Novel Pyrimidine Compound as Kinase Inhibitors with Biological Activities on EGFR Mutants

This application claims the benefit of U.S. provisional application: 63/376,253 filed on September 19, 2022.

FIELD OF THE INVENTION

This present invention relates to compounds that feature the inhibition of protein tyrosine kinases (PTKs), including EGFR mutants, their pharmaceutical compositions that comprising a therapeutically effective amount of the corresponding compounds and methods of use therefor.

BACKGROUND OF THE INVENTION

Protein tyrosine kinases (PTKs) are a large series of enzymes that catalyze the phosphorylation process of transferring phosphate groups from nucleoside triphosphates (often ATP) to protein amino acid residues. They span the cell membrane and play roles as “switches” in the cellular signal transduction cascades from extracellular signals through membrane to the cytoplasm part and even the inner nucleus. Epidermal growth factor receptor (EGFR) belongs to a family of receptor tyrosine kinases (RTKs) that include EGFR/ERBB1, HER2/ERBB2/NEU, HER3/ERBB3, and HER4/ERBB4. The binding of a ligand, such as epidermal growth factor (EGF), induces a conformational change in EGFR that facilitates receptor homo- or heterodimer formation, leading to activation of EGFR tyrosine kinase activity. EGFR overexpression or activation and acquired EGFR T790M mutation is observed in human cancers and is associated with high rates of cancer cell proliferation and drug resistance. The EGFR T790M mutation was present in approximately 50 to 60 % of resistant cases which are acquired gatekeeper mutations of threonine-to-methionine (T790M) in the EGFR gene.

This present invention disclosed herein are compounds with inhibitory activity against EGFR mutants, such as L858R, T790M, C797S, exon 20 insertions, HER2, etc. Examples of compounds that are similar in structure to those of the present invention are disclosed in the following literatures: WO2009158571, WO2013014448, WO2015127872, WO2015188777, WO2015195228, WO2016023422, WO2016029839, WO2016054987, WO2016070816, WO2016173438, WO2017086830, WO2017120429, WO2017162510,

WO2017205459.

SUMMARY OF THE INVENTION

Several embodiments disclosed herein pertain to inhibitors of PTKs, mainly inhibition to EGFR mutants, represented by Formula I:

Formula I

Wherein:

Q is a bicyclic heterocyclyl, selected from:

R is selected from H, halogen, halogen-lower alkyl, -CN, carboxylic acid, carboxylic ester or carboxylic amide;

X is selected from direct bond, -O-, -S-, or -N(R')-;

R’ is selected from H, halogen, halogeno-lower alkyl, lower alkyl, hydroxyl, lower alkoxy, amino, hydroxyl alkylamino, aryl or heterocyclyl;

R” is selected from:

Q’ is a heterocyclyl, selected from pyrimidinyl and pyridinyl:

Y is selected from H, or -NR’R’. R’R’ can form an aliphatic, heterocyclic ring; or a pharmaceutically acceptable salt thereof

DETAILED DESCRIPTION OF THE INVENTION

The present invention is the directed to compounds which can inhibit protein tyrosine kinase, such as various EGFR mutants.

In the compounds of Formula I:

Q is a bicyclic heterocyclyl, selected from:

R is selected from H, halogen, methyl, trifluoromethyl, -CN, carboxylic acid, carboxylic lower alkyl ester or carboxylic lower alkyl amide with nitrogen mono or dual substituted; preferably selected from Cl, Br and carboxylic acid.

X is selected from -O-, or -N(R’)-; preferably -NH-;

R’ is selected from H, halogen, halogeno-lower alkyl, lower alkyl; preferably lower alkoxy or a halogen.

R” is selected from: preferably the

Q’ is selected from pyrimidinyl and pyridinyl:

Y is selected from H, or -NR’R’, R’R’ can form an aliphatic, heterocyclic ring; preferably the -NR’R’ group is selected from substituted or unsubstituted N,N- dimethyl amino (-NMe ₂ ), pyrrolidine, morpholine, piperidine and piperazine or a pharmaceutically acceptable salt thereof.

In the compounds of Formula I:

Formula I

Q is:

X is -NH-;

R is selected from chlorine, bromine,;

R’ is selected from: H, F, Cl, -CH ₃ , -0CH ₃ , -C00H;

R” is ; Y is selected from: or a pharmaceutically acceptable salt thereof.

The term “halogen”, as used herein, unless otherwise indicated, includes fluoro (-F), chloro (-C1), bromo (-Br) or iodo (-1), such as fluoro (-F) and chloro (-C1).

The term “lower alkyl”, as used herein, unless otherwise indicated, includes 1 to 6 saturated monovalent hydrocarbon radicals having straight or branched moieties, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl, tert-butyl, and the like. The term “lower alkenyl”, as used herein, unless otherwise indicated, includes lower alkyl groups, as defined above, having at least one carbon-carbon double bond, such as -CH ₂ -CH=CH ₂ .

The term “lower alkynyl”, as used herein, unless otherwise indicated, includes lower alkyl groups, as defined above, having at least one carbon-carbon triple bond, such as CH ₂ - C = CH.

The term “halogen-lower alkyl”, as used herein, unless otherwise indicated, includes 1 to 6 halogen substituted alkyl, such as trifluoromethyl (-CF ₃ ).

The term “carboxyl acid, carboxyl acid lower alkyl ester” as used herein, unless otherwise indicated, includes a carboxylic acid and/or carboxyl acid lower alkyl ester.The term “lower alkoxy”, as used herein, unless otherwise indicated, includes -O-lower alkyl groups wherein lower alkyl is as defined above, such as methoxy (-OCH ₃ ) and ethoxy (- OCH ₂ CH ₃ ).

The term “amino”, as used herein, unless otherwise indicated, includes -NH ₂ group, -NH-lower alkyl group, or -N(lower alkyl) ₂ group wherein lower alkyl is as defined above, such as methylamino (-NHMe), dimethylamino (-NMe ₂ ) and diethylamino (-NEt ₂ ).

