USEFUL FOR TREATING CANCER

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 2 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 ^a , R ^b , R ^c , R ^d represent independently of each other -H, -F, or -CFI ₃ ; B represents R ¹ represents -H, -F, -Cl, -Br, -I, -OH, -CN, cyclo-C ₃ H ₅ , -OCH ₃ , 2,

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

— OC ₂ H5, or — OC3H ₇ ;

R ³ and R ⁴ represent independently of each other -H, -F, -Cl, -CN, -CF ₃ ,

-OCH3, -OC ₂ H ₅ , -OC ₃ H ₇ , -OC ₂ H ₄ OCH ₃ , -CH ₂ OCH ₃ , -CH ₃ , -C ₂ H ₅ , or -C ₃ H ₇ , -CH ₂ CH ₂ OCH ₃ , -CH(CH ₃ ) ₂ , -C ₄ H9, -cyclo-CsHs, -cyclo-C4H ₇ , R ⁷ represents -H, — CH ₃ , or -C ₂ Fl ₅ ;

R ⁸ - R ¹¹ represent independently of each other -H, -F, -Cl, -CN, -OCH _3I -OC2H5, -OC3H7, -0CH(CH ₃ ) ₂ , -0C(CH ₃ ) ₃ , -OC ₄ H9, -OCH ₂ CH(CH ₃ ) _2I

-OC ₂ H ₄ OCH ₃ , -CH ₂ OCH ₃ , -CH _3I -CF _3I -C ₂ H _5I or -C3H7;

R ¹² represents -H, -CH ₃ , -CF ₃ , — C ₂ H ₅ , — C ₃ H ₇ , -CH(CH ₃ ) _2I -K -K>

R ¹³ and R ¹⁴ represent independently of each other -H, — CH ₃ , -CF ₃ , -C2H5,

-C ₃ H _7I -CH ₂ CH ₂ OCH _3I -CH(CH ₃ ) _2I -C ₄ H ₉ , -cyclo-C ₃ H ₅ or -cyclo-C ₄ H ₇ ;

R ¹⁵ represents -H, — CH ₃ , or -C ₂ Fl ₅ ;

R ¹⁶ represents -H, -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -CH ₂ CH ₂ OCH ₃ , -CH(CH ₃ ) ₂ ,

— C ₄ H ₉ , -cyclo-C ₃ Fl ₅ , -cyclo-C ₄ Fl ₇ , -cyclo-CsFIg, -cyclo-CeFI-i-i, or -C(CFI ₃ ) ₃ ;

R ¹⁷ , R ¹⁸ , R ¹⁹ , and R ²⁰ represent independently of each other -H, -CH _3I -CF _3I -C ₂ H _5I -C ₃ H _7I -CH(CH ₃ ) _2I -CN, -N0 ₂ , -COCH ₃ , -COC ₂ H ₅ , -COCsHy, -COCH(CH ₃ ) _2I -COC(CH ₃ ) _3I -COOH, -COOCHS, -COOC ₂ H ₅ , -COOCsHy, -COOCH(CH ₃ ) ₂ , or -COOC(CH ₃ ) ₃ ; R ²¹ and R ²² represent independently of each other

-H, -CH _3I -CF ₃ -C2H5, -C ₃ H _7I -CH(CH ₃ ) _2I -Ph, -CH ₂ Ph, -COCHs, -COCFS, -COC ₂ H _5I -COCH(CH ₃ ) _2I -COC(CH ₃ ) ₃ , -COPh, -C0 ₂ CH _3I -C0 ₂ C ₂ H _5I -C0 ₂ CH(CH ₃ ) ₂ , -C0 ₂ C(CH ₃ ) _3I -C0 ₂ Ph,

-C0 ₂ CH ₂ Ph, -S0 ₂ CH _3I -S0 ₂ C ₂ H ₅ , -S0 ₂ CF _3I or -S0 ₂ Ph;

R ²³ represents -F, -Br, -Cl, or -I; 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 the definition of R ¹ , R ^N , R ³ , R ⁴ , and R ¹² the dotted line “ ” or indicated the position of connection of the respective substituent. All substituents without such a dottet line are connected through the bond drawn to the left side of the substituent. However, the connection of the substituents to the ring system is also evident from the examples.

Preferred are compounds of general formula (I) wherein B represents have the same meanings as defined herein.

Also preferred are compounds of general formula (I) wherein A represents and R ⁶ , R ⁷ and R ⁹ - R ¹¹ have the meanings as defined herein. Moreover, R ¹ represents preferably R ³ , R ⁴ , R ¹⁵ , R ¹⁶ , and R ^N have the meanings as defined herein.

Furthermore, compounds of general formula (I) are preferred wherein R ⁵ represents and R ³ and R ⁴ are independently of each other selected from -CH ₃ , -CN, -C ₂ H ₅ , and -OCH ₃ , and R ^N has the meanings as defined herein.

More preferred are compounds of general formula (I) wherein

A represents R ³ , R ⁴ , R ¹⁶ , and R ^N have the meanings as defined herein.

R ² represents -H, -F, -Cl, -Br, -CN, -CH ₃ , -C ₂ H ₅ , -OCH ₃ , or -OC ₂ H ₅ ;

R ³ and R ⁴ represent independently of each other -H, -Cl, -CN, -CF ₃ , -OCFI ₃ , -OC ₂ H ₅ , -CH ₃ , or -C ₂ H ₅ , ;

R ^N represent -CH ₃ , -CF _3, -C ₂ H ₅ , -C ₃ H ₇ , -CH(CH ₃ ) ₂ ,

R ⁶ represents

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

R ⁸ represents -FI;

R ⁹ - R ¹¹ represent independently of each other -FI, -F, -Cl, -CN, -OCFI ₃ , -OC ₂ H ₅ , -OCsHy, -CH ₂ OCH ₃ , -CH _3I -CF _3I -C ₂ H ₅ , or -C ₃ H ₇ ;

R ¹² represents -H, -CH ₃ , -CF ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -CH(CH ₃ ) ₂ , -i<] -K> R ¹³ and R ¹⁴ represent independently of each other -H, -CH ₃ , or -C ₂ H ₅ ;

R ¹⁷ , R ¹⁸ , R ¹⁹ , and R ²⁰ represent independently of each other -H, -CH ₃ , -CF ₃ ,

-C ₂ H ₅ , -CN, -NO ₂ , -COCHs, -COC ₂ H ₅ , -COOH, -COOCHs, -COOC ₂ H ₅ ;

R ²¹ and R ²² represent independently of each other -H, -CH ₃ , -CF ₃ , — C ₂ H ₅ , or -C ₃ H ₇ ; 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 Fl5,

-OC ₃ H ₇ , -CH ₂ OCH _3I -CH _3I -C ₂ H _5I 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 Fl5, — CH ₃ , or — C ₂ H ₅ , still more preferably -FI, -CN, -OCFI ₃ , — CFH ₃ , or — C ₂ FH 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 -CH ₃ , -CF _3,

-C ₂ H ₅ , -C ₃ H _7I -CH(CH ₃ ) _2I -CH ₂ CH(CH ₃ ) ₂ , -C ₄ H ₉ , -cyclo-C ₃ H ₅ , -cyclo-C ₄ H ₇ ,

In regard to all general formula disclosed herein, R ⁶ represent preferably still more preferably

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

— CH ₃ ; most preferably — CH _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 -FI, -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, -OCFI ₃ , -OC ₂ FI ₅ , -OC ₃ FI ₇ , -CF) ₂ OCFI ₃ , — CFH ₃ , — C ₂ H ₅ , or — C ₃ FH ₇ ; more preferably -FI, -OCFI ₃ , -OC ₂ FI ₅ , — CFH ₃ , or -C ₂ FI ₅ ; still more preferably -FI, -OCFI ₃ , or — CFH ₃ ;

In regard to all general formula disclosed herein, R ¹⁰ represent preferably -CF) ₂ OCFI ₃ , — CH ₃ , -C ₂ FI ₅ , or — C ₃ FH ₇ ; more preferably — CFH ₃ , — C ₂ H ₅ , or — C ₃ FH ₇ ; still more preferably — CFH ₃ or -C ₂ FI ₅ ; and most preferably — CFH _3.

In regard to all general formula disclosed herein, R ¹² represent preferably -FI, — CFH ₃ , Thus, in regard to all general formula disclosed herein, R ¹³ and R ¹⁴ preferably represent -H, -CH ₃ , -CF _3I -C ₂ H ₅ , -C ₃ H ₇ , -CH(CH ₃ ) ₂ , -C4H9, or -cyclo-C ₃ H ₅ ; more preferably -H, -CH ₃ , -C ₂ H ₅ , or -C ₃ H ₇ ; more preferably -H, -CH ₃ , or -C ₂ H ₅ ; still more preferably -H or -CH ₃ ; and most preferably -H.

In regard to all general formula disclosed herein, R ¹⁶ represent preferably -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -CH ₂ CH ₂ OCH ₃ , -CH(CH ₃ ) ₂ , -C ₄ H ₉ , -cyclo-C ₃ H ₅ , or -C(CH ₃ ) ₃ ; more preferably -C ₂ H ₅ , -C ₃ H ₇ , -CH(CH ₃ ) ₂ , -C ₄ H ₉ , -cyclo-C ₃ H ₅ , or -C(CH ₃ ) ₃ ; more preferably -C ₃ H ₇ , -CH(CH ₃ ) ₂ , or -C ₄ H ₉ ; and most preferably -CH(CH ₃ ) ₂ .

In regard to all general formula disclosed herein, R ¹⁷ , R ¹⁸ , R ¹⁹ , and R ²⁰ preferably represent independently of each other -H, -CH ₃ , -CF ₃ , — C ₂ H ₅ , -CN, -NO ₂ , -COCHs, -COC ₂ H ₅ , -COOH, -COOCHs, -COOC ₂ H ₅ ; more preferably -H, — CH ₃ , -CF _3I — C ₂ H ₅ , more preferably -H, — CH ₃ , — C ₂ H ₅ , more preferably -H, — CH ₃ , and most preferably -H;

In regard to all general formula disclosed herein, R ²¹ and R ²² preferably represent independently of each other -H, — CH ₃ , -CF ₃ , -C ₂ H ₅ , -C ₃ H ₇ , — CH(CH ₃ ) ₂ ,

-COCHs, -COCFs, -COC ₂ H ₅ , -COCH(CH ₃ ) ₂ , -C0 ₂ CH ₃ , -C0 ₂ C ₂ H ₅ , or

-C0 ₂ CH(CH ₃ ) ₂ ; more preferably -H, -CH ₃ , -CF ₃ , -C ₂ H ₅ , or -C ₃ H ₇ ; still more preferably -H, -CH ₃ , -C ₂ H ₅ , or -C ₃ H ₇ ; still more preferably -CH ₃ or -C ₂ H ₅ ; and most preferably -CH _3.

Also preferred are compounds of general formula (I) wherein A represents

B represents R ¹³ and R ,1 14 4 represent -H; 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 2 which exhibit inhibition of HER2 Exon20 A775_G776insYVMA (and similar mutations) and/or EGFR Exon20 H773_V774insNPH (and similar mutations). The present invention provides these compounds as mutant-selective ErbB inhibitors, especially for the Exon20 EGFR/Her2 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 2 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 in order to obtain inhibitors which exhibit metabolic stability against liver microsomes the 2-position at the phenyl ring next to the warhead should be substituted. The warhead is preferably a but-2-enamide residue. 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 can be part of a ring system preferably containing the nitrogen atom of the warhead (like in compounds No. 106 - 111). Moreover it was found that an aromatic nitrogen heterocyclic 5-membered ring should be present at position 2 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. In addition to that it is very preferred that also an aromatic nitrogen heterocyclic 5-membered ring is present at position 5 of the pyrrolo[2,3- b]pyridine moiety in order to achieve the desired inhibitory activity. Most preferably this aromatic ring at position 5 should contain two nitrogen atoms. Especially preferred is the pyrazol ring at position 2 and also 5 of the pyrrolo[2,3-b/pyridine and even more preferred a pyrazol-4-yl ring at position 2 and 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 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 (NO2) 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 FIO-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: perfoming a second cross coupling reaction of the compound 12* with a compound 5 ^*

R ^' O \

B-B 5*

/

R ^' O 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) perfoming a first cross coupling reaction of pyridine compound 1 with alkyne compound 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: performing 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

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 - 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 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) perfoming 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: perfoming a second cross coupling reaction of the compound 12c* with a compound 5*

R ^' O \

/ B-B 5*

R ^' O 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

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 , Pd(PPh ₃ )CI 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 - 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(CH3)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 (NFI2) 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, HO At, 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 HER2. 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 inhibiting 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/FIER2 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 CFIINA PFIARMAFIUB, 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), IMC11 F8 (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/mTOR 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/HER2 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 H-NMR and ¹³ C-NMR were recorded on a Bruker DRX400 (400 MHz). 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 Hertz (Hz). 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); CDCI ₃ (deuterated chloroform); cHex (cyclohexane); 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,/\/',iV'-tetramethyluroniu m hexafluorophosphate); HCI (hydrochloric acid); HOAc (acetic acid); H ₂ 0 (water); K ₂ C0 ₃ (potassium carbonate); KOH (potassium hydroxide); LiBr (lithium bromide); MeOH (methanol); MgS0 ₄ (magnesium sulfate); MS (mass spectrometry); Mwt (molecular weight); NaHCOs (sodium hydrogencarbonate); Na ₂ S ₂ 0 ₃ (sodium thiosulfate); NH ₃ (ammonia); NH ₄ CI (ammonium chloride); NIS (/V-lodosuccinimide); NMP (N-methyl-2- pyrrolidon); NMR (nuclear magnetic resonance); Pd(dppf)CI ₂ ([1,1’- 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 :

Isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(1 -methyl-1 H-pyrazol-4-yl)-1H- pyrrolor2.3-blpyridine-5-carboxylate 2,2.2-trifluoroacetate (A5)

Step 1: Isopropyl 3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1H-pyrrolor2.3 - b1pyridine-5-carboxylate (A1

Isopropyl 6-amino-5-iodonicotinate (11.4g, 37.2mmol, 1.0eq.), trimethyl((4-methyl-3- nitrophenyl)ethynyl)silane (8.68g, 37.2mmol, 1.0eq.), 1 ,4-diazabicyclo[2.2.2]octane (7.08g, 63.2mmol, 1.7eq.) and dichlorobis(triphenylphosphine)palladium(ll) (2.61 g, 3.72mmol, 0.1eq.) in dry DMF (60ml_) under N ₂ atmosphere was splitted in six microwave vials. Each vial was heated in the microwave at 145°C for 2 h. EtOAc (250m L) was added and the organic phase was washed three times with aq. sat. NaHC0 ₃ -solution. The organic phase was dried over MgSC and solvents were removed in vacuo. The crude product was purified by flash chromatography on silica gel (cHex/EtOAc = 100:0 to 1 : 1 ) to yield the desired product A1 (7.1 g, 17.3mmol, 46%) as a beige solid. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 0.23 (s, 9H), 1.31 (d, J = 6.2 Hz, 6H), 2.60 (s, 3H), 5.15 (septet, J = 6.2 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.71 (dd, J = 1.8 Hz, J = 7.8 Hz, 1 H), 7.97 (d, J = 1.8 Hz, 1H), 8.25 (d, J = 1.9 Hz, 1H), 8.88 (d, J = 1.9 Hz, 1 H), 12.17 (s, 1 H). MS (ES) CiyH^NsC Si requires: 411, found: 412 (M+H) ⁺ . Step 2: Isopropyl 3-(3-amino-4-methylphenyl)-2-(trimethylsilyl)-1H-pyrrolor2.3 - blpyridine-5-carboxylate (A2

A solution of isopropyl 3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1 H-pyrrolo[2,3- b]pyridine-5-carboxylate A1 (7.1 g, 17.3mmol, 1.0eq.) and iron (2.0g, 36.4mmol, 2.1 eq.) in EtOH (400ml_) and aq. sat. NH ₄ CI-solution (40ml_) was stirred for 8h at 80°C. The solution was filtered through a pad of Celite®. Solvents were removed in vacuo. The crude was solved in EtOAc and washed twice with aq. sat. NaHCOs-solution. The organic phase was dried over MgS0 ₄ and solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel (cHex/EtOAc = 100:0 to 30:70) to yield the desired product A2 (5.4g, 14.2mmol, 82%) as a beige solid. MS (ES) C _2i H ₂₇ N ₃ 0 ₂ Si requires: 381 , found: 382 (M+H) ⁺ .

