Compositions and methods for inhibiting EGFR

Abstract

Disclosed herein are compounds, compositions, and methods for inhibiting EGFR. Also disclosed herein are compounds, compositions, and methods for treating brain cancer (e.g., glioblastoma).

Description

[0001] COMPOSITIONS AND METHODS FOR INHIBITING EGFR

[0002] RELATED APPLICATIONS

[0003] This application claims the benefit of PCT Application No. PCT / CN2024 / 125163, filed October 16, 2024, the contents of which are fully incorporated by reference herein.

[0004] BACKGROUND

[0005] The epidermal growth factor (EGFR) is mutated and / or amplified in -50% of patients with glioblastoma (GBM). However, conventional EGFR inhibitors developed for non-CNS malignancies have failed in clinical trials for GBM. This is attributed to 1) inadequate brain penetration of existing EGFR tyrosine kinase inhibitors (TKIs) and 2) the unique EGFR alterations (e.g., EC domain mutant in GBM vs. kinase domain mutant for lung cancer) in GBM that can significantly impact drug affinity. The use of covalent EGFR TKIs may enable more potent activity against EGFR-driven GBM cells, while potentially sparing normal tissues driven by WT EGFR (e.g., skin and GI). In view of the foregoing, there is an unmet need to develop covalent inhibitors of EGFR tyrosine kinase activity.

[0006] SUMMARY OF THE INVENTION

[0007] In one aspect, the present disclosure relates to a compound having a structure represented by formula (I), or a pharmaceutically acceptable salt thereof:

[0008] I wherein:

[0009] A1is aryl, heteroaryl, or heterocyclyl;

[0010] E is an electrophile;

[0011] X1and X2are each independently N or CR1; as valence and stability permit, each instance of R1is independently selected from hydrogen, halo, alkyl, alkoxy, alkenyl, alkynyl, cyano, nitro, amino, amido, acyl, sulfonyl, sulfonamido, and phosphoryl;

[0012] X3is selected from a bond, -CH2-, -NH-, -S-, and -O-;

[0013] R1is a bond, aryl, heteroaryl, cycloalkyl, or heterocyclyl; and as valence and stability permit, R2is selected from hydrogen, halo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cyano, nitro, amino, amido, acyl, sulfonyl, sulfonamido, and phosphoryl.

[0014] In some embodiments, the present disclosure provides a pharmaceutical composition comprising the compound of the present disclosure and a pharmaceutically acceptable excipient.

[0015] In certain embodiments, the present disclosure provides a method of treating a cancer in a subject in need thereof, comprising administering to the subject an amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0016] BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 shows an exemplary synthesis and structure-activity relationship of the compounds of this disclosure.

[0018] DETAILED DESCRIPTION OF THE INVENTION

[0019] The present disclosure provides compositions and methods for inhibiting EGFR tyrosine kinase activity with inhibitors disclosed herein. The inhibitors disclosed herein may comprise an electrophilic warhead, which facilitates irreversible binding to and inhibition of the EGFR.

[0020] In some aspects, the present disclosure relates to compound having a structure represented by formula (I), or a pharmaceutically acceptable salt thereof:

[0021] I wherein:

[0022] A1is aryl, heteroaryl, or heterocyclyl;

[0023] E is an electrophile;

[0024] X1and X2are each independently N or CR1; as valence and stability permit, each instance of R> is independently selected from hydrogen, halo, alkyl, alkoxy, alkenyl, alkynyl, cyano, nitro, amino, amido, acyl, sulfonyl, sulfonamido, and phosphoryl; X3is selected from a bond, -CH2-, -NH-, -S-, and -O-;

[0025] R1is a bond, aryl, heteroaryl, cycloalkyl, or heterocyclyl; and as valence and stability permit, R2is selected from hydrogen, halo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cyano, nitro, amino, amido, acyl, sulfonyl, sulfonamido, and phosphoryl.

[0026] In some embodiments, the electrophile has a structure represented by a formula selected from:

[0027] (i-46); wherein: indicates the position of attachment to R1; as valence and stability permit, L3is a bond or an C1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with -C=O-, -O-, -S-, -NRL3a-, -NRL3aC(=O)-, -C(=O)NRL3a-, -SC(=O)-, -C(=O)S- -OC(=O)-, -C(=O)O-, -NRL3aC(=S)-, -C(=S)NRL3a-, trans-CRL3b=CRL3b-, cis- CRL3b=CRL3b-, -C=C- -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NRL3a-, - NRL3aS(=O)-, -S(=O)2-, -S(=O)2O-, -OS(=O)2-, -S(=O)2NRL3a-, or -NRL3aS(=O)2- , wherein RL3ais hydrogen, or alkyl, and wherein each occurrence of RL3bis independently hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or two RL3bgroups are joined to form a cycloalkyl or heterocyclyl;

[0028] L4is a bond or alkyl; as valence and stability permit, each instance of RE1, RE2, and RE3is independently hydrogen, halogen, amido, carboxy, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, aryl, heteroaryl, -CN, -CH2OREE, -CH2N(REE)2, -CH2SREE, -OREE, -N(REE)2, -Si(REE)3, or

[0029] -SREE, wherein each instance of REEis independently hydrogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or two REEgroups are joined to form a heterocyclyl; or RE1and RE3, or RE2and RE3, or RE1and RE2are joined to form a cycloalkyl or heterocyclyl;

[0030] RE4is a leaving group or alkyl;

[0031] RE5is halogen;

[0032] RE6is hydrogen or alkyl; each instance of Y is independently O, S, or NRE7, wherein RE7is hydrogen or alkyl; a is 1 or 2; each instance of z is independently 0, 1, 2, 3, 4, 5, or 6; and as valence and stability permit, each instance of RE8, if present, is independently selected from hydrogen, halogen, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -ORD1, -N(RDla)2, and -SRD1, wherein each occurrence of RD1is independently selected from hydrogen, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein each occurrence of RDlais independently selected from hydrogen, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or optionally two instances of RDlaare taken together with their intervening atoms to form a heterocyclyl or heteroaryl ring; or two RE8groups are joined to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring.

[0033] In some embodiments, the electrophile has a structure represented by a formula selected from:

[0034] (i-47) (i-47) wherein: indicates the position of attachment to R1; as valence and stability permit, L3is a bond or an C1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with -C=O-, -O-, -S-, -NRL3a-, -NRL3aC(=O)-, -C(=O)NRL3a-, -SC(=O)-, -C(=O)S- -OC(=O)-, -C(=O)O-, -NRL3aC(=S)-, -C(=S)NRL3a-, trans-CRL3b=CRL3b-, cis- CRL3b=CRL3b-, -C=C- -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NRL3a-, - NRL3aS(=O)-, -S(=O)2-, -S(=O)2O-, -OS(=O)2-, -S(=O)2NRL3a-, or -NRL3aS(=O)2- , wherein RL3ais hydrogen, or alkyl, and wherein each occurrence of RL3bis independently hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or two RL3bgroups are joined to form a cycloalkyl or heterocyclyl; as valence and stability permit, each instance of RE1and RE2is independently hydrogen, halogen, amido, carboxy, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, aryl, heteroaryl, -CN, -CH2OREE, -CH2N(REE)2, -CH2SREE, -OREE, -N(REE)2, -Si(REE)3, or

[0035] -SREE, wherein each instance of REEis independently hydrogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or two REEgroups are joined to form a heterocyclyl; or RE1and RE3, or RE2and RE3, or RE1and RE2are joined to form a cycloalkyl or heterocyclyl; and each instance of Y is independently O, S, or NRE7, wherein RE7is hydrogen or alkyl.

[0036] In certain embodiments, the electrophile has a structure represented by Formula i-1 :

[0037] In certain embodiments, L3is a bond.

[0038] In certain embodiments, RE1is hydrogen. In certain other embodiments, RE1is halogen.

[0039] In certain embodiments, RE2is hydrogen.

[0040] In certain embodiments, RE3is hydrogen.

[0041] In certain embodiments, Y is O.

[0042] In certain embodiments, R1is a bond.

[0043] In certain embodiments, R1is selected from: wherein represents the connection to the remainder of the compound.

[0044] In certain embodiments, R1is selected from: wherein represents the connection to the remainder of the compound.

[0045] In certain embodiments, E is selected from:

[0046] In certain embodiments, E is wherein indicates the connection to variable R1. In certain embodiments, X1is N.

[0047] In certain embodiments, X2is N.

[0048] In certain embodiments, X3is NH.

[0049] In certain embodiments, R1is a bond. In certain embodiments, R1is In certain embodiments, R1is

[0050] In certain embodiments, E is ; wherein indicates the connection to variable R1certain preferred embodiments, E-R1- is

[0051] In certain embodiments, A1is aryl (e.g., phenyl, indanyl, or naphthyl). In certain such embodiments, A1is phenyl.

[0052] In certain embodiments, A1is heteroaryl (e.g., dibenzofuryl, benzofuryl, benzothiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, pyridyl, pyrazinyl, benzotriazolyl, benzothiophenyl, dibenzopyrrolyl, dibenzothiophenyl, indazolyl, xanthenyl, or indolyl).

[0053] In certain embodiments, A1is heterocyclyl (e.g., dibenzoxepinyl, dibenzoxocinyl, dioxinyl, dibenzodioxinyl, 2,3,4,5-tetrahydrobenzo[b]oxepinyl, 2,3- dihydrobenzo[b][l,4]dioxinyl, or benzodioxinyl).

[0054] In some preferred embodiments, the compound is represented by formula la, or a pharmaceutically acceptable salt thereof: la; wherein: as valence and stability permit, each R3is independently selected from halo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl), aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, amino, amido, acyl, sulfonyl, sulfonamido, and phosphoryl; and n is 1, 2, 3, 4, 5, 6, 7, 8, or 9.

[0055] In some embodiments, n is 1. In other embodiments, n is 2. In yet other embodiments, n is 3.

[0056] In certain embodiments, the compound is represented by formula lb, or a pharmaceutically acceptable salt thereof:

[0057] In some preferred embodiments, the compound is represented by formula Ic, or a pharmaceutically acceptable salt thereof:

[0058] Ic.

[0059] In certain embodiments, the compound is represented by formula Id, or a pharmaceutically acceptable salt thereof:

[0060] Id. In certain embodiments, the compound is represented by formula le, or a pharmaceutically acceptable salt thereof: le.

[0061] In other embodiments, the compound is represented by formula If, or a pharmaceutically acceptable salt thereof:

[0062] In yet other embodiments, the compound is represented by formula Ig, or a pharmaceutically acceptable salt thereof:

[0063] In some embodiments, the compound is represented by formula Ih, or a pharmaceutically acceptable salt thereof: In certain embodiments, the compound is represented by formula li, or a pharmaceutically acceptable salt thereof:

[0064] In some preferred embodiments, the compound is represented by formula Ij, or a pharmaceutically acceptable salt thereof: wherein:

[0065] A2is aryl, heteroaryl, cycloalkyl, or heterocyclyl; p is 1, 2, 3, 4, or 5; and each R6is independently selected from halo, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl.

[0066] In some embodiments, each R3is halo (e.g., chloro).

[0067] In some preferred embodiments, the compound is represented by formula Ik, or a pharmaceutically acceptable salt thereof: In some preferred embodiments, the compound is represented by formula II, or a pharmaceutically acceptable salt thereof:

[0068] II each R4and R5are each independently selected from halo, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;

[0069] A2is aryl, heteroaryl, cycloalkyl, or heterocyclyl; p is 1, 2, 3, 4, or 5; and each R6is independently selected from halo, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl.

[0070] In certain preferred embodiments, R4and R5are each halogen. In certain preferred embodiments, R4is chloro and R5is fluoro.

[0071] In some embodiments, the compound is represented by formula Im, or a pharmaceutically acceptable salt thereof:

[0072] Im wherein:

[0073] A2is aryl, heteroaryl, cycloalkyl, or heterocyclyl; p is 0, 1, 2, 3, 4, or 5; and each R6is independently selected from halo, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl. In some embodiments, A2is aryl (e.g., phenyl, indanyl, or naphthyl). In certain such embodiments, A2is phenyl. In some embodiments, A2is wherein represents the connection to the oxygen atom. In other embodiments, A2is ; wherein represents the connection to the oxygen atom.

[0074] In some embodiments, A2is heteroaryl (e.g., dibenzofuryl, naphthyl, benzothiazolyl, benzimidazolyl, pyridyl, [l,2,4]triazolo[l,5-a]pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, benzofuryl, or benzotriazolyl).

[0075] In some embodiments, A2is heterocyclyl (e.g., tetrahydropyranyl). In some embodiments, R2is H or alkoxy e.g., methoxy). In some embodiments, A2is selected from:

[0076]

[0077] In certain embodiments, the compound is selected from: pharmaceutically acceptable salt thereof.

[0078] In certain embodiments, the compound is selected from:

[0079]

[0080] In some aspects, the present disclosure provides a pharmaceutical composition comprising the compound of the present disclosure and a pharmaceutically acceptable excipient.

[0081] In some aspects, the present disclosure provides a method of treating a cancer in a subject in need thereof, comprising administering to the subject an amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is breast cancer, head and neck cancer, lung cancer, prostate cancer, or ovarian cancer. In other embodiments, the cancer is testicular cancer, cervical cancer, bladder cancer, esophageal cancer, mesothelioma, or brain cancer (e.g., glioblastoma). In certain preferred embodiments, the cancer is brain cancer (e.g., glioblastoma). Pharmaceutical Compositions

[0082] The compositions and methods of the present invention may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.

[0083] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0084] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0085] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.

[0086] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0087] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0088] Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

[0089] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0090] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0091] The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0092] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0093] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0094] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0095] Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0096] The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0097] Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0098] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0099] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0100] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0101] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0102] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0103] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

[0104] For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0105] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

[0106] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0107] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0108] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

[0109] In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0110] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present invention, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

[0111] The patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines, cattle, swine, sheep, cats, and dogs; poultry; and pets in general.

[0112] In certain embodiments, compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.

[0113] The present disclosure includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, IH-imidazole, lithium, L- lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, l-(2- hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, l-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2- hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, 1-ascorbic acid, 1-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptonic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, 1-malic acid, malonic acid, mandelic acid, methanesulfonic acid , naphthal ene-l,5-disulfonic acid, naphthal ene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, 1 -pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, 1-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid acid salts.

[0114] The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0115] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0116] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0117] Definitions

[0118] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well known and commonly used in the art. The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g. “Principles of Neural Science”, McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed ”, W. H. Freeman & Co., N.Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed ”, Sinauer Associates, Inc., Sunderland, MA (2000).

[0119] Chemistry terms used herein, unless otherwise defined herein, are used according to conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).

[0120] All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.

[0121] The term “agent” is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Agents include, for example, agents whose structure is known, and those whose structure is not known.

[0122] A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).

[0123] “Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. The term “preventing” is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and / or clinically significant amount.

[0124] “Administering” or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0125] Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and / or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, a compound or an agent is administered orally, e.g., to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.

[0126] As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.

[0127] A “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.

[0128] As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted.

[0129] It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.

[0130] As used herein, the term “optionally substituted” refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O- alkyl, -OP(O)(O-alkyl)2or -CH2-OP(O)(O-alkyl)2. Preferably, “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted.

[0131] As used herein, the term “alkyl” refers to saturated aliphatic groups, including but not limited to C1-C10 straight-chain alkyl groups or C1-C10 branched-chain alkyl groups. Preferably, the “alkyl” group refers to Ci-Ce straight-chain alkyl groups or Ci-Ce branched-chain alkyl groups. Most preferably, the “alkyl” group refers to C1-C4 straight-chain alkyl groups or C1-C4 branched-chain alkyl groups. Examples of “alkyl” include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1 -pentyl, 2-pentyl, 3 -pentyl, neo-pentyl, 1- hexyl, 2-hexyl, 3 -hexyl, 1 -heptyl, 2-heptyl, 3 -heptyl, 4-heptyl, 1 -octyl, 2-octyl, 3 -octyl or 4- octyl and the like. The “alkyl” group may be optionally substituted.

[0132] The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0133] The term “acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0134] The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0135] The term “alkoxy” refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

[0136] The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0137] The term “alkyl” refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-30for straight chains, C3-30for branched chains), and more preferably 20 or fewer.

[0138] Moreover, the term “alkyl” as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2- trifluoroethyl, etc.

[0139] The term “Cx-y” or “Cx-Cy”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. Coalkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. A C1-6alkyl group, for example, contains from one to six carbon atoms in the chain.

[0140] The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group. The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0141] The term “amido”, as used herein, refers to a group wherein R9and R10each independently represent a hydrogen or hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0142] The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by wherein R9, R10, and R10’ each independently represent a hydrogen or a hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0143] The term “aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group.

[0144] The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group.

[0145] The term “aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0146] The term “carbamate” is art-recognized and refers to a group wherein R9and R10independently represent hydrogen or a hydrocarbyl group. The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.

[0147] The term “carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct- 3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-lH- indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.

[0148] The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.

[0149] The term “carbonate” is art-recognized and refers to a group -OCO2-.

[0150] The term “carboxy”, as used herein, refers to a group represented by the formula -CO2H.

[0151] The term “cycloalkyl” includes substituted or unsubstituted non-aromatic single ring structures, preferably 4- to 8-membered rings, more preferably 4- to 6-membered rings. The term “cycloalkyl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adj oining rings wherein at least one of the rings is cycloalkyl and the substituent (e.g., R100) is attached to the cycloalkyl ring, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, denzodioxane, tetrahydroquinoline, and the like.

[0152] The term “ester”, as used herein, refers to a group -C(O)OR9wherein R9represents a hydrocarbyl group. The term “ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.

[0153] The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

[0154] The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.

[0155] The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

[0156] The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0157] The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.

[0158] The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0159] The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =0 or =S substituent, and typically has at least one carbon- hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =0 substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.

[0160] The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.

[0161] The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

[0162] The terms “polycyclyl”, “poly cycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the poly cycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

[0163] The term “sulfate” is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0164] The term “sulfonamido” is art-recognized and refers to the group represented by the general formulae wherein R9and R10independently represents hydrogen or hydrocarbyl.

[0165] The term “sulfoxide” is art-recognized and refers to the group-S(O)-.

[0166] The term “sulfonate” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof. The term “sulfone” is art-recognized and refers to the group -S(O)2-.

[0167] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

[0168] The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group.

[0169] The term “thioester”, as used herein, refers to a group -C(O)SR9or -SC(O)R9wherein R9represents a hydrocarbyl.

[0170] The term “thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.

[0171] The term “urea” is art-recognized and may be represented by the general formula wherein R9and R10independently represent hydrogen or a hydrocarbyl. The term “modulate” as used herein includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.

[0172] The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers and other materials and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0173] “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.

[0174] The term “pharmaceutically acceptable acid addition salt” as used herein means any non-toxic organic or inorganic salt of any base compounds represented by Formula I. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection of the appropriate salt will be known to one skilled in the art. Other non- pharmaceutically acceptable salts, e.g., oxalates, may be used, for example, in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0175] The term “pharmaceutically acceptable basic addition salt” as used herein means any non-toxic organic or inorganic base addition salt of any acid compounds represented by Formula I or any of their intermediates. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art. Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01 / 062726.

[0176] Furthermore, certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the disclosure includes both mixture and separate individual isomers.

[0177] The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.

[0178] The term “Log of solubility”, “LogS” or “logS” as used herein is used in the art to quantify the aqueous solubility of a compound. The aqueous solubility of a compound significantly affects its absorption and distribution characteristics. A low solubility often goes along with a poor absorption. LogS value is a unit stripped logarithm (base 10) of the solubility measured in mol / liter.

[0179] An electrophile is a chemical group or moiety that is capable of accepting electrons (e.g., bonding electrons) from a reaction partner (e.g., a nucleophile). Examples of electrophiles are groups or moieties comprising positive dipoles or highly strained rings. Illustrative examples of an electrophile may include, but are not limited to, a substituted or unsubstituted carbonyl, an a-halocarbonyl, an α,β-unsaturated carbonyl, an epoxide, a nitrile, an electron- deficient heteroaryl, a haloalkyl, a substituted or unsubstituted sulfone or sulfoxide, a substituted or unsubstituted cycloalkyl (such as a cyclopropyl, bicyclobutane, propellane), a phthalimide, a mal eimide, an ester (such as a lactone), a quinone, a substituted or unsubstituted alkenyl or alkynyl, a squaramide, an amido, or a heterocyclyl (such as a 1, 2,3,4- tetrahydropyridine).

[0180] EXAMPLES

[0181] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention and are not intended to limit the invention.

[0182] Example 1: Synthesis of Exemplary Compounds of the Disclosure

[0183] Preparation of compound 3.

[0184] General procedure for preparation of compound 3.

[0185] To a solution of compound 1 (4.59 g, 15.36 mmol, 1.1 eq) and compound 2 (3.8 g, 13.97 mmol, 1 eq) in toluene (80 mL) was added Pd(O Ac)2(313.54 mg, 1.40 mmol, 0.1 eq), Xantphos (808.06 mg, 1.40 mmol, 0.1 eq) and CS2CO3(9.10 g, 27.93 mmol, 2 eq). Then the mixture was stirred at 110 °C for 16 h under N2. LCMS showed desired mass was observed. The mixture was filtered and the solution was concentrated. Then to the crude was added water (50 mL) and extracted with EtOAc (60 mL x 2). The organic phase was washed by water (20 mL), dried by Na2SO4, filtered and concentrated. The crude was purified on silica gel column chromatography (EtOAc in petroleum ether from 0% to 50%, then DCM in MeOH from 10% to 10%) to give compound 3 (7.1 g, 12.62 mmol, 90.38% yield, 95% purity) as a yellow solid. LCMS: ([M+H] = 534.2)

[0186] 1H NMR: (400 MHz, CDCI3) δ ppm: 8.56 (s, 1H), 8.16 (s, 1H), 7.92 (d, J= 2.4 Hz, 1H), 7.66 (s, 1H), 7.52 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.12-7.15 (m, 1H), 6.95-7.02 (m, 2H), 6.74-6.78 (m, 1H), 3.48-3.76 (m, 4H), 2.93-2.96 (m, 4H), 1.50 (s, 9H).

[0187] Preparation of compound 4.

[0188]

[0189] General procedure for preparation of compound 4.

[0190] To a solution of compound 3 (7.1 g, 13.29 mmol, 1 eq) in DCM (20 mL) was added HCI / dioxane (2 M, 66.43 mL, 10.00 eq). Then the mixture was stirred at 25 °C for 16 h. LCMS showed desired mass was observed. The mixture was concentrated to give compound 4 (5.5 g, crude, HC1 salt) as a white solid.

[0191] LCMS: ([M+H] = 433.9)

[0192] Preparation of 267.

[0193] 4 267

[0194] General procedure for preparation of 267.

[0195] To a solution of compound 4 (5.15 g, 10.94 mmol, 1 eq, HC1 salt) and DIPEA (4.24 g, 32.82 mmol, 5.72 mL, 3 eq) in DCM (80 mL) was added compound 5 (990.15 mg, 10.94 mmol, 888.82 μL, 1 eq) at 0 °C. Then the mixture was stirred at 0 °C for 0.5 h. LCMS showed desired mass was observed. The mixture was quenched by water (50 mL). Then to the crude was extracted with DCM (60 mL x 2). The organic phase was washed by water (20 mL), dried by Na2SO4, filtered and concentrated. The crude was purified on silica gel column chromatography (Ethyl acetate in Petroleum ether from 0% to 100%). Then the product was dissolved in EtOAc (45 mL) at 50 °C and petroleum ether was added dropwise at 25 °C. A solid precipitates from the solution and the mixture was stirred at 25 °C for 2 h. The crystallized substance was collected by filtration, washed with petroleum ether (15 mL). The solution was concentrated and purified by purified by prep-HPLC (column: C18 150x40mm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 47%-77% B over 11 min) to give 267 (0.22 g). The cake was dried under reduced pressure at 50 °C and added DCM (12 mL) and petroleum ether (45 mL). The mixture was stirred at 25 °C for 16 h. Then the mixture was filtered. The cake was added EtOH (25 mL) and dried under reduced pressure at 50 °C for 10 min (repeat this procedure three times) to give 267 (2.4 g). The two batches (2.4 g and 0.22 g) were combined and freeze-dried to give 267 (2.62 g, 5.32 mmol, 99.168% purity) as a white solid.

[0196] LCMS: ([M+H] = 488.1)

[0197] HPLC: (purity: 99.17%)1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.66 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.11 (d, J= 2.8 Hz, 1H), 7.81 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.34-7.38 (m, 1H), 7.17-7.25 (m, 2H), 6.84-6.91 (m, 2H), 6.16 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.73 (dd, J= 10.4 Hz, 2.0 Hz, 1H), 3.80-3.84 (m, 4H), 2.92-2.93 (m, 4H).

[0198] Preparation of compound 2.

[0199] 1 2

[0200] General procedure for preparation of compound 2.

[0201] To a solution of compound 1 (3 g, 10.11 mmol, 1 eq) in THF (40 mL) was added / r-BuLi (2.5 M, 8.09 mL, 2 eq) at -65 °C under N2. The reaction mixture was stirred for another 1 h at the same temperature, then I2 (3.85 g, 15.16 mmol, 3.05 mL, 1.5 eq) in THF (5 mL) was added dropwise. The reaction mixture was stirred at -65 °C for 0.5 h. LCMS showed desired mass was observed. The mixture was quenched by 0.1 N AcOH (15 mL), added water (30 mL) and extracted with EtOAc (60 mL x 2). The organic phase was concentrated. The crude was purified on silica gel column chromatography (MeOH in DCM from 0% to 12%) to give compound 2 (2.75 g, 5.86 mmol, 57.93% yield, 90% purity) as a yellow solid.

[0202] LCMS: ([M+H] = 423.1)1H NMR : (400 MHz, CDCI3) δ ppm: 8.65 (s, 1H), 7.07 (s, 1H), 4.70-4.73 (m, 2H), 3.56 (q,

[0203] J=6.0 Hz, 2H), 1.36 (s, 9H).

[0204] Preparation of compound 3.

[0205] General procedure for preparation of compound 3.

[0206] To a solution of compound 2 (600 mg, 1.42 mmol, 1 eq) in DMA (15 mL) was added LBuOK (238.95 mg, 2.13 mmol, 1.5 eq) at 0 °C and the mixture was stirred at 25 °C for 2 h. LCMS showed desired mass was observed. The mixture was added water (30 mL) and extracted with EtOAc (40 mL x 2). The organic phase was washed by water (20 mL x 2), dried by Na2SO4, filtered and concentrated to give compound 3 (330 mg, crude) as a yellow solid.

[0207] LCMS: ([M+H] = 295.0)1H NMR : (400 MHz, CDCI3) δ ppm: 8.57 (s, 1H), 6.10 (br s, 1H), 4.56-4.60 (m, 2H), 4.41- 4.45 (m, 2H), 1.59 (s, 9H).

[0208] Preparation of compound 4.

[0209] General procedure for preparation of compound 4.

[0210] To a solution of compound 3 (300 mg, 1.02 mmol, 1 eq) in DCM (10 mL) was added TFA(1.16 g, 10.18 mmol, 756.07 μL, 10 eq). The mixture was stirred at 25 °C for 16 h. LCMS showed desired mass was observed. The mixture was concentrated to give compound 4 (300 mg, crude, TFA salt) as yellow oil. LCMS: ([M+H] = 195.1)

[0211] Preparation of compound 6.

[0212] General procedure for preparation of compound 6.

[0213] To a solution of compound 4 (300 mg, 971.99 μmol, 1 eq, TFA salt) and DIEA (502.48 mg, 3.89 mmol, 677.20 μL, 4 eq) in DCM (10 mL) was added compound 5 (175.95 mg, 1.94 mmol, 157.94 μL, 2 eq) .The mixture was stirred at 0 °C for 1 h. LCMS showed desired mass was observed. The mixture was added water (30 mL) and extracted with DCM (30 mL x 2). The organic phase was washed by water (20 mL x 2), dried by Na2SO4, filtered and concentrated to give compound 6 (220 mg, crude) as a gray solid.

[0214] LCMS: ([M+H] = 249.0)

[0215] 1H NMR: (400 MHz, CDCI3) δ ppm: 8.61 (s, 1H), 6.54-6.66 (m, 2H), 6.06-6.22 (m, 2H), 4.63- 4.64 (m, 4H).

[0216] Preparation of 273.

[0217] General procedure for preparation of 273.

[0218] To a solution of compound 6 (200 mg, 551.43 μmol, 1 eq) and compound 7 (75.02 mg, 275.72 μmol, 0.5 eq) in z-PrOH (10 mL) was added PyHCl (159.31 mg, 1.38 mmol, 2.5 eq) and the mixture was stirred at 80 °C for 2 h. LCMS showed desired mass was observed. The mixture was concentrated. The crude was purified by prep-HPLC (column: Boston Prime C18 150*30mm*5pm; mobile phase: [water (NH3·H2O+NH4HCO3)-ACN]; gradient: 46%-76% B over 11 min) to give 273 (14.5 mg, 28.36 μmol, 5.14% yield, 94.72% purity) as a gray solid.

[0219] LCMS: ([M+H] = 484.1)

[0220] HPLC: (purity: 94.72%)

[0221] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.65 (s, 1H), 8.30 (s, 1H), 7.99 (d, J= 2.4 Hz, 1H), 7.67 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.33-7.37 (m, 1H), 7.17-7.24 (m, 2H), 6.86-6.90 (m, 1H), 6.73-6.81 (m, 1H), 6.42 (d, J= 16.4 Hz, 1H), 6.30 (s, 1H), 5.95-5.98 (m, 1H), 4.72-4.75 (m, 4H).

[0222] Preparation of 274.

[0223] General procedure for preparation of 274.

[0224] To a solution of compound 2 (14.84 mg, 205.93 μmol, 14.12 μL, 1.1 eq) in DCM (6 mL) was added HOBt (35.41 mg, 262.09 μmol, 1.4 eq) and EDCI (50.24 mg, 262.09 μmol, 1.4 eq). Then compound 1 (90 mg, 187.21 μmol, 1 eq, HC1 salt) and DIPEA (60.49 mg, 468.02 μmol, 81.52 μL, 2.5 eq) in DCM (0.5 mL) were added. The reaction mixture was stirred at 20 °C for 3 h. LCMS showed desired mass was observed. The mixture was quenched by water (0.1 mL) and concentrated. The crude was purified by prep-HPLC (column: Welch Xtimate Cl 8 150*25mm*5pm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 45%-75% B over 11 min) to give 274 (12 mg, 23.60 μmol, 12.61% yield, 98% purity) as a white solid.

[0225] LCMS: [M+H] = 498.1

[0226] HPLC: (purity: 98.00%)

[0227] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.75 (d, J=7.2 Hz, 1H), 8.57 (s, 1H), 8.29 (s, 1H), 8.00 (d, .7=2.4 Hz, 1H), 7.69-7.72 (m, 1H), 7.33-7.36 (m, 1H), 7.17-7.23 (m, 2H), 6.86-6.90 (m, 1H), 6.30 (s, 1H), 6.13-6.24 (m, 2H), 5.63-5.66 (m, 1H), 5.00-5.03 (m, 1H), 4.77-4.81 (m, 1H), 4.35-4.39 (m, 1H), 3.40-3.42 (m, 1H), 2.95-3.00 (m, 1H).

[0228] Preparation of compound 2.

[0229] General procedure for preparation of compound 2.

[0230] To a solution of compound 1 (2.5 g, 9.57 mmol, 1 eq in Acetone (50 mL) was added TsOH (82.37 mg, 478.35 μmol, 0.05 eq . The reaction mixture was stirred at 20 °C for 72 h. LCMS showed desired mass was observed. The mixture was concentrated. Then a.q Na2CO3(20 mL) was added and extracted with EtOAc (25 mL x 2). The organic phase was washed by water (10 mL), dried by Na2SO4, filtered and concentrated to give compound 2 (2.2 g, crude) as yellow oil.

[0231] LCMS: ([M+H-56] =160.1)

[0232] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 4.77 (d, J= 3.2 Hz, 1H), 4.04-4.06 (m, 2H), 3.56- 3.62 (m, 2H), 2.15-2.21 (m, 2H), 1.43 (s, 9H).

[0233] Preparation of compound 4.

[0234] General procedure for preparation of compound 4.

[0235] To a solution of compound 2 (2.2 g, 8.18 mmol, 1 eq in EtOH (20 mL) was added compound 3 (540.16 mg, 8.18 mmol, 514.93 μL, 1 eq). The mixture was stirred at 25 °C for 10 min, diethylamine (598.01 mg, 8.18 mmol, 842.27 μL, 1 eq was added dropwise at 25 °C. The mixture was stirred at 25 °C for 16 hours. LCMS showed desired mass was observed. The mixture was added water (20 mL) and extracted with EtOAc (40 mL x 2). The organic phase was washed by water (20 mL), dried by Na2SO4, filtered and concentrated. The crude was purified on silica gel column chromatography (EtOAc in petroleum ether from 0% to 30%) to give compound 4 (800 mg, 2.73 mmol, 33.44% yield, 90% purity) as a yellow solid.

[0236] LCMS: ([M+H] = 264.2)

[0237] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 7.33 (s, 2H), 4.19 (s, 2H), 3.52 (t, J= 5.6 Hz, 2H), 2.32-2.34 (m, 2H), 1.40 (s, 9H).

[0238] Preparation of compound 5.

[0239] 4 5

[0240] General procedure for preparation of compound 5.

[0241] A solution of compound 4 (800 mg, 3.04 mmol, 1 eq) in DMF-DMA (10 mL) was stirred at 110 °C for 0.5 h. LCMS showed desired mass was observed. The mixture was concentrated to give compound 5 (800 mg, crude) as a yellow solid.

[0242] LCMS: ([M+H] = 319.1)

[0243] 1H NMR: (400 MHz, CDCI3) δ ppm: 8.10 (s, 1H), 4.32 (s, 2H), 3.62-3.62 (m, 2H), 3.01(s, 3H), 3.08 (s, 3H), 2.50-2.52 (m, 2H), 1.47 (s, 9H).

[0244] Preparation of compound 7. General procedure for preparation of compound 7.

[0245] A solution of compound 5 (350 mg, 1.10 mmol, 1 eq) and compound 6 (747.84 mg, 2.75 mmol, 2.5 eq) in IP Ac (8 mL) and AcOH (2 mL) was stirred for 40 h at 100 °C. LCMS showed desired mass was observed. The mixture was added a.q NaHCO3(30 mL) and extracted with EtOAc (40 mL x 2). The organic phase was washed by water (10 mL), dried by Na2SO4, filtered and concentrated. The crude was purified on silica gel column chromatography (EtOAc in petroleum ether from 0% to 20%) to give compound 7 (85 mg, 140.27 μmol, 12.76% yield, 90% purity) as a yellow solid.

[0246] LCMS: ([M+H] = 545.1)

[0247] 1H NMR: (400 MHz, CDCI3) δ ppm: 8.48 (s, 1H), 7.88-7.89 (m, 1H), 7.45-7.48 (m, 1H), 7.14- 7.18 (m, 1H), 6.98-7.02 (m, 2H), 6.78-6.83 (m, 1H), 6.56 (s, 1H), 4.63 (s, 2H), 3.79-3.80 (m, 2H), 2.84-2.86 (m, 2H), 1.51 (s, 9H).

[0248] Preparation of compound 8.

[0249] General procedure for preparation of compound 8.

[0250] To a solution of compound 7 (85 mg, 155.85 μmol, 1 eq) in DCM (5 mL) was added HCl / dioxane (2 M, 779.26 μL, 10 eq) and the mixture was stirred at 25 °C for 12 h. TLC (Petroleum ether / Ethyl acetate=3 / l, Rf=0.0) showed compound 7 was consumed. The mixture was concentrated to give compound 8 (75 mg, crude, HC1 salt) as a yellow solid.

[0251] Preparation of 275.

[0252] General procedure for preparation of 275.

[0253] To a solution of compound 8 (75 mg, 155.69 μmol, 1 eq, HC1 salt) and DIPEA (60.36 mg, 467.06 μmol, 81.35 μL, 3 eq) in DCM (10 mL) was added compound 9 (14 mg, 154.68 μmol, 12.57 μL, 9.94e-l eq at 0 °C. Then the mixture was stirred at 0 °C for 0.5 h. LCMS showed desired mass was observed. The mixture was quenched by water (0.1 mL) and concentrated. The crude was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5pm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 50%-80% B over 11 min) to give 275 (29 mg, 58.04 μmol, 37.28% yield, 99.93% purity) as a white solid.

[0254] LCMS: ([M+H] = 499.1)

[0255] HPLC: (purity: 99.93%)

[0256] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.78 (s, 1H), 8.41 (s, 1H), 7.98 (s, 1H), 7.66-7.69 (m, 1H), 7.35-7.39 (m, 1H), 7.18-7.24 (m, 2H), 6.89-7.01 (m, 2H), 6.19 (d, J= 16.8 Hz, 1H), 5.74- 5.79 (m, 1H), 4.87 (s, 1H), 4.76 (s, 1H), 3.87-3.90 (m, 2H), 2.95-2.99 (m, 2H).

[0257] Preparation of compound 2.

[0258] General procedure for preparation of compound 2.

[0259] To a solution of BnOH (22.49 g, 207.96 mmol, 21.54 mL, 2 eq) in DMF (200 mL) was added t- BuOK (23.34 g, 207.96 mmol, 2 eq) at 0 °C. Then compound 1 (25 g, 103.98 mmol, 1 eq was added at 0 °C and the mixture was stirred at 25 °C for 1.5 h. LCMS showed desired mass was observed. The mixture was added a.q NH4CI (100 mL) and extracted with EtOAc (250 mL x 2). The organic phase was washed by water (50 mL x 2), dried by Na2SO4, filtered and concentrated. The crude was purified on silica gel column chromatography (EtOAc in petroleum ether from 0% to 10%) to give compound 2 (21 g, 53.83 mmol, 51.77% yield, 80% purity) as yellow oil.

