Field of the Invention

The present invention relates to 2,3,5-substituted 1/-/-pyrrolo[2,3-b]pyridine compounds of general formula (I) with aromatic 5-membered heterocyclic substituents at position 5 as well as pharmaceutically acceptable salts thereof.

These compounds are used for the treatment or prevention of a disease or medical condition mediated through certain mutated forms of ErbB receptor, especially of Exon20 Her2 and EGFR mutations.

Background of the Invention Receptor tyrosine kinases (RTKs) are cell surface receptors that transmit signals from the extracellular environment to control growth, differentiation and survival of cells. Deregulated expression of protein kinases by gene deletion, -mutation or -amplification has been found to be important for tumor initiation and -progression, involving cancer cell proliferation, -survival, -motility and -invasivity as well tumor angiogenesis and chemotherapy resistance. Because of the advanced understanding of their critical role, protein kinases are important targets for novel therapies, especially for cancer.

In humans the receptor tyrosine kinase family ErbB comprises four members: EGFR (Fieri), ErbB2 (Her2), ErbB3 (Fler3) and ErbB4 (Fler4). The binding of a ligand induces conformational change in receptors to form homo- and heterodimerization. The extracellular domain of Fler2 is already fixed in a conformation without ligand binding that resembles the other ligand-activated ErbB members and hereby acts as a preferred dimerization partner for other ligand-bound ErbBs. The dimerization of receptors activates the intrinsic kinase activity and hereby yielding to the phosphorylation of its substrates, resulting in activation of multiple downstream pathways within the cell, including the anti-apoptotic/survival PI3K-AKT-mTOR and the mitogenic RAS-RAF- MEK-ERK-MAPK pathways (Chong et al. Nature Med. 2013; 19 (11 ): 1389-1400). There is strong precedent for the involvement of ErbB kinase family in human cancer as overexpression and/or mutations of ErbB is commonly found in cancers (for example breast, lung, head, neck and bladder). First generation small molecule EGFR inhibitors like Tarceva (Erlotinib) and Iressa (Gefitinib), both binding reversibly to EGFR, are currently first-line therapy for non-small cell lung cancer patients with tumors harbouring EGFR mutations in exon 19 and 21 (like L858R and delE746-A750). Second and third generation small molecule EGFR inhibitors have been designed as irreversible EGFR inhibitors. These compounds (for example Afatinib, HKI-272, CI-1033, EKB-569, WZ- 4002, AZ9291, CO-1686) bind irreversibly to EGFR, preferably to cysteine 797.

Approximately 10% of patients with NSCLC in the United States are reported to have tumor-associated EGFR mutations (Lynch et al. N Engl J Med. 2004, 350 (21): 2129- 39). The EGFR mutations mostly occur within EGFR Exon 18-21 (Yasuda et al. Sci Transl Med. 2013, 18, 5(216): 216ra177; Leduc et al. Annals of Oncology 2017, 28, 11: 2715-2724; Arcila et al. Mol Cancer Ther. 2013, 12 (2): 220-229). These mutations increase the kinase activity of EGFR, leading to hyperactivation of downstream pro survival signalling pathways (Pao et al. Nat Rev Cancer 2010, 10: 760-774). EGFR Exon 20 insertions reportedly comprise approximately 4-9.2 % of all EGFR mutant lung tumors (Arcila et al. Mol Cancer Ther. 2013, 12 (2): 220-9; Oxnard et al. J Thorac Oncol. 2013, 8(2): 179-184; Yasuda et al. Lancet Oncol. 2012, 13 (1): e23-31). Most EGFR Exon 20 insertions occur in the region encoding amino acids 767 through 774 of exon 20 within the loop that follows the C-helix of the kinase donmain of EGFR. Analysis of patients with tumors harbouring EGFR Exon 20 insertion mutations mostly displayed progressive disease in the course of treatment with Gefitinib, Erlotinib or Afatinib (Yasuda et al. Lancet Oncol. 2012, 13 (1): e23-31; Yasuda et al. Sci Transl Med. 2013, 18, 5(216): 216ra177).

Her2 mutations are reportedly present in ~2-4% of NSCLC (Buttitta et al. Int J Cancer. 2006, 119: 2586-2591). The most common mutation is an in-frame insertion within Exon 20. In 83% of patients having Her2 associated NSCLC, a four amino acid YVMA insertion mutation occurs at codon 775 in Exon 20 of Her2 (Arcila et al. Clin Cancer Res 2012, 18: 4910-4918). The Her2 Exon 20 insertion results in increased kinase activity and enhanced signalling through downstream pathways, resulting in increased survival, invasiveness, and tumorgenicity (Wang et al. Cancer Cell 2006; 10: 25-38). Tumors harbouring the Her2 YVMA mutation are largely resistant to known EGFR inhibitors (Arcila et al. Clin Cancer Res 2012, 18: 4910-4918).

It is the objective of the present invention to provide compounds and pharmaceutic compositions comprising these compounds as mutant-selective ErbB inhibitors, especially for the Exon 20 EGFR/Her2 mutations, which can be used as pharmaceutically active agents, especially for prophylaxis and/or treatment of cell proliferative diseases such as cancer. The present invention provides novel 2,3,5-substituted pyrrolo[2,3-b]pyridines being mutant-selective ErbB inhibitors, especially for the Exon 20 EGFR/Her2 mutations, and additionally being inhibitors for other mutants like EGFR T790ML858R mutation.

Thus, the objective of the present invention is solved by the teachings of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the figures, and the examples of the present application. Description of the invention

The present invention is directed to compounds of the general formula (I)

R ¹ represents

R ² represents -H, -F, -Cl, -Br, -CN, -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -OCH3,

— OC2H5, or — OC3H7; R ³ and R ⁴ represent independently of each other -H, -F, -Cl, -CN, -CF ₃ ,

-OCH3, -OC2H5, -CH2OCH3, -CH _3I -C2H5, or -C3H7;

R ^N represent -H, -CH ₃ , -CF _3, -C ₂ H ₅ , -C ₃ H ₇ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C ₄ H ₉ , -cyclo-CsHs, -cyclo-C H ₇ , -CH ₂ CH ₂ OH, -CH ₂ CH(CH ₃ )OH,

-CH ₂ CH ₂ OCH3, -CH ₂ CH ₂ CH ₂ OH, -CH ₂ CH ₂ CH ₂ OCH3, or -CH ₂ CH ₂ N(CH ₃ ) ₂ ;

R ⁷ represents -H, — CH ₃ , or -C2FI5;

R ⁸ - R ¹¹ represent independently of each other -H, -F, -Cl, -CN, -OCH3,

-OC2H5, -CHs, -CFS, or -C2H5; R ¹² , R ^12* , R ^12** , and R ¹ '* represent independently of each other -H, -CH ₃ , or -C ₂ H ₅ ;

R ¹⁴ , R ¹⁵ , and R ¹⁶ represent independently of each other -H, -CH ₃ , -CF ₃ , -CN,

-NO ₂ , -COCHs, or -COC ₂ H ₅ ; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of diastereomers, a tautomer, a hydrate, a solvate, or pharmaceutically acceptable salts thereof.

Preferred are compounds of general formula (I) wherein B represents and R ¹² , R ^12* , R ^12** , and R ¹³ have the meanings as defined herein.

Also preferred are compounds of general formula (I) wherein A represents Moreover, R ¹ represents preferably N

R ³ , R ⁴ , and R ^IXI have the meanings as defined in Claim 1 .

Furthermore, compounds of general formula (I) are preferred wherein R ⁶ represents More preferred are compounds of general formula (I) wherein A represents

R ² represents -H, -F, -Cl, -Br, -CN, -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -OCH ₃ ,

— OC ₂ H ₅ , or — OC ₃ H ₇ ; R ³ and R ⁴ represent independently of each other -H, -F, -Cl, -CN, -CF ₃ ,

-OCH3, -OC ₂ H5, -CH ₂ OCH3, -CH _3I -C ₂ H5, or -C3H7;

R ^N represent -H, -CH ₃ , -CF _3, -C ₂ H ₅ , -C ₃ H ₇ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C ₄ H ₉ , -cyclo-CsHs, -cyclo-C H ₇ , -CH ₂ CH ₂ OH, -CH ₂ CH(CH ₃ )OH,

-CH ₂ CH ₂ OCH3, -CH ₂ CH ₂ CH ₂ OH, -CH ₂ CH ₂ CH ₂ OCH3, or -CH ₂ CH ₂ N(CH ₃ ) ₂ ;

R ⁶ represents

R ⁷ represents -FI, — CH ₃ , or -C ₂ FI ₅ ;

R ⁸ - R ¹¹ represent independently of each other -FI, -F, -Cl, -CN, -OCFI ₃ , -OC ₂ H5, -CHs, -CFS, or -C ₂ H5;

R ¹² , R ^12* , R ^12** , and R ¹³ represent independently of each other -FI or -CFI ₃ ; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of diastereomers, a tautomer, a hydrate, a solvate, or pharmaceutically acceptable salts thereof.

In regard to all general formula disclosed herein, A represents preferably more preferably and most preferably and R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , and R ¹¹ have the meanings as defined herein.

In regard to all general formula disclosed herein, R ¹ represents preferably and more preferably and R ³ , R ⁴ , and R ^N have the meanings as defined herein.

In regard to all general formula disclosed herein, R ² represents preferably -H, -F, -Cl, -CN, -CH ₃ , -C ₂ H ₅ , -OCH ₃ , or -OC ₂ H ₅ , more preferably -H, -Cl, -CN, -CH ₃ , -C ₂ H ₅ , or -OCH ₃ , still more preferably -H, -Cl, -CH ₃ , -C ₂ H ₅ , or -OCH ₃ , still more preferably -H, -Cl, -CH ₃ , or -OCH ₃ , still more preferably -H, -Cl, or — CH ₃ , still more preferably -H or -CH ₃ , and most preferably -CH _3.

In regard to all general formula disclosed herein, R ³ and R ⁴ preferably represent independently of each other -H, -F, -Cl, -CN, -CF ₃ , -OCFI ₃ , -OC ₂ FI ₅ ,

-OC ₃ H ₇ , -CH ₂ OCH ₃ , -CH _3I -C ₂ H ₅ , or -C ₃ H ₇ , -CH(CH ₃ ) ₂ , -C ₄ H ₉ , -cyclo-C ₃ H ₅ , more preferably -FI, -Cl, -CN, -CF ₃ , -OCFI ₃ , -OC ₂ FI ₅ , — CH ₃ , or — C ₂ H ₅ , still more preferably -FI, -CN, -OCFI ₃ , — CFH ₃ , or -C ₂ FI ₅ , still more preferably -FI, -CN, -OCFI ₃ , or — CFH ₃ , still more preferably -FI, -CN, or — CFH ₃ , and most preferably -FI or — CFH _3.

In regard to all general formula disclosed herein, R ^N represent preferably -FI, — CFH ₃ , -CF _3, -C ₂ H ₅ , -C ₃ H ₇ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C ₄ H ₉ , -cyclo-C ₃ H ₅ ,

-cyclo-C ₄ H ₇ , -CH ₂ CH ₂ OH, -CH ₂ CH(CH ₃ )OH, -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ CH ₂ OH, or -CH ₂ CH ₂ CH ₂ OCH ₃ ; more preferably -H, -CH ₃ , -CF _3, -C ₂ H ₅ , -C ₃ H ₇ ,

-CH(CH ₃ ) ₂ , -cyclo-C ₃ H ₅ , -CH ₂ CH ₂ OH, -CH ₂ CH(CH ₃ )OH, -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ CH ₂ OH, or -CH ₂ CH ₂ CH ₂ OCH ₃ ; still more preferably -H, -CH ₃ , -CF _3,

-C ₂ H ₅ , -C ₃ H ₇ , -CH(CH ₃ ) ₂ , -cyclo-C ₃ H ₅ , -CH ₂ CH ₂ OH, -CH ₂ CH(CH ₃ )OH, or

-CH ₂ CH ₂ OCH _3.

In regard to all general formula disclosed herein, R ⁷ represent preferably -FI or — CFH ₃ , and more preferably -FI.

In regard to all general formula disclosed herein, R ⁸ - R ¹¹ preferably represent independently of each other -FI, -F, -Cl, -CN, -OCFI ₃ , -OC ₂ FI ₅ , -OC ₃ FI ₇ , -CH ₂ OCH ₃ , -CH _3I -CF _3I -C ₂ H ₅ , or -C ₃ H ₇ ; more preferably -H, -F, -CN,

-OCFI ₃ , -OC ₂ FI ₅ , — CH ₃ , or -C ₂ FI ₅ ; still more preferably -FI, -F, or -OCFI ₃ ,

— CFH ₃ ; most preferably — CFH _3.

More preferably R ⁸ represents -FI.

Thus, in regard to all general formula disclosed herein, R ⁹ - R ¹¹ preferably represent independently of each other -FI, -F, -Cl, -CN, -OCFI ₃ , -OC ₂ FI ₅ , -OC ₃ FI ₇ , -CH ₂ OCH ₃ , -CH _3I -CF _3I -C ₂ H ₅ , or -C ₃ H ₇ ; more preferably -H, -F, -CN,

-OCFI ₃ , -OC ₂ FI ₅ , — CH ₃ , or -C ₂ FI ₅ ; still more preferably -FI, -F, or -OCFI ₃ ,

— CFH ₃ ; most preferably — CFH ₃ . More preferably R ⁹ represents -H, -F, -Cl, -CF ₃ , or -CN, and still more preferably -FI or -F.

Thus, in regard to all general formula disclosed herein, R ¹⁰ and R ¹¹ preferably represent independently of each other -FI, -OCFI3, -OC2FI5, -OC3FI7, -CFI2OCFI3, -CFI3, — C2H5, or -C3FI7; more preferably -FI, -OCFI3, -OC2FI5, -CFI3, or -C2FI5; still more preferably -FI, -OCFI3, or -CFI3;

In regard to all general formula disclosed herein, R ¹⁰ represent preferably -CFI2OCFI3, -CFI3, -C2FI5, or -C3FI7; more preferably -CFI3, — C2H5, or -C3FI7; still more preferably -CFI3 or -C2FI5; and most preferably -CFI3.

In regard to all general formula disclosed herein, R ¹⁴ , R ¹⁵ , and R ¹⁶ preferably represent independently of each other -FI, -CFI3, -CF ₃ , -CN, -NO2, or -COCFI3; more preferably other -FI, -CF ₃ , -CN, or -COCFI3; more preferably -FI, -CN, or -COCFI3; more preferably -FI, -COCFI3, and most preferably -FI.

Also preferred are compounds of general formula (I) wherein

A represents

B represents

R ¹ represents R ² represents -H, -Cl, — CH ₃ , — C ₂ H ₅ , -OCFI ₃ ;

R ³ and R ⁴ represent independently of each other -H, -CN, or -CH ₃ ;

R ^N represent -H, — CH ₃ , -CF _3, — C ₂ H ₅ , -CH(CH ₃ ) ₂ , -cyclo-C ₃ H ₅ ,

-CH ₂ CH ₂ OH, -CH ₂ CH(CH ₃ )OH, or -CH ₂ CH ₂ OCH ₃ ;

R ⁶ represents

R ⁷ represents -H or -CH ₃ ;

R ⁸ - R ¹¹ represent independently of each other -H, -F, -OCH ₃ , or -CH ₃ ;

R ¹² , R ^12* , R ^12** , and R ¹³ represent independently of each other -H or -CH ₃ ; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of diastereomers, a tautomer, a hydrate, a solvate, or pharmaceutically acceptable salts thereof.

The present invention provides 2,3,5-substituted 1/-/-pyrrolo[2,3-b]pyridine compounds with an aromatic 5-membered heterocyclic substituent at position 5 which exhibit inhibition of HER2 Exon20 A775_G776insYVMA (and similar mutations) and/or EGFR Exon20 FI773_V774insNPFI (and similar mutations). The present invention provides these compounds as mutant-selective ErbB inhibitors, especially for the Exon20 EGFR/Fler2 mutations, and additionally as inhibitors for other mutants like EGFR T790ML858R mutation. In certain embodiments the current invention is directed towards 2,3,5-substituted 1/-/-pyrrolo[2,3-b]pyridine compounds which are mutant- specific for Exon20 of EGFR and Fler2. In one aspect, the invention provides 2,3,5- substituted 1/-/-pyrrolo[2,3-b]pyridine compounds as irreversible kinase inhibitors. The 2,3,5-substituted 1/-/-pyrrolo[2,3-b]pyridine compounds covalently modify the cysteine 797/805 in EGFR/Her2.

The 2,3,5-substituted 1/-/-pyrrolo[2,3-b]pyridine compounds with an aromatic 5- membered heterocyclic substituent at position 5 and/or the pharmaceutically acceptable salts thereof are used as pharmaceutical active ingredients for the treatment and/or prophylxis of a cell proliferative disease such as cancer.

The cell proliferative disease is selected from breast cancer, colon cancer, prostate cancer, lung cancer, gastric cancer, ovarian cancer, endometrial cancer, renal cancer, hepatocellular cancer, thyroid cancer, uterine cancer, esophagus cancer, squamous cell cancer, leukemia, osteosarcoma, melanoma, glioblastoma and neuroblastoma. In an especially preferred embodiment, the disorders are selected from breast cancer, glioblastoma, renal cancer, non-small cell lung cancer (NSCLC), and melanoma. The compounds are also suitable for the prevention and/or treatment of other hyperproliferative disorders, particulary benign hyperproliferative disorders such as benign prostate hyperplasia.

Especially preferred compounds according to the present invention include compounds presented by Table 1.

Table 1

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of diastereomers, a tautomer, a prodrug, a hydrate, a solvate of the above mentioned compounds, or pharmaceutically acceptable salts thereof.

The expression prodrug is defined as a substance, which is applied in an inactive or significantly less active form. Once applied and incorporated, the prodrug is metabolized in the body in vivo into the active compound. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example in “Design of Prodrugs”, ed. H. B. Bundgaard, Elsevier, 1985.

The present invention also includes within its scope N-oxides of the compounds of formula (I) above. In general, such N-oxides may be formed by conventional means, such as reacting the compound of formula (I) with oxone in the presence of wet alumina.

The expression tautomer is defined as an organic compound that is interconvertible by a chemical reaction called tautomerization. Tautomerization can be catalyzed preferably by bases or acids or other suitable compounds.

The compounds of the present invention may form salts with organic or inorganic acids or bases. Examples of suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic acid, china acid, mandelic acid, o- methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, D-o- tolyltartaric acid, tartronic acid, (o, m, p)-toluic acid, naphthylamine sulfonic acid, trifluoroacetic acid, and other mineral or carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form of the compounds of formula (I) with a sufficient amount of the desired acid to produce a salt in the conventional manner well known to those skilled in the art.

The inventive compounds may exist in a number of different polymorphic forms.

In the case the inventive compounds bear acidic groups, salts could also be formed with inorganic or organic bases. Examples for suitable inorganic or organic bases are, for example, NaOH, KOH, NH ₄ OH, tetraalkylammonium hydroxide, lysine or arginine and the like. Salts may be prepared in a conventional manner using methods well known in the art, for example by treatment of a solution of the compound of the general formula (I) with a solution of an acid, selected out of the group mentioned above.

The inventors found that preferred inhibitors should have a substituent at the 2-position of the phenyl ring next to the warhead. The warhead is most preferably a but-2- enamide. The position 2 on the phenyl ring next to the warhead should be different from hydrogen and is preferably an alkyl or alkylenyl residue such as a methyl group or a fluoro substituent (like in compounds No. 50 - 60) or can be part of a ring system preferably containing the nitrogen atom of the warhead (like in compounds No. 61 - 64). Moreover it was found that an aromatic nitrogen heterocyclic 5-membered ring should be present at position 5 of the pyrrolo[2,3-b]pyridine in order to achieve the desired inhibitory activity. This N-heterocyclic aromatic ring should most preferably contain two nitrogen atoms. The nitrogen atom not attached to the carbon atom linked to the pyrrolo[2,3-b]pyridine moiety should preferably be substituted in order to obtain quite potent inhibitors. Especially preferred is the pyrazol ring and even more preferred a pyrazol-4-yl ring at position 5 of the pyrrolo[2,3-b]pyridine moiety.

Syntheses of the compounds

The compound of formula (I) is prepared by reference to the methods illustrated by the following reaction protocols. The compound of formula (I) is produced as outlined below by the suitable selection of reagents with appropriate substitution. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or readily prepared by one of ordinary skill in the art. Procedure A

The present invention is also directed to a method for producing the compounds of formula (I), the method comprises the following steps in the row as described below:

Step A1: performing a first cross coupling reaction of pyridine compound 1* with alkyne compound 2a* wherein the substituents R ¹ , R ² and R ⁸ - R ¹¹ have the meanings as defined in claim 1 and X is a leaving group and represents Cl, Br, I, or OTf, to obtain a compound 3* in the presence of a first palladium catalyst, and a first base;

Step B1: converting a trimethylsilyl group of the compound 3* to a halide like an iodide to obtain a compound 4*

Step C1: performing a second cross coupling reaction of 4* with a compound 5*

RO

B-B 5 RO wherein R’ is H or an alkyl chain with 1-10 carbon atoms or a cycloalkyl chain with 3 to 12 carbon atoms or both residues R’ represent together a residue derived from pinacol, in the presence of a second palladium catalyst, and a second base to obtain a compound 6* Step D1: reducing nitro (N0 ₂ ) group of the compound 6* to a primary amine (NH ₂ ) group to obtain a compound 7*; and Step E1: performing a coupling reaction of the compound 7* with a compound HO-R ⁶ or AG-R ⁶ , wherein the substituent R ⁶ has the meanings as defined in claim 1 and AG is an activating group of a carboxylic acid, to obtain a product compound of the general formula (I) Thus, Step A (e.g. Step A1 , Step A3 or A4) comprises performing the Sonogashira reaction followed by cyclisation with, for instance, Pd°, (Cul), base and enhanced temperature. The iodination in Step B (e.g. Step B1 , Step B2, Step B3 or B4) is carried out by means of NIS (N-iodosuccinimide) and Step C (e.g. Step C1, Step C2, Step C3 or C4) is a Suzuki-coupling with compound 5* Pd°, base and enhanced temperature. Reduction of the nitro group to the amino group in Step D (e.g. Step D1 or D2) is achieved by use of Fe or H ₂ + Pd/C and finally Step E (e.g. Step E1, Step E2, Step E3 or E4) is a coupling reaction with HO-R ⁶ or AG-R ⁶ and base.

Procedure B

Furthermore, the present invention is directed to a method for producing the compounds of formula (I), the method comprises the following steps in the row as described below:

Step A1: performing a first cross coupling reaction of pyridine compound 1* with alkyne compound 2a* wherein the substituents R ¹ , R ² and R ⁸ - R ¹¹ have the meanings as defined in claim 1 and X is a leaving group and represents Cl, Br, I, or OTf, to obtain a compound 3* in the presence of a first palladium catalyst, and a first base;

Step D2: reducing nitro (NO2) group of the compound 3* to a primary amine (NH ₂ ) group to obtain a compound 10

Step E2: performing a coupling reaction of the compound 10* with a compound HO-R ⁶ or AG-R ⁶ , wherein the substituent R ⁶ has the meanings as defined in claim 1 and AG is an activating group of a carboxylic acid, to obtain a compound 11*

Step B2: converting a trimethylsilyl group of the compound 11* to a halide like an iodide to obtain a compound 12 Step C2: performing a second cross coupling reaction of the compound 12* with a compound 5* RO

B-B 5*

RO wherein R’ is H or an alkyl chain with 1-10 carbon atoms or a cycloalkyl chain with 3 to 12 carbon atoms or both residues R’ represent together a residue derived from pinacol, in the presence of a second palladium catalyst, and a second base to obtain a product compound of the formula

Procedure C

Furthermore, the present invention is directed to a method for producing the compounds of formula (I), the method comprises the following steps in the row as described below:

Step A3: i) performing a first cross coupling reaction of pyridine compound 1* with alkyne compound 2b* wherein the substituents R ¹ , R ² , R ⁸ , R ⁹ , R ¹¹ , and R ^a - R ^d have the meanings as defined in claim 1 and X is a leaving group and represents Cl, Br, I, or OTf and PG is an amino protecting group, in the presence of a first palladium catalyst, and a first base; and ii) removing a protecting group PG of a resulting compound after the step i) to obtain a compound 3b* Step E3: perfoming a coupling reaction of the compound 3b* with a compound HO-R ⁶ or AG-R ⁶ , wherein the substituent R ⁶ has the meanings as defined in claim 1 and AG is an activating group of a carboxylic acid, to obtain a compound 11b*

Step B3: converting a trimethylsilyl group of the compound 11b* to a halide like an iodide to obtain a compound 12b*

Step C3: perfoming a second cross coupling reaction of the compound 12b* with a compound 5 ^*

RO

B-B 5*

RO wherein R’ is H or an alkyl chain with 1-10 carbon atoms or a cycloalkyl chain with 3 to 12 carbon atoms or both residues R’ represent together a residue derived from pinacol, in the presence of a second palladium catalyst, and a second base to obtain a product compound of the formula (I)

Procedure D

Furthermore, the present invention is directed to a method for producing the compounds of formula (I), the method comprises the following steps in the row as described below:

Step A4: i) performing a first cross coupling reaction of pyridine compound 1 with alkyne compound 2c* wherein the substituents R ¹ , R ² , R ⁸ , R ⁹ , R ¹¹ , and R ^a - R ^d have the meanings as defined in claim 1 and X is a leaving group and represents Cl, Br, I, or OTf and PG is an amino protecting group, in the presence of a first palladium catalyst, and a first base; and ii) removing a protecting group PG of a resulting compound after the step i) to obtain a compound 3c* Step E4: performing a coupling reaction of the compound 3c* with a compound HO-R ⁶ or AG-R ⁶ , wherein the substituent R ⁶ has the meanings as defined in claim 1 and AG is an activating group of a carboxylic acid, to obtain a compound

Step B4: converting a trimethylsilyl group of the compound 11c* to a halide like an iodide to obtain a compound 12c*

Step C4: performing a second cross coupling reaction of the compound 12c* with a compound 5 ^*

RO

B-B 5*

RO wherein R’ is H or an alkyl chain with 1 -10 carbon atoms or a cycloalkyl chain with 3 to 12 carbon atoms or both residues R’ represent together a residue derived from pinacol, in the presence of a second palladium catalyst, and a second base to obtain a product compound of the formula (I) In each of the steps A1, A3, and A4 Sonogashia coupling reaction of compound 1* and domino cyclization of the resulting coupling compound is performed in the present of the first palladium catalyst, and the base. Optionally, copper catalyst may be used as cocatalyst and is preferred Cu(l) and more preferred Cul.