Step 3: Isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(trimethylsilyl)-1H- Pvrrolor2,3-blpvridine-5-carboxvlate (A3)

To a solution dry THF (250ml_) at 0°C was added slowly acrylolyl chloride (2.34g, 26.0mmol, 1.2eq.) in dry THF (10mL). The mixture was stirred for 5min. The solution was diluted with EtOAc and washed twice with aq. sat. NaHCOs-solution. The organic phase was dried over MgS0 ₄ and solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel (cHex/EtOAc = 100:0 to 1 :1) to yield the desired product A3 (8.794g, 20.2mmol, 93%) as a white solid. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 0.23 (s, 9H), 1.32 (J = 6.3 Hz, 6H), 2.31 (s, 3H), 5.15 (septet, J = 6.3 Hz, 1 H), 5.75 (dd, J = 2.1 Hz, J = 10.2 Hz, 1 H), 6.25 (dd, J = 2.1 Hz, J = 16.7 Hz, 1 H), 6.58 (dd, J = 10.2 Hz, J = 16.7 Hz, 1 H), 7.13 (dd, J = 1.9 Hz, J = 7.7 Hz, 1 H), 7.34 (d, J = 7.7 Hz, 1 H), 7.66 (m, 1 H), 8.29 (d, J = 2.0 Hz, 1 H), 8.85 (d, J = 2.0 Hz, 1 H), 9.42 (s, 1 H), 11 .96 (s, 1 H). MS (ES) C ₂₄ H ₂₉ N ₃ 0 ₃ Si requires: 435, found: 436 (M+H) ⁺ . Step 4: Isopropyl 3-(3-acrylamido-4-methylphenyl)-2-iodo-1H-pyrrolor2.3- blpyridine-5-carboxylate (A4

Isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridine-5- carboxylate A3 (8.794g, 20.2mmol, 1.0eq.) and N-iodosuccinimide (5.9g, 26.3mmol, 1.3eq.) were solved in dry dichloromethane (700ml_) and stirred for 15h at RT. The organic phase was washed once with aq. sat. Na ₂ S203-sol. and three times with aq. sat. NaHC03-solution. The organic phase was dried over Na ₂ S04 and solvents were removed in vacuo. The crude product was stirred 30m in at RT in DCM (50m L) and the the solid was filtered off yielding the desired product A4 (6.92g, 14.2mmol, 70%) as a yellow solid. The crude was used without purification in the next step. MS (ES) C ₂ IH ₂ OIN ₃ 03 requires: 489, found: 490 (M+H) ⁺ .

Step 5: Isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(1 -methyl-1 H-pyrazol-4-vD- 1 H-pyrrolor2.3-blpyridine-5-carboxylate 2.2.2-trifluoroacetate (A5)

A mixture of isopropyl 3-(3-acrylamido-4-methylphenyl)-2-iodo-1 H-pyrrolo[2,3- b]pyridine-5-carboxylate A4 (60.0mg, 0.123mmol, 1.0eq.), K3PO4 (52.1 mg, 0.245mmol, 2.0eq.), 1-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (33.2mg, 0.159mmol, 1.3eq.) and [1 ,T-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (10.0mg, 0.012mmol, 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 = 95:5 to 40:60, 30 min). The desired fractions were combined and lyophilized to yield the title compound A5 (16.6mg, 0.025mmol, 20%) as a yellow solid. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 1.33 (d, J = 6.2 Hz, 6H), 2.31 (s, 3H), 3.85 (s, 3H), 5.10-5.21 (m, 1 H), 5.76 (dd, J = 10.2, 2.1 Hz, 1 H), 6.26 (dd, J = 17.0, 2.0 Hz, 1 H), 6.57 (dd, J = 17.0, 10.2 Hz, 1 H), 7.20 (dd, J = 7.7, 1.8 Hz, 1 H), 7.37 (d, J = 7.9 Hz, 1 H), 7.64 (s, 1 H), 7.74 (s, 1 H), 8.07 (s, 1 H), 8.25 (d, J = 2.0 Hz, 1 H), 8.78 (d, J = 2.0 Hz, 1 H), 9.60 (s, 1 H), 12.41 (s, 1 H). MS (ES) C25H25N5O3 requires: 443, found: 444 (M+H) ⁺ .

The Examples in the following table were prepared according to the procedure described for A5 (Example 1 ).

Example 2:

Isopropyl 3-(3-acrylamido-5-fluoro-4-methylphenyl)-2-(1 -methyl-1 H-pyrazol-4-vD- 1 H-pyrrolor2.3-blpyridine-5-carboxylate 2,2.2-trifluoroacetate (B3)

Step 1 : Isopropyl 3-(3-acrylamido-5-fluoro-4-methylphenyl)-2-(trimethylsilyl)- 1H- pyrrolor2.3-blpyridine-5-carboxylate (B1 ) B1 was prepared from isopropyl 6-amino-5-iodonicotinate and ((3-fluoro-4-methyl-5- nitrophenyl)ethynyl)trimethylsilane following the general procedure reported in Preparative Example 1 Step 1 to 3. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 0.24 (s, 9H), 1.33 (d, J = 6.3 Hz, 6H), 2.21 (s, 3H), 5.15 (septet, J = 6.3 Hz, 1 H), 5.78 (dd, J = 2.0 Hz, J 10.3 Hz, 1 H), 6.27 (dd, J = 2.0 Hz, J = 17.0 Hz, 1 H), 6.58 (m, 1 H), 7.05 (dd, J = 1.6 Hz, J = 10.1 Hz, 1 H), 7.52 (d, J = 7.0 Hz, 1 H), 8.30 (d, J = 12.0 Hz, 1 H), 8.56 (d, J = 2.0 Hz, 1 H), 9.69 (s, 1 H), 12.04 (s, 1 H). MS (ES) Ca^sFNsOsSi requires: 453, found: 454 (M+H) ⁺ . Step 2: Isopropyl 3-(3-acrylamido-5-fluoro-4-methylphenyl)-2-iodo-1H-pyrrolor2 .3- blpvridine-5-carboxvlate (B2

Isopropyl 3-(3-acrylamido-5-fluoro-4-methylphenyl)-2-(trimethylsilyl)- 1 H-pyrrolo[2,3- b]pyridine-5-carboxylate B1 (2.0g, 4.41 mmol, 1.0eq.) and N-iodosuccinimide (1.3g, 57.3mmol, 1.3eq.) were solved in dry dichloromethane (300ml_) and stirred for 15h at RT. The organic phase was washed once with aq. sat. Na ₂ S203-sol. and three times with aq. sat. NaHCOs-solution. The organic phase was dried over Na ₂ S04 and solvents were removed in vacuo. The crude product was stirred 30min at RT in DCM (40ml_) and the solid was filtered off yielding the desired product B2 (1.34g, 2.6mmol, 60%) as a yellow solid. The crude was used without purification in the next step. MS (ES) C ₂ IHI ₉ FIN ₃ 03 requires: 507, found: 508 (M+H) ⁺ .

Step 3: Isopropyl 3-(3-acrylamido-5-fluoro-4-methylphenyl)-2-(1 -methyl-1 H-

A mixture of isopropyl 3-(3-acrylamido-5-fluoro-4-methylphenyl)-2-iodo-1 H-pyrrolo[2,3- b]pyridine-5-carboxylate B2 (31 mg, 0.06mmol, 1.0eq.), 1-methyl-4-(4,4, 5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (17mg, 0.08mmol, 1.3eq.), and K3PO4 (39mg, 0.18mmol, 3.0 eq) in dioxane/H ₂ 0 (3mL/0.6mL) was degassed with a stream of N ₂ for 5min. [1 ,T-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (5mg, 0.006mmol, 0.1 eq) was added and the reaction mixture heated to 130°C for 2 h in the microwave oven. The reaction mixture was diluted with EtOAc, washed three times with aq. sat. NaHCOs-solution. The organic phase was dried over MgS04 and solvents were removed in vacuo. The crude was purified by reversed phase HPLC (column: C18), using H ₂ 0 (0.1 %TFA) and ACN (0.1 %TFA) as eluents. The desired fractions were lyophilized to yield the title compound B3 (15mg, 0.02mmol, 36%) as a yellow powder. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 1.32 (d, J = 6.2 Hz, 6 H), 2.19 (s, 3H), 3.84 (s, 3H), 5.13 (septet, J = 6.2 Hz, 1 H), 5.76 (dd, J = 2.0 Hz, J = 10.1 Hz, 1 H), 6.25 (dd, J = 2.0 Hz, J = 16.9 Hz, 1 H), 6.55 (dd, J = 10.1 Hz, J = 16.9 Hz, 1 H), 7.08 (d, J = 9.9 Hz, 1 H), 7.49 (s, 1 H), 7.73 (s, 1 H), 8.05 (s, 1 H), 8.25 (d, J = 2.1 Hz, 1 H), 8.77 (d, J = 2.1 Hz, 1 H), 9.75 (s, 1 H), 12.46 (s, 1 H). MS (ES) C25H24FN5O3 requires: 461 , found: 462 (M+H) ⁺ .

The Examples in the following table were prepared according to the procedure described for B3 (Example 2).

Example 3:

N-(5-(5-ethoxy-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3-blpyridin-3-yl)-3-fluoro- 2-methvlphenvl)acrvlamide 2,2,2-trifluoroacetate (C1)

C1 was prepared from 3-bromo-5-ethoxypyridin-2-amine and ((3-fluoro-4-methyl-5- nitrophenyl)ethynyl)trimethylsilane following the general procedure reported in Preparative Example 2. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 1.33 (t, J = 7.0 Hz, 3H), 2.18 (d, J = 1.9 Hz, 3H), 3.85 (s, 3H), 4.07 (q, J = 7.0 Hz, 2H), 5.78 (dd, J = 10.2, 2.0

Hz, 1 H), 6.27 (dd, J = 17.0, 2.0 Hz, 1 H), 6.56 (dd, J = 17.0, 10.2 Hz, 1 H), 7.04 (dd, J = 10.5, 1.7 Hz, 1 H), 7.38 (d, J = 2.7 Hz, 1 H), 7.47 (s, 1 H), 7.70 (d, J = 0.7 Hz, 1 H), 7.95 (d, J = 2.7 Hz, 1 H), 8.01 (s, 1 H), 9.74 (s, 1 H), 11.85 (s, 1 H). MS (ES) C23H22FN5O2 requires: 419, found: 420 (M+H) ⁺ .

Example 4:

N-(5-(5-isobutoxy-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3-blpyridin-3-yl)-2- methylphenvDacrylamide 2 Step 1 : 5-lsobutoxy-3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1 H-rnitoIoG2.3- blpyridine (D1)

3-Bromo-5-isobutoxypyridin-2-amine (2.44g, 10mmol, 1eq) and trimethyl[2-(4-methyl-3- nitrophenyl)ethynyl]silane (2.9g, 12mmol, 1.25eq) were added into a pressure tube, and dissolved in DMF (25ml_). Next, triethylenediamine (1.89g, 17mmol, 1.7eq) and bis(triphenylphosphine)palladium (II) dichloride (0.7g, 0.99mmol, 0.1 eq) were added, and the tube was purged with argon. The reaction mixture was heated in MW at 145°C for 2h, diluted with saturated aqueous NaHCOs solution, and extracted with EtOAc (3x150ml_). The organic layers were washed with saturated aqueous NaCI solution, dried over Na ₂ S04, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH, 9:1), and repurified by reversed flash chromatography (ACN: H ₂ 0, 40:60) to afford the pure product D1 as an orange solid (1 5g, Y:37%). ¹ H NMR (300 MHz, DMSO -d ₆ ) d 11.35 (s, 1 H), 7.85 (d, J = 2.7 Hz, 1 H), 7.70 (d, J = 1.9 Hz, 1 H), 7.47 (dd, J = 8.2, 1.7 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.08 (d, J = 2.7 Hz, 1 H), 3.54 (d, J = 6.5 Hz, 2H), 2.37 (s, 3H), 1.90 - 1.75 (m, 1 H), 0.76 (d, J = 6.7 Hz, 6H), 0.00 (s, 9H). MS (ES) C _2i H ₂₇ N ₃ 0 ₃ Si requires: 397, found: 398 (M+H) ⁺ .

Step _ 2\ _ 5-(5-lsobutoxy-2-(trimethylsilyl)-1H-pyrrolor2.3-blpyridin-3 -yl)-2- methylaniline (D2)

A suspension of 3-(4-methyl-3-nitrophenyl)-5-(2-methylpropoxy)-2-(trimethyls ilyl)-1 H- pyrrolo[2,3-b]pyridine D1 (1.5g, 3.8mmol, 1eq), iron (1.69g, 30mmol, 8eq) in 15ml_ of EtOH and saturated aqueous NH ₄ CI solution (1.5ml_) was stirred for 6h at 80°C. Then, the reaction mixture was filtered through a pad of silica gel, washed with DCM (200m L), and EtOAc (200m L). The solvents were evaporated, and the crude product was purified by column chromatography (DCM:MeOH 9:1), next repurified by reversed flash chromatography (ACN:H ₂ 0, 50:50) to obtain two fractions of the desired product D2 as a yellow solid: F1: 620mg (LCMS: 97%of DP), F2: 540mg (LCMS: 60%). MS (ES) C _2i H ₂₉ N ₃ OSi requires: 367, found: 368 (M+H) ⁺ . Step 3: N-(5-(5-isobutoxy-2-(trimethylsilyl)-1 H-pyrrolor2.3-blpyridin-3-yl)-2- methylphenvDacrylamide (

2-Methyl-5-[5-(2-methylpropoxy)-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl]aniline D2 (620mg, 1.7mmol, 1eq) was dissolved in THF (5ml_) at -10°C. DIPEA (2.9mL, 17mmol, 10eq) was dropped, and the mixture was stirred for 5min at -10°C, then a solution of acryloyl chloride (73pL, 1.7mmol, 1eq) in 5mL of THF was added dropwise. The reaction mixture was slowly warmed to room temperature. After 30min, LCMS showed full conversion. The reaction mixture was diluted with water (100ml_), and the desired product was extracted with DCM (3x100ml_). The organic phase was dried over Na ₂ S04, and concentrated under reduced pressure. The crude product was triturated with DCM to obtain 700mg (Y: 98%) of the pure product D3 as a creamy solid. ¹ H NMR (300 MHz, DMSO-de) d 11.13 (s, 1H), 9.27 (s, 1H), 7.81 (d, J = 2.7 Hz, 1H), 7.42 (s, 1 H), 7.14 (d, J = 2.7 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.89 (dd, J = 7.7, 1.8 Hz, 1H), 6.37 (dd, J = 16.9, 10.1 Hz, 1H), 6.04 (dd, J = 17.0, 2.2 Hz, 1H), 5.54 (dd, 1H), 3.55 (d, J = 6.6 Hz, 2H), 2.07 (s, 3H), 1.91 - 1.70 (m, 1 H), 0.76 (d, J = 6.6 Hz, 6H), 0.00 (s, 9H). MS (ES) C ₂₄ H _3i N ₃ 0 ₂ Si requires: 421, found: 422(M+H) ⁺ .