[0260] LCMS: ([M+H] = 312.9)

[0261] 1H NMR: (400 MHz, CDCI3) δ ppm: 8.77 (s, 1H), 8.66 (s, 1H), 7.47-7.49 (m, 2H), 7.34-7.40 (m, 3H), 5.51 (s, 2H).

[0262] Preparation of compound 4.

[0263] General procedure for preparation of compound 4.

[0264] To a solution of compound 2 (10 g, 32.04 mmol, 1 eq) and compound 3 (17.90 g, 96.12 mmol, 3 eq) in Dioxane (120 mL) was added Cs2CO3(31.32 g, 96.12 mmol, 3 eq) and Xphos Pd G3 (1.36 g, 1.60 mmol, 0.05 eq) under N2. Then the mixture was stirred at 90 °C for 16 h under N2. LCMS showed desired mass was observed. The mixture was filtered and concentrated. The crude was purified on silica gel column chromatography (EtOAc in petroleum ether from 0% to 50%) to give compound 4 (5.3 g, 11.45 mmol, 35.72% yield, 80% purity) as yellow oil. LCMS: ([M+H] = 371.2)

[0265] 1H NMR: (400 MHz, CDCI3) δ ppm: 8.46 (s, 1H), 8.02 (s, 1H), 7.34-7.46 (m, 5H), 5.50 (s, 2H), 3.56 (t, J= 5.2 Hz, 4H), 3.08 (t, J= 4.8 Hz, 4H), 1.47 (s, 9H).

[0266] Preparation of compound 5. General procedure for preparation of compound 5.

[0267] To a solution of compound 4 (5.3 g, 11.45 mmol, 1 eq) in MeOH (80 mL) was added Pd / C (1.5 g, 1.41 mmol, 10% purity, 1.23e-l eq) under N2. Then the mixture was stirred at 50 °C for 16 h under H2 (45 psi). LCMS showed desired mass was observed. The mixture was filtered and concentrated. The crude was purified on silica gel column chromatography (EtOAc in petroleum ether from 0% to 100%) to give compound 5 (2.8 g, 8.99 mmol, 78.54% yield, 90% purity) as a white solid.

[0268] LCMS: ([M+H] = 281.1)

[0269] 1H NMR: (400 MHz, MeOD) 6 ppm: 7.95 (s, 1H), 7.44 (s, 1H), 3.56 (t, J= 5.2 Hz, 4H), 3.08 (t, J= 5.2 Hz, 4H), 1.48 (s, 9H).

[0270] Preparation of compound 6.

[0271] 5 6

[0272] General procedure for preparation of compound 6.

[0273] To a solution of compound 5 (500 mg, 1.78 mmol, 1 eq) in DCE (15 mL) was added DMF (260.74 mg, 3.57 mmol, 274.46 μL, 2 eq) and oxalyl dichloride (452.80 mg, 3.57 mmol, 312.28 μL, 2 eq) and the mixture was stirred at 80 °C for 15 min. LCMS showed the reaction was completed. The mixture was added a.q NaHCCE (20 mL) and extracted with DCM (20 mL x 2). The organic phase was washed by water (10 mL x 2), dried by Na2SO4, filtered and concentrated to give compound 6 (330 mg, crude) as a yellow solid.

[0274] LCMS: ([M+H] = 299.1)

[0275] 1H NMR: (400 MHz, CDCI3) δ ppm: 8.67 (s, 1H), 8.32 (s, 1H), 3.62 (t, J= 4.8 Hz, 4H), 3.11 (t, J= 5.2 Hz, 4H), 1.49 (s, 9H).

[0276] Preparation of compound 8.

[0277] General procedure for preparation of compound 8.

[0278] To a solution of compound 6 (269.21 mg, 901.08 μmol, 1.3 eq) and compound 7 (180 mg, 693.14 μmol, 1 eq) in toluene (10 mL) was added CS2CO3(451.68 mg, 1.39 mmol, 2 eq), Pd(OAc)2(15.56 mg, 69.31 μmol, 0.1 eq) and Xantphos (40.11 mg, 69.31 μmol, 0.1 eq). Then the mixture was stirred at 110 °C for 16 h under N2. LCMS showed desired mass was observed. The mixture was added water (20 mL) and extracted with EtOAc (30 mL x 2). The organic phase was washed by water (15 mL), dried by Na2SO4, filtered and concentrated. The crude was purified on silica gel column chromatography (EtOAc in petroleum ether from 0% to 45%) to give compound 8 (260 mg, 448.28 μmol, 64.67% yield, 90% purity) as a yellow solid.

[0279] LCMS: ([M+H] = 522.1)

[0280] 1H NMR: (400 MHz, MeOD) δ ppm: 8.38 (s, 1H), 8.12 (s, 1H), 8.01 (d, J= 2.4 Hz, 1H), 7.76 (d, J= 2.4 Hz, 1H), 7.53 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.38-7.41 (m, 1H), 7.17 (t, J= 8.0 Hz, 1H), 6.96 (d, J= 8.4 Hz, 1H), 6.90 (d, J= 2.0 Hz, 1H), 6.78 (d, J= 8.0 Hz, 1H ), 3.66-3.68 (m, 4H), 2.94-2.96 (m, 4H), 1.49 (s, 9H).

[0281] Preparation of compound 9. General procedure for preparation of compound 9.

[0282] To a solution of compound 8 (260 mg, 498.09 μmol, 1 eq) in DCM (5 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 13.51 eq). Then the mixture was stirred at 25 °C for 16 h. LCMS showed desired mass was observed. The mixture was concentrated to give compound 9 (260 mg, crude, TFA salt) as yellow oil.

[0283] LCMS: ([M+H] = 422.1)

[0284] Preparation of 276.

[0285] General procedure for preparation of 276.

[0286] To a solution of compound 9 (230 mg, 429.18 μmol, 1 eq, TFA salt) and DIEA (166.40 mg, 1.29 mmol, 224.26 μL, 3 eq) in DCM was added compound 10 (38.84 mg, 429.18 μmol, 34.87 μL, 1 eq) at 0 °C. Then the mixture was stirred at 0 °C for 0.5 h. LCMS showed desired mass was observed. The mixture was quenched by water (0.1 mL) and concentrated. The crude was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 42%-72% B over 11 min) to give 276 (60 mg, 125.86 μmol, 29.32% yield, 99.83% purity) as a white solid.

[0287] LCMS: ([M+H] = 476.2)

[0288] HPLC: (purity: 99.83%)

[0289] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.62 (s, 1H), 8.42 (s, 1H), 8.22 (s, 1H), 8.08 (d, J= 2.4 Hz, 1H), 8.03 (d, J= 2.4 Hz, 1H), 7.73 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.44 (d, J= 7.6 Hz, 1H), 7.20 (t, J= 8.0 Hz, 1H), 7.11 (d, J= 9.2 Hz, 1H), 7.04 (d, J= 2.0 Hz, 1H), 6.83-6.90 (m, 1H), 6.76 (d, J= 7.6 Hz, 1H ), 6.16 (dd, J= 16.4 Hz, 2.4 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.80-3.83 (m, 4H), 2.92-2.93 (m, 4H). Preparation of compound 3.

[0290] General procedure for preparation of compound 3.

[0291] To a solution of compound 1 (2.0 g, 11.39 mmol, 1 eq and compound 2 (1.92 g, 11.96 mmol, 1.05 eq) in ACN (20.0 mL) was added KOH (799.02 mg, 14.24 mmol, 1.25 eq) at 25 °C. The mixture was stirred at 40 °C for 16 hours. TLC (Petroleum ether / EtOAc = 8 / 1) showed new spot was observed. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g Sepa Flash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / DCM gradient @ 30 mL / min) to give compound 3 (2.42 g, 6.89 mmol, 60.47% yield, 90% purity) as a light-yellow solid.

[0292] 1H NMR: (400 MHz, CDCI3) δ ppm: 8.33 (d, J = 2.4 Hz, 1H), 8.14 (dd, J= 9.2 Hz, 2.8 Hz, 1H), 7.45 (t, J= 8.0 Hz, 1H), 7.28 (dd, J= 9.2 Hz, 2.4 Hz, 1H), 7.15-7.23 (m, 1H), 7.01 (d, J = 8.8 Hz, 1H), 5.22 (s, 2H).

[0293] Preparation of compound 4.

[0294] 3 4

[0295] General procedure for preparation of compound 4.

[0296] To a solution of compound 3 (2.42 g, 7.66 mmol, 1 eq in EtOH (20.0 mL) and H2O (4.0 mL) was added Fe (3.42 g, 61.24 mmol, 8 eq) and NH4CI (3.28 g, 61.24 mmol, 8 eq) at 25 °C. The mixture was stirred at 75 °C for 2 hours. TLC (Petroleum ether / EtOAc = 2 / 1) showed new spot was observed. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g Sepa Flash® Silica Flash Column, Eluent of 0~5% Ethyl acetate / DCM gradient @ 30 mL / min) to give compound 4 (1.92 g, 6.04 mmol, 78.89% yield, 90% purity) as a white solid.

[0297] 1H NMR: (400 MHz, CDCI3) δ ppm: 7.39 (t, J= 7.6 Hz, 1H), 7.26-7.32 (m, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.74-6.77 (m, 2H), 6.50 (dd, J= 8.4 Hz, 2.4 Hz, 1H), 4.99 (s, 2H), 3.51 (br s, 2H).

[0298] Preparation of compound 6.

[0299] General procedure for preparation of compound 6.

[0300] To a solution of compound 5 (225.54 mg, 754.91 μmol, 1.2 eq) and compound 4 (180.0 mg, 629.09 μmol, 1 eq) in toluene (10.0 mL) was added CS2CO3(409.94 mg, 1.26 mmol, 2 eq), Xantphos (36.40 mg, 62.91 μmol, 0.1 eq) and Pd(OAc)2(14.12 mg, 62.91 μmol, 0.1 eq) at 25 °C. The mixture was stirred at 110 °C for 16 hours under N2. TLC (Petroleum ether / EtOAc = 1 / 1) showed new spots were observed. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0-80% Ethyl acetate / Petroleum ether gradient @ 20 mL / min) to give compound 6 (239.0 mg, 392.21 μmol, 62.35% yield, 90% purity) as light-brown oil.

[0301] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.39 (br s, 1H), 8.36 (s, 1H), 8.16 (s, 1H), 7.89 (d, J = 2.8 Hz, 1H), 7.61-7.66 (m, 2H), 7.50 (dd, J= 10.0 Hz, 1.6 Hz, 1H), 7.34 (dd, J= 8.4 Hz, 1.2 Hz, 1H), 7.20 (d, J= 9.2 Hz, 1H), 5.23 (s, 2H), 3.56 (br s, 4H), 2.85 (t, J= 4.8 Hz, 4H), 1.43 (s, 9H).

[0302] Preparation of compound 7.

[0303] General procedure for preparation of compound 7.

[0304] To a solution of compound 6 (214.0 mg, 390.20 μmol, 1 eq) in DCM (1.0 mL) was added HCI / dioxane (2 M, 5.0 mL, 25.63 eq) at 25 °C. The mixture was stirred at 25 °C for 16 hours. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure to give compound 7 (180.0 mg, crude, HC1 salt) as a light-yellow solid.

[0305] LCMS: ([M+H] = 448.1)

[0306] Preparation of 278.

[0307] General procedure for preparation of 278.

[0308] To a solution of compound 7 (180.0 mg, 371.30 μmol, 1 eq, HC1 salt) in DCM (5.0 mL) was added DIPEA (143.96 mg, 1.11 mmol, 194.02 μL, 3 eq) at 25 °C. The mixture was cooled to 0 °C with ice-bath and compound 8 (33.61 mg, 371.30 μmol, 30.17 μL, 1 eq) in DCM (0.5 mL) was added to the mixture. The mixture was stirred at 0 °C for 30 mins. LCMS showed the reaction was completed. H2O (0.5 mL) was added to the mixture and concentrated under reduced pressure to give the residue, which was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 45%-75% B over 11 min) to give 278 (85.0 mg, 168.64 μmol, 45.42% yield, 99.67% purity) as a white solid.

[0309] LCMS: ([M+H] = 502.0)

[0310] HPLC: (purity: 99.67%)

[0311] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.46 (br s, 1H), 8.36 (s, 1H), 8.16 (s, 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.62-7.66 (m, 2H), 7.50 (dd, J= 10.4 Hz, 2.0 Hz, 1H), 7.34 (dd, J= 8.4 Hz, 1.2 Hz, 1H), 7.21 (d, J = 9.2 Hz, 1H), 6.82-6.89 (m, 1H), 6.15 (dd, J = 16.8 Hz, 2.4 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 5.23 (s, 2H), 3.80 (br s, 4H), 2.90 (t, J= 4.4 Hz, 4H).

[0312] Preparation of compound 3.

[0313] General procedure for preparation of compound 3.

[0314] To a solution of compound 2 (203.86 mg, 682.35 μmol, 1.2 eq) and compound 1 (180 mg, 568.62 μmol, 1 eq) in toluene (10 mL) was added Pd(O Ac)2(12.77 mg, 56.86 μmol, 0.1 eq), Xantphos (32.90 mg, 56.86 μmol, 0.1 eq) and CS2CO3(370.54 mg, 1.14 mmol, 2 eq). Then the mixture was stirred at 110 °C for 16 h under N2. LCMS showed desired mass was observed. The mixture was added water (20 mL) and extracted with EtOAc (30 mL x 2). The organic phase was washed by water (15 mL), dried by Na?SO4, filtered and concentrated. The crude was purified on silica gel column chromatography (EtOAc in petroleum ether from 0% to 45%) to give compound 3 (220 mg, 304.05 μmol, 53.47% yield, 80% purity) as a yellow solid.

[0315] LCMS: ([M+H] = 580.1)

[0316] 1H NMR: (400 MHz, CDCI3) δ ppm: 8.58 (s, 1H), 8.18 (s, 1H), 7.93-7.95 (m, 1H), 7.67-7.68 (m, 1H), 7.53-7.56 (m, 1H), 7.30-7.33 (m, 1H), 7.02-7.04 (m, 1H), 6.96-6.98 (m, 1H), 6.81- 6.86 (m, 1H), 3.53-3.74 (m, 4H), 2.94-2.96 (m, 4H), 1.52 (s, 9H). Preparation of compound 4.

[0317] General procedure for preparation of compound 4.

[0318] To a solution of compound 3 (220 mg, 380.06 μmol, 1 eq) in DCM (6 mL) was added TFA (921.00 mg, 8.08 mmol, 0.6 mL, 21.25 eq). Then the mixture was stirred at 25 °C for 16 h. LCMS showed desired mass was observed. The mixture was concentrated to give compound 4 (220 mg, crude, TFA salt) as yellow oil.

[0319] LCMS: ([M+H] = 479.9)

[0320] Preparation of 280.

[0321] 4 280

[0322] General procedure for preparation of 280.

[0323] To a solution of compound 4 (200 mg, 337.40 μmol, 1 eq, TFA salt) and DIEA (218.03 mg, 1.69 mmol, 293.84 μL, 5 eq) in DCM (10 mL) was added compound 5 (30.54 mg, 337.40 μmol, 27.41 μL, 1 eq) at 0 °C. Then the mixture was stirred at 0 °C for 0.5 h. LCMS showed desired mass was observed. The mixture was quenched by water (0.1 mL) and concentrated. The crude was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5pm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 50%-80% B over 11 min) to give 280 (48.1 mg, 90.24 μmol, 26.75% yield, 99.96% purity) as a white solid.

[0324] LCMS: ([M+H] = 534.0)

[0325] HPLC: (purity: 99.96%)

[0326] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.65 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.10 (d, J= 2.4 Hz, 1H), 7.80 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.44-7.48 (m, 1H), 7.22 (d, J= 8.8 Hz, 1H), 7.11- 7.16 (m, 1H), 6.83-6.94 (m, 2H), 6.15 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.80-3.84 (m, 4H), 2.92-2.93 (m, 4H).

[0327] Preparation of compound 3.

[0328] General procedure for preparation of compound 3.

[0329] To a solution of compound 2 (234.59 mg, 785.20 μmol, 1.2 eq) and compound 1 (200.0 mg, 654.33 μmol, 1 eq) in toluene (10.0 mL) was added CS2CO3(426.39 mg, 1.31 mmol, 2 eq), Xantphos (37.86 mg, 65.43 μmol, 0.1 eq) and Pd(OAc)2(14.69 mg, 65.43 μmol, 0.1 eq) at 25 °C. The mixture was stirred at 110 °C for 16 hours under N2. TLC (Petroleum ether / EtOAc = 1 / 1) showed the new spots were observed. The mixture was concentrated under reduced pressure to give the residue, which was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0-80% Ethyl acetate / Petroleum ether gradient @ 20 mL / min) to give compound 3 (265.0 mg, 326.61 μmol, 49.91% yield, 70% purity) as light-brown oil.

[0330] LCMS: ([M+H] = 568.1)

[0331] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.59 (s, 1H), 8.44 (s, 1H), 8.24 (s, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.84-7.87 (m, 1H), 7.50-7.54 (m, 1H), 7.34-7.39 (m, 1H), 7.29 (d, J= 8.8 Hz, 1H), 7.19-7.24 (m, 1H), 3.57-3.60 (m, 4H), 2.86-2.89 (m, 4H), 1.43 (s, 9H).

[0332] Preparation of compound 4.

[0333] 3 4

[0334] General procedure for preparation of compound 4.

[0335] To a solution of compound 3 (210.0 mg, 369.74 μmol, 1 eq) in DCM (1.0 mL) was added HCI / di oxane (2 M, 3.0 mL, 16.23 eq) at 25 °C. The mixture was stirred at 25 °C for 2 hours. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure to give compound 4 (180.0 mg, crude, HC1 salt) as a light-yellow solid.

[0336] LCMS: ([M+H] = 468.0)

[0337] Preparation of 281.

[0338] General procedure for preparation of 281.

[0339] To a solution of compound 4 (200.0 mg, 396.58 μmol, 1 eq, HC1 salt) in DCM (5.0 mL) was added DIEA (153.77 mg, 1.19 mmol, 207.23 μL, 3 eq) at 25 °C. The mixture was cooled to 0 °C with ice-bath and compound 5 (35.89 mg, 396.58 μmol, 32.22 μL, 1 eq) in DCM (0.5 mL) was added to the mixture. The mixture was stirred at 0 °C for 30 mins. LCMS showed that -47% of the desired mass was detected. H2O (0.5 mL) was added to the mixture and concentrated under reduced pressure to give the residue, which was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 46%-67% B over 11 min) to give 281 (70.0 mg, 92.48% purity) as a white solid. Then the crude product was purified by prep-HPLC (column: Phenomenex Gemini NX 150x30mm, 5μm; mobile phase: [water (NH3·H2O+NH4HCO3)-ACN]; gradient: 44%-84% B over 9 min) to give 281 (41.0 mg, 76.50 μmol, 19.29% yield, 97.38% purity) as a white solid.

[0340] LCMS: ([M+H] = 522.0)

[0341] HPLC: (purity: 97.38%)

[0342] *H NMR: (400 MHz, MeOD) δ ppm: 8.40 (s, 1H), 8.16 (s, 1H), 8.06 (d, J= 2.4 Hz, 1H), 7.68 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 7.39-7.43 (m, 1H), 7.25-7.29 (m, 1H), 7.12-7.17 (m, 2H), 6.82 (dd, J = 16.8 Hz, 2.4 Hz, 1H), 6.25 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.79 (dd, J= 10.8 Hz, 2.0 Hz, 1H), 3.75-4.00 (m, 4H), 2.95-3.10 (m, 4H).

[0343] Preparation of compound 2.

[0344] 1 2

[0345] General procedure for preparation of compound 2.

[0346] To a solution of compound 1 (3 g, 10.11 mmol, 1 eq) in THF (40 mL) was added n-BuLi (2.5 M, 8.09 mL, 2 eq) at -65 °C under N2. The reaction mixture was stirred for another 1 h at the same temperature, then I2 (3.85 g, 15.16 mmol, 3.05 mL, 1.5 eq) in THF (5 mL) was added dropwise. The reaction mixture was stirred at -65 °C for 0.5 h. LCMS showed desired mass was observed. The mixture was quenched by 0.1 N AcOH (15 mL), added water (30 mL) and extracted with EtOAc (60 mL x 2). The organic phase was concentrated. The crude was purified on silica gel column chromatography (MeOH in DCM from 0% to 12%) to give compound 2 (2.75 g, 5.86 mmol, 57.93% yield, 90% purity) as a yellow solid.

[0347] LCMS: ([M+H] = 423.1)

[0348] 1H NMR: (400 MHz, CDCI3) δ ppm: 8.65 (s, 1H), 7.07 (s, 1H), 4.70-4.73 (m, 2H), 3.56 (q, J=6.0 Hz, 2H), 1.36 (s, 9H).

[0349] Preparation of compound 3.

[0350] General procedure for preparation of compound 3.

[0351] To a solution of compound 2 (600 mg, 1.42 mmol, 1 eq in DMA (15 mL) was added LBuOK (238.95 mg, 2.13 mmol, 1.5 eq) at 0 °C and the mixture was stirred at 25 °C for 2 h. LCMS showed desired mass was observed. The mixture was added water (30 mL) and extracted with EtOAc (40 mL x 2). The organic phase was washed by water (20 mL x 2), dried by Na2SO4, filtered and concentrated to give compound 3 (330 mg, crude) as a yellow solid.

[0352] LCMS: ([M+H] = 295.0)

[0353] 1H NMR: (400 MHz, CDCI3) δ ppm: 8.57 (s, 1H), 6.10 (br s, 1H), 4.56-4.60 (m, 2H), 4.41- 4.45 (m, 2H), 1.59 (s, 9H).

[0354] Preparation of compound 4.

[0355] General procedure for preparation of compound 4.

[0356] To a solution of compound 3 (300 mg, 1.02 mmol, 1 eq) in DCM (10 mL) was added TFA (1.16 g, 10.18 mmol, 756.07 μL, 10 eq . The mixture was stirred at 25 °C for 16 h. LCMS showed desired mass was observed. The mixture was concentrated to give compound 4 (300 mg, crude, TFA salt) as yellow oil.

[0357] LCMS: ([M+H] = 195.1)

[0358] Preparation of compound 6.

[0359] 4 6

[0360] General procedure for preparation of compound 6.

[0361] To a solution of compound 4 (300 mg, 971.99 μmol, 1 eq, TFA salt) and DIEA (502.48 mg, 3.89 mmol, 677.20 μL, 4 eq) in DCM (10 mL) was added compound 5 (175.95 mg, 1.94 mmol, 157.94 μL, 2 eq .The mixture was stirred at 0 °C for 1 h. LCMS showed desired mass was observed. The mixture was added water (30 mL) and extracted with DCM (30 mL x 2). The organic phase was washed by water (20 mL x 2), dried by Na2SO4, filtered and concentrated to give compound 6 (220 mg, crude) as a gray solid.

[0362] LCMS: ([M+H] = 249.0)

[0363] 1H NMR: (400 MHz, CDCI3) δ ppm: 8.61 (s, 1H), 6.54-6.66 (m, 2H), 6.06-6.22 (m, 2H), 4.63- 4.64 (m, 4H).

[0364] Preparation of 282.

[0365] 6

[0366] 282

[0367] General procedure for preparation of 282.

[0368] To a solution of compound 6 (200 mg, 551.43 μmol, 1 eq and compound 7 (75.02 mg, 275.72 μmol, 0.5 eq) in z-PrOH (10 mL) was added PyHCl (159.31 mg, 1.38 mmol, 2.5 eq) and the mixture was stirred at 80 °C for 2 h. LCMS showed desired mass was observed. The mixture was concentrated. The crude was purified by prep-HPLC (column: Boston Prime Cl 8 150*30mm*5pm; mobile phase: [water (NH3·H2O+NH4HCO3)-ACN]; gradient: 46%-76% B over 11 min) to give 282 (14.5 mg, 28.36 μmol, 5.14% yield, 94.72% purity) as a gray solid.

[0369] LCMS: ([M+H] = 484.1)

[0370] HPLC: (purity: 94.72%)

[0371] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.65 (s, 1H), 8.30 (s, 1H), 7.99 (d, J= 2.4 Hz, 1H), 7.67 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.33-7.37 (m, 1H), 7.17-7.24 (m, 2H), 6.86-6.90 (m, 1H), 6.73-6.81 (m, 1H), 6.42 (d, J= 16.4 Hz, 1H), 6.30 (s, 1H), 5.95-5.98 (m, 1H), 4.72-4.75 (m, 4H).

[0372] Preparation of compound 2.

[0373] 1 2

[0374] General procedure for preparation of compound 2.

[0375] To a solution of compound 1 (820 mg, 3.87 mmol, 1 eq) in DMF (12 mL) was added Cui (95.92 mg, 503.67 μmol, 0.13 eq). Then the mixture was stirred at 110 °C for 0.5 h. LCMS showed desired mass was observed. The mixture was added water (25 mL) and extracted with DCM (40 mL x 2). The organic phase was washed by water (15 mL x 2), dried by Na2SO4, filtered and concentrated to give compound 2 (800 mg, crude) as yellow oil.

[0376] LCMS: ([M+H] = 211.9)

[0377] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 12.21 (s, 1H), 8.57 (s, 1H), 6.50 (s, 1H), 4.60 (t, J=5.2 Hz, 1H), 3.47 (q, J=6,4 Hz, 2H), 2.87 (t, J=7.6 Hz, 2H), 1.84-1.91 (m, 2H).

[0378] Preparation of compound 3.

[0379] General procedure for preparation of compound 3.

[0380] To a solution of compound 2 (750 mg, 3.54 mmol, 1 eq in THF (15 mL) was added PPh3(1.86 g, 7.09 mmol, 2 eq) and DIAD (1.43 g, 7.09 mmol, 1.37 mL, 2 eq). The reaction mixture was stirred at 25 °C for 1.5 h. LCMS showed desired mass was observed. The mixture was added water (30 mL) and extracted with EtOAc (40 mL x 2). The organic phase was washed by water (20 mL), dried by Na2SO4, filtered and concentrated. The crude was purified on silica gel column chromatography (EtOAc in petroleum ether from 0% to 55%) to give compound 3 (1.2 g, 3.10 mmol, 87.44% yield, 50% purity) as a yellow solid.

[0381] LCMS: ([M+H] = 194.1)

[0382] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.52 (s, 1H), 6.47 (s, 1H), 4.40 (t, J=6.8 Hz, 2H), 3.09 (t, J=7,6 Hz, 2H), 2.55-2.60 (m, 2H).

[0383] Preparation of 283.

[0384] General procedure for preparation of 283.

[0385] To a solution of compound 3 (550 mg, 1.42 mmol, 1 eq and compound 4 (270.51 mg, 994.15 μmol, 0.7 eq) in z-PrOH (20 mL) was added PyHCl (492.36 mg, 4.26 mmol, 3 eq) and the mixture was stirred at 80 °C for 2 h. LCMS showed desired mass was observed. The mixture was added water (30 mL) and extracted with DCM (30 mL x 2). The organic phase was concentrated. The crude was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5pm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 50%-80% B over 11 min) to give 283 (190 mg, 438.98 μmol, 30.91% yield, 99.18% purity) as a white solid.

[0386] LCMS: ([M+H] = 429.0)

[0387] HPLC: (purity: 99.18%)

[0388] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.54 (s, 1H), 8.28 (s, 1H), 8.02 (d, J= 2.8 Hz, 1H), 7.70 (dd, J= 10.4 Hz, 2.8 Hz, 1H), 7.32-7.36 (m, 1H), 7.17-7.24 (m, 2H), 6.86-6.90 (m, 1H), 6.24 (s, 1H), 4.48 (t, J= 7.2 Hz, 2H), 3.02 (t, J= 7.6 Hz, 2H), 2.53-2.58 (m, 2H).

[0389] Preparation of compound 2.

[0390] General procedure for preparation of compound 2.

[0391] To a solution of compound 1 (800.0 mg, 4.81 mmol, 1 eq and TEA (535.87 mg, 5.30 mmol, 737.10 μL, 1.1 eq) in THF (8.0 mL) was added ethyl carb onochlori date (548.58 mg, 5.05 mmol, 483.33 μL, 1.05 eq) in THF (0.5 mL) at 0 °C. The mixture was stirred at 0 °C for 30 mins. TLC (petroleum ether / EtOAc = 1 / 1) showed new spots were observed. The resulting precipitate was filtered off, and the filtrate was concentrated under reduced pressure to give the residue. The residue was diluted with NaHCO3(10.0 mL), brine (10.0 mL) and extracted with EtOAc (10.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 2 (1.17 g, 4.42 mmol, 91.81% yield, 90% purity) as a light-brown oil.

[0392] 1H NMR: (400 MHz, CDCI3) δ ppm: 6.96-7.03 (m, 2H), 6.85-6.90 (m, 1H), 4.25-4.34 (m, 3H), 4.11-4.14 (m, 2H), 3.11 (dd, J= 16.8 Hz, 4.8 Hz, 1H), 2.84 (dd, J= 16.8 Hz, 4.8 Hz, 1H), 1.39 (t, J = 6.8 Hz, 3H).

[0393] Preparation of compound 3.

[0394] 23

[0395] General procedure for preparation of compound 3.

[0396] To a solution of compound 2 (1.17 g, 4.91 mmol, 1 eq) in DCM (15.0 mL) was added TEA (1.49 g, 14.73 mmol, 2.05 mL, 3 eq), TsCl (1.40 g, 7.37 mmol, 1.5 eq) and DMAP (90.00 mg, 736.66 μmol, 0.15 eq) at25 °C. The mixture was stirred at 25 °C for 16 hours. TLC (Petroleum ether / EtOAc = 1 / 1) showed new spots were observed. The mixture was concentrated under reduced pressure to give the residue, which was purified by flash silica gel chromatography (ISCO®; 20 g Sepa Flash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient @ 25 mL / min) to give compound 3 (1.7 g, 3.90 mmol, 79.39% yield, 90% purity) as a light-yellow solid.

[0397] 1H NMR: (400 MHz, CDCI3) δ ppm: 7.80 (d, J= 8.4 Hz, 2H), 7.34 (d, J= 8.0 Hz, 2H), 6.95- 6.99 (m, 1H), 6.82-6.86 (m, 2H), 4.92-4.98 (m, 1H), 4.26-4.32 (m, 2H), 4.12-4.15 (m, 2H), 3.06-3.13 (m, 1H), 2.95-3.01 (m, 1H), 2.46 (s, 3H), 1.37 (t, J= 6.8 Hz, 3H).

[0398] Preparation of compound 4.

[0399] General procedure for preparation of compound 4.

[0400] To a solution of compound 3 (1.7 g, 4.33 mmol, 1 eq) in MeOH (10.0 mL) was added NaOH (1.73 g, 4.33 mmol, 10.0 mL, 10% purity, 1 eq) at 25 °C. The mixture was stirred at 80 °C for 16 hours. TLC (Petroleum ether / EtOAc = 1 / 1) showed the starting material was consumed and new spot was observed. The mixture was concentrated under reduced pressure to give the residue, which was purified by flash silica gel chromatography (ISCO®; 20 g Sepa Flash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient @ 25 mL / min) to give compound 4 (484.0 mg, 2.94 mmol, 67.87% yield, 90% purity) as a light-brown oil.

[0401] 1H NMR: (400 MHz, CDCI3) δ ppm: 6.74-6.80 (m, 2H), 6.53-6.56 (m, 1H), 6.41-6.44 (m, 1H), 5.76-5.80 (m, 1H), 4.86-4.87 (m, 2H).

[0402] Preparation of compound 6.

[0403] 4 6

[0404] General procedure for preparation of compound 6.

[0405] To a solution of compound 4 (168.80 mg, 1.14 mmol, 1 eq) and compound 5 (200.0 mg, 1.14 mmol, 1 eq) in DMF (5.0 mL) was added K2CO3(472.39 mg, 3.42 mmol, 3 eq) at 25 °C. The mixture was stirred at 80 °C for 16 hours. TLC (Petroleum ether / EtOAc = 10 / 1) showed new spot was observed. The reaction mixture was diluted with H2O (10.0 mL), brine (5.0 mL) and extracted with EtOAc (5.0 mL x 2). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient @ 25 mL / min) to give compound 6 (258.0 mg, 764.58 μmol, 67.11% yield, 90% purity) as a yellow oil.

[0406] 1H NMR: (400 MHz, CDCI3) δ ppm: 8.35 (d, J = 2.4 Hz, 1H), 8.02 (dd, J= 9.2 Hz, 2.8 Hz, 1H), 6.88-6.97 (m, 3H), 6.78 (d, J= 92 Hz, 1H), 6.44-6.48 (m, 1H), 5.78-5.83 (m, 1H), 4.75- 4.76 (m, 2H).

[0407] Preparation of compound 7.

[0408] General procedure for preparation of compound 7.

[0409] To a solution of compound 6 (258.0 mg, 849.53 μmol, 1 eq in EtOH (5.0 mL) and H2O (1.0 mL) was added Fe (379.54 mg, 6.80 mmol, 8 eq) and NH4CI (363.54 mg, 6.80 mmol, 8 eq) at 25 °C. The mixture was stirred at 75 °C for 3 hours. TLC (Petroleum ether / EtOAc = 1 / 1) showed the new spot was observed. The mixture was concentrated under reduced pressure to give the residue, which was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to give compound 7 (210.0 mg, 690.50 μmol, 81.28% yield, 90% purity) as colorless oil.

[0410] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 6.72-6.76 (m, 3H), 6.69 (d, J= 2.4 Hz, 1H), 6.45- 6.53 (m, 3H), 5.90-5.95 (m, 1H), 5.21 (s, 2H), 4.77-4.79 (m, 2H).

[0411] Preparation of compound 9.

[0412] General procedure for preparation of compound 9.

[0413] To a solution of compound 7 (200.0 mg, 730.69 μmol, 1 eq and compound 8 (261.97 mg, 876.83 μmol, 1.2 eq in toluene (6.0 mL) was added CS2CO3(476.15 mg, 1.46 mmol, 2 eq), Xantphos (42.28 mg, 73.07 μmol, 0.1 eq and Pd(OAc)2(16.40 mg, 73.07 μmol, 0.1 eq at 25 °C. The mixture was stirred at 110 °C for 16 hours under N2. TLC (Petroleum ether / EtOAc = 1 / 1) showed new spots were observed. The mixture was concentrated under reduced pressure to give the residue, which was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0-60% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to give compound 9 (352.0 mg, 558.19 μmol, 76.39% yield, 85% purity) as colorless oil.

[0414] LCMS: ([M+H] = 536.1)

[0415] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.47 (s, 1H), 8.38 (s, 1H), 8.18 (s, 1H), 7.97 (d, J = 2.8 Hz, 1H), 7.60-7.64 (m, 1H), 6.90-6.92 (m, 1H), 6.84-6.88 (m, 2H), 6.76 (dd, J= 8.0 Hz, 2.0 Hz, 1H), 6.53-6.57 (m, 1H), 5.91-5.96 (m, 1H), 4.75-4.77 (m, 2H), 3.56 (br s, 4H), 2.85- 2.87 (m, 4H), 1.43 (s, 9H).

[0416] Preparation of compound 10.

[0417] General procedure for preparation of compound 10.

[0418] To a solution of compound 9 (330.0 mg, 615.65 μmol, 1 eq) in DCM (5.0 mL) was added HCl / dioxane (2 M, 10.0 mL, 32.49 eq) at 25 °C. The mixture was stirred at 25 °C for 4 hours. LCMS showed the desired mass was detected. The mixture was concentrated under reduced pressure to give compound 10 (260.0 mg, crude, HC1 salt) as a white solid.

[0419] LCMS: ([M+H] = 438.0)

[0420] Preparation of 286.

[0421] General procedure for preparation of 286.

[0422] To a solution of compound 10 (260.0 mg, 550.42 μmol, 1 eq, HC1 salt) in DCM (5.0 mL) was added DIPEA (213.41 mg, 1.65 mmol, 287.61 μL, 3 eq) at 25 °C. The mixture was cooled to 0 °C with ice bath, then compound 11 (49.82 mg, 550.42 μmol, 44.72 μL, 1 eq) in DCM (0.5 mL) was added to the mixture and stirred at 0 °C for 30 mins. LCMS showed the reaction was completed. H2O (0.5 mL) was added to the mixture and concentrated under reduced pressure to give the residue, which was purified by prep-HPLC (column: C18 150x30mm; mobile phase: [Water (NH4HCO3)-MeCN]; gradient: 39%-79% B over 9 min) to give 286 (86.0 mg, 174.47 μmol, 31.70% yield, 99.40% purity) as a white solid.

[0423] LCMS: ([M+H] = 490.0)

[0424] HPLC: (purity: 99.40%)

[0425] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.55 (s, 1H), 8.39 (s, 1H), 8.19 (s, 1H), 7.97 (d, J =

[0426] 2.4 Hz, 1H), 7.63 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 6.83-6.93 (m, 4H), 6.77 (dd, J= 8.0 Hz, 2.0 Hz, 1H), 6.54-6.58 (m, 1H), 6.16 (dd, J = 17.2 Hz, 2.4 Hz, 1H), 5.92-5.96 (m, 1H), 5.72 (dd, J =

[0427] 10.4 Hz, 2.4 Hz, 1H), 4.76-4.77 (m, 2H), 3.82 (br s, 4H), 2.86-2.94 (m, 4H).

[0428] Preparation of compound 3. General procedure for preparation of compound 3.

[0429] To a solution of compound 2 (1.5 g, 5.51 mmol, 1 eq and compound 1 (1.02 g, 5.51 mmol, 1 eq) in DCM (30 mL) was added TEA (1.39 g, 13.78 mmol, 1.92 mL, 2.5 eq . The mixture was stirred at 25 °C for 3 h. TLC (Petroleum ether / Ethyl acetate = 3 / 1, Rf = 0.45) showed Reactant 1 was consumed. To the mixture was added water (20 mL) and extracted with DCM (30 mL x 2). The organic phase was dried by Na2SO4and concentrated. The crude was purified on silica gel column chromatography (Ethyl acetate in Petroleum ether from 0% to 25%) to give compound 3 (2.0 g, 4.29 mmol, 77.73% yield, 90% purity) as a yellow solid.

