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WO2024220866A1 - Novel aminopyrimidine derivatives as cyclin-dependent kinase inhibitors - Google Patents

Novel aminopyrimidine derivatives as cyclin-dependent kinase inhibitors Download PDF

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Publication number
WO2024220866A1
WO2024220866A1 PCT/US2024/025495 US2024025495W WO2024220866A1 WO 2024220866 A1 WO2024220866 A1 WO 2024220866A1 US 2024025495 W US2024025495 W US 2024025495W WO 2024220866 A1 WO2024220866 A1 WO 2024220866A1
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Prior art keywords
cancer
fluoro
mmol
alkyl
isopropyl
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French (fr)
Inventor
Xiangzhu Wang
Jie Su
Jie Fan
Yimin Qian
Wei He
Robert Luo
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Accutar Biotechnology Inc
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Accutar Biotechnology Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • CDKs Cyclin-Dependent Kinases
  • CDKs are a family of protein kinases that participate in regulating a wide range of physiological processes. For instance, CDKs have been identified as regulators of the cell cycle, mRNA processing, and differentiation of nerve cells.
  • CDK inhibitors have been shown to be useful in treating cancer. Increased activity or temporally abnormal activation of CDKs has been shown to result in the development of human tumors, and human tumor development is commonly associated with alterations in either the CDK proteins themselves or their regulators.
  • CDK4 and CDK6 are important regulators of cell cycle progression at the G1-S checkpoint, which are controlled by D-type cyclins and INK4 endogenous CDK inhibitors, such as p16 INK4a (CDKN2A). Dysregulation of the cyclin D-CDK4/6-INK4- retinoblastoma (Rb) pathway has been reported to be associated with development of endocrine therapy resistance.
  • CDK4 a member of the CDK family, is a catalytic subunit of the protein kinase complex that is involved in controlling the transition from the G1-phase to the S-phase in the cell-cycle.
  • this process is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16(INK4a). Mutations in the CDK4 gene as well as in the related proteins including D-type cyclins, p16(INK4a), and Rb have been linked to tumorigenesis of a variety of cancers (“Germline mutations in the pl6INK4a binding domain of CDK4 in familial melanoma”, Nature Genet, 1996, 12, 97-99; “Cyclin D-dependent kinases, INK4 inhibitors and cancer”, Biochim. Biophys.
  • CDK4/6 inhibitors at times, also cause adverse effects, such as gastrointestinal and hematologic toxicities, and tumors may acquire resistance over time. Because CDK4 has been identified as the singular oncogenic driver in many breast cancers, a selective CDK4 inhibitor may provide improved safety profile and enhanced effectiveness. [0007] Accordingly, there is a need in the art for improved therapies (e.g., greater efficacy, potential to reduce side effects, potential to overcome resistance mechanisms) for the treatment of diseases, such as cancers.
  • the present disclosure provides, according to some embodiments, compounds, compositions, and methods for modulating the activity of CDK, including CDK4 and/or CDK6.
  • the compounds are selective for CDK4.
  • the present disclosure provides a compound represented by Formula (I), or a tautomer, a stereoisomer or a mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, or a deuterated derivative thereof: wherein: Ring A is selected from , , , , , wherein RC is selected from C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl and RD is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heteroaryl, and 3- to 6-membered heterocycle;
  • X2 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C
  • a therapeutically effective amount of a pharmaceutical composition of the present disclosure may be administered to a subject diagnosed with the disease or disorder.
  • the disease or disorder is cancer.
  • the cancer is selected from breast cancer, prostate cancer, bone cancer, brain cancer, colorectal cancer, lung cancer, ovarian cancer, uterine cancer, liposarcoma, liver cancer, rhabdoid cancer, sarcoma, skin cancer, kidney cancer, stomach cancer, pancreatic cancer, esophageal cancer, head and neck cancer, bladder cancer, leukemia, lymphoma and thyroid cancer.
  • FIGURE 1 is a diagram illustrating general synthesis method 1.
  • FIGURE 2 is a diagram illustrating the synthesis of intermediate-1.
  • FIGURE 3 is a diagram illustrating the synthesis of intermediate-2.
  • FIGURE 4 is a diagram illustrating the synthesis of intermediate-3.
  • FIGURE 5 is a diagram illustrating the synthesis of intermediate-4.
  • FIGURE 6 is a diagram illustrating the synthesis of intermediate-5.
  • FIGURE 7 is a diagram illustrating the synthesis of intermediate-6.
  • FIGURE 8 is a diagram illustrating the synthesis of intermediate-7.
  • FIGURE 9 is a diagram illustrating the synthesis of intermediate-8.
  • FIGURE 10 is a diagram illustrating the synthesis of intermediate-9.
  • FIGURE 11 is a diagram illustrating the synthesis of intermediate-13.
  • FIGURE 12 is a diagram illustrating the synthesis of intermediate-14.
  • FIGURE 13 is a diagram illustrating the synthesis of intermediate-16.
  • FIGURE 14 is a diagram illustrating the synthesis of intermediate-17.
  • FIGURE 15 is a diagram illustrating the synthesis of intermediate-20.
  • FIGURE 16 is a diagram illustrating the synthesis of intermediate-22.
  • FIGURE 17 is a diagram illustrating the synthesis of intermediate-23.
  • FIGURE 18 is a diagram illustrating the synthesis of intermediate-24.
  • FIGURE 19 is a diagram illustrating the synthesis of intermediate-25.
  • FIGURE 20 is a diagram illustrating the synthesis of intermediate-26.
  • FIGURE 21 is a diagram illustrating the synthesis of intermediate-27.
  • FIGURE 22 is a diagram illustrating the synthesis of intermediate-28.
  • FIGURE 23 is a diagram illustrating the synthesis of intermediate-29.
  • FIGURE 24 is a diagram illustrating the synthesis of intermediate-30.
  • FIGURE 25 is a diagram illustrating the synthesis of intermediate-31.
  • FIGURE 26 is a diagram illustrating the synthesis of intermediate-32.
  • FIGURE 27 is a diagram illustrating the synthesis of compounds 2 and 3.
  • FIGURE 28 is a diagram illustrating the synthesis of compounds 5 and 6.
  • FIGURE 29 is a diagram illustrating the synthesis of compounds 31 and 32.
  • FIGURE 30 is a diagram illustrating the synthesis of compound 99.
  • FIGURE 31 is a diagram illustrating the synthesis of compounds 101 and 102.
  • FIGURE 32 is a diagram illustrating the synthesis of compound 120.
  • FIGURE 33 is a diagram illustrating the synthesis of compound 189.
  • FIGURE 34 is a diagram illustrating the synthesis of compound 190.
  • FIGURE 35 is a diagram illustrating the synthesis of compound 195.
  • FIGURE 36 is a diagram illustrating the synthesis of compound 199.
  • FIGURE 37 is a diagram illustrating the synthesis of compounds 93 and 94.
  • FIGURE 38 is a diagram illustrating the synthesis of compounds 43 and 44.
  • FIGURE 39 is a diagram illustrating the synthesis of compounds 164 and 165.
  • FIGURE 40 is a diagram illustrating the synthesis of compounds 227 and 228.
  • FIGURE 41 is a diagram illustrating the synthesis of compounds 223 and 224.
  • FIGURE 42 is a diagram illustrating the synthesis of compounds 35 and 36.
  • FIGURE 43 is a diagram illustrating the synthesis of compounds 130 and 131.
  • FIGURE 44 is a diagram illustrating the synthesis of compounds 240 and 241.
  • FIGURE 45 is a diagram illustrating the synthesis of compound 274.
  • FIGURE 46 is a diagram illustrating the synthesis of compound 277.
  • FIGURE 47 is a diagram illustrating the synthesis of compound 278.
  • FIGURE 48 is a diagram illustrating the synthesis of compounds 282 and 283.
  • FIGURE 49 is a diagram illustrating the synthesis of compounds 295 and 296.
  • FIGURE 50 is a diagram illustrating the synthesis of compounds 291 and 292. Definitions [0062]
  • cancer refers to diseases, disorders, and conditions that involve abnormal cell growth with the potential to invade or spread to other parts of the body.
  • Exemplary cancers include, but are not limited to, breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, lung cancer, stomach cancer, esophageal cancer, colorectal cancer, small bowel cancer, pancreatic cancer, liver cancer, kidney cancer, head and neck cancer, skin cancer, bone cancer, thyroid cancer, peritoneal cancer, and brain cancer.
  • Subject refers to an animal, such as a mammal, that has been or will be the object of treatment, observation, or experiment. The methods described herein may be useful for both human therapy and veterinary applications. In one embodiment, the subject is a human.
  • treatment refers to an amelioration of a disease or disorder, or at least one discernible symptom thereof.
  • treatment refers to an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient.
  • treatment or “treating” refers to inhibiting the progression of a disease or disorder, either physically, e.g., stabilization of a discernible symptom, physiologically, e.g., stabilization of a physical parameter, or both.
  • treatment or “treating” refers to delaying the onset of a disease or disorder.
  • a dash “” that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -CN is attached through the carbon atom.
  • C 1 -C 6 alkyl is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C 4-6 , C 4-5 , and C 5-6 alkyl.
  • alkenyl refers to an unsaturated, two-carbon group having a carbon-carbon double bond, referred to herein as C2-alkenyl.
  • alkoxy refers to an alkyl or cycloalkyl covalently bonded to an oxygen atom.
  • alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-8 carbon atoms, referred to herein as “C1-C8 alkyl”.
  • exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl- 2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t- butyl, pentyl, t- butyl,
  • alkyl is a straight-chain hydrocarbon. In some embodiments, “alkyl” is a branched hydrocarbon.
  • alkynyl refers to an unsaturated, two-carbon group having a carbon-carbon triple bond, referred to herein as C2-alkynyl.
  • aryl refers to a mono-, bi-, or other multi-carbocyclic, aromatic ring system with 5 to 14 ring atoms. The aryl group can optionally be fused to one or more rings selected from aryls, cycloalkyls, heteroaryls, and heterocyclyls.
  • aryl groups of this present disclosure can be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.
  • aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8- tetrahydronaphthyl.
  • Exemplary aryl groups also include but are not limited to a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as “C 6 -aryl.”
  • cycloalkyl refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-16 carbons, or 3-8 carbons, referred to herein as “C 3 -C 8 cycloalkyl,” derived from a cycloalkane.
  • Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, and cyclopentenes.
  • Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
  • Cycloalkyl groups can be fused to other cycloalkyl (saturated or partially unsaturated), aryl, or heterocyclyl groups, to form a bicycle, tetracycle, etc.
  • the term “cycloalkyl” also includes bridged and spiro-fused cyclic structures which may or may not contain heteroatoms.
  • halo or “halogen” as used herein refer to -F, -Cl, -Br, and/or -I.
  • haloalkyl group refers to an alkyl group substituted with one or more halogen atoms.
  • heteroaryl refers to a mono-, bi-, or multi-cyclic, aromatic ring system containing one or more heteroatoms, for example 1-4 heteroatoms, such as nitrogen, oxygen, and sulfur.
  • Heteroaryls can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heteroaryls can also be fused to non-aromatic rings.
  • heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and oxazolyl.
  • heteroaryl groups include, but are not limited to, a monocyclic aromatic ring, wherein the ring comprises 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as "(C2-C5)heteroaryl.”
  • a heteroaryl contains 5 to 10 ring atoms, 1 to 4 of which are heteroatoms selected from N, O, and S.
  • a heteroaryl contains 5 to 8 ring atoms, 1 to 4 of which are heteroatoms selected from N, O, and S.
  • heterocycle refers to a saturated or unsaturated 3- to 18-membered ring containing one, two, three, or four heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur.
  • Heterocycles can be aromatic (heteroaryls) or non-aromatic.
  • Heterocycles can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
  • substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocycly
  • Heterocycles also include bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from aryls, cycloalkyls, and heterocycles. Heterocycles also include bridged and spiro-fused cyclic structures which may or may not contain heteroatoms.
  • heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrida
  • a heterocycle contains 5 to 10 ring atoms, 1 to 4 of which are heteroatoms selected from N, O, and S. In some embodiments, a heterocycle contains 5 to 8 ring atoms, 1 to 4 of which are heteroatoms selected from N, O, and S.
  • hydroxy and “hydroxyl” as used herein refer to -OH.
  • compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • pharmaceutically acceptable salt refers to a salt form of a compound of this disclosure wherein the salt is nontoxic.
  • Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. A “free base” form of a compound, for example, does not contain an ionically bonded salt.
  • Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19.
  • Non-limiting examples of pharmaceutically acceptable acid addition salts include: salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids, such as AcOH, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; and salts formed by using other methods used in the art, such as ion exchange.
  • Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C1-4alkyl)4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • Suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.
  • nomenclature for compounds including organic compounds can be given using common names, IUPAC, IUBMB, or CAS recommendations for nomenclature.
  • One of skill in the art can readily ascertain the structure of a compound if given a name, either by systemic reduction of compound structure using naming conventions, or by commercially available software, such as CHEMDRAW TM (Cambridgesoft Corporation, U.S.A.).
  • the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers, or diastereomers.
  • stereoisomers when used herein consist of all geometric isomers, enantiomers, or diastereomers. These compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated “( ⁇ )” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. In some embodiments, an enantiomer or stereoisomer may be provided substantially free of the corresponding enantiomer.
  • the compound is a racemic mixture of (S)- and (R)- isomers.
  • provided herein is a mixture of compounds wherein individual compounds of the mixture exist predominately in an (S)- or (R)-isomeric configuration.
  • the compound mixture has an (S)-enantiomeric excess of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more.
  • the compound mixture has an (S)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more.
  • the compound mixture has an (R)-enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more.
  • the compound mixture has an (R)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5% or more.
  • Individual stereoisomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by: (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary; (2) salt formation employing an optically active resolving agent; or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
  • Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known stereoselective synthesis methods.
  • Geometric isomers can also exist in the compounds of the present disclosure. The present disclosure encompasses the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon- carbon double bond or arrangement of substituents around a carbocyclic ring.
  • Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the E and Z isomers. [0091] Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
  • the arrangements of substituents around a carbocyclic ring are designated as “cis” or “trans.”
  • the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring.
  • Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.”
  • the present disclosure includes within its scope all possible tautomers. Furthermore, the present disclosure includes in its scope both the individual tautomers and any mixtures thereof. Each compound disclosed herein includes within its scope all possible tautomeric forms. Furthermore, each compound disclosed herein includes within its scope both the individual tautomeric forms and any mixtures thereof.
  • references to a compound or compounds is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof. Where a compound of the present application is depicted in one tautomeric form, that depicted structure is intended to encompass all other tautomeric forms.
  • structures described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium ( 2 H) or tritium ( 3 H), or the replacement of a carbon by a 13 C- or 14 C-carbon atom are within the scope of this disclosure.
  • the present disclosure is directed to a compound of Formula (I), or a tautomer, a stereoisomer or a mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, or a deuterated derivative thereof: wherein: Ring A is selected from: , , , , , , wherein R C is selected from C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl and R D is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heteroaryl, and 3- to 6-membered heterocycle; X 2 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 3 -
  • Ring A is selected from: , [0097] In some embodiments, Ring A is selected from: , , , , , [0098] In some embodiments, RC is selected from C 1 -C 3 alkyl and C 3 -C 6 cycloalkyl. [0099] In some embodiments, RC is selected from C 1 -C 3 alkyl. In some embodiments, RC is selected from C1 alkyl. In some embodiments, RC is selected from C2 alkyl. In some embodiments, RC is selected from C3 alkyl. In some embodiments, R C is methyl. In some embodiments, R C is ethyl.
  • RC is selected from C 3 -C 6 cycloalkyl. In some embodiments, RC is selected from C3 cycloalkyl. In some embodiments, RC is selected from C4 cycloalkyl. In some embodiments, RC is selected from C5 cycloalkyl. In some embodiments, RC is selected from C6 cycloalkyl. [00101] In some embodiments, R D is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 6- to 8-membered aryl, 5- to 6-membered heteroaryl, and 6-membered heterocycle.
  • RD is selected from C 1 -C 6 alkyl. In some embodiments, R D is selected from C 1 alkyl. In some embodiments, R D is selected from C2 alkyl. In some embodiments, RD is selected from C3 alkyl. In some embodiments, R D is selected from C 4 alkyl. In some embodiments, R D is selected from C5 alkyl. In some embodiments, RD is selected from C6 alkyl. [00103] In some embodiments, RD is selected from C 3 -C 6 cycloalkyl. In some embodiments, R D is selected from C 3 cycloalkyl. In some embodiments, R D is selected from C4 cycloalkyl.
  • RD is selected from C5 cycloalkyl. In some embodiments, R D is selected from C 6 cycloalkyl. [00104] In some embodiments, R D is selected from 6- to 8-membered aryl. In some embodiments, RD is selected from 6-membered aryl. In some embodiments, RD is selected from 7-membered aryl. In some embodiments, R D is selected from 8- membered aryl. [00105] In some embodiments, RD is selected from 5- to 6-membered heteroaryl. In some embodiments, R D is selected from 5-membered heteroaryl. In some embodiments, RD is selected from 6-membered heteroaryl.
  • RD is selected from 6-membered heterocycle. [00107] In some embodiments, RD is selected from methyl, ethyl, i-propyl, cyclopropyl, phenyl, pyridinyl, morpholinyl, and imidazolyl. In some embodiments, R D is methyl. In some embodiments, RD is selected from ethyl. In some embodiments, R D is i-propyl. In some embodiments, R D is cyclopropyl. In some embodiments, R D is phenyl. In some embodiments, RD is pyridinyl. In some embodiments, RD is morpholinyl.
  • R D is imidazolyl.
  • Ring A is selected from: , , .
  • X2 is selected from hydrogen, F, Cl, Br, methyl, -CHF 2 , -CF 3 , and -CN.
  • X 2 is hydrogen.
  • X2 is F.
  • X2 is Cl.
  • X2 is Br.
  • X 2 is methyl.
  • X 2 is -CHF 2 .
  • X2 is -CF3.
  • X2 is -CN.
  • Ring B is: .
  • W1 is S. In some embodiments, W1 is NRB. In some embodiments, W 1 is CR B . In some embodiments, W 1 is selected from 3- to 6- membered cycloalkyl, wherein the 3- to 6-membered cycloalkyl is optionally substituted with 1-3 RH. [00112] In some embodiments, R B is selected from C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1-3 RH. In some embodiments, RB is selected from C 1 alkyl, wherein the C 1 alkyl is optionally substituted with 1-3 R H .
  • RB is selected from C2 alkyl, wherein the C2 alkyl is optionally substituted with 1-3 RH. In some embodiments, RB is selected from C3 alkyl, wherein the C3 alkyl is optionally substituted with 1-3 RH. In some embodiments, RB is selected from C4 alkyl, wherein the C4 alkyl is optionally substituted with 1-3 RH. In some embodiments, R B is selected from C 5 alkyl, wherein the C 5 alkyl is optionally substituted with 1-3 RH. In some embodiments, RB is selected from C6 alkyl, wherein the C 6 alkyl is optionally substituted with 1-3 R H .
  • RB is selected from C 3 -C 6 cycloalkyl, wherein the C 3 -C 6 cycloalkyl is optionally substituted with 1-3 RH. In some embodiments, RB is selected from C3 cycloalkyl, wherein the C3 cycloalkyl is optionally substituted with 1- 3 RH. In some embodiments, RB is selected from C4 cycloalkyl, wherein the C4 cycloalkyl is optionally substituted with 1-3 RH. In some embodiments, RB is selected from C5 cycloalkyl, wherein the C5 cycloalkyl is optionally substituted with 1-3 RH.
  • R B is selected from C 6 cycloalkyl, wherein the C 6 cycloalkyl is optionally substituted with 1-3 RH.
  • RB is selected from hydrogen, methyl, and i-propyl. In some embodiments, RB is hydrogen. In some embodiments, RB is methyl. In some embodiments, RB is i-propyl.
  • Ring B is selected from: , wherein Ring C is selected from 3- to 6-membered cycloalkyl, wherein the 3- to 6- membered cycloalkyl is optionally substituted with 1-3 RH. [00116] In some embodiments, Ring B is selected from: .
  • Ring B is selected from: . [00118] In some embodiments, Ring B is selected from: . [00119] In some embodiments, Ring B is selected from: from 3- to 6-membered cycloalkyl, wherein the 3- to 6-membered cycloalkyl is optionally substituted with 1-3 RH. [00120] In some embodiments, Ring B is: . [00121] In some embodiments, Ring C is selected from 3-membered cycloalkyl optionally substituted with 1-3 RH. In some embodiments, Ring C is selected from 4- membered cycloalkyl optionally substituted with 1-3 R H .
  • Ring C is selected from 5-membered cycloalkyl optionally substituted with 1-3 RH. In some embodiments, Ring C is selected from 6-membered cycloalkyl optionally substituted with 1-3 RH. [00122] In some embodiments, Ring B is selected from , . [00123] In some embodiments, Ring B is: . [00124] In some embodiments, Ring B is: [00125] In some embodiments, Ring B is: . [00126] In some embodiments, Ring B is: . [00127] In some embodiments, Ring B is: . [00128] In some embodiments, Ring B is: . [00129] In some embodiments, Ring B is: .
  • Ring B is: . [00131] In some embodiments, Ring B is: . [00132] In some embodiments, Ring B is: . [00133] In some embodiments, at least one R H is hydroxy. In some embodiments, at least one RH is halogen. In some embodiments, at least one RH is F. In some embodiments, at least one R H is Cl. In some embodiments, at least one R H is Br. In some embodiments, at least one RH is selected from C 1 -C 3 alkyl. In some embodiments, at least one RH is selected from C1 alkyl. In some embodiments, at least one R H is selected from C 2 alkyl.
  • At least one R H is selected from C3 alkyl. In some embodiments, at least one RH is methyl. In some embodiments, at least one R H is ethyl. In some embodiments, at least one R H is i- propyl. [00134] In some embodiments, each RH is hydroxy. In some embodiments, each RH is halogen. In some embodiments, each RH is F. In some embodiments, each RH is Cl. In some embodiments, each RH is Br. In some embodiments, each RH is selected from C 1 -C 3 alkyl. In some embodiments, each R H is selected from C 1 alkyl. In some embodiments, each RH is selected from C2 alkyl.
  • each R H is selected from C 3 alkyl. In some embodiments, each R H is methyl. In some embodiments, each RH is ethyl. In some embodiments, each RH is i-propyl. [00135] In some embodiments, W1 and R1 are taken together with the C atom to which both are attached to form a 6-membered heterocycle selected from morpholine, piperazine, and piperidine, wherein the N atom of morpholine, piperazine, and piperidine rings is adjacent to Z, and wherein the piperazine is optionally substituted with 1-2 groups independently selected from methyl and oxo and wherein the piperidine is optionally substituted with 1-4 groups independently selected from methyl and hydroxy.
  • W1, Z, R2 and the C atom to which R2 is directly attached are taken together to form a 6-membered heterocycle selected from morpholine, piperidine, thiomorpholine, and piperazine, wherein the N atom of the morpholine, piperidine, thiomorpholine, and piperazine rings is adjacent to Z, and wherein the piperazine is optionally substituted with 1-2 groups independently selected from methyl and oxo.
  • R 2 is selected from C 1 -C 6 alkyl.
  • R2 is selected from C1 alkyl.
  • R2 is selected from C 2 alkyl.
  • R 2 is selected from C 3 alkyl. In some embodiments, R2 is selected from C4 alkyl. In some embodiments, R2 is selected from C 5 alkyl. In some embodiments, R 2 is selected from C 6 alkyl. [00138] In some embodiments, R 2 is selected from C 3 -C 6 cycloalkyl. In some embodiments, R2 is selected from C3 cycloalkyl. In some embodiments, R2 is selected from C4 cycloalkyl. In some embodiments, R2 is selected from C5 cycloalkyl. In some embodiments, R 2 is selected from C 6 cycloalkyl. [00139] In some embodiments, R2 is selected from C 1 -C 6 alkoxy.
  • R2 is selected from C1 alkoxy. In some embodiments, R2 is selected from C2 alkoxy. In some embodiments, R2 is selected from C3 alkoxy. In some embodiments, R2 is selected from C4 alkoxy. In some embodiments, R2 is selected from C5 alkoxy. In some embodiments, R2 is selected from C6 alkoxy. [00140] In some embodiments, R2 is selected from C 3 -C 6 cyclic alkoxy. In some embodiments, R 2 is selected from C 3 cyclic alkoxy. In some embodiments, R 2 is selected from C4 cyclic alkoxy. In some embodiments, R2 is selected from C5 cyclic alkoxy.
  • R2 is selected from C6 cyclic alkoxy.
  • R 2 is selected from C 1 -C 6 haloalkoxy.
  • R2 is selected from C1 haloalkoxy.
  • R2 is selected from C 2 haloalkoxy.
  • R 2 is selected from C 3 haloalkoxy.
  • R2 is selected from C4 haloalkoxy.
  • R2 is selected from C5 haloalkoxy.
  • R2 is selected from C6 haloalkoxy.
  • R2 is selected from hydrogen, halogen, methyl, i- propyl, -OMe, and -OCF3. In some embodiments, R2 is hydrogen. In some embodiments, R2 is halogen. In some embodiments, R2 is methyl. In some embodiments, R2 is i-propyl. In some embodiments, R2 is -OMe. In some embodiments, R2 is -OCF3. [00143] In some embodiments, Ring B is . [00144] In some embodiments, Ring B is selected from: [00145] In some embodiments, Ring B is: . [00146] In some embodiments, Ring B is: . [00147] In some embodiments, Ring B is: .
  • Ring B is selected from: [00149] In some embodiments, Ring B is: . [00150] In some embodiments, Ring B is selected from . [00151] In some embodiments, Ring B is selected from: . [00152] In some embodiments, Ring B is: . [00153] In some embodiments, Ring B is: . [00154] In some embodiments, Ring B is: . [00155] In some embodiments, Ring B is . [00156] In some embodiments, Ring B is . [00157] In some embodiments, Ring B is . [00158] In some embodiments, each R E is independently selected from halogen. In some embodiments, each RE is F. In some embodiments, each RE is Cl.
  • each R E is Br. In some embodiments, at least one R E is selected from halogen. In some embodiments, at least one RE is F. In some embodiments, at least one R E is Cl. In some embodiments, at least one R E is Br. [00159] In some embodiments, each R E is independently selected from C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1-3 RF. In some embodiments, each R E is independently selected from C 1 alkyl, wherein the C 1 alkyl is optionally substituted with 1-3 RF. In some embodiments, each RE is independently selected from C 2 alkyl, wherein the C 2 alkyl is optionally substituted with 1-3 R F .
  • each RE is independently selected from C3 alkyl, wherein the C3 alkyl is optionally substituted with 1-3 R F .
  • each R E is independently selected from C4 alkyl, wherein the C4 alkyl is optionally substituted with 1-3 R F .
  • each R E is independently selected from C 5 alkyl, wherein the C5 alkyl is optionally substituted with 1-3 RF.
  • each RE is independently selected from C6 alkyl, wherein the C6 alkyl is optionally substituted with 1-3 RF.
  • At least one RE is selected from C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1-3 R F .
  • at least one RE is selected from C1 alkyl, wherein the C1 alkyl is optionally substituted with 1-3 RF.
  • at least one RE is selected from C2 alkyl, wherein the C2 alkyl is optionally substituted with 1-3 RF.
  • at least one RE is selected from C3 alkyl, wherein the C3 alkyl is optionally substituted with 1-3 RF.
  • At least one RE is selected from C4 alkyl, wherein the C4 alkyl is optionally substituted with 1-3 R F .
  • at least one R E is selected from C5 alkyl, wherein the C5 alkyl is optionally substituted with 1-3 RF.
  • at least one R E is selected from C 6 alkyl, wherein the C 6 alkyl is optionally substituted with 1-3 RF.
  • each RE is independently selected from C 3 -C 6 cycloalkyl, wherein the C 3 -C 6 cycloalkyl is optionally substituted with 1-3 RF.
  • each RE is independently selected from C3 cycloalkyl, wherein the C3 cycloalkyl is optionally substituted with 1-3 R F .
  • each R E is independently selected from C4 cycloalkyl, wherein the C4 cycloalkyl is optionally substituted with 1-3 R F .
  • each R E is independently selected from C5 cycloalkyl, wherein the C5 cycloalkyl is optionally substituted with 1-3 RF.
  • each R E is independently selected from C 6 cycloalkyl, wherein the C6 cycloalkyl is optionally substituted with 1-3 RF.
  • At least one RE is selected from C 3 -C 6 cycloalkyl, wherein the C 3 -C 6 cycloalkyl is optionally substituted with 1-3 R F .
  • at least one RE is selected from C3 cycloalkyl, wherein the C3 cycloalkyl is optionally substituted with 1-3 R F .
  • at least one RE is selected from C4 cycloalkyl, wherein the C4 cycloalkyl is optionally substituted with 1-3 R F .
  • at least one R E is selected from C 5 cycloalkyl, wherein the C5 cycloalkyl is optionally substituted with 1-3 RF.
  • At least one R E is selected from C 6 cycloalkyl, wherein the C 6 cycloalkyl is optionally substituted with 1-3 RF.
  • each RE is hydrogen.
  • at least one R E is hydrogen.
  • X 1 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 haloalkyl, and -CN.
  • X1 is selected from halogen.
  • X 1 is F.
  • X 1 is Cl.
  • X 1 is Br.
  • X 1 is selected from C 1 -C 6 alkyl. In some embodiments, X1 is selected from C1 alkyl. In some embodiments, X1 is selected from C2 alkyl. In some embodiments, X1 is selected from C3 alkyl. In some embodiments, X 1 is methyl. In some embodiments, X 1 is ethyl. [00167] In some embodiments, X1 is selected from C 3 -C 6 cycloalkyl. In some embodiments, X1 is selected from C3 cycloalkyl. In some embodiments, X1 is selected from C4 cycloalkyl. In some embodiments, X1 is selected from C5 cycloalkyl.
  • X1 is selected from C6 cycloalkyl. [00168] In some embodiments, X 1 is selected from C 1 -C 3 haloalkyl. In some embodiments, X1 is selected from C1 halalkyl. In some embodiments, X1 is selected from C 2 haloalkyl. In some embodiments, X 1 is selected from C 3 haloalkyl. [00169] In some embodiments, X 1 is selected from hydrogen, F, Cl, Br, methyl, - CHF2, and -CN. In some embodiments, X1 is hydrogen. In some embodiments, X1 is -CHF 2 . In some embodiments, X 1 is -CN.
  • Ring B is selected from: , F
  • R1 is selected from: C , wherein RT is selected from hydrogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl and wherein C 1 -C 6 alkyl of R 1 is optionally substituted with 1-2 R 1A , wherein each R 1A is independently selected from halogen, -NH2, hydroxy, C 1 -C 6 alkoxy, and C 1 -C 6 alkyl.
  • RT is hydrogen.
  • R T is selected from C 1 -C 6 alkyl.
  • RT is selected from C1 alkyl. In some embodiments, RT is selected from C2 alkyl. In some embodiments, RT is selected from C3 alkyl. In some embodiments, R T is selected from C 4 alkyl. In some embodiments, R T is selected from C5 alkyl. In some embodiments, RT is selected from C6 alkyl. In some embodiments, R T is methyl. In some embodiments, R T is ethyl. [00174] In some embodiments, RT is selected from C 3 -C 6 cycloalkyl. In some embodiments, RT is selected from C3 cycloalkyl. In some embodiments, RT is selected from C4 cycloalkyl.
  • RT is selected from C5 cycloalkyl. In some embodiments, R T is selected from C 6 cycloalkyl.
  • each R1A is independently selected from halogen. In some embodiments, each R1A is F. In some embodiments, each R1A is Cl. In some embodiments, each R1A is Br. In some embodiments, at least one R1A is selected from halogen. In some embodiments, at least one R1A is F. In some embodiments, at least one R1A is Cl. In some embodiments, at least one R1A is Br. [00176] In some embodiments, each R1A is independently selected from C 1 -C 6 alkyl .
  • each R 1A is independently selected from C 1 alkyl . In some embodiments, each R1A is independently selected from C2 alkyl. In some embodiments, each R1A is independently selected from C3 alkyl. In some embodiments, each R1A is independently selected from C4 alkyl. In some embodiments, each R1A is independently selected from C5 alkyl. In some embodiments, each R 1A is independently selected from C 6 alkyl . [00177] In some embodiments, at least one R1A is selected from C 1 -C 6 alkyl. In some embodiments, at least one R1A is selected from C1 alkyl. In some embodiments, at least one R1A is selected from C2 alkyl.
  • At least one R1A is selected from C3 alkyl. In some embodiments, at least one R1A is selected from C 4 alkyl . In some embodiments, at least one R 1A is selected from C 5 alkyl. In some embodiments, at least one R1A is selected from C6 alkyl. [00178] In some embodiments, each R1A is independently selected from C 3 -C 6 cycloalkyl. In some embodiments, each R1A is independently selected from C3 cycloalkyl. In some embodiments, each R1A is independently selected from C4 cycloalkyl . In some embodiments, each R 1A is independently selected from C 5 cycloalkyl.
  • each R1A is independently selected from C6 cycloalkyl .
  • at least one R1A is selected from C 3 -C 6 cycloalkyl.
  • at least one R1A is selected from C3 cycloalkyl.
  • at least one R 1A is selected from C 4 cycloalkyl .
  • at least one R1A is selected from C5 cycloalkyl.
  • at least one R 1A is selected from C 6 cycloalkyl .
  • each R1A is independently selected from C 1 -C 6 alkoxy .
  • each R 1A is independently selected from C 1 alkoxy . In some embodiments, each R1A is independently selected from C2 alkoxy. In some embodiments, each R 1A is independently selected from C 3 alkoxy . In some embodiments, each R1A is independently selected from C4 alkoxy. In some embodiments, each R 1A is independently selected from C 5 alkoxy . In some embodiments, each R1A is independently selected from C6 alkoxy. [00181] In some embodiments, at least one R1A is selected from C 1 -C 6 alkoxy. In some embodiments, at least one R 1A is selected from C 1 alkoxy . In some embodiments, at least one R1A is selected from C2 alkoxy.
  • At least one R 1A is selected from C 3 alkoxy . In some embodiments, at least one R 1A is selected from C4 alkoxy. In some embodiments, at least one R1A is selected from C5 alkoxy . In some embodiments, at least one R 1A is selected from C 6 alkoxy . [00182] In some embodiments, each R 1A is independently selected from C 3 -C 6 cyclic alkoxy. In some embodiments, each R1A is independently selected from C3 cyclic alkoxy . In some embodiments, each R 1A is independently selected from C 4 cyclic alkoxy. In some embodiments, each R1A is independently selected from C5 cyclic alkoxy .
  • each R 1A is independently selected from C 6 cyclic alkoxy. [00183] In some embodiments, at least one R1A is selected from C 3 -C 6 cyclic alkoxy . In some embodiments, at least one R 1A is selected from C 3 cyclic alkoxy . In some embodiments, at least one R1A is selected from C4 cyclic alkoxy. In some embodiments, at least one R 1A is selected from C 5 cyclic alkoxy . In some embodiments, at least one R1A is selected from C6 cyclic alkoxy. [00184] In some embodiments, each R1A is independently selected from -N(RK)2.
  • each RK is independently selected from C2 alkyl. In some embodiments, each R K is independently selected from C 3 alkyl . In some embodiments, each RK is independently selected from C4 alkyl. In some embodiments, each R K is independently selected from C 5 alkyl . In some embodiments, each RK is independently selected from C6 alkyl. [00187] In some embodiments, at least one RK is selected from C 1 -C 6 alkyl. In some embodiments, at least one R K is selected from C 1 alkyl . In some embodiments, at least one RK is selected from C2 alkyl. In some embodiments, at least one RK is selected from C 3 alkyl .
  • At least one R K is selected from C 4 alkyl. In some embodiments, at least one RK is selected from C5 alkyl. In some embodiments, at least one R K is selected from C 6 alkyl . [00188] In some embodiments, each R K is independently selected from C 3 -C 6 cycloalkyl. In some embodiments, each RK is independently selected from C3 cycloalkyl . In some embodiments, each R K is independently selected from C 4 cycloalkyl. In some embodiments, each RK is independently selected from C5 cycloalkyl . In some embodiments, each R K is independently selected from C 6 cycloalkyl.
  • At least one RK is selected from C 3 -C 6 cycloalkyl. In some embodiments, at least one R K is selected from C 3 cycloalkyl . In some embodiments, at least one RK is selected from C4 cycloalkyl. In some embodiments, at least one R K is selected from C 5 cycloalkyl . In some embodiments, at least one R K is selected from C6 cycloalkyl. [00190] In some embodiments, each RG is independently selected from C 1 -C 6 alkyl. In some embodiments, each R G is independently selected from C 1 alkyl . In some embodiments, each RG is independently selected from C2 alkyl.
  • each R G is independently selected from C 3 alkyl . In some embodiments, each RG is independently selected from C4 alkyl. In some embodiments, each R G is independently selected from C 5 alkyl . In some embodiments, each RG is independently selected from C6 alkyl. [00191] In some embodiments, at least one RG is selected from C 1 -C 6 alkyl. In some embodiments, at least one R G is selected from C 1 alkyl . In some embodiments, at least one RG is selected from C2 alkyl. In some embodiments, at least one RG is selected from C 3 alkyl . In some embodiments, at least one R G is selected from C 4 alkyl.
  • At least one RG is selected from C5 alkyl. In some embodiments, at least one R G is selected from C 6 alkyl . [00192] In some embodiments, each RG is independently selected from C 3 -C 6 cycloalkyl. In some embodiments, each RG is independently selected from C3 cycloalkyl . In some embodiments, each R G is independently selected from C 4 cycloalkyl. In some embodiments, each RG is independently selected from C5 cycloalkyl . In some embodiments, each R G is independently selected from C 6 cycloalkyl. [00193] In some embodiments, at least one RG is selected from C 3 -C 6 cycloalkyl.
  • At least one R G is selected from C 3 cycloalkyl . In some embodiments, at least one RG is selected from C4 cycloalkyl. In some embodiments, at least one R G is selected from C 5 cycloalkyl . In some embodiments, at least one R G is selected from C6 cycloalkyl. [00194] In some embodiments, R1 is selected from: , , , , , , , , , , , and .
  • compositions of the present disclosure comprise at least one entity selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof, with at least one pharmaceutically acceptable carrier.
  • formulations include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration.
  • parenteral e.g., subcutaneous, intramuscular, intradermal, or intravenous
  • the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
  • Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of a compound of the present disclosure as powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association at least one compound of the present disclosure as the active compound and a carrier or excipient (which may constitute one or more accessory ingredients).
  • the carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient.
  • the carrier may be a solid or a liquid, or both, and may be formulated with at least one compound described herein as the active compound in a unit-dose formulation, for example, a tablet, which may contain from about 0.05% to about 95% by weight of the at least one active compound.
  • Other pharmacologically active substances may also be present including other compounds.
  • formulations of the present disclosure may be prepared by any of the well-known techniques of pharmacy consisting essentially of admixing the components.
  • conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • Liquid pharmacologically administrable compositions can, for example, be prepared by, for example, dissolving or dispersing, at least one active compound of the present disclosure as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
  • suitable formulations may be prepared by uniformly and intimately admixing the at least one active compound of the present disclosure with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • a tablet may be prepared by compressing or molding a powder or granules of at least one compound of the present disclosure, which may be optionally combined with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, at least one compound of the present disclosure in a free-flowing form, such as a powder or granules, which may be optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s).
  • Molded tablets may be made by molding, in a suitable machine, where the powdered form of at least one compound of the present disclosure is moistened with an inert liquid diluent.
  • Formulations suitable for buccal (sub-lingual) administration include lozenges comprising at least one compound of the present disclosure in a flavored base, usually sucrose and acacia or tragacanth, and pastilles comprising the at least one compound in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations of the present disclosure suitable for parenteral administration comprise sterile aqueous preparations of at least one entity selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof, which are approximately isotonic with the blood of the intended recipient.
  • compositions suitable for rectal administration are presented as unit-dose suppositories. These may be prepared by admixing at least one compound as described herein with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
  • Formulations suitable for topical application to the skin may take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers and excipients which may be used include Vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof.
  • the active compound i.e., at least one entity selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof
  • the active compound is generally present at a concentration of from about 0.1% to about 15% w/w of the composition, for example, from about 0.5 to about 2%.
  • the amount of active compound administered may be dependent on the subject being treated, the subject's weight, the manner of administration and the judgment of the prescribing physician.
  • a dosing schedule may involve the daily or semi-daily administration of the encapsulated compound at a perceived dosage of about 1 ⁇ g to about 1000 mg.
  • intermittent administration such as on a monthly or yearly basis, of a dose of the encapsulated compound may be employed.
  • Encapsulation facilitates access to the site of action and allows the administration of the active ingredients simultaneously, in theory producing a synergistic effect.
  • physicians will readily determine optimum dosages and will be able to readily modify administration to achieve such dosages.
  • a therapeutically effective amount of a compound or composition disclosed herein can be measured by the therapeutic effectiveness of the compound.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being used.
  • the therapeutically effective amount of a disclosed compound is sufficient to establish a maximal plasma concentration.
  • Preliminary doses as, for example, determined according to animal tests, and the scaling of dosages for human administration is performed according to art-accepted practices.
  • Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 /ED 50 .
  • Compositions that exhibit large therapeutic indices are preferable.
  • Data obtained from the cell culture assays or animal studies can be used in formulating a range of dosage for use in humans.
  • Therapeutically effective dosages achieved in one animal model may be converted for use in another animal, including humans, using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Reports 50(4):219-244 (1966) and the following table (Table 3) for Equivalent Surface Area Dosage Factors).
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • a therapeutically effective amount may vary with the subject's age, condition, and gender, as well as the severity of the medical condition in the subject.
  • the dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.
  • the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer and thyroid cancer.
  • the cancer is breast cancer.
  • the cancer is ovarian cancer.
  • the cancer is bladder cancer.
  • the cancer is uterine cancer.
  • the cancer is prostate cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is thyroid cancer.
  • At least one entity selected from the compounds of Formula (I), or tautomers thereof, stereoisomers or a mixture of stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and deuterated derivatives thereof is administered to treat cancer in a subject in need thereof.
  • the cancer is selected from breast cancer, prostate cancer, bone cancer, brain cancer, colorectal cancer, lung cancer, ovarian cancer, uterine cancer, liposarcoma, liver cancer, rhabdoid cancer, sarcoma, skin cancer, kidney cancer, stomach cancer, pancreatic cancer, esophageal cancer, head and neck cancer, bladder cancer, leukemia, lymphoma and thyroid cancer.
  • the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is bone cancer. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is liposarcoma. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is rhabdoid cancer. In some embodiments, the cancer is sarcoma. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is stomach cancer.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is thyroid cancer. [00211] In some embodiments, the lung cancer is selected from non-small cell lung cancer NSCLC, small cell lung cancer (SCLC), squamous cell carcinoma, and adenocarcinoma. In some embodiments, the lung cancer is non-small cell lung cancer NSCLC. In some embodiments, the lung cancer is small cell lung cancer (SCLC).
  • SCLC small cell lung cancer
  • the lung cancer is squamous cell carcinoma. In some embodiments the lung cancer is adenocarcinoma.
  • the breast cancer is selected from ER-positive/HR- positive, HER2-negative breast cancer; ER-positive/HR-positive, HER2-positive breast cancer; triple negative breast cancer (TNBC), and inflammatory breast cancer.
  • the breast cancer is ER-positive/HR-positive.
  • the breast cancer is HER2-negative breast cancer.
  • the breast cancer is ER-positive/HR-positive.
  • the breast cancer is HER2-positive breast cancer.
  • the breast cancer is triple negative breast cancer (TNBC).
  • the breast cancer is inflammatory breast cancer.
  • the breast cancer is selected from endocrine resistant breast cancer, trastuzumab or pertuzumab resistant breast cancer, breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition.
  • the breast cancer is endocrine resistant breast cancer.
  • the breast cancer is trastuzumab or pertuzumab resistant breast cancer.
  • the breast cancer is breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition.
  • the breast cancer is advanced or metastatic breast cancer. In some embodiments, the breast cancer is advanced breast cancer. In some embodiments, the breast cancer is metastatic breast cancer.
  • At least one entity selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof, is administered as a pharmaceutical composition.
  • the subject has been previously treated with an anti-cancer agent.
  • the anti-cancer agent is enzalutamide, apalutamide, bicalutamide, darolutamide, flutamide, abiratarone, or a combination of any of the foregoing.
  • the anti-cancer agent is enzalutamide.
  • the cancer is selected from breast cancer, prostate cancer, bone cancer, brain cancer, colorectal cancer, lung cancer, ovarian cancer, uterine cancer, liposarcoma, liver cancer, rhabdoid cancer, sarcoma, skin cancer, kidney cancer, stomach cancer, pancreatic cancer, esophageal cancer, head and neck cancer, bladder cancer, leukemia, lymphoma and thyroid cancer.
  • the cancer is breast cancer.
  • the cancer is prostate cancer.
  • the cancer is bone cancer. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is liposarcoma. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is rhabdoid cancer. In some embodiments, the cancer is sarcoma. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is esophageal cancer.
  • the cancer is head and neck cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is thyroid cancer. [00218] In some embodiments, provided herein is a use of at least one entity selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof, in the preparation of a medicament. In some embodiments, the medicament is for the treatment of cancer.
  • the cancer is selected from breast cancer, prostate cancer, bone cancer, brain cancer, colorectal cancer, lung cancer, ovarian cancer, uterine cancer, liposarcoma, liver cancer, rhabdoid cancer, sarcoma, skin cancer, kidney cancer, stomach cancer, pancreatic cancer, esophageal cancer, head and neck cancer, bladder cancer, leukemia, lymphoma and thyroid cancer.
  • the cancer is breast cancer.
  • the cancer is prostate cancer.
  • the cancer is bone cancer.
  • the cancer is brain cancer.
  • the cancer is colorectal cancer.
  • the cancer is lung cancer.
  • the cancer is ovarian cancer.
  • the cancer is uterine cancer. In some embodiments, the cancer is liposarcoma. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is rhabdoid cancer. In some embodiments, the cancer is sarcoma. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is thyroid cancer.
  • a method of treating a disease or condition modulated at least in part by CDK4 in a subject comprising administering to the subject in need thereof with at least one entity selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof.
  • at least one compound e.g., entity
  • is selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof may be administered in combination with another therapeutic agent.
  • the other therapeutic agent can provide additive or synergistic value relative to the administration of a compound of the present disclosure alone.
  • the therapeutic agent can be selected from, for example, hormones and hormonal analogues; signal transduction pathway inhibitors; topoisomerase I inhibitors; topoisomerase II inhibitors; antimetabolite neoplastic agents; antibiotic neoplastic agents; alkylating agents; anti-microtubule agents; platinum coordination complexes; aromatase inhibitors; and anti-mitotic agents.
  • the therapeutic agent may be a hormone or hormonal analogue.
  • the therapeutic agent may be a signal transduction pathway inhibitor.
  • the therapeutic agent may be a topoisomerase I inhibitor.
  • the therapeutic agent may be a topoisomerase II inhibitor.
  • the therapeutic agent may be an antimetabolite neoplastic agent. In some embodiments, the therapeutic agent may be an antibiotic neoplastic agent. In some embodiments, the therapeutic agent may be an alkylating agent. In some embodiments, the therapeutic agent may be an anti- microtubule agent. In some embodiments, the therapeutic agent may be a platinum coordination complex. In some embodiments, the therapeutic agent may be an aromatase inhibitor. In some embodiments, the therapeutic agent may be an anti- mitotic agent. [00222] In some embodiments, the aromatase inhibitor may be selected from anastrazole, letrozole, vorozole, fadrozole, exemestane, and formestane.
  • the aromatase inhibitor is anastrazole. In some embodiments, the aromatase inhibitor may be letrozole. In some embodiments, the aromatase inhibitor may be vorozole. In some embodiments, the aromatase inhibitor may be fadrozole. In some embodiments, the aromatase inhibitor may be exemestane. In some embodiments, the aromatase inhibitor may be formestane. [00223] In some embodiments, the anti-mitotic agent may be selected from paclitaxel, docetaxel, and Abraxane. In some embodiments, the anti-mitotic agent may be paclitaxel. In some embodiments, the anti-mitotic agent may be docetaxel.
  • the anti-mitotic agent may be Abraxane.
  • at least one entity selected from the compounds of Formula (I), or tautomers thereof, stereoisomers or a mixture of stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and deuterated derivatives thereof may be administered in combination with a hormone or hormonal analog.
  • at least one entity selected from the compounds of Formulae (I), or tautomers thereof, stereoisomers or a mixture of stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and deuterated derivatives thereof may be administered in combination with a signal transduction pathway inhibitor.
  • At least one entity selected from the compounds of Formula (I), or tautomers thereof, stereoisomers or a mixture of stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and deuterated derivatives thereof may be administered in combination with an antimetabolite neoplastic agent.
  • at least one entity selected from the compounds of Formula (I), or tautomers thereof, stereoisomers or a mixture of stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and deuterated derivatives thereof may be administered in combination with a topoisomerase I inhibitor.
  • At least one entity selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof may be administered in combination with a topoisomerase II inhibitor. In some embodiments, at least one entity selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof, may be administered in combination with an aromatase inhibitor. Examples [00225] The examples and preparations provided below further illustrate and exemplify the compounds as disclosed herein and methods of preparing such compounds. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations.
  • Step 2 Preparation of (1S*,2R*,5R*)-( ⁇ )-2-(benzyloxy)-3,3-dimethoxy-8- oxabicyclo[3.2.1]octane
  • 1S*,2R*,5R*)-( ⁇ )-3,3-dimethoxy-8-oxabicyclo[3.2.1]octan- 2-ol (4 g, 21.25 mmol, 1 eq) in DMF (40 mL) was added NaH (1.36 g, 34.00 mmol, 60% purity, 1.6 eq) at 0 °C, and the mixture was stirred for 30 min at that temperature, followed by slow addition of bromomethylbenzene (5.45 g, 31.88 mmol, 3.79 mL, 1.5 eq).
  • Step 3 Preparation of (1S*,2R*,5R*)-( ⁇ )-2-(benzyloxy)-8-oxabicyclo[3.2.1]octan-3- one [00232] To a solution of (1S*,2R*,5R*)-( ⁇ )-2-(benzyloxy)-3,3-dimethoxy-8- oxabicyclo[3.2.1]octane (5.3 g, 19.04 mmol, 1 eq) in acetone (50 mL) and water (2.5 mL) was added TsOH ⁇ H2O (9.05 g, 47.60 mmol, 2.5 eq). The mixture was stirred at 60 °C for 12 h.
  • Step 4 Preparation of (1S*,2S*,3S*,5R*)-( ⁇ )2-(benzyloxy)-8-oxabicyclo[3.2.1]octan- 3-ol
  • 1S*,2R*,5R*)-( ⁇ )-2-(benzyloxy)-8-oxabicyclo[3.2.1]octan- 3-one (4.2 g, 18.08 mmol, 1 eq) in MeOH (50 mL) was added NaBH 4 (1.37 g, 36.16 mmol, 2 eq) portionwise at 0 °C.
  • the mixture was then warmed up to 25 °C and stirred for 1 h under N 2 atmosphere.
  • Step 5 Preparation of (1S*,2R*,3S*,5R*)-( ⁇ )-2-(benzyloxy)-8-oxabicyclo[3.2.1]octan- 3-yl methanesulfonate
  • 1S*,2S*,3S*,5R*)-( ⁇ )2-(benzyloxy)-8- oxabicyclo[3.2.1]octan-3-ol 500.00 mg, 2.13 mmol, 1 eq
  • DMAP 2.09 g, 17.07 mmol, 8 eq
  • TEA 1.73 g, 17.07 mmol, 2.38 mL, 8 eq
  • methanesulfonyl chloride 3.15 g, 27.50 mmol, 2.13 mL, 12.89 eq
  • the mixture was then stirred at 80 °C for 12 h.
  • the reaction mixture was cooled to room temperature and poured into sat. NaHCO3 solution (20 mL).
  • the organic layer was isolated, and the aqueous phase was extracted with ethyl acetate (20 mL x 2).
  • the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step 6 Preparation of (1S*,2S*,3R*,5R*)-( ⁇ )-3-azido-2-(benzyloxy)-8- oxabicyclo[3.2.1]octane
  • 1S*,2R*,3S*,5R* a solution of (1S*,2R*,3S*,5R*)-( ⁇ )-2-(benzyloxy)-8- oxabicyclo[3.2.1]octan-3-yl methanesulfonate (600 mg, 1.92 mmol, 1 eq) in DMF (8 mL) was added NaN 3 (374.60 mg, 5.76 mmol, 3 eq). The mixture was stirred at 100 °C for 2 h under N2 atmosphere.