Step 4: N-(5-(2-iodo-5-isobutoxy-1 H-pyrrolor2.3-blpyridin-3-yl)-2- methvlphenvDacrvlamide (D

To a solution of N-(5-(5-isobutoxy-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2- methylphenyl)acrylamide D3 (84.0mg, 0.199mmol, 1.0eq.) in dry DCM (8ml_) was added N-iodosuccinimide (80.7mg, 0.359mmol, 1.8eq.) at room temperature. The resulting solution was stirred overnight under light exclusion. The mixture was then diluted with DCM and washed with sat. Na ₂ S ₂ 0 ₃ solution, three times with sat. NaHC0 ₃ solution, brine and dried over MgSC . The solvent was removed under reduced pressure and the residue was lyophilized to yield the desired product D4 as a beige brown solid (83.0mg, 0.175mmol, 88%). The compound was used in the next step without further purification. MS (ES) C _2i H ₂₂ lN ₃ 0 ₂ requires: 475, found: 476 (M+H) ⁺ . Step 5: N-(5-(5-isobutoxy-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3-blpyridin-3- yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (D5)

A mixture of N-(5-(2-iodo-5-isobutoxy-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2- methylphenyl)acrylamide D4 (40.0mg, 0.084mmol, 1.0eq.), K3PO4 (35.7mg, 0.168mmol, 2.0eq.), 1-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (22.8mg, 0.109mmol, 1.3eq.) and [1 ,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (6.9mg, 0.008mmol, 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 = 90:10 to 35:65, 30 min). The desired fractions were combined and lyophilized to yield the title compound D5 (11.5mg, 0.017mmol, 20%) as a yellow solid. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 0.98 (d, J = 6.7 Hz, 6H), 1.96-2.08 (m, 1 H), 2.29 (s, 3H), 3.79 (d, J = 6.6 Hz, 2H), 3.84 (s, 3H), 5.76

(dd, J = 10.1, 2.1 Hz, 1H), 6.26 (dd, J = 17.0, 2.1 Hz, 1H), 6.58 (dd, J = 17.0, 10.2 Hz, 1 H), 7.18 (dd, J = 7.7, 1.8 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 2.7 Hz, 1H), 7.63 (s, 1 H), 7.70 (s, 1H), 7.95 (d, J = 2.7 Hz, 1H), 8.01 (s, 1H), 9.57 (s, 1H), 11.78 (s, 1 H). MS (ES) C25H27N5O2 requires: 429, found: 430 (M+H) ⁺ .

The Examples in the following table were prepared according to the procedure described for D5 (Example 4).

Example 7:

Isopropyl 3-(3-acrylamido-4-methylphenyl)-4-methyl-2-(1 -methyl-1 H-pyrazol-4-nP- 1 H-pyrrolor2.3-blpyridine-5-carboxylate 2,2.2-trifluoroacetate (E2)

Step 1 : Isopropyl 3-(3-acrylamido-4-methylphenyl)-2-iodo-4-methyl-1H- pyrrolor2.3-blpyridine-5-carboxylate (E1 )

E1 was prepared from isopropyl 6-amino-5-iodo-4-methylnicotinate and trimethyl((4- methyl-3-nitrophenyl)ethynyl)silane following the general procedure reported in Preparative Example 1 Step 1 to 4. MS (ES) C22H22IN3O3 requires: 503, found: 504 (M+H) ⁺ .

Step 2: Isopropyl 3-(3-acrylamido-4-methylphenyl)-4-methyl-2-(1 -methyl-1 H- A mixture of isopropyl 3-(3-acrylamido-4-methylphenyl)-2-iodo-4-methyl-1 H-pyrrolo[2,3- b]pyridine-5-carboxylate E1 (30mg, 0.06mmol, 1.0eq.), 1-methyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (16mg, 0.08mmol, 1.3eq.), and K ₃ PO ₄ (38mg, 0.18mmol, 3.0 eq) in dioxane/H ₂ 0 (3mL/0.6mL) was degassed with a stream of N ₂ for 5min. [1 ,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (5mg, 0.006mmol, 0.1 eq) was added and the reaction mixture heated to 130°C for 2 h in the microwave oven. The reaction mixture was diluted with EtOAc, washed three times with aq. sat. NaHCOs-solution. The organic phase was dried over MgSC and solvents were removed in vacuo. The crude was purified by reversed phase RP- HPLC (column: C18), using H ₂ 0 (0.1%TFA) and ACN (0.1%TFA) as eluents. The desired fractions were lyophilized to yield the title compound E2 (5mg, 0.009mmol, 15%) as a yellow powder. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 1.32 (d, J = 6.2 Hz, 6 H), 2.30 (s, 3H), 2.32 (s, 3H), 3.78 (s, 3H), 5.12 (septet, J = 6.2 Hz, 1H), 5.74 (dd, J = 2.0 Hz, J = 10.2 Hz, 1 H), 6.22 (dd, J = 2.0 Hz, J = 17.0 Hz, 1H), 6.55 (dd, J = 10.2 Hz, J = 17.0 Hz, 1 H), 7.10 (dd, J = 1.8 Hz, J = 7.7 Hz, 1H), 7.34 (d, J = 4.7 Hz, 1 H), 7.37 (s,

1 H), 7.54 (s, 1 H), 7.72 (s, 1H), 8.59 (s, 1H), 9.57 (s, 1H), 12.26 (s, 1H). MS (ES) 0 ₂₆ H ₂₇ N ₅ 0 ₃ requires: 457, found: 458 (M+H) ⁺ .

The Examples in the following table were prepared according to the procedure described for E2 (Example 7).

Example 26:

N-(5-(2,5-bis(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3-b1pyridin-3-yl)-2- methylphenvDacrylamide 2,

Step 1 : 5-Bromo-3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1 H-rnitoIoG2.3- blpyridine (F1) 5-Bromo-3-iodopyridin-2-amine trimethyl[2-(4-methyl-3- nitrophenyl)ethynyl]silane (9.76g, 41.8mmol, 1.25eq) were dissolved in DMF (200ml_) in a pressure tube. Next, triethylenediamine (6.38g, 56.9mmol, 1.7eq), and bis(triphenylphosphine)palladium (II) dichloride (2.36g, 33.4mmol, 0.1 eq) were added, and the tube was purged with argon. The reaction mixture was heated at 145°C for 16h, next diluted with a saturated aqueous NaHCOs solution, and the product was extracted with DCM (3x250ml_). The organic layer was washed with saturated aqueous NaCI solution, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography (DCM:MeOH, 0-10% of MeOH), and repurified by RP flash column chromatography (ACN: H ₂ 0, 50:50) to afford the product F1 as a brown solid (4.83g, Y:36%). ¹ H NMR (300 MHz, DMSO -d ₆ ) d 11.74 (s, 1 H), 8.14 (d, J = 2.2 Hz, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.48 - 7.29 (m, 2H), 2.35 (s, 3H). MS (ES) Ci ₇ H ₁₈ BrN ₃ 0 ₂ Si requires: 403/405, found: 404/406 (M+H) ⁺ . Step 2: 5-Bromo-2-iodo-3-(4-methyl-3-nitrophenyl)-1H-pyrrolor2.3-blp yridine (F2)

The mixture of 5-bromo-3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1 H-pyrrolo[2,3- b]pyridine F1 (4.83g, 11.9mmol, 1eq) and NIS (4.84g, 21.5mmol, 1.8eq) was dissolved in dry DCM (145ml_), and stirred for 4h at room temperature. The reaction mixture was quenched with a saturated aqueous Na ₂ S ₂ 0 ₃ solution, and the desired product was extracted with DCM (3x200ml_). The organic phase was washed with a saturated aqueous NaHCOs solution, dried over Na ₂ S0 ₄ , and the solvent was removed under vacuo. The crude material F2 as an orange solid (4g, Y:98%) was immediately used without purification in the next step. MS (ES) Ci ₄ H ₉ BrlN ₃ 0 ₂ requires: 457/459, found: 458/460 (M+H) ⁺ .

Step 3: 5-Bromo-2-(1 -methyl-1 H-pyrazol-4-yl)-3-(4-methyl-3-nitrophenyl)-1H- Pvrrolor2,3-blpvridine (F3) In a pressure tube, 5-bromo-2-iodo-3-(4-methyl-3-nitrophenyl)-1 H-pyrrolo[2,3-b]pyridine F2 (2g, 4.4mmol, 1eq), 1-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole (0.91 g, 4.4mmol, 1eq), and Na ₂ C0 ₃ (0.93g, 8.7mmol, 2eq) were suspended in the mixture of THF/MeOH/H ₂ 0 (24ml_; 1:0.1:0.1 vol), degassed under vacuum, and purged with argon. Next, Pd(PPh ₃ ) ₂ CI ₂ (0.61 g, 0.87mmol, 0.2eq) was added, and the reaction mixture was heated at 80°C for 16h, then was cooled, and the desired product was extracted with DCM (3x100ml_). The organic phase was dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM : MeOH, 0-15% of MeOH), then repurified by 2 ^nd column chromatography (CHCI ₃ : iPrOH, 0-10% of iPrOH) to afford the product F3 as an orange solid (5.15g, yield >100%). The obtained product was used for the next step. MS (ES) Ci ₈ H ₁₄ BrN ₅ 0 ₂ requires: 411/413, found: 412/414 (M+H) ⁺ .

Step 4: 5-(5-Bromo-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3-blpyridin-3-yl)-2- methvlaniline (F4)

4-[5-Bromo-3-(4-methyl-3-nitrophenyl)-1 H-pyrrolo[2,3-b]pyridin-2-yl]-1 -methyl-1 H- pyrazole F3 (5.15g, 12.5mmol, 1eq) and iron (3.49g, 62.5mmol, 5eq) were suspended in a mixture EtOH (50ml_) and a saturated aqueous NH ₄ CI solution (5ml_), and stirred for 4h at 80°C. Then, the solvents were evaporated under vacuum, and the crude material was purified by column chromatography (DCM:MeOH, 0-15% of MeOH), and then repurified by 2 ^nd column chromatography (CHCI ₃ : iPrOH, 0-10% of iPrOH) to obtain the desired product F4 as a yellow solid (1.3g, Y:27%). ¹ H NMR (300 MHz, DMSO-de) d 12.09 (s, 1H), 8.22 (d, J = 2.2 Hz, 1H), 7.88 (s, 1H), 7.77 (d, J = 2.2 Hz, 1 H), 7.63 (d, J = 0.7 Hz, 1 H), 7.01 (d, J = 7.6 Hz, 1 H), 6.71 (d, J = 1.7 Hz, 1 H), 6.51 (dd, J = 7.5, 1.7 Hz, 1 H), 4.92 (s, 2H), 3.83 (s, 3H), 2.11 (s, 3H). MS (ES) Ci ₈ H ₁₆ BrN ₅ requires: 381/383, found: 382/384 (M+H) ⁺ .

Step 5: N-(5-(5-bromo-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3-blpyridin-3-yl)- 2-methvlphenvl)acrvlamide (F5) 5-[5-Bromo-2-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrrolo[2,3-b]pyridin-3-yl]-2-methylaniline F4 (1.3g, 3.4mmol, 1eq) was dissolved in THF (50ml_) at -10°C. Next, DIPEA (5.92ml_, 34.0mmol, 10eq) was dropped, and the mixture was stirred for 5min at -10°C, then a solution of acryloyl chloride (280pl_, 3.4mmol, 1.0eq) in THF (10ml_) was added dropwise. LCMS showed ~70% conversion. Another portion of acryloyl chloride (140mI_, 5.1 mmol, 0.5q) in THF (5mL) was added dropwise. After 30min, LCMS showed full conversion. The reaction mixture was slowly warmed to room temperature. The reaction mixture was diluted with water (100mL), and the desired product was extracted with DCM (3x100mL). The organic phase was dried over Na ₂ S04, and concentrated under reduced pressure to obtain 1.23g (Y: 83%) of the pure product F5 as a beige solid. ¹ H NMR (300 MHz, DMSO -cfe) d 12.21 (s, 1 H), 9.60 (s, 1 H), 8.25 (d, J = 2.2 Hz, 1 H), 8.06 (s, 1 H), 7.86 (d, J = 2.2 Hz, 1H), 7.74 (s, 1H), 7.60 (s, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.19 (dd, J = 7.7, 1.8 Hz, 1H), 6.57 (dd, J = 17.0, 10.1 Hz, 1H), 6.26 (dd, J = 17.0, 2.1 Hz, 1 H), 5.76 (dd, J = 10.2, 2.1 Hz, 1H), 3.85 (s, 3H), 2.29 (s, 3H). MS (ES) C _2i H ₁₈ BrN ₅ 0 requires: 435/437, found: 436/438 (M+H) ⁺ .

Step 6: N-(5-(2,5-bis(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3-blpyridin-3-yl)-2- methylphenvDacrylamide 2,2.2-trifluoroacetate (F6)

A mixture of N-(5-(5-bromo-2-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)- 2-methylphenyl)acrylamide F5 (55.0mg, 0.126mmol, 1.0eq.), K ₃ PO ₄ (53.5mg,

0.252mmol, 2.0eq.), 1 -methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole (34.1 mg, 0.164mmol, 1.3eq.) and [1 ,T-bis(diphenylphosphino)ferrocene]- palladium dichloride dichloromethane adduct (10.3mg, 0.013mmol, 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 = 95:5 to 55:45, 30 min). The desired fractions were combined and lyophilized to yield the title compound F6 (19.9mg, 0.030mmol, 24%) as a yellow solid. ¹ H NMR (400MHz, d ₆ - DMSO, 300K) d 2.31 (s, 3H), 3.85 (s, 3H), 3.86 (s, 3H), 5.77 (dd, J = 10.1, 2.1 Hz, 1H), 6.28 (dd, J = 17.0, 2.0 Hz, 1H), 6.58 (dd, J = 17.0, 10.2 Hz, 1H), 7.22 (dd, J = 7.7, 1.8 Hz, 1 H), 7.34 (d, J = 7.9 Hz, 1H), 7.66 (s, 1H), 7.73 (s, 1H), 7.90 (s, 1H), 7.96 (d, J = 2.0 Hz, 1 H), 8.05 (s, 1H), 8.17 (s, 1H), 8.46 (d, J = 2.0 Hz, 1H), 9.60 (s, 1H), 12.00 (s, 1H). MS (ES) C25H23N7O requires: 437, found: 438 (M+H) ⁺ .

The Examples in the following table were prepared according to the procedure described for F6 (Example 26).

Example 36:

N-(3-fluoro-5-(5-isobutoxy-2-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrrolor2.3-blpyridin-3- yl)-2-methylphenyl)acrylam

G1 was prepared from 3-bromo-5-isobutoxypyridin-2-amine and ((3-fluoro-4-methyl-5- nitrophenyl)ethynyl)trimethylsilane following the general procedure reported in Preparative Example 4 Step 1 to 5. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 0.99 (d, J = 6.7 Hz, 6H), 2.02 (septet, J = 6.7 Hz, 1 H), 2.19 (s, 3H), 3.80 (d, J = 6.6 Hz, 2H), 3.85 (s, 3H), 5.79 (dd, J = 2.0 Hz, J = 10.2 Hz, 1 H), 6.28 (dd, J = 2.0 Hz, J = 17.0 Hz, 1 H), 6.57

(dd, J = 10.2 Hz, J = 17.0 Hz, 1 H), 7.05 (dd, J = 1.6 Hz, J = 10.1 Hz, 1 H), 7.40 (d, J = 2.6 Hz, 1 H), 7.49 (s, 1 H), 7.70 (s, 1 H), 7.95 (d, J = 2.6 Hz, 1 H), 8.01 (s, 1 H), 9.74 (s, 1 H), 11 .84 (s, 1 H). MS (ES) C ₂₅ H ₂₆ FN ₅ O ₂ requires: 447, found: 448 (M+H) ⁺ . The Examples in the following table were prepared according to the procedure described for G1 (Example 36). Example 42:

N-(5-(5-isobutoxy-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3-blpyridin-3-yl)-2- methylphenvDethenesulfonamide 2,2.2-trifluoroacetate

To a solution of 5-(5-isobutoxy-2-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrrolo[2,3-b]pyridin-3- yl)-2-methylaniline (50mg, 0.11 mmol, 1.0eq.) and pyridine (14mg, 0.11 mmol, 1.0eq.) in dry NMP (2mL) at 0°C was added slowly 2-chloroethanesulfonyl chloride (13mg, 0.11 mmol, 1.0eq.) in dry NMP (0.5ml_). After 10min stirring at 0°C, the mixture was directly purified by reversed phase HPLC (column: C18), using H ₂ 0 (0.1 %TFA) and ACN (0.1 %TFA) as eluents. The desired fractions were lyophilized to yield the title compound H1 (15mg, 0.02mmol, 20%) as a yellow powder. ¹ FI NMR (400MFIz, d ₆ - DMSO, 300K) d 0.98 (d, J = 6.7 Hz, 6H), 2.01 (septet, J = 6.7 Hz, 1 H), 2.35 (s, 3H), 3.77 (d, J = 6.7 Hz, 2H), 3.83 (s, 3H), 5.93 (d, J = 10.0 Hz, 1 H), 5.97 (d, J = 16.4 Hz, 1 H), 6.88 (dd, J = 10.0 Hz, J = 16.4 Hz, 1 H), 7.21 (dd, J = 1.8 Hz, J = 7.7 Hz, 1 H), 7.30 (m, 3H), 7.62 (s, 1 H), 7.85 (s, 1 H), 7.95 (d, J = 2.6 Hz, 1 H), 9.39 (s, 1 H), 11 .83 (s, 1 H). MS (ES) C24H27N5O3S requires: 465, found: 466 (M+H) ⁺ .