[0430] 1H NMR: (400 MHz, CDCI3) δ ppm: 7.80 (d, J=2,4 Hz, 1H), 7.53-7.56 (m, 2H), 7.20-7.24 (m, 1H), 7.03-7.08 (m, 1H), 6.98 (d, J=8.8 Hz, 1H), 6.88-6.93 (m, 1H).

[0431] Preparation of compound 4.

[0432] General procedure for preparation of compound 4.

[0433] MeSCLNa (1.46 g, 14.28 mmol, 3 eq was added to solution of compound 3 (2.0 g, 4.76 mmol, 1 eq in DMF (30 mL). Stirring was continued for 2 h at 60 °C. LCMS showed desired mass was observed. The mixture was added water (35 mL) and extracted with EtOAc (40 mL x 2). The organic phase was washed with water (20 mL x 2), dried by Na2SO4and concentrated. To the crude was added EtOAc (5 mL) and petroleum ether (30 mL) and the mixture was stirred at 25 °C for 1 h. The crystallized substance was collected by filtration, washed with petroleum ether (20 mL) to give compound 4 (1.45 g, 3.09 mmol, 64.98% yield, 95% purity) as a yellow solid.

[0434] LCMS: ([M+H] = 445.0)1H NMR: (400 MHz, DMSO-d6) δ ppm: 13.34 (s, 1H), 9.33 (s, 1H), 8.07 (s, 1H), 7.55-7.58 (m, 1H), 7.40-7.43 (m, 1H), 7.19-7.25 (m, 2H), 6.99-7.03 (m, 1H), 3.44 (s, 3H).

[0435] Preparation of compound 5.

[0436] General procedure for preparation of compound 5.

[0437] To a solution of compound 4 (1 g, 2.25 mmol, 1 eq in THF (25 mL) was added Li A1H4(2.5 M, 4.49 mL, 5 eq) at 0 °C under N2. The reaction mixture was stirred at 0-10 °C for 2 h under N2. LCMS showed desired mass was observed. The mixture was added 0.5 N HC1 (10 mL) and added water (10 mL), then extracted with EtOAc (35 mL x 2) and the organic phase was concentrated. The crude was purified on silica gel column chromatography (Ethyl acetate in Petroleum ether from 0% to 60%) to compound 5 (350 mg, 762.61 μmol, 33.96% yield, 80% purity) as a yellow solid.

[0438] LCMS: ([M+H] = 367.0)

[0439] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 12.35 (s, 1H), 10.48 (s, 1H), 8.28 (s, 1H), 7.57-7.65 (m, 2H), 7.36-7.40 (m, 1H), 7.18-7.25 (m, 2H), 6.92-6.97 (m, 1H).

[0440] Preparation of compound 6.

[0441] 5 6

[0442] General procedure for preparation of compound 6.

[0443] To a solution of compound 5 (350 mg, 953.26 μmol, 1 eq) in DCE (10 mL) was added BnN Me3C1- (542.81 mg, 2.38 mmol, 2.5 eq), N, N-Dimethylaniline (231.03 mg, 1.91 mmol, 241.67 μL, 2 eq) and POCl3(876.98 mg, 5.72 mmol, 533.12 μL, 6 eq). Then the mixture was stirred at 100 °C for 0.1 h. LCMS showed desired mass was observed. The mixture was added a.q NaHCO3(30 mL). The mixture was added water (10 mL) and extracted with DCM (30 mL x 2). The organic phase was dried by Na2SO4and concentrated. The crude was purified on silica gel column chromatography (Ethyl acetate in Petroleum ether from 0% to 50%) to give compound 6 (120 mg, 248.96 μmol, 26.12% yield, 80% purity) as a yellow solid.

[0444] LCMS: ([M+H] = 386.8)

[0445] Preparation of compound 8.

[0446] 6 8

[0447] General procedure for preparation of compound 8.

[0448] A solution of compound 6 (120 mg, 311.20 μmol, 1 eq) and compound 7 (115.92 mg, 622.39 μmol, 2 eq) in n-BuOH (10 mL) was stirred at 120 °C for 16 h. LCMS showed desired mass was observed. The mixture was added water (20 mL) and extracted with EtOAc (30 mL x 2). The organic phase was dried by Na2SO4and concentrated. The crude was purified on silica gel column chromatography (Ethyl acetate in Petroleum ether from 0% to 50%) to give compound 8 (130 mg, 206.39 μmol, 66.32% yield, 85% purity) as a yellow solid.

[0449] LCMS: ([M+H] = 535.1)

[0450] 1H NMR: (400 MHz, CDCI3) δ ppm: 8.18 (s, 1H), 7.87 (d, J= 2.4 Hz, 1H), 7.40-7.43 (m, 1H), 7.33-7.35 (m, 1H), 7.16-7.20 (m, 1H), 6.96-7.04 (m, 2H), 6.81-6.85 (m, 1H), 3.84-3.86 (m, 4H), 3.53 (t, J= 4.8 Hz, 4H), 1.49 (s, 9H).

[0451] Preparation of compound 9.

[0452] 8 9

[0453] General procedure for preparation of compound 9.

[0454] A solution of compound 8 (130 mg, 242.81 μmol, 1 eq) and HCI / dioxane (2 M, 1.21 mL, 10 eq in DCM (3 mL) was stirred at 25 °C for 1 h. LCMS showed desired mass was observed. The mixture was concentrated to give compound 9 (100 mg, crude) as a yellow solid.

[0455] LCMS: ([M+H] = 435.0)

[0456] Preparation of 287.

[0457] 9 287 General procedure for preparation of 287.

[0458] To a solution of compound 9 (100 mg, 211.98 μmol, 1 eq, HC1 salt) and DIEA (82.19 mg, 635.94 μmol, 110.77 μL, 3 eq) in DCM (6 mL) was added compound 10 (17.27 mg, 190.78 μmol, 15.50 μL, 0.9 eq) at 0 °C. Then the mixture was stirred at 0 °C for 10 min. LCMS showed desired mass was observed. The mixture was quenched by water (20 mL). Then to the crude was extracted with DCM (25 mL x 2). The organic phase was washed by water (20 mL), dried by Na2SO4, filtered and concentrated. The crude was purified on silica gel column chromatography (Ethyl acetate in Petroleum ether from 0% to 100%). Then the product was purified further by prep-TLC (Ethyl acetate / MeOH = 25 / 1, Rf= 0.45) to give 287 (22 mg, 42.68 μmol, 20.13% yield, 94.93% purity) as a white solid.

[0459] LCMS: ([M+H] = 489.1)

[0460] HPLC: (purity: 94.93%)

[0461] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 10.16 (s, 1H), 8.19 (s, 1H), 8.03 (d, J= 2.4 Hz, 1H), 7.66 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.36-7.40 (m, 1H), 7.18-7.23 (m, 2H), 6.94-6.98 (m, 1H), 6.86 (dd, J= 16.4 Hz, 10.4 Hz, 1H), 6.15 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.71 (dd, J= 10.4 Hz, 2.0 Hz, 1H), 3.76-3.78 (m, 4H), 3.65-3.70 (m, 4H).

[0462] Preparation of compound 3&3A.

[0463] General procedure for preparation of compound 3&3A.

[0464] To a solution of compound 2 (760 mg, 3.93 mmol, 1 eq) and compound 1 (287.74 mg, 1.96 mmol, 0.5 eq) in DMF (10.0 mL) was added K2CO3(1.09 g, 7.85 mmol, 2 eq) at 25 °C. The mixture was stirred at 80 °C for 16 hours. TLC (Petroleum ether / EtOAc = 10 / 1) showed new spots were observed. The reaction mixture was diluted with H2O (50.0 mL), brine (10.0 mL) and extracted with EtOAc (30.0 mL x 3). The combined organic layers were washed with brine (50.0 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (ISCO®; 20 g Sepa Flash® Silica Flash Column, Eluent of 0~l% Ethyl acetate / Petroleum ether gradient @ 25 mL / min) to give compound 3&3A (437.0 mg, 901.10 μmol, 22.95% yield, 66% purity) as a yellow oil.

[0465] Preparation of compound 4&4A.

[0466] General procedure for preparation of compound 4&4A.

[0467] To a solution of compound 3&3A (435 mg, 1.36 mmol, 1 eq in EtOH (5.0 mL) and H2O (1.0 mL) was added Fe (607.17 mg, 10.87 mmol, 8 e ) and NH4CI (581.58 mg, 10.87 mmol, 8 eq) at 25 °C. The mixture was stirred at 75 °C for 2 hours. TLC (Petroleum ether / EtOAc = 1 / 1) showed the starting material was consumed and new spots were observed. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 25 mL / min) to give compound 4&4A (271.0 mg, 560.51 μmol, 41.24% yield, 60% purity) was obtained as brown oil.

[0468] Preparation of compound 6&6A.

[0469] General procedure for preparation of compound 6&6A. To a solution of compound 4&4A (390.0 mg, 1.34 mmol, 1 eq) and compound 5 (482.0 mg, 1.61 mmol, 1.2 eq in toluene (10.0 mL) was added CS2CO3(876.06 mg, 2.69 mmol, 2 eq), Xantphos (77.79 mg, 134.44 μmol, 0.1 eq) and Pd(OAc)2(30.18 mg, 134.44 μmol, 0.1 eq) at 25 °C. The mixture was stirred at 110 °C for 16 hours under N2. LCMS showed the desired mass was detected. The mixture was concentrated under reduced pressure to give the residue, which was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient @ 25 mL / min) to give compound 6&6A (620.0 mg, 628.53 μmol, 46.75% yield, 56% purity) as yellow oil, which was purified by prep-HPLC (column: C18 150x40mm; mobile phase: [Water (FA)- MeCN]; gradient: 45%-85% B over 9 min) to give compound 6&6A (370.0 mg, 455.47 μmol, 37.55% yield, 68% purity) as yellow oil.

[0470] LCMS: ([M+H] = 552.1)

[0471] Preparation of compound 7& 7A.

[0472] General procedure for preparation of compound 7& 7A.

[0473] To a solution of compound 6&6A (350.0 mg, 633.60 μmol, 1 eq) in DCM (1.0 mL) was added HCl / dioxane (2 M, 5.0 mL, 15.78 eq) at 25 °C. The mixture was stirred at 25 °C for 2 hours. LCMS showed the desired mass was detected. The mixture was concentrated under reduced pressure to give compound 7&7A (300.0 mg, crude, HC1 salt) as a white solid.

[0474] LCMS: ([M+H] = 453.9)

[0475] Preparation of 288.

[0476] General procedure for preparation of 288&288A-Notebook Page: ES22530-739-P1.

[0477] To a solution of compound 7&7A (300 mg, 613.82 μmol, 1 eq, HC1 salt) in DCM (5.0 mL) was added DIEA (237.99 mg, 1.84 mmol, 320.74 μL, 3 eq) at 25 °C. The mixture was cooled to 0 °C with ice bath, then compound 8 (55.56 mg, 613.82 μmol, 49.87 μL, 1 eq) in DCM (0.5 mL) was added to the mixture and stirred at 0 °C for 0.5 hour. LCMS showed the desired mass was detected. H2O (0.5 mL) was added to the mixture and concentrated under reduced pressure to give the residue, which was purified by prep-HPLC (column: C18 150x40mm; mobile phase: [water (NH4HCO3)-MeCN] ; gradient: 45%-85% B over 9 min) to give 288A (55.0 mg, 108.62 μmol, 17.70% yield, 100% purity) as a white solid and 288 (120.0 mg, 235.34 μmol, 38.34% yield, 99.30% purity) as a white solid.

[0478] Spectra of 288A

[0479] LCMS: ([M+H] = 505.9)

[0480] HPLC: (purity: 100%)

[0481] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.34 (s, 2H), 8.14 (s, 1H), 8.04 (dd, J= 9.2 Hz, 5.6 Hz, 1H), 7.51 (t, J = 8.8 Hz, 1H), 7.24-7.28 (m, 1H), 7.02-7.04 (m, 1H), 6.76-6.84 (m, 1H), 6.66-6.70 (m, 1H), 6.13 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.71 (dd, J= 10.8 Hz, 2.4 Hz, 1H), 3.46- 3.53 (m, 4H), 2.59-2.68 (m, 4H).

[0482] Spectra of 288

[0483] LCMS: ([M+H] = 505.9)

[0484] HPLC: (purity: 99.30%)

[0485] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.56 (s, 1H), 8.32 (s, 1H), 8.18 (s, 1H), 7.63 (t, J = 8.8 Hz, 1H), 7.43-7.48 (m, 1H), 7.24-7.29 (m, 1H), 7.09-7.13 (m, 1H), 6.98-7.04 (m, 1H), 6.83- 6.70 (m, 1H), 6.16 (dd, J= 16.4 Hz, 2.0 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.68-3.78 (m, 4H), 2.90-2.98 (m, 4H).

[0486] Preparation of compound 3.

[0487] 1 3

[0488] General procedure for preparation of compound 3.

[0489] To a solution of compound 2 (300 mg, 1.71 mmol, 1 eq and compound 1 (230.92 mg, 1.71 mmol, 1 eq) in DMF (10 mL) was added CS2CO3(835.22 mg, 2.56 mmol, 1.5 eq . Then the mixture was stirred at 80 °C for 16 h. TLC (Petroleum ether / Ethyl acetate=3 / l, Rf=0.3) showed Reactant 1 was consumed. The mixture was added water (30 mL) and extracted with EtOAc (40 mL x 2). The organic phase was washed with water (15 mL x 2), dried by Na2SO4and concentrated. To the crude was added DCM (3 mL) and petroleum ether (20 mL) and the mixture was stirred at 25 °C for 1 h. The crystallized substance was collected by filtration, washed with petroleum ether (20 mL) to give compound 3 (450 mg, 1.47 mmol, 86.06% yield, 95% purity) as a yellow solid.

[0490] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.61 (d, J= 7.2 Hz, 1H), 8.46 (d, J= 2.8 Hz, 1H), 8.32 (s, 1H), 8.23 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.29 (d, J= 8.8 Hz, 1H), 7.06 (d, J= 2.4 Hz, 1H), 6.92 (dd, J= 7.2 Hz, 2.4 Hz, 1H).

[0491] Preparation of compound 4.

[0492] 3 4

[0493] General procedure for preparation of compound 4.

[0494] Fe (432.29 mg, 7.74 mmol, 5 eq and NH4CI (414.07 mg, 7.74 mmol, 5 eq were added to a solution of compound 3 (450 mg, 1.55 mmol, 1 eq in EtOH (10 mL) and H2O (5 mL). The resultant mixture was heated to 90 °C for 2 h. TLC (Petroleum ether / Ethyl acetate=l / l, Rf=0.25) showed compound 3 was consumed. The mixture was filtered. To the solution was added water (20 mL) and extracted with EtOAc (30 mL x 2). The organic phase was washed with a.q Na2CO3(20 mL x 2) and water (20 mL), dried by Na2SO4and concentrated. To the crude was added DCM (3 mL) and petroleum ether (15 mL) and the mixture was stirred at 25 °C for 1 h. The crystallized substance was collected by filtration, washed with petroleum ether (20 mL) to give compound 4 (350 mg, 1.28 mmol, 82.39% yield, 95% purity) as a yellow solid.

[0495] 1H NMR: (400 MHz, CDCI3) δ ppm: 8.47 (d, J= 7.6 Hz, 1H), 8.21 (s, 1H), 6.99 (d, J= 8.4 Hz, 1H), 6.87 (dd, J= 7.6 Hz, 2.8 Hz, 1H), 6.80-6.82 (m, 2H), 6.62 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 3.80 (br s, 2H).

[0496] Preparation of compound 6.

[0497] General procedure for preparation of compound 6.

[0498] To a solution of compound 4 (130 mg, 498.70 μmol, 1 eq) and compound 5 (163.89 mg, 548.57 μmol, 1.1 eq) in toluene (10 mL) was added Pd(OAc)2(11.20 mg, 49.87 μmol, 0.1 eq), Xantphos (28.86 mg, 49.87 μmol, 0.1 eq) and CS2CO3(324.97 mg, 997.40 μmol, 2 eq). Then the mixture was stirred at 110 °C for 16 h under N2. LCMS showed desired mass was observed. The mixture was filtered. Then to the crude was added water (30 mL) and extracted with EtOAc (30 mL x 2). The organic phase was washed by water (20 mL), dried by Na2SO4, filtered and concentrated. The crude was purified on silica gel column chromatography (EtOAc in petroleum ether from 0% to 85%) to give compound 6 (210 mg, 361.39 μmol, 72.47% yield, 90% purity) as yellow oil.

[0499] LCMS: ([M+H]=523.2)

[0500] 1H NMR: (400 MHz, CDCI3) δ ppm: 8.60 (s, 1H), 8.51 (d, J= 7.6 Hz, 1H), 8.23 (s, 1H), 8.19 (s, 1H), 8.03 (d, J= 2.4 Hz, 1H), 7.76 (s, 1H), 7.63 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.22 (d, J= 8.4 Hz, 1H), 6.91 (dd, J= 7.6 Hz, 2.8 Hz, 1H), 6.84 (d, J= 2.4 Hz, 1H), 3.44-3.86 (m, 4H), 2.95- 2.97 (m, 4H), 1.50 (s, 9H). Preparation of compound 7.

[0501] General procedure for preparation of compound 7.

[0502] To a solution of compound 6 (210 mg, 401.54 μmol, 1 eq) in DCM (6 mL) was added TFA (457.85 mg, 4.02 mmol, 298.27 μL, 10 eq and the mixture was stirred at 25 °C for 16 h. LCMS showed desired mass was observed. The mixture was concentrated to give compound 7 (210 mg, crude, TFA salt) as yellow oil.

[0503] LCMS: ([M+H]=423.1)

[0504] Preparation of 290. 290

[0505] General procedure for preparation of 290.

[0506] To a solution of compound 7 (190 mg, 353.89 μmol, 1 eq, TFA salt) and DIEA (228.68 mg, 1.77 mmol, 308.20 μL, 5 eq) in DCM (15 mL) was added compound 8 (32.03 mg, 353.89 μmol, 28.75 μL, 1 eq) at 0 °C. Then the mixture was stirred at 0 °C for 10 min. LCMS showed desired mass was observed. The mixture was quenched by water (0.1 mL) and concentrated. The crude was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5pm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 30%-60% B over 11 min) to give 290 (101 mg, 210.14 μmol, 59.38% yield, 99.227% purity) as a white solid.

[0507] LCMS: ([M+H]=477.1)

[0508] HPLC: (purity: 99.23%)1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.96 (d, J= 7.6 Hz, 1H), 8.71 (s, 1H), 8.47 (s, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 8.19 (d, J= 2.4 Hz, 1H), 7.93 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.44 (d, J= 8.8 Hz, 1H), 7.05 (dd, J= 7.6 Hz, 2.8 Hz, 1H), 6.84-6.91 (m, 2H), 6.16 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.73 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.82-3.84 (m, 4H), 2.94-2.95 (m, 4H).

[0509] Preparation of compound 3.

[0510] General procedure for preparation of compound 3.

[0511] To a solution of compound 1 (200.0 mg, 1.14 mmol, 1 eq) and compound 2 (152.82 mg, 1.14 mmol, 1 eq) in DMF (8.0 mL) was added K2CO3(472.38 mg, 3.42 mmol, 3 eq) at 25 °C. The mixture was stirred at 80 °C for 16 hours. TLC (Petroleum ether / EtOAc = 1 / 1) showed new spot was observed. The reaction mixture was diluted with H2O (20.0 mL), brine (10.0 mL) and extracted with EtOAc (15.0 mL x 2). The combined organic layers were washed with brine (30.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (ISCO®; 10 g Sepa Flash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 25 mL / min) to give compound 3 (200.0 mg, 621.39 μmol, 54.54% yield, 90% purity) as a yellow solid.

[0512] 1H NMR: (400 MHz, CDCI3) δ ppm: 8.42 (d, J= 2.4 Hz, 1H), 8.17 (d, J= 7.6 Hz, 1H), 8.14 (dd, J= 9.2 Hz, 2.8 Hz, 1H), 7.64 (s, 1H), 7.59 (s, 1H), 7.15 (d, J = 9.2 Hz, 1H), 7.08-7.12 (m, 1H), 6.69 (dd, J = 7.2 Hz, 2.0 Hz, 1H).

[0513] Preparation of compound 4. General procedure for preparation of compound 4.

[0514] To a solution of compound 3 (200.0 mg, 690.43 μmol, 1 eq) in EtOH (5.0 mL) and H2O (1 mL) was added Fe (308.46 mg, 5.52 mmol, 8 eq) and NH4CI (295.46 mg, 5.52 mmol, 8 eq) at 25 °C. The mixture was stirred at 75 °C for 3 hours. TLC (EtOAc) showed the new spot was observed. The mixture was concentrated under reduced pressure to give the residue, which was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 18 mL / min) to give compound 4 (167.0 mg, 578.77 μmol, 83.83% yield, 90% purity) as off-white solid.

[0515] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.49 (d, J= 7.2 Hz, 1H), 7.81 (s, 1H), 7.41 (s, 1H), 7.02 (d, J= 8.8 Hz, 1H), 6.73-6.76 (m, 2H), 6.60 (dd, J= 8.4 Hz, 2.8 Hz, 1H), 6.41 (d, J= 2.4 Hz, 1H), 5.44 (br s, 2H).

[0516] Preparation of compound 6.

[0517] 4 6

[0518] General procedure for preparation of compound 6.

[0519] To a solution of compound 4 (100.0 mg, 385.07 μmol, 1 eq) and compound 5 (138.06 mg, 462.09 μmol, 1.2 eq) in toluene (10.0 mL) was added CS2CO3(250.93 mg, 770.15 μmol, 2 eq), Xantphos (22.28 mg, 38.51 μmol, 0.1 eq) and Pd(OAc)2(8.65 mg, 38.51 μmol, 0.1 eq) at 25 °C. The mixture was stirred at 110 °C for 16 hours under N2. TLC (EtOAc) showed new spots was observed. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0- 100% Ethyl acetate / Petroleum ether gradient @ 18 mL / min) to give compound 6 (157.0 mg, 270.69 μmol, 70.30% yield, 90% purity) as a yellow solid.

[0520] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.60 (s, 1H), 8.55 (d, J = 7.6 Hz, 1H), 8.45 (s, 1H), 8.24 (s, 1H), 8.15 (d, J= 2.4 Hz, 1H), 7.85-7.89 (m, 2H), 7.45 (d, J= 2.0 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.82 (dd, J= 7.6 Hz, 2.8 Hz, 1H), 6.58 (d, J= 2.4 Hz, 1H), 3.59 (br s, 4H), 2.87- 2.90 (m, 4H), 1.43 (s, 9H).

[0521] Preparation of compound 7.

[0522] General procedure for preparation of compound 7.

[0523] To a solution of compound 6 (145 mg, 277.78 μmol, l eq) in DCM (5.0 mL) was added HCl / dioxane (2 M, 5.0 mL, 36.00 eq) at 25 °C. The mixture was stirred at 25 °C for 3 hours. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure to give compound 7 (125.0 mg, crude, HC1 salt) as a light-yellow solid.

[0524] LCMS: ([M+H] = 422.0)

[0525] Preparation of 293.

[0526] General procedure for preparation of 293.

[0527] To a solution of compound 7 (125.0 mg, 272.72 μmol, 1 eq, HC1 salt) in DCM (5.0 mL) was added DIEA (105.74 mg, 818.16 μmol, 142.51 μL, 3 eq) at 25 °C. The mixture was cooled to 0 °C with ice-bath, compound 8 (24.68 mg, 272.72 μmol, 22.16 μL, 1 eq) in DCM (0.1 mL) was added to the mixture and stirred at 0 °C for 40 mins. LCMS showed the reaction was completed. H2O (0.5 mL) was added to the mixture and concentrated under reduced pressure to give the residue, which was purified by prep -HPLC (column: Welch Xtimate Cl 8 150*25mm*5um; mobile phase: [H2O (lOmM NH4HCO3)-ACN]; gradient: 25%-55% B over 11.0 min) to give 293 (35.0 mg, 71.22 μmol, 26.11% yield, 96.84% purity) as a white solid. LCMS: ([M+H] = 476.2) HPLC: (purity: 96.84%)

[0528] 1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.67 (s, 1H), 8.56 (d, J= 7.6 Hz, 1H), 8.46 (s, 1H), 8.24 (s, 1H), 8.15 (d, J= 2.8 Hz, 1H), 7.85-7.90 (m, 2H), 7.45 (d, J= 0.8 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.87 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 6.82 (dd, J= 7.6 Hz, 2.8 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 6.16 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.84 (br s, 4H), 2.89-2.98 (m, 4H).

[0529] Experimental Section:

[0530] General: THF was distilled from sodium under an argon atmosphere. Methylene chloride was distilled from calcium hydride under an argon atmosphere. All other solvents or reagents were purified according to literature procedures.1H NMR spectra were recorded on Bruker spectrometers at 400 MHz or 500 MHz and are reported relative to deuterated solvent signals. Data for1H NMR spectra are reported as follows: chemical shift (δ ppm), multiplicity, coupling constant (Hz) and integration. Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and br, broad.13C NMR spectra were recorded on Bruker Spectrometers at 100 MHz or 125 MHz. Data for13C NMR spectra are reported as follows: chemical shift ( δ ppm), multiplicity and coupling constant (Hz). Splitting patterns are designated as the same in1H NMR. High resolution mass spectrometry was taken on a Thermo Fisher Scientific Exactive Plus mass spectrometer equipped with an lonSense ID- CUBE DART ion source.

[0531] General Procedure 7:

[0532]

[0533] Preparation of Gp7-2: To a solution of Gp7-1 (2.0 eq) and Gpl-4 (1.0 eq) in z-PrOH (5.0 M) was added PyHCl (0.1 eq). The mixture was stirred at 80 °C for 3 h. The mixture was cooled down to 21 °C. The solvent was removed under vacuum. The residue was dissolved in NaHCO3(aq.) and extracted 3 times with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (DCM / MeOH) to give compound Gp7-2.

[0534] Preparation of Gp7-3: To a solution of Gpl-6 (2.4 eq) in dry THF (3.0 M) was dropwise added zz-BuLi (2.4 eq, 1.6 M in Hexane) at -78 °C. The mixture was stirred at -78 °C for 30 min. Then a solution of Gp7-2 in dry THF (5.0 M) was dropwise added. The mixture was stirred at -78 °C for 15 min and then gradually warmed to 21 °C. The mixture was stirred at 21 °C for 1 hour and then poured into NH4CI (aq.), extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (DCM / MeOH) to give Gp7-3.

[0535] Preparation of Gp7-4: To a solution of Gp7-3 (1.0 eq) in DCM (5.2 M) was added HC1 in dioxane (4 M, 4.0 eq). The mixture was stirred at 21 °C for 4 h. The mixture was concentrated to give compound Gp7-4 which was used to next step directly.

[0536] Preparation of final Test Compounds: To a solution of Gp7-4 (1.0 eq) in DCM (5.0 M) was added DIPEA (3.0 eq) and acryloyl chloride (1.0 eq). The mixture was stirred at 0 °C for 0.5 h. Then the mixture was diluted with DCM and washed with NaHCO3(aq.), brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (DCM / MeOH) to give Test compounds.

[0537] General Procedure 8:

[0538] Preparation of Gp8-2: To a solution of BnOH (2.0 eq) in DMF (1.0 M) was added t-BuOK (2.0 eq) at 0 °C. Then compound Gp8-1 (1.0 eq) was added at 0 °C and the mixture was stirred at 25 °C for 1.5 h. LCMS showed desired mass was observed. The mixture was added NH4CI (aq.) and extracted with EtOAc. The organic phase was washed by water, dried over Na2SO4, filtered and concentrated. The crude was purified on silica gel column chromatography (EtOAc / Petroleum ether) to give Gp8-2.

[0539] Preparation of Gp8-3: To a solution of Gpl-6 (3.0 eq) and Gp8-2 (1.0 eq) in dioxane (3.8 M) was added CS2CO3(3.0 eq) and Xphos Pd G3 (0.05 eq) under N2. Then the mixture was stirred at 90 °C for 16 h under N2. LCMS showed desired mass was observed. The mixture was filtered and concentrated. The crude was purified on silica gel column chromatography (EtOAc / Petroleum ether) to giveGp8-3.

[0540] Preparation of Gp8-4: To a solution of Gp8-3 (1.0 eq) in MeOH (7.0 M) was added Pd / C (10% purity, 1.23e-1eq) under N2. Then the mixture was stirred at 50 °C for 16 h under H2 (45 psi). LCMS showed desired mass was observed. The mixture was filtered and concentrated. The crude was purified on silica gel column chromatography (EtOAc / Petroleum ether) to give Gp8-4.

[0541] Preparation of Gp8-5: To a solution of Gp8-4 (1.0 eq) in DCE (8.5 M) was added DMF (2.0 eq) and oxalyl chloride (2.0 eq). The mixture was stirred at 80 °C for 15 min. LCMS showed the reaction was completed. The mixture was added NaHCO3(aq.) and extracted with DCM. The organic phase was washed by water, dried over Na2SO4, filtered and concentrated to give compound Gp8-5.

[0542] Preparation of Gp7-3: To a solution of Gp8-5 (1.3 eq) and Gpl-4 (1.0 eq) in toluene (14.4 M) was added CS2CO3(2.0 eq), Pd(OAc)2(0.1 eq) and XantPhos (0.1 eq). Then the mixture was stirred at 110 °C for 16 h under N2. LCMS showed desired mass was observed. The mixture was added water and extracted with EtOAc. The organic phase was washed by water, dried over Na2SO4, filtered and concentrated. The crude was purified on silica gel column chromatography (EtOAc / Petroleum ether) to give Gp7-3.

[0543] Preparation of Gp8-6: To a solution of Gp7-3 (1.0 eq) in DCM (10.0 M) was added TFA (13.5 eq). Then the mixture was stirred at 25 °C for 16 h. LCMS showed desired mass was observed. The mixture was concentrated to give Gp8-6 as TFA salt.

[0544] In an alternative method, Gp8-6 may also be prepared by treating Gp7-3 with hydrochloric acid (HC1) following the same procedure used for the synthesis of Gp7-4. In this case, Gp8-6 is obtained as HC1 salt.

[0545] Preparation of final Test compounds: To a solution of Gp8-6 (1.0 eq) and DIPEA (3.0 eq) in DCM (5.0 M) was added acryloyl chloride (1.0 eq) at 0 °C. Then the mixture was stirred at 0 °C for 0.5 h. LCMS showed desired mass was observed. The mixture was quenched by water and concentrated. The crude was purified by prep-HPLC (column: Welch Xtimate Cl 8; mobile phase: [water ( NH4HCO3) -ACN]) to give Test compounds.

[0546] General Procedure 9:

[0547] Preparation of Gp9-2 and Gp9-2': To a solution of compound Gp9-1 (1.0 eq) and compound R2OH (0.5 eq) in DMF (2.5 M) was added K2CO3(2.0 eq) at 25 °C. The mixture was stirred at 80 °C for 16 h. TLC (Petroleum ether / EtOAc) showed new spots were observed. The reaction mixture was diluted with H2O and brine (v / v 5: 1) and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (ISCO®; Sepa Flash® Silica Flash Column, Eluent of

[0548] Ethyl acetate / Petroleum ether gradient @ 25 mL / min) to give a mixture of Gp9-2 and Gp9- 2'.

[0549] Preparation of Gp9-3 and Gp9-3': To a solution of compounds Gp9-2 and Gp9-2' (1.0 eq) in EtOH (4.0 M) and H2O (0.80 M) was added Fe (8.0 eq) and NH4CI (8.0 eq) at 25 °C. The mixture was stirred at 75 °C for 2 h. TLC (Petroleum ether / EtOAc) showed the starting material was consumed and new spots were observed. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; Sepa Flash® Silica Flash Column, Eluent of

[0550] Ethyl acetate / Petroleum ether gradient @ 25 mL / min) to give a mixture of Gp9-3 and Gp9- 3'. Preparation of Gp9-4 and Gp9-4': To a solution of compounds Gp9-3 and Gp9-3' (1.0 eq), and compound Gp8-5 (1.2 eq) in toluene (10.0 mL, 7.5 M) was added CS2CO3(2.0 eq), Xantphos (0.1 eq) and Pd(OAc)2(0.1 eq) at 25 °C. The mixture was stirred at 110 °C for 16 h under N2. LCMS showed the desired mass was detected. The mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (ISCO®; Sepa Flash® Silica Flash Column, Eluent of

[0551] Ethyl acetate / Petroleum ether gradient @ 25 mL / min) to give a mixture of Gp9-4 and Gp9- 4'.

[0552] Preparation of Gp9-5 and Gp9-5': To a solution of compounds Gp9-4 and Gp9-4' (1.0 eq) in DCM (1.6 M) was added HCl / dioxane (2 M, 15.0 eq) at 25 °C. The mixture was stirred at 25 °C for 2 h. LCMS showed the desired mass was detected. The mixture was concentrated under reduced pressure to give compound Gp9-5 and Gp9-5'.

