yes

[0280]

[0281] In some embodiments, R 1 yes

[0282]

[0283] In some embodiments, R 1 yes

[0284]

[0285] In some embodiments, R 1 yes

[0286]

[0287] In some embodiments, R 1 yes

[0288]

[0289] In some embodiments, R 1 yes

[0290]

[0291] In some embodiments, R 1 -CONHR 7 , where R 7 It is H, C3-C6 cycloalkyl or C1-C6 alkyl.

[0292] In some embodiments, R 1 is -CONH(C3-C6 cycloalkyl). In some embodiments, R 1 is -CONH(C3-C5 cycloalkyl). In some embodiments, R 1 It is -CONH(C3-C4 cycloalkyl).

[0293] In some embodiments, R 1 It is -CONH (cyclopropyl).

[0294] In some embodiments, R 1 It is -CONH2.

[0295] In some embodiments, R 1 In some embodiments, R 1 is -CONH(C1-C3 alkyl). In some embodiments, R 1 It is -CON(H)(CH3) or -CON(H)(C2H5).

[0296] In some embodiments, R 2 is an optionally substituted C1-C3 alkyl. In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 is an optionally substituted isopropyl group. In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 is n-pentyl, sec-pentyl, 3-pentyl or sec-isopentyl. 2 is an optionally substituted C3-C4 cycloalkyl. In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 is a 4 to 6 membered heterocyclic group. In some embodiments, R 2 is a 4- to 6-membered heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen. 2 In some embodiments, R 2In some embodiments, R 2 In some embodiments, R 2 In any of these embodiments, R 2 is optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, 4- to 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 1-3 substituents selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C3-C5 cycloalkyl, 4- to 6-membered heterocyclyl, cyano, oxo, -C(O)NH(C1-C3 alkyl) and -C(O)NH(C3-C6 cycloalkyl). In some variations, R 2 Substituted with 1-3 substituents selected from the group consisting of fluoro, chloro, bromo, hydroxy, methoxy, ethoxy, methyl, ethyl, cyclopropyl, cyclobutyl, oxetanyl, cyano, oxo, -C(O)NH(CH3), -C(O)NH(CH2CH3), -C(O)NH(cyclopropyl), -C(O)NH(cyclobutyl), -C(O)NH(cyclopentyl) and -C(O)NH(cyclohexyl).

[0297] In some embodiments, R 2 It’s H.

[0298] In some embodiments, R 2 yes

[0299]

[0300] In some embodiments, R 2 yes

[0301]

[0302] In some embodiments, R 2 yes

[0303]

[0304] In some embodiments, R 2 yes

[0305]

[0306] In some embodiments, R 2 yes

[0307]

[0308] In some embodiments, R 2 yes

[0309]

[0310] In some embodiments, R 2 yes

[0311]

[0312] In some embodiments, R 2 yes

[0313]

[0314] In some embodiments, R 2 yes

[0315]

[0316] In some embodiments, R 2 yes

[0317]

[0318] In some embodiments, R 2 yes

[0319]

[0320] In some embodiments, R 2 yes

[0321]

[0322] In some embodiments, R 2 yes

[0323]

[0324] In some embodiments, R 2 yes

[0325]

[0326] In some embodiments, R 2 yes

[0327]

[0328] In some embodiments, R 2 yes

[0329]

[0330] In some embodiments, R 2yes

[0331]

[0332] In some embodiments, R 2 yes

[0333]

[0334] In some embodiments, R 2 yes

[0335]

[0336] In some embodiments, R 2 yes

[0337]

[0338] In some embodiments, R 2 yes

[0339]

[0340] In some embodiments, R 2 yes

[0341]

[0342] In some embodiments, R 2 yes

[0343]

[0344] In some embodiments, R 2 yes

[0345]

[0346] In some embodiments, R 2 yes

[0347]

[0348] In some embodiments, R 2 yes

[0349]

[0350] In some embodiments, R 2 yes

[0351]

[0352] In some embodiments, R 2 yes

[0353]

[0354] In some embodiments, R 2 yes

[0355]

[0356] In some embodiments, R 2 yes

[0357]

[0358] In some embodiments, R 2 yes

[0359]

[0360] In some embodiments, R 2 yes

[0361]

[0362] In some embodiments, R 2 yes

[0363]

[0364] In some embodiments, R 2 and R 3 Together with the intervening atoms, they form Ring A, which is an optionally substituted 5- to 6-membered heterocycloalkyl group. In some embodiments, Ring A is optionally substituted with 1-3 substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkyl-OH, -C(O)(C1-C6 alkyl), and oxo. In some variations, Ring A is substituted with 1-3 substituents selected from the group consisting of C1-C3 alkyl, hydroxyl, C1-C3 alkyl-OH, -C(O)(C1-C3 alkyl), and oxo. In some variations, Ring A is substituted with 1-3 substituents selected from the group consisting of methyl, ethyl, hydroxyl, -CH2OH, -CH2CH2-OH, -C(O)CH3, -C(O)CH2CH3, and oxo.

[0365] In some embodiments, R 2 and R 3 Together they form:

[0366]

[0367] In some embodiments, R 2 and R 3 Together they form:

[0368]

[0369] In some embodiments, R 2 and R 3 Together they form:

[0370]

[0371] In some embodiments, R 2 and R 3 Together they form:

[0372]

[0373] In some embodiments, R 2 and R 3 Together they form:

[0374]

[0375] In some embodiments, R 2 and R 3 Together they form:

[0376]

[0377] In some embodiments, R 2 and R 3 Together they form:

[0378]

[0379] In some embodiments, R 2 and R 3 Together they form:

[0380]

[0381] In some embodiments, R 2 and R 3 Together they form:

[0382]

[0383] In some embodiments, R 2 and R 3 Together they form:

[0384]

[0385] In some embodiments, R 2 and R 3 Together they form:

[0386]

[0387] In some embodiments, R2 and R 3 Together they form:

[0388]

[0389] In some embodiments, R 2 and R 3 Together they form:

[0390]

[0391] In some embodiments, R 2 and R 3 Together they form:

[0392]

[0393] In some embodiments, R 2 and R 3 Together they form:

[0394]

[0395] In some embodiments, R 2 and R 3 Together they form:

[0396]

[0397] In some embodiments, R 2 and R 3 Together they form:

[0398]

[0399] In some embodiments, R 2 and R 3 Together they form:

[0400]

[0401] In some embodiments, R 2 and R 3 Together they form:

[0402]

[0403] In some embodiments, R 2 and R 3 Together they form:

[0404]

[0405] In some embodiments, R 2 and R 3 Together they form:

[0406]

[0407] In some embodiments, R 2 and R 3 Together they form:

[0408]

[0409] In some embodiments, R 2 and R 3 Together they form:

[0410]

[0411] In some embodiments, R 2 and R 3 Together they form:

[0412]

[0413] In some embodiments, R 2 and R 3 Together they form:

[0414]

[0415] In some embodiments, R 2 and R 3 Together they form:

[0416]

[0417] In some embodiments, R 3 is H. In some embodiments, R 3 is C1-C6 alkyl optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxyl, and -O(C1-C6 alkyl). In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 is -C(Me)2OH. In some embodiments, R 3 is -CH(Me)OH. In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3In some embodiments, R 3 is a C3-C6 cycloalkyl substituted with 1-3 substituents selected from the group consisting of halogen, C1-C6 alkyl, and hydroxy. In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 Yes-OR 6 , where R 6 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 is a 4 to 6 membered heterocyclic group. In some embodiments, R 3 is a 4- to 6-membered heterocyclic group substituted with 1-3 substituents selected from the group consisting of halogen, C1-C6 alkyl, and hydroxy. In some embodiments, R 3 It is tetrahydropyranyl.

[0418] In some embodiments, R 4 is an optionally substituted C1-C3 alkyl. In some embodiments, R 4 is a C1-C3 alkyl group, wherein the alkyl group is substituted with one or more halo substituents. In some embodiments, R 4 is a C1-C3 alkyl group substituted with 1-3 halo substituents. 4 is CF3. In some embodiments, R 4 It is CF2Cl.

[0419] In one aspect, a compound of formula (I) is provided, wherein the compound has one or more of the following characteristics:

[0420] (I)R 1 yes:

[0421] (i) a 5-6 membered heteroaryl group optionally substituted by 1-3 substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkoxy, C3-C6 cycloalkyl and C1-C6 alkyl; or

[0422] (ii) a 4-5 membered heterocyclyl optionally substituted by 1-3 substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkyl and oxo; or

[0423] (iii)R 1 Yes-CONHR 7 , where R 7 is H, C3-C6 cycloalkyl or C1-C6 alkyl;

[0424] (II)R 2 yes:

[0425] (iv) C1-C6 alkyl optionally substituted by 1-3 substituents selected from the group consisting of halogen, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, cyano, -C(O)NH(C1-C6 alkyl) and -C(O)NH(C3-C6 cycloalkyl); or

[0426] (v)R 2 is a C3-C6 cycloalkyl group optionally substituted by 1-3 substituents selected from the group consisting of halogen, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, cyano, oxo, -C(O)NH(C1-C3 alkyl) and -C(O)NH(C3-C6 cycloalkyl); or

[0427] (vi) a 4- to 6-membered heterocyclyl optionally substituted by 1-3 substituents selected from the group consisting of halogen, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, a 4- to 6-membered heterocyclyl, cyano, oxo, -C(O)NH(C1-C3 alkyl) and -C(O)NH(C3-C6 cycloalkyl); or

[0428] (vii)H;

[0429] (III)R 3 yes

[0430] (viii) H; or

[0431] (ix) C1-C6 alkyl optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxyl and -O(C1-C6 alkyl); or

[0432] (x)-OR 6 , where R 6 is C1-C6 alkyl; or

[0433] (xi) C3-C6 cycloalkyl optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-C6 alkyl and hydroxy; or

[0434] (xii) a 4- to 6-membered heterocyclic group optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-C6 alkyl and hydroxy;

[0435] (IV)R 2 and R 3Together with the intervening atoms, they form Ring A, which is a 5- to 6-membered heterocycloalkyl group optionally substituted with 1-3 substituents selected from the group consisting of C1-C6 alkyl, hydroxy, C1-C6 alkyl-OH, -C(O)(C1-C6 alkyl), and oxo;

[0436] (V)R 4 is a C1-C3 alkyl group optionally substituted by 1-3 halogens;

[0437] (VI) L is -NH-CO-;

[0438] (VII) Z is -CH, C-halo or N;

[0439] (VIII) X is -O.

[0440] 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.

[0441] In one aspect, compounds of formula (I), such as those provided in the Examples below (e.g., Examples 1-49) and tabulated in Table 1 (Examples 50-232), or tautomers or N-oxides thereof, or isotopic variants of each thereof, or prodrugs of each of the foregoing, or stereoisomers of the foregoing, or pharmaceutically acceptable salts of each of the foregoing, or solvates of each of the foregoing are provided.

[0442] The present disclosure also includes all salts of the compounds mentioned herein, such as pharmaceutically acceptable salts. The present disclosure also includes any or all stereochemical forms of the compounds, including any enantiomer or diastereomeric forms, and any tautomers and other forms, such as N-oxides, solvates, prodrugs, or isotopic variants. 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. In addition, where a specific stereochemical form is depicted, it should be understood that the present invention also encompasses other stereochemical forms. The present invention also encompasses all forms of the compounds, such as crystalline or non-crystalline forms of the compounds. Compositions comprising the compounds of the present invention, such as compositions of substantially pure compounds, including their specific stereochemical forms, are also intended to be encompassed. The present invention also encompasses compositions comprising mixtures of the compounds of the present invention in any ratio, including mixtures of two or more stereochemical forms of the compounds of the present invention in any ratio, such that racemic, non-racemic, enantiomerically enriched, and proportionate racemic mixtures of the compounds are encompassed.

[0443] In the description herein, it is understood that each description, variation, embodiment or aspect of a portion can be combined with each description, variation, embodiment or aspect of any other portion, as if each and every combination of descriptions were explicitly and individually listed. For example, the description herein of R of formula (I) 1 Each description, variation, embodiment or aspect provided may be combined with R 2 、R 3 、R 4 、R 5 、R 6 、R 7, X, L, Y and / or Z, each description, variation, embodiment or aspect combination, as each and each combination clearly and individually listed.It should also be understood that all descriptions, variations, embodiments or aspects of formula (I) are equally applicable to other formulas described in detail herein in applicable situations, and are also described, as each description, variation, embodiment or aspect are individually and individually listed for all formulas.For example, all descriptions, variations, embodiments or aspects of formula (I) are equally applicable to any one of formula (Ii), (Ia), (IA), (IA-1), (IIA), (IIB), (IIC), (IID), (IIE), (IIF), (IIG), (IIH), (Ib), (Ic), (Id) and (Ie) described in detail herein in applicable situations, and are also described, as each and each description, variation, embodiment or aspect are individually and individually listed for all formulas.

[0444] The present invention also includes all salts of the compounds mentioned herein, such as pharmaceutically acceptable salts. The present invention also includes any or all stereochemical forms of the compounds, including any mirror-image isomeric or non-mirror-image isomeric forms, and any tautomers and other forms, such as N-oxides, solvates, prodrugs, or isotopic variants. 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. In addition, where a specific stereochemical form is depicted, it should be understood that the present invention also encompasses other stereochemical forms. The present invention also encompasses all forms of the compound, such as crystalline or non-crystalline forms of the compound. It is also intended to encompass compositions comprising the compounds of the present invention, such as compositions of substantially pure compounds, including their specific stereochemical forms. The present invention also encompasses compositions comprising mixtures of the compounds of the present invention in any ratio, including mixtures of two or more stereochemical forms of the compounds of the present invention in any ratio, such that racemic, non-racemic, mirror-image enriched, and proportional racemic mixtures of the compounds are encompassed.

[0445] Pharmaceutical compositions and formulations

[0446] The present invention encompasses pharmaceutical compositions of any of the compounds described herein. Thus, 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, a pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. The pharmaceutical compositions of 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.

[0447] The compounds as detailed herein may be in purified form in one aspect, and compositions comprising compounds in purified form are detailed herein. Compositions comprising the compounds as detailed herein or their salts are provided, for example, compositions of substantially pure compounds. In some embodiments, compositions containing the compounds as detailed herein or their salts are in substantially pure form. In one variation, "substantially pure" means that the composition contains no more than 35% impurities, where impurities represent compounds other than the compound or its salt that constitutes the majority of the composition. For example, a composition of substantially pure compounds selected from Table 1 (A, B, etc.) means that the composition contains no more than 35% impurities, where impurities represent compounds other than the compound or its salt. In one variation, compositions of substantially pure compounds or their salts are provided, where the composition contains no more than 25% impurities. In another variation, compositions of substantially pure compounds or their salts are provided, where the composition contains no more than 20% impurities. In another variation, compositions of substantially pure compounds or their salts are provided, where the composition contains no more than 10% impurities. In yet another variation, a composition of a substantially pure compound or its salt is provided, wherein the composition contains no more than 5% impurities. In another variation, a composition of a substantially pure compound or its salt is provided, wherein the composition contains no more than 3% impurities. In another variation, a composition of a substantially pure compound or its salt is provided, wherein the composition contains no more than 1% impurities. In yet another variation, a composition of a substantially pure compound or its salt is provided, wherein the composition contains no more than 0.5% impurities. In other variations, a composition of a substantially pure compound means that the composition contains no more than 15%, or preferably no more than 10%, or more preferably no more than 5%, or even more preferably no more than 3% impurities and most preferably no more than 1% impurities, which may be compounds in different stereochemical forms. For example, and without limitation, a composition of a substantially pure (S) compound means that the composition contains no more than 15%, or no more than 10%, or no more than 5%, or no more than 3%, or no more than 1% of the (R) form of the compound.

[0448] In one variation, the compounds herein are synthetic compounds prepared for administration to a subject (e.g., a human). In another variation, compositions containing the compounds in substantially pure form are provided. In another variation, the present invention encompasses pharmaceutical compositions comprising the compounds detailed herein and a pharmaceutically acceptable carrier or excipient. In another variation, methods of administering the compounds are provided. The purified forms, pharmaceutical compositions, and methods of administering the compounds are suitable for any compound or form thereof described in detail herein.

[0449] The compounds can be formulated for any available route of delivery, 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 suitable carriers to provide delivery forms including, but not limited to, tablets, caplets, capsules (e.g., hard gelatin capsules or soft elastic gelatin capsules), cachets, sugar tablets, lozenges, gums, dispersions, suppositories, ointments, poultices, pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs.

[0450] One or more compounds described herein can be used to prepare formulations, such as pharmaceutical formulations, by combining one or more compounds as active ingredients with pharmaceutically acceptable carriers (such as those mentioned above). Depending on the treatment form of the system (such as a transdermal patch versus an oral tablet), the carrier can be in various forms. In addition, the pharmaceutical formulation may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, and salts, buffers, coating agents, or antioxidants for regulating osmotic pressure. The formulation comprising the compound may also contain other substances with valuable therapeutic properties. Pharmaceutical formulations can be prepared by known pharmaceutical methods. Suitable formulations can be found in, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams and Wilkins, 21st edition (2005), which is incorporated herein by reference.

[0451] The compounds described herein can be administered to individuals (e.g., humans) in the form of widely accepted oral compositions such as tablets, coated tablets, and gel capsules in hard or soft shells, emulsions, or suspensions. Examples of carriers that can be used to prepare such compositions are lactose, corn starch or its derivatives, talc, stearates or their salts, and the like. Acceptable carriers for gel capsules with soft shells are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols, and the like. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, and salts for regulating osmotic pressure, buffers, coating agents, or antioxidants.

[0452] Any of the compounds described herein can be formulated in a tablet in any of the dosage forms described.

[0453] Also described are compositions comprising the compounds provided herein. In one variation, the compositions comprise the compound and a pharmaceutically acceptable carrier or excipient. In another variation, compositions of substantially pure compounds are provided.

[0454] Use / treatment methods

[0455] The compounds and compositions described in detail herein, for example, pharmaceutical compositions containing a compound or salt thereof provided herein and a pharmaceutically acceptable carrier or excipient, can be used in methods of administration and treatment as provided herein. The compounds and compositions can also be used in in vitro methods, for example, in vitro methods of administering a compound or composition to cells for screening purposes and / or for performing quality control analysis.

[0456] In one aspect, provided herein is a method for suppressing the tyrosine kinase activity of a protein selected from Abeson protein (ABL1), Abeson-related protein (ABL2) or chimeric protein BCR-ABL1, comprising contacting an effective amount of provided herein compound or composition with protein. In one embodiment, provided herein is a method for suppressing the tyrosine kinase activity of Abeson protein (ABL1), comprising contacting an effective amount of provided herein compound or composition with ABL1. In another embodiment, provided herein is a method for suppressing the tyrosine kinase activity of Abeson-related protein (ABL2), comprising contacting an effective amount of provided herein compound or composition with ABL2. In another embodiment, provided herein is a method for suppressing the tyrosine kinase activity of chimeric protein BCR-ABL1, comprising contacting an effective amount of provided herein compound or composition with chimeric protein.

[0457] In one aspect, provided herein is a method of 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 a salt thereof, or a composition is administered according to the dosages described herein.

[0458] It is believed that the compounds described herein or their salts and compositions described herein are effective in treating various diseases and conditions. In some embodiments, the compounds described herein or their salts or compositions described herein can be used in methods for treating diseases mediated by ABL1, ABL2 and / or BCR-ABL1.

[0459] In one aspect, provided herein are methods for treating a disease in a patient, wherein the regulation of BCR-ABL1 activity prevents, inhibits or improves the pathology and / or symptomology of the disease, the method comprising administering to the patient a therapeutically effective amount of a compound or composition as provided herein. In one embodiment, provided herein are methods for treating a disease in a patient, wherein the regulation of BCR-ABL1 activity prevents the pathology and / or symptomology of the disease, the method comprising administering to the patient a therapeutically effective amount of a compound or composition as provided herein. In one embodiment, provided herein are methods for treating a disease in a patient, wherein the regulation of BCR-ABL1 activity inhibits the pathology and / or symptomology of the disease, the method comprising administering to the patient a therapeutically effective amount of a compound or composition as provided herein. In one embodiment, provided herein are methods for treating a disease in a patient, wherein the regulation of BCR-ABL1 activity improves the pathology and / or symptomology of the disease, the method comprising administering to the patient a therapeutically effective amount of a compound or composition as provided herein.

[0460] In certain embodiments, the disease is leukemia. In certain embodiments, the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). In certain embodiments, the leukemia is chronic myeloid leukemia (CML).

[0461] In one aspect, provided herein is a method for treating the leukemia of a patient, comprising administering to the patient a compound or composition provided herein of a therapeutically effective amount. In one aspect, provided herein is a method for treating the leukemia of a patient, comprising administering to the patient a compound or composition provided herein of a therapeutically effective amount, wherein the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).

[0462] 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.

[0463] 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 barfitinib. In some embodiments, CML is resistant to standard of care treatment (treatment with one or more of imatinib, nilotinib and dasatinib). In some embodiments, the leukemia progressed during a previous treatment. In some embodiments, the previous treatment included administration of imatinib, nilotinib, dasatinib, bosutinib, ponatinib and / or barfitinib.