The term “hydroxyl alkylamino”, as used herein, unless otherwise indicated, includes HO-lower alkyl-NH ₂ group, HO-lower alkyl-NH-lower alkyl group, or HO- lower alkyl-N(lower alkyl) ₂ group wherein lower alkyl is as defined above, such as -NH- CH ₂ CH ₂ OH.

The term “aliphatic”, as used herein, is selected from lower alkyl, lower alkenyl, lower alkynyl or cyclic alkyl, alkenyl, alkynyl.

The term “aryl”, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, preferably phenyl, and is un-substituted or substituted by one or two substituents, selected from halogen, halogeno-lower alkyl, lower alkyl, lower alkenyl, lower alkynyl, cyano, lower alkylcyano, hydroxy, lower alkoxy, carboxy, carboxyalkyl, amino, carbamoyl, cabamate, ureido, mercapto, sulfo, lower alkysulfinyl, lower alkanesulfonyl, sulfonamide; aryl includes one aromatic ring fused with an aliphatic ring, such as a saturated or partially saturated ring. The term “heterocyclyl” or “heterocyclic”, as used herein, unless otherwise indicated, includes ring contains from about 3 to 12 atoms, preferred 4 to 8 atoms, wherein one or more atoms are selected from 0, N and S, whereas the remain of the ring atoms are carbon. The conception of heterocyclyl maybe a monocyclic, a bicyclic, a spirocyclic or even a bridged ring system. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring which may be aromatic or partially saturated or saturated. A bicyclic or tricyclic ring system may include a carbocyclic ring. Carbocyclic ring includes cycloalkyl, cycloalkenyl or aryl ring. Examples of heterocyclyl groups include but not limited: azetidine, pyrrolidine, pyrrolidione, piperidine, piperidinone, piperazine, morpholine, oxetane, tetrahydrofuran, tetrahydropyran, imidazolidine, pyrazolidine and hydantoin, pyrrole, indole, pyrazole, indazole, trizole, benzotrizole, imidazole, benzoimdazole, thiophene, benzothiophene, thiozole, benzothiozole, furan, benzofuran, oxazole, bezoxazole, isoxazole, tetrazole, pyridine, pyrimidine, trizine, quinoline, isoquinoline, quinazoline, indoline, indolinone, benzotetrahydrofuran, tetrahydroquinoline, tetrahydroisoquinoline, methylene-dioxyphenyl. The heterocyclic and heterocyclic rings may be optionally substituted and substituents selected from the group defined above as substituents for aryl.

This invention also discloses a method of treating a PTK expression related disease or disorder in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I. As used herein, the term “subject” refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human.

Compounds listed in the following examples are able to show inhibition against receptor tyrosine kinases (PTKs). The compounds can be administered to the subjects in the form of free base. It can also be administered in the form of salts, hydrates and/or prodrugs (which will be converted into the active form in vivo).

The compounds in the following examples can be administered to the subjects via various routes. These routes include but not limited to orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, via inhalation, vaginally, intraocularly, via local administration, subcutaneously, intraadiposally, intraarticularly, intraperitoneally or intrathecally. In this described embodiment, the compounds are preferred to be administered orally.

The pharmaceutical compositions feature Formula I or their pharmaceutically acceptable salts suitable for oral administration include, but not limited to tablets, capsules, dusts, granulates, drip pills, pastes, powders and tinctures. The preferred pharmaceutical compositions among them are tablets and capsule.

The following examples are intended to illustrate further certain embodiments of the invention and are not considered to limit the scope of the invention. Any feature, structure, component, material, step, or method that is described and/or illustrated in any embodiment in this specification can be used with or instead of any feature, structure, component, material, step, or method that is described and/or illustrated in any other embodiment in this specification.

The inhibition results to epidermal growth factor receptor (EGFR) mutants including L858R, T790M of example compounds are listed in the table below.

Table 1. Inhibition to epidermal growth factor receptor (EGFR) (L858R, T790M)

*: Inhabitation percentage of enzyme activity (relative to DMSO controls) of each compound at 0.05 pM concentration. The lower percentage, the higher inhibitory activity. The following examples of Formula I, but not limited, can be prepared according to the methods described in Scheme I - Scheme II which are used to provide possible synthetic routes for this series of compounds and in no way to be interpreted as restrictive. These series of compounds might be synthesized from other alternative approaches as well.

Formula I

Scheme I Scheme II

Wherein R, R’, R”, X, Q and Q’ are as defined previously.

The following examples, but not limited, can be prepared according to the chemistry process scope described above in Scheme I - II.

The following abbreviations are used and have the meaning for ease of reference:

EtOH: ethanol, MeOH: methanol, IPA: isopropanol, EtOAc: ethyl acetate, RT: room temperature,

DIPEA: diisopropylethylamine, DCM: di chloromethane, DMF: N,N- dimethylformamide, DMAP: 4- N,N-dimethylaminopyridine, MsCl: methanesulfonyl chloride, THF: tetrahydrofuran, TFA: trifluoroacetic acid, TEA: triethylamine, Pd/C: Palladium on active carbon, EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, CDI: 1,1'-carbonyldiimidazole, DCC: N,N'-dicyclohexylcarbodiimide, HBTU: 2-(1h- benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, BOC: tert- Butyloxycarbonyl protecting group, eq: equivalent, g: gram, mg: milligram, ml: milliliter, min: minutes, mmol: millimolar, bis=di: two or double,

TLC: thin layer chromatography,

Example 1(E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro- 4- methoxyphenyl)-4-(dimethylamino)but-2-enamide

Method A:

The solution of 2,4-dichloropyrimidine (4.0g) and 1H-indole (4.0g, 2.0 eq of pyrimidine) in anhydrous THF (10 mL) was cooled in ice/salt bath and the solution of methyl magnesium bromide (12 mL, 3N in Hexanes) was added dropwise. After the addition was accomplished, the resulting mixture was stirred at room temperature overnight. The resulting mixture was then diluted with ethyl acetate (50 mL) and washed thoroughly with saturated NaHCO ₃ (25mL) and brine (25mL). The organic layer was dried over with anhydrous Na ₂ SO ₄ and concentrated to dryness, yielding yellow solid as 3-(2- chloropyrimidin-4-yl)-1H-indole (4.4 g). Mass: (M + 1), 231.