[0553] Preparation of Gp9-6 and Gp9-6' (Final Test Compounds): To a solution of compounds Gp9-5 and Gp9-5' (1.0 eq, HC1 salt) in DCM (8.0 M) was added DIPEA (3.0 eq) at 25 °C. The mixture was cooled to 0 °C with ice bath, then acryloyl chloride (1.0 eq) in DCM (0.8 M) was added to the mixture and stirred at 0 °C for 0.5 h. LCMS showed that the desired mass was detected. H2O was added to the mixture and concentrated under reduced pressure to give a residue which contained the mixture of Gp9-6 and Gp9-6'. The two compounds were separated by prep-HPLC affording pure Gp9-6 and pure Gp9-6'. l-( 4-( 4-(( 3-chloro-4-(3-chloro-2-fluorophenoxy)phenyl)amino)pyrimidin-5-yl)piperazin-l- yl)prop-2-en-l-one (267)

[0554] 267 was prepared by following General Procedure 7.1H NMR. (500 MHz, DMSO-d6) δ ppm: 8.63 (s, 1H), 8.42 (s, 1H), 8.21 (br s, 1H), 8.08 (d, J= 2.5 Hz, 1H), 7.79 (dd, J= 9.0, 2.5 Hz, 1H), 7.33 (m, 1H), 7.21 (d, J= 9.0 Hz, 1H), 7.17 (td, J= 8.3, 2.0 Hz, 1H), 6.88-6.82 (m, 2H), 6.14 (dd, J= 16.5, 2.5 Hz, 1H), 5.70 (dd, J= 10.5, 2.5 Hz, 1H), 3.81 (br s, 4H), 2.90 (br s, 4H);13C NMR (125 MHz, DMSO-d6) δ ppm: 164.8, 155.3, 153.6, 148.7 (d, J= 246.5 Hz), 146.9, 146.1, 146.0 (d, J= 10.6 Hz), 137.7, 132.5, 128.7, 128.1, 126.0 (d, J= 5.0 Hz), 125.2, 124.5, 123.5, 122.3, 121.6 (d, J= 14.8 Hz), 121.5, 117.9, 51.7, 51.0, 45.5, 41.9;

[0555] HRMS (ESI, m / z): calcd for C23H19CI2FN5O2([M-H]'): 486.0905, Found: 486.0896 l-( 4-( 4-( 3-chloro-4-(3-chloro-2-fluorophenoxy)phenyl)amino)-6-methoxypyrimidm-5- yl)piperazin-l-yl)prop-2-en-l-one (270)

[0556] 270 was prepared by following General Procedure 7. One modification was replacing the Gp7-1 with compound Intl-270: The final product 270 was obtained as a white foamy solid.1H NMR (500 MHz, DMSO-d6) δ ppm: 9.50 (d, = 1.5 Hz, 1H), 8.19 (s, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.61 (dd, J= 9.0, 2.5 Hz, 1H), 7.24 (dd, = 8.5, 1.5 Hz, 1H), 7.11 (t, J= 8.3 Hz, 1H), 6.98 (d, J = 9.0 Hz, 1H), 6.78 (dd, J = 16.5, 10.5 Hz, 1H), 6.68 (dd, J = 8.0, 1.5 Hz, 1H), 6.07 (dd, J = 16.5, 2.5 Hz, 1H), 5.64 (dd, J = 10.5, 2.0 Hz, 1H), 3.94 (s, 3H), 3.35-3.28 (m, 4H), 3.12-3.02 (m, 4H);13C NMR (125 MHz, DMSO-d6) δ ppm: 164.8, 156.5 (d, J = 6.6 Hz), 155.5, 151.9 (d, J= 11.9 Hz), 149.6 (d, J = 6.9 Hz), 147.0, 138.4, 137.0, 134.0, 131.7 (d, J= 255.5 Hz), 128.7, 128.0, 127.2, 125.6, 124.0, 122.5, 121.3, 120.6, 117.7, 54.6, 51.1, 50.4, 46.6, 42.9; HRMS (ESI, m / z): calcd for C24H21CI2FN5O3 ([M-H]'): 516.1010, Found: 516.1000 l-( 4-( 4-(( 3-chloro-4-(3-chloro-2-fluorophenoxy)phenyl)ammo)pyrimidin-5-yl)piperazm-l- yl)propan-l-one (271)

[0557] 271 was prepared by following General Procedure 8. One modification was replacing the acryloyl chloride in the last synthetic step with propionyl chloride.1H NMR (500 MHz, DMSO-d6) δ ppm: 8.62 (s, 1H), 8.41 (s, 1H), 8.19 (s, 1H), 8.08 (d, J= 3.0 Hz, 1H), 7.78 (dd, J= 9.0, 2.5 Hz, 1H), 7.33 (m, 1H), 7.21 (d, J= 9.0 Hz, 1H), 7.17 (td, J= 8.3, 2.0 Hz, 1H), 6.88-6.84 (m, 1H), 3.67 (br s, 4H), 2.89-2.85 (m, 4H), 2.35 (q, J= 7.5 Hz, 2H), 1.00 (t, J = 7.5 Hz, 3H);13C NMR (125 MHz, DMSO-d6) δ ppm: 171.9, 155.2, 153.6, 148.7 (d, J= 246.5 Hz), 146.8, 146.04, 145.98 (d, J= 10.6 Hz), 137.7, 132.7, 126.0 (d, J= 5.0 Hz), 125.2, 124.5, 123.5, 122.3, 121.6 (d, J= 14.5 Hz), 121.5, 117.9, 51.5, 51.1, 45.2, 41.4, 26.0, 9.9; HRMS (ESI, m / z): calcd for C23H21CI2FN5O2 ([M-H]'): 488.1061, Found: 488.1046

[0558] 1-( 4-( 4-(( 4-(benzofuran- 7-yloxy)-3-chlorophenyl)amino)pyrimidin-5-yl)piperazin-l-yl)prop-

[0559] 2-en-l-one (276)

[0560] 276 was prepared by following General Procedure 8.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.62 (s, 1H), 8.42 (s, 1H), 8.22 (s, 1H), 8.08 (d, J= 2.4 Hz, 1H), 8.03 (d, J= 2.4 Hz, 1H), 7.73 (dd, J= 8.8, 2.4 Hz, 1H), 7.44 (d, J= 7.6 Hz, 1H), 7.20 (t, J= 8.0 Hz, 1H), 7.11 (d, J= 9.2 Hz, 1H), 7.04 (d, J= 2.0 Hz, 1H), 6.83-6.90 (m, 1H), 6.76 (d, J= 7.6 Hz, 1H ), 6.16 (dd, J= 16.4, 2.4 Hz, 1H), 5.72 (dd, J= 10.4, 2.4 Hz, 1H), 3.80-3.83 (m, 4H), 2.92-2.93 (m, 4H); MS (m / z) [M+H]+calcd for C25H23C1N5O3+, 476.1, found, 476.2 l-( 4-( 4-(( 4-(3-chloro-2-fluorophenoxy)-3-fluorophenyl)ammo)pyrimidm-5-yl)piperazm-l- yl)prop-2-en-l-one (277)

[0561] 277 was prepared by following General Procedure 8.1H NMR (500 MHz, DMSO-d6) δ ppm: 8.63 (s, 1H), 8.42 (s, 1H), 8.21 (s, 1H), 7.96 (dd, J= 13.5, 2.5 Hz, 1H), 7.61 (d, J= 8.5 Hz, 1H), 7.34-7.31 (m, 1H), 7.25 (t, J= 9.0 Hz, 1H), 7.17 (td, J= 16.5, 1.5 Hz, 1H), 6.94 (t, J = 7.8 Hz, 1H), 6.84 (dd, J= 16.5, 10.0 Hz, 1H), 6.13 (dd, J= 17.0, 2.5 Hz, 1H), 5.70 (dd, J = 10.5, 2.5 Hz, 1H), 3.81 (br s, 4H), 2.90 (br s, 4H);13C NMR (125 MHz, DMSO-d6) δ ppm: 164.8, 155.2, 153.6, 153.1 (d, J = 243.0 Hz), 148.7 (d, J= 246.3 Hz), 146.9, 146.3 (d, J= 7.0 Hz), 137.8 (d, J= 9.6 Hz), 137.3 (d, J= 11.9 Hz), 132.6, 128.7, 128.1, 126.0 (d, J= 5.0 Hz), 125.1, 122.1, 121.6 (d, J= 14.4 Hz), 118.5 (d, J= 2.8 Hz), 117.6, 110.5 (d, J= 22.3 Hz), 51.7, 51.0, 45.5, 41.9; HRMS (ESI, m / z): calcd for C23H19CIF2N5O2 ([M-H]'): 470.1200, Found: 470.1188 l-( 4-( 4-(( 3-chloro-4-( ( 4-chloro-3-fluorobenzyl)oxy)phenyl )amino)pyrimidin-5-yl)piperazm- l-yl)prop-2-en-l-one (278)

[0562] 278 was prepared by following General Procedure 8.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.46 (br s, 1H), 8.36 (s, 1H), 8.16 (s, 1H), 7.88 (d, J= 2.8 Hz, 1H), 7.62-7.66 (m, 2H), 7.50 (dd, J= 10.4, 2.0 Hz, 1H), 7.34 (dd, J= 8.4, 1.2 Hz, 1H), 7.21 (d, J= 9.2 Hz, 1H), 6.82- 6.89 (m, 1H), 6.15 (dd, J= 16.8, 2.4 Hz, 1H), 5.72 (dd, J= 10.4, 2.4 Hz, 1H), 5.23 (s, 2H), 3.80 (br s, 4H), 2.90 (t, J= 4.4 Hz, 4H); MS (m / z) [M+H]+calcd for C24H23C12FN5O2+, 502.1, found, 502.0 l-( 4-( 4-(( 3-bromo-4-(3-chloro-2-fluorophenoxy)phenyl)ammo)pyrimidm-5-yl)piperazin-l- yl)prop-2-en-l-one (279) 279 was prepared by following General Procedure 8.1H NMR (500 MHz, DMSO-d6) δ ppm: 8.63 (s, 1H), 8.41 (s, 1H), 8.20-8.19 (m, 2H), 7.84 (dd, J= 9.0, 2.5 Hz, 1H), 7.32 (t, J = 7.0 Hz, 1H), 7.20-7.15 (m, 2H), 6.87-6.81 (m, 2H), 6.13 (dd, J= 17.0, 2.0 Hz, 1H), 5.70 (dd, J= 10.5, 2.0 Hz, 1H), 3.80 (br s, 4H), 2.90 (br s, 4H);13C NMR (125 MHz, DMSO-d6) δ ppm: 164.8, 155.3, 153.6, 148.7 (d, J = 246.3 Hz), 147.2, 146.9, 146.0 (d, J = 10.5 Hz), 137.9, 132.5, 128.7, 128.1, 126.4, 126.0 (d, J= 4.8 Hz), 125.1, 122.9, 121.6 (d, J= 14.8 Hz), 121.4, 117.9, 113.9, 51.7, 51.0, 45.6, 41.9; HRMS (ESI, m / z): calcd for C23H21BrClFN5O2(M+H)+: 532.0546, Found: 532.0531 l-( 4-( 4-(( 4-(3-bromo-2-fluorophenoxy)-3-chlorophenyl)amino)pyrimidm-5-yl)piperazm-l- yl)prop-2-en-l-one (280)

[0563] 280 was prepared by following General Procedure 8.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.65 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.10 (d, J= 2.4 Hz, 1H), 7.80 (dd, J= 8.8, 2.4 Hz, 1H), 7.44-7.48 (m, 1H), 7.22 (d, J= 8.8 Hz, 1H), 7.11-7.16 (m, 1H), 6.83-6.94 (m, 2H), 6.15 (dd, J= 16.8, 2.4 Hz, 1H), 5.72 (dd, J= 10.4, 2.4 Hz, 1H), 3.80-3.84 (m, 4H), 2.92-2.93 (m, 4H); MS (m / z) [M+H]+calcd for C23H2iBrClFN5O2+, 534.1, found, 534.0 l-( 4-( 4-(( 3-chloro-4-(2-fluoro-3-(trifluoromethyl)phenoxy)phenyl)ammo)pyrimidm-5- yl)piperazin-l-yl)prop-2-en-l-one (281 )

[0564] 281 was prepared by following General Procedure 8.1H NMR (400 MHz, MeOD) δ ppm: 8.40 (s, 1H), 8.16 (s, 1H), 8.06 (d, J= 2.4 Hz, 1H), 7.68 (dd, J= 8.8, 2.8 Hz, 1H), 7.39-7.43 (m, 1H), 7.25-7.29 (m, 1H), 7.12-7.17 (m, 2H), 6.82 (dd, J = 16.8, 2.4 Hz, 1H), 6.25 (dd, J =

[0565] - 96 - 16.8, 2.0 Hz, 1H), 5.79 (dd, J= 10.8, 2.0 Hz, 1H), 3.75-4.00 (m, 4H), 2.95-3.10 (m, 4H); MS (m / z) [M+H]+calcd for C24H21ClF4N5O2+, 522.1, found, 522.0 l-( 4-( 4-( 3-chloro-4-(2-fluorophenoxy)phenyl)amino)pyrimidin-5-yl)piperazin-l-yl)prop-2- en-l-one (284)

[0566] 284 was prepared by following General Procedure 8.1H NMR. (500 MHz, DMSO-d6) δ ppm: 8.60 (s, 1H), 8.40 (s, 1H), 8.20 (s, 1H), 8.04 (d, J= 2.5 Hz, 1H), 7.73 (dd, J= 9.0, 2.5 Hz, 1H), 7.39-7.35 (m, 1H), 7.17-7.15 (m, 2H), 7.08 (d, J= 9.0 Hz, 1H), 6.95-6.92 (m, 1H), 6.84 (dd, J= 16.5, 10.5 Hz, 1H), 6.14 (dd, J= 16.5, 2.5 Hz, 1H), 5.70 (dd, J= 10.5, 2.5 Hz, 1H), 3.80 (br s, 4H), 2.89 (br s, 4H);13C NMR (125 MHz, DMSO-d6) δ ppm: 164.8, 155.3, 153.7, 152.9 (d, J= 244.3 Hz), 146.9, 146.8, 144.4 (d, J= 10.6 Hz), 137.0, 132.5, 128.7, 128.1, 125.8 (d, J= 3.9 Hz), 125.2 (d, = 6.9 Hz), 124.0, 123.7, 122.4, 120.5, 119.8, 117.7 (d, J= 17.6 Hz), 51.7, 51.0, 45.6, 41.9; HRMS (ESI, m / z): calcd for C23H22CIFN5O2 (M+H)+: 454.1441, Found: 454.1429 l-( 4-( 4-( 3-chloro-4-(3-chloro-2-fluorophenoxy)phenyl)amino)-6-methylpyrimidm-5- yl)piperazin-l-yl)prop-2-en-l-one (285)

[0567] 285 was prepared by following General Procedure 8. One modification was replacing Gp8- 1 with compound Intl-285.1H NMR (500 MHz, DMSO-d6) δ ppm: 9.59 (s, 1H), 8.32 (d, J = 1.0 Hz, 1H), 8.09 (d, J= 2.5 Hz, 1H), 7.68 (dd, J= 9.0, 2.5 Hz, 1H), 7.24 (dd, J= 8.0, 1.0 Hz, 1H), 7.11 (t, J= 8.0 Hz, 1H), 6.99 (d, J= 9.0 Hz, 1H), 6.78 (dd, J= 16.5, 10.5 Hz, 1H), 6.70 (dd, J= 8.0, 1.0 Hz, 1H), 6.07 (dd, J= 16.5, 2.5 Hz, 1H), 5.64 (dd, J= 10.5, 2.5 Hz, 1H), 3.76 (br s, 4H), 3.08 (br s, 4H), 2.34 (d, J= 2.5 Hz, 3H);13C NMR (125 MHz, DMSO-d6) δ ppm: 164.9, 155.4, 152.8 (d, J= 10.5 Hz), 149.8 (d, J= 11.6 Hz), 149.3 (d, J = 9.6 Hz), 147.3, 143.9 (d, J= 257.1 Hz), 138.5, 136.6, 134.0, 128.7, 128.0, 127.3, 125.7, 123.9, 122.8, 121.5, 120.5, 117.9, 51.1, 50.4, 46.6, 42.9, 17.3; HRMS (ESI, m / z): cal cd for C24H21CI2FN5O2([M-H]-): 500.1061, Found: 500.1052 l-( 4-( 4-((4-(( 2H-chromen-8-yl)oxy)-3-chlorophenyl)amino)pyrimidin-5-yl)piperazin-l- yl)prop-2-en-l-one (286)

[0568] 286 was prepared by following General Procedure 8.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.55 (s, 1H), 8.39 (s, 1H), 8.19 (s, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.63 (dd, J= 8.8, 2.4 Hz, 1H), 6.83-6.93 (m, 4H), 6.77 (dd, J= 8.0, 2.0 Hz, 1H), 6.54-6.58 (m, 1H), 6.16 (dd, J = 17.2, 2.4 Hz, 1H), 5.92-5.96 (m, 1H), 5.72 (dd, J= 10.4, 2.4 Hz, 1H), 4.76-4.77 (m, 2H), 3.82 (br s, 4H), 2.86-2.94 (m, 4H); MS (m / z) [M+H]+calcd for C26H25C1N5O3+, 490.2, found, 490.0 l-(4-(5-((3-chloro-4-(3-chloro-2-fluorophenoxy)phenyl)ammo)-l,2,4-triazm-6-yl)piperazm- l-yl)prop-2-en-l-one (287)

[0569]

[0570] Preparation of Intl-287: To a solution of Gpl-4-1 (1.5 g, 5.51 mmol, 1.0 eq) and 3,5,6- trichloro-l,2,4-triazine (1.02 g, 5.51 mmol, 1.0 eq) in DCM (30 mL) was added TEA (1.39 g, 13.78 mmol, 1.92 mL, 2.5 eq). The mixture was stirred at 25 °C for 3 h. TLC (Petroleum ether / Ethyl acetate = 3 / 1, Rf= 0.45) showed 3,5,6-trichloro-l,2,4-triazine was consumed The mixture was added water (20 mL) and extracted with DCM (30 mL x 2). The organic phase was dried over Na2SO4and concentrated. The crude was purified on silica gel column chromatography (Ethyl acetate in Petroleum ether from 0% to 25%) to give Intl-287 (2.0 g, 4.29 mmol, 77.73% yield, 90% purity) as a yellow solid.1H NMR (400 MHz, CDCI3) δ ppm: 7.80 (d, J=2,4 Hz, 1H), 7.53-7.56 (m, 2H), 7.20-7.24 (m, 1H), 7.03-7.08 (m, 1H), 6.98 (d, J =8.8 Hz, 1H), 6.88-6.93 (m, 1H). Preparation of Int2-287: MeSO2Na (1.46 g, 14.28 mmol, 3.0 eq) was added to the solution of Intl-287 (2.0 g, 4.76 mmol, 1.0 eq) in DMF (30 mL). Stirring continued for 2 h at 60 °C. LCMS showed desired mass was observed. The mixture was added water (35 mL) and extracted with EtOAc (40 mL x 2). The organic phase was washed with water (20 mL x 2), dried over Na2SO4and concentrated. To the crude was added EtOAc (5 mL) and petroleum ether (30 mL) and the mixture was stirred at 25 °C for 1 h. The crystallized substance was collected by filtration, washed with petroleum ether (20 mL) to give Int2-287 (1.45 g, 3.09 mmol, 64.98% yield, 95% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 13.34 (s, 1H), 9.33 (s, 1H), 8.07 (s, 1H), 7.55-7.58 (m, 1H), 7.40-7.43 (m, 1H), 7.19-7.25 (m, 2H), 6.99-7.03 (m, 1H), 3.44 (s, 3H); MS (m / z) [M+H]+calcd for , 445.0, found, 445.0

[0571] Preparation of Int3-287: To a solution of Int2-287 (1.0 g, 2.25 mmol, 1.0 eq) in THF (25 mL) was added LiAlH4 (2.5 M, 4.49 mL, 5.0 eq) at 0 °C under N2. The reaction mixture was stirred at 0-10 °C for 2 h under N2. LCMS showed desired mass was observed. The mixture was added 0.5 N HC1 (10 mL) and water (10 mL), then extracted with EtOAc (35 mL x 2). The organic phase was concentrated, and the crude was purified on silica gel column chromatography (Ethyl acetate in Petroleum ether from 0% to 60%) to Int3-287 (350 mg, 762.61 μmol, 33.96% yield, 80% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 12.35 (s, 1H), 10.48 (s, 1H), 8.28 (s, 1H), 7.57-7.65 (m, 2H), 7.36-7.40 (m, 1H), 7.18- 7.25 (m, 2H), 6.92-6.97 (m, 1H); MS (m / z) [M+H]+calcd for C15H10C12FN4O2+, 367.0, found, 367.0

[0572] Preparation of Int4-287: To a solution of Int3-287 (350 mg, 953.26 μmol, 1.0 eq) in DCE (10 mL) was added BnN+Me3CI- (542.81 mg, 2.38 mmol, 2.5 eq), N, A-Dimethylaniline (231.03 mg, 1.91 mmol, 241.67 μL, 2.0 eq) and POCI3(876.98 mg, 5.72 mmol, 533.12 μL, 6.0 eq). Then the mixture was stirred at 100 °C for 0.1 h. LCMS showed desired mass was observed. The mixture was added aq. NaHCCL (30 mL) and water (10 mL) and extracted with DCM (30 mL x 2). The organic phase was dried over Na2SO4and concentrated. The crude was purified on silica gel column chromatography (Ethyl acetate in Petroleum ether from 0% to 50%) to give Int4-287 (120 mg, 248.96 μmol, 26.12% yield, 80% purity) as a yellow solid. MS (m / z) [M+H]+calcd for C15H9CI3FN4O+, 385.0, found, 386.8 Preparation of Int5-287: A solution of Int4-287 (120 mg, 311.20 μmol, 1.0 eq) and tert-butyl piperazine- 1 -carboxylate (115.92 mg, 622.39 μmol, 2.0 eq) in n-BuOH (10 mL) was stirred at 120 °C for 16 h. LCMS showed desired mass was observed. The mixture was added water (20 mL) and extracted with EtOAc (30 mL x 2). The organic phase was dried over Na2SO4and concentrated. The crude was purified on silica gel column chromatography (Ethyl acetate in Petroleum ether from 0% to 50%) to give Int5-287 (130 mg, 206.39 μmol, 66.32% yield, 85% purity) as a yellow solid.1H NMR (400 MHz, CDCI3) δ ppm: 8.18 (s, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.40-7.43 (m, 1H), 7.33-7.35 (m, 1H), 7.16-7.20 (m, 1H), 6.96-7.04 (m, 2H), 6.81-6.85 (m, 1H), 3.84-3.86 (m, 4H), 3.53 (t, J= 4.8 Hz, 4H), 1.49 (s, 9H); MS (m / z) [M+H]+calcd for C24H26C12FN6O3+, 535.1, found, 535.1

[0573] Preparation of Int6-287: A solution of Int5-287 (130 mg, 242.81 μmol, 1.0 eq) and HCl / dioxane (2 M, 1.21 mL, 10.0 eq) in DCM (3 mL) was stirred at 25 °C for 1 h. LCMS showed desired mass was observed. The mixture was concentrated to give Int6-287 (100 mg, crude) as a yellow solid. MS (m / z) [M+H]+calcd for C19H18Cl2N6O+, 435.1, found, 435.0

[0574] Preparation of 287: To a solution of Int6-287 (100 mg, 211.98 μmol, 1.0 eq, HC1 salt) and DIPEA (82.19 mg, 635.94 μmol, 110.77 μL, 3.0 eq) in DCM (6 mL) was added compound acryloyl chloride (17.27 mg, 190.78 μmol, 15.50 μL, 0.9 eq) at 0 °C. Then the mixture was stirred at 0 °C for 10 min. LCMS showed desired mass was observed. The mixture was quenched by water (20 mL) and extracted with DCM (25 mL x 2). The organic phase was washed with water (20 mL), dried over Na2SO4, filtered and concentrated. The crude was purified on silica gel column chromatography (Ethyl acetate in Petroleum ether from 0% to 100%). Then the product was purified further by prep-TLC (Ethyl acetate / MeOH = 25 / 1, Rf= 0.45) to give 287 (22 mg, 42.68 μmol, 20.13% yield, 94.93% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 10.16 (s, 1H), 8.19 (s, 1H), 8.03 (d, J= 2.4 Hz, 1H), 7.66 (dd, J= 8.8, 2.4 Hz, 1H), 7.36-7.40 (m, 1H), 7.18-7.23 (m, 2H), 6.94-6.98 (m, 1H), 6.86 (dd, J= 16.4, 10.4 Hz, 1H), 6.15 (dd, J= 16.8, 2.4 Hz, 1H), 5.71 (dd, J= 10.4, 2.0 Hz, 1H), 3.76-3.78 (m, 4H), 3.65-3.70 (m, 4H); MS (m / z) [M+H]+calcd for C22H20CI2FN6O2+, 489.1, found, 489.1 l-( 4-( 4-(( 3-chloro-4-(3-chloro-2-fluorophenoxy)-2-fluorophenyl)ammo)pyrimidm-5- yl)piperazin-l-yl)prop-2-en-l-one (288) and l-(4-(4-((3-chloro-2-(3-chloro-2- fluorophenoxy)-4-fluorophenyl)amino)pyrimidin-5-yl)piperazin-l-yl)prop-2-en-l-one (289)

[0575] 288 and 289 were prepared by following General Procedure 9. The resulting mixture was purified by prep-HPLC (column: Cl 8 150 x 40mm; mobile phase: [Water (NH4HCO3)- MeCN]; gradient: 45%-85% B over 9 min) to give 289 (17.70% yield, 100% purity) as a white solid and 288 (38.34% yield, 99.30% purity) as a white solid.

[0576] Characterization data of 288:1H NMR (400 MHz, DMSO-d6) δ ppm: 8.56 (s, 1H), 8.32 (s, 1H), 8.18 (s, 1H), 7.63 (t, J= 8.8 Hz, 1H), 7.43-7.48 (m, 1H), 7.24-7.29 (m, 1H), 7.09-7.13 (m, 1H), 6.98-7.04 (m, 1H), 6.83-6.70 (m, 1H), 6.16 (dd, J= 16.4, 2.0 Hz, 1H), 5.72 (dd, J = 10.4, 2.4 Hz, 1H), 3.68-3.78 (m, 4H), 2.90-2.98 (m, 4H); 2D NMR analyses (HSQC, COSY, NOE, and HOESY) were conducted to confirm the structure of 288; MS (m / z) [M+H]+calcd for C23H20CI2F2N5O2, 506.1, found, 505.9

[0577] Characterization data of 289:1H NMR (400 MHz, DMSO-d6) δ ppm: 8.34 (s, 2H), 8.14 (s, 1H), 8.04 (dd, J= 9.2, 5.6 Hz, 1H), 7.51 (t, J= 8.8 Hz, 1H), 7.24-7.28 (m, 1H), 7.02-7.04 (m, 1H), 6.76-6.84 (m, 1H), 6.66-6.70 (m, 1H), 6.13 (dd, J= 16.8, 2.4 Hz, 1H), 5.71 (dd, J = 10.8, 2.4 Hz, 1H), 3.46-3.53 (m, 4H), 2.59-2.68 (m, 4H); 2D NMR analyses (HSQC, COSY, NOE, and HOESY) were conducted to confirm the structure of 289; MS (m / z) [M+H]+calcd for C23H20CI2F2N5O2 , 506.1, found, 505.9 l-( 4-( 4-((4-([l,2,4 ]triazolo[ 1, 5-a Jpyridin- 7-yloxy)-3-chlorophenyl)amino)pyrimidin-5- yl)piperazin-l-yl)prop-2-en-l-one (290) 290 was prepared by following General Procedure 8.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.96 (d, J= 7.6 Hz, 1H), 8.71 (s, 1H), 8.47 (s, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.93 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.44 (d, J= 8.8 Hz, 1H), 7.05 (dd, J= 7.6 Hz, 2.8 Hz, 1H), 6.84-6.91 (m, 2H), 6.16 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.73 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.82-3.84 (m, 4H), 2.94-2.95 (m, 4H); MS (m / z) [M+H]+calcd for C23H22C1N8O2+, 477.2, found, 477.1. l-( 4-( 4-(( 3-chloro-4-(3-chloro-2-fluorophenoxy)phenyl)amino)pyrimidm-5-yl)-l, 4-diazepan- l-yl)prop-2-en-l-one (291 )

[0578] 291 was prepared by following General Procedure 8. One modification was replacing Gpl- 6 with compound Intl-291.1H NMR (500 M, DMSO-d6), described as a mixture of rotamers, a molar ratio ca. 2: 1, signals of minor isomer marked with asterisk, 6 ppm: 8.51*(s, 0.5H), 8.40 (s, 1H), 8.37 (s, 1H), 8.21 (s, 1.5H), 8.19 (d, J= 2.5 Hz, 1H), 8.10* (d, J= 2.5 Hz, 0.5H), 7.87 (dd, J= 9.0, 2.5 Hz, 1H), 7.77* (dd, J= 9.0, 2.5 Hz, 0.5H), 7.34-7.30 (m, 1.5H), 7.24-7.21 (m, 1.5H), 7.18-7.14 (m, 1.5H), 6.88-6.83 (m, 2.5H), 6.76* (dd, J= 17.0,

[0579] 10.5 Hz, 0.5H), 6.21 (dd, J= 16.5, 2.5 Hz, 1H), 6.14* (dd, J= 16.5, 2.5 Hz, 0.5H), 5.73 (dd, J= 10.0, 2.5 Hz, 1H), 5.65* (dd, J= 10.5, 2.5 Hz, 0.5H), 3.82-3.66 (m, 6H), 3.16-3.03 (m, 6H), 1.98-1.96* (m, 1H), 1.85-1.83 (m, 2H);13C NMR (125 MHz, DMSO-t / 6), described as a mixture of rotamers, a molar ratio ca. 2: 1, signals of minor isomer marked with asterisk, 6 ppm: 166.8, 166.0*, 155.4*, 155.0, 153.4*, 153.1, 148.72* (d, J = 246.5 Hz), 148.71 (d, J=

[0580] 246.5 Hz), 148.3*, 148.2, 146.1 (d, J= 10.5 Hz), 146.0* (d, J= 10.8 Hz), 145.9*, 145.8, 137.9, 137.8*, 134.7, 134.3*, 129.1*, 128.9, 128.3, 127.9*, 126.03*, 125.99, 125.2*, 125.1, 124.7, 124.6*, 122.8*, 122.6, 121.8, 121.72*, 121.66, 121.61*, 121.5*, 121.4, 117.84*, 117.80, 55.7*, 54.1, 54.0, 53.9*, 47.9*, 47.7, 46.3, 45.0*, 29.9, 27.6*; HRMS (ESI, m / z): calcd for C24H21CI2FN5O2 ([M-H]’): 500.1061, Found: 500.1048 l-( 4-( ( 4-( ( 3-chloro-4-(3-chloro-2-fluorophenoxy)phenyl)ammo)pyrimidin-5-yl)oxy)piperidm- l-yl)prop-2-en-l-one (292)

[0581] Gp7-2-l was prepared by following General Procedure 7.

[0582] Preparation of Intl-292: To a solution of tert-butyl 4-hydroxypiperidine-l -carboxylate (100.6 mg, 0.5 mmol, 2.5 eq) in THF (4.0 mL) was slowly added NaH (20.0 mg, 0.5 mmol, 60% purity, 2.5 eq) at 21 °C under N2. The mixture was heated to 60 °C and stirred for 30 minutes. Then the mixture was cooled down to 21 °C and Gp7-2-l (73.6 mg, 0.2 mmol, 1.0 eq) was added. The mixture was heated to 100 °C in microwave reactor and reacted for 6 h under N2. The reaction mixture was cooled down to 21 °C and then quenched by addition of aq. NH4CI (30 mL) at 0 °C under N2and then diluted with H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (DCM / MeOH) to give Intl-292 (100.0 mg, 91% yield) as a foamy solid.1H NMR (500 MHz, CDCI3) δ ppm: 8.56 (s, 1H), 8.24 (br s, 1H), 7.97 (d, J= 2.0 Hz, 1H), 7.44 (dd, J= 9.0, 2.0 Hz, 1H), 7.24 (br s, 1H), 7.19 (dd, J= 8.0, 1.5 Hz, 1H), 6.98 (t, J= 8.3 Hz, 1H), 6.85 (d, J = 9.0 Hz, 1H), 6.79 (dd, J= 8.0, 1.5 Hz, 1H), 4.54-4.51 (m, 1H), 3.84-3.81 (m, 2H), 3.20- 3.15 (m, 2H), 1.87-1.85 (m, 2H), 1.83-1.77 (m, 2H).

[0583] Preparation of Int2-292: To a solution of Intl-292 (100.0 mg, 182.0 μmol, 1.0 eq) in DCM (1.0 mL) was added HCl / dioxane (4 M, 3.0 mL) at 21 °C. The mixture was stirred at 21 °C for 4 h. The mixture was concentrated under reduced pressure to give Int2-292 (88.5 mg, 182.0 μmol, 100% yield, HC1 salt) as a white solid.

[0584] Preparation of 292: To a solution of Int2-292 (88.5 mg, 182.0 μmol, 1.0 eq, HC1 salt) in DCM (6.0 mL) was added DIPEA (117.6 mg, 910.1 μmol, 158.5 μL, 5.0 eq) at 21 °C. The mixture was cooled to 0 °C, then acryloyl chloride (16.5 mg, 182.0 μmol, 14.8 μL, 1.0 eq) in DCM (0.2 mL) was added to the mixture and stirred at 0 °C for 30 mins. TLC showed the reaction was completed. H2O (0.5 mL) was added to the mixture and concentrated under reduced pressure to give a residue which was purified by column chromatography (DCM / MeOH) to give 292 (50.5 mg, 100.3 μmol, 55% yield) as a white solid.1H NMR (500 MHz, DMSO-d6) δ ppm: 9.78 (d, J= 1.0 Hz, 1H), 8.47 (d, J= 2.5 Hz, 1H), 8.41 (d, J= 3.5 Hz, 1H), 8.14 (d, J= 3.0 Hz, 1H), 7.70 (dd, J = 9.0, 2.5 Hz, 1H), 7.27 (dd, J= 8.0, 1.5 Hz, 1H), 7.09 (t, J= 8.3 Hz, 1H), 7.03 (d, J= 9.0 Hz, 1H), 6.81-6.76 (m, 2H), 6.06 (dd, J= 16.5, 2.5 Hz, 1H), 5.64 (dd, J= 10.5, 2.5 Hz, 1H), 4.57-4.52 (m, 1H), 3.93-3.85 (m, 2H), 3.31-3.21 (m, 2H), 1.87 (br s, 2H), 1.68-1.63 (m, 2H);13C NMR (125 MHz, DMSO-d6) δ ppm: 164.9, 153.9 (d, J = 8.1 Hz), 150.9, 149.9 (d, J= 9.0 Hz), 146.8, 146.0 (d, J = 260.3 Hz), 144.2, 140.7 (d, J= 17.4 Hz), 136.5, 128.93 (d, = 6.4 Hz), 128.90, 127.8, 125.6 (2C), 124.0, 122.9, 121.8, 120.7, 117.7, 79.1, 42.8, 39.3, 32.5, 31.5; HRMS (ESI, m / z): calcd for C24H20CI2FN4O3 ([M-H]-): 501.0901, Found: 501.0895 l-( 4-( 4-(( 3-chloro-4-(imidazo[ 1, 2 -a pyridin- 7-yloxy)phenyl)amino)pyrimidin-5-yl)piperazin- l-yl)prop-2-en-l-one (293)

[0585] 293 was prepared by following General Procedure 8.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.67 (s, 1H), 8.56 (d, J= 7.6 Hz, 1H), 8.46 (s, 1H), 8.24 (s, 1H), 8.15 (d, J= 2.8 Hz, 1H), 7.85-7.90 (m, 2H), 7.45 (d, J= 0.8 Hz, 1H), 7.35 (d, J= 8.8 Hz, 1H), 6.87 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 6.82 (dd, J= 7.6 Hz, 2.8 Hz, 1H), 6.59 (d, J= 2.4 Hz, 1H), 6.16 (dd, J = 16.8 Hz, 2.4 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.84 (br s, 4H), 2.89-2.98 (m, 4H); MS (m / z) [M+H]+calcd for C24H23C1N7O2+, 476.2, found, 476.2 l-( 4-( 4-(( 3-chloro-4-(3-chloro-2-fluorophenoxy)phenyl)ammo)pyrimidin-5-yl)piperidm-l- yl)prop-2-en-l-one (294)

[0586] Preparation of Intl-294: To a solution of 4-( tert-butoxy)-5-iodopyrimidine (278.1 mg, 1.0 mmol, 1.0 eq) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-l(2H)-carboxylate (340.1 mg, 1.1 mol, 1.1 eq) in dioxane (12.0 mL) and H2O (3.0 mL) was added K2CO3(414.6 mg, 3.0 mmol, 3.0 eq) and Pd(dppf)C12 (146.3 mg, 0.2 mmol, 0.2 eq) at 21 °C. The mixture was stirred at 100 °C for 16 h under N2. TLC (Hexanes / Ethyl acetate) showed a new spot. The mixture was concentrated under reduced pressure to give a residue which was purified by column chromatography (Hexanes / Ethyl acetate) to give Intl-294 (291.0 mg, 872.7 μmol, 87.3% yield).1H NMR (400 MHz, CDCI3) δ ppm: 8.68 (s, 1H), 8.31 (br s, 1H), 5.96 (br s, 1H), 4.11 (br d, J= 2.8 Hz, 2H), 3.62 (t, J= 7.4 Hz, 2H), 2.48 (t, J= 8.2 Hz, 2H), 1.69 (s, 9H), 1.54 (s, 9H).

[0587] Preparation of Int2-294: To a solution of Intl-294 (291.0 mg, 872.7 μmol, 1.0 eq) in MeOH (20 mL) was added Pd / C (188.0 mg, 176.7 μmol, 10% purity, 0.2 eq) under N2. The suspension was degassed under vacuum and purged with H2 (3 times). The mixture was stirred under H2 (200 psi) at 21 °C for 6 h. TLC (Hexanes: Ethyl acetate) showed a new spot. The reaction mixture was filtered, and the filtrate was concentrated. The crude was purified on silica gel column chromatography (Hexanes: Ethyl acetate) to give Int2-294 (180 mg, 536.6 μmol, 61.5% yield).

[0588] Preparation of Int3-294: The solution of Int2-294 (180 mg, 536.6 μmol, 1.0 eq) in HOAc (4.0 mL) and dioxane (4.0 mL) was stirred at 90 °C for 2 h. LCMS showed several peaks were detected and a peak with desired MS was found. The reaction was concentrated on giving a crude product, which was redissolved in DCM (50 mL), washed with NaHCCL (aq.), brine and dried over Na2SO4. DCM was removed under vacuum to give the crude product which was purified by flash silica gel column chromatography (DCM / MeOH) to give Int3- 294 (118 mg, 422.4 μmol, 78.7% yield) as a white solid.

[0589] Preparation of Int4-294: To a solution of Int3-324 (118 mg, 422.4 μmol, 1.0 eq) in dioxane (5.0 mL) was added DIPEA (222.6 mg, 1.722 mmol, 300.0 μL, 4.0 eq) and slowly dropwise POCI3 (164.5 mg, 1.073 mmol, 100.0 μL, 2.5 eq) at 21 °C. The mixture was slowly heated up to 90 °C and stirred at 90 °C for 0.5 h under N2. The reaction mixture turned clear. TLC (Hexanes / EtOAc) showed a new spot was observed and the starting material was consumed. DCM (15 mL) was added to the mixture at 21 °C and then slowly poured into aq. NaHCCL (20 mL) and extracted with DCM (15 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (Hexanes / EtOAc) to give Int4-294 (107 mg, 359.3 μmol, 85.1% yield).

[0590] Preparation of Int5-294: To a solution of Int4-294 (107 mg, 359.3 μmol, 1.0 eq) and Gpl-4- 1 (98.0 mg, 360.2 μmol, 1.0 eq) in toluene (8.0 mL) was added CS2CO3(255.0 mg, 782.6 μmol, 2.0 eq), Xantphos (46.0 mg, 79.5 μmol, 0.22 eq) and Pd(OAc)2(18.0 mg, 80.2 μmol, 0.22 eq) at 21 °C. The mixture was stirred at 110 °C for 6 h under N2. LCMS showed the desired mass was detected. The mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (DCM / MeOH) to give Int5- 294 (118.0 mg, 221.2 μmol, 61.6% yield).

[0591] Preparation of Int6-294: To a solution of Int5-294 (118.0 mg, 221.2 μmol, 1.0 eq) in DCM (1.5 mL) was added HCl / dioxane (4 M, 3.0 mL) at 21 °C. The mixture was stirred at 21 °C for 4 h. The mixture was concentrated under reduced pressure to give Int6-294 (103.9 mg, 221.2 μmol, 100% yield, HC1 salt) as a white solid.