The first palladium catalyst for C-C coupling reaction is Pd(0) or Pd(ll) catalyst, preferred PdCI ₂ , Pd(PPh ₃ ) ₄ , Pd(acac) ₂ , PdCI ₂ (CH ₃ CN) ₂ , PdCI ₂ (PCy ₃ ) ₂ , PdCI ₂ (PPh ₃ ) ₂ , [(TT-ally)PdCI] ₂ , (SIPr)PdCI ₂ (TEA). Optionally, further phosphine ligand may be used together with the first palladium catalyst.

A ratio of the palladium catalyst to the starting material is in the range of 0.01 to 20 mol- %, preferred 0.01-10 mol-%, more preferred 0.01-5 mol-%, most preferred 0.01-1 mol- %.

The first base may be an organic base or inorganic bases. The organic base may be tertiary amine such as Et ₃ N, and DIPEA, DABCO, DBU, pyrrolidine or piperidine. The inorganic base may be K ₂ C0 ₃ , Cs ₂ C0 ₃ or K ₃ P0 ₄ . A ratio of the first base to the starting material is in the range of 1.0 to 5.0 equivalents, preferred 1.0 to 3.0 equivalents, more preferred 1.0 to 3.0 equivalents, most preferred 1.0 to 1.5 equivalents.

Preferred, this reaction is performed in a polar aprotic solvent such as DMF or DMSO under N ₂ atmosphere at a temperature in a range of 80°C to 200°C, preferred 100°C to 180°C, more preferred 100°C to 150°C, most preferred 120°C to 150°C.

In each of the steps B1, B2, B3, and B4, conversion of trimethylsilyl (TMS) group to iodide group is performed by treating with N-iodosuccinimide (NIS) as an idonation reagent for 15 h at a temperature in a range of 10°C to 35°C, preferred, 15°C to 30°C, more preferred 20°C to 30°C. A polar aprotic solvent such as dichlorormethane or chlororform is used.

In each of the steps C1, C2, C3, and C4 Suzuki coupling reaction of iodinated or brominated compound 4*, 12*, 12b*, or 12c* with a compound 5* as a boronic acid derivative is performed in the present in the second palladium catalyst and the second base.

RO

B-B 5*

RO

In compound 5* the two substituents R’ are H or an alkyl chain with 1-10 carbon atoms or a cycloalkyl chain with 3 to 12 carbon atoms or both residues R’ represent together a residue derived from pinacol. Preferably, the boronic acid derivative may be a boronic acid (R’ = -H) or an ester of the boronic acid, e.g. its isopropyl ester (R’ = -CH(CH ₃ ) ₂ ), an ester derived from pinacol (R’-R’ = -C(CH ₃ ) ₂ -C(CH ₃ ) ₂ -). The second palladium catalyst is Pd(0) or Pd(ll) catalyst. The Pd(0) catalyst may be tetrakis(triphenylphosphine)palladium(0) [Pd(PPh ₃ ) ₄ ], tris(dibenzylideneacetone)di- palladium(O) [Pd ₂ (dba) ₃ ]. Pd(ll) catalyst may be dichlorobis(triphenylphosphine)- palladium(ll) [Pd(PPh ₃ ) ₂ Cl2], palladium(ll) acetate and triphenylphosphine or more preferred [1 ,T-bis(diphenylphosphino)ferrocene]palladium dichloride. The reaction is preferably carried out in a mixture of a solvent like dioxane, DMF, DME, THF, or isopropanol with water and in the presence of the second base like aqueous sodium bicarbonate or K ₃ P0 _4.

In each of the Steps D1 and D2 a nitro (N0 ₂ ) group is reduced to a primary amine (NH ₂ ) group with the treatment of a reducing agent. Preferably, Fe, or Pd/H ₂ is used as a reducing agent.

In each of the Steps E1, E2, E3, and E4 group is introduced by a coupling reaction with HO-R ⁶ or AG-R ⁶

For performing the coupling reaction, firstly carboxylic acid or sulfonic acid group of FIO-R ⁶ is activated in situ to promote the coupling reaction with amino group of intermediate compound. If FIO-R ⁶ is a carboxylic acid, the activating group (AG) of carboxylic acid may be introduced in situ reaction. Preferably, the activating group (AG) may be selected from the group consisting of or comprising: halides such as -F, -Br, -Cl, -I, anhydride group such as -OCOCFI ₃ , N-oxy-benzotriazol group and N-oxy-succinimide.

Further, a carboxylic acid of FIO-R ⁶ is coupled with the amine group of intermediate compound by a well-known amide coupling reaction. Any of the following coupling reagent can be used for amide coupling reaction: BOP, PyBOP, AOP, PyAOP, TBTU, EEDQ, Polyphosphoric Acid (PPA), DPPA, HATU, HOBt, HOAt, DCC, EDCI, BOP-CI, TFFH, Brop, PyBrop, and CIP.

For performing the coupling reaction, also an activated compound AG-R ⁶ having activated carboxyl sulfony group can be used.

As above described, the activating group (AG) may be selected from the group consisting of or comprising: halides such as -F, -Br, -Cl, -I, anhydride group such as -OCOCH ₃ , N-oxy-benzotriazol group and N-oxy-succinimide, preferably AG is Cl.

In the Step A3, A4, and E4, a protecting group (PG) is an amino protecting group. The amine protecting group may be t-butyloxycarbonyl (Boc) or benzyloxycarbonyl (Cbz) and removed under acidic condition, for example, treating with HCI, or TFA. The structure activity relationship (SAR) of the compounds of the present invention shows covalent inhibitors as cellular potent mutant-selective ErbB inhibitors. The covalent binding mode, obtained for example through the introduction of an acrylic moiety, is crucial for cellular activity.

It was found that the compound of the present invention is useful for the prophylaxis and/or the treatment of cancer having activating mutation of a receptor belonging to the ErbB family of receptor, preferred, the mutation is an insertion within exon 20 of EGFR or within exon 20 of HER2.

The compound of the present invention is a selective inhibitor of mutants of EGFR and Her2, preferred Exon 20 mutations as shown in Table 3.

Thus, the compound of the present invention is useful as a medicament or as pharmaceutically active agent. The compound of the present invention is useful for the prophylaxis and/or the treatment of cell proliferative diseases, especially cancer.

Said cancer is selected from breast cancer, colon cancer, prostate cancer, lung cancer, gastric cancer, ovarian cancer, endometrial cancer, renal cancer, hepatocellular cancer, thyroid cancer, uterine cancer, esophagus cancer, squamous cell cancer, leukemia, lymphoma, osteosarcoma, mamma carcinoma, melanoma, glioblastoma and neuroblastoma.

In specific embodiment, the compound is useful for in the the prophylaxis and/or the treatment of non small cell lung cancer (NSCLC) or mamma carcinoma.

Preferably, the mutation is an insertion within exon 20 of EGFR or within exon 20 of FIER2. One aspect herein are the compounds of the present invention for use in the prophylaxis and/or the treatment of cancer caused by or associated with mutations associated with EGFR TKI resistance and in particular caused by or associated with in frame insertions and/or duplications of 3 to 21 base pairs (bp) between codons 763 and 775 of the Fler2 gene or the EGFR (Fieri) gene. More preferred, the mutation is selected from the group consisting of Fler2 INS8 INS YVMA, EGFR D770_N771 insSVD, EGFR H773_V774insNPH, EGFR V769_D770insASV, EGFR P772_H773insPR, EGFR T790M and EGFR T790ML858R. The important sequences are shown in SEQ-ID No. 1 to SEQ:NO 7 in Figure 1

In an embodiment, the present invention is directed to the compound of in combination with at least one anticancer drug for use in treatment of cancer. The at least one anticancer is anticancer drug inhibting EGFR/FIER2 tyrosine kinases, anticancer drug targeting the RAS/RAF/MEK/ERK signal pathway, anticancer drug targeting PI3K/AKT/mTOR signal pathway, and/or anticancer drug targeting JAK/STAT signal pathway.

The anticancer drug inhibting EGFR/HER2 tyrosine kinases is selected from the group consisting of A928605, ABT414, ABT806, AC480, Adgef (gefitinib), AEE788, AF802 (alectinib hydrochloride), Afatinib, Afinitor (everolimus), AFM21, AG1478, AGT2000, AL6802, ALL3, AMG595, Anti-Cripto-1 monoclonal antibodies PRIMA BIOMED, AP23464, AP26113, ARQ197 (tivantinib), ARRY380, ARRY543 (varlitinib tosylate), ASP7487 (linsitinib), ASP8273, AV203, AVL291, AZD4769, AZD9291, B-Peptimetics ANTYRA, BGB324, BIBW2948BS, Bispecific Anti-Her2 Zybodies ZYNGENIA (trastuzumab), Bispecific Anti-Fler3 Zybodies ZYNGENIA (cetuximab), Bispecific Antibody Drug Conjugate Program AVIDBIOLOGICS, BL7030, BMS536924,

BMS582664 (brivanib alaninate), BMS690514, BMSATI2, BT2111 (trastuzumab), CAB051, Canertinib, Caprelsa (vandetanib), CCX140, CDX110, CetuGEX, Cetuximab AMGEN, Cetuximab BIOXPRESS THERAPEUTICS, Cetuximab HARVEST MOON, Cetuximab ONCOBIOLOGICS, Cetuximab PANACEA BIOTECH, Cetuximab PLANTFORM, Cetuximab ZENOTECH, CGP59326A, Chemofit (gefitinib), CM 033 (canertinib dihydrochloride), CIMAher (nimotuzumab), Citoprot-P, CMAB009 (cetuximab), cMet-EGFR Dual Inhibitor CRYSTALGENOMICS, CO-1686, Cometriq (cabozantinib), Conmana (icotinib hydrochloride), CTP15 (cetuximab), CTX023, CUDC101 , CYC202 (seliciclib), DC101, DXL1218, EDP13, EGF816, EGFR Antibody Drug Conjugate AVIDBIOLOGICS, EGFR BiTE antibody MICROMET, EGFR Monoclonal Antibody REVO, EGFR Probody Drug Conjugate CYTOMX, EGFR- Antibody-Targeted Endostatin Payload, EGFR501, EKB569 (pelitinib), EM1-mAb GENMAB, EMD121974 (cilengitide), EMD72000 (matuzumab), Emfib (gefitinib), Epidermal Growth Factor Receptor (EGFR) humanized antibody CHINA PHARMAHUB, Erbitux (cetuximab), Erlobenz (erlotinib), Erlocip (erlotinib), Erlonat NATCO (erlotinib), Erlonat RADIANCE (erlotinib), Erlons (erlotinib hydrochloride), Erlostar (erlotinib), Erloswift (erlotinib), Erlotad (erlotinib), Erlotaz (erlotinib), Erlotinib CYNO PHARMACEUTICALS (erlotinib hydrochloride), Erlotinib hydrochloride HETERO, Erlotinib Hydrochloride MYLAN, Erlotinib hydrochloride TEVA, Erlotinib LABORATORIOS INDUQUIMICA, Erlotinib NAPROD, Erlotinib P2D BIOSCEINCE, Erlotinib SALIUS, Erlotinib SRS PHARMA, Erlotinib UNITED BIOTECH, Etk/Bmx Kinase Inhibitor ASTEX, EZN3920, Fderceptin SHANGHAI FUDAN-ZHANGJIANG, FV225, Geffy (gefitinib), Geficad (gefitinib), Gefitinib CELOGEN, Gefitinib CYNO PHARMACEUTICALS, Gefitinib HETERO, Gefitinib LABORATORIOS INDUQUIMICA, Gefitinib MARKSANS, Gefitinib MISSION VIVACARE, Gefitinib NAPROD, Gefitinib SALIUS, Gefitinib SAVA, Gefitinib SRS PHARMA, Gefitinib UNITED BIOTECH, Gefitoz (gefitinib), GefiTrust (gefitinib), Gefnib (gefitinib), Geftex (gefitinib), Geftib (gefitinib), Gefticip (gefitinib), Geftifos (gefitinib), Geftiget (gefitinib), Geftin (gefitinib), Geftinat NATCO (gefitinib), Geftinat RADIANCE (gefitinib), Geftistar (gefitinib), Genasense (oblimersen sodium), GI3000, Gilotrif (aftinib), GSK2136773, HC15, HD201

(trastuzumab), HE39, HER-1 therapeutic cancer vaccine BIOVEN, HER1 Cancer Vaccine, HER2 BiTE Antibody AMGEN, Herzuma (trastuzumab), HKI357, HM60390, HM61713, HM78136B (poziotinib), HMPL309 (theliatinib), HMPL504 (volitinib),

HMPL813 (epitinib), HuMax-EGFr (zalutumumab), HyERB (cetuximab), ICS283, Imatinib Ecker hydrochloride, Imbruvica (ibrutinib), IMC11F8 (necitumumab), IMCA12 (cixutumumab), IMGN289, INC280, INCB7839 (aderbasib), Inlyta (axitinib), Iressa (gefitinib), ISU101 (cetuximab), JNJ26483327, JNJ28871063, JX929, Kabigef (gefitinib), KD019, KD020, KHK2866, KRN633, KRN951 (tivozanib), KSB102, KT6587, Lapatinib AQVIDA, Lapatinib ditosylate, Lapatinib SRS PHARMA, Lefibenz (gefitinib), Lortinib (erlotinib), LY2875358 (emibetuzumab), MabionEGFR (cetuximab), MDP01, MDX214 (CD89 monoclonal antibody), MDX447, Meftinib (gefitinib), MEHD7945A, Menadione TALON, MGCD265, mir-7 mimetic SILENCE, MM121, MM151, MP412, MP470 (amuvatinib), MT062, Novel Tyrosine kinase Inhibitor MEBIOPHARM, NT004, NT113, ORIL003, ORIL007, OSI632, Panitumumab BIOXPRESS THERAPEUTICS (panitumumab), Panitumumab PANPHARMACEUTICALS, PB272 (neratinib), PBI1737, PBI4050, Perjeta (pertuzumab), PF00299804 (dacomitinib), PKI166, PM92102

(kahalalide F), RadioTheraCIM, RAF and HER inhibitors DECIPHERA, RBLX200, RC3095, Reglycosylated Cetuximab FOUNTAIN BIOPHARM, RG3638 (onartuzumab), RG7160 (imgatuzumab), RX1792, S222611, SAB-Y1 SYNTAB, Sai Pu Ting, SAI- EGFR-ECD MICROMET, SAR103168, SC100, Selatinib Ditosilate QILU, Selective EGFR Inhibitors VICHEM, SL175, SL176, SL433, SL461, SL634, SRXMs MAXOCARE, STIA020X, STIA050X, Stivarga (regorafenib), STP523, STP801, Stridessa (gefitinib), Surrobody Drug Conjugate SEA LANE, Sym004, Sym013, TaiXinSheng

(nimotuzumab), TAK285, Tarceva (erlotinib hydrochloride), Targretin (bexarotene), TAS2913, TG03 (apricoxib), TGF therapeutic cancer vaccine BIOVEN, TGF-alpha Cancer Vaccine MICROMET, Trastuzumab ZENOTECH, Trisilensa, Trispecific Anti- Her1/Her3 Zybodies ZYNGENIA (cetuximab), Tykerb (lapatinib ditosylate), Tyrogef, Tyrokinin 100 (erlotinib hydrochloride), U31287 (partitumab), Ultragef (gefitinib), VCC395122, VCC868449, Vectibix (panitumumab), V114442, Xefta (gefitinib),

YMB1005, Zefotib (gefitinib), and Zufinib (gefitinib).

The anticancer drug targeting the RAS/RAF/MEK/ERK signal pathway is selected from the group consisting of: Dabrafenib, GSK2118436, LGX818, Vemurafenib, RAF265, R05126766, Sorafenib, XL281 (Raf inhibitor); ARRY-300, AZD8330, E6201, PD- 0325901, R04987655, Bimetinib (ARRY-162/ MEK162), Cobimetinib (GDC- 0973/XL518), Refametinib (BAY86-9766/RDEA119), Pisasertib (AS703026), Selumetinib (AZD6244/ARRY-142886), TAK-733, Trametinib (GSK1120212) (MEK inhibitor), BVD-523, and MK8553 (ERK inhibitor) . The anticancer drug targeting PI3K/AKT/mT0R signal pathway is selected from the group consisting of : BGT226, BEZ235, GDC-0980, GSK2126458, PF-04691502, PF-05212384/P KI-587, SF1126, XL765/SAR245409, BKM120, BYL719, CAL-101, GDC-0032, GDC-0941, GSK2636771, IPI-145, NVP-BEZ235, PX866, XL147 (PI3K inhibitor); Erucylphosphocholine, GSK2141795, GSK690693, Miltefosine, MK2206, PBI-05204, Perifosine, RX-0201, SR13668, XL-418 (AKT inhibitor), AZD2014, AZD8055, CC-223, Everolimus (RAD001), Ridaforolimus (MK-8669), OSI-027,

Sirolimus (Rapamycin), and Temsirolmus (Torisel®, CCI-779) (mTOR inhibitor).

The anticancer drug targeting JAK/STAT signal pathway is JAK kinase inhibitor or STAT inhibitor. JAK kinase inhibitor has inhibitory activity against JAK1 , JAK2, and/or JAK3 and is selected from the group consisting of ABT-494, AT9283, atiprimod dihydrochloride, AZD1480, Baricitinib, BMS-911543, CP 690550, Cucurbitacin I, Decernotinib, Filgotinib, Gandotinib, GSK2586184, Itacitinib (INCB039110), INCB018424, INCB047986, INCB052793, Lestaurtinib, Momelotinib (CYT387), NS- 018, NSC 33994, Pacritinib, Peficitinib, Ruxolitinib (Jakafi), PF-04965842, SD 1008, Tofacitinib, Upadacitinib, XL019, and WP1066.

STAT inhibitor has inhibitory activity against STATs 1, 2, 3, 4, 5a, 5b, and 6, in particular STAT3 and STAT5b and is selected from the group consisting of AZD9150, Capsaicin, CPA-1, CPA-7, FLLL11, FLLL12, FLLL32, FLLL62, IS3295, JQ1, OPB-111077, OPB- 31121, OPB-51602 and pimozide.

Pharmaceutical Composition

The pharmaceutical compositions according to the present invention comprise at least one compound according to the present invention as an active ingredient together with at least one pharmaceutically acceptable (i.e. non-toxic) carrier, excipient and/or diluent. The pharmaceutical compositions of the present invention can be prepared in a conventional solid or liquid carrier or diluent and a conventional pharmaceutically made adjuvant at suitable dosage level in a known way. The preferred preparations are adapted for oral application. These administration forms include, for example, pills, tablets, film tablets, coated tablets, capsules, powders and deposits.

Optionally, the pharmaceutical compositions according to the present invention comprise further at least one anticancer drug. The at least one anticancer is anticancer drug inhibting EGFR/FIER2 tyrosine kinases, anticancer drug targeting the RAS/RAF/MEK/ERK signal pathway, anticancer drug targeting PI3K/AKT/mTOR signal pathway, and/or anticancer drug targeting JAK/STAT signal pathway as defined above. Furthermore, the present invention also includes pharmaceutical preparations for parenteral application, including dermal, intradermal, intragastral, intracutaneous, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutan, rectal, subcutaneous, sublingual, topical, or transdermal application, which preparations in addition to typical vehicles and/or diluents contain at least one compound according to the present invention and/or a pharmaceutical acceptable salt thereof as active ingredient.

The pharmaceutical compositions according to the present invention containing at least one compound according to the present invention and/or a pharmaceutical acceptable salt thereof as active ingredient will typically be administered together with suitable carrier materials selected with respect to the intended form of administration, i.e. for oral administration in the form of tablets, capsules (either solid filled, semi-solid filled or liquid filled), powders for constitution, gels, elixirs, dispersable granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable carrier, preferably with an inert carrier like lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid filled capsules) and the like. Moreover, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the tablet or capsule. Powders and tablets may contain about 5 to about 95-weight % of the derivatives according to the general formula (I) or analogues compound thereof or the respective pharmaceutically active salt as active ingredient.

Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among suitable lubricants there may be mentioned boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Suitable disintegrants include starch, methylcellulose, guar gum, and the like. Sweetening and flavoring agents as well as preservatives may also be included, where appropriate. The disintegrants, diluents, lubricants, binders etc. are discussed in more detail below.

Moreover, the pharmaceutical compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimise the therapeutic effect(s), e.g. anti cancer activity or activity against cancer metastases and the like. Suitable dosage forms for sustained release include tablets having layers of varying disintegration rates or controlled release, polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.

Liquid form preparations include solutions, suspensions, and emulsions. As an example, there may be mentioned water or water/propylene glycol solutions for parenteral injections or addition of sweeteners and opacifiers for oral solutions, suspensions, and emulsions. Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be present in combination with a pharmaceutically acceptable carrier such as an inert, compressed gas, e.g. nitrogen.

For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides like cocoa butter is melted first, and the active ingredient is then dispersed homogeneously therein e.g. by stirring. The molten, homogeneous mixture is then poured into conveniently sized moulds, allowed to cool, and thereby solidified.

Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

The compounds according to the present invention may also be delivered transdermally. The transdermal compositions may have the form of a cream, a lotion, an aerosol and/or an emulsion and may be included in a transdermal patch of the matrix or reservoir type as is known in the art for this purpose.

The term capsule as recited herein refers to a specific container or enclosure made e.g. of methylcellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredient(s). Capsules with hard shells are typically made of blended of relatively high gel strength gelatins from bones or pork skin. The capsule itself may contain small amounts of dyes, opaquing agents, plasticisers and/or preservatives.

Under tablet a compressed or moulded solid dosage form is understood which comprises the active ingredients with suitable diluents. The tablet may be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation, or by compaction well known to a person of ordinary skill in the art.

Oral gels refer to the active ingredients dispersed or solubilised in a hydrophilic semi solid matrix. Powders for constitution refers to powder blends containing the active ingredients and suitable diluents which can be suspended e.g. in water or in juice.

Suitable diluents are substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol, and sorbitol, starches derived from wheat, corn, rice, and potato, and celluloses such as microcrystalline cellulose. The amount of diluent in the composition can range from about 5 to about 95 % by weight of the total composition, preferably from about 25 to about 75 weight %, and more preferably from about 30 to about 60 weight %.

The term disintegrants refers to materials added to the composition to support break apart (disintegrate) and release the pharmaceutically active ingredients of a medicament. Suitable disintegrants include starches, “cold water soluble” modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses, and cross-linked microcrystalline celluloses such as sodium croscaramellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures. The amount of disintegrant in the composition may range from about 2 to about 20 weight % of the composition, more preferably from about 5 to 10 weight %.

Binders are substances which bind or “glue” together powder particles and make them cohesive by forming granules, thus serving as the “adhesive” in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose, starches derived from wheat, corn, rice and potato, natural gums such as acacia, gelatin and tragacanth, derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate, cellulose materials such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminum silicate. The amount of binder in the composition may range from about 2 to about 20 weight % of the composition, preferably from about 3 to about 10 weight %, and more preferably from about 3 to about 6 weight %.