Method B:

In a 100 mL seal tube was charged with 3-(2-chloropyrimidin-4-yl)-1H-indole (4.0 g, 17 mmol), 4-fluoro-2-methoxy-5-nitroaniline (4.8 g, 26 mmol), methanesulfonic acid (0.9 mL) and isopropanol (15 mL). The resulting mixture was stirred at 120 °C for 10 hours and TLC indicated that no starting material 3-(2-chloropyrimidin-4-yl)-1H-indole remained. This reaction was ceased at this point. The resulting mixture was condensed and diluted with ethyl acetate (250 mL). The organic layer was thoroughly washed with HC1 (1M, 50 mL x 3), brine (50 mL) and dried over with anhydrous Na ₂ SO ₄ . After concentrated to dryness, yellow sold was obtained as crude product N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H- indol-3-yl)pyrimidin-2-amine (~ 4g). Mass: (M + 1), 380.

Method C:

The N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimi din-2-amine (580 mg, 1.50 mmol) was dissolved in a mixing solvent of MeOH and DCM (20 mL, 1 : 1 ratio). This solution was cooled with ice bath and well stirred. Zinc powder (400 mg, 6.25 mmol, 5.0 eq) and ammonium formate (400 mg, 6.25 mmol, 5.0 eq) were added in sequence. The reaction progress was monitored with TLC and it was indicated to be accomplished within half an hour. The resulting solution was worked up with sat NaHCO ₃ solution (20 mL) and brine (20 mL). After being dried with anhydrous Na ₂ SO ₄ , the solution was allowed to pass through celite to remove the high polarity impurities at the baseline of TLC. Hereby, the solvent was removed by rotary evaporation and yielding sticky brown solid (450 mg) as crude product. Further purification could be accomplished with column chromatography (eluent: hexanes to Hexanes: EtOAc = 2:1), giving tan colored solid as product N ¹ -(4-(1H- indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxybenzene- 1,3 -diamine (340 mg). Mass: (M + 1), 350.

In large scale reaction, the purification of N ¹ -(4-(1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6- methoxybenzene- 1,3 -diamine can be accomplished by following this protocol: the crude product was dissolved into minimum amount of DMF (0.5 mL in this case) and the solution was added into large amount of water (10 mL in this case) to precipitate the product. Suction filtration was applied to isolate the product and it was dried by running air. A second purification might be necessary if the purity did not meet the criteria.

Method D:

In a 50 mL round bottom flask was charged with 4-bromo crotonic acid (500 mg, 3,0 mmol), THF (3 mL) and anhydrous DMF (180 μL). The mixture was cooled in ice bath and oxalyl chloride (260 μL, 1.0 eq of acid) was added dropwise. Large amount of air bubbles were formed during the addition. The resulting mixture was stirred in ice bath for half an hour and then at room temperature for another half an hour to achieve a bright yellow solution. The excess amount of oxalyl chloride was removed by rotary evaporation and extracted with toluene (~ ImL), yielding yellow oil as crude acidic chloride, which was diluted with anhydrous THF and kept aside for further reactions.

On the other side, N ¹ -(4-(1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxyb enzene-1,3- diamine (500 mg, 1.2 mmol) and potassium carbonate (400 mg, 3.0 mmol) were dissolved into a mixing solvent of THF:H ₂ O (5 mL: 2.5 mL). The solution was cooled in ice bath and the pre-prepared acidic chloride solution in THF was added dropwised until TLC indicated no amine remained.

The resulting mixture was diluted with DCM (20 mL). After being worked up with sat NaHCO ₃ (~ 10 mL) and brine (~ 10mL), the organic layer was dried over with anhydrous Na ₂ SO ₄ and allowed to pass through silica gel plug to remove the high polarity impurities at the baseline of TLC. Removal of the solvent by rotary evaporation yielded 500 mg crude product as brown solid. Further purification could be accomplished with column chromatography (Eluent: hexanes to Hexanes: EtOAc = 1 :2), giving tan colored solid (250 mg) as product (E)-4-bromo-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2- fluoro-4- methoxyphenyl)but-2-enamide. Mass: (M + 1), 497,

Method E:

(E)-4-bromo-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino) -2-fluoro-4- methoxyphenyl)but-2-enamide (1.0 g, 2.0 mmol) was dissolved in DMF (1.0 mL). N,N- dimethyl amine hydrochloride (500 mg, 6.0 mmol, 3.0 eq) and A,N-diisopropylethylamine (1.1 mL, 6.0 mmol, 3.0 eq) were added in sequence and the resulting mixture was stirred at room temperature overnight. Meanwhile, TLC analysis indicated the starting material was completely consumed. Large amount of water (mL) was added inside to precipice the product. Filtration was applied to isolate the crude product as tan solid (1.0 g). Further purification could be accomplished with column chromatography (eluent: DCM to 10% MeOH in DCM), giving tan colored solid (400 mg) as desired product (E)-N-(5-((4-(1H- indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4 -(dimethylamino)but-2- enamide.

At this stage, the purity of the product varies from 95% - 99%. A second purification could be done by a recrystallization from EtOH (260 mg pure product in this case, >99% HPLC purity).

Mass: (M + 1), 461.

Due to the limitation of length and space, only the full preparation procedures of (E)-N-(5- ((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyp henyl)-4- (dimethylamino)but-2-enamide was disclosed in details in Examples 1. Other compounds can be prepared via similar approach, by changing particular chemicals in specific steps, which will be shown in the following examples, respectively. About Protection Groups

It is worthwhile to mention that in some special scenario the protection of reactive function groups may be necessary to achieve some of the abovementioned reactions. In general, the need for such protecting groups will be obvious to those skilled in the field of organic synthesis as well as the conditions for addition and/or removal of such groups.