[0592] Preparation of 294: To a solution of Int6-294 (103.9 mg, 221.2 μmol, 1.0 eq, HC1 salt) in DCM (6.0 mL) was added DIPEA (142.9 mg, 1.106 mmol, 192.7 μL, 5.0 eq) at 21 °C. The mixture was cooled to 0 °C and acryloyl chloride (20.0 mg, 221.2 μmol, 17.9 μL, 1.0 eq) in DCM (0.2 mL) was added to the mixture and stirred at 0 °C for 30 mins. TLC showed the reaction was completed. H2O (0.5 mL) was added to the mixture and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (DCM / MeOH) to give 294 (57.1 mg, 117.2 μmol, 53% yield) as a white solid.1H NMR (500 MHz, DMSO-d6) δ ppm: 8.77 (s, 1H), 8.48 (s, 1H), 8.23 (s, 1H), 7.93 (d, J= 2.0 Hz, 1H), 7.65 (dd, J= 9.0, 2.0 Hz, 1H), 7.34 (t, J= 7.0 Hz, 1H), 7.20-7.16 (m, 2H), 6.89 (t, J= 7.8 Hz, 1H), 6.83 (dd, J= 16.5, 10.5 Hz, 1H), 6.10 (dd, J= 17.0, 1.5 Hz, 1H), 5.66 (dd, J= 10.5, 1.5 Hz, 1H), 4.61 (d, J= 12.0 Hz, 1H), 4.20 (d, J= 13.0 Hz, 1H), 3.22-3.11 (m, 2H), 2.75 (t, J = 12.0 Hz, 1H), 1.89-1.86 (m, 2H), 1.55-1.50 (m, 2H);13C NMR (125 MHz, DMSO-d6) δ ppm: 164.7, 157.7, 155.9, 153.2, 148.9 (d, J= 246.5 Hz), 146.4, 145.8 (d, J= 10.6 Hz), 137.9,

[0593] 129.1, 127.6, 126.1 (d, J= 5.0 Hz), 125.4, 124.5, 124.2, 123.2, 122.9, 121.6 (d, J= 14.6 Hz),

[0594] 121.2, 118.2, 46.1, 42.5, 33.2, 32.1, 31.1; HRMS (ESI, m / z): calcd for C24H20CI2FN4O2 ([M- H]’): 485.0952, Found: 485.0942 l-( 4-( 4-(( 4-(benzofuran- 7-yloxy)-3-chlorophenyl)amino)pyrimidin-5-yl)piperazin-l- yl)propan-l-one (295) 295 was prepared by following General Procedure 8. One modification was replacing the acryloyl chloride in the last synthetic step with propionyl chloride1H NMR (400 MHz, DMSO-d6) δ ppm: 8.61 (s, 1H), 8.42 (s, 1H), 8.20 (s, 1H), 8.08 (d, J= 2.8 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.73 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.43-7.45 (m, 1H), 7.20 (t, J= 8.0 Hz, 1H), 7.11 (d, J= 9.2 Hz, 1H), 7.04 (d, J= 2.4 Hz, 1H), 6.76 (d, J= 8.0 Hz, 1H), 3.68-3.71 (m, 4H), 2.87-2.91 (m, 4H), 2.37 (q, J= 7.2 Hz, 2H), 1.02 (t, J= 7.6 Hz, 3H); MS (m / z) [M+H]+calcd for C25H25C1N5O3+, 478.2, found, 478.2 l-( 4-( 4-((4-(( 2H-chromen-8-yl)oxy)-3-chlorophenyl)amino)pyrimidm-5-yl)piperazm-l- yl)propan-l-one (296)

[0595] 296 was prepared by following General Procedure 8. One modification was replacing the acryloyl chloride in the last synthetic step with propionyl chloride.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.53 (s, 1H), 8.38 (s, 1H), 8.17 (s, 1H), 7.97 (d, J= 2.8 Hz, 1H), 7.62 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 6.91 (dd, J= 7.6 Hz, 2.4 Hz, 1H), 6.84-6.89 (m, 2H), 6.77 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 6.54-6.58 (m, 1H), 5.91-5.96 (m, 1H), 4.76-4.77 (m, 2H), 3.68 (br s, 4H), 2.85-2.90 (m, 4H), 2.34-2.40 (m, 2H), 1.02 (t, J= 7.6 Hz, 3H); MS (m / z) [M+H]+calcd for C26H27CIN5O3 , 492.2, found, 492.0 l-( 4-( ( 4-( ( 3-chloro-4-(3-chloro-2-fluorophenoxy)phenyl)amino)pyrimidin-5- yl)methyl)piperazin-l-yl)prop-2-en-l-one (297)

[0596]

[0597] Preparation of Intl-297: To a stirred solution of 4-chloro-5-methyl-pyrimidine (120 mg, 933.4 μmol, 1.0 eq) in CCI4 (6.0 mL) was added NBS (266 mg, 1.494 mmol, 1.6 eq) and AIBN (31 mg, 188.8 μmol, 0.2 eq) at 21 °C and was stirred at 80 °C for 4 h. The reaction was quenched by the addition of saturated aqueous Na2SO3(8.0 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 10.0 mL). The combined organic layers were washed with brine, filtered and concentrated under reduced pressure to give the crude material. Purification by column chromatography (Hexanes :Ethyl acetate) afforded Intl-297 (50 mg, 241.0 μmol, 25.8%) as a colorless oil.

[0598] Preparation of Int2-297: To a stirred solution of Intl-297 (45 mg, 216.9 μmol, 1.0 eq) in DMF (2.0 mL) was added tert-butyl piperazine- 1 -carboxylate (113.4 mg, 1.3 mmol, 1.0 eq) and K2CO3(393.3 mg, 2.9 mmol, 2.0 eq) and the mixture was stirred at 21 °C for 1.5 h. The DMF was removed under vacuum, and the residue was suspended into ethyl acetate (50 mL) and washed successively with water and brine. The organic layer was then dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude material. Purification by column chromatography (Hexanes :Ethyl acetate) afforded Int2-297 (33 mg, 105.5 μmol, 48.6% yield).

[0599] Preparation of Int3-297: To a solution of Int2-297 (33 mg, 105.5 μmol, 1.0 eq) and Gpl-4-1 (28.7 mg, 105.5 μmol, 1.0 eq) in toluene (2.0 mL) was added CS2CO3(68.7 mg, 211.0 μmol, 2.0 eq), Xantphos (13.4 mg, 23.2 μmol, 0.22 eq) and Pd(OAc)2(5.2 mg, 23.2 μmol, 0.22 eq) at 21 °C. The mixture was stirred at 110 °C for 6 h under N2. LCMS showed the desired mass was detected. The mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (DCM / MeOH) to give Int3-297 (48.4 mg, 88.3 μmol, 83.7% yield).

[0600] Preparation of Int4-297: To a solution of Int3-297 (48.4 mg, 88.3 μmol, 1.0 eq) in DCM (1.0 mL) was added HCl / dioxane (4 M, 2.0 mL) at 21 °C. The mixture was stirred at 21 °C for 4 h. The mixture was concentrated under reduced pressure to give Int4-297 (42.8 mg, 88.3 μmol, 100% yield, HC1 salt) as a white solid.

[0601] Preparation of 297: To a solution of Int4-297 (42.8 mg, 88.3 μmol, 1.0 eq, HC1 salt) in DCM (3.0 mL) was added DIPEA (57.1 mg, 441.5 μmol, 76.9 μL, 5.0 eq) at 21 °C. The mixture was cooled to 0 °C and acryloyl chloride (8.0 mg, 88.3 μmol, 7.2 μL, 1.0 eq) in DCM (0.1 mL) was added and the mixture was stirred at 0 °C for 30 mins. TLC showed the reaction was completed. H2O (0.5 mL) was added to the mixture and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (DCM / MeOH) to give 297 (25.3 mg, 50.4 μmol, 57.1% yield) as a white solid.1H NMR (500 MHz, DMSO-d6) δ ppm: 9.95 (s, 1H), 8.62 (s, 1H), 8.22 (s, 1H), 8.18 (d, J= 2.5 Hz, 1H), 7.58 (dd, J = 9.0, 2.5 Hz, 1H), 7.33 (td, J= 6.8, 1.5 Hz, 1H), 7.20 (d, J= 9.0 Hz, 1H), 7.16 (td, J= 8.5, 1.5 Hz, 1H), 6.85 (td, J= 7.8, 1.0 Hz, 1H), 6.78 (dd, J= 16.5, 10.0 Hz, 1H), 6.09 (dd, J= 16.5, 2.5 Hz, 1H), 5.67 (dd, J= 10.5, 2.5 Hz, 1H), 3.61 (br s, 6H), 2.44 (br s, 4H);13C NMR (125 MHz, DMSO-d6) δ ppm: 164.8, 158.9, 157.4, 155.3, 148.6 (d, J= 246.3 Hz), 146.0 (d, J= 10.0 Hz), 145.7, 137.7, 128.6, 128.0, 125.9 (d, J= 5.0 Hz), 125.1, 124.8, 122.1, 121.9, 121.5 (d, J= 15.0 Hz), 121.2, 117.8, 114.9, 56.6, 52.8, 52.1, 45.5, 41.9; HRMS (ESI, m / z): calcd for C24H23CI2FN5O2 (M+H)+: 502.1208, Found: 502.1191 l-( 4-( 4-(( 3-chloro-4-(3-chloro-2-fluorophenoxy)phenyl)amino)pyrimidin-5-yl)piperazin-l- yl)-2-fluoroprop-2-en-l-one (299)

[0602] - I l l -

[0603] Intl-299 was prepared by following General Procedure 8.

[0604] Preparation of 299: To a solution of Intl-299 (150 mg, 273.56 μmol, 1.0 eq) and DIPEA (176.78 mg, 1.37 mmol, 238.24 μL, 5.0 eq) in DCM (10 mL) was added 2-fluoroacryloyl chloride (59.36 mg, 273.56 μmol, 1.0 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. LCMS showed desired mass was observed. The mixture was quenched by water (0.1 mL) and concentrated. The crude was purified by prep-HPLC (column: 55-Boston Prime C18 150x30mm, 5pm; mobile phase: [H2O (0.05% NH3 H2O + 10 mM NH4HCO3)-ACN]; gradient: 57%-87% B over 10.0 min) to give 299 (75 mg, 147.58 μmol, 53.95% yield, 99.633% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.66 (s, 1H), 8.44 (s, 1H), 8.24 (s, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.81 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.34-7.38 (m, 1H), 7.17-7.25 (m, 2H), 6.86-6.91 (m, 1H), 5.16-5.36 (m, 2H), 3.76-3.40 (m, 4H), 2.97 (t, J= 4.4 Hz, 4H); MS (m / z) [M+H]+calcd for C23H2oC12F2N5O2+, 506.1, found, 506.2 l-( 4-( 4-(( 4-(benzofuran- 7-yloxy)-3-chloro-2-fluorophenyl)amino)pyrimidm-5-yl)piperazm-l- yl)prop-2-en-l-one (300) and l-(4-(4-((2-(benzofuran-7-yloxy)-3-chloro-4- fluorophenyl)amino)pyrimidin-5-yl)piperazin-l-yl)prop-2-en-l-one (301)

[0605] 300 and 301 were prepared by following General Procedure 9. The resulting mixture was purified by prep-HPLC (column: 56-Boston Green ODS 150x30mm, 5pm; mobile phase: [H2O (0.075% TFA)-ACN]; gradient: 12%-52% B over 9.0 min) to give 301 (110.0 mg, 91.49% purity) as a white solid and 300 (65.0 mg, 99.91% purity) as a white solid. The product 301 was further purified by prep-HPLC (column: 52-Welch Xtimate C18 150x30mm, 5pm; mobile phase: [08-Water (0.05% NH3·O+10mM NH4HCO3)-01-MeCN]; gradient: 38%-78% B over 11.0 min) to give 301 (83.0 mg, 166.72 μmol, 19.85% yield, 99.20% purity) as a white solid and 300 was further purified by prep-HPLC (column: 52- Welch Xtimate C18 150x30mm, 5pm; mobile phase: [08-Water (0.05% NH3·O+10mM NH4HCO3)-01-MeCN]; gradient: 39%-79% B over 11.0 min) to give 300 (33.0 mg, 64.51 μmol, 7.68% yield, 96.03% purity) as a white solid.

[0606] Characterization data of 300:1H NMR (400 MHz, DMSO-d6) δ ppm: 8.55 (s, 1H), 8.31 (s, 1H), 8.16 (s, 1H), 8.03 (d, J= 2.0 Hz, 1H), 7.51-7.55 (m, 2H), 7.28 (t, J= 8.0 Hz, 1H), 7.06 (d, J= 2.0 Hz, 1H), 6.99 (d, J= 7.6 Hz, 1H), 6.83-6.90 (m, 2H), 6.16 (dd, J= 16.4 Hz, 2.0 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.65-3.87 (m, 4H), 2.87-3.00 (m, 4H); 2D NMR analyses (HSQC, COSY, HMBC, NOE and HOESY) were conducted to confirm the structure of the compound; MS (m / z) [M+H]+calcd for C25H22C1FNSO3+, 494.1, found, 494.1

[0607] Characterization data of 301:1H NMR (400 MHz, DMSO-d6) δ ppm: 8.41 (s, 1H), 8.31 (s, 1H), 8.27 (dd, J= 9.2 Hz, 6.0 Hz, 1H), 8.10 (s, 1H), 7.99 (d, J= 2.0 Hz, 1H), 7.51 (t, J= 8.8 Hz, 1H), 7.34 (t, J= 7.6 Hz, 1H), 7.05 (t, J= 8.0 Hz, 1H), 7.00 (d, J= 2.0 Hz, 1H), 6.69 (dd, J= 16.8 Hz, 10.4 Hz, 1H), 6.45 (d, J= 8.0 Hz, 1H), 6.09 (dd, J= 16.4 Hz, 2.0 Hz, 1H), 5.69 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.06-3.27 (m, 4H), 2.35-2.48 (m, 4H); 2D NMR analyses (HSQC, COSY and HOESY) were conducted to confirm the structure of the compound; MS (m / z) [M+H]+calcd for C25H22C1FN5O3+, 494.1, found, 494.2 l-(4-(4-((5-chloro-4-(3-chloro-2-fluorophenoxy)-2-fluorophenyl)amino)pyrimidin-5- yl)piperazin-l-yl)prop-2-en-l-one (302)

[0608] 302 was prepared by following General Procedure 8.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.46 (s, 1H), 8.37 (s, 1H), 8.20 (s, 1H), 8.05 (d, J= 8.0 Hz, 1H), 7.40-7.44 (m, 1H), 7.33 (d, J= 10.8 Hz, 1H), 7.22-7.27 (m, 1H), 7.01-7.06 (m, 1H), 6.86 (dd, J= 16.4 Hz, 10.4 Hz, 1H), 6.15 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.75-3.78 (m, 4H), 2.93-2.96 (m, 4H); MS (m / z) [M+H]+calcd for C23H20Cl2F2N5O2+, 506.1, found, 506.2 l-( 4-( 4-(( 3-chloro-4-(chroman-8-yloxy)phenyl)amino)pyrimidm-5-yl)piperazm-l-yl)prop-2- en-l-one (303)

[0609] 303 was prepared by following General Procedure 8.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.54 (s, 1H), 8.38 (s, 1H), 8.18 (s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.59 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 6.91 (d, J= 8.0 Hz, 1H), 6.81-6.87 (m, 1H), 6.75-6.80 (m, 2H), 6.70 (d, J= 7.6 Hz, 1H), 6.15 (dd, J= 16.4 Hz, 2.4 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 4.11-4.14 (m, 2H), 3.81 (br s, 4H), 2.85-2.95 (m, 4H), 2.77-2.81 (m, 2H), 1.90-1.96 (m, 2H); MS (m / z) [M+H]+calcd for C26H27C1N5O3+, 492.2, found, 492.2. l-(l-(4-(( 3-chloro-4-(3-chloro-2-fluorophenoxy)phenyl)amino)pyrimidm-5-yl)-5, 6-dihydro- 1, 2, 4-triazin-4( lH)-yl)pr op-2 -en-1 -one (304)

[0610] Int4-3O4 Int5-3O4 Int6-3O4

[0611] Preparation of Intl-304: A solution of benzaldehyde (5 g, 47.12 mmol, 4.76 mL, 1.0 eq) and tert-butyl hydrazinecarboxylate (6.23 g, 47.12 mmol, 1.0 eq) in MeOH (60 mL) and AcOH (12 mL) was stirred at 70 °C for 4 h. Then NaBH3CN (7.40 g, 117.79 mmol, 2.5 eq) was added at 25 °C under N2. The reaction mixture was slowly brought to 70 °C and stirred at 70 °C for 12 h. LCMS showed desired mass was observed. The mixture was concentrated, and the residue was treated with aq. NaHCO3(60 mL), followed by extraction with EtOAc (2 x 80 mL). The organic phase was washed with water (30 mL) and concentrated. The crude was purified on silica gel column chromatography (EtOAc in petroleum ether from 0% to 15%) to give Intl-304 (7.5 g, 30.37 mmol, 64.45% yield, 90% purity) as yellow oil.1H NMR (400 MHz, CDCI3) δ ppm: 7.28-7.35 (m, 5H), 6.09 (br s, 1H), 3.99 (s, 2H), 1.46 (s, 9H).

[0612] Preparation of Int2-304: To a solution of Intl-304 (13 g, 58.48 mmol, 1.0 eq) and AcOH (14.05 g, 233.94 mmol, 13.39 mL, 4.0 eq) in MeOH (100 mL) was added tert-butyl (2- oxoethyl)carbamate (11.17 g, 70.18 mmol, 1.2 eq) under N2and stirred at 25 °C for 2 h. Then NaBH3CN (7.35 g, 116.97 mmol, 2.0 eq) was added by portion (6 times, every 5 min) and stirred at 25 °C for 16 h under N2. LCMS showed desired mass was observed. The mixture was concentrated, and the residue was treated with aq. NaHCO3(75 mL), followed by extraction with EtOAc (2 x 65 mL). The organic phase was washed with water (30 mL) and concentrated. The crude was purified on silica gel column chromatography (EtOAc in petroleum ether from 0% to 25%) to give Int2-304 (18 g, 44.33 mmol, 75.79% yield, 90% purity) as colorless oil.1H NMR (400 MHz, CDCI3) δ ppm: 7.28-7.32 (m, 5H), 5.55 (hr s, 1H), 3.96 (s, 2H), 3.18-3.20 (m, 2H), 2.74-2.76 (m, 2H), 1.43 (s, 9H), 1.38 (s, 9H); MS (m / z) [M+H]+calcd for C19H32N3O4+, 366.2, found, 366.1

[0613] Preparation of Int3-304: To a solution of Int2-304 (18 g, 49.25 mmol, 1.0 eq) in DCM (120 mL) was added TFA (44.93 g, 394.02 mmol, 29.27 mL, 8.0 eq) and the mixture was stirred at 40 °C for 2.0 h. LCMS showed desired mass was observed. The mixture was concentrated and Int3-304 (20 g, crude, TFA salt) was obtained as yellow oil. MS (m / z) [M+H]+calcd for

[0614] C9HI6N3+, 166.1, found, 166.2

[0615] Preparation of Int4-304: To a solution of Int3-304 (20 g, 50.85 mmol, 1.0 eq, TFA salt) in MeOH (80 mL) was added CH(OCH3)3 (7.34 g, 152.56 mmol, 3.0 eq) and the mixture was stirred at 65 °C for 1.0 h. LCMS showed desired mass was observed. The mixture was concentrated, and the crude residue was treated with aq. Na2CO3(70 mL) and extracted with DCM (3 x 50 mL). The organic phase was washed with water (35 mL), dried over Na2SO4, filtered and concentrated to give Int4-304 (5.2 g, crude) as yellow oil. MS (m / z) [M+H]+calcd for CIOHI4N3+, 176.1, found, 176.2

[0616] Preparation of Int5-304: To a solution of Int4-304 (5.2 g, 17.81 mmol, 1.0 eq) in DCM (60 mL) was added (BochO (4.27 g, 19.59 mmol, 4.50 mL, 1.1 eq). The reaction mixture was stirred at 25 °C for 16 h. LCMS showed desired mass was observed. The mixture was concentrated. The crude was purified on silica gel column chromatography (EtOAc in petroleum ether from 0% to 25%) to give Int5-304 (3.3 g, 10.79 mmol, 60.58% yield, 90% purity) as colorless oil.1H NMR (400 MHz, CDCI3) δ ppm: 7.24-7.37 (m, 6H), 4.12 (s, 2H), 3.69 (t, J= 5.2 Hz, 2H), 2.79-2.82 (m, 2H), 1.49 (s, 9H); MS (m / z) [M+H]+calcd for C15H22N3O2, 276.2, found, 276.2

[0617] Preparation of Int6-304: To a solution of Int5-304 (2.3 g, 8.35 mmol, 1.0 eq) in THF (35 mL) was added Pd / C (400 mg, 375.87 μmol, 10% purity, 4.50e"2eq) under N2. The suspension was degassed under vacuum and purged with H2 (3 times). The mixture was stirred under H2 (15 psi) at 25 °C for 5 h. TLC (Petroleum ether: Ethyl acetate = 2: 1, Rf = 0.45) showed a new spot was observed. The reaction mixture was filtered, and the filtrate was concentrated. The crude was purified on silica gel column chromatography (EtOAc in petroleum ether from 0% to 40%) to give Int6-304 (500 mg, 2.43 mmol, 29.08% yield, 90% purity) as colorless oil.

[0618] Preparation of Int7-304: To a solution of Int6-304 (204.26 mg, 1.10 mmol, 1.5 eq) and Intl- 306 (350 mg, 735.19 μmol, 1.0 eq, which was prepared as described for compound 306) in dioxane (15 mL) was added CS2CO3(598.85 mg, 1.84 mmol, 2.5 eq) and Pd-PEPPSI- iHept-Cl (71.52 mg, 73.52 μmol, 0.1 eq) under N2and the mixture was stirred at 110 °C for 16 h. LCMS showed desired mass was observed. Water (25 mL) was added to the mixture, and the resulting solution was extracted with EtOAc (2 x 30 mL). The organic phase was washed with water (20 mL) and concentrated. The crude was purified on silica gel column chromatography (EtOAc in petroleum ether from 0% to 40%) to give Int7-304 (270 mg, 455.58 μmol, 61.97% yield, 90% purity) as yellow oil. MS (m / z) [M+H]+calcd for C24H24C12FN6O3+, 533.1, found, 533.1

[0619] Preparation of Int8-304: To a solution of Int7-304 (270 mg, 506.20 μmol, 1.0 eq) in DCM (6.0 mL) was added TFA (577.17 mg, 5.06 mmol, 376.01 μL, 10 eq). The mixture was stirred at 25 °C for 16 h. LCMS showed desired mass was observed. The mixture was concentrated to give Int8-304 (270 mg, crude, TFA salt) as yellow oil. MS (m / z) [M+H]+calcd for Ci9Hi6C12FN6O+, 433.1, found, 433.0

[0620] Preparation of 304: To a solution of Int8-304 (270 mg, 493.34 μmol, 1.0 eq, TFA salt) and acryloyl chloride (35.55 mg, 493.34 μmol, 33.83 μL, 1.0 eq) in DMF (3 mL) was added DIPEA (318.80 mg, 2.47 mmol, 429.65 μL, 5.0 eq) and HATU (243.86 mg, 641.34 μmol, 1.3 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 h under N2. LCMS showed desired mass was observed. The mixture was quenched by water (0.1 mL) and concentrated. The crude was purified by prep-HPLC (column: 55-Boston Prime C18 150x30mm, 5pm; mobile phase: [H2O (0.05% NH3H2O+10mM NH4HCO3)-ACN]; gradient: 59%-89% B over 10.0 min) to give 304 (82 mg, 165.57 μmol, 33.56% yield, 98.395% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.99 (s, 1H), 8.47 (s, 1H), 8.24 (s, 1H), 8.11 (d, J = 2.8 Hz, 1H), 8.04 (s, 1H), 7.78 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.33-7.37 (m, 1H), 7.01-7.24 (m, 3H), 6.86-6.91 (m, 1H), 6.38 (dd, J= 15.6 Hz, 1.2 Hz, 1H), 5.97 (dd, J= 10.4 Hz, 1.6 Hz, 1H), 4.02-4.04 (m, 2H), 3.46 (t, J= 5.2 Hz, 2H); MS (m / z) [M+H]+calcd for C22Hi8C12FN6O2+, 487.2, found, 487.1 l-( 4-( 4-(( 3-chloro-4-(imidazo[ 1, 2 -a ]pyridin-8-yloxy)phenyl)ammo)pyrimidm-5-yl)piperazm- l-yl)prop-2-en-l-one (305)

[0621] 305 was prepared by following General Procedure 8.1H NMR (500 MHz, DMSO-d6) δ ppm: 8.63 (s, 1H), 8.40 (s, 1H), 8.32 (d, J= 7.0 Hz, 1H), 8.20 (s, 1H), 8.07 (d, J= 2.5 Hz, 1H), 8.01 (s, 1H), 7.75 (dd, J= 8.5, 3.0 Hz, 1H), 7.54 (s, 1H), 7.17 (d, J= 9.0 Hz, 1H), 6.84 (dd, J= 17.0, 10.5 Hz, 1H), 6.78 (t, J= 7.3 Hz, 1H), 6.44 (d, J= 7.5 Hz, 1H), 6.14 (dd, J =

[0622] 16.5, 2.5 Hz, 1H), 5.70 (dd, J= 10.5, 2.5 Hz, 1H), 3.81 (br s, 4H), 2.90 (br s, 4H);13C NMR (125 MHz, DMSO-d6) δ ppm: 164.8, 155.3, 153.7, 146.8, 146.25, 146.21, 139.2, 137.3, 133.2, 132.5, 128.7, 128.1, 124.6, 123.5, 122.7, 122.3, 121.8, 115.0, 112.1, 107.8, 51.7, 51.0,

[0623] 45.6, 41.9; HRMS (ESI, m / z): calcd for C24H21CIN7O2 ([M-H]-): 474.1450, Found: 475.1436 l-( 4-( 4-(( 3-chloro-4-(3-chloro-2-fluorophenoxy)phenyl)amino)pyrimidm-5-yl)-3, 6- dihydropyridin- 1 ( 2H) -yl) prop-2-en- 1 -one (306)

[0624] Preparation of Intl-306: To a solution of Gpl-4-1 (1.13 g, 4.16 mmol, 1.0 eq) and 4-chloro- 5-iodopyrimidine (1.0 g, 4.16 mmol, 1.0 eq) in z-PrOH (10.0 mL) was added Py HCl (961.29 mg, 8.32 mmol, 2.0 eq) at 25 °C. The mixture was stirred at 80 °C for 1 h. The reaction was cooled to 25 °C for 1 h, solid was precipitated. The slurry was filtered, and the solid was dried under reduced pressure to give Intl-306 (1.73 g, 2.91 mmol, 69.90% yield, 80% purity) as a light-yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 9.45 (br s, 1H), 8.83 (s, 1H), 8.71 (s, 1H), 7.87 (d, J= 2.4 Hz, 1H), 7.55 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.39-7.43 (m, 1H), 7.21-7.26 (m, 1H), 7.18 (d, J= 8.8 Hz, 1H), 6.98-7.03 (m, 1H).

[0625] Preparation of Int2-306: To a solution of Intl-306 (400.0 mg, 840.21 μmol, 1.0 eq) and tert- butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2rt)-carboxylate (259.80 mg, 840.21 μmol, 1.0 eq) in dioxane (10.0 mL) and H2O (2.0 mL) was added K2CO3(348.37 mg, 2.52 mmol, 3.0 eq) and Pd(dppf)C12 (61.48 mg, 84.02 μmol, 0.1 eq) at 25 °C. The mixture was stirred at 100 °C for 16 h under N2. TLC (Commercial hexanes / Ethyl acetate = 2 / 1) showed a new spot. The mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ethergradient @ 25 mL / min) to give Int2-306 (365.0 mg, 618.17 μmol, 73.57% yield, 90% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.59 (br s, 1H), 8.55 (s, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.66 (d, J= 8.0 Hz, 1H), 7.33-7.37 (m, 1H), 7.12-7.25 (m, 2H), 6.86-6.91 (m, 1H), 5.94 (br s, 1H), 4.00 (br s, 2H), 3.55-3.62 (m, 2H), 2.35 (br s, 2H), 1.44 (s, 9H).

[0626] Preparation of Int3-306: To a solution of Int2-306 (365.0 mg, 686.86 μmol, 1.0 eq) in DCM (5.0 mL) was added HCl / dioxane (2 M, 25.0 mL, 72.80 eq) at 25 °C. The mixture was stirred at 25 °C for 3 h. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure to give Int3-306 (320.0 mg, crude, HC1 salt) as a white solid. MS (m / z) [M+H]+calcd for C21H18Cl2FN4O+, 431.1, found, 430.9

[0627] Preparation of 306: To a solution of Int3-306 (320.0 mg, 684.13 μmol, 1.0 eq, HC1 salt) in DCM (10.0 mL) was added DIPEA (265.25 mg, 2.05 mmol, 357.48 μL, 3.0 eq) at 25 °C. The mixture was cooled to 0 °C and acryloyl chloride (61.92 mg, 684.13 μmol, 55.58 μL, 1.0 eq) in DCM (0.1 mL) was added and the mixture was stirred at 0 °C for 0.5 h. LCMS showed the desired mass was detected. H2O (0.5 mL) was added to the mixture and concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: 41-WePure Biotech XP tC 18 150x40mm, 7pm; mobile phase: [08-Water (0.05% NH3H2O+10mM NH4HCO3)-01-MeCN]; gradient: 37%-77% B over 11.0 min) to give 306 (96.5 mg, 197.54 μmol, 28.87% yield, 99.35% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.60 (d, J= 10.4 Hz, 1H), 8.55 (s, 1H), 8.18 (s, 1H), 7.95 (d, J= 2.8 Hz, 1H), 7.66 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.33-7.38 (m, 1H), 7.16-7.22 (m, 2H), 6.77-6.93 (m, 2H), 6.13-6.20 (m, 1H), 5.95-5.98 (m, 1H), 5.69-5.75 (m, 1H), 4.19-4.27 (m, 2H), 3.79-3.83 (m, 2H), 2.37-2.43 (m, 2H); MS (m / z) [M+H]+calcd for C24H2oC12FN4O2+, 485.1, found,

[0628] 485.1 l-( 4-( 4-(( 3-chloro-4-(pyridin-2-yloxy)phenyl)ammo)pyrimidm-5-yl)piperazin-l-yl)prop-2-en-

[0629] 1-one (307)

[0630] 307 was prepared by following General Procedure 8.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.62 (s, 1H), 8.44 (s, 1H), 8.22 (s, 1H), 8.10-8.11 (m, 1H), 8.02 (d, J= 2.4 Hz, 1H), 7.86-7.90 (m, 1H), 7.78 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.29 (d, J= 8.8 Hz, 1H), 7.09-7.15 (m, 2H), 6.87 (dd, J= 16.8 Hz, 10.4 Hz, 1H), 6.16 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.73 (dd, J = 10.4 Hz, 2.4 Hz, 1H), 3.81-3.83 (m, 4H), 2.94 (t, J= 4.4 Hz, 4H); MS (m / z) [M+H]+calcd for C22H22C1N6O2+, 437.1, found, 437.2 l-( 4-( 4-( 4-([ 1, 2, 4 ]triazolo[ 1, 5-a]pyridin-8-yloxy)-3-chlorophenyl)ammo)pyrimidm-5- yl)piperazin-l-yl)prop-2-en-l-one (308)

[0631] 308 was prepared by following General Procedure 8.1H NMR (500 MHz, DMSO-d6) δ ppm: 8.72 (dd, J= 7.0, 1.0 Hz, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 8.21 (s, 1H), 8.11 (d, J= 2.5 Hz, 1H), 7.79 (dd, J= 9.0, 3.0 Hz, 1H), 7.28 (d, J= 9.0 Hz, 1H), 7.10 (t, J= 7.3 Hz, 1H), 6.89-6.82 (m, 2H), 6.14 (dd, J= 17.0, 2.5 Hz, 1H), 5.70 (dd, J= 10.5, 2.5 Hz, 1H), 3.81 (br s, 4H), 2.91 (br s, 4H);13C NMR (125 MHz, DMSO-d6) δ ppm: 164.9, 155.3, 153.9, 153.7, 146.9, 146.0, 145.6, 145.0, 137.9, 132.6, 128.7, 128.2, 124.8, 124.7, 123.5, 122.3,

[0632] 122.2, 114.5, 113.3, 51.8, 51.1, 45.6, 41.9; HRMS (ESI, m / z): calcd for C23H2OC1N802([M-

[0633] H]’): 475.1403, Found: 475.1391

[0634] 1-( 4-( 4-(( 4-(benzofuran-5-yloxy)-3-chlorophenyl)amino)pyrimidm-5-yl)piperazm-l-yl)prop-

[0635] 2-en-l-one (309)

[0636] 309 was prepared by following General Procedure 8.1H NMR. (500 MHz, DMSO-d6) δ ppm: 8.59 (s, 1H), 8.40 (s, 1H), 8.19 (s, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.98 (d, J= 2.5 Hz, 1H), 7.72 (dd, J= 9.0, 2.5 Hz, 1H), 7.58 (d, J= 9.0 Hz, 1H), 7.13 (d, J= 2.5 Hz, 1H), 7.09 (d, J= 9.0 Hz, 1H), 6.98 (dd, J= 9.0, 3.0 Hz, 1H), 6.90 (d, J= 1.5 Hz, 1H), 6.84 (dd, J= 16.5, 10.5 Hz, 1H), 6.14 (dd, J= 16.5, 2.5 Hz, 1H), 5.70 (dd, J= 10.5, 2.5 Hz, 1H), 3.81 (br s, 4H), 2.90 (br s, 4H);13C NMR (125 MHz, DMSO-d6) δ ppm: 164.9, 155.4, 153.7, 153.6, 151.0, 148.0, 147.9, 146.7, 136.7, 132.5, 128.8, 128.7, 128.2, 124.7, 123.7, 122.5, 121.6, 115.4, 112.8, 109.2, 107.6, 51.7, 51.1, 45.6, 41.9; HRMS (ESI, m / z): calcd for C25H21CIN5O3 ([M- H]’): 474.1338, Found: 474.1321 l-( 4-( 4-( 3-chloro-4-(3-chloro-2-fluorophenoxy)-2, 6-difluorophenyl)amino)pyrimidin-5- yl)piperazin-l-yl)prop-2-en-l-one (310) and l-(4-(4-((3-chloro-2-(3-chloro-2- fluorophenoxy)-4,6-difluorophenyl)amino)pyrimidin-5-yl)piperazin-l-yl)prop-2-en-l-one (317)

[0637]

[0638] Preparation of Intl-310, Intl-317 and 2-Chloro-5-(3-chloro-2-fluorophenoxy)-l,3-difluoro- 4-nitrobenzene: To a solution of 3-chloro-2-fluorophenol (1.07 g, 7.33 mmol, 1.0 eq) and 2- chloro-l,3,5-trifluoro-4-nitrobenzene (1.55 g, 7.33 mmol, 1.0 eq) in ACN (20.0 mL) was added DIPEA (2.84 g, 21.98 mmol, 3.83 mL, 3.0 eq) at 25 °C. The mixture was stirred at 25 °C for 16 h. TLC (Commercial hexanes / Ethyl acetate = 10 / 1) showed new spots were observed. The reaction mixture was concentrated under reduced pressure to give a mixture of Intl-310, Intl-317 and 2-chloro-5-(3-chloro-2-fluorophenoxy)-l,3-difluoro-4-nitrobenzene (2.4 g, crude) as yellow oil.

[0639] Preparation of Int2-310, Int2-317 and 3-Chloro-6-(3-chloro-2-fluorophenoxy)-2,4- difluoroaniline: To a solution of Intl-310, Intl-317 and 2-Chloro-5-(3-chloro-2- fluorophenoxy)-l,3-difluoro-4-nitrobenzene (2.4 g, 7.10 mmol, 1.0 eq) in EtOH (25.0 mL) and H2O (5.0 mL) was added Fe (3.17 g, 56.79 mmol, 8.0 eq) and NH4CI (3.04 g, 56.79 mmol, 8.0 eq) at 25 °C. The mixture was stirred at 75 °C for 3 h. TLC (Commercial hexanes / Ethyl acetate = 5 / 1) showed new spots were observed. The mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Commercial hexanes gradient @ 20 mL / min) to give a mixture of the products (1.98 g, crude). The crude product was purified by prep-HPLC (column: 41-WePure Biotech XP tC18 150x40mm, 7pm; mobile phase: [H2O (0.05% NH3 H2O+ 10mM NH4HCO3)-ACN]; gradient: 44%-84% B over 11.0 min) to give compound Int2-310 and Int2-317 (835 mg, 1.36 mmol, 19.09% yield, 50% purity) as light-yellow oil and 3-chloro-6- (3-chloro-2-fhiorophenoxy)-2,4-difhioroaniline (68.5 mg, 177.87 μmol, 2.51% yield, 80% purity) as light-yellow oil.

[0640] Int2-310 and Int2-317:1H NMR (400 MHz, DMSO-d6) δ ppm: 7.29-7.33 (m, 1H), 7.11-7.17 (m, 2H), 6.82-6.87 (m, 1H), 5.54 (s, 2H); MS (m / z) [M+H]+calcd for C12H7CI2F3NO+, 308.0, found, 307.9.

[0641] 3-Chloro-6-(3-chloro-2-fluorophenoxy)-2,4-difluoroaniline:1H NMR (400 MHz, DMSO-d6) δ ppm: 7.32-7.37 (m, 1H), 7.14-7.19 (m, 1H), 6.92-6.97 (m, 2H), 5.35 (s, 2H); 2D NMR analyses (HSQC, HMBC and NOE) were conducted to confirm the structure of the compound.

[0642] The mixture of Int2-310 and Int2-317 was then carried forward in the synthesis, following General Procedure 9, to afford a mixture of 310 and 317. The mixture was purified by prep- HPLC (column: 52-Welch Xtimate C18 150x30mm, 5 pm; mobile phase: [H2O (0.05% NH3·H2O+10mM NH4HCO3)-ACN]; gradient: 39%-79% B over 11.0 min) to give impure 317 (180 mg, 90.99% purity) as a white solid and 310 (210.0 mg, 398.47 μmol, 16.83% yield, 99.49% purity) as a white solid. The impure 317 was further purified by prep-HPLC (column: 41-WePure Biotech XP tC18 150x40mm, 7pm; mobile phase: [H2O (0.05% NH3H2O+10 mM NH4HCO3)-ACN]; B%:42%, isocratic elution mode) to give 317 (85.0 mg, 159.37 μmol, 6.73% yield, 98.31% purity) as a white solid.