Example 43:

N-(5-(5-isobutoxy-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3-blpyridin-3-yl)-2- methylphenyl)but-2-vnamide 2.2.2-trifluoroacetate (ID

To a solution of 2-butynoic acid (20mg, 0.24mmol, 3.0eq.) and a drop of dry DMF in dry DCM (1 ml_) at 0°C was added slowly oxalyl chloride (17uL, 0.20mmol, 2.5eq.) in dry DCM (0.2ml_). After 60min the mixture was added to a solution of 5-(5-isobutoxy-2-(1- methyl-1 H-pyrazol-4-yl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylaniline (30mg, 0.08mmol, 1.0eq.) in dry NMP (1 ml_) at 0°C. The mixture was stirred for 10min. The solution was diluted with DCM and washed twice with aq. sat. NaHCOs-solution. The organic phase was dried over MgSC and solvent was removed in vacuo. The crude product was purified by reversed phase HPLC (column: C18), using H ₂ 0 (0.1 %TFA) and ACN (0.1%TFA) as eluents. The desired fractions were lyophilized to yield the title compound 11 (25mg, O.C mmol, 32%) as a yellow powder. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 0.98 (d, J = 6.7 Hz, 6H), 2.01 (septet, J = 6.7 Hz, 1 H), 2.04 (s, 3H), 2.26 (s, 3H), 3.77 (d, J = 6.7 Hz, 2H), 3.82 (s, 3H), 7.20 (dd, J = 1.8 Hz, J = 7.7 Hz, 1 H), 7.31 (m, 2H), 7.40 (d, J = 1.7 Hz, 1 H), 7.70 (s, 1 H), 7.94 (s, 1 H), 7.95 (d, J = 2.7 Hz, 1 H), 10.09 (s, 1 H), 11 .80 (s, 1 H). MS (ES) C ₂₆ H ₂₇ N ₅ O ₂ requires: 441 , found: 442 (M+H) ⁺ .

Example 44:

4-(Dimethylamino)-N-(5-(5-isobutoxy-2-(1 -methyl-1 H-pyrazol-4-yl)-1 H-rnitoIoG2.3- blpyridin-3-yl)-2-methylphenyl)but-2-enamide 2,2.2-trifluoroacetate (J1 )

To a solution of trans-4-dimethylaminocrotonic acid hydrochloride (53mg, 0.32mmol, 3.0eq.) and a drop of dry DMF in dry DCM (1 ml_) at 0°C was added slowly oxalyl chloride (23uL, 0.27mmol, 3.0eq.) in dry DCM (0.2ml_). After 60min the mixture was added to a solution of 5-(5-isobutoxy-2-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrrolo[2, 3- b]pyridin-3-yl)-2-methylaniline (52mg, 0.11 mmol, 1.0eq.) in dry NMP (1ml_) at 0°C. The mixture was stirred for 10min. The solution was diluted with DCM and washed twice with aq. sat. NaHCCVsolution. The organic phase was dried over MgSC and solvent was removed in vacuo. The crude product was purified by reversed phase HPLC (column: C18), using H ₂ 0 (0.1 %TFA) and ACN (0.1 %TFA) as eluents. The desired fractions were lyophilized to yield the title compound J1 (25mg, 0.04mmol, 32%) as a yellow powder. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 0.99 (d, J = 6.6 Hz, 6H), 2.02 (septet, J = 6.6 Hz, 1 H), 2.30 (s, 3H), 2.81 (s, 3H), 2.82 (s, 3H), 3.78 (d, J = 6.6 Hz, 2H), 3.84 (s, 3H), 3.95 (m, 2H), 6.60 (d, J = 15.4 Hz, 1 H), 6.74 (dt, J = 7.0 Hz, J = 15.4 Hz, 1 H), 7.20 (dd, J = 2.2 Hz, J = 7.9 Hz, 1 H), 7.31 (d, J = 2.6 Hz, 1 H), 7.34 (d, J = 7.9 Hz, 1 H), 7.61 (m, 1 H), 7.68 (d, J = 0.9 Hz, 1 H), 7.95 (d, J = 2.6 Hz, 1 H), 7.99 (s, 1 H), 9.75 (s, 1 H), 11.77 (s, 1 H). MS (ES) C ₂₈ H ₃₄ N ₆ O ₂ requires: 486, found: 487 (M+H) ⁺ .

Example 45:

N-(2-methyl-5-(4-methyl-2,5-bis(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2, 3- b1pyridin-3-yl)phenyl)acrylamide 2,2,2-trifluoroacetate (K6) Step 1 : 5-Bromo-4-methyl-3-(4-methyl-3-nitrophenyl)-2-(trimethylsily l)-1 H- pyrrolor2.3-blpyridine (K1) 5-Bromo-3-iodo-4-methylpyridin-2-amine (4.5g, 14mmol, 1eq) and trimethyl[2-(4-methyl- 3-nitrophenyl)ethynyl]silane (4.2g, 180mmol, 1.25eq) were dissolved in DMF. Next, triethylenediamine (2.75g, 24mmol, 1.7eq), and bis(triphenylphosphine)palladium (II) dichloride (2.75g, 1.4mmol, 0.1 eq) were added, and the tube was purged with argon. The reaction mixture was heated at 145°C for 24h. The resulting mixture was diluted with saturated aqueous NaHCOs solution, and extracted with EtOAc. 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, 6:4) to afford the pure product K1 as an orange solid (3.6g, Y:62%). ¹ H NMR (300 MHz, DMSO -d ₆ ) d 11.76 (s, 1 H), 8.25 (s, 1 H), 7.83 (d, J = 1.8 Hz, 1 H), 7.57 (dd, J = 7.8, 1.8 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 2.50 (s, 3H), 2.02

(s, 3H), 0.00 (s, 9H). MS (ES) Ci ₈ H ₂ oBrN ₃ 0 ₂ Si requires: 417/419, found: 418/420 (M+H) ⁺ .

Step 2: 5-Bromo-2-iodo-4-methyl-3-(4-methyl-3-nitrophenyl)-1 H-rnitoIoG2.3- blpyridine (K2)

5-Bromo-4-methyl-3-(4-methyl-3-nitrophenyl)-2-(trimethyls ilyl)-1 H-pyrrolo[2,3]pyridine K1 (3.6g, 8.6mmol, 1eq) and NIS (3.4g,7.8mmol, 1.8eq) were dissolved in dry DCM (50m L), and stirred for 4h at room temperature. The reaction mixture was quenched with saturated aqueous Na ₂ S ₂ 0 ₃ solution, and the desired product was extracted with DCM (3x100ml_). The organic phase was washed with saturated aqueous NaHCOs solution, dried over Na ₂ S0 ₄ , and solvent were removed in vacuo. The crude material K2 as an orange solid (4g, Y:98%) was immediately used without purification in the next step.

Step 3: 5-Bromo-4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-3-(4-methyl-3-nitrophenyl)- 1H-pyrrolor2.3-blpyridine (K3)

5-Bromo-2-iodo-4-methyl-3-(4-methyl-3-nitrophenyl)-1 H-pyrrolo[2,3]pyridine K2 (4g, 8.5mmol, 1eq), 1-methylpyrazole-4-boronic acid, pinacol ester (1.8g, 8.5mmol, 1eq), and Na ₂ C03 (1.8g, 17mmol, 2eq) were dissolved in the mixture of solvents: THF 40ml_/MeOH 4mL/H ₂ 0 4mL (1:0.1:0.1 vol), degassed under vacuum, and purged with argon. Next, Pd(PPh ₃ ) ₂ CI ₂ (1.18g, 1.7mmol, 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. The organic phase was dried over Na ₂ S04, and concentrated under reduced pressure. The crude product was purified by column chromatography (CHCI3: 2-propanol) to afford the product K3 as a yellow solid (1.8g, Y:44%). ¹ H NMR (300 MHz, DMSO-de) d 12.26 (s, 1 H), 8.26 (s, 1 H), 7.97 (d, J = 1.7 Hz, 1 H), 7.75 - 7.55 (m, 3H), 7.32 (d, J = 0.8 Hz, 1H), 3.78 (s, 3H), 2.62 (s, 3H), 2.09 (s, 3H). MS (ES) Ci ₉ H ₁₆ BrN ₅ 0 ₂ requires: 425/427, found: 426/428 (M+H) ⁺ .

Step 4: 5-(5-Bromo-4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3-blpyridin- 3-yl)-2-methylaniline (K4)

A suspension of 4-[5-bromo-4-methyl-3-(4-methyl-3-nitrophenyl)-1 H- pyrrolo[2,3]pyridine-2-yl]-1 -methyl-1 H-pyrazole K3 (1.8g, 4.2mmol, 1eq) and iron (1.18g, 21 mmol, 5eq) in 18ml_ of EtOH and saturated aqueous NH ₄ CI solution (1.8ml_) was stirred for 3h at 80°C. Then, the reaction mixture was filtered on pad of silica gel, desired product was washed with DCM (200ml_), and EtOAc (200m L). The solvents were evaporated to obtain the desired product K4 as a yellow solid (1.2g, Y:75%). MS (ES) Ci ₉ H ₁₈ BrN ₅ requires: 395/397, found: 396/398 (M+H) ⁺ . Step 5: N-(5-(5-bromo-4-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrro lor2.3- blpvridin-3-vl)-2-methvlphenvl)acrvlamide (K5, Example 145)

5-[5-Bromo-4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrrolo[2,3]pyridine-3-yl]-2- methylaniline K4 (1.15g, 2.9mmol, 1eq) was dissolved in THF (30ml_) at -10°C. DIPEA (5mL, 29mmol, 10eq) was dropped, and the mixture was stirred for 5min at -10°C, then a solution of acryloyl chloride (400pL, 4.8mmol, 1.65eq) in 10mL of THF was added dropwise. The reaction mixture was slowly warmed to room temperature. After 30min, LCMS showed full conversion. The reaction mixture was diluted with water (100ml_), and the desired product was extracted with DCM (3x100ml_). The organic phase was dried over Na ₂ S04, and concentrated under reduced pressure. The crude product was purified by column chromatography (chloroform: 2-propanol (8:2)) to yield the material that was triturated with DCM to obtain 350mg (Y: 30%) of the pure product K5 as a creamy solid. ¹ H NMR (300 MHz, DMSO -cfe) d 12.10 (s, 1 H), 9.57 (s, 1H), 8.22 (s, 1H), 7.73 (s, 1 H), 7.54 (s, 1H), 7.44 - 7.25 (m, 2H), 7.15 - 7.04 (m, 1H), 6.55 (dd, J = 16.9, 10.0 Hz, 1 H), 6.22 (dd, J = 17.0, 2.1 Hz, 1H), 5.74 (d, J = 9.7 Hz, 1H), 3.77 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H). MS (ES) C ₂₂ H ₂ oBrN ₅ 0 requires: 451/449, found: 452/450 (M+H) ⁺ .

Step 6: N-(2-methyl-5-(4-methyl-2,5-bis(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3- blpyridin-3-yl)phenyl)acrylamide 2,2.2-trifluoroacetate (K6)

A mixture of N-(5-(5-bromo-4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrrolo[2, 3- b]pyridin-3-yl)-2-methylphenyl)acrylamide K5 (50.0mg, 0.111 mmol, 1.0eq.), K ₃ PO ₄ (47.1 mg, 0.222mmol, 2.0eq.), 1-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1H-pyrazole (34.7mg, 0.167mmol, 1.5eq.) and [1,1'- bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (9.1 mg, 0.011 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 55:45, 30 min). The desired fractions were combined and lyophilized to yield the title compound K6 (4.4mg, 0.006mmol, 5%) as a pale yellow solid. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 2.10 (s, 3H), 2.31 (s, 3H), 3.78 (s, 3H), 3.87 (s, 3H), 5.74 (dd, J = 10.2, 2.0 Hz, 1 H), 6.22 (dd, J = 17.0, 2.0 Hz, 1 H), 6.55 (dd, J = 17.0, 10.2 Hz, 1 H), 7.11 (dd, J = 7.7, 1.8 Hz, 1 H), 7.33 (d, J = 7.7 Hz, 1 H), 7.36 (s,

1 H), 7.55-7.59 (m, 2H), 7.73 (s, 1 H), 7.85 (s, 1 H), 8.11 (s, 1 H), 9.55 (s, 1 H), 12.01 (s, 1 H). MS (ES) C ₂₆ H ₂₅ N ₇ O requires: 451 , found: 452 (M+H) ⁺ .

The Examples in the following table were prepared according to the procedure described for K6 (Example 45).

Example 60:

N-(5-(4-chloro-2,5-bis(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3-b1pyridin-3-yl)-2- methylphenvDacrylamide 2,

Step 1 : 5-Bromo-4-chloro-3-(4-methyl-3-nitrophenyl)-2-(trimethylsily l)-1 H- Pvrrolor2,3-b1pvridine (L1) 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. The crude compound was purified by flash column chromatography (cHex/EtOAc, gradient from 10:1 to 100% EtOAc) to obtain the desired product L1 (2.5 g, 95%) as a yellow solid. MS (ES) Ci ₇ H ₁₇ BrCIN ₃ 02Si requires: 438, found: 439 (M+H) ⁺ .

Step 2: 5-(5-Bromo-4-chloro-2-(trimethylsilyl)-1 H-pyrrolor2.3-blpyridin-3-yl)-2- methvlaniline 2,2,2-trifluoroacetate (L2)

To a stirred solution of 5-bromo-4-chloro-3-(4-methyl-3-nitrophenyl)-2-(trimethylsily l)-1 H- pyrrolo[2,3-b]pyridine L1 (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 6 h. 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 L2 (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 (L3)

5-(5-Bromo-4-chloro-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylaniline L2 (1.67 g, 4.1 mmol, 1eq) was dissolved in 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 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 was 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 L3 (1.70g, 89%) as a beige solid. ¹ H NMR (400 MHz, DMSO -d ₆ ) d: 12.04 (s, 1 H), 9.43 (s, 1 H), 8.43 (s, 1 H), 7.55 (s, 1 H), 7.23 (d, J = 7.6 Hz, 1 H), 7.05 (dd, J = 1.8 Hz, J = 7.6 Hz, 1 H), 6.56 (dd, J = 10.1 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 = 10.1 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-(4-chloro-2.5-bis(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3-blpyridin-3- yl)-2-methylphenyl)acrylamide 2,2.2-trifluoroacetate (L4)

L4 (5mg, 0.008mmol, yellow solid) was prepared from L3 following the general procedure reported in Preparative Example 26 Step 2, 3 and 6. ¹ H NMR (400 MHz, DMSO -c/e) d 12.26 (s, 1 H), 9.54 (s, 1 H), 8.27 (s, 1 H), 8.05 (s, 1 H), 7.76 (s, 1 H), 7.75 (d, J = 0.8 Hz, 1 H), 7.53 (s, 1 H), 7.42 (s, 1 H), 7.30 (d, J = 7.7 Hz, 1 H), 7.11 (d, J = 7.7 Hz, 1 H), 6.54 (dd, J = 10.1 Hz, J = 17.0 Hz, 1 H), 6.22 (dd, J = 17.0 Hz, J = 2.0 Hz, 1 H), 5.73 (dd, J = 10.1 Hz, J = 2.0 Hz, 1 H), 3.88 (s, 3H), 3.79 (s, 3H), 2.31 (s, 3H). MS (ES) C ₂₅ H ₂₂ CIN ₇ 0 requires: 471 , found: 472 (M+H) ⁺ .

The Examples in the following table were prepared according to the procedure described for L4 (Example 60).