[0464] In some embodiments, the method further comprises administering a therapeutically effective amount of a compound selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafitinib.

[0465] In some embodiments, the AML is secondary AML, which develops after myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN).

[0466] In one aspect, provided herein are methods 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.

[0467] In one aspect, provided herein are methods 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.

[0468] In another aspect, methods are provided for delaying the onset and / or development of a disease or condition mediated by BCR-ABL1 activity in a patient (e.g., a human) who is at risk of developing the disease or condition. It will be understood that delayed development can encompass prevention in cases where the individual or patient does not develop the disease or condition. In one aspect, the individual or patient at risk of developing a disease or condition mediated by BCR-ABL1 activity has one or more risk factors for developing the disease or condition, such as a family history of the individual or patient having the disease or condition, or having an underlying genetic condition that is associated with an increased likelihood of developing the disease or condition.

[0469] In one aspect, provided herein is a method for delaying the onset and / or development of leukemia in a patient in need, comprising administering to the patient a compound or composition provided herein of a therapeutically effective amount. In a variation, provided herein is a method for delaying the onset and / or development of CML in a patient in need, comprising administering to the patient a compound or composition provided herein of a therapeutically effective amount. In a variation, provided herein is a method for delaying the onset and / or development of AML in a patient in need, comprising administering to the patient a compound or composition provided herein of a therapeutically effective amount. In a variation, provided herein is a method for delaying the onset and / or development of ALL in a patient in need, comprising administering to the patient a compound or composition provided herein of a therapeutically effective amount.

[0470] Methods for treating diseases mediated by BCR-ABL1, such as various leukemias and the like, are well known to those skilled in the art and can be adapted for use in treating such diseases using the compounds or compositions provided herein.

[0471] In some embodiments, the patient is a mammal. In some embodiments, the patient is a primate, dog, cat, rabbit, or rodent. In some embodiments, the patient is a primate. In some embodiments, the patient is a human. In some embodiments, the human is at least about or about any one of 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is less than about or about any one of 21, 18, 15, 10, 5, 4, 3, 2, or 1 year old. 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.

[0472] Provided herein are compounds or compositions that can be administered to patients according to effective administration regimens for a desired time period or duration, for example, at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, in some variations, for the duration of a patient's lifespan. In one variation, the compound is administered daily or on an intermittent schedule. The compound can be administered continuously (for example, at least once a day) to the patient over a period of time. The frequency of administration can also be less than once a day, for example, administered approximately once a week. The frequency of administration can exceed once a day, for example, twice or three times a day. The frequency of administration can also be intermittent (for example, administered once a day for 7 days, followed by no dose for 7 days, repeating any 14-day time period, for example, about 2 months, about 4 months, about 6 months, or longer). Any one of the frequency of administration can adopt any one of the compounds described herein and any one of the dosages described herein.

[0473] The compounds provided herein, or salts thereof, can be administered to patients via various routes, including, for example, intravenous, intramuscular, subcutaneous, oral, and transdermal.

[0474] The dosage of the compound administered to a patient may 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.

[0475] In one aspect, the effective amount of the compound may be a dose between about 0.01 and about 100 mg / kg. The effective amount or dosage of the compound of the present invention can be determined by conventional methods, such as modeling, dose escalation or clinical trials, taking into account conventional factors (such as the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the health status, condition and weight of the individual). The range of exemplary dosages is about 0.7 mg to 7 g per day, or about 7 mg to 350 mg per day, or about 350 mg to 1.75 g per day, or about 1.75 to 7 g per day.

[0476] Also provided herein are uses of a compound described herein, or a salt thereof, or a composition described herein, in the manufacture of a medicament. In some embodiments, the manufacture of the medicament is for treating a disease described herein. In some embodiments, the manufacture of the medicament is for treating a disease mediated by ABL1, ABL2, and / or BCR-ABL1.

[0477] Products and kits

[0478] The present invention further provides an article of manufacture comprising a compound or salt thereof described herein, a composition described herein, or one or more unit doses described herein in suitable packaging. In certain embodiments, the article of manufacture is used in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, jars, flexible packaging, and the like. The article of manufacture may be further sterilized and / or sealed.

[0479] The present invention further provides kits for practicing the methods of the present invention, comprising one or more compounds described herein or compositions comprising compounds described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kits employ a compound described herein or a salt thereof. The kits may be used for any one or more of the uses described herein and, therefore, may contain instructions for treating any disease or condition described herein, such as, for example, treating cancer.

[0480] The kit may be in unit dosage form, bulk packaging (e.g., multi-dose packaging), or subunit dosage. For example, a kit containing a sufficient dose of a compound as disclosed herein and / or an additional pharmaceutically active compound useful for the diseases detailed herein to provide effective treatment of 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 longer, may be provided. The kit may also include multiple unit doses of the compound and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and pharmacies that perform compounding).

[0481] The kit may optionally include a set of instructions, typically written instructions, but an electronic storage medium (e.g., a magnetic or optical disk) containing instructions for use of the components of the methods of the invention is also acceptable. The instructions included with the kit typically include information about the components and their administration to a patient.

[0482] Example embodiments

[0483] The present invention is further described by the following examples. The features of each of the embodiments may be combined with any of the other embodiments if appropriate and practical.

[0484] Example 1. A compound of formula (I) or (Ia),

[0485]

[0486] or its tautomer or N-oxide, or an isotopic variant of each thereof, or a prodrug of each thereof, or a stereoisomer of the foregoing, or a pharmaceutically acceptable salt of each thereof, or a solvate of each thereof, wherein:

[0487] L is -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-;

[0488] R 1 is an optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocycle, C(O)NR 6 R 7 、S(O)2NR 6 R 7 NR 6 COR 7 or NR 6 SO2R 7 or C(O)OR 6 ;

[0489] 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 optionally substituted 5-10 membered heteroaryl;

[0490] 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 intervening atoms, they form a cycloalkyl or heterocycloalkyl, preferably an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 membered heterocycloalkyl;

[0491] R 4 is optionally substituted C1-C6 alkyl, preferably C1-C3 haloalkyl, such as CF3 or CF2Cl; optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl;

[0492] X is O or S;

[0493] Y is CH, C-(C1-C2 alkyl) or C-halogen or N;

[0494] Z is CR 5 or N;

[0495] When Z is CH, R 5 is H or halogen;

[0496] 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 optionally substituted 5-10 membered heteroaryl; and

[0497] 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 optionally substituted 5-10 membered heteroaryl; or R 6 and R 7 Together with the nitrogen to which it is attached, it forms an optionally substituted 4-7 membered heterocyclic ring.

[0498] Example 2. The compound of Example 1, which has formula (IA):

[0499]

[0500] wherein the variables are as defined in Example 1.

[0501] Example 3. The compound of Example 2, which is selected from Formula IIA-IIE:

[0502]

[0503] where R 10 is a 5-6 membered heteroaryl group, preferably, the heteroaryl moiety has a maximum of 2 ring nitrogen atoms;

[0504] R 20 is an optionally substituted C1-C3 alkyl group or an optionally substituted C3-C4 cycloalkyl group, preferably, R 20 is methyl, optionally substituted isopropyl or cyclopropyl;

[0505] R 30 is H, optionally substituted C1-C3 alkyl or optionally substituted C3-C4 cycloalkyl, preferably optionally substituted cyclopropyl; and

[0506] The remaining variables are as defined in Example 1.

[0507] Embodiment 4. The compound of embodiment 2 or 3, wherein X is O.

[0508] Embodiment 5. The compound of any one of embodiments 2 to 4, wherein R 1 is a 5-10 membered heteroaryl moiety, preferably a heteroaryl moiety containing up to 2 ring nitrogen atoms, or R 1 It is a heterocyclyl moiety having 4 to 10 members, preferably containing up to 2 ring nitrogen atoms.

[0509] Embodiment 6. The compound of any one of embodiments 2 to 5, wherein R 1 yes:

[0510] -CONH(cyclopropyl), -CONH2, -CONHMe,

[0511]

[0512] Embodiment 7. The compound of any one of embodiments 2 to 6, wherein R 1 is pyrimidinyl or pyrazolyl.

[0513] Embodiment 8. The compound of any one of embodiments 2 to 7, wherein R2 is an optionally substituted C1-C3 alkyl group or an optionally substituted C3-C4 cycloalkyl group, preferably, R 2 is methyl, optionally substituted isopropyl or cyclopropyl.

[0514] Embodiment 9. The compound of any one of embodiments 2 to 7, wherein R 2 are: methyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl,

[0515]

[0516] Embodiment 10. The compound of any one of embodiments 2 to 9, wherein R 3 is: H, methyl, isopropyl, difluoromethyl, hydroxyethyl, cyclopropyl, cyclobutyl, -C(Me)2OH, methoxymethyl, hydroxymethyl, methoxy, hydroxyethyl, -CH2CH2OH or tetrahydropyranyl.

[0517] Embodiment 11. The compound of any one of embodiments 2 to 6, wherein R 2 and R 3 Together they form:

[0518]

[0519] Embodiment 12. The compound of any one of embodiments 2 to 11, wherein R 4 is an optionally substituted C1-C3 alkyl group, preferably, wherein the alkyl group is substituted with one or more halo substituents, more preferably, R 4 It is CF3 or CF2Cl.

[0520] Embodiment 13. The compound of any one of embodiments 2 to 12, wherein R 5 It’s H.

[0521] Embodiment 14. The compound of any one of embodiments 2 to 13, wherein Y is CH.

[0522] Example 15. The compound of Example 1, which has formula (Ib) or (Ic):

[0523]

[0524] The remaining variables are as defined in Example 1.

[0525] Embodiment 16. A compound of formula (I) selected from Examples 1 to 26 and a compound of Table 1, or a tautomer or N-oxide thereof, or an isotopic variant thereof, or a prodrug of each of the foregoing, or a stereoisomer thereof, or a pharmaceutically acceptable salt of each of the foregoing, or a solvate of each of the foregoing.

[0526] Embodiment 17. A composition comprising the compound of any one of embodiments 2 to 16 and at least one pharmaceutically acceptable excipient.

[0527] Example 18. A method of inhibiting the tyrosine kinase activity of a protein selected from Abesin (ABL1), Abesin-related protein (ABL2), or chimeric protein BCR-ABL1, comprising contacting an effective amount of the compound of any one of Examples 2 to 16 or the composition of Example 17 with the protein.

[0528] Embodiment 19. A method of treating a disease in a patient wherein modulation of BCR-ABL1 activity prevents, inhibits, or ameliorates the pathology and / or symptomology of the disease, comprising administering to the patient a therapeutically effective amount of a compound of any one of embodiments 2 to 16 or a composition of embodiment 17.

[0529] 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 to 16 or a composition of embodiment 17, wherein the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL).

[0530] Embodiment 21. The method of embodiment 20, wherein the leukemia is CML or ALL, and the method further comprises administering a therapeutically effective amount of a compound selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafitinib.

[0531] Embodiment 22. The method of embodiment 20 or 21, wherein the CML is resistant to standard of care treatment (treatment with one or more of imatinib, nilotinib, and dasatinib).

[0532] Example 23. The method of Example 20 or 21, wherein the AML is secondary AML that develops after myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN).

[0533] Examples

[0534] The following abbreviations may be relevant for your application.

[0535] abbreviation

[0536] Ac:Acetyl

[0537] Bn: benzyl

[0538] Bu: Butyl

[0539] Bz: benzoyl

[0540] CMC: Carboxymethylcellulose

[0541] DCM: dichloromethane

[0542] DIPEA: diisopropylethylamine

[0543] DMF: dimethylformamide

[0544] DMEDA: N,N′-dimethylethylenediamine

[0545] DSC: N,N′-disuccinimidyl carbonate or bis(2,5-dioxopyrrolidin-1-yl) carbonate

[0546] dppf: 1,1'-bis(diphenylphosphino)ferrocene

[0547] Et: ethyl

[0548] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate,

[0549] NBS: N-bromosuccinimide

[0550] PEG: polyethylene glycol

[0551] PMB: p-methoxybenzyl

[0552] Pr: Propyl

[0553] Py: pyridine

[0554] rt: room temperature

[0555] TEA: triethylamine

[0556] TBDPS: tert-butyldiphenylsilyl

[0557] TBAF: Tetrabutylammonium fluoride

[0558] THF: Tetrahydrofuran

[0559] TMS: trimethylsilyl

[0560] TFA: trifluoroacetic acid

[0561] Ts: Tosyl

[0562] Xphos: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0563] Synthesis Example

[0564] Preparation of compounds of formula (I): Schematic synthesis scheme

[0565] As illustrated in the Examples of compounds of Formula (I) below, in certain exemplary embodiments, compounds of Formula (I) are prepared according to the following general procedures. It should be understood that although the general methods illustrate the synthesis of certain compounds of the present invention, the following general methods and other methods known to those skilled in the art can be applied to all compounds as described herein and subclasses and species of each of these compounds.

[0566] Schematic Scheme 1

[0567]

[0568] where R 1 and R 2 is as defined for the compound of formula (I).

[0569] Compounds of formula (S7) can be prepared by the general synthetic method shown in Schematic Scheme 1. Nitroaniline (S2) can be readily produced by treating 1a with various primary amines (S1) and a base (such as, but not limited to, triethylamine) in a suitable solvent (such as ethanol) at a temperature of about room temperature to reflux temperature and for a period of time varying from about 30 minutes to about 8 hours. Phenylenediamine (S3) can be formed by reducing nitroaniline (S2) 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 room temperature to reflux temperature and for a period of time varying from about 1 hour. Cyclization of phenylenediamine (S3) to benzimidazole (S4) can be carried out using a reagent (such as, but not limited to, trimethyl o-formate) in the presence of an acid (such as, but not limited to, p-TsOH) at a temperature of about room temperature to 100° C. and for a period of time varying from about 10 minutes to 1 hour. Compounds of formula (S5) can be prepared from bromide (S4) after treatment with an aryl, heteroaryl, or heterocyclic boronic acid or boronic ester under palladium catalyst conditions (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) produces a carboxylic acid of formula (S6). Reaction of the carboxylic acid (S6) with a coupling agent (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).

[0570] Schematic Scenario 2

[0571]

[0572] where R 1 and R 2 is as defined for compounds of formula (I); X is halogen; and Z is CH or N.

[0573] Compounds of formula (S10) can be prepared by the general synthetic method shown in Schematic Scheme 2. Ester (S5) is treated 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) to produce a carboxylic acid of formula (S8). Carboxylic acid (S8) is reacted with a coupling agent (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) to provide an amide of formula (S9). Compounds of formula (S10) can be prepared from halide (S9) by treatment with an aryl, heteroaryl or heterocyclic boronic acid or boronic ester under palladium catalyst conditions (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.

[0574] Schematic Scheme 3

[0575]

[0576] where R 1 and R 3 is as defined for the compound of formula (I).

[0577] Compounds of formula (S15) can be prepared by the general synthetic method shown in Schematic Scheme 3. Compound (3a) can be treated with various carboxylic acids at a temperature of about 80°C to 130°C for a period of time varying from about 1 hour to 2 hours to produce benzimidazoles of formula (S11). Benzimidazole (S11) is treated with iodomethane in an organic solvent (such as but not limited to N,N-dimethylformamide) at a temperature of about 50°C in the presence of a base (such as but not limited to potassium carbonate) for a period of about 3 hours to produce benzimidazole (S12). Ester (S12) is treated 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) to produce a carboxylic acid of formula (S13). The carboxylic acid (S13) is reacted with a coupling agent (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 to provide an amide of formula (S14). Compounds of formula (S15) can be prepared from bromide (S14) treated with an aryl, heteroaryl, or heterocyclic boronic acid or boronic ester under palladium catalyst conditions (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.

[0578] Schematic Scheme 4

[0579]

[0580] where R 1 、R 2 and R 3 is as defined for the compound of formula (I).

[0581] Compounds of formula (S20) can be prepared by the general synthetic method shown in Schematic Scheme 4. Substituted phenylenediamines of formula (S16) can be treated with various carboxylic acids at a temperature of about 80°C to 130°C for a period of time varying from about 1 hour to 2 hours to produce benzimidazoles of formula (S17). Treatment of the ester (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) produces the carboxylic acid of formula (S18). The carboxylic acid (S18) is reacted with a coupling agent (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 a period of about 30 minutes to provide an amide of formula (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 catalyst conditions (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.

[0582] Schematic Scheme 5

[0583]

[0584] where R 1 、R 2 and R 3 is as defined for the compound of formula (I).

[0585] Compounds of formula (S26) can be prepared by the general synthetic method shown in Schematic Scheme 5. Ester (S21) is treated 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) to produce a carboxylic acid of formula (S22). Carboxylic acid (S22) is reacted with a coupling agent (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 room temperature to 50°C for a period of about 2 hours to provide an amide of formula (S23). Phenylenediamine (S24) can be formed by reducing nitroaniline (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 a period of time varying from about 3 hours. Substituted phenylenediamines of formula (S24) can be treated with various carboxylic acids at temperatures of about 80° C. to 130° C. for times varying from about 1 to 2 hours to produce benzimidazoles of formula (S25). Compounds of formula (S26) can be prepared from bromide (S25) after treatment with an aryl, heteroaryl, or heterocyclic boronic acid or boronic ester under palladium catalyst conditions 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 temperatures.

[0586] Schematic Scheme 6

[0587]

[0588] where R 1 、R 2 and R 3 is as defined for the compound of formula (I).

[0589] Compounds of formula (S29) can be prepared by the general synthetic method as shown in Schematic Scheme 6. Compounds of formula (S27) can be prepared from bromides (S25) after treatment with aryl, heteroaryl or heterocyclic boronic acids or boronic esters under palladium catalyst conditions (such as, but not limited to, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) in 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 esters (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) produces carboxylic acids of formula (S28). The carboxylic acid (S28) is reacted with a coupling agent (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 of room temperature to 50° C. and for a period of about 2 hours to provide an amide of formula (S29).

[0590] Schematic Scheme 7

[0591]

[0592] where R 1 is as defined for compounds of formula (I); X is a halide; and as used herein, R 15 and R 16 is an optional substituent.

[0593] Compounds of formula (S38) can be prepared by the general synthetic method shown in Schematic 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 and for a period of about 2 hours. Nitroaniline (S32) can be readily produced by treating amine (S31) with (1a) in a suitable solvent (such as, but not limited to, ethanol) and a base (such as, but not limited to, triethylamine) at a temperature of about 15°C and for a period of about 1 hour. Phenylenediamine (S33) can be formed by reducing nitroaniline (S32) 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 room temperature to reflux temperature and for a period of time varying from about 1 hour. The carboxylic acid (S33) is reacted with a coupling agent (such as, but not limited to, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) and a base (such as, but not limited to, diisopropylethylamine) in an organic solvent (such as, but not limited to, N,N-dimethylformamide) at about room temperature and for about 16 hours to provide a benzimidazole of formula (S34). The ester (S34) is treated 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) to produce a carboxylic acid of formula (S35). The carboxylic acid (S35) is reacted with a coupling agent (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. and for a period of about 6 hours to provide an amide of formula (S36). Compounds of formula (S37) can be prepared from bromide (S36) under palladium catalyst conditions (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 after treatment with an aryl, heteroaryl, or heterocyclic boronic acid or boronic ester. Alternatively, compounds of formula (S37) can be prepared by Stille coupling. The bromide (S36) is converted to stannane (S38) at elevated temperature under palladium catalyst conditions (such as, but not limited to, tetrakis(triphenylphosphine)palladium) in an organic solvent (such as, but not limited to, toluene). Stannane (S38) can be treated with various aryl or heteroaryl halides at elevated temperature under palladium catalyst conditions (such as, but not limited to, tetrakistriphenylphosphine palladium) in an organic solvent (such as, but not limited to, DMSO).

[0594] Schematic Scheme 8

[0595]

[0596] where R 1 and R 6 is as defined for the compound of formula (I).

[0597] Compounds of formula (S40) can be prepared by the general synthetic method shown in Schematic Scheme 8. Compound (S38) can be treated with a tetramethoxy-alkane at a temperature of about 50° C. for a period of about 16 hours to obtain compounds of formula (S39). Compounds of formula (S40) can be prepared from bromide (S39) by treatment with an aryl, heteroaryl, or heterocyclic boronic acid or boronic ester under palladium catalyst conditions (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.

[0598] Schematic Scheme 9

[0599]

[0600] where R 1 and R 2 is as defined for the compound of formula (I); and R 15 and R 16 is an optional substituent.

[0601] Compounds of formula (S37 and S41) can be prepared by the general synthetic method shown in Schematic Scheme 9. Compound (S36) can be treated with various aryl and heteroaryl stannanes in an organic solvent (such as but not limited to toluene) under palladium catalyst conditions (such as but not limited to tetrakistriphenylphosphine palladium) at elevated temperature to provide compound (S37). Alternatively, bromide (S36) can be treated with various amines in an organic solvent (such as but not limited to tetrahydrofuran or 1,4-dioxane) under palladium catalyst or copper conditions (such as but not limited to [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium (II) or (Bu4NCuI2)2) at elevated temperature to provide compound (S41).