[0643] 310:1H NMR (400 MHz, DMSO-d6) δ ppm: 8.44 (br s, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 7.49- 7.54 (m, 1H), 7.23-7.33 (m, 2H), 7.15 (dd, J= 10.4 Hz, 1.6 Hz, 1H), 6.83-6.90 (m, 1H), 6.16 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.68-3.87 (m, 4H), 2.95 (t, J= 4.4 Hz, 4H); 2D NMR analyses (HSQC, COSY and HMBC) were conducted to confirm the structure of 310; MS (m / z) [M+H]+calcd for C23H19C12F3N5O2+, 524.1, found, 524.2 317:1H NMR (400 MHz, DMSO-d6) δ ppm: 8.21 (br s, 1H), 8.15 (s, 1H), 8.00 (s, 1H), 7.73 (t, J= 9.6 Hz, 1H), 7.16-7.20 (m, 1H), 6.95-7.00 (m, 1H), 6.76-6.86 (m, 2H), 6.13 (dd, J = 16.8 Hz, 2.4 Hz, 1H), 5.71 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.55-3.72 (m, 4H), 2.57-2.73 (m, 4H); 2D NMR analyses (HSQC, HMBC and HOESY) were conducted to confirm the structure of 317; MS (m / z) [M+H]+calcd for C23H19C12F3N5O2+, 524.1, found, 524.1

[0644] (S)-l-( 4-( 4-( 3-chloro-4-( 3-chloro-2-fluorophenoxy)phenyl)amino)pyrimidm-5-yl)-6-methyl- 3, 6-dihydropyridin-l(2H)-yl)prop-2-en-l-one (311 )

[0645] Int1-311

[0646] 311 was prepared by following the synthetic procedure of 306. One modification was replacing the compound tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-l(2H)-carboxylate with Intl-311. 311 was obtained as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.55 (s, 1H), 8.36 (br s, 1H), 8.18 (s, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.62 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.32-7.36 (m, 1H), 7.18-7.22 (m, 1H), 7.16 (d, J= 8.8 Hz, 1H), 6.90-6.95 (m, 1H), 6.77-6.84 (m, 1H), 6.12-6.20 (m, 1H), 5.92-5.94 (m, 1H), 5.70 (dd, J= 10.8 Hz, 2.0 Hz, 1H), 4.88 (br s, 1H), 4.29 (br s, 1H), 3.16-3.36 (m, 1H), 2.54- 2.63 (m, 1H), 2.21-2.26 (m, 1H), 1.30 (d, J= 6.8 Hz, 3H); MS (m / z) [M+H]+calcd for C25H22CI2FN4O2 , 499.1, found, 499.1

[0647] 1-( 4-( 4-(( 3-chloro-4-(2, 3-difluorophenoxy)phenyl)amino)pyrimidm-5-yl)piperazm-l-yl)prop-

[0648] 2-en-l-one (312)

[0649] 312 was prepared by following General Procedure 8.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.66 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.81 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.16-7.26 (m, 3H), 6.83-6.90 (m, 1H), 6.70-6.74 (m, 1H), 6.16 (dd, J= 16.4 Hz, 2.0 Hz, 1H), 5.72 (dd, J= 10.0 Hz, 2.4 Hz, 1H), 3.82 (br s, 4H), 2.87-2.95 (m, 4H); MS (m / z) [M+H]+calcd for C23H21ClF2N5O2+, 472.1, found, 472.2 l-(( 3aR, 6aS)-5-( 4-(( 3-chloro-4-(3-chloro-2-fluorophenoxy)phenyl)amino)pyrimidm-5- yl)hexahydropyrrolo[ 3, 4-c Jpyrrol-2(lH)-yl)prop-2-en-l-one (314)

[0650] 314 was prepared by following the synthetic procedure of 304. One modification was replacing Int6-304 with Intl-314. 314 was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.42 (s, 1H), 8.36 (s, 1H), 8.15 (s, 1H), 8.04 (d, J= 2.8 Hz, 1H), 7.74 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.32-7.37 (m, 1H), 7.16-7.23 (m, 2H), 6.85-6.89 (m, 1H), 6.64 (dd, J = 16.4 Hz, 10.0 Hz, 1H), 6.14 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.67 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.77-3.82 (m, 1H), 3.54-3.67 (m, 3H), 3.37-3.41 (m, 1H), 2.94-3.11 (m, 5H); MS (m / z) [M+H]+calcd for C25H23C12FN5O2+, 514.1, found, 514.1

[0651] 1-( 4-( 4-(( 3-chloro-4-(pyridin-2-ylmethoxy)phenyl)ammo)pyrimidm-5-yl)piperazm-l-yl)prop-

[0652] 2-en-l-one (315)

[0653] 315 was prepared by following General Procedure 8.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.58-8.60 (m, 1H), 8.46 (s, 1H), 8.36 (s, 1H), 8.15 (s, 1H), 7.85-7.89 (m, 2H), 7.56-7.64 (m, 2H), 7.35-7.38 (m, 1H), 7.22 (d, J= 9.2 Hz, 1H), 6.86 (dd, J= 16.4 Hz, 10.4 Hz, 1H), 6.15 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 5.27 (s, 2H), 3.80-3.83 (m, 4H), 2.89-2.92 (m, 4H); MS (m / z) [M+H]+calcd for C23H24C1N6O2+, 451.2, found, 451.2 1-( 4-( 4-(( 4-(benzofuran-6-yloxy)-3-chlorophenyl)amino)pyrimidm-5-yl)piperazm-l-yl)prop-

[0654] 2-en-l-one (318)

[0655] 318 was prepared by following General Procedure 8.1H NMR (500 MHz, DMSO-d6) δ ppm: 8.61 (s, 1H), 8.41 (s, 1H), 8.20 (s, 1H), 8.06 (d, J= 2.5 Hz, 1H), 7.93 (d, J= 2.0 Hz, 1H), 7.76 (dd, J= 9.0, 2.5 Hz, 1H), 7.62 (d, J= 8.5 Hz, 1H), 7.16-7.13 (m, 2H), 6.93-6.90 (m, 2H), 6.85 (dd, J= 16.5, 10.5 Hz, 1H), 6.14 (dd, J= 16.5, 2.5 Hz, 1H), 5.70 (dd, J= 10.5, 2.5 Hz, 1H), 3.81 (br s, 4H), 2.90 (br s, 4H);13C NMR (125 MHz, DMSO-d6) δ ppm: 164.8, 155.5, 155.33, 155.32, 153.7, 147.2, 146.8, 146.7, 137.0, 132.5, 128.7, 128.1, 124.9, 123.6, 123.3, 122.45, 122.36, 121.9, 113.8, 107.1, 100.7, 51.7, 51.0, 45.6, 41.9; HRMS (ESI, m / z): calcd for C25H21CIN5O3 ([M-H]’): 474.1338, Found: 474.1327

[0656] 1-( 4-( 4-(( 3-chloro-4-(2, 3-dichlorophenoxy)phenyl )amino)pyrimidin-5-yl)piperazin-l-yl)prop-

[0657] 2-en-l-one (319)

[0658] 319 was prepared by following General Procedure 8.1HNMR (400 MHz, DMSO-d6) <3 ppm: 8.66 (s, 1H), 8.44 (s, 1H), 8.24 (s, 1H), 8.12 (d, J= 2.4 Hz, 1H), 7.83 (dd, J= 9.2 Hz, 2.4 Hz, 1H), 7.40-7.44 (m, 1H), 7.31-7.35 (m, 1H), 7.22 (d, J= 9.2 Hz, 1H), 6.83-6.90 (m, 1H), 6.75-6.81 (m, 1H), 6.16 (dd, J= 16.4 Hz, 2.0 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.83 (br s, 4H), 2.87-2.97 (m, 4H); MS (m / z) [M+H]+calcd for C23H21Cl3N5O2+, 506.1, found, 506.2 l-( 4-( 4-( 3-chloro-4-( (2, 3-dihydrobenzo[b ][ 1, 4 ]dioxin-5-yl)oxy)phenyl)ammo)pyrimidm-5- yl)piperazin-l-yl)prop-2-en-l-one (320)

[0659] 320 was prepared by following General Procedure 8.1H NMR (500 MHz, DMSO-d6) δ ppm: 8.54 (s, 1H), 8.37 (s, 1H), 8.17 (s, 1H), 7.96 (d, = 3.0 Hz, 1H), 7.62 (dd, J= 9.0, 2.5 Hz, 1H), 6.88-6.76 (m, 3H), 6.70 (dd, J= 8.5, 1.5 Hz, 1H), 6.42 (dd, J= 8.5, 1.5 Hz, 1H), 6.13 (dd, J= 16.5, 2.5 Hz, 1H), 5.70 (dd, J= 10.5. 2.5 Hz, 1H), 4.26-4.25 (m, 2H), 4.24-4.23 (m, 2H), 3.80 (br s, 4H), 2.89 (br s, 4H);13C NMR (125 MHz, DMSO-d6) δ ppm: 164.8,

[0660] 155.4, 153.7, 148.3, 146.6, 145.4, 144.9, 135.72, 135.71, 132.3, 128.7, 128.1, 123.9, 122.9,

[0661] 122.4, 120.8, 118.7, 113.4, 111.9, 64.5 (2C), 51.7, 51.0, 45.6, 41.9; HRMS (ESI, m / z): calcd for C25H23CIN5O4 ([M-H]-): 492.1444, Found: 492.1427 l-( 4-( 4-(( 4-(3-bromo-2-chlorophenoxy)-3-chlorophenyl)amino)pyrimidm-5-yl)piperazm-l- yl)prop-2-en-l-one (321 )

[0662] 321 was prepared by following General Procedure 8.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.66 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.12 (d, =2.8 Hz, 1H), 7.82 (dd, J =8.8 Hz, 2.4 Hz, 1H), 7.54-7.56 (m, 1H), 7.19-7.28 (m, 2H), 6.81-6.90 (m, 2H), 6.16 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.72 (dd, J=10.4 Hz, 2.4 Hz, 1H), 3.81-3.84 (m, 4H), 2.90-2.94 (m, 4H); MS (m / z) [M+H]+calcd for C23H21BrCl2N5O2+, 550.0, found, 550.1

[0663] 2-chloro-l-(4-(4-((3-chloro-4-(3-chloro-2-fluorophenoxy)-2-fluorophenyl)amino)pyrimidin- 5-yl)piperazin-l-yl)ethan-l-one (322 )

[0664] Preparation of Gp9-2-l and Gp9-2-l': To a solution of 2-chloro-l,3-difluoro-4-nitrobenzene (3.0 g, 15.50 mmol, 1.0 eq) and 3-chloro-2-fluorophenol (1.14 g, 7.75 mmol, 0.5 eq) in ACN (50.0 mL) was added DIPEA (6.01 g, 46.50 mmol, 8.10 mL, 3.0 eq) at 25 °C. The mixture was stirred at 25 °C for 16 h. TLC (Commercial hexanes / EtOAc = 10 / 1) showed new spots were observed. The mixture was concentrated under reduced pressure to give a mixture of Gp9-2-l and Gp9-2-l' (4.47 g, 8.38 mmol, 54.06% yield, 60% purity) as yellow oil.

[0665] Preparation of Gp9-3-l: To a solution of Gp9-2-l and Gp9-2-l' (4.47 g, 13.97 mmol, 1.0 eq) in EtOH (50.0 mL) and H2O (10 mL) was added Fe (6.24 g, 111.72 mmol, 8.0 eq) and NH4CI (5.98 g, 111.72 mmol, 8.0 eq) at 25 °C. The mixture was stirred at 75 °C for 2 h. TLC (Commercial hexanes / EtOAc = 1 / 1) showed the starting material was consumed and new spots were observed. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 40 g Sepa Flash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Commercial hexanes gradient @ 25 mL / min) to give Gp9-3-l (1.18 g, 2.85 mmol, 20.39% yield, 70% purity) as yellow oil.1H NMR (400 MHz, DMSO-d6) δ ppm: 7.25-7.30 (m, 1H), 7.09-7.15 (m, 1H), 6.89 (dd, J= 9.2 Hz, 1.6 Hz, 1H), 6.73-6.80 (m, 2H), 5.47 (s, 2H); MS (m / z) [M+H]+calcd for C12H8Cl2F2NO+, 290.0, found, 289.8.

[0666] Preparation of Gp9-4-l: To a solution of Gp9-3-l (500.0 mg, 1.72 mmol, 1.0 eq) and Gp8-5 (514.95 mg, 1.72 mmol, 1.0 eq) in toluene (15.0 mL) was added CS2CO3(1.12 g, 3.45 mmol, 2.0 eq), Xantphos (99.73 mg, 172.36 μmol, 0.1 eq) and Pd(OAc)2(38.70 mg, 172.36 μmol, 0.1 eq) at 20 °C. The mixture was stirred at 110 °C for 2.5 h under N2. LCMS showed the desired mass was detected. The mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 20 g Sepa Flash® Silica Flash Column, Eluent of 0-60% Ethyl acetate / Commercial hexanes gradient @ 20 mL / min) to give Gp9-4-l (745.0 mg, 971.04 μmol, 56.34% yield, 72% purity) as a light- yellow solid.

[0667] Preparation of Gp9-5-l: To a solution of Gp9-4-l (745.0 mg, 1.35 mmol, 1.0 eq) in DCM (5.0 mL) was added HCl / dioxane (2 M, 10.0 mL, 14.83 eq) at 25 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure to give Gp9-5-l (750.0 mg, crude, HC1 salt) as a white solid.

[0668] Preparation of 322: To a solution of Gp9-5-l (350.0 mg, 716.12 μmol, 1.0 eq, HC1 salt) in DCM (10.0 mL) was added DIPEA (277.66 mg, 2.15 mmol, 374.20 μL, 3.0 eq) at 20 °C. The mixture was cooled to 0 °C and chloroacetyl chloride (80.88 mg, 716.12 μmol, 57.04 μL, 1.0 eq) in DCM (1.0 mL) was added. The mixture was stirred at 0 °C for 30 mins. LCMS showed the desired mass was detected. H2O (0.5 mL) was added and the mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: 40- WePure Biotech XP tC18 150x30mm, 7pm; mobile phase: [H2O (0.05% NH3 H2O+10mM NH4HCO3)-ACN]; gradient:40%-80% B over 11.0 min) to give the crude product (100.0 mg) as a white solid. The crude product was further purified by prep-TLC (DCM / MeOH = 10 / 1) to give 322 (54.0 mg, 98.16 μmol, 13.71% yield, 96.12% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.55 (s, 1H), 8.32 (s, 1H), 8.17 (s, 1H), 7.62 (t, J= 8.8 Hz, 1H), 7.44-7.48 (m, 1H), 7.24-7.29 (m, 1H), 7.09-7.14 (m, 1H), 7.02 (dd, J= 9.2 Hz, 1.6 Hz, 1H), 4.45 (s, 2H), 3.60-3.74 (m, 4H), 2.90-2.98 (m, 4H); MS (m / z) [M+H]+calcd for

[0669] C22H19CI3F2N5O2 ., 530.1, found, 530.0 l-( (2R, 5S)-4-( 4-( 3-chloro-4-(3-chloro-2-fluorophenoxy)phenyl)amino)pyrimidm-5-yl)-2, 5- dimethylpiperazin-1 -yl)prop-2-en-l -one (324) lnt1-324 lnt2-324 lnt3-324

[0670] Preparation of Int2-324: To a solution of 5-bromopyrimidine (2.0 g, 12.58 mmol, 1.0 eq) and compound Intl-324 (8.09 g, 37.74 mmol, 3.0 eq) in toluene (40.0 mL) was added LBuONa (2.42 g, 25.16 mmol, 2.0 eq), BINAP (783.31 mg, 1.26 mmol, 0.1 eq) and Pd2(dba)3(575.98 mg, 628.99 μmol, 0.05 eq) at 20 °C. The mixture was stirred at 80 °C for 5 h under N2. LCMS showed the desired mass was detected. The mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 40 g Sepa Flash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Commercial hexanes gradient @ 30 mL / min) to give Int2-324 (3.86 g, 10.56 mmol, 83.96% yield, 80% purity) as a yellow solid.1H NMR (400 MHz, CDCI3) δ ppm: 8.65 (s, 1H), 8.31 (s, 2H), 4.46- 4.49 (m, 1H), 3.83-3.86 (m, 1H), 3.97 (br s, 1H), 3.35 (br d, J= 13.2 Hz, 1H), 3.33 (dd, J = UA Hz, 4.0 Hz, 1H), 3.17 (br d, J= 12.4 Hz, 1H), 1.49 (s, 9H), 1.27 (d, J= 6.8 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H); MS (m / z) [M+H]+calcd for C15H25N4O2+, 293.2, found, 293.0

[0671] Preparation of Int3-324: To a solution of Int2-324 (1.5 g, 5.13 mmol, 1.0 eq) in DCM (25.0 mL) was added slowly m-CPBA (3.12 g, 15.39 mmol, 85% purity, 3.0 eq) at 0 °C under N2. The mixture warmed to 20 °C and stirred at 20 °C for 3 h under N2. TLC (EtOAc) showed a new spot was observed. The mixture was diluted H2O (25 mL), NaHSO3(25 mL) and extracted with DCM (25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0-10% Methyl alcohol / Dichloromethane gradient @ 20 mL / min) to give Int3-324 (500.0 mg, 1.30 mmol, 25.28% yield, 80% purity) as yellow oil.1H NMR (400 MHz, CDCI3) δ ppm: 8.40 (s, 1H), 7.92 (s, 1H), 7.83 (d, J= 2.0 Hz, 1H), 4.48-4.50 (m, 1H), 3.74-3.82 (m, 2H), 3.24-3.29 (m, 2H), 3.04 (br d, J= 12.4 Hz, 1H), 1.42 (s, 9H), 1.18 (t, J= 5.6 Hz, 3H), 1.09 (d, J= 6.4 Hz, 3H).

[0672] Preparation of Int4-324: To a solution of Int3-324 (500.0 mg, 1.62 mmol, 1.0 eq) in dioxane (8.0 mL) was added DIPEA (628.66 mg, 4.86 mmol, 847.25 μL, 3.0 eq) and slowly dropwise POCI3 (497.23 mg, 3.24 mmol, 302.27 μL, 2.0 eq) at 20 °C. The mixture was slowly heated up to 90 °C and stirred at 90 °C for 0.5 h under N2. The reaction mixture turned clear. TLC (Commercial hexanes / EtOAc = 3 / 1) showed one new spot was observed and the starting material was consumed. DCM (15 mL) was added to the mixture at 20 °C and then slowly poured into aq. NaHCCL (20 mL) and extracted with DCM (15 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 4 g Sepa Flash® Silica Flash Column, Eluent of 0-60% Ethyl acetate / Commercial hexanes gradient @ 20 mL / min) to give Int4-324 (300.0 mg, 642.55 umol, 39.63% yield, 70% purity) as light- yellow oil.1H NMR (400 MHz, CDCI3) δ ppm: 8.67 (s, 1H), 8.24 (s, 1H), 4.48 (br s, 1H), 3.90 (br s, 1H), 3.89 (br d, J= 13.2 Hz, 1H), 3.71 (dd, J= 11.6 Hz, 4.0 Hz, 1H), 3.57 (dd, J = 13.2 Hz, 3.6 Hz, 1H), 2.72 (d, J= 11.6 Hz, 1H), 1.51 (s, 9H), 1.33 (d, J = 6.4 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H).

[0673] The Int4-324 was then carried forward in the synthesis, following the procedures from Gp8- 5 to the final Test Compounds described in General Procedure 8, to afford the final product 324 as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.39 (s, 1H), 8.32 (s, 1H), 8.08 (s, 1H), 8.01 (d, J= 2.8 Hz, 1H), 7.74 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.34-7.39 (m, 1H), 7.24 (d, J= 8.8 Hz, 1H), 7.18-7.21 (m, 1H), 6.87-6.92 (m, 1H), 6.79-6.86 (m, 1H), 6.15 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.71 (dd, J= 10.4 Hz, 2.0 Hz, 1H), 4.61 (br s, 1H), 3.93 (br s, 2H), 3.60 (br dd, J= 10.4 Hz, 1H), 3.42-3.50 (m, 1H), 2.61 (br d, J= 11.6 Hz, 1H), 1.40 (br d, J= 6.4 Hz, 3H), 0.83 (d, J= 6.4 Hz, 3H); MS (m / z) [M+H]+calcd for C25H25C12FN5O2+,

[0674] 516.1, found, 516.1 l-( (2S, 5R)-4-( 4-( 3-chloro-4-(3-chloro-2-fluorophenoxy)phenyl)amino)pyrimidm-5-yl)-2, 5- dimethylpiperazin-1 -yl)prop-2-en-l -one (325) lnt1-325

[0675] 325 was prepared by following the synthetic procedure of 324. One modification was replacing Intl-324 with Intl-325.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.39 (s, 1H), 8.32 (s, 1H), 8.08 (s, 1H), 8.01 (d, J= 2.4 Hz, 1H), 7.74 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.34 - 7.39 (m, 1H), 7.23 (d, J = 9.2 Hz, 1H), 7.18 - 7.21 (m, 1H), 6.87 - 6.92 (m, 1H), 6.83 (br dd, J = 16.4 Hz, 10.4 Hz, 1H), 6.15 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.69-5.72 (m, 1H), 4.64 (br s, 1H), 3.92 (br s, 2H), 3.60 (br dd, J= 11.2 Hz, 3.2 Hz, 1H), 3.47 (br d, J= 4.8 Hz, 1H), 2.61 (br d, J= 12.0 Hz, 1H), 1.40 (br d, J= 6.8 Hz, 3H), 0.84 (d, J= 6.4 Hz, 3H); MS (m / z) [M+H]+calcd for C25H25C12FN5O2+, 516.1, found, 516.2

[0676] 2-chloro-l-(4-(4-((3-chloro-4-(3-chloro-2-fluorophenoxy)-2-fluorophenyl)ammo)pyrimidm-

[0677] 5-yl)piperazin-l-yl)-2-fluoroethan-l-one (326)

[0678] Gp9-5-l was prepared following the procedures described for the synthesis of compound 322.

[0679] Preparation of 326: To a solution of Gp9-5-l (350.0 mg, 716.12 μmol, 1.0 eq, HC1 salt) and 2-chloro-2-fluoroacetic acid (402.77 mg, 3.58 mmol, 5.0 eq) in DCM (10.0 mL) was added TEA (217.39 mg, 2.15 mmol, 299.02 μL, 3.0 eq) and T4P (2.58 g, 3.58 mmol, 50% purity, 5.0 eq) at 20 °C. The mixture was stirred at 20 °C for 30 mins. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: 41-WePure Biotech XP tC18 150x40mm, 7pm; mobile phase: [H2O (0.05% NH3H20+10mM NH4HC03)-ACN]; gradient: 44%-69% B over 15.0 min) to give 326 (82.0 mg, 149.24 μmol, 20.84% yield, 99.51% purity) as a white solid.JH NMR (400 MHz, DMSO-d6) δ ppm: 8.56 (s, 1H), 8.32 (s, 1H), 8.18 (s, 1H), 7.60 (t, J= 8.8 Hz, 1H), 7.44-7.48 (m, 1H), 7.36 (d, J= 48.8 Hz, 1H), 7.25-7.28 (m, 1H), 7.10-7.14 (m, 1H), 7.02 (dd, J= 9.2 Hz, 1.6 Hz, 1H), 3.61-3.78 (m, 4H), 2.92-2.99 (m, 4H); MS (m / z) [M+H]+calcd for C22HI8C13F3N5O2+, 546.0, found, 546.1 l-( 4-( 4-( 3-chloro-4-(2-chlorophenoxy)-2-fluorophenyl)ammo)pyrimidin-5-yl)piperazm-l- yl)prop-2-en-l-one (327)

[0680] 327 was synthesized according to General Procedure 9, using 2-chlorophenol and 2-chloro- l,3-difluoro-4-nitrobenzene as starting materials. An improvement to the procedure involved the successful isolation of Intl-327 by flash silica gel chromatography. The purified Intl- 327 was then carried forward in the synthesis, following General Procedure 9, to afford the final product 327.1H NMR (400 MHz, DMSO-c / ) 3 ppm: 8.54 (br s, 1H), 8.31 (s, 1H), 8.17 (s, 1H), 7.65 (d, J= 6.4 Hz, 1H), 7.58 (t, J= 6.8 Hz, 1H), 7.41-7.42 (m, 1H), 7.26-7.28 (m, 1H), 7.12 (dd, J= 8.8 Hz, 1.6 Hz, 1H), 6.78-6.81 (m, 2H), 6.15 (dd, J= 16.4 Hz, 2.4 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.76-3.78 (m, 4H), 2.94-2.95 (m, 4H); MS (m / z) [M+H]+calcd for C23H21Cl2FN5O2+, 488.1, found, 488.2 l-( 4-( 4-(( 4-chloro-5-(3-chloro-2-fluorophenoxy)pyridm-2-yl)amino)pyrimidm-5- yl)piperazin-l-yl)prop-2-en-l-one (328)

[0681] Preparation of Intl-328: To a solution of 3-chloro-2-fluorophenol (895.3 mg, 6.11 mmol, 1.5 eq) in THF (20.0 mL) was added slowly NaH (325.8 mg, 8.15 mmol, 60% purity, 2.0 eq) at 0 °C under N2. The mixture was stirred at 0 °C for 30 mins, then 2-bromo-5-fluoro-4- nitropyridine (900.0 mg, 4.07 mmol, 1.0 eq) was added to the mixture at 0 °C. The mixture was stirred at 20 °C for 30 mins under N2. TLC (Commercial hexanes / EtOAc = 5 / 1) showed a new spot was observed. The reaction mixture was quenched by addition aq. NH4CI (30 mL) at 0 °C under N2and then diluted with H2O (20 mL) and extracted with DCM (25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 4 g Sepa Flash® Silica Flash Column, Eluent of 0-10% EtOAc / Commercial hexanes gradient @ 20 mL / min) to give Intl-328 (1.1 g, 69.95% yield, 90% purity) as yellow oil.1H NMR (400 MHz, CDCI3) δ ppm: 8.17 (s, 1H), 7.95 (s, 1H), 7.33-7.35 (m, 1H), 7.14-7.16 (m, 1H), 7.07-7.10 (m, 1H). Preparation of Int2-328: To a solution of Intl-328 (1.1 g, 3.17 mmol, 1.0 eq) and NH2B0C (444.9 mg, 3.80 mmol, 1.2 eq) in dioxane (20.0 mL) was added CS2CO3(2.1 g, 6.33 mmol, 2 eq), Pd2(dba)3(289.9 mg, 316.52 μmol, 0.1 eq) and SPhos (259.9 mg, 633.05 μmol, 0.2 eq) at 20 °C under N2. The resulting mixture was stirred at 100 °C for 3 h under N2. TLC (Commercial hexanes / EtOAc = 5 / 1) showed new spots were observed. The mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0-30% EtOAc / commercial hexanes gradient @ 20 mL / min) to give Int2-328 (1.3 g, 85.62% yield, 80% purity) as a brown solid.1H NMR (400 MHz, CDCI3) δ ppm: 8.50 (s, 1H), 8.11 (s, 1H), 7.65 (s, 1H), 7.22-7.25 (m, 1H), 7.03-7.05 (m, 1H), 6.90-6.92 (m, 1H), 1.53 (s, 9H).

[0682] Preparation of Int3-328: To a solution of Int2-328 (1.2 g, 3.13 mmol, 1.0 eq) in EtOH (15.0 mL) and water (3.0 mL) was added Fe (1.4 g, 25.02 mmol, 8.0 eq) and NH4CI (1.3 g, 25.02 mmol, 8.0 eq) at 20 °C. The mixture was stirred at 75 °C for 2 h. LCMS showed the desired mass was detected. The mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 20 g Sepa Flash® Silica Flash Column, Eluent of 0-60% EtOAc / Commercial hexanes gradient @ 20 mL / min) to give Int3-328 (890.0 mg, 64.36% yield, 80% purity) as a brown solid.1H NMR (400 MHz, CDCI3) δ ppm: 7.98 (br s, 1H), 7.76 (s, 1H), 7.47 (s, 1H), 7.12-7.15 (m, 1H), 6.97-6.99 (m, 1H), 6.81-6.82 (m, 1H), 4.40 (br s, 2H), 1.52 (s, 9H).

[0683] Preparation of Int4-328: To a solution of Int3-328 (700.0 mg, 1.98 mmol, 1.0 eq), CuCl (293.8 mg, 2.97 mmol, 70.97 μL, 1.5 eq) in MeCN (10.0 mL) was added t-BuONO (408.1 mg, 3.96 mmol, 470.68 μL, 2.0 eq) at 50 °C under N2. The mixture was stirred at 50 °C for 2 h under N2. LCMS showed the desired mass was detected. The mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 4 g Sepa Flash® Silica Flash Column, Eluent of 0-50% EtOAc / Commercial hexanes gradient @ 20 mL / min) to give Int4-328 (150.0 mg, 16.25% yield, 80% purity) as a yellow solid.1H NMR (400 MHz, CDCI3) δ ppm: 8.21 (br s, 1H), 8.01 (br s, 1H), 7.87 (s, 1H), 7.13-7.16 (m, 1H), 6.96-7.00 (m, 1H), 6.72 (t, J = 7.2 Hz, 1H), 1.51 (s, 9H).

[0684] Preparation of Int5-328: To a solution of Int4-328 (335.5 mg, 898.97 μmol, 1.0 eq) in DCM (3.0 mL) was added TFA (1.5 g, 13.46 mmol, 1.0 mL, 14.98 eq). The resulting mixture was stirred at 20 °C for 2 h. LCMS showed the desired mass was detected. The mixture was adjusted pH = 9 with NH3 H2O and then diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give Int5-328 (220.8 mg, 71.95% yield, 80% purity) as yellow oil.1H NMR (400 MHz, MeOD-d4) δ ppm: 7.80 (s, 1H), 7.14-7.16 (m, 1H), 7.04-7.07 (m, 1H), 6.75 (s, 1H), 6.72-6.73 (m, 1H).

[0685] Int5-328 was then carried forward in the synthesis, following the procedures from Gp8-5 to the final Test Compounds described in General Procedure 8, to afford the final product 328 as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.82 (br s, 1H), 8.65 (s, 1H), 8.62 (s, 1H), 8.41 (s, 1H), 8.38 (s, 1H), 7.37 (t, J= 8.0 Hz, 1H), 7.18 (t, J= 8.0 Hz, 1H), 6.96 (t, J= 8.4 Hz, 1H), 6.83-6.90 (m, 1H), 6.16 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.77-3.80 (m, 4H), 2.93-2.95 (m, 4H); MS (m / z) [M+H]+calcd for C22H2OC12FN6O2+, 489.1, found, 489.1 l-( 4-( 4-( 4-(2-bromophenoxy)-3-chloro-2-fluorophenyl)ammo)pyrimidm-5-yl)piperazin-l- yl)prop-2-en-l-one (329)

[0686] 329 was synthesized according to General Procedure 9, using 2-bromophenol and 2-chloro- l,3-difluoro-4-nitrobenzene as starting materials. An improvement to the procedure involved the successful isolation of Intl-329 by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0-50% EtOAc / Commercial hexanes gradient @ 25 mL / min). Intl-329 was obtained as yellow gum.1H NMR (400 MHz, DMSO-d6) δ ppm: 7.67-7.69 (m, 1H), 7.29-7.31 (m, 1H), 7.00-7.02 (m, 1H), 6.69-6.78 (m, 2H), 6.67 (d, J= 6.8 Hz, 1H), 5.42 (s, 2H); 2D NMR analyses (HSQC-DEPT, COSY, HMBC and NOESY) were conducted to confirm the structure of 329.

[0687] Intl-329 was then carried forward in the synthesis, following General Procedure 9, to afford the final product 329 as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.55 (s, 1H), 8.31 (s, 1H), 8.17 (s, 1H), 7.79 (d, J= 6.4 Hz, 1H), 7.57 (t, J= 8.8 Hz, 1H), 7.45 (t, = 8.0 Hz, 1H), 7.21 (t, J= 8.0 Hz, 1H), 7.09 (d, J= 8.0 Hz, 1H), 6.78-6.86 (m, 1H), 6.76 (d, J = 5.6 Hz, 1H), 6.15 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.73 (dd, J= 10.4 Hz, 2.0 Hz, 1H), 3.77-3.79 (m, 4H), 2.93-2.95 (m, 4H); MS (m / z) [M+H]+calcd for C23H21BrClFN5O2+, 534.1, found, 534.2 l-( 4-( 4-( 4-(benzofuran- 7-yloxy)-3-chloro-2-fluorophenyl)amino)pyrimidm-5-yl)piperazm-l- yl)-2-chloroethan-l-one (330)

[0688] Preparation of Gp9-2-2 and Gp9-2-2': To a solution of benzofuran-7-ol (500.0 mg, 3.73 mmol, 1.0 eq) in DMF (10.0 mL) was added 2-chl oro-1, 3-difluoro-4-nitrobenzene (721.4 mg, 3.73 mmol, 1.0 eq) and K2CO3(1.6 g, 11.18 mmol, 3.0 eq). The resulting mixture was stirred at 80 °C for 2 h. TLC (Commercial hexanes / EtOAc = 10 / 1) showed the starting material was consumed and new spots were observed. The reaction was added into H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0-10% EtOAc / Commercial hexanes gradient @ 20 mL / min) to give a mixture of Gp9-2-2 and Gp9-2-2' (882.6 mg, 65.41% yield, 85% purity) as yellow oil.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.08-8.35 (m, 1H), 8.01-8.08 (m, 1H), 7.65-7.67 (m, 1H), 7.37-7.42 (m, 1H), 7.11-7.13 (m, 1H), 7.04-7.06 (m, 1H), 6.68-6.70 (m, 1H).

[0689] Preparation of Gp9-3-2 and Gp9-3-2': A mixture of Gp9-2-2 and Gp9-2-2' (882.6 mg, 2.87 mmol, 1.0 eq) in EtOH (10.0 mL) and H2O (2 mL) was added Fe (960.6 mg, 17.21 mmol, 6.0 eq) and NH4CI (920.1 mg, 17.21 mmol, 6.0 eq). The resulting mixture was stirred at 75 °C for 2 h. TLC (Commercial hexanes / EtOAc = 5 / 1) showed the starting material was consumed and the new spots were observed. The reaction was filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0-20% EtOAc / Commercial hexanes gradient @ 20 mL / min) to give a mixture of Gp9-3-2 and Gp9- 3-2' (442.5 mg, 47.22% yield, 85% purity) as yellow oil.

[0690] Preparation of Gp9-4-2 and Gp9-4-2': A mixture of Gp9-3-2 and Gp9-3-2' (440.0 mg, 1.58 mmol, 1.0 eq), CS2CO3(1.0 g, 3.17 mmol, 2.0 eq), Pd(OAc)2(35.6 mg, 158.46 μmol, 0.1 eq), compound Gp8-5 (473.4 mg, 1.58 mmol, 1.0 eq) and Xantphos (91.7 mg, 158.46 μmol, 0.1 eq) in toluene (10.0 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 110 °C for 2 h under N2. TLC (Commercial hexanes / EtOAc = 1 / 1) showed the starting material was consumed and new spots were observed. The mixture was concentrated in vacuum to give a residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0-50% EtOAc / Commercial hexanes gradient @ 20mL / min) to give a mixture of Gp9-4-2 and Gp9-4-2' (758.0 mg, 70.87% yield, 80% purity) as yellow oil.

[0691] Preparation of GP9-5-2: To a solution of the mixture Gp9-4-2 and Gp9-4-2' (750.0 mg, 1.39 mmol, 1.0 eq) in DCM (5.0 mL) was added HCl / dioxane (2 M, 4.94 mL, 7.12 eq). The resulting mixture was stirred at 20 °C for 3 h. LCMS showed the starting material was consumed and the desired mass was detected. The reaction was concentrated in vacuum. The mixture was further purification by prep-HPLC (column: 41-WePure Biotech XP tC18 150x40mm, 7pm; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 14%-34% B over 10.0 min) to give a residue. The residue was adjusted to pH = 8 with NH3 H2O and extracted with DCM (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give Gp9-5-2 (250.0 mg, 38.87% yield, 95% purity) as colorless oil.

[0692] Preparation of 330: To a solution of free GP9-5-2 (120.0 mg, 272.81 μmol, 1.0 eq) in DCM (3.0 mL) was added DIEPA (105.8 mg, 818.43 μmol, 142.55 μL, 3.0 eq), then 2-chloroacetyl chloride (30.8 mg, 272.81 μmol, 21.73 μL, 1.0 eq) was added to the mixture at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h. LCMS showed the starting material was consumed and the desired mass was detected. The reaction was quenched with H2O and the mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC (column: 41-WePure Biotech XP tC18 150 x 40mm, 7pm; mobile phase: [H2O (0.225% FA)- ACN]; gradient: 25%-55% B over 10.0 min]; gradient: 35%-65% B over 10.0 min) to give 330 (75.2 mg, 52.14% yield, 97.67% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.53 (br s, 1H), 8.31 (s, 1H), 8.15 (s, 1H), 8.03 (d, J= 2.4 Hz, 1H), 7.53-7.54 (m, 2H), 7.28 (t, J= 8.0 Hz, 1H), 7.07 (d, J= 2.0 Hz, 1H), 6.99 (d, J= 7.8 Hz, 1H), 6.84 (dd, J= 9.2 Hz, 2.0 Hz, 1H), 4.45 (s, 2H), 3.67-3.69 (m, 4H), 2.94-2.98 (m, 4H); MS (m / z) [M+H]+calcd for C24H21Cl2FN5O3+, 516.1, found, 516.1 l-( 4-( 4-(( 4-(benzofuran- 7-yloxy)-3-chloro-2-fluorophenyl)amino)pyrimidm-5-yl)piperazm-l- yl)-2-chloro-2-fluoroethan-l-one (331 )

[0693] Gp9-5-2 was prepared following the procedures described for the synthesis of compound 330. Preparation of 331: To a solution of free Gp9-5-2 (60.0 mg, 136.40 μmol, 1.0 eq) and 2- chloro-2-fluoroacetic acid (76.72 mg, 682.02 μmol, 5.0 eq) in DCM (5.0 mL) was added TEA (41.41 mg, 409.21 μmol, 56.96 μL, 3.0 eq) and T4P (491.41 mg, 682.02 μmol, 50% purity, 5.0 eq) at 20 °C. The mixture was stirred at 20 °C for 1.5 h. LCMS showed the desired mass was detected. The mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: 55-Boston Prime C18 150x30mm, 5pm; mobile phase: [H2O (0.05% NH3H20+10mM NH4HC03)-ACN]; gradient: 50%-80% B over 10.0 min) to give 331 (30 mg, 53.90 μmol, 39.51% yield, 96% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.54 (s, 1H), 8.31 (s, 1H), 8.17 (s, 1H), 8.03 (t, J= 2.4 Hz, 1H), 7.49-7.55 (m, 2H), 7.26-7.36 (m, 2H), 7.07 (d, J= 2.0 Hz, 1H), 6.99 (d, J= 7.6 Hz, 1H), 6.84 (dd, J= 8.8 Hz, 1.6 Hz, 1H), 3.63-3.80 (m, 4H), 2.95-3.01 (m, 4H); MS (m / z) [M+H]+calcd for C24H20C12F2N503+, 534.1, found, 534.0 l-( 4-( 4-(( 3-chlor o-2 -fluor o-4-phenoxyphenyl)amino)pyrimidin-5-yl)piper azin- l-yl)pr op-2 - en-l-one (332)

[0694] Int1 -332

[0695] 332 332 was synthesized according to General Procedure 9, using phenol and 2-chloro-l,3- difluoro-4-nitrobenzene as starting materials. An improvement to the procedure involved the successful isolation of Intl-332 by prep-HPLC (column: 41-WePure Biotech XP tC18 150 x 40mm, 7pm; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 10%-30% B over 10.0 min). The Intl-332 was obtained as a white solid.