  • Step 7 Preparation of (1S*,2S*,3R*,5R*)-( ⁇ )-3-amino-8-oxabicyclo[3.2.1]octan-2-ol
  • 1S*,2S*,3R*,5R* a solution of (1S*,2S*,3R*,5R*)-( ⁇ )-3-azido-2-(benzyloxy)-8- oxabicyclo[3.2.1]octane (100 mg, 0.386 mmol, 1 eq) in MeOH (5 mL) was added Pd/C (100.00 mg, 0.094 mmol, 10% purity) and Pd(OH)2/C (100 mg, 0.386 mmol, 10% purity).
  • Step 2 Preparation of tert-butyl (1S*,2R*,5R*)-( ⁇ )-2-(benzyloxy)-3,3-dimethoxy-8- azabicyclo[3.2.1]octane-8-carboxylate [00238] To a solution of tert-butyl (1S*,2R*,5R*)-( ⁇ )-2-hydroxy-3,3-dimethoxy-8- azabicyclo[3.2.1]octane-8-carboxylate (30 g, 104.40 mmol, 1 eq) in THF (200 mL) was added NaH (4.59 g, 114.84 mmol, 60% purity, 1.1 eq) at 0 °C.
  • Step 3 Preparation of tert-butyl (1S*,2R*,5R*)-( ⁇ )-2-(benzyloxy)-3-oxo-8- azabicyclo[3.2.1]octane-8-carboxylate [00239]
  • Step 4 Preparation of tert-butyl (1S*,2R*,3S*,5R*)-( ⁇ )-2-(benzyloxy)-3-hydroxy-8- azabicyclo[3.2.1]octane-8-carboxylate [00240] To a solution of tert-butyl (1S*,2R*,5R*)-( ⁇ )-2-(benzyloxy)-3-oxo-8- azabicyclo[3.2.1]octane-8-carboxylate (16.2 g, 48.88 mmol, 1 eq) in MeOH (200 mL) was added NaBH 4 (2.98 g, 78.77 mmol, 1.61 eq) at 0 °C under N 2 .
  • Step 5 Preparation of tert-butyl (1S*,2R*,3S*,5R*)-( ⁇ )-2-(benzyloxy)-3- ((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate [00241] To a solution of tert-butyl (1S*,2R*,3S*,5R*)-( ⁇ )-2-(benzyloxy)-3-hydroxy- 8-azabicyclo[3.2.1]octane-8-carboxylate (19 g, 56.99 mmol, 1 eq), DIEA (29.46 g, 227.94 mmol, 39.70 mL, 4 eq), DMAP (27.85 g, 227.94 mmol, 4 eq) in DCE (500 mL) was added methanesulfonyl chloride (21.71 g, 189.52 mmol, 14.67 m
  • Step 6 Preparation of tert-butyl (1S*,2R*,3R*,5R*)-( ⁇ )3-azido-2-(benzyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate [00242] To a solution of tert-butyl (1S*,2R*,3S*,5R*)-( ⁇ )-2-(benzyloxy)-3- ((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (11 g, 26.73 mmol, 1 eq) in DMF (150 mL) was added NaN 3 (4.33 g, 66.61 mmol, 2.49 eq).
  • Step 7 Preparation of tert-butyl (1S*,2S*,3R*,5R*)-( ⁇ )-3-amino-2-hydroxy-8- azabicyclo[3.2.1]octane-8-carboxylate [00243] To a solution of tert-butyl (1S*,2R*,3R*,5R*)-( ⁇ )-3-azido-2-(benzyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (4 g, 11.16 mmol, 1 eq) in MeOH (20 mL) was added Pd/C (2.00 g, 1.88 mmol, 10% purity) and Pd(OH)2 (2.00 g, 1.42 mmol, 10% purity).
  • Step 2 Preparation of 5-bromo-3-fluoro-N 1 -isopropylbenzene-1,2-diamine
  • MeOH 300 mL
  • H 2 O 100 mL
  • Fe powder 52.40 g, 938.32 mmol, 5 eq
  • NH4Cl 50.19 g, 938.32 mmol, 5 eq
  • Step 3 Preparation of N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)acetamide
  • a mixture of 5-bromo-3-fluoro-N 1 -isopropylbenzene-1,2-diamine (3 g, 12.14 mmol, 1 eq), Ac 2 O (1.36 g, 13.35 mmol, 1.25 mL, 1.1 eq) and DIEA (4.71 g, 36.42 mmol, 6.34 mL, 3 eq) in THF (40 mL) was stirred at 50 °C for 12 h. The reaction mixture was poured to sat. aq. NaHCO 3 (100 mL).
  • Step 4 Preparation of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole [00247] A solution of N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)acetamide (3.2 g, 11.07 mmol, 1 eq) in AcOH (60 mL) was stirred at 140 °C for 2 h. The mixture was cooled to room temperature and the volatiles were removed under reduced pressure.
  • Step 5 Preparation of 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazole
  • Step 2 Preparation of 2-(6-bromo-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)propan-2-ol
  • the reaction vessel was cooled to 25 °C, and the reaction mixture was concentrated under reduced pressure.
  • Step 3 Preparation of 2-(4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)propan-2-ol
  • Step 2 Preparation of 6-bromo-4-fluoro-1H-indole [00253] To a solution of (E)-2-(4-bromo-2-fluoro-6-nitrophenyl)-N,N-dimethylethen- 1-amine (30 g, 103.77 mmol, 1 eq) in H 2 O (70 mL) and EtOH (350 mL) was added Fe powder (28.98 g, 518.85 mmol, 5 eq) and AcOH (31.16 g, 518.85 mmol, 29.70 mL, 5 eq), and the mixture was stirred for 2 h at 80 °C.
  • Step 3 Preparation of 6-bromo-4-fluoro-1-(phenylsulfonyl)-1H-indole
  • 6-bromo-4-fluoro-1H-indole 11 g, 51.39 mmol, 1 eq
  • THF 150 mL
  • NaH 2.47 g, 61.67 mmol, 60% purity, 1.2 eq
  • the mixture was stirred for 5 min, and benzenesulfonyl chloride (18.15 g, 102.79 mmol, 13.12 mL, 2 eq) was subsequently added at 0 °C.
  • the reaction mixture was warmed to 25 °C and stirred for 3h.
  • the reaction mixture was quenched with aq. NH 4 Cl (300 mL) slowly, and the aqueous phase was extracted with EtOAc (200 mL x3).
  • the combined organic phase was washed with brine (50 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuum.
  • the resulting crude product was purified by flash silica gel chromatography to give 6- bromo-4-fluoro-1-(phenylsulfonyl)-1H-indole (9.4 g, 48.02% yield) as a yellow solid.
  • Step 4 Preparation of 6-bromo-4-fluoro-2-methyl-1-(phenylsulfonyl)-1H-indole
  • 6-bromo-4-fluoro-1-(phenylsulfonyl)-1H-indole 7.4 g, 20.89 mmol, 1 eq
  • LDA 2 M, 15.67 mL, 1.5 eq
  • Step 5 Preparation of 6-bromo-4-fluoro-2-methyl-1H-indole
  • aqueous KOH 4.27 g, 76.04 mmol, 5 eq
  • the reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (100 mL x 3).
  • Step 6 Preparation of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-indole [00257]
  • a solution of 6-bromo-4-fluoro-2-methyl-1H-indole (2.4 g, 10.52 mmol, 1 eq), 2-bromopropane (2.59 g, 21.05 mmol, 1.98 mL, 2 eq), Cs 2 CO 3 (6.86 g, 21.05 mmol, 2 eq) in DMF (24 mL) was stirred at 80 °C for 12 h under N2 atmosphere.
  • the reaction mixture was cooled to room temperature, poured into water (50 mL) and extracted with EtOAc (50 mL x3).
  • Step 7 Preparation of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-indole-3-carbonitrile
  • 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-indole 300 mg, 1.11 mmol, 1 eq
  • acetonitrile 1 mL
  • N-(oxomethylene)sulfamoyl chloride 314.36 mg, 2.22 mmol, 193.33 ⁇ L, 2 eq
  • Step 8 Preparation of 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indole-3-carbonitrile
  • 6-bromo-4-fluoro-1-isopropyl- 2-methyl-1H-indole-3-carbonitrile 120 mg, 0.406 mmol, 1 eq
  • 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane 154.87 mg, 0.61 mmol, 1.5 eq
  • 1,4-dioxane 3 mL
  • Pd(dppf)Cl2 29.75 mg, 0.00407 mmol, 0.1 eq
  • KOAc 79.80 mg, 0.813 mmol
  • Step 1 Preparation of isopropyl 6-bromo-4-fluoro-1-isopropyl-1H-indole-2- carboxylate [00260] To a solution of ethyl 6-bromo-4-fluoro-1H-indole-2-carboxylate (1.1 g, 3.88 mmol, 1.0 eq) in DMF (3 mL) was added Cs 2 CO 3 (3.8 g, 11.64 mmol, 3.0 eq) under N2.
  • Step 2 Preparation of 2-(6-bromo-4-fluoro-1-isopropyl-1H-indol-2-yl)propan-2-ol [00261] To a cooled solution of isopropyl 6-bromo-4-fluoro-1-isopropyl-1H-indole- 2-carboxylate (1.2 g, 3.50 mmol, 1.0 eq) in THF (10 mL) was added MeMgBr (3.0 M, 7.00 mL, 6.0 eq) at 0 °C.
  • Step 3 Preparation of 2-(6-bromo-4-fluoro-3-iodo-1-isopropyl-1H-indol-2-yl)propan- 2-ol
  • 2-(6-bromo-4-fluoro-1-isopropyl-indol-2-yl) propan-2-ol 230.0 mg, 0.732 mmol, 1.0 eq
  • NIS 247.0 mg, 1.10 mmol, 1.5 eq
  • Step 4 Preparation of 6-bromo-4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H- indole-3-carbonitrile
  • 2-(6-bromo-4-fluoro-3-iodo-1-isopropyl-1H-indol-2- yl)propan-2-ol 250.0 mg, 0.568 mmol, 1.0 eq
  • CuCN 61.0 mg, 0.682 mmol, 1.2 eq
  • DMF 8 mL
  • Pd(PPh3)4 131.3 mg, 0.114 mmol, 0.2 eq
  • Step 5 Preparation of 4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carbonitrile
  • a mixture of 6-bromo-4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H- indole-3-carbonitrile (50.0 mg, 0.147 mmol, 1.0 eq)
  • Pin2B2 (93.6 mg, 0.369 mmol, 2.5 eq)
  • Pd(dppf)Cl 2 (43.1 mg, 0.059 mmol, 0.4 eq)
  • KOAc 43.4 mg, 0.442 mmol, 3.0 eq) in dioxane (3 mL) was degassed and backfilled with N2 for three times, and then stirred at 90 °C for 4 h under N 2 atmosphere.
  • Step 2 Preparation of 2-amino-6-bromo-4-fluoro-3-nitrophenol [00266] To a solution of 6-bromo-4-fluoro-2,3-dinitrophenol (7.7 g, 27.40 mmol, 1.0 eq) in MeOH (150 mL) was added HCl (12 M, 77 mL) and SnCl2 (15.6 g, 82.21 mmol, 3.0 eq) under N 2 atmosphere. The mixture was stirred at 20 °C for 15 min until starting material was consumed. The reaction mixture was poured into water (200 mL) and then extracted with EtOAc (200 mL x 2).
  • Step 3 Preparation of 8-bromo-6-fluoro-5-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one [00267]
  • 2-amino-6-bromo-4-fluoro-3-nitrophenol 2.0 g, 7.97 mmol, 1.0 eq
  • 2-chloroacetyl chloride 1.4 g, 11.95 mmol, 1.5 eq
  • DME 300 mL
  • Na2CO3 2.5 g, 23.90 mmol, 3.0 eq
  • Step 4 Preparation of 8-bromo-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-amine
  • 8-bromo-6-fluoro-5-nitro-2H-benzo[b][1,4]oxazin-3(4H)- one 2.0 g, 6.87 mmol, 1.0 eq
  • THF 100 mL
  • NaBH4 3.2 g, 85.64 mmol, 12.5 eq
  • I2 4.4 g, 17.18 mmol, 2.5 eq
  • Step 5 Preparation of N-(8-bromo-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)- 2-hydroxy-2-methylpropanamide
  • 2-hydroxy-2-methyl-propanoic acid 83.4 mg, 0.801 mmol, 2.3 eq
  • DIEA 282.5 mg, 2.19 mmol, 6.4 eq
  • HATU 415.5 mg, 1.09 mmol, 3.2 eq).
  • Step 6 Preparation of 2-(6-bromo-8-fluoro-3,4-dihydro-5-oxa-1,2a- diazaacenaphthylen-2-yl)propan-2-ol
  • a mixture of N-(8-bromo-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)- 2-hydroxy-2-methylpropanamide (300.0 mg, 0.900 mmol, 1.0 eq) in AcOH (10 mL) was stirred at 130 °C for 12 h under N 2 atmosphere. The reaction mixture was cooled to room temperature and poured into water (20 mL).
  • Step 7 Preparation of 2-(8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4- dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)propan-2-ol [00271] The mixture of 2-(6-bromo-8-fluoro-3,4-dihydro-5-oxa-1,2a- diazaacenaphthylen-2-yl)propan-2-ol (110.0 mg, 0.349 mmol, 1.0 eq), 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (88.6 mg, 0.349 mmol, 1.0 eq) and KOAc (102.8 mg, 1.05 mmol, 3.0 eq) in dioxane (2
  • Step 2 Preparation of methyl 3-bromo-4-methyl-2-oxopentanoate [00273] To a solution of methyl 4-methyl-2-oxopentanoate (4.9 g, 33.92 mmol, 1.0 eq) in DCM (50 mL) was added Br 2 (5.4 g, 33.92 mmol, 1.8 mL, 1.0 eq) at 0 °C. After the completion of addition, the solution was stirred at 25 °C for 12 h. The reaction was carefully quenched with saturated aqueous NaHCO 3 (100 mL), and the aqueous phase was extracted with EtOAc (100 mL x 3).
  • Step 3 Preparation of methyl 6-bromo-8-fluoro-3-isopropylimidazo[1,2-a]pyridine-2- carboxylate
  • a solution of 5-bromo-3-fluoro-pyridin-2-amine (1.0 g, 5.24 mmol, 1.0 eq) and methyl 3-bromo-4-methyl-2-oxo-pentanoate (2.9 g, 13.09 mmol, 2.5 eq) in MeOH (8 mL) was stirred at 70 °C for 24 h. After the starting material was consumed, the reaction was cooled to room temperature. The volatiles were evaporated under reduced pressure to give the crude product, which was purified by flash silica gel chromatography.
  • Step 4 Preparation of 2-(6-bromo-8-fluoro-3-isopropylimidazo[1,2-a]pyridin-2- yl)propan-2-ol
  • methyl 6-bromo-8-fluoro-3-isopropylimidazo[1,2- a]pyridine-2-carboxylate 470.0 mg, 1.49 mmol, 1.0 eq
  • MeMgBr 3 M, 1.19 mL, 2.4 eq
  • Step 5 Preparation of (8-fluoro-2-(2-hydroxypropan-2-yl)-3-isopropylimidazo[1,2- a]pyridin-6-yl)boronic acid
  • Step 2 Preparation of (2R)-1-methoxycarbonylpyrrolidine-2-carboxylic acid [00278] To a solution of 2-benzyl 1-methyl (R)-pyrrolidine-1,2-dicarboxylate (2.44 g, 9.27 mmol, 1 eq) in MeOH (30 mL) was added Pd/C (300 mg, 10% purity). The suspension was degassed and backfilled with H 2 three times. After the mixture was stirred under H2 (30psi) at 25 °C for 12 h., the mixture was filtered through a pad of the Celite and the filtrate was concentrated in vacuo.
  • Step 3 Preparation of methyl (R)-2-((4-bromo-2-fluoro-6- (isopropylamino)phenyl)carbamoyl)pyrrolidine-1-carboxylate
  • (2R)-1-methoxycarbonylpyrrolidine-2-carboxylic acid 200 mg, 1.15 mmol, 1 eq
  • DIEA 298.54 mg, 2.31 mmol, 402.35 uL, 2 eq
  • HATU 658.73 mg, 1.73 mmol, 1.5 eq
  • Step 4 Preparation of methyl (R)-2-(6-bromo-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate
  • Step 5 Preparation of methyl (R)-2-(4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate
  • the mixture of methyl (R)-2-(6-bromo-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate 150 mg, 0.390 mmol, 1 eq)
  • 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane 148.70 mg, 0.586 mmol, 1.5 eq
  • KOAc 114.94 mg, 1.17 mmol, 3 eq
  • Pd(dppf)Cl2 28
  • Step 2 Preparation of 2-(bicyclo[1.1.1]pentan-1-yl)-6-bromo-4-fluoro-1-isopropyl-1H- benzo[d]imidazole [00286] A mixture of N-(4-bromo-2-fluoro-6- (isopropylamino)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (196.0 mg, 0.574 mmol, 1.0 eq) in AcOH (3 mL) was stirred at 140 °C for 1 h under N 2 atmosphere. The mixture was cooled to room temperature, and the volatiles were concentrated under reduced pressure.
  • Step 3 Preparation of 2-(bicyclo[1.1.1]pentan-1-yl)-4-fluoro-1-isopropyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole
  • 2-(1-bicyclo[1.1.1]pentanyl)-6-bromo-4-fluoro-1-isopropyl- benzimidazole (185.0 mg, 0.572 mmol, 1.0 eq)
  • B 2 pin 2 218.0 mg, 0.859 mmol, 1.5 eq
  • KOAc (168.5 mg, 1.72 mmol, 3.0 eq) in dioxane (1 mL) was degassed, backfilled with nitrogen three times, and then Pd(dppf)Cl2 (41.9 mg, 0.0572 mmol, 0.1 eq) was added under N 2 atmosphere.
  • Step 2 Preparation of (R)-6-bromo-4-fluoro-1-isopropyl-2-(pyrrolidin-3-yl)-1H- benzo[d]imidazole
  • Step 3 Preparation of tert-butyl (R)-3-(6-bromo-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate [00290] To a solution of (R)-6-bromo-4-fluoro-1-isopropyl-2-(pyrrolidin-3-yl)-1H- benzo[d]imidazole (2.06 g, 6.32 mmol, 1 eq) in DCM (50 mL) was added NaHCO 3 (aq) (5.31 g, 63.15 mmol, 2.46 mL, 10 eq in H2O (50 mL)) and Boc2O (689.12 mg, 3.16 mmol, 725.39 ⁇ L, 0.5 eq), and the mixture was stirred at 20 °C for 1 h.
  • Step 4 Preparation of tert-butyl (R)-3-(4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate
  • Step 2 Preparation of 2-fluoro-5-isopropylaniline
  • Pd/C 9.15 g, 8.60 mmol, 10% purity, 0.1 eq
  • Step 3 Preparation of 4-bromo-2-fluoro-5-isopropylaniline [00295] To a solution of 2-fluoro-5-isopropylaniline (6 g, 39.17 mmol, 1 eq) in CH 3 CN (100 mL) was added NBS (6.62 g, 37.21 mmol, 0.95 eq), and the mixture was stirred at 0 °C for 1 h.
  • Step 4 Preparation of N-(4-bromo-2-fluoro-5-isopropylphenyl)acetamide
  • 4-bromo-2-fluoro-5-isopropylaniline (4.74 g, 20.42 mmol, 1 eq) in THF (94 mL) was added Ac2O (2.29 g, 22.47 mmol, 2.11 mL, 1.1 eq) and DIEA (7.92 g, 61.27 mmol, 10.67 mL, 3 eq).
  • the mixture was stirred at 50 °C for 12 h.
  • the reaction mixture was cooled to room temperature, and the volatiles were removed under reduced pressure.
  • Step 5 Preparation of N-(4-bromo-6-fluoro-3-isopropyl-2-nitrophenyl)acetamide
  • N-(4-bromo-2-fluoro-5-isopropylphenyl)acetamide 5 g, 18.24 mmol, 1 eq
  • DCM 50 mL
  • HNO 3 45.97 g, 729.58 mmol, 32.84 mL, 40 eq
  • the mixture was warmed and stirred at 20 °C for 2 h and then at 40 °C for 16 hs.
  • Step 6 Preparation of N-(2-amino-4-bromo-6-fluoro-3-isopropylphenyl)acetamide
  • N-(4-bromo-6-fluoro-3-isopropyl-2-nitrophenyl)acetamide 200 mg, 0.627 mmol, 1 eq
  • EtOH 3 mL
  • NH4Cl 1 mL
  • Fe 35.00 mg, 0.627 mmol, 1 eq
  • Step 7 Preparation of 6-bromo-4-fluoro-7-isopropyl-2-methyl-1H-benzo[d]imidazole [00299] N-(2-amino-4-bromo-6-fluoro-3-isopropylphenyl)acetamide (120 mg, 0.415 mmol, 1 eq) in AcOH (3 mL) was stirred at 140 °C for 2 h. The reaction mixture was cooled to room temperature, and the volatiles were removed under reduced pressure. The remaining residue was diluted with 20 mL of water, and the aqueous phase was extracted with EtOAc (20 mL x 2).
  • Step 8 Preparation of 4-fluoro-7-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazole
  • Step 2 Preparation of (R)-1-methyl-5-oxopyrrolidine-3-carboxylic acid
  • Step 3 Preparation of (R)-N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)-1-methyl- 5-oxopyrrolidine-3-carboxamide
  • Step 4 Preparation of 4-(6-bromo-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)-1- methylpyrrolidin-2-one
  • the solution of (3R)-N-[4-bromo-2-fluoro-6-(isopropylamino)phenyl]-1- methyl-5-oxo-pyrrolidine-3-carboxamide (50 mg, 0.134 mmol, 1 eq) in AcOH (1 mL) was stirred at 100 °C for 12 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and the volatiles were evaporated under reduced pressure.
  • Step 5 Preparation of 4-(4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-1-methylpyrrolidin-2-one [00305] A mixture of 4-(6-bromo-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)-1- methylpyrrolidin-2-one (35 mg, 0.0988 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (37.64 mg, 0.148 mmol, 1.5 eq), KOAc (19.39 mg, 0.198 mol, 2 eq) and Pd(dppf)Cl 2 (7.23 mg, 0.00988 mmol, 0.1
  • Step 2 Preparation of methyl 4-fluoro-6-nitrobenzo[d]thiazole-2-carboxylate [00309] To a solution of methyl 2-((2,6-difluoro-4-nitrophenyl)amino)-2-oxoacetate (5.01 g, 19.26 mmol, 1 eq) in xylene (50 mL) was added Lawesson’s reagent (4.67 g, 11.55 mmol, 0.6 eq), and the mixture was stirred at 110 °C for 1 h under N2 atmosphere. Cs2CO3 (18.83 g, 57.78 mmol, 3 eq) was then added and the mixture was stirred at 140 °C for 12 h.
  • Lawesson’s reagent 4.67 g, 11.55 mmol, 0.6 eq
  • the reaction was cooled to room temperature.
  • the reaction mixture was filtered via a short pad of celite, rinsed with ethyl acetate (100 mL).
  • the filtrate was washed with H2O (20 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure.
  • Step 3 Preparation of methyl 6-amino-4-fluorobenzo[d]thiazole-2-carboxylate [00310] To a solution of methyl 4-fluoro-6-nitrobenzo[d]thiazole-2-carboxylate (1.34 g, 5.23 mmol, 1 eq) in ethanol (12 mL) and H 2 O (3 mL) were added Fe (876.22 mg, 15.69 mmol, 3 eq) and NH4Cl (839.29 mg, 15.69 mmol, 3 eq), and the mixture was stirred at 70 °C for 1 h.
  • Step 4 Preparation of methyl 6-amino-7-bromo-4-fluorobenzo[d]thiazole-2- carboxylate [00311] To a solution of methyl 6-amino-4-fluorobenzo[d]thiazole-2-carboxylate (710 mg, 3.14 mmol, 1 eq) in DMF (8 mL) was added NBS (614.45 mg, 3.45 mmol, 1.1 eq), and the mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into H2O (15 mL) and the aqueous phase was extracted with EtOAc (15 mL x 3).
  • Step 5 Preparation of 6-amino-4-fluoro-7-(prop-1-en-2-yl)benzo[d]thiazole-2- carboxylic acid
  • Step 6 Preparation of methyl 6-amino-4-fluoro-7-(prop-1-en-2-yl)benzo[d]thiazole-2- carboxylate [00313] To a solution of 6-amino-4-fluoro-7-isopropenyl-1, 3-benzothiazole-2- carboxylic acid (170 mg, 0.674 mmol, 1 eq) in methanol (3 mL) and DCM (9 mL) was added TMSCHN 2 (230.92 mg, 2.02 mmol, 3 eq), and the reaction solution was stirred at 0 °C for 0.5 h. The reaction mixture was poured into H2O (15 mL) and extracted with EtOAc (15 mL x 3).
  • Step 7 Preparation of methyl 6-amino-4-fluoro-7-isopropylbenzo[d]thiazole-2- carboxylate
  • Step 8 Preparation of methyl 6-bromo-4-fluoro-7-isopropylbenzo[d]thiazole-2- carboxylate [00315]
  • the ice-cooled mixture of tert-butyl nitrite (211.38 mg, 2.05 mmol, 243.81 ⁇ L, 2.5 eq) and CuBr 2 (183.14 mg, 0.820 mmol, 38.40 ⁇ L, 1 eq) in acetonitrile (10 mL) was added dropwise a solution of methyl 6-amino-4-fluoro-7-isopropyl-1, 3- benzothiazole-2-carboxylate (220 mg, 0.820 mmol, 1 eq) in acetonitrile (10 mL).
  • Step 9 Preparation of 2-(6-bromo-4-fluoro-7-isopropylbenzo[d]thiazol-2-yl)propan-2- ol
  • MeMgBr 3 M, 376.29 ⁇ L, 2.5 eq
  • Step 10 Preparation of 2-(4-fluoro-7-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzo[d]thiazol-2-yl)propan-2-ol [00317] To a degassed and nitrogen backfilled solution of 2-(6-bromo-4-fluoro-7- isopropylbenzo[d]thiazol-2-yl)propan-2-ol (80 mg, 0.241 mmol, 1 eq) and 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (122.29 mg, 0.482 mmol, 2 eq) in 1,4-dioxane (1 mL) were added Pd(dppf)Cl 2 (17.62 mg, 0.0241 mmol, 0.1 eq) and KOAc
  • Step 2 Preparation of N-(4-bromo-6-fluoro-3-isopropyl-2-nitrophenyl)acetamide
  • N-(4-bromo-2-fluoro-5-isopropylphenyl)acetamide 1.9 g, 6.93 mmol, 1 eq
  • DCM 20 mL
  • HNO 3 6.93 mmol, 72.3 mmol, 4.8 mL, 68% purity, 10.4 eq
  • H2SO4 6.80 g, 69.31 mmol, 3.69 mL, 10 eq
  • Step 3 Preparation of 4-bromo-6-fluoro-3-isopropyl-2-nitroaniline
  • a mixture of N-(4-bromo-6-fluoro-3-isopropyl-2-nitrophenyl)acetamide (1 g, 3.13 mmol, 1 eq) and H 2 SO 4 (1.54 g, 15.7 mmol, 5 eq) in EtOH (10 mL) was stirred at 90 °C for 2 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2).
  • Step 4 Preparation of 4-bromo-6-fluoro-3-isopropylbenzene-1,2-diamine
  • Step 5 Preparation of 2-(6-bromo-4-fluoro-7-isopropyl-1H-benzo[d]imidazol-2- yl)propan-2-ol
  • DIEA 653.8 mg, 5.06 mmol, 2.5 eq
  • HATU 923.2 mg, 2.43 mmol, 1.2 eq
  • Step 6 Preparation of 2-(4-fluoro-7-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)propan-2-ol
  • Pin 2 B 2 362.6 mg, 1.43 mmol, 1.5 eq
  • KOAc 280.2 mg, 2.86 mmol, 3 eq
  • Pd(dppf)Cl2 69.6 mg, 0.095 mmol, 0.1 eq) in dioxane (4 mL) was degassed and backfilled with N 2 for 3 times, and then stirred at 90 °C for 1 hour under N2 atmosphere.
  • Step 2 Preparation of (1R*,2R*,5S*)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3-one [00326] To a solution of (((1R*,5S*)-8-oxabicyclo[3.2.1]oct-2-en-3- yl)oxy)trimethylsilane (3 g, 15.13 mmol, 1 eq) in THF (30 mL) and water (30 mL) was added m-CPBA (3.38 g, 16.64 mmol, 85% purity, 1.1 eq) at -10 °C, and the mixture was stirred at -10 °C for 2 hours.
  • m-CPBA 3.38 g, 16.64 mmol, 85% purity, 1.1 eq
  • Step 4 Preparation of (1R,2S,3R,5S)-3-amino-8-oxabicyclo[3.2.1]octan-2-ol
  • 1R*,2S*,5S* 2-hydroxy-8-oxabicyclo[3.2.1]octan-3- one oxime (1.6 g, 10.18 mmol, 1 eq) and MoO 3 (5.13 g, 35.6 mmol, 3.5 eq) in MeOH (20 mL) was added NaBH4 (10.4 g, 274.9 mmol, 27 eq) in portions.
  • Step 2 Preparation of 6-bromo-2-(3,3-difluorocyclopentyl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazole [00330] A mixture of N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)-3,3- difluorocyclopentane-1-carboxamide (1.2 g, 3.16 mmol, 1 eq) in AcOH (5 mL) was stirred at 140 °C for 1 hour under N2 atmosphere.
  • Step 3 Preparation of 2-(3,3-difluorocyclopentyl)-4-fluoro-1-isopropyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole
  • Pin2B2 (1.16 g, 4.57 mmol, 1.5 eq)
  • KOAc 896.6 mg, 9.14 mmol, 3 eq
  • Pd(dppf)Cl2 111.4 mg, 0.152 mmol, 0.05 eq
  • Step 2 Preparation of 3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-4H-thiopyran- 4-one
  • DCM dimethylethyl
  • 2-(chloromethoxy)ethyl)trimethylsilane 1.11 g, 6.66 mmol, 1.1 eq
  • DIEA 2.35 g, 18.16 mmol, 3 eq
  • Step 3 Preparation of (3S*,4S*)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-2H- thiopyran-4-ol
  • 3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-4H- thiopyran-4-one (1 g, 3.81 mmol, 1 eq) in THF (40 mL) was added L-Selectride (1 M, 4.19 mL, 1.1 eq) at -78 °C, and the mixture was stirred at -78 °C for 2 hours under N 2 atmosphere.
  • Step 4 Preparation of (3S*,4S*)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-2H- thiopyran-4-yl methanesulfonate
  • MsCl 3.19 g, 27.85 mmol, 2.16 mL, 8.18 eq
  • TEA 3.64 g, 35.97 mmol, 5 mL, 10.57 eq
  • DMAP 207.88 mg, 1.70 mmol, 0.5 eq
  • Step 5 Preparation of (2-((((3S,4R)-4-azidotetrahydro-2H-thiopyran-3- yl)oxy)methoxy)ethyl)trimethylsilane
  • 3S*,4S*)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro- 2H-thiopyran-4-yl methanesulfonate 750 mg, 2.19 mmol, 1 eq
  • DMF 10 mL
  • NaN3 550 mg, 8.46 mmol, 3.8 eq
  • Step 6 Preparation of (3S*,4R*)-4-azido-3-((2-(trimethylsilyl)ethoxy) methoxy) tetrahydro -2H-thiopyran 1,1-dioxide
  • m-CPBA 438 mg, 2.16 mmol, 85% purity, 2.5 eq
  • Step 7 Preparation of (3S*,4R*)-4-amino-3-((2-(trimethylsilyl)ethoxy)methoxy) tetrahydro-2H-thiopyran 1,1-dioxide
  • 3S*,4R*)-4-azido-3-((2- (trimethylsilyl)ethoxy)methoxy)tetrahydro-2H-thiopyran 1,1-dioxide 300 mg, 0.933 mmol, 1 eq
  • THF 0.5 mL
  • H 2 O 0.5 mL
  • PPh 3 489.5 mg, 1.87 mmol, 2 eq
  • Step 8 Preparation of (3S*,4R*)-4-amino-3-hydroxytetrahydro-2H-thiopyran 1,1- dioxide [00339] To a solution of (3S*,4R*)-4-amino-3-((2- (trimethylsilyl)ethoxy)methoxy)tetrahydro-2H-thiopyran 1,1-dioxide (100 mg, 0.338 mmol, 1 eq) in MeOH (5 mL) was added HCl/MeOH (4 M, 1 mL, 11.8 eq), and the mixture was stirred at 20 °C for 8 hours. After the completion of the reaction, the reaction mixture was filtered.
  • Step 2 Preparation of (((5,5-difluoro-2,2-dimethoxycyclohexyl)oxy)methyl)benzene [00341] To the suspension of NaH (2.8 g, 70.26 mmol, 60% purity, 1.84 eq) in THF (150 mL) was added 5,5-difluoro-2,2-dimethoxycyclohexan-1-ol (7.5 g, 38.23 mmol, 1 eq) at 0 °C, and the mixture was kept stirring for 0.5 hours at 0 °C. Then, BnBr (15 g, 87.7 mmol, 2.3 eq) was added at 0 °C.
  • Step 3 Preparation of 2-(benzyloxy)-4,4-difluorocyclohexan-1-one [00342] To a solution of (((5,5-difluoro-2,2- dimethoxycyclohexyl)oxy)methyl)benzene (3 g, 10.5 mmol, 1 eq) in aqueous acetone (prepared from acetone (30 mL) and H 2 O (1.5mL)), TsOH (180.4 mg, 1.05 mmol, 0.1 eq)was added, and the mixture was stirred at 60 °C for 3 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature.
  • Step 4 Preparation of (1S*,2R*)-2-(benzyloxy)-4,4-difluorocyclohexan-1-ol
  • 2-(benzyloxy)-4,4-difluorocyclohexan-1-one 1.5 g, 6.24 mmol, 1 eq
  • MeOH MeOH
  • NaBH 4 7.6 mg, 18.73 mmol, 3 eq
  • the mixture was slowly warmed to 20 °C and kept stirring for 2 hours. After the completion of the reaction, the mixture was quenched with saturated aqueous NH 4 Cl (100 mL) and extracted with EtOAc (100 mL x 2).
  • Step 5 Preparation of (1S,2R)-2-(benzyloxy)-4,4-difluorocyclohexyl methanesulfonate [00344] To a solution of (1S*,2R*)-2-(benzyloxy)-4,4-difluorocyclohexan-1-ol (700 mg, 2.9 mmol, 1 eq) in DCM (20 mL) was added Ms 2 O (1.26 g, 7.22 mmol, 2.5 eq) and TEA (1.17 g, 11.56 mmol, 4 eq), and the mixture was stirred at 20 °C for 16 hours .After the completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure.
  • Step 6 Preparation of ((((1R*,2R*)-2-azido-5,5-difluorocyclohexyl)oxy)methyl) benzene [00345] To a solution of (1S*,2R*)-2-(benzyloxy)-4,4-difluorocyclohexyl methanesulfonate (500 mg, 1.56 mmol, 1 eq) in DMF (20 mL) was added NaN3 (0.5 g, 7.69 mmol, 4.9 eq), and the mixture was stirred at 100 °C for 2 hours. After the completion of the reaction, the mixture was cooled to room temperature. The volatiles were removed under reduced pressure.
  • Step 7 Preparation of (1R,2R)-2-amino-5,5-difluorocyclohexan-1-ol
  • ((((1R*,2R*)-2-azido-5,5- difluorocyclohexyl)oxy)methyl)benzene (320 mg, 1.2 mmol, 1 eq) in MeOH (20 mL) was added Pd/C (1.27 g, 1.2 mmol, 10% purity, 1 eq) under N 2 atmosphere.
  • Pd/C (1.27 g, 1.2 mmol, 10% purity, 1 eq
  • Step 2 Preparation of (1R,2R)-2-((2-amino-5-bromo-3-fluorophenyl)amino)-1- methylcyclopentan-1-ol
  • (1R,2R)-2-((5-bromo-3-fluoro-2-nitrophenyl)amino)-1- methylcyclopentan-1-ol (2.1 g, 6.30 mmol, 1 eq) in DMF (20 mL) was added hypoboric acid (2.26 g, 25.21 mmol, 4 eq) and 4-(4-pyridyl)pyridine (98.45 mg, 0.630 mmol, 0.1 eq) at 0 °C, and the mixture was stirred at 20 °C for 16 hours under N 2 atmosphere.
  • Step 3 Preparation of N-(4-bromo-2-fluoro-6-(((1R,2R)-2-hydroxy-2- methylcyclopentyl)amino)phenyl)acetamide
  • (1R,2R)-2-((2-amino-5-bromo-3-fluorophenyl)amino)-1- methylcyclopentan-1-ol (1 g, 3.3 mmol, 1 eq)
  • HOAc 20 mL
  • Ac2O 505 mg, 4.95 mmol, 1.5 eq
  • Step 4 Preparation of (1R,2R)-2-(6-bromo-4-fluoro-2-methyl-1H-benzo[d]imidazol-1- yl)-1-methylcyclopentan-1-ol
  • N-(4-bromo-2-fluoro-6-(((1R,2R)-2-hydroxy-2- methylcyclopentyl)amino)phenyl)acetamide 700 mg, 2 mmol, 1 eq
  • POCl 3 (1.87 g, 12.17 mmol, 6 eq)
  • DIEA (1.57 g, 12.17 mmol, 6 eq
  • Step 5 Preparation of (1R,2R)-2-(4-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)-1-methylcyclopentan-1-ol
  • the mixture of (1R,2R)-2-(6-bromo-4-fluoro-2-methyl-1H- benzo[d]imidazol-1-yl)-1-methylcyclopentan-1-ol 400 mg, 1.22 mmol, 1 eq), Pin 2 B 2 (465.7 mg, 1.83 mmol, 1.5 eq), KOAc (360 mg, 3.67 mmol, 3 eq) and Pd(dppf)Cl2 (89 mg, 0.122 mmol, 0.1 eq) in dioxane (5 mL) was degassed and backfilled with N 2 for 3 times, and then stirred at 90 °C for 2 hours under
  • Step 2 Preparation of 4-chloro-2-fluoro-N-methyl-6-(3-methyl-1-oxobutan-2- yl)benzamide
  • TEA 765.3 mg, 7.56 mmol, 4 eq
  • AlMe3 2 M, 2.84 mL, 3 eq
  • Step 3 Preparation of 6-chloro-8-fluoro-4-isopropyl-2-methylisoquinolin-1(2H)-one
  • the solution of 4-chloro-2-fluoro-N-methyl-6-(3-methyl-1-oxobutan-2- yl)benzamide (500 mg, 1.84 mmol, 1 eq) in AcOH (10 mL) was stirred at 90 °C for 3 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (50 mL x 2).
  • Step 4 Preparation of 8-fluoro-4-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoquinolin-1(2H)-one
  • Pin 2 B 2 518.5 mg, 2.04 mmol, 2 eq
  • Pd(dppf)Cl 2 74.7 mg, 0.102 mmol, 0.1 eq
  • KOAc 300 mg, 3.06 mmol, 3 eq
  • Step 2 Preparation of ethyl (E)-3-(5-bromo-4-methylthiophen-2-yl)-4-methylpent-2- enoate [00357] To a suspension of NaH (2.75 g, 68.8 mmol, 60% purity, 2.5 eq) in THF (70 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (6.79 g, 30.26 mmol, 6 mL, 1.1 eq) dropwise at 0 °C. After the completion of the addition, the mixture was stirred at 0 °C for 0.5 hour and at 20 °C for an additional 0.5 hour.
  • Step 3 Preparation of (E)-3-(5-bromo-4-methylthiophen-2-yl)-4-methylpent-2-enoic acid [00358] To a solution of ethyl (E)-3-(5-bromo-4-methylthiophen-2-yl)-4-methylpent- 2-enoate (10 g, 31.5 mmol, 1 eq) in MeOH (60 mL) was added a solution of NaOH (6.3 g, 157.6 mmol, 5 eq) in H2O (60 mL) dropwise at 20 °C. The mixture was then stirred at 65 °C for 1 hour. After the completion of the reaction, the mixture was cooled to room temperature.
  • Step 4 Preparation of 2-bromo-7-isopropyl-3-methylthieno[3,2-c]pyridin-4(5H)-one [00359] To a solution of (E)-3-(5-bromo-4-methylthiophen-2-yl)-4-methylpent-2- enoic acid (5.5 g, 19 mmol, 1 eq) in diphenylether (55 mL) was added dropwise DPPA (7.85 g, 28.5 mmol, 6.2 mL, 1.5 eq). The mixture was stirred at 20 °C for 0.5 hour and subsequently heated at 140 °C for another 0.5 hour. After the completion of the reaction, the mixture was cooled to room temperature.
  • Step 5 Preparation of 2-bromo-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)- one [00360] To a solution of 2-bromo-7-isopropyl-3-methylthieno[3,2-c]pyridin-4(5H)- one (1.08 g, 3.77 mmol, 1 eq) in DMF (10 mL) was added Cs2CO3 (2.46 g, 7.55 mmol, 2 eq) and CH3I (1.07 g, 7.55 mmol, 2 eq), and the mixture was stirred at 20 °C for 1 hour.
  • Step 6 Preparation of 7-isopropyl-3,5-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)thieno[3,2-c]pyridin-4(5H)-one
  • a mixture of 2-bromo-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)- one 400 mg, 1.33 mmol, 1 eq
  • Pin2B2 507.5 mg, 2 mmol, 1.5 eq
  • KOAc 261.5 mg, 2.66 mmol, 2 eq
  • CataCXium A Pd G 2 (CAS: 1375477-29-4) (89.1 mg, 0.133 mmol, 0.1 eq) (89.1 mg, 0.133 mmol, 0.1 eq) in dioxane (5 mL) was degassed and backfilled with N 2 for 3 times and stirred at 100 °C for 1
  • Step 2 Preparation of 6-bromo-2-(2,2-difluorocyclopropyl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazole
  • N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)-2,2- difluorocyclopropane-1-carboxamide 500 mg, 1.42 mmol, 1 eq
  • POCl3 655 mg, 4.27 mmol, 3 eq
  • DIEA 552 mg, 4.27 mmol, 3 eq
  • Step 3 Preparation of 2-(2,2-difluorocyclopropyl)-4-fluoro-1-isopropyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole
  • Step 2 preparation of 2-(6-bromo-8-fluoroquinolin-3-yl)propan-2-ol
  • MeMgBr 3.0 M, 0.98 mL, 2.5 eq
  • Step 3 preparation of 2-(8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinolin-3-yl)propan-2-ol
  • Step 2 (Z)-1-(4-chloro-2-fluoro-phenyl)-3-(isopropylamino)but-2-en-1-one [00369] A mixture of (Z)-1-(4-chloro-2-fluoro-phenyl)-3-(dimethylamino)but-2-en-1- one (11.05 g, 45.7 mmol, 1 eq) and propan-2-amine (3.58 g, 60.5 mmol, 5.2 mL, 1.32 eq) in DMSO (150 mL) was stirred for 16 hours at 110 °C under N 2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature and concentrated in vacuo.
  • Step 3 7-chloro-1-isopropyl-2-methyl-quinolin-4-one
  • a mixture of (Z)-1-(4-chloro-2-fluoro-phenyl)-3-(isopropylamino)but-2-en-1- one (10.6 g, 41.45 mmol, 1 eq) and Cs 2 CO 3 (27.01 g, 82.90 mmol, 2 eq) in DMF (120 mL) was stirred for 16 hours at 100 °C under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The mixture was filtered through a short pad of celite, and the filtrate was concentrated in vacuo.
  • Step 4 7-chloro-3-iodo-1-isopropyl-2-methyl-quinolin-4-one [00371] A mixture of 7-chloro-1-isopropyl-2-methyl-quinolin-4-one (3 g, 12.73 mmol, 1 eq), I 2 (3.23 g, 12.73 mmol, 2.56 mL, 1 eq) and cerium ammonium nitrate (697.75 mg, 1.27 mmol, 0.1 eq) in MeCN (60 mL) was stirred for 2 hours at 70 °C under N 2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature and concentrated in vacuo.
  • Step 5 7-chloro-1-isopropyl-2,3-dimethyl-quinolin-4-one
  • Step 6 2-(bromomethyl)-7-chloro-1-isopropyl-3-methyl-quinolin-4-one
  • Step 7 7-chloro-2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-1-isopropyl-3- methylquinolin-4(1H)-one
  • 2-(bromomethyl)-7-chloro-1-isopropyl-3-methyl-quinolin-4- one 360 mg, 1.1 mmol, 1 eq
  • (3S,5S)-3,5-dimethylmorpholine 189.2 mg, 1.64 mmol, 1.5 eq
  • DIEA 424.7 mg, 3.29 mmol, 572.42 ⁇ L, 3 eq
  • Step 8 2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-1-isopropyl-3-methyl-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one
  • the mixture of 7-chloro-2-[[(3S,5S)-3,5-dimethylmorpholin-4-yl]methyl]-1- isopropyl-3-methyl-quinolin-4-one (382 mg, 1.05 mmol, 1 eq), Pin 2 B 2 (401 mg, 1.58 mmol, 1.5 eq), KOAc (309.9 mg, 3.16 mmol, 3 eq) and Pd(dppf)Cl2 (85.96 mg, 0.105 mmol, 0.1 eq) in dioxane (6 mL) was stirred at 100 °C for 2 hours under N 2 atmosphere.
  • Example 1 Synthesis of (1S, 2S, 3R, 5R)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (configuration was assigned randomly )(Compound 2) and (1R, 2R, 3S, 5S)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (configuration was assigned randomly) (Compound 3) Step 1: Preparation of 2-(6-(2,5-dichloro
  • reaction mixture was cooled to room temperate and diluted with water (10 mL).
  • the aqueous phase was extracted with ethyl acetate (10 mL x2).
  • the combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • Step 3 Preparation of (1S, 2S, 3R, 5R)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan- 2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol (configuration was assigned randomly) (compound 2) and (1R, 2R, 3S, 5S)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl- 1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (configuration was assigned randomly)(compound 3) [00378] The 60 mg of racemic (1S*,2S*,3R*,5R*)-( ⁇
  • reaction mixture was cooled to room temperate and diluted with water (10 mL).
  • the aqueous phase was extracted with ethyl acetate (10 mL x2).
  • the combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step 2 Preparation of (1S*,2R*,3R*,5R*)-( ⁇ )-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- azabicyclo[3.2.1]octan-2-ol TFA salt [00380] To a solution of tert-butyl (1S*,2S*,3R*,5R*)-( ⁇ )3-((5-chloro-4-(4-fluoro-2- (2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- 2-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (257 mg, 0.436 mmol, 1 eq
  • Step 3 Preparation of (1R*,2S*,3R*,5S*)-( ⁇ )-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- (methylsulfonyl)-8-azabicyclo[3.2.1]octan-2-ol (compound 4) [00381] To a solution of (1S*,2R*,3R*,5R*)-( ⁇ )-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- azabicyclo[3.2.1]octan-2-ol TFA salt (200 mg, 0.409 mmol
  • reaction mixture was poured into sat.aq.NaHCO 3 (10 mL) and the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step 4 Preparation of 1S,2S,3R,5R)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2- yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-(methylsulfonyl)-8- azabicyclo[3.2.1]octan-2-ol (compound 5) and (1R,2R,3S,5S)-3-((5-chloro-4-(4- fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)-8-(methylsulfonyl)-8-azabicyclo[3.2.1]octan-2-ol (compound 6) [00382] The racemic (1R*,2S*,3R*,5S
  • Step 2 Preparation of tert-butyl (1R*,2S*,3R*,5S*)-( ⁇ )-3-((5-chloro-4-(3-cyano-4- fluoro-1-isopropyl-2-methyl-1H-indol-6-yl)pyrimidin-2-yl)amino)-2-hydroxy-8- azabicyclo[3.2.1]octane-8-carboxylate [00384] A mixture of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl- 1H-indole-3-carbonitrile (55 mg, 0.151 mmol, 1 eq), tert-butyl (1S*,2S*,3R*,5R*)-( ⁇ )- 3-amino-2-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (55.04 mg, 0.227 mmol, 1.5 eq
  • Step 3 Preparation of 6-(5-chloro-2-(((1R*,2R*,3R*,5S*)-( ⁇ )-2-hydroxy-8- azabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H- indole-3-carbonitrile HCl salt.
  • Step 4 Preparation of 6-(5-chloro-2-(((1R*,2S*,3R*,5S*)-( ⁇ )-2-hydroxy-8- (methylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1- isopropyl-2-methyl-1H-indole-3-carbonitrile [00386] To a solution of 6-(5-chloro-2-(((1R*,2R*,3R*,5S*)-( ⁇ )-2-hydroxy-8- azabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H- indole-3-carbonitrile HCl salt (40 mg, 0.0791 mmol, 1 eq, HCl) in DCM (1 mL) was added DIEA (52 mg
  • Step 5 Preparation of 6-(5-chloro-2-(((1R,2S,3R,5S)-2-hydroxy-8-(methylsulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H- indole-3-carbonitrile (compound 31) and 6-(5-chloro-2-(((1R,2R,3S,5S)-2-hydroxy-8- (methylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1- isopropyl-2-methyl-1H-indole-3-carbonitrile (compound 32) [00387] The racemic 6-(5-chloro-2-(((1R*,2S*,3R*,5S*)-( ⁇ )-2-hydroxy-8
  • the mixture was stirred at 90 °C for 1 h under N 2 until the starting materials were consumed.
  • the reaction mixture was cooled to room temperature and filtered via a short pad of celite. The filtrate was concentrated, and the remaining content was diluted with water (20mL).
  • the aqueous phase was extracted with ethyl acetate (100 mL x3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography.
  • Step 2 preparation of tert-butyl (R)-3-(6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro- 2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate [00391] The mixture of tert-butyl (R)-3-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (2 g, 4.05 mmol, 1 eq), (3S,4R)-4-aminotetrahydropyran-3-ol HCl salt (932.10 mg, 6.07 mmol, 1.5 eq,), Na2CO3 (857.54 mg, 8.09 mmol
  • reaction mixture was cooled to room temperature and poured into H2O (100 mL). Then aqueous phase was extracted withethyl acetate(100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure.
  • Step 3 preparation of (3S,4R)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2-((R)-pyrrolidin-3- yl)-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol HCl salt
  • Step 4 Preparation of methyl (R)-3-(6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate [00393] To a solution of (3S,4R)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2-((R)- pyrrolidin-3-yl)-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3- ol HCl salt (130 mg, 0.274 mmol, 1 eq) in DCM (5 mL) was added TEA (138.48 mg, 1.37 mmol, 190.48
  • reaction mixture was poured into saturated aqueous NaHCO 3 (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step 5 Preparation of methyl (R)-3-(6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate (compound 102) and methyl (S)-3-(6-(5-chloro-2- (((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (compound 101) [00394] The partially racemized methyl (R)-3-(6-(5-chloro-2-(((3S,4R)-3- hydroxytetrahydr
  • Step 2 Preparation of (3S,4R)-4-((5-chloro-4-(4-fluoro-7-isopropyl-2-methyl-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol
  • (3S,4R)-4-aminotetrahydropyran- 3-ol 27.17 mg, 0.177 mmol, 3 eq, HCl
  • DIEA 22.86 mg, 0.177 mmol, 30.81 ⁇ L, 3 eq
  • the reaction was cooled to room temperature and the volatiles were removed under reduced pressure. The remaining content was diluted with water (20 mL) and the aqueous phase was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with water (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • Step 2 Preparation of (3S,4R)-4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-7- isopropylbenzo[d]thiazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (compound 190) [00401] The solution of 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-7- isopropylbenzo[d]thiazol-2-yl)propan-2-ol (60 mg, 0.139 mmol, 1 eq.), (3S,4R)-4- aminotetrahydropyran-3-ol (32.12 mg, 0.209 mmol, 1.5 eq., HCl), Na 2 CO 3 (29.55 mg, 0.279 mmol, 2 eq.) and KF (80.98 mg, 1.39 mmol, 10 eq.)
  • the reaction was cooled to room temperature and the volatiles were removed under reduced pressure. The remaining content was diluted with water (20 mL) and the aqueous phase was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with water (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure.