[0602] Schematic Scheme 10

[0603]

[0604] where R 1 and R 2 is as defined for the compound of formula (I).

[0605] Compounds of formula (S46) can be prepared by the general synthetic method shown in Schematic Scheme 10. Compound (S42) can be cyclized to compounds of formula (S43) in the presence of iron and acetic acid. Treatment of the 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) produces a carboxylic acid of formula (S44). The carboxylic acid (S44) is reacted with a coupling agent (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 to provide an amide 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 catalyst conditions (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.

[0606] Example 1 (General Procedure A)

[0607] N-(4-(Chlorodifluoromethoxy)phenyl)-1-methyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0608] The title compound was prepared according to Schematic Scheme 1. The General Procedure A illustrates Schematic Scheme 1 and provides specific synthetic details as applied to the title compound.

[0609]

[0610] 3-Bromo-4-(methylamino)-5-nitrobenzoic acid methyl ester (1c). To a solution of 3-bromo-4-fluoro-5-nitro-benzoic acid methyl ester (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 hours. TLC (petroleum ether:ethyl acetate = 5:1, R f =0.50) detected a new major spot with greater polarity. 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 yield 1c as a yellow solid. 1H NMR (400MHz, CDCl3-d) δ8.52 (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).

[0611] 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 hour. Another portion 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 hour. TLC (petroleum ether:ethyl acetate = 3:1, R f =0.30) indicated complete consumption of 1c, and a new major spot with greater 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), and 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 (400MHz, CDCl3-d) δ7.63 (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).

[0612] 7-Bromo-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (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 hr. LCMS showed complete consumption of 1d 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 afford 1e as a white solid. The product was used in the next step without further purification. 1H NMR (400MHz, CDCl3-d) δ8.43 (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).

[0613] 1-Methyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (1f). To a mixture of 7-bromo-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (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 H2O (0.3 mL) was added Pd(dppf)Cl2 (19.03 mg, 0.026 mmol, 0.07 eq) and Na2CO3 (78.77 mg, 0.743 mmol, 2 eq) under N2. The mixture was stirred at 100°C for 12 hours. LCMS showed 1e remaining and one major peak of the desired mass was detected. The mixture was filtered and concentrated to give a crude residue. The residue was purified by preparative TLC (SiO 2 , ethyl acetate:methanol=9:1) to obtain compound 1f as a brown solid. 1 H NMR (400MHz, CDCl3-d) δ9.35 (s, 1H), 8.90 (s, 2H), 8.62 (d, J = 1.5Hz, 1H), 7.97-7.88 (m, 2H), 3.98 (s, 3H), 3.51 (s, 3H).

[0614] 1-Methyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid (1 g). 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) at 15 °C under N2. The mixture was stirred at 15 °C for 12 hours. LCMS showed complete consumption of 1f and one major peak of 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.

[0615] 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) and 4-(chlorodifluoromethoxy)aniline (33.50 mg, 0.173 mmol, 1.1 eq), 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 uL, 3 eq) at 15°C. The mixture was stirred at 15°C for 12 hours. LCMS showed complete consumption of 1 g and the desired mass was detected. The mixture was concentrated and the 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 (400MHz, MeOD-d4) δ9.31 (s, 1H), 9.06 (s, 2H), 8.45 (d, J = 1.5Hz, 1H), 8.39 (s, 1H) ), 7.91 (d, J = 1.5Hz, 1H), 7.84 (d, J = 9.0Hz, 2H), 7.31 (d, J = 9.0Hz, 2H), 3.60 (s, 3H).

[0616] Example 2 (General Procedure B)

[0617] N-(4-(Chlorodifluoromethoxy)phenyl)-1-((1s,3s)-3-hydroxycyclobutyl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0618] The title compound was prepared according to Schematic Scheme 2. The General Procedure B illustrates Schematic Scheme 2 and provides specific synthetic details as applied to the title compound.

[0619]

[0620] 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 hr. LCMS showed complete consumption of 2a and the desired MS was detected. The aqueous phase was adjusted to pH=5 by adding aqueous HCl. The mixture was filtered and concentrated in vacuo to afford compound 2b as a white solid. 1 H NMR (400MHz, DMSO-d6) δ13.10 (br s, 1H) 8.72 (s, 1H) 8.19 (d, J = 1.1Hz, 1H) 7.96 (s, 1H) 5.37 (br d,J=6.2Hz,1H)4.94-5.07(m,1H)4.01-4.11(m,1H)2.86-2.95(m,2H)2.37-2.44(m,2H).

[0621] 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 uL, 2 eq). The mixture was stirred at 15 °C for 12 hr. 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 x 3). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:methanol = 10:1) to yield 2c as a white solid. 1H NMR(400MHz, DMSO-d6)δ10.48(s,1H)8.72(s,1H)8.40(d,J=1.3Hz,1H)8.05(d,J=1.3Hz,1H)7.92(d,J=9.0Hz,2H)7 .36(d,J=9.0Hz,2H)5.37(d,J=6.4Hz,1H)4.96-5.08(m,1H)4.01-4.13(m,1H)2.89-2.98(m,2H)2.36-2.43(m,2H).

[0622] N-(4-(Chlorodifluoromethoxy)phenyl)-1-((1s,3s)-3-hydroxycyclobutyl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (2c). 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 H2O (0.3 mL) were added Pd(dppf)Cl2 (6.01 mg, 8.22 umol, 0.1 eq) and K3PO4 (52.34 mg, 0.247 mmol, 3 eq). The mixture was stirred at 100 ° C for 12 hours. LCMS showed that 2c was completely consumed and the desired MS was detected. The aqueous phase was extracted with H2O (5mL) and ethyl acetate (5mL×3). The combined organic layers were washed with brine (5mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was purified by preparative HPLC (NH4HCO3 conditions, column: Waters Xbridge Prep OBD C18 150*30 10u; mobile phase: [water (10mMNH4HCO3)-ACN]; B%: 25%-45%, 10min) to produce the title compound 2 as a white solid. [M+H] + (C 23 H 18 MS mass requirement calculated for (4-(4-(4-oxo-2-nitropropene)-4-nitropropene) m / z 486.1, LCMS found m / z 486.1. 1H NMR(400MHz, DMSO-d6)δ10.46(s,1H)9.36(s,1H)9.06(s,2H)8.62(s,1H)8.51(d,J=1.5Hz,1H)7.94(d,J=9.0Hz,2H)7.81(d, J=1.5Hz,1H)7.37(d,J=8.8Hz,2H)5.21(d,J=6.6Hz,1H)3.97(quin,J=8.0Hz,1H)3.66(sxt,J=7.1Hz,1H)2.06-2.16(m,4H).

[0623] Example 3 (General Procedure C)

[0624] N-(4-(Chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-methyl-4-(pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carboxamide

[0625] The title compound was prepared according to Schematic Scheme 3. The General Procedure C illustrates Schematic Scheme 3 and provides specific synthetic details as applied to the title compound.

[0626]

[0627] 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 CHF2COOH (3 mL), and the mixture was stirred at 130°C for 1 hr. TLC (petroleum ether:ethyl acetate = 3:1) showed consumption of the starting material 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 aq. NaHCO3 (5 mL x 3) and then concentrated to afford 3b as a brown solid. The crude product was used in the next step without further purification.

[0628] 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 hr. TLC (petroleum ether:ethyl acetate = 2:1) showed consumption of the starting material. The mixture was concentrated and the residue was purified by preparative TLC (SiO , petroleum ether:ethyl acetate = 2:1) to afford 3c as a yellow solid. 1 H NMR (400MHz, CDCl3-d) δ8.24 (d, J = 1.1Hz, 1H), 8.17 (d, J = 1.1Hz, 1H), 7.17-6.85 (m, 1H), 4.04 (s, 3H), 3.98 (s, 3H).

[0629] 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 hr. TLC (petroleum ether:ethyl acetate = 2:1) showed consumption of the starting material. The mixture was concentrated and aq.HCl (1 M) was added until pH = 3-4. The suspension was filtered, and the solid was washed with HO (1 mL) and dried to yield 3d as a yellow solid. The crude product was used in the next step without further purification. 1 H NMR (400MHz, MeOD-d4) δ8.35(s,1H),8.07(s,1H),7.70-7.32(m,1H),4.02(s,3H).

[0630] 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-carboxamide (3d, 110 mg, 0.361 mmol, 1 eq) in DMF (3 mL) was added DIPEA (93.20 mg, 0.721 mmol, 125.61 uL, 3 eq) and HATU (205.65 mg, 0.541 mmol, 1.2 eq). The mixture was stirred at 25° C. for 0.5 hr, followed by the addition of 4-(chlorodifluoromethoxy)aniline (1h, 83.76 mg, 0.433 mmol, 1.2 eq). The reaction mixture was stirred at 25° C. for 3.5 hr. 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 purified by column chromatography using preparative TLC (SiO2, petroleum ether:ethyl acetate=1:1) to give 3e as a yellow solid. 1 H NMR (400MHz, CDCl3-d) δ8.10(d,J=1.2Hz,1H),7.98-7.91(m,2H),7.74(d,J=8.9Hz,2H),7.30(d,J=8.9Hz,2H),7.18-6.88(m,1H),4.07(s,3H).

[0631] 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 H2O (1 mL) was added K3PO4 (132.49 mg, 0.624 mmol, 3 eq) and Pd(dppf)Cl2 (15.22 mg, 0.021 mmol, 0.1 eq) under N2. The mixture was stirred at 100°C for 4 hr under N2. LCMS showed consumption of the starting material and detection of the desired product. 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 conditions, column: Waters X-bridge Prep OBD C18 150*30 10u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 30%-50%, 10 min) to yield the title compound 3 as a white solid. [M+H] +(C 21 H 14 MS mass requirement calculated for ClF4N5O2) m / z 480.1, LCMS found m / z 480.1. 1 HNMR (400MHz, DMSO-d6) δ10.58(s,1H),9.55(s,2H),9.26(s,1H),8.46(s,1H),8.32(s,1H),7.93(d,J=9.2Hz,2H),7.69-7.37(m,3H),4.08(s,3H).

[0632] Example 4

[0633] N-(4-(Chlorodifluoromethoxy)phenyl)-1,2-dimethyl-4-(pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carboxamide

[0634]

[0635] 7-Bromo-2-methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (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) was added 4-toluenesulfonic acid (11.24 mg, 0.065 mmol, 0.1 eq) at 20°C. The mixture was stirred at 100°C for 3 hours. LCMS showed the desired MS. 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 NaSO, filtered, and concentrated in vacuo to yield 4a as a brown oil.

[0636] 4-Bromo-1,2-dimethyl-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (4b). To a mixture of 7-bromo-2-methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (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 CH3I (158.24 mg, 1.11 mmol, 69.40 uL, 2 eq). The mixture was stirred at 15 ° C for 16 hours. 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 Na2SO4, filtered and concentrated in vacuo to produce the product. The product was analyzed by preparative TLC (petroleum ether:ethyl acetate=0:1, R f =0.40) to give 4b as a brown oil.

[0637] 1,2-Dimethyl-4-(pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (4c). To a mixture of 4-bromo-1,2-dimethyl-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (4b, 0.02 g, 0.071 mmol, 1 eq), pyrimidin-5-yl-boronic acid (26.26 mg, 0.212 mmol, 3 eq) and K3PO4 (44.98 mg, 0.212 mmol, 3 eq) in dioxane (2 mL) and H2O (0.2 mL) was added Pd(dppf)Cl2 (5.17 mg, 7.06 umol, 0.1 eq) under N2. The mixture was stirred at 110°C for 16 hours. LCMS showed the desired MS. The mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product. The crude product was identified by preparative TLC (petroleum ether:ethyl acetate = 0:1, R f =0.37) to give 4c as a yellow oil.

[0638] 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 hours. 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 yield 4d as a red solid. The crude product was used in the next step without further purification.

[0639] 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) and 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 hours. 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 yield the crude product. The residue was purified by preparative HPLC (TFA conditions, column: Nano-Micro UniSil 5-100C18 ULTRA 100*250mm 5um; mobile phase: [water (0.1% TFA)-ACN]; B%: 25%-50%, 11 min) to afford the title compound 4 as a white solid. [M+1] + (C 21 H 16 MS mass requirement calculated for ClF2N5O2) m / z 444.1, LCMS found m / z 444.1. 1 H NMR (400MHz, MeOD-d4) δ 9.33-9.25 (m, 3H), 8.48 (s, 1H), 8.25 (s, 1H), 7.88 (d, J = 9.0Hz, 2H), 7.33 (d, J = 8.8Hz, 2H), 4.07 (s, 3H), 2.85 (s, 3H).

[0640] Example 5 (General Procedure D)

[0641] (R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0642] The title compound was prepared according to Schematic Scheme 4. The General Procedure D illustrates Schematic Scheme 4 and provides specific synthetic details as applied to the title compound.

[0643]

[0644] (R)-7-bromo-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (5b). A solution of (R)-3-amino-5-bromo-4-((1-hydroxypropan-2-yl)amino)benzoic acid methyl ester (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 hr. LCMS showed complete consumption of 5a and the desired MS was detected. The mixture was filtered and concentrated under reduced pressure to give a crude residue. The residue was purified by preparative TLC (SiO 2 , petroleum ether:ethyl acetate=0:1) to provide 5b as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.34(s,1H)8.11(s,1H),7.37-7.75(m,1H),5.95-6 .10(m,1H),5.31(t,J=5.2Hz,1H),3.90(s,3H),3.74-3.87(m,2H),1.59(br d,J=7.3Hz,3H).

[0645] (R)-7-Bromo-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-1H-benzo[d]imidazole-5-carboxylic acid (5c). To a solution of (R)-7-bromo-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (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 hr. LCMS showed complete consumption of 5b and the desired MS was detected. The aqueous phase was acidified to pH 5 with aqueous HCl. 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.

[0646] (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-carboxamide (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 uL, 4 eq). The mixture was stirred at 15° C. for 12 hr. LCMS showed that 5c was completely consumed and the required 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 Na2SO4, filtered, and concentrated under reduced pressure to produce a crude residue. The residue was purified by preparative TLC (SiO2, ethyl acetate: methanol = 10: 1) to obtain 5e as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ10.56(s,1H),8.49(s,1H),8.21(s,1H),7.93(d,J=9.3Hz,2H),7.43-7.71(m,1H),7.38(br d,J=9.0Hz,2H),6.02(br d,J=6.2Hz,1H),5.23-5.45(m,1H),3.72-3.93(m,2H),1.60(br d,J=6.8Hz,3H).

[0647] (R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (5). To (R)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-1H-benzo[d]imidazole-5-carboxamide (5e , 60mg, 0.114mmol, 1eq) and pyrimidin-5-ylboronic acid (28.34mg, 0.229mmol, 2eq) in dioxane (1mL) and H2O (0.1mL) were added Pd(dppf)Cl2 (8.37mg, 11.44umol, 0.1eq) and K3PO4 (72.82mg, 0.343mmol, 3eq). The mixture was stirred at 100 ° C for 16 hours. LCMS showed that 5e was completely consumed and the required MS was detected. The mixture was filtered and concentrated under reduced pressure to produce a crude residue. The residue was purified by preparative TLC (SiO2, ethyl acetate: methanol = 10: 1) to obtain the title compound 5 as a white solid. [M+H] + (C 23 H 18 MS mass requirement calculated for (C12H2O3N5ClF4) m / z 524.1, LCMS found m / z 524.1. 1 H NMR(400MHz, DMSO-d6)δ10.50(s,1H)9.35(s,1H)9.07(s,2H)8.58(d,J=1.5Hz,1H)7.93(d,J=9.3Hz,2H)7.84(d,J= 1.8Hz,1H)7.42-7.70(m,1H)7.38(d,J=9.0Hz,2H)5.11(t,J=5.1Hz,1H)4.25-4.45(m,1H)3.41-3.63(m,2H)1.37(br d,J=7.1Hz,3H).

[0648] Example 6 (General Procedure E)

[0649] N-(4-(Chlorodifluoromethoxy)phenyl)-2-isopropyl-1-methyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0650] The title compound was prepared according to Scheme 5. The General Procedure E illustrates Scheme 5 and provides specific synthetic details as applied to the title compound.

[0651]

[0652] 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 H2O (4 mL) was added LiOH.H2O (493.55 mg, 11.76 mmol, 2 eq) in one portion. The mixture was stirred at 60°C for 12 hours. TLC (petroleum ether:ethyl acetate = 3:1, R f =0.0) indicated complete consumption of 1c, and a new major spot with greater 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 H2O (10 mL) to yield 6b as a yellow solid. The product was used in the next step without further purification.

[0653] 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) were 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 hours. LC-MS showed that a major peak with the desired mass was detected. The mixture was concentrated and the resulting residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate = 20:1 to 5:1) to give 6b as a yellow solid.

[0654] 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) was added Fe (2.60 g, 46.60 mmol, 10 eq) in one portion at 20°C. The mixture was stirred at 35°C for 3 h. TLC (petroleum ether:ethyl acetate = 1:1, R f =0.6) indicated complete consumption of 6b and formation of a new spot. Ethyl acetate (40 mL) was added and the mixture was stirred for 2 h. The mixture was filtered through a pad of Celite®. The filtrate was washed with H2O (30 mL), saturated NaHCO3 solution (20 mL x 3) and brine (20 mL), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 6c as a yellow solid. The crude product was used in the next step without further purification.

[0655] 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) in 2-methylpropionic acid (314.18 mg, 3.57 mmol, 330.72 uL, 20 eq) was stirred at 130° C. for 12 hours. The mixture turned from brown to dark. LC-MS showed complete consumption of 6e and the desired mass was detected. The residue was purified by preparative TLC (SiO 2 , petroleum ether:ethyl acetate = 1:1) to give 6d as a yellow oil.

[0656] 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 H2O (0.3 mL) was added Pd(dppf)Cl2 (4.64 mg, 6.35 umol, 0.1 eq) and K3PO4 (40.41 mg, 0.190 mmol, 3 eq) in one portion at 15°C under N2. The mixture was stirred at 110°C for 12 h. LC-MS showed complete consumption of the starting material and one major peak with the desired mass was detected. The mixture was filtered through a pad of Celite® 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 provide the title compound 6 as a white solid. [M+H] + (C 23 H 20 MS mass calculated for (4-(4-(2-nitropropene)- ... 1H NMR(400MHz,MeOD-d4)δ9.34(s,1H),9.07(s,2H),8.43(d,J=1.5Hz,1H),8.01(d,J=1.5Hz, 1H), 7.84 (d, J = 9.0Hz, 2H), 7.31 (d, J = 9.0Hz, 2H), 3.64-3.55 (m, 4H), 1.52 (d, J = 6.8Hz, 6H).

[0657] Example 7 (General Procedure F)

[0658] N-(4-(Chlorodifluoromethoxy)phenyl)-1,2-dimethyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0659] The title compound was prepared according to Schematic Scheme 6. The General Procedure F illustrates Schematic Scheme 6 and provides specific synthetic details as applied to the title compound.

[0660]

[0661] 1,2-Dimethyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (7b). To a mixture of 7-bromo-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (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 H2O (0.5 mL) was added Pd(dppf)Cl2 (38.77 mg, 0.53 mmol, 0.1 eq) and K3PO4.3H2O (423.28 mg, 1.59 mmol, 3 eq) under N2. The mixture was stirred at 110°C for 16 hours. TLC (ethyl acetate:methanol = 8:1, R f =0.20) indicated complete consumption of 7a and a new major spot with greater polarity was detected. LC-MS showed complete consumption of 7a and a major peak with the desired mass was detected. The mixture was filtered and concentrated to produce a residue, which was purified by preparative TLC (SiO , ethyl acetate:methanol=8:1) to afford 7b as a light brown solid. 1 H NMR (400MHz, DMSO-d6) δ9.30 (s, 1H), 9.01 (s, 2H), 8.21 (d, J = 1.3Hz, 1H), 7.67 (d, J = 1.3Hz, 1H), 3.87 (s, 3H), 3.32-3.31 (m, 3H), 2.55 (s, 3H).

[0662] 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 hours. LC-MS showed complete consumption of 7b and the detection of a major peak of the desired mass. The mixture was adjusted to pH = 5 with aqueous HCl (1 M) and concentrated to yield 7c as a brown solid. The product was used in the next step without further purification.

[0663] To a mixture of 1,2-dimethyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (7) was added DIEA (82.38 mg, 0.637 mmol, 111.03 uL, 3 eq) 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). The mixture was stirred at 15° C. for 12 hours. LC-MS showed complete consumption of 7c and one major peak of the desired mass was 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. [M+H] + (C 21 H 16 MS mass calculated for ClF2N5O2) m / z 444.1, LCMS found m / z 444.2. 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),9.32(s,1H),9.06(s,2H),8.35(d,J=1.3Hz,1H),7.9 2(d,J=9.0Hz,2H),7.76(d,J=1.5Hz,1H),7.36(d,J=9.0Hz,2H),3.37(s,3H),2.57(s,3H).