[0696] The Intl-332 was then carried forward in the synthesis, following General Procedure 9, to afford the final product 332 as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.53 (br s, 1H), 8.32 (s, 1H), 8.17 (s, 1H), 7.62 (t, J= 8.8 Hz, 1H), 7.36-7.48 (m, 2H), 7.18 (t, J= 7.6 Hz, 1H), 6.87-7.04 (m, 3H), 6.83-6.90 (m, 1H), 6.16 (dd, J= 16.4 Hz, 2.4 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.76-3.78 (m, 4H), 2.95-2.96 (m, 4H); MS (m / z) [M+H]+calcd for C23H22C1FN5O2+, 454.1, found, 454.2 l-( 4-( 4-( 3-chloro-4-(3-chloro-2-fluorophenoxy)-2-fluorophenyl)ammo)pyrimidm-5- yl)piperazin-l-yl)propan-l-one (333)

[0697] Gp9-5-l was prepared following the procedures described for the synthesis of compound 322.

[0698] Preparation of 333: To a solution of Gp9-5-l (170.0 mg, 347.83 μmol, 1.0 eq, HC1 salt) in DCM (10.0 mL) was added DIPEA (134.86 mg, 1.04 mmol, 181.75 μL, 3.0 eq) at 20 °C. The mixture was cooled to 0 °C and propionyl chloride (32.18 mg, 347.83 μmol, 32.18 μL, 1.0 eq) in DCM (0.1 mL) was added and the mixture was stirred at 0 °C for 30 mins. LCMS showed the reaction was completed. H2O (0.5 mL) was added and the mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: 41-WePure Biotech XP tC18 150x40mm, 7pm; mobile phase: [H2O (0.05% NH3H2O+10mM NH4HCO3)-ACN]; gradient: 37%-67% B over 10.0 min) to give 333 (75.0 mg, 147.17 μmol, 42.31% yield, 99.75% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.54 (s, 1H), 8.32 (s, 1H), 8.17 (s, 1H), 7.64 (t, J= 8.8 Hz, 1H), 7.43-7.47 (m, 1H), 7.24-7.29 (m, 1H), 7.36 (t, J= 7.6 Hz, 1H), 7.01 (d, J= 8.8 Hz, 1H), 3.59-3.75 (m, 4H), 2.85-3.00 (m, 4H), 2.37 (q, J= 7.6 Hz, 2H), 1.02 (t, J= 7.2 Hz, 3H); MS (m / z) [M+H]+calcd for C23H22C12F2N5O2+, 508.1, found, 508.2 l-( 4-( 4-( 4-(benzofuran- 7-yloxy)-3-chloro-2fluorophenyl)amino)pyrimidin-5-yl)piperazin-l- yl)propan-l-one (334)

[0699] Gp9-5-2 was prepared following the procedures described for the synthesis of compound 330.

[0700] Preparation of 334: To a solution of Gp9-5-2 (100.0 mg, 227.34 μmol, 1.0 eq) in DCM (3.0 mL) was added DIPEA (88.1 mg, 682.02 μmol, 118.79 μL, 3.0 eq). Then propionyl chloride (21.0 mg, 227.34 μmol, 21.03 μL, 1.0 eq) was added to the mixture at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h. LCMS showed the starting material was consumed and the desired mass was detected. The reaction was quenched with H2O and concentrated in vacuum. The obtained residue was purified by prep-HPLC (column: 41-WePure Biotech XP tC18 150x40mm, 7pm; mobile phase: [H2O (0.05% NH3H2O+10mM NH4HCO3)-ACN]; gradient: 35%-65% B over 10.0 min) to give 334 (82.2 mg, 69.62% yield, 95.49% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.52 (s, 1H), 8.31 (s, 1H), 8.15 (s, 1H), 8.03 (d, J= 2.0 Hz, 1H), 7.52-7.57 (m, 2H), 7.28 (t, J= 8.0 Hz, 1H), 7.07 (d, J= 2.0 Hz, 1H), 6.99 (d, J= 8.0 Hz, 1H), 6.84 (dd, J= 9.2 Hz, 1.6 Hz, 1H), 3.64-3.66 (m 4H), 2.89-2.94 (m, 4H), 2.37 (q, J= 7.6 Hz, 2H), 1.02 (t, J= 7.6 Hz, 3H); MS (m / z) [M+H]+calcd for C25H24CIFN5O?, 496.2, found, 496.3

[0701] N-(l-(4-( (3-chloro-4-( 3-chlor o-2 -fluorophenoxy) -2-fluor ophenyl)amino)pyrimidin-5- yl)piperidin-4-yl)acrylamide (335)

[0702] Gp9-3-l was prepared following the procedures described for the synthesis of compound 322.

[0703] Preparation of Intl-335: To a solution of Gp9-3-l (500.0 mg, 1.72 mmol, 1.0 eq) and 4- chloro-5-iodopyrimidine (497.28 mg, 2.07 mmol, 1.2 eq) in z-PrOH (10.0 mL) was added PyHCl (398.36 mg, 3.45 mmol, 2.0 eq) at 20 °C. The mixture was stirred at 80 °C for 1 h. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Commercial hexanes gradient @ 20 mL / min) to give Intl-335 (122.0 mg, 197.55 μmol, 11.46% yield, 80% purity) as a light-yellow solid and the crude product (700.0 mg, 40% purity) as a brown oil. The crude product was further purified by prep-HPLC (column: 41-WePure Biotech XP tC18 150x40mm, 7pm; mobile phase: [H2O (0.05% NH3 H2O+ 10mM N H4HCO39)ACN]; gradient: 48%-78% B over 10.0 min) to give another batch of Intl-335 (125 mg, 253.01 μmol, 14.68% yield, 100% purity) as a white solid.1H NMR (400 MHz, CDCI3) δ ppm: 8.69 (s, 1H), 8.60 (s, 1H), 8.20 (t, J= 8.8 Hz, 1H), 7.19-7.23 (m, 1H), 7.01-7.06 (m, 1H), 6.86-6.91 (m, 1H), 6.79 (dd, J= 9.2 Hz, 2.0 Hz, 1H); MS (m / z) [M+H]+calcd for C16H9CI2F2IN3O+, 495.9, found, 495.8

[0704] Preparation of Int2-335: To a solution of Intl-335 (125.0 mg, 253.01 μmol, 1.0 eq) and tert- butyl piperidin-4-ylcarbamate (101.34 mg, 506.01 μmol, 2.0 eq) in dioxane (10.0 mL) was added CS2CO3(164.87 mg, 506.01 μmol, 2.0 eq) and Pd-PEPPSI-iHept-Cl (24.61 mg, 25.30 μmol, 0.1 eq) at 20 °C. The mixture was stirred at 110 °C for 16 h under N2. LCMS showed the desired mass was detected. The mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 4 g Sepa Flash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Commercial hexanes gradient @ 20 mL / min) to give Int2-335 (89.0 mg, 125.70 μmol, 49.68% yield, 80% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.34 (s, 1H), 8.32 (s, 1H), 8.19 (s, 1H), 7.82 (t, J= 8.8 Hz, 1H), 7.42-7.46 (m, 1H), 7.22-7.28 (m, 1H), 7.06-7.10 (m, 1H), 7.03 (dd, J= 8.8 Hz, 1.2 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 3.31-3.32 (m, 2H), 3.12-3.15 (m, 1H), 2.73-2.79 (m, 2H), 1.83-1.87 (m, 2H), 1.61-1.69 (m, 2H), 1.40 (s, 9H); MS (m / z) [M+H]+calcd for C26H28C12F2N5O3+, 566.2, found, 565.9

[0705] Preparation of Int3-335: To a solution of Int2-335 (150.0 mg, 264.82 μmol, 1.0 eq) in DCM (5.0 mL) was added HCl / dioxane (2 M, 5.0 mL, 33.32 eq) at 20 °C. The mixture was stirred at 20 °C for 2 h. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure to give Int3-335 (140.0 mg, 208.84 μmol, 78.86% yield, 75% purity, HC1 salt) as a white solid; MS (m / z) [M+H]+calcd for C21H20CI2F2N5CO+, 466.1, found, 465.9

[0706] Preparation of 335: To a solution of Int3-335 (140.0 mg, 278.46 μmol, 1.0 eq, HC1 salt) in DCM (10.0 mL) was added DIPEA (107.96 mg, 835.37 μmol, 145.50 μL, 3.0 eq) at 20 °C. The mixture was cooled to 0 °C and acryloyl chloride (25.20 mg, 278.46 μmol, 22.62 μL, 1.0 eq) in DCM (0.05 mL) was added and the mixture was stirred at 0 °C for 30 mins. LCMS showed the reaction was completed. H2O (0.5 mL) was added and the mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: 41-WePure Biotech XP tC18 150x40mm, 7pm; mobile phase: [H2O (0.05% NH3H2O+10mM NH4HCO3)-ACN]; gradient: 37%-67% B over 11.0 min) to give 335 (58.0 mg, 110.84 μmol, 39.80% yield, 99.44% purity) as a white solid.1HNMR (400 MHz, DMSO-d6) δ ppm: 8.35 (s, 1H), 8.34 (s, 1H), 8.21 (s, 1H), 8.14 (d, J= 7.2 Hz, 1H), 7.85 (t, J = 8.8 Hz, 1H), 7.44 (t, J= 7.2 Hz, 1H), 7.23-7.27 (m, 1H), 7.02-7.10 (m, 2H), 6.23-6.31 (m, 1H), 6.08-6.12 (m, 1H), 5.57-5.61 (m, 1H), 3.75-3.85 (m, 1H), 3.11-3.19 (m, 2H), 2.84 (t, J= 11.2 Hz, 2H), 1.91-1.94 (m, 2H), 1.65-1.74 (m, 2H); MS (m / z) [M+H]+calcd for C24H22CI2F2N5O2 , 520.1, found, 520.2 l-( 4-( 4-(( 4-(3-bromophenoxy)-3-chloro-2-fluorophenyl)amino)pyrimidin-5-yl)piperazin-l- yl)prop-2-en-l-one (336)

[0707] 336

[0708] 336 was synthesized according to General Procedure 9, using 3 -bromophenol and 2-chloro- l,3-difluoro-4-nitrobenzene as starting materials. An improvement to the procedure involved the successful isolation of Intl-336 by prep-HPLC (column: 41-WePure Biotech XP tC18 150x40mm, 7pm; mobile phase: [H2O (0.05% NH3 H2O+ 10mM N H4HCO3)ACN]; gradient: 51%-71% B over 10.0 min). Intl-336 was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.38 (s, 1H), 8.35 (s, 1H), 8.17 (s, 1H), 7.84 (t, J= 8.8 Hz, 1H), 7.36-7.40 (m, 2H), 7.17-7.21 (m, 1H), 7.11 9.2 Hz, 1.2 Hz, 1H), 7.00-7.03 (m, 1H), 2.84-2.94 (m, 8H); MS (m / z) [M+H]+calcd for C2oHi9BrClFN50+, 480.0, found, 479.8.

[0709] The Intl-336 was then carried forward in the synthesis, following General Procedure 9, to afford the final product 336.1H NMR (400 MHz, DMSO-d6) <5 ppm: 8.55 (s, 1H), 8.34 (s, 1H), 8.19 (s, 1H), 7.70 (t, J= 8.8 Hz, 1H), 7.36-7.39 (m, 2H), 7.20-7.22 (m, 1H), 7.09-7.13 (m, 1H), 7.01-7.04 (m, 1H), 6.83-6.90 (m, 1H), 6.16 (dd, J= 16.4 Hz, 2.4 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.70-3.87 (m, 4H), 2.91-2.99 (m, 4H); MS (m / z) [M+H]+calcd for C23H21BrClFN5O2+, 534.1, found, 534.0 l-( 4-( 4-(( 3-chloro-2-fluoro-4-(3-fluorophenoxy)phenyl)ammo)pyrimidm-5-yl)piperazm-l- yl)prop-2-en-l-one (337)

[0710] 337 was synthesized according to General Procedure 9, using 3 -fluorophenol and 2-chloro- l,3-difluoro-4-nitrobenzene as starting materials. An improvement to the procedure involved the successful isolation of Intl-337 by prep-HPLC (column: 40-WePure Biotech XP tC18 150x30mm, 7pm; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 17%-27% B over 10.0 min). Intl-337 was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.42 (s, 1H), 8.34 (d, J= 2.0 Hz, 1H), 8.23 (s, 1H), 8.18 (s, 1H), 7.76-7.84 (m, 1H), 7.41-7.49 (m, 1H), 7.08-7.13 (m, 1H), 6.99-7.04 (m, 1H), 6.90-6.94 (m, 1H), 6.80-6.85 (m, 1H), 2.95-2.99 (m, 4H), 2.90-2.94 (m, 4H); MS (m / z) [M+H]+calcd for C2OHI9C1F2N50+, 418.1, found, 418.0 The Intl-337 was then carried forward in the synthesis, following General Procedure 9, to afford the final product 337.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.55 (s, 1H), 8.34 (s, 1H), 8.19 (s, 1H), 7.70 (t, J= 8.8 Hz, 1H), 7.41-7.49 (m, 1H), 7.10 (dd, J= 8.8 Hz, 1.2 Hz, 1H), 6.99-7.04 (m, 1H), 6.91-6.95 (m, 1H), 6.84-6.90 (m, 1H), 6.81-6.83 (m, 1H), 6.16 (dd, J = 16.8 Hz, 2.4 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.71-3.83 (m, 4H), 2.92-2.99 (m, 4H); MS (m / z) [M+H]+calcd for C23H21ClF2N5O2+, 472.1, found, 472.1 l-( 4-( 4-( 3-chloro-4-(3-chloro-2-fluorophenoxy)-2-fluorophenyl)amino)pyrimidin-5- yl)piperazin-l-yl)prop-2-yn-l-one (338)

[0711] Gp9-5-l was prepared following the procedures described for the synthesis of compound 322.

[0712] Preparation of 338: To a solution of Gp9-5-l (150.0 mg, 306.91 μmol, 1.0 eq, HC1 salt) and propiolic acid (107.49 mg, 1.53 mmol, 94.45 μL, 5.0 eq) in DCM (10.0 mL) was added TEA (93.17 mg, 920.73 μmol, 128.15 μL, 3.0 eq) and T4P (1.11 g, 1.53 mmol, 50% purity, 5.0 eq) at 25 °C. The mixture was stirred at 25 °C for 30 mins. LCMS showed the reaction was completed. H2O (0.1 mL) was added to the mixture and concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: 41-WePure Biotech XP tC18 150x40mm, 7pm; mobile phase: [H2O (0.05% NH3·H2O+10mM NH4HCO3)-ACN]; gradient: 48%-68% B over 11.0 min) to give 338 (33 mg, 64.51 μmol, 21.02% yield, 98.58% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.56 (s, 1H), 8.32 (s, 1H), 8.19 (s, 1H), 7.62 (t, J= 8.4 Hz, 1H), 7.43-7.48 (m, 1H), 7.24-7.29 (m, 1H), 7.09-7.14 (m, 1H), 7.00-7.03 (m, 1H), 4.62 (s, 1H), 3.90 (br s, 2H), 3.73 (br s, 2H), 3.02 (t, J= 4.4 Hz, 2H), 2.93 (t, J= 4.4 Hz, 2H); MS (m / z) [M+H]+calcd for C23H18C12F2N5O2+, 504.1, found, 504.1 l-( 4-( 4-( 3-chloro-4-(3-chloro-2-fluorophenoxy)-2-fluorophenyl)amino)pyrimidin-5- yl)piperazin-l-yl)but-2-yn-l-one (339)

[0713] Gp9-5-l was prepared following the procedures described for the synthesis of compound 322.

[0714] Preparation of 339: To a solution of Gp9-5-l (162 mg, 331.65 μmol, 1.0 eq, HC1 salt) and tetrolic acid (139.4 mg, 1.66 mmol, 5.0 eq) in DCM (5.0 mL) was added TEA (100.7 mg, 994.95 μmol, 138.49 μL, 3.0 eq) and T4P (1.2 g, 1.66 mmol, 50% purity, 5.0 eq). The mixture was stirred at 25 °C for 2 h. LCMS showed the reaction was completed. The mixture was concentrated, and the obtained residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 72%-92% B over 10.0 min) to give 339 (60 mg, 110.89 μmol, 33.44% yield, 95.80% purity) as a white solid.1HNMR (400 MHz, DMSO-d6) δ ppm: 8.55 (s, 1H), 8.32 (s, 1H), 8.19 (s, 1H), 7.62 (t, J = 8.8 Hz, 1H), 7.44-7.46 (m, 1H), 7.25-7.27 (m, 1H), 7.11-7.14 (m, 1H), 6.03 (d, J= 8.8 Hz, 1H), 3.88 (s, 2H), 3.70 (s, 2H), 3.00 (s, 2H), 2.91(s, 2H), 3.05 (s, 3H); MS (m / z) [M+H]+calcd for C24H20Cl2F2N5O2+, 518.1, found, 518.2 l-( 4-( 4-( 3-chloro-4-(3-chlorophenoxy)-2-fluorophenyl)amino)pyrimidin-5-yl)piperazin-l- yl)prop-2-en-l-one (340)

[0715]

[0716] Preparation of Intl-340 and Intl-340': To a solution of 3 -chlorophenol (2.0 g, 15.56 mmol, 1.64 mL, 1.0 eq), 2-chloro-l,3-difhioro-4-nitrobenzene (3.01 g, 15.56 mmol, 1.0 eq) in DMF (40 mL) was added K2CO3(4.30 g, 31.11 mmol, 2.0 eq). The mixture was stirred at 0 °C for 4 h. TLC (commercial hexanes / Ethyl acetate = 10 / 1) showed new spots were observed. The mixture was added water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give a mixture of compound Intl-340 and Intl-340' (5.0 g, crude) as a yellow oil.

[0717] Preparation of Int2-340 and Int2-340': To a solution of Intl-340 and Intl-340' (5.0 g, 16.55 mmol, 1.0 eq) in EtOH (40 mL) and H2O (8 mL) was added Fe (4.6 g, 82.76 mmol, 5.0 eq) and NH4CI (5.3 g, 99.31 mmol, 6.0 eq). The mixture was stirred at 75 °C for 6 h. TLC (commercial hexanes / Ethyl acetate = 10 / 1) showed new spots were observed. The mixture was filtered and washed with EtOAc (30 mL x 2). The filtrate was concentrated. The residue was purified by prep-HPLC (column: 58-Phenomenex Gemini NX C18 150x40mm, 5pm; mobile phase: [H2O (0.075% TFA)-CAN]; gradient: 45%-75% B over 10.0 min) to give a mixture of Intl-340 and Intl-340' (2.8 g, 10.29 mmol, 62.17% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ ppm: 7.33-7.35 (m, 1H), 7.12-7.14 (m, 2H), 6.89-6.90 (m, 1H), 6.78-6.82 (m, 2H), 5.17-5.47 (m, 2H).

[0718] Preparation of Int3-340: To a solution of Intl-340 and Intl-340' (2.79 g, 10.25 mmol, 1.0 eq) in THF (40 mL) was added BOC2O (6.7 g, 30.76 mmol, 7.07 mL, 3.0 eq), DIPEA (2.6 g, 20.51 mmol, 3.57 mL, 2.0 eq) and DMAP (125.3 mg, 1.03 mmol, 0.1 eq). The mixture was stirred at 25 °C for 16 h. TLC (commercial hexanes / Ethyl acetate = 10 / 1) showed new spots were observed. The mixture was concentrated and the obtained residue was purified by prep- HPLC (column: 58-Phenomenex Gemini NX C18 150x40mm, 5pm; mobile phase: [H2O (0.2% TFA)-ACN]; gradient: 70-95% B over 10.0 min) to give Int3-340 (950 mg, 2.01 mmol, 19.62% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) <5 ppm: 7.44-7.48 (m, 2H), 7.28-7.31 (m, 1H), 6.06-7.07 (m, 2H), 6.98-7.04 (m, 1H), 1.40 (s, 18H).

[0719] Preparation of Int2-340: To a solution of Int3-340 (950 mg, 2.01 mmol, 1.0 eq) in DCM (5 mL) was added HCl / dioxane (2 M, 10 mL, 9.94 eq). The mixture was stirred at 25 °C for 16 h. TLC (Hexane / EtOAc=5 / l) showed the reaction was completed. The mixture was neutralized with NH3 H2O to pH = 8. The mixture was added water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated1 to give Int2-340 (350 mg, 1.29 mmol, 63.95% yield) as a yellow oil.1H NM (R400 MHz, DMSO-d6) δ ppm: 7.32-7.36 (m, 1H), 7.19-7.21 (m, 1H), 6.87-6.90 (m, 2H), 6.78-6.81 (m, 2H).

[0720] The purified Int2-340 was then carried forward in the synthesis, following General Procedure 9 as described from GP9-3 to the final step, to afford the final product 340 as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.56 (s, 1H), 8.34 (s, 1H), 8.19 (s, 1H), 7.70 (t, J= 8.8 Hz, 1H), 7.44 (t, J= 8.4 Hz, 1H), 7.24 (dd, J= 8.0 Hz, 2.0 Hz, 1H), 7.08-7.13 (m, 2H), 6.97-7.00 (m, 1H), 6.83-6.90 (m, 1H), 6.15 (dd, J= 16.4 Hz, 2.0 Hz, 1H), 5.73 (dd, J= 10.4 Hz, 1.6 Hz, 1H), 3.77-3.39 (m, 4H), 2.96 (d, J= 4.4 Hz, 4H); MS (m / z) [M+H]+calcd for C23H21Cl2FN5O2+, 488.1, found, 488.1 l-( 4-( 4-(( 3-bromo-4-(3-chloro-2-fluorophenoxy)-2-fluorophenyl)amino)pyrimidin-5- yl)piperazin-l-yl)prop-2-en-l-one (341 )

[0721] 341 was synthesized according to General Procedure 9, using 3-chloro-2-fluorophenol and 2-bromo-l,3-difluoro-4-nitrobenzene as starting materials. An improvement to the procedure involved the successful isolation of Intl-341 by -HPLpCre bpy -HPLCp (rceoplumn: Welch Xtimate C18 150*25mm*5um; mobile phase: [H2O (lOmM NH4HCO3)-ACN]; gradient: 75%-90% B over 11.0 min). Intl-341 was obtained as yellow oil.1H NMR (400 MHz, CDCI3) δ ppm: 8.53-8.57 (m, 2H), 8.17 (s, 1H), 8.05 (s, 1H), 7.18-7.20 (m, 1H), 7.00-7.02 (m, 1H), 6.80-6.85 (m, 2H), 3.25-4.37 (m, 4H), 2.96 (s, 4H), 1.50 (s, 9H).

[0722] The Intl-341 was then carried forward in the synthesis, following General Procedure 9, to afford the final product 341 as a white solid.1H NMR (400 MHz, DMSO-d6) <5 ppm: 8.56 (s, 1H), 8.34 (s, 1H), 8.19 (s, 1H), 7.70 (t, J= 8.8 Hz, 1H), 7.43-7.47 (m, 1H), 7.24-7.28 (m, 1H), 7.05-7.09 (m, 1H), 6.99-7.01 (m, 1H), 6.87 (dd, J= 16.8 Hz, 10.4 Hz, 1H), 6.18 (dd, J = 16.8 Hz, 2.4 Hz, 1H), 5.74 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.69-3.87 (m, 4H), 2.94-2.96 (m, 4H); MS (m / z) [M+H]+calcd for C23H2oBrClF2N502+, 552.0, found, 552.1 N-(l-(4-(( 4-(benzofuran- 7-yloxy)-3-chloro-2-fluorophenyl)amino)pyrimidm-5-yl)piperidm-4- yl)acrylamide (342)

[0723] The mixture of Gp9-3-2 and Gp9-3-2' was prepared following the procedures described for the synthesis of compound 330.

[0724] Preparation of lntl-342 and lntl-342': To a solution of 4-chloro-5-iodopyrimidine (800.0 mg, 3.33 mmol, 1.0 eq) and the mixture of Gp9-3-2 and Gp9-3-2' (923.94 mg, 3.33 mmol, 1.0 eq) in z-PrOH (15.0 mL) was added Py HC1 (769.03 mg, 6.65 mmol, 2.0 eq) at 20 °C. The mixture was stirred at 80 °C for 8 h. TLC (Commercial hexanes / EtOAc = 5 / 1) showed new spots were observed. The reaction mixture was diluted with H2O (20.0 mL) and extracted with EtOAc (10.0 mL x 3). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / DCM gradient @ 20 mL / min) to give a mixture of Intl-342 and Intl-342' (450.0 mg, 840.87 μmol, 25.27% yield, 90% purity) as a light-yellow solid. MS (m / z) [M+H]+calcd for CI8HHC1FIN3O2+, 482.0, found, 481.7

[0725] Preparation of Int2-342: To a solution of Intl-342 and Intl-342' (445.0 mg, 923.92 μmol, 1.0 eq) and tert-butyl piperidin-4-ylcarbamate (370.08 mg, 1.85 mmol, 2.0 eq) in dioxane (10.0 mL) was added CS2CO3(602.06 mg, 1.85 mmol, 2.0 eq) and Pd-PEPPSI-iHept-Cl (89.88 mg, 92.39 μmol, 0.1 eq) at 25 °C. The mixture was stirred at 110 °C for 16 h under N2. TLC (commercial hexanes / EtOAc = 1 / 2) showed new spots were observed. The mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Commercial hexanes gradient @ 20 mL / min) to give a crude product (300.0 mg, purity: 58%) as yellow oil. Then the crude product was further purified by prep-HPLC (column: 41-WePure Biotech XP tC18 150x40mm, 7pm; mobile phase: [H2O (0.225% FA)- ACN]; gradient: 36%-76% B over 10.0 min) to give Int2-342 (100.0 mg, 162.45 μmol, 17.58% yield, 90% purity) as a light-yellow gum. MS (m / z) [M+H]+calcd for C28H3OC1FN504+, 554.2, found, 554.0

[0726] Preparation of Int3-342: To a solution of Int2-342 (100.0 mg, 180.50 μmol, 1.0 eq) in DCM (5.0 mL) was added HCl / dioxane (2 M, 5.0 mL, 55.40 eq) at 25 °C. The mixture was stirred at 25 °C for 2 h. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure to give Int3-342 (90.0 mg, crude, HC1 salt) as colorless gum.JH NMR (400 MHz, DMSO-d6) δ ppm: 9.69 (br s, 1H), 8.66 (s, 1H), 8.20-8.35 (m, 4H), 8.03 (d, J= 2.0 Hz, 1H), 7.57 (t, J= 7.6 Hz, 1H), 7.50 (t, J= 8.8 Hz, 1H), 7.31 (t, J= 8.0 Hz, 1H), 7.08 (d, J= 1.6 Hz, 1H), 7.06 (d, J= 8.0 Hz, 1H), 6.84 (d, J= 8.8 Hz, 1H), 3.13-3.22 (m, 3H), 2.81 (t, J= 11.2 Hz, 2H), 2.00-2.05 (m, 2H), 1.86-1.95 (m, 2H); 2D NMR analyses (HSQC, COSY, HMBC and NOESY) were conducted to confirm the structure of Int3-342; MS (m / z) [M+H]+calcd for C23H22C1FN5O2+, 454.1, found, 453.9

[0727] Preparation of 342: To a solution of Int3-342 (88.0 mg, 179.46 μmol, 1.0 eq, HC1) in DCM (8.0 mL) was added DIPEA (69.58 mg, 538.38 μmol, 93.77 μL, 3.0 eq) at 25 °C. The mixture was cooled to 0 °C and acryloyl chloride (16.24 mg, 179.46 μmol, 14.58 μL, 1.0 eq) in DCM (0.1 mL) was dropwise added and the mixture was stirred at 0 °C for 30 mins. LCMS showed the reaction was completed. H2O (0.5 mL) was added and the mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: 41- WePure Biotech XP tC18 150x40mm, 7pm; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 33%-53% B over 10.0 min) to give 342 (40.0 mg, 78.75 μmol, 43.88% yield, 100% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) <5 ppm: 8.34 (br s, 1H), 8.32 (s, 1H), 8.20 (s, 1H), 8.14 (d, J= 7.6 Hz, 1H), 8.03 (d, J= 2.0 Hz, 1H), 7.74 (t, J= 8.8 Hz, 1H), 7.52 (d, J= 7.2 Hz, 1H), 7.26 (t, J= 8.0 Hz, 1H), 7.06 (d, J= 2.4 Hz, 1H), 6.95 (d, J= 7.6 Hz, 1H), 6.87 (dd, J= 9.2 Hz, 1.6 Hz, 1H), 6.24-6.31 (m, 1H), 6.10 (dd, J= 16.8 Hz, 2.0 Hz, 1H), 5.59 (dd, J= 10.0 Hz, 2.0 Hz, 1H), 3.75-3.85 (m, 1H), 3.14-3.17 (m, 2H), 2.83 (t, J= 10.8 Hz, 2H), 1.90-1.94 (m, 2H), 1.65-1.75 (m, 2H); MS (m / z) [M+H]+calcd for C26H24C1FN5O3+, 508.2, found, 508.2 l-( 4-( 4-( 3-chloro-4-(3-chloro-2-fluorophenoxy)-2-fluorophenyl)amino)pyrimidin-5- yl)piperazin-l-yl-2, 2, 3, 3, 5, 5, 6, 6-d8)prop-2-en-l-one (343)

[0728] 343 was prepared by following General Procedure 8. One modification was replacing Gpl- 6 with tert-butyl piperazine-l-carboxylate-2,2,3,3,5,5,6,6-t / s.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.53 (s, 1H), 8.29 (s, 1H), 8.14 (br s, 1H), 7.59 (t, J= 8.8 Hz, 1H), 7.44-7.40 (m, 1H), 7.23 (td, J= 8.4, 2.0 Hz, 1H), 7.10-7.05 (m, 1H), 6.98 (dd, J = 9.2, 1.6 Hz, 1H), 6.82 (dd, J = 16.8, 10.4 Hz, 1H), 6.12 (dd, J = 16.8, 2.4 Hz, 1H), 5.68 (dd, J = 10.4, 2.4 Hz, 1H); HRMS (ESI, m / z): calcd for C23Hi2D8Cl2F2N5O2 (M+H)+: 514.1459, Found: 514.1464 l-( 4-( 4-(( 4-(benzofuran- 7-yloxy)-3-chloro-2-fluorophenyl)amino)pyrimidm-5-yl)piperazm-l- yl-2, 2, 3, 3, 5, 5, 6, 6-d8)prop-2-en-l -one (344 ) 344 was prepared by following General Procedure 8. One modification was replacing Gpl- 6 with tert-butyl piperazine-l-carboxylate-2,2,3,3,5,5,6,6-t / s. (4001MHH NzM, DRMSO-d6) δ ppm: 8.52 (s, 1H), 8.27 (s, 1H), 8.12 (br s, 1H), 7.99 (d, J= 2.0 Hz, 1H), 7.51-7.47 (m, 2H), 7.24 (t, J= 8.0 Hz, 1H), 7.03 (d, J= 2.0 Hz, 1H), 6.95 (dd, J= 8.0, 0.8 Hz, 1H), 8.85-6.79 (m, 2H), 6.12 (dd, J= 16.8, 2.4 Hz, 1H), 5.68 (dd, J= 10.4, 2.4 Hz, 1H); HRMS (ESI, m / z): calcd for C25H14D8CIFN5O3 (M+H)+: 502.1892, Found: 502.1890 l-( 4-( 4-( 4-(benzofuran- 7-yloxy)-3-bromo-2-fluorophenyl)ammo)pyrimidin-5-yl)piperazm-l- yl)prop-2-en-l-one (345)

[0729] 345 was synthesized according to General Procedure 9, using benzofuran-7-ol and 2- bromo-l,3-difluoro-4-nitrobenzene as starting materials. An improvement to the procedure involved the successful isolation of Intl-345 by prep-HPLC (column: 41-WePure Biotech XP tC18 150x40mm, 7pm; mobile phase: [H2O (0.05% NH3H2O+10mM NH4HCO3)-ACN]; B%: 50%, isocratic elution mode). Intl-345 was obtained as a light-red solid. (4001H NMR MHz, DMSO-d6) δ ppm: 8.02 (d, J= 2.4 Hz, 1H), 7.35 (d, J= 7.6 Hz, 1H), 7.12 (t, J= 8.0 Hz, 1H), 7.01 (d, J= 2.0 Hz, 1H), 6.76-6.82 (m, 2H), 6.56 (d, J= 8.0 Hz, 1H), 5.37 (s, 2H); 2D NMR analyses (HSQC, HMBC and NOESY) were conducted to confirm the structure of Intl-345; MS (m / z) [M+H]+calcd for CuHioBrFNC , 322.0, found, 323.8

[0730] The Intl-345 was then carried forward in the synthesis, following General Procedure 9, to afford the final product 345 as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.53 (s, 1H), 8.30 (s, 1H), 8.16 (s, 1H), 8.03 (d, J= 2.4 Hz, 1H), 7.58 (t, J= 9.2 Hz, 1H), 7.53 (d, J = 6.8 Hz, 1H), 7.27 (t, J= 8.0 Hz, 1H), 7.06 (d, J= 2.0 Hz, 1H), 6.96 (d, J= 8.0 Hz, 1H), 6.83- 6.90 (m, 1H), 6.82 (dd, J= 9.2 Hz, 1.6 Hz, 1H), 6.16 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.8 Hz, 1H), 3.71-3.81 (m, 4H), 2.90-2.99 (m, 4H); MS (m / z) [M+H]+calcd for C25H22BrFN5O3+, 540.1, found, 540.1

[0731] (E)-N-(4-((3-chloro-4-(3-chloro-2-fluorophenoxy)-2-fluorophenyl)ammo)pyrimidm-5-yl)-4- morpholinobut-2-enamide (346)

[0732] Preparation of Intl-346: To a solution of Gp9-3-l (300 mg, 1.03 mmol, 1.0 eq) and 4- chloropyrimidin-5-amine (133.9 mg, 1.03 mmol, 1.0 eq) in z-PrOH (10 mL) was added HCl / dioxane (2.0 M, 2.07 mL, 4.0 eq). The mixture was stirred at 80 °C for 16 h. LCMS analysis showed 73% conversion to the desired product. The reaction mixture was concentrated, and the obtained residue was purified by flash silica gel column chromatography (from hexane / EtOAc = 1 / 1 to 0 / 1; TLC: hexane / EtOAc = 0 / 1) to afford Intl-346 (340 mg, 887.31 μmol, 85.80% yield) as yellow oil.1H NMR (400 MHz, CDC13) d ppm: 8.43 (s, 1H), 8.30 (t, J = 9.2 Hz, 1H), 8.05 (s, 1H), 7.15-7.18 (m, 1H), 7.01-7.04 (m, 2H), 6.83-6.85 (m, 2H).