  • Step 2 Preparation of 6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-indole-3- carbonitrile [00403] To a solution of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-(2-hydroxypropan- 2-yl)-1-isopropyl-1H-indole-3-carbonitrile (30.0 mg, 0.0737 mmol, 1.0 eq) and (3S,4R)-4-aminotetrahydropyran-3-ol (25.9 mg, 0.169 mmol, 2.3 eq, HCl) in MeCN (1 mL) was added DIEA (47.6 mg, 0.368 mmol, 5.0 eq), and the mixture was stirred at 100
  • Step 2 preparation of methyl (R)-3-(6-(5-chloro-2-(((1S,2S,3R,5R)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (compound 93) and methyl (R)-3-(6- (5-chloro-2-(((1R,2R,3S,5S)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3- yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1- carboxylate (compound 94) [00407] Methyl (R)-3-(6-(5-chloro-2-
  • Example 12 Synthesis of (1S,2S,3R,5R)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-7-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (compound 43) and (1R,2R,3S,5S)-3-((5- chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-7-isopropyl-1H-benzo[d]imidazol-6- yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (compound 44) Step 1: Preparation of 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-7-isopropyl-1H- benzo
  • Step 2 Preparation of (1S*,2S*,3R*,5R*)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-7-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol [00411] To a solution of 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-7-isopropyl-1H- benzo[d]imidazol-2-yl)propan-2-ol (70 mg, 0.183 mmol, 1 eq) and (1R*,2S*,3R*,5S*)- 3-amino-8-oxabicyclo[3.2.1]octan-2-ol (39 mg, 0.274 mmol, 1.5 eq) in DMSO (2 mL)
  • Step 3 Preparation of (1S,2S,3R,5R)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2- yl)-7-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol and (1R,2R,3S,5S)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-7-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol [00412] (1S*,2S*,3R*,5R*)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-7
  • Step 6 Preparation of (1R,2S,3R,5S)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2- yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol and (1R,2R,3S,5S)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol [00416] (1R*,2S*,3R*,5S*)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1
  • Example 14 Synthesis of methyl (R)-3-(6-(5-chloro-2-(((1R,2S,3R,5S)-2- hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (compound 227) and methyl (R)-3-(6-(5-chloro-2-(((1S,2R,3S,5R)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (compound 228) Step 1: preparation of methyl (R)-3-(6-(5-chloro-2-(
  • Step 2 preparation of methyl (R)-3-(6-(5-chloro-2-(((1R,2S,3R,5S)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate and methyl (R)-3-(6-(5-chloro-2- (((1S,2R,3S,5R)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4- fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate [00420] Methyl (R)-3-(6-(5-chloro-2-(((1R*,2S*,3
  • Example 16 Synthesis of 6-(5-chloro-2-(((1S, 2S, 3R, 5R)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino) pyrimidin-4-yl)-4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-indole-3-carbonitrile (Compound 35) and 6-(5-chloro-2-(((1R, 2R, 3S, 5S)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino) pyrimidin-4-yl)-4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-indole-3- carbonitrile (Compound 36) Step 1: Preparation of 6-(5-chloro-2-(((1S*,2S*,3R*,5R*)-2-hydroxy-8- oxabi
  • Step 2 Preparation of 6-(5-chloro-2-(((1S,2S,3R,5R)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-2-(2-hydroxypropan-2-yl)- 1-isopropyl-1H-indole-3-carbonitrile (compound 35) and 6-(5-chloro-2- (((1R,2R,3S,5S)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4- fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-indole-3-carbonitrile (compound 36) [00429] 6-(5-chloro-2-(((1S*,2S*,3R*,5R*)-2-hydroxy-8-oxabicyclo[3.2.1
  • Example 18 Synthesis of methyl (R)-3-(6-(5-chloro-2-(((1R,2R)-4,4-difluoro-2- hydroxycyclohexyl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (compound 241) and methyl (R)-3-(6-(5-chloro-2-(((1S,2S)-4,4-difluoro-2- hydroxycyclohexyl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (compound 240) Step 1: Preparation of methyl (R)-3-(6-(5-chloro-2-(((1R*,2R*)-4,4-diflu
  • Step 2 Preparation of methyl (R)-3-(6-(5-chloro-2-(((1R,2R)-4,4-difluoro-2- hydroxycyclohexyl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate and methyl (R)-3-(6-(5-chloro-2-(((1S,2S)-4,4-difluoro-2- hydroxycyclohexyl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate [00437] Methyl (R)-3-(6-(5-chloro-2-(((1R*,2R*)-4
  • Example 20 Synthesis of 6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)-8-fluoro-4-isopropyl-2-methylisoquinolin- 1(2H)-one (compound 277)
  • Step 1 Preparation of 6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4-isopropyl-2- methylisoquinolin-1(2H)-one
  • Step 2 Preparation of 6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-8-fluoro-4-isopropyl-2-methylisoquinolin-1(2H)-one [00443] To a solution of 6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4-isopropyl-2- methylisoquinolin-1(2H)-one (50 mg, 0.136 mmol, 1 eq) in DMSO (1 mL) was added DIEA (53 mg, 0.409 mmol, 3 eq) and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol (31.5 mg, 0.205 mmol, 1.5 eq, HCl), and the mixture was stirred at 90 °C for 16 hours under N2 atmosphere.
  • DIEA 53 mg, 0.409
  • Step 2 Preparation of 2-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one [00445] To a solution of 2-(2-chloro-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5- dimethylthieno[3,2-c]pyridin-4(5H)-one (50 mg, 0.142 mmol, 1 eq), (3S,4R)-4- aminotetrahydro-2H-pyran-3-ol (33 mg, 0.214 mmol, 1.5 eq, HCl) in DMSO (1 mL) was added DIEA (36 mg, 0.284 mmol, 2 eq), and the mixture was stirred at 90 °C for 16 hours under N2 atmosphere.
  • Step 3 Preparation of (3S,4R)-4-((5-chloro-4-(2-((S)-2,2-difluorocyclopropyl)-4- fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H- pyran-3-ol and (3S,4R)-4-((5-chloro-4-(2-((R)-2,2-difluorocyclopropyl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol [00448] The (3S,4R)-4-((5-chloro-4-(2-(2,2-difluorocyclopropyl)-4-fluoro-1- isopropyl-1H-benzo[d]imida
  • Example 23 Synthesis of (1S,2S,3R,5R)-3-((5-chloro-4-(8-fluoro-3-(2- hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol (compound 295) and (1R,2R,3S,5S)-3-((5-chloro-4- (8-fluoro-3-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol (compound 296)
  • Step 1 preparation of 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoroquinolin-3-yl)propan- 2-ol [00451] The mixture of 2-(8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-
  • Step 2 preparation of (1S*,2S*,3R*,5R*)-3-((5-chloro-4-(8-fluoro-3-(2- hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol
  • 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoroquinolin-3- yl)propan-2-ol (90 mg, 0.256 mmol, 1 eq) in DMSO (2 mL) was added (1S*,2S*,3R*,5R*)-3-amino-8-oxabicyclo[3.2.1]octan-2-ol (73.2 mg, 0.511 mmol, 2 eq) and DIEA (99 mg, 0.767 mmol, 3 eq), and the mixture was stirred at 100 °C for 16
  • Step 3 preparation of (1S,2S,3R,5R)-3-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2- yl)quinolin-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol and (1R,2R,3S,5S)-3-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)quinolin-6- yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol [00453] (1S*,2S*,3R*,5R*)-3-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2- yl)quinolin-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2
  • Example 24 Synthesis of 2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-7-(5- fluoro-2-(((1S,2S,3R,5R)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3- yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one (compound 291) and 2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-7-(5-fluoro-2- (((1R,2R,3S,5S)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)- 1-isopropyl-3-methylquinolin-4(1H)-one (compound 292) Step 1: 7-(2-chloro-5-fluoropyrimidin-4-yl)-2-(((3S,
  • Step 2 2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-7-(5-fluoro-2- (((1S*,2S*,3R*,5R*)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-1- isopropyl-3-methylquinolin-4(1H)-one [00457] A mixture of 7-(2-chloro-5-fluoro-pyrimidin-4-yl)-2-[[(3S,5S)-3,5- dimethylmorpholin-4-yl]methyl]-1-isopropyl-3-methyl-quinolin-4-one (130 mg, 0.283 mmol, 1 eq), (1S*,2S*,3R*,5R*)-3-amino-8-oxabicyclo[3.2.1]octan-2-ol (81 mg, 0.565 mmol, 2 eq) and
  • Example 11 Phospho-Rb expression inhibition in MCF7 cells quantified by in- cell Western [00462] MCF7 cells were obtained from American Type Culture Collection (ATCC, HTB-22). MCF7 cells were plated in 96-well plates (VWR #10062-900, or Corning #3904) in 90 uL culture medium at a density of 20,000 cells/well in the DMEM growth medium containing 10% FBS and 1% Penicillin Streptomycin, and then incubated at 37°C overnight. The following day, the test compound was administered to the cells by using 1000x compound stock solution prepared in DMSO at various concentrations.1000x compound stock solution was first diluted in culturing medium to 10x, then 10 uL compound medium was added to each well in the cell plates.
  • the cells were then incubated at 37°C for 24 hours. Upon completion, the cells were washed with PBS briefly.150 uL/well of 4% formaldehyde was added and the plates were incubated at room temperature for 20 mins. The cells were washed with PBS briefly, and permeabilized with 150 uL/well of ice cold 100% methanol for 10 mins. The cells were washed with PBS briefly and blocked with 100 uL/well LI-COR blocking buffer for 1 hr at room temperature with gentle shaking.
  • the cells were incubated overnight at 4°C with 50 uL primary antibody rabbit anti-Phospho-Rb (Ser807/811) (1: 500, Cell Signaling, #8516) and anti-Rb (1:200, Santa Cruz, sc-73598) diluted in Intercept Blocking Buffer (LI-COR, #927-60001) containing 0.1% Tween 20.
  • the cells were washed with 200 uL PBS containing 0.1% Tween 20, 5 x 5 mins at room temperature with gentle shaking, and incubated with 50 uL secondary antibody, IRDye® 800CW Goat anti- Rabbit IgG (1:1000, LI-COR, #926-32211) and IRDye® 680RD Goat anti-Mouse IgG (1:1000, LI-COR, #926-68070), in LI-COR blocking buffer with 0.2% Tween 20 for 1 hr at room temperature with gentle shaking.
  • the cells were washed with 200 uL PBS containing 0.1% Tween 20, 5 x 5 mins at room temperature with gentle shaking.
  • Example 12 Cell growth inhibition of 22RV1 cells
  • 22RV1 cells were obtained from American Type Culture Collection (ATCC, CRL-2505). 22RV1 cells were seeded in 96-well plates at 1000 cells/well in 90 ⁇ L of RPMI1640 growth medium containing 10% FBS and 1% Penicillin Streptomycin, and then incubated at 37°C overnight.
  • test compound was administered to the cells by using 1000x compound stock solution prepared in DMSO at various concentrations.1000x compound stock solution was first diluted in culturing medium to 10x, then 10 uL compound medium was added to each well in the cell plates. After administration of the compound, the cells were then incubated at 37°C for 5 days. Upon completion, the plates were equilibrated at room temperature for approximately 10 minutes.100 uL of CellTiter-Glo® Reagent (Promega) was added to each well. The plates were then incubated at room temperature for 10 minutes and luminescence was recorded by EnSpire plate reader (PerkinElmer).

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Abstract

The present disclosure relates to a compound of Formula (I), a tautomer, a stereoisomer or a mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, or a deuterated derivative thereof and their use in, e.g., treating a disease or disorder associated with CDK. The present disclosure also relates to pharmaceutical compositions containing such compounds, and their use in treating or preventing a disease or disorder associated with CDK.

Description

NOVEL AMINOPYRIMIDINE DERIVATIVES AS CYCLIN-DEPENDENT KINASE INHIBITORS [0001] This application claims the benefit of priority to United States Provisional Patent Application No.63/497,015, filed April 19, 2023, which is hereby incorporated by reference in its entirety. [0002] The present disclosure relates to novel aminopyrimidine compounds, pharmaceutical compositions containing such compounds, and their use in prevention and treatment of diseases and conditions, e.g., cancer. [0003] Cyclin-Dependent Kinases (CDKs) are a family of protein kinases that participate in regulating a wide range of physiological processes. For instance, CDKs have been identified as regulators of the cell cycle, mRNA processing, and differentiation of nerve cells. The majority of known CDK complexes regulate progression through the cell cycle and are present in all eukaryotes. CDKs are also implicated in the development and proliferation of cancer cells through unregulated and abnormal expression of CDKs (“Cell cycle, CDKs and cancer: a changing paradigm, Nature Review Cancer, 2009, 9, 153-166; and “Inhibiting CDK in Cancer Therapy: Current Evidence and Future Directions”, Target Oncology, 2018, 13, 21- 38). [0004] CDK inhibitors have been shown to be useful in treating cancer. Increased activity or temporally abnormal activation of CDKs has been shown to result in the development of human tumors, and human tumor development is commonly associated with alterations in either the CDK proteins themselves or their regulators. [0005] CDK4 and CDK6 are important regulators of cell cycle progression at the G1-S checkpoint, which are controlled by D-type cyclins and INK4 endogenous CDK inhibitors, such as p16INK4a (CDKN2A). Dysregulation of the cyclin D-CDK4/6-INK4- retinoblastoma (Rb) pathway has been reported to be associated with development of endocrine therapy resistance. CDK4, a member of the CDK family, is a catalytic subunit of the protein kinase complex that is involved in controlling the transition from the G1-phase to the S-phase in the cell-cycle. Specifically, this process is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16(INK4a). Mutations in the CDK4 gene as well as in the related proteins including D-type cyclins, p16(INK4a), and Rb have been linked to tumorigenesis of a variety of cancers (“Germline mutations in the pl6INK4a binding domain of CDK4 in familial melanoma”, Nature Genet, 1996, 12, 97-99; “Cyclin D-dependent kinases, INK4 inhibitors and cancer”, Biochim. Biophys. Acta, 2002, 1602, 73-87; “Identification of a novel subgroup of melanomas with KIT/cyclin-dependent kinase-4 overexpression”, Cancer Res, 2008, 68, 5743-52). [0006] However, CDK4/6 inhibitors, at times, also cause adverse effects, such as gastrointestinal and hematologic toxicities, and tumors may acquire resistance over time. Because CDK4 has been identified as the singular oncogenic driver in many breast cancers, a selective CDK4 inhibitor may provide improved safety profile and enhanced effectiveness. [0007] Accordingly, there is a need in the art for improved therapies (e.g., greater efficacy, potential to reduce side effects, potential to overcome resistance mechanisms) for the treatment of diseases, such as cancers. [0008] The present disclosure provides, according to some embodiments, compounds, compositions, and methods for modulating the activity of CDK, including CDK4 and/or CDK6. In some embodiments, the compounds are selective for CDK4. [0009] In some embodiments, the present disclosure provides a compound represented by Formula (I), or a tautomer, a stereoisomer or a mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, or a deuterated derivative thereof:
Figure imgf000003_0001
wherein: Ring A is selected from
Figure imgf000003_0002
, ,
Figure imgf000004_0001
,
Figure imgf000005_0001
,
Figure imgf000006_0001
,
Figure imgf000007_0001
wherein RC is selected from C1-C6 alkyl and C3-C6 cycloalkyl and RD is selected from C1-C6 alkyl, C3-C6 cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heteroaryl, and 3- to 6-membered heterocycle; X2 is selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, and -CN; Ring B is selected from:
Figure imgf000007_0002
; wherein represents a single bond or a double bond; Z is C or N; Q1 is N or CRA, wherein RA is selected from hydrogen, halogen, and -CN; Q2 and W2 are independently selected from CRE and NRE, wherein one and only one of Q2 or W2 must be NRE; W3 is selected from CRE and N; Q3 is selected from NRE and CRE; each RE is independently selected from hydrogen, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1-3 RF, wherein each RF is independently selected from hydroxy, halogen, and C1-C3 alkyl; R1 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, C5-C8 bicyclic alkyl, -C1-C3 alkylene-(3- to 8- membered heterocycle), and 3- to 8-membered heterocycle, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, C5-C8 bicyclic alkyl, -C1-C3 alkylene-(3- to 8-membered heterocycle), and 3- to 8-membered heterocycle is each optionally substituted with 1-3 R1A, wherein each R1A is independently selected from halogen, hydroxy, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cyclic alkoxy, -N(RK)2, -C(=O)ORG, -S(=O)2RG, and -N(RK)C(=O)ORG, wherein each RK is independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl and each RG is independently selected from C1-C6 alkyl and C3-C6 cycloalkyl; R2 is selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cyclic alkoxy, and C1-C6 haloalkoxy; W1 is selected from S, NRB, CRB, and 3- to 6-membered cycloalkyl, wherein the 3- to 6-membered cycloalkyl is optionally substituted with 1-3 RH and wherein RB is selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1-3 RH, wherein each RH is independently selected from hydroxy, halogen, and C1-C3 alkyl; or W1 and R1 may be taken together with the C atom to which both are attached to form a 6-membered heterocycle, wherein the 6-membered heterocycle is optionally substituted with 1-4 groups independently selected from C1-C6 alkyl, hydroxy, and oxo; or W1, Z, R2 and the C atom to which R2 is directly attached may be taken together to form a 6-membered heterocycle, wherein the 6-membered heterocycle is optionally substituted with 1-4 groups independently selected from C1-C6 alkyl, hydroxy, and oxo; and X1 is selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, and -CN; with the proviso that when the compound of Formula (I) is selected from compounds of Formula (IA)
Figure imgf000009_0001
then Z is N, R2 is selected from C3 alkyl, or R1 is substituted with at least one R1A selected from oxo, -C(=O)ORG, -S(=O)2RG, and -N(RK)C(=O)ORG. [0010] Also disclosed herein is a method of treating a disease or disorder, in a subject in need thereof, comprising administering to said subject at least one entity selected from the compounds of Formula (I), tautomers thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and deuterated derivatives thereof, or a pharmaceutical composition comprising at least one entity selected from the compounds of Formula (I), tautomers thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and deuterated derivatives thereof, and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition of the present disclosure may be for use in (or in the manufacture of medicaments for) the treatment of the disease or disorder in the subject in need thereof. [0011] In some embodiments, a therapeutically effective amount of a pharmaceutical composition of the present disclosure may be administered to a subject diagnosed with the disease or disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is selected from breast cancer, prostate cancer, bone cancer, brain cancer, colorectal cancer, lung cancer, ovarian cancer, uterine cancer, liposarcoma, liver cancer, rhabdoid cancer, sarcoma, skin cancer, kidney cancer, stomach cancer, pancreatic cancer, esophageal cancer, head and neck cancer, bladder cancer, leukemia, lymphoma and thyroid cancer. BRIEF DESCRIPTION OF THE DRAWINGS [0012] FIGURE 1 is a diagram illustrating general synthesis method 1. [0013] FIGURE 2 is a diagram illustrating the synthesis of intermediate-1. [0014] FIGURE 3 is a diagram illustrating the synthesis of intermediate-2. [0015] FIGURE 4 is a diagram illustrating the synthesis of intermediate-3. [0016] FIGURE 5 is a diagram illustrating the synthesis of intermediate-4. [0017] FIGURE 6 is a diagram illustrating the synthesis of intermediate-5. [0018] FIGURE 7 is a diagram illustrating the synthesis of intermediate-6. [0019] FIGURE 8 is a diagram illustrating the synthesis of intermediate-7. [0020] FIGURE 9 is a diagram illustrating the synthesis of intermediate-8. [0021] FIGURE 10 is a diagram illustrating the synthesis of intermediate-9. [0022] FIGURE 11 is a diagram illustrating the synthesis of intermediate-13. [0023] FIGURE 12 is a diagram illustrating the synthesis of intermediate-14. [0024] FIGURE 13 is a diagram illustrating the synthesis of intermediate-16. [0025] FIGURE 14 is a diagram illustrating the synthesis of intermediate-17. [0026] FIGURE 15 is a diagram illustrating the synthesis of intermediate-20. [0027] FIGURE 16 is a diagram illustrating the synthesis of intermediate-22. [0028] FIGURE 17 is a diagram illustrating the synthesis of intermediate-23. [0029] FIGURE 18 is a diagram illustrating the synthesis of intermediate-24. [0030] FIGURE 19 is a diagram illustrating the synthesis of intermediate-25. [0031] FIGURE 20 is a diagram illustrating the synthesis of intermediate-26. [0032] FIGURE 21 is a diagram illustrating the synthesis of intermediate-27. [0033] FIGURE 22 is a diagram illustrating the synthesis of intermediate-28. [0034] FIGURE 23 is a diagram illustrating the synthesis of intermediate-29. [0035] FIGURE 24 is a diagram illustrating the synthesis of intermediate-30. [0036] FIGURE 25 is a diagram illustrating the synthesis of intermediate-31. [0037] FIGURE 26 is a diagram illustrating the synthesis of intermediate-32. [0038] FIGURE 27 is a diagram illustrating the synthesis of compounds 2 and 3. [0039] FIGURE 28 is a diagram illustrating the synthesis of compounds 5 and 6. [0040] FIGURE 29 is a diagram illustrating the synthesis of compounds 31 and 32. [0041] FIGURE 30 is a diagram illustrating the synthesis of compound 99. [0042] FIGURE 31 is a diagram illustrating the synthesis of compounds 101 and 102. [0043] FIGURE 32 is a diagram illustrating the synthesis of compound 120. [0044] FIGURE 33 is a diagram illustrating the synthesis of compound 189. [0045] FIGURE 34 is a diagram illustrating the synthesis of compound 190. [0046] FIGURE 35 is a diagram illustrating the synthesis of compound 195. [0047] FIGURE 36 is a diagram illustrating the synthesis of compound 199. [0048] FIGURE 37 is a diagram illustrating the synthesis of compounds 93 and 94. [0049] FIGURE 38 is a diagram illustrating the synthesis of compounds 43 and 44. [0050] FIGURE 39 is a diagram illustrating the synthesis of compounds 164 and 165. [0051] FIGURE 40 is a diagram illustrating the synthesis of compounds 227 and 228. [0052] FIGURE 41 is a diagram illustrating the synthesis of compounds 223 and 224. [0053] FIGURE 42 is a diagram illustrating the synthesis of compounds 35 and 36. [0054] FIGURE 43 is a diagram illustrating the synthesis of compounds 130 and 131. [0055] FIGURE 44 is a diagram illustrating the synthesis of compounds 240 and 241. [0056] FIGURE 45 is a diagram illustrating the synthesis of compound 274. [0057] FIGURE 46 is a diagram illustrating the synthesis of compound 277. [0058] FIGURE 47 is a diagram illustrating the synthesis of compound 278. [0059] FIGURE 48 is a diagram illustrating the synthesis of compounds 282 and 283. [0060] FIGURE 49 is a diagram illustrating the synthesis of compounds 295 and 296. [0061] FIGURE 50 is a diagram illustrating the synthesis of compounds 291 and 292. Definitions [0062] As used herein, “cancer” refers to diseases, disorders, and conditions that involve abnormal cell growth with the potential to invade or spread to other parts of the body. Exemplary cancers include, but are not limited to, breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, lung cancer, stomach cancer, esophageal cancer, colorectal cancer, small bowel cancer, pancreatic cancer, liver cancer, kidney cancer, head and neck cancer, skin cancer, bone cancer, thyroid cancer, peritoneal cancer, and brain cancer. [0063] “Subject” refers to an animal, such as a mammal, that has been or will be the object of treatment, observation, or experiment. The methods described herein may be useful for both human therapy and veterinary applications. In one embodiment, the subject is a human. [0064] As used herein, “treatment” or “treating” refers to an amelioration of a disease or disorder, or at least one discernible symptom thereof. In another embodiment, “treatment” or “treating” refers to an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient. In yet another embodiment, “treatment” or “treating” refers to inhibiting the progression of a disease or disorder, either physically, e.g., stabilization of a discernible symptom, physiologically, e.g., stabilization of a physical parameter, or both. In yet another embodiment, “treatment” or “treating” refers to delaying the onset of a disease or disorder. [0065] A dash
Figure imgf000012_0001
“” that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CN is attached through the carbon atom. [0066] By “optional” or “optionally”, it is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which is does not. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and/or inherently unstable. [0067] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C1-C6 alkyl” is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl. [0068] The term “alkenyl” as used herein refers to an unsaturated, two-carbon group having a carbon-carbon double bond, referred to herein as C2-alkenyl. [0069] The term “alkoxy” as used herein refers to an alkyl or cycloalkyl covalently bonded to an oxygen atom. [0070] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-8 carbon atoms, referred to herein as “C1-C8 alkyl”. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl- 2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. In some embodiments, “alkyl” is a straight-chain hydrocarbon. In some embodiments, “alkyl” is a branched hydrocarbon. [0071] The term “alkynyl” as used herein refers to an unsaturated, two-carbon group having a carbon-carbon triple bond, referred to herein as C2-alkynyl. [0072] The term “aryl” as used herein refers to a mono-, bi-, or other multi-carbocyclic, aromatic ring system with 5 to 14 ring atoms. The aryl group can optionally be fused to one or more rings selected from aryls, cycloalkyls, heteroaryls, and heterocyclyls. The aryl groups of this present disclosure can be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8- tetrahydronaphthyl. Exemplary aryl groups also include but are not limited to a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as “C6-aryl.” [0073] The term “cycloalkyl” as used herein refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-16 carbons, or 3-8 carbons, referred to herein as “C3-C8 cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, and cyclopentenes. Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Cycloalkyl groups can be fused to other cycloalkyl (saturated or partially unsaturated), aryl, or heterocyclyl groups, to form a bicycle, tetracycle, etc. The term “cycloalkyl” also includes bridged and spiro-fused cyclic structures which may or may not contain heteroatoms. [0074] The terms “halo” or “halogen” as used herein refer to -F, -Cl, -Br, and/or -I. [0075] The term “haloalkyl group” as used herein refers to an alkyl group substituted with one or more halogen atoms. [0076] The term “heteroaryl” as used herein refers to a mono-, bi-, or multi-cyclic, aromatic ring system containing one or more heteroatoms, for example 1-4 heteroatoms, such as nitrogen, oxygen, and sulfur. Heteroaryls can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heteroaryls can also be fused to non-aromatic rings. Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups include, but are not limited to, a monocyclic aromatic ring, wherein the ring comprises 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as "(C2-C5)heteroaryl.” In some embodiments, a heteroaryl contains 5 to 10 ring atoms, 1 to 4 of which are heteroatoms selected from N, O, and S. In some embodiments, a heteroaryl contains 5 to 8 ring atoms, 1 to 4 of which are heteroatoms selected from N, O, and S. [0077] The terms “heterocycle,” “heterocyclyl,” or “heterocyclic” as used herein each refer to a saturated or unsaturated 3- to 18-membered ring containing one, two, three, or four heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. Heterocycles can be aromatic (heteroaryls) or non-aromatic. Heterocycles can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heterocycles also include bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from aryls, cycloalkyls, and heterocycles. Heterocycles also include bridged and spiro-fused cyclic structures which may or may not contain heteroatoms. Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranyl, and triazolyl. In some embodiments, a heterocycle contains 5 to 10 ring atoms, 1 to 4 of which are heteroatoms selected from N, O, and S. In some embodiments, a heterocycle contains 5 to 8 ring atoms, 1 to 4 of which are heteroatoms selected from N, O, and S. [0078] The terms “hydroxy” and “hydroxyl” as used herein refer to -OH. [0079] The term “oxo” as used herein refers to a double bond to an oxygen atom (i.e., =O). For example, when two geminal groups on a carbon atom are “taken together to form an oxo”, then a carbonyl (i.e., C=O) is formed. [0080] The term “pharmaceutically acceptable carrier” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions. [0081] As used herein, the term “pharmaceutically acceptable salt” refers to a salt form of a compound of this disclosure wherein the salt is nontoxic. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. A “free base” form of a compound, for example, does not contain an ionically bonded salt. [0082] The phrase “and pharmaceutically acceptable salts and deuterated derivatives thereof” is used interchangeably with “and pharmaceutically acceptable salts thereof and deuterated derivatives of any of the forgoing” in reference to one or more compounds or formulae of the disclosure. These phrases are intended to encompass pharmaceutically acceptable salts of any one of the referenced compounds, deuterated derivatives of any one of the referenced compounds, and pharmaceutically acceptable salts of those deuterated derivatives. [0083] One of ordinary skill in the art would recognize that, when an amount of “a compound or a pharmaceutically acceptable salt thereof” is disclosed, the amount of the pharmaceutically acceptable salt form of the compound is the amount equivalent to the concentration of the free base of the compound. It is noted that the disclosed amounts of the compounds or their pharmaceutically acceptable salts thereof herein are based upon their free base form. [0084] Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19. For example, Table 1 of that article provides the following pharmaceutically acceptable salts: Table 1: Pharmaceutically Acceptable Salts
Figure imgf000017_0001
[0085] Non-limiting examples of pharmaceutically acceptable acid addition salts include: salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids, such as AcOH, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; and salts formed by using other methods used in the art, such as ion exchange. Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4alkyl)4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts. [0086] As used herein, nomenclature for compounds including organic compounds, can be given using common names, IUPAC, IUBMB, or CAS recommendations for nomenclature. One of skill in the art can readily ascertain the structure of a compound if given a name, either by systemic reduction of compound structure using naming conventions, or by commercially available software, such as CHEMDRAWTM (Cambridgesoft Corporation, U.S.A.). [0087] The compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers, or diastereomers. The term “stereoisomers” when used herein consist of all geometric isomers, enantiomers, or diastereomers. These compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. In some embodiments, an enantiomer or stereoisomer may be provided substantially free of the corresponding enantiomer. [0088] In some embodiments, the compound is a racemic mixture of (S)- and (R)- isomers. In other embodiments, provided herein is a mixture of compounds wherein individual compounds of the mixture exist predominately in an (S)- or (R)-isomeric configuration. For example, the compound mixture has an (S)-enantiomeric excess of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more. In other embodiments, the compound mixture has an (S)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more. In other embodiments, the compound mixture has an (R)-enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more. In some other embodiments, the compound mixture has an (R)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5% or more. [0089] Individual stereoisomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by: (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary; (2) salt formation employing an optically active resolving agent; or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known stereoselective synthesis methods. [0090] Geometric isomers can also exist in the compounds of the present disclosure. The present disclosure encompasses the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon- carbon double bond or arrangement of substituents around a carbocyclic ring. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the E and Z isomers. [0091] Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond. The arrangements of substituents around a carbocyclic ring are designated as “cis” or “trans.” The term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.” [0092] The present disclosure includes within its scope all possible tautomers. Furthermore, the present disclosure includes in its scope both the individual tautomers and any mixtures thereof. Each compound disclosed herein includes within its scope all possible tautomeric forms. Furthermore, each compound disclosed herein includes within its scope both the individual tautomeric forms and any mixtures thereof. With respect to the methods, uses, and compositions of the present application, reference to a compound or compounds is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof. Where a compound of the present application is depicted in one tautomeric form, that depicted structure is intended to encompass all other tautomeric forms. [0093] Additionally, unless otherwise stated, structures described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium (2H) or tritium (3H), or the replacement of a carbon by a 13C- or 14C-carbon atom are within the scope of this disclosure. Such compounds may be useful as, for example, analytical tools, probes in biological assays, or therapeutic agents. Compounds [0094] In some embodiments, the present disclosure is directed to a compound of Formula (I), or a tautomer, a stereoisomer or a mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, or a deuterated derivative thereof:
Figure imgf000021_0001
wherein: Ring A is selected from:
Figure imgf000021_0002
, ,
Figure imgf000022_0001
,
Figure imgf000023_0001
,
Figure imgf000024_0001
Figure imgf000025_0001
, wherein RC is selected from C1-C6 alkyl and C3-C6 cycloalkyl and RD is selected from C1-C6 alkyl, C3-C6 cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heteroaryl, and 3- to 6-membered heterocycle; X2 is selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, and -CN; Ring B is selected from:
Figure imgf000025_0002
; wherein: represents a single bond or a double bond; Z is C or N; Q1 is N or CRA, wherein RA is selected from hydrogen, halogen, and -CN; Q2 and W2 are independently selected from CRE and NRE, wherein one and only one of Q2 or W2 must be NRE; W3 is selected from CRE and N; Q3 is selected from NRE and CRE; each RE is independently selected from hydrogen, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1-3 RF, wherein each RF is independently selected from hydroxy, halogen, and C1-C3 alkyl; R1 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, C5-C8 bicyclic alkyl, -C1-C3 alkylene-(3- to 8-membered heterocycle), and 3- to 8-membered heterocycle, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, C5-C8 bicyclic alkyl, -C1-C3 alkylene-(3- to 8-membered heterocycle), and 3- to 8-membered heterocycle is each optionally substituted with 1-3 R1A, wherein each R1A is independently selected from halogen, hydroxy, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cyclic alkoxy, -N(RK)2, -C(=O)ORG, -S(=O)2RG, and -N(RK)C(=O)ORG, wherein each RK is independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl and each RG is independently selected from C1-C6 alkyl and C3-C6 cycloalkyl; R2 is selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cyclic alkoxy, and C1-C6 haloalkoxy; W1 is selected from S, NRB, CRB, and 3- to 6-membered cycloalkyl, wherein the 3- to 6-membered cycloalkyl is optionally substituted with 1-3 RH and wherein RB is independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1-3 RH, wherein each RH is independently selected from hydroxy, halogen, and C1-C3 alkyl; W1 and R1 may be taken together with the C atom to which both are attached to form a 6-membered heterocycle, wherein the 6-membered heterocycle is optionally substituted with 1-4 groups independently selected from C1-C6 alkyl, hydroxy, and oxo; or W1, Z, R2 and the C atom to which R2 is directly attached may be taken together to form a 6-membered heterocycle, wherein the 6-membered heterocycle is optionally substituted with 1-4 groups independently selected from C1-C6 alkyl, hydroxy, and oxo; and X1 is selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, and -CN; with the proviso that when the compound of Formula (I) is selected from compounds of Formula (IA):
Figure imgf000027_0001
then Z is N, R2 is selected from C3 alkyl, or R1 is substituted with at least one R1A selected from oxo, -C(=O)ORG, -S(=O)2RG, and -N(RK)C(=O)ORG. [ ,
Figure imgf000027_0002
[0096] In some embodiments, Ring A is selected from: ,
Figure imgf000027_0003
[0097] In some embodiments, Ring A is selected from:
Figure imgf000027_0004
, , ,
Figure imgf000028_0001
Figure imgf000029_0001
, ,
Figure imgf000030_0001
[0098] In some embodiments, RC is selected from C1-C3 alkyl and C3-C6 cycloalkyl. [0099] In some embodiments, RC is selected from C1-C3 alkyl. In some embodiments, RC is selected from C1 alkyl. In some embodiments, RC is selected from C2 alkyl. In some embodiments, RC is selected from C3 alkyl. In some embodiments, RC is methyl. In some embodiments, RC is ethyl. [00100] In some embodiments, RC is selected from C3-C6 cycloalkyl. In some embodiments, RC is selected from C3 cycloalkyl. In some embodiments, RC is selected from C4 cycloalkyl. In some embodiments, RC is selected from C5 cycloalkyl. In some embodiments, RC is selected from C6 cycloalkyl. [00101] In some embodiments, RD is selected from C1-C6 alkyl, C3-C6 cycloalkyl, 6- to 8-membered aryl, 5- to 6-membered heteroaryl, and 6-membered heterocycle. [00102] In some embodiments, RD is selected from C1-C6 alkyl. In some embodiments, RD is selected from C1 alkyl. In some embodiments, RD is selected from C2 alkyl. In some embodiments, RD is selected from C3 alkyl. In some embodiments, RD is selected from C4 alkyl. In some embodiments, RD is selected from C5 alkyl. In some embodiments, RD is selected from C6 alkyl. [00103] In some embodiments, RD is selected from C3-C6 cycloalkyl. In some embodiments, RD is selected from C3 cycloalkyl. In some embodiments, RD is selected from C4 cycloalkyl. In some embodiments, RD is selected from C5 cycloalkyl. In some embodiments, RD is selected from C6 cycloalkyl. [00104] In some embodiments, RD is selected from 6- to 8-membered aryl. In some embodiments, RD is selected from 6-membered aryl. In some embodiments, RD is selected from 7-membered aryl. In some embodiments, RD is selected from 8- membered aryl. [00105] In some embodiments, RD is selected from 5- to 6-membered heteroaryl. In some embodiments, RD is selected from 5-membered heteroaryl. In some embodiments, RD is selected from 6-membered heteroaryl. [00106] In some embodiments, RD is selected from 6-membered heterocycle. [00107] In some embodiments, RD is selected from methyl, ethyl, i-propyl, cyclopropyl, phenyl, pyridinyl, morpholinyl, and imidazolyl. In some embodiments, RD is methyl. In some embodiments, RD is selected from ethyl. In some embodiments, RD is i-propyl. In some embodiments, RD is cyclopropyl. In some embodiments, RD is phenyl. In some embodiments, RD is pyridinyl. In some embodiments, RD is morpholinyl. In some embodiments, RD is imidazolyl. [00108] In some embodiments, Ring A is selected from: , ,
Figure imgf000032_0001
Figure imgf000033_0001
. [00109] In some embodiments, X2 is selected from hydrogen, F, Cl, Br, methyl, -CHF2, -CF3, and -CN. In some embodiments, X2 is hydrogen. In some embodiments, X2 is F. In some embodiments, X2 is Cl. In some embodiments, X2 is Br. In some embodiments, X2 is methyl. In some embodiments, X2 is -CHF2. In some embodiments, X2 is -CF3. In some embodiments, X2 is -CN. [00110] In some embodiments, Ring B is:
Figure imgf000033_0002
. [00111] In some embodiments, W1 is S. In some embodiments, W1 is NRB. In some embodiments, W1 is CRB. In some embodiments, W1 is selected from 3- to 6- membered cycloalkyl, wherein the 3- to 6-membered cycloalkyl is optionally substituted with 1-3 RH. [00112] In some embodiments, RB is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1-3 RH. In some embodiments, RB is selected from C1 alkyl, wherein the C1 alkyl is optionally substituted with 1-3 RH. In some embodiments, RB is selected from C2 alkyl, wherein the C2 alkyl is optionally substituted with 1-3 RH. In some embodiments, RB is selected from C3 alkyl, wherein the C3 alkyl is optionally substituted with 1-3 RH. In some embodiments, RB is selected from C4 alkyl, wherein the C4 alkyl is optionally substituted with 1-3 RH. In some embodiments, RB is selected from C5 alkyl, wherein the C5 alkyl is optionally substituted with 1-3 RH. In some embodiments, RB is selected from C6 alkyl, wherein the C6 alkyl is optionally substituted with 1-3 RH. [00113] In some embodiments, RB is selected from C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with 1-3 RH. In some embodiments, RB is selected from C3 cycloalkyl, wherein the C3 cycloalkyl is optionally substituted with 1- 3 RH. In some embodiments, RB is selected from C4 cycloalkyl, wherein the C4 cycloalkyl is optionally substituted with 1-3 RH. In some embodiments, RB is selected from C5 cycloalkyl, wherein the C5 cycloalkyl is optionally substituted with 1-3 RH. In some embodiments, RB is selected from C6 cycloalkyl, wherein the C6 cycloalkyl is optionally substituted with 1-3 RH. [00114] In some embodiments, RB is selected from hydrogen, methyl, and i-propyl. In some embodiments, RB is hydrogen. In some embodiments, RB is methyl. In some embodiments, RB is i-propyl. [00115] In some embodiments, Ring B is selected from:
Figure imgf000034_0001
, wherein Ring C is selected from 3- to 6-membered cycloalkyl, wherein the 3- to 6- membered cycloalkyl is optionally substituted with 1-3 RH. [00116] In some embodiments, Ring B is selected from:
Figure imgf000034_0002
. [00117] In some embodiments, Ring B is selected from:
Figure imgf000034_0003
. [00118] In some embodiments, Ring B is selected from:
Figure imgf000035_0001
. [00119] In some embodiments, Ring B is selected from:
Figure imgf000035_0002
from 3- to 6-membered cycloalkyl, wherein the 3- to 6-membered cycloalkyl is optionally substituted with 1-3 RH. [00120] In some embodiments, Ring B is:
Figure imgf000035_0003
. [00121] In some embodiments, Ring C is selected from 3-membered cycloalkyl optionally substituted with 1-3 RH. In some embodiments, Ring C is selected from 4- membered cycloalkyl optionally substituted with 1-3 RH. In some embodiments, Ring C is selected from 5-membered cycloalkyl optionally substituted with 1-3 RH. In some embodiments, Ring C is selected from 6-membered cycloalkyl optionally substituted with 1-3 RH. [00122] In some embodiments, Ring B is selected from
Figure imgf000035_0004
,
Figure imgf000036_0001
. [00123] In some embodiments, Ring B is:
Figure imgf000036_0002
. [00124] In some embodiments, Ring B is:
Figure imgf000036_0003
[00125] In some embodiments, Ring B is:
Figure imgf000036_0004
. [00126] In some embodiments, Ring B is:
Figure imgf000036_0005
. [00127] In some embodiments, Ring B is:
Figure imgf000036_0006
. [00128] In some embodiments, Ring B is:
Figure imgf000037_0001
. [00129] In some embodiments, Ring B is:
Figure imgf000037_0002
. [00130] In some embodiments, Ring B is:
Figure imgf000037_0003
. [00131] In some embodiments, Ring B is:
Figure imgf000037_0004
. [00132] In some embodiments, Ring B is:
Figure imgf000037_0005
. [00133] In some embodiments, at least one RH is hydroxy. In some embodiments, at least one RH is halogen. In some embodiments, at least one RH is F. In some embodiments, at least one RH is Cl. In some embodiments, at least one RH is Br. In some embodiments, at least one RH is selected from C1-C3 alkyl. In some embodiments, at least one RH is selected from C1 alkyl. In some embodiments, at least one RH is selected from C2 alkyl. In some embodiments, at least one RH is selected from C3 alkyl. In some embodiments, at least one RH is methyl. In some embodiments, at least one RH is ethyl. In some embodiments, at least one RH is i- propyl. [00134] In some embodiments, each RH is hydroxy. In some embodiments, each RH is halogen. In some embodiments, each RH is F. In some embodiments, each RH is Cl. In some embodiments, each RH is Br. In some embodiments, each RH is selected from C1-C3 alkyl. In some embodiments, each RH is selected from C1 alkyl. In some embodiments, each RH is selected from C2 alkyl. In some embodiments, each RH is selected from C3 alkyl. In some embodiments, each RH is methyl. In some embodiments, each RH is ethyl. In some embodiments, each RH is i-propyl. [00135] In some embodiments, W1 and R1 are taken together with the C atom to which both are attached to form a 6-membered heterocycle selected from morpholine, piperazine, and piperidine, wherein the N atom of morpholine, piperazine, and piperidine rings is adjacent to Z, and wherein the piperazine is optionally substituted with 1-2 groups independently selected from methyl and oxo and wherein the piperidine is optionally substituted with 1-4 groups independently selected from methyl and hydroxy. [00136] In some embodiments, W1, Z, R2 and the C atom to which R2 is directly attached are taken together to form a 6-membered heterocycle selected from morpholine, piperidine, thiomorpholine, and piperazine, wherein the N atom of the morpholine, piperidine, thiomorpholine, and piperazine rings is adjacent to Z, and wherein the piperazine is optionally substituted with 1-2 groups independently selected from methyl and oxo. [00137] In some embodiments, R2 is selected from C1-C6 alkyl. In some embodiments, R2 is selected from C1 alkyl. In some embodiments, R2 is selected from C2 alkyl. In some embodiments, R2 is selected from C3 alkyl. In some embodiments, R2 is selected from C4 alkyl. In some embodiments, R2 is selected from C5 alkyl. In some embodiments, R2 is selected from C6 alkyl. [00138] In some embodiments, R2 is selected from C3-C6 cycloalkyl. In some embodiments, R2 is selected from C3 cycloalkyl. In some embodiments, R2 is selected from C4 cycloalkyl. In some embodiments, R2 is selected from C5 cycloalkyl. In some embodiments, R2 is selected from C6 cycloalkyl. [00139] In some embodiments, R2 is selected from C1-C6 alkoxy. In some embodiments, R2 is selected from C1 alkoxy. In some embodiments, R2 is selected from C2 alkoxy. In some embodiments, R2 is selected from C3 alkoxy. In some embodiments, R2 is selected from C4 alkoxy. In some embodiments, R2 is selected from C5 alkoxy. In some embodiments, R2 is selected from C6 alkoxy. [00140] In some embodiments, R2 is selected from C3-C6 cyclic alkoxy. In some embodiments, R2 is selected from C3 cyclic alkoxy. In some embodiments, R2 is selected from C4 cyclic alkoxy. In some embodiments, R2 is selected from C5 cyclic alkoxy. In some embodiments, R2 is selected from C6 cyclic alkoxy. [00141] In some embodiments, R2 is selected from C1-C6 haloalkoxy. In some embodiments, R2 is selected from C1 haloalkoxy. In some embodiments, R2 is selected from C2 haloalkoxy. In some embodiments, R2 is selected from C3 haloalkoxy. In some embodiments, R2 is selected from C4 haloalkoxy. In some embodiments, R2 is selected from C5 haloalkoxy. In some embodiments, R2 is selected from C6 haloalkoxy. [00142] In some embodiments, R2 is selected from hydrogen, halogen, methyl, i- propyl, -OMe, and -OCF3. In some embodiments, R2 is hydrogen. In some embodiments, R2 is halogen. In some embodiments, R2 is methyl. In some embodiments, R2 is i-propyl. In some embodiments, R2 is -OMe. In some embodiments, R2 is -OCF3. [00143] In some embodiments, Ring B is
Figure imgf000039_0001
. [00144] In some embodiments, Ring B is selected from:
Figure imgf000040_0001
[00145] In some embodiments, Ring B is:
Figure imgf000040_0002
. [00146] In some embodiments, Ring B is:
Figure imgf000040_0003
. [00147] In some embodiments, Ring B is:
Figure imgf000040_0004
. [00148] In some embodiments, Ring B is selected from:
Figure imgf000040_0005
[00149] In some embodiments, Ring B is:
Figure imgf000040_0006
. [00150] In some embodiments, Ring B is selected from
Figure imgf000041_0001
. [00151] In some embodiments, Ring B is selected from:
Figure imgf000041_0002
. [00152] In some embodiments, Ring B is:
Figure imgf000041_0003
. [00153] In some embodiments, Ring B is:
Figure imgf000041_0004
. [00154] In some embodiments, Ring B is:
Figure imgf000041_0005
. [00155] In some embodiments, Ring B is
Figure imgf000041_0006
. [00156] In some embodiments, Ring B is
Figure imgf000042_0001
. [00157] In some embodiments, Ring B is
Figure imgf000042_0002
. [00158] In some embodiments, each RE is independently selected from halogen. In some embodiments, each RE is F. In some embodiments, each RE is Cl. In some embodiments, each RE is Br. In some embodiments, at least one RE is selected from halogen. In some embodiments, at least one RE is F. In some embodiments, at least one RE is Cl. In some embodiments, at least one RE is Br. [00159] In some embodiments, each RE is independently selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1-3 RF. In some embodiments, each RE is independently selected from C1 alkyl, wherein the C1 alkyl is optionally substituted with 1-3 RF. In some embodiments, each RE is independently selected from C2 alkyl, wherein the C2 alkyl is optionally substituted with 1-3 RF. In some embodiments, each RE is independently selected from C3 alkyl, wherein the C3 alkyl is optionally substituted with 1-3 RF. In some embodiments, each RE is independently selected from C4 alkyl, wherein the C4 alkyl is optionally substituted with 1-3 RF. In some embodiments, each RE is independently selected from C5 alkyl, wherein the C5 alkyl is optionally substituted with 1-3 RF. In some embodiments, each RE is independently selected from C6 alkyl, wherein the C6 alkyl is optionally substituted with 1-3 RF. [00160] In some embodiments, at least one RE is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1-3 RF. In some embodiments, at least one RE is selected from C1 alkyl, wherein the C1 alkyl is optionally substituted with 1-3 RF. In some embodiments, at least one RE is selected from C2 alkyl, wherein the C2 alkyl is optionally substituted with 1-3 RF. In some embodiments, at least one RE is selected from C3 alkyl, wherein the C3 alkyl is optionally substituted with 1-3 RF. In some embodiments, at least one RE is selected from C4 alkyl, wherein the C4 alkyl is optionally substituted with 1-3 RF. In some embodiments, at least one RE is selected from C5 alkyl, wherein the C5 alkyl is optionally substituted with 1-3 RF. In some embodiments, at least one RE is selected from C6 alkyl, wherein the C6 alkyl is optionally substituted with 1-3 RF. [00161] In some embodiments, each RE is independently selected from C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with 1-3 RF. In some embodiments, each RE is independently selected from C3 cycloalkyl, wherein the C3 cycloalkyl is optionally substituted with 1-3 RF. In some embodiments, each RE is independently selected from C4 cycloalkyl, wherein the C4 cycloalkyl is optionally substituted with 1-3 RF. In some embodiments, each RE is independently selected from C5 cycloalkyl, wherein the C5 cycloalkyl is optionally substituted with 1-3 RF. In some embodiments, each RE is independently selected from C6 cycloalkyl, wherein the C6 cycloalkyl is optionally substituted with 1-3 RF. [00162] In some embodiments, at least one RE is selected from C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with 1-3 RF. In some embodiments, at least one RE is selected from C3 cycloalkyl, wherein the C3 cycloalkyl is optionally substituted with 1-3 RF. In some embodiments, at least one RE is selected from C4 cycloalkyl, wherein the C4 cycloalkyl is optionally substituted with 1-3 RF. In some embodiments, at least one RE is selected from C5 cycloalkyl, wherein the C5 cycloalkyl is optionally substituted with 1-3 RF. In some embodiments, at least one RE is selected from C6 cycloalkyl, wherein the C6 cycloalkyl is optionally substituted with 1-3 RF. [00163] In some embodiments, each RE is hydrogen. In some embodiments, at least one RE is hydrogen. [00164] In some embodiments, X1 is selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, and -CN. [00165] In some embodiments, X1 is selected from halogen. In some embodiments, X1 is F. In some embodiments, X1 is Cl. In some embodiments, X1 is Br. [00166] In some embodiments, X1 is selected from C1-C6 alkyl. In some embodiments, X1 is selected from C1 alkyl. In some embodiments, X1 is selected from C2 alkyl. In some embodiments, X1 is selected from C3 alkyl. In some embodiments, X1 is methyl. In some embodiments, X1 is ethyl. [00167] In some embodiments, X1 is selected from C3-C6 cycloalkyl. In some embodiments, X1 is selected from C3 cycloalkyl. In some embodiments, X1 is selected from C4 cycloalkyl. In some embodiments, X1 is selected from C5 cycloalkyl. In some embodiments, X1 is selected from C6 cycloalkyl. [00168] In some embodiments, X1 is selected from C1-C3 haloalkyl. In some embodiments, X1 is selected from C1 halalkyl. In some embodiments, X1 is selected from C2 haloalkyl. In some embodiments, X1 is selected from C3 haloalkyl. [00169] In some embodiments, X1 is selected from hydrogen, F, Cl, Br, methyl, - CHF2, and -CN. In some embodiments, X1 is hydrogen. In some embodiments, X1 is -CHF2. In some embodiments, X1 is -CN. [00170] In some embodiments, Ring B is selected from: ,
Figure imgf000044_0001
F
Figure imgf000045_0001
[00171] In some embodiments, R1 is selected from: C
Figure imgf000045_0002
,
Figure imgf000046_0001
, wherein RT is selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl and wherein C1-C6 alkyl of R1 is optionally substituted with 1-2 R1A, wherein each R1A is independently selected from halogen, -NH2, hydroxy, C1-C6 alkoxy, and C1-C6 alkyl. [00172] In some embodiments, RT is hydrogen. [00173] In some embodiments, RT is selected from C1-C6 alkyl. In some embodiments, RT is selected from C1 alkyl. In some embodiments, RT is selected from C2 alkyl. In some embodiments, RT is selected from C3 alkyl. In some embodiments, RT is selected from C4 alkyl. In some embodiments, RT is selected from C5 alkyl. In some embodiments, RT is selected from C6 alkyl. In some embodiments, RT is methyl. In some embodiments, RT is ethyl. [00174] In some embodiments, RT is selected from C3-C6 cycloalkyl. In some embodiments, RT is selected from C3 cycloalkyl. In some embodiments, RT is selected from C4 cycloalkyl. In some embodiments, RT is selected from C5 cycloalkyl. In some embodiments, RT is selected from C6 cycloalkyl. [00175] In some embodiments, each R1A is independently selected from halogen. In some embodiments, each R1A is F. In some embodiments, each R1A is Cl. In some embodiments, each R1A is Br. In some embodiments, at least one R1A is selected from halogen. In some embodiments, at least one R1A is F. In some embodiments, at least one R1A is Cl. In some embodiments, at least one R1A is Br. [00176] In some embodiments, each R1A is independently selected from C1-C6 alkyl. In some embodiments, each R1A is independently selected from C1 alkyl. In some embodiments, each R1A is independently selected from C2 alkyl. In some embodiments, each R1A is independently selected from C3 alkyl. In some embodiments, each R1A is independently selected from C4 alkyl. In some embodiments, each R1A is independently selected from C5 alkyl. In some embodiments, each R1A is independently selected from C6 alkyl. [00177] In some embodiments, at least one R1A is selected from C1-C6 alkyl. In some embodiments, at least one R1A is selected from C1 alkyl. In some embodiments, at least one R1A is selected from C2 alkyl. In some embodiments, at least one R1A is selected from C3 alkyl. In some embodiments, at least one R1A is selected from C4 alkyl. In some embodiments, at least one R1A is selected from C5 alkyl. In some embodiments, at least one R1A is selected from C6 alkyl. [00178] In some embodiments, each R1A is independently selected from C3-C6 cycloalkyl. In some embodiments, each R1A is independently selected from C3 cycloalkyl. In some embodiments, each R1A is independently selected from C4 cycloalkyl. In some embodiments, each R1A is independently selected from C5 cycloalkyl. In some embodiments, each R1A is independently selected from C6 cycloalkyl. [00179] In some embodiments, at least one R1A is selected from C3-C6 cycloalkyl. In some embodiments, at least one R1A is selected from C3 cycloalkyl. In some embodiments, at least one R1A is selected from C4 cycloalkyl. In some embodiments, at least one R1A is selected from C5 cycloalkyl. In some embodiments, at least one R1A is selected from C6 cycloalkyl. [00180] In some embodiments, each R1A is independently selected from C1-C6 alkoxy. In some embodiments, each R1A is independently selected from C1 alkoxy. In some embodiments, each R1A is independently selected from C2 alkoxy. In some embodiments, each R1A is independently selected from C3 alkoxy. In some embodiments, each R1A is independently selected from C4 alkoxy. In some embodiments, each R1A is independently selected from C5 alkoxy. In some embodiments, each R1A is independently selected from C6 alkoxy. [00181] In some embodiments, at least one R1A is selected from C1-C6 alkoxy. In some embodiments, at least one R1A is selected from C1 alkoxy. In some embodiments, at least one R1A is selected from C2 alkoxy. In some embodiments, at least one R1A is selected from C3 alkoxy. In some embodiments, at least one R1A is selected from C4 alkoxy. In some embodiments, at least one R1A is selected from C5 alkoxy. In some embodiments, at least one R1A is selected from C6 alkoxy. [00182] In some embodiments, each R1A is independently selected from C3-C6 cyclic alkoxy. In some embodiments, each R1A is independently selected from C3 cyclic alkoxy. In some embodiments, each R1A is independently selected from C4 cyclic alkoxy. In some embodiments, each R1A is independently selected from C5 cyclic alkoxy. In some embodiments, each R1A is independently selected from C6 cyclic alkoxy. [00183] In some embodiments, at least one R1A is selected from C3-C6 cyclic alkoxy. In some embodiments, at least one R1A is selected from C3 cyclic alkoxy. In some embodiments, at least one R1A is selected from C4 cyclic alkoxy. In some embodiments, at least one R1A is selected from C5 cyclic alkoxy. In some embodiments, at least one R1A is selected from C6 cyclic alkoxy. [00184] In some embodiments, each R1A is independently selected from -N(RK)2. In some embodiments, each R1A is independently selected from -C(=O)ORG. In some embodiments, each R1A is independently selected from -S(=O)2RG. In some embodiments, at least one R1A is selected from -N(RK)2. In some embodiments, at least one R1A is selected from -C(=O)ORG. In some embodiments, at least one R1A is selected from -S(=O)2RG. [00185] In some embodiments, each RK is hydrogen. In some embodiments, at least one RK is hydrogen. [00186] In some embodiments, each RK is independently selected from C1-C6 alkyl. In some embodiments, each RK is independently selected from C1 alkyl. In some embodiments, each RK is independently selected from C2 alkyl. In some embodiments, each RK is independently selected from C3 alkyl. In some embodiments, each RK is independently selected from C4 alkyl. In some embodiments, each RK is independently selected from C5 alkyl. In some embodiments, each RK is independently selected from C6 alkyl. [00187] In some embodiments, at least one RK is selected from C1-C6 alkyl. In some embodiments, at least one RK is selected from C1 alkyl. In some embodiments, at least one RK is selected from C2 alkyl. In some embodiments, at least one RK is selected from C3 alkyl. In some embodiments, at least one RK is selected from C4 alkyl. In some embodiments, at least one RK is selected from C5 alkyl. In some embodiments, at least one RK is selected from C6 alkyl. [00188] In some embodiments, each RK is independently selected from C3-C6 cycloalkyl. In some embodiments, each RK is independently selected from C3 cycloalkyl. In some embodiments, each RK is independently selected from C4 cycloalkyl. In some embodiments, each RK is independently selected from C5 cycloalkyl. In some embodiments, each RK is independently selected from C6 cycloalkyl. [00189] In some embodiments, at least one RK is selected from C3-C6 cycloalkyl. In some embodiments, at least one RK is selected from C3 cycloalkyl. In some embodiments, at least one RK is selected from C4 cycloalkyl. In some embodiments, at least one RK is selected from C5 cycloalkyl. In some embodiments, at least one RK is selected from C6 cycloalkyl. [00190] In some embodiments, each RG is independently selected from C1-C6 alkyl. In some embodiments, each RG is independently selected from C1 alkyl. In some embodiments, each RG is independently selected from C2 alkyl. In some embodiments, each RG is independently selected from C3 alkyl. In some embodiments, each RG is independently selected from C4 alkyl. In some embodiments, each RG is independently selected from C5 alkyl. In some embodiments, each RG is independently selected from C6 alkyl. [00191] In some embodiments, at least one RG is selected from C1-C6 alkyl. In some embodiments, at least one RG is selected from C1 alkyl. In some embodiments, at least one RG is selected from C2 alkyl. In some embodiments, at least one RG is selected from C3 alkyl. In some embodiments, at least one RG is selected from C4 alkyl. In some embodiments, at least one RG is selected from C5 alkyl. In some embodiments, at least one RG is selected from C6 alkyl. [00192] In some embodiments, each RG is independently selected from C3-C6 cycloalkyl. In some embodiments, each RG is independently selected from C3 cycloalkyl. In some embodiments, each RG is independently selected from C4 cycloalkyl. In some embodiments, each RG is independently selected from C5 cycloalkyl. In some embodiments, each RG is independently selected from C6 cycloalkyl. [00193] In some embodiments, at least one RG is selected from C3-C6 cycloalkyl. In some embodiments, at least one RG is selected from C3 cycloalkyl. In some embodiments, at least one RG is selected from C4 cycloalkyl. In some embodiments, at least one RG is selected from C5 cycloalkyl. In some embodiments, at least one RG is selected from C6 cycloalkyl. [00194] In some embodiments, R1 is selected from: ,
Figure imgf000050_0001
Figure imgf000051_0001
, , , , , , , , , , , , and . [00195] In some embodiments, provided herein is an entity selected from the compounds listed in Table 2 or a tautomer, a stereoisomer or a mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, or a deuterated derivative thereof. [00196] Exemplary compounds of the present disclosure are listed in Table 2. Table 2. Exemplary Compounds
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Pharmaceutical Compositions [00197] Pharmaceutical compositions of the present disclosure comprise at least one entity selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof, with at least one pharmaceutically acceptable carrier. These formulations include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration. The most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. [00198] Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of a compound of the present disclosure as powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association at least one compound of the present disclosure as the active compound and a carrier or excipient (which may constitute one or more accessory ingredients). The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient. The carrier may be a solid or a liquid, or both, and may be formulated with at least one compound described herein as the active compound in a unit-dose formulation, for example, a tablet, which may contain from about 0.05% to about 95% by weight of the at least one active compound. Other pharmacologically active substances may also be present including other compounds. The formulations of the present disclosure may be prepared by any of the well-known techniques of pharmacy consisting essentially of admixing the components. [00199] For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmacologically administrable compositions can, for example, be prepared by, for example, dissolving or dispersing, at least one active compound of the present disclosure as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. In general, suitable formulations may be prepared by uniformly and intimately admixing the at least one active compound of the present disclosure with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet may be prepared by compressing or molding a powder or granules of at least one compound of the present disclosure, which may be optionally combined with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, at least one compound of the present disclosure in a free-flowing form, such as a powder or granules, which may be optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets may be made by molding, in a suitable machine, where the powdered form of at least one compound of the present disclosure is moistened with an inert liquid diluent. [00200] Formulations suitable for buccal (sub-lingual) administration include lozenges comprising at least one compound of the present disclosure in a flavored base, usually sucrose and acacia or tragacanth, and pastilles comprising the at least one compound in an inert base such as gelatin and glycerin or sucrose and acacia. [00201] Formulations of the present disclosure suitable for parenteral administration comprise sterile aqueous preparations of at least one entity selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof, which are approximately isotonic with the blood of the intended recipient. These preparations are administered intravenously, although administration may also be affected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing at least one compound described herein with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the present disclosure may contain from about 0.1 to about 5% w/w of the active compound. [00202] Formulations suitable for rectal administration are presented as unit-dose suppositories. These may be prepared by admixing at least one compound as described herein with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture. [00203] Formulations suitable for topical application to the skin may take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers and excipients which may be used include Vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound (i.e., at least one entity selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof) is generally present at a concentration of from about 0.1% to about 15% w/w of the composition, for example, from about 0.5 to about 2%. [00204] The amount of active compound administered may be dependent on the subject being treated, the subject's weight, the manner of administration and the judgment of the prescribing physician. For example, a dosing schedule may involve the daily or semi-daily administration of the encapsulated compound at a perceived dosage of about 1 µg to about 1000 mg. In another embodiment, intermittent administration, such as on a monthly or yearly basis, of a dose of the encapsulated compound may be employed. Encapsulation facilitates access to the site of action and allows the administration of the active ingredients simultaneously, in theory producing a synergistic effect. In accordance with standard dosing regimens, physicians will readily determine optimum dosages and will be able to readily modify administration to achieve such dosages. [00205] A therapeutically effective amount of a compound or composition disclosed herein can be measured by the therapeutic effectiveness of the compound. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being used. In one embodiment, the therapeutically effective amount of a disclosed compound is sufficient to establish a maximal plasma concentration. Preliminary doses as, for example, determined according to animal tests, and the scaling of dosages for human administration is performed according to art-accepted practices. [00206] Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compositions that exhibit large therapeutic indices are preferable. [00207] Data obtained from the cell culture assays or animal studies can be used in formulating a range of dosage for use in humans. Therapeutically effective dosages achieved in one animal model may be converted for use in another animal, including humans, using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Reports 50(4):219-244 (1966) and the following table (Table 3) for Equivalent Surface Area Dosage Factors).