[0664] Example 8 (General Procedure G)

[0665] N-[4-[Chloro(difluoro)methoxy]phenyl]-6-pyrimidin-5-yl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxamide

[0666] The title compound was prepared according to Scheme 7. The General Procedure G illustrates Scheme 7 and provides specific synthetic details as applied to the title compound.

[0667]

[0668] 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 hr. LCMS showed complete consumption of 8) and the desired MS was detected. The mixture was filtered and concentrated under reduced pressure to yield 8b as a white solid. The product was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ 12.76 (br s, 1H) 8.09 (br s, 3H) 4.06 (s, 2H) 3.66 (t, J = 5.2Hz, 2H) 2.87-3.02 (m, 2H).

[0669] 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 uL, 2.5 eq). The mixture was stirred at 15° C. for 1 hr. 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 Na 2 SO 4 , filtered, and concentrated under reduced pressure to yield a crude residue. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 200-300 mesh silica gel, petroleum ether / ethyl acetate = 5 / 1, ethyl acetate / methanol / CH 3 COOH = 5 / 1 / 0.1%) to give 8c as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 8.28 (d, J = 1.7Hz, 1H) 8.18 (d, J = 1.7Hz, 1H) 7.09 (br s, 1H) 3.89 (s, 2H) 3.83 (s, 3H) 3.65 (br t, J = 5.0Hz, 2H) 3.19-3.28 (m, 2H).

[0670] 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 hr. LCMS showed complete consumption of 8c and the desired MS was detected. The mixture was filtered through a pad of Celite® and washed with ethyl acetate. The mixture was concentrated under reduced pressure to give a crude residue, which was purified by preparative HPLC (HCl conditions, column: Phenomenex Luna C18 200*40mm*10um; mobile phase: [water (0.05% HCl)-ACN]; B%: 15%-45%, 10 min) to give 8d as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ7.53 (s, 1H) 7.49 (s, 1H) 4.16 (brs, 2H) 4.05 (s, 3H) 3.60 (br t, J = 4.9Hz, 2H) 3.26-3.35 (m, 2H).

[0671] 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 hr. LCMS showed complete consumption of 8d 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 Na 2 SO 4 , filtered, and concentrated under reduced pressure to yield a crude residue. The residue was purified by preparative TLC (SiO 2 , petroleum ether:ethyl acetate=0:1) to give 8e as a white solid.1 H NMR (400MHz, CDCl3-d) δ 8.34 (d, J = 1.3Hz, 1H) 8.11 (d, J = 1.3Hz, 1H) 5.05 (s, 2H) 4.71 (t, J = 5.3Hz, 2H) 4.15-4.26 (m, 2H) 3.95 (s, 3H).

[0672] 6-Bromo-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxylic acid (8f). To a solution of methyl 6-bromo-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxylate (8e, 50 mg, 0.161 mmol, 1 eq) in MeOH (1 mL), THF (1 mL), and H2O (0.5 mL) was added LiOH.H2O (13.49 mg, 0.321 mmol, 2 eq). The mixture was stirred at 40°C for 6 hr. TLC (petroleum ether:ethyl acetate = 0:1, R f =0) showed complete consumption of 8e and a new major spot with greater polarity was detected. The mixture was concentrated in vacuo. The mixture was added to H2O (3 mL) and the aqueous phase was adjusted 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 (400MHz, DMSO-d6) δ 8.13 (d, J = 1.2Hz, 1H) 7.94 (d, J = 1.3Hz, 1H) 5.00 (s, 2H) 4.63 (t, J = 5.3Hz, 2H) 4.16 (t, J = 5.3Hz, 2H).

[0673] 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-carboxamide (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 hr. LCMS showed complete consumption of 8f 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 crude residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1) to afford 8 g as a white solid.1 H NMR (400MHz, CDCl3-d) δ8.11 (s, 1H) 8.00 (s, 1H) 7.96 (br s, 1H) 7.73 (d, J = 8.9Hz, 2H) 7.29 (br s,2H)5.06(s,2H)4.73(t,J=5.3Hz,2H)4.22(t,J=5.1Hz,2H).

[0674] 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 H2O (0.1 mL) were added Pd(dppf)Cl2 (6.19 mg, 8.46 umol, 0.1 eq) and K3PO4 (53.89 mg, 0.254 mmol, 3 eq). The mixture was stirred at 110 ° C for 16 hours. LCMS showed that 8g was completely consumed and the required MS was detected. The mixture was diluted with water (15mL) and extracted with EtOAc (15mL×3). The combined organic layers were washed with brine (10mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a crude residue. The residue was purified by preparative TLC (SiO2, ethyl acetate: methanol = 10: 1) to obtain the title compound 8 as a yellow solid. [M+H] + (C 22 H 16 O3N5ClF2) calculated MS mass requirement m / z 472.1, LCMS experimental value m / z 472.1 1 H NMR(400MHz, DMSO-d6)δ10.46(s,1H)9.32(s,1H)9.10(s,2H)8.42(s,1H)7.93(d,J=9.0Hz,2H)7.82(s,1H)7.26-7.45(m,1H)7.36(br d,J=8.8Hz,1H)5.03(s,2H)3.98(br t,J=4.9Hz,2H)3.70-3.83(m,2H).

[0675] Example 9 (General Procedure H)

[0676] N-(4-(Chlorodifluoromethoxy)phenyl)-1-isopropyl-2-methoxy-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0677] The title compound was prepared according to Schematic Scheme 8. The General Procedure H illustrates Schematic Scheme 8 and provides specific synthetic details as applied to the title compound.

[0678]

[0679] 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 hr. LCMS showed complete consumption of 9a and the desired MS was detected. TLC (petroleum ether:ethyl acetate = 3:1, R f =0.4) showed complete consumption of 9a, with a new major spot of less polarity detected. The reaction mixture was concentrated under reduced pressure. The mixture was washed with a saturated aqueous NaHCO solution, dried over NaSO and evaporated to dryness. The crude residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=3:1) to afford 9b as a white solid.

[0680] 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 umol, 0.1 eq) and KPO (52.12 mg, 0.246 mmol, 3 eq) in dioxane (4 mL) and H0 (0.4 mL) was degassed and purged with N3 three times. The mixture was stirred at 110°C under N2 atmosphere for 16 hr. 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 (SiO2, petroleum ether:ethyl acetate = 1:1) to yield the title compound 9 as a white solid. [M+1] + (C 23 H20 MS mass requirement calculated for ClF2N5O3) m / z 488.1, LCMS found m / z 488.0. 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),9.33(s,1H),9.06(s,2H),8.21(d,J=1.5Hz,1H),7.94-7.89(m,2 H), 7.64 (d, J = 1.5Hz, 1H), 7.35 (d, J = 9.0Hz, 2H), 4.18 (s, 3H), 3.99-3.91 (m, 1H), 1.29 (d, J = 6.8Hz, 6H).

[0681] Example 10

[0682] N-(4-(Chlorodifluoromethoxy)phenyl)-7-(4-cyclopropyl-1H-imidazol-1-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide

[0683]

[0684] N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-cyclopropyl-1H-imidazol-1-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (10). 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 A mixture of 2-[4-[ ... f=0.2) to give a crude product, which was further purified by preparative HPLC (NH4HCO3, column: Waters X-bridge Prep OBD C18 150*30 10u; mobile phase: [water (10mMNH4HCO3)-ACN]; B%: 35%-55%, 10min) to give the title compound 10 as a white solid. [M+1] + (C 24 H 22 ClF2N5O2) calculated MS mass requirement m / z 486.1, LCMS experimental value m / z 486.1; 1 H NMR(400MHz,MeOD-d4)δ8.61(s,1H),8.49(d,J=1.5Hz,1H),7.92(s,2H),7.87-7.81 (m,2H),7.33-7.24(m,3H),3.78(td,J=6.7,13.4Hz,1H),2.01-1.89(m,1H),1.46(br s, 6H), 0.93 (dd, J = 2.0, 8.4Hz, 2H), 0.77 (br s, 2H).

[0685] Example 11

[0686] N-(4-(Chlorodifluoromethoxy)phenyl)-7-(1H-imidazol-1-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide

[0687]

[0688] 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 uL, 3 eq). The mixture was stirred at 120° C. for 12 hr. The mixture was dissolved in EtOAc (20 ml), washed with water (10 mL x 5), and the organic layer was concentrated. The residue was purified by preparative HPLC (NH4HCO3 conditions, column: Waters X-bridge PrepOBD C18 150*30 10u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 35%-55%, 10 min) to produce the title compound 11 as a white solid. [M+1] + (C 21 H 18 ClF2N5O2) calculated MS mass requirement m / z 446.1, LCMS experimental value m / z 446.1; 1 H NMR(400MHz,MeOD-d4)δ8.63(s,1H),8.51(d,J=1.5Hz,1H),8.11(s,1H),7.95(d,J=1.5Hz,1H), 7.89-7.78(m,2H),7.58(d,J=1.3Hz,1H),7.35-7.21(m,3H),3.70(quin,J=6.7Hz,1H),1.43(br s,6H).

[0689] Example 12

[0690] N-(4-(Chlorodifluoromethoxy)phenyl)-2-(2-hydroxyethyl)-1-methyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0691]

[0692] 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 warmed to 30 °C and stirred for 0.5 hr. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to give 12a as a brown solid.

[0693] 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 hours. LC-MS showed complete consumption of the reactants and one major peak with the desired mass was detected. The mixture was poured into EtOAc and washed with water, saturated NaHCO3, and brine. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by preparative TLC to yield 12b as a yellow solid.

[0694] 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 was added LiBH (10.83 mg, 0.497 mmol, 5 eq) slowly in one portion at 20°C under N2. The mixture was heated to 30°C and stirred for 50 min. LC-MS showed complete consumption of the reactants and one major peak of the desired mass was detected. After the reaction mixture was cooled to 0°C, it was quenched by the addition of H2O and acidified to pH = 6 with 1N HCl. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative TLC (SiO 2 , ethyl acetate:methanol=10:1) to give 12c as a yellow solid.

[0695] 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 H2O (0.3 mL) at 20°C under N2 were added Pd(dppf)Cl2 (6.17 mg, 8.43 umol, 0.1 eq) and K3PO4 (53.66 mg, 0.253 mmol, 3 eq) in one portion. The mixture was heated to 110°C and stirred for 12 hours. LC-MS showed complete consumption of the reactants and one major peak with the desired mass was detected. The mixture was filtered through a pad of Celite®, and the filtrate was concentrated to give a crude product, which was purified by preparative HPLC (FA conditions, column: Waters Atlantis T3 150*30*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 10%-50%, 13 min) to obtain the title compound 12 as a white solid. [M+1] + (C 22 H 18 ClF2N5O3) calculated MS mass requirement m / z 474.1, LCMS experimental value m / z 474.0; 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),9.33(s,1H),9.07(s,2H),8.40(s,1H),7.94(d,J=9.2Hz,2H),7.77( s, 1H), 7.37 (d, J = 9.0Hz, 2H), 4.89 (t, J = 5.6Hz, 1H), 3.96-3.86 (m, 2H), 3.41 (s, 3H), 3.07 (t, J = 6.9Hz, 2H).

[0696] Example 13

[0697] N 5 -(4-(chlorodifluoromethoxy)phenyl)-N 7 -cyclopropyl-1-isopropyl-1H-benzo[d]imidazole-5,7-dicarboxamide

[0698]

[0699] 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 uL, 4 eq) in MeOH (20 mL) was added Pd(PPh) (50.39 mg, 0.044 mmol, 0.1 eq) in one portion at 20° C. under N2. The mixture was heated to 100° C. and stirred under CO (0.436 mmol, 3 MPa) for 24 h. LC-MS showed approximately 60% of the reactant remained. A new peak was observed by LC-MS and about 30% of the desired compound was detected. HPLC showed 60% of the reactants remained. The mixture was filtered through a pad of Celite® and the filtrate was concentrated to give a crude product. The residue was purified by preparative HPLC (NH 4 HCO 3 , column: YMC-Actus Triart C18 100*30mm*5um; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B%: 45%-65%, 12 min) to give 13b as a white solid. 1 H NMR (400MHz, MeOD-d4) δ8.64(s,1H),8.54(d,J=1.7Hz,1H),8.45(d,J=1.7Hz,1H),7.90-7.84( m, 2H), 7.33 (d, J = 9.0Hz, 2H), 5.40 (td, J = 6.6, 13.3Hz, 1H), 4.06 (s, 3H), 1.62 (d, J = 6.7Hz, 6H).

[0700]

[0148] 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), H2O (1 mL), and MeOH (0.5 mL) was added LiOH.H2O (1.92 mg, 0.046 mmol, 2 eq) in one portion at 20°C. The mixture was heated to 45°C and stirred for 2 hours. LC-MS showed complete consumption of the reactants and one major peak of the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was poured into H2O (0.5 mL) and acidified to pH = 5 with 1N HCl. The mixture was filtered, and the filter cake was washed with 0.5 mL of H 2 O and dried in vacuo to give the crude product. The crude residue 13c was obtained as a white solid and used in the next step without further purification.

[0701] 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 cyclopropylamine (6.47 mg, 0.113 mmol, 7.85 uL, 1.2 eq) in DMF (2 mL) at 20°C were added HATU (39.48 mg, 0.104 mmol, 1.1 eq) and DIEA (24.40 mg, 0.189 mmol, 32.88 uL, 2 eq) in one portion. The mixture was stirred at 20°C for 12 h. LC-MS showed 40% of the reactant remained. A new peak was observed by LC-MS and 60% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. EtOAc (15 mL) was added to the residue. The organic layer was washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure to produce a crude product. The residue was purified by preparative TLC (SiO2, EtOAc:MeOH=10:1) to produce the title compound 13 as a white solid. [M+1] + (C 22 H 21 ClF2N4O3) calculated MS mass requirement m / z 463.1, LCMS experimental value m / z 463.1; 1H NMR (400MHz, DMSO-d6) δ10.49(s,1H),8.88(d,J=4.3Hz,1H),8.61(s,1H),8.48(d,J=1.6Hz,1H),7.96(d,J=9.0Hz,2H),7.89(d,J=1.6H z,1H),7.37(d,J=9.0Hz,2H),4.96(quin,J=6.7Hz,1H),3.02-2.87(m,1H),1.50(d,J=6.7Hz,6H),0.85-0.70(m,2H),0.65-0.56(m,2H).

[0702] Example 14

[0703] N-(4-(Chlorodifluoromethoxy)phenyl)-1-((1-hydroxycyclopropyl)methyl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0704]

[0705]

[0266] 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) was stirred at 25 °C for 16 hr. Water (10 ml) was added and the mixture was extracted with DCM (20 mL x 3). The organic layer was dried over NaSO 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(400MHz, CDCl3-d)δ8.43(d,J=2.0Hz,1H),8.22(d,J=2.0Hz,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=4.4Hz,2H),0.89(s,9H),0.84-0.79(m,2H),0.39-0.29(m,2H).

[0706] 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 hr. EtOAc (20 ml) was added and the mixture was filtered. The filtrate was washed with water (20 mL x 3), the organic layer was dried over Na2SO4, and the mixture was concentrated. Compound 14c was obtained as a yellow oil without 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).

[0707] 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 hr. 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. 1 H NMR (400MHz, CDCl3-d) δ8.46 (s, 1H), 8.38 (s, 1H), 8.12 (s, 1H), 7.61 (d, J = 7.1Hz, 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).

[0708] 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 H2O (1 mL) was added K3PO4 (497.19 mg, 2.34 mmol, 3 eq) and Pd(dppf)Cl2 (28.56 mg, 0.039 mmol, 0.05 eq) under N2. The mixture was stirred at 100°C for 4 hr. The mixture was concentrated and the residue was purified by column chromatography to obtain Compound 14f as a yellow solid. 1 H NMR (400MHz, CDCl3-d) δ9.20 (s, 1H), 8.60-8.52 (m, 2H), 8.39 (s, 2H), 7.70 (d, J = 1.5Hz, 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).

[0709] 1-((1-((tert-Butyldiphenylsilyl)oxy)cyclopropyl)methyl)-7-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxylic acid (14 g). 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 H2O (2 mL) was added LiOH.H2O (40.26 mg, 0.96 mmol, 1.5 eq) at 25°C. The reaction was stirred at 25°C for 3 hr. 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 a pH of 3-4. The aqueous phase was extracted again with EtOAc (10 mL x 3), and the organic layer was dried over Na2SO4, filtered, and concentrated to yield the crude product. No further purification was required. 14 g of the compound was obtained as a red solid.

[0710] 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-carboxamide (14i) was added DIPEA (63.59 mg, 0.492 mmol, 85.71 uL, 3 eq) and HATU (93.55 mg, 0.246 mmol, 1.5 eq) in DMF (3 mL) at 25° C. The mixture was stirred at 25° C. for 12 hr. EtOAc (10 ml) was added, the mixture was washed with water (10 mL x 5), the organic layer was dried over Na2SO4 and concentrated to give a crude product. The residue was purified by column chromatography to obtain compound 14i as a light yellow solid.

[0711] 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 anhydrous THF (3 mL) was added TBAF (1 M, 41.42 uL, 1 eq) at 25 °C under N2. The mixture was stirred at 25 °C for 2 hr and concentrated. The residue was purified by preparative HPLC (NH4HCO3 conditions, column: Waters X-bridge Prep OBD C18 150*3010u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 35%-55%, 10 min) to give the title compound 14 as a yellow solid. [M+1] + (C 23 H 18 ClF2N5O3) calculated MS mass requirement m / z 486.1, LCMS experimental value m / z 486.1; 1H NMR (400MHz, DMSO-d6) δ10.45(s,1H),9.33(s,1H),9.04(s,2H),8.53(s,2H),7.98-7.93(m,J=9.2Hz,2H), 7.81(s,1H),7.42-7.33(m,J=9.0Hz,2H),5.46(s,1H),3.94(s,2H),0.61-0.52(m,2H),0.49-0.41(m,2H).

[0712] Example 15

[0713] N-(4-(Chlorodifluoromethoxy)phenyl)-1-cyclopropyl-2-(difluoromethyl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0714]

[0715] 3-Bromo-4-(cyclopropylamino)-5-(2,2-difluoroacetamido)benzoic acid methyl ester (15c). To a solution of 3-amino-5-bromo-4-(cyclopropylamino)benzoic acid methyl ester (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 N2 atmosphere for 2 hr. LCMS showed that a peak with the desired MS was detected. The reaction mixture was concentrated. The product was purified by preparative TLC (petroleum ether: ethyl acetate = 3: 1, R f =0.4) to give 15c as a yellow solid.

[0716] 7-Bromo-1-cyclopropyl-2-(difluoromethyl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (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 hours. LCMS showed a peak with the desired MS. The reaction mixture was concentrated and analyzed by preparative TLC (petroleum ether: ethyl acetate = 1: 1, R f =0.4) to give 15d as a yellow solid. 1H NMR(400MHz, CDCl3-d)δ8.43(d,J=1.3Hz,1H),8.29(d,J=1.3Hz,1H),7.18-6.8 5(m,1H),3.97(s,3H),3.70-3.60(m,1H),1.46-1.39(m,2H),1.39-1.34(m,2H)

[0717] 7-Bromo-1-cyclopropyl-2-(difluoromethyl)-1H-benzo[d]imidazole-5-carboxylic acid (15e). To a solution of 15d (1520 mg, 0.058 mmol, 1 eq) in THF (1 mL), MeOH (1 mL) and H2O (0.5 mL) was added LiOH.H2O (4.86 mg, 0.116 mmol, 2 eq). The mixture was stirred at 50°C for 2 hr. LCMS showed a peak with the desired MS. The mixture was concentrated and poured into H2O (1 mL) and the pH was adjusted to 5 by HCl (1 M in H2O). The mixture was concentrated to yield 15e as a yellow solid. 1 H NMR (400MHz, CDCl3-d) δ8.49(s,1H),8.32(d,J=1.3Hz,1H),7.04-6.89(m,1H),3.65(br dd,J=3.4,7.2Hz,1H),1.46-1.41(m,2H),1.37(br s,2H).

[0718] 7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-2-(difluoromethyl)-1H-benzo[d]imidazole-5-carboxamide (15 g). 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 hr. LCMS showed a peak with the desired MS. The reaction mixture was concentrated and the product was purified by preparative TLC (petroleum ether:ethyl acetate = 2:1, R f =0.5) to give the crude product as a yellow solid (15 g). 1H NMR (400MHz, CDCl3-d) δ8.20(d,J=1.5Hz,1H),8.16(d,J=1.5Hz,1H),7.85(s,1H),7.72(d,J=9.0Hz,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=4.4Hz,2H).