Example 72:

N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-ethyl-2-(1 -methyl-1 H-pyrazol-4-yl)-1H- Step 1: 5-Bromo-4-ethylPyridin-2-amine (M1)

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 M1 (13 g, 79%) as a pale yellow solid. ¹ H NMR (300 MHz, CDCIs) d 8.08 (s, 1 H), 6.40 (s, 1 H), 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-ethyl-3-iodopyridin-2-amine (M2)

To a stirred solution of 5-bromo-4-ethylpyridin-2-amine M1 (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 M2 (14 g, 66%) as a pale yellow solid. ¹ H NMR (300 MHz, CDCI ₃ ) d 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 (M3) To a stirred solution of 5-bromo-4-ethyl-3-iodopyridin-2-amine M2 (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 M3 (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 (M4)

To a stirred solution of 5-bromo-4-ethyl-3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl )-1 H- pyrrolo[2,3-b]pyridine M3 (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 M4 (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, 1H), 6.46 - 6.44 (m, 1H), 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 (M5)

A mixture of 5-(5-bromo-4-ethyl-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2- methylaniline M4 (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 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 M5 as an white solid (2.1 g, 63%). MS (ES) 0 ₃₂ H ₃₃ N ₇ 0 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 (M6)

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 M5 (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 (gradient elution from 10:1 to 0:100) to yield the desired product M6 (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 (M7)

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 M6 (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 M7 as an reddish solid (1.65g, quant.) was used without purification in the next step. MS (ES) C24H25IN5O requires: 525, found: 526 (M+H) ⁺ .

Step 8: N-(5-(5-(1.5-dimethyl-1 H-pyrazol-4-yl)-4-ethyl-2-(1 -methyl-1 H-pyrazol-4-vD- 1H-pyrrolor2.3-blpyridin-3-yl)-2-methylphenyl)acrylamide 2,2.2-trifluoroacetate (M8)

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 M7 (60mg, 0.1 mmol, 1.0eq.), K3PO4 (73mg, 0.3mmol, 3.0eq.), 1 -methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (59mg, 0.3mmol, 2.5eq.) and [1 ,T-bis(diphenylphosphino)ferrocene]-palladium dichloride dichloromethane adduct (18mg, 0.02mmol, 0.2eq.) 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 M8 (11 mg, 0.02mmol, 17%) as a yellow solid. MS (ES) C ₂₈ H ₂₉ N ₇ O requires: 479, found: 480 (M+H) ⁺ .

The Examples in the following table were prepared according to the procedure described for M8 (Example 72).

The Examples in the following table were prepared from 5-bromo-3-iodo-4- methoxypyridin-2-amine and trimethyl((4-methyl-3-nitrophenyl)ethynyl)silane according to the procedure described for K6 (Example 45).

The Examples in the following table were prepared from 5-bromo-3-iodopyridin-2-amine and ((2,4-dimethyl-3-nitrophenyl)ethynyl)trimethylsilane according to the procedure described for K6 (Example 45). Example 87:

N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-1H- pyrrolor2.3-blpyridin-3-yl)-2.6-dimethylphenyl)acrylamide 2,2.2-trifluoroacetate

Step 1: 5-Bromo-3-(2, 4-dimethyl-3-nitrophenyl)-4-methyl-2-(trimethylsilyl)-1H- pyrrolo G2, 3-bl pyridine

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 (PPh ₃ ) ₂ Cl ₂ (1.1 g, 1.59 mmol) was added at room temperature. The resulting reaction mixture was stirred at 120 °C for 48 h 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. The crude compound was purified by column chromatography (5% ethyl acetate in pet ether) to obtain N1 (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 (N2) To a stirred solution of 5-bromo-3-(2, 4-dimethyl-3-nitrophenyl)-4-methyl-2- (trimethylsilyl)-l H-pyrrolo [2, 3-b] pyridine N1 (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 16 h. 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. The crude compound was purified by column chromatography (5% ethyl acetate in pet ether) to obtain the desired product N2 (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, 1 H), 6.38 (d, J = 7.2 Hz, 1 H), 4.55 (s, 2H), 2.15 (s, 3H), 1.99 (s, 3H), 1.76 (s, 3H), 0.01 (s, 9H). MS (ES) Ci ₉ H ₂ 4BrN 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 (N3)

A mixture of N3-(5-bromo-4-methyl-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2,6- dimethylaniline N2 (977mg, 2.43mmol, 1.0eq.), K3PO4 (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 NaHCOs solution, and extracted with EtOAc (3x100ml_). 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 N3 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) C ₂ 4H _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- 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 N3 (1019mg, 2.4mmol, 1eq) was dissolved in dry THF (90ml_) at -78°C. DIPEA (4.1mL, 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 N4 (509mg, 44%) as a white solid. ¹ H NMR (300 MHz, DMSO -cfe) d 11.42 (s, 1 H), 9.56 (s, 1H), 7.94 (s, 1H), 7.30 (s, 1H), 7.10 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1 H), 6.47 (dd, J = 10.3 Hz, J = 17.1 Hz, 1H), 6.22 (dd, J = 2.1 Hz, J = 17.1 Hz, 1 H), 5.71 (dd, J = 2.1 Hz, J = 10.3 Hz, 1H), 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) C ₂ 7H ₃ 3N ₅ OSi requires: 471, found: 472 (M+H) ⁺ .

Step 5: N-(3-(5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-2-iodo-4-methyl-1 H-rnitoIoG2,3- blpyridin-3-yl)-2,6-dimethylphenyl)acrylamide (N5)

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 N4 (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 N5 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-1 H-pyrazol-4-yl)-4-methyl-2-(1 -methyl -1 H-pyrazol-4- yl)-1H-pyrrolor2,3-blpyridin-3-yl)-2,6-dimethylphenyl)acryla mide 2,2,2- trifluoroacetate (N6) A mixture of N-(3-(5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-2-iodo-4-methyl-1 H-pyrrolo[2,3- b]pyridin-3-yl)-2,6-dimethylphenyl)acrylamide N5 (60mg, 0.1 mmol, 1.0eq.), K ₃ PO ₄ (48mg, 0.2mmol, 2.0eq.), 1-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole (31 mg, 0.1 mmol, 1.3eq.) and [1 ,1'-bis(diphenylphosphino)ferrocene]-palladium dichloride dichloromethane adduct (9mg, 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 N6 (22mg, 33%) as a yellow solid. 1H NMR (300 MHz, DMSO -cfe) d 12.16 (s, 1 H), 9.65 (s, 1 H), 7.94 (s, 1 H), 7.58 (s, 1 H), 7.36 (s, 1 H), 7.28 (br s, 1 H), 7.20 (d, J = 7.8 Hz, 1 H), 7.12 (d, J = 7.8 Hz, 1 H), 6.48 (dd, J = 10.3 Hz, J = 17.1 Hz, 1 H), 6.23 (dd, J = 2.0 Hz, J = 17.1 Hz, 1 H), 5.74 (dd, J = 2.0 Hz, J = 10.3 Hz, 1 H), 3.81 (s, 3H), 3.77 (s, 3H), 2.24 (s, 3H), 2.12 (s, 3H), 1.91 (s, 3H), 1.89 (s, 3H). MS (ES) C ₂₈ H ₂₉ N ₇ O requires: 479, found: 480 (M+H) ⁺ .

The Examples in the following table were prepared according to the procedure described for N6 (Example 87).

Example 104:

N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-1H- pyrrolor2.3-blpyridin-3-yl)-3-fluoro-2-methylphenyl)acrylami de 2,2,2- trifluoroacetate

Step 1: r2-(3-Fluoro-4-methyl-5-nitrophenyl)ethvnvntrimethylsilane

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 S04, 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 01 as a yellow solid (5g, Y:93%). ¹ H NMR (300 MHz, DMSO -d ₆ ) d 7.63 (t, J = 1.5 Hz, 1H), 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- pyrrolor2.3-blpyridine (02)

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 (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 02 as a pale yellow solid (2g, Y:29%). ¹ H NMR (300 MHz, DMSO-c/6) d 11.80 (s, 1H), 8.23 (s, 1H), 7.70 (t, J = 1.4 Hz, 1H), 7.59 (dd, J = 9.9, 1.7 Hz, 1H), 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-Bromo-3-(3-fluoro-4-methyl-5-nitrophenyl)-2-iodo-4-methyl- 1 H- pyrrolor2.3-blpyridine (03)

5-Bromo-3-(3-fluoro-4-methyl-5-nitrophenyl)-4-methyl-2-(t rimethylsilyl)-1 H-pyrrolo[2,3- b]pyridine 02 (2g, 4.6mmol, 1 eq) and NIS (1.9g, 8.2mmol, 1.8eq) were dissolved in dry DCM (45ml_). The reaction mixture was stirred for 4h 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 (3x100ml_). 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 03 as an orange solid (2.1 g, Y:94%) was used without purification for the next step. MS (ES) Ci ₅ HioBrFIN ₃ 0 ₂ requires: 488/490, found: 489/491 (M+H) ⁺ . Step 4: 5-Bromo-3-(3-fluoro-4-methyl-5-nitrophenyl)-4-methyl-2-(1 -methyl-1 H- Pvrazol-4-vD-1 H-pvrrolor2,3-blpvridine (04)

5-Bromo-3-(3-fluoro-4-methyl-5-nitrophenyl)-2-iodo-4-meth yl-1 H-pyrrolo[2,3-b]pyridine 03 (2.1 g, 4.3mmol, 1eq), 1-methyl-4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (980mg, 4.3mmol, 1eq), and Na ₂ C0 ₃ (902mg, 8.6mmol, 2eq) were placed in a pressure tube, dissolved in a mixture of THF (20ml_)-MeOH (2mL)-H ₂ 0 (2ml_), and purged with argon. Next, Pd(PPh ₃ ) ₂ CI ₂ (600mg, 0.86mmol, 0.1 eq) 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 (3x45ml_). The organic layers were combined, dried over Na ₂ S0 ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (Hexane:Acetone, 1:1) to afford the product 04 as a yellow solid (1.28g, Y:67%). 1H NMR (300 MHz, DMSO-d6) d 12.31 (s, 1H), 8.27 (s, 1 H), 7.84 (d, J = 1.6 Hz, 1H), 7.76 - 7.64 (m, 2H), 7.41 (s, 1H), 3.80 (s, 3H), 2.13 (s, 3H). MS (ES) Ci ₉ H ₁₅ BrFN ₅ 0 ₂ requires: 445/443, found: 446/444 (M+H) ⁺ .

Step 5: 5-(5-Bromo-4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3-blpyridin- 3-vD-3-fluoro-2-methvlaniline (

A suspension of 4-[5-bromo-3-(3-fluoro-4-methyl-5-nitrophenyl)-4-methyl-1 H- pyrrolo[2,3-b]pyridin-2- yl]-1 -methyl-1 H-pyrazole 04 (1.88g, 4.2mmol, 1eq) and iron (1.89g, 3.4mmol, 8eq) in a mixture of EtOH (20ml_) and saturated aqueous NH ₄ CI solution (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 (Aceton: Hexane 9:1) to obtain the desired product 05 as a yellow solid (1.2g, Y:68%). 1 H NMR (300 MHz, DMSO-c/6) d 12.05 (s, 1H), 8.21 (d, J = 4.7 Hz, 1H), 7.65 (s, 1H), 7.37 - 7.24 (m, 1H), 6.43 (s, 1H), 6.36 - 6.29 (m, 1H), 5.28 (s, 2H), 3.79 (s, 3H), 2.16 (s, 3H), 2.05 (d, J = 1.7 Hz, 3H). MS (ES) Ci ₉ H ₁₇ BrFN ₅ requires: 415/413, found: 416/414 (M+H) ⁺ . Step 6: N-(5-(5-bromo-4-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrro lor2.3- blpyridin-3-yl)-3-fluoro-2-methylphenyl)acrylamide (06, Example 144)

5-[5-Bromo-4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrrolo[2,3-b]pyridin-3-yl]-3- fluoro-2-methyl-aniline 05 (1.2g, 2.9mmol, 1eq) was dissolved in THF (10ml_). The solution was cooled down to -10°C, DIPEA (5ml_, 29mmol, 10eq) was dropwise added, and the mixture was stirred for 5min at -10°C. A solution of acryloyl chloride (0.13mL, 2.9mmol, 1eq) in THF (10mL) 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 (3x1 OmL). The organic layers were combined together, dried over Na ₂ S04, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (DCM:MeOH 9:1) to obtain the desired product 06 (510mg, Y: 38%) as a creamy solid. 1H NMR (300 MHz, DMSO-d6) d 12.17 (s, 1H), 9.76 (s, 1H), 8.23 (s, 1 H), 7.74 (s, 1 H), 7.41 (s, 2H), 7.05 (dd, J = 10.1, 1.6 Hz, 1H), 6.55 (dd, J = 17.0, 10.2 Hz, 1 H), 6.24 (dd, J = 17.0, 2.0 Hz, 1H), 5.77 (dd, J = 10.0, 2.1 Hz, 1H), 3.79 (s, 3H), 2.22 (d, J = 2.0 Hz, 3H), 2.12 (d, J = 19.7 Hz, 3H). MS (ES) C ₂₂ Hi ₉ BrFN ₅ 0 requires: 469/467, found: 470/468 (M+H) ⁺ .

Step 7: N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(1 -methyl-1 H-pyrazol-4- yl)-1H-pyrrolor2.3-blpyridin-3-yl)-3-fluoro-2-methylphenyl)a crylamide 2,2,2- trifluoroacetate (07)

A mixture of N-(5-(5-bromo-2-(1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)- 3-fluoro-2-methylphenyl)acrylamide 06 (50.0mg, 0.1 mmol, 1.0eq.), K ₃ PO ₄ (68mg, 0.3mmol, 3.0eq.), 1 ,5-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole (59mg, 0.3mmol, 2.5eq.) and [1 ,T-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (9mg, 0.01 mmol, 0.1eq.) in dioxane/water (4:1, 2. OmL) 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 55:45, 30 min). The desired fractions were combined and lyophilized to yield the title compound 07 (2mg, 3%) as a pale yellow solid. ¹ FI NMR (400MFIz, d ₆ -DMSO, 300K) d 11 .93 (s, 1 H), 9.70 (s, 1 H), 7.88 (s, 1 H), 7.71 (s, 1 H), 7.40 (br s, 1 H), 7.37 (s, 1 H), 7.31

(s, 1 H), 7.04 (d, J = 9.5 Hz, 1 H), 6.51 (dd, J = 10.3 Hz, J = 17.1 Hz, 1 H), 6.22 (dd, J = 2.0 Hz, J = 17.1 Hz, 1 H), 5.74 (dd, J = 2.0 Hz, J = 10.3 Hz, 1 H), 3.77 (s, 3H), 3.76 (s, 3H), 2.19/2.18 (s, 3H), 2.10 (s, 3H), 1.93 (s, 3H). MS (ES) C27H26FN7O requires: 483, found: 484 (M+H) ⁺ .

The Examples in the following table were prepared according to the procedure The Examples in the following table were prepared from 5-bromo-3-iodopyridin-2-amine and ((3-fluoro-4-methyl-5-nitrophenyl)ethynyl)trimethylsilane according to the procedure described for 07 (Example 104).

Example 107:

1 -(4-(5-(1 ,5-Dimethyl-1 H-pyrazol-4-yl)-4-methyl-2-(1 -methyl -1 H-pyrazol-4-yl)-1 H- Pvrrolor2,3-blpvridin-3-vl)indolin-1 -vl)prop-2-en-1 -one 2,2,2-trifluoroacetate

The Example 107 was prepared were prepared from 5-bromo-3-iodo-4-methylpyridin-2- amine and tert-butyl 4-((trimethylsilyl)ethynyl)indoline-1-carboxylate according to the procedure described for Example 26. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 12.19 (s, 1 H), 8.27 (d, J = 8.1 Hz, 1 H), 7.94 (s, 1 H), 7.59 (s, 1 H), 7.37 (s, 1 H), 7.32 (m, 1 H), 7.26 (s, 1 H), 7.05 (d, J = 7.4 Hz, 1 H), 6.72 (dd, J = 10.3 Hz, J = 16.6 Hz, 1 H), 6.30 (dd, J =

2.4 Hz, J 16.6 Hz, 1 H), 5.82 (dd, J = 2.4 Hz, J = 10.3 Hz, 1 H), 4.16 (m, 2H), 3.78 (s, 6H), 2.80 (m, 2H), 2.13 (s, H), 1.88 (s, 3H). MS (ES) C ₂₈ H ₂₇ N ₇ O requires: 477, found: 478 (M+H) ⁺ . The Examples in the following table were prepared according to the procedure described for Example 107.

The Examples in the following table were prepared from 5-bromo-3-iodo-4- methylpyridin-2 -amine and tert-butyl 6-((trimethylsilyl)ethynyl)indoline-1-carboxylate according to the procedure described for K6 (Example 45).