Table 3. Equivalent Surface Area Dosage Factors.
Figure imgf000100_0001
[00208] The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Generally, a therapeutically effective amount may vary with the subject's age, condition, and gender, as well as the severity of the medical condition in the subject. The dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment. Methods of Treatment [00209] In some embodiments, at least one entity selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof, is administered to treat cancer in a subject in need thereof. In some embodiments, the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer and thyroid cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is thyroid cancer. [00210] In some embodiments, at least one entity selected from the compounds of Formula (I), or tautomers thereof, stereoisomers or a mixture of stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and deuterated derivatives thereof, is administered to treat cancer in a subject in need thereof. In some embodiments, the cancer is selected from breast cancer, prostate cancer, bone cancer, brain cancer, colorectal cancer, lung cancer, ovarian cancer, uterine cancer, liposarcoma, liver cancer, rhabdoid cancer, sarcoma, skin cancer, kidney cancer, stomach cancer, pancreatic cancer, esophageal cancer, head and neck cancer, bladder cancer, leukemia, lymphoma and thyroid cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is bone cancer. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is liposarcoma. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is rhabdoid cancer. In some embodiments, the cancer is sarcoma. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is thyroid cancer. [00211] In some embodiments, the lung cancer is selected from non-small cell lung cancer NSCLC, small cell lung cancer (SCLC), squamous cell carcinoma, and adenocarcinoma. In some embodiments, the lung cancer is non-small cell lung cancer NSCLC. In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, the lung cancer is squamous cell carcinoma. In some embodiments the lung cancer is adenocarcinoma. [00212] In some embodiments, the breast cancer is selected from ER-positive/HR- positive, HER2-negative breast cancer; ER-positive/HR-positive, HER2-positive breast cancer; triple negative breast cancer (TNBC), and inflammatory breast cancer. In some embodiments, the breast cancer is ER-positive/HR-positive. In some embodiments, the breast cancer is HER2-negative breast cancer. In some embodiments, the breast cancer is ER-positive/HR-positive. In some embodiments, the breast cancer is HER2-positive breast cancer. In some embodiments, the breast cancer is triple negative breast cancer (TNBC). In some embodiments, the breast cancer is inflammatory breast cancer. [00213] In some embodiments, the breast cancer is selected from endocrine resistant breast cancer, trastuzumab or pertuzumab resistant breast cancer, breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition. In some embodiments, the breast cancer is endocrine resistant breast cancer. In some embodiments, the breast cancer is trastuzumab or pertuzumab resistant breast cancer. In some embodiments, the breast cancer is breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition. [00214] In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments, the breast cancer is advanced breast cancer. In some embodiments, the breast cancer is metastatic breast cancer. [00215] In some embodiments, at least one entity selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof, is administered as a pharmaceutical composition. [00216] In some embodiments, the subject has been previously treated with an anti-cancer agent. In some embodiments, the anti-cancer agent is enzalutamide, apalutamide, bicalutamide, darolutamide, flutamide, abiratarone, or a combination of any of the foregoing. In some embodiments, the anti-cancer agent is enzalutamide. [00217] In some embodiments, provided herein is a use of at least one entity selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof, for treating cancer. In some embodiments, the cancer is selected from breast cancer, prostate cancer, bone cancer, brain cancer, colorectal cancer, lung cancer, ovarian cancer, uterine cancer, liposarcoma, liver cancer, rhabdoid cancer, sarcoma, skin cancer, kidney cancer, stomach cancer, pancreatic cancer, esophageal cancer, head and neck cancer, bladder cancer, leukemia, lymphoma and thyroid cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is bone cancer. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is liposarcoma. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is rhabdoid cancer. In some embodiments, the cancer is sarcoma. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is thyroid cancer. [00218] In some embodiments, provided herein is a use of at least one entity selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof, in the preparation of a medicament. In some embodiments, the medicament is for the treatment of cancer. In some embodiments, the cancer is selected from breast cancer, prostate cancer, bone cancer, brain cancer, colorectal cancer, lung cancer, ovarian cancer, uterine cancer, liposarcoma, liver cancer, rhabdoid cancer, sarcoma, skin cancer, kidney cancer, stomach cancer, pancreatic cancer, esophageal cancer, head and neck cancer, bladder cancer, leukemia, lymphoma and thyroid cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is bone cancer. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is liposarcoma. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is rhabdoid cancer. In some embodiments, the cancer is sarcoma. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is thyroid cancer. [00219] In some embodiments, provided herein is a method of treating a disease or condition modulated at least in part by CDK4 in a subject comprising administering to the subject in need thereof with at least one entity selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof. [00220] In some embodiments, at least one compound (e.g., entity) is selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof, may be administered in combination with another therapeutic agent. The other therapeutic agent can provide additive or synergistic value relative to the administration of a compound of the present disclosure alone. The therapeutic agent can be selected from, for example, hormones and hormonal analogues; signal transduction pathway inhibitors; topoisomerase I inhibitors; topoisomerase II inhibitors; antimetabolite neoplastic agents; antibiotic neoplastic agents; alkylating agents; anti-microtubule agents; platinum coordination complexes; aromatase inhibitors; and anti-mitotic agents. [00221] In some embodiments, the therapeutic agent may be a hormone or hormonal analogue. In some embodiments, the therapeutic agent may be a signal transduction pathway inhibitor. In some embodiments, the therapeutic agent may be a topoisomerase I inhibitor. In some embodiments, the therapeutic agent may be a topoisomerase II inhibitor. In some embodiments, the therapeutic agent may be an antimetabolite neoplastic agent. In some embodiments, the therapeutic agent may be an antibiotic neoplastic agent. In some embodiments, the therapeutic agent may be an alkylating agent. In some embodiments, the therapeutic agent may be an anti- microtubule agent. In some embodiments, the therapeutic agent may be a platinum coordination complex. In some embodiments, the therapeutic agent may be an aromatase inhibitor. In some embodiments, the therapeutic agent may be an anti- mitotic agent. [00222] In some embodiments, the aromatase inhibitor may be selected from anastrazole, letrozole, vorozole, fadrozole, exemestane, and formestane. In some embodiments, the aromatase inhibitor is anastrazole. In some embodiments, the aromatase inhibitor may be letrozole. In some embodiments, the aromatase inhibitor may be vorozole. In some embodiments, the aromatase inhibitor may be fadrozole. In some embodiments, the aromatase inhibitor may be exemestane. In some embodiments, the aromatase inhibitor may be formestane. [00223] In some embodiments, the anti-mitotic agent may be selected from paclitaxel, docetaxel, and Abraxane. In some embodiments, the anti-mitotic agent may be paclitaxel. In some embodiments, the anti-mitotic agent may be docetaxel. In some embodiments, the anti-mitotic agent may be Abraxane. [00224] In some embodiments, at least one entity selected from the compounds of Formula (I), or tautomers thereof, stereoisomers or a mixture of stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and deuterated derivatives thereof, may be administered in combination with a hormone or hormonal analog. In some embodiments, at least one entity selected from the compounds of Formulae (I), or tautomers thereof, stereoisomers or a mixture of stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and deuterated derivatives thereof, may be administered in combination with a signal transduction pathway inhibitor. In some embodiments, at least one entity selected from the compounds of Formula (I), or tautomers thereof, stereoisomers or a mixture of stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and deuterated derivatives thereof, may be administered in combination with an antimetabolite neoplastic agent. In some embodiments, at least one entity selected from the compounds of Formula (I), or tautomers thereof, stereoisomers or a mixture of stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and deuterated derivatives thereof, may be administered in combination with a topoisomerase I inhibitor. In some embodiments, at least one entity selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof, may be administered in combination with a topoisomerase II inhibitor. In some embodiments, at least one entity selected from the compounds of Formula (I) and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof, may be administered in combination with an aromatase inhibitor. Examples [00225] The examples and preparations provided below further illustrate and exemplify the compounds as disclosed herein and methods of preparing such compounds. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations. General Synthesis Figures [00226] The compounds of Formula (I), tautomers thereof, stereoisomers or a mixture of stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and deuterated derivatives thereof can be prepared according to the figures. The figures represent the general methods used in preparing these compounds. However, the synthesis of these compounds is not limited to these representative methods, as they can also be prepared by various other methods those skilled in the art in synthetic chemistry, for example, in a stepwise or modular fashion, can readily envision. [00227] As depicted in Figure 1, the Suzuki coupling reaction between commercially available (or prepared) 5-substituted 2,4-dichloropyrimidine 1A and prepared (or purchased) organoboranes 1B in the presence of Pd(PPh3)4, Pd(dppf)2Cl2 etc. and bases such as K2CO3, K3PO4 etc., in polar solvents such as Dioxane, DMF etc. is applied to yield 5-substituted-4- aryl- (or heteroaryl)-2- chloropyrimidines 1C. Subsequently, the displacement of 2-Cl in the pyrimidine intermediate 1C with amine provides the desired target molecules. In a similar method, the key intermediates 2C, 3C, and 4C were prepared and the final target molecules were obtained. Abbreviations [00228] The following abbreviations have the meanings set forth below: ACN : Acetonitrile Ac2O : Acetic anhydride AcOH : Acetic acid Aq : Aqueous B2pin2 : 4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi-1,3,2-dioxaborolane Bn : Benzyl Boc : tert-Butyloxycarbonyl protecting group Cs2CO3 : Cesium carbonate (COCl)2 : Oxalyl chloride CuI : Copper iodide DCE : 1,2-Dichloroethane DCM : Dichloromethane DIEA : N,N-Diisopropylethylamine DMAP : 4-Dimethylaminopyridine DME : Dimethoxyethane DMF : Dimethylformamide DMFDMA : 1,1-Dimethoxy-N,N-dimethylmethylamine DMSO : Dimethyl sulfoxide DIPEA : N, N-Diisopropylethylamine EA : Ethyl acetate EtOAc : Ethyl acetate EtOH : Ethanol Eq : Equivalent FA : Formic acid HATU : 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate HFIP : 1,1,1,3,3,3-Hexafluoro-2-propanol KOAc : Potassium acetate KOH : Potassium hydroxide LDA : Lithium Diisopropylamide LiOH : Lithium hydroxide LR : Lawesson’s reagent MeI : Methyl Iodide MeOH : Methanol MeMgBr : Methylmagnesium bromide Ms2O : Methanesulfonic anhydride MsCl : Methanesulfonyl chloride NaBH4 : Sodium borohydride NaH : Sodium hydride NBS : N-Bromosuccinimide NEt3 : Triethylamine NHPI : N-Hydroxyphthalimide NIS : N-Iodosuccinimide NMP : N-Methyl-2-pyrrolidone Pd(dppf)Cl2 : [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3)4 : Tetrakis(triphenylphosphine)palladium(0) PPh3 : Triphenylphosphine Py : Pyridine RT : Room temperature Sat. : Saturated SFC : Supercritical fluid chromatography T3P : 2,4,6-Tripropyl-1,3,5,2λ5,4λ5,6λ5-trioxatriphosphinane-2,4,6-trione TEA : Triethylamine TFA : Trfluoroacetic Acid THF: Tetrahydrofuran TMSCHN2 : Trimethylsilyldiazomethane TMSCl : Trimethylsilyl chloride TsOH : 4-Methylbenzene-1-sulfonic acid Pd(OH)2/C : Palladium hydroxide on carbon Pd/C : Palladium on carbon [00229] Compounds described in the experimental section were prepared from commercially available starting materials. Purity of all final compounds was analyzed by HPLC with detection at 214 nm and 254 nm wavelength. All final compounds exhibited purity greater than 95%. All final compounds were characterized by LC/MS and 1H-NMR. The following are representative examples demonstrating how the claimed molecules can be made. However, a person skilled in the art would understand that the compounds could be prepared by other synthesis methods. Representative Intermediate Synthesis Intermediate-1: Preparation of (1S*,2S*,3R*,5R*)-(±)-3-amino-8- oxabicyclo[3.2.1]octan-2-ol (Int-1) Step 1: Preparation of (1S*,2R*,5R*)-(±)-3,3-dimethoxy-8-oxabicyclo[3.2.1]octan-2-ol [00230] To an ice-cooled solution of KOH (8.01 g, 142.68 mmol, 4.5 eq) in MeOH (30 mL) was added the solution of 8-oxabicyclo[3.2.1]octan-3-one (4 g, 31.71 mmol, 1 eq) in MeOH (20 mL) dropwise while maintaining the internal temperature range 0- 3 °C. The mixture was stirred for 20 min and (diacetoxyiodo)benzene (15.32 g, 47.56 mmol, 1.5 eq) was added portionwise. The mixture was warmed and stirred at 20 °C for 2 h. The volatiles were removed under reduced pressure. The resulting residue was diluted with water (60 mL), and the aqueous phase was extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The remaining residue was purified by column chromatography to afford (1S*,2R*,5R*)- (±)-3,3-dimethoxy-8-oxabicyclo[3.2.1]octan-2-ol (3.3 g, 55.29% yield) as yellow oil. Step 2: Preparation of (1S*,2R*,5R*)-(±)-2-(benzyloxy)-3,3-dimethoxy-8- oxabicyclo[3.2.1]octane [00231] To a solution of (1S*,2R*,5R*)-(±)-3,3-dimethoxy-8-oxabicyclo[3.2.1]octan- 2-ol (4 g, 21.25 mmol, 1 eq) in DMF (40 mL) was added NaH (1.36 g, 34.00 mmol, 60% purity, 1.6 eq) at 0 °C, and the mixture was stirred for 30 min at that temperature, followed by slow addition of bromomethylbenzene (5.45 g, 31.88 mmol, 3.79 mL, 1.5 eq). The mixture was then stirred at 20 °C for 8 h and carefully quenched with water (150 mL) at 0 °C. The aqueous phase was extracted with ethyl acetate (150 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford (1S*,2R*,5R*)-(±)- 2-(benzyloxy)-3,3-dimethoxy-8-oxabicyclo[3.2.1]octane (5.3 g, 89.60% yield) as yellow oil.1H-NMR (400 MHz, CHLOROFORM-d) δ 7.38 - 7.34 (m, 5H), 4.80 - 4.73 (m, 1H), 4.67 - 4.62 (m, 1H), 4.38 - 4.30 (m, 1H), 4.25 (dd, J = 4.4, 7.4 Hz, 1H), 3.69 (d, J = 4.0 Hz, 1H), 3.39 (s, 3H), 3.29 (s, 3H), 2.01 (dd, J = 1.6, 14.1 Hz, 1H), 1.96 - 1.77 (m, 3H), 1.76 - 1.65 (m, 2H) ppm. Step 3: Preparation of (1S*,2R*,5R*)-(±)-2-(benzyloxy)-8-oxabicyclo[3.2.1]octan-3- one [00232] To a solution of (1S*,2R*,5R*)-(±)-2-(benzyloxy)-3,3-dimethoxy-8- oxabicyclo[3.2.1]octane (5.3 g, 19.04 mmol, 1 eq) in acetone (50 mL) and water (2.5 mL) was added TsOH ^H2O (9.05 g, 47.60 mmol, 2.5 eq). The mixture was stirred at 60 °C for 12 h. The reaction mixture was adjusted to pH=8 by aqueous NaOH (1 M) at 0 °C, followed by addition of water (200 mL). The aqueous phase was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford (1S*,2R*,5R*)-(±)- 2-(benzyloxy)-8-oxabicyclo[3.2.1]octan-3-one (4.2 g, 94.96% yield) as a yellow oil. 1H-NMR (400 MHz, CHLOROFORM-d) δ 7.42 - 7.29 (m, 5H), 4.93 (d, J = 12.0 Hz, 1H), 4.73 - 4.66 (m, 1H), 4.64 - 4.55 (m, 2H), 4.03 (d, J = 5.2 Hz, 1H), 2.72 (dd, J = 5.2, 14.7 Hz, 1H), 2.34 (d, J = 14.8 Hz, 1H), 2.05 - 1.86 (m, 3H), 1.78 - 1.66 (m, 1H) ppm. Step 4: Preparation of (1S*,2S*,3S*,5R*)-(±)2-(benzyloxy)-8-oxabicyclo[3.2.1]octan- 3-ol [00233] To a solution of (1S*,2R*,5R*)-(±)-2-(benzyloxy)-8-oxabicyclo[3.2.1]octan- 3-one (4.2 g, 18.08 mmol, 1 eq) in MeOH (50 mL) was added NaBH4 (1.37 g, 36.16 mmol, 2 eq) portionwise at 0 °C. The mixture was then warmed up to 25 °C and stirred for 1 h under N2 atmosphere. The reaction mixture was subsequently quenched by addition of NH4Cl aq (100 mL). The aqueous phase was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford (1S*,2S*,3S*,5R*)-(±)2-(benzyloxy)-8-oxabicyclo[3.2.1]octan-3-ol (3.2 g, 75.53% yield) as a white solid.1H-NMR (400 MHz, CHLOROFORM-d) δ 7.41 - 7.32 (m, 5H), 4.72 - 4.61 (m, 2H), 4.37 - 4.27 (m, 2H), 4.12 (br t, J = 4.4 Hz, 1H), 3.62 (t, J = 4.4 Hz, 1H), 2.64 (s, 1H), 2.39 - 2.30 (m, 1H), 2.25 - 2.15 (m, 1H), 2.02 - 1.94 (m, 1H), 1.94 - 1.84 (m, 2H), 1.84 - 1.74 (m, 1H) ppm. Step 5: Preparation of (1S*,2R*,3S*,5R*)-(±)-2-(benzyloxy)-8-oxabicyclo[3.2.1]octan- 3-yl methanesulfonate [00234] To a solution of (1S*,2S*,3S*,5R*)-(±)2-(benzyloxy)-8- oxabicyclo[3.2.1]octan-3-ol (500.00 mg, 2.13 mmol, 1 eq) and DMAP (2.09 g, 17.07 mmol, 8 eq) in DCE (8 mL) was added TEA (1.73 g, 17.07 mmol, 2.38 mL, 8 eq), followed by methanesulfonyl chloride (3.15 g, 27.50 mmol, 2.13 mL, 12.89 eq) at 0 °C. The mixture was then stirred at 80 °C for 12 h. The reaction mixture was cooled to room temperature and poured into sat. NaHCO3 solution (20 mL). The organic layer was isolated, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford (1S*,2R*,3S*,5R*)-(±)-2- (benzyloxy)-8-oxabicyclo[3.2.1]octan-3-yl methanesulfonate (600 mg, 1.92 mmol, 90.00% yield) as yellow oil.1H-NMR (400 MHz, CHLOROFORM-d) δ 7.41 - 7.29 (m, 5H), 4.74 - 4.58 (m, 2H), 4.37 (br s, 2H), 3.70 (br s, 1H), 2.97 (d, J = 1.6 Hz, 3H), 2.45 - 2.32 (m, 1H), 2.24 - 2.11 (m, 2H), 2.05 (d, J = 1.6 Hz, 2H), 2.02 - 1.80 (m, 2H) ppm. Step 6: Preparation of (1S*,2S*,3R*,5R*)-(±)-3-azido-2-(benzyloxy)-8- oxabicyclo[3.2.1]octane [00235] To a solution of (1S*,2R*,3S*,5R*)-(±)-2-(benzyloxy)-8- oxabicyclo[3.2.1]octan-3-yl methanesulfonate (600 mg, 1.92 mmol, 1 eq) in DMF (8 mL) was added NaN3 (374.60 mg, 5.76 mmol, 3 eq). The mixture was stirred at 100 °C for 2 h under N2 atmosphere. The reaction mixture was cooled to room temperature and poured into sat. NaHCO3 solution (40 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford (1S*,2S*,3R*,5R*)-(±)-3-azido-2-(benzyloxy)-8-oxabicyclo[3.2.1]octane (300 mg, 60.23% yield) as a colorless oil.1H-NMR (400 MHz, CHLOROFORM-d) δ 7.43 - 7.30 (m, 5H), 4.73 - 4.62 (m, 2H), 4.45 - 4.34 (m, 2H), 3.62 - 3.45 (m, 2H), 2.12 - 1.92 (m, 2H), 1.91 - 1.76 (m, 2H), 1.73 - 1.59 (m, 2H) ppm. Step 7: Preparation of (1S*,2S*,3R*,5R*)-(±)-3-amino-8-oxabicyclo[3.2.1]octan-2-ol [00236] To a solution of (1S*,2S*,3R*,5R*)-(±)-3-azido-2-(benzyloxy)-8- oxabicyclo[3.2.1]octane (100 mg, 0.386 mmol, 1 eq) in MeOH (5 mL) was added Pd/C (100.00 mg, 0.094 mmol, 10% purity) and Pd(OH)2/C (100 mg, 0.386 mmol, 10% purity). The suspension was degassed and backfilled with H2 for three times. The mixture was stirred under H2 (50 Psi) at 80 °C for 5 h. The reaction was cooled to room temperature. The hydrogen was released and exchanged with N2 for three times. The solid was filtered and the filtrate was concentrated to afford (1S*,2S*,3R*,5R*)-(±)-3-amino-8-oxabicyclo[3.2.1]octan-2-ol (50 mg, 90.55% yield) as a yellow oil. The crude product was used into reactions without further purification.1H-NMR (400 MHz, CHLOROFORM-d) δ 4.49 - 4.35 (m, 1H), 4.34 - 4.22 (m, 1H), 3.57 - 3.31 (m, 1H), 2.78 - 2.62 (m, 1H), 2.58 - 2.33 (m, 1H), 2.07 - 1.91 (m, 2H), 1.90 - 1.74 (m, 2H), 1.71 - 1.28 (m, 4H) ppm. Intermediate-2: Preparation of tert-butyl (1S*,2S*,3R*,5R*)-(±)-3-amino-2- hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate Step 1: Preparation of tert-butyl (1S*,2R*,5R*)-(±)-2-hydroxy-3,3-dimethoxy-8- azabicyclo[3.2.1]octane-8-carboxylate [00237] To a cold solution of KOH (56.04 g, 998.74 mmol, 4.5 eq) in MeOH (400 mL) was added dropwise the solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8- carboxylate (50 g, 221.94 mmol, 1 eq) in MeOH (200 mL) while maintaining the internal temperature range 0-3 °C. The mixture was stirred for 20 min, and (diacetoxyiodo)benzene acetate (107.23 g, 332.91 mmol, 1.5 eq) was subsequently added in portions. The mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was partitioned between EtOAc (200 mL) and water (100 mL). The organic layer was isolated, and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford tert-butyl (1S*,2R*,5R*)- (±)-2-hydroxy-3,3-dimethoxy-8-azabicyclo[3.2.1]octane-8-carboxylate (65 g, crude) as a white solid.1H-NMR (400 MHz, DMSO-d6) δ 4.90 (d, J = 8.0 Hz, 1H), 3.96 (br s, 1H), 3.80 (br s, 1H), 3.66 - 3.55 (m, 1H), 3.20 (d, J = 6.4 Hz, 6H), 2.17 - 2.02 (m, 2H), 1.88 - 1.71 (m, 1H), 1.67 - 1.51 (m, 3H), 1.39 (s, 9H) ppm. Step 2: Preparation of tert-butyl (1S*,2R*,5R*)-(±)-2-(benzyloxy)-3,3-dimethoxy-8- azabicyclo[3.2.1]octane-8-carboxylate [00238] To a solution of tert-butyl (1S*,2R*,5R*)-(±)-2-hydroxy-3,3-dimethoxy-8- azabicyclo[3.2.1]octane-8-carboxylate (30 g, 104.40 mmol, 1 eq) in THF (200 mL) was added NaH (4.59 g, 114.84 mmol, 60% purity, 1.1 eq) at 0 °C. After the mixture was stirred for 30 min at that temperature, bromomethylbenzene (23.21 g, 135.72 mmol, 16.12 mL, 1.3 eq) was added slowly. The mixture was then warmed to 25 °C and stirred for 18 h. The volatiles were removed under reduced pressure, and the remaining residue was diluted with H2O (200 mL). The basic aqueous phase was carefully adjusted with concentrated HCl to pH=5. The precipitate was collected by filtration and discarded. The filtrate was extracted with EtOAc (100 mL x 3). The combined layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford tert-butyl (1S*,2R*,5R*)-(±)-2- (benzyloxy)-3,3-dimethoxy-8-azabicyclo[3.2.1]octane-8-carboxylate (35 g, 88.81% yield) as a white solid. Step 3: Preparation of tert-butyl (1S*,2R*,5R*)-(±)-2-(benzyloxy)-3-oxo-8- azabicyclo[3.2.1]octane-8-carboxylate [00239] The solution of tert-butyl (1S*,2R*,5R*)-(±)-2-(benzyloxy)-3,3-dimethoxy-8- azabicyclo[3.2.1]octane-8-carboxylate (35 g, 92.72 mmol, 1 eq) in acetone (400 mL) and H2O (3 mL) was treated with TsOH ^H2O (839.86 mg, 4.88 mmol, 0.0526 eq) at 25 °C for 1 h. The volatiles were evaporated, and the remaining residue was diluted with water (200 mL). The aqueous phase was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a white solid (30 g, 97.63% yield), which was used for the next step reaction without further purification. 1H-NMR (400 MHz, CHLOROFORM-d) δ 7.53 - 7.30 (m, 5H), 4.91 (br d, J = 11.6 Hz, 1H), 4.68 - 4.36 (m, 3H), 2.87 - 2.55 (m, 1H), 2.38 (br d, J = 15.2 Hz, 1H), 2.25 - 1.88 (m, 4H), 1.59 - 1.18 (m, 9H) ppm. Step 4: Preparation of tert-butyl (1S*,2R*,3S*,5R*)-(±)-2-(benzyloxy)-3-hydroxy-8- azabicyclo[3.2.1]octane-8-carboxylate [00240] To a solution of tert-butyl (1S*,2R*,5R*)-(±)-2-(benzyloxy)-3-oxo-8- azabicyclo[3.2.1]octane-8-carboxylate (16.2 g, 48.88 mmol, 1 eq) in MeOH (200 mL) was added NaBH4 (2.98 g, 78.77 mmol, 1.61 eq) at 0 °C under N2. The mixture was stirred at 0-25 °C for 2 h. The reaction mixture was quenched by addition of aq. NH4Cl (30 mL) at 0 °C and then extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give tert-butyl (1S*,2R*,3S*,5R*)-(±)-2-(benzyloxy)-3-hydroxy-8-azabicyclo[3.2.1]octane-8- carboxylate (25 g, crude) as a white solid.1H-NMR (400 MHz, CHLOROFORM-d) δ 7.90 - 7.75 (m, 5H), 5.25 - 5.05 (m, 2H), 4.48 - 4.47 (m, 3H), 4.25 - 3.95 (m, 1H), 3.16 (s, 1H), 2.75 - 2.65 (m, 1H), 2.58 - 2.48 (m, 1H), 2.45 - 2.25 (m, 3H), 2.20 - 2.08 (m, 1H), 1.88 (br s, 9H) ppm. Step 5: Preparation of tert-butyl (1S*,2R*,3S*,5R*)-(±)-2-(benzyloxy)-3- ((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate [00241] To a solution of tert-butyl (1S*,2R*,3S*,5R*)-(±)-2-(benzyloxy)-3-hydroxy- 8-azabicyclo[3.2.1]octane-8-carboxylate (19 g, 56.99 mmol, 1 eq), DIEA (29.46 g, 227.94 mmol, 39.70 mL, 4 eq), DMAP (27.85 g, 227.94 mmol, 4 eq) in DCE (500 mL) was added methanesulfonyl chloride (21.71 g, 189.52 mmol, 14.67 mL, 3.33 eq) at 0 °C. After the completion of addition, the temperature was raised to 80 °C, and the mixture was stirred for 12 h at that temperature under N2. The reaction mixture was cooled to room temperature and quenched with water (200 mL). The mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography. The desired tert-butyl (1S*,2R*,3S*,5R*)-(±)-2-(benzyloxy)-3-((methylsulfonyl)oxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (27 g, crude) was obtained as a white solid. LCMS: 434.1 [M+Na]+. Step 6: Preparation of tert-butyl (1S*,2R*,3R*,5R*)-(±)3-azido-2-(benzyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate [00242] To a solution of tert-butyl (1S*,2R*,3S*,5R*)-(±)-2-(benzyloxy)-3- ((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (11 g, 26.73 mmol, 1 eq) in DMF (150 mL) was added NaN3 (4.33 g, 66.61 mmol, 2.49 eq). The mixture was stirred at 100 °C for 6 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with saturated Na2CO3 aqueous (50 mL). The aqueous phase was extracted with EtOAc (100 mL x 3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude was purified by column chromatography to give tert- butyl (1S*,2R*,3R*,5R*)-(±)3-azido-2-(benzyloxy)-8-azabicyclo[3.2.1]octane-8- carboxylate (14.3 g, crude) as a white solid.1H-NMR (400 MHz, CHLOROFORM-d) δ 7.49 - 7.17 (m, 5H), 4.73 - 4.70 (m, 1H), 4.67 - 4.56 (m, 1H), 4.29 - 4.09 (br s, 1H), 3.85 - 3.75 (m, 1H), 3.48 - 3.21 (m, 2H), 1.88 - 1.63 (m, 5H), 1.40 (s, 9H) ppm. Step 7: Preparation of tert-butyl (1S*,2S*,3R*,5R*)-(±)-3-amino-2-hydroxy-8- azabicyclo[3.2.1]octane-8-carboxylate [00243] To a solution of tert-butyl (1S*,2R*,3R*,5R*)-(±)-3-azido-2-(benzyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (4 g, 11.16 mmol, 1 eq) in MeOH (20 mL) was added Pd/C (2.00 g, 1.88 mmol, 10% purity) and Pd(OH)2 (2.00 g, 1.42 mmol, 10% purity). The suspension was degassed and backfilled with H2 for three times. The mixture was stirred under H2 (50 Psi) at 80 °C for 12 h. The reaction was cooled to room temperature. The hydrogen was released and exchanged with N2 for three times. The solid was filtered, and the filtrate was concentrated. The resulting tert- butyl (1S*,2S*,3R*,5R*)-(±)-3-amino-2-hydroxy-8-azabicyclo[3.2.1]octane-8- carboxylate (3 g, crude) was obtained as a white solid, which was used for next step reaction without further purification.1H-NMR (400 MHz, DMSO-d6) δ 5.09 (s, 1H), 3.98 (s, 1H), 3.85 (s, 1H), 3.05 (s, 1H), 2.67 - 2.55 (m, 1H), 1.96 - 1.43 (m, 6H), 1.50 (br m, 2H), 1.40 (s, 9H) ppm. Intermediate-3: Preparation of 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole Step 1: Preparation of 5-bromo-3-fluoro-N-isopropyl-2-nitroaniline [00244] To a solution of 5-bromo-1,3-difluoro-2-nitro-benzene (50 g, 210.10 mmol, 1 eq) and Cs2CO3 (136.91 g, 420.19 mmol, 2 eq) in DMF(500 mL) was added dropwise propan-2-amine (14.90 g, 252.12 mmol, 21.66 mL, 1.2 eq) at 0 °C. Then, the reaction was warmed to 25 °C and stirred for 5 h. The reaction mixture was diluted with 1000 mL of EtOAc and stirred for 5 min. The solid was filtered off and rinsed with EtOAc (500 mL). The filtrate was washed with H2O (1000 ml), brine (1000 mL), and dried over Na2SO4. The solution was filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 5-bromo-3-fluoro-N-isopropyl-2-nitroaniline (52 g, 89% yield) as a deep brown oil. LCMS: 276.8, 278.8 [M+H]+. Step 2: Preparation of 5-bromo-3-fluoro-N1-isopropylbenzene-1,2-diamine [00245] To a solution of 5-bromo-3-fluoro-N-isopropyl-2-nitro-aniline (52 g, 187.66 mmol, 1 eq) in MeOH (300 mL) and H2O (100 mL) was added Fe powder (52.40 g, 938.32 mmol, 5 eq) and NH4Cl (50.19 g, 938.32 mmol, 5 eq), and the reaction was stirred for 16 h at 70 °C. The reaction was cooled to room temperature, and the volatiles were evaporated under reduced pressure. The resulting residue was then triturated with ethyl acetate (300 mL). The solid was filtered off and the cake was washed with MeOH (500 mL x 3). The combined filtrates were concentrated, and the resulting residue was partitioned between water (500 mL) and ethyl acetate (500 mL). The organic layer was isolated, and the aqueous phase was extracted by EtOAc (500 mL x 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated. The remaining residue was purified by column chromatography to afford 5-bromo-3-fluoro-N1-isopropylbenzene-1,2-diamine (41.5 g, 89% yield) as a deep brown oil. LCMS: 246.9/248.9 [M+H]+; 1H-NMR (400 MHz, CHLOROFORM-d) δ 6.67 (dd, J = 2.0, 9.4 Hz, 1H), 6.56 (s, 1H), 3.67 - 3.50 (m, 1H), 1.27 - 1.24 (m, 6H) ppm. Step 3: Preparation of N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)acetamide [00246] A mixture of 5-bromo-3-fluoro-N1-isopropylbenzene-1,2-diamine (3 g, 12.14 mmol, 1 eq), Ac2O (1.36 g, 13.35 mmol, 1.25 mL, 1.1 eq) and DIEA (4.71 g, 36.42 mmol, 6.34 mL, 3 eq) in THF (40 mL) was stirred at 50 °C for 12 h. The reaction mixture was poured to sat. aq. NaHCO3 (100 mL). The aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to afford N-(4-bromo- 2-fluoro-6-(isopropylamino)phenyl)acetamide (3.2 g, crude) as a brown oil. LCMS: 288.7, 290.7 [M+H]+. Step 4: Preparation of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole [00247] A solution of N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)acetamide (3.2 g, 11.07 mmol, 1 eq) in AcOH (60 mL) was stirred at 140 °C for 2 h. The mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography to afford 6- bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (2.54 g, 83.53%) as a deep brown solid. LCMS: 271.1, 273.1 [M+H]+. Step 5: Preparation of 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazole [00248] A mixture of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (1.5 g, 5.53 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.11 g, 8.30 mmol, 1.5 eq), Pd(dppf)Cl2 (404.81 mg, 0.553 mmol, 0.1 eq), and KOAc (1.08 g, 11.06 mmol, 2 eq) in dioxane (20 mL) was stirred at 90 °C for 2 h under N2. The mixture was cooled to room temperature and filtered through a pad of the Celite. The filtrate was concentrated in vacuo to give a crude residue that was purified by column chromatography to afford desired 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-benzo[d]imidazole (1.5 g) as a green solid. LCMS: 319.2 [M+H]+. Intermediate-4: Preparation of 2-(4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)propan-2-ol Step 1: Preparation of N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)-2-hydroxy-2- methylpropanamide [00249] To a solution of 5-bromo-3-fluoro-N1-isopropyl-benzene-1,2-diamine (40.5 g, 163.90 mmol, 1 eq) and 2-hydroxy-2-methyl-propanoic acid (17.06 g, 163.90 mmol, 1 eq) in DMF (500 mL) was added DIEA (42.36 g, 327.79 mmol, 57.10 mL, 2 eq) at 0 °C, followed by HATU (68.55 g, 180.29 mmol, 1.1 eq) in portions while the inner temperature was maintained at 0 °C. After completion of addition, the reaction was warmed and stirred for 6 h at 25 °C. The reaction mixture was quenched with H2O (2000 mL), and the aqueous phase was extracted by EtOAc (1000 mL x 2). The combined organic layers were washed with brine (1000 mL), dried over Na2SO4, filtered, and then concentrated under reduced pressure. The resulting residue was purified to give N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)-2-hydroxy-2- methylpropanamide (14.7 g, 26.92% yield) as a deep brown oil. LCMS: 332.9/334.9 [M+H]+. Step 2: Preparation of 2-(6-bromo-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)propan-2-ol [00250] A solution of N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)-2-hydroxy-2- methylpropanamide (7.25 g, 21.76 mmol, 1 eq) in AcOH (60 mL) was stirred for 8 h at 140 °C in a sealed tube. The reaction vessel was cooled to 25 °C, and the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (200 mL) and then carefully washed with saturated Na2CO3 (50 mL), brine (50 mL). The organic phase was dried over Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography to give 2-(6-bromo-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)propan-2-ol (5.4 g, 39.37% yield) as an off-white solid. LCMS: 314.9/316.9 [M+H]+; 1H-NMR (400 MHz, CHLOROFORM-d) δ 7.42 (s, 1H), 7.02 - 7.00 (d, J = 8.0 Hz, 1H), 5.40 - 5.37 (m, 1H), 1.70 (s, 6H), 1.50 (s, 6H) ppm. Step 3: Preparation of 2-(4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)propan-2-ol [00251] The mixture of 2-(6-bromo-4-fluoro-1-isopropyl-benzimidazol-2-yl)propan- 2-ol (5.4 g, 17.13 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.22 g, 20.56 mmol, 1.2 eq) and KOAc (5.04 g, 51.40 mmol, 3 eq) in dioxane (100 mL) was degassed and backfilled with N2 atmosphere for three times, and then Pd(dppf)Cl2 (1.25 g, 1.71 mmol, 0.1 eq) was added under N2 atmosphere. The reaction mixture was stirred for 12 h at 100 °C under N2 atmosphere. After the starting material was consumed, the reaction was cooled to room temperature and the volatiles were removed under reduced pressure. The remaining residue was diluted with 100 mL of EtOAc and stirred for 10 min. Then the solid was filtered off and the filtration was concentrated. The resulting residue was purified by column chromatography to give 2-(4-fluoro-1-isopropyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)propan-2-ol (4.9 g, 78.95% yield) as an off-white solid. LCMS: 363.1 [M+H]+. Intermediate-5: Preparation of 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carbonitrile Step 1: Preparation of (E)-2-(4-bromo-2-fluoro-6-nitrophenyl)-N,N-dimethylethen-1- amine [00252] A solution of 5-bromo-1-fluoro-2-methyl-3-nitrobenzene (25 g, 106.83 mmol, 1 eq), DMFDMA (15.28 g, 128.19 mmol, 17.03 mL, 1.2 eq) and TEA (11.89 g, 117.51 mmol, 16.36 mL, 1.1 eq) in DMF (250 mL) was stirred at 130 °C for 3 h. The reaction mixture was cooled to room temperature, and the volatiles were removed under reduced pressure to give (E)-2-(4-bromo-2-fluoro-6-nitrophenyl)-N,N- dimethylethen-1-amine (30 g, crude) as a black solid. LCMS: 289.2/291.2[M+H]+. Step 2: Preparation of 6-bromo-4-fluoro-1H-indole [00253] To a solution of (E)-2-(4-bromo-2-fluoro-6-nitrophenyl)-N,N-dimethylethen- 1-amine (30 g, 103.77 mmol, 1 eq) in H2O (70 mL) and EtOH (350 mL) was added Fe powder (28.98 g, 518.85 mmol, 5 eq) and AcOH (31.16 g, 518.85 mmol, 29.70 mL, 5 eq), and the mixture was stirred for 2 h at 80 °C. The reaction was cooled to room temperature, and the volatiles were evaporated under reduced pressure. The resulting content was diluted with water (200 mL), and the aqueous phase was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give 6-bromo-4-fluoro-1H-indole (13.37 g, 41.74% yield) as a reddish oil.1H-NMR (400 MHz, DMSO-d6) δ = 11.56 (br s, 1H), 7.52 - 7.38 (m, 2H), 7.04 - 6.98 (m, 1H), 6.51 (t, J = 2.06 Hz, 1H) ppm. Step 3: Preparation of 6-bromo-4-fluoro-1-(phenylsulfonyl)-1H-indole [00254] To a solution of 6-bromo-4-fluoro-1H-indole (11 g, 51.39 mmol, 1 eq) in THF (150 mL) was added NaH (2.47 g, 61.67 mmol, 60% purity, 1.2 eq) at 0 °C in portions. After the completion of addition, the mixture was stirred for 5 min, and benzenesulfonyl chloride (18.15 g, 102.79 mmol, 13.12 mL, 2 eq) was subsequently added at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 3h. The reaction mixture was quenched with aq. NH4Cl (300 mL) slowly, and the aqueous phase was extracted with EtOAc (200 mL x3). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The resulting crude product was purified by flash silica gel chromatography to give 6- bromo-4-fluoro-1-(phenylsulfonyl)-1H-indole (9.4 g, 48.02% yield) as a yellow solid. 1H-NMR (400 MHz, CHLOROFORM-d) δ 8.00 (s, 1H), 7.94 - 7.88 (m, 2H), 7.64 - 7.58 (m, 1H), 7.56 - 7.46 (m, 3H), 7.10 (dd, J = 1.4, 9.0 Hz, 1H), 6.74 (dd, J = 0.6, 3.8 Hz, 1H) ppm. Step 4: Preparation of 6-bromo-4-fluoro-2-methyl-1-(phenylsulfonyl)-1H-indole [00255] To a solution of 6-bromo-4-fluoro-1-(phenylsulfonyl)-1H-indole (7.4 g, 20.89 mmol, 1 eq) in THF (300 mL) was added LDA (2 M, 15.67 mL, 1.5 eq) dropwise at -78 °C, and the mixture was stirred for 0.5 h at that temperature under N2 atmosphere. The solution of iodomethane (4.45 g, 31.34 mmol, 1.95 mL, 1.5 eq) in THF (20 mL) was then added to the reaction mixture and stirred for 1 h at -78 °C. The reaction mixture was quenched with aq. NH4Cl (300 mL), and the aqueous phase was extracted with EtOAc (200 mL x 3). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The resulting crude product was purified by flash silica gel chromatography to give 6- bromo-4-fluoro-2-methyl-1-(phenylsulfonyl)-1H-indole (5.6 g, 62.60% yield) as a light-yellow solid.1H-NMR (400 MHz, CHLOROFORM-d) δ 8.18 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.66 -7.58 (m, 1H), 7.56 - 7.46 (m, 3H), 7.08 (dd, J = 1.1, 8.8 Hz, 1H), 6.40 (s, 1H), 2.58 (s, 3H) ppm. Step 5: Preparation of 6-bromo-4-fluoro-2-methyl-1H-indole [00256] To a solution of 6-bromo-4-fluoro-2-methyl-1-(phenylsulfonyl)-1H-indole (5.6 g, 15.21 mmol, 1 eq) in MeOH (60 mL) was added aqueous KOH (4.27 g, 76.04 mmol, 5 eq) in water (12 mL), and the mixture was stirred at 60 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (100 mL x 3). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The resulting crude product was purified by column chromatography to give 6-bromo-4- fluoro-2-methyl-1H-indole (2.8 g, 58.12% yield) as a yellow oil.1H-NMR (400 MHz, CHLOROFORM-d) δ 7.96 (br s, 1H), 7.25 - 7.20 (m, 1H), 6.92 (dd, J = 1.5, 9.6 Hz, 1H), 6.32 - 6.24 (m, 1H), 2.42 (d, J = 0.6 Hz, 3H) ppm. Step 6: Preparation of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-indole [00257] A solution of 6-bromo-4-fluoro-2-methyl-1H-indole (2.4 g, 10.52 mmol, 1 eq), 2-bromopropane (2.59 g, 21.05 mmol, 1.98 mL, 2 eq), Cs2CO3 (6.86 g, 21.05 mmol, 2 eq) in DMF (24 mL) was stirred at 80 °C for 12 h under N2 atmosphere. The reaction mixture was cooled to room temperature, poured into water (50 mL) and extracted with EtOAc (50 mL x3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by reversed-phase HPLC (0.05% v/v FA condition, 40% to 80%) to give 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H- indole (940 mg, 33.00% yield) as an orange liquid. LCMS: 270.1/272.1 [M+H]+; 1H- NMR (400 MHz, CHLOROFORM-d) δ 7.40 (s, 1H), 6.88 (dd, J = 1.3, 9.4 Hz, 1H), 6.28 (s, 1H), 4.62 (spt, J = 7.0 Hz, 1H), 2.42 (s, 3H), 1.60 (d, J = 7.0 Hz, 6H) ppm. Step 7: Preparation of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-indole-3-carbonitrile [00258] To a solution of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-indole (300 mg, 1.11 mmol, 1 eq) in acetonitrile (1 mL) was added N-(oxomethylene)sulfamoyl chloride (314.36 mg, 2.22 mmol, 193.33 μL, 2 eq) dropwise at 0 °C, and the mixture was stirred for 1 h at that temperature. DMF (162.35 mg, 2.22 mmol, 170.89 μL, 2 eq) was then added, and the mixture was warmed to 25 °C and stirred for 3 h. The reaction mixture was poured into iced water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to give 6-bromo-4-fluoro-1- isopropyl-2-methyl-1H-indole-3-carbonitrile (57 mg, 17.39% yield) as a yellow solid. LCMS: 295.0 [M+H]+. Step 8: Preparation of 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indole-3-carbonitrile [00259] To a degassed and N2 backfilled solution of 6-bromo-4-fluoro-1-isopropyl- 2-methyl-1H-indole-3-carbonitrile (120 mg, 0.406 mmol, 1 eq) and 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (154.87 mg, 0.61 mmol, 1.5 eq) in 1,4-dioxane (3 mL) was added Pd(dppf)Cl2 (29.75 mg, 0.00407 mmol, 0.1 eq) and KOAc (79.80 mg, 0.813 mmol, 2 eq), and the reaction solution was stirred at 90 °C for 2 h under N2 atmosphere. The reaction mixture was cooled to room temperature and filtered via a short pad of celite. The filtrate was evaporated under reduced pressure to give 4-fluoro-1-isopropyl-2-methyl- 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carbonitrile (139.1 mg, 80.2% yield) as a brown oil. LCMS: 343.2 [M+H]+. Intermediate-6: Preparation of 4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carbonitrile Step 1: Preparation of isopropyl 6-bromo-4-fluoro-1-isopropyl-1H-indole-2- carboxylate [00260] To a solution of ethyl 6-bromo-4-fluoro-1H-indole-2-carboxylate (1.1 g, 3.88 mmol, 1.0 eq) in DMF (3 mL) was added Cs2CO3 (3.8 g, 11.64 mmol, 3.0 eq) under N2. The mixture was stirred at 0 °C for 0.5 h, 2-iodopropane (2.0 g, 11.64 mmol, 1.2 mL, 3.0 eq) was then added. The mixture was stirred at 120 °C for 16 h under N2. The reaction mixture was cooled to room temperature and poured into aqueous NH4Cl (50 mL). The aqueous phase was extracted with EtOAc (50 mL x 3), and the combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was further purified by flash chromatography to give isopropyl 6-bromo-4-fluoro-1-isopropyl-1H-indole-2- carboxylate (1.3 g, 98% yield) as a white solid. Step 2: Preparation of 2-(6-bromo-4-fluoro-1-isopropyl-1H-indol-2-yl)propan-2-ol [00261] To a cooled solution of isopropyl 6-bromo-4-fluoro-1-isopropyl-1H-indole- 2-carboxylate (1.2 g, 3.50 mmol, 1.0 eq) in THF (10 mL) was added MeMgBr (3.0 M, 7.00 mL, 6.0 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h and then poured into aqueous NH4Cl (50 mL). The mixture was extracted with EtOAc (50 mL x 3), the combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting desired 2-(6-bromo-4-fluoro-1- isopropyl-indol-2-yl) propan-2-ol (980.0 mg, 89% yield) was obtained as a yellow solid, which was used without further purification. LCMS: 627.3 [2M+H]+. Step 3: Preparation of 2-(6-bromo-4-fluoro-3-iodo-1-isopropyl-1H-indol-2-yl)propan- 2-ol [00262] To a solution of 2-(6-bromo-4-fluoro-1-isopropyl-indol-2-yl) propan-2-ol (230.0 mg, 0.732 mmol, 1.0 eq) in DMF (6 mL) was added dropwise NIS (247.0 mg, 1.10 mmol, 1.5 eq) at 0 °C. After completion of addition, the mixture was stirred at 25 °C for 2 h and then quenched by addition of saturated aqueous Na2SO3 (5 mL). The mixture was extracted withethyl acetate(10 mL x 2). The combined organic layers were washed with saturated brine 10 mL, dried over Na2SO4, filtered, and concentrated under reduced pressure. The desired 2-(6-bromo-4-fluoro-3-iodo-1- isopropyl-1H-indol-2-yl)propan-2-ol (250.0 mg, 77% yield) was obtained as a yellow solid. LCMS: 422.1/424.1 [M+H-18]+. Step 4: Preparation of 6-bromo-4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H- indole-3-carbonitrile [00263] The mixture of 2-(6-bromo-4-fluoro-3-iodo-1-isopropyl-1H-indol-2- yl)propan-2-ol (250.0 mg, 0.568 mmol, 1.0 eq) , CuCN (61.0 mg, 0.682 mmol, 1.2 eq) in DMF (8 mL) was degassed and backfilled with N2 for three times, and then Pd(PPh3)4 (131.3 mg, 0.114 mmol, 0.2 eq) was added under N2 atmosphere. The mixture was stirred at 110 °C for 2 h under N2 atmosphere. The reaction was cooled to room temperature and quenched with H2O (10 mL). The aqueous phase was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with saturated brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 6-bromo-4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-indole-3-carbonitrile (53.0 mg, 27% yield) as a yellow solid. LCMS: 341.2 [M+H] +. Step 5: Preparation of 4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carbonitrile [00264] A mixture of 6-bromo-4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H- indole-3-carbonitrile (50.0 mg, 0.147 mmol, 1.0 eq), Pin2B2 (93.6 mg, 0.369 mmol, 2.5 eq), Pd(dppf)Cl2 (43.1 mg, 0.059 mmol, 0.4 eq) and KOAc (43.4 mg, 0.442 mmol, 3.0 eq) in dioxane (3 mL) was degassed and backfilled with N2 for three times, and then stirred at 90 °C for 4 h under N2 atmosphere. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting crude 4-fluoro-2-(1-hydroxy-1-methyl-ethyl)-1-isopropyl-6-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indole-3-carbonitrile (40 mg) was used for the next step reaction without further purification. LCMS: 387.4 [M+H] +. Intermediate-7: Preparation of 2-(8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)propan-2-ol Step 1: Preparation of 6-bromo-4-fluoro-2,3-dinitrophenol [00265] To a solution of 2-bromo-4-fluoro-5-nitrophenol (6.5 g, 27.54 mmol, 1.0 eq) in CHCl3 (48 mL) was added dropwise a solution of HNO3 (11.0 g, 118.27 mmol, 7.8 mL, 68.0% purity, 4.3 eq) in CHCl3 (36 mL) at 20 °C. The mixture was stirred at 20 °C for 15 min. The reaction mixture was then poured into water (120 mL) and extracted with DCM (120 mL x 2). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated to give 6-bromo-4- fluoro-2,3-dinitrophenol (7.7 g, 99% yield) as a yellow solid. Step 2: Preparation of 2-amino-6-bromo-4-fluoro-3-nitrophenol [00266] To a solution of 6-bromo-4-fluoro-2,3-dinitrophenol (7.7 g, 27.40 mmol, 1.0 eq) in MeOH (150 mL) was added HCl (12 M, 77 mL) and SnCl2 (15.6 g, 82.21 mmol, 3.0 eq) under N2 atmosphere. The mixture was stirred at 20 °C for 15 min until starting material was consumed. The reaction mixture was poured into water (200 mL) and then extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 2-amino-6-bromo-4-fluoro-3-nitrophenol (6.0 g, 60% yield) as a yellow solid.1H- NMR (400 MHz, DMSO-d6) δ 9.80 (br s, 1H), 6.80 (d, J = 11.6 Hz, 3H) ppm. Step 3: Preparation of 8-bromo-6-fluoro-5-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one [00267] To a solution of 2-amino-6-bromo-4-fluoro-3-nitrophenol (2.0 g, 7.97 mmol, 1.0 eq) and 2-chloroacetyl chloride (1.4 g, 11.95 mmol, 1.5 eq) in DME (300 mL) was added Na2CO3 (2.5 g, 23.90 mmol, 3.0 eq) under N2 atmosphere. The mixture was stirred at 85 °C for 6 h and then cooled to room temperature. The reaction mixture was poured into water (200 mL), and the aqueous phase was extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated to give 8-bromo-6-fluoro-5-nitro-2H- benzo[b][1,4]oxazin-3(4H)-one (2.3 g, 99% yield) as a yellow solid.1H-NMR (400 MHz, DMSO-d6) δ 11.60 - 10.53 (m, 1H), 7.39 (d, J = 10.0 Hz, 1H), 4.65 (s, 2H) ppm. Step 4: Preparation of 8-bromo-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-amine [00268] To a solution of 8-bromo-6-fluoro-5-nitro-2H-benzo[b][1,4]oxazin-3(4H)- one (2.0 g, 6.87 mmol, 1.0 eq) in THF (100 mL) was added NaBH4 (3.2 g, 85.64 mmol, 12.5 eq) and I2 (4.4 g, 17.18 mmol, 2.5 eq) at 0 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into ice NH4Cl (aq., 200 mL) and the aqueous phase was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography to give 8-bromo-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-amine (1.0 g, 4.05 mmol, 59% yield) as a brown solid.1H-NMR (400 MHz, DMSO-d6) δ 6.61 (d, J = 10.4 Hz, 1H), 5.25 (br s, 1H), 4.58 (s, 2H), 4.14 - 4.06 (m, 2H), 3.31 (d, J = 4.8 Hz, 2H) ppm. Step 5: Preparation of N-(8-bromo-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)- 2-hydroxy-2-methylpropanamide [00269] To a solution of 2-hydroxy-2-methyl-propanoic acid (83.4 mg, 0.801 mmol, 2.3 eq) in DMF (2 mL) was added DIEA (282.5 mg, 2.19 mmol, 6.4 eq) and HATU (415.5 mg, 1.09 mmol, 3.2 eq). After the mixture was stirred at 20 °C for 0.5 h, 8- bromo-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-amine (180.0 mg, 0.342 mmol, 1.0 eq) was added. The mixture was stirred at 20 °C for 12 h until the starting material was consumed. The reaction mixture was poured into water (20 mL), and the aqueous phase was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography to give N-(8-bromo-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)-2-hydroxy-2- methylpropanamide (100.0 mg, 87% yield) as a yellow oil. LCMS: 332.9/334.9 [M+H] +. Step 6: Preparation of 2-(6-bromo-8-fluoro-3,4-dihydro-5-oxa-1,2a- diazaacenaphthylen-2-yl)propan-2-ol [00270] A mixture of N-(8-bromo-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)- 2-hydroxy-2-methylpropanamide (300.0 mg, 0.900 mmol, 1.0 eq) in AcOH (10 mL) was stirred at 130 °C for 12 h under N2 atmosphere. The reaction mixture was cooled to room temperature and poured into water (20 mL). The aqueous phase was carefully adjusted with NaHCO3 (aq.) to pH=7 and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give 2-(6-bromo-8-fluoro-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)propan-2- ol (110.0 mg, 38% yield) as a yellow oil. LCMS: 314.8/316.8 [M+H]+. Step 7: Preparation of 2-(8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4- dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)propan-2-ol [00271] The mixture of 2-(6-bromo-8-fluoro-3,4-dihydro-5-oxa-1,2a- diazaacenaphthylen-2-yl)propan-2-ol (110.0 mg, 0.349 mmol, 1.0 eq), 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (88.6 mg, 0.349 mmol, 1.0 eq) and KOAc (102.8 mg, 1.05 mmol, 3.0 eq) in dioxane (2 mL) was degassed and backfilled with N2 for three times, and Pd(dppf)Cl2 (25.5 mg, 0.0349 mmol, 0.1 eq) was added under N2 atmosphere. The mixture was then stirred at 90 °C for 1 h under N2 atmosphere until the starting material was consumed. The reaction mixture was cooled to room temperature and filtered via a short pad of celite. The filtrate was concentrated. The residue was purified by prep-TLC to give 2- (8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-5-oxa-1,2a- diazaacenaphthylen-2-yl)propan-2-ol (30.0 mg, 24% yield) as a yellow solid. LCMS: 280.9 [M+H-82] +. (Observed as boric acid form). Intermediate-8: Preparation of (8-fluoro-2-(2-hydroxypropan-2-yl)-3- isopropylimidazo[1,2-a]pyridin-6-yl)boronic acid Step 1: Preparation of methyl 4-methyl-2-oxopentanoate [00272] To a solution of 4-methyl-2-oxopentanoic acid (5.0 g, 38.42 mmol, 4.72 mL, 1.0 eq) in 2, 2-dimethoxypropane (70 mL) and MeOH (17 mL) was slowly added TMSCl (513.6 mg, 4.73 mmol, 0.6 mL, 0.1 eq) and the mixture was stirred at 25 °C for 12 h. The volatiles were evaporated under reduced pressure, and the desired methyl 4-methyl-2-oxopentanoate (4.9 g, 88% yield) was obtained as yellow oil.1H- NMR (400 MHz, CDCl3) δ 3.86 (s, 3H), 2.72 (d, J = 6.8 Hz, 2H), 2.26 - 2.13 (m, 1H), 0.96 (d, J = 6.8 Hz, 6H) ppm. Step 2: Preparation of methyl 3-bromo-4-methyl-2-oxopentanoate [00273] To a solution of methyl 4-methyl-2-oxopentanoate (4.9 g, 33.92 mmol, 1.0 eq) in DCM (50 mL) was added Br2 (5.4 g, 33.92 mmol, 1.8 mL, 1.0 eq) at 0 °C. After the completion of addition, the solution was stirred at 25 °C for 12 h. The reaction was carefully quenched with saturated aqueous NaHCO3 (100 mL), and the aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The desired methyl 3-bromo-4-methyl-2-oxopentanoate (6.7 g, 30.04 mmol, 88% yield) was obtained as a yellow oil.1H-NMR (400 MHz, CDCl3) δ = 4.87 (d, J = 8.0 Hz, 1H), 3.94 (s, 3H), 2.46 - 2.29 (m, 1H), 1.17 (d, J = 7.2 Hz, 3H), 1.08 (d, J = 7.2 Hz, 3H) ppm. Step 3: Preparation of methyl 6-bromo-8-fluoro-3-isopropylimidazo[1,2-a]pyridine-2- carboxylate [00274] A solution of 5-bromo-3-fluoro-pyridin-2-amine (1.0 g, 5.24 mmol, 1.0 eq) and methyl 3-bromo-4-methyl-2-oxo-pentanoate (2.9 g, 13.09 mmol, 2.5 eq) in MeOH (8 mL) was stirred at 70 °C for 24 h. After the starting material was consumed, the reaction was cooled to room temperature. The volatiles were evaporated under reduced pressure to give the crude product, which was purified by flash silica gel chromatography. The desired methyl 6-bromo-8-fluoro-3- isopropylimidazo[1,2-a]pyridine-2-carboxylate (520.0 mg, 1.65 mmol, 32% yield) was obtained as a yellow solid. LCMS: 315.1; 317.1 [M+H] +. Step 4: Preparation of 2-(6-bromo-8-fluoro-3-isopropylimidazo[1,2-a]pyridin-2- yl)propan-2-ol [00275] To a solution of methyl 6-bromo-8-fluoro-3-isopropylimidazo[1,2- a]pyridine-2-carboxylate (470.0 mg, 1.49 mmol, 1.0 eq) in THF (6 mL) was slowly added MeMgBr (3 M, 1.19 mL, 2.4 eq) at 0 °C. After the completion of addition, the mixture was stirred at 0 °C for 2 h under N2 atmosphere. The reaction was quenched with saturated NH4Cl (10 mL), and the aqueous phase was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure to give the crude, which was purified by flash silica gel chromatography. The desired portions were collected and evaporated under reduced pressure to give 2-(6-bromo-8-fluoro-3- isopropylimidazo[1,2-a]pyridin-2-yl)propan-2-ol (220.0 mg, 46% yield) as a yellow solid. LCMS: 315.2; 317.2 [M+H] +. Step 5: Preparation of (8-fluoro-2-(2-hydroxypropan-2-yl)-3-isopropylimidazo[1,2- a]pyridin-6-yl)boronic acid [00276] A solution of 2-(6-bromo-8-fluoro-3-isopropyl-imidazo[1,2-a]pyridin-2- yl)propan-2-ol (200.0 mg, 0.635 mmol, 1.0 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (322.3 mg, 1.27 mmol, 2.0 eq) and KOAc (186.8 mg, 1.90 mmol, 3.0 eq) in dioxane (3 mL) was degassed and backfilled with N2 three times, and then Pd(dppf)Cl2•CH2Cl2 (51.8 mg, 0.0635 mmol, 0.1 eq) was added under N2 atmosphere. The reaction mixture was stirred at 90 °C for 1 h under N2 atmosphere until the starting material was consumed. The reaction was cooled to room temperature and, the reaction solution was filtered via a short pad of celite. The filtrate was evaporated under reduced pressure to give the crude product, which was purified by Prep-HPLC (FA). The desired portions were collected and lyophilized to give (8-fluoro-2-(2-hydroxypropan-2-yl)-3-isopropylimidazo[1,2- a]pyridin-6-yl)boronic acid (110.0 mg, 62% yield) as a white solid. LCMS: 281.3 [M+H] +. Intermediate-9: Preparation of methyl (R)-2-(4-fluoro-1-isopropyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1- carboxylate Step 1: Preparation of 2-benzyl 1-methyl (R)-pyrrolidine-1,2-dicarboxylate [00277] To a cooled solution of benzyl (2R)-pyrrolidine-2-carboxylate hydrochloride (2 g, 8.27 mmol, 1 eq) in DCM (20 mL) was added TEA (2.91 g, 28.74 mmol, 4 mL, 3.47 eq) and methyl chloroformate (1.96 g, 20.74 mmol, 1.61 mL, 2.51 eq) at 0 °C. The reaction mixture was then warmed and stirred at 25 °C for 12 h. After the starting material was consumed, the mixture was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The 2-benzyl 1-methyl (R)-pyrrolidine-1,2-dicarboxylate (2.44 g, crude) was obtained as a colorless oil, which was used in the next step reaction without further purification. LCMS: 264.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ 7.32 – 7.24 (m, 5H), 5.16 – 5.09 (m, 2H), 4.38 – 4.26 (m, 1H), 3.65 – 3.37 (m, 5H), 2.15 – 1.90 (m, 1H), 1.89- 1.82 (m, 2H) ppm. Step 2: Preparation of (2R)-1-methoxycarbonylpyrrolidine-2-carboxylic acid [00278] To a solution of 2-benzyl 1-methyl (R)-pyrrolidine-1,2-dicarboxylate (2.44 g, 9.27 mmol, 1 eq) in MeOH (30 mL) was added Pd/C (300 mg, 10% purity). The suspension was degassed and backfilled with H2 three times. After the mixture was stirred under H2 (30psi) at 25 °C for 12 h., the mixture was filtered through a pad of the Celite and the filtrate was concentrated in vacuo. The resulting crude (2R)-1- methoxycarbonylpyrrolidine-2-carboxylic acid (1.57 g, 97.83% yield) was obtained as a colorless oil, which was used in the next step reaction without further purification. LCMS: 271.0 [M+H] +; 1H-NMR (400 MHz, DMSO-d6) δ 4.34 – 4.32 (m, 1H), 3.69 (s, 3H), 3.51 – 3.36(m, 2H), 2.20– 2.09 (m, 1H), 2.07– 2.02 (m, 1H), 1.92- 1.86 (m, 2H) ppm. Step 3: Preparation of methyl (R)-2-((4-bromo-2-fluoro-6- (isopropylamino)phenyl)carbamoyl)pyrrolidine-1-carboxylate [00279] To a solution of (2R)-1-methoxycarbonylpyrrolidine-2-carboxylic acid (200 mg, 1.15 mmol, 1 eq) and DIEA (298.54 mg, 2.31 mmol, 402.35 uL, 2 eq) in DCM (6 mL) was added HATU (658.73 mg, 1.73 mmol, 1.5 eq), and the mixture was stirred at 25 °C for 0.5 h. To the mixture, 5-bromo-3-fluoro-N1-isopropyl-benzene-1, 2- diamine (314 mg, 1.27 mmol, 1.1 eq) was added, and the reaction mixture was stirred at 25 °C for 12 h. After the starting materials were consumed, the reaction mixture was quenched with H2O (20 mL). The aqueous phase was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give methyl (R)-2-((4-bromo-2- fluoro-6-(isopropylamino)phenyl)carbamoyl)pyrrolidine-1-carboxylate (0.234 g, 50.37% yield) as a white solid. LCMS: 402.1 [M+H] +. Step 4: Preparation of methyl (R)-2-(6-bromo-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate [00280] A solution of methyl (R)-2-((4-bromo-2-fluoro-6- (isopropylamino)phenyl)carbamoyl)pyrrolidine-1-carboxylate (234 mg, 0.582 mmol, 1 eq) in AcOH (5 mL) was stirred at 140 °C for 12 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, and the volatiles were evaporated under reduced pressure. The resulting residue was dissolved in EtOAc (20 mL) and then carefully washed with saturated Na2CO3 (5 mL), brine (10 mL). The organic phase was dried over Na2SO4, filtered, and then concentrated under reduced pressure. The resulting residue was purified by prep-TLC to give methyl (R)-2-(6- bromo-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (150 mg, 67.11% yield) as a yellow oil. LCMS: 384.0 [M+H] +. Step 5: Preparation of methyl (R)-2-(4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate [00281] The mixture of methyl (R)-2-(6-bromo-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (150 mg, 0.390 mmol, 1 eq), 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (148.70 mg, 0.586 mmol, 1.5 eq), KOAc (114.94 mg, 1.17 mmol, 3 eq) and Pd(dppf)Cl2 (28.56 mg, 0.039 mmol, 0.1 eq) in dioxane (5 mL) was degassed, backfilled with nitrogen for three times, and then stirred at 90 °C for 2 h under N2 atmosphere. The mixture was cooled to room temperature and filtered through a pad of the Celite. The filtrate was concentrated in vacuo to yield methyl (R)-2-(4-fluoro-1- isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate (180 mg, crude) as a brown oil, which was used in the next step reaction without further purification. LCMS: 432.2 [M+H] +. Intermediate-10: Preparation of methyl (S)-2-(4-fluoro-1-isopropyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1- carboxylate [00282] Methyl (S)-2-(4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate was prepared in a similar method described in the preparation of Intermediate-9. Intermediate-11: Preparation of methyl (2S,4S)-2-(4-fluoro-1-isopropyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-4- hydroxypyrrolidine-1-carboxylate [00283] Methyl (2S,4S)-2-(4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate was prepared in a similar method described in the preparation of Intermediate-9. Intermediate-12: Preparation of methyl (2S,4R)-4-fluoro-2-(4-fluoro-1-isopropyl- 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate [00284] Methyl (2S,4R)-4-fluoro-2-(4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate was prepared in a similar method described in the preparation of intermediate-9. Intermediate-13: Preparation of 2-(bicyclo[1.1.1]pentan-1-yl)-4-fluoro-1- isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole Step 1: Preparation of N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl) bicyclo[1.1.1]pentane-1-carboxamide [00285] A mixture of 5-bromo-3-fluoro-N1-isopropylbenzene-1,2-diamine (220.4 mg, 0.892 mmol, 1.0 eq), bicyclo[1.1.1]pentane-1-carboxylic acid (100 mg, 0.892 mmol, 1.0 eq), HATU (1.0 g, 2.68 mmol, 3.0 eq) and DIEA (345.8 mg, 2.68 mmol, 3.0 eq) in DMF (2 mL) was stirred at 25 °C for 1 h. The reaction was quenched with saturated aqueous sodium bicarbonate (20 mL), and the aqueous phase was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC to give N-(4-bromo-2- fluoro-6-(isopropylamino)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (196.0 mg, 0.571 mmol, 64% yield) as a yellow solid. LCMS: 343.0; 345.0 [M+H]+. Step 2: Preparation of 2-(bicyclo[1.1.1]pentan-1-yl)-6-bromo-4-fluoro-1-isopropyl-1H- benzo[d]imidazole [00286] A mixture of N-(4-bromo-2-fluoro-6- (isopropylamino)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (196.0 mg, 0.574 mmol, 1.0 eq) in AcOH (3 mL) was stirred at 140 °C for 1 h under N2 atmosphere. The mixture was cooled to room temperature, and the volatiles were concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (20 mL) and then carefully washed with saturated Na2CO3 (5 mL) and brine (10 mL). The organic phase was dried over Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by prep-TLC to give 2-(1-bicyclo[1.1.1]pentanyl)- 6-bromo-4-fluoro-1-isopropyl-benzimidazole (185.0 mg, 99% yield) as a yellow oil. Step 3: Preparation of 2-(bicyclo[1.1.1]pentan-1-yl)-4-fluoro-1-isopropyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole [00287] The solution of 2-(1-bicyclo[1.1.1]pentanyl)-6-bromo-4-fluoro-1-isopropyl- benzimidazole (185.0 mg, 0.572 mmol, 1.0 eq),B2pin2 (218.0 mg, 0.859 mmol, 1.5 eq) and KOAc (168.5 mg, 1.72 mmol, 3.0 eq) in dioxane (1 mL) was degassed, backfilled with nitrogen three times, and then Pd(dppf)Cl2 (41.9 mg, 0.0572 mmol, 0.1 eq) was added under N2 atmosphere. The reaction was stirred at 90 °C for 12 h under N2 atmosphere until the starting material was consumed completely. The mixture was cooled to room temperature and filtered through a pad of the Celite. The filtrate was concentrated in vacuo to afford the desired 2-(bicyclo[1.1.1]pentan-1-yl)- 4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- benzo[d]imidazole (211.0 mg, 99% yield) as a brown oil, which was used without further purification. LCMS: 371.2 [M+H] + Intermediate-14: Preparation of tert-butyl (R)-3-(4-fluoro-1-isopropyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1- carboxylate Step 1: Preparation of tert-butyl (R)-3-((4-bromo-2-fluoro-6- (isopropylamino)phenyl)carbamoyl)pyrrolidine-1-carboxylate [00288] To a solution of (3R)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (2.18 g, 10.12 mmol, 1 eq) in DMF (70 mL) was added T3P (9.66 g, 15.18 mmol, 9.04 mL, 50% purity, 1.50 eq) and DIPEA (3.92 g, 30.35 mmol, 5.29 mL, 3 eq) at 0 °C, followed by 5-bromo-3-fluoro-N1-isopropylbenzene-1,2-diamine (3 g, 12.14 mmol, 1.2 eq), and the mixture was then stirred at 20 °C for 12 h. The reaction mixture was quenched with sat. aq. NaHCO3 (100 mL) and the aqueous phase was extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford tert-butyl (R)- 3-((4-bromo-2-fluoro-6-(isopropylamino)phenyl)carbamoyl)pyrrolidine-1-carboxylate (2.9 g, 58% yield) as a deep brown oil. LCMS: 444.1/446.1 [M+H]+. Step 2: Preparation of (R)-6-bromo-4-fluoro-1-isopropyl-2-(pyrrolidin-3-yl)-1H- benzo[d]imidazole [00289] A solution of tert-butyl (R)-3-((4-bromo-2-fluoro-6- (isopropylamino)phenyl)carbamoyl)pyrrolidine-1-carboxylate (2.8 g, 6.30 mmol, 1 eq) in AcOH (60 mL) was stirred at 80 °C for 12 h. The reaction mixture was cooled to room temperature, and the volatiles were removed under reduced pressure. The remaining residue was carefully neutralized with sat. aq. NaHCO3 (100 mL), and the aqueous phase was extracted with DCM (100 mL x3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. (R)-6-bromo-4-fluoro-1-isopropyl-2-(pyrrolidin-3-yl)-1H- benzo[d]imidazole (2.06 g, crude) was obtained as a yellow oil. LCMS: 325.8/327.8 [M+H]+. Step 3: Preparation of tert-butyl (R)-3-(6-bromo-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate [00290] To a solution of (R)-6-bromo-4-fluoro-1-isopropyl-2-(pyrrolidin-3-yl)-1H- benzo[d]imidazole (2.06 g, 6.32 mmol, 1 eq) in DCM (50 mL) was added NaHCO3 (aq) (5.31 g, 63.15 mmol, 2.46 mL, 10 eq in H2O (50 mL)) and Boc2O (689.12 mg, 3.16 mmol, 725.39 μL, 0.5 eq), and the mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into sat. aq. NaHCO3 (100 mL) and the organic layer was isolated. The aqueous phase was extracted withethyl acetate(100 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford tert-butyl (R)-3-(6-bromo-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (2.49 g, 79.78% yield) as a yellow oil. LCMS: 426.1, 428.1 [M+H]+. Step 4: Preparation of tert-butyl (R)-3-(4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate [00291] A mixture of tert-butyl (R)-3-(6-bromo-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (2 g, 4.69 mmol, 1 eq), 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.79 g, 7.04 mmol, 1.5 eq), Pd(dppf)Cl2 (343.26 mg, 0.469 mmol, 0.1 eq) and KOAc (1.30 g, 9.38 mmol, 2 eq) in dioxane (30 mL) was stirred at 90 °C for 12 h under nitrogen atmosphere. The mixture was cooled to room temperature and filtered via a short pad of celite. The filtrate was concentrated to afford tert-butyl (R)-3-(4-fluoro-1- isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate (2.2 g, crude) as a brown oil, which was used directly for next step. LCMS: 474.4 [M+H]+. Intermediate-15: Preparation of tert-butyl (S)-3-(4-fluoro-1-isopropyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1- carboxylate [00292] tert-Butyl (S)-3-(4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate was prepared in a similar method described in the preparation of intermediate-14. Intermediate 16: Preparation of 4-fluoro-7-isopropyl-2-methyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole Step 1: Preparation of 2-fluoro-5-(prop-1-en-2-yl)aniline [00293] To a degassed and nitrogen backfilled solution of 5-bromo-2-fluoro-aniline (25 g, 131.57 mmol, 1 eq) and potassium trifluoro(prop-1-en-2-yl)borate (58.41 g, 394.71 mmol, 3 eq) in dioxane (300 mL) and H2O (60 mL) was added Cs2CO3 (128.60 g, 394.71 mmol, 3 eq) and Pd(PPh3)4 (7.60 g, 6.58 mmol, 0.05 eq) under N2, and the mixture was heated to 100 °C for 8 h under N2 atmosphere. The reaction mixture was cooled to room temperature and filtrated. The cake was washed with EtOAc (300 mL). The combined filtrate was washed with brine (200 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography to give 2-fluoro-5-(prop-1-en-2-yl)aniline (16 g, 105.83 mmol, 80.44% yield) as a yellow oil. LCMS: 152.5 [M+H] +. Step 2: Preparation of 2-fluoro-5-isopropylaniline [00294] To a solution of 2-fluoro-5-isopropenyl-aniline (13 g, 85.99 mmol, 1 eq) in EtOH (200 mL) was added Pd/C (9.15 g, 8.60 mmol, 10% purity, 0.1 eq) under N2 atmosphere. The suspension was degassed and backfilled with H2 for three times, and stirred under H2 (15 psi) at 25 °C for 3 h. The mixture was filtered via a pad Celite, and the filtrate was concentrated in vacuo. The resulting product, 2-fluoro-5-isopropylaniline (13.2 g, crude), was obtained as a yellow oil, which was used in the next step without further purification. LCMS: 154.6 [M+H] +. Step 3: Preparation of 4-bromo-2-fluoro-5-isopropylaniline [00295] To a solution of 2-fluoro-5-isopropylaniline (6 g, 39.17 mmol, 1 eq) in CH3CN (100 mL) was added NBS (6.62 g, 37.21 mmol, 0.95 eq), and the mixture was stirred at 0 °C for 1 h. After the starting material was consumed, the volatiles were removed under reduced pressure and the residue was diluted with water (100 mL). The aqueous phase was extracted with EtOAc (100 mL x 2). The combined organic layers dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield 4-bromo-2-fluoro-5-isopropylaniline (4.74 g, 52.15% yield) as a yellow oil. LCMS: 232.1 [M+H] +. Step 4: Preparation of N-(4-bromo-2-fluoro-5-isopropylphenyl)acetamide [00296] To a solution of 4-bromo-2-fluoro-5-isopropylaniline (4.74 g, 20.42 mmol, 1 eq) in THF (94 mL) was added Ac2O (2.29 g, 22.47 mmol, 2.11 mL, 1.1 eq) and DIEA (7.92 g, 61.27 mmol, 10.67 mL, 3 eq). The mixture was stirred at 50 °C for 12 h. The reaction mixture was cooled to room temperature, and the volatiles were removed under reduced pressure. The residue was diluted with H2O (100 mL) and extracted with EtOAc (150 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. N-(4-bromo-2- fluoro-5-isopropylphenyl)acetamide (5 g, crude) was obtained as a red solid. LCMS: 274.1 [M+H] +. Step 5: Preparation of N-(4-bromo-6-fluoro-3-isopropyl-2-nitrophenyl)acetamide [00297] To a solution of N-(4-bromo-2-fluoro-5-isopropylphenyl)acetamide (5 g, 18.24 mmol, 1 eq) in DCM (50 mL) was added dropwise HNO3 (45.97 g, 729.58 mmol, 32.84 mL, 40 eq) at 0 °C. After the completion of addition, the mixture was warmed and stirred at 20 °C for 2 h and then at 40 °C for 16 hs. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The organic layer was isolated, and the aqueous phase was extracted with DCM (50 mL x 2). The combined organic layers were washed with water (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give N-(4-bromo-6-fluoro-3-isopropyl-2- nitrophenyl)acetamide (1.5 g, 4.70 mmol, 25.77% yield) as a white solid. LCMS: 318.9 [M+H] +. Step 6: Preparation of N-(2-amino-4-bromo-6-fluoro-3-isopropylphenyl)acetamide [00298] To a solution of N-(4-bromo-6-fluoro-3-isopropyl-2-nitrophenyl)acetamide (200 mg, 0.627 mmol, 1 eq) in EtOH (3 mL) and NH4Cl (1 mL) was added Fe (35.00 mg, 0.627 mmol, 1 eq), and the mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with 20 mL of water and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with 20 mL of water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The desired crude N-(2-amino-4-bromo-6-fluoro-3- isopropylphenyl)acetamide (180 mg, 99.33% yield) was obtained as a white solid, which was used in the next step without further purification. LCMS: 289.0 [M+H] +. Step 7: Preparation of 6-bromo-4-fluoro-7-isopropyl-2-methyl-1H-benzo[d]imidazole [00299] N-(2-amino-4-bromo-6-fluoro-3-isopropylphenyl)acetamide (120 mg, 0.415 mmol, 1 eq) in AcOH (3 mL) was stirred at 140 °C for 2 h. The reaction mixture was cooled to room temperature, and the volatiles were removed under reduced pressure. The remaining residue was diluted with 20 mL of water, and the aqueous phase was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with water (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The desired 6-bromo-4-fluoro-7-isopropyl-2-methyl-1H- benzimidazole (100 mg, 88.87% yield) was obtained as a yellow oil, which was used in the next step without further purification. LCMS: 289.0 [M+H] +. Step 8: Preparation of 4-fluoro-7-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazole [00300] A mixture of 6-bromo-4-fluoro-7-isopropyl-2-methyl-1H-benzimidazole (100 mg, 0.369 mmol, 1 eq), B2pin2 (140.49 mg, 0.553 mmol, 1.5 eq), Pd(dppf)Cl2 (26.99 mg, 0.0369 mmol, 0.1 eq), KOAc (72.40 mg, 0.738 mmol, 2 eq) in dioxane (5 mL) was degassed and backfilled with N2 for three times, and then the mixture was stirred at 90 °C for 2 h under N2 atmosphere. The reaction mixture was cooled to room temperature and filtered via a short pad of celite. The filtrate was concentrated under reduced pressure to give 4-fluoro-7-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (100 mg, crude) as a black oil, which was used in the next step without further purification. LCMS: 319.2 [M+H] +. Intermediate-17: Preparation of 4-(4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-1-methylpyrrolidin-2-one Step 1: Preparation of methyl (R)-1-methyl-5-oxopyrrolidine-3-carboxylate [00301] To the solution of (3R)-5-oxopyrrolidine-3-carboxylic acid (300 mg, 2.32 mmol, 1 eq) in THF (8 mL) was added NaH (232.33 mg, 5.81 mmol, 60% purity, 2.5 eq) at 0 °C, and the mixture was stirred for 0.5 h under N2 atmosphere. Iodomethane (989.39 mg, 6.97 mmol, 433.94 μL, 3 eq) was then added, and the reaction mixture was stirred for 0.5 h at 0 °C. After the starting material was consumed, the mixture was quenched with sat. aq. NH4Cl (50 mL). The aqueous phase was extracted with EtOAc (30 mL x 2), and the organic layers were discarded. The aqueous layer was then concentrated in vacuo. The resulting residue was suspended in DCM/MeOH (10/1, 50 mL) and filtered. The filtrate was concentrated in vacuo to yield crude methyl (R)-1-methyl-5-oxopyrrolidine-3-carboxylate (230 mg, 1.46 mmol, 62.98% yield) as a yellow oil, which was used in the next step without further purification. LCMS: 157.9 [M+H]+; 1H-NMR (400 MHz, CHLOROFORM-d) δ 3.76 (s, 3 H), 3.67 - 3.58 (m, 2 H), 3.31 - 3.23 (m, 1 H), 2.88 (s, 3 H), 2.72 - 2.64 (m, 2 H) ppm. Step 2: Preparation of (R)-1-methyl-5-oxopyrrolidine-3-carboxylic acid [00302] A mixture of methyl (3R)-1-methyl-5-oxo-pyrrolidine-3-carboxylate (230 mg, 1.46 mmol, 1 eq) and LiOH ^H2O (184.23 mg, 4.39 mmol, 3 eq) in co-solvent of THF (2 mL)-MeOH (2 mL)-H2O (2 mL) was stirred at 25 °C for 1 h. The volatiles were evaporated under reduced pressure, and the resulting residue was dissolved in 10 mL of H2O. The aqueous phase was adjusted to pH= 3~4 by 1N HCl. The solution was lyophilized to give (3R)-1-methyl-5-oxo-pyrrolidine-3-carboxylic acid (400 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS: 143.9 [M+H]+; 1H-NMR (400 MHz, METHANOL-d4) δ 3.74 - 3.59 (m, 2H), 3.30 - 3.24 (m, 1H), 2.83 (s, 3H), 2.65 (d, J = 8.2 Hz, 2H) ppm. Step 3: Preparation of (R)-N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)-1-methyl- 5-oxopyrrolidine-3-carboxamide [00303] To a solution of (3R)-1-methyl-5-oxo-pyrrolidine-3-carboxylic acid (200 mg, 1.40 mmol, 1 eq) in DCM (2 mL) was added 5-bromo-3-fluoro-N1-isopropylbenzene- 1,2-diamine (362.53 mg, 1.47 mmol, 1.05 eq), DIEA (541.75 mg, 4.19 mmol, 730.12 μL, 3 eq) and T4P (1.51 g, 2.10 mmol, 50% purity, 1.5 eq). The mixture was stirred at 25 °C for 1 h, and then quenched with 30 mL of water. The aqueous phase was extracted by EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-TLC to give (R)-N-(4-bromo-2-fluoro-6- (isopropylamino)phenyl)-1-methyl-5-oxopyrrolidine-3-carboxamide (50 mg, 8.65% yield, 90% purity) was as a deep brown solid. LCMS: 372.1, 374.1[M+H]+. Step 4: Preparation of 4-(6-bromo-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)-1- methylpyrrolidin-2-one [00304] The solution of (3R)-N-[4-bromo-2-fluoro-6-(isopropylamino)phenyl]-1- methyl-5-oxo-pyrrolidine-3-carboxamide (50 mg, 0.134 mmol, 1 eq) in AcOH (1 mL) was stirred at 100 °C for 12 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and the volatiles were evaporated under reduced pressure. The resulting residue was purified by prep-TLC to give racemic 4-(6- bromo-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)-1-methylpyrrolidin-2-one (35 mg, 73.56% yield) as a black solid. LCMS: 354.0 [M+H] +. Step 5: Preparation of 4-(4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-1-methylpyrrolidin-2-one [00305] A mixture of 4-(6-bromo-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)-1- methylpyrrolidin-2-one (35 mg, 0.0988 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (37.64 mg, 0.148 mmol, 1.5 eq), KOAc (19.39 mg, 0.198 mol, 2 eq) and Pd(dppf)Cl2 (7.23 mg, 0.00988 mmol, 0.1 eq) in dioxane (1 mL) was degassed and backfilled with N2 for three times, and then the mixture was stirred at 90 °C for 1 h under N2 atmosphere. The mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated in vacuo to yield crude 4-(4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-1-methylpyrrolidin-2-one (40 mg, crude) as a black solid, which was used in the next step without further purification. LCMS: 402.2 [M+H] +. Intermediate-18: Preparation of (R)-5-(4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-1-isopropylpyrrolidin-2-one [00306] (R)-5-(4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- benzo[d]imidazol-2-yl)-1-isopropylpyrrolidin-2-one was prepared in a similar method described in the preparation of Intermediate-17. Intermediate-19: Preparation of (R)-5-(4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one [00307] (R)-5-(4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one was prepared in a similar method described in the preparation of Intermediate-17. Intermediate-20: Preparation of 2-(4-fluoro-7-isopropyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)propan-2-ol Step 1: Preparation of methyl 2-((2,6-difluoro-4-nitrophenyl)amino)-2-oxoacetate [00308] To a solution of 2,6-difluoro-4-nitroaniline (4.8 g, 27.57 mmol, 1 eq) in DCM (50 mL), pyridine (6.54 g, 82.71 mmol, 6.68 mL, 3 eq) was added methyl 2- chloro-2-oxo-acetate (4.05 g, 33.08 mmol, 3.05 mL, 1.2 eq) at 0 °C and the mixture was stirred at 0 °C for 8 h. The reaction was quenched with water (25 mL). The organic layer was isolated, and the aqueous phase was extracted with EtOAc (25 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting crude product was purified by column chromatography to give methyl 2-((2,6-difluoro-4- nitrophenyl)amino)-2-oxoacetate (5.01 g, 69.85% yield) as a light-yellow solid. LCMS: 261.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.21 (d, J = 7.4 Hz, 2H), 3.88 (s, 3H) ppm. Step 2: Preparation of methyl 4-fluoro-6-nitrobenzo[d]thiazole-2-carboxylate [00309] To a solution of methyl 2-((2,6-difluoro-4-nitrophenyl)amino)-2-oxoacetate (5.01 g, 19.26 mmol, 1 eq) in xylene (50 mL) was added Lawesson’s reagent (4.67 g, 11.55 mmol, 0.6 eq), and the mixture was stirred at 110 °C for 1 h under N2 atmosphere. Cs2CO3 (18.83 g, 57.78 mmol, 3 eq) was then added and the mixture was stirred at 140 °C for 12 h. The reaction was cooled to room temperature. The reaction mixture was filtered via a short pad of celite, rinsed with ethyl acetate (100 mL). The filtrate was washed with H2O (20 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting crude product was purified by column chromatography (PE/EA=10/1~3/1) to give methyl 4-fluoro-6- nitrobenzo[d]thiazole-2-carboxylate (1.44 g, 28.01% yield) as a yellow solid.1H-NMR (400 MHz, DMSO-d6) δ 9.27 - 9.14 (m, 1H), 8.39 (dd, J = 2.1, 10.3 Hz, 1H), 4.03 (s, 3H) ppm. Step 3: Preparation of methyl 6-amino-4-fluorobenzo[d]thiazole-2-carboxylate [00310] To a solution of methyl 4-fluoro-6-nitrobenzo[d]thiazole-2-carboxylate (1.34 g, 5.23 mmol, 1 eq) in ethanol (12 mL) and H2O (3 mL) were added Fe (876.22 mg, 15.69 mmol, 3 eq) and NH4Cl (839.29 mg, 15.69 mmol, 3 eq), and the mixture was stirred at 70 °C for 1 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated. The resulting content was diluted with EtOAc (100 mL), washed with water (50 mL) and dried over Na2SO4. The solid was filtered off, and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography (PE/EA = 10/1~3/1) to give methyl 6-amino-4- fluorobenzo[d]thiazole-2-carboxylate (710 mg, 57.01% yield) as a yellow solid. LCMS: 225.0 [M-H] +. Step 4: Preparation of methyl 6-amino-7-bromo-4-fluorobenzo[d]thiazole-2- carboxylate [00311] To a solution of methyl 6-amino-4-fluorobenzo[d]thiazole-2-carboxylate (710 mg, 3.14 mmol, 1 eq) in DMF (8 mL) was added NBS (614.45 mg, 3.45 mmol, 1.1 eq), and the mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into H2O (15 mL) and the aqueous phase was extracted with EtOAc (15 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting crude product was purified by column chromatography (PE/EA=15/1~3/1) to give methyl 6-amino-7-bromo-4- fluorobenzo[d]thiazole-2-carboxylate (550 mg, 48.19% yield) as a yellow solid. LCMS: 304.9, 306.9 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ 6.94 (d, J = 12.6 Hz, 1H), 6.40 (s, 2H), 3.94 (s, 3H) ppm. Step 5: Preparation of 6-amino-4-fluoro-7-(prop-1-en-2-yl)benzo[d]thiazole-2- carboxylic acid [00312] To a degassed and nitrogen backfilled solution of methyl 6-amino-7- bromo-4-fluorobenzo[d]thiazole-2-carboxylate (530 mg, 1.74 mmol, 1 eq), 2- isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (437.83 mg, 2.61 mmol, 1.5 eq) and K2CO3 (720.19 mg, 5.21 mmol, 3 eq) in 1,4-dioxane (15 mL) and H2O (3 mL) was added Pd(dppf)Cl2 (127.10 mg, 0.174 mmol, 0.1 eq), and the reaction solution was stirred at 90 °C for 2 h under N2 atmosphere. The reaction mixture was cooled to room temperature, filtered and the filtrate was evaporated under reduced pressure. The resulting residue was purified by reversed phase HPLC to afford 6- amino-4-fluoro-7-(prop-1-en-2-yl)benzo[d]thiazole-2-carboxylic acid (170 mg, 36.86% yield) as yellow solid and methyl 6-amino-4-fluoro-7-(prop-1-en-2- yl)benzo[d]thiazole-2-carboxylate (150 mg, 29.19% yield) as a yellow solid. LCMS 253.0 [M+H] +; and LCMS 267.1 [M+H]+. Step 6: Preparation of methyl 6-amino-4-fluoro-7-(prop-1-en-2-yl)benzo[d]thiazole-2- carboxylate [00313] To a solution of 6-amino-4-fluoro-7-isopropenyl-1, 3-benzothiazole-2- carboxylic acid (170 mg, 0.674 mmol, 1 eq) in methanol (3 mL) and DCM (9 mL) was added TMSCHN2 (230.92 mg, 2.02 mmol, 3 eq), and the reaction solution was stirred at 0 °C for 0.5 h. The reaction mixture was poured into H2O (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting crude product was purified by column chromatography (PE/EA=10/1~2/1) to give methyl 6-amino-4-fluoro-7-(prop-1-en-2-yl)benzo[d]thiazole-2-carboxylate (90 mg, 47.80% yield) as a yellow solid. LCMS: 267.1 [M+H]+. Step 7: Preparation of methyl 6-amino-4-fluoro-7-isopropylbenzo[d]thiazole-2- carboxylate [00314] The mixture of methyl 6-amino-4-fluoro-7-(prop-1-en-2-yl)benzo[d]thiazole- 2-carboxylate (240 mg, 0.901 mmol, 1 eq) and Pd/C (95.91 mg, 0.0901 mmol, 10% purity, 0.1 eq) in methanol (30 mL) was degassed, backfilled with H2 for three times, and then stirred under H2 atmosphere (15 psi) at 25 °C for 2 h. The solid was filtered off and the filtrate was evaporated under reduced pressure to give methyl 6-amino-4- fluoro-7-isopropylbenzo[d]thiazole-2-carboxylate (220 mg, 76.51% yield) as a yellow solid. LCMS: 267.0 [M+H]+. Step 8: Preparation of methyl 6-bromo-4-fluoro-7-isopropylbenzo[d]thiazole-2- carboxylate [00315] The ice-cooled mixture of tert-butyl nitrite (211.38 mg, 2.05 mmol, 243.81 μL, 2.5 eq) and CuBr2 (183.14 mg, 0.820 mmol, 38.40 μL, 1 eq) in acetonitrile (10 mL) was added dropwise a solution of methyl 6-amino-4-fluoro-7-isopropyl-1, 3- benzothiazole-2-carboxylate (220 mg, 0.820 mmol, 1 eq) in acetonitrile (10 mL). After the completion of the addition, the mixture was stirred at 0 °C for 1h, then heated at 80 °C for 12 h. The reaction mixture was cooled to room temperature and filtered via a short pad of celite, rinsed with acetonitrile (20 mL). The filtrate was evaporated under reduced pressure to give the crude product, which was purified by column chromatography to give methyl 6-bromo-4-fluoro-7- isopropylbenzo[d]thiazole-2-carboxylate (160 mg, 56.86% yield) as a yellow solid. LCMS: 332.0/334.0 [M+H]+. Step 9: Preparation of 2-(6-bromo-4-fluoro-7-isopropylbenzo[d]thiazol-2-yl)propan-2- ol [00316] To a solution of methyl 6-bromo-4-fluoro-7-isopropylbenzo[d]thiazole-2- carboxylate (150 mg, 0.452 mmol, 1 eq) in THF (5 mL) was added MeMgBr (3 M, 376.29 μL, 2.5 eq), and the reaction mixture was stirred at 25 °C for 1 h under N2 atmosphere. The mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting crude product was purified by column chromatography to give 2-(6-bromo- 4-fluoro-7-isopropylbenzo[d]thiazol-2-yl)propan-2-ol (120 mg, 78.39% yield) as a light-yellow solid. LCMS: 332.0/334.0 [M+H] +; 1H-NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 10.0 Hz, 1H), 6.39 (s, 1H), 3.83 - 3.66 (m, 1H), 1.59 (s, 6H), 1.37 (d, J = 7.1 Hz, 6H) ppm. Step 10: Preparation of 2-(4-fluoro-7-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzo[d]thiazol-2-yl)propan-2-ol [00317] To a degassed and nitrogen backfilled solution of 2-(6-bromo-4-fluoro-7- isopropylbenzo[d]thiazol-2-yl)propan-2-ol (80 mg, 0.241 mmol, 1 eq) and 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (122.29 mg, 0.482 mmol, 2 eq) in 1,4-dioxane (1 mL) were added Pd(dppf)Cl2 (17.62 mg, 0.0241 mmol, 0.1 eq) and KOAc (70.90 mg, 0.722 mmol, 3 eq), and the reaction was stirred at 90 °C for 2 h under N2 atmosphere. The reaction mixture was cooled to room temperature and filtered via a short pad of celite, rinsed with acetonitrile (20 mL). The filtrate was evaporated under reduced pressure to give 2-(4-fluoro-7- isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)propan- 2-ol (91.33 mg, 50.40% yield) as a light-yellow oil. LCMS: 380.1 [M+H]+. Intermediate-21: Preparation of 2-(4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzo[d]thiazol-2-yl)propan-2-ol [00318] 2-(4-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol- 2-yl)propan-2-ol was prepared in a similar method described in the preparation of intermediate 20. Intermediate-22: Preparation of 2-(4-fluoro-7-isopropyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)propan-2-ol Step 1: Preparation of N-(4-bromo-2-fluoro-5-isopropylphenyl)acetamide [00319] To a solution of 4-bromo-2-fluoro-5-isopropylaniline (2 g, 8.62 mmol, 1 eq) in THF (20 mL) was added Ac2O (1.76 g, 17.23 mmol, 1.6 mL, 2 eq) and DIEA (3.34 g, 25.85 mmol, 4.5 mL, 3 eq), and the mixture was stirred at 60 °C for 4 hours. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford N-(4-bromo-2-fluoro-5- isopropylphenyl)acetamide (1.9 g, 80% yield) as a yellow solid. LCMS: 274.0, 276.0 [M+H]+. Step 2: Preparation of N-(4-bromo-6-fluoro-3-isopropyl-2-nitrophenyl)acetamide [00320] To a solution of N-(4-bromo-2-fluoro-5-isopropylphenyl)acetamide (1.9 g, 6.93 mmol, 1 eq) in DCM (20 mL) was added HNO3 (6.7 g, 72.3 mmol, 4.8 mL, 68% purity, 10.4 eq) and H2SO4 (6.80 g, 69.31 mmol, 3.69 mL, 10 eq) at 0 °C, and the mixture was stirred for at 20 °C for 2 hours. After the completion of the reaction, the mixture was diluted with water (100 mL) and extracted with DCM (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford N-(4-bromo-6-fluoro-3- isopropyl-2-nitrophenyl)acetamide (1 g, 45% yield) as a yellow solid. LCMS: 319.0, 321.0 [M+H]+. Step 3: Preparation of 4-bromo-6-fluoro-3-isopropyl-2-nitroaniline [00321] A mixture of N-(4-bromo-6-fluoro-3-isopropyl-2-nitrophenyl)acetamide (1 g, 3.13 mmol, 1 eq) and H2SO4 (1.54 g, 15.7 mmol, 5 eq) in EtOH (10 mL) was stirred at 90 °C for 2 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 4-bromo-6-fluoro-3-isopropyl-2-nitroaniline (0.8 g, 2.89 mmol, 92% yield) as a yellow oil. Step 4: Preparation of 4-bromo-6-fluoro-3-isopropylbenzene-1,2-diamine [00322] A mixture of 4-bromo-6-fluoro-3-isopropyl-2-nitroaniline (0.8 g, 2.89 mmol, 1 eq), Fe (967.4 mg, 17.32 mmol, 6 eq) and NH4Cl (926.6 mg, 17.32 mmol, 6 eq) in EtOH (6 mL) and H2O (2 mL) was stirred at 80 °C for 2 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 4- bromo-6-fluoro-3-isopropylbenzene-1,2-diamine (0.58 g, 81% yield) as a yellow solid. Step 5: Preparation of 2-(6-bromo-4-fluoro-7-isopropyl-1H-benzo[d]imidazol-2- yl)propan-2-ol [00323] To a solution of 4-bromo-6-fluoro-3-isopropylbenzene-1,2-diamine (0.5 g, 2.02 mmol, 1 eq) and 2-hydroxy-2-methylpropanoic acid (231.1 mg, 2.23 mmol, 1.1 eq) in DMF (5 mL) was added DIEA (653.8 mg, 5.06 mmol, 2.5 eq) and HATU (923.2 mg, 2.43 mmol, 1.2 eq), and the mixture was stirred at 45 °C for 12 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The residue was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 2-(6-bromo-4- fluoro-7-isopropyl-1H-benzo[d]imidazol-2-yl)propan-2-ol (300 mg, 47% yield) as a yellow solid. LCMS: 315.1, 317.1 [M+H]+. Step 6: Preparation of 2-(4-fluoro-7-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)propan-2-ol [00324] A mixture of 2-(6-bromo-4-fluoro-7-isopropyl-1H-benzo[d]imidazol-2- yl)propan-2-ol (300 mg, 0.952 mmol, 1 eq), Pin2B2 (362.6 mg, 1.43 mmol, 1.5 eq), KOAc (280.2 mg, 2.86 mmol, 3 eq) and Pd(dppf)Cl2 (69.6 mg, 0.095 mmol, 0.1 eq) in dioxane (4 mL) was degassed and backfilled with N2 for 3 times, and then stirred at 90 °C for 1 hour under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 2-(4-fluoro-7-isopropyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)propan-2-ol (200 mg, 58% yield) as a yellow solid. LCMS: 363.2 [M+H]+. Intermediate-23: Preparation of (1R*,2S*,3R*,5S*)-3-amino-8- oxabicyclo[3.2.1]octan-2-ol Step 1: Preparation of (((1R,5S)-8-oxabicyclo[3.2.1]oct-2-en-3-yl)oxy)trimethylsilane [00325] To a solution of LDA (2 M, 23.78 mL, 1.2 eq) in THF (40 mL) was added 8- oxabicyclo[3.2.1]octan-3-one (5 g, 39.63 mmol, 1 eq) in THF (20 mL) at -78 °C under N2. After the completion of the addition, the mixture was kept stirring at -78 °C for 15 min under N2 atmosphere, followed by the addition of TMSCl (6.46 g, 59.45 mmol, 7.55 mL, 1.5 eq). The mixture was then stirred at -78 °C for 45 min under N2 atmosphere. After the completion of the reaction, the mixture was warmed to 0 °C, and then quenched with saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give (((1R*,5S*)-8-oxabicyclo[3.2.1]oct-2-en-3-yl)oxy)trimethylsilane (5.5 g, 70% yield) as a light yellow oil. Step 2: Preparation of (1R*,2R*,5S*)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3-one [00326] To a solution of (((1R*,5S*)-8-oxabicyclo[3.2.1]oct-2-en-3- yl)oxy)trimethylsilane (3 g, 15.13 mmol, 1 eq) in THF (30 mL) and water (30 mL) was added m-CPBA (3.38 g, 16.64 mmol, 85% purity, 1.1 eq) at -10 °C, and the mixture was stirred at -10 °C for 2 hours. After the completion of the reaction, the reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give (1R*,2R*,5S*)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-one (1.4 g, 65% yield) as a light yellow oil.1H NMR (400 MHz, DMSO-d6) δ 5.83 - 5.81 (d, J=2.4 Hz, 1 H), 4.60 - 4.57 (t, J=6.0 Hz, 1 H), 4.39 - 4.37 (d, J=7.6 Hz, 1 H), 3.41 – 3.40 (d, J=4.8 Hz, 1 H), 2.93 - 2.88 (dd, J=14.8 Hz, 4.8 Hz, 1 H), 2.06 - 2.03 (d, J= 15.2Hz, 1 H), 1.95 - 1.74 (m, 1 H), 1.56 - 1.50 (m, 2 H), 1.46 - 1.40 (m, 2H) ppm Step 3: Preparation of (1R*,2S*,5S*)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3-one oxime [00327] To a solution of (1R*,2R*,5S*)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3-one (1.4 g, 9.85 mmol, 1 eq) in water (10 mL) and MeOH (10 mL) was added hydroxylamine hydrochloride (1.03 g, 14.8 mmol, 1.5 eq) and NaHCO3 (8.27 g, 98.5 mmol, 3.8 mL, 10 eq), and the mixture was stirred at 20 °C for 1 hour. After the completion of the reaction, the mixture was concentrated in vacuo. The resulting residue was purified by column chromatography to give (1R*,2S*,5S*)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-one oxime (1.6 g, 79% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1 H), 5.18 (s, 1 H), 4.37 (s, 1 H), 4.26 - 4.25 (s, 1 H), 3.61 (s, 1 H), 2.76 - 2.72 (m, 1 H), 2.26 - 2.12 (m, 1 H), 1.78 - 1.76 (m, 2 H), 1.46 - 1.32 (m, 2H) ppm. Step 4: Preparation of (1R,2S,3R,5S)-3-amino-8-oxabicyclo[3.2.1]octan-2-ol [00328] To a suspension of (1R*,2S*,5S*)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3- one oxime (1.6 g, 10.18 mmol, 1 eq) and MoO3 (5.13 g, 35.6 mmol, 3.5 eq) in MeOH (20 mL) was added NaBH4 (10.4 g, 274.9 mmol, 27 eq) in portions. After gas evolution ceased, another batch of MoO3 (5.13 g, 35.63 mmol, 3.5 eq) was added, and the resulting mixture was stirred at 20 °C for 1 hour. After the completion of the reaction, the reaction mixture was treated with aqueous KOH (0.2M, 100 mL) and stirred at 20 °C for 1 hour. The mixture was filtered, and the filter cake was washed with MeOH (100 mL). The filtrate was evaporated, and the resulting residue was dissolved in DCM (50 mL) and washed with saturated aqueous NH4Cl (50 mL). The aqueous phase was extracted with DCM (50 mL x 3). The organic layers were evaporated to give (1R*,2S*,3R*,5S*)-3-amino-8-oxabicyclo[3.2.1]octan-2-ol (1.1 g, crude) as a light yellow oil. Intermediate-24: Preparation of 2-(3,3-difluorocyclopentyl)-4-fluoro-1- isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole Step 1: Preparation of N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)-3,3- difluorocyclopentane-1-carboxamide [00329] A mixture of 5-bromo-3-fluoro-N1-isopropylbenzene-1,2-diamine (1.23 g, 5 mmol, 1.5 eq), 3,3-difluorocyclopentane-1-carboxylic acid (500 mg, 3.33 mmol, 1 eq), HATU (1.9 g, 5 mmol, 1.5 eq) and DIEA (1.29 g, 9.99 mmol, 1.7 mL, 3 eq) in DMF (5 mL) was stirred at 20 °C for 12 hours. After the completion of the reaction, the mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-TLC to afford N-(4-bromo-2-fluoro-6- (isopropylamino)phenyl)-3,3-difluorocyclopentane-1-carboxamide (1.2 g, 95% yield) as a yellow soil. LCMS: 379.0/381.0 [M+H]+. Step 2: Preparation of 6-bromo-2-(3,3-difluorocyclopentyl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazole [00330] A mixture of N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)-3,3- difluorocyclopentane-1-carboxamide (1.2 g, 3.16 mmol, 1 eq) in AcOH (5 mL) was stirred at 140 °C for 1 hour under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature, and then carefully quenched with saturated aqueous NaHCO3 (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-TLC to afford 6-bromo-2-(3,3-difluorocyclopentyl)-4- fluoro-1-isopropyl-1H-benzo[d]imidazole (1.1 g, 96% yield) as a yellow oil. LCMS: 361.0/363.0 [M+H]+. Step 3: Preparation of 2-(3,3-difluorocyclopentyl)-4-fluoro-1-isopropyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole [00331] A mixture of 6-bromo-2-(3,3-difluorocyclopentyl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazole (1.1 g, 3.05 mmol, 1 eq), Pin2B2 (1.16 g, 4.57 mmol, 1.5 eq), KOAc (896.6 mg, 9.14 mmol, 3 eq) and Pd(dppf)Cl2 (111.4 mg, 0.152 mmol, 0.05 eq) in dioxane (10 mL) was degassed and backfilled with N2 for 3 times, and then stirred at 90 °C for 12 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-(3,3- difluorocyclopentyl)-4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-benzo[d]imidazole (1.2 g, crude) as a brown oil, which was used in the next step without further purification. LCMS: 409.1 [M+H]+. Intermediate-25: Preparation of (3S*,4R*)-4-amino-3-hydroxytetrahydro-2H- thiopyran 1,1-dioxide Step 1: Preparation of 3-hydroxytetrahydro-4H-thiopyran-4-one [00332] A mixture of tetrahydro-4H-thiopyran-4-one (2 g, 17.2 mmol, 1 eq), nitrosobenzene (5.52 g, 51.64 mmol, 3 eq) and L-proline (396.4 mg, 3.44 mmol, 0.2 eq) in DCM (120 mL) was stirred at 20 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the reaction mixture was concentrated, diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 3-hydroxytetrahydro-4H-thiopyran-4-one (800 mg, 35% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 3.82 - 3.78 (t, J = 7.6 Hz, 1H), 3.31 - 3.27 (t, J = 7.6 Hz, 1H), 2.84 - 2.63 (m, 1H), 1.67 - 1.61 (m, 5H) ppm. Step 2: Preparation of 3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-4H-thiopyran- 4-one [00333] To a solution of 3-hydroxytetrahydro-4H-thiopyran-4-one (800 mg, 6.05 mmol, 1 eq) in DCM (10 mL) was added (2-(chloromethoxy)ethyl)trimethylsilane (1.11 g, 6.66 mmol, 1.1 eq) and DIEA (2.35 g, 18.16 mmol, 3 eq), and the mixture was stirred at 20 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine 100 mL, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography to afford 3-((2- (trimethylsilyl)ethoxy)methoxy)tetrahydro-4H-thiopyran-4-one (1.2 g, 75% yield) as a light yellow oil. Step 3: Preparation of (3S*,4S*)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-2H- thiopyran-4-ol [00334] To a solution of 3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-4H- thiopyran-4-one (1 g, 3.81 mmol, 1 eq) in THF (40 mL) was added L-Selectride (1 M, 4.19 mL, 1.1 eq) at -78 °C, and the mixture was stirred at -78 °C for 2 hours under N2 atmosphere. After the completion of the reaction, the mixture was quenched with saturated aqueous NaHCO3 (200 mL) and extracted with ethyl acetate (300 mL x 2). The combined organic layers were washed with water (300 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The desired (3S*,4S*)-3-((2-(trimethylsilyl)ethoxy) methoxy) tetrahydro-2H-thiopyran-4-ol (1.3 g, crude) was obtained as a colorless oil, which was used into the next step without further purification.1H NMR (400 MHz, MeOD) δ 4.76 (s, 2H), 3.90 - 3.88 (m, 1 H), 3.80 - 3.60 (m, 3H), 2.99 - 2.97 (m, 2H), 2.52 -2.41 (m, 1H), 2.29 - 2.14 (m, 2H), 1.94 - 1.90 (m, 1H), 1.15 -1.05 (m, 2H), 0.03 (s, 9H) ppm. Step 4: Preparation of (3S*,4S*)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-2H- thiopyran-4-yl methanesulfonate [00335] To a solution of (3S*,4S*)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro- 2H-thiopyran-4-ol (900 mg, 3.40 mmol, 1 eq) in DCM (50 mL) was added MsCl (3.19 g, 27.85 mmol, 2.16 mL, 8.18 eq), TEA (3.64 g, 35.97 mmol, 5 mL, 10.57 eq) and DMAP (207.88 mg, 1.70 mmol, 0.5 eq) at 0 °C, and the reaction was then warmed to 50 °C and stirred for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was poured into ice water (50 mL) and extracted with dichloromethane (100 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford (3S*,4S*)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro-2H-thiopyran-4-yl methanesulfonate (750 mg, 2.19 mmol, 64.3% yield) as a yellow oil. Step 5: Preparation of (2-((((3S,4R)-4-azidotetrahydro-2H-thiopyran-3- yl)oxy)methoxy)ethyl)trimethylsilane [00336] To a solution of (3S*,4S*)-3-((2-(trimethylsilyl)ethoxy)methoxy)tetrahydro- 2H-thiopyran-4-yl methanesulfonate (750 mg, 2.19 mmol, 1 eq) in DMF (10 mL) was added NaN3 (550 mg, 8.46 mmol, 3.8 eq), and the mixture was stirred at 110 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature and diluted with H2O (50 mL). The pH was then adjust to > 9 with saturated aqueous Na2CO3. The aqueous phase was extracted with EtOAc 150 mL (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford (2- ((((3S*,4R*)-4-azidotetrahydro-2H-thiopyran-3-yl)oxy)methoxy)ethyl)trimethylsilane (500 mg, 79% yield) as a colorless liquid.1H NMR (400 MHz, CDCl3) δ 4.88 - 4.78 (m, 2H), 3.75 - 3.65 (m, 3H), 3.32 -3.25 (m, 1H), 2.95 - 2.89 (m, 1H), 2.60 - 2.54 (m, 3H), 2.40 - 2.30 (m, 1H), 1.81 -1.76 (m, 1H), 0.99 -0.93 (m, 2H), 0.03 (s, 9H) ppm. Step 6: Preparation of (3S*,4R*)-4-azido-3-((2-(trimethylsilyl)ethoxy) methoxy) tetrahydro -2H-thiopyran 1,1-dioxide [00337] To a solution of (2-((((3S*,4R*)-4-azidotetrahydro-2H-thiopyran-3- yl)oxy)methoxy) ethyl) trimethylsilane (250 mg, 0.863 mmol, 1 eq) in DCM (3 mL) was added m-CPBA (438 mg, 2.16 mmol, 85% purity, 2.5 eq) at 0 °C, and the mixture was warmed to 20 °C and kept stirring for 2 hours. After the completion of the reaction, the mixture was quenched with saturated aqueous Na2SO3 (60 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The desired (3S,4R)-4-azido-3-((2- (trimethylsilyl)ethoxy)methoxy)tetrahydro-2H-thiopyran 1,1-dioxide (320 mg, crude) was obtained as a white solid, which was used into the next step without further purification. Step 7: Preparation of (3S*,4R*)-4-amino-3-((2-(trimethylsilyl)ethoxy)methoxy) tetrahydro-2H-thiopyran 1,1-dioxide [00338] To a solution of (3S*,4R*)-4-azido-3-((2- (trimethylsilyl)ethoxy)methoxy)tetrahydro-2H-thiopyran 1,1-dioxide (300 mg, 0.933 mmol, 1 eq) in THF (0.5 mL) and H2O (0.5 mL) was added PPh3 (489.5 mg, 1.87 mmol, 2 eq), and the mixture was stirred at 20 °C for 5 hours. After the completion of the reaction, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give (3S*,4R*)-4-amino-3-((2- (trimethylsilyl)ethoxy)methoxy)tetrahydro-2H-thiopyran 1,1-dioxide (220 mg, crude) as a white solid, which was used in the next step without further purification. Step 8: Preparation of (3S*,4R*)-4-amino-3-hydroxytetrahydro-2H-thiopyran 1,1- dioxide [00339] To a solution of (3S*,4R*)-4-amino-3-((2- (trimethylsilyl)ethoxy)methoxy)tetrahydro-2H-thiopyran 1,1-dioxide (100 mg, 0.338 mmol, 1 eq) in MeOH (5 mL) was added HCl/MeOH (4 M, 1 mL, 11.8 eq), and the mixture was stirred at 20 °C for 8 hours. After the completion of the reaction, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give (3S*,4R*)-4-amino-3-hydroxytetrahydro-2H-thiopyran 1,1-dioxide (50 mg, crude) as a white solid, which was used without further purification. Intermediate-26: Preparation of (1R,2R)-2-amino-5,5-difluorocyclohexan-1-ol Step 1: Preparation of 5,5-difluoro-2,2-dimethoxycyclohexan-1-ol [00340] To a solution of KOH (9 g, 160.4 mmol, 2.4 eq) in MeOH (200 mL) was added 4,4-difluorocyclohexan-1-one (9 g, 67.1 mmol, 1 eq) at 0 °C, followed by I2 (17 g, 67 mmol, 1 eq), and the mixture was stirred at 20 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The desired 5,5-difluoro-2,2- dimethoxycyclohexan-1-ol (380 mg, crude) was obtained as a brown oil, which was used in the next step without further purification. Step 2: Preparation of (((5,5-difluoro-2,2-dimethoxycyclohexyl)oxy)methyl)benzene [00341] To the suspension of NaH (2.8 g, 70.26 mmol, 60% purity, 1.84 eq) in THF (150 mL) was added 5,5-difluoro-2,2-dimethoxycyclohexan-1-ol (7.5 g, 38.23 mmol, 1 eq) at 0 °C, and the mixture was kept stirring for 0.5 hours at 0 °C. Then, BnBr (15 g, 87.7 mmol, 2.3 eq) was added at 0 °C. After the completion of the addition, the mixture was warmed to 20 °C and stirred for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was quenched with saturated aqueous NH4Cl (500 mL) and extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford (((5,5-difluoro-2,2- dimethoxycyclohexyl)oxy)methyl)benzene (10 g, 34.93 mmol, 91% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 7.41 - 7.30 (m, 5H), 4.75 - 4.52 (m, 2H), 3.80 - 3.70 (m, 1H), 3.65 - 3.27 (m, 6H), 2.41 - 2.38 (m, 1H), 2.14 - 2.07 (m, 2H), 1.95 - 1.26 (m, 3H) ppm. Step 3: Preparation of 2-(benzyloxy)-4,4-difluorocyclohexan-1-one [00342] To a solution of (((5,5-difluoro-2,2- dimethoxycyclohexyl)oxy)methyl)benzene (3 g, 10.5 mmol, 1 eq) in aqueous acetone (prepared from acetone (30 mL) and H2O (1.5mL)), TsOH (180.4 mg, 1.05 mmol, 0.1 eq)was added, and the mixture was stirred at 60 °C for 3 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was concentrated, the residue was diluted with saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 2-(benzyloxy)-4,4- difluorocyclohexan-1-one (1.7 g, 7.08 mmol, 67% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 7.40 - 7.28 (m, 5H), 4.88 - 4.51 (m, 2H), 4.20 - 4.11 (m, 1H), 2.80 - 2.75 (m, 1H), 2.65 - 2.06 (m, 5H) ppm. Step 4: Preparation of (1S*,2R*)-2-(benzyloxy)-4,4-difluorocyclohexan-1-ol [00343] To a solution of 2-(benzyloxy)-4,4-difluorocyclohexan-1-one (1.5 g, 6.24 mmol, 1 eq) in MeOH (30 mL) was added NaBH4 (708.6 mg, 18.73 mmol, 3 eq) at 0 °C. The mixture was slowly warmed to 20 °C and kept stirring for 2 hours. After the completion of the reaction, the mixture was quenched with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep- TLC (Petroleum ether/Ethyl acetate=2/1) to afford (1S*,2R*)-2-(benzyloxy)-4,4- difluorocyclohexan-1-ol (702 mg, 46% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.40 - 7.27 (m, 5H), 4.64 - 4.56 (m, 2H), 4.10 - 4.05 (m, 1H), 3.67 - 3.61 (m, 1H), 2.30 - 1.86 (m, 6H), 1.64 - 1.57 (m, 1H) ppm. Step 5: Preparation of (1S,2R)-2-(benzyloxy)-4,4-difluorocyclohexyl methanesulfonate [00344] To a solution of (1S*,2R*)-2-(benzyloxy)-4,4-difluorocyclohexan-1-ol (700 mg, 2.9 mmol, 1 eq) in DCM (20 mL) was added Ms2O (1.26 g, 7.22 mmol, 2.5 eq) and TEA (1.17 g, 11.56 mmol, 4 eq), and the mixture was stirred at 20 °C for 16 hours .After the completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, Petroleum ether/Ethyl acetate=100/1 to 3/1) to afford (1S*,2R*)-2-(benzyloxy)-4,4-difluorocyclohexyl methanesulfonate (500 mg, 1.56 mmol, 54% yield) as a colorless oil. Step 6: Preparation of ((((1R*,2R*)-2-azido-5,5-difluorocyclohexyl)oxy)methyl) benzene [00345] To a solution of (1S*,2R*)-2-(benzyloxy)-4,4-difluorocyclohexyl methanesulfonate (500 mg, 1.56 mmol, 1 eq) in DMF (20 mL) was added NaN3 (0.5 g, 7.69 mmol, 4.9 eq), and the mixture was stirred at 100 °C for 2 hours. After the completion of the reaction, the mixture was cooled to room temperature. The volatiles were removed under reduced pressure. The residue was diluted with saturated aqueous NaHCO3 (80 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford ((((1R*,2R*)-2-azido-5,5- difluorocyclohexyl)oxy)methyl)benzene (327 mg, 1.22 mmol, 78 % yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 7.36 - 7.27 (m, 5H), 4.66 (s, 2H), 3.57 - 3.47 (m, 2H), 2.55 - 2.45 (m, 1H), 2.11 - 1.99 (m, 2H), 1.89 - 1.54 (m, 3H) ppm. Step 7: Preparation of (1R,2R)-2-amino-5,5-difluorocyclohexan-1-ol [00346] To a solution of ((((1R*,2R*)-2-azido-5,5- difluorocyclohexyl)oxy)methyl)benzene (320 mg, 1.2 mmol, 1 eq) in MeOH (20 mL) was added Pd/C (1.27 g, 1.2 mmol, 10% purity, 1 eq) under N2 atmosphere. The suspension was degassed and backfilled with H2 for 3 times and stirred under H2 atmosphere at 20 °C for 2 hours. After the completion of the reaction, the mixture was filtered through a Celite pad, and the filtrate was concentrated to give (1R*,2R*)- 2-amino-5,5-difluorocyclohexan-1-ol (170 mg, crude) as a white solid, which was used in the next step without further purification. Intermediate-27: Preparation of (1R,2R)-2-(4-fluoro-2-methyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)-1- methylcyclopentan-1-ol Step 1: Preparation of (1R,2R)-2-((5-bromo-3-fluoro-2-nitrophenyl)amino)-1- methylcyclopentan-1-ol [00347] To a solution of 5-bromo-1,3-difluoro-2-nitrobenzene (2.07 g, 8.68 mmol, 1 eq) in THF (20 mL) was added Cs2CO3 (565.5 mg, 1.74 mmol, 0.2 eq) and (1R,2R)- 2-amino-1-methylcyclopentan-1-ol (1 g, 8.68 mmol, 1 eq), and the mixture was stirred at 20 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford (1R,2R)-2-((5-bromo-3-fluoro-2-nitrophenyl)amino)-1-methylcyclopentan-1-ol (2.1 g, 72% yield) as a yellow solid. LCMS: 315.1, 317.1 [M+H-H2O]+. Step 2: Preparation of (1R,2R)-2-((2-amino-5-bromo-3-fluorophenyl)amino)-1- methylcyclopentan-1-ol [00348] To a solution of (1R,2R)-2-((5-bromo-3-fluoro-2-nitrophenyl)amino)-1- methylcyclopentan-1-ol (2.1 g, 6.30 mmol, 1 eq) in DMF (20 mL) was added hypoboric acid (2.26 g, 25.21 mmol, 4 eq) and 4-(4-pyridyl)pyridine (98.45 mg, 0.630 mmol, 0.1 eq) at 0 °C, and the mixture was stirred at 20 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was quenched with H2O (200 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography to afford (1R,2R)-2-((2-amino-5-bromo-3-fluorophenyl)amino)-1- methylcyclopentan-1-ol (1.9 g, 98% yield) as a yellow oil. LCMS: 303.1, 305.1 [M+H]+. Step 3: Preparation of N-(4-bromo-2-fluoro-6-(((1R,2R)-2-hydroxy-2- methylcyclopentyl)amino)phenyl)acetamide [00349] To a solution of (1R,2R)-2-((2-amino-5-bromo-3-fluorophenyl)amino)-1- methylcyclopentan-1-ol (1 g, 3.3 mmol, 1 eq) in HOAc (20 mL) was added Ac2O (505 mg, 4.95 mmol, 1.5 eq), and the mixture was stirred at 60 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography to afford N-(4-bromo- 2-fluoro-6-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)phenyl)acetamide (800 mg, 2.32 mmol, 70% yield) as a yellow oil. LCMS: 345.0, 347.0 [M+H]+. Step 4: Preparation of (1R,2R)-2-(6-bromo-4-fluoro-2-methyl-1H-benzo[d]imidazol-1- yl)-1-methylcyclopentan-1-ol [00350] To a solution of N-(4-bromo-2-fluoro-6-(((1R,2R)-2-hydroxy-2- methylcyclopentyl)amino)phenyl)acetamide (700 mg, 2 mmol, 1 eq) and POCl3 (1.87 g, 12.17 mmol, 6 eq) in acetonitrile (1 mL) was added DIEA (1.57 g, 12.17 mmol, 6 eq) dropwise, and the mixture was stirred at 20 °C for 5 hours under N2 atmosphere. After the completion of the reaction, the mixture was carefully quenched with saturated aqueous NaHCO3 (50 mL) at 0 °C, and then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford (1R,2R)-2-(6- bromo-4-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-1-methylcyclopentan-1-ol (400 mg, 67% yield) as a yellow solid. LCMS: 327.1, 329.1 [M+H]+. Step 5: Preparation of (1R,2R)-2-(4-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)-1-methylcyclopentan-1-ol [00351] The mixture of (1R,2R)-2-(6-bromo-4-fluoro-2-methyl-1H- benzo[d]imidazol-1-yl)-1-methylcyclopentan-1-ol (400 mg, 1.22 mmol, 1 eq), Pin2B2 (465.7 mg, 1.83 mmol, 1.5 eq), KOAc (360 mg, 3.67 mmol, 3 eq) and Pd(dppf)Cl2 (89 mg, 0.122 mmol, 0.1 eq) in dioxane (5 mL) was degassed and backfilled with N2 for 3 times, and then stirred at 90 °C for 2 hours under N2 atmosphere. After the completion of the reaction, the reaction was cooled to room temperature. The mixture was filtered through a short pad of celite and rinsed with dioxane (5 mL). The combined filtrate was concentrated under reduced pressure to give (1R,2R)-2-(4- fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol- 1-yl)-1-methylcyclopentan-1-ol (420 mg, crude) as a brown oil, which was used in the next step without further purification. LCMS: 375.2 [M+H]+. Intermediate-28: Preparation of 8-fluoro-4-isopropyl-2-methyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1(2H)-one Step 1: Preparation of 6-chloro-8-fluoro-4-isopropyl-1H-isochromen-1-one [00352] The mixture of methyl 2-bromo-4-chloro-6-fluorobenzoate (2 g, 7.48 mmol, 1 eq), 3-methylbutanal (966 mg, 11.22 mmol, 1.5 eq), Cs2CO3 (4.87 g, 14.95 mmol, 2 eq), XantPhos Pd G3 (709 mg, 0.747 mmol, 0.1 eq) and 4Å molecular sieve (2 g) in dioxane (40 mL) was stirred at 90 °C for 7 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was filtered, rinsed with dioxane ( 20 mL) and the combined filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 6-chloro-8-fluoro-4-isopropyl-1H-isochromen-1-one (480 mg, 1.99 mmol, 27% yield) as a yellow solid LCMS: 241.1 [M+H]+. Step 2: Preparation of 4-chloro-2-fluoro-N-methyl-6-(3-methyl-1-oxobutan-2- yl)benzamide [00353] To a solution of methanamine hydrochloride (510.6 mg, 7.56 mmol, 4 eq) in DCM (9 mL) was added TEA (765.3 mg, 7.56 mmol, 4 eq) and AlMe3 (2 M, 2.84 mL, 3 eq) at 0 °C under nitrogen. The mixture was stirred at 20 °C for 0.5 hour, followed by the addition of 6-chloro-8-fluoro-4-isopropyl-1H-isochromen-1-one (455 mg, 1.89 mmol, 1 eq). The mixture was further stirred at 20 °C for 12 hours. After the completion of the reaction, the mixture was quenched with H2O (50 mL) and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The desired 4-chloro-2-fluoro-N-methyl-6-(3-methyl-1- oxobutan-2-yl)benzamide (500 mg, crude product) was obtained as a yellow oil, which was used into the next step without further purification. LCMS: 272.2 [M+H]+. Step 3: Preparation of 6-chloro-8-fluoro-4-isopropyl-2-methylisoquinolin-1(2H)-one [00354] The solution of 4-chloro-2-fluoro-N-methyl-6-(3-methyl-1-oxobutan-2- yl)benzamide (500 mg, 1.84 mmol, 1 eq) in AcOH (10 mL) was stirred at 90 °C for 3 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine 50 mL, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo The resulting residue was purified by column chromatography to afford 6- chloro-8-fluoro-4-isopropyl-2-methylisoquinolin-1(2H)-one (270 g, 57% yield) as a white solid. LCMS: 254.2 [M+H]+. Step 4: Preparation of 8-fluoro-4-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoquinolin-1(2H)-one [00355] A mixture of 6-chloro-8-fluoro-4-isopropyl-2-methylisoquinolin-1(2H)-one (260 g, 1.02 mmol, 1 eq), Pin2B2 (518.5 mg, 2.04 mmol, 2 eq), Pd(dppf)Cl2 (74.7 mg, 0.102 mmol, 0.1 eq) and KOAc (300 mg, 3.06 mmol, 3 eq) in dioxane (5 mL) was degassed and backfilled with N2 for 3 times, and stirred at 90 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature, filtered through a short pad of celite and rinsed with dioxane ( 5 mL). The combined filtrate was concentrated under reduced pressure to give 8-fluoro-4- isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1(2H)- one (350 mg, crude) as a brown oil, which was used in the next step without further purification. LCMS: 346.3 [M+H]+. Intermediate-29: Preparation of 7-isopropyl-3,5-dimethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)thieno[3,2-c]pyridin-4(5H)-one Step 1: Preparation of 1-(5-bromo-4-methylthiophen-2-yl)-2-methylpropan-1-one [00356] AlCl3 (8.28 g, 62.1 mmol, 3.4 mL, 1.1 eq) was placed in a pre-dried flask and stirred in DCM (120 mL) under N2 atmosphere. To the suspension, isobutyryl chloride (6.62 g, 62.13 mmol, 6.5 mL, 1.1 eq) was added dropwise at 0 °C, followed by 2-bromo-3-methylthiophene (10 g, 56.48 mmol, 1 eq). After the completion of the addition, the mixture was stirred at 20 °C for 12 hours under N2 atmosphere. The mixture was then carefully quenched with H2O (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography to afford 1-(5-bromo-4- methylthiophen-2-yl)-2-methylpropan-1-one (13 g, 93% yield) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ 7.40 (1 H, s), 3.28 (1 H, m), 2.23 (3 H, s), 1.23 (6 H, d, J=6.8 Hz) ppm. Step 2: Preparation of ethyl (E)-3-(5-bromo-4-methylthiophen-2-yl)-4-methylpent-2- enoate [00357] To a suspension of NaH (2.75 g, 68.8 mmol, 60% purity, 2.5 eq) in THF (70 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (6.79 g, 30.26 mmol, 6 mL, 1.1 eq) dropwise at 0 °C. After the completion of the addition, the mixture was stirred at 0 °C for 0.5 hour and at 20 °C for an additional 0.5 hour. Then, a solution of 1-(5- bromo-4-methylthiophen-2-yl)-2-methylpropan-1-one (6.8 g, 27.5 mmol, 1 eq) in THF (16 mL) was added at 20 °C, and the reaction mixture was kept stirring at 20 °C for 48 hours. After the completion of the reaction, the mixture was quenched with H2O (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The desired ethyl (E)-3-(5-bromo-4- methylthiophen-2-yl)-4-methylpent-2-enoate (10 g, crude) was obtained as a brown oil, which was used in the next step without further purification. LCMS: 317.3/319.3 [M+H]+. Step 3: Preparation of (E)-3-(5-bromo-4-methylthiophen-2-yl)-4-methylpent-2-enoic acid [00358] To a solution of ethyl (E)-3-(5-bromo-4-methylthiophen-2-yl)-4-methylpent- 2-enoate (10 g, 31.5 mmol, 1 eq) in MeOH (60 mL) was added a solution of NaOH (6.3 g, 157.6 mmol, 5 eq) in H2O (60 mL) dropwise at 20 °C. The mixture was then stirred at 65 °C for 1 hour. After the completion of the reaction, the mixture was cooled to room temperature. The volatiles were evaporated, and the resulting residue was dissolved in EtOAc (100 mL) and acidify with aqueous HCl (2N, 20 mL). The organic phase was collected, and the aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give (E)-3-(5-bromo-4-methylthiophen-2-yl)-4-methylpent-2-enoic acid (5.5 g, 60% yield) as a yellow oil, which was used in the next step without further purification. LCMS: 289.0/291.0 [M+H]+. Step 4: Preparation of 2-bromo-7-isopropyl-3-methylthieno[3,2-c]pyridin-4(5H)-one [00359] To a solution of (E)-3-(5-bromo-4-methylthiophen-2-yl)-4-methylpent-2- enoic acid (5.5 g, 19 mmol, 1 eq) in diphenylether (55 mL) was added dropwise DPPA (7.85 g, 28.5 mmol, 6.2 mL, 1.5 eq). The mixture was stirred at 20 °C for 0.5 hour and subsequently heated at 140 °C for another 0.5 hour. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was quenched with aqueous NaOH (1 N, 30 mL) and stirred at room temperature for 30 min. The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 2-bromo-7-isopropyl-3-methylthieno[3,2-c]pyridin- 4(5H)-one (1.1 g, 20% yield) as a brown solid. LCMS: 285.9, 287.9 [M+H]+. Step 5: Preparation of 2-bromo-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)- one [00360] To a solution of 2-bromo-7-isopropyl-3-methylthieno[3,2-c]pyridin-4(5H)- one (1.08 g, 3.77 mmol, 1 eq) in DMF (10 mL) was added Cs2CO3 (2.46 g, 7.55 mmol, 2 eq) and CH3I (1.07 g, 7.55 mmol, 2 eq), and the mixture was stirred at 20 °C for 1 hour. After the completion of the reaction, the mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography to afford 2-bromo-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin- 4(5H)-one (930 mg, 82% yield) as a brown solid.1H NMR (400 MHz, CHLOROFORM-d) δ 7.09 (s, 1H), 3.76 (s, 3H), 3.01 (m, 1H), 2.80 (s, 3H), 1.49 (d, J = 6.8 Hz, 6H) ppm. Step 6: Preparation of 7-isopropyl-3,5-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)thieno[3,2-c]pyridin-4(5H)-one [00361] A mixture of 2-bromo-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)- one (400 mg, 1.33 mmol, 1 eq), Pin2B2 (507.5 mg, 2 mmol, 1.5 eq), KOAc (261.5 mg, 2.66 mmol, 2 eq) and CataCXium A Pd G2 (CAS: 1375477-29-4) (89.1 mg, 0.133 mmol, 0.1 eq) (89.1 mg, 0.133 mmol, 0.1 eq) in dioxane (5 mL) was degassed and backfilled with N2 for 3 times and stirred at 100 °C for 1 hour under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was filtered via a short pad of celite and rinsed with dioxane (5 mL). The filtrate was concentrated under reduced pressure to give 7-isopropyl-3,5- dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-c]pyridin-4(5H)- one (430 mg, crude) as a brown oil, which was used in the next step without further purification. LCMS: 348.2 [M+H]+. Intermediate-30: Preparation of 2-(2,2-difluorocyclopropyl)-4-fluoro-1- isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole Step 1: Preparation of N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)-2,2- difluorocyclopropane-1-carboxamide [00362] To a solution of 5-bromo-3-fluoro-N1-isopropylbenzene-1,2-diamine (800 mg, 3.24 mmol, 1 eq) and 2,2-difluorocyclopropane-1-carboxylic acid (592.8 mg, 4.86 mmol, 1.5 eq) in DMF (6 mL) was added DIEA (1.26 g, 9.7 mmol, 3 eq) and T4P (4.67 g, 6.47 mmol, 50% purity, 2 eq), and the mixture was stirred at 20 °C for 6 hours. After the completion of the reaction, the mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography to afford N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)-2,2- difluorocyclopropane-1-carboxamide (1 g, 2.85 mmol, 87% yield) as a white solid. LCMS: 351.1, 353.1 [M+H]+. Step 2: Preparation of 6-bromo-2-(2,2-difluorocyclopropyl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazole [00363] To a solution of N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)-2,2- difluorocyclopropane-1-carboxamide (500 mg, 1.42 mmol, 1 eq) in acetonitrile (5 mL) was added dropwise POCl3 (655 mg, 4.27 mmol, 3 eq) and DIEA (552 mg, 4.27 mmol, 3 eq) at 0 °C. After the completion of the addition, the mixture was stirred at 20 °C for 16 hours. The mixture was then quenched with H2O (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography to afford 6- bromo-2-(2,2-difluorocyclopropyl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazole (400 mg, 1.20 mmol, 84% yield) as a brown solid. LCMS: 333.0, 335.0 [M+H]+. Step 3: Preparation of 2-(2,2-difluorocyclopropyl)-4-fluoro-1-isopropyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole [00364] A mixture of 6-bromo-2-(2,2-difluorocyclopropyl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazole (300 mg, 0.9 mmol, 1 eq), Pin2B2 (343 mg, 1.35 mmol, 1.5 eq), KOAc (177 mg, 1.8 mmol, 2 eq) and Pd(dppf)Cl2 (66 mg, 0.09 mmol, 0.1 eq) in dioxane (5 mL) was degassed and backfilled with N2 for 3 times and stirred at 100 °C for 2 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was filtered through a short pad of celite, rinsed with dioxane (5 mL) and the filtrate was concentrated under reduced pressure. The desired 2-(2,2-difluorocyclopropyl)-4-fluoro-1-isopropyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (320 mg, crude) was obtained as a brown oil, which was used in the next step without further purification. LCMS: 381.0 [M+H]+. Intermediate-31: Preparation of 2-(8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinolin-3-yl)propan-2-ol Step 1: preparation of ethyl 6-bromo-8-fluoroquinoline-3-carboxylate [00365] The mixture of 2-amino-5-bromo-3-fluorobenzaldehyde (500 mg, 2.29 mmol, 1 eq) and ethyl 3,3-diethoxypropanoate (1.33 g, 7.01 mmol, 3.06 eq) in AcOH (10 mL) was stirred at 100 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by column chromatography to afford ethyl 6-bromo-8-fluoroquinoline-3-carboxylate (680 mg, 99 % yield) as a yellow oil. LCMS: 297.9, 299.9 [M+H]+. Step 2: preparation of 2-(6-bromo-8-fluoroquinolin-3-yl)propan-2-ol [00366] To a solution of ethyl 6-bromo-8-fluoroquinoline-3-carboxylate (350 mg, 1.17 mmol, 1 eq) in THF (5 mL) was added MeMgBr (3.0 M, 0.98 mL, 2.5 eq) at -78 °C, and then the mixture was warmed to 20 °C and stirred at that temperature for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was quenched with aqueous NH4Cl (1M, 100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography to afford 2-(6-bromo-8- fluoroquinolin-3-yl)propan-2-ol (330 mg, 1.16 mmol, 99 % yield) as a light yellow oil. LCMS: 284.0, 286.0 [M+H]+. Step 3: preparation of 2-(8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinolin-3-yl)propan-2-ol [00367] A mixture of 2-(6-bromo-8-fluoroquinolin-3-yl)propan-2-ol (330 mg, 1.16 mmol, 1 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (442.4 mg, 1.74 mmol, 1.5 eq), KOAc (342 mg, 3.48 mmol, 3 eq) and Pd(dppf)Cl2 (85 mg, 0.116 mmol, 0.1 eq) in dioxane (5 mL) was degassed and backfilled with N2 for 3 times, and then stirred at 100 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature, filtered through a short pad of celite and rinsed with dioxane (5 mL). The combined filtrate was concentrated in vacuo to give a crude product of 2-(8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinolin-3-yl)propan-2-ol (350 mg, crude) as a black brown oil, which was used into the next step without further purification. LCMS: 250.1 [M+H]+. Intermediate-32: Preparation of 2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-1- isopropyl-3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin- 4(1H)-one Step 1: (Z)-1-(4-chloro-2-fluoro-phenyl)-3-(dimethylamino)but-2-en-1-one [00368] A mixture of 1-(4-chloro-2-fluoro-phenyl)ethanone (15 g, 86.9 mmol, 1 eq) and 1,1-dimethoxy-N,N-dimethyl-ethanamine (25 g, 187.7 mmol, 27.5 mL, 2.16 eq) was stirred for 1 hour at 120 °C under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by column chromatography to afford (Z)-1-(4- chloro-2-fluoro-phenyl)-3-(dimethylamino)but-2-en-1-one (16.7 g, 79% yield) as a yellow solid. LCMS: 242.0 [M+H]+. Step 2: (Z)-1-(4-chloro-2-fluoro-phenyl)-3-(isopropylamino)but-2-en-1-one [00369] A mixture of (Z)-1-(4-chloro-2-fluoro-phenyl)-3-(dimethylamino)but-2-en-1- one (11.05 g, 45.7 mmol, 1 eq) and propan-2-amine (3.58 g, 60.5 mmol, 5.2 mL, 1.32 eq) in DMSO (150 mL) was stirred for 16 hours at 110 °C under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by column chromatography to afford (Z)-1-(4-chloro-2-fluoro-phenyl)-3-(isopropylamino)but-2- en-1-one (11.05 g, 62% yield) as a yellow oil. LCMS: 256.2 [M+H]+. Step 3: 7-chloro-1-isopropyl-2-methyl-quinolin-4-one [00370] A mixture of (Z)-1-(4-chloro-2-fluoro-phenyl)-3-(isopropylamino)but-2-en-1- one (10.6 g, 41.45 mmol, 1 eq) and Cs2CO3 (27.01 g, 82.90 mmol, 2 eq) in DMF (120 mL) was stirred for 16 hours at 100 °C under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The mixture was filtered through a short pad of celite, and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography to afford 7-chloro-1- isopropyl-2-methyl-quinolin-4-one (8.73 g, 86% yield) as a brown solid. LCMS: 236.1 [M+H]+. Step 4: 7-chloro-3-iodo-1-isopropyl-2-methyl-quinolin-4-one [00371] A mixture of 7-chloro-1-isopropyl-2-methyl-quinolin-4-one (3 g, 12.73 mmol, 1 eq), I2 (3.23 g, 12.73 mmol, 2.56 mL, 1 eq) and cerium ammonium nitrate (697.75 mg, 1.27 mmol, 0.1 eq) in MeCN (60 mL) was stirred for 2 hours at 70 °C under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by column chromatography to afford 7-chloro-3-iodo-1-isopropyl-2-methyl-quinolin-4- one (2.4 g, 52% yield) as a yellow solid. LCMS: 361.8 [M+H]+. Step 5: 7-chloro-1-isopropyl-2,3-dimethyl-quinolin-4-one [00372] A mixture of 7-chloro-3-iodo-1-isopropyl-2-methyl-quinolin-4-one (2.4 g, 6.64 mmol, 1 eq), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (3.33 g, 13.27 mmol, 3.71 mL, 2 eq), Cs2CO3 (4.32 g, 13.27 mmol, 2 eq) and Pd(dppf)Cl2 (486 mg, 0.663 mmol, 0.1 eq) in dioxane (60 mL) and H2O (6 mL) was degassed and backfilled with N2 for three times, and then stirred for 8 hours at 75 °C under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The mixture was filtered through a pad of the Celite, and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography to afford 7- chloro-1-isopropyl-2,3-dimethyl-quinolin-4-one (1.2 g, 72% yield) as a yellow solid. LCMS: 250.1 [M+H]+. Step 6: 2-(bromomethyl)-7-chloro-1-isopropyl-3-methyl-quinolin-4-one [00373] A mixture of 7-chloro-1-isopropyl-2,3-dimethyl-quinolin-4-one (1.2 g, 4.81 mmol, 1 eq), AIBN (143.6 mg, 0.874 mmol, 1.82e-1 eq) and NBS (1.03 g, 5.77 mmol, 1.2 eq) in DCM (30 mL) was stirred for 5 hours at 50 °C under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The mixture was quenched with saturated aqueous Na2SO3 (50 mL) and extracted with DCM (50 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, PE/EtOAc =1/0 to 1/1) to afford 2- (bromomethyl)-7-chloro-1-isopropyl-3-methyl-quinolin-4-one (1.25 g, 78% yield) as a yellow solid. LCMS: 328.0, 330.0 [M+H]+. Step 7: 7-chloro-2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-1-isopropyl-3- methylquinolin-4(1H)-one [00374] The mixture of 2-(bromomethyl)-7-chloro-1-isopropyl-3-methyl-quinolin-4- one (360 mg, 1.1 mmol, 1 eq), (3S,5S)-3,5-dimethylmorpholine (189.2 mg, 1.64 mmol, 1.5 eq) and DIEA (424.7 mg, 3.29 mmol, 572.42 μL, 3 eq) in DMF (5 mL) was stirred at 60 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The desired 7- chloro-2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-1-isopropyl-3-methylquinolin- 4(1H)-one (382 mg, crude) was obtained as a yellow oil, which was used in the next step without further purification. LCMS: 363.2 [M+H]+. Step 8: 2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-1-isopropyl-3-methyl-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one [00375] The mixture of 7-chloro-2-[[(3S,5S)-3,5-dimethylmorpholin-4-yl]methyl]-1- isopropyl-3-methyl-quinolin-4-one (382 mg, 1.05 mmol, 1 eq), Pin2B2 (401 mg, 1.58 mmol, 1.5 eq), KOAc (309.9 mg, 3.16 mmol, 3 eq) and Pd(dppf)Cl2 (85.96 mg, 0.105 mmol, 0.1 eq) in dioxane (6 mL) was stirred at 100 °C for 2 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was filtered through a short pad of Celite, rinsed with dioxane (6 mL) and the filtrate was concentrated under reduced pressure. The desired 2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-1-isopropyl-3-methyl-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one (391mg, crude) was obtained as a yellow oil, which was used in the next step without further purification. LCMS: 455.5 [M+H]+. Preparation of Example Compounds Examples Example 1: Synthesis of (1S, 2S, 3R, 5R)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (configuration was assigned randomly )(Compound 2) and (1R, 2R, 3S, 5S)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (configuration was assigned randomly) (Compound 3) Step 1: Preparation of 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)propan-2-ol [00376] A solution of 2-(4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)propan-2-ol (2 g, 5.52 mmol, 1 eq), 2,4,5-trichloropyrimidine (1.32 g, 7.18 mmol, 1.3 eq) and Na2CO3 (1.76 g, 16.56 mmol, 3 eq) in 1,4-dioxane (30 mL) and H2O (9 mL) was degassed and backfilled with nitrogen for three times, and then Pd(PPh3)4 (638.00 mg, 0.552 mmol, 0.1 eq) was added under nitrogen atmosphere. The mixture was stirred at 100 °C for 16 h under N2 until the starting materials were consumed. The reaction was cooled to room temperature and the volatiles were removed under reduced pressure. The resulting residue was diluted with 300 mL of EtOAc, washed with brine (100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated to give a crude product, which was purified by the column chromatography. The desired 2-(6-(2,5- dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)propan-2-ol (1.73 g, 81.76% yield) was obtained as a light-yellow solid. LCMS: 383.0 [M+H]+. Step 2: Preparation of (1S*,2S*,3R*,5R*)-(±)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol (compound 1) [00377] To a solution of 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)propan-2-ol (70 mg, 0.183 mmol, 1 eq) and (1S*,2S*,3R*,5R*)- (±)-3-amino-8-oxabicyclo[3.2.1]octan-2-ol (52.30 mg, 0.365 mmol, 2 eq) in DMSO (1 mL) was added Na2CO3 (38.72 mg, 0.365 mmol, 2 eq), and the mixture was stirred at 120 °C for 12 h under N2 atmosphere. The reaction mixture was cooled to room temperate and diluted with water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL x2). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC and further by reversed-phase column chromatography (C18, mobile phase: water (0.1% FA )-ACN; B%: 60%) to afford (1S*,2S*,3R*,5R*)-(±)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl- 1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (compound 1) (60 mg) as a yellow solid. LCMS: 490.3 [M+H]+. Step 3: Preparation of (1S, 2S, 3R, 5R)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan- 2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol (configuration was assigned randomly) (compound 2) and (1R, 2R, 3S, 5S)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl- 1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (configuration was assigned randomly)(compound 3) [00378] The 60 mg of racemic (1S*,2S*,3R*,5R*)-(±)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol (compound 1) was purified by prep-SFC (column: DAICEL CHIRALPAK IC (250mm*30mm,10um); mobile phase: [CO2-EtOH(0.1% NH3 ^H2O)]; B%: 42.5%, isocratic elution mode) to afford 15 mg of (1S, 2S, 3R, 5R)-3- ((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6- yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (configuration was assigned randomly)(compound 2) as a white solid. LCMS: 490.4 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 8.40 (br s, 1H), 8.11 - 7.79 (m, 1H), 7.60 - 7.22 (m, 2H), 5.94 - 5.64 (m, 2H), 5.08 - 4.84 (m, 1H), 4.28 (br d, J = 5.1 Hz, 1H), 4.15 - 3.88 (m, 2H), 3.58 (br d, J = 2.9 Hz, 1H), 2.03 - 1.94 (m, 1H), 1.91 - 1.76 (m, 2H), 1.66 (s, 7H), 1.60 (br d, J = 6.8 Hz, 6H), 1.59 - 1.45 (m, 2H)ppm. and 17.3 mg of (1R, 2R, 3S, 5S)-3-((5-chloro-4- (4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (configuration was assigned randomly)(compound 3) as a white solid. LCMS: 490.1 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 8.48 - 8.34 (m, 1H), 8.09 - 7.82 (m, 1H), 7.56 - 7.25 (m, 2H), 5.96 - 5.65 (m, 2H), 4.97 (br s, 1H), 4.36 - 4.21 (m, 1H), 4.14 - 3.88 (m, 2H), 3.70 - 3.48 (m, 1H), 2.05 - 1.94 (m, 1H), 1.90 - 1.76 (m, 2H), 1.66 (s, 7H), 1.61 (br d, J = 6.8 Hz, 6H), 1.57 - 1.41 (m, 2H) ppm. Example 2: Synthesis of (1S,2S,3R,5R)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)-8-(methylsulfonyl)-8-azabicyclo[3.2.1]octan-2-ol (configuration was assigned randomly ) (Compound 5) and (1R,2R,3S,5S)-3-((5-chloro-4-(4-fluoro- 2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)-8-(methylsulfonyl)-8-azabicyclo[3.2.1]octan-2-ol (configuration was assigned randomly ) (Compound 6) Step 1: Preparation of tert-butyl (1S*,2S*,3R*,5R*)-(±)3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2- hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate [00379] To a solution of 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)propan-2-ol (100 mg, 0.261 mmol, 1 eq) and tert-butyl (1S*,2S*,3R*,5R*)-(±)-3-amino-2-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (69.55 mg, 0.287 mmol, 1.1 eq) in NMP (3 mL) was added Na2CO3 (82.97 mg, 0.783 mmol, 3 eq), and the reaction was stirred for 12 h at 120 °C under N2. The reaction mixture was cooled to room temperate and diluted with water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL x2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by pre-TLC with PE/EtOAc=1/1 (Rf = 0.5) to give tert-butyl (1S*,2S*,3R*,5R*)-(±)3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2- hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (134 mg, 87.18% yield) as a brown oil. LCMS: 589.5 [M+H]+. Step 2: Preparation of (1S*,2R*,3R*,5R*)-(±)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- azabicyclo[3.2.1]octan-2-ol TFA salt [00380] To a solution of tert-butyl (1S*,2S*,3R*,5R*)-(±)3-((5-chloro-4-(4-fluoro-2- (2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- 2-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (257 mg, 0.436 mmol, 1 eq) in DCM (5 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 30.96 eq), and the reaction was stirred for 0.5 h at 25 °C. The volatiles were removed in vacuo, and the crude (1S*,2R*,3R*,5R*)-(±)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl- 1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-2-ol TFA salt (404 mg, crude) was obtained as a brown oil. LCMS: 489.2 [M+H]+. Step 3: Preparation of (1R*,2S*,3R*,5S*)-(±)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- (methylsulfonyl)-8-azabicyclo[3.2.1]octan-2-ol (compound 4) [00381] To a solution of (1S*,2R*,3R*,5R*)-(±)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- azabicyclo[3.2.1]octan-2-ol TFA salt (200 mg, 0.409 mmol, 1 eq) in DCM (6 mL) was added TEA (206.94 mg, 2.05 mmol, 0.3 mL, 5 eq) and methylsulfonyl methanesulfonate (71.25 mg, 0.409 mmol, 1 eq), and the mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into sat.aq.NaHCO3 (10 mL) and the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water (FA)-ACN]; gradient: 38%-68% B over 7 min) to afford (1R*,2S*,3R*,5S*)-(±)-3-((5-chloro-4-(4- fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)-8-(methylsulfonyl)-8-azabicyclo[3.2.1]octan-2-ol (80 mg, 95.7% purity) as a yellow solid. LCMS: 567.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.40 (br s, 1H), 8.06 - 7.87 (m, 1H), 7.60 - 7.24 (m, 2H), 5.91 - 5.75 (m, 2H), 5.39 - 5.06 (m, 1H), 4.15 - 4.08 (m, 1H), 4.04 - 3.88 (m, 2H), 3.68 (br dd, J = 3.4, 9.0 Hz, 1H), 2.96 (s, 3H), 2.07 - 1.84 (m, 4H), 1.69 - 1.65 (m, 6H), 1.62 - 1.50 (m, 7H), 1.32 - 1.07 (m, 1H) ppm. Step 4: Preparation of 1S,2S,3R,5R)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2- yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-(methylsulfonyl)-8- azabicyclo[3.2.1]octan-2-ol (compound 5) and (1R,2R,3S,5S)-3-((5-chloro-4-(4- fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)-8-(methylsulfonyl)-8-azabicyclo[3.2.1]octan-2-ol (compound 6) [00382] The racemic (1R*,2S*,3R*,5S*)-(±)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- (methylsulfonyl)-8-azabicyclo[3.2.1]octan-2-ol (80 mg) was separated by chiral-prep- SFC ((column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: [CO2-ACN/i-PrOH(0.1% NH3H2O)]; B%: 36%, isocratic elution mode) to afford 1S,2S,3R,5R)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-(methylsulfonyl)-8- azabicyclo[3.2.1]octan-2-ol (configuration was assigned randomly ) (compound 5) (19.96 mg, 98.89% purity) as a white solid. LCMS: 567.3 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ = 8.42 (d, J = 12.8 Hz, 1H), 8.05 - 7.89 (m, 1H), 7.62 - 7.44 (m, 2H), 7.44 - 7.24 (m, 1H), 5.98 - 5.62 (m, 2H), 4.13 - 4.09 (m, 1H), 4.03 - 3.93 (m, 2H), 3.70 - 3.65 (m, 1H), 2.96 (s, 3H), 2.08 - 1.96 (m, 3H), 1.92 - 1.86 (m, 1H), 1.67 (s, 6H), 1.61 (m, 7H), 1.56 - 1.50 (m, 1H) ppm. and (1R,2R,3S,5S)-3-((5-chloro-4-(4- fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)-8-(methylsulfonyl)-8-azabicyclo[3.2.1]octan-2-ol (configuration was assigned randomly )(compound 6) (23.29 mg, 97.586% purity) as a white solid. LCMS: 567.