Example 2 (E)-4- (dimethylamino)-N-(2-fluoro-4-methoxy-5-((4-(1-methyl-1H-ind ol-3- yl)pyrimidin-2-yl)amino)phenyl)but-2-enamide

This compound was similarly prepared following Example 1 by substituting 1 -methyl-1H- indole for 1H-indole in Method A. Mass: (M + 1), 475.

Example 3 (E)-N-(5-((4-(1H-indol-3-yl)-5-methylpyrimidin-2-yl)amino)-2 -fluoro-4- methoxyphenyl)-4-(dimethylamino)but-2-enamide

This compound was prepared following Example 1, by substituting 2,4-dichloro-5- methylpyrimidine for 2,4-dichloropyrimidine for in Method A. Mass: (M + 1), 445.

Example 4 (E)-N-(5-((4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)-2- fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide

This compound was similarly prepared following Example 1, by substituting 2,4-dichloro- 5-(trifluoromethyl)pyrimidine for 2,4-dichloropyrimidine in Method A. Mass: (M + 1), 529. Example 5 (E)-4- (dimethylamino)-N-(2-fhroro-5-((5-fluoro-4-(1H-indol-3-yl)py rimidin-2- yl)amino)-4-methoxyphenyl)but-2-enamide

This compound was similarly prepared following Example 1, by substituting 2,4-dichloro- 5-fluoropyrimidine for 2,4-dichloropyrimidine in Method A. Mass: (M + 1), 479.

Example 6 (E)-N-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2 -fluoro-4- methoxyphenyl)-4-(dimethylamino)but-2-enamide

This compound was similarly prepared following Example 1, by substituting 2,4,5- tri chloropyrimidine for 5- 2,4-dichloropyrimidine in Method A. Mass: (M + 1), 495.

Example 7 (E)-N-(5-((5-bromo-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2- fluoro-4- methoxyphenyl)-4-(dimethylamino)but-2-enamide

This compound was similarly prepared following Example 1, by substituting 5-bromo-2,4- dichloropyrimidine for 2,4-dichloropyrimidine in Method A. Mass: (M + 1), 495. Example 8 (E)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol- 3- yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobut-2-enamide

This compound was similarly prepared following Example 1 by substituting 1 -methyl-1H- indole for 1H- indole in Method A, with an addition of a S _N Ar step with dimethylamine before the reduction step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 542.

Typical Method of S _N _Ar reaction

A seal tube was charged with N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H- indol-3-yl)pyrimidin-2-amine (300 mg, 0.75 mmol, 1.0 eq), dimethylamine hydrochloric acid salt (600 mg, 10 eq), K ₂ CO ₃ (1.0 g, 10 eq) and acetonitrile (20 mL). The resulting mixture was stirred at about 75-80 °C for 12 hours. The resulting mixture was filtered and the filtrate was diluted with DCM (20 mL). After worked up with brine (10 mL), the organic layer was dried over anhydrous Na ₂ SO ₄ and condensed. Column chromatography give brown solid (200 mg) as desired product 2-methoxy-N ⁴ ,N ⁴ -dimethyl-N ¹ -(4-(1-methyl- 177-indol-3-yl)pyrimidin-2-yl)-5-nitrobenzene-l,4-diamine.

Example 9 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2,4-dimeth oxyphenyl)-4- (dimethylamino)but-2-enamide

This compound was similarly prepared following Example 1 by substituting 2,4- dimethoxy-5 -nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 473.

Example 10 (E)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-y l)amino)-2- (methylamino)phenyl)-4-morpholinobut-2-enamide

This compound was similarly prepared following Example 1 by substituting 1 -methyl-1H- indole for1H- indole in Method A, with an addition of a S _N Ar step with methylamine before the reduction step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 528. Example 11 (E)-4-(dimethylamino)-N-(4-methoxy-5-((4-(1-methyl-1H-indol- 3- yl)pyrimidin-2-yl)amino)-2-(methylamino)phenyl)but-2-enamide

This compound was similarly prepared following Example 1 by substituting 1 -methyl-1H- indole for 1H-indol in Method A, with an addition of a S _N Ar step with methylamine before the reduction step (Method C). Mass: (M + 1), 486.

Example 12 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy- 2- (methylamino)phenyl)-4-(dimethylamino)but-2-enamide

This compound was similarly prepared following Example 1 with an addition of a S _N Ar step with methylamine before the reduction step (Method C). Mass: (M + 1), 472,

Example 13 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)a mino)-2,4- dimethoxyphenyl)-4-(dimethylamino)but-2-enamide

This compound was similarly prepared following Example 9 by substituting 7-azaindole for 1H-indol in Method A. Mass: (M + 1), 474.

Example 14 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)a mino)-4- methoxy-2-methylphenyl)-4-(dimethylamino)but-2-enamide

This compound was similarly prepared following Example 13 by substituting 2-methoxy- 4-methyl-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 458.

Example 15 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)a mino)-2-chloro-

4-methoxyphenyl)-4-(dimethylamino)but-2-enamide

This compound was similarly prepared following Example 13 by substituting 4-chloro-2- m ethoxy-5 -nitroaniline for 4-fluoro-2-methoxy-5 -nitroaniline in Method B. Mass: (M + 1), 478.

Example 16 (E)-N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)a mino)-4- methoxyphenyl)-4-(dimethylamino)but-2-enamide

This compound was similarly prepared following Example 13 by substituting 2-methoxy-

5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 444.

Example 17 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy- 2- methylphenyl)-4-(dimethylamino)but-2-enamide This compound was similarly prepared following Example 1 by substituting 2-methoxy-4- methyl-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 457.

Example 18(E)- 4-(dimethylamino)-N-(4-methoxy-2-methyl-5-((4-( 1 -methyl-1H-indol -3 - yl)pyrimidin-2-yl)amino)phenyl)but-2-enamide

This compound was similarly prepared following Example 17 by substituting 1-methyl-1H-indol for 1H-indol in Method A. Mass: (M + 1), 471.