[0719] N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-2-(difluoromethyl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (15). A mixture of 15 g (35 mg, 0.069 mmol, 1 eq), pyrimidin-5-ylboronic acid (25.68 mg, 0.207 mmol, 3 eq), Pd(dppf)Cl2 (5.05 mg, 6.91 umol, 0.01 eq), K3PO4 (43.99 mg, 0.207 mmol, 3 eq) in dioxane (2 mL) and H2O (0.2 mL) was degassed and purged with N2 three times. The reaction mixture was stirred at 100°C under N2 atmosphere for 8 hr. LCMS showed peaks with the desired MS. The reaction mixture was concentrated and purified by preparative TLC (petroleum ether:ethyl acetate = 0:1, R f =0.45) to give the title compound 15 as a white solid. [M+H] + (C 23 H 16 MS mass requirement calculated for ClF4N5O2) m / z 506.1, LCMS found m / z 506.1. 1 H NMR (400MHz, CH3OD-d4) δ9.29(s,1H),9.15(s,2H),8.50(d,J=1.5Hz,1H),8.02(d,J=1. 5Hz,1H),7.86(d,J=9.0Hz,2H),7.48-7.21(m,3H),3.45(td,J=3.3,7.1Hz,1H),0.80(br s, 2H), 0.60 (br d, J = 6.6Hz, 2H).

[0720] Example 16

[0721] N-(4-(Chlorodifluoromethoxy)phenyl)-1-(1-hydroxy-2-methylpropan-2-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0722]

[0723] 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), and TEA (131.02 mg, 1.29 mmol) in EtOH (5 mL) was stirred at 15° C. for 3 hr. The reaction mixture was concentrated and analyzed by preparative TLC (petroleum ether:ethyl acetate=3:1, R f = 0.5) to give 16b as a yellow oil. 1 H NMR (400MHz, CDCl3-d) δ8.41 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 5.06 (brs, 1H), 3.95 (s, 3H), 3.48 (s, 2H), 1.19 (s, 6H).

[0724] 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)Cl2 (21.08 mg, 0.029 mmol), K3PO4 (366.86 mg, 1.73 mmol) in dioxane (4 mL) and H2O (0.4 mL) was degassed and purged with N2 three times. The mixture was stirred at 110 °C under N2 atmosphere for 6 hr. LCMS showed a peak with the desired MS. The reaction mixture was concentrated and the product was analyzed by preparative TLC (petroleum ether:ethyl acetate = 0:1, R f =0.4) to give 16d as a yellow solid. 1 HNMR(400MHz, CDCl3-d)δ9.25(s,1H),9.02(s,2H),8.63(d,J=2.0Hz,1H),8.14(d,J=2.0Hz,1H),5.79(s,1H),4.02-3.93(m,3H),3.15(br s,2H),0.76(s,6H).

[0725] 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 hr. LCMS showed a peak with the desired MS. The mixture was filtered through a Celite® pad and the filtrate was concentrated. f =0.3) to give 16e as a yellow solid. 1 H NMR (400MHz, CDCl3-d) δ9.19 (s, 1H), 8.90 (s, 2H), 7.48 (d, J = 2.0Hz, 1H), 7.39 (d, J = 2.0Hz, 1H), 3.91 (s, 3H), 3.50 (s, 2H), 3.25 (s, 2H), 0.76 (s, 6H).

[0726] 1-(1-(dimethoxymethoxy)-2-methylpropan-2-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (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 umol). The mixture was stirred at 80° C. for 1 hr. LCMS showed a peak with the desired MS. The reaction mixture was concentrated and analyzed by preparative TLC (ethyl acetate:methanol=10:1, R f = 0.4) to give 16f as a yellow oil. 1 H NMR(400MHz, CDCl3-d)δ9.33(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(brs,1H).

[0727] Methyl 1-(1-hydroxy-2-methylpropan-2-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylate (16 g). To a solution of 16f (10 mg, 0.025 mmol) in MeOH (2 mL) was added HCl (0.1 M, 499.47 uL). The mixture was stirred at 15 °C for 3 hr. LCMS showed a peak with the desired MS. The reaction mixture was concentrated to yield 16 g as a yellow oil. The product was used in the next step without purification.

[0728] 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 hr. 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 by the addition of HCl (1 M in HO), resulting in 16h as a white solid. The product was used in the next step without further purification.

[0729] 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 hr. LCMS showed peaks with the desired MS. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (NH4HCO3, column: Agela Durashell C18 150*25 5u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 35%-65%, 10 min) to give the title compound 16 as a white solid. [M+1] + (C 23 H 20 MS mass requirement calculated for ClF2N5O3) m / z 488.1, LCMS found m / z 488.1. 1H NMR(400MHz,MeOD-d4)δ9.31(s,1H),8.98(s,2H),8.55(s,1H),8.47(d,J=1.8Hz,1H),7.8 3(d,J=9.0Hz,2H),7.71(d,J=1.8Hz,1H),7.29(d,J=9.0Hz,2H),3.56(s,2H),1.41(s,6H).

[0730] Example 17

[0731] N-(4-(Chlorodifluoromethoxy)phenyl)-7-(4-fluoro-1H-pyrazol-5-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide

[0732]

[0733] 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 hr. TLC (petroleum ether:ethyl acetate = 5:1, R f =0.4) indicated the formation of a new spot. LCMS showed a peak with the desired MS. The reaction mixture was concentrated. H2O (20 mL) was added to the residue and the aqueous phase was extracted with ethyl acetate (60 mL). The organic layer was washed with brine (5 mL × 2), dried over anhydrous Na2SO4, 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 produce 17b as a yellow oil. 1 H NMR (400MHz, CDCl3-d) δ7.35 (d, J = 4.0Hz, 1H), 7.21-7.17 (m, 3H), 6.91-6.87 (m, 2H), 5.14 (s, 2H), 3.81 (s, 3H).

[0734] 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 n-BuLi solution (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 continuously stirred for an additional 2 hr. TLC (petroleum ether:ethyl acetate = 3:1, R f =0.6) indicates the generation of a new spot. LCMS shows a peak with the desired MS. The reaction mixture is quenched by adding water H2O (20 mL) and then adding ethyl acetate (80 mL). After quenching the reaction, the reaction mixture is poured into a separatory funnel and separated. The organic layer is concentrated and the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 45: 1 ~ 10: 1) to produce 17d as a yellow solid. 1 H NMR (400MHz, CDCl3-d) δ7.43 (d, J = 4.8Hz, 1H), 7.20 (d, J = 8.8Hz, 2H), 6.89-6.85 (m, 2H), 5.23 (s, 2H), 3.80 (s, 3H).

[0735] 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(PPh3)4 (121.59 mg, 0.105 mmol) in toluene (5 mL) was degassed and purged with N2 three times. The mixture was stirred at 130°C under N2 atmosphere for 16 hr. TLC (petroleum ether:ethyl acetate = 3:1, R f =0.7) indicates the generation of a new spot. LCMS shows that a peak with the desired MS is detected. The reaction mixture is quenched by adding KF (5 mL) and then ethyl acetate (40 mL). After quenching the reaction, the reaction mixture is poured into a separatory funnel and separated. The organic layer is concentrated and analyzed by preparative TLC (petroleum ether: ethyl acetate = 3: 1, R f = 0.7) to give 17e as a yellow oil. 1 H NMR (400MHz, CDCl3-d) δ7.40 (d, J = 4.8Hz, 1H), 6.92 (t, J = 8.4Hz, 2H), 6.88-6.83 (m, 2H), 5.21 (s, 2H), 3.79 (s, 3H), 0.25 (s, 9H).

[0736] N-(4-(Chlorodifluoromethoxy)phenyl)-7-(4-fluoro-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (17 g). 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 at 100 °C under N atmosphere for 16 hr. LCMS showed that a peak with the desired MS was detected. The mixture was quenched by adding water (40 mL) and extracted with ethyl acetate (60 mL×3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a crude product. The crude product was characterized by preparative TLC (ethyl acetate:methanol=10:1, R f = 0.6) to give a yellow oil 17 g. 1 H NMR (400MHz, CDCl3-d) δ8.49(d,J=1.5Hz,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=8.6Hz,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=6.6Hz,2H),1.34(d,J=6.6Hz,3H),1.15(d,J=6.6Hz,3H).

[0737] N-(4-(Chlorodifluoromethoxy)phenyl)-7-(4-fluoro-1H-pyrazol-5-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (17). A solution of 17 g (80 mg, 0.137 mmol) in TFA (2 mL) was stirred at 15° C. for 16 hr. LCMS showed that a peak with the desired MS was detected. The reaction mixture was concentrated. The product was purified by preparative TLC (ethyl acetate:methanol=10:1, R f =0.4) to give the title compound 17 as a white solid. [M+H] + (C 21 H 17MS mass calculated for ClF3N5O2) m / z 464.1, LCMS found m / z 464.0. 1 H NMR(400MHz,MeOD-d4)δ8.56(br s,1H),8.43(br s,1H),7.93(d,J=1.8Hz,1H),7.87-7.80(m,3H),7.29(d,J=9.0Hz,2H),4.67(brs,1H),1.43(d,J=6.6Hz,6H).

[0738] Example 18

[0739] N-(4-(Chlorodifluoromethoxy)phenyl)-1-cyclopropyl-7-(4-fluoro-1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0740]

[0741] 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(PPh3)4 (12.65 mg, 0.011 mmol, 0.05 eq). The reaction mixture was stirred at 100°C for 16 hr. LCMS showed that a peak with the desired MS was detected. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL×2). The combined organic layers were concentrated and purified by preparative TLC (EtOAc:MeOH=10:1, R f =0.6) to afford 18b as a yellow oil.

[0742] N-(4-(Chlorodifluoromethoxy)phenyl)-1-cyclopropyl-7-(4-fluoro-1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide (18b). 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 hr. LCMS showed that a peak with the desired MS was detected. The solvent was evaporated under vacuum and the residue was dissolved in EtOAc (5 mL). The organic layer was washed with saturated NaHCO 3 (2 mL), brine (2 mL) and concentrated to give a crude residue which was identified by preparative TLC (EtOAc:MeOH=10:1, R f =0.3) to give the title compound 18 as a white solid. [M+H] + (C 21 H 15 MS mass calculated for ClF3N5O2) m / z 462.1, LCMS found m / z 462.0. 1 H NMR (400MHz, 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=4.6Hz,1H),7.22(br d,J=8.8Hz,2H),3.42(br d,J=3.3Hz,1H),0.80-0.63(m,4H).

[0743] Example 19

[0744] N-(4-(Chlorodifluoromethoxy)phenyl)-1-(1,1-dioxothietan-3-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0745]

[0746] 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), K3PO4 (169.38 mg, 0.798 mmol, 3 eq) in dioxane (2 mL) and H2O (0.2 mL) was added Pd(dppf)Cl2 (19.46 mg, 0.27 mmol, 0.1 eq) under N2. The mixture was stirred at 100 ° C for 16 hours. 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 produce a crude product. The crude product was analyzed by preparative TLC (ethyl acetate: methanol = 10: 1, R f =0.30) to give 19c as a white solid. 1 H NMR (400MHz, CDCl3-d) δ9.36(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=8.8Hz,2H),7.22(br s, 2H), 5.06 (quin, J = 8.2Hz, 1H), 3.63 (t, J = 9.0Hz, 2H), 3.14 (t, J = 9.0Hz, 2H).

[0747] N-(4-(Chlorodifluoromethoxy)phenyl)-1-(1,1-dioxothietan-3-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (19c). 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) was dissolved in DCM (2 mL) at 0°C, and saturated aqueous sodium bicarbonate solution and mCPBA (70.74 mg, 0.328 mmol, 80% purity, 4 eq) were added. The reaction mixture was stirred at 15°C for 16 hours. 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 product was characterized by preparative TLC (ethyl acetate:methanol=10:1, R f=0.37) to purify the residue to afford the title compound 19 as a white solid. [M+1] + (C 22 H 16 MS mass requirement calculated for ClF2N5O4S) m / z 520.1, LCMS observed m / z 520.0. 1 HNMR (400MHz, DMSO-d6) δ10.50(s,1H),9.38(s,1H),9.03(s,2H),8.83(s,1H),8.55(s,1H),7.95(br d,J=8.8Hz,2H),7.88-7.77(m,1H),7.38(br d,J=8.6Hz,2H),4.94-4.83(m,1H),4.74(br d,J=13.2Hz,2H),4.41-4.26(m,2H).

[0748] Example 20

[0749] N-(4-(Chlorodifluoromethoxy)phenyl)-6-fluoro-1-isopropyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0750]

[0751] 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 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 hr. TLC (petroleum ether:EtOAc=5:1, R f =0.50) indicated complete consumption of 20a, and a new major spot was detected. The aqueous phase was extracted with EtOAc (20 mL x 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 (400MHz, CDCl3-d) δ8.91 (d, J = 7.8Hz, 1H), 8.29 (br d,J=4.9Hz,1H),6.52(d,J=13.7Hz,1H),3.90(s,3H),3.83-3.70(m,1H),1.36(d,J=6.4Hz,6H).

[0752] 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 hr. TLC (petroleum ether:EtOAc=5:1, R f =0.50) indicated that 20b was completely consumed. The reaction mixture was quenched by adding saturated Na2SO3 (5 mL). The residue was diluted with H2O (20 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a crude product. The residue was purified by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate = 10: 1) to obtain 20c as a yellow solid. 1 H NMR (400MHz, CDCl3-d) δ8.72 (d, J = 7.3Hz, 1H), 4.49-4.34 (m, 1H), 3.93 (s, 3H), 1.29-1.27 (m, 6H).

[0753] 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 NHCl (1.60 g, 29.84 mmol, 1.04 mL, 10 eq). The mixture was stirred at 80°C for 6 hr. TLC (petroleum ether:EtOAc=3:1) indicated complete consumption of 20c. 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 yield the crude product. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 1:1) to obtain compound 20d as a brown oil. 1 H NMR (400MHz, CDCl3-d) δ7.21 (d, J = 6.8Hz, 1H), 3.90 (s, 3H), 3.80-3.71 (m, 1H), 1.17 (d, J = 6.4Hz, 6H).

[0754] 7-Bromo-6-fluoro-1-isopropyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (20e). To a solution of 5-amino-3-bromo-2-fluoro-4-(isopropylamino)benzoic acid methyl ester (20d, 180 mg, 0.590 mmol, 1 eq) in CH(OMe)3 (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 hr. TLC (petroleum ether: ethyl acetate = 1: 1) indicated that 20d was completely consumed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (20 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce the crude product. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1: 1). Compound 20e was obtained as a white solid. 1 H NMR (400MHz, CDCl3-d) δ8.34 (d, J=5.9Hz, 1H), 8.15 (s, 1H), 5.64 (quind, J=6.7, 13.4Hz, 1H), 3.97 (s, 3H), 1.65 (d, J=6.4Hz, 6H).

[0755] 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 hr. TLC (petroleum ether:ethyl acetate=1:1) indicated complete consumption of 20e. The mixture was adjusted to pH=5 with aqueous HCl (1 M) and concentrated to yield 20f as a white solid, which was used in the next step without further purification.

[0756] 7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-fluoro-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (20 g). 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 uL, 3 eq). The mixture was stirred at 50° C. for 3 hr. TLC (petroleum ether:ethyl acetate = 1:1) indicated complete consumption of 20f. The reaction mixture was concentrated under reduced pressure. 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 produce a crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1:1). 20 g of the compound was obtained as a white solid. 1 H NMR(400MHz,MeOD-d4)δ8.57(s,1H),8.01(d,J=6.4Hz,1H),7.82(d,J=8.8Hz,2 H), 7.30 (d, J = 9.3Hz, 2H), 5.70 (td, J = 6.7, 13.6Hz, 1H), 1.67 (d, J = 6.8Hz, 6H).

[0757] 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 H2O (0.5 mL) was added Pd(dppf)Cl2 (7.68 mg, 0.01 mmol, 0.1 eq), pyrimidin-5-ylboronic acid (38.99 mg, 0.315 mmol, 3 eq) and K3PO4 (66.80 mg, 0.315 mmol, 3 eq). The mixture was stirred at 100°C for 6 hr. LC-MS showed complete consumption of 20 g and the detection of a major peak with the desired MS. The mixture was concentrated to yield the crude product. The residue was purified by preparative HPLC (NH4HCO3 conditions, column: Waters X-Bridge 150*50 10u; mobile phase: [water (10 mM NH4HCO3)-MeOH]; B%: 55%-75%, 12 min) to afford the title compound 20 as a white solid. [M+H] + (C 22 H 17 ClF3N5O2) calculated MS mass requirement m / z 476.1, LCMS experimental value m / z 476.1; 1 H NMR (400MHz, CDCl3-d) δ9.42 (s, 1H), 8.93 (s, 2H), 8.74 (d, J = 7.3Hz, 1H), 8.44 (br d,J=15.7Hz,1H),8.18(s,1H),7.72(d,J=8.8Hz,2H),7.25(d,J=8.8Hz,2H),3.96(td,J=6.8,13.3Hz,1H),1.38(d,J=6.8Hz,6H).

[0758] Example 21

[0759] N-(4-(Chlorodifluoromethoxy)phenyl)-1-(2-(cyclopropylamino)-2-oxoethyl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0760]

[0761] 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 K2CO3 (18.58 mg, 0.134 mmol, 0.7 eq) under N2. The mixture was stirred at 80°C for 4 hours. TLC (ethyl acetate:methanol = 10:1, R f =0.32) showed that the reaction was complete. The mixture was poured into water (20 mL) and then extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to produce a crude product. The crude product was analyzed by preparative TLC (ethyl acetate: methanol = 10: 1, R f =0.32) to give 21c as a white solid. 1 H NMR (400MHz, MeOD-d4) δ8.21(d,J=6.2Hz,2H),8.01(s,1H),7.74(d,J=8.9Hz,2H),7.20(br d,J=8.9Hz,2H),5.19(s,2H),2.61(dt,J=3.7,7.5Hz,1H),0.65(br d,J=5.1Hz,2H),0.46(br d,J=2.4Hz,2H).

[0762] 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 H2O (0.4 mL) were added Pd(dppf)Cl2 (1.42 mg, 1.95 umol, 0.1 eq) and K3PO4 (12.40 mg, 0.058 mmol, 3 eq). The reaction mixture was stirred at 100 ° C for 6 hours. LCMS showed that a peak with the desired MS was detected. The reaction mixture was concentrated, and the residue was dissolved in EtOAc (5 mL) and washed with H2O (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. [M+H] + (C 24 H 19 MS mass requirement calculated for ClF2N6O3) m / z 513.1, LCMS found m / z 513.1. 1 H NMR(400MHz,MeOD-d4)δ8.91(s,1H),8.54(s,2H),8.08(d,J=1.5Hz,1H),7.91(s,1H),7.50-7.41(m,3H) ,6.92(d,J=9.0Hz,2H),4.32(s,2H),2.05(tt,J=3.9,7.2Hz,1H),0.31-0.21(m,2H),0.01-0.00(m,2H).

[0763] Example 22 (General Procedure I)

[0764] N-(4-(Chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(thiazol-4-yl)-1H-benzo[d]imidazole-5-carboxamide

[0765] The title compound was prepared using coupling reactions analogous to those outlined in Scheme 9. The General Procedure I illustrates Scheme 9 and provides specific synthetic details as applied to the title compound.

[0766]

[0767] N-(4-(Chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(thiazol-4-yl)-1H-benzo[d]imidazole-5-carboxamide (22). To a microwave tube were added 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(PPh3)4 (25.19 mg, 0.022 mmol, 0.1 eq) in dioxane (4 mL). The sealed tube was heated to 150°C under microwave irradiation for 3 hr. Water (5 ml) was added to the reaction mixture and extracted with EtOAc (10 mL x 2). The combined organic layers were concentrated, and the crude residue was purified by preparative HPLC (TFA conditions, column: Luna C18 100*30 5u; mobile phase: [water (0.1% TFA)-ACN]; B%: 15%-50%, 10 min) to give the title compound 22 as a yellow solid. [M+1] + (C 21 H 17 MS mass requirement calculated for ClF2N4O2S) m / z 463.1, LCMS found m / z 463.0. 1 H NMR(400MHz, CDCl3-d)δ8.95-8.91(m,1H),8.86(d,J=1.6Hz,1H),8.40(s,1H),8.03(s,1H),7.84(s,1H),7.74(br d,J=8.8Hz,2H),7.50(d,J=1.6Hz,1H),7.24-7.15(m,2H),4.53(td,J=6.6,13.3Hz,1H),1.26(d,J=6.6Hz,6H).

[0768] Example 23

[0769] N-(4-(Chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(4H-1,2,4-triazol-4-yl)-1H-benzo[d]imidazole-5-carboxamide

[0770]

[0771] 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 PMBNH2 (323.00 mg, 2.35 mmol, 304.71 uL), NaOBu-t (565.70 mg, 5.89 mmol), XPhos (93.54 mg, 0.196 mmol), and Pd2(dba)3 (179.68 mg, 0.196 mmol). The mixture was stirred at 100° C. under N2 atmosphere for 12 hr. 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 layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1, 1 / 3) to obtain 23b as a yellow solid. [M+1] + (C 26 H 25 MS mass requirement calculated for ClF2N4O3) m / z 515.2, LCMS found m / z 515.2. 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),8.38-8.36(m,1H),7.93-7.89(m,2H),7.78(d,J=1.2Hz,1H),7.38(d,J=8.6Hz,2H),7.33(br d,J=9.0Hz,2H),7.04(s,1H),6.91(d,J=8.7Hz,2H),6.01-5.94(m,1H),5.32-5.23(m,1H),4.40(br d,J=5.3Hz,2H),3.72(s,3H),1.57(d,J=6.5Hz,6H).