Lubricants refer to a class of substances which are added to the dosage form to enable the tablet granules etc. after being compressed to release from the mould by reducing friction or wear. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate, or potassium stearate, stearic acid, high melting point waxes, and other water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L-leucine. Lubricants are usually added at the very last step before compression, since they must be present at the surface of the granules. The amount of lubricant in the composition may range from about 0.2 to about 5 weight % of the composition, preferably from about 0.5 to about 2 weight %, and more preferably from about 0.3 to about 1.5 weight % of the composition.

Glidents are materials that prevent caking of the components of the pharmaceutical composition and improve the flow characteristics of granulate so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the composition may range from about 0.1 to about 5 weight % of the final composition, preferably from about 0.5 to about 2 weight %.

Coloring agents are excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of the coloring agent may vary from about 0.1 to about 5 weight % of the composition, preferably from about 0.1 to 1.0 weight %.

The compounds of the present invention are suitable for use in medicine, particulary in human medicine, but also in veterinary medicine. The dosage of the compounds may be determined by a skilled practitioner according to the type and severity of the disorder to be treated.

The compounds of the present invention may be admistered as a monotherapy or together with further active agents, particulary chemotherapeutic agents or antitumor antibodies. Furthermore they may be used in combination with surgery and/or irradiation.

Description of Figures

Figure 1: core sequences of EGFR mutants EGFR D770_N771 insSVD, EGFR H773_V774insNPH, EGFR V769_D770insASV, EGFR P772_H773insPR, EGFR T790M and EGFR T790ML858R and HER mutant Her2 INS8 INS YVMA.

Figure 2: shows a representative example of a compound according to the invention. Preparation of compounds

General Information:

All reactions involving air- or moisture-sensitive reagents or intermediates were carried out in flame-dried glassware under an argon atmosphere. Dry solvents (THF, toluene, MeOH, DMF, DCM) were used as commercially available. ¹ FI-NMR and ¹³ C-NMR were recorded on a Bruker DRX400 (400 MFIz). Multiplicities are indicated as: br s (broadened singlet), s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), m (multiplet); and coupling constants (J) are given in Flertz (Flz). HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using Waters Acquity Performance Liquid Chromatography (UPLC) equipped SQ 3100 Mass detector spectrometer. Column: Acquity UPLC BEH C18 1.7um, 2.1x50mm. Flow: 0.5ml/min. Eluents: A: H ₂ 0 with 0.05% formic acid and B: ACN with 0.05% TFA. All chemicals and solvents were purchased from commercial sources like Sigma-Aldrich, Fluka, TCI, Acros Organics, ABCR, Alfa Aesar, Enamine, VWR, Combi-Blocks, Apollo Scientific, Aquilla Pharmatech, Ark Pharm, D-L Chiral Chemicals, ChemBridge, Renno Tech, Accela, KeyOrganics, Pharmablock and Chem Impex. Unless otherwise noted, all commercially available compounds were used as received without further purifications.

Abbreviations used in the description of the chemistry and in the Examples that follow are:

ACN (acetonitrile); br (broad); CDCI3 (chloroform); cHex (cyclohexane); DABCO (1,4- Diazabicyclo[2.2.2]octan); DCM (dichloromethane); DIPEA (di-iso-propylethylamine); DMF (dimethylformamide); DMSO (dimethyl sulfoxide); eq. (equivalent); ES (electrospray); EtOAc (ethyl acetate); EtOH (ethanol); HATU (0-(7-azabenzotriazol-1- yl)-/V,/V,/V',/\/'-tetramethyluronium hexafluorophosphate); HCI (hydrochloric acid); HOAc (acetic acid); H ₂ 0 (water); K ₂ C03 (potassium carbonate); KOH (potassium hydroxide); K3PO4 (Tripotassium phosphate); MeOH (methanol); MS (mass spectrometry); Mwt (molecular weight); NaCI (sodium chloride); NaHCOs (sodium hydrogencarbonate); Na ₂ S04 (sodium sulfate); NH ₃ (ammonia); NH ₄ CI (ammonium chloride); NIS ( N - lodosuccinimide); NMP (N-methyl-2-pyrrolidon); NMR (nuclear magnetic resonance); Pd(dppf)CI ₂ ([1,T-bis(diphenylphosphino)ferrocene]dichloro palladium(ll) complex with dichloromethane); pet ether (petroleum ether); iPrOH (iso-propanol); PyBroP (Bromotripyrrolidinophosphonium hexafluorophosphate); RP (reversed-phase); RT (room temperature); sat. aq. (saturated aqueous); Si0 ₂ (silica gel); TFA (trifluoroacetic acid); THF (tetrahydrofurane); TMS: Trimethylsilyl. Preparative Examples

Example 1 :

N-(2-methyl-5-(5-(1 -methyl-1 H-pyrazol-4-yl)-2-(4-(4-methylpiperazin-1 -vDphenyl)- 1 H-pyrrolor2.3-blpyridin-3-yl)phenyl)acrylamide 2,2.2-trifluoroacetate

Step 1 : 5-Bromo-3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1 H-rnitoIoG2.3- blpyridine

In a pressure tube, 5-bromo-3-iodopyridin-2-amine (1 g, 3.3mmol, 1.0eq) and trimethyl[2-(4-methyl-3-nitrophenyl)ethynyl]silane (1.03g, 4.2mmol, 1.25eq) were dissolved in DMF (20ml_). Next, triethylenediamine (0.64g, 5.7mmol, 1.7eq) and bis(triphenylphosphine)palladium (II) dichloride (0.23g, 0.33mmol, 0.1 eq) were added, the tube was purged with argon, and then heated at 145°C for 24h. The resulting mixture was diluted with saturated aqueous NaHCOs solution, and extracted with EtOAc (3x50ml_). The organic layer was washed with saturated aqueous NaCI solution, dried over Na ₂ S04, and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane: EtOAc, 6:4) to afford the pure product A1 as an orange solid (0.8g, Y:62%). ¹ H NMR (300 MHz, DMSO -cfe) d 11.80 (s, 1H), 8.23 (s, 1 H), 7.70 (s, 2H), 7.59 (dd, J = 9.9 Hz, J = 1.7 Hz, 2H), 2.03 (s, 3H), 0.00 (s, 9H). MS (ES) Ci ₇ H ₁₈ BrN ₃ 0 ₂ Si requires: 404, found: 405 (M+H) ⁺ . Step 2: 5-Bromo-2-iodo-3-(4-methvl-3-nitrophenvl)-1H-pvrrolor2,3-blp vridine (A2)

5-Bromo-3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridine A1 (0.8g, 2mmol, 1.0eq) and NIS (0.8g, 3.4mmol, 1.8eq) were dissolved in dry DCM (30ml_). The reaction mixture was stirred for 4h at room temperature, and was quenched with saturated aqueous Na ₂ S203 solution. The desired product was extracted with DCM (3x100ml_), the organic phase was washed with saturated aqueous NaHCOs solution, dried over Na ₂ S04, and solvent were removed in vacuo. The crude material A2 as an orange solid (0.6g, Y:66%) was immediately used without purification in the next step. MS (ES) 0I H ₉ BGIN ₃ 0 ₂ requires: 458, found: 459 (M+H) ⁺ .

Step 3: 5-Bromo-3-(4-methyl-3-nitrophenyl)-2-(4-(4-methylpiperazin-1 -vDphenyl)- 1H-pvrrolor2,3-blpvridine

5-Bromo-2-iodo-3-(4-methyl-3-nitrophenyl)-1 H-pyrrolo[2,3-b]pyridine A2 (600mg, 1.3mmol, 1.0eq), [4-(4-methylpiperazin-1-yl)phenyl]boronic acid (288mg, 1.3mmol, 1.0eq) and Na ₂ C03 (278mg, 2.6mmol, 2eq) were dissolved in the mixture of solvents: THF 6ml_ / MeOH 0.6ml_ / H ₂ 0 0.6mL (1 :0.1 :0.1 vol), degassed under vacuum, and purged with argon. Next, Pd(PPh3) ₂ CI ₂ (184mg, 0.26mmol, 0.2eq) was added, and the reaction mixture heated at 80°C for 24h. The resulting mixture was cooled, the desired product was extracted with DCM (3x45ml_) after addition of saturated aqueous NaHCOs solution. The organic phase was dried over Na ₂ S04, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH, 8:2) to afford the product A3 as a brown solid (500mg, 75%). MS (ES) C ₂₅ H ₂₄ BrN ₅ 0 ₂ requires: 506, found: 507 (M+H) ⁺ .

Step 4: 5-(5-Bromo-2-(4-(4-methylpiperazin-1 -yl)phenyl)-1 H-pyrrolor2.3-blpyridin- 3-vl)-2-methvlaniline (A4)

A suspension of 1-{4-[5-bromo-3-(4-methyl-3-nitrophenyl)-1 H-pyrrolo[2,3-b]pyridin-2- yl]phenyl}-4-methylpiperazine A3 (500mg, 1 mmol, 1eq) and iron (276mg, 4.9mmol, 5eq) in a mixture of EtOH (5ml_) and saturated aqueous NH ₄ CI solution (0.5mL) was stirred for 3h at 80°C. Then, the reaction mixture was filtered through a pad of silica gel, washed with DCM (200m L), next EtOAc (200m L). The solvents were evaporated under reduced pressure to obtain the desired product A4 as a yellow solid (300mg, 63%). ¹ H NMR (300 MHz, DMSO-d ₆ ) d 12.31 (s, 1 H), 8.27 (s, 2H), 7.84 (d, J = 1 .6 Hz, 2H), 7.77- 7.61 (m, 4H), 7.47 (s, 1 H), 7.41 (s, 2H), 3.81-3.75 (m, 4H), 2.48-2.44 (m, 4H), 2.13 (d, 6H). MS (ES) C ₂ 5H ₂ 6BrN ₅ requires: 476, found: 477 (M+H) ⁺ .

Step 5: N-(5-(5-Bromo-2-(4-(4-methylpiperazin-1 -yl)phenyl)-1 H-rnitoIoG2.3- blpvridin-3-vl)-2-methvlphenvl)acrvlamide (A5)

5-{5-Bromo-2-[4-(4-methylpiperazin-1-yl)phenyl]-1 H-pyrrolo[2,3-b]pyridin-3-yl}-2- methylaniline A4 (300mg, 0.6mmol, 1eq) was dissolved in dry THF (10ml_) at -10°C. Next, DIPEA (1.1 mL, 6mmol, 10eq) was dropwise added, and the mixture was stirred for 5min at -10°C. A solution of acryloyl chloride (27pL, 0.6mmol, 1eq) in dry THF (10ml_) was dropwise added, and the reaction mixture was slowly warmed to room temperature. After 30min, LCMS showed full conversion. The reaction mixture was diluted with water (10ml_), and the desired product was extracted with DCM (3x1 OmL). The organic phase was dried over Na ₂ S04 and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane: EtOAc, 0-50% of EtOAc) to yield the material that was triturated with DCM to obtain 120mg (36%) of the pure product A5 as a creamy solid. ¹ H NMR (300 MHz, DMSO-d6) d 12.18 (s, 1 H), 9.53 (s, 1 H), 8.26 (d, J = 2.2 Hz, 1 H), 7.94 (d, J = 2.2 Hz, 1 H), 7.59 (s, 1 H), 7.39 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 7.9 Hz, 1 H), 6.98 (d, J = 7.7 Hz, 1 H), 6.92 (d, J = 8.9 Hz, 2H), 6.55 (dd, J = 17.0, 10.3 Hz, 1 H), 6.24 (dd, J = 17.0, 2.1 Hz, 1 H), 5.75 (d, J = 9.4 Hz, 1 H), 3.22 - 3.13 (m, 4H), 2.46 - 2.38 (m, 4H), 2.23 (d, J = 10.9 Hz, 6H). MS (ES) C ₂₈ H ₂₈ BrN ₅ 0 requires: 530, found: 531 (M+H) ⁺ .

Step 6: N-(2-methyl-5-(5-(1 -methyl-1 H-pyrazol-4-yl)-2-(4-(4-methylpiperazin-1 - yl)phenyl)-1H-pyrrolor2.3-blpyridin-3-yl)phenyl)acrylamide 2.2.2-trifluoroacetate (A6)

A mixture of N-(5-(5-bromo-2-(4-(4-methylpiperazin-1-yl)phenyl)-1 H-pyrrolo[2,3- b]pyridin-3-yl)-2-methylphenyl)acrylamide A5 (37.0mg, 0.07mmol, 1.0eq.), K ₃ PO ₄ (29.6mg, 0.139mmol, 2.0eq.), 1-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H-pyrazole (18.9mg, 0.09mmol, 1.3eq.) and [1 ,T-bis(diphenylphosphino)ferrocene]- palladium dichloride dichloromethane adduct (5.7mg, 0.007mmol, 0.1eq.) in dioxane/water (4:1 , 1.9ml_) was degassed by bubbling nitrogen through it for a few minutes. The mixture was then heated in the microwave at 130°C for 2h. The resulting reaction mixture was filtered through a syringe filter and the filtrate was directly used for reversed phase HPLC (C18 column) separation (water + 0.1 % TFA/ACN + 0.1 % TFA = 95:5 to 65:35, 30 min). The desired fractions were combined and lyophilized to yield the title compound A6 (3.0mg, 0.004mmol, 6%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d6) d 11.93 (s, 1 H), 9.62 (br s, 1 H), 9.52 (s, 1 H), 8.47 (d, J = 2.0 Hz, 1 H), 8.15 (s, 1 H), 8.01 (d, J = 2.0 Hz, 1 H), 7.89 (d, J = 0.9 Hz, 1 H), 7.66 (s, 1 H), 7.43 (d, J = 9.0 Hz, 2H), 7.20 (d, J = 7.9 Hz, 1 H), 6.98 (d, J = 9.0 Hz, 2H), 6.57 (dd, J = 10.1 Hz, J = 17.0 Hz, 1 H), 6.24 (dd, J = 2.0 Hz, J = 17.0 Hz, 1 H), 5.74 (dd, J = 2.0 Hz, J = 10.1 Hz, 1 H), 3.91 (d, J = 13.3 Hz, 2H), 3.84 (s, 3H), 3.50 (d, J = 12.1 Hz, 2H), 3.13 (m, 2H), 2.97 (t, J = 11.7 Hz, 2H), 2.85 (d, J = 3.2 Hz, 3H), 2.25 (s, 3H). MS (ES) C32H33N7O requires: 531 , found: 532 (M+H) ⁺ .

Example 10:

N-(5-(5-(5-cvano-1 -methyl-1 H-pyrazol-4-yl)-2-(4-(4-methylpiperazin-1 -vDphenvD-

1H-pyrrolor2,3-blpyridin-3-yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate

A mixture of N-(5-(5-bromo-2-(4-(4-methylpiperazin-1-yl)phenyl)-1 H-pyrrolo[2,3- b]pyridin-3-yl)-2-methylphenyl)acrylamide A5 (25mg, 0.05mmol, 1.0eq.), K3PO4 (30mg, 0.14mmol, 3.0eq.), 1 -methyl-4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole-5- carbonitrile (14mg, 0.06mmol, 1.3eq.) and [1 ,1'-bis(diphenylphosphino)ferrocene]- palladium dichloride dichloromethane adduct (4mg, 0.005mmol, 0.1eq.) in dioxane/water (4:1 , 2ml_) was degassed by bubbling nitrogen through it for a few minutes. The mixture was then heated in the microwave at 130°C for 2h. The resulting reaction mixture was filtered through a syringe filter and the filtrate was directly used for reversed phase HPLC (C18 column) separation (water + 0.1 % TFA / ACN + 0.1 % TFA = 95:5 to 30:70, 30 min). The desired fractions were combined and lyophilized to yield the title compound Example 10 (12mg, 0.015mmol, 33%) as a yellow solid. ¹ FI NMR (300 MHz, DMSO-d6) d 12.22 (s, 1 H), 9.63 (br s, 1 H), 9.50 (s, 1 H), 8.56 (d, J = 2.2 Hz, 1 H), 8.19 (s, 1 H), 8.14 (d, J = 2.0 Hz, 1 H), 7.66 (s, 1 H), 7.48 (d, J = 9.9 Hz, 2H), 7.25 (d, J = 7.9 Hz, 1 H), 7.05 (d, J = 7.9 Hz, 1 H), 7.02 (d, J = 9.9 Hz, 2H), 6.56 (dd, J = 10.2 Hz, J = 17.0 Hz, 1 H), 6.22 (dd, J = 2.0 Hz, J = 17.0 Hz, 1 H), 5.73 (dd, J = 2.0 Hz, J = 10.2 Hz, 1 H), 4.06 (s, 3H), 3.94 (d, J = 13.4 Hz, 2H), 3.52 (d, J = 12.0 Hz, 2H), 3.14 (m, 2H), 3.00 (t, J = 12.5 Hz, 2H), 2.87/2.86 (s, 3H), 2.27 (s, 3H). MS (ES) C33H32N8O requires: 556, found: 557 (M+H) ⁺ .

The Examples in the following table were prepared according to the procedure

Example 21:

N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-ethyl-2-(4-(4-me thylpiperazin-1-yl)phenyl)- 1H-pyrrolor2.3-blpyridin-3-yl)-2-methylphenyl)acrylamide 2,2.2-trifluoroacetate (B6)

Step 1: 5-Bromo-4-ethylpyridin-2-amine (B1)

To a stirred solution of 4-ethylpyridin-2-amine (10 g, 81.9 mmol, 1 eq.) in acetonitrile (300 ml_) were added ammonium acetate (630 mg, 8.20 mmol, 0.1 eq.) and N- bromosuccinimide (16 g, 90.2 mmol, 1.1 eq.) portionwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature. After completion of reaction (monitored by TLC), the reaction mixture was poured into ice cold 1.0% sodium thiosulfate solution (500 ml_). The precipitated solid was filtered and the crude compound was purified by flash column chromatography (gradient elution of 20% EtOAc in pet ether) to afford 5-bromo-4-ethylpyridin-2-amine B1 (13 g, 79%) as a pale yellow solid. ¹ H NMR (300 MHz, CDCI ₃ ) 5: 8.08 (s, 1H), 6.40 (s, 1H), 4.36 (br s, 2H), 2.62 (q, J = 7.5 Hz, 2H), 1.21 (t, J = 7.5 Hz, 3H). MS (ES) C ₇ H ₉ BrN ₂ requires: 200, found: 201 (M+H) ⁺ .

Step 2: 5-Bromo-4-ethvl-3-iodopvridin-2-amine (B2)

To a stirred solution of 5-bromo-4-ethylpyridin-2-amine B1 (13 g, 64.7 mmol, 1.0 eq.) in dimethylformamide (130 ml_) were added trifluoroacetic acid (5.9 ml_, 77.6 mmol, 1.2 eq.) and /V-iodosuccinimide (21.8 g, 96.9 mmol, 1.5 eq.) portionwise at 0 °C under nitrogen atmosphere. The resulting reaction mixture was heated at 60°C for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, poured into ice water (500 mL), neutralized with solid sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (2 x 200 mL). The combined organic layer was washed with 10% sodium thiosulfate solution (100 mL), water (2 x 100 mL), brine (100 mL), dried over anhydrous Na ₂ S04, filtered and concentrated under reduced pressure to obtain crude compound. The crude compound was purified by flash column chromatography (gradient elution of 20% EtOAc in pet ether) to afford 5-bromo- 4-ethyl-3-iodopyridin-2-amine B2 (14 g, 66%) as a pale yellow solid. ¹ H NMR (300 MHz, CDCIs) 5: 8.00 (s, 1H), 5.00 (br s, 2H), 2.97 (q, J = 7.5 Hz, 2H), 1.15 (t, J = 7.5 Hz, 3H). MS (ES) C ₇ H ₉ BrN ₂ requires: 326, found: 327 (M+H) ⁺ .

Step 3: 5-Bromo-4-ethyl-3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl )-1 H- pyrrolor2.3-blpyridine (B3)

To a stirred solution of 5-bromo-4-ethyl-3-iodopyridin-2-amine B2 (14 g, 42.8 mmol, 1.0 eq.) and trimethyl ((4-methyl-3-nitrophenyl)ethynyl)silane (12.0 g, 51.4 mmol, 1.2 eq.) in dimethylformamide (140 mL) was added 1 ,4-diazabicyclo[2.2.2]octane (8 g, 72.8 mmol, 1.7 eq.) at room temperature in a seal tube. The resulting reaction mixture was degassed with argon for 15 mins. Then bis-(triphenylphosphine) palladium (II) dichloride (3 g, 4.28 mmol, 0.1 eq.) was added at room temperature under argon atmosphere. The resulting reaction mixture was heated to 120°C for 16 h. After completion of reaction, the reaction mixture was filtered through a small pad of Celite and washed with ethyl acetate (200 ml_). The filtrate was washed with water (2 x 100 ml_), brine (200 ml_), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to afford crude compound. The crude compound was purified by flash column chromatography (gradient elution of 20% ethyl acetate in pet ether) to obtain 5-bromo-4- ethyl-3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridine B3 (9.5 g, 51 %) as an off white solid. ¹ H NMR (400 MHz, CDCI ₃ ) 5: 8.90 (br s, 1 H), 8.39 (s, 1 H), 8.04 (d, J = 1 .6 Hz, 1 H), 7.56 (dd, J = 8.0 Hz, J = 1 .6 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 1 H), 2.73 (s, 3H), 2.60 (q, J = 7.2 Hz, 2H), 0.94 (t, J = 7.6 Hz, 3H), 0.15 (s, 9H). MS (ES) Ci ₉ H ₂₂ BrN ₃ 0 ₂ Si requires: 431 , found: 432 (M+H) ⁺ .

Step 4: 5-(5-Bromo-4-ethyl-2-(trimethylsilyl)-1 H-pyrrolor2.3-blpyridin-3-yl)-2- methylaniline (B4)

To a stirred solution of 5-bromo-4-ethyl-3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl )-1 H- pyrrolo[2,3-b]pyridine B3 (9.5 g, 22.0 mmol, 1.0 eq.) in ethanol (400 ml_) were added saturated ammonium chloride solution (60 ml_) and iron powder (6.1 g, 110 mmol, 5 eq.) at room temperature. The resulting reaction mixture was heated to 90°C for 6 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a small pad of Celite and washed with ethyl acetate (200 ml_). The filtrate was washed with water (2 x 100 ml_), brine (200 ml_), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give crude compound. The crude compound was purified by flash column chromatography (gradient elution of 20% ethyl acetate in pet ether) to afford 5-(5-bromo-4-ethyl-2- (trimethylsilyl)-l H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylaniline B4 (7.2 g, 81 %) as an off white solid. ¹ H NMR (400 MHz, DMSO -d ₆ ) d: 11 .54 (s, 1 H), 8.25 (s, 1 H), 6.92 (d, J = 7.6 Hz, 1 H), 6.61 (d, J = 1.6 Hz, 1 H), 6.46 - 6.44 (m, 1 H), 4.83 (br s, 2H), 2.59 (q, J = 7.2 Hz, 2H), 2.11 (s, 3H), 0.87 (t, J = 7.2 Hz, 3H), 0.06 (m, 9H). MS (ES) Ci ₉ H ₂₄ BrN ₃ Si requires: 401 , found: 402 (M+H) ⁺ .

Step 5: 5-(5-(1.5-Dimethyl-1H-pyrazol-4-yl)-4-ethyl-2-(trimethylsily l)-1H-pyrrolor2.3- blpyridin-3-yl)-2-methylaniline (B5) A mixture of 5-(5-bromo-4-ethyl-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2- methylaniline B4 (3.2g, 8.0mmol, 1.0eq.), K ₃ PO ₄ (3.38g, 16.0mmol, 2.0eq.), 1,5- dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (2,66g, 12.0mmol, 1.5eq.) and [1 ,1'-bis(diphenylphosphino)ferrocene]-palladium dichloride dichloromethane adduct (654mg, 0.8mmol, 0.1eq.) in dioxane/water (10:1) was degassed by bubbling nitrogen through it for a few minutes. The mixture was then heated in the microwave at 130°C for 2h. The resulting mixture was diluted with saturated aqueous NaHCOs solution, and extracted with EtOAc (3x50ml_). The organic layer was washed with saturated aqueous NaCI solution, dried over Na ₂ S04, and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane: EtOAc, gradient elution from 10:1 to 0:100) to afford the pure product B5 as an white solid (2.1 g, 63%). MS (ES) C32H33N7O requires: 531, found: 532 (M+H) ⁺ .