Example 19 (E)-4-(dimethylamino)-N-(4-methoxy-3-((4-(1-methyl-1H-indol- 3- yl)pyrimidin-2-yl)amino)phenyl)but-2-enamide

This compound was prepared following Example 8 by substituting 2-methoxy-5- nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 457.

Example 20 (E)-N-(3-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyp henyl)-4- (dimethylamino)but-2-enamide

This compound was similarly prepared following Example 1 by substituting 2-methoxy-5- nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 443.

Example 21 (E)-N-(2-chloro-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)-4-(dimethylamino)but-2-enamide

This compound was prepared following Example 19, by substituting 4-chloro-5- nitroaniline for 2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 491.

Example 22 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-chloro-4 - methoxyphenyl)-4-(dimethylamino)but-2-enamide

This compound was similarly prepared following Example 1 by substituting 4-chloro-2- m ethoxy-5 -nitroaniline for 4-fluoro-2-methoxy-5 -nitroaniline in Method B. Mass: (M + 1), 477.

Example 23 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethy lamino)-4- methoxyphenyl)-4-(piperazin-1-yl)but-2-enamide

This compound was similarly prepared following Example 1, with an addition of a S _N Ar step with dimethylamine before the reduction step (Method C) and substituting piperazine for dimethylamine in Method E. Mass: (M + 1), 527.

Example 24 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy- 2- morpholinophenyl)-4-morpholinobut-2-enamide This compound was similarly prepared following Example 1, with an addition of a S _N Ar step with morpholine before the reduction step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 570.

Example 25(E)- N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)am ino)-2- morpholinophenyl)-4-morpholinobut-2-enamide

This compound was similarly prepared following Example 1 by substituting 1 -methyl-1H- indole for 1H-indole in Method A, with an addition of a S _N Ar step with morpholine before the reduction step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 584.

Example 26(E)- N-(5-((4-(1H-pyrrolo[2,3-/]pyridin-1-yl)pyrimidin-2-yl)amino )-4- methoxy-2-(methylamino)phenyl)-4-morpholinobut-2-enamide

This compound was similarly prepared following Example 1 by substituting 7-azaindole for1H- indole in Method A, with an addition of a S _N Ar step with methylamine before the reduction step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 515.

Example 27 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy- 2- (methylamino)phenyl)-4-morpholinobut-2-enamide

This compound was similarly prepared following Example 1, with an addition of a S _N Ar step with methylamine before the reduction step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 514.

Example 28 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethy lamino)-4- methoxyphenyl)-4-(piperidin- 1 -yl)but-2-enamide

This compound was similarly prepared following Example 1, with an addition of a S _N Ar step with dimethylamine before the reduction step (Method C) and substituting piperidine for dimethylamine in Method E. Mass: (M + 1), 526.

Example 29 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethy lamino)-4- methoxyphenyl)-4-(4-methylpiperazin-1-yl)but-2-enamide

This compound was similarly prepared following Example 1, with an addition of a S _N Ar step with dimethylamine before the reduction step (Method C) and substituting 1- methylpiperazine for dimethylamine in Method E. Mass: (M + 1), 541. Example 30 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethy lamino)-4- methoxyphenyl)-4-morpholinobut-2-enamide

This compound was similarly prepared following Example 1, with an addition of a S _N Ar step with dimethylamine before the reduction step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 528.

Example 31 (E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3 - yl)pyrimidin-2-yl)amino)phenyl)-4-(piperidin-1-yl)but-2-enam ide

This compound was similarly prepared following Example 1 by substituting 1-methyl-1H- indole for 1H-indole in Method A with an addition of a S _N Ar step with diethylamine before the reduction step (Method C) and substituting piperidine for dimethylamine in Method E. Mass: (M + 1), 568.

Example 32 (E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3 - yl)pyrimidin-2-yl)amino)phenyl)-4-(4-methylpiperazin-1-yl)bu t-2-enamide

This compound was similarly prepared following Example 1 by substituting 1-methyl-1H- indole for 1H-indole in Method A with an addition of a S _N Ar step with diethylamine before the reduction step (Method C) and substuting 1 -methylpiperazine for dimethylamine in Method E. Mass: (M + 1), 583.

Example 33 (E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3 - yl)pyrimidin-2-yl)amino)phenyl)-4-(piperazin-1-yl)but-2-enam ide

This compound was similarly prepared following Example 1 by substituting 1-methyl-1H- indole for 1H-indole in Method A with an addition of a S _N Ar step with diethylamine before the reduction step (Method C) and substituting piperazine for dimethylamine in Method E. Mass: (M + 1), 569.

Example 34(E)- N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)phenyl)-4-(pyrrolidin-1-yl)but-2-ena mide

This compound was prepared following Example 1 by substituting 1 -methyl- IH-indole for ///-indole in Method A with an addition of a S _N Ar step with diethylamine before the reduction step (Method C) and substituting pyrrolidine for dimethylamine in Method E. Mass: (M + 1), 554.

Example 35 (E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3 - yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobut-2-enamide This compound was similarly prepared following Example 1 by substituting 1-methyl-1H- indole for 1H-indole in Method A with an addition of a S _N Ar step with diethylamine before the reduction step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 570.

Example 36 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)a mino)-2- (dimethylamino)-4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)b ut-2-enamide

This compound was similarly prepared following Example 29 by substituting 7-azaindole for1H- indole in Method A. Mass: (M + 1), 542.

Example 37 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)a mino)-2- (dimethylamino)-4-methoxyphenyl)-4-(piperazin-1-yl)but-2-ena mide

This compound was similarly prepared following Example 23 by substituting 7-azaindole for1H- indole in Method A. Mass: (M + 1), 528.

Example 38 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)a mino)-2- (dimethylamino)-4-methoxyphenyl)-4-(pyrrolidin-1-yl)but-2-en amide

This compound was similarly prepared following Example 34, by substituting 7-azaindole for1H- indole in Method A and substituting dimethylamine for di ethylamine to in Method E. Mass: (M + 1), 513.