[0772] 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 hr. LCMS showed the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The mixture was purified by preparative HPLC (NH4HCO3 conditions, column: Agia Dashner C18 150*25 5u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 35%-65%, 10 min) to give 23c as a yellow solid. [M+1] + (C 18 H 17 MS mass requirement calculated for ClF2N4O2) m / z 395.1, LCMS found m / z 395.1. 1 H NMR(400MHz,MeOD-d4)δ8.34(br s,1H),7.82(d,J=9.0Hz,2H),7.69(d,J=1.6Hz,1H),7.29(d,J=9.2Hz,2H),7.23(d,J=1.6Hz,1H),5.25-5.12(m,1H),1.66(d,J=6.7Hz,6H).

[0773] 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-formamidoformamide (9.37 mg, 0.106 mmol) in pyridine (1.5 mL) was added chloro-trimethyl-silane (57.79 mg, 0.532 mmol, 67.51 uL) and TEA (25.12 mg, 0.248 mmol, 34.55 uL). The mixture was stirred at 100 °C for 18 hr. LCMS showed complete consumption of 23c and one major peak of the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Atlantis T3150*30*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 20%-60%, 13 min) to obtain the title compound 23 as a white solid. [M+1] + (C 20 H17 MS mass requirement calculated for ClF2N6O2) m / z 447.1, LCMS found m / z 447.1. 1 H NMR (400MHz, CDCl3-d) δ8.50-8.45(m,3H),8.23(s,2H),7.91(d,J=1.0Hz,1H),7.75(d,J=8.8Hz,2H),7.29(br d,J=9.3Hz,2H),3.74-3.61(m,1H),1.45(d,J=6.4Hz,6H).

[0774] Example 24 (General Procedure J)

[0775] (S)-N-(4-(Chlorodifluoromethoxy)phenyl)-1-(5-oxopyrrolidin-3-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0776] The General Procedure J provides specific synthetic details as applied to the title compound. Additional compounds can be prepared according to this method by varying the coupling reagent.

[0777]

[0778] 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 hr. The mixture was added dropwise to ice water (2 L) with vigorous stirring. The precipitate was filtered to afford 24b as a white solid. 1 H NMR (400MHz, CDCl3-d) δ8.72 (dd, J=2.2, 6.4Hz, 1H), 8.58 (dd, J=2.2, 5.5Hz, 1H).

[0779] 3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluoro-5-nitrobenzamide (24c). A suspension of 3-bromo-4-fluoro-5-nitrobenzoic acid (24b, 150 mg, 0.568 mmol) in SOCl2 (2 mL) was stirred at 60 ° C for 3 hours. The mixture was concentrated to give 3-bromo-4-fluoro-5-nitro-benzoyl 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 uL) in THF (2 mL) under N2 was added 3-bromo-4-fluoro-5-nitro-benzoyl chloride (213.97 mg, 0.758 mmol). The mixture was stirred at 20 ° C for 3 hours. LCMS showed the desired MS. The mixture was extracted with ethyl acetate (2 mL x 3), and the combined organic layers were washed with brine (5 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The product was analyzed by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, R f =0.3) to purify the residue to obtain compound 24c as a white solid.

[0780] (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 uL). 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 2 , petroleum ether:ethyl acetate = 3:1, R f =0.1) to afford 24e as a yellow solid. 1 H NMR (400MHz, MeOD-d4) δ8.62(d,J=2.2Hz,1H),8.45(d,J=2.2Hz,1H),7.84-7.80(m,2H),7.30(d,J=8.8Hz,2H),4.64(br s, 1H), 3.80 (dd, J = 6.8, 10.7Hz, 1H), 3.39 (dd, J = 4.2, 10.7Hz, 1H), 2.80 (dd, J = 7.9, 17.1Hz, 1H), 2.41 (dd, J = 4.8, 17.1Hz, 1H).

[0781] (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 2 was added Fe (56.95 mg, 1.02 mmol) in one portion, and the mixture was stirred at 35° C. for 2 h. LCMS showed the desired MS. The mixture was poured into saturated NaHCO 3 and extracted with ethyl acetate (5 mL×2). The combined organic layers were washed with brine (5 mL×2), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to give 24f as a yellow solid.

[0782] (S)-7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(5-oxopyrrolidin-3-yl)-1H-benzo[d]imidazole-5-carboxamide (24 g). 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) was added TsOH (1.26 mg, 7.31 umol) in one portion at 20° C. under N2, 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 Na2SO4, filtered, and concentrated in vacuo to afford 24 g as a yellow solid.

[0783] (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 H2O (0.1 mL) and dioxane (1 mL) was added Pd(dppf)Cl2 (5.17 mg, 7.06 umol) and K3PO4 (29.99 mg, 0.141 mmol) in one portion under N2. The mixture was stirred at 100°C for 12 h. LCMS showed the desired MS. 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 Na 2 SO 4 , filtered and concentrated in vacuo. The product was analyzed by preparative TLC (SiO 2 , petroleum ether: ethyl acetate = 1:5, R f =0.1) to give the title compound 24 as a brown solid. [M+1]+(C 23 H 17 MS mass requirement calculated for ClF2N6O3) m / z 499.1, LCMS found m / z 499.1. 1 H NMR(400MHz,DMSO-d6)δ9.39(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=6.5,11.1Hz,1H),3.51(br d,J=11.7Hz,1H),2.82-2.60(m,2H).

[0784] Example 25

[0785] N-(4-(Chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1H-benzo[d]imidazole-5-carboxamide

[0786]

[0787] 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 layers were washed with brine (5 mL×2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. By preparative TLC (SiO2, petroleum ether: ethyl acetate = 0:1, R f =0.67) to give 1b as a white solid. 1 H NMR(400MHz, CDCl3-d)δ8.52(s,1H),8.30-8.21(m,2H),8.09(s,1H),7.73(d,J=8 .8Hz, 2H), 7.28 (d, J = 8.6Hz, 2H), 5.32 (spt, J = 6.7Hz, 1H), 1.72 (d, J = 6.6Hz, 6H).

[0788] (Z)-N-(4-(chlorodifluoromethoxy)phenyl)-7-(N'-hydroxycarbamoyl)-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 hours. LCMS showed the desired MS. The aqueous phase was extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. By preparative TLC (SiO2, petroleum ether: ethyl acetate = 0:1, R f =0.5) to purify the residue to afford 25c as a white solid. [M+1] + (C 19 H 18 MS mass requirement calculated for ClF2N5O3) m / z 438.1, LCMS found m / z 438.3.

[0789] 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'-hydroxycarbamoyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (25c, 0.02 g, 0.046 mmol) in THF (2 mL) 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 uL) under N2. The mixture was stirred at 60°C for 12 hours. LCMS showed the desired MS. The aqueous phase was extracted with ethyl acetate (3 mL x 3), and the combined organic layers were washed with brine (5 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The product was analyzed by preparative TLC (SiO2, ethyl acetate:methanol=10:1, R f =0.1) to give the title compound 25 as a yellow solid. [M+1] + (C 20 H 16 ClF2N5O4) calculated MS mass requirement m / z 464.1, LCMS experimental value m / z 464.1; 1 H NMR (400MHz, MeOD-d4) δ8.55(s,1H),8.43(d,J=1.6Hz,1H),8.09(d,J=1.6Hz,1H),7.85(d , J=9.0Hz, 2H), 7.29 (d, J=8.9Hz, 2H), 5.25 (td, J=6.6, 13.3Hz, 1H), 1.53 (d, J=6.7Hz, 6H).

[0790] Example 26

[0791] N 5 -(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5,7-dicarboxamide

[0792]

[0793] 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 NH2OH.HCl (41.20 mg, 0.593 mmol) and TEA (13.86 mg, 0.137 mmol). The mixture was stirred at 80°C for 12 hours. 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 product was analyzed by preparative TLC (SiO2, petroleum ether:ethyl acetate=0:1, R f =0.5) to purify the residue to afford the title compound 26 as a white solid. [M+1] + (C 19 H 17 MS mass requirement calculated for ClF2N4O3) m / z 423.1, LCMS found m / z 423.0. 1 HNMR (400MHz, DMSO-d6) δ10.48(s,1H),8.62(s,1H),8.48(d,J=1.6Hz,1H),8.27(s,1H),7.98(d,J=1.7Hz,1H ),7.97-7.94(m,2H),7.78(s,1H),7.37(d,J=9.0Hz,2H),5.09(quin,J=6.6Hz,1H),1.52(s,3H),1.50(s,3H).

[0794] Example 27

[0795] N-(4-(Chlorodifluoromethoxy)phenyl)-3-isopropyl-4-(pyrimidin-5-yl)-3H-imidazo[4,5-c]pyridine-6-carboxamide

[0796]

[0797] 4-Chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-carboxylic acid methyl ester (27b). To a solution of 4-chloro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid methyl ester (27a, 200 mg, 0.945 mmol) and 2-iodopropane (482.01 mg, 2.84 mmol, 283.53 uL) in DMF (3 mL) was added KCO (391.88 mg, 2.84 mmol). The mixture was stirred at 30° C. for 16 hr. 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 yield a residue. The residue was purified by preparative TLC (SiO 2 , petroleum ether:ethyl acetate=1:2) to give 27c as a white solid. 1 H NMR (400MHz, CDCl3-d) δ8.54 (s, 1H), 8.30 (s, 1H), 5.60-5.42 (m, 1H), 4.04 (s, 3H), 1.70 (d, J = 6.7Hz, 6H).

[0798] 3-Isopropyl-4-(pyrimidin-5-yl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid methyl ester (27c). To a solution of 4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-carboxylic acid methyl ester (27b, 70 mg, 0.276 mmol) and pyrimidin-5-ylboronic acid (68.38 mg, 0.552 mmol) in dioxane (1 mL) and H2O (0.1 mL) was added Pd(dppf)Cl2 (20.19 mg, 27.59 umol) and K3PO4 (175.71 mg, 0.828 mmol). The mixture was stirred at 110°C under N2 for 16 hr. 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 x 3). The combined organic layers were washed with brine (5 mL), dried over Na 2 SO 4 , 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 (400MHz, MeOD-d4) δ9.36 (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 = 6.6Hz, 6H).

[0799] 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 H2O (0.25 mL) was added LiOH.H2O (9.88 mg, 0.235 mmol). The mixture was stirred at 20°C for 2 hours. TLC (ethyl acetate:methanol = 10:1, R f =0.0) showed complete consumption of 27c and the detection of a new major spot with greater polarity. The mixture was concentrated in vacuo. The mixture was then added to H2O (3 mL) and the aqueous phase was acidified to pH = 5 with aqueous HCl. The mixture was concentrated in vacuo. The product was used in the next step without further purification. Compound 27d was obtained as a white solid. 1 H NMR (400MHz, MeOD-d4) δ9.69 (s, 1H), 9.46 (s, 1H), 9.22 (s, 2H), 8.80-8.67 (m, 1H), 4.42 (s, 1H), 1.50 (d, J = 6.6Hz, 6H).

[0800] 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-carboxamide (27d, 32 mg, 0.113 mmol) and 1h (32.80 mg, 0.169 mmol) in DMF (2 mL) was added DIEA (43.80 mg, 0.339 mmol, 59.03 uL) and HATU (51.54 mg, 0.136 mmol). The mixture was stirred at 25 °C for 4 hr. 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 x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1) to afford 27 as a white solid. [M+H] + (C 21 H 17 MS mass calculated for (4-(4-(4-oxo-2-nitropropene)-4-nitropropene)-2-nitropropene ... 1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),9.42(s,1H),9.30(s,2H),8.94(s,1H),8.50(s,1 H), 8.05-7.95 (m, 2H), 7.37 (d, J = 9.0Hz, 2H), 4.38-4.09 (m, 1H), 1.38 (d, J = 6.7Hz, 6H).

[0801] Example 28 (General Procedure K)

[0802] (R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-fluoropropan-2-yl)-7-(1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0803] The General Procedure K provides specific synthetic details as applied to the title compound. Additional compounds can be prepared according to this method by varying the coupling reagent.

[0804]

[0805] N-(4-(Chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-((R)-1-fluoroprop-2-yl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide (28b). To (R)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-fluoroprop-2-yl)-1H-benzo[d]imidazole-5-carboxamide (synthesized in a similar manner to 15g; 28a, To a solution of 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 H2O (0.3 mL) was added Pd(PPh3)2Cl2 (4.00 mg, 5.70 umol) and Na2CO3 (12.07 mg, 0.114 mmol). The mixture was stirred at 80°C for 2 hours. LCMS showed complete consumption of 28a 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 yield a residue. The residue was purified by preparative TLC (SiO 2 , petroleum ether:ethyl acetate=2:1) ​​to give 28b as a yellow solid.

[0806] (R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-fluoropropan-2-yl)-7-(1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide (28b). 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 hr. LCMS showed complete consumption of 28b 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 yield a residue. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 1: 1) to afford 28 as a white solid. [M+H] + (C 22 H 17 MS mass requirement calculated for (C12H2O2N5ClF5) m / z 514.1, LCMS found m / z 514.1. 1 H NMR(400MHz,MeOD-d4)δ8.47(d,J=1.3Hz,1H),7.98(d,J=1.7Hz,1H),7.88(brs,1H),7.87-7.81 (m,2H),7.44-7.15(m,3H),6.66(d,J=2.2Hz,1H),4.70-4.67(m,1H),4.63-4.45(m,2H),1.52(br d,J=7.2Hz,3H).

[0807] Example 29

[0808] 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

[0809]

[0810] 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 umol) in acetone (0.5 mL) and H2O (0.1 mL) was added potassium persulfate (5.03 mg, 8.18 umol). The mixture was stirred at 20°C for 24 hours. TLC (petroleum ether:ethyl acetate = 0:1, R f =0.77) indicates that 29a is completely consumed and a new main spot with greater polarity is detected. The reactant is quenched by sodium sulfide. The reaction mixture is concentrated under reduced pressure to remove acetone. The residue is diluted with H2O (10mL) and extracted with EtOAc (10mL×3). The combined organic layers are washed with brine (10mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue. The residue is purified by preparative TLC (SiO2, petroleum ether: ethyl acetate=0:1) to obtain 29b as a brown solid. 1 H NMR (400MHz, MeOD-d4) δ8.18(d,J=1.5Hz,1H),8.05(d,J=1.5Hz,1H),7.73(d,J=8.8Hz,2H),7.20(br d,J=8.8Hz,2H),5.17-5.12(m,2H),5.08(s,2H),3.81-3.75(m,2H).

[0811] 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). 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 A mixture of 1,4-dioxane (1 mL) and 1,4-dioxane (1 mL) and 1,4-dioxane (0.1 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 110°C under N2 atmosphere for 16 hours. TLC (petroleum ether:ethyl acetate=0:1, R f=0.3) indicated complete consumption of 29b and a new major spot with greater polarity was detected. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was diluted with H2O (1 mL) and extracted with ethyl acetate (1 mL x 3). The combined organic layers were washed with brine (1 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 0:1) to afford 29 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.49(s,1H),9.33(s,1H),9.09(s,2H),8.45(d,J=1.0Hz,1H),7 .91(d,J=9.3Hz,2H),7.83(d,J=1.5Hz,1H),7.36(d,J=8.8Hz,2H),5.09(s,2H),4.12(br t,J=5.9Hz,2H),3.75(br t,J=5.6Hz,2H).

[0812] Example 30 (General Procedure L)

[0813] N-(4-(Chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0814] The General Procedure L provides specific synthetic details as applied to the title compound. Additional compounds can be prepared according to this method by varying the coupling and / or deprotecting reagents.

[0815]

[0816] 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 uL) in TEA (1 mL) was added CuI (3.32 mg, 0.017 mmol) and Pd(PPh3)2Cl2 (12.24 mg, 0.017 mmol) under N2, and the mixture was stirred at 80°C for 2 hours. 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 x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The product was analyzed by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, Rf = 0.4) to give 30a as a white solid. 1 H NMR (400MHz, CDCl3-d) δ8.31 (s, 1H), 8.15 (br d, J = 7.2Hz, 2H), 8.00 (s, 1H), 7.75 (br d,J=8.9Hz,2H),7.30-7.27(m,2H),5.65(td,J=6.8,13.4Hz,1H),1.66(d,J=6.7Hz,6H),0.31(s,9H).

[0817] 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 KCO (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 a new main spot with greater 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 product 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(400MHz, CDCl3-d)δ8.33(d,J=1.6Hz,1H),8.22-8.13(m,2H),8.06(d,J=1.5Hz,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=6.7Hz,6H).

[0818] 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 N-(4-(Chlorodifluoromethoxy)phenyl)-7-ethynyl-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (30b, 50 mg, 0.124 mmol) and 1-( To a mixture of (1 mL)-4-methoxy-benzene (22.23 mg, 0.136 mmol) in THF (1 mL) and H2O (1 mL) were added CuSO4.5H2O (1.55 mg, 6.19 umol) and sodium (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (2.45 mg, 0.012 mmol). The mixture was stirred at 20°C for 3 hours. LCMS showed the desired 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 Na2SO4, filtered and concentrated in vacuo. The product was analyzed by preparative TLC (SiO2, petroleum ether:ethyl acetate=0:1, R f =0.4) to give 30c as a yellow solid. 1 H NMR (400MHz, CDCl3-d) δ8.28(s,1H),8.20(s,1H),8.09(br s,1H),7.79-7.66(m,4H),7.32(br d,J=8.4Hz,2H),7.26-7.25(m,1H),6.95(d,J=8.4Hz,2H),5.59(s,2H),5.11-5.02(m,1H),3.84(s,3H),1.36(d,J=6.7Hz,6H).

[0819] N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide (30c). 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 x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The product was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f=0.3) to purify the residue to give 30 as an off-white solid. [M+1] + (C 20 H 17 ClF2N6O2) calculated MS mass requirement m / z 447.1, LCMS experimental value m / z 447.0; 1 H NMR (400MHz, DMSO-d6) δ10.47(s,1H),8.62(s,1H),8.48(d,J=1.3Hz,1H),8.31(br s, 1H), 7.95 (d, J = 9.0Hz, 2H), 7.85 (d, J = 1.3Hz, 1H), 7.36 (d, J = 9.0Hz, 2H), 4.63 (br s, 1H), 1.32 (d, J = 6.6Hz, 6H).

[0820] Example 31 (General Procedure M)

[0821] N-(4-(Chlorodifluoromethoxy)phenyl)-7-(4-cyano-1H-pyrazol-3-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide

[0822] The General Procedure M provides specific synthetic details as applied to the title compound. Additional compounds can be prepared according to this method by varying the coupling and / or deprotecting reagents.

[0823]

[0824] 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 uL) 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 hours. LCMS showed the desired MS. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The product was analyzed by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, R f = 0.4) to give 31a as a colorless oil.

[0825] 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(PPh3)4 (10.65 mg, 9.22 umol) under N2. 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 layers were washed with brine (5 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The product was analyzed by preparative TLC (SiO2, petroleum ether: ethyl acetate = 0: 1, R f =0.6) to purify the residue to give 31b as a yellow oil. [M+1] + (C 28 H 31 MS mass requirement calculated for ClF2N6O3Si) m / z 601.2, LCMS found m / z 601.2.

[0826] N-(4-(Chlorodifluoromethoxy)phenyl)-7-(4-cyano-1H-pyrazol-3-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (31b). 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 the desired MS. The mixture was concentrated under reduced pressure. The product was analyzed by preparative TLC (SiO 2 , petroleum ether:ethyl acetate = 0:1, R f =0.4) to purify the residue to give 31 as a yellow solid. [M+1] + (C 22 H 17 ClF2N6O2) calculated MS mass requirement m / z 471.1, LCMS experimental value m / z 471.0; 1HNMR(400MHz,DMSO-d6)δ14.16(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=9.0Hz,2H),7.91(s,1H),7.37(br d,J=8.8Hz,2H),4.39(brs,1H),1.36(br d,J=6.7Hz,6H).

[0827] Example 32

[0828] (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

[0829]

[0830] (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 methyl ester (32b). To (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) was added under N2. Pd(dppf)Cl2 (15.03 mg, 0.021 mmol), TEA (51.98 mg, 0.514 mmol, 71.50 uL), 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 to a solution of MeOH (1 mL) and DMF (3 mL). The suspension was degassed under vacuum and purged with CO2 several times. The mixture was stirred at 120 ° C for 12 hours under CO2 (2 MPa). LCMS showed that the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (10 mL), and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue. The product was analyzed by preparative TLC (SiO 2 , ethyl acetate: petroleum ether = 3:1, R f=0.3) to give the title compound 32b as a brown solid. 1 H NMR (400MHz, MeOD-d4) δ8.53-8.42(m,2H),7.88-7.81(m,2H),7.30(d,J=9.0Hz,2H),5.41(br dd,J=1.8,6.5Hz,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=6.5Hz,3H).