[0733] Preparation of 346: To a solution of Intl-346 (220 mg, 574.14 μmol, 1.0 eq) and (£)-4- morpholinobut-2-enoyl chloride (435.5 mg, 2.30 mmol, 4.0 eq) in DCM (10 mL) was added TEA (116.2 mg, 1.15 mmol, 159.83 μL, 2.0 eq). The mixture was stirred at 25 °C for 1 h. LCMS analysis indicated 67% conversion to the desired product. The reaction mixture was concentrated, and the residue was purified by zc -HPLC (column: Welch Xtimate Cl 8, 150 x 25 mm, 5 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 41-71% B over 11 min) to afford 346 (135 mg, 249.96 μmol, 43.54% yield, 99.31% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 9.73 (s, 1H), 8.90 (s, 1H), 8.44 (s, 1H), 8.41 (s, 1H), 7.46-7.51 (m, 2H), 7.26-7.27 (m, 1H), 7.13-7.18 (m, 1H), 6.98-6.99 (m, 1H), 6.75-6.99 (m, 1H), 6.30-6.35 (m, 1H), 3.60 (t, J= 4.4 Hz, 4H), 3.14-3.16 (m, 2H), 2.41 (s, 4H); MS (m / z) [M+H]+calcd for C24H22C12F2N5O3+, 536.1, found, 536.1. l-( 4-( 4-(( 4-(3-chloro-2-fluorophenoxy)-2-fluoro-3-methylphenyl)ammo)pyrimidm-5- yl)piperazin-l-yl)prop-2-en-l-one (347)

[0734] 347 was synthesized according to General Procedure 9, using 3-chloro-2-fluorophenol and l,3-difhioro-2-methyl-4-nitrobenzene as starting materials. An improvement to the procedure involved the successful isolation of Intl-347 by prep-HPLC (column: 41-WePure Biotech XP tC18 150x40 mm, 7pm; mobile phase: [H2O (0.075% TFA)-ACN]; B%:61%, isocratic elution mode). Intl-347 was obtained as a light-yellow solid.1H NMR (400 MHz, DMSO- dd) 3 ppm: 7.25 (t, J= 8.0 Hz, 1H), 7.08-7.13 (m, 1H), 6.71-6.75 (m, 1H), 6.63-6.70 (m, 2H), 2.02 (d, J = 1.6 Hz, 3H); 2D NMR analyses (HSQC, HMBC and NOESY) were conducted to confirm the structure of Intl-347; MS (m / z) [M+H]+calcd for C13H11CIF2NCE, 270.0, found, 270.0

[0735] The Intl-347 was then carried forward in the synthesis, following General Procedure 9, to afford the final product 347 as a white solid.1HNMR (400 MHz, DMSO-d6) δ ppm: 8.37 (s, 1H), 8.31 (s, 1H), 8.15 (s, 1H), 7.57 (t, J= 8.8 Hz, 1H), 7.37-7.42 (m, 1H), 7.20-7.25 (m, 1H), 6.98-7.03 (m, 1H), 6.83-6.90 (m, 1H), 6.79 (t, J= 8.8 Hz, 1H), 6.16 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.72 (dd, J= 10.0 Hz, 2.0 Hz, 1H), 3.70-3.85 (m, 4H), 2.90-2.98 (m, 4H), 2.18 (d, J = 1.6 Hz, 3H); MS (m / z) [M+H]+calcd for C24H23C1F2N5O2+, 486.2, found, 486.2 l-( 4-( 4-(( 3-chloro-4-(3-chloro-2-fluorophenoxy)-2-fluorophenyl)ammo)-2-methylpyrimidm-

[0736] 5-yl)piperazin-l-yl)prop-2-en-l-one (348)

[0737] 348 was prepared by following General Procedure 8. One modification was replacing GP8- 1 with 5-bromo-4-chloro-2-methylpyrimidine.1H NMR (400 MHz, DMSO-d6) <5 ppm: 8.42 (s, 1H), 8.10 (s, 1H), 7.82-7.84 (m, 1H), 7.43-7.45 (m, 1H), 7.24-7.26 (m, 1H), 7.10 - 7.15 (m, 1H), 7.01-7.04 (m, 1H), 6.85-6.87 (m, 1H), 6.15 (dd, J= 2.4 Hz, 16.4 Hz, 1H), 5.72 (dd, J= 2.4 Hz, 10.4 Hz, 1H), 3.71-3.75 (m, 4H), 2.87-2.90 (m, 4H), 2.33 (s, 3H); MS (m / z) [M+H]+calcd for C24H22C12F2N5O2+, 520.1, found, 520.1 l-( 4-( 4-(( 4-(benzo[b ] thiophen- 7-yloxy)-3-chloro-2-fluorophenyl)amino)pyrimidm-5- yl)piperazin-l-yl)prop-2-en-l-one (350)

[0738]

[0739] 350 was synthesized according to General Procedure 9, using benzo[Z»]thiophen-7-ol and 2- chloro-l,3-difluoro-4-nitrobenzene as starting materials. An improvement to the procedure involved the successful isolation of Intl-350 by prep-HPLC (column: 56-Boston Green ODS 150x30 mm, 5pm; mobile phase: [H2O (0.075% TFA)-ACN]; gradient: 16%-56% B over 9.0 min). Intl-350 was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 9.07 (br s, 1H), 8.79 (br s, 2H), 8.49 (s, 1H), 8.29 (s, 1H), 7.85 (d, J= 5.6 Hz, 1H), 7.76 (d, J= 8.0 Hz, 1H), 7.57 (d, J= 5.2 Hz, 1H), 7.51 (t, J= 8.8 Hz, 1H), 7.44 (d, J= 8.0 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.90 (d, J= 8.0 Hz, 1H), 3.32-3.38 (m, 4H), 3.14-3.20 (m, 4H).

[0740] The Intl-350 was then carried forward in the synthesis, following General Procedure 9, to afford the final product 350 as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.58 (s, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 7.84 (d, J= 5.2 Hz, 1H), 7.73 (d, J= 8.0 Hz, 1H), 7.64 (t, J= 8.8 Hz, 1H), 7.56 (d, J= 5.2 Hz, 1H), 7.41 (d, J= 8.0 Hz, 1H), 7.03 (d, J= 8.0 Hz, 1H), 6.83- 6.90 (m, 2H), 6.16 (dd, J= 16.4 Hz, 2.0 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.69- 3.86 (m, 4H), 2.90-3.00 (m, 4H); MS (m / z) [M+H]+calcd for C25H22C1FN5O2S+, 510.1, found, 510.1 l-( 4-( 4-(( 4-(3-bromo-2-fluorophenoxy)-3-chloro-2-fluorophenyl)ammo)pyrimidm-5- yl)piperazin-l-yl)prop-2-en-l-one (351 )

[0741] 351 was synthesized according to General Procedure 9, using 3-bromo-2-fluorophenol and 2-chloro-l,3-difluoro-4-nitrobenzene as starting materials. An improvement to the procedure involved the successful isolation of Intl-351 by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 80-88% B over 11.0 min). Intl-351 was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.30 (s, 1H), 8.15 (s, 1H), 7.64 (t, J= 8.8 Hz, 1H), 7.55-7.58 (m, 1H), 7.19-7.21 (m, 1H), 7.13-7.15 (m, 1H), 6.99-7.01 (m, 1H), 3.52-3.54 (m, 4H), 2.90-2.92 (m, 4H), 1.43 (s, 9H).

[0742] The Intl-351 was then carried forward in the synthesis, following General Procedure 9, to afford the final product 351 as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.55 (s, 1H), 8.32 (s, 1H), 8.18 (s, 1H), 7.63 (t, J= 8.8 Hz, 1H), 7.54-7.59 (m, 1H), 7.19-7.23 (m, 1H), 7.13-7.16 (m, 1H), 6.98-7.01 (m, 1H), 6.83-6.90 (m, 1H), 6.16 (dd, J= 16.4 Hz, 2.0 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.71-3.83 (m, 4H), 2.91-2.98 (m, 4H); MS (m / z)

[0743] [M+H]+calcd for C23H20BrClF2N502+, 552.0, found, 552.0 l-( 4-( 4-(( 3-bromo-4-(3-bromo-2-fluorophenoxy)-2-fluorophenyl)ammo)pyrimidm-5- yl)piperazin-l-yl)prop-2-en-l-one (352)

[0744] 352 was synthesized according to General Procedure 9, using 3-bromo-2-fluorophenol and 2-bromo-l,3-difluoro-4-nitrobenzene as starting materials. An improvement to the procedure involved the successful isolation of Intl-352 by flash silica gel chromatography (Ethyl acetate / Hexanes). The Intl-352 was then carried forward in the synthesis, following General Procedure 9, to afford the final product 352 as a white solid. ' NMR (500 MHz, DMSO-d6) δ ppm: 8.53 (s, 1H), 8.30 (s, 1H), 8.16 (br s, 1H), 7.66 (t, J = 9.0 Hz, 1H), 7.55-7.52 (m, 1H), 7.18 (t, J= 9.0 Hz, 1H), 7.10-7.07 (m, 1H), 6.96 (d, J= 9.0 Hz, 1H), 6.84 (dd, J= 16.5, 10.5 Hz, 1H), 6.14 (dd, J= 16.5, 2.0 Hz, 1H), 5.70 (dd, J= 10.5, 2.0 Hz, 1H), 3.76 (br s, 4H), 2.93 (br s, 4H);13C NMR (125 MHz, DMSO-d6) δ ppm: 164.8, 155.8, 154.4 (d, J= 245.3 Hz), 153.7, 150.9 (d, J= 2.4 Hz), 150.2 (d, J= 245.3 Hz), 146.3, 144.6 (d, J= 11.9 Hz), 132.2,

[0745] 129.2, 128.6, 128.1, 127.3 (d, J= 2.4 Hz), 126.9 (d, J= 4.5 Hz), 124.8 (d, J= 13.0 Hz),

[0746] 120.2, 114.7 (d, J= 3.1 Hz), 110.2 (d, J= 17.8 Hz), 101.9 (d, J= 22.1 Hz), 51.4, 50.7, 45.7, 42.0; HRMS (ESI, m / z): calcd for C23H20Br2F2N5O2(M+H)+: 595.9926, Found: 595.9954 l-( 4-( 4-( 3-chloro-4-(2-chlorophenoxy)phenyl)amino)pyrimidm-5-yl)piperazin-l-yl)prop-2- en-l-one (353)

[0747] 353 was prepared by following General Procedure 8.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.64 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.10 (d, J= 2.4 Hz, 1H), 7.79 (dd, J= 8.8, 2.4 Hz, 1H), 7.60 (dd, J= 8.0, 1.6 Hz, 1H), 7.33 (td, = 8.0, 1.6 Hz, 1H), 7.18 (td, J= 8.0, 1.6 Hz, 1H), 7.10 (d, J= 8.8 Hz, 1H), 6.83-6.91 (m, 2H), 6.16 (dd, J= 16.8, 2.8 Hz, 1H), 5.72 (dd, J= 10.8, 2.4 Hz, 1H), 3.83 (br s, 4H), 2.92-2.94 (m, 4H); MS (m / z) [M+H]+calcd for C23H22CI2N5O2 , 470.1, found, 470.1 l-( 4-( 4-(( 4-(2-bromophenoxy)-3-chlorophenyl)amino)pyrimidm-5-yl)piperazm-l-yl)prop-2- en-l-one (354)

[0748] 354 was prepared by following General Procedure 8.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.63 (s, 1H), 8.43 (s, 1H), 8.22 (s, 1H), 8.09 (d, J= 2.4 Hz, 1H), 7.65-7.86 (m, 2H), 7.31-7.41 (m, 1H), 7.04-7.14 (m, 2H), 6.76-6.94 (m, 2H), 6.16 (dd, J= 16.8, 2.4 Hz, 1H), 5.72 (dd, J= 10.8, 2.4 Hz, 1H), 3.82 (br s, 4H), 2.92-2.94 (m, 4H); MS (m / z) [M+H]+calcd for C23H22BrClN5O2+, 514.1, found, 514.1 l-( 4-( 4-((2, 3-dichloro-4-(3-chloro-2-fluorophenoxy)phenyl)ammo)pyrimidin-5-yl)piperazm- l-yl)prop-2-en-l-one (355)

[0749]

[0750] 355 was prepared by following General Procedure 8.1H NMR (500 MHz, DMSO-d6) δ ppm: 8.68 (s, 1H), 8.38 (s, 1H), 8.24 (br s, 1H), 8.11 (d, J= 9.0 Hz, 1H), 7.42-7.39 (m, 1H), 7.24-7.20 (m, 2H), 7.00 (td, J= 9.0, 1.5 Hz, 1H), 6.85 (dd, J= 17.0, 10.5 Hz, 1H), 6.14 (dd, J = 17.0, 2.5 Hz, 1H), 5.70 (dd, J= 10.5, 2.5 Hz, 1H), 3.78 (br s, 4H), 2.96 (br s, 4H);13C NMR (125 MHz, DMSO-d6) δ ppm: 164.9, 155.6, 153.8, 149.1 (d, J = 246.9 Hz), 148.7, 146.9, 145.0 (d, J= 10.8 Hz), 134.7, 132.4, 128.6, 128.2, 127.5, 126.2 (d, J= 5.0 Hz), 126.1, 124.4, 124.0, 121.8 (d, J= 14.6 Hz), 119.0 (2C), 51.6, 50.9, 46.0, 42.3; HRMS (ESI, m / z): calcd for C23H20CI3FN5O2 (M+H)+: 522.0662, Found: 522.0656 l-( 4-( 4-( 4-(benzofuran-4-yloxy)-3-chloro-2-fluorophenyl)ammo)pyrimidm-5-yl)piperazm-l- yl)prop-2-en-l-one (356) lnt1 -356 Inti -356'

[0751] 356 was synthesized according to General Procedure 9, using benzofuran-4-ol and 2-chloro- l,3-difluoro-4-nitrobenzene as starting materials. An improvement to the procedure involved the successful isolation of Intl-356 by flash silica gel chromatography (Ethyl acetate / Hexanes). The Intl-356 was then carried forward in the synthesis, following General Procedure 9, to afford the final product 356 as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.56 (s, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 8.02 (d, J= 2.4 Hz, 1H), 7.62 (t, J= 8.8 Hz, 1H), 7.47 (d, J= 8.0 Hz, 1H), 7.33 (t, J= 8.0 Hz, 1H), 6.98 (dd, J= 8.8 Hz, 1.6 Hz, 1H), 6.82-6.90 (m, 2H), 6.76 (d, J= 8.0 Hz, 1H), 6.16 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.72 (dd, J = 10.4 Hz, 2.4 Hz, 1H), 3.70-3.85 (m, 4H), 2.91-2.98 (m, 4H); MS (m / z) [M+H]+calcd for C25H22C1FN5O3+, 494.1, found, 494.2 l-( 4-( 4-(( 3-chloro-4-(2-fluorophenoxy)phenyl)amino)pyrimidm-5-yl)piperazm-l-yl)prop-2- en-l-one (357)

[0752] 357 was synthesized according to General Procedure 9, using 2-fluorophenol and 2-chloro- l,3-difluoro-4-nitrobenzene as starting materials. An improvement to the procedure involved the successful isolation of Intl-357 by prep-HPLC (column: 41-WePure Biotech XP tC18 150x40mm, 7pm; mobile phase: [H2O (0.075% TFA)-ACN]; B%: 54%, isocratic elution mode). The Intl-357 was then carried forward in the synthesis, following General Procedure 9, to afford the final product 357 as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.54 (s, 1H), 8.30 (s, 1H), 8.16 (s, 1H), 7.56 (t, J= 8.8 Hz, 1H), 7.41-7.47 (m, 1H), 7.23-7.32 (m, 2H), 7.16-7.21 (m, 1H), 6.83-6.90 (m, 2H), 6.16 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.67-3.87 (m, 4H), 2.89-3.00 (m, 4H); MS (m / z) [M+H]+calcd for C23H21ClF2N5O2+, 472.1, found, 472.1 l-( 4-( 4-( 3-chloro-2-fluoro-4-( 3-fluorobenzofuran- 7-yl)oxy)phenyl)amino)pyrimidin-5- yl)piperazin-l-yl)prop-2-en-l-one (358)

[0753] 358 was synthesized according to General Procedure 9, using 3-fluorobenzofuran-7-ol and 2-chloro-l,3-difluoro-4-nitrobenzene as starting materials. An improvement to the procedure involved the successful isolation of Intl-358 by flash silica gel chromatography (Ethyl acetate / Hexanes). The Intl-358 was then carried forward in the synthesis, following General Procedure 9, to afford the final product 358 as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.56 (s, 1H), 8.34 (d, J= 4.4 Hz, 1H), 8.31 (s, 1H), 8.17 (s, 1H), 7.53-7.60 (m, 2H), 7.36 (t, J= 8.0 Hz, 1H), 7.05 (d, J= 7.6 Hz, 1H), 6.95 (d, J= 9.2 Hz, 1H), 6.83-6.86 (m, 1H), 6.15 (dd, J= 16.8 Hz, 2.4 Hz, 1H), 5.72 (dd, J= 10.4 Hz, 2.4 Hz, 1H), 3.77-3.79 (m, 4H), 2.93-2.95 (m, 4H); MS (m / z) [M+H]+calcd for C25H21ClF2N5O3+, 512.1, found, 512.2 l-( 4-( 4-(( 4-73-ch loro-2 -fluorophenoxy) be nzofur an- 7-yl)amino)pyrimidm-5-yl)piperazin-l- yl)prop-2-en-l-one (359)

[0754] 359 was prepared by following General Procedure 8.1H NMR (500 MHz, DMSO-d6) δ ppm: 8.63 (s, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.98 (d, = 2.0 Hz, 1H), 7.53 (d, J= 8.5 Hz, 1H), 7.39 (m, 1H), 7.21 (td, J= 8.5, 1.5 Hz, 1H), 7.06 (m, 1H), 6.87-6.82 (m, 3H), 6.14 (dd, J= 16.5, 2.0 Hz, 1H), 5.70 (dd, J= 10.5, 2.0 Hz, 1H), 3.77 (br s, 4H), 2.96 (br s, 4H);13C NMR (125 MHz, DMSO-d6) δ ppm: 164.8, 156.1, 153.8, 150.2, 149.6 (d, J = 247.0 Hz), 146.6, 146.3, 146.0, 145.5 (d, J= 10.6 Hz), 132.2, 128.6, 128.1, 126.1 (d, J= 4.8 Hz), 125.9, 121.7 (d, J= 14.8 Hz), 121.3, 121.2 (d, J = 18.5 Hz), 119.94, 119.91 (d, J = 6.6 Hz), 111.5, 104.6, 51.5, 50.9, 45.8, 42.1; HRMS (ESI, m / z): calcd for C25H22CIFN5O3 (M+H)+: 494.1390, Found: 494.1385

[0755] Table 1. Ri, R2, and R3 Exemplary Substituents of Certain Compounds of the Disclosure

[0756] Table 2, Ri, R2, R3, R4, and Rs Exemplary Substituents of Certain Compounds of the

[0757] Disclosure

[0758] Table 3, E-R1, R4, R5, and A2Exemplary Substituents of Certain Compounds of the

[0759] Disclosure

[0760] Example 2: Exemplary Biological Data

[0761] Table 4, Biological data *SKBR3 Cellular IC50 also measured at 1000 nM.

[0762] Table 5, Biological data for modified pyrimidine series

[0763] Table 6, In vivo oral administration pharmacokinetic data in CD-I mice

[0764] Example 3: Exemplary Biological Materials and Methods

[0765] EGFR / HER2 kinase IC50 analysis

[0766] Kinase IC50 assays were conducted at WuXi AppTec (Lab Testing Division, Biology Services). To determine the IC50 values of test compounds targeting EGFR, HER2, and HER4, a homogeneous time-resolved fluorescence (HTRF) assay was employed using the HTRF KinEASE-TK kit (Cisbio, 62TK0PEJ). Control (lapatinib (EGFR, HER2), tucatinib (HER2)) and test compounds were prepared at a stock concentration of 0.1 mM and subjected to an 11- point, 3-fold serial dilution in DMSO to achieve final concentrations from 1,000 nM to 0.017 nM. Assay buffer was prepared by mixing HEPES buffer (pH 7.5), MgC12, MnC12, EDTA, Brij-35, DTT, and water. Enzyme and peptide mixtures (2X) were prepared with EGFR (Carna, 08-115) and HER2 (Invitrogen, PV359), and HER4 (Invitrogen, PR6308B), along with 1 pM TK peptide. ATP (Sigma, A7699) mixtures were prepared at 50 pM for EGFR, 60 pM for HER2, and 20 pM for HER4. Detection solution was prepared with a 1 :400 dilution of TK antibody and 62.5 nM Streptavidin-XL665 in Detection buffer. For the kinase reaction, 5 μL of the 2X enzyme and peptide mixture, high control mixtures, and low control mixtures were added the assay plate. The assay plate was centrifuged at 1,000 rpm for 1 min and pre-incubated at 25°C for 15 min, followed by the addition of 5 μL of the 2X ATP solution mixture per well, centrifugation at 1,000 rpm for 1 min, and incubation at 25°C for 60 min. For detection, 10 μL of detection reagent was added per well, and the plate was centrifuged at 1,000 rpm for 1 min and incubated at 25°C for 60 min before reading on the Perkin Elmer Envision instrument. Inhibition percentages were calculated relative to DMSO, high, and low controls, and curves were fitted using a four-parameter logistic concentration response model. Data were fit with a top plateau constrained to 100% and a lower plateau constrained to 0%. Immortalized cell lines

[0767] SKBR3 (HER2 amplified), BT474 (HER2 amplified), A431 (EGFRWTamplified), and Normal Human Astrocyte (NHA) cell lines were obtained from ATCC. All cells were grown as adherent monolayer cultures in recommended medium (SKBR3 and A431 : DMEM, Gibco, 11995065; BT474: RPMI-1640, Invitrogen, 2240010) supplemented with 10% fetal bovine serum (FBS), heat inactivated (Gibco, 16140071) and 1% penicillin / streptomycin (Invitrogen, 15140122) and maintained at 37°C in a humidified incubator at 5% CO2. When passaged, adherent cell monolayers were dissociated with TryμLE (ThermoFisher, 12605028). All cell lines were routinely tested and confirmed negative for the presence of mycoplasma contamination (My coAlert, Lonza, LT07-318). Cell lines were used at fewer than 20 passages for all biological assays. All cells were authenticated by short tandem repeat (STR) analysis.

[0768] Patient-derived GBM gliomaspheres

[0769] All patient-derived tumor tissue was obtained through the UCLA Institutional Review Board (IRB) protocol 10-000655 after explicit informed consent was obtained from patients. Tumor resections were mechanically and enzymatically dissociated using the Miltenyi Biotec human tumor dissociation kit (130-094-929) within 6 hours of surgery, followed by removal of red blood cells with ACK lysis buffer (Gibco, A10492-01). Next, antibody-conjugated magnetic beads were used to remove CD45+ cells (Miltenyi, 130-045-801) and myelinated cells (Miltenyi, 130-096-433) via column-based filtrations. Primary GBM cells GS025 (EGFRWTamplified), GS187 (EGFRA289Damplified), GBM39 (EGFRvIII amplified) were established and cultured as suspension gliomaspheres in media consisting of DMEMZF12 (Gibco, 11330032), B27 supplement without vitamin A (Invitrogen, 12587010), penicillin- streptomycin (Invitrogen, 15140122), and GlutaMAX (Invitrogen, 35050061), supplemented with heparin (5 mg / mL, Sigma H3149), EGF (20 ng / mL, Sigma PHG0313), and bFGF (20 ng / mL, Sigma PHG0263). When passaged, gliomaspheres were dissociated to single cell suspensions with TryμLE (ThermoFisher, 12605028). All cells were grown at 37°C, 20% O2, and 5% CO2 and were routinely tested and confirmed negative for the presence of mycoplasma contamination (My coAlert, Lonza, LT07-318). Gliomaspheres were used at fewer than 15 passages for all biological assays, with the exception of GBM39, which was used between 20 and 30 passages. All cells were authenticated by short tandem repeat (STR) analysis.

[0770] Cell proliferation and IC50 analysis Cells were seeded in 384-well tissue culture treated plates and incubated with serial dilutions of test compounds or DMSO control (0.4% v / v) for 72 h. Cell viability was determined by CellTiter-Glo reagent (Promega, G7573) according to the manufacturer’s protocols. Luminescence was detected using a CLARIOstar Plus microplate reader (BMG Labtech). Luminescence signal was normalized to vehicle-treated wells (normalized signal (%) = (luminescence (treated) / mean luminescence (vehicle)) x 100%). Data were plotted as logfinhibitor (nM)] vs normalized luminescence signal, and a four-parameter logistic concentration response model was fitted to the data in GraphPad Prism to calculate the IC50 of each test compound. Data were fit with a top plateau constrained to 100% and an unconstrained lower plateau.

[0771] MDR1-MDCK permeability and efflux

[0772] Permeability and efflux assays were conducted at WuXi AppTec (Lab Testing Division, Drug Metabolism and Pharmacokinetics Service). MDR1-MDCK II cells were cultured for 5 days to form confluent monolayers. Cells were seeded onto 96-well polycarbonate membrane inserts at a density of 3.33 x 10A5 cells / mL. Digoxin (10 pM), nadolol, and metoprolol (both 2.00 pM) served as control reference compounds. Test and reference compounds were diluted to 2.00 pM with transport buffer (HBSS with 10 mM HEPES and 1% BSA, pH 7.4) and applied to either the apical (A) or basolateral (B) side of the cell monolayer. Permeation was assessed in both directions (A to B and B to A) with and without the P-gp inhibitor GF120918 (10 pM). Plates were incubated for 2.5 hours at 37°C, 5% CO2, and saturated humidity. Efflux ratios were calculated for each compound. Monolayer integrity was confirmed using a lucifer yellow rejection assay, with fluorescence measured at 425 / 528 nm. The apparent permeability coefficient (Papp) was calculated as Papp = (dCr / dt) x Vr / (A x CO), where dCr / dt is the cumulative concentration in the receiver chamber, Vr is the receiver volume, A is the monolayer surface area, and CO is the initial donor concentration. Efflux ratios were determined as Papp (BA) / Papp (AB). Percent recovery was calculated using %recovery = 100 x [(Vr x Cr) + (Vd x Cd)] / (Vd x CO), and %total recovery included cell lysate concentrations. The lucifer yellow permeability was assessed, with %lucifer yellow calculated from fluorescence values and volumes in apical and basolateral wells, requiring less than 2% permeability for acceptable monolayer integrity. Analysis was performed using an ACQUITY UPLC BEH Cl 8 1.7 pm column (2.1 x 50 mm). Mobile phases consisted of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B). Quantification was based on peak area ratios of analyte to internal standard.

[0773] Human liver microsome stability

[0774] Human liver microsome stability assays were conducted at WuXi AppTec (Lab Testing Division, Drug Metabolism and Pharmacokinetics Service). Test and control compounds (testosterone, diclofenac, and propafenone) were prepared as 10 mM stock solutions in DMSO. Working solutions were made by diluting 5 μL of prepared 10 mM stocks with 495 μL of acetonitrile (100 pM). NADPH cofactor was prepared from P-Nicotinamide adenine dinucleotide phosphate reduced form in 2 mM MgC12. Human liver microsomes were prepared in 100 mM potassium phosphate buffer. The stop solution consisted of cold acetonitrile with 250 nM buspirone and labetalol as internal standards. Using an Apricot automation workstation, 2 μL / well of working solutions were added to 96-well reaction plates, followed by 100 μL / well of microsome solution, and pre-incubated at 37°C for 10 minutes. NADPH was added to start the reaction (except for NCF60 plate), and plates were incubated at 37°C. The reaction was terminated by adding 600 μL / well of stop solution, plates were sealed, shaken for, and centrifuged. Supernatants were transferred to sterile plates for LC-MS / MS analysis. Analysis was performed using an ACQUITY UPLC BEH C18 1.7 pm column (2.1 x 50 mm). Mobile phases consisted of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B). Quantification was based on peak area ratios of analyte to internal standard. Test compound half-life (ti / 2) and intrinsic clearance (CLint(mic)) were calculated using first-order kinetics where Clint(mic) = 0.693 / tn x 1 / mg protein / mL (microsomal protein concentration in the incubation medium).

[0775] In vivo pharmacokinetics in CD-I mice

[0776] In vivo pharmacokinetics studies were conducted at the University of California, Los Angeles (UCLA) Medical Center. Male CD-I mice were purchased from The Jackson Laboratory (RRID:ISMR_JAX:003814) at 6-8 weeks of age. All mice were kept under defined pathogen-free conditions at an animal facility approved by the AAALAC of the Division of Laboratory Animal Medicine (DLAM) at UCLA. Mice were drug and test naive prior to initiation of pharmacokinetic studies. All animal experiments were performed with the approval of the UCLA Office of Animal Resource Oversight (OARO) in accordance with protocol guidelines approved by the UCLA Animal Research Committee (ARC). Test compounds were formulated in vehicle 2% hydroxypropyl cellulose as clear solutions or fine suspensions depending on the test compound. Blood plasma and brain concentrations of test compounds were determined using LC-MS / MS methods. Brain tissue samples were homogenized in sterile water, and blood plasma and brain homogenates were precipitated with a 3x volume of acetonitrile / FLO (9: 1 v / v). Samples were vortexed, centrifuged, and analyzed on an Agilent 6460C triple quadrupole mass spectrometer equipped with an Agilent 1290 Infinity II UPLC system. Mobile phases consisted of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B). Test compounds were detected by positive electrospray ionization using multiple reaction monitoring (m / z dependent on test compound).

[0777] INCORPORATION BY REFERENCE

[0778] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0779] EQUIVALENTS

[0780] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

We claim:

1. A compound having a structure represented by formula (I), or a pharmaceutically acceptable salt thereof:wherein:A1is aryl, heteroaryl, or heterocyclyl;E is an electrophile;X1and X2are each independently N or CR1; as valence and stability permit, each instance of R1is independently selected from hydrogen, halo, alkyl, alkoxy, alkenyl, alkynyl, cyano, nitro, amino, amido, acyl, sulfonyl, sulfonamido, and phosphoryl;X3is selected from a bond, -CH2-, -NH-, -S-, and -O-;R1is a bond, aryl, heteroaryl, cycloalkyl, or heterocyclyl; and as valence and stability permit, R2is selected from hydrogen, halo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cyano, nitro, amino, amido, acyl, sulfonyl, sulfonamido, and phosphoryl.

2. The compound of claim 1, wherein the electrophile has a structure represented by a formula selected from:wherein: indicates the position of attachment to R1; as valence and stability permit, L3is a bond or an C1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with -C=O-, -O-, -S-, -NRL3a-, -NRL3aC(=O)-, -C(=O)NRL3a-, -SC(=O)-, -C(=O)S- -OC(=O)-, -C(=O)O-, -NRL3aC(=S)-, -C(=S)NRL3a-, trans-CR, 3b=CR, 3b-, cis- CRL3b=CRL3b-, -C=C- -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NRL3a-, - NRL3aS(=O)-, -S(=O)2-, -S(=O)2O-, -OS(=O)2-, -S(=O)2NRL3a-, or -NRL3aS(=O)2- , wherein RL3ais hydrogen, or alkyl, and wherein each occurrence of RL3bisindependently hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or two RL3bgroups are joined to form a cycloalkyl or heterocyclyl;L4is a bond or alkyl; as valence and stability permit, each instance of RE1, RE2, and RE3is independently hydrogen, halogen, amido, carboxy, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, aryl, heteroaryl, -CN, -CH2OREE, -CH2N(REE)2, -CH2SREE, -OREE, -N(REE)2, -Si(REE)3, or-SREE, wherein each instance of REEis independently hydrogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or two REEgroups are joined to form a heterocyclyl; or RE1and RE3, or RE2and RE3, or RE1and RE2are joined to form a cycloalkyl or heterocyclyl;RE4is a leaving group or alkyl;RE5is halogen;RE6is hydrogen or alkyl; each instance of Y is independently O, S, or NRE7, wherein RE7is hydrogen or alkyl; a is 1 or 2; each instance of z is independently 0, 1, 2, 3, 4, 5, or 6; and as valence and stability permit, each instance of RE8, if present, is independently selected from hydrogen, halogen, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -ORD1, -N(RDla)2, and -SRD1, wherein each occurrence of RD1is independently selected from hydrogen, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein each occurrence of RDlais independently selected from hydrogen, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or optionally two instances of RDlaare taken together with their intervening atoms to form a heterocyclyl or heteroaryl ring; or two RE8groups are joined to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring.

3. The compound of claim 1, wherein the electrophile has a structure represented by a formula selected from:(i-47) (i-47) wherein: indicates the position of attachment to R1; as valence and stability permit, L3is a bond or an C1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with -C=O-, -O-, -S-, -NRL3a-, -NRL3aC(=O)-, -C(=O)NRL3a-, -SC(=O)-, -C(=O)S- -OC(=O)-, -C(=O)O-, -NRL3aC(=S)-, -C(=S)NRL3a-, trans-CRL3b=CRL3b-, cis- CRL3b=CRL3b-, -C=C- -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NRL3a-, - NRL3aS(=O)-, -S(=O)2-, -S(=O)2O-, -OS(=O)2-, -S(=O)2NRL3a-, or -NRL3aS(=O)2- , wherein RL3ais hydrogen, or alkyl, and wherein each occurrence of RL3bis independently hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or two RL3bgroups are joined to form a cycloalkyl or heterocyclyl; as valence and stability permit, each instance of RE1and RE2is independently hydrogen, halogen, amido, carboxy, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, aryl, heteroaryl, -CN, -CH2OREE, -CH2N(REE)2, -CH2SREE, -OREE, -N(REE)2, -Si(REE)3, or-SREE, wherein each instance of REEis independently hydrogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or two REEgroups are joined to form a heterocyclyl; or RE1and RE3, or RE2and RE3, or RE1and RE2are joined to form a cycloalkyl or heterocyclyl; and each instance of Y is independently O, S, or NRE7, wherein RE7is hydrogen or alkyl.

4. The compound of any one of claims 1-3, wherein the electrophile has a structure represented by Formula i-1 :(i-1)5. The compound of claim 4, wherein L3is a bond.

6. The compound of claim 4 or 5, wherein RE1is hydrogen.

7. The compound of claim 4 or 5, wherein RE1is halogen.

8. The compound of any one of claims 3-7, wherein RE2is hydrogen.The compound of any one of claims 3-8, wherein RE3is hydrogen.

10. The compound of any one of claims 3-9, wherein Y is O.

11. The compound of any one of claims 1-10, wherein R1is a bond.

12. The compound of any one of claims 1-10, wherein R1is selected from:compound.

13. The compound of any one of claims 1-12, wherein R1is selected from:wherein represents the connection to the remainder of the compound.

14. The compound of any one of claims 1-13, wherein E is selected from:

15. The compound of any one of claims 1-14, wherein E is O ; and wherein indicates the connection to variable R1.

16. The compound of any one of claims 1-15, wherein X1is N.

17. The compound of any one of claims 1-16, wherein X2is N.

18. The compound of any one of claims 1-17, wherein X3is NH.

19. The compound of any one of claims 1-18, wherein R1is a bond.

20. The compound of any one of claims 1-18, wherein R1is21. The compound of any one of claims 1-18, wherein R1is22. The compound of any one of claims 1-14 and 16-21, wherein E is O ; and wherein indicates the connection to variable R1.

23. The compound of any one of claims 1-22, wherein A1is aryl (e.g., phenyl, indanyl, or naphthyl).

24. The compound of claim 23, wherein A1is phenyl.

25. The compound of any one of claims 1-22, wherein A1is heteroaryl (e.g., dibenzofuryl, benzofuryl, benzothiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, pyridyl, pyrazinyl, benzotri azolyl, benzothiophenyl, dibenzopyrrolyl, dibenzothiophenyl, indazolyl, xanthenyl, or indolyl).

26. The compound of any one of claims 1-22, wherein A1is heterocyclyl (e.g., dibenzoxepinyl, dibenzoxocinyl, dioxinyl, dibenzodioxinyl, 2, 3,4,5- tetrahydrobenzo[b]oxepinyl, 2,3-dihydrobenzo[b][l,4]dioxinyl, or benzodioxinyl).

27. The compound of any one of claims 1-26, wherein the compound is represented by formula la, or a pharmaceutically acceptable salt thereof:la; wherein: as valence and stability permit, each R3is independently selected from halo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl), aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, amino, amido, acyl, sulfonyl, sulfonamido, and phosphoryl; and n is 1, 2, 3, 4, 5, 6, 7, 8, or 9.

28. The compound of claim 27, wherein n is 1.

29. The compound of claim 27, wherein n is 2.

30. The compound of claim 27, wherein n is 3.

31. The compound of any one of claims 1-28, wherein the compound is represented by formula lb, or a pharmaceutically acceptable salt thereof:

32. The compound of any one of claims 1-29 or 31, wherein the compound is represented by formula Ic, or a pharmaceutically acceptable salt thereof:Ic.

33. The compound of any one of claims 1-27 or 30, wherein the compound is represented by formula Id, or a pharmaceutically acceptable salt thereof:

34. The compound of any one of claims 31-33, wherein the compound is represented by formula le, or a pharmaceutically acceptable salt thereof:

35. The compound of any one of claims 31-33, wherein the compound is represented by formula If, or a pharmaceutically acceptable salt thereof:

36. The compound of claim 34, wherein the compound is represented by formula Ig, or a pharmaceutically acceptable salt thereof:

37. The compound of claim 34, wherein the compound is represented by formula Ih, or a pharmaceutically acceptable salt thereof:

38. The compound of claim 34, wherein the compound is represented by formula li, or a pharmaceutically acceptable salt thereof:

39. The compound of claim 37, wherein the compound is represented by formula Ij, or a pharmaceutically acceptable salt thereof:wherein:A2is aryl, heteroaryl, cycloalkyl, or heterocyclyl; p is 1, 2, 3, 4, or 5; and each R6is independently selected from halo, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl.

40. The compound of any one of claims 27-39, wherein each R3is halo (e.g., chloro).

41. The compound of claim 39, wherein the compound is represented by formula Ik, or a pharmaceutically acceptable salt thereof:

42. The compound of any one of claims 1-27, wherein the compound is represented by formula II, or a pharmaceutically acceptable salt thereof:each R4and R5are each independently selected from halo, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;A2is aryl, heteroaryl, cycloalkyl, or heterocyclyl; p is 1, 2, 3, 4, or 5; and each R6is independently selected from halo, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl.

43. The compound of any one of claims 1-27, wherein the compound is represented by formula Im, or a pharmaceutically acceptable salt thereof:wherein:A2is aryl, heteroaryl, cycloalkyl, or heterocyclyl; p is 0, 1, 2, 3, 4, or 5; and each R6is independently selected from halo, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl.

44. The compound of any one of claims 39-42, wherein A2is aryl (e.g., phenyl, indanyl, or naphthyl).

45. The compound of claim 44, wherein A2is phenyl.

46. The compound of claim 44, whereinwhereinrepresents the connection to the oxygen atom.

47. The compound of claim 44, whereinwhereinrepresents the connection to the oxygen atom.

48. The compound of any one of claims 39-42, wherein A2is heteroaryl (e.g., dibenzofuryl, naphthyl, benzothiazolyl, benzimidazolyl, pyridyl, [l,2,4]triazolo[l,5- a]pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, benzofuryl, or benzotri azolyl).

49. The compound of any one of claims 39-42, wherein A2is heterocyclyl (e.g., tetrahydropyranyl).

50. The compound of any one of claims 1-49, wherein R2is H or alkoxy (e.g., methoxy).

51. The compound of any one of claims 1-50, wherein A2is selected from:

52. The compound of claim 1, wherein the compound is selected from:pharmaceutically acceptable salt thereof.

53. The compound of claim 1, wherein the compound is selected from:

54. A pharmaceutical composition comprising the compound of any one of claims 1-53 and a pharmaceutically acceptable excipient.

55. A method of treating a cancer in a subject in need thereof, comprising administering to the subject an amount of a compound of any one of claims 1-53 or a pharmaceutically acceptable salt thereof.

56. The method of claim 55, wherein the cancer is breast cancer, head and neck cancer, lung cancer, prostate cancer, or ovarian cancer.

57. The method of claim 55, wherein the cancer is testicular cancer, cervical cancer, bladder cancer, esophageal cancer, mesothelioma, or brain cancer (e.g, glioblastoma).

58. The method of claim 57, wherein the cancer is brain cancer (e.g, glioblastoma).

Images