Step 6: N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-ethyl-2-(trimethyls ilyl)-1H- pyrrolor2.3-blpyridin-3-yl)-2-methylphenyl)acrylamide (B6)

5-(5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-4-ethyl-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridin-3- yl)-2-methylaniline B5 (2.1 g, 5.0mmol, 1eq) was dissolved in THF (200ml_) at -50°C. Next, DIPEA (8.7ml_, 50mmol, 10eq) was added and the mixture was stirred for 2m in. A solution of acryloyl chloride (589mg, 6.5mmol, 1.3eq) in THF (10ml_) was dropwise added, and the reaction mixture was warmed to -10°C. After 15min, LCMS showed full conversion. The reaction mixture was diluted with water (2m L) and the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (hexane: EtOAc, gradient elution from 10:1 to 0:100) to yield the desired product B6 (1.41 g, 60%) as a white solid. MS (ES) C27H33N5OS1 requires: 471, found: 472 (M+H) ⁺ .

Step 7: N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-ethyl-2-iodo-1H-pyr rolor2.3- blpyridin-3-yl)-2-methylphenyl)acrylamide (B7) N-(5-(5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-4-ethyl-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridin- 3-yl)-2-methylphenyl)acrylamide B6 (1.41 g, 3.0mmol, 1eq) and NIS (0.87g, 3.9mmol, 1.3eq) were dissolved in dry DCM (300ml_). The reaction mixture was stirred for 16h at room temperature, and was quenched with saturated aqueous Na ₂ S203 solution. The desired product was extracted with DCM (3x100ml_), the organic phase was washed with saturated aqueous NaHCOs solution, dried over Na ₂ S04, and solvent were removed in vacuo. The crude material B7 as an reddish solid (1.65g, quant.) was used without purification in the next step. MS (ES) C ₂ 4H ₂ 5lN ₅ 0 requires: 525, found: 526 (M+H) ⁺ .

Step 8: N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-ethyl-2-(4-(4-methy lpiperazin-1- yl)phenyl)-1H-pyrrolor2.3-blpyridin-3-yl)-2-methylphenyl)acr ylamide 2,2,2- trifluoroacetate (B8)

A mixture of N-(5-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-4-ethyl-2-iodo-1H-pyr rolo[2,3- b]pyridin-3-yl)-2-methylphenyl)acrylamide B7 (40mg, 0.08mmol, 1.0eq.), K3PO4 (32mg, 0.15mmol, 2.0eq.), [4-(4-methylpiperazin-1-yl)phenyl]boronic acid (25mg, 0.11 mmol, 1.5eq.) and [1 ,T-bis(diphenylphosphino)ferrocene]-palladium dichloride dichloromethane adduct (9mg, 0.01 mmol, 0.15eq.) in dioxane/water (4:1, 2ml_) was degassed by bubbling nitrogen through it for a few minutes. The mixture was then heated in the microwave at 130°C for 90min. The resulting reaction mixture was filtered through a syringe filter and the filtrate was directly used for reversed phase HPLC (C18 column) separation (water + 0.1% TFA/ACN + 0.1% TFA). The desired fractions were combined and lyophilized to yield the title compound B8 (2mg, 0.01 mmol, 3%) as a yellow solid. ¹ H NMR (300 MHz, MeOH-d ₄ ) d 7.95 (s, 1H), 7.59 (s, 1H), 7.42 (d, J = 8.9 Hz, 2H), 7.41 ( s, 1 H), 7.28 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 8.9 Hz, 2H), 6.51 (dd, J = 10.2 Hz, J = 17.0 Hz, H), 6.33 (dd, J = 1.6 Hz, J = 17.0 Hz, 1H), 5.77 (dd, J = 10.2 Hz, J = 1.6 Hz, 1H), 3.91 (m, 2H), 3.86 (s, 3H), 3.58 (m, 2H), 3.26 (m, 2H), 3.04 (m, 2H), 2.96 (s, 3H), 2.58 (m, 2H), 2.33 (s, 3H), 2.17 (s, 3H), 0.67 (t, J = 7.6 Hz, 3H). MS (ES) C35H39N7O requires: 573, found: 574 (M+H) ⁺ . The Example in the following table was prepared according to the procedure described for B8 (Example 10). Example 22:

N-(5-(4-chloro-5-(1 -methyl-1 H-pyrazol-4-yl)-2-(4-(4-methylpiperazin-1 -vDphenyl)- 1H-pyrrolor2.3-blpyridin-3-yl)-2-methylphenyl)acrylamide 2,2.2-trifluoroacetate Step 1 : 5-Bromo-4-chloro-3-(4-methyl-3-nitrophenyl)-2-(trimethylsily l)-1 H- pyrrolor2.3-blpyridine (C1)

A solution of 5-bromo-4-chloro-3-iodopyridin-2-amine (2.00 g, 42.8 mmol, 1.0 eq.) and trimethyl ((4-methyl-3-nitrophenyl)ethynyl)silane (1.54 g, 6.6 mmol, 1.1 eq.), 1 ,4- diazabicyclo[2.2.2]octane (1.14 g, 10.2 mmol, 1.7 eq.) and bis-(thphenylphosphine) palladium (II) dichloride (0.4 g, 0.6 mmol, 0.1 eq.) in dimethylformamide (38 ml_) under nitrogen atmosphere, divided in two microwave vials, was heated at 145°C for 2h in the microwave. The reaction mixture was diluted with ethyl acetate (200 ml_) and was washed twice with aq. sat. NaHCOs-solution. The organic phase was dried over anhydrous Na ₂ S04, filtered and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by flash column chromatography (cHex/EtOAc, gradient from 10:1 to 100% EtOAc) yielding the desired product C1 (2.5 g, 95%) as a yellow solid. MS (ES) Ci ₇ Hi ₇ BrCIN ₃ 0 ₂ Si requires: 438, found: 439 (M+H) ⁺ .

Step 2: 5-(5-Bromo-4-chloro-2-(trimethylsilyl)-1 H-pyrrolor2.3-blpyridin-3-yl)-2- methylaniline (C2)

To a stirred solution of 5-bromo-4-chloro-3-(4-methyl-3-nitrophenyl)-2-(trimethylsily l)-1 H- pyrrolo[2,3-b]pyridine C1 (2.14 g, 4.9 mmol, 1.0 eq.) in ethanol (200 ml_) were added saturated ammonium chloride solution (20 ml_) and iron powder (1.37 g, 24.5 mmol, 5 eq.) at room temperature. The resulting reaction mixture was heated to 90°C for 6h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a small pad of Celite and washed with ethyl acetate (200 ml_). The filtrate was washed with water (2 x 100 ml_), brine (200 ml_), dried over anhydrous Na ₂ S04, filtered and concentrated under reduced pressure. The crude compound was purified by RP flash column chromatography (water/ACN with 0.1 %TFA) to afford the desired product C2 (1.7 g, 85%) as a beige solid. ¹ H NMR (400 MHz, DMSO -d ₆ ) d 12.05 (s, 1 H), 8.44 (s, 1 H), 7.19 (d, J = 7.7 Hz, 1 H), 7.02 (s, 1 H), 6.96 (d, J = 7.7 Hz, 1 H), 2.28 (s, 3H), 0.10 (s, 9H). MS (ES) Ci ₇ H ₁₉ BrCIN ₃ Si requires: 408, found: 409 (M+H) ⁺ . Step 3: N-(5-(5-bromo-4-chloro-2-(trimethylsilyl)-1 H-pyrrolor2.3-blpyridin-3-yl)-2- methylphenvDacrylamide (C3

5-(5-Bromo-4-chloro-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylaniline C2 (1.67 g, 4.1 mmol, 1eq) was dissolved in dry THF (30ml_) at 0°C. Next, DIPEA (7.1mL,

41 mmol, 10eq) was added and the mixture was stirred for 2min. A solution of acryloyl chloride (444mg, 4.9mmol, 1.2eq) in dry THF (2ml_) was dropwise added, and the reaction mixture was stirred at 0°C. After 15min, LCMS showed full conversion. A few drops of water were added and the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (cHex/EtOAc, gradient elution from 10:1 to 0:100) to yield the desired product C3 (1.70g, 89%) as a beige solid. ¹ H NMR (400 MHz, DMSO -d ₆ ) d 12.04 (s, 1H), 9.43 (s, 1H), 8.43 (s, 1H), 7.55 (s, 1 H), 7.23 (d, J = 7.6 Hz, 1H), 7.05 (dd, J = 1.8 Hz, J = 7.6 Hz, 1H), 6.56 (dd, J = 10.1 Hz, J = 17.0 Hz, 1 H), 6.22 (dd, J = 2.0 Hz, J = 17.0 Hz, 1H), 5.73 (dd, J = 2.0 Hz, J = 10.1 Hz, 1 H), 2.29 (s, 3H), 0.10 (s, 9H). MS (ES) C ₂ oH _2i BrCIN ₃ OSi requires: 462, found:

463 (M+H) ⁺ .

Step 4: N-(5-(5-bromo-4-chloro-2-iodo-1 H-pyrrolor2.3-blpyridin-3-yl)-2- methvlphenvDacrvlamide (C4

N-(5-(5-bromo-4-chloro-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2- methylphenyl)acrylamide C3 (0.70g, 1.51 mmol, 1eq) and NIS (0.68g, 3.02mmol, 2.0eq) were dissolved in dry DCM (300m L). The reaction mixture was stirred for 16h at room temperature, and was quenched with saturated aqueous Na ₂ S ₂ 0 ₃ solution. The precipitated solid was filtered off, washed with small amounts of water and DCM, and finally dried in vacuo yielding the desired product C4 as a beige solid (0.25g, 32%). The crude was used without purification in the next step. MS (ES) Ci ₇ Hi ₂ BrCIIN ₃ 0 requires: 516, found: 517 (M+H) ⁺ . Step 5: N-(5-(5-bromo-4-chloro-2-(4-(4-methylpiperazin-1 -yl)phenyl)-1 H- pyrrolor2.3-blpyridin-3-yl)-2-methylphenyl)acrylamide (C5)

A mixture of N-(5-(5-bromo-4-chloro-2-iodo-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2- methylphenyl)acrylamide C4 (100mg, 0.2mmol, 1.0eq.), Na ₂ C03 (41 mg, 0.4mmol, 2.0eq.), [4-(4-methylpiperazin-1-yl)phenyl]boronic acid (47mg, 0.2mmol, 1.1eq.) and [1 ,1'-bis(diphenylphosphino)ferrocene]-palladium dichloride dichloromethane adduct (16mg, 0.02mmol, 0.1eq.) in dioxane/MeOH/water (4:2:1, 2ml_) was degassed by bubbling nitrogen through it for a few minutes. The mixture was then heated at 80°C for 3h. The resulting mixture was diluted with saturated aqueous NaHCOs solution, and extracted with EtOAc (3x30ml_). The organic layer was dried over Na ₂ S04, and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane: EtOAc, gradient elution from 10:1 to 0:100) to afford the pure product C5 as a yellow solid (3mg, 3%). ¹ H NMR (400 MHz, DMSO -d ₆ ) d 12.51 (s, 1H), 9.46 (s, 1 H), 8.39 (s, 1H), 7.56 (s, 1H), 7.37 (d, J = 8.9 Hz, 2H), 7.23 (d, J = 7.9 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.94 (d, J = 8.9 Hz, 2H), 6.53 (dd, J = 10.1 Hz, J = 17.0 Hz, 1 H), 6.20 (dd, J = 2.0 Hz, J = 17.0 Hz, 1H), 5.72 (dd, J = 2.0 Hz, J = 10.1 Hz, 1H), 3.93 (d, J = 13.3 Hz, 2H), 3.48 (d, J = 11.9 Hz, 2H), 3.10 (m, 2H), 2.97 (m, 2H), 2.84 (s, 3H), 2.28 (s, 3H). MS (ES) C ₂₈ H ₂₇ BrCIN ₅ 0 requires: 564, found: 565 (M+H) ⁺ .

Step 6: N-(5-(4-chloro-5-(1 -methyl-1 H-pyrazol-4-yl)-2-(4-(4-methylpiperazin-1 - yl)phenyl)-1H-pyrrolor2.3-blpyridin-3-yl)-2-methylphenyl)acr ylamide 2,2,2- trifluoroacetate (C6)

A mixture of N-(5-(5-bromo-4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)- 1 H- pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide C5 (30mg, 0.05mmol, 1.0eq.), K ₃ PO ₄ (34mg, 0.15mmol, 3.0eq.), 1-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 H-pyrazole (22mg, O.lmmol, 1.1eq.) and [1 ,T-bis(diphenylphosphino)ferrocene]- palladium dichloride dichloromethane adduct (4mg, 0.05mmol, 0.1eq.) in dioxane/ water (5:1 , 2m L) was degassed by bubbling nitrogen through it for a few minutes. The mixture was then heated in the microwave at 130°C for 90m in. The resulting reaction mixture was filtered through a syringe filter and the filtrate was directly used for reversed phase HPLC (C18 column) separation (water + 0.1% TFA/ACN + 0.1 % TFA). The desired fractions were combined and lyophilized to yield the title compound C6 (2.0mg, 5%) as a yellow solid. ¹ H NMR (400 MHz, DMSO -d ₆ ) d: 12.29 (s, 1 H), 9.59 (br s, 1 H), 9.46 (s, 1 H), 8.31 (s, 1 H), 8.05 (d, J = 0.9 Hz, 1 H), 7.75 (d, J = 0.9 Hz, 1 H), 7.57 (s, 1 H), 7.36 (d, J = 8.9 Hz, 2H), 7.22 (d, J = 7.8 Hz, 1 H), 7.05 (d, J = 7.8 Hz, 1 H), 6.94 (d, J = 8.9 Hz, 2H), 6.54 (dd, J = 10.4 Hz, J = 17.1 Hz, 1 H), 6.19 (dd, J = 2.1 Hz, J = 17.1 Hz, 1 H), 5.71 (dd, J = 2.1 Hz, J = 10.4 Hz, 1 H), 3.92 (d, J = 13.8 Hz, 2H), 3.88 (s, 3H), 3.48 (d, J = 12.1 Hz, 2H), 3.11 (m, 2H), 2.96 (m, 2H), 2.84 (s, 3H), 2.28 (s, 3H). MS (ES) C32H32CIN7O requires: 566, found: 567 (M+H) ⁺ .

Example 23:

N-(5-(4-chloro-5-(1.5-dimethyl-1H-pyrazol-4-yl)-2-(4-(4-m ethylpiperazin-1- yl)phenyl)-1H-pyrrolor2.3-blpyridin-3-yl)-2-methylphenyl)acr ylamide 2,2,2- trifluoroacetate (DD

A mixture of N-(5-(5-bromo-4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)- 1 H- pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide C5 (120mg, 0.21 mmol, 1.0eq.), K3PO4 (135mg, 0.63mmol, 3.0eq.), 1 ,5-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (142mg, 0.63mmol, 3.0eq.) and [1 ,1'- bis(diphenylphosphino)ferrocene]-palladium dichloride dichloromethane adduct (17mg, 0.02mmol, 0.1eq.) in dioxane/ water (5:1 , 2ml_) was degassed by bubbling nitrogen through it for a few minutes. The mixture was then heated in the microwave at 130°C for 90min. The resulting reaction mixture was filtered through a syringe filter and the filtrate was directly used for reversed phase HPLC (C18 column) separation (water + 0.1 % TFA/ACN + 0.1 % TFA). The desired fractions were combined and lyophilized to yield the title compound D1 (4.0mg, 2%) as a yellow solid. ¹ H NMR (400 MHz, DMSO -de) d 12.32 (s, 1 H), 9.56 (br s, 1 H), 9.45 (s, 1 H), 8.05 (s, 1 H), 7.56 (s, 1 H), 7.40 (s, 1 H), 7.37 (d, J = 8.9 Hz, 2H), 7.21 (d, J = 7.8 Hz, 1 H), 7.07 (d, J = 7.8 Hz, 1 H), 6.94 (d, J = 8.9 Hz, 2H), 6.54 (dd, J = 10.4 Hz, J = 17.1 Hz, 1 H), 6.19 (dd, J = 1.8 Hz, J = 17.1 Hz, 1 H), 5.72 (dd, J = 1.8 Hz, J = 10.4 Hz, 1 H), 3.92 (d, J = 13.5 Hz, 2H), 3.78 (s, 3H), 3.48 (d, J = 11.8 Hz, 2H), 3.11 (m, 2H), 2.97 (m, 2H), 2.84 (s, 3H), 2.27 (s, 3H), 2.16 (s, 3H). MS (ES) C33H34CIN7O requires: 580, found: 581 (M+H) ⁺ . The Examples in the following table were prepared according to the procedure described for D1 (Example 23). The Examples in the following table were prepared from 5-bromo-3-iodo-4- methoxypyridin-2-amine, trimethyl((4-methyl-3-nitrophenyl)ethynyl)silane and 4-(4- methylpiperazin-1-yl)phenylboronic acid according to the procedure described for A6 (Example 1). The Examples in the following table were prepared from 5-bromo-3-iodo-4- methylpyridin-2-amine, trimethyl((4-methyl-3-nitrophenyl)ethynyl)silane and 4-(4- methylpiperazin-1-yl)phenylboronic acid according to the procedure described for A6 (Example 1).

Example 122:

N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-m ethylpiperazin-1- yl)phenyl)-1H-pyrrolor2.3-blpyridin-3-yl)-2.6-dimethylphenyl )acrylamide 2,2,2- trifluoroacetate (E6)

Step 1 : 5-Bromo-3-(2.4-dimethyl-3-nitrophenyl)-4-methyl-2-(trimethyl silyl)-1 H- pyrrolo G2, 3-bl pyridine (E1) To a stirred solution of 5-bromo-3-iodo-4-methylpyridin-2-amine (5 g, 15.9 mmol, 1 eq.) in DMF (40 ml_) was added ((2,4-dimethyl-3-nitrophenyl)ethynyl)trimethylsilane (4.34 g, 17.5 mmol, 1.1 eq.) and DABCO (3.03 g, 27 mmol, 1.7 eq.) at room temperature under nitrogen atmosphere. The reaction mixture was degassed for 10 minutes using nitrogen at gas. Then Pd (PPh3) ₂ Cl2 (1.1 g, 1.59 mmol) was added at room temperature. The resulting reaction mixture was stirred at 120°C for 48h in sealed tube. The reaction mixture was quenched with water (50 ml_) and the aqueous layer was extracted with

EtOAc (2 x150 ml_), combined organic layer was washed with cooled water (2 x 50 ml_) and brine (50 ml_), dried over anhydrous Na ₂ S04, filtered and concentrated under reduced pressure to get the crude compound. The crude compound was purified by column chromatography (5% ethyl acetate in pet ether) to obtain 5-bromo-3-(2,4- dimethyl-3-nitrophenyl)-4-methyl-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridine E1 (1.5 g, 21%) as a pale yellow solid. MS (ES) Ci ₉ H ₂₂ BrN ₃ 0 ₂ Si requires: 431/433, found: 432/434 (M+H) ⁺ .

Step 2: 3-(5-Bromo-4-methyl-2-(trimethylsilyl)-1 H-pyrrolor2.3-blpyridin-3-yl)-2.6- dimethylaniline (E2)

To a stirred solution of 5-bromo-3-(2,4-dimethyl-3-nitrophenyl)-4-methyl-2- (trimethylsilyl)-l H-pyrrolo [2, 3-b] pyridine E1 (2.95 g, 6.82 mmol, 1 eq.) in ethanol:H ₂ 0 (1:1, 60 ml_) were added Zinc-dust (2.2 g, 34.1 mmol, 5.0 eq.) and NH ₄ CI (1.85 g, 34.1 mmol, 5.0 eq.) at room temperature. The resulting reaction mixture was stirred at 80°C for 16h. The reaction mixture was filtered through a small pad of Celite and the Celite pad was washed with ethanol (50 ml_). The filtrate was evaporated under reduced pressure to get crude compound. The crude compound was purified by column chromatography (5% ethyl acetate in pet ether) to obtain the desired product E2 (1.4 g, 34%) as an off white solid. ¹ H NMR (400 MHz, DMSO -d ₆ ) d 11.53 (s, 1 H), 8.25 (s, 1 H), 6.82 (d, J = 7.6 Hz, 1H), 6.38 (d, J = 7.2 Hz, 1H), 4.55 (s, 2H), 2.15 (s, 3H), 1.99 (s, 3H), 1.76 (s, 3H), 0.01 (s, 9H). MS (ES) Ci9H ₂₄ BrN ₃ Si requires: 403/401, found: 404/402 (M+H) ⁺ .

Step 3: _ 3-(5-(1.5-Dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(trimethylsil yl)-1H-

Pvrrolor2,3-blpvridin-3-vD-2,6-dimethvlaniline (E3)

A mixture of N3-(5-bromo-4-methyl-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2,6- dimethylaniline E2 (977mg, 2.43mmol, 1.0eq.), K ₃ P0 ₄ (1030mg, 4.86mmol, 2.0eq.), 1,5- dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (81 Omg,

3.65mmol, 1.5eq.) and [1 ,T-bis(diphenylphosphino)ferrocene]-palladium dichloride dichloromethane adduct (199mg, 0.24mmol, 0.1eq.) in dioxane/water (10:1) was degassed by bubbling nitrogen through it for a few minutes. The mixture was then heated in the microwave at 130°C for 90min. The resulting mixture was diluted with saturated aqueous NaHC0 ₃ solution, and extracted with EtOAc (3x100ml_). The organic layer was washed with saturated aqueous NaCI solution, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane: EtOAc, gradient elution from 10:1 to 0:100) to afford the pure product E3 as a yellow solid (1.3g, 63%). ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 11.30 (s, 1 H), 7.92 (s, 1 H), 7.31 (s, 1 H), 6.80 (d, J = 7.5 Hz, 1 H), 6.41 (d, J = 7.5 Hz, 1 H), 4.50 (br s, 2H), 3.76 (s, 3H), 2.14 (s, 3H), 2.08 (s, 3H), 1.80 (s, 6H), 0.03 (s, 9H). MS (ES) C24H _3i N ₅ Si requires: 417, found: 418 (M+H) ⁺ .

Step 4: N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(trimethyl silyl)-1H- pyrrolor2.3-blpyridin-3-yl)-2.6-dimethylphenyl)acrylamide (E4)

3-(5-(1 ,5-Dimethyl-1 H-pyrazol-4-yl)-4-methyl-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridin- 3-yl)-2,6-dimethylaniline E3 (1019mg, 2.4mmol, 1eq) was dissolved in dry THF (90ml_) at -78°C. DIPEA (4.1 ml_, 24mmol, 10eq) was dropped, and then a solution of acryloyl chloride (220mg, 2.4mmol, 1.0eq) in 10ml_ of THF was added dropwise. The reaction mixture was slowly warmed to room temperature. After 30min, additional acryloyl chloride (110mg, 1 .2mmol, 0.5eq) was added and after 20min a few drops of water was added. The mixture was evaporated in vacuo and the crude was purified by column chromatography (hexane: EtOAc, gradient elution from 10:1 to 0:100) to yield the desired material E4 (509mg, 44%) as a white solid. ¹ H NMR (300 MHz, DMSO -do) d 11.42 (s, 1 H), 9.56 (s, 1 H), 7.94 (s, 1 H), 7.30 (s, 1 H), 7.10 (d, J = 7.8 Hz, 1 H), 7.07 (d, J = 7.8 Hz, 1 H), 6.47 (dd, J = 10.3 Hz, J = 17.1 Hz, 1 H), 6.22 (dd, J = 2.1 Hz, J = 17.1 Hz, 1 H), 5.71 (dd, J = 2.1 Hz, J = 10.3 Hz, 1 H), 3.77 (s, 3H), 2.18 (s, 3H), 2.08 (s, 3H), 1.84 (s, 3H), 1.80 (s, 3H), 0.05 (s, 9H). MS (ES) C27H33N5OS1 requires: 471 , found: 472 (M+H) ⁺ .

Step 5: N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-2-iodo-4-methyl-1H-py rrolor2.3- blpyridin-3-yl)-2.6-dimethylphenyl)acrylamide (E5)

N-(3-(5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-4-methyl-2-(trimethylsilyl)-1 H-pyrrolo[2,3- b]pyridin-3-yl)-2,6-dimethylphenyl)acrylamide E4 (545mg, 1.15mmol, 1eq) and NIS (468mg, 2.08mmol, 1.8eq) were dissolved in dry DCM (90ml_), and stirred for 16h at room temperature. The reaction mixture was quenched with saturated aqueous Na ₂ S203 solution, and the desired product was extracted with DCM (3x100ml_). The organic phase was washed with saturated aqueous NaHCOs solution, dried over Na ₂ S04, and solvent were removed in vacuo. The crude material E5 as an orange solid (548mg, 90%) was used without purification in the next step. MS (ES) C^H^INsO requires: 525, found: 526 (M+H) ⁺ .