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 12.6 Hz, 1H), 8.04 - 7.89 (m, 1H), 7.60 - 7.47 (m, 2H), 7.45 - 7.28 (m, 1H), 6.01 - 5.63 (m, 2H), 4.13 - 4.09 (m, 1H), 4.02 - 3.94 (m, 2H), 3.70 - 3.66 (m, 1H), 2.96 (s, 3H), 2.07 - 1.97 (m, 3H), 1.92 - 1.86 (m, 1H), 1.67 (s, 6H), 1.61 (m, 7H), 1.55 - 1.51 (m, 1H) ppm. Example 3: Synthesis of 6-(5-chloro-2-(((1R,2S,3R,5S)-2-hydroxy-8- (methylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1- isopropyl-2-methyl-1H-indole-3-carbonitrile (Compound 31) and 6-(5-chloro-2- (((1R,2R,3S,5S)-2-hydroxy-8-(methylsulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-indole-3-carbonitrile (Compound 32) Step 1: Preparation of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl- 1H-indole-3-carbonitrile [00383] A solution of 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indole-3-carbonitrile (139.14 mg, 0.326 mmol, 1 eq.), 2,4,5- trichloropyrimidine (89.72 mg, 0.489 mmol, 1.5 eq.) and K2CO3 (90.13 mg, 0.652 mmol, 2 eq.) in 1,4-dioxane (3.0 mL) and H2O (0.5 mL) was degassed and backfilled with nitrogen for three times, and then Pd(dppf)Cl2 (23.86 mg, 0.0326 mmol, 0.1 eq.) was added under nitrogen atmosphere. The mixture was stirred at 90 °C for 1 h under N2 until the starting materials were consumed. The reaction mixture was cooled to room temperature and filtered via a short pad of celite. The filtrate was concentrated to give a crude product, which was purified by the column chromatography. The desired 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-2- methyl-1H-indole-3-carbonitrile (65 mg, 54.88% yield) was obtained as a white solid. LCMS: 363.0 [M+H]+. Step 2: Preparation of tert-butyl (1R*,2S*,3R*,5S*)-(±)-3-((5-chloro-4-(3-cyano-4- fluoro-1-isopropyl-2-methyl-1H-indol-6-yl)pyrimidin-2-yl)amino)-2-hydroxy-8- azabicyclo[3.2.1]octane-8-carboxylate [00384] A mixture of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl- 1H-indole-3-carbonitrile (55 mg, 0.151 mmol, 1 eq), tert-butyl (1S*,2S*,3R*,5R*)-(±)- 3-amino-2-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (55.04 mg, 0.227 mmol, 1.5 eq), Na2CO3 (32.10 mg, 0.303 mmol, 2 eq) and KF (87.97 mg, 1.51 mmol, 10 eq) in DMSO (2 mL) was stirred at 120 °C for 2 h under nitrogen atmosphere. After the starting material was consumed completely, the reaction mixture was cooled to room temperature and diluted with water (10 mL). The aqueous phase was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with aq. NaCl (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-TLC. The desired tert-butyl (1R*,2S*,3R*,5S*)- (±)-3-((5-chloro-4-(3-cyano-4-fluoro-1-isopropyl-2-methyl-1H-indol-6-yl)pyrimidin-2- yl)amino)-2-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (54 mg, 94.89 μmol, 62.67% yield) was obtained as a white solid. LCMS: 513.2 [M+H]+. Step 3: Preparation of 6-(5-chloro-2-(((1R*,2R*,3R*,5S*)-(±)-2-hydroxy-8- azabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H- indole-3-carbonitrile HCl salt. [00385] A mixture of tert-butyl (1R*,2S*,3R*,5S*)-(±)-3-((5-chloro-4-(3-cyano-4- fluoro-1-isopropyl-2-methyl-1H-indol-6-yl)pyrimidin-2-yl)amino)-2-hydroxy-8- azabicyclo[3.2.1]octane-8-carboxylate (54 mg, 0.949 mmol, 1 eq) in HCl/EtOAc (4 M, 3 mL, 126 eq) was stirred at 25 °C for 1 h. The volatiles were removed under reduced pressure and the desired 6-(5-chloro-2-(((1R*,2R*,3R*,5S*)-(±)-2-hydroxy-8- azabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H- indole-3-carbonitrile HCl salt (52 mg, crude product, HCl salt) was obtained as a yellow solid, which was used into the next step without further purification. LCMS: 469.2 [M+H]+. Step 4: Preparation of 6-(5-chloro-2-(((1R*,2S*,3R*,5S*)-(±)-2-hydroxy-8- (methylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1- isopropyl-2-methyl-1H-indole-3-carbonitrile [00386] To a solution of 6-(5-chloro-2-(((1R*,2R*,3R*,5S*)-(±)-2-hydroxy-8- azabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H- indole-3-carbonitrile HCl salt (40 mg, 0.0791 mmol, 1 eq, HCl) in DCM (1 mL) was added DIEA (52 mg, 0.396 mmol, 5 eq) and methylsulfonyl methanesulfonate (14 mg, 79.14 μmol, 1 eq), and the mixture was stirred at 20 °C for 1 h. The reaction mixture was then concentrated under reduced pressure to give a residue, which was purified by prep-TLC. The desired 6-(5-chloro-2-(((1R*,2S*,3R*,5S*)-(±)-2-hydroxy-8- (methylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1- isopropyl-2-methyl-1H-indole-3-carbonitrile (25 mg, 57.74% yield) was obtained as a yellow oil. LCMS: 547.3 [M+H]+. Step 5: Preparation of 6-(5-chloro-2-(((1R,2S,3R,5S)-2-hydroxy-8-(methylsulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H- indole-3-carbonitrile (compound 31) and 6-(5-chloro-2-(((1R,2R,3S,5S)-2-hydroxy-8- (methylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1- isopropyl-2-methyl-1H-indole-3-carbonitrile (compound 32) [00387] The racemic 6-(5-chloro-2-(((1R*,2S*,3R*,5S*)-(±)-2-hydroxy-8- (methylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1- isopropyl-2-methyl-1H-indole-3-carbonitrile (25 mg) was separated by chiral-prep- SFC (condition: column: DAICEL CHIRALPAK IG (250mm*30mm,10um);mobile phase: [CO2-EtOH (0.1%NH3 ^H2O)]; B%: 62%, isocratic elution mode) to give 11.4 mg of 6-(5-chloro-2-(((1R,2S,3R,5S)-2-hydroxy-8-(methylsulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H- indole-3-carbonitrile (compound 31) (configuration was assigned randomly ) as a yellow solid. LCMS: 547.3 [M+H] +; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.34 (s, 1H), 7.84 (s, 1H), 7.40 (d, J = 10.8 Hz, 1H), 5.46 - 5.30 (m, 1H), 5.24 - 5.12 (m, 1H), 4.74 (td, J = 7.1, 14.0 Hz, 1H), 4.44 - 4.28 (m, 1H), 4.18 (br dd, J = 4.3, 6.5 Hz, 1H), 3.98 - 3.88 (m, 1H), 3.86 - 3.78 (m, 1H), 2.96 (s, 3H), 2.66 (s, 3H), 2.26 (br d, J = 2.4 Hz, 1H), 2.20 - 2.06 (m, 2H), 2.04 - 1.90 (m, 1H), 1.88 - 1.76 (m, 2H), 1.68 (dd, J = 2.0, 7.0 Hz, 6H) ppm. and 8.9 mg of 6-(5-chloro-2-(((1R,2R,3S,5S)-2-hydroxy-8- (methylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1- isopropyl-2-methyl-1H-indole-3-carbonitrile (compound 32) (configuration was assigned randomly ) as a yellow solid. LCMS: 547.3 [M+H]+; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.34 (s, 1H), 7.84 (s, 1H), 7.40 (d, J = 10.3 Hz, 1H), 5.18 (br d, J = 6.4 Hz, 1H), 4.82 - 4.66 (m, 1H), 4.44 - 4.28 (m, 1H), 4.18 (br dd, J = 4.4, 7.0 Hz, 1H), 3.98 - 3.88 (m, 1H), 3.86 - 3.80 (m, 1H), 2.96 (s, 3H), 2.66 (s, 3H), 2.32 - 2.20 (m, 1H), 2.18 - 2.05 (m, 3H), 2.04 - 1.90 (m, 2H), 1.84 (br s, 1H), 1.68 (dd, J = 1.8, 7.0 Hz, 6H) ppm. Example 4: Synthesis of (3S,4R)-4-((4-(2-(bicyclo[1.1.1]pentan-1-yl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-6-yl)-5-chloropyrimidin-2-yl)amino)tetrahydro- 2H-pyran-3-ol (compound 99) Step 1: preparation of 2-(bicyclo[1.1.1]pentan-1-yl)-6-(2,5-dichloropyrimidin-4-yl)-4- fluoro-1-isopropyl-1H-benzo[d]imidazole [00388] The mixture of 2-(bicyclo[1.1.1]pentan-1-yl)-4-fluoro-1-isopropyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (211.0 mg, 0.570 mmol, 1.0 eq), 2,4,5-trichloropyrimidine (156.8 mg, 0.855 mmol, 1.5 eq) and Na2CO3 (181.2 mg, 1.71 mmol, 3.0 eq) in dioxane (1 mL) and H2O (0.1 mL) was degassed and backfilled with N2 three times, and Pd(PPh3)4 (65.9 mg, 0.0570 mmol, 0.1 eq) was added under N2 atmosphere. The mixture was stirred at 90 °C under N2 atmosphere for 12 h until the starting material was consumed completely. The reaction mixture was cooled to room temperature and filtered through a pad of the Celite. The filtrate was concentrated in vacuo and the residue was purified by prep-TLC to give 2- (bicyclo[1.1.1]pentan-1-yl)-6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazole (101.0 mg, 45% yield) as a yellow solid. LCMS: 391.0 [M+H] +. Step 2: Preparation of (3S,4R)-4-((4-(2-(bicyclo[1.1.1]pentan-1-yl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-6-yl)-5-chloropyrimidin-2-yl)amino)tetrahydro-2H- pyran-3-ol [00389] The mixture of 2-(bicyclo[1.1.1]pentan-1-yl)-6-(2,5-dichloropyrimidin-4-yl)- 4-fluoro-1-isopropyl-1H-benzo[d]imidazole (50.0 mg, 0.128 mmol, 1.0 eq), (3S,4R)-4- aminotetrahydropyran-3-ol (23.6 mg, 0.153 mmol, 1.2 eq, HCl) and DIEA (165.2 mg, 1.28 mmol, 222.6 μL, 10.0 eq) in ACN (3 mL) was stirred at 100 °C for 3 h. The reaction mixture was cooled to room temperature and the volatiles were concentrated in vacuo. The resulting residue was purified by prep-HPLC {column: Phenomenex luna C18150*25mm*10um; mobile phase: [water (FA)-ACN]; gradient: 38%-68% B over 10 min} to give (3S,4R)-4-((4-(2-(bicyclo[1.1.1]pentan-1-yl)-4- fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-chloropyrimidin-2-yl)amino)tetrahydro- 2H-pyran-3-ol (24.4 mg, 38.5% yield) as a white solid. LCMS: 472.2 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.28 (s, 1H), 8.07 - 7.84 (m, 1H), 7.69 - 7.14 (m, 3H), 5.18 - 4.57 (m, 2H), 3.94 - 3.74 (m, 3H), 3.58 - 3.45 (m, 2H), 3.04 (t, J = 10.4 Hz, 1H), 2.64 (s, 1H), 2.38 (s, 6H), 1.60 (d, J = 7.2 Hz, 6H) ppm. Example 5: Synthesis of methyl (S)-3-(6-(5-chloro-2-(((3S,4R)-3- hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl- 1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (compound 101) and methyl (R)-3-(6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate (Compound 102) Step 1: Preparation of tert-butyl (R)-3-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate [00390] A mixture of tert-butyl (R)-3-(4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (2.2 g, 4.65 mmol, 1 eq), 2,4,5-trichloropyrimidine (1.28 g, 6.97 mmol, 1.5 eq), and K2CO3 (1.28 g, 9.29 mmol, 2 eq) in dioxane (30 mL) and H2O (5 mL) was degassed and backfilled with nitrogen for three times, and then Pd(PPh3)4 (268.52 mg, 0.232 mmol, 0.05 eq) was added. The mixture was stirred at 90 °C for 1 h under N2 until the starting materials were consumed. The reaction mixture was cooled to room temperature and filtered via a short pad of celite. The filtrate was concentrated, and the remaining content was diluted with water (20mL). The aqueous phase was extracted with ethyl acetate (100 mL x3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography. The desired tert-butyl (R)-3-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.75 g, 58.65% yield) was obtained as a yellow oil. LCMS: 494.2 [M+H]+. Step 2: preparation of tert-butyl (R)-3-(6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro- 2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate [00391] The mixture of tert-butyl (R)-3-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (2 g, 4.05 mmol, 1 eq), (3S,4R)-4-aminotetrahydropyran-3-ol HCl salt (932.10 mg, 6.07 mmol, 1.5 eq,), Na2CO3 (857.54 mg, 8.09 mmol, 2 eq) and KF (2.35 g, 40.45 mmol, 10 eq) in DMSO (30 mL) was stirred at 120 °C for 1 h under N2 atmosphere. The reaction mixture was cooled to room temperature and poured into H2O (100 mL). Then aqueous phase was extracted withethyl acetate(100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford the desired tert-butyl (R)-3-(6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate (1.7 g, 67.96% yield) as a yellow oil. LCMS: 575.3 [M+H]+. Step 3: preparation of (3S,4R)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2-((R)-pyrrolidin-3- yl)-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol HCl salt [00392] The solution of tert-butyl (R)-3-(6-(5-chloro-2-(((3S,4R)-3- hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (500 mg, 0.869 mmol, 1 eq) in HCl/EtOAc (5 mL) was stirred at 20 °C for 0.5 h. The volatiles were removed under reduced pressure and the desired (3S,4R)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2- ((R)-pyrrolidin-3-yl)-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H- pyran-3-ol HCl salt (400 mg, 98.37% purity, HCl) was obtained as a yellow solid, which was used directly for next step. LCMS: 475.2 [M+H]+. Step 4: Preparation of methyl (R)-3-(6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate [00393] To a solution of (3S,4R)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2-((R)- pyrrolidin-3-yl)-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3- ol HCl salt (130 mg, 0.274 mmol, 1 eq) in DCM (5 mL) was added TEA (138.48 mg, 1.37 mmol, 190.48 μL, 5 eq) and methyl chloroformate (31.04 mg, 0.328 mmol, 25.38 μL, 1.2 eq), and the mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into saturated aqueous NaHCO3 (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (dichloromethane/ methanol: 10/1) to afford partially racemized methyl (R)-3-(6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1- carboxylate (70 mg, 96% purity) as a light-yellow solid. LCMS: 533.3 [M+H]+. Step 5: Preparation of methyl (R)-3-(6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate (compound 102) and methyl (S)-3-(6-(5-chloro-2- (((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (compound 101) [00394] The partially racemized methyl (R)-3-(6-(5-chloro-2-(((3S,4R)-3- hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (70 mg) was separated by chiral- prep-SFC (column: DAICEL CHIRALPAK IC (250 mm * 30 mm,10 um); mobile phase: [CO2 - ACN/i-PrOH (0.1% NH3H2O)]; B%: 60%, isocratic elution mode) to afford 9.71 mg of methyl (S)-3-(6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate (compound 101) as a light pink solid LCMS: 533.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.05 - 7.85 (m, 1H), 7.56 - 7.27 (m, 2H), 5.11 - 4.78 (m, 2H), 3.97 - 3.89 (m, 1H), 3.85 - 3.78 (m, 4H), 3.74 - 3.66 (m, 1H), 3.62 (s, 3H), 3.58 - 3.40 (m, 4H), 3.08 - 2.99 (m, 1H), 2.37 - 2.31 (m, 1H), 2.27 - 2.16 (m, 1H), 2.03 - 1.91 (m, 1H), 1.61 (d, J = 6.8 Hz, 6H), 1.55 - 1.47 (m, 1H) ppm. [00395] The SFC separation also afforded 44.3 mg of methyl (R)-3-(6-(5-chloro-2- (((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (compound 102) (44.3 mg, 99.7% purity) as a light pink solid. LCMS: 533.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.06 - 7.86 (m, 1H), 7.54 - 7.31 (m, 2H), 5.04 - 4.88 (m, 2H), 4.02 - 3.88 (m, 1H), 3.86 - 3.78 (m, 4H), 3.75 - 3.67 (m, 1H), 3.62 (s, 3H), 3.60 - 3.35 (m, 4H), 3.08 - 3.00 (m, 1H), 2.39 - 2.32 (m, 1H), 2.28 - 2.14 (m, 1H), 2.02 - 1.88 (m, 1H), 1.61 (d, J = 6.8 Hz, 6H), 1.56 - 1.47 (m, 1H) ppm. Example 6: Synthesis of methyl (R)-2-(6-(5-chloro-2-(((3S,4R)-3- hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl- 1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (Compound 120) Step 1: Preparation of methyl (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate [00396] A mixture of methyl (R)-2-(4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (180 mg, 0.431 mmol, 1 eq), 2,4,5-trichloropyrimidine (79.12 mg, 0.431 mmol, 1 eq) and Na2CO3 (137.16 mg, 1.29 mmol, 3 eq) in dioxane (5.4 mL) and H2O (1.8 mL) was degassed and backfilled with N2 for three times, and then Pd(PPh3)4 (49.85 mg, 0.0431 mmol, 0.1 eq) was added under N2 atmosphere. The mixture was subsequently stirred at 90 °C for 2 h under N2 atmosphere until the starting materials were consumed. The reaction was cooled to room temperature and the volatiles were removed under reduced pressure. The resulting residue was diluted with 30 mL of EtOAc, washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated to give a crude product, which was purified by prep-TLC. The desired methyl (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (150 mg,79.3% yield) was obtained as a yellow oil. LCMS: 438.2 [M+H] +. Step 2: Preparation of methyl (R)-2-(6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate (compound 120) [00397] The mixture of methyl (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (100 mg, 0.228 mmol, 1 eq), (3S,4R)-4-aminotetrahydropyran-3-ol HCl salt (105.14 mg, 0.684 mmol, 3 eq) and DIEA (294.89 mg, 2.28 mmol, 397.42 uL, 10 eq) in ACN (5 mL) was stirred at 100 °C for 24 h. The reaction was cooled to room temperature and the volatiles were removed under reduced pressure. The residue was purified by prep-HPLC {column: Phenomenex Luna C18150 * 25 mm * 10 um; mobile phase: [water (FA)-ACN]; B%: 29%-59%, 10 min}. to give methyl (R)-2-(6-(5-chloro-2-(((3S,4R)-3- hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (15.92 mg, 13.04% yield, 96.9% purity) as a yellow solid. LCMS: 438.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.99 (s, 1H), 7.43 (br d, J = 11.9 Hz, 1H), 7.30 - 7.02 (m, 1H), 5.32 (br dd, J = 2.7, 7.8 Hz, 1H), 5.17 - 4.95 (m, 1H), 3.93 - 3.79 (m, 3H), 3.73 - 3.64 (m, 1H), 3.55 - 3.44 (m, 4H), 3.43 - 3.24 (m, 3H), 3.13 - 3.02 (m, 1H), 2.43 - 2.29 (m, 2H), 2.26 - 2.08 (m, 1H), 2.05 - 1.90 (m, 3H), 1.74 - 1.51 (m, 7H) ppm. Example 7: Synthesis of (3S,4R)-4-((5-chloro-4-(4-fluoro-7-isopropyl-2-methyl- 1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (compound 189) Step 1: Preparation of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-7-isopropyl-2-methyl- 1H-benzo[d]imidazole [00398] A mixture of 4-fluoro-7-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazole (100 mg, 0.314 mmol, 1 eq), 2,4,5- trichloropyrimidine (115.29 mg, 0.629 mmol, 2 eq), and Na2CO3 (66.62 mg, 0.629 mmol, 2 eq) in dioxane (5 mL) and H2O (1 mL) was degassed and backfilled with N2 for three times, and then Pd(PPh3)4 (36.32 mg, 0.0314 mmol, 0.1 eq) was added under N2 atmosphere. The mixture was subsequently stirred at 100 °C for 1 h under N2 atmosphere until the starting materials were consumed. The reaction mixture was cooled to room temperature and filtered via a short pad of celite. The filtrate was concentrated under reduced pressure to give a residue that was purified by prep- TLC. The desired 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-7-isopropyl-2-methyl-1H- benzo[d]imidazole (50 mg, 46.90% yield) was obtained as a yellow oil. LCMS: 339.0 [M+H]+. Step 2: Preparation of (3S,4R)-4-((5-chloro-4-(4-fluoro-7-isopropyl-2-methyl-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol [00399] The mixture of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-7-isopropyl-2-methyl- 1H-benzo[d]imidazole (20 mg, 0.0590 mmol, 1 eq), (3S,4R)-4-aminotetrahydropyran- 3-ol (27.17 mg, 0.177 mmol, 3 eq, HCl) and DIEA (22.86 mg, 0.177 mmol, 30.81 μL, 3 eq) in DMSO (3 mL) was stirred at 80 °C for 16 h under N2 atmosphere. The reaction was cooled to room temperature and the volatiles were removed under reduced pressure. The remaining content was diluted with water (20 mL) and the aqueous phase was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with water (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by reversed-phase HPLC (column: Phenomenex Luna C18150*25mm*10um; mobile phase: [water (FA)-ACN]; gradient: 14%-44% B over 10 min) to give (3S,4R)-4-((5-chloro-4-(4- fluoro-7-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)tetrahydro-2H-pyran-3-ol (6.62 mg, 26.74% yield) as a white solid. LCMS: 420.2[M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.52 - 8.31 (m, 1H), 7.83 - 7.18 (m, 1H), 6.91 - 6.49 (m, 1H), 5.13 - 4.78 (m, 1H), 3.93 - 3.63 (m, 3H), 3.52 - 3.43 (m, 1H), 3.08 - 2.78 (m, 2H), 2.56 (br s, 3H), 2.49 - 2.42 (m, 1H), 2.00 - 1.84 (m, 1H), 1.54 - 1.21 (m, 7H) ppm. Example 8: Synthesis of (3S,4R)-4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2- yl)-7-isopropylbenzo[d]thiazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran- 3-ol (compound 190) Step 1: Preparation of 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-7- isopropylbenzo[d]thiazol-2-yl)propan-2-ol [00400] The mixture of 2-(4-fluoro-7-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzo[d]thiazol-2-yl)propan-2-ol (91.33 mg, 0.241 mmol, 1 eq.), 2,4,5-trichloropyrimidine (66.25 mg, 0.361 mmol, 1.5 eq.) and K2CO3 (99.83 mg, 0.722 mmol, 3 eq.) in 1,4-dioxane (4 mL) and H2O (0.8 mL) was degassed and backfilled with nitrogen three times, and then Pd(dppf)Cl2 (17.62 mg, 0.0241 mmol, 0.1 eq.) was added under nitrogen atmosphere. The mixture was stirred at 100 °C for 12 h under N2 until the starting materials were consumed. The reaction mixture was cooled to room temperature and filtered via a short pad of celite. The filtrate was concentrated to give a crude product, which was purified by the column chromatography. The desired 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-7- isopropylbenzo[d]thiazol-2-yl)propan-2-ol (60 mg, 57.89% yield) was obtained as a light-yellow solid. LCMS: 400.1 [M+H]+. Step 2: Preparation of (3S,4R)-4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-7- isopropylbenzo[d]thiazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (compound 190) [00401] The solution of 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-7- isopropylbenzo[d]thiazol-2-yl)propan-2-ol (60 mg, 0.139 mmol, 1 eq.), (3S,4R)-4- aminotetrahydropyran-3-ol (32.12 mg, 0.209 mmol, 1.5 eq., HCl), Na2CO3 (29.55 mg, 0.279 mmol, 2 eq.) and KF (80.98 mg, 1.39 mmol, 10 eq.) in DMSO (3 mL) was stirred at 120 °C for 2 h. The reaction was cooled to room temperature and the volatiles were removed under reduced pressure. The remaining content was diluted with water (20 mL) and the aqueous phase was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with water (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by reversed-phase HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; gradient: 35%-65% B over 10 min) to give (3S,4R)-4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-7- isopropylbenzo[d]thiazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (12.77 mg, 18.28% yield) as a white solid. LCMS: 481.2 [M+H]+; 1HNMR (400 MHz, DMSO- d6) δ 8.45 (s, 1H), 7.54 (br d, J = 1.8 Hz, 1H), 7.30 - 7.17 (m, 1H), 6.37 (s, 1H), 4.91 (br d, J = 4.9 Hz, 1H), 3.93 - 3.60 (m, 3H), 3.55 - 3.41 (m, 1H), 3.30 - 3.26 (m, 1H), 3.13 - 2.85 (m, 2H), 2.06 - 1.79 (m, 1H), 1.62 (s, 6H), 1.53 - 1.41 (m, 1H), 1.40 - 1.23 (m, 6H) ppm. Example 9: Synthesis of 6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran- 4-yl)amino)pyrimidin-4-yl)-4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H- indole-3-carbonitrile (compound 195) Step 1: Preparation of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-(2-hydroxypropan-2- yl)-1-isopropyl-1H-indole-3-carbonitrile [00402] A mixture of 4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carbonitrile (40.0 mg, 0.104 mmol, 1.0 eq), 2,4,5-trichloropyrimidine (38.0 mg, 0.207 mmol, 2.0 eq) and Na2CO3 (22.0 mg, 0.207 mmol, 2.0 eq) in dioxane (1 mL) and H2O (0.2 mL) was degassed and backfilled with nitrogen three times, and then Pd(PPh3)4 (12.0 mg, 0.0104 mmol, 0.1 eq) was added under N2 atmosphere. The mixture was stirred at 90 °C for 1 h under N2 atmosphere until the starting material was consumed completely. The reaction mixture was cooled to room temperature and filtered via a short pad of celite. The filtrate was concentrated to give a crude product, which was purified by prep-TLC to afford 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl- 1H-indole-3-carbonitrile (35.0 mg, 72% yield) as a yellow solid. LCMS: 407.0 [M+H]+. Step 2: Preparation of 6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-indole-3- carbonitrile [00403] To a solution of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-(2-hydroxypropan- 2-yl)-1-isopropyl-1H-indole-3-carbonitrile (30.0 mg, 0.0737 mmol, 1.0 eq) and (3S,4R)-4-aminotetrahydropyran-3-ol (25.9 mg, 0.169 mmol, 2.3 eq, HCl) in MeCN (1 mL) was added DIEA (47.6 mg, 0.368 mmol, 5.0 eq), and the mixture was stirred at 100 °C for 1 h under N2 atmosphere. The reaction mixture was cooled to room temperature and filtered via a short pad of celite. The filtrate was concentrated to give a crude product, which was purified by reversed-phase HPLC (column: Phenomenex luna C18150*25mm*10 um; mobile phase: [water (FA)-ACN]; B%: 39%-69%, 10min). The desired portions were collected and lyophilized to provide 6- (5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4- fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-indole-3-carbonitrile (7.4 mg, 20% yield, 98.3% purity) as a white solid. LCMS: 488.1 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 8.56 - 8.38 (m, 2H), 8.16 - 7.92 (m, 1H), 7.65 - 7.26 (m, 2H), 6.14 (br d, J = 5.2 Hz, 1H), 5.79 (td, J = 6.4, 13.4 Hz, 1H), 5.13 - 4.84 (m, 1H), 3.89 - 3.74 (m, 3H), 3.57 - 3.45 (m, 2H), 3.11 - 2.93 (m, 1H), 2.08 - 1.90 (m, 1H), 1.77 (s, 6H), 1.62 (br d, J = 7.2 Hz, 6H), 1.53 - 1.41 (m, 1H) ppm. Example 10: Synthesis of (3S,4R)-4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan- 2-yl)-3-isopropylimidazo[1,2-a]pyridin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H- pyran-3-ol (compound 199) Step 1: Preparation of 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-3- isopropylimidazo[1,2-a]pyridin-2-yl)propan-2-ol [00404] To a solution of (8-fluoro-2-(2-hydroxypropan-2-yl)-3-isopropylimidazo[1,2- a]pyridin-6-yl)boronic acid (50.0 mg, 0.179 mmol, 1.0 eq), 2,4,5-trichloropyrimidine (36.0 mg, 0.196 mmol, 1.1 eq) and Na2CO3 (56.8 mg, 0.536 mmol, 3.0 eq) in dioxane (2 mL) and H2O (0.4mL) was degassed and backfilled with nitrogen three times, and then Pd(PPh3)4 (20.6 mg, 0.0179 mmol, 0.1 eq) was added under N2 atmosphere. The mixture was stirred at 90 °C for 12 h under N2 atmosphere until the starting material was consumed completely. The reaction mixture was cooled to room temperature and filtered via a short pad of celite. The filtrate was concentrated to give a crude product, which was purified by prep-TLC give 2-(6-(2,5- dichloropyrimidin-4-yl)-8-fluoro-3-isopropylimidazo[1,2-a]pyridin-2-yl)propan-2-ol (27.0 mg, 39 % yield) as yellow solid. LCMS: 383.2 [M+H]+. Step 2: Preparation of (3S,4R)-4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3- isopropylimidazo[1,2-a]pyridin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol [00405] To a solution of 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-3- isopropylimidazo[1,2-a]pyridin-2-yl)propan-2-ol (27.0 mg, 0.0705 mmol, 1.0 eq) and (3S,4R)-4-aminotetrahydropyran-3-ol (12.4 mg, 0.106 mmol, 1.5 eq) in ACN (2 mL) was added DIEA (27.3 mg, 0.211 mmol, 36.8 µL, 3.0 eq), and the mixture was stirred at 80 °C for 12 h. Additional (3S,4R)-4-aminotetrahydropyran-3-ol (12.4 mg, 0.106 mmol, 1.5 eq) was added and the reaction was stirred at 80 °C for an extra 12 h. The reaction was cooled to room temperature and the volatiles were removed under reduced pressure. The resulting crude product was purified by Prep-HPLC (column: Phenomenex luna C18150*25mm*10µm; mobile phase: [water (FA)-ACN]; B%: 22%-52%, 9 min) and lyophilized to give the desired (3S,4R)-4-((5-chloro-4-(8-fluoro- 2-(2-hydroxypropan-2-yl)-3-isopropylimidazo[1,2-a]pyridin-6-yl)pyrimidin-2- yl)amino)tetrahydro-2H-pyran-3-ol (6.7 mg, 21% yield) as a white solid. LCMS: 464.2 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.46 (s, 1H), 7.63 - 7.34 (m, 2H), 5.16 (s, 1H), 4.95 (d, J = 5.2 Hz, 1H), 4.55 - 4.35 (m, 1H), 3.91 - 3.76 (m, 4H), 3.58 - 3.45 (m, 2H), 3.04 (t, J =1.2 Hz, 1H), 2.03 - 1.89 (m, 1 H), 1.56 (s, 6H), 1.41 (d, J = 7.2 Hz, 6H) ppm. Example 11: Synthesis of methyl (R)-3-(6-(5-chloro-2-(((1S,2S,3R,5R)-2- hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (compound 93) and methyl (R)-3-(6-(5-chloro-2-(((1R,2R,3S,5S)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (compound 94) Step 1: preparation of methyl (R)-3-(6-(5-chloro-2-(((1S*,2S*,3R*,5R*)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate [00406] To a solution of methyl (R)-3-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (100 mg, 0.221 mmol, 1 eq) in DMSO (2 mL) was added DIEA (86 mg, 0.663 mmol, 3 eq) and (1S*,2S*,3R*,5R*)-3-amino-8-oxabicyclo[3.2.1]octan-2-ol (47 mg, 0.331 mmol, 1.5 eq), and the mixture was stirred at 100 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The mixture was diluted with H2O (2 mL) and extracted with EtOAc (2 mL x 3). The combined organic layers were washed with brine (2 mL x 3), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford methyl (R)-3-(6-(5-chloro- 2-(((1S*,2S*,3R*,5R*)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)- 4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (54 mg, 0.088 mmol, 40% yield) as a light yellow oil. LCMS: 559.4 [M+H]+. Step 2: preparation of methyl (R)-3-(6-(5-chloro-2-(((1S,2S,3R,5R)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (compound 93) and methyl (R)-3-(6- (5-chloro-2-(((1R,2R,3S,5S)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3- yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1- carboxylate (compound 94) [00407] Methyl (R)-3-(6-(5-chloro-2-(((1S*,2S*,3R*,5R*)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (54 mg, 0.088 mmol) was purified by SFC (column: DAICEL CHIRALCEL OX (250mm*30mm,10um);mobile phase: [CO2- MeOH/ACN];B%:60%, isocratic elution mode) to give methyl (R)-3-(6-(5-chloro-2- (((1S,2S,3R,5R)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4- fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (22.3 mg, 41% yield) as a white solid and methyl (R)-3-(6-(5-chloro-2-(((1R,2R,3S,5S)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (20 mg, 36% yield) as a white solid. [00408] Methyl (R)-3-(6-(5-chloro-2-(((1S,2S,3R,5R)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate. LCMS: 559.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1 H), 8.08 - 7.85 (m, 1 H), 7.59 - 7.25 (m, 2 H), 4.95 - 4.85 (m, 2 H), 4.28 - 4.25 (m, 1 H), 4.15 - 4.08 (m, 1 H), 4.02 - 3.85 (m, 2 H), 3.78 - 3.74 (t, J=4.8 Hz, 1 H), 3.65 - 3.61 (m, 1 H), 3.58 - 3.52 (m, 3 H), 3.49 - 3.42 (m, 2 H), 3.38 - 3.32 (m, 2 H), 2.40 - 2.35 (m, 1 H), 2.25 - 2.18 (m, 1 H), 2.05 - 1.85 (m, 1 H), 1.81 - 1.72 (m, 2H), 1.58 - 1.48 (m, 6 H), 1.55 - 1.51 (m, 1 H) ppm. [00409] Methyl (R)-3-(6-(5-chloro-2-(((1R,2R,3S,5S)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate. LCMS: 559.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1 H), 8.06 - 7.91 (m, 1 H), 7.59 - 7.25 (m, 2 H), 4.98 - 4.85 (m, 2 H), 4.28 - 4.25 (m, 1 H), 4.15 - 4.08 (m, 1 H), 4.02 - 3.85 (m, 2 H), 3.78 - 3.74 (m, 1 H), 3.65 - 3.61 (m, 1 H), 3.58 - 3.52 (m, 3 H), 3.49 - 3.42 (m, 1 H), 3.42 - 3.40 (m, 1 H), 3.38 - 3.32 (m, 1 H), 2.40 - 2.35 (m, 2 H), 2.25 - 2.18 (m, 1 H), 2.05 - 1.85 (m, 1 H), 1.81 - 1.72 (m, 2H), 1.58 - 1.48 (m, 6 H), 1.55 - 1.51 (m, 1 H) ppm. Example 12: Synthesis of (1S,2S,3R,5R)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-7-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (compound 43) and (1R,2R,3S,5S)-3-((5- chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-7-isopropyl-1H-benzo[d]imidazol-6- yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (compound 44) Step 1: Preparation of 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-7-isopropyl-1H- benzo[d]imidazol-2-yl)propan-2-ol [00410] A mixture of 2-(4-fluoro-7-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)propan-2-ol (200 mg, 0.552 mmol, 1 eq), 2,4,5-trichloropyrimidine (152 mg, 0.828 mmol, 1.5 eq), Pd(dppf)Cl2 (80.8 mg, 0.110 mmol, 0.2 eq), K2CO3 (228.9 mg, 1.66 mmol, 3 eq) and H2O (0.6 mL) in dioxane (6 mL) was degassed and backfilled with N2 for 3 times, and then stirred at 90 °C for 4 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-7- isopropyl-1H-benzo[d]imidazol-2-yl)propan-2-ol (80 mg, 38% yield) as a yellow solid. LCMS: 383.1 [M+H]+. Step 2: Preparation of (1S*,2S*,3R*,5R*)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-7-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol [00411] To a solution of 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-7-isopropyl-1H- benzo[d]imidazol-2-yl)propan-2-ol (70 mg, 0.183 mmol, 1 eq) and (1R*,2S*,3R*,5S*)- 3-amino-8-oxabicyclo[3.2.1]octan-2-ol (39 mg, 0.274 mmol, 1.5 eq) in DMSO (2 mL) was added DIEA (71 mg, 0.548mol, 3 eq), and the mixture was stirred at 100 °C for 6 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The residue was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give (1S*,2S*,3R*,5R*)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-7-isopropyl- 1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (70 mg, 78% yield) as a yellow solid. LCMS: 490.2 [M+H]+. Step 3: Preparation of (1S,2S,3R,5R)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2- yl)-7-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol and (1R,2R,3S,5S)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-7-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol [00412] (1S*,2S*,3R*,5R*)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-7- isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2- ol (70 mg, 0.143 mmol) was purified by prep-SFC (column: DAICEL CHIRALPAK IC(250mm*30mm,10um);mobile phase: [CO2-MeOH(0.1%NH3H2O)];B%:40%, isocratic elution mode) to afford (1S,2S,3R,5R)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-7-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol (24.91 mg, 35% yield) as a white solid and (1R,2R,3S,5S)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-7-isopropyl-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (32.25 mg, 46% yield) as a white solid. [00413] (1S,2S,3R,5R)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-7- isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2- ol. LCMS: 490.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ = 8.38 (s, 1H), 7.43 - 7.41 (m, 1H), 6.77 - 6.73 (m, 1H), 5.57 - 5.53 (m, 1H), 4.96 - 4.95 (m, 1H), 4.26 - 4.25 (m, 1H), 4.06 - 4.05 (m, 1H), 3.91 - 3.85 (m, 1H), 3.56 - 3.33 (m, 1H), 3.14 - 2.78 (m, 1H), 1.99 - 1.66 (m, 4H), 1.52 (m, 6H), 1.46 - 1.36 (m, 8H) ppm. [00414] (1R,2R,3S,5S)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-7- isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2- ol. LCMS: 490.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ = 8.38 (s, 1H), 7.43 - 7.41 (m, 1H), 6.76 - 6.73 (m, 1H), 5.64 (m, 1H), 4.96 - 4.95 (m, 1H), 4.26 - 4.25 (m, 1H), 4.06 - 4.05 (m, 1H), 3.89 - 3.84 (m, 1H), 3.56 - 3.33 (m, 1H), 3.14 - 2.78 (m, 1H), 2.10 - 1.61 (m, 4H), 1.52 (m, 6H), 1.46 - 1.29 (m, 8H) ppm. Example 13: Synthesis of (1R,2S,3R,5S)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (compound 165) and (1R,2R,3S,5S)-3- ((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (compound 164) Step 5: Preparation of (1R*,2S*,3R*,5S*)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol [00415] To a solution of (1R*,2S*,3R*,5S*)-3-amino-8-oxabicyclo[3.2.1]octan-2-ol (500 mg, 3.49 mmol, 1 eq) and 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl- 1H-benzo[d]imidazol-2-yl)propan-2-ol (1.34 g, 3.49 mmol, 1 eq) in DMSO (10 mL) was added DIEA (2.26 g, 17.46 mmol, 3 mL, 5 eq), and the mixture was stirred at 80 °C for 12 hours under N2 atmosphere. After the completion of the reaction, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by prep-TLC to afford (1R*,2S*,3R*,5S*)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol (46 mg, 0.094 mmol, 3% yield) as a light yellow solid. LCMS: 490.3 [M+H]+. Step 6: Preparation of (1R,2S,3R,5S)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2- yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol and (1R,2R,3S,5S)-3-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol [00416] (1R*,2S*,3R*,5S*)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1- isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2- ol (56 mg, 0.114 mmol, 1 eq) was purified by prep-SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [CO2-i- PrOH(0.1%NH3H2O)];B%:50%, isocratic elution mode) to afford (1R,2S,3R,5S)-3-((5- chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6- yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (14.86 mg, 26% yield) as a white solid and (1R,2R,3S,5S)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1- isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2- ol (17.92 mg, 31% yield) as an off-white solid. [00417] (1R,2S,3R,5S)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1- isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2- ol. LCMS: 490.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1 H), 8.00 (s, 1 H), 7.46 – 7.42 (m, 1 H), 7.37 - 7.35 (d, J=5.6 Hz, 1 H), 5.83 (s, 1 H), 5.79 – 5.73 (m, 1 H), 4.87 – 4.86 (d, J=6.0 Hz, 1 H), 4.28 - 4.25 (m, H), 4.11 - 4.09 (d, J=7.2 Hz, 2H), 3.75 - 3.70 (m, 1H), 3.52 - 3.51 (m, 1H), 2.29 - 2.22 (m, 1H), 1.96 - 1.90 (m, 2H), 1.84 - 1.72 (m, 2H), 1.67 (s, 6 H), 1.61 - 1.60 (d, J=6.8 Hz, 6H), 1.49 - 1.42 (m, 1H) ppm. [00418] (1R,2R,3S,5S)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1- isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2- ol. LCMS: 490.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1 H), 8.00 (s, 1 H), 7.44 – 7.41 (m, 1 H), 7.37 - 7.35 (d, J=5.2 Hz, 1 H), 5.83 (s, 1 H), 5.80 – 5.73 (m, 1 H), 4.87 – 4.86 (d, J=5.2 Hz, 1 H), 4.28 - 4.25 (m, H), 4.11 - 4.10 (d, J=7.6 Hz, 2H), 3.73 (s, 1H), 3.50 (s, 1H), 2.29 - 2.22 (m, 1H), 1.96 - 1.90 (m, 2H), 1.84 - 1.70 (m, 2H), 1.66 (s, 6 H), 1.61 - 1.60 (d, J=6.8 Hz, 6H), 1.50 - 1.44 (m, 1H) ppm. Example 14: Synthesis of methyl (R)-3-(6-(5-chloro-2-(((1R,2S,3R,5S)-2- hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (compound 227) and methyl (R)-3-(6-(5-chloro-2-(((1S,2R,3S,5R)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (compound 228) Step 1: preparation of methyl (R)-3-(6-(5-chloro-2-(((1R*,2S*,3R*,5S*)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate [00419] To a solution of methyl (R)-3-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (100 mg, 0.221 mmol, 1 eq) in DMSO (2 mL) was added DIEA (143 mg, 1.1 mmol, 5 eq) and (1R*,2S*,3R*,5S*)-3-amino-8-oxabicyclo[3.2.1]octan-2-ol (47 mg, 0.331 mmol, 1.5 eq), and the mixture was stirred at 80 °C for 10 hours under N2 atmosphere. After the completion of the reaction, the mixture was warmed to room temperature and diluted with EtOAc (5 mL). The organic phase was collected, and the aqueous phase was extracted with EtOAc (5 mLx3). The combined organic layers were washed with water (5 mL x 2) and brine (5 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by prep-TLC (Petroleum ether/Ethyl acetate=0/1) to afford methyl (R)-3-(6-(5-chloro-2- (((1R*,2S*,3R*,5S*)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4- fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (34 mg, 25% yield) as a light yellow solid. LCMS: 559.3 [M+H]+. Step 2: preparation of methyl (R)-3-(6-(5-chloro-2-(((1R,2S,3R,5S)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate and methyl (R)-3-(6-(5-chloro-2- (((1S,2R,3S,5R)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4- fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate [00420] Methyl (R)-3-(6-(5-chloro-2-(((1R*,2S*,3R*,5S*)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (34 mg, 0.061 mmol) was further separated by SFC (column: DAICEL CHIRALCEL OX (250mm*30mm,10um);mobile phase: [CO2-ACN/i-PrOH(0.1% NH3H2O)];B%:50%, isocratic elution mode) to give methyl (R)-3-(6-(5-chloro-2-(((1R,2S,3R,5S)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3- yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1- carboxylate (8.5 mg, 24% yield) as an off-white solid and methyl (R)-3-(6-(5-chloro-2- (((1S,2R,3S,5R)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4- fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (4.7 mg, 14% yield) as a white solid. [00421] Methyl (R)-3-(6-(5-chloro-2-(((1R,2S,3R,5S)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate. LCMS: 559.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1 H), 8.02 - 8.01 (m, 1 H), 7.48 - 7.45 (m, 1 H), 7.44 - 7.37 (m, 1 H), 4.97 - 4.96 (m, 1 H), 4.87 - 4.86 (m, 1 H), 4.27 - 4.21 (d, J=4.8 Hz, 1 H), 4.15 - 4.12 (d, J=4.0 Hz, 1 H), 3.85 - 3.80 (m, 1 H), 3.61 - 3.52 (m, 2 H), 3.51 - 3.22 (m, 4 H), 2.48 - 2.22 (m, 4 H), 1.95 - 1.85 (m, 2 H), 1.66 - 1.62 (m, 2H), 1.55 - 1.45 (m, 6 H), 1.41 - 1.38 (m, 6 H) ppm. [00422] Methyl (R)-3-(6-(5-chloro-2-(((1S,2R,3S,5R)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate. LCMS: 559.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1 H), 8.02 - 8.01 (m, 1 H), 7.48 - 7.45 (m, 1 H), 7.44 - 7.37 (m, 1 H), 4.97 - 4.96 (m, 1 H), 4.87 - 4.86 (m, 1 H), 4.27 - 4.21 (d, J=4.8 Hz, 1 H), 4.15 - 4.12 (d, J=4.0 Hz, 1 H), 3.85 - 3.80 (m, 1 H), 3.61 - 3.52 (m, 2 H), 3.51 - 3.22 (m, 4 H), 2.48 - 2.35 (m, 2 H), 2.31 - 2.22 (m, 4 H), 1.95 - 1.85 (m, 2 H), 1.66 - 1.62 (m, 2H), 1.55 - 1.45 (m, 6 H), 1.41 - 1.38 (m, 6 H) ppm. Example 15: Synthesis of (3S,4R)-4-((5-chloro-4-(2-((R)-3,3- difluorocyclopentyl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)tetrahydro-2H-pyran-3-ol (compound 223) and (3S,4R)-4-((5-chloro-4- (2-((S)-3,3-difluorocyclopentyl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6- yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (compound 224) Step 1: Preparation of 6-(2,5-dichloropyrimidin-4-yl)-2-(3,3-difluorocyclopentyl)-4- fluoro-1-isopropyl-1H-benzo[d]imidazole [00423] A mixture of 2-(3,3-difluorocyclopentyl)-4-fluoro-1-isopropyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (1.2 g, 2.94 mmol, 1 eq), 2,4,5-trichloropyrimidine (1.6 g, 8.82 mmol, 3 eq), Pd(dppf)Cl2 (107.5 mg, 0.147 mmol, 0.05 eq), KOAc (1.73 g, 17.64 mmol, 6 eq) and H2O (0.6 mL) in dioxane (15 mL) was degassed and backfilled with N2 for 3 times, and then stirred at 90 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep- TLC to afford 6-(2,5-dichloropyrimidin-4-yl)-2-(3,3-difluorocyclopentyl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazole (1 g, 79% yield) as a light-yellow oil. LCMS: 429.1 [M+H]+. Step 2: Preparation of (3S,4R)-4-((5-chloro-4-(2-(3,3-difluorocyclopentyl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol [00424] To a solution of 6-(2,5-dichloropyrimidin-4-yl)-2-(3,3-difluorocyclopentyl)-4- fluoro-1-isopropyl-1H-benzo[d]imidazole (250 mg, 0.578 mmol, 1 eq), (3S,4R)-4- aminotetrahydro-2H-pyran-3-ol (133 mg, 0.867 mmol, 1.5 eq) in ACN (3 mL) was added DIEA (224 mg, 1.73 mol, 3 eq), and the mixture was stirred at 100 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water(FA)-ACN];gradient:42%-72% B over 10 min) to give (3S,4R)-4-((5-chloro-4-(2-(3,3-difluorocyclopentyl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (90 mg, 31% yield) as a yellow solid. LCMS: 510.3 [M+H]+. Step 3: Preparation of (3S,4R)-4-((5-chloro-4-(2-((R)-3,3-difluorocyclopentyl)-4- fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H- pyran-3-ol and (3S,4R)-4-((5-chloro-4-(2-((S)-3,3-difluorocyclopentyl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol [00425] (3S,4R)-4-((5-chloro-4-(2-(3,3-difluorocyclopentyl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (90 mg, 0.172 mmol) was further separated by prep-SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [CO2-i-PrOH(0.1%NH3H2O)];B%:25%, isocratic elution mode) to afford (3S,4R)-4-((5-chloro-4-(2-((R)-3,3- difluorocyclopentyl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)tetrahydro-2H-pyran-3-ol (35.17 mg, 39% yield) as a white solid and (3S,4R)-4-((5-chloro-4-(2-((S)-3,3-difluorocyclopentyl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (35.96 mg, 40% yield) as a white solid. [00426] (3S,4R)-4-((5-chloro-4-(2-((R)-3,3-difluorocyclopentyl)-4-fluoro-1-isopropyl- 1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol. LCMS: 510.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ = 8.50 (s, 1H), 8.10 - 7.85 (m, 1H), 7.68 - 7.45 (m, 2H), 5.05 - 4.95 (m, 2H), 3.93 - 3.86 (m, 4H), 3.65 - 3.52 (m, 1H), 3.85 - 3.28 (m, 1H), 2.85 - 2.62 (m, 2H), 2.45 - 2.35 (m, 2H), 2.31 - 2.18 (m, 1H), 2.15 - 2.10 (m, 1H), 2.08 - 1.95 (m, 1H), 1.67 - 1.63 (m, 6H), 1.58 - 1.48 (m, 1H) ppm. [00427] (3S,4R)-4-((5-chloro-4-(2-((S)-3,3-difluorocyclopentyl)-4-fluoro-1-isopropyl- 1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol. LCMS: 510.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ = 8.43 (s, 1H), 7.99 - 7.94 (m, 1H), 7.51 - 7.31 (m, 2H), 5.05 - 4.95 (m, 2H), 3.93 - 3.86 (m, 4H), 3.65 - 3.52 (m, 1H), 3.28 - 3.23 (m, 1H), 3.08 - 3.01 (m, 1H), 2.45 - 2.35 (m, 2H), 2.28 - 2.15 (m, 1H), 2.15 - 2.10 (m, 1H), 2.08 - 1.95 (m, 1H), 1.67 - 1.63 (m, 6H), 1.48 - 1.35 (m, 1H) ppm. Example 16: Synthesis of 6-(5-chloro-2-(((1S, 2S, 3R, 5R)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino) pyrimidin-4-yl)-4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-indole-3-carbonitrile (Compound 35) and 6-(5-chloro-2-(((1R, 2R, 3S, 5S)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino) pyrimidin-4-yl)-4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-indole-3- carbonitrile (Compound 36) Step 1: Preparation of 6-(5-chloro-2-(((1S*,2S*,3R*,5R*)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-2-(2-hydroxypropan-2-yl)- 1-isopropyl-1H-indole-3-carbonitrile [00428] To a solution of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-(1-hydroxy-1- methyl-ethyl)-1-isopropyl-indole-3-carbonitrile (100 mg, 0.246 mmol, 1.0 eq) and 3- amino-8-oxabicyclo[3.2.1]octan-2-ol (53 mg, 0.368 mmol, 1.5 eq) in DMSO (2 mL) was added DIEA (95 mg, 0.736mol, 3.0 eq), and the mixture was stirred at 100 °C for 3 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (FA condition: column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water(FA)-ACN]; gradient: 40%-70% B over 10 min) to give 6-(5-chloro-2-(((1S*,2S*,3R*,5R*)-2- hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-indole-3-carbonitrile (45 mg, 36% yield) as a white solid. LCMS: 514.2 [M+H]+. Step 2: Preparation of 6-(5-chloro-2-(((1S,2S,3R,5R)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-2-(2-hydroxypropan-2-yl)- 1-isopropyl-1H-indole-3-carbonitrile (compound 35) and 6-(5-chloro-2- (((1R,2R,3S,5S)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4- fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-indole-3-carbonitrile (compound 36) [00429] 6-(5-chloro-2-(((1S*,2S*,3R*,5R*)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3- yl)amino)pyrimidin-4-yl)-4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-indole-3- carbonitrile (45 mg, 0.087 mmol) was further purified by prep-SFC (condition: DAICEL CHIRALPAK IC(250mm*30mm, 10um); mobile phase: [CO2- EtOH(0.1%NH3H2O)]; B%:50%, isocratic elution mode) to afford 6-(5-chloro-2- (((1S,2S,3R,5R)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4- fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-indole-3-carbonitrile (18.78 mg, 42% yield) as a white solid and 6-(5-chloro-2-(((1R,2R,3S,5S)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-2-(2-hydroxypropan-2-yl)- 1-isopropyl-1H-indole-3-carbonitrile (15.51 mg, 34% yield) as a white solid. [00430] 6-(5-chloro-2-(((1S,2S,3R,5R)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3- yl)amino)pyrimidin-4-yl)-4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-indole-3- carbonitrile: LCMS: 514.