Example 113:

N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-

Pyrrolor2,3-b1pyridin-3-yl)phenyl)-N-methylacrylamide 2,2,2-trifluoroacetate (P6) Step 1: 5-Bromo-3-iodo-4-methvlPvridin-2-amine (P1)

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 P1 (8 g, 95%) as a brown solid. ¹ H NMR (400 MHz, CDCI ₃ ) 5 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) phenyl) (methyl) carbamate (P2)

Boc

To a stirred solution of 5-bromo-3-iodo-4-methylpyridin-2-amine P1 (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 C0 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 CI 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 S04, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (EtOAc / pet ether) to obtain P2 (4.9 g, 62%) as a pale brown solid. ¹ H NMR (400 MHz, DMSO -d _e )\ d 11.69 (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, 1 H), 3.18 (s, 3H), 2.09 (s, 3H), 1.35 (s, 9H), 0.07 (s, 9H). MS (ES) CasHsoBrNsOaSi 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-pyrrolor2.3-blpyridin-3-yl)phenyl)(methyl)carbamate (P3)

A mixture of tert-butyl (3-(5-bromo-4-methyl-2-(trimethylsilyl)-1 H-pyrrolo [2, 3-b] pyridin- 3-yl) phenyl) (methyl) carbamate P2 (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 P3 (1.04g, 83%) as a yellow solid. MS (ES) C ₂₈ H ₃₇ N ₅ 0 ₂ Si 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 (P4)

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 P3 (1.04g, 2.05mmol) in 30% TFA in DCM (30ml_) was stirred for 1 h 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 THF 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 P4 (610mg, 65%) as a white solid. MS (ES) C26H31N5OS1 requires: 457, found: 458 (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)phenyl)-N-methylacrylamide (P5)

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 P4 (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 P5 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-(1 -methyl-1 H-pyrazol-4- yl)-1H-pyrrolor2.3-blpyridin-3-yl)phenyl)-N-methylacrylamide 2,2.2-trifluoroacetate

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 P5 (100mg, 0.20mmol, 1.0eq.), K ₃ PO ₄ (83mg, 0.39mmol, 2.0eq.), 1-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole (61 mg, 0.29mmol, 1.5eq.) and [1 ,1'-bis(diphenylphosphino)ferrocene]- palladium dichloride dichloromethane adduct (16mg, 0.02mmol, 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 P6 (40mg, 35%) as a yellow solid. ¹ H NMR (300 MHz, DMSO -cfe) d 12.18 (s, 1 H), 7.95 (s, 1 H), 7.61 (s, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.36 (s, 1 H), 7.38 - 7.32 (m, 2H), 7.29 (s, 1H), 6.14 (d, J = 6.2 Hz, 2H), 5.56 (t, J = 6.2 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.28 (s, 3H), 2.13 (s, 3H), 1.95 (s, 3H). MS (ES) C27H27N7O requires: 465, found: 466 (M+H) ⁺ .

The Examples in the following table were prepared according to the procedure described for P6 (Example 113).

The Examples in the following table were prepared from 5-bromo-3-iodo-4- methylpyridin-2 -amine and ((2-methoxy-4-methyl-3-nitrophenyl)ethynyl)trimethylsilane according to the procedure described for K6 (Example 45).

Example 51:

N-(5-(5-isobutoxy-4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3-blpyridin-

3-yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (Q5)

Step 1 : 4-Methyl-3-(4-methyl-3-nitrophenyl)-5-(2-methylpropoxy)-2-(t rimethylsilyl)- 1H-pyrrolor2.3-blpyridine (Q1

In a pressure tube, 3-bromo-4-methyl-5-(2-methylpropoxy)pyridin-2-amine (2.48g, 0.06mol, 1eq) and trimethyl[2-(4-methyl-3-nitrophenyl)ethynyl]silane (2.79g, 12mmol, 1.25eq) were dissolved in DMF (25ml_). Next, triethylenediamine (1.83g, 16.3mmol, 1.7eq) and bis(triphenylphosphine)palladium (II) dichloride (0.95g, 1.25mmol, 0.1 eq) were added, the tube was purged with argon, and then heated at 145°C overnight. The resulting mixture was diluted with saturated aqueous NaHCOs solution, and extracted with DCM (3x150ml_). 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 (DCM:MeOH, 0-10% of DCM), next by reversed phase flash chromatography (ACN:H ₂ 0, 50:50), and re-purified by column chromatography (Hexane:Acetone, 0-20% of acetone) to afford the pure product Q1 as a creamy solid (470mg, Y:12%). ¹ H NMR (300 MHz, DMSO -d ₆ ) d 11.42 (s, 1H), 8.05 (s, 1 H), 7.87 (d, J = 1.8 Hz, 1 H), 7.61 (dd, J = 7.8, J = 1.8 Hz, 1 H), 7.51 (d, J = 8.0 Hz, 1 H),

3.75 (d, J = 6.4 Hz, 2H), 2.56 (s, 3H), 1.99 (dt, J = 13.2, J = 6.6 Hz, 1 H), 1.92 (s, 3H),

0.97 (d, J = 6.7 Hz, 6H), 0.06 (s, 9H). MS (ES) C ₂₂ H ₂₉ N ₃ O ₃ S1 requires: 411 , found: 412 (M+H) ⁺ .

Step 2: 2-Methyl-5-r4-methyl-5-(2-methylpropoxy)-2-(trimethylsilyl)- 1 H-rnitoIoG2.3- blpyridin-3-vnaniline (Q2)

4-Methyl-3-(4-methyl-3-nitrophenyl)-5-(2-methylpropoxy)-2 -(trimethylsilyl)-1 H- pyrrolo[2,3-b]pyridine Q1 (470mg, 1.15mmol, 1eq) and iron (319mg, 5.7mmol, 5eq) were suspended in a mixture of EtOH (50ml_) and saturated aqueous NH ₄ CI solution (5ml_), and stirred for 1.5h at 80°C. The resulting mixture was filtered through a pad of silica gel, and the product was extracted with DCM (3x50ml_). The organic layer was washed with saturated aqueous NaCI solution, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure to obtain 410mg of the desired product Q2, which was used for next step without purification. ¹ H NMR (300 MHz, DMSO -cfe) d 11.03 (s, 1 H), 7.92 (s, 1 H), 6.83 (d, J = 7.5 Hz, 1 H), 6.50 (d, J = 1.7 Hz, 1 H), 6.34 (dd, J = 7.5, 1.7 Hz, 1 H), 4.73 (s, 2H), 3.67 (d, J = 6.4 Hz, 2H), 2.03 (s, 3H), 1.99 - 1.92 (m, 1 H), 1.90 (s, 3H), 0.91 (d, J = 6.7 Hz, 6H), 0.12 (s, 9H). MS (ES) C ₂₂ H _3i N ₃ OSi requires: 381 , found: 382 (M+H) ⁺ .

Step 3: A 2-methyl-5-r4-methyl-5-(2-methylpropoxy)-2-(trimethylsilyl)- 1 H- Pvrrolor2,3-blpvridin-3-vllphenvl>prop-2-enamide (Q3)

2-Methyl-5-[4-methyl-5-(2-methylpropoxy)-2-(trimethylsily l)-1 H-pyrrolo[2,3-b]pyridin-3- yl]aniline Q2 (410mg, 1.1 mmol, 1eq) was dissolved in THF (15ml_) at -10°C. Next, DIPEA (1.9mL, 11 mmol, 10eq) was dropped, and the mixture was stirred for 5min at - 10°C, then a solution of acryloyl chloride (150pL, 1.8mmol, 1.0eq) in THF (15ml_) was dropwise added. After 60min, LCMS showed full conversion. The reaction mixture was slowly warmed to room temperature, diluted with water (100ml_), and the desired product was extracted with DCM (3x70ml_). The organic phase was dried over Na ₂ S0 ₄ , and concentrated under reduced pressure to obtain of the product Q3 (455g, Y:97%) as a beige solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 11.16 (s, 1H), 9.39 (s, 1H), 7.96 (s, 1H), 7.61 - 7.46 (m, 1H), 7.16 (d, J = 7.7 Hz, 1H), 6.99 - 6.90 (m, 1H), 6.49 (dd, J = 17.1, 10.2 Hz, 1 H), 6.15 (dd, J = 17.0, 2.1 Hz, 1H), 5.66 (dd, J = 10.1, 2.1 Hz, 1H), 3.68 (d, J

= 6.4 Hz, 2H), 2.22 (s, 3H), 1.99 - 1.91 (m, 1H), 1.89 (s, 3H), 0.92 (d, J = 6.6 Hz, 6H), 0.00 (s, 9H). MS (ES) C ₂₅ H ₃₃ N ₃ 0 ₂ Si requires: 435, found: 436 (M+H) ⁺ .

Step 4: N-(5-(2-iodo-5-isobutoxy-4-methyl-1 H-pyrrolor2.3-blpyridin-3-yl)-2- methylphenvDacrylamide (Q

A/-{2-methyl-5-[4-methyl-5-(2-methylpropoxy)-2-(trimethyl silyl)-1 H-pyrrolo[2,3-b]pyridin- 3-yl]phenyl}prop-2-enamide Q3 (448mg, 1.03mmol, 1.0eq) and NIS (416mg,1 85mmol, 1.8eq) were dissolved in dry DCM (6ml_), and stirred for 16h at room temperature. The reaction mixture was quenched with saturated aqueous Na ₂ S ₂ 0 ₃ solution, and the desired product was extracted with DCM (3x100ml_). The organic phase was washed with saturated aqueous NaHCOs solution, dried over Na ₂ S0 ₄ , and solvent were removed in vacuo. The crude material Q4 as a greenish solid (351 mg, 70%) was used without purification in the next step. MS (ES) C ₂₂ H ₂₄ lN ₃ 0 ₂ requires: 489, found: 490 (M+H) ⁺ .

Step 5: N-(5-(5-isobutoxy-4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-1 H-rnitoIoG2.3- blpyridin-3-yl)-2-methylphenyl)acrylamide 2,2.2-trifluoroacetate (Q5) A mixture of N-(5-(2-iodo-5-isobutoxy-4-methyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2- methylphenyl)acrylamide Q4 (50mg, O.IOmmol, 1.0eq.), 1-methyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (28mg, 0.13mmol, 1.3eq.), and K ₃ PO ₄ (43mg, 0.20mmol, 2.0 eq) in dioxane/H ₂ 0 (3mL/0.6mL) was degassed with a stream of N ₂ for 5min. [1 ,T-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (8mg, 0.01 mmol, 0.1 eq) was added and the reaction mixture heated to 130°C for 2 h in the microwave oven. 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 Q5 (5mg, 7%) as a pale yellow solid. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 0.97 (d, J = 6.7 Hz, 6H), 1.96 (s, 3H), 2.00 (septet, J = 6.7 Hz, 1 H), 2.30 (s, 3H), 3.75 (s, 3H), 3.76 (d, J = 6.7 Hz, 2H),

5.72 (dd, J = 2.1 Hz, J = 10.2 Hz, 1 H), 6.20 (dd, J = 2.1 Hz, J = 17.1 Hz, 1 H), 6.53 (dd, J = 10.2 Hz, J = 17.1 Hz, 1 H), 7.07 (dd, J = 1.8 Hz, J = 7.6 Hz, 1 H), 7.29 (d, J = 7.6 Hz, 1 H), 7.35 (d, J = 0.8 Hz, 1 H), 7.51 (s, 1 H), 7.70 (s, 1 H), 7.93 (s, 1 H), 9.52 (s, 1 H), 11 .75 (s, 1 H). MS (ES) C ₂₆ H ₂₉ N5 ₃ O ₂ requires: 443, found: 444 (M+H) ⁺ .

The Examples in the following table were prepared according to the procedure described for Q5 (Example 51 ).

Example 12:

(S)-N-(5-(5-(sec-butoxy)-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3-blpyridin-3- yl)-2-methylphenyl)acrylam

Step 1 : 3-(4-Methyl-3-nitrophenyl)-2-(trimethylsilyl)-1 H-pyrrolor2.3-blpyridin-5-ol A mixture of 6-amino-5-bromopyridin-3-ol (2.60g, 13.8mmol, 1.0eq.), trimethyl((4- methyl-3-nitrophenyl)ethynyl)silane (4.01 g, 17.2mmol, 1.25eq.), 1 ,4-diazabicyclo[2.2.2] octane (2.62g, 23.4mmol, 1.7eq.) and dichlorobis(triphenylphosphine)palladium(ll) (0.97g, 1.38mmol, 0.1eq.) in dry DMF (34mL) was equally splitted into two microwave vials. Each mixture was degassed by bubbling nitrogen through it for several minutes. Both vials were heated in the microwave at 145°C for 2h. Both mixtures were then combined, diluted with DCM and filtered through a pad of Celite®. The pad was washed several times with DCM and the combined filtrates were concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM/MeOH = 100:0 to 92:8). The resulting product was further purified by reversed phase (C18 column) flash chromatography (water + 0.05% TFA/ACN + 0.05% TFA = 100:0 to 15:85). The desired fractions were combined and lyophilized. The resulting TFA salt of the product was dissolved in DCM and the solution was washed twice with sat. NaHCOs solution, brine and dried over MgSC . The solvent was then removed under reduced pressure and the residue was finally lyophilized to yield the desired product R1 (278mg, 0.814mmol, 6%) as a beige solid. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 0.21 (s, 9H), 2.58 (s, 3H), 7.14 (d, J = 2.6 Hz, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.64 (dd, J = 7.9, 1.8 Hz, 1 H), 7.89-7.96 (m, 2H), 9.19 (s, 1 H), 11.41 (s, 1 H). MS (ES) CiyH^NsOsSi requires: 341 , found: 342 (M+H) ⁺ .

Step 2: (S)-5-(sec-butoxy)-3-(4-methyl-3-nitrophenyl)-2-(trimethylsi lyl)-1 H- pyrrolor2.3-blpyridine 2.2.2-trifluoroacetate (R2)

To a mixture of 3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridin-5-ol R1 (275mg, 0.81 mmol, 1.0eq.), triphenylphosphine (423mg, 1.61 mmol, 2.0eq.) and (R)- butan-2-ol (92.6pL, 74.6mg, 1.01 mmol, 1.25eq.) in dry DCM (25ml_) was added at 0°C a solution of DIAD (238pL, 244mg, 1.21 mmol, 1.5eq.) in dry DCM (2ml_) dropwise. After 15 min at 0°C, the reaction was brought to ambient temperature and stirred for an additional hour. Reaction was again cooled to 0°C and same amounts of DIAD, triphenylphosphine and (R)-butan-2-ol as indicated above were added. After 15 min at 0°C, the mixture was brought to ambient temperature and stirred for additional 3h. If necessary, this procedure can be repeated to ensure good conversion. The mixture was then diluted with DCM and washed with sat. NaHCOs solution, brine and dried over MgS0 _4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (cHex/EtOAc = 100:0 to 85:15). The resulting product was further purified by reversed phase (C18 column) flash chromatography (water + 0.05% TFA/ACN + 0.05% TFA = 100:0 to 5:95). The desired fractions were combined and lyophilized to yield the desired product R2 as a colorless TFA salt (247mg, 0.482mmol, 60%). ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 0.22 (s, 9H), 0.92 (t, J = 7.5 Hz, 3H), 1.19 (d, J = 6.1 Hz, 3H), 1.49-1.71 (m, 2H), 2.58 (s, 3H), 4.27-4.36 (m, 1 H), 7.33 (d, J = 2.6 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.68 (dd, J = 7.8, 1.9 Hz, 1H), 7.92 (d, J = 1.9 Hz, 1 H), 8.03 (d, J = 2.6 Hz, 1 H), 11.57 (s, 1 H). MS (ES) C21H27N3O3S1 requires: 397, found: 398 (M+H) ⁺ .