Step 6: N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-meth ylpiperazin-1- yl)phenyl)-1H-pyrrolor2.3-blpyridin-3-yl)-2.6-dimethylphenyl )acrylamide 2,2,2- trifluoroacetate (E6)

A mixture of N-(3-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-2-iodo-4-methyl-1H-py rrolo[2,3- b]pyridin-3-yl)-2,6-dimethylphenyl)acrylamide E5 (50mg, 0.1 mmol, 1.0eq.), K3PO4 (40mg, 0.2mmol, 2.0eq.), [4-(4-methylpiperazin-1-yl)phenyl]boronic acid (27mg, O.lmmol, 1.3eq.) and [1 ,T-bis(diphenylphosphino)ferrocene]-palladium dichloride dichloromethane adduct (7mg, 0.01 mmol, 0.1eq.) in dioxane/water (4:1, 2ml_) was degassed by bubbling nitrogen through it for a few minutes. The mixture was then heated in the microwave at 130°C for 90min. The resulting reaction mixture was filtered through a syringe filter and the filtrate was directly used for reversed phase HPLC (C18 column) separation (water + 0.1% TFA/ACN + 0.1% TFA). The desired fractions were combined and lyophilized to yield the title compound E6 (19mg, 25%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 11.96 (s, 1H), 9.67 (br s, 1H), 9.58 (s, 1H), 7.91 (s, 1 H), 7.33 (d, J = 8.9 Hz, 2H), 7.30 (s, 1H), 7.10 (d, J= 7.8 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1 H), 6.88 (d, J = 8.9 Hz, 2H), 6.47 (dd, J = 10.3 Hz, J = 17.2 Hz, 1H), 6.20 (dd, J = 2.0 Hz, J = 17.2 Hz, 1 H), 5.71 (dd, J = 2.0 Hz, J = 10.3 Hz, 1 H), 3.88 (d, J = 13.4 Hz, 2H), 3.76 (s, 3H), 3.46 (m, 2H), 3.08 (m, 2H), 2.94 (t, J = 12.4 Hz, 2H), 2.83 (s, 3H), 2.19 (s, 3H), 2.08 (s, 3H), 1.86 (s, 3H), 1.77 (s, 3H). MS (ES) C35H39N7O requires: 573, found: 574 (M+H) ⁺ .

The Examples in the following table were prepared to the procedure described for E6 (Example 122).

Example 127:

N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-2-(4-(2-(dimethyla mino)ethoxy)phenyl)-4- methyl-1 H-pyrrolor2.3-blpyridin-3-yl)-3-fluoro-2-methylphenyl)acryla mide 2,2,2- trifluoroacetate (F7) Step 1: r2-(3-Fluoro-4-methyl-5-nitrophenyl)ethvnvntrimethylsilane (F1) In a pressure tube, 5-bromo-1-fluoro-2-methyl-3-nitrobenzene (5g, 214mmol, 1eq) and Cul (407mg, 21 mmol, 0.05eq) were dissolved in DMF (50ml_). Next, triethylamine (8.97mL, 886mmol, 4.15eq) and bis(triphenylphosphine)palladium (II) dichloride (1.5g, 21 mmol, 0.05eq) were added. The tube was purged with argon, and then trimethylsilylacetylen (4.65ml_, 321 mmol, 1.25eq) was added. The reaction mixture was stirred at room temperature for 24h. The resulting mixture was diluted with an aqueous solution of NH ₄ CI, and extracted with DCM (4x 50ml_). The organic layers were combined, washed with brine, dried over Na ₂ S0 ₄ , filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (hexane: EtOAc, 0-30% of EtOAc) to afford the pure product F1 as a yellow solid (5g, Y:93%). ¹ H NMR (300 MHz, DMSO -d ₆ ) d 7.63 (t, J = 1.5 Hz, 1 H), 7.48 (dd, J = 9.8, 1.6

Hz, 1 H), 2.11 (d, J = 2.2 Hz, 3H), 0.00 (s, 9H).

Step 2: 5-Bromo-3-(3-fluoro-4-methyl-5-nitrophenyl)-4-methyl-2-(trim ethylsilyl)-1 H- Pvrrolor2,3-blpvridine (F2)

In a pressure tube, 5-bromo-3-iodo-4-methylpyridin-2-amine (5g, 16mmol, 1eq) and [2- (3-fluoro-4-methyl-5-nitrophenyl)ethynyl]trimethylsilane F1 (5.02g, 20mmol, 1.25eq) were dissolved in DMF (50ml_). Next, triethylenediamine (3.05g, 27mmol, 1.7eq) and bis(triphenylphosphine)palladium (II) dichloride (1.13g, 0.16mmol, 0.1eq) were added, the tube was purged with argon, and the reaction mixture was heated at 145°C for 24h. The resulting mixture was diluted with saturated aqueous NaHCOs solution, and extracted with EtOAc (3x50ml_). The organic layers were combined, washed with saturated aqueous NaCI solution, dried over Na ₂ S0 ₄ , filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (hexane: acetone 1 :1) to afford the pure product F2 as a pale yellow solid (2g, Y:29%). 1 H NMR (300 MHz, DMSO-c/6) d 11.80 (s, 1 H), 8.23 (s, 1 H), 7.70 (t, J = 1.4 Hz, 1 H), 7.59 (dd, J = 9.9, 1.7 Hz, 1 H), 2.34 (d, J = 2.1 Hz, 3H), 2.03 (s, 3H), 0.00 (s, 9H). MS (ES) Ci ₇ H ₁₇ BrFN ₃ 0 ₂ Si requires: 437/435, found: 438/436 (M+H) ⁺ .

Step 3: 5-(1.5-Dimethyl-1H-pyrazol-4-yl)-3-(3-fluoro-4-methyl-5-nitr ophenyl)-4- methyl-2-(trimethylsilyl)-1 H-pyrrolor2.3-blpyridine (F3)

5-Bromo-3-(3-fluoro-4-methyl-5-nitrophenyl)-4-methyl-2-(t rimethylsilyl)-1 H-pyrrolo[2,3- b]pyridine F2 (23.18g, 53mmol, 1eq), 1 ,5-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (11.8g, 53mmol, 1eq), and Na ₂ C03 (51.42g, 372mmol, 7eq) were placed in a pressure tube, treated with a mixture of DME (390ml_) - EtOH (350ml_), and purged with argon. Next, Pd(PPh ₃ )4 (14.12g, 12mmol, 0.23eq) was added, and the reaction mixture was heated at 80°C for 24h. The resulting mixture was cooled down, diluted with water, and extracted with DCM (3x1 OmL). The organic layers were combined, dried over Na ₂ S04, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH, 9:1) to afford the product F3 as a yellow solid (6g, Y:42%). MS (ES) C ₂₃ H ₂ 6FN50 ₂ Si requires: 451 , found: 452 (M+H) ⁺ .

Step 4: 5-(5-(1.5-Dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(trimethylsil yl)-1H- Pvrrolor2,3-blpvridin-3-vl)-3-fluoro-2-methvlaniline (F4)

A suspension of 4-[3-(3-fluoro-4-methyl-5-nitrophenyl)-4-methyl-2-(trimethyl silyl)-1 H- pyrrolo[2,3-b]pyridin-5-yl]-1 ,5-dimethyl-1 H-pyrazole F3 (6g, 14mmol, 1eq) and iron (3.9g, 71 mmol, 5eq) in a mixture of EtOH (60ml_) and saturated aqueous NH ₄ CI solution (6m L) was stirred at 80°C for 4h. Then, the solvents were removed under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH 9:1 ) to obtain the desired product F4 as a yellow solid (5g, Y:80%). MS (ES) C ₂₃ H ₂₈ FN ₅ Si requires: 421 , found: 422 (M+H) ⁺ . Step 5: N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(trimethyl silyl)-1H- Pvrrolor2,3-blpvridin-3-vD-3-fluoro-2-methvlphenvl)acrvlamid e (F5)

5-[5-(1 ,5-Dimethyl-1 H-pyrazol-4-yl)-4-methyl-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridin-3- yl]-3-fluoro-2-methylaniline F4 (3.4g, 8mmol, 1eq) was dissolved in THF (15ml_). The solution was cooled down to -10°C, DIPEA (14ml_, 80mmol, 10eq) was dropwise added, and the mixture was stirred for 5min at -10°C. A solution of acryloyl chloride (1 ml_, 13mmol, 1.65eq) in THF (5ml_) was dropwise added, and the reaction mixture was slowly warmed to room temperature. After 2h, LCMS showed full conversion. The reaction mixture was quenched with water (20ml_), and the product was extracted with DCM (3x1 OmL). The organic layers were combined together, dried over Na ₂ S04, filtered, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (CHCl3:/PrOH 9:1) to obtained the product F5 (667mg, 18%) as a creamy solid. ¹ H NMR (300 MHz, DMSO -cfe) d 11 .40 (s, 1 H), 9.54 (s, 1 H), 7.84 (d, J = 8.5 Hz, 1 H), 7.32 (s, 1 H), 7.21 (s, 1 H), 6.91 (dd, J = 10.0 Hz, J = 1.6 Hz, 1 H), 6.57 - 6.33 (m, 1 H), 6.21 - 6.04 (m, 1 H), 5.65 (dd, J = 10.1 Hz, J = 2.0 Hz, 1 H), 3.66 (d, J = 9.3 Hz, 3H), 2.08 (d, J = 2.1 Hz, 3H), 2.00 (s, 3H), 1 .84 (s, 3H), 0.00 (d, J = 2.1 Hz, 9H). MS (ES) C ₂₆ H ₃ oFN ₅ OSi requires: 475, found: 476 (M+H) ⁺ .

Step 6: N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-2-iodo-4-methyl-1H-py rrolor2.3- blpyridin-3-yl)-3-fluoro-2-methylphenyl)acrylamide (F6)

N-(5-(5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-4-methyl-2-(trimethylsilyl)-1 H-pyrrolo[2,3- b]pyridin-3-yl)-3-fluoro-2-methylphenyl)acrylamide F5 (750mg, 1.58mmol, 1eq) and NIS (639g, 2.84mmol, 1.8eq) were dissolved in dry DCM (lOOrriL). The reaction mixture was stirred for 4h at room temperature. After this time, the reaction mixture was quenched with saturated aqueous Na ₂ S203 solution. The desired product was extracted with DCM (3x100ml_). The organic layers were combined, washed with saturated aqueous NaHC03 solution, dried over Na ₂ S04, filtered, and solvent were removed in vacuo. The crude material F6 as a beige solid (616mg, Y:74%) was used without purification for the next step. MS (ES) C23H21FINO requires: 529, found: 530 (M+H) ⁺ .

Step 7: N-(5-(5-(1.5-Dimethyl-1H-pyrazol-4-vn-2-(4-(2- (dimethylamino)ethoxy)phenyl)-4-methyl-1H-pyrrolor2.3-blpyri din-3-yl)-3-fluoro-2- methylphenvDacrylamide 2,2.2-trifluoroacetate (F7)

A mixture of N-(5-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-2-iodo-4-methyl-1H-py rrolo[2,3- b]pyridin-3-yl)-3-fluoro-2-methylphenyl)acrylamide F6 (60mg, 0.1 mmol, 1.0eq.), K ₃ PO ₄ (48mg, 0.2mmol, 2.0eq.), (4-(2-(dimethylamino)ethoxy)phenyl)boronic acid (31 mg,

0.15mmol, 1.3eq.) and [1 ,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (9mg, 0.01 mmol, 0.1eq.) in dioxane/water (4:1, 2.0ml_) was degassed by bubbling nitrogen through it for a few minutes. The mixture was then heated in the microwave at 130°C for 2h. The resulting reaction mixture was filtered through a syringe filter and the filtrate was directly used for reversed phase HPLC (C18 column) separation (water + 0.1% TFA/ACN + 0.1% TFA = 95:5 to 60:40, 30 min). The desired fractions were combined and lyophilized to yield the title compound F7 (20mg, 22%) as a pale yellow solid. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 12.09 (s, 1H), 9.65 (s, 1 H), 9.56 (br s, 1 H), 7.95 (s, 1 H), 7.43 (s, 1 H), 7.39 (d, J = 8.9 Hz, 2H), 7.32 (s, 1 H), 6.99 (s, 1 H), 6.96 (d, J = 7.8 Hz, 2H), 6.51 (dd, J = 10.2 Hz, J = 17.1 Hz, 1H), 6.20 (dd,

J = 2.0 Hz, J = 17.1 Hz, 1 H), 5.73 (dd, J = 2.0 Hz, J = 10.2 Hz, 1H), 4.30 (t, J = 5.1 Hz, 2H), 3.78 (s, 3H), 3.49 (q, J = 5.1 Hz, 2H), 2.84 (s, 3H), 2.83 (s, 3H), 2.16 / 2.15 (s, 3H), 2.11 (s, 3H), 1.94 (s, 3H). MS (ES) C ₃₃ H ₃₅ FN ₆ O ₂ requires: 566, found: 567 (M+H) ⁺ . The Examples in the following table were prepared to the procedure described for F7 (Example 127).

The Examples in the following table were prepared from 5-bromo-3-iodopyridin-2- amine, ((3-fluoro-4-methyl-5-nitrophenyl)ethynyl)trimethylsilane and 4-(4- methylpiperazin-1-yl)phenylboronic acid according to the procedure described for A6 (Example 1).

The Examples in the following table were prepared from 5-bromo-3-iodopyridin-2- amine, ((5-fluoro-2,4-dimethyl-3-nitrophenyl)ethynyl)trimethylsilan e and 4-(4- methylpiperazin-1-yl)phenylboronic acid according to the procedure described for A6 (Example 1).

The Examples in the following table were prepared from 5-bromo-3-iodopyridin-2- amine, tert-butyl 6-((trimethylsilyl)ethynyl)indoline-1-carboxylate and 4-(4- methylpiperazin-1-yl)phenylboronic acid according to the procedure described for A6 (Example 1 ). Instead of the reduction in Step 4 of Example 1 for these Examples the protecting group tert-butyloxycarbonyl ( Boc ) was removed under standard conditions using TFA in DCM at ambient temperature.

The Examples in the following table were prepared from 5-bromo-3-iodopyridin-2- amine, tert-butyl 4-((trimethylsilyl)ethynyl)indoline-1-carboxylate and 4-(4- methylpiperazin-1-yl)phenylboronic acid according to the procedure described for A6 (Example 1 ). Instead of the reduction in Step 4 of Example 1 for these Examples the protecting group tert-butyloxycarbonyl {Boc) was removed under standard conditions using TFA in DCM at ambient temperature.

The Examples in the following table were prepared from 5-bromo-3-iodopyridin-2- amine, ((2-methoxy-4-methyl-3-nitrophenyl)ethynyl)trimethylsilane and 4-(4- methylpiperazin-1-yl)phenylboronic acid according to the procedure described for A6 (Example 1).

The Examples in the following table were prepared from 5-bromo-3-iodopyridin-2- amine, tert-butyl methyl(3-((trimethylsilyl)ethynyl)phenyl)carbamate and and 4-(4- methylpiperazin-1-yl)phenylboronic acid according to the procedure described for A6 (Example 1).

The Examples in the following table were prepared from 5-bromo-3-iodopyridin-2- amine, trimethyl((4-methyl-3-nitrophenyl)ethynyl)silane and (R)-1 ,2-dimethyl-4-(4- (4,4,5,5-tetramethyM ,3,2-dioxaborolan-2-yl)phenyl)piperazine according to the procedure described for A6 (Example 1 ).

The Examples in the following table were prepared from 5-bromo-3-iodo-4- methylpyridin-2-amine, trimethyl((4-methyl-3-nitrophenyl)ethynyl)silane and {R)~ 1 ,2- dimethyl-4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)piperazine according to the procedure described for A6 (Example 1 ).

The Examples in the following table were prepared from 5-bromo-3-iodo-pyridin-2- amine, trimethyl((4-methyl-3-nitrophenyl)ethynyl)silane and (S)-1 ,2-dimethyl-4-(4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)piperazine according to the procedure described for A6 (Example 1 ).

The Examples in the following table were prepared from 5-bromo-3-iodo-4- methylpyridin-2-amine, trimethyl((4-methyl-3-nitrophenyl)ethynyl)silane and (S)-1,2- dimethyl-4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)piperazine according to the procedure described for A6 (Example 1 ).

The Examples in the following table were prepared from 5-bromo-3-iodo-pyridin-2- amine, trimethyl((4-methyl-3-nitrophenyl)ethynyl)silane and N1 ,N1 ,N2-trimethyl-N2-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1 ,2-diamine according to the procedure described for A6 (Example 1 ).

Example 125:

N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-m ethylpiperazin-1- yl)phenyl)-1H-pyrrolor2.3-blpyridin-3-yl)phenyl)-N-methylacr ylamide 2,2,2- trifluoroacetate (G6)

Step-1: 5-Bromo-3-iodo-4-methvlPvridin-2-amine (G1)

To a stirred solution of 5-bromo-4-methylpyridin-2-amine (5 g, 26.7 mmol, 1 eq.) in DMF (100 ml_) were added TFA (2.47 ml_, 32 mmol, 1.2 eq.) and NIS (9.02 g, 40.1 mmol, 1.5 eq) at 0 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at 55 °C for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice water (50 ml_) and the aqueous layer was extracted with EtOAc (2 x 100 ml_). The combined organic layer was washed with cooled water (100 ml_) and saturated sodium thiosulphate solution followed by brine (50 ml_), dried over anhydrous Na ₂ S04, filtered and concentrated under reduced pressure to get crude compound. The crude compound was purified by column chromatography (EtOAc / pet ether) to obtain 5-bromo-3-iodo-4-methylpyridin-2-amine G1 (8 g, 95%) as a brown solid. ¹ H NMR (400 MHz, CDCIs) d 8.02 (s, 1H), 4.98 (br s, 2H), 2.59 (s, 3H). MS (ES) C ₆ H ₆ BrlN ₂ requires: 313, found: 314 (M+H) ⁺ .

Step-2: Tert-butyl (3-(5-bromo-4-methyl-2-(trimethylsilyl)-1H-pyrrolo G2, 3-bl pyridin-3-yl) phenvl) (methyl) carbamate (G2)

Boc

To a stirred solution of 5-bromo-3-iodo-4-methylpyridin-2-amine G1 (5 g, 15.9 mmol, 1 eq.) in 1, 4-dioxane (25 ml_) were added tert- butyl methyl (3-((trimethylsilyl) ethynyl) phenyl) carbamate (5.78 g, 19.0 mmol, 1.2 eq), K ₂ CO ₃ (4.38 g, 31.8 mmol, 2 eq.) and followed by LiBr (1.37 g, 15.9 mmol, 1 eq.) at room temperature under nitrogen atmosphere. The reaction mixture was degassed for 10 minutes under nitrogen atmosphere. Then Pd(PPh ₃ ) ₂ Cl ₂ (1.11 g, 1.59 mmol, 0.1 eq.) was added at room temperature. The resulting reaction mixture was stirred at 120°C for 16 h. The reaction mixture was quenched with water (50 ml_) and the aqueous layer was extracted with EtOAc(2 x 150 ml_), combined organic layer was washed with brine (50 ml_), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (EtOAc / pet ether) to obtain tert- butyl(3-(5-bromo-4-methyl-2-(trimethylsilyl)-1H-pyrrolo[2,3- b]pyridin-3- yl)phenyl)(methyl)carbamate G2 (4.9 g, 62%) as a pale brown solid. ¹ H NMR (400 MHz, DMSO -d ₆ ) d 11.69 (br s, 1 H), 8.30 (br s, 1 H), 7.40 - 7.36 (m, 1 H), 7.30 - 7.27 (m, 1 H), 7.22 (t, J = 2.0 Hz, 1 H), 7.19 - 7.15 (m, 1H), 3.18 (s, 3H), 2.09 (s, 3H), 1.35 (s, 9H), 0.07 (s, 9H). MS (ES) C ₂₃ H ₃ oBrN ₃ 0 ₂ Si requires: 487, found: 488 (M+H) ⁺ .

Step 3: Tert-butyl (3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(trimethylsi lyl)- 1 H-pvrrolor2,3-blpvridin-3-vl)phenvl)(methyl)carbamate (G3)

A mixture of tert-butyl (3-(5-bromo-4-methyl-2-(trimethylsilyl)-1 H-pyrrolo [2, 3-b] pyridin- 3-yl) phenyl) (methyl) carbamate G2 (1.0g, 2.05mmol, 1.0eq.), K ₃ PO ₄ (0.9g, 4.24mmol, 2.0eq.), 1 ,5-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (0.7g, 3.15mmol, 1.5eq.) and [1 ,T-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (0.2g, 0.25mmol, 0.1eq.) in dioxane/water (4:1, 16ml_) was degassed by bubbling nitrogen through it for a few minutes. The mixture was then heated in the microwave at 130°C for 2h. The resulting reaction mixture was evaporated in vacuo and the crude was purified by column chromatography (EtOAc/cHex) to obtain the desired product G3 (1.04g, 83%) as a yellow solid. MS (ES) C28H37N5O2S1 requires: 503, found: 504 (M+H) ⁺ .

Step 4: N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(trimethyl silyl)-1H- pyrrolor2.3-blpyridin-3-yl)phenyl)-N-methylacrylamide (G4)

A solution of tert-butyl (3-(5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-4-methyl-2-(trimethylsilyl)- 1 H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)(methyl)carbamate G3 (1.04g, 2.05mmol) in 30% TFA in DCM (30ml_) was stirred for 1h at RT. The mixture was evaporated in vacuo. The crude was resolved in dry THF (100ml_) and DIPEA (3.5ml_, 20mmol, 10eq) was added at -30°C. Then a solution of acryloyl chloride (216mg, 2.4mmol, 1.2eq) in 10mL of TFIF was added dropwise. After 15m in a few drops of water were added and the mixture was evaporated in vacuo. The crude was purified by column chromatography (hexane: EtOAc, gradient elution from 10:1 to 0:100) to yield the desired material G4 (610mg, 65%) as a white solid. MS (ES) C26H3iN ₅ OSi requires: 457, found: 458 (M+FI) ⁺ .

Step 5: N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-2-iodo-4-methyl-1H-py rrolor2.3- blpyridin-3-yl)phenyl)-N-methylacrylamide (G5)

N-(3-(5-(1 ,5-dimethyl-1 FI-pyrazol-4-yl)-4-methyl-2-(trimethylsilyl)-1 H-pyrrolo[2,3- b]pyridin-3-yl)phenyl)-N-methylacrylamide G4 (610mg, 1.33mmol, 1eq) and NIS (388mg, 1.73mmol, 1.3eq) were dissolved in dry DCM (300ml_), and stirred for 16h at room temperature. The reaction mixture was quenched with saturated aqueous Na ₂ S203 solution, and the desired product was extracted with DCM (3x100ml_). The organic phase was washed with saturated aqueous NaHCOs solution, dried over Na ₂ S04, and solvent were removed in vacuo. The crude material G5 as an yellow solid (489mg, 72%) was used without purification in the next step. MS (ES) C23H22IN5O requires: 511, found: 512 (M+H) ⁺ .