Example 39 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)a mino)-2- (dimethylamino)-4-methoxyphenyl)-4-morpholinobut-2-enamide

This compound was similarly prepared following Example 30 by substituting 7-azaindole for1H- indole in Method A. Mass: (M + 1), 529.

Example 40 (E)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol- 3- yl)pyrimidin-2-yl)amino)phenyl)-4-(4-methylpiperazin-1-yl)bu t-2-enamide

This compound was similarly prepared following Example 29 by substituting 1-methyl- IH-indole for 1H-indole in Method A. Mass: (M + 1), 555.

Example 41 (E)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol- 3- yl)pyrimidin-2-yl)amino)phenyl)-4-(piperazin-1-yl)but-2-enam ide

This compound was similarly prepared following Example 23 by substituting 1-methyl- IH-indole for 1H-indole in Method A. Mass: (M + 1), 541.

Example 42 (E)-N-(2-((2-hydroxyethyl)amino)-4-methoxy-5-((4-( 1 -methyl- 1H-indol-3 - yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobut-2-enamide This compound was similarly prepared following Example 35, with an addition of a S _N Ar step with 2-aminoethanol before the reduction step (Method C). Mass: (M + 1), 558.

Example 43 (E)-N-(2-((2-hydroxyethyl)amino)-4-methoxy-5-((4-( 1 -methyl-1H-indol -3 - yl)pyrimidin-2-yl)amino)phenyl)-4-(pyrrolidin-1-yl)but-2-ena mide

This compound was similarly prepared following Example 34, with an addition of a S _N Ar step with 2-aminoethanol before the reduction step (Method C). Mass: (M + 1), 542.

Example 44 (E)- 4-(dimethylamino)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-me thyl- 1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)but-2-enamide

This compound was similarly prepared following Example 1 by substituting 1-methyl-1H- indole for1H- indole in Method A with an addition of a S _N Ar step with dimethylamine before the reduction step (Method C). Mass: (M + 1), 500.

Example 45 (E)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol- 3- yl)pyrimidin-2-yl)amino)phenyl)-4-(pyrrolidin-1-yl)but-2-ena mide

This compound was similarly prepared following Example 44 by substituting pyrrolidine for dimethylamine in Method E. Mass: (M + 1), 526.

Example 46(E)- N-(2,4-dimethoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)-4-(dimethylamino)but-2-enamide

This compound was similarly prepared following Example 1, by substituting 1 -methyl-1H- indole for1H- indole in Method A and substituting 2,4-dimethoxy-5-nitroaniline for 4- fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 487.

Example 47 (E)-N-(2-fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyri midin-2- yl)amino)phenyl)-4-morpholinobut-2-enamide

This compound was similarly prepared following Example 1 by substituting 1 -methyl-1H- indole for1H- indole in Method A and by substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 517.

Example 48 (E)-N-(2-fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyri midin-2- yl)amino)phenyl)-4-(pyrrolidin-1-yl)but-2-enamide

This compound was similarly prepared following Example 1 by substituting 1 -methyl-1H- indole for1H- indole in Method A and by substituting pyrrolidine for dimethylamine in Method E. Mass: (M + 1), 501. Example 49 2-((5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl) pyrimidin-2- yl)amino)-2-(pyridin-2-ylamino)phenyl)amino)ethan-1-ol

This compound was similarly prepared following Example 43, with substitution of 1- methyl-1H-pyrrolo[2,3-b]pyridine for 1 -methyl- 1H-indole and changing Method D to a pyridine displacement approach with 2-chloropyridine. Mass: (M + 1), 483.

Method of pyridine displacement via Buchwald reaction

2-((2-amino-5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]py ridin-3-yl)pyrimidin-2- yl)amino)phenyl)amino)ethyl benzoate (100 mg, 0.22 mmol, 1.0 eq), 2-chloropyridine (25 mg, 1.0 eq), K ₃ PO ₄ (140 mg, 3.0 eq), Pd ₂ (dba) ₃ (10 mg, -10% wt) and BINAP (10 mg, -10% wt) were added into Toluene (2 mL). The resulting mixture was flushed via nitrogen and heated at about 110 °C in a seal tube for 12 hours. The reaction was ceased at this time and the resulting mixture was worked up with sat NaHCO ₃ (5 mL) solution and brine (5 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. Prep-TLC gave off yellow solid as desire product (55 mg, 48 % yield).

Example 50 N-(2-((2-hydroxyethyl)(methyl)amino)-4-methoxy-5-((4-(1 -methyl- 1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acryl amide

This compound was similarly prepared following Example 8, by substituting 1 -methyl-1H- pyrrolo[2,3-b]pyridine for 1 -methyl-1H-indole in Method A altogether with the substitution of 2-(methylamino)ethan-1-ol for dimethylamine in the S^Ar step. The following steps were applied as well to get access to the final product. Mass: (M + 1), 473.

Typical Method of EDC esterification reaction:

A round bottom flask was charged with 2-((5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3- b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-nitrophenyl)(methyl)a mino)ethan-1-ol (450 mg, 1.0 mmol), benzoic acid (145 mg, 1.2 mmol, 1.2 eq.), EDC hydrochloride (290 mg, 1.5 mmol, 1.5 eq), 4-dimethylaminopyridine (12 mg, 0.1 mmol, 0.1 eq), and DCM (10 mL). The resulting mixture was stirred at room temperature overnight (~ 12 hours) and TLC analysis indicated that the starting material 2-((5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl) pyrimidin-2-yl)amino)-2-nitrophenyl)(methyl)amino)ethan-1-ol was completely consumed. The reaction was ceased at this time and the resulting mixture was worked up with sat NaHCO ₃ (5 mL) solution and brine (5 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. Column chromatography gave off white solid as desire product (390 mg, 0.7 mmol, 70 % yield).

*DCC, CDI or HBTU can be used as coupling reagent instead of EDC hydrochloride in some scenario.