[0831] (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)-8-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-6-carboxylic acid methyl ester (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 hr. LCMS showed the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. H2O was added, and to the mixture was added 1 M HCl dropwise until pH = 5. The mixture was concentrated to give the crude product, which was used in the next step without purification. 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.55(d,J=1.7Hz,1H),8.38(d,J=1.7Hz,1H),7.96(d,J=9.2Hz,2H ),7.38(d,J=9.0Hz,2H),5.38-5.26(m,1H),5.16-4.90(m,2H),4.29-3.98(m,2H),1.31(d,J=6.5Hz,3H).

[0832] (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 (32c). 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 methylamine hydrochloride (31.38 mg, 0.465 mmol) in DMF (2 mL) were added HATU (53.02 mg, 0.139 umol) and DIEA (48.06 mg, 0.372 mmol, 64.77 uL). The mixture was stirred at 20° C. for 24 hr. LCMS showed that the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (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 yield a residue. The residue was analyzed by preparative TLC (SiO2, petroleum ether: ethyl acetate = 0: 1, R f =0.60) to purify the residue to afford the title compound 32 as a white solid. [M+1] + (C 21 H 19 MS mass calculated for ClF2N4O4) m / z 465.1, LCMS found m / z 465.1. 1 H NMR (400MHz, DMSO-d6) δ10.50 (s, 1H), 8.85-8.73 (m, 1H), 8.42 (d, J = 1.6Hz, 1H), 8.04-7.90 (m, 3H), 7.3 7(d,J=9.0Hz,2H),5.13-4.89(m,3H),4.18-3.95(m,2H),2.87(d,J=4.6Hz,3H),1.28(d,J=6.5Hz,3H).

[0833] Example 33 (General Procedure N)

[0834] (R)-N-(4-(Chlorodifluoromethoxy)phenyl)-3-methyl-5-(1H-pyrazol-5-yl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide

[0835] The General Procedure N provides specific synthetic details as applied to the title compound. Additional compounds can be prepared according to this method by varying the coupling reagent.

[0836]

[0837] (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 -(3-amino-5-bromo-4-((1-hydroxypropyl-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 hr. 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. 1 H 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). A batch of crude product 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 (400MHz, CDCl3-d) δ8.49(s,1H),8.02(d,J=1.3Hz,1H),7.92(d,J=1.5Hz,1H),7.79-7.72(m,2H),7.28(br s,1H),7.26(s,1H),5.37(quin,J=6.6Hz,1H),4.26(dd,J=7.2,11.1Hz,1H),4.13(q,J=7.2Hz,1H),3.46(d,J=11.0Hz,1H),1.56(d,J=6.4Hz,3H).

[0838] (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). (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-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide (33c, 20 mg, 0.042 mmol), A mixture of oxaborolan-2-yl)-1H-pyrazole (32.84 mg, 0.169 mmol), K 3 PO 4 (26.94 mg, 0.127 mmol), Pd(dppf)Cl 2 (6.19 mg, 8.46 umol) and Boc 2 O (4.62 mg, 0.021 umol, 4.86 uL) in dioxane (2 mL) and H 2 O (0.2 mL) was degassed and purged with N 2 three times. The mixture was stirred at 110° C. under N 2 atmosphere for 16 hr. LCMS showed 33c remaining. To this mixture were added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (24.63 mg, 0.127 mmol), K 3 PO 4 (17.96 mg, 0.085 mmol), and Pd(dppf)Cl 2 (6.19 mg, 8.46 umol). The mixture was stirred at 110° C. under a N 2 atmosphere for 4 hours. LCMS showed that a peak with the desired MS was detected. TLC (ethyl acetate:methanol = 10:1, R f =0.48) showed 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×3). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The product was analyzed by preparative TLC (ethyl acetate: methanol = 10: 1, R f =0.48) to give a crude product, which was purified by preparative TLC (DCM:methanol=10:1, R f =0.5) was further purified to give 33 as a white solid. [M+1] + (C 21 H 16 MS mass requirement calculated for ClF2N5O3) m / z 460.1, LCMS found m / z 460.1. 1H NMR (400MHz, MeOD-d4) δ8.00(br d,J=9.7Hz,2H),7.88-7.81(m,3H),7.29(d,J=8.8Hz,2H),6.79(br s,1H),5.29(br d,J=7.9Hz,2H),4.79(br d, J=5.7Hz, 1H), 1.00 (brd, J=4.9Hz, 3H).

[0839] Example 34 (General Procedure O)

[0840] (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

[0841] The General Procedure O provides specific synthetic details as applied to the title compound. Additional compounds can be prepared according to this method by varying the coupling and / or deprotecting reagents.

[0842]

[0843] (R)-6-bromo-4-(hydroxymethyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxylic acid methyl ester (34b). A solution of (R)-4-((benzyloxy)methyl)-6-bromo-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxylic acid methyl ester (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 hours. LCMS showed the desired MS. The mixture was concentrated to give 34b as a yellow oil. [M+1] + (C 13 H 13 MS mass calculated for (BrN2O4) m / z 341.0, LCMS found m / z 341.0.

[0844] (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)-6-bromo-4-(hydroxymethyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxylic acid methyl ester (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 hour. 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 (400MHz, DMSO-d6) δ8.12(s,1H),7.95(d,J=1.2Hz,1H),5.45-5.36(m,1H),5.13-5.05(m,1H),4.97-4.88(m,1H),4.38(d,J=12.1Hz,1H),4.02(br d, J=11.9Hz, 1H), 3.90 (br d,J=10.1Hz, 1H), 3.67 (dt, J=5.9, 10.1Hz, 1H).

[0845] (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 hours. LCMS showed the 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 layers were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The product was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 100:1 to 0:1, R f =0.4) to purify the residue to give 34d as a white solid. [M+1] + (C 19 H15 BrClF2N3O4) calculated mass requirement m / z 502.0, LCMS found m / z 502.0; 1 H NMR (400MHz, CDCl3-d) δ8.10(brs,1H),8.04(d,J=1.3Hz,1H),7.98(d,J=1.3Hz,1H),7.72(d,J=9.0Hz,2H),7.28(s,2H),5.16(d,J=16 .5Hz,1H),5.12-5.06(m,1H),4.94(d,J=16.3Hz,1H),4.57(d,J=12.3Hz,1H),4.22(dd,J=2.8,10.5Hz,1H),4.15-4.08(m,2H),2.27(br s,1H).

[0846] (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 (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 under N2 To a mixture of (34d, 0.5 g, 0.995 mmol) and pyrimidin-5-ylboronic acid (369.72 mg, 2.98 mmol) in dioxane (5 mL) and H2O (0.5 mL) were added K3PO4 (422.27 mg, 1.99 mmol), Pd(dppf)Cl2 (72.78 mg, 0.099 mmol), (Boc)2O (217.08 mg, 0.995 mmol, 228.51 uL). The mixture was stirred at 110 ° C for 16 hours. LCMS showed the desired MS. The mixture was filtered and concentrated. The product was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 100: 1 to 0: 1, R f =0.3) to purify the residue to give 34 as a yellow solid. [M+1] + (C 22 H 18 ClF2N5O4) calculated mass requirement m / z 490.1, LCMS found m / z 490.1; 1H NMR (400MHz, MeOD-d4) δ8.29(br s,1H),7.95(s,1H),7.84(br d,J=8.6Hz,3H),7.30(br d,J=8.8Hz,2H),6.71(br s,1H),5.17-4.93(m,2H),4.37(br d,J=12.2Hz,1H),4.08(br d,J=11.0Hz,1H),3.60(s,1H),3.53-3.40(m,2H).

[0847] Example 35

[0848] (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

[0849]

[0850] (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 N2. The mixture was stirred at 25°C for 8 hours. LCMS showed the desired MS. The product was analyzed by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f =0.6) to purify the crude product to give 35a as a white solid. [M+1] + (C 19 H 14 MS mass requirement calculated for (BrClF3N3O3) m / z 504.0, LCMS found m / z 504.0.

[0851] (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 (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 m To a mixture of 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 H₂O (0.2 mL) were added (Boc)₂O (4.32 mg, 0.02 mmol, 4.55 uL), Pd(dppf)Cl₂ (1.45 mg, 1.98 umol), and K₃PO₄ (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 Cromosel C18 100*30mm 5um; mobile phase: [water (0.1% TFA)-ACN]; B%: 36%-53%, 10 min) to give 35 as a white solid. [M+1] + (C 22 H 17 ClF3N5O3) calculated MS mass requirement m / z 492.1, LCMS experimental value m / z 492.1; 1 H NMR (400MHz, CDCl3-d) δ8.21(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=16.1Hz,1H),5.05-4.92(m,1H),4.49-4.27(m,2H),4.17-3.98(m,2H).

[0852] Example 36

[0853] (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

[0854]

[0855] (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) and azetidin-3-ol (36a, 15.02 mg, 0.205 mmol) in THF (0.8 mL) under N2 was added BrettPhos Pd G3 (3.73 mg, 4.11 umol) and t-BuONa (2 M, 41.09 uL). The mixture was stirred at 100°C in a sealed tube for 16 hours. 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 results were analyzed by preparative TLC (ethyl acetate:methanol=10:1, R f =0.47) and further purified by preparative HPLC (column: Waters X-bridge 150*25 5u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 25%-55%, 7 min) to afford 36 as a white solid. [M+1] + (C 22 H 21 ClF2N4O4) calculated MS mass requirement m / z 479.1, LCMS experimental value m / z 479.1; 1 H NMR(400MHz,MeOD-d4)δ7.91(d,J=1.3Hz,1H),7.86-7.81(m,2H),7.54(d,J=1.3Hz,1 H),7.30(d,J=9.0Hz,2H),5.05-4.99(m,2H),4.95(s,1H),4.72-4.65(m,1H),4.36(br t,J=6.5Hz,1H),4.22(dd,J=3.3,12.0Hz,1H),4.10-4.04(m,2H),4.02-3.96(m,1H),3.54(t,J=6.3Hz,1H),1.56(d,J=6.4Hz,3H).

[0856] Example 37

[0857] N-(4-(Chlorodifluoromethoxy)phenyl)-9-(1H-pyrazol-5-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide

[0858]

[0859] 9-Bromo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (37b). To a solution of 3-amino-5-bromo-4-(piperidin-1-yl)benzoic acid methyl ester (synthesized in a manner similar to 1d; 37a, 160 mg, 0.511 mmol) in formic acid (3 mL) was added H2O2 (521.32 mg, 4.60 mmol, 441.79 uL, 30% purity). The mixture was heated at reflux temperature for 40 min. LCMS showed complete consumption of 37a and the detection of a major peak of the desired mass. TLC (petroleum ether:ethyl acetate = 2:1, R f =0.20) indicated that the reactant was completely consumed and a new spot was formed. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL). The organic layer was washed with saturated NaHCO3 aqueous solution (10 mL×3), dried over Na2SO4, filtered and concentrated. By preparative TLC (petroleum ether: ethyl acetate = 2:1, R f =0.20) to afford 37b as a white solid. 1 H NMR(400MHz, CDCl3-d)δ8.24-8.18(m,1H),8.00(d,J=1.3Hz,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).

[0860] 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 hr. LCMS showed that 37b was completely consumed and a major peak with the desired mass was detected. The mixture was concentrated to remove THF and MeOH. 1M HCl in water 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 afford 37 as a white solid.1 H NMR (400MHz, CDCl3-d) δ8.34 (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).

[0861] 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) were added HATU (72.66 mg, 0.191 mmol), DIEA (61.75 mg, 0.478 mmol, 83.22 uL), and 4-(chlorodifluoromethoxy)aniline (1h, 61.66 mg, 0.319 umol). The mixture was stirred at 15° C. for 16 hr. LCMS showed complete consumption of 37c and the detection of a major peak of the desired mass. TLC (ethyl acetate:methanol = 10:1, R f =0.36) indicated that 37c was completely consumed and a new spot was formed. H2O (20 mL) was added to the mixture. The mixture was extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The product was analyzed by preparative TLC (ethyl acetate:methanol=10:1, R f =0.36) to afford 37d as a white oil. 1 H NMR(400MHz, CDCl3-d)δ8.01(d,J=1.5Hz,1H),7.96(d,J=1.5Hz,1H),7.75-7.67(m,2H),7.15(d, J=8.8Hz,2H),4.60(t,J=6.2Hz,2H),3.02(t,J=6.5Hz,2H),2.09-2.04(m,2H),1.97-1.88(m,2H).

[0862] N-(4-(chlorodifluoromethoxy)phenyl)-9-(1H-pyrazol-5-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide (37). 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) A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (24.73 mg, 0.127 mmol), Pd(dppf)Cl2 (3.11 mg, 4.25 umol) and K3PO4 (27.06 mg, 0.127 mmol) in dioxane (1 mL) and H2O (0.1 mL) was degassed and purged with N2 three times. The mixture was stirred at 110°C under N2 atmosphere for 16 hours. LCMS showed complete consumption of 37d and a major peak with the desired mass was detected. TLC (dichloromethane:methanol=10:1, R f =0.44) indicated that 37d was completely consumed and a new spot was formed. The mixture was concentrated and H2O (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The product was analyzed by preparative TLC (dichloromethane:methanol=10:1, R f =0.30) to purify the crude product to afford 37 as a white solid. [M+1] + (C 22 H 18 ClF2N5O2) calculated MS mass requirement m / z 458.1, LCMS experimental value m / z 458.1; 1 H NMR (400MHz, MeOD-d4) δ8.26-8.23(m,1H),7.86-7.81(m,4H),7.29(d,2H,J=9.0Hz),6.62(s,1H),3.86(br s,2H),3.12(br t,2H,J=6.1Hz),1.99(br s,4H).

[0863] Example 38 (General Procedure P)

[0864] (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

[0865] The title compound was prepared according to Schematic Scheme 10. The General Procedure P illustrates Schematic Scheme 10 and provides specific synthetic details as applied to the title compound.

[0866]

[0867] (R)-9-bromo-2-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (39b) and (R)-9-bromo-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (38c). A solution of methyl (R)-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 slowly added portionwise to the reaction mixture over 32 hours. TLC (ethyl acetate:methanol = 10:1, R f =0.37) shows that two new spots are generated. LCMS shows that two peaks with required MS are detected. The reaction mixture is filtered, and the filtrate is distributed between ethyl acetate (50mL) and H2O (50mL). The separated organic layer is washed with water (50mL×3), and then washed with saturated NaHCO3 aqueous solution (30mL×3), dried over Na2SO4 and evaporated to dryness. 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). By preparative TLC (ethyl acetate: methanol = 10: 1, R f =0.37) to give 38c as a yellow solid. 1 HNMR(400MHz,MeOD-d4)δ8.27(d,J=0.9Hz,1H),8.07(d,J=1.1Hz,1H),4.97( t,J=5.4Hz,1H),4.79-4.70(m,1H),4.65-4.52(m,1H),3.94(s,3H),2.38(br dd,J=6.8,13.5Hz,1H),2.26-2.04(m,3H).

[0868] (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)-9-bromo-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (38c, 25 mg, 0.077 mmol) in MeOH (1 mL), H2O (1 mL), and THF (1 mL) was added LiOH.H2O (6.45 mg, 0.154 mmol). The mixture was stirred at 50°C for 2 hours. TLC (ethyl acetate:methanol = 10:1, R f =0.0) showed the formation of a new spot. The mixture was concentrated to remove the solvent. 1 M HCl was added dropwise to the reaction mixture until pH = 5. The mixture was concentrated and the crude product was used in the next step without further purification.

[0869] (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) were added HATU (54.99 mg, 0.145 mmol), DIEA (124.62 mg, 0.964 mmol, 167.95 uL), 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) indicates the generation of a new spot. LCMS shows that a peak with the desired MS is detected. The mixture is quenched with water (20 mL) and the mixture is extracted with ethyl acetate (30 mL×3). The combined organic layer is washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. By preparative TLC (ethyl acetate: methanol = 10: 1, R f =0.3) to give 38e as a yellow solid.

[0870] (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). (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. A mixture of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (17.94 mg, 0.092 mmol), Pd(dppf)Cl2 (4.51 mg, 6.16 umol), and K3PO4 (19.63 mg, 0.092 mmol) in dioxane (2 mL) and H2O (0.2 mL) was degassed and purged with N2 three times. The mixture was stirred at 120°C under N2 atmosphere for 16 hr. 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 yield 38 as a white solid. [M+1] + (C 22 H 18 ClF2N5O2) calculated mass requirement m / z 474.1, LCMS found m / z 474.1; 1 H NMR(400MHz,MeOD-d4)δ8.34(s,1H),7.88(d,J=1.6Hz,1H),7.87-7.82(m,3H),7.29(d, J=8.9Hz,2H),6.62(d,J=2.1Hz,1H),5.01(t,J=5.1Hz,1H),3.95-3.76(m,2H),2.19(br d,J=6.7Hz,2H),2.07-1.88(m,2H).

[0871] Example 39 (General Procedure Q)

[0872] (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

[0873] The General Procedure Q provides specific synthetic details as applied to the title compound. Additional compounds can be prepared according to this method by varying the coupling reagent.

[0874]

[0875] (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, 0.4 To the product was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (939.17 mg, 3.70 mmol), Pd(OAc)2(9.23 mg, 0.041 mmol), XPhos (48.97 mg, 0.103 mmol) and K3PO4 (261.68 mg, 1.23 mmol) in dioxane (6.2 mL) degassed and purged with N2 three times. The mixture was stirred at 60 ° C under N2 atmosphere in a microwave for 16 hr. LCMS showed that the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 0: 1) to give 39a as a white solid.

[0876] (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). (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 A mixture of 39a (5 mg, 9.37 umol), 2-bromopyridin-4-ol (2.44 mg, 0.014 mmol), Pd(dppf)Cl2 (685.43 ug, 9.37 umol), Na2CO3 (2.98 mg, 0.028 mmol) in DME (0.5 mL) and H2O (0.1 mL) was degassed and purged with N2 three times. The mixture was stirred at 120 ° C. under N2 atmosphere in a microwave reactor for 1 hr. LCMS showed complete consumption of 39a 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 (10mMNH4HCO3)-ACN]; B%: 25%-55%, 10min) to obtain 39 as a white solid. [M+1] + (C 24 H 19 ClF2N4O4) calculated MS mass requirement m / z 501.1, LCMS experimental value m / z 501.1; 1 H NMR (400MHz, MeOD-d4) δ8.41(d,J=1.5Hz,1H),8.03(br d,J=6.8Hz,1H),7.96(d,J=1.5Hz,1H),7.88-7.81(m,2H),7.29(d,J=8.8Hz,2H),6.79(br s,1H),6.68(br d,J=6.8Hz,1H),5.15-4.96(m,2H),4.46(br s,1H),4.13(br d,J=3.1Hz,1H),3.99(d,J=12.3Hz,1H),1.14(d,J=6.6Hz,3H).

[0877] Example 40 (General Procedure R)

[0878] (S)-N-(4-(Chlorodifluoromethoxy)phenyl)-2-(1-hydroxyethyl)-1-isopropyl-7-(1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide

[0879] The General Procedure R provides specific synthetic details as applied to the title compound. Additional compounds can be prepared according to this method by varying the coupling reagent.

[0880]

[0881] (S)-3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-5-(2-hydroxypropionamido)-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 uL), (2S)-2-hydroxypropanoic acid (140.53 mg, 1.56 mmol, 116.14 uL), and 2-chloro-1,3-dimethylimidazolinium chloride (158.24 mg, 0.936 mmol). The mixture was stirred at 15°C for 4 hr. TLC (petroleum ether:ethyl acetate = 1:1, R f =0.45) indicated that 9a was completely consumed and a new major spot with greater polarity was detected. The desired MS was detected by LCMS. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 1:1) to obtain 40b as a white solid. 1 H NMR(400MHz,MeOD-d4)δ8.53(d,J=2.4Hz,1H),7.99(d,J=2.0Hz,1H),7.83-7.80(m,2H),7.30(br d, J=9.3Hz, 2H), 4.34 (q, J=6.8Hz, 1H), 3.56 (td, J=6.4, 12.7Hz, 1H), 1.49 (d, J=6.8Hz, 3H), 1.24 (d, J=6.4Hz, 6H).

[0882] (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-hydroxypropionamido)-4-(isopropylamino)benzamide (40a, 40 mg, 0.077 mmol) in toluene (1 mL) was added 4-toluenesulfonic 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 and a new major spot with greater polarity was detected. The desired MS was detected by LCMS. The residue was diluted with H2O (20 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate=1:1) to afford 40b as a white solid. 1 H NMR (400MHz, MeOD-d4) δ8.29(s,1H),8.14(br s,1H),7.86(d,J=9.3Hz,2H),7.32(br d,J=9.3Hz,2H),4.92-4.92(m,1H),4.87-4.86(m,1H),1.91(br s, 3H), 1.76 (br d, J = 6.4Hz, 6H).