Step 6: N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-meth ylpiperazin-1- yl)phenyl)-1H-pyrrolor2.3-blpyridin-3-yl)phenyl)-N-methylacr ylamide 2,2,2- trifluoroacetate (G6)

A mixture of N-(3-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-2-iodo-4-methyl-1H-py rrolo[2,3- b]pyridin-3-yl)phenyl)-N-methylacrylamide G5 (75mg, 0.15mmol, 1.0eq.), K3PO4 (64mg, 0.30mmol, 2.0eq.), [4-(4-methylpiperazin-1-yl)phenyl]boronic acid (49mg, 0.22mmol,

1.5eq.) and [1 ,1'-bis(diphenylphosphino)ferrocene]-palladium dichloride dichloromethane adduct (12mg, 0.015mmol, 0.1eq.) in dioxane/water (4:1, 3ml_) was degassed by bubbling nitrogen through it for a few minutes. The mixture was then heated in the microwave at 130°C for 90min. The resulting reaction mixture was filtered through a syringe filter and the filtrate was directly used for reversed phase HPLC (C18 column) separation (water + 0.1% TFA/ACN + 0.1% TFA). The desired fractions were combined and lyophilized to yield the title compound G6 (22mg, 19%) as a yellow solid. 1H NMR (300 MHz, DMSO-d ₆ ) d 12.09 (s, 1 H), 9.63 (br s, 1 H), 7.95 (s, 1 H), 7.51 (t, J = 7.7 Hz, 1 H), 7.42 (d, J = 7.7 Hz, 1 H), 7.34 (s, 1 H), 7.32 - 7.21 (m, 4H), 6.94 (d, J = 9.0 Hz, 2H), 6.15 - 5.95 (m, 2H), 5.50 (dd, J = 2.4 Hz, J = 9.9 Hz, 1H), 3.90 (d, J = 13.1 Hz,

2H), 3.79 (s, 3H), 3.50 (d, J = 12.0 Hz, 2H), 3.23 (s, 3H), 3.11 (q, J = 11.0 Hz, 2H), 2.93 (t, J = 12.0 Hz, 2H), 2.86/2.85 (s, 3H), 2.12 (s, 3H), 1.95 (s, 3H). MS (ES) C34H37N7O requires: 559, found: 560 (M+H) ⁺ . The Example in the following table were prepared according to the procedure described for G6 (Example 125). Example 134:

N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-m ethylpiperazin-1- yl)phenyl)-1H-pyrrolor2.3-blpyridin-3-yl)phenyl)-N-methylmet hacrylamide 2,2,2- trifluoroacetate (H1)

To a solution of 3-(5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-4-methyl-2-(4-(4-methylpiperazin-1- yl)phenyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylaniline (50mg, 0.068mmol, 1.0eq) in dry DMF (0.9mL) at 0°C was added DIPEA (58uL, 0.341 mmol, 5eq), HATU (39mg, 0.102mmol, 1.5eq) and finally methacrylic acid (8mg, 0.089mmol, 1.3 eq). After 45min again HATU (39mg, 0.102mmol, 1.5eq) and methacrylic acid (8mg, 0.089mmol, 1.3 eq) were added. The reaction was stirred for 16h at RT. The resulting reaction mixture was diluted with MeOH, filtered through a syringe filter and the filtrate was directly used for reversed phase HPLC (C18 column) separation (water + 0.1 % TFA/ACN + 0.1 % TFA). The desired fractions were combined and lyophilized to yield the title compound H1 (13mg, 23%) as a yellow solid. ¹ H NMR (300 MHz, DMSO -cfe) d 12.04 (s, 1 H), 9.73 (br s, 1 H), 7.93 (d, J = 2.0 Hz, 1 H), 7.37 (dt, J = 2.0 Hz, J = 7.9 Hz, 1 H), 7.31 (d, J = 2.0 Hz, 1 H), 7.28 - 7.19 (m, 5H), 6.89 (d, J = 9.1 Hz, 2H), 5.03 (s, 1 H), 4.82 (s, 1 H), 3.88 (d, J = 13.6 Hz, 2H), 3.76 (s, 3H), 3.48 (d, J = 12.1 Hz, 2H), 3.21 (s, 3H), 3.10 (m, 2H), 2.93 (t, J = 12.9 Hz, 2H), 2.83 (s, 3H), 2.10 (s, 3H), 1.88 (s, 3H), 1.67 (s, 3H). MS (ES) C35H39N7O requires: 573, found: 574 (M+H) ⁺ .

Example 135:

N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-ethyl-2-(4-(4-me thylpiperazin-1-yl)phenyl)- 1H-pyrrolor2.3-blpyridin-3-yl)-2-methylphenyl)methacrylamide 2,2,2- trifluoroacetate (ID

To a solution of 5-(5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-4-ethyl-2-(4-(4-methylpiperazin-1- yl)phenyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylaniline (50mg, 0.096mmol, 1.0eq) in dry THF (2ml_) at -40°C was added DIPEA (0.17ml_, 0.96mmol, 10eq) and methacryloyl chloride (12mg, 0.12mmol, 1.2 eq). After stirring for 15min, a drop of water was added and the mixture was directly used for reversed phase HPLC (C18 column) separation (water + 0.1 % TFA/ACN + 0.1 % TFA). The desired fractions were combined and lyophilized to yield the title compound 11 (8mg, 10%) as a yellow solid. ¹ FI NMR (300 MHz, DMSO-de) d 12.08 (s, 1 H), 9.75 (br s, 1 H), 9.30 (s, 1 H), 7.89 (s, 1 H), 7.40 (d, J = 1.7 Hz, 1 H), 7.35 (d, J = 8.9 Hz, 2H), 7.32 (s, 1 H), 7.25 (d, J = 7.8 Hz, 1 H), 7.12 (dt, J = 1.7 Hz, J = 7.8 Hz, 1 H), 6.90 (d, J = 8.9 Hz, 2H), 5.84 (s, 1 H), 5.47 (s, 1 H), 3.90 (d, J = 13.5 Hz, 2H), 3.79 (s, 3H), 3.48 (d, J = 12.0 Hz, 2H), 3.10 (m, 2H), 2.96 (t, J = 12.7 Hz, 2H), 2.85 (s, 3H), 2.36 (m, 2H), 2.26 (s, 3H), 2.09 (s, 3H), 1.94 (3H), 0.58 (t, J = 7.4 Hz, 3H). MS (ES) C ₃₆ H ₄₁ N ₇ O requires: 587, found: 588 (M+H) ⁺ .

Example 136:

N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-m ethylpiperazin-1- yl)phenyl)-1H-pyrrolor2.3-blpyridin-3-yl)phenyl)-N-methylbut -2-enamide 2,2,2- trifluoroacetate (J1)

To a solution of 3-(5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-4-methyl-2-(4-(4-methylpiperazin-1- yl)phenyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylaniline (50mg, 0.068mmol, 1.0eq) in dry THF (lOrnL) at -78°C was added DIPEA (116uL, 0.68mmol, 10eq) and but-2-enoyl chloride (8mg, 0.089mmol, 1.3 eq). After 45 min again but-2-enoyl chloride (7mg, 0.069mmol, 1.0 eq) in dry THF (0.3ml_) was added. After stirring 1 h, a drop of water was added and the mixture was directly used for reversed phase HPLC (C18 column) separation (water + 0.1 % TFA/ACN + 0.1 % TFA). The desired fractions were combined and lyophilized to yield the title compound J1 (4mg, 6%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-de) d 12.08 (s, 1 H), 9.71 (br s, 1 H), 7.93 (s, 1 H), 7.47 (t, J = 7.8 Hz, 1 H), 7.35 (d, J = 7.8 Hz, 1 H), 7.32 - 7.21 (m, 5H), 6.92 (d, J = 8.9 Hz, 2H), 6.66 (dq, J = 6.9 Hz, 15.0 Hz, 1 H), 5.73 (d, J = 15.0 Hz, 1 H), 3.86 (d, J = 13.5 Hz, 2H), 3.76 (s, 3H), 3.47 (d, J = 11.8 Hz, 2H), 3.19 (s, 3H), 3.08 (m, 2H), 2.92 (t, J = 12.7 Hz, 2H), 2.83 (s, 3H), 2.10 (s, 3H), 1.92 (s, 3H), 1.62 (d, J = 6.9 Hz, 3H). MS (ES) C ₃₅ H ₃₉ N ₇ O requires: 573, found: 574 (M+H) ⁺ . Example 137:

(N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4- methylpiperazin-1- yl)phenyl)-1H-pyrrolor2.3-blpyridin-3-yl)-2-methylphenyl)-N- methylacrylamide

2,2.2-trifluoroacetate (K2

Step 1: N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-2-iodo-4-methyl-1H-py rrolor2.3- blpyridin-3-yl)-2-methylphenyl)-N-methylacrylamide (K1 )

N-(5-(5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-4-methyl-2-(trimethylsilyl)-1 H-pyrrolo[2,3- b]pyridin-3-yl)-2-methylphenyl)-N-methylacrylamide (600mg, 1.2mmol, 1eq) and NIS (350mg, 1.6mmol, 1.6eq) were dissolved in dry DCM (20ml_). The reaction mixture was stirred for 16h at room temperature. After this time, the reaction mixture was quenched with saturated aqueous Na ₂ S203 solution. The desired product was extracted with DCM (3x100ml_). The organic layers were combined, washed with saturated aqueous NaHCOs solution, dried over Na ₂ S04, filtered, and solvent were removed in vacuo. The crude material K1 as a beige solid (624mg, Y:99%) was used without purification for the next step. MS (ES) C^H^INsO requires: 525, found: 526 (M+H) ⁺ .

Step 2: (N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-met hylpiperazin-1- yl)phenyl)-1H-pyrrolor2.3-blpyridin-3-yl)-2-methylphenyl)-N- methylacrylamide 2.2.2-trifluoroacetate (K2

A mixture of N-(5-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-2-iodo-4-methyl-1H-py rrolo[2,3- b]pyridin-3-yl)-2-methylphenyl)-N-methylacrylamide K1 (60mg, 0.1 mmol, 1.0eq.), K ₃ PO ₄ (49mg, 0.2mmol, 2.0eq.), 4-(4-methylpiperazin-1-yl)phenylboronic acid (38mg, 0.2mmol, 1.5eq.) and [1 ,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (14mg, 0.02mmol, 0.15eq.) in dioxane/water (4:1, 3.0ml_) was degassed by bubbling nitrogen through it for a few minutes. The mixture was then heated in the microwave at 130°C for 2h. The resulting reaction mixture was filtered through a syringe filter and the filtrate was directly used for reversed phase HPLC (C18 column) separation (water + 0.1% TFA/ACN + 0.1% TFA). The desired fractions were combined and lyophilized to yield the title compound K2 (14mg, 15%) as a pale yellow solid. ¹ FI NMR (400MHz, d ₆ -DMSO, 300K) d 12.11 (s, 1H), 9.68 (s, 1H), 7.96 (s, 1H), 7.42 - 7.23 (m, 6H), 6.94 (d, J = 8.9 Hz, 2H), 6.14 (dd, J = 2.5 Hz, J = 16.4 Hz, 1H), 5.87 (dd, J =

16.4 Hz, J = 10.3 Hz, 1H), 5.54 (dd, J = 2.5 Hz, J = 10.3 Hz, 1H), 3.90 (d, J = 13.4 Hz, 2H), 3.79 (s, 3H), 3.50 (d, J = 12.1 Hz, 2H), 3.13 (s, 3H), 3.10 (m, 2H), 2.95 (t, J = 12.7 Hz, 2H), 2.86 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H), 1.97 (s, 3H). MS (ES) C35H39N7O requires: 573, found: 574 (M+H) ⁺ .

The Examples in the following table were prepared according to the procedure described for K2 (Example 137). Example 142:

N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-m ethylpiperazin-1- yl)phenyl)-1H-pyrrolor2.3-blpyridin-3-yl)-5-fluoro-2.6-dimet hylphenyl)acrylamide

2,2.2-trifluoroacetate (L1

A mixture of N-(3-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-2-iodo-4-methyl-1H-py rrolo[2,3- b]pyridin-3-yl)-5-fluoro-2,6-dimethylphenyl)acrylamide (55mg, O.IOmmol, 1.0eq.), which was prepared according to the procedure Example 21 Step 1-7, K3PO4 (43mg, 0.20mmol, 2.0eq.), 4-(4-methylpiperazin-1-yl)phenylboronic acid (29mg, 0.13mmol, 1.3eq.) and [1 ,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (8mg, 0.01 mmol, 0.1eq.) in dioxane/water (4:1, 2.2ml_) was degassed by bubbling nitrogen through it for a few minutes. The mixture was then heated in the microwave at 130°C for 2h. The resulting reaction mixture was filtered through a syringe filter and the filtrate was directly used for reversed phase HPLC (C18 column) separation (water + 0.1% TFA/ACN + 0.1% TFA). The desired fractions were combined and lyophilized to yield the title compound L1 (13mg, 15%) as a pale yellow solid. ¹ FI NMR (400MHz, d ₆ -DMSO, 300K) d 12.02 (s, 1H), 9.74 (s, 1 H), 9.62 (br s, 1H), 7.92 (s, 1 H), 7.31 (s, 1 H), 7.31 (d, J = 8.9 Hz, 2H), 7.02 (d, J = 9.7 Hz, 1H), 6.91 (d, J = 8.9 Hz, 2H), 6.47 (dd, J = 10.3 Hz, J = 17.1 Hz, 1H), 6.22 (dd, J = 1.9 Hz, J = 17.1 Hz, 1H), 5.74 (dd, J = 1.9 Hz, J = 10.3 Hz, 1H), 3.91 (d, J = 13.5 Hz, 2H), 3.76 (s, 3H), 3.36 (m, 2H), 3.08 (q, J = 11.3 Hz, 2H), 2.95 (t, J = 12.7 Hz, 2H), 2.83 (s, 3H), 2.10 (s, 3H), 2.09 (s, 3H), 1.83 (s, 3H), 1.80 (s, 3H). MS (ES) C35H38FN7O requires: 591, found: 592 (M+H) ⁺ .

Example 143:

N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-m ethylpiperazin-1- yl)phenyl)-1H-pyrrolor2.3-blpyridin-3-yl)-3-methoxy-2- methylphenyl)acrylamide2,2,2-trifluoroacetate (M7) Step 1: ((3-Methoxy-4-methyl-5-nitrophenyl)ethvnyl)trimethylsilane (M1)

In a pressure tube, 5-bromo-1-methoxy-2-methyl-3-nitrobenzene (500mg, 2mmol, 1eq) and Cul (19mg, 0.1 mmol, 0.05eq) were dissolved in DMF (5ml_). Next, triethylamine (1.17mL, 8.4mmol, 4.15eq) and bis(triphenylphosphine)palladium (II) dichloride (72mg, 0.1 mmol, 0.05eq) were added. The tube was purged with argon, and then trimethylsilylacetylen (0.58ml_, 4.1 mmol, 1.25eq) was added. The reaction mixture was stirred at room temperature for 24h. The resulting mixture was diluted with an aqueous solution of NH ₄ CI, and extracted with DCM (4x 10ml_). The organic layers were combined, washed with brine, dried over Na ₂ S0 ₄ , filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (hexane: EtOAc, 0-30% of EtOAc) to afford the pure product M1 as a yellow solid (500mg, Y:93%). ¹ H NMR (300 MHz, DMSO -d ₆ ) d 7.28 (d, J = 1.5 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1 H), 3.66 (s, 3H), 1.99 (s, 3H), 0.00 (s, 9H).

Step 2: 5-Bromo-3-(3-methoxy-4-methyl-5-nitrophenyl)-4-methyl-2-(tri methylsilyl)- 1H-pyrrolor2.3-blpyridine (M2)

In a pressure tube, 5-bromo-1-methoxy-2-methyl-3-nitrobenzene M1 (475mg, 1.5mmol, 1eq) and [2-(3-methoxy-4-methyl-5-nitrophenyl)ethynyl]trimethylsilane (500mg, 1.9mmol, 1.25eq) were dissolved in DMF (10ml_). Next, triethylenediamine (289g, 2.5mmol, 1.7eq) and bis(triphenylphosphine)palladium (II) dichloride (107mg, 0.15mmol, 0.1 eq) were added, the tube was purged with argon, and the reaction mixture was heated at 145°C for 24h. The resulting mixture was diluted with saturated aqueous NaHCOs solution, and extracted with EtOAc (3x1 OmL). The organic layers were combined, washed with saturated aqueous NaCI solution, dried over Na ₂ S0 ₄ , filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (hexane: acetone 1:1) to afford the pure product M2 as an pale yellow solid (380mg, Y:62%). ¹ H NMR (300 MHz, DMSO -d ₆ ) d 11.82 (s, 1H), 8.33 (s, 1 H), 7.41 (d, J = 1.5 Hz, 1H), 7.31 (s, 1H), 3.88 (s, 3H), 2.31 (s, 3H), 2.15 (s, 3H), 0.10 (s, 9H). MS (ES) Ci ₉ H ₂₂ BrN ₃ 0 ₃ Si requires: 449/447, found: 450/448 (M+H) ⁺ . Step 3: 4-r3-(3-Methoxy-4-methyl-5-nitrophenyl)-4-methyl-2-(trimethy lsilyl)-1 H- Pvrrolor2,3-blpvridin-5-vll-1 ,5-dimethvl-1 H-pvrazole (M3)

5-Bromo-3-(3-methoxy-4-methyl-5-nitrophenyl)-4-methyl-2-( trimethylsilyl)-1 H- pyrrolo[2,3-b]pyridine M2 (270mg, 0.6mmol, 1eq), (1 ,5-dimethyl-1 H-pyrazol-4-yl)boronic acid (101 mg, 0.7mmol, 1.2eq), and K ₃ PO ₄ (256mg, 1.2mmol, 2eq) were placed in a pressure tube, dissolved in a mixture of dioxane (8ml_) - H ₂ 0 (0.2ml_), and purged with argon. Next, Pd(dppf)Cl2DCM (49mg, 0.06mmol, 0.2eq) was added, and the reaction mixture was heated at 100°C for 24h. The resulting mixture was cooled down, diluted with water, and extracted with DCM (3x1 OmL). The organic layers were combined, dried over Na ₂ S04, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH, 9:1 ) to afford the product M3 as a yellow solid (140mg, Y:50%). MS (ES) C^H^NsOsSi requires: 463, found: 464 (M+H) ⁺ .

Step 4: 5-r5-(1.5-Dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(trimethylsil yl)-1H- Pvrrolor2,3-blpvridin-3-vll-3-methoxv-2-methvlaniline (M4)

A suspension of 4-[3-(3-methoxy-4-methyl-5-nitrophenyl)-4-methyl-2-(trimethy lsilyl)-1 H- pyrrolo[2,3-b]pyridin-5-yl]-1 ,5-dimethyl-1 H-pyrazole M3 (205mg, 0.4mmol, 1eq) and iron (123mg, 2.2mmol, 5eq) in a mixture of EtOH (2ml_) and saturated aqueous NH ₄ CI solution (0.2m L) was stirred at 80°C for 4h. Then, the solvents were removed under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH 9:1) to obtain the desired product M4 as a yellow solid (95mg, Y:49%). MS (ES) C ₂ H3iN ₅ OSi requires: 433, found: 434 (M+H) ⁺ .

Step 5: N-{5-r5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(trimethyl silyl)-1H- pyrrolor2.3-blpyridin-3-vn-3-methoxy-2-methylphenyl)prop-2-e namide (M5) 5-[5-(1 ,5-Dimethyl-1 H-pyrazol-4-yl)-4-methyl-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridin-3- yl]-3-methoxy-2-methylaniline M4 (95mg, 0.2mmol, 1eq) was dissolved in THF (3ml_). The solution was cooled down to -10°C, DIPEA (0.38ml_, 2mmol, 10eq) was dropwise added, and the mixture was stirred for 5min at -10°C. A solution of acryloyl chloride (9pL, 0.2mmol, 1eq) in THF (2ml_) was dropwise added, and the reaction mixture was slowly warmed to room temperature. After 2h, LCMS showed full conversion. The reaction mixture was quenched with water (10ml_), and the product was extracted with DCM (3x5ml_). The organic layers were combined together, dried over Na ₂ S0 ₄ , filtered, and concentrated under reduced pressure. The crude material was purified by preparative HPLC to obtain the desired product M5 (56mg, Y: 54%) as a creamy solid. ¹ HNMR (300 MHz, DMSO-d6) d 11.31 (s, 1 H), 9.41 (s, 1 H), 7.84 (s, 1 H), 7.21 (s, 1 H), 7.02 (s, 1 H), 6.69 (s, 1 H), 6.42 (dd, J = 17.2, 10.2 Hz, 1 H), 6.10 (dd, J = 17.0, 2.1 Hz, 1 H), 5.61 (dd, J = 10.1 , 2.1 Hz, 1 H), 3.67 (s, 6H), 1.99 (d, J = 4.2 Hz, 6H), 1.86 (s, 3H), 0.00 (s, 9H). MS (ES) C ₂₇ H ₃₃ N ₅ 0 ₂ Si requires: 487, found: 488 (M+H) ⁺ .

Step 6: N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-2-iodo-4-methyl-1H-py rrolor2.3- blpyridin-3-yl)-3-methoxy-2-methylphenyl)acrylamide (M6)

N-{5-[5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-4-methyl-2-(trimethylsilyl)-1 H-pyrrolo[2,3- b]pyridin-3-yl]-3-methoxy-2-methylphenyl}prop-2-enamide M5 (53mg, 0.109mmol, 1eq) and NIS (44mg, 0.196mmol, 1.8eq) were dissolved in dry DCM (5ml_). The reaction mixture was stirred for 16h at room temperature. After this time, the reaction mixture was quenched with saturated aqueous Na ₂ S ₂ 0 ₃ solution. The desired product was extracted with DCM (3x30ml_). The organic layers were combined, washed with saturated aqueous NaHCOs solution, dried over Na ₂ S0 ₄ , filtered, and solvent were removed in vacuo. The crude material M6 as a beige solid (46mg, Y:78%) was used without purification for the next step. MS (ES) C ₂₄ H ₂₄ lN ₅ 0 ₂ requires: 541 , found: 542 (M+H) ⁺ . Step 7: N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-meth ylpiperazin-1- yl)phenyl)-1H-pyrrolor2.3-blpyridin-3-yl)-3-methoxy-2- methylphenyl)acrylamide2.2.2-trifluoroacetate (M7)

A mixture of N-(5-(5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-2-iodo-4-methyl-1 H-pyrrolo[2,3- b]pyridin-3-yl)-3-methoxy-2-methylphenyl)acrylamide M6 (46mg, 0.085mmol, 1.0eq.), K ₃ PO ₄ (36mg, 0.17mmol, 2.0eq.), 4-(4-methylpiperazin-1-yl)phenylboronic acid (24mg, O.U mmol, 1.3eq.) and [1 ,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (7mg, 0.008mmol, 0.1eq.) in dioxane/water (4:1 , 1.8mL) was degassed by bubbling nitrogen through it for a few minutes. The mixture was then heated in the microwave at 130°C for 2h. The resulting reaction mixture was filtered through a syringe filter and the filtrate was directly used for reversed phase purification (C18 column, water + 0.1 % TFA/ACN + 0.1 % TFA). The desired fractions were combined and lyophilized to yield the title compound M7 (22mg, 31 %) as a pale yellow solid. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 12.05 (s, 1 H), 9.66 (br s, 1 H), 9.51 (s, 1 H),

7.92 (s, 1 H), 7.41 (d, J = 8.9 Hz, 2H), 7.32 (s, 1 H), 7.11 (s, 1 H), 6.92 (d, J = 8.9 Hz, 2H),

6.81 (s, 1 H), 6.49 (dd, J = 17.1 Hz, J = 10.1 Hz, 1 H), 6.16 (dd, J = 2.0 Hz, J = 17.1 Hz, 1 H), 5.68 (dd, J = 2.0 Hz, J = 10.1 Hz, 1 H), 3.88 (d, J = 13.3 Hz, 2H), 3.76 (s, 3H), 3.70

(s, 3H), 3.46 (d, J = 11.9 Hz, 2H), 3.08 (q, J = 11.1 Hz, 2H), 2.94 (t, J = 12.7 Hz, 2H), 2.83 (s, 3H), 2.10 (s, 3H), 2.07 (s, 3H), 1.93 (s, 3H). MS (ES) C35H39N7O2 requires: 589, found: 590 (M+H) ⁺ . Example 144:

N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-m ethylpiperazin-1- yl)phenyl)-1H-pyrrolor2.3-blpyridin-3-yl)-2-methylphenyl)-N- methylmethacrylamide 2.2.2-trifluoroacetate (N1) To a solution of 5-(5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-4-methyl-2-(4-(4-methylpiperazin-1- yl)phenyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-N,2-dimethylaniline (50mg, 0.1 mmol, 1.0eq) in dry THF (2mL) at -40°C was added DIPEA (0.2ml_, lOmmol, 10eq) and methacryloyl chloride (12mg, 0.1 mmol, 1.2 eq). After stirring 15min, a drop of water was added and the mixture was directly used for reversed phase HPLC (C18 column) separation (water + 0.1 % TFA/ACN + 0.1 % TFA). The desired fractions were combined and lyophilized to yield the title compound N1 (6mg, 8%) as a yellow solid. ¹ FI NMR (300 MFIz, DMSO -c/e) d 12.07 (s, 1 H), 9.73 (br s, 1 H), 7.95 (s, 1 H), 7.33 (s, 1 H), 7.32 - 7.16 (m, 5H), 6.92 (d, J = 8.6 Hz, 2H), 5.00 (s, 1 H), 4.81 (s, 1 H), 3.91 (d, J = 13.5 Hz, 2H), 3.79 (s, 3H), 3.50 (d, J = 12.1 Hz, 2H), 3.14 (m, 2H), 3.11 (s, 3H), 2.95 (t, J =12.7 Hz, 2H), 2.86 (s, 3H), 2.27 (s, 3H), 2.13 (s, 3H), 1.89 (s, 3H), 1.63 (s, 3H). MS (ES) C ₃₆ H IN ₇ 0 requires: 587, found: 588 (M+H) ⁺ .