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1 H), 8.13 - 7.96 (m, 1 H), 7.51 - 7.31 (m, 2 H), 5.85 - 5.74 (m, 1 H), 4.28 (d, J = 4.0 Hz, 1 H), 4.16 - 3.89 (m, 2 H), 3.68 - 3.52 (m, 1 H), 2.58 - 2.54 (m, 1 H), 2.42 (d, J = 1.6 Hz, 1 H), 2.03 - 1.94 (m, 1 H), 1.90 - 1.81 (m, 2 H), 1.77 (s, 6 H), 1.72 (s, 1 H), 1.63 (d, J = 6.0 Hz, 6 H), 1.58 - 1.49 (m, 2 H) ppm. [00431] 6-(5-chloro-2-(((1R,2R,3S,5S)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3- yl)amino)pyrimidin-4-yl)-4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-indole-3- carbonitrile: LCMS: 514.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ = 8.53 (s, 1 H), 8.41 (s, 1 H), 8.19 - 7.91 (m, 1 H), 7.59 - 7.32 (m, 2 H), 5.79 (dt, J = 13.8, 6.6 Hz, 1 H), 4.29 (d, J = 5.2 Hz, 1 H), 4.15 - 3.90 (m, 2 H), 3.58 (d, J = 5.2 Hz, 1 H), 2.54 (s, 1 H), 2.47 - 2.38 (m, 1 H), 2.05 - 1.94 (m, 1 H), 1.82 (d, J = 4.0 Hz, 1 H), 1.77 (s, 6 H), 1.75 (s, 1 H), 1.63 (d, J = 6.8 Hz, 6 H), 1.59 - 1.49 (m, 2 H) ppm. Example 17: Synthesis of (3S,4R)-4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan- 2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-3- hydroxytetrahydro-2H-thiopyran 1,1-dioxide (compound 130) and (3R,4S)-4-((5- chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6- yl)pyrimidin-2-yl)amino)-3-hydroxytetrahydro-2H-thiopyran 1,1-dioxide (compound 131) Step 1: Preparation of (3S*,4R*)-4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1- isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-3-hydroxytetrahydro-2H- thiopyran 1,1-dioxide [00432] To a solution of (3S*,4R*)-4-amino-3-hydroxytetrahydro-2H-thiopyran 1,1- dioxide (48 mg, 0.293 mmol, 1.5 eq) and 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-2-yl)propan-2-ol (75 mg, 0.195 mmol, 1 eq) in DMSO (1 mL) was added DIEA (50.6 mg, 0.391 mmol, 2 eq), and the mixture was stirred at 80 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The residue was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Phenomenex Luna C18150*25mm*10um;mobile phase: [water(FA)- ACN];gradient:23%-53% B over 10 min) to give (3S*,4R*)-4-((5-chloro-4-(4-fluoro-2- (2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- 3-hydroxytetrahydro-2H-thiopyran 1,1-dioxide (65 mg, 0.114 mmol, 65% yield) as a white solid. LCMS: 512.3/514.2 [M+H]+. Step 2: Preparation of (3S,4R)-4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1- isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-3-hydroxytetrahydro-2H- thiopyran 1,1-dioxide (compound 130) and (3R,4S)-4-((5-chloro-4-(4-fluoro-2-(2- hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-3- hydroxytetrahydro-2H-thiopyran 1,1-dioxide (compound 131) [00433] (3S*,4R*)-4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl- 1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-3-hydroxytetrahydro-2H-thiopyran 1,1-dioxide (65 mg, 0.114 mmol) was further purified by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [CO2-ACN/EtOH(0.1% NH3H2O)];B%:60%, isocratic elution mode) to afford (3S,4R)-4-((5-chloro-4-(4-fluoro- 2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)-3-hydroxytetrahydro-2H-thiopyran 1,1-dioxide (16.18 mg, 25% yield) as an off-white solid and (3R,4S)-4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1- isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-3-hydroxytetrahydro-2H- thiopyran 1,1-dioxide (20.74 mg, 0.040 mmol, 32% yield) as an off-white solid. [00434] (3S,4R)-4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-3-hydroxytetrahydro-2H-thiopyran 1,1- dioxide: LCMS: 512.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.12 - 7.80 (m, 1H), 7.54 (d, J = 1.2 Hz, 1H), 7.44 - 7.29 (m, 1H), 5.90 - 5.56 (m, 2H), 4.08 - 3.87 (m, 2H), 3.26 (d, J = 7.2 Hz, 2H), 3.07 (d, J = 13.6 Hz, 1H), 2.30 - 2.17 (m, 1H), 1.96 - 1.71 (m, 2H), 1.66 (s, 6H), 1.60 (d, J = 7.2 Hz, 6H), 1.23 (s, 1H) ppm. [00435] (3R,4S)-4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-3-hydroxytetrahydro-2H-thiopyran 1,1- dioxide: LCMS: 512.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.04 - 7.89 (m, 1H), 7.54 (dd, J = 4.0, J = 6.8 Hz, 1H), 7.46 - 7.29 (m, 1H), 5.76 (td, J = 6.8, J = 13.6 Hz, 2H), 4.06 - 3.90 (m, 2H), 3.26 (d, J = 6.8 Hz, 2H), 3.07 (d, J = 12.8 Hz, 1H), 2.27 - 2.15 (m, 1H), 1.83 (dd, J = 1.2, J = 10.4 Hz, 2H), 1.66 (s, 6H), 1.60 (d, J = 7.2 Hz, 6H), 1.23 (s, 1H) ppm. Example 18: Synthesis of methyl (R)-3-(6-(5-chloro-2-(((1R,2R)-4,4-difluoro-2- hydroxycyclohexyl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (compound 241) and methyl (R)-3-(6-(5-chloro-2-(((1S,2S)-4,4-difluoro-2- hydroxycyclohexyl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (compound 240) Step 1: Preparation of methyl (R)-3-(6-(5-chloro-2-(((1R*,2R*)-4,4-difluoro-2- hydroxycyclohexyl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate [00436] To a solution of (1R*,2R*)-2-amino-5,5-difluorocyclohexan-1-ol (60 mg, 0.397 mmol, 1 eq) and methyl (R)-3-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (215.4 mg, 0.476mol, 1.2 eq) in DMSO (5 mL) was added DIEA (256.5 mg, 1.98 mmol, 5 eq), and the mixture was stirred at 100 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature, diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep- HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water (ammonia hydroxide v/v)-ACN];gradient:40%-70% B over 10 min ) to give methyl (R)-3-(6-(5- chloro-2-(((1R*,2R*)-4,4-difluoro-2-hydroxycyclohexyl)amino)pyrimidin-4-yl)-4-fluoro- 1-isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (100 mg, 0.176 mmol, 44% yield) as a white solid. LCMS: 567.3 [M+H]+. Step 2: Preparation of methyl (R)-3-(6-(5-chloro-2-(((1R,2R)-4,4-difluoro-2- hydroxycyclohexyl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate and methyl (R)-3-(6-(5-chloro-2-(((1S,2S)-4,4-difluoro-2- hydroxycyclohexyl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate [00437] Methyl (R)-3-(6-(5-chloro-2-(((1R*,2R*)-4,4-difluoro-2- hydroxycyclohexyl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate (100 mg, 0.176 mmol) was further purified by prep-SFC (column: DAICEL CHIRALPAK AS(250mm*30mm,10um);mobile phase: [CO2- MeOH(0.1%NH3H2O)];B%:35%, isocratic elution mode) to afford methyl (R)-3-(6-(5- chloro-2-(((1R,2R)-4,4-difluoro-2-hydroxycyclohexyl)amino)pyrimidin-4-yl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (33.7 mg, 34% yield) as a light yellow solid and methyl (R)-3-(6-(5-chloro-2-(((1S,2S)-4,4-difluoro-2- hydroxycyclohexyl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate (39.2 mg, 39% yield) as a light yellow solid. [00438] Methyl (R)-3-(6-(5-chloro-2-(((1R,2R)-4,4-difluoro-2- hydroxycyclohexyl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate: LCMS: 567.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ = 8.41 (s, 1H), 8.06 - 7.83 (m, 1H), 7.55 - 7.25 (m, 2H), 5.08 (br s, 1H), 5.01 - 4.87 (m, 1H), 3.93 (td, J = 7.2, 13.6 Hz, 1H), 3.82 (br dd, J = 7.6, 10.4 Hz, 2H), 3.74 - 3.65 (m, 2H), 3.62 (s, 3H), 3.59 - 3.52 (m, 1H), 3.49 - 3.40 (m, 1H), 2.40 - 2.14 (m, 3H), 2.06 - 1.80 (m, 4H), 1.60 (br d, J = 6.8 Hz, 6H), 1.52 - 1.38 (m, 1H) ppm. [00439] Methyl (R)-3-(6-(5-chloro-2-(((1S,2S)-4,4-difluoro-2- hydroxycyclohexyl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate: LCMS: 567.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ = 8.42 (s, 1H), 8.05 - 7.81 (m, 1H), 7.42 (br d, J = 6.4 Hz, 2H), 5.06 (br d, J = 4.8 Hz, 1H), 4.95 (td, J = 7.2, 14.0 Hz, 1H), 3.98 - 3.87 (m, 1H), 3.82 (br dd, J = 7.6, 10.0 Hz, 2H), 3.75 - 3.64 (m, 2H), 3.62 (s, 3H), 3.59 - 3.51 (m, 1H), 3.48 - 3.41 (m, 1H), 2.39 - 2.16 (m, 3H), 2.05 - 1.82 (m, 4H), 1.60 (d, J = 6.8 Hz, 6H), 1.51 - 1.38 (m, 1H) ppm. Example 19: Synthesis of (3S,4R)-4-((5-chloro-4-(4-fluoro-1-((1R,2R)-2-hydroxy- 2-methylcyclopentyl)-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)tetrahydro-2H-pyran-3-ol (compound 274) Step 1: Preparation of (1R,2R)-2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-methyl- 1H-benzo[d]imidazol-1-yl)-1-methylcyclopentan-1-ol [00440] The mixture of (1R,2R)-2-(4-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)-1-methylcyclopentan-1-ol (420 mg, 1.12 mmol, 1 eq), 2,4,5-trichloropyrimidine (309 mg, 1.68 mmol, 1.5 eq) and K2CO3 (465 mg, 3.37 mmol, 3 eq) in aqueous dioxane (5 mL)-H2O (0.5 mL) was degassed and backfilled with N2 for 3 times, followed by the addition of Pd(PPh3)4 (130 mg, 0.112 mmol, 0.1 eq) under N2 atmosphere. The mixture was then stirred at 90 °C for 2 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature, filtered through a short pad of celite and rinsed with dioxane (5 mL). The combined filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford (1R,2R)-2-(6- (2,5-dichloropyrimidin-4-yl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-1- methylcyclopentan-1-ol (370 mg, 83% yield) as a yellow solid. LCMS: 395.1 [M+H]+. Step 2: Preparation of (3S,4R)-4-((5-chloro-4-(4-fluoro-1-((1R,2R)-2-hydroxy-2- methylcyclopentyl)-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)tetrahydro-2H-pyran-3-ol [00441] To a solution of (1R,2R)-2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2- methyl-1H-benzo[d]imidazol-1-yl)-1-methylcyclopentan-1-ol (50 mg, 0.126 mmol, 1 eq) and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol (29 mg, 0.189 mmol, 1.5 eq, HCl) in DMSO (0.5 mL) was added DIEA (49 mg, 0.379 mmol, 3 eq), and the mixture was stirred at 90 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was concentrated in vacuo. The resulting residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:19%-49% B over 10 min ) to give (3S,4R)-4-((5-chloro-4- (4-fluoro-1-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-methyl-1H-benzo[d]imidazol- 6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (19.83 mg, 32% yield) as a yellow solid. LCMS: 476.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1 H), 7.79 (s, 1 H), 7.52 - 7.32 (m, 2 H), 5.05 (s, 1 H), 4.93 (s, 1 H), 4.72 (t, J = 8.8 Hz, 1 H), 3.89 - 3.76 (m, 3 H), 3.60 - 3.38 (m, 2 H), 3.08 - 2.95 (m, 1 H), 2.67 (s, 3 H), 2.47 - 2.40 (m, 1 H), 2.38 - 2.28 (m, 1 H), 2.01 - 1.79 (m, 5 H), 1.60 - 1.38 (m, 1 H), 0.90 (s, 3 H) ppm. Example 20: Synthesis of 6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)-8-fluoro-4-isopropyl-2-methylisoquinolin- 1(2H)-one (compound 277) Step 1: Preparation of 6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4-isopropyl-2- methylisoquinolin-1(2H)-one [00442] The mixture of 8-fluoro-4-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoquinolin-1(2H)-one (350 mg, 1.02 mmol, 1 eq), 2,4,5- trichloropyrimidine (187 mg, 1.02 mmol, 1 eq), Pd(PPh3)4 (117.8 mg, 0.102 mmol, 0.1 eq) and Na2CO3 (324.22 mg, 3.06 mmol, 3 eq) in dioxane (15 mL) and H2O (1.5 mL) was degassed and backfilled with N2 for 3 times, and then stirred at 90 °C for 4 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The mixture was filtered, rinsed with dioxane (10 mL) and the combined filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 6-(2,5-dichloropyrimidin-4- yl)-8-fluoro-4-isopropyl-2-methylisoquinolin-1(2H)-one (337 mg, 90% yield) as a yellow solid. LCMS: 366.0 [M+H]+. Step 2: Preparation of 6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-8-fluoro-4-isopropyl-2-methylisoquinolin-1(2H)-one [00443] To a solution of 6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4-isopropyl-2- methylisoquinolin-1(2H)-one (50 mg, 0.136 mmol, 1 eq) in DMSO (1 mL) was added DIEA (53 mg, 0.409 mmol, 3 eq) and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol (31.5 mg, 0.205 mmol, 1.5 eq, HCl), and the mixture was stirred at 90 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was concentrated in vacuo. The resulting residue was purified by prep-HPLC (FA condition:column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:33%-63% B over 10 min) to give 6-(5-chloro-2-(((3S,4R)-3- hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-8-fluoro-4-isopropyl-2- methylisoquinolin-1(2H)-one (23.09 mg, 37% yield) as a yellow solid. LCMS: 447.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.06 - 7.85 (m, 1H), 7.64 - 7.48 (m, 2H), 7.44 - 7.37 (m, 1H), 4.99 - 4.87 (m, 1H), 3.85 - 3.76 (m, 3H), 3.50 (s, 4H), 3.10 - 2.98 (m, 2H), 2.01 - 1.89 (m, 1H), 1.56 - 1.45 (m, 1H), 1.27 (br d, J = 6.6 Hz, 6H) ppm. Example 21: Synthesis of 2-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin- 4(5H)-one (compound 278) Step 1: Preparation of 2-(2-chloro-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5- dimethylthieno[3,2-c]pyridin-4(5H)-one [00444] A mixture of 7-isopropyl-3,5-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)thieno[3,2-c]pyridin-4(5H)-one (430 mg, 1.24 mmol, 1 eq), 2,4- dichloro-5-fluoropyrimidine (310 mg, 1.86 mmol, 1.5 eq), K3PO4 (525.6 mg, 2.48 mmol, 2 eq) and CataCXium A Pd G2 (CAS: 1375477-29-4) (82.8 mg, 0.124 mmol, 0.1 eq) (82.8 mg, 0.124 mmol, 0.1 eq) in dioxane (7 mL) and H2O (0.7 mL) was degassed and backfilled with N2 for 3 times and stirred at 100 °C for 1 hour under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was filtered via a short pad of celite, rinsed with dioxane (7 mL) and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 2-(2-chloro-5- fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one (290 mg, 66% yield) as a yellow solid. LCMS: 352.0, 354.0 [M+H]+. Step 2: Preparation of 2-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one [00445] To a solution of 2-(2-chloro-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5- dimethylthieno[3,2-c]pyridin-4(5H)-one (50 mg, 0.142 mmol, 1 eq), (3S,4R)-4- aminotetrahydro-2H-pyran-3-ol (33 mg, 0.214 mmol, 1.5 eq, HCl) in DMSO (1 mL) was added DIEA (36 mg, 0.284 mmol, 2 eq), and the mixture was stirred at 90 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The residue was diluted with H2O (5 mL) and extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Welch Xtimate C18150*25mm*5um;mobile phase: [water(FA)-ACN];gradient:34%-64% B over 10 min) to give 2-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one (15.34 mg, 25% yield) as a light yellow solid. LCMS: 433.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 2.8 Hz, 1H), 7.51 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 4.91 (d, J = 5.2 Hz, 1H), 3.89 - 3.69 (m, 3H), 3.58 - 3.44 (m, 4H), 3.03 (t, J = 10.4 Hz, 1H), 2.87 (td, J = 6.8, J = 13.6 Hz, 1H), 2.66 (d, J = 2.4 Hz, 3H), 2.03 - 1.88 (m, 1H), 1.56 - 1.40 (m, 1H), 1.29 (d, J = 6.8 Hz, 6H) ppm. Example 22: Synthesis of (3S,4R)-4-((5-chloro-4-(2-((S)-2,2- difluorocyclopropyl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin- 2-yl)amino)tetrahydro-2H-pyran-3-ol (compound 282) and (3S,4R)-4-((5-chloro- 4-(2-((R)-2,2-difluorocyclopropyl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6- yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (compound 283) Step 1: Preparation of 6-(2,5-dichloropyrimidin-4-yl)-2-(2,2-difluorocyclopropyl)-4- fluoro-1-isopropyl-1H-benzo[d]imidazole [00446] A mixture of 2-(2,2-difluorocyclopropyl)-4-fluoro-1-isopropyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (320 mg, 0.842 mmol, 1 eq), 2,4,5-trichloropyrimidine (232 mg, 1.26 mmol, 1.5 eq), Pd(PPh3)4 (97 mg, 0.084 mmol, 0.1 eq) and K2CO3 (232.6 mg, 1.68 mmol, 2 eq) in dioxane (6 mL) and H2O (0.6 mL) was degassed and backfilled with N2 for 3 times and stirred at 90 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was filtered via a short pad of celite, rinsed with dioxane (6 mL) and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 6- (2,5-dichloropyrimidin-4-yl)-2-(2,2-difluorocyclopropyl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazole (200 mg, 59% yield) as a yellow oil. LCMS: 401.0, 403.0 [M+H]+. Step 2: Preparation of (3S,4R)-4-((5-chloro-4-(2-(2,2-difluorocyclopropyl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol [00447] To a solution of 6-(2,5-dichloropyrimidin-4-yl)-2-(2,2-difluorocyclopropyl)-4- fluoro-1-isopropyl-1H-benzo[d]imidazole (90 mg, 0.224 mmol, 1 eq) and (3S,4R)-4- aminotetrahydro-2H-pyran-3-ol (52 mg, 0.337 mmol, 1.5 eq) in DMSO (1 mL) was added DIEA (58 mg, 0.448mol, 2 eq), and the mixture was stirred at 100 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature. The residue was diluted with H2O (5 mL) and extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:39%-69% B over 10 min) to give (3S,4R)-4-((5-chloro-4-(2-(2,2-difluorocyclopropyl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (55 mg, 0.114 mmol, 50% yield) as a white solid. LCMS: 482.1 [M+H]+. Step 3: Preparation of (3S,4R)-4-((5-chloro-4-(2-((S)-2,2-difluorocyclopropyl)-4- fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H- pyran-3-ol and (3S,4R)-4-((5-chloro-4-(2-((R)-2,2-difluorocyclopropyl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol [00448] The (3S,4R)-4-((5-chloro-4-(2-(2,2-difluorocyclopropyl)-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (55 mg, 0.114 mmol) was further purified by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [CO2-EtOH(0.1%NH3H2O)];B%:50%, isocratic elution mode) to afford (3S,4R)-4-((5-chloro-4-(2-((S)-2,2- difluorocyclopropyl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- yl)amino)tetrahydro-2H-pyran-3-ol (28 mg, 51% yield) as an off-white solid and (3S,4R)-4-((5-chloro-4-(2-((R)-2,2-difluorocyclopropyl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (23 mg, 43% yield) as an off-white solid. [00449] (3S,4R)-4-((5-chloro-4-(2-((S)-2,2-difluorocyclopropyl)-4-fluoro-1-isopropyl- 1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol: LCMS: 582.2 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.08 - 7.85 (m, 1H), 7.56 - 7.27 (m, 2H), 4.97 (td, J = 6.8, J = 13.8 Hz, 2H), 3.82 (dd, J = 5.2, J = 10.8 Hz, 3H), 3.69 - 3.57 (m, 1H), 3.50 (d, J = 3.6 Hz, 1H), 3.31 - 3.27 (m, 1H), 3.03 (t, J = 10.4 Hz, 1H), 2.47 - 2.38 (m, 1H), 2.34 - 2.22 (m, 1H), 2.03 - 1.87 (m, 1H), 1.66 (d, J = 6.8 Hz, 3H), 1.59 (d, J = 6.8 Hz, 3H), 1.55 - 1.44 (m, 1H) ppm. [00450] (3S,4R)-4-((5-chloro-4-(2-((R)-2,2-difluorocyclopropyl)-4-fluoro-1-isopropyl- 1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol: LCMS: 482.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.05 - 7.87 (m, 1H), 7.54 - 7.29 (m, 2H), 5.10 - 4.82 (m, 2H), 3.82 (dd, J = 5.2, 10.8 Hz, 3H), 3.68 - 3.57 (m, 1H), 3.55 - 3.46 (m, 1H), 3.25 - 3.18 (m, 1H), 3.03 (t, J = 10.4 Hz, 1H), 2.41 (d, J = 2.4 Hz, 1H), 2.31 - 2.21 (m, 1H), 2.03 - 1.87 (m, 1H), 1.66 (d, J = 6.8 Hz, 3H), 1.59 (d, J = 6.8 Hz, 3H), 1.53 - 1.47 (m, 1H) ppm. Example 23: Synthesis of (1S,2S,3R,5R)-3-((5-chloro-4-(8-fluoro-3-(2- hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol (compound 295) and (1R,2R,3S,5S)-3-((5-chloro-4- (8-fluoro-3-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol (compound 296) Step 1: preparation of 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoroquinolin-3-yl)propan- 2-ol [00451] The mixture of 2-(8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinolin-3-yl)propan-2-ol (340 mg, 1.03 mmol, 1 eq), 2,4,5-trichloropyrimidine (282.5 mg, 1.54 mmol, 1.5 eq), Pd(PPh3)4 (118.6 mg, 0.103 mmol, 0.1 eq), K2CO3 (425.65 mg, 3.08 mmol, 3 eq) in dioxane (5 mL) and H2O (0.5 mL) was degassed and backfilled with N2 for 3 times, and then stirred at 90 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature, filtered via a short pad of celite, rinsed with dioxane (5 mL) and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 2-(6-(2,5-dichloropyrimidin-4-yl)-8- fluoroquinolin-3-yl)propan-2-ol (300 mg, 82% yield). LCMS: 352.0 [M+H]+. Step 2: preparation of (1S*,2S*,3R*,5R*)-3-((5-chloro-4-(8-fluoro-3-(2- hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol [00452] To a solution of 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoroquinolin-3- yl)propan-2-ol (90 mg, 0.256 mmol, 1 eq) in DMSO (2 mL) was added (1S*,2S*,3R*,5R*)-3-amino-8-oxabicyclo[3.2.1]octan-2-ol (73.2 mg, 0.511 mmol, 2 eq) and DIEA (99 mg, 0.767 mmol, 3 eq), and the mixture was stirred at 100 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The resulting residue was then purified by prep-HPLC {column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(FA)-ACN]; gradient:28%-58% B over 15 min} to afford (1S*,2S*,3R*,5R*)-3-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)quinolin- 6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (40 mg, 0.87 mmol, 34 % yield) as a yellow solid. LCMS: 459.1 [M+H]+. Step 3: preparation of (1S,2S,3R,5R)-3-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2- yl)quinolin-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol and (1R,2R,3S,5S)-3-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)quinolin-6- yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol [00453] (1S*,2S*,3R*,5R*)-3-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2- yl)quinolin-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (40 mg, 0.087 mmol) was further purified by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [CO2-ACN/EtOH(0.1% NH3.H2O)];B%:70%, isocratic elution mode) to give (1S,2S,3R,5R)-3-((5-chloro-4-(8-fluoro-3-(2- hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol (18.02 mg, 44% yield) as an off-white solid and (1R,2R,3S,5S)-3-((5-chloro-4-(8- fluoro-3-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)-8- oxabicyclo[3.2.1]octan-2-ol (16.52 mg, 41% yield) as an off-white solid. [00454] (1S,2S,3R,5R)-3-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)quinolin-6- yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol. LCMS: 459.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.22 - 9.16 (m, 1H), 8.58 - 8.51 (m, 1H), 8.50 - 8.43 (m, 1H), 8.38 - 8.19 (m, 1H), 7.99 - 7.76 (m, 1H), 7.60 (s, 1H), 5.55 - 5.44 (m, 1H), 4.90 (br d, J = 3.0 Hz, 1H), 4.34 - 4.24 (m, 1H), 4.15 (s, 1H), 3.90 (s, 1H), 3.65 - 3.50 (m, 1H), 2.02 - 1.96 (m, 1H), 1.91 - 1.77 (m, 2H), 1.65 (br s, 2H), 1.58 (s, 6H), 1.54 - 1.46 (m, 1H) ppm. [00455] (1R,2R,3S,5S)-3-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)quinolin- 6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol. LCMS: 459.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.19 (d, J = 2.1 Hz, 1H), 8.57 - 8.52 (m, 1H), 8.50 - 8.43 (m, 1H), 8.38 - 8.18 (m, 1H), 7.96 - 7.75 (m, 1H), 7.60 - 7.46 (m, 1H), 5.57 - 5.43 (m, 1H), 5.08 - 4.88 (m, 1H), 4.29 (br d, J = 3.4 Hz, 1H), 4.09 (dd, J = 4.7, 6.3 Hz, 1H), 4.03 - 3.91 (m, 1H), 3.64 - 3.50 (m, 1H), 2.02 - 1.97 (m, 1H), 1.91 - 1.78 (m, 2H), 1.73 - 1.62 (m, 2H), 1.58 (s, 6H), 1.55 - 1.48 (m, 1H) ppm. Example 24: Synthesis of 2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-7-(5- fluoro-2-(((1S,2S,3R,5R)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3- yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one (compound 291) and 2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-7-(5-fluoro-2- (((1R,2R,3S,5S)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)- 1-isopropyl-3-methylquinolin-4(1H)-one (compound 292) Step 1: 7-(2-chloro-5-fluoropyrimidin-4-yl)-2-(((3S,5S)-3,5- dimethylmorpholino)methyl)-1-isopropyl-3-methylquinolin-4(1H)-one [00456] The mixture of 2-[[(3S,5S)-3,5-dimethylmorpholin-4-yl]methyl]-1-isopropyl- 3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-one (239 mg, 0.526mmol, 1 eq), 2,4-dichloro-5-fluoro-pyrimidine (131.7 mg, 0.789 mmol, 1.5 eq), K2CO3 (218 mg, 1.58 mmol, 3 eq) and Pd(PPh3)4 (60.8 mg, 0.053 mmol, 0.1 eq) in dioxane (5 mL) and H2O (0.5 mL) was stirred at 90 °C for 16 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature, filtered via a short pad of celite, rinsed with dioxane (5 mL) and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chouromatography to give 7-(2-chloro-5-fluoropyrimidin-4-yl)-2-(((3S,5S)- 3,5-dimethylmorpholino)methyl)-1-isopropyl-3-methylquinolin-4(1H)-one (143 mg, 59% yield) as a yellow oil. LCMS: 459.3 [M+H]+. Step 2: 2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-7-(5-fluoro-2- (((1S*,2S*,3R*,5R*)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-1- isopropyl-3-methylquinolin-4(1H)-one [00457] A mixture of 7-(2-chloro-5-fluoro-pyrimidin-4-yl)-2-[[(3S,5S)-3,5- dimethylmorpholin-4-yl]methyl]-1-isopropyl-3-methyl-quinolin-4-one (130 mg, 0.283 mmol, 1 eq), (1S*,2S*,3R*,5R*)-3-amino-8-oxabicyclo[3.2.1]octan-2-ol (81 mg, 0.565 mmol, 2 eq) and DIPEA (73.22 mg, 0.566 mmol, 2 eq) in DMSO (5 mL) was stirred at 100 °C for 12 hours under N2 atmosphere. After the completion of the reaction, the mixture was cooled to room temperature, and the volatiles were removed under reduced pressure. The resulting residue was purified by prep-HPLC directly (column: Phenomenex luna C18150*40mm* 15um;mobile phase: [water(FA)- ACN];gradient:50%-80% B over 10 min) and lyophilization to give 2-(((3S,5S)-3,5- dimethylmorpholino)methyl)-7-(5-fluoro-2-(((1S*,2S*,3R*,5R*)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)- one (65 mg, 0.111 mmol, 39% yield, 96.8% purity) as a white solid. LCMS: 566.4 [M+H]+. Step 11: 2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-7-(5-fluoro-2-(((1S,2S,3R,5R)- 2-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-1-isopropyl-3- methylquinolin-4(1H)-one (compound 291) and 2-(((3S,5S)-3,5- dimethylmorpholino)methyl)-7-(5-fluoro-2-(((1R,2R,3S,5S)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)- one (compound 292) [00458] The racemic compound 2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-7-(5- fluoro-2-(((1S*,2S*,3R*,5R*)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3- yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one (65 mg, 0.114 mol, 1 eq) was further purified by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [CO2-ACN/i-PrOH(0.1% NH3H2O)];B%:65%, isocratic elution mode) to give 2-(((3S,5S)-3,5- dimethylmorpholino)methyl)-7-(5-fluoro-2-(((1S,2S,3R,5R)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)- one (6.99 mg, 7.70% yield) as a white solid and 2-(((3S,5S)-3,5- dimethylmorpholino)methyl)-7-(5-fluoro-2-(((1R,2R,3S,5S)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)- one (18.52 mg, 28% yield) as a white solid. [00459] 2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-7-(5-fluoro-2-(((1S,2S,3R,5R)- 2-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-1-isopropyl-3- methylquinolin-4(1H)-one. LCMS: 566.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.49 (d, J = 3.6 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 5.63 - 5.48 (m, 1H), 4.96 (d, J = 4.8 Hz, 1H), 4.33 - 4.25 (m, 1H), 4.19 (d, J = 15.2 Hz, 1H), 4.10 (dd, J = 4.4, 6.8 Hz, 1H), 4.04 - 3.93 (m, 1H), 3.86 (d, J = 15.2 Hz, 1H), 3.60 (br dd, J = 2.8, 10.8 Hz, 3H), 3.29 - 3.23 (m, 2H), 2.80 (br s, 2H), 2.23 (s, 3H), 2.05 - 1.97 (m, 1H), 1.86 (br dd, J = 5.2, 11.2 Hz, 2H), 1.78 (br d, J = 6.8 Hz, 3H), 1.70 (br d, J = 7.2 Hz, 3H), 1.68 - 1.49 (m, 3H), 1.00 (d, J = 6.4 Hz, 6H) ppm. [00460] 2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-7-(5-fluoro-2-(((1R,2R,3S,5S)- 2-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-1-isopropyl-3- methylquinolin-4(1H)-one. LCMS: 566.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.60 (br s, 1H), 8.49 (d, J = 3.6 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.86 (br d, J = 8.4 Hz, 1H), 7.25 (br d, J = 8.4 Hz, 1H), 5.63 - 5.48 (m, 1H), 4.97 (d, J = 4.8 Hz, 1H), 4.32 - 4.27 (m, 1H), 4.19 (br d, J = 15.2 Hz, 1H), 4.10 (dd, J = 4.4, 6.8 Hz, 1H), 4.00 (br dd, J = 2.0, 4.4 Hz, 1H), 3.86 (br d, J = 15.2 Hz, 1H), 3.64 - 3.56 (m, 3H), 3.31 - 3.23 (m, 2H), 2.79 (br s, 2H), 2.23 (s, 3H), 2.06 - 1.98 (m, 1H), 1.91 - 1.82 (m, 2H), 1.79 (br d, J = 6.8 Hz, 3H), 1.69 (br d, J = 7.2 Hz, 3H), 1.68 - 1.50 (m, 3H), 1.00 (br d, J = 6.4 Hz, 6H) ppm. [00461] Additional compounds prepared according to the methods described in the Examples are depicted in the Table below.
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Example 11: Phospho-Rb expression inhibition in MCF7 cells quantified by in- cell Western [00462] MCF7 cells were obtained from American Type Culture Collection (ATCC, HTB-22). MCF7 cells were plated in 96-well plates (VWR #10062-900, or Corning #3904) in 90 uL culture medium at a density of 20,000 cells/well in the DMEM growth medium containing 10% FBS and 1% Penicillin Streptomycin, and then incubated at 37°C overnight. The following day, the test compound was administered to the cells by using 1000x compound stock solution prepared in DMSO at various concentrations.1000x compound stock solution was first diluted in culturing medium to 10x, then 10 uL compound medium was added to each well in the cell plates. After administration of the compound, the cells were then incubated at 37°C for 24 hours. Upon completion, the cells were washed with PBS briefly.150 uL/well of 4% formaldehyde was added and the plates were incubated at room temperature for 20 mins. The cells were washed with PBS briefly, and permeabilized with 150 uL/well of ice cold 100% methanol for 10 mins. The cells were washed with PBS briefly and blocked with 100 uL/well LI-COR blocking buffer for 1 hr at room temperature with gentle shaking. The cells were incubated overnight at 4°C with 50 uL primary antibody rabbit anti-Phospho-Rb (Ser807/811) (1: 500, Cell Signaling, #8516) and anti-Rb (1:200, Santa Cruz, sc-73598) diluted in Intercept Blocking Buffer (LI-COR, #927-60001) containing 0.1% Tween 20. The next day, the cells were washed with 200 uL PBS containing 0.1% Tween 20, 5 x 5 mins at room temperature with gentle shaking, and incubated with 50 uL secondary antibody, IRDye® 800CW Goat anti- Rabbit IgG (1:1000, LI-COR, #926-32211) and IRDye® 680RD Goat anti-Mouse IgG (1:1000, LI-COR, #926-68070), in LI-COR blocking buffer with 0.2% Tween 20 for 1 hr at room temperature with gentle shaking. The cells were washed with 200 uL PBS containing 0.1% Tween 20, 5 x 5 mins at room temperature with gentle shaking. The cells were washed with PBS for 5 mins.100 uL fresh PBS was added to each well and the plates were imaged on a LI-COR Odyssey CLX plate reader. Example 12: Cell growth inhibition of 22RV1 cells [00463] 22RV1 cells were obtained from American Type Culture Collection (ATCC, CRL-2505). 22RV1 cells were seeded in 96-well plates at 1000 cells/well in 90 μL of RPMI1640 growth medium containing 10% FBS and 1% Penicillin Streptomycin, and then incubated at 37°C overnight. The following day, the test compound was administered to the cells by using 1000x compound stock solution prepared in DMSO at various concentrations.1000x compound stock solution was first diluted in culturing medium to 10x, then 10 uL compound medium was added to each well in the cell plates. After administration of the compound, the cells were then incubated at 37°C for 5 days. Upon completion, the plates were equilibrated at room temperature for approximately 10 minutes.100 uL of CellTiter-Glo® Reagent (Promega) was added to each well. The plates were then incubated at room temperature for 10 minutes and luminescence was recorded by EnSpire plate reader (PerkinElmer). [00464] The inhibition profile of exemplary compounds disclosed herein against MCF and 22RV1 cells is summarized in Table 4 below. [00465] Table 4: Inhibition of cellular Rb phosphorylation in MCF7 cells and inhibition of growth in 22RV1 cells by Exemplary Compounds
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001

Claims

WHAT IS CLAIMED IS: 1. At least one entity selected from compound of Formula (I), tautomers, stereoisomers or a mixture of stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivative thereof:
Figure imgf000236_0001
wherein: Ring A is selected from: ,
Figure imgf000236_0002
, , , , , , , ,
Figure imgf000237_0001
Figure imgf000238_0001
, ,
Figure imgf000239_0001
wherein RC is selected from C1-C6 alkyl and C3-C6 cycloalkyl and RD is selected from C1-C6 alkyl, C3-C6 cycloalkyl, 6- to 10-membered aryl, 4- to 10- membered heteroaryl, and 3- to 6-membered heterocycle; X2 is selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, and -CN; Ring B is selected from:
Figure imgf000239_0002
; wherein: represents a single bond or a double bond; Z is C or N; Q1 is N or CRA, wherein RA is selected from hydrogen, halogen, and - CN; Q2 and W2 are independently selected from CRE and NRE, wherein one and only one of Q2 or W2 must be NRE; W3 is selected from CRE and N; Q3 is selected from NRE and CRE; each RE is independently selected from hydrogen, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1-3 RF, wherein each RF is independently selected from hydroxy, halogen, and C1-C3 alkyl; R1 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, C5-C8 bicyclic alkyl, -C1-C3 alkylene-(3- to 8- membered heterocycle), and 3- to 8-membered heterocycle, wherein the C1- C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, C5-C8 bicyclic alkyl, -C1-C3 alkylene-(3- to 8-membered heterocycle), and 3- to 8- membered heterocycle is each optionally substituted with 1-3 R1A, wherein each R1A is independently selected from halogen, hydroxy, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cyclic alkoxy, -N(RK)2, -C(=O)ORG, -S(=O)2RG, and -N(RK)C(=O)ORG, wherein each RK is independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl and each RG is independently selected from C1-C6 alkyl, and C3-C6 cycloalkyl; R2 is selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cyclic alkoxy, and C1-C6 haloalkoxy; W1 is selected from S, NRB, CRB, and 3- to 6-membered cycloalkyl, wherein the 3- to 6-membered cycloalkyl is optionally substituted with 1-3 RH and wherein RB is selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1- 3 RH, wherein each RH is independently selected from hydroxy, halogen, and C1-C3 alkyl; or W1 and R1 may be taken together with the C atom to which both are attached to form a 6-membered heterocycle, wherein the 6-membered heterocycle is optionally substituted with 1-4 groups independently selected from C1-C6 alkyl, hydroxy, and oxo; or W1, Z, R2 and the C atom to which R2 is directly attached may be taken together to form a 6-membered heterocycle, wherein the 6-membered heterocycle is optionally substituted with 1-4 groups independently selected from C1-C6 alkyl, hydroxy, and oxo; and X1 is selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, and -CN; with the proviso that when the compound of Formula (I) is selected from
Figure imgf000241_0001
then Z is N, R2 is selected from C3 alkyl, or R1 is substituted with at least one R1A selected from oxo, -C(=O)ORG, -S(=O)2RG, and -N(RK)C(=O)ORG.
2 ,
Figure imgf000241_0002
3. The at least one entity according to claim 1, wherein Ring A is selected from: ,
Figure imgf000241_0003
4. The at least one entity according to claim 1, wherein Ring A is selected from: ,
Figure imgf000242_0001
, , , , , ,
Figure imgf000243_0001
, , , , , , ,
Figure imgf000244_0001
5. The at least one entity according to any one of claims 1, 2, and 4, wherein RC is selected from C1-C3 alkyl and C3-C6 cycloalkyl.
6. The at least one entity according to any one of claims 1, 2, 4, and 5, wherein RD is selected from C1-C3 alkyl, C3-C4 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocycle.
7. The at least one entity according to claim 1, wherein Ring A is selected from: ,
Figure imgf000245_0001
, , , , ,
Figure imgf000246_0001
8. The at least one entity according to any one of claims 1, 2, and 4 to 6, wherein RC is methyl.
9. The at least one entity according to any one of claims 1, 2, 4, and 5, wherein RD is selected from C1-C6 alkyl, C3-C6 cycloalkyl, 6- to 8-membered aryl, 5- to 6- membered heteroaryl, and 6-membered heterocycle.
10. The at least one entity according to claim 9, wherein RD is selected from methyl, ethyl, i-propyl, cyclopropyl, phenyl, pyridinyl, morpholinyl, and imidazolyl.
11. The at least one entity according to any one of claims 1 to 10, wherein X2 is selected from hydrogen, F, Cl, Br, methyl, -CHF2, -CF3, and -CN.
12. The at least one entity according to any one of claims 1 to 11, wherein Ring B is
Figure imgf000246_0002
.
13. The at least one entity according to claim 12, wherein Ring B is selected from: ,
Figure imgf000247_0001
wherein Ring C is selected from 3- to 6-membered cycloalkyl, wherein the 3- to 6- membered cycloalkyl is optionally substituted with 1-3 RH.
14. The at least one entity according to claim 12, wherein Ring B is selected from:
Figure imgf000247_0002
.
15. The at least one entity according to any one of claims 13 and 14, wherein each RH is independently selected from hydrogen, methyl, and i-propyl.
16. The at least one entity according to any one of claims 1 to 13, wherein each RB is selected from hydrogen, halogen, methyl, and i-propyl.
17. The at least one entity according to claim 12, wherein W1 and R1 are taken together with the C atom to which both are attached to form a 6-membered heterocycle selected from morpholine, piperazine, and piperidine, wherein the N atom of morpholine, piperazine, and piperidine rings is adjacent to Z, and wherein the piperazine is optionally substituted with 1-2 groups independently selected from methyl and oxo and wherein the piperidine is optionally substituted with 1-4 groups independently selected from methyl and hydroxy.
18. The at least one entity according to claim 12, wherein W1, Z, R2 and the C atom to which R2 is directly attached are taken together to form a 6-membered heterocycle selected from morpholine, piperidine, thiomorpholine, and piperazine, wherein the N atom of the morpholine, piperidine, thiomorpholine, and piperazine rings is adjacent to Z, and wherein the piperazine is optionally substituted with 1-2 groups independently selected from methyl and oxo.
19. The at least one entity according to any one of claims 12 to 17, wherein R2 is selected from hydrogen, halogen, methyl, i-propyl, -OMe, and -OCF3.
20. The at least one entity according to any one of claims 1 to 11, wherein Ring B is
Figure imgf000248_0001
.
21. The at least one entity according to claim 20, wherein Ring B is selected from:
Figure imgf000248_0002
.
22. The at least one entity according to claim 20, wherein Ring B is selected from:
Figure imgf000248_0003
.
23. The compound according to any one of claims 1 to 11, wherein Ring B is
Figure imgf000249_0001
.
24. The at least one entity according to claim 23, wherein Ring B is selected from
Figure imgf000249_0002
.
25. The at least one entity according to claim 24, wherein Ring B is selected from
Figure imgf000249_0003
.
26. The at least one entity according to any one of claims 1 to 11, wherein Ring B is
Figure imgf000249_0004
.
27. The at least one entity according to claim 26, wherein Ring B is
Figure imgf000249_0005
.
28. The at least one entity according to claim 26, wherein Ring B is
Figure imgf000250_0001
.
29. The at least one entity according to any one of claims 1 to 11, 20 to 24, 26, and 27, wherein RE is independently selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl.
30. The at least one entity according to any one of claims 12 to 29, wherein X1 is selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, and -CN.
31. The at least one entity according to claim 30, wherein X1 is selected from hydrogen, F, Cl, Br, methyl, -CHF2, and -CN.
32. The at least one entity according to any one of claims 1 to 11, wherein Ring B is selected from: ,
Figure imgf000250_0002
Figure imgf000251_0001
33. The at least one entity according to any one of claims 1 to 16 and 18 to 32, wherein R1 is selected from: ,
Figure imgf000252_0001
, wherein RT is selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl and wherein C1-C6 alkyl of R1 is optionally substituted with 1-2 R1A, wherein each R1A is independently selected from halogen, -NH2, hydroxy, C1-C6 alkoxy, and C1-C6 alkyl. 34. The at least one entity according to any one of claims 1 to 16 and 18 to 32, wherein R1 is selected from: m
Figure imgf000253_0001
,
Figure imgf000254_0001
35. The at least one entity according to claim 1, wherein the at least one entity is selected from: (1S,2S,3R,5R)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol, (1R,2R,3S,5S)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol, (1S,2S,3R,5R)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-(methylsulfonyl)-8- azabicyclo[3.2.1]octan-2-ol, (1R,2R,3S,5S)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-(methylsulfonyl)-8- azabicyclo[3.2.1]octan-2-ol, 6-(5-chloro-2-(((1S,2S,3R,5R)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3- yl)amino)pyrimidin-4-yl)-4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-indole-3- carbonitrile, methyl (R)-3-(6-(5-chloro-2-(((1S,2S,3R,5R)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3- yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1- carboxylate, methyl (S)-3-(6-(5-chloro-2-(((1S,2S,3R,5R)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3- yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1- carboxylate, methyl (R)-3-(6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1- carboxylate, (1S,2S,3R,5R)-3-((5-fluoro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol, 6-(5-chloro-2-(((1S,2S,3R,5R)-2-hydroxy-8-(methylsulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-4-fluoro-2-(2-hydroxypropan-2-yl)- 1-isopropyl-1H-indole-3-carbonitrile, (1S,2S,3R,5R)-3-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl-6-d)amino)-8-oxabicyclo[3.2.1]octan-2-ol, 2-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-7- isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one, (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)quinoxalin-6-yl)pyrimidin-2- yl)amino)tetrahydro-2H-pyran-3-ol, 2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-7-(5-fluoro-2-(((1S,2S,3R,5R)-2- hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-1-isopropyl-3- methylquinolin-4(1H)-one, 7-(5-chloro-2-(((1S,2S,3R,5R)-2-hydroxy-8-oxabicyclo[3.2.1]octan-3- yl)amino)pyrimidin-4-yl)-2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-1-isopropyl-3- methylquinolin-4(1H)-one, methyl (R)-3-(4-fluoro-6-(5-fluoro-2-(((1S,2S,3R,5R)-2-hydroxy-8- oxabicyclo[3.2.1]octan-3-yl)amino)pyrimidin-4-yl)-1-isopropyl-1H-benzo[d]imidazol-2- yl)pyrrolidine-1-carboxylate, and (1S,2S,3R,5R)-3-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)-4-methylquinolin-6- yl)pyrimidin-2-yl)amino)-8-oxabicyclo[3.2.1]octan-2-ol. 36. A pharmaceutical composition comprising the at least one entity according to any one of claims 1 to 35 and at least one pharmaceutically acceptable carrier or excipient. 37. A method of treating a disease or condition modulated at least in part by cyclin dependent kinases (CDKs) in a subject, the method comprising administering to the subject in need thereof the at least one entity according to any one of claims 1 to 35 or the pharmaceutical composition of claim 36. 38. A method of inhibiting CDK in a subject, the method comprising administering to the subject in need thereof the at least one entity according to any one of claims 1 to 35 or the pharmaceutical composition of claim 36. 39. A method of treating a disease or disorder associated with CDK in a subject, the method comprising administering to the subject in need thereof the at least one entity according to any one of claims 1 to 35 or the pharmaceutical composition of claim 36, wherein the disease or disorder is associated with an amplification of the cyclin E1 (CCNE1) gene and/or overexpression of CCNE1. 40. The method according to any one of claims 37 to 39, wherein the CDK is CDK4. 41. The method according to any one of claims 37, 39, and 40, wherein the disease, disorder, or condition is cancer. 42. The method according to claim 41, wherein the cancer is selected from breast cancer, prostate cancer, bone cancer, brain cancer, colorectal cancer, lung cancer, ovarian cancer, uterine cancer, liposarcoma, liver cancer, rhabdoid cancer, sarcoma, skin cancer, kidney cancer, stomach cancer, pancreatic cancer, esophageal cancer, head and neck cancer, bladder cancer, leukemia, lymphoma, and thyroid cancer. 43. The method according to claim 41, wherein the cancer is selected from breast cancer, ovarian cancer, uterine cancer, and prostate cancer. 44. The method according to claim 41, wherein the cancer is selected from brain cancer, skin cancer, bone cancer, liposarcoma, rhabdoid cancer, and sarcoma. 45. The method according to claim 41, wherein the cancer is lung cancer. 46. The method according to claim 41, wherein the cancer is selected from colorectal cancer, liver cancer, kidney cancer, stomach cancer, pancreatic cancer, and esophageal cancer.
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