Step 3: (S)-5-(5-(sec-butoxy)-2-(trimethylsilyl)-1 H-pyrrolor2.3-blpyridin-3-yl)-2- methylaniline (R3)

A suspension of (S)-5-(sec-butoxy)-3-(4-methyl-3-nitrophenyl)-2-(trimethylsi lyl)-1 H- pyrrolo[2,3-b]pyridine 2,2,2-trifluoroacetate R2 (244mg, 0.48mmol, 1.0eq.) and iron powder (133mg, 2.39mmol, 5.0eq.) in a mixture of ethanol (3.2ml_) and sat. NH ₄ CI solution (0.32ml_) was stirred in a closed vial for 3h at 80°C. The mixture was then diluted with methanol and filtered through a pad of Celite®. The pad was washed several times with small portions of methanol and the combined filtrates were concentrated under reduced pressure. The residue was dissolved in DCM and the resulting solution was washed twice with sat. NaHCOs solution, brine and dried over MgS0 _4. The solvent was removed under reduced pressure and the residue was dried in vacuo to yield the desired product R3 as a beige brown solid (160mg, 0.44mmol, 91%). ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 0.19 (s, 9H), 0.92 (t, J = 7.5 Hz, 3H), 1.19 (d, J = 6.1 Hz, 3H), 1.49-1.72 (m, 2H), 2.10 (s, 3H), 4.20-4.29 (m, 1H), 4.85 (bs, 2H), 6.47 (dd, J = 7.4, 1.7 Hz, 1 H), 6.65 (d, J = 1.7 Hz, 1H), 6.96 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 2.7 Hz, 1 H), 7.97 (d, J = 2.7 Hz, 1H), 11.21 (s, 1H). MS (ES) C21H29N3OS1 requires: 367, found: 368 (M+H) ⁺ .

Step 4: (S)-N-(5-(5-(sec-butoxy)-2-(trimethylsilyl)-1 H-pyrrolor2,3-blpyridin-3-yl)-2- methylphenvDacrylamide (R4) To a mixture of (S)-5-(5-(sec-butoxy)-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2- methylaniline R3 (156mg, 0.42mmol, 1.0eq.) and DIPEA (0.72ml_, 549mg, 4.24mmol, 10eq.) in dry DCM (7mL) was added at 0°C a solution of acryloyl chloride (34.6pl_, 38.4mg, 0.42mmol, 1.0eq.) in dry DCM (1ml_) dropwise. Mixture was further stirred at 0°C for an additional hour. To drive the conversion, small amounts of acryloyl chloride (0.2eq.) dissolved in dry DCM (0.5ml_) were added from time to time at same temperature until the starting material was consumed. Then the reaction was quenched by adding a few drops of water at 0°C and stirring was continued for a few minutes. The mixture was then concentrated under reduced pressure at ambient temperature. The crude material was purified by flash chromatography on silica gel (cHex/EtOAc = 100:0 to 70:30). The compound was dried in vacuo to yield the desired product R4 as a beige solid (74.1 mg, 0.18mmol, 41 %). ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 0.21 (s, 9H), 0.92 (t, J = 7.4 Hz, 3H), 1.20 (d, J = 6.0 Hz, 3H), 1.50-1.72 (m, 2H), 2.29 (s, 3H), 4.25- 4.35 (m, 1 H), 5.75 (dd, J = 10.2, 2.1 Hz, 1 H), 6.25 (dd, J = 17.0, 2.1 Hz, 1 H) 6.58 (dd, J = 17.0, 10.2 Hz, 1 H), 7.11 (dd, J = 7.7, 1.9 Hz, 1 H), 7.29 (d, J = 7.7 Hz, 1 H), 7.36 (d, J = 2.7 Hz, 1 H), 7.63 (s, 1 H), 7.99 (d, J = 2.6 Hz, 1 H), 9.47 (s, 1 H), 11 .34 (s, 1 H). MS (ES) C ₂₄ H _3i N ₃ 0 ₂ Si requires: 421 , found: 422 (M+H) ⁺ .

Step 5: (S)-N-(5-(5-(sec-butoxy)-2-iodo-1 H-pyrrolor2.3-blpyridin-3-yl)-2- methylphenvDacrylamide (R

To a solution of (S)-N-(5-(5-(sec-butoxy)-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)- 2-methylphenyl)acrylamide R4 (72.0mg, 0.17mmol, 1.0eq.) in dry DCM (6ml_) was added N-iodosuccinimide (69.2mg, 0.31 mmol, 1.8eq.) at ambient temperature. The resulting solution was stirred for 3h under light exclusion. The mixture was then diluted with DCM and washed with sat. Na ₂ S ₂ 0 ₃ solution, three times with sat. NaHC0 ₃ solution, brine and dried over MgSC . The solvent was removed under reduced pressure and the residue was lyophilized to yield the desired product R5 as a beige brown solid (69.4mg, 0.15mmol, 88%). The compound was used in the next step without further purification. MS (ES) C _2i H ₂₂ lN ₃ 0 ₂ requires: 475, found: 476 (M+H) ⁺ . Step 6: (S)-N-(5-(5-(sec-butoxy)-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3- blpvridin-3-vl)-2-methvlphenvl)acrvlamide 2,2,2-trifluoroacetate (R6)

A mixture of (S)-N-(5-(5-(sec-butoxy)-2-iodo-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2- methylphenyl)acrylamide R5 (35mg, 0.07mmol, 1.0eq.), 1-methyl-4-(4,4, 5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (20mg, O.IOmmol, 1.3eq.), and K ₃ PO ₄ (47mg, 0.21 mmol, 3.0 eq) in dioxane/H ₂ 0 (3mL/0.6mL) was degassed with a stream of N ₂ for 5min. [1 ,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (6mg, 0.007mmol, 0.1 eq) was added and the reaction mixture heated to 130°C for 45min in the microwave oven. The reaction mixture was diluted with

EtOAc, washed three times with aq. sat. NaHCOs-solution. The organic phase was dried over MgSC and solvents were removed in vacuo. The crude was purified by reversed phase HPLC (column: C18), using H ₂ 0 (0.1 %TFA) and ACN (0.1 %TFA) as eluents. The desired fractions were lyophilized to yield the title compound R6 (5mg, 0.007mmol, 11 %) as a yellow powder. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 0.93 (t, J

= 7.5 Hz, 3H), 1.21 (d, J = 6.1 Hz, 3H), 1.60 (m, 2H), 2.29 (s, 3H), 3.84 (s, 3H), 4.31 (sextett, J = 6.1 Hz, 1 H), 5.76 (dd, J = 2.1 Hz, J = 10.3 Hz, 1 H), 6.26 (dd, J = 2.1 Hz, J = 17.0 Hz, 1 H), 6.58 (dd, J = 10.3 Hz, J = 17.0Hz, 1 H), 7.17 (dd, J = 1.8 Hz, J = 7.8 Hz, 1 H), 7.31 (d, J = 7.8 Hz, 1 H), 7.36 ( d, J = 2.7 Hz, 1 H), 7.62 (s, 1 H), 7.70 (s, 1 H), 7.92 (d, J = 2.7 Hz, 1 H), 8.01 (s, 1 H), 9.56 (s, 1 H), 11.78 (s, 1 H). MS (ES) C ₂₅ H ₂₇ N ₅ 02 requires: 429, found: 430 (M+H) ⁺ .

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

Example 121 :

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

Step-1 : 5-(((1 -Methyl-1 H-pyrazol-4-yl) oxy) methyl)-3-(4-methyl-3-nitrophenyl)-2- (trimethylsilyl)-IH-pyrrolo G2

To a stirred solution of 3-bromo-5-(isopropoxymethyl) pyridin-2-amine (1.7 g, 6.93 mmol, 1 eq.) in 1,4-dioxane (30 ml_) were added trimethyl ((4-methyl-3-nitrophenyl) ethynyl) silane (1.77 g, 7.63 mmol, 1.1 eq.), K2CO3 (1.91 g, 13.8 mmol, 2.0 eq.) and LiBr (0.3 g, 13.8 mmol, 2.0 eq.) at room temperature under nitrogen atmosphere. The reaction mixture was degassed for 10 minutes using nitrogen gas. Then Pd(PPh3) ₂ Cl2 (0.48 g, 0.69 mmol, 0.1 eq.) was added at room temperature. The resulting reaction mixture was stirred at 120 °C for 3 days. The reaction mixture was quenched with water (20 ml_) and the aqueous layer was extracted with EtOAc (2 x 100 ml_), combined organic layer was washed with brine (70 ml_), dried over anhydrous Na ₂ S04, filtered and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (ethyl acetate/pet ether) to obtain the desired product S1 (1.5 g, 66%) as an off white solid. ¹ H NMR (400 MHz, CDCI ₃ ) d 8.83 (br s, 1H), 8.36 (d, J = 2.0 Hz, 1 H), 8.07 (d, J = 2.0 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.60 (dd, J = 7.6 Hz, 2.0 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 1 H), 4.60 (s, 2H), 3.71 (m, 1 H), 2.68 (s, 3H), 1.22-1.20 (m, 6H), 0.28 (s, 9H). MS (ES) C21 H27N3O2S1 requires: 397, found: 398(M+H) ⁺ .

Step-2: 5-(5-(lsopropoxymethyl)-2-(trimethylsilyl)-1H-pyrrolo G2, 3-bl pyridin-3-yl)-

2-methylaniline (S2)

To a stirred solution of 5-(isopropoxymethyl)-3-(4-methyl-3-nitrophenyl)-2- (trimethylsilyl)-l H-pyrrolo[2,3-b]pyridine S1 (1.5 g, 3.76 mmol, 1 eq.) in ethanol:H ₂ 0 (1:1, 30 ml_) were added Fe (1.05 g, 18.8 mmol, 5.0 eq.) and NH ₄ CI (1.01 g, 118.8 mmol, 5.0 eq.) at room temperature. The resulting reaction mixture was stirred at 70 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through the Celite pad, and the Celite pad was washed with ethanol (30 ml_). The filtrate was evaporated under reduced pressure to get crude compound. The crude compound was purified by flash column chromatography (EtOAc/pet ether) to obtain S2 (1.26 g, 91%) as an off white solid. ¹ H NMR (400 MHz, DMSO -d ₆ ) d 11.36 (br s, 1H), 8.20 (d, J = 2.0 Hz, 1 H), 7.66 (d, J = 1.6 Hz, 1 H), 6.97 (d, J = 7.6 Hz, 1 H), 6.64 (d, J = 1.6 Hz, 1 H), 6.47 (dd, J = 7.2 Hz, 1.6 Hz, 1H), 4.87 (br s, 2H), 4.51 (s, 2H), 3.64 (m, 1H), 2.11 (s, 3H), 1.11 (d, J = 6.0 Hz, 6H), 0.19 (s, 9H). MS (ES) C2iH ₂ 9N ₃ OSi requires: 367, found: 368 (M+H) ⁺ .

Step 3: N-(5-(5-(isopropoxymethyl)-2-(trimethylsilyl)-1 H-pyrrolor2.3-blpyridin-3-yl)- 2-methvlphenvl)acrvlamide (S3) 5-(5-(isopropoxymethyl)-2-(trimethylsilyl)-1 H-pyrrolo [2, 3-b] pyridin-3-yl)-2-methylaniline S2 (1000mg, 2.7mmol, 1eq) was dissolved in THF (30ml_) at -78°C. Next, DIPEA (4.6ml_, 27mmol, 10eq) was dropped and then a solution of acryloyl chloride (246mg, 2.7mmol, 1.0eq) in THF (10mL) was dropwise added. After 30min, again acryloyl chloride (25mg, 0.27mmol, 0.1 eq) in THF (1ml_) was added. After another 30min a few drops of water was added and the solvents were removed in vacuo. The crude compound was purified by flash column chromatography (EtOAc/cHex) to obtain the desired product S3 (908mg, 79%) as a white solid. ¹ H NMR (300 MHz, DMSO -do) d 11.51 (s, 1 H), 9.49 (s, 1 H), 8.23 (d, J = 2.0 Hz, 1 H), 7.71 (d, J = 2.0 Hz, 1 H), 7.62 (s,

1 H), 7.30 (d, J = 7.8 Hz, 1 H), 7.11 (dd, J = 1.8 Hz, J = 7.8 Hz, 1 H), 6.58 (dd, J = 10.1 Hz, J = 17.0 Hz, 1 H), 6.25 (dd, J = 2.1 Hz, J = 17.0Hz, 1 H), 5.74 (dd, J = 2.1 Hz, J = 10.1 Hz, 1 H), 4.52 (s, 2H), 3.63 (septet, J = 6.1 Hz, 1 H), 2.29 (s, 3H), 1.11 (d, J = 6.1 Hz, 6H), 0.21 (s, 9H). MS (ES) C ₂₄ H _3i N ₃ 0 ₂ Si requires: 421 , found: 422 (M+H) ⁺ .

Step 4: N-(5-(2-iodo-5-(isopropoxymethyl)-1 H-pyrrolor2,3-blpyridin-3-yl)-2- methylphenvDacrylamide (S

S4 (843mg, 1.8mmol, yellow solid) was prepared from S3 following the general procedure reported in Preparative Example 1 Step 4. MS (ES) C ₂₁ H ₂₂ IN ₃ O ₂ requires: 475, found: 476 (M+H) ⁺ .

Step 5: N-(5-(5-(isopropoxymethyl)-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3- blpyridin-3-yl)-2-methylphenyl)acrylamide 2.2.2-trifluoroacetate (S5) S5 (13mg, 0.2mmol, yellow solid) was prepared from S4 following the general procedure reported in Preparative Example 1 Step 5. ¹ H NMR (300 MHz, DMSO-c/e) d 12.06 (s, 1 H), 9.60 (s, 1 H), 8.17 (d, J = 1.9 Hz, 1 H), 8.05 (s, 1 H), 7.73 (d, J = 1.9 Hz, 1 H), 7.72 (s, 1 H), 7.61 (s, 1 H), 7.35 (d, J = 7.8 Hz, 1 H), 7.18 (dd, J = 1.9 Hz, J = 7.8 Hz, 1 H), 6.57 (dd, J = 10.1 Hz, J = 17.0 Hz, 1 H), 6.25 (dd, J = 2.1 Hz, J = 17.0 Hz, 1 H), 5.76

(dd, J = 2.1 Hz, J = 10.1 Hz, 1 H), 4.52 (s, 2H), 3.84 (s, 3H), 3.65 (septet, J = 6.1 Hz, 1 H), 2.30 (s, 3H), 1.12 (d, J = 6.1 Hz, 6H). MS (ES) C25H27N5O2 requires: 475, found: 476 (M+H) ⁺ . The Examples in the following table were prepared according to the procedure described for S5 (Example 121).

Example 143: N-(5-(5-bromo-4-chloro-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3-blpyridin-3-yl)-

2-methvlphenvl)acrvlamide (T Step 1 : 5-Bromo-4-chloro-3-(4-methyl-3-nitrophenyl)-2-(trimethylsily l)-1 H- pyrrolor2.3-blpyridine (T1)

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. The crude compound was purified by flash column chromatography (cHex/EtOAc, gradient from 10:1 to 100% EtOAc) yielding the desired product T1 (2.5 g, 95%) as a yellow solid. MS (ES) Ci ₇ H ₁₇ 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- methvlaniline 2,2,2-trifluoroacetate (T2)

To a stirred solution of 5-bromo-4-chloro-3-(4-methyl-3-nitrophenyl)-2-(trimethylsily l)-1 H- pyrrolo[2,3-b]pyridine T1 (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 6 h. 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 to give crude compound. The crude compound was purified by RP flash column chromatography (water/ACN with 0.1 %TFA) to afford the desired product T2 (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 T2 (1.67 g, 4.1 mmol, 1eq) was dissolved in 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 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 T3 (1.70g, 89%) as a beige solid. ¹ H NMR (400 MHz, DMSO -d ₆ ) d 12.04 (s, 1 H), 9.43 (s, 1 H), 8.43 (s, 1 H), 7.55 (s, 1 H), 7.23 (d, J = 7.6 Hz, 1 H), 7.05 (dd, J = 1.8 Hz, J = 7.6 Hz, 1 H), 6.56 (dd, J = 10.1 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 = 10.1 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 (T4)

T4 (0.25g, 0.48mmol, yellow solid) was prepared from T3 following the general procedure reported in Preparative Example 1 Step 4. MS (ES) Ci ₇ Hi ₂ BrCIIN ₃ 0 requires: 516, found: 517 (M+H) ⁺ .