[0883] (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-dioxaborolane) A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11.58 mg, 0.06 mmol), K PO (12.67 mg, 0.06 mmol), Pd(dppf)Cl (1.46 mg, 1.99 umol), 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 H 0 (0.1 mL) was degassed and purged with N 3 times. The mixture was stirred at 115° C. under a N atmosphere for 4 hr. TLC (ethyl acetate:methanol=20:1, R f=0.24) indicated that 40b was completely consumed, and a new main spot with greater polarity was detected. The desired MS was detected by LCMS. 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 produce a residue. The residue was purified by preparative TLC (ethyl acetate: methanol = 20: 1) to obtain 40 as a white solid. [M+1] + (C 23 H 22 ClF2N5O3) calculated mass requirement m / z 490.1, LCMS found m / z 490.1; 1 H NMR (400MHz, MeOD-d4) δ8.34(br s,1H),7.92-7.79(m,4H),7.29(d,J=9.3Hz,2H),6.61(d,J=2.0Hz,1H),5.29(q,J=6.0Hz,1H),4.76(br s, 1H), 1.73 (d, J = 6.4Hz, 3H), 1.45 (dd, J = 7.1, 12.0Hz, 6H).

[0884] Example 41

[0885] (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

[0886]

[0887] (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). (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) was added. A mixture of 4-nitro-1-oxo-2-nitropropane (5-nitro-1-oxo-2-nitropropane) (438.39 mg, 6.16 mmol, 514.54 uL), (Bu4NCuI2)2 (23.00 mg, 0.021 mmol), Cs2CO3 (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 N2 three times. The mixture was stirred at 120 ° C under N2 atmosphere for 16 hr. LCMS showed that the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO2, ethyl acetate: methanol = 20: 1) to give 41 as a white solid. [M+1] + (C 23 H 23 ClF2N4O3) calculated mass requirement m / z 477.1, LCMS found m / z 477.1. 1 H NMR (400MHz, CDCl3-d)8.61(s,1H),7.74(d,J=9.0Hz,2H),7.25(s,1H),7.22(d,J=6.6Hz,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=6.6Hz,3H).

[0888] Example 42 (General Procedure S)

[0889] (R)-N-(4-(Chlorodifluoromethoxy)phenyl)-3-methyl-5-(pyridazin-3-yl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide

[0890] The General Procedure S provides specific synthetic details as applied to the title compound. Additional compounds can be prepared according to this method by varying the coupling reagent.

[0891]

[0892] (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 N2 three times, and then the mixture was stirred at 15°C under N2 atmosphere for 2 hr. TLC (petroleum ether:ethyl acetate=3:1, R f =0.5) showed the formation of a new spot. LCMS showed that a peak with the desired MS was detected. 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 produce 42a as a yellow oil. 1 H NMR (400MHz, CDCl3-d) δ7.69(br s,1H),7.66(d,J=9.0Hz,2H),7.37(d,J=1.8Hz,1H),7.25(br d,J=8.8Hz,2H),7.14(d,J=1.8Hz,1H),4.31(br s, 2H), 3.78-3.66 (m, 2H), 3.62-3.50 (m, 2H), 1.15 (d, J = 6.2Hz, 3H), 0.94 (s, 9H), 0.11 (s, 6H).

[0893]

[0146] (R)-7-Bromo-1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-2-thione-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 at 60°C under N atmosphere for 16 hr. TLC (petroleum ether:ethyl acetate=2:1, R f=0.54) indicated the formation of a new spot. LCMS showed that a peak with the desired MS was detected. 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=8:1-2:1) to produce 42b as a yellow solid. 1 H NMR (400MHz, CDCl3-d) δ11.21(s,1H),7.96(s,1H),7.86(d,J=1.1Hz,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=9.6Hz,1H),3.95(dd,J=5.1,10.4Hz,1H),1.86(d,J=7.1Hz,3H),0.68(s,9H),0.00(s,3H),-0.12(s,3H).

[0894] (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-thione-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 uL) and KCO (1.07 g, 7.73 mmol). The mixture was stirred at 15° C. for 2 hr. TLC (petroleum ether:ethyl acetate = 2:1, R f =0.72) indicated the formation of a new spot. LCMS showed that a peak with the desired MS was detected. 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 Na 2 SO 4 , 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 yield 42c as a yellow oil. 1H NMR (400MHz, CDCl3-d) δ8.03(d,J=1.6Hz,1H),7.97(d,J=1.6Hz,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=9.2,10.4Hz,1H),3.89(dd,J=5.7,10.6Hz,1H),2.83(s,3H),1.67(d,J=7.3Hz,3H),0.67(s,9H),-0.04(s,3H),-0.18(s,3H)

[0895] (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 hr. TLC (petroleum ether:ethyl acetate = 0:1, R f =0.65) showed 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 produce 42d as a yellow solid. 1 H NMR (400MHz, CDCl3-d) δ8.63(s,1H),7.87(d,J=9.0Hz,2H),7.62(d,J=1.7Hz,2H),7.31(d,J=8.8Hz,2H),6.14(ddd,J= 4.6, 7.4, 10.0Hz, 1H), 4.59 (dd, J = 10.0, 12.7Hz, 1H), 3.91 (dd, J = 4.4, 12.8Hz, 1H), 2.84 (s, 3H), 1.59 (d, J = 7.3Hz, 3H).

[0896] (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 umol) 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 at 0-15°C under O2 for 6 hr. TLC (petroleum ether:ethyl acetate = 1:2, R f =0.5) showed the formation of a new spot. LCMS showed that a peak with the desired MS was detected. 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 yield 42e as a white solid. 1 HNMR(400MHz, CDCl3-d)δ8.24(s,1H),7.90(dd,J=1.3,15.9Hz,2H),7.74(d,J=9.0Hz,2H),7.25 (s,1H),5.29-5.19(m,1H),5.09-4.98(m,1H),4.78(dd,J=2.2,8.6Hz,1H),1.69(d,J=6.4Hz,3H)

[0897] A mixture of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-3-methyl-5-(pyridazin-3-yl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide (42e, 25 mg, 52.89 umol), tributyl(pyridazin-3-yl)stannane (39.05 mg, 105.78 umol, 2 eq), tri-tert-butylphosphane palladium (2.70 mg, 5.29 umol, 0.1 eq) in dioxane (2 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 110 °C under N2 for 16 hr. TLC (ethyl acetate:methanol=10:1, R f=0.31) showed that a new spot was generated. LCMS showed that a peak with the desired MS was detected. 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 layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. By preparative TLC (ethyl acetate: methanol = 10: 1, R f =0.31) to give a crude product, which was further purified by preparative HPLC (column: Luna C18 100*305u; mobile phase: [water (0.225% FA)-ACN]; B%: 20%-70%, 12 min.) to give 42 as a light yellow solid. [M+1] + (C 22 H 16 ClF2N5O3) calculated MS mass requirement m / z 472.1, LCMS experimental value m / z 472.0; 1 H NMR (400MHz, MeOD-d4) δ9.28(dd,J=1.5,4.9Hz,1H),8.33(dd,J=1.5,8.6Hz,1H),8.21-8.17(m,1H),8.16(d,J=1.6Hz,1H),7.95(dd ,J=5.0,8.6Hz,1H),7.88-7.84(m,2H),7.31(d,J=9.0Hz,2H),5.39-5.26(m,2H),4.83(dd,J=2.8,8.4Hz,1H),0.94(d,J=6.4Hz,3H).

[0898] Example 43 (General Procedure T)

[0899] (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

[0900] The General Procedure T provides specific synthetic details as applied to the title compound. Additional compounds can be prepared according to this method by varying the coupling reagent.

[0901]

[0902] (S)-3-amino-5-bromo-4-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)benzoic acid methyl ester (43b). To a mixture of (S)-3-amino-5-bromo-4-(3-hydroxypiperidin-1-yl)benzoic acid methyl ester (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) was added TBSCl (666.18 mg, 4.42 mmol) and DMAP (36.00 mg, 0.295 mmol) in one portion at 20°C under N2. The mixture was stirred at 20°C for 12 hours. TLC (petroleum ether:ethyl acetate = 3:1, R f =0.7) indicated complete consumption of 43a and the formation of a new spot. The mixture was washed with water (8 mL x 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.

[0903] (S)-9-bromo-2-((tert-butyldimethylsilyl)oxy)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (43c). To a solution of (S)-3-amino-5-bromo-4-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)benzoic acid methyl ester (43b, 1.18 g, 2.66 mmol) in 2,2,2-trifluoroethanol (10 mL) at 20°C under N2 was added iridium chloride; (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 hours. LCMS showed complete consumption of 43b and the detection of a major peak of the desired mass. TLC (petroleum ether:ethyl acetate = 1:1, R f =0.4) indicated complete consumption of 43b and the formation of a new spot. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 2 / 1) to give 43c as a yellow oil. 1 H NMR(400MHz, CDCl3-d)δ8.30(s,1H),8.08(s,1H),4.69-4.57(m,2H),4.46(br d,J=3.9Hz,1H),4.15-4.06(m,1H),3.95(s,3H),3.41-3.29(m,1H),3.12-3.07(m,1H),2.13-2.09(m,1H),0.88(s,9H),0.15(br d,J=6.4Hz,6H).

[0904] (S)-9-bromo-2-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (43d). To a solution of (S)-9-bromo-2-((tert-butyldimethylsilyl)oxy)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (43c, 550 mg, 1.25 mmol) in THF (10 mL) was added TBAF (1 M, 1.38 mL) in one portion at 20°C. The mixture was stirred at 20°C for 30 min. TLC (ethyl acetate:methanol = 10:1) indicated complete consumption of 43c and the formation of a new spot. The mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (20 mL), washed with water (7 mL×3) and brine (5 mL), dried over Na 2 SO 4 , filtered and concentrated to give 43d as a yellow oil, which was used in the next step without further purification. 1 H NMR(400MHz, DMSO-d6)δ8.09(d,J=1.3Hz,1H),7.90(d,J=1.5Hz,1H),5.34(d,J=3.4Hz,1H), 4.57(d,J=3.9Hz,2H),4.37-4.28(m,1H),3.87(s,3H),3.18-2.96(m,2H),2.04-1.99(m,2H).

[0905] (S)-9-Bromo-2-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylic acid (43e). To a solution of (S)-9-bromo-2-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (43d, 320 mg, 0.984 mmol) in THF (5 mL) and H2O (2 mL) was added LiOH.H2O (61.95 mg, 1.48 mmol) in one portion at 20°C. The mixture was stirred at 20°C for 16 hours. LCMS showed complete consumption of 43d and a major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was dissolved in H2O (1 mL) and the pH was adjusted to 4-5 by HCl (1 M). The mixture was filtered and the filter cake was washed with H2O (0.5 mL) to give 43e as a white solid, which was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ8.05(s,1H),7.88(s,1H),5.41-5.28(m,1H),4.56(br s,2H),4.38-4.25(m,1H),3.16-2.91(m,2H),1.99(br s,2H).

[0906] (S)-9-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide (43f). To a mixture of (S)-9-bromo-2-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylic acid (43e, 280 mg, 899.94 umol) and HATU (376.40 mg, 989.93 umol) in DMF (3 mL) were added 4-(chlorodifluorometho...

Claims

1. A compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt thereof, in: L is -NHC(O)-; X is -O-; Y is CH; Z is CR 5 ; R 1 It is C(O)NR 6 R 7 , 4-10 membered heterocyclyl or 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, C 1- C6 alkyl, OH, OC1-C6 alkyl and C3-C6 cycloalkyl; R 2 is H, C1-C6 alkyl, C3-C8 cycloalkyl or 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of oxo, halo, CN, C1-C6 alkyl, C(O)NHC1-C6 alkyl, C(O)NHC3-C6 cycloalkyl, OH, OC1-C6 alkyl, C3-C6 cycloalkyl and 4-6 membered heterocyclyl; R 3 is H, C1-C6 alkyl, OR 6 , C3-C8 cycloalkyl or 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C1-C6 alkyl and OH; or R 2 and R 3 and the intervening atoms to which it is attached form a 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: oxo, C 1- C6 alkyl, C 1- C6 haloalkyl, C1-C6 alkyl-OH, C(O)C1-C6 alkyl and OH; R 4 is C1-C6 alkyl, said C1-C6 alkyl being optionally substituted with 1, 2 or 3 independently selected halogen substituents; R 5 is H or a halogen; R 6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-10 membered heterocycloalkyl, wherein said C1-C6 alkyl, C3-C8 cycloalkyl, or 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, C1-C6 alkyl, and OH; and R 7 is H, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-10 membered heterocycloalkyl, wherein said C1-C6 alkyl, C3-C8 cycloalkyl, or 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, C1-C6 alkyl, and OH; or R 6 and R 7 Together with the nitrogen to which it is attached, it forms a 4-7 membered heterocyclyl, wherein the 4-7 membered heterocyclyl is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C1-C6 alkyl and OH.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IA-1): in: R 1 It is C(O)NR 6 R 7 , a 4-6 membered heterocyclyl having 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, or a 5-6 membered heteroaryl having 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, C 1- C6 alkyl, OH, OC1-C6 alkyl and C3-C6 cycloalkyl; R 2 is H, C1-C6 alkyl, C3-C8 cycloalkyl or 4-10 membered heterocycloalkyl, wherein said C1-C6 alkyl, C3-C8 cycloalkyl or 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of oxo, halo, CN, C1-C6 alkyl, C(O)NHC1-C6 alkyl, C(O)NHC3-C6 cycloalkyl, OH, OC1-C6 alkyl, C3-C6 cycloalkyl and 4 to 6 membered heterocyclyl; R 3 H, C1-C6 alkyl, OR 6 , C3-C6 cycloalkyl or 4 to 6 membered heterocycloalkyl, wherein said C1-C6 alkyl, C3-C6 cycloalkyl or 4 to 6 membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: halo, C1-C6 alkyl and OH; or R 2 and R 3 and the intervening atoms to which it is attached form a 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: oxo, C 1- C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C(O)C1-C6 alkyl and OH; R 4 is C1-C6 alkyl, said C1-C6 alkyl being optionally substituted with 1, 2 or 3 independently selected halogen substituents; R 5 It is H; R 6 is H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C1-C6 alkyl and OH; and R 7 is H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C1-C6 alkyl and OH; or R 6 and R 7 Together with the nitrogen to which it is attached, it forms a 4-7 membered heterocyclyl, wherein the 4-7 membered heterocyclyl is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C1-C6 alkyl and OH.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIC):

4. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IID): in: R 10 is a 5-6 membered heteroaryl having 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, C1-C6 alkyl, OH, OC1-C6 alkyl and C3-C6 cycloalkyl; R 20 is a C1-C3 alkyl group, a C3-C4 cycloalkyl group or a 4-6 membered heterocycloalkyl group, wherein the C1-C3 alkyl group, the C3-C4 cycloalkyl group and the 4-6 membered heterocycloalkyl group are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of oxo, halo, CN, C1-C6 alkyl group, C(O)NHC1-C6 alkyl group, C(O)NHC3-C6 cycloalkyl group, OH, OC1-C6 alkyl group, C3-C6 cycloalkyl group and 4 to 6 membered heterocyclyl group.

5. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIE): in: R 10 is a 5-6 membered heteroaryl having 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, C1-C6 alkyl, OH, OC1-C6 alkyl and C3-C6 cycloalkyl; R 20 is C1-C3 alkyl, C3-C4 cycloalkyl or 4-6 membered heterocycloalkyl, wherein said C1-C3 alkyl, C3-C4 cycloalkyl and 4-6 membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of oxo, halo, CN, C1-C6 alkyl, C(O)NHC1-C6 alkyl, C(O)NHC3-C6 cycloalkyl, OH, OC1-C6 alkyl, C3-C6 cycloalkyl and 4 to 6 membered heterocyclyl; R 30 is H, C1-C3 alkyl, C3-C4 cycloalkyl or 5-6 membered heterocycloalkyl, wherein said C1-C3 alkyl, C3-C4 cycloalkyl or 5-6 membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C1-C6 alkyl and OH.

6. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIG): in: Ring A is a 5-6 membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of oxo, C1-C6 alkyl, C1-C6 alkyl-OH, C(O)C1-C6 alkyl and OH.

7. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIH): in: R 10 is a 5-6 membered heteroaryl having 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, C1-C6 alkyl, OH, OC1-C6 alkyl and C3-C6 cycloalkyl; and Ring A is a 5-6 membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of oxo, C1-C6 alkyl, C1-C6 alkyl-OH, C(O)C1-C6 alkyl and OH.

8. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 30 is C1-C3 alkyl, C3-C4 cycloalkyl or 5-6 membered heterocycloalkyl, wherein said C1-C3 alkyl, C3-C4 cycloalkyl or 5-6 membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C1-C6 alkyl and OH.

9. The compound according to claim 3 or 6 or a pharmaceutically acceptable salt thereof, wherein R 1 is a 5-6 membered heterocyclyl having 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen or a 5-6 membered heteroaryl having 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, wherein the 5-6 membered heterocyclyl having 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen and the 5-6 membered heteroaryl having 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, C1-C6 alkyl, OH, OC1-C6 alkyl and C3-C6 cycloalkyl.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)NH2, C(O)NHCH3, C(O)NH(cyclopropyl), 11. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 1 is pyrazolyl or pyrimidinyl, wherein the pyrazolyl and pyrimidinyl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, C 1- C6 alkyl, OH, OC1-C6 alkyl and C3-C6 cycloalkyl.

12. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 It is a C1-C3 alkyl group or a C3-C4 cycloalkyl group, wherein the C1-C3 alkyl group and the C3-C4 cycloalkyl group are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of an oxo group, a halo group, a CN, a C1-C6 alkyl group, a C(O)NHC1-C6 alkyl group, a C(O)NHC3-C6 cycloalkyl group, an OH group, an OC1-C6 alkyl group, a C3-C6 cycloalkyl group and a 4- to 6-membered heterocyclyl group.

13. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 is CH3, CH2CH3, CH(CH3)2, C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl, 14. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 3 It is H, CH3, CHF2, CH2OH, CH2CH2OH, CH(CH3)OH, CH(CH3)2, C(CH3)2OH, OCH3, OCH2CH3, cyclopropyl, cyclobutyl or tetrahydropyranyl.

15. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Together they form:

16. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 4 is C1-C3 alkyl, optionally substituted with 1, 2 or 3 independently selected halogen substituents.

17. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 4 It is CF3 or CF2Cl.

18. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (Id) or Formula (Ie):

19. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 1 is a 4-6 membered heterocyclyl having 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, a C6-C 10 aryl or 5-6 membered heteroaryl having 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, C 1- C6 alkyl, OH, OC1-C6 alkyl and C3-C6 cycloalkyl; R 2 is C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocycloalkyl having 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen, wherein said C1-C6 alkyl, C3-C6 cycloalkyl, and 4-6 membered heterocycloalkyl having 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, CN, C1-C6 alkyl, C(O)NHC1-C6 alkyl, C(O)NHC3-C6 cycloalkyl, OH, OC1-C6 alkyl, C3-C6 cycloalkyl, and 4 to 6 membered heterocyclyl; R 3 is C1-C6 alkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocycloalkyl having 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen, wherein said C1-C6 alkyl, C3-C6 cycloalkyl, and 4- to 6-membered heterocycloalkyl having 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, C1-C6 alkyl, and OH; or R 2 and R 3 and the intervening atoms to which it is attached form a 4-10 membered heterocycloalkyl having 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, wherein the 4-10 membered heterocycloalkyl having 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of oxo, C 1- C6 alkyl, C1-C6 alkyl-OH, C(O)C1-C6 alkyl and OH; R 4 is C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1, 2 or 3 independently selected halogen substituents; R 6 is C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C1-C6 alkyl and OH; and R 7 is C1-C6 alkyl, wherein each of the C1-C6 alkyl groups is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C1-C6 alkyl and OH; or R 6 and R 7 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclyl having 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, wherein the 4-7 membered heterocyclyl having 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C1-C6 alkyl and OH.

20. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

21. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for preparing a medicament for inhibiting tyrosine kinase activity in a cell, wherein the tyrosine kinase is selected from the group consisting of: Abelson homolog 1, Abelson homolog 2 and breakpoint cluster region-Abelson homolog 1, and the medicament is specifically used for treating leukemia.

22. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting tyrosine kinase activity in a patient, wherein the tyrosine kinase is selected from the group consisting of: Abelson protein, Abelson-related protein and breakpoint cluster region-Abelson protein, and the medicament is specifically used to treat leukemia.

23. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating leukemia in a patient, wherein the leukemia is selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia and chronic myeloid leukemia.

24. The use according to claim 23, wherein: (a) the leukemia is selected from the group consisting of acute lymphoblastic leukemia and chronic myeloid leukemia; and (b) further comprising administering to said patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of bafitinib, bosutinib, dasatinib, imatinib, nilotinib and ponatinib.

25. The use according to claim 23, wherein the chronic myeloid leukemia is resistant to standard of care treatment.

26. The use according to claim 23, wherein the chronic myeloid leukemia is resistant to treatment with a compound selected from the group consisting of dasatinib, imatinib and nilotinib, or a combination thereof.

27. The use according to claim 23, wherein the acute myeloid leukemia is secondary acute myeloid leukemia that develops after myelodysplastic syndrome or myeloproliferative neoplasm.

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