Zinc reduction:

The reduction procedure was performed similarly as described in Method C of Example 1. Starting with 2-((5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl) pyrimidin-2- yl)amino)-2-nitrophenyl)(methyl)amino)ethyl benzoate (280 mg, 0.5 mmol) to get desired product 2-((2-amino-5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyrid in-3-yl)pyrimidin- 2-yl)amino)phenyl)(methyl)amino)ethyl benzoate (200 mg, 0.38 mmol, 76 % yield). Typical Method of EDC coupling reaction for amide formation:

The starting material acrylic acid (20 mg, ~1.1 eq) and HOBt hydrate (32 mg, -1.0 eq) were added into DCM (2 mL). Meanwhile, EDC hydrochloride (70 mg, ~1.5 eq) was added and followed by the starting material 2-((2-amino-5-methoxy-4-((4-(1 -methyl- 1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)(meth yl)amino)ethyl benzoate (130 mg, 0.25 mmol, 1.0 eq). The resulting mixture was stirred overnight until the starting material amine completely consumed from TLC analysis. The reaction was ceased at this time and the resulting mixture was worked up with sat NaHCCE (5 mL) solution and brine (5 mL). The organic layer was dried over anhydrous Na ₂ SO4 and concentrated to dryness. Prep-TLC gave off white solid as desire product (82 mg, 0.14 mmol, 56 % yield).

The starting material 2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3- b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)eth yl benzoate (30 mg, 0.05 mmol) was dissolved in a mixing solvent of methanol:H ₂ O (0.9 mL:0.1 mL). Meanwhile, LiOH (2.5 mg, 2.0 eq) was added in the solution and stirred under room temperature for 2 hours. TLC analysis indicated the reaction was accomplished and the resulting mixture was condensed to dryness. The residue was dissolved in DCM (5mL) and worked up with sat NH ₄ Cl (5 mL) solution and brine (5 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. Prep-TLC gave off white solid as desire product (15 mg, 0.03 mmol, 60 % yield).

Example 51 N-(2-((2-hydroxyethyl)amino)-4-methoxy-5-((4-(1-methyl-1H-in dol-3- yl)pyrimidin-2-yl)amino)phenyl)acrylamide

This compound was similarly prepared following Example 42, by changing Method D to a EDC catalyzed coupling reaction with acrylic acid. Mass: (M + 1), 459.

Example 52 N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ⁴ -(4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)-N ² -(pyrimidin-4-yl)benzene-1,2,4-triamine

This compound was similarly prepared following Example 48, with an addition of a S _N Ar step with N ¹ ,N ¹ -dimethylethane- 1,2-diamine before the reduction step (Method C) and changing Method D to a Buchwald approach with a 4-chloropyrimidine. Mass: (M + 1), 510.

Example 53 2-((5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)a mino)-2- (pyridin-2-ylamino)phenyl)amino)ethan- 1 -ol

This compound was similarly prepared following Example 42 by changing Method D to Buchwald approach with a 2-chloropyridine. Mass: (M + 1), 482.

Example 54 N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methyl -N ⁴ -(4-(1-methyl-1H- indol-3-yl)pyrimidin-2-yl) -N ² -(pyridin-2-yl)benzene-1,2,4-triamine

This compound was similarly prepared following Example 43, with an addition of a S _N Ar step with N ¹ ,N ¹ -dimethylethane- 1,2-diamine before the reduction step (Method C) and changing Method D to a Buchwald approach with 4-chloropyrimidine. Mass: (M + 1), 523. Example 55 2-((4-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amin o)-5-methoxy- 2-(pyrimidin-4-ylamino)phenyl)amino)ethan-1-ol

This compound was similarly prepared following Example 49 by substituting 7-azaindole for 1 -methyl- 1H-indole in Method A. Mass: (M + 1), 470.

Example 56 2-((4-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-( pyrimidin-4- ylamino)phenyl)amino)ethan- 1 -ol

This compound was similarly prepared following Example 49 by substituting 1H-indol for 1 -methyl-1H-indole in Method A. Mass: (M + 1), 469.

Example 57 2-((4-((4-(5-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)am ino)-5- methoxy-2-(pyrimidin-4-ylamino)phenyl)amino)ethan-1-ol This compound was similarly prepared following Example 49 by substituting 5-fluoro-1- m ethyl- 1H-indole for 1 -methyl-1H-indole in Method A. Mass: (M + 1), 501.

Example 58 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(5-fluoro -l -methyl-1H- indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)but-2-ynami de

This compound was similarly prepared following Example 54 by substituting 5-fluoro-1- m ethyl- 1H-indole for 1 -methyl- 1H-indole in Method A, and changing Method D to an EDC catalyzed coupling reaction with but-2-ynoic acid. Mass: (M + 1), 530.

Example 59 (E)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(5-fl uoro-1-methyl- 1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)but-2-en amide

This compound was similarly prepared similar following Example 58 by changing Method D to a EDC catalyzed coupling reaction with crotonic acid. Mass: (M + 1), 532.

Example 60 2-((5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)a mino)-2- (pyrimidin-4-ylamino)phenyl)amino)ethan-1-ol

This compound was similarly prepared following Example 53 by changing Method D to Buchwald approach with a 4-chloropyrimidine. Mass: (M + 1),483.

Example 61 (E)-N-(5-((4-(5-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl )amino)-2-((2- hydroxyethyl)(methyl)amino)-4-methoxyphenyl)but-2-enamide

This compound was similarly prepared following Example 59 by substituting 2- (methylamino)ethan-1-ol instead for N ¹ , N ¹ -dimethylethane- 1,2-diamine as S _N Ar reaction reagent before the reduction step (Method C). Mass: (M + 1), 504.

Example 62 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)a mino)-2-fluoro- 4-methoxyphenyl)-4-morpholinobut-2-enamide

This compound was similarly prepared following Example 1 by substituting 7-azaindole for1H- indole in Method A and substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 504.