Step 5: N-(5-(5-bromo-4-chloro-2-(1-methvl-1H-pvrazol-4-vl)-1H-pvrro lor2,3- blpyridin-3-yl)-2-methylphenyl)acrylamide (T5) A mixture of (N-(5-(5-bromo-4-chloro-2-iodo-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2- methylphenyl)acrylamide T4 (500mg, I .Ommol, 1eq.), 1-methyl-4-(4,4, 5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (201 mg, I .Ommol, 1eq.) and Na ₂ C03 (205mg, 1.9mmol, 1.9 eq) in THF/Me0H/H ₂ 0 (20mL/2mL/2mL) was degassed with a stream of N ₂ for 5min. [1 ,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (79mg, 0.1 mmol, 0.1 eq) was added and the reaction mixture heated to 80°C for 3h. The reaction mixture was diluted with EtOAc, washed three times with aq. sat. NaHCOs-solution. The organic phase was dried over MgSC and solvents were removed in vacuo. The crude was purified by column chromatography (cHex/EtOAc, gradient elution from 10:1 to 0:100) to yield the title compound T5 (150mg, 32%) as a yellow powder. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 12.49 (s, 1 H), 9.55 (s, 1 H), 8.35 (s, 1 H), 7.79 (s, 1 H), 7.53 (s, 1 H), 7.44 (s, 1 H), 7.31 (d, J = 7.8 Hz, 1 H), 7.10 (dd, J = 1.8 Hz, J = 7.8 Hz, 1 H), 6.54 (dd, J = 10.1 Hz, J = 17.0 Hz, 1 H), 6.22 (dd, J = 2.0 Hz, J = 17.0 Hz, 1 H), 5.74 (dd, J = 2.0 Hz, J = 10.1 Hz, 1 H), 3.79 (s, 3H), 2.31 (s, 3H). MS (ES) C _2i H ₁₇ BrCIN ₅ 0 requires: 470, found: 471 (M+H) ⁺ .

Example 147:

N-(5-(4-chloro-2.5-bis(1.5-dimethyl-1H-pyrazol-4-yl)-1H-p yrrolor2.3-blpyridin-3-yl)- 2-methylphenyl)acrylamide 2

A mixture of N-(5-(5-bromo-4-chloro-2-iodo-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2- methylphenyl)acrylamide (30mg, 0.1 mmol, 1eq.), 1 ,5-dimethyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 Hpyrazole (39mg, 0.2mmol, 3eq.) and K ₃ PO ₄ (37mg, 0.2mmol, 3 eq) in dioxane/water (2ml_/0.2ml_) was degassed with a stream of N ₂ for 5min. [1 ,T-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (5mg, 0.01 mmol, 0.1 eq) was added and the reaction mixture heated to 130°C for 45min in the microwave oven. 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 U1 (1 mg, 2%) as a yellow solid. ¹ H NMR (400MHz, de-DMSO, 300K) d 12.12 (s, 1 H), 9.43 (s, 1 H), 8.05 (s, 1 H), 7.44 (s, 1 H), 7.41 (s, 1 H), 7.27 (s, 1 H), 7.16 (d, J = 7.8 Hz, 1 H), 7.04 (s, J = 7.8 Hz, 1 H), 6.51 (dd, J = 17.1 Hz, J = 10.5 Hz, 1 H), 6.19 (dd, J = 2.1 Hz, J = 17.1 Hz, 1 H), 5.71 (dd, J = 2.1 Hz, J = 10.5 Hz, 1 H), 3.79 (s, 3H), 3.69 (s, 3H), 2.22 (s, 3H), 2.17 (s, 3H), 2.01 (s, 3H). MS (ES) C27H26CIN7O requires: 500, found: 501 (M+H) ⁺ .

Example 151 :

N-(3-(5-isobutoxy-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2,3-blpyridin-3-yl)-2, 6- dimethylphenvDacrylamide 2,2,2-trifluoroacetate (V2)

Step 1 : N-(3-(2-iodo-5-isobutoxy-1 H-pyrrolor2,3-blpyridin-3-yl)-2,6- dimethylphenvDacrylamide (V1)

N-(3-(5-isobutoxy-2-(trimethylsilyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2,6-dimethylphenyl) acrylamide (95mg, 0.22mmol, 1 eq) and NIS (88mg, 0.39mmol, 1 .8eq) were dissolved in dry DCM (5ml_). The reaction mixture was stirred for 16h at room temperature, and was quenched with saturated aqueous Na ₂ S203 solution. The precipitated solid was filtered off, washed with small amounts of water and DCM, and finally dried in vacuo yielding the desired product V1 as a greenish solid (99mg, 93%). The crude was used without purification in the next step. MS (ES) C22H24IN3O2 requires: 489, found: 490 (M+H) ⁺ .

Step 2: N-(3-(5-isobutoxy-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2,3-blpyridin-3- vl)-2,6-dimethvlphenvl)acrvlamide 2,2,2-trifluoroacetate (V2) A mixture dimethylphenyl)acrylamide V1 (49mg, O.lmmol, 1eq.), 1-methyl-4-(4,4, 5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (31 mg, 0.15mmol, 1.5eq.) and K ₃ PO ₄ (42mg, 0.2mmol, 2.0 eq) in dioxane/H ₂ 0 (2mL/0.3mL) was degassed with a stream of N ₂ for 5min. [1 ,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (8mg, 0.01 mmol, 0.1 eq) was added and the reaction mixture heated to 130°C for 2h in the microwave oven. 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 V2 (13mg, 20%) as a yellow solid. ¹ FI NMR (400MHz, de-DMSO, 300K) d 11.83 (s, 1 H), 9.63 (s, 1 H), 7.93 (d, J = 2.7 Hz, 1 H), 7.65 (s, 1 H), 7.41 (br s, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 2.7 Hz, 1 H), 6.51 (dd, J = 10.1 Hz, J = 17.1 Hz, 1 H), 6.24 (dd, J = 2.1 Hz, J = 17.1 Hz, 1 H), 5.75 (dd, J = 2.1 Hz, J = 10.1 Hz, 1H), 3.79 (s, 3H), 3.71 (d, J = 6.6 Hz, 2H), 2.24 (s, 3H), 1.98 (m, 1H), 1.85 (s, 3H), 0.98 (d, J = 6.6 Hz, 6H). MS (ES) C ₂₆ H ₂₉ N ₅ 0 ₂ requires: 443, found: 444 (M+H) ⁺ .

Example 161:

N-(3-(5-bromo-4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3-blpyridin-3- yl)phenyl)-N-methylacrylamide (W1 )

A mixture of N-(3-(5-bromo-2-iodo-4-methyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)-N- methylacrylamide (170mg, 0.34mmol, 1eq.), 1-methyl-4-(4,4, 5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (213mg, 1.02mmol, 3eq.) and K ₃ PO ₄ (216mg,

1.02mmol, 3eq.) in dioxane/H ₂ 0 (14ml_/1.4ml_) was degassed with a stream of N ₂ for 5min. [1 ,T-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (28mg, 0.03mmol, 0.1 eq) was added and the reaction mixture heated to 130°C for 90min in the microwave oven. The reaction mixture was diluted with EtOAc, washed three times with aq. sat. NaHCOs-solution. The organic phase was dried over MgSC and solvents were removed in vacuo. The crude was purified by column chromatography (cHex/EtOAc, gradient elution from 10:1 to 0:100) to yield the title compound W1 (27mg, 14%) as a yellow powder. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 12.21 (s, 1 H), 8.24 (s, 1H), 7.59 (s, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.39 (t, J = 7.7 Hz, 2H), 7.32 - 7.27 (m, 2H), 6.14 (d, J = 6.1 Hz, 2H), 5.58 (t, J = 6.1 Hz, 1H), 3.79 (s, 3H), 3.38 (s, 3H), 2.12 (s, 3H). MS (ES) C ₂₂ H ₂₀ BrN ₅ O requires: 451/449, found: 452/450 (M+H) ⁺ . Example 127:

N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-2-(1-(2-(dimethyla mino)ethyl)-1H-pyrazol-4- yl)-4-methyl-1H-pyrrolor2.3-blpyridin-3-yl)-3-fluoro-2-methy lphenyl)acrylamide

2,2.2-trifluoroacetate (X7)

Step 1: r2-(3-Fluoro-4-methyl-5-nitrophenyl)ethvnvntrimethylsilane (X1)

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 X1 as an yellow solid (5g, Y:93%). ¹ H NMR (300 MHz, DMSO -d ₆ ) d 7.63 (t, J = 1.5 Hz, 1H), 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 (X2)

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 X1 (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 S04, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (hexane:acetone 1 :1 ) to afford the pure product X2 as an pale yellow solid (2g, Y:29%). ¹ H NMR (300 MHz, DMSO -cfe) 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 (X3)

5-Bromo-3-(3-fluoro-4-methyl-5-nitrophenyl)-4-methyl-2-(t rimethylsilyl)-1 H-pyrrolo[2,3- b]pyridine (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 X3 as a yellow solid (6g, Y:42%). MS (ES) C ₂₃ H ₂₆ FN ₅ 0 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 (X4)

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 X3 (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 X4 as a yellow solid (5g, Y:80%). MS (ES) C23H ₂ 8FN 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 (X5)

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 X4 (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 TFIF (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:/P rOH 9:1 ) to obtained the product X5 (667mg, 18%) as a creamy solid. ¹ FI NMR (300 MFIz, DMSO-de) 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, 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 , 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 (X6) X6 (616mg, 1.16mmol, yellow solid) was prepared from X5 following the general procedure reported in Preparative Example 1 Step 4. MS (ES) C23H21FINO requires: 529, found: 530 (M+H) ⁺ .

Step 7: N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-2-(1-(2-(dimethylamin o)ethyl)-1H- pyrazol-4-yl)-4-methyl-1H-pyrrolor2.3-blpyridin-3-yl)-3-fluo ro-2- methylphenvDacrylamide 2.2.2-trifluoroacetate (X7)

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-fluoro-2-methylphenyl)acrylamide X6 (60mg, 0.1 mmol, 1.0eq.), K3PO4 (48mg, 0.2mmol, 2.0eq.), N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 h-pyrazol-1-yl)ethanamine (39mg, 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 , 2.2ml_) 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 65:35, 30 min). The desired fractions were combined and lyophilized to yield the title compound X7 (20mg, 23%) as a pale yellow solid. ¹ FI NMR (400MHz, d ₆ -DMSO, 300K) d 12.06 (s, 1 H), 9.75 (s, 1 H), 9.33 (br s, 1 H), 7.91 (s, 1 H), 7.86 (s, 1 H), 7.60 (d, J = 0.7 Hz, 1 H), 7.42 (s, 1 H), 7.31 (s, 1 H), 7.06 (dd, J = 1.6 Hz, J = 10.0 Hz, 1 H), 6.54 (dd, J = 17.0 Hz, J = 10.3 Hz, 1 H), 6.22 (dd, J = 2.0 Hz, J = 17.0 Hz, 1 H), 5.76 (dd, J = 2.0 Hz, J = 10.3 Hz, 1 H), 4.48 (t, J = 6.1 Hz, 2H), 3.76 (s, 3H), 3.52 (m, 2H), 2.78 (s, 6H), 2.20 / 2.19 (s, 3H), 2.11 (s, 3H), 1.94 (s, 3H). MS (ES) C30H33FN8O requires: 540, found: 541 (M+H) ⁺ .

Example 168:

N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-1H- pyrrolor2.3-blpyridin-3-yl)-2-methylphenyl)-N-methylacrylami de 2.2.2- trifluoroacetate (Y2) 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 (Y1 )

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 S ₂ 0 ₃ solution. The desired product was extracted with DCM (3x100ml_). 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 Y1 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-(1 -methyl-1 H-pyrazol-4- yl)-1H-pyrrolor2.3-blpyridin-3-yl)-2-methylphenyl)-N-methyla crylamide 2,2,2- trifluoroacetate (Y2)

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 Y1 (60mg, O.lmmol, 1.0eq.), K ₃ PO ₄ (49mg, 0.2mmol, 2.0eq.), 1-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole (36mg, 0.2mmol, 1.5eq.) and [1 ,T-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 Y2 (13mg, 19%) as a pale yellow solid. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 12.29 (s, 1H), 7.98 (s, 1H), 7.65 (m, 1 H), 7.47 (d, J = 7.8 Hz, 1H), 7.41 - 7.25 (m, 4H), 6.18 (d, J = 17.2 Hz, 1H), 6.03 (m, 1 H), 5.56 (d, J = 8.8 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.18 (s, 3H), 2.23 (s, 3H), 2.13 (s, 3H), 1.97 (s, 3H). MS (ES) C ₂₈ H ₂₉ N ₇ O requires: 479, found: 480 (M+H) ⁺ .

The Examples in the following table were prepared according to the procedure described for Y2 (Example 168).

Example 169:

N-(5-(5-(isopropoxymethyl)-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3-blpyridin- 3-vl)-2-methvlphenvl)-N-methvlacrvlamide 2,2,2-trifluoroacetate (Z5)

Step 1: Tert-butyl (5-(5-(isopropoxymethyl)-2-(trimethylsilyl)-1H-pyrrolor2.3- blpyridin-3-yl)-2-methylphenyl)(methyl)carbamate (Z1 ) To a stirred solution of 3-iodo-5-(isopropoxymethyl)pyridin-2-amine (3 g, 10.26 mmol, 1.0 eq.), tert- butyl methyl(2-methyl-5-((trimethylsilyl)ethynyl)phenyl)carbamate (4.9 g, 15.40 mmol, 1.5 eq.) in dimethylformamide (50 ml_) was added 1,4- diazabicyclo[2.2.2]octane (1.72 g, 15.40 mmol, 1.5 eq.) at room temperature. The resulting mixture was degassed with nitrogen for 15 min. Then b/s(triphenylphosphine)palladium(ll) dichloride (720 mg, 1.02 mmol, 0.1 eq.) was added at room temperature. The resultant reaction mixture was heated to 120 °C for 16 h. The reaction mixture was diluted with ethyl acetate (200 ml_), washed with ice water (5 x 100 ml_), brine (2 x 100 ml_). The organic layer was dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (elution of 20% ethyl acetate in pet ether) to obtain Z1 (3 g, 61 %) as brown solid. MS (ES) C27H39N3O3S1 requires: 481 , found: 482 (M+H) ⁺ .

Step 2: 5-(5-(lsopropoxymethyl)-2-(trimethylsilyl)-1 H-pyrrolor2.3-blpyridin-3-yl)- N,2-dimethvlaniline (Z2)

To a stirred solution tert- butyl (5-(5-(isopropoxymethyl)-2-(trimethylsilyl)-1/-/-pyrrolo[2,3 - b]pyridin-3-yl)-2-methylphenyl)(methyl)carbamate Z1 (5.5 g, 11.41 mmol, 1.0 eq.) in DCM (100 ml_) was added TFA (9 ml_, 114.1 mmol, 10.0eq.) at 0°C under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The crude compound was diluted with EtOAc (150 ml_), washed with sat. NaHCOs solution (2 x 100 ml_) and brine (100 ml_). The organic layer was dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to get Z2 (4.2 g, 97%) as brown solid. ¹ H NMR (400 MHz, CDCI ₃ ) d 8.73 ( br s, 1 H), 8.32 (d, J = 2.0 Hz, 1 H), 7.90 (d, J = 1 .2 Hz, 1 H), 7.22 (dd, J = 7.6 Hz, 0.4 Hz, 1 H), 6.76-6.69 (m, 2H), 4.57 (s, 2H), 3.70-3.65 (m, 2H), 2.92 (s, 3H), 2.21 (s, 3H), 1.19 (d, J = 6.0 Hz, 6H), 0.27 (s, 9H). MS (ES) C ₂₂ H _3i N ₃ OSi requires: 381 , found: 382 (M+H) ⁺ .

Step 3: N-(5-(5-(isopropoxymethyl)-2-(trimethylsilyl)-1 H-pyrrolor2.3-blpyridin-3-yl)- 2-methvlphenvD-N-methvlacrvlamide (Z3)

To a stirred solution 5-(5-(isopropoxymethyl)-2-(trimethylsilyl)-1/-/-pyrrolo[2,3- b]pyridin-3- yl)-/V,2-dimethylaniline Z2 (4.2 g, 11.0 mmol, 1 .0 eq.) in THF (200 ml_) was added N,N- diisopropylethylamine (5.7 ml_, 33.01 mmol, 3 eq.) followed by acryloyl chloride (1.3 ml_, 16.50 mmol, 1.5 eq.) in THF (10 ml_) at -78 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at -78 °C for 30 min. The reaction mixture was quenched with water (50 ml_), diluted with EtOAc (200 ml_). Two layers was separated, organic layer was washed with sat. NaHCOs (2