Example 145:

N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-m ethylpiperazin-1- yl)phenyl)-1H-pyrrolor2,3-blpyridin-3-yl)-2-methylphenyl)-N- methylbut-2-enamide

2,2,2-trifluoroacetate (0

To a solution of 5-(5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-4-methyl-2-(4-(4-methylpiperazin-1- yl)phenyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-N,2-dimethylaniline (50mg, 0.1 mmol, 1.0eq) in dry THF (2ml_) at -40°C was added DIPEA (0.2ml_, lOmmol, 10eq) and crotonoyl chloride (12mg, 0.1 mmol, 1.2 eq). After stirring 15min, a drop of water was added and the mixture was directly used for reversed phase HPLC (C18 column) separation (water + 0.1 % TFA/ACN + 0.1 % TFA). The desired fractions were combined and lyophilized to yield the title compound 01 (4mg, 5%) as a yellow solid. ¹ H NMR (300 MHz, DMSO -c/e) d 12.07 (s, 1 H), 9.69 (br s, 1 H), 7.95 (s, 1 H), 7.39 (d, J = 7.6 Hz, 1 H), 7.36 - 7.30 (m, 4H), 7.19 (m, 1 H), 6.93 (d, J = 8.7 Hz, 2H), 6.71 (dq, J = 7.1 Hz, J = 15.0 Hz, 1 H), 5.59 (dd, J = 15.0 Hz, J = 1.7 Hz, 1 H), 3.88 (d, J = 13.2 Hz, 2H), 3.78 (s, 3H), 3.49 (d, J = 12.5 Hz, 2H), 3.11 (s, 3H), 3.10 (m, 2H), 2.95 (t, J = 12.4 Hz, 2H), 2.85 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H), 1.95 (s, 3H), 1.67 (br s, 3H). MS (ES) C ₃₆ H ₄ IN ₇ 0 requires: 587, found: 588 (M+H) ⁺ . Example 146:

N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-2-(4-(2-(dimethyla mino)ethoxy)phenyl)-4- methyl-1H-pyrrolor2.3-blpyridin-3-yl)-2-methoxyphenyl)-N-met hylacrylamide 2,2,2- trifluoroacetate (P10)

Step 1: Tert-butyl (5-iodo-2-methoxyphenyl)carbamate (P1)

Boc

Di-tert-butyl dicarbonate (5 g, 22.9 mmol, 1.15 eq) was added to 5-iodo-2- methoxyaniline (5 g, 20.08 mmol, 1 eq.) at room temperature. The resulted reaction mixture was heated to 85°C for 3 h. After completion of reaction (monitored by TLC), the reaction mixture was cooled to room temperature and washed with n-pentane. The n- pentane layer was concentrated under reduced pressure to obtain P1 (5.8 g, 83%) as a pale yellow solid. ¹ H NMR (400 MHz, CDCI ₃ ) 5 8.43 (br s, 1H), 7.23-7.25 (m, 1H), 7.03 (br s, 1 H), 6.58 (d, J = 8.4 Hz, 1H), 3.84 (s, 3H), 1.53 (s, 9H). MS (ES) Ci ₂ H ₁₆ IN0 ₃ requires: 349, found: 294 (M-C4H ₉ +H) ⁺ .

Step 2: Tert-butyl (5-iodo-2-methoxyphenyl)(methyl)carbamate (P2)

To a stirred solution of sodium hydride (0.80 g, 19.9 mmol, 1.2 eq.) in THF (50 ml_) was added a solution of tert- butyl (5-iodo-2-methoxyphenyl)carbamate P1 (5.8 g, 16.6 mmol, 1 eq.) in THF (20 ml_) dropwise at 0°C under nitrogen atmosphere and stirred for 30 minutes at 0°C. Then methyl iodide (4.3 ml_, 66.4 mmol, 4 eq.) was added at 0 °C under nitrogen atmosphere. The resulted mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with ice water (100 ml_) and extracted with ethyl acetate (2 x 70 ml_). The organic layer was separated and washed with brine (100 ml_), dried over anhydrous Na ₂ S04, filtered and concentrated under reduced pressure to obtain P2 (5.7 g, 95%) as a pale yellow solid compound. ¹ H NMR (400 MHz, CDCI ₃ ) d 7.51-7.44 (m, 2H), 6.66 (d, J = 8.8 Hz, 1H), 3.80 (s, 3H), 3.10 (s, 3H), 1.36 (br s, 9H). MS (ES) C _I3 H _I8 IN0 ₃ requires: 363, found: 308 (M-C4H ₉ +H) ⁺ . Step 3: Tert-butyl (2-methoxy-5-((trimethylsilyl)ethvnyl)phenyl)(methyl)carbama te (P3)

Boc

To a stirred solution of tert- butyl (5-iodo-2-methoxyphenyl)(methyl)carbamate P2 (4.7 g, 12.9 mmol, 1 eq.) in triethylamine (50 ml_) was added copper (I) iodide (246 mg, 1.29 mmol, 0.1 eq.) at room temperature. The mixture was degassed with a stream of nitrogen for 15 mins. Then bis (triphenylphosphine) palladium (II) dichloride (0.9 g, 1.29 mmol, 0.10 eq.) followed by trimethylsilylacetylene (5.5 ml_, 38.8 mmol, 3.0 eq.) were added at room temperature. The reaction mixture was heated to 80°C and stirred for 4 h. After completion of reaction (monitored by LC-MS), the reaction mixture was evaporated in vacuum. The crude compound was purified by flash column chromatography (gradient elution of 15-20% ethyl acetate in pet ether) to obtain P3 (3.7 g, 86%) as an off white solid. MS (ES) C-isH^NOsSi requires: 333, found: 334 (M+H) ⁺ .

Step 4: 5-Bromo-3-iodo-4-methylPyridin-2-amine (P4)

To a stirred solution of 5-bromo-4-methylpyridin-2-amine (30 g, 160 mmol, 1 eq.) in dimethylformamide (300 ml_) were added trifluoroacetic acid (14.7 ml_, 192 mmol, 1.2 eq.) and /V-iodosuccinimide (54.1 g, 240.59 mmol, 1.5 eq.) portionwise at 0°C under nitrogen atmosphere. The reaction mixture was heated at 60°C for 2 h. The reaction mixture was cooled to room temperature, poured into ice water (500 ml_) and neutralized with solid sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (2 x 300 ml_). The combined organic layer was washed with 10% sodium thiosulfate solution (200 ml_), water (2 x 200 ml_), brine (200 ml_), dried over anhydrous Na ₂ S04, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography using silica gel (gradient elution of 10% EtOAc in pet ether) to yield P4 (40 g, 80%) as a pale yellow solid. ¹ H NMR (300 MHz, CDCI3) d 8.01 (s, 1 H), 5.00 (br s, 2H), 2.59 (s, 3H). MS (ES) C ₆ H ₆ BrlN ₂ requires: 314/312, found: 315/313 (M+H) ⁺ .

Step 5: Tert-butyl (5-(5-bromo-4-methyl-2-(trimethylsilyl)-1H-pyrrolor2,3-blpyr idin-

3-yl)-2-methoxyphenyl)(methyl)carbamate (P5) To a stirred solution of 5-bromo-3-iodo-4-methylpyridin-2-amine P3 (5.2 g, 16.6 mmol, 1 eq.), tert- butyl (2-methoxy-5-((trimethylsilyl)ethynyl)phenyl)(methyl)carbama te P4 (7.2 g, 21.6 mmol, 1.3 eq.) in dimethylformamide (60 ml_) was added 1,4- diazabicyclo[2.2.2]octane (2.8 g, 24.9 mmol, 1.5 eq.) at room temperature. The mixture was degassed with a stream of nitrogen for 15 min. Then b/s(triphenylphosphine) palladium (II) dichloride (1.17 g, 1.66 mmol, 0.1 eq.) was added at room temperature. The mixture was heated to 120°C for 16 h. The reaction mixture was filtered through a small pad of Celite and washed with ethyl acetate (100 ml_). The filtrate was washed with water (2 x 50 ml_), brine (50 ml_), dried over anhydrous Na ₂ S04, filtered and concentrated under reduced pressure to give crude compound. The crude compound was purified by flash column chromatography (gradient elution of 10-20% ethyl acetate in pet ether) to afford P5 (5.3 g, 61%) as a pale yellow solid. MS (ES) C ₂₄ H ₃₂ BrN ₃ 0 ₃ Si requires: 519/517, found: 520/518 (M+H) ⁺ .

Step 6: Tert-butyl (5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(trimethylsi lyl)- 1H-pyrrolor2.3-blpyridin-3-yl)-2-methoxyphenyl)(methyl)carba mate (P6)

To a stirred solution of tert- butyl (5-(5-bromo-4-methyl-2-(trimethylsilyl)-1/-/-pyrrolo[2,3- b]pyridin-3-yl)-2-methoxyphenyl)(methyl)carbamate P5 (5.3 g, 10.2 mmol, 1 eq.) and 1 ,5-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1/-/-pyrazole (3.4 g, 15.3 mmol, 1.5 eq.) in 1,4-dioxane (45 ml_) and H ₂ 0 (5 ml_) was added sodium carbonate (2.17 g, 20.4 mmol, 2.0 eq.) at room temperature. The reaction mixture was degassed with stream of nitrogen for 15 mins. Then Pd(dppf)Cl2-DCM (834 mg, 1.02 mmol, 0.1 eq.) was added at room temperature under nitrogen atmosphere. The mixture was heated to 100°C for 16 h. The reaction mixture was cooled to room temperature, filtered through a small pad of Celite and washed with ethyl acetate (100 ml_). The filtrate was washed with water (2 x 50 ml_), brine (50 ml_), dried over anhydrous Na ₂ S04, filtered and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (gradient elution of 70% ethyl acetate in pet ether) to afford P6 (4.3 g, 79%) as a pale yellow solid. ¹ H NMR (400 MHz, CDCI ₃ ) d 8.77 (s, 1 H), 8.07 (s, 1 H), 7.37 (s, 1 H), 7.26-7.15 (m, 2H), 6.91 (d, J = 8.0 Hz, 1 H), 3.89 (s, 3H), 3.86 (s, 3H), 3.14 (s, 3H), 2.13 (s, 3H), 2.00 (s, 3H), 1.28 (br s, 9H), 0.16 (s, 9H). MS (ES) CagHsgNsOsSi requires: 533, found: 534 (M+H) ⁺ .

Step 7: 5-(5-(1.5-Dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(trimethylsil yl)-1H- pyrrolor2.3-blpyridin-3-yl)-2-methoxy-N-methylaniline (P7)

To a stirred solution tert- butyl (5-(5-(1 ,5-dimethyl-1/-/-pyrazol-4-yl)-4-methyl-2- (trimethylsilyl)-1/-/-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyp henyl)(methyl)carbamate P6 (4.3 g, 8.05 mmol, 1 eq.) in DCM (40 ml_) was added TFA (6.1 ml_) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. The crude compound was diluted with EtOAc (100 ml_), washed with sat. NaHCOs solution (2 x 50 ml_) and brine (50 ml_). The organic layer was dried over anhydrous Na ₂ S04, filtered and concentrated under reduced pressure to give P7 (3.2 g, 91 %) as an off white solid. MS (ES) C ₂ 4H _3i N ₅ OSi requires: 433, found: 434 (M+H) ⁺ .

Step 8: N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(trimethyl silyl)-1H- Pvrrolor2,3-blpvridin-3-vl)-2-methoxvphenvD-N-methvlacrvlami de (P8)

To a stirred solution 5-(5-(1 ,5-dimethyl-1/-/-pyrazol-4-yl)-4-methyl-2-(trimethylsilyl)-1 /-/- pyrrolo[2,3-b]pyridin-3-yl)-2-methoxy-/V-methylaniline P7 (2.8 g, 6.45 mmol, 1 eq.) in THF (50 ml_) was added L/,/V-diisopropylethylamine (3.4 ml_, 19.3 mmol, 3.0 eq.), followed by acryloyl chloride (584 mg, 6.45 mmol, 1 eq.) in THF (10 ml_) at -78 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at -78 °C for 15 min. The reaction mixture was quenched with water (50 ml_), diluted with EtOAc (100 ml_). The organic layer was separated and washed with sat. NaHC0 ₃ (2 x 50 ml_) and brine (2 x 50 ml_). The organic layer was dried over anhydrous Na ₂ S04 _, filtered and concentrated under reduced pressure to get crude compound. The crude compound was purified by flash column chromatography (gradient elution of 70%-90% EtOAc in pet ether) to obtained P8 (1.43 g, 45%) as an off white solid. ¹ H NMR (400 MHz, DMSO-de) d 11 .46 (d, J = 3.6 Hz, 1 H), 7.96 (s, 1 H), 7.36 (dd, J = 2.0 Hz, 8.0 Hz, 1 H), 7.31 (s, 1 H), 7.23 (d, J = 7.2 Hz, 1 H), 7.17 (d, J = 8.4 Hz, 1 H), 6.14-5.96 (m, 2H), 5.50 (dd, J = 2.4 Hz, 10.0 Hz, 1 H), 3.84 (s, 3H), 3.77 (s, 3H), 3.13 (d, J = 2.8 Hz, 3H), 2.09 (d, J = 3.6 Hz, 3H), 1.91 (d, J = 4.4 Hz, 3H), 0.09 (d, J = 4.4 Hz, 9H). MS (ES) C27H33N5O2S1 requires: 487, found: 488 (M+H) ⁺ .

Step 9: N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-2-iodo-4-methyl-1H-py rrolor2.3- blpvridin-3-vl)-2-methoxvphenvl)-N-methvlacrvlamide (P9)

N-(5-(5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-4-methyl-2-(trimethylsilyl)-1 H-pyrrolo[2,3- b]pyridin-3-yl)-2-methoxyphenyl)-N-methylacrylamide P8 (500mg, I .Ommol, 1eq) and NIS (283mg, 1.3mmol, 1.3eq) were dissolved in dry DCM (50ml_). The reaction mixture was stirred for 16h at room temperature. After this time, the reaction mixture was quenched with saturated aqueous Na ₂ S203 solution. The desired product was extracted with DCM (3x50ml_). The organic layers were combined, washed with saturated aqueous NaHCOs solution, dried over Na ₂ S04, filtered, and solvent were removed in vacuo. The crude material P9 as a beige solid (512mg, Y:98%) was used without purification for the next step. MS (ES) C24H24IN5O2 requires: 541 , found: 542 (M+H) ⁺ .

Step 10: N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-vn-2-(4-(2- (dimethylamino)ethoxy)phenyl)-4-methyl-1H-pyrrolor2.3-blpyri din-3-yl)-2- methoxvphenvD-N-methvlacrvlamide 2,2,2-trifluoroacetate (P10)

A mixture of N-(5-(5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-2-iodo-4-methyl-1 H-pyrrolo[2,3- b]pyridin-3-yl)-2-methoxyphenyl)-N-methylacrylamide P9 (50mg, 0.1 mmol, 1.0eq.), K ₃ PO ₄ (39mg, 0.2mmol, 2.0eq.), {4-[2-(dimethylamino)ethoxy]phenyl}boronic acid (29mg, O.lmmol, 1.5eq.) and [1 ,T-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (11 mg, 0.01 mmol, 0.1eq.) in dioxane/water (4:1 , 1.5ml_) was degassed by bubbling nitrogen through it for a few minutes. The mixture was then heated in the microwave at 130°C for 2h. The resulting reaction mixture was filtered through a syringe filter and the filtrate was directly used for reversed phase purification (C18 column, water + 0.1% TFA/ACN + 0.1% TFA). The desired fractions were combined and lyophilized to yield the title compound P10 (10mg, 13%) as a pale yellow solid. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 12.07 (s, 1H), 9.59 (br s, 1H), 7.96 (s, 1H), 7.46 - 7.32 (m, 4H), 7.19 (d, J = 8.6 Hz, 1H), 7.17 (m, 1H), 6.96 (d, J = 9.0 Hz, 2H), 6.08 (dd, J = 2.5 Hz, J = 16.8 Hz, 1H), 5.95 (m, 1H), 5.47 (d, J = 10.2 Hz, 1H), 4.30 (t, J = 5.1 Hz, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 3.50 (q, J = 5.1 Hz, 2H), 3.10 (s, 3H), 2.86 (s, 3H), 2.85 (s, 3H), 2.12 (s, 3H), 1.99 (s, 3H). MS (ES) CwHseNeOs requires: 578, found:

579 (M+H) ⁺ .

The Examples in the following table were prepared according to the procedure described for P10 (Example 146).

Example 149:

N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-ethyl-2-(4-(4-me thylpiperazin-1-yl)phenyl)- 1H-pyrrolor2.3-blpyridin-3-yl)-2-methylphenyl)-N-methylacryl amide 2,2,2- trifluoroacetate (Q1)

A mixture of N-(5-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-4-ethyl-2-iodo-1H-pyr rolo[2,3- b]pyridin-3-yl)-2-methylphenyl)-N-methylacrylamide (70mg, 0.13mmol, 1.0eq.), which was prepared according to the procedure Example 21 Step 1-7, K ₃ PO ₄ (55mg, 0.26mmol, 2.0eq.), 4-(4-methylpiperazin-1-yl)phenylboronic acid (37mg, 0.17mmol, 1.3eq.) and [1 ,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (11 mg, 0.01 mmol, 0.1eq.) in dioxane/water (4:1 , 2.2ml_) was degassed by bubbling nitrogen through it for a few minutes. The mixture was then heated in the microwave at 130°C for 2h. The resulting reaction mixture was filtered through a syringe filter and the filtrate was directly used for reversed phase HPLC (C18 column) separation (water + 0.1 % TFA/ACN + 0.1 % TFA). The desired fractions were combined and lyophilized to yield the title compound Q1 (10mg, 10%) as a pale yellow solid. ¹ FI NMR (400MHz, d ₆ -DMSO, 300K) d 12.08 (s, 1 H), 9.69 (br s, 1 H), 7.88 (s, 1 H), 7.42 - 7.11 (m, 6H), 6.91 (d, J = 8.5 Hz, 2H), 6.11 (m, 1 H), 5.84 (dd, J = 16.3 Hz, J = 10.3 Hz, 1 H), 5.52 (dd, J = 2.4 Hz, J = 10.3 Hz, 1 H), 3.88 (d, J = 13.5 Hz, 2H), 3.77 (s, 3H), 3.48 (d, J = 12.0 Hz, 2H), 3.10 (s, 3H), 3.09 (m, 2H), 2.93 (t, J = 17.7 Hz, 2H), 2.84 (s, 3H), 2.42 (m, 2H), 2.17 (s, 3H), 2.08 (s, 3H), 0.58 (m, 3H). MS (ES) C ₃₆ H IN ₇ 0 requires: 587, found: 588 (M+H) ⁺ .

Example 150:

N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-m ethylpiperazin-1- yl)phenyl)-1H-pyrrolor2.3-blpyridin-3-yl)-2.6-dimethylphenyl )-N-methylacrylamide

2.2.2-trifluoroacetate (R1

A mixture of N-(5-(5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-4-ethyl-2-iodo-1 H-pyrrolo[2,3- b]pyridin-3-yl)-2-methylphenyl)-N-methylacrylamide (70mg, 0.13mmol, 1.0eq.), which was prepared according to the procedure Example 21 Step 1-7, K ₃ PO ₄ (55mg, 0.26mmol, 2.0eq.), 4-(4-methylpiperazin-1-yl)phenylboronic acid (37mg, 0.17mmol, 1.3eq.) and [1 ,T-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (11 mg, 0.01 mmol, 0.1eq.) in dioxane/water (4:1 , 2.2ml_) was degassed by bubbling nitrogen through it for a few minutes. The mixture was then heated in the microwave at 130°C for 2h. The resulting reaction mixture was filtered through a syringe filter and the filtrate was directly used for reversed phase HPLC (C18 column) separation (water + 0.1 % TFA/ACN + 0.1 % TFA). The desired fractions were combined and lyophilized to yield the title compound R1 (20mg, 20%) as a pale yellow solid. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 12.02 / 12.01 (s, 1 H), 9.59 (br s, 1 H), 7.92 / 7.92 (s, 1 H), 7.34 - 7.19 (m, 5H), 6.91 / 6.89 (d, J = 6.8 Hz, 2H), 6.17 / 6.15 (dd, J = 2.3 Hz, J = 16.7 Hz, 1 H), 5.84 / 5.82 (dd, J = 10.3 Hz, J = 16.7 Hz, 1 H), 5.54 (dd, J = 2.3 Hz, J = 10.3 Hz, 1 H), 3.88 (d, J = 13.5 Hz, 2H), 3.76 / 3.76 (s, 3H), 3.48 (m, 2H), 3.10 / 3.09 (s, 3H), 3.08 (m, 2H), 2.93 (m, 2H), 2.83 (s, 3H), 2.18 (s, 3H), 2.10 / 2.07 (s, 3H), 1.85 / 1.81 (s, 3H), 1.78 / 1.72 (s, 3H). MS (ES) C ₃₆ H _I N ₇ 0 requires: 587, found: 588 (M+H) ⁺ .

Example 151:

N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-m ethylpiperazin-1- yl)phenyl)-1H-pyrrolor2.3-blpyridin-3-yl)phenyl)-N-ethylacry lamide 2,2,2- trifluoroacetate (S9)

Step 1 : 5-Bromo-4-methyl-3-(3-nitrophenyl)-2-(trimethylsilyl)-1 H-rnitoIoG2.3- blpyridine

To a stirred solution of 5-bromo-3-iodo-4-methylpyridin-2-amine P4 (8 g, 25.5 mmol, 1 eq.) in DMF (50 ml_) were added trimethyl((3-nitrophenyl)ethynyl)silane (6.15 g, 28.1 mmol, 1.1 eq) and DABCO (4.86 g, 43.3 mmol, 1.7 eq.) at room temperature under nitrogen atmosphere. The reaction mixture was degassed for 10 minutes using nitrogen gas. Then Pd(PPh ) ₂ Cl (1.79 g, 2.55 mmol, 0.1 eq.) was added at room temperature. The resulting reaction mixture was stirred at 120 °C for 4 h. The reaction mixture was quenched with water (50 ml_) and the aqueous layer was extracted with EtOAc(2 x 150 ml_), combined organic layer was washed with brine (50 ml_), dried over anhydrous Na S , filtered and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (10% ethyl acetate in pet-ether) to obtain S1 (7 g, 67%) as a pale yellow solid. MS (ES) Ci ₇ Hi ₈ BrN ₃ 0 ₂ Si requires: 405/403, found: 406/404 (M+H) ⁺ .

Step 2: 5-(1.5-Dimethyl-1H-pyrazol-4-yl)-4-methyl-3-(3-nitrophenyl)- 2-

(trimethvlsilvD-1 H-pvrrolor2,3-blpvridine (S2) To a stirred solution of 5-bromo-4-methyl-3-(3-nitrophenyl)-2-(trimethylsilyl)-1/-/-p yrrolo [2,3-b]pyridine S1 (8 g, 19.8 mmol, 1 eq.) in DMF (50 ml_) were added 1 ,5-dimethyl-4- (4,4,5,5-tetramethyM ,3,2-dioxaborolan-2-yl)-1/-/-pyrazole (6.59 g, 29.7 mmol, 1.5 eq) and K2CO3 (4.10 g, 29.7 mmol, 1.5 eq.) at room temperature under nitrogen atmosphere. The reaction mixture was degassed for 10 minutes using nitrogen gas. Then PdCl2(dppf).DCM (1.61 g, 1.98 mmol, 0.1 eq.) was added at room temperature. The resulting reaction mixture was stirred at 100 °C for 48 h. The reaction mixture was filtered through a small pad of Celite and wash with EtOAc (150 ml_). Then the filtrate was evaporated under reduced pressure. The crude compound was purified by flash column chromatography (60% ethyl acetate in pet-ether) to obtain S2 (4 g, 48%) as a white solid. MS (ES) C ₂₂ H ₂₅ N ₅ 0 ₂ Si requires: 419, found: 420 (M+H) ⁺ .

Step 3: 5-(1.5-Dimethyl-1H-pyrazol-4-yl)-2-iodo-4-methyl-3-(3-nitrop henyl)-1H- pyrrolor2.3-blpyridine (S3)

To a stirred solution of 5-(1 ,5-dimethyl-1/-/-pyrazol-4-yl)-4-methyl-3-(3-nitrophenyl)-2- (trimethylsilyl)-l /-/-pyrrolo [2, 3-b] pyridine S2 (4 g, 9.54 mmol, 1 eq.) in dichloromethane (300 ml_) was added /V-iodosuccinimide (2.57 g, 11.4 mmol, 1.2 eq.) at 0 °C under nitrogen atmosphere. The resulting reaction mixture was warmed to room temperature and stirred for 16 h. After completion of reaction (monitored by TLC), 50% of solvent was concentrated from reaction mixture then diethyl ether (200 ml_) was added. The mixture was stirred for 10 mins at room temperature. The precipitated solid was filtered and washed with diethyl ether (50 ml_) to afford S3 (4.4 g, 97%) as a pale brown solid. MS (ES) Ci9H ₁₆ IN ₅ 02 requires: 473, found: 474 (M+H) ⁺ .