Example 63(E)- N-(5-((4-(1H-pyrrolo[2,3-/»]pyridin-1-yl)pyrimidin-2-yl)ami no)-2-chloro- 4-methoxyphenyl)-4-morpholinobut-2-enamide

This compound was similarly prepared following Example 62 by substituting 4-chloro-2- m ethoxy-5 -nitroaniline for 4-fluoro-2-methoxy-5 -nitroaniline in Method B. Mass: (M + 1), 520. Example 64(E)-N-( 5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4 - methoxy-2-methylphenyl)-4-morpholinobut-2-enamide

This compound was similarly prepared following Example 62 by substituting 2-methoxy-

4-methyl-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 500.

Example 65(E)-N-( 3-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4 - methoxyphenyl)-4-morpholinobut-2-enamide

This compound was similarly prepared following Example 62 by substituting 2-methoxy -

5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 486, Example 66 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)a mino)-2-fluoro- 4-methoxyphenyl)-4-(piperidin-1-yl)but-2-enamide

This compound was similarly prepared following Example 62 by substituting piperidine for morpholine in Method E. Mass: (M + 1), 502.

Example 67 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)a mino)-2-chloro- 4-methoxyphenyl)-4-(piperidin-1-yl)but-2-enamide

This compound was similarly prepared following Example 63 by substituting piperidine for morpholine in Method E. Mass: (M + 1), 519.

Example 68 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)a mino)-4- methoxy-2-methylphenyl)-4-(piperidin- 1 -yl)but-2-enamide

This compound was similarly prepared following Example 64 by substituting piperidine for morpholine in Method E. Mass: (M + 1), 498.

Example 69(E)-N-( 3-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4 - methoxyphenyl)-4-(piperidin- 1 -yl)but-2-enamide

This compound was similarly prepared following Example 65 by substituting piperidine for morpholine in Method E. Mass: (M + 1), 484.

Example 70 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)a mino)-2,4- dimethoxyphenyl)-4-(piperidin-1-yl)but-2-enamide

This compound was similarly prepared following Example 66 by substituting 2,4- dimethoxy-5 -nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 514. Example 71 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)a mino)-2-fluoro- 4-methoxyphenyl)-4-(dimethylamino)but-2-enamide

This compound was similarly prepared following Example 62 by substituting dimethylamine for morpholine in Method E. Mass: (M + 1), 462.

Example 72(E)-N-( 5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2 ,4- dimethoxyphenyl)-4-morpholinobut-2-enamide

This compound was similarly prepared following Example 62 by substituting by substituting 2,4-dimethoxy-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 517.

Example 73 (E)-N-(5- ((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4- methoxy-2-(methylamino)phenyl)-4-(dimethylamino)but-2-enamid e

This compound was similarly prepared following Example 71 by adding addition a S _N Ar winh methylamine before the reduction step (Method C). Mass: (M + 1), 473.

Example 74(E)-N-( 5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4 - methoxy-2-(methylamino)phenyl)-4-(piperidin-1-yl)but-2-enami de

This compound was similarly prepared following Example 66 by adding addition a S _N Ar step with methylamine before the reduction step (Method C). Mass: (M + 1), 514.

Example 75 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)a mino)-4- methoxy-2-(methylamino)phenyl)-4-(7-hydroxy-5-azaspiro[2.4]h eptan-5-yl)but-2-enamide This compound was similarly prepared following Example 73 by substituting 5- azaspiro[2.4]heptan-7-ol for dimethylamineine Method E. Mass: (M + 1), 542.

Example 76(E)-N-( 5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2 - (dimethylamino)-4-methoxyphenyl)-4-(dimethylamino)but-2-enam ide

This compound was similarly prepared following Example 71 by adding addition a S _N Ar step with dimethylamine before the reduction step (Method C). Mass: (M + 1), 488.

Example 77(E)-N-( 5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2 - (dimethylamino)-4-methoxyphenyl)-4-(piperidin-1-yl)but-2-ena mide

This compound was similarly prepared following Example 76 substituting piperidine for dimethylamineine Method E. Mass: (M + 1), 528.

Example 78(E)-N-( 5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2 -amino- 4-methoxyphenyl)-4-morpholinobut-2-enamide This compound was similarly prepared following Example 62 by adding addition a S _N Ar step with ammonium before the reduction step (Method C) and the -NH ₂ group was then protected via -Boc. Other steps were accomplished via routine protocol and the -Boc group was removed with an additional step with TFA after Method E. Mass: (M + 1), 502.

Example 79 (E)-N-(5-((5-cyano-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl) amino)-2- fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide

This compound was similarly prepared following Example 2 by substituting 2,4- dichloropyrimidine for 2,4-dichloropyrimidine-5-carbonitrile. Mass: (M+l), 500.

Example 80 (E)-2-((5-(4-(dimethylamino)but-2-enamido)-4-fluoro-2- methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5- carboxylic acid

This compound was similarly prepared following Example 79 by with a subsequently acid hydrolysis process. Mass: (M+l), 519.

Example 81 ethyl (E)-2-((5-(4-(dimethylamino)but-2-enamido)-4-fluoro-2- methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5- carboxylate

This compound was similarly prepared following Example 80 by a subsequently EDC esterification process with ethanol. Mass: (M+l), 547.

Example 82 (E)-N-(5-((5-cyano-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2- fluoro-4- methoxyphenyl)-4-(dimethylamino)but-2-enamide

This compound was prepared following Example 1, by substituting 2,4-dichloro-5- methylpyrimidine for 2,4-dichloropyrimidine-5-carbonitrile in Method A. Mass: (M + 1), 486.

Example 83 (E)-2-((5-(4-(dimethylamino)but-2-enamido)-4-fluoro-2- methoxyphenyl)amino)-4-(1H-indol-3-yl)pyrimidine-5-carboxyli c acid

This compound was similarly prepared following Example 82 by with a subsequently acid hydrolysis process. Mass: (M+l), 505.

Example 84 ethyl (E)-2-((5-(4-(dimethylamino)but-2-enamido)-4-fluoro-2- methoxyphenyl)amino)-4-(1H-indol-3-yl)pyrimidine-5-carboxyla te

This compound was similarly prepared following Example 83 by a subsequently EDC esterification process with ethanol. Mass: (M+l), 533.