Step 4: 5-(1.5-Dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-methylpipe razin-1- yl)phenyl)-3-(3-nitrophenyl)-1 H-pyrrolor2.3-blpyridine (S4)

To a stirred solution of 5-(1,5-dimethyl-1/-/-pyrazol-4-yl)-2-iodo-4-methyl-3-(3- nitrophenyl)-1/-/-pyrrolo[2,3-b]pyridine S3 (4.4 g, 9.30 mmol, 1 eq.) and (4-(4- methylpiperazin-1-yl)phenyl)boronic acid (2.45 g, 11.1 mmol, 1.2 eq.) in 1 ,4-dioxane (90 ml_), H2O (10 ml_) was added sodium carbonate (1.48 g, 13.9 mmol, 1.5 eq.) at room temperature under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for 15 mins. Then PdCl2(dppf).DCM (0.76 g, 0.93 mmol, 0.1 eq.) was added at room temperature. The resulting reaction mixture was heated to 100 °C for 16 h. The reaction mixture was cooled to room temperature, filtered through a small pad of Celite and washed with EtOAc (100 ml_). Then the filtrate was wash with water (50 ml_), brine (50 ml_), dried over sodium sulphate filtered and concentrated under vacuum to get the crude compound. The crude compound was diluted with CH2CI2 and diethyl ether was added. The precipitated solid was filtered to obtain S4 (4.4 g, 91%) as a brown solid. ¹ H NMR (400 MHz, DMSO -d ₆ ) 5: 12.09 (s, 1H), 8.24-8.21 (m, 1H), 8.15 (t, J = 2.0 Hz, 1H), 7.96 (s, 1 H), 7.87-7.85 (m, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.33 (s, 1H), 7.19 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 3.78 (s, 3H), 3.16-3.13 (m, 4H), 2.44-2.36 (m, 4H), 2.21 (s, 3H), 2.14 (s, 3H), 1.89 (s, 3H). MS (ES) C30H31N7O2 requires: 521, found: 522 (M+H) ⁺ .

Step 5: 5-(1.5-Dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-methylpipe razin-1- yl)phenyl)-3-(3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)me thyl)-1H-pyrrolor2.3- blpyridine (S5)

To a stirred solution of 5-(1 ,5-dimethyl-1/-/-pyrazol-4-yl)-4-methyl-2-(4-(4- methylpiperazin-1-yl) phenyl)-3-(3-nitrophenyl)-1/-/-pyrrolo [2,3-b] pyridine S4 (4.4 g, 8.44 mmol, 1 eq.) in THF was added NaH (0.50 g, 12.6 mmol, 1.5 eq.) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 1 h. Then SEM-CI (1.7 g, 10.1 mmol, 1.2 eq.) was added into the reaction mixture. The resulting reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by LC-MS), the reaction mixture was quenched with ice water (10 ml_) and extracted with EtOAc (2 x 150 ml_), the combined organic layer was washed with brine (1 00 ml_), dried over sodium sulphate filtered and concentrated under vacuum to get crude compound. The crude compound was purified by flash column chromatography (5% methanol in DCM) to obtain S5 (3 g, 54%) as a yellow solid. MS (ES) C36H45N7O3S1 requires: 651, found: 652 (M+H) ⁺ .

Step 6: 3-(5-(1.5-Dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-methylp iperazin-1- yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolor2 .3-blpyridin-3-yl)aniline

(S6) To a stirred solution of 5-(1 ,5-dimethyl-1/-/-pyrazol-4-yl)-4-methyl-2-(4-(4- methylpiperazin-1 -yl)phenyl)-3-(3-nitrophenyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H- pyrrolo[2,3-b]pyridine S5 (3 g, 4.60 mmol, 1eq.) in ethanol:H ₂ 0 (8:2) (400 mL) were added iron powder (1.28 g, 23.0 mmol, 5 eq.) and NH ₄ CI ( 1.22 g, 23.0 mmol, 5 eq.) at room temperature. The reaction mixture was heated to 90 °C for 2 h. The reaction mixture was cooled to room temperature, filtered through a celite pad and the pad was washed with EtOAc (500 mL). The filtrate was wash with water (50 mL), brine (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtained S6 (2.7 g, 94%) as a brown solid which used for the next reaction without further purification. MS (ES) C36H4 ₇ N ₇ OSi requires: 621, found: 622 (M+H) ⁺ .

Step 7: N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-meth ylpiperazin-1- yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolor2 .3-blpyridin-3- vDphenvDacrylamide (S

To a stirred solution 3-(5-(1 ,5-dimethyl-1/-/-pyrazol-4-yl)-4-methyl-2-(4-(4- methylpiperazin-1 -yl)phenyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 /-/-pyrrolo[2,3- b]pyridin-3-yl)aniline S6 (2 g, 3.22 mmol, 1.0 eq.) in THF (120 mL) was added N,N- diisopropylethylamine (1.72 mL, 9.66 mmol, 3.0 eq.) followed by acryloyl chloride (0.4 mL, 4.83 mmol, 1.5 eq.) at -40 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at -40 °C for 30 min. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (2 x150 mL). The combined organic layer washed with saturated NaHCOs solution (50 mL) followed by brine (200 mL), dried over anhydrous Na ₂ S04 _, filtered and concentrated under reduced pressure to afford S7 (2.0 g, 92%) as a pale brown solid. ¹ H NMR (400 MHz, DMSO-d _e ) 5 10.11 (s, 1H), 8.03 (s, 1H), 7.62- 7.60 (m, 2H), 7.34 (s, 1 H), 7.26-7.23 (m, 3H), 6.97 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 9.2 Hz, 2H), 6.44-6.37 (m, 1H), 6.21 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.73 (dd, J = 10.0 Hz, 2.0 Hz, 1 H), 5.54 (s, 2H), 3.79 (s, 3H), 3.52 (t, J = 8.0 Hz, 2H), 3.17-3.14 (m, 4H), 2.42- 2.40 (m, 4H), 2.20 (s, 3H), 2.13 (s, 3H), 1.95 (s, 3H), 0.82-0.78 (m, 2H), -0.09 (s, 9H). MS (ES) C ₃₉ H ₄₉ N ₇ O ₂ S1 requires: 675, found: 676 (M+H) ⁺ .

Step 8: N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-meth ylpiperazin-1- yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolor2 .3-blpyridin-3- yl)phenyl)-N-ethylacrylamide (S8)

To a stirred suspension of NaH (35 mg, 0.88 mmol, 3.0 eq.) in THF (10 ml_) was added N-( 3-(5-(1 ,5-dimethyl-1 /-/-pyrazol-4-yl)-4-methyl-2-(4-(4-methylpiperazin-1 -yl)phenyl)-1 - ((2-(trimethylsilyl)ethoxy)methyl)-1 /-/-pyrrolo[2,3-b]pyridin-3-yl)phenyl)acrylamide S7 (200 mg, 0.29 mmol, 1.0 eq.) at 0 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at 0 °C for 1 h. Then iodoethane (0.072 ml_, 0.88 mmol, 3.0 eq.) was added at 0 °C. The resulting reaction mixture was stirred at room temperature for 48 h. The reaction mixture was quenched with ice cold water (5 ml_) and extracted with EtOAc (2 x 25 ml_). The combined organic layer was washed with brine (30 ml_). The organic layer was dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to get crude compound. The crude compound was purified by flash column chromatography (5% methanol in CH ₂ CI ₂ ) to obtain S8 (120 mg, 57%) as a brown solid. ¹ H NMR (400 MHz, DMSO -d ₆ ) d 8.14 (s, 1H), 7.52-7.45 (m, 3H), 7.28-7.23 (m, 3H), 7.08 (t, J = 3.4 Hz, 1 H), 6.97 (d, J = 8.8 Hz, 2H), 6.16 (dd, J = 2.4 Hz, J = 16.8

Hz, 1 H), 5.90-5.85 (m, 1H), 5.58-5.56 (m, 1H), 3.89 (s, 3H), 3.89-3.70 (m, 3H), 3.63- 3.59 (m, 2H), 3.24 (t, J = 4.8 Hz, 4H), 2.55-2.52 (m, 4H), 2.31 (s, 3H), 2.23 (s, 3H), 2.12 (s, 3H), 1.35-1.33 (m, 5H), 0.98 (s, 9H). MS (ES) C _4i H ₅₃ N ₇ 0 ₂ Si requires: 704, found: 705 (M+H) ⁺ .

Step 9: N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(4-(4-meth ylpiperazin-1- yl)phenyl)-1H-pyrrolor2.3-blpyridin-3-yl)phenyl)-N-ethylacry lamide 2,2,2- trifluoroacetate (S9) To a stirred solution L/-(3-(5-(1 ,5-dimethyl-1/-/-pyrazol-4-yl)-4-methyl-2-(4-(4- methylpiperazin-1 -yl)phenyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 /-/-pyrrolo[2,3- b]pyridin-3-yl)phenyl)-/V-ethylacrylamide S8 (110 mg, 0.15 mmol, 1eq.) in DCM (5 mL) was added TFA (5 mL) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred at 50 °C for 3 days. The reaction mixture was concentrated under reduced pressure to get the crude compound. The crude compound was purified by reversed phase prep-HPLC to get the desired product S9 (8.6 mg, 10%) as an off white solid. ¹ H NMR (400 MHz, DMSO -d ₆ ) d 11.96 (br s, 1H), 8.55 (s, 1H), 7.92 (s, H), 7.51 (t, J = 8.0 Hz, 1 H), 7.41 (d, J = 7.6 Hz, 1H), 7.33 (s, 1H), 7.26-7.23 (m, 1H), 7.19 (d, J = 9.2 Hz, 2H), 7.13 (s, 1H), 6.83 (d, J = 9.2 Hz, 2H), 6.08 (dd, J = 2.4 Hz, 16.8 Hz, 1 H), 5.97-5.94 (m, 1H), 5.50-5.47 (m, 1H), 3.78 (m, 3H), 3.73-3.71 (m, 2H), 3.14 (t, J = 4.8 Hz, 4H), 2.41 (t, J = 4.8 Hz, 4H), 2.20 (s, 3H), 2.12 (s, 3H), 1.95 (s, 3H), 0.97 (t, J = 7.2 Hz, 3H). MS (ES) C ₃₅ H ₃₉ N ₇ O requires: 573, found: 574 (M+H) ⁺ .

Example 152:

N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-ethyl-2-(4-(4-me thylpiperazin-1-yl)phenyl)-

1H-pyrrolor2.3-blpyridin-3-yl)-2-methylphenyl)but-2-enami de2.2.2-trifluoroacetate

(T1)

To a solution of 5-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-4-ethyl-2-(4-(4-methylpi perazin-1- yl)phenyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylaniline (80mg, 0.15mmol, 1.0eq) in dry THF (3.5mL) at -78°C was added DIPEA (0.26mL, 1.5mmol, 10eq) and crotonoyl chloride (18mg, 0.17mmol, 1.1 eq). After stirring 60min, a drop of water was added and the mixture was directly used for reversed phase HPLC (C18 column) separation (water + 0.1% TFA/ACN + 0.1% TFA). The desired fractions were combined and lyophilized to yield the title compound T1 (4mg, 6%) as a yellow solid. ¹ H NMR (300 MHz, DMSO -c/e) d 12.07 (s, 1 H), 9.64 (br s, 1 H), 9.26 (s, 1 H), 7.88 (s, 1 H), 7.64 (s, 1 H), 7.34 (d, J = 8.6 Hz, 2H), 7.32 (s, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.91 (d, J = 8.6 Hz, 2H), 6.72 (qd, J = 7.0 Hz, J = 15.1 Hz, 1H), 6.23 (d, J =15.1 Hz, 1H), 3.91 (d, J = 13.1 Hz, 2H), 3.79 (s, 3H), 3.48 (d, J = 11.8 Hz, 2H), 3.10 (q, J = 11.0 Hz, 2H), 2.95 (t, J = 12.3 Hz, 2H), 2.85 / 2.84 (s, 3H), 2.35 (q, J = 7.2 Hz, 2H), 2.28 (s, 3H), 2.09 (s, 3H), 1.84 (d, J = 7.0 Hz, 3H), 0.57 (t, J = 7.2 Hz, 3H). MS (ES) C ₃₆ H ₄₁ N ₇ O requires: 587, found: 588 (M+H) ⁺ . Biological Assays

The exemplified compounds described herein were tested for activity and were found to have an IC50 value less than 10 uM, particularly less than 500 nM, in one of the following assays:

1. Measurement of HER2 INS YVMA kinase activity

This protocol describes how the Lance Kinase Activity Assay was performed to determine IC50 values of compounds of general formula (I) against HER2 INS YVMA. The principle behind this enzymatic assay is based upon the phosphorylation of the Ulight-peptide substrate. It is detected by using a specific EU-labeled anti-phospho peptide antibody. The binding of the Eu labeled anti-phospho peptide antibody to the phosphorylated ULight labeled peptide gives rise to a FRET-signal.

Binding of an inhibitor to the kinase prevents phosphorylation of the Ulight-substrate, resulting in a loss of FRET. In table 2 is summarized the relevant information for the LANCE assay. Table 2: Reagents, stock concentrations and final assay concentrations for Her2 INS YVMA. The compounds of general formula (I) summarized in Table 3 were serial diluted from a 10 mM DMSO stock solution 1 :3 over 8 steps in a total volume of 20 pi.

For every sample, 8 mI of kinase-substrate mix was transferred into a suitable assay plate (e.g. Corning #3673). Compound was added via pintool transfer (1 Onl/well) using a Biomek FX robot (BeckmanCoulter). Reaction was started by addition of 2mI ATP working solution and mixed using variomag teleshaker (Thermo Fischer Scientific). After 1 h incubation at room temperature the reaction was stopped with 10mI detection mix containing the Eu-labeled phosphospecific antibody and 10mM EDTA. After a second incubation period of 1 h at room temperature the FRET signal was measured at 340 nm excitation, 665 nm and 615 nm emission (for the U Light-substrate and Eu-AB, respectively) with an Envision spectrophotometer (Perkin Elmer, Waltham, MA, USA) with 50 ps delay and 300 ps integration time. IC50 values were determined from the sigmoidal dose response curves with the software Quattro Workflow (Quattro GmbFI, Munich, Germany).

2. Measurement of cellular activity

The CellTiter-Glo Luminescent Cell Viability Assay (Promega) is a homogeneous method of determining the number of viable cells in culture. It is based on quantification of ATP, indicating the presence of metabolically active cells. Cells are seeded on day 1 at cell numbers that assure assay linearity and optimal signal intensity. After incubation for 24h in humidified chambers at 37°C and 5% CO2, compounds in DMSO are added at different concentrations. Cells are further incubated for 72 h at 37°C and 5% CO2. Cells treated with the compound vehicle DMSO are used as positive controls and cells treated with 10 pM Staurosporine serve as negative controls. At day 5 the CellTiter Glo Reagent is prepared according to the instructions of the kit (Promega Inc.): Reagent is mixed 1:1 with cell culture medium. Thereon, mixture and assay plates are equilibrated at room temperature for 20 min. Equal volumes of the reagent-medium-mixture is added to the volume of culture medium present in each well. The plates are mixed at ~200 rpm for 2 minutes on an orbital shaker. The microplates are then incubated at room temperature for 10 minutes for stabilization of the luminescent signal. Following incubation the luminescence is recorded on a Victor microplate reader (Perkin Elmer) using a 200 ms integration time. The data is then analyzed with Excel using the XLFIT Plugin (dose response Fit 205) for ICso-determination. As quality control the Z ^' -factor is calculated from 16 positive and negative control values. Only assay results showing a Z ^' -factor > 0.5 are used for further analysis.

Table 3 shows activity data in the biochemical EGFR Exon 20 InsNPG and Fler2 Exon 20 INSYVMA Lance assays as well in the cellular EGFR Exon 20 INSNPFI Ba/F3 CellTiter-Glo, Her2 Exon 20 INSYVMA Ba/F3 CellTiter-Glo and Cuto-17 CellTiter-Glo assays. Inhibition is indicated as IC50 [nM] (“-“ = not measured). Compounds having an activity designated as ”A” provided an IC50 £ 50nM; compounds having an activity designated as ”B” provided an 50nM < IC50 £ 100nM; compounds having an activity designated as ”C” provided an 100nM < IC50 £ 500nM; compounds having an activity designated as ”D” provided an 500nM < ICso £ 1000nM; compounds having an activity designated as ”E” provided an 1000nM < ICso £ IOOOOhM; and compounds having an activity designated as ”F” provided an ICso > lOOOOnM. Table 3:

Table 4 shows activity data in the biochemical EGFR T790ML858R Lance, EGFR L858R Lance, EGFR (del746-750) Lance and EGFR wt Lance assays. Inhibition is indicated as IC50 [nM] = not measured). Compounds having an activity designated as ”A” provided an IC50 £ 50nM; compounds having an activity designated as ”B” provided an 50nM < IC50 £ 100nM; compounds having an activity designated as ”C” provided an 100nM < IC50 £ 500nM; compounds having an activity designated as ”D” provided an 500nM < ICso £ 1000nM; compounds having an activity designated as ”E” provided an 1000nM < ICso £ IOOOOhM; and compounds having an activity designated as ”F” provided an ICso > lOOOOnM.

Table 4:

Table 5 shows activity data in the cellular H1975 CellTiter-Glo, A431 CellTiter-Glo, EGFR L858RT790M Ba/F3 CellTiter-Glo, EGFR L858R Ba/F3 CellTiter-Glo and EGFR vlll Ba/F3 CellTiter-Glo assays. Inhibition is indicated as = not measured). Compounds having an activity designated as ”A” provided an ICso£ 50nM; compounds having an activity designated as ”B” provided an 50nM < IC ₅₀ £ 100nM; compounds having an activity designated as ”C” provided an 100nM < IC ₅₀ £ 500nM; compounds having an activity designated as ”D” provided an 500nM < ICso £ 1000nM; compounds having an activity designated as ”E” provided an 1000nM < IC ₅₀ £ IOOOOhM; and compounds having an activity designated as ”F” provided an ICso> lOOOOnM.

Table 5: The compounds 8, 9, 11 to 20 show similar activity in comparison to compounds 1 to 7, 10, 21 to 23, 121 to 152 so that compounds 1 to 7, 10, 21 to 23, 121 to 152 are regarded as selected representative examples of all 152 compounds explicitly disclosed herein.

SEQUENCE LIST

SEQ-ID No. 1: EGFR p.D770_N771insSVD ttcaaaaaga tcaaagtgct gggctccggt gcgttcggca cggtgtataa gggactctgg atcccagaag gtgagaaagt taaaattccc gtcgctatca aggaattaag agaagcaaca tctccgaaag ccaacaagga aatcctcgat gaagcctacg tgatggccag cgtggactca gtagacaacc cccacgtgtg ccgcctgctg ggcatctgcc tcacctccac cgtgcagctc atcacgcagc tcatgccctt cggctgcctc ctggactatg tccgggaaca caaagacaat attggctccc agtacctgct caactggtgt gtgcagatcg caaag

SEQ-ID No. 2: EGFR p.H773_V774insNPH ttcaaaaaga tcaaagtgct gggctccggt gcgttcggca cggtgtataa gggactctgg atcccagaag gtgagaaagt taaaattccc gtcgctatca aggaattaag agaagcaaca tctccgaaag ccaacaagga aatcctcgat gaagcctacg tgatggccag cgtggacaac ccccacaatc cacatgtgtg ccgcctgctg ggcatctgcc tcacctccac cgtgcagctc atcacgcagc tcatgccctt cggctgcctc ctggactatg tccgggaaca caaagacaat attggctccc agtacctgct caactggtgt gtgcagatcg caaag

SEQ-ID No. 3: EGFR p.V769_D770insASV ttcaaaaaga tcaaagtgct gggctccggt gcgttcggca cggtgtataa gggactctgg atcccagaag gtgagaaagt taaaattccc gtcgctatca aggaattaag agaagcaaca tctccgaaag ccaacaagga aatcctcgat gaagcctacg tgatggccag cgtggcctca gtcgacaacc cccacgtgtg ccgcctgctg ggcatctgcc tcacctccac cgtgcagctc atcacgcagc tcatgccctt cggctgcctc ctggactatg tccgggaaca caaagacaat attggctccc agtacctgct caactggtgt gtgcagatcg caaag

SEQ-ID No. 4: EGFR p.P772_H773insPR ttcaaaaaga tcaaagtgct gggctccggt gcgttcggca cggtgtataa gggactctgg atcccagaag gtgagaaagt taaaattccc gtcgctatca aggaattaag agaagcaaca tctccgaaag ccaacaagga aatcctcgat gaagcctacg tgatggccag cgtggacaac cccccgcgtc acgtgtgccg cctgctgggc atctgcctca cctccaccgt gcagctcatc acgcagctca tgcccttcgg ctgcctcctg gactatgtcc gggaacacaa agacaatatt ggctcccagt acctgctcaa ctggtgtgtg cagatcgcaa ag

SEQ-ID No. 5: HER2 INS8 INS YVMA acacctagcg gagcgatgcc caaccaggcg cagatgcgga tcctgaaaga gacggagctg aggaaggtga aggtgcttgg atctggcgct tttggcacag tctacaaggg catctggatc cctgatgggg agaatgtgaa aattccagtg gccatcaaag tgttgaggga aaacacatcc cccaaagcca acaaagaaat cttagacgaa gcatacgtga tggcttacgt gatggctggt gtgggctccc catatgtctc ccgccttctg ggcatctgcc tgacatccac ggtgcagctg gtgacacagc ttatgcccta tggctgcctc ttagaccatg tccgggaaaa ccgcggacgc ctgggctccc aggacctgct gaactggtgt atgcagattg ccaaggggat gagctacctg gaggatgtgc ggctcgtaca cagggacttg gccgctcgga acgtgctggt caagagtccc aaccatgtca aaattacaga c 6. SEQ-ID No. 6: EGFR T790M tccaaactgc acctacggat gcactgggcc aggtcttgaa ggctgtccaa cgaatgggcc taagatcccg tccatcgcca ctgggatggt gggggccctc ctcttgctgc tggtggtggc cctggggatc ggcctcttca tgcgaaggcg ccacatcgtt cggaagcgca cgctgcggag gctgctgcag gagagggagc ttgtggagcc tcttacaccc agtggagaag ctcccaacca agctctcttg aggatcttga aggaaactga attcaaaaag atcaaagtgc tgggctccgg tgcgttcggc acggtgtata agggactctg gatcccagaa ggtgagaaag ttaaaattcc cgtcgctatc aaggaattaa gagaagcaac atctccgaaa gccaacaagg aaatcctcga tgaagcctac gtgatggcca gcgtggacaa cccccacgtg tgccgcctgc tgggcatctg cctcacctcc accgtgcagc tcatcatgca gctcatgccc ttcggctgcc tcctggacta tgtccgggaa cacaaagaca atattggctc ccagtacctg ctcaactggt gtgtgcagat cgcaaagggc atgaactact tggaggaccg tcgcttggtg caccgcgacc tggcagccag gaacgtactg gtgaaaacac cgcagcatgt caagatcaca gattttgggc tggccaaact gctgggtgcg gaagagaaag aataccatgc agaaggaggc aaagtgccta tcaagtggat ggcattggaa tcaattttac acagaatcta tacccaccag agtgatgtct ggagctacgg ggtgaccgtt tgggagttga tgacctttgg atccaagcca tatgacggaa tccctgccag cgagatctcc tccatcctgg agaaaggaga acgcctccct cagccaccca tatgtaccat cgatgtctac atgatcatgg

7. SEQ-ID No. 7: EGFR T790ML858R tccaaactgc acctacggat gcactgggcc aggtcttgaa ggctgtccaa cgaatgggcc taagatcccg tccatcgcca ctgggatggt gggggccctc ctcttgctgc tggtggtggc cctggggatc ggcctcttca tgcgaaggcg ccacatcgtt cggaagcgca cgctgcggag gctgctgcag gagagggagc ttgtggagcc tcttacaccc agtggagaag ctcccaacca agctctcttg aggatcttga aggaaactga attcaaaaag atcaaagtgc tgggctccgg tgcgttcggc acggtgtata agggactctg gatcccagaa ggtgagaaag ttaaaattcc cgtcgctatc aaggaattaa gagaagcaac atctccgaaa gccaacaagg aaatcctcga tgaagcctac gtgatggcca gcgtggacaa cccccacgtg tgccgcctgc tgggcatctg cctcacctcc accgtgcagc tcatcatgca gctcatgccc ttcggctgcc tcctggacta tgtccgggaa cacaaagaca atattggctc ccagtacctg ctcaactggt gtgtgcagat cgcaaagggc atgaactact tggaggaccg tcgcttggtg caccgcgacc tggcagccag gaacgtactg gtgaaaacac cgcagcatgt caagatcaca gattttgggc gggccaaact gctgggtgcg gaagagaaag aataccatgc agaaggaggc aaagtgccta tcaagtggat ggcattggaa tcaattttac acagaatcta tacccaccag agtgatgtct ggagctacgg ggtgaccgtt tgggagttga tgacctttgg atccaagcca tatgacggaa tccctgccag cgagatctcc tccatcctgg agaaaggaga acgcctccct cagccaccca tatgtaccat cgatgtctac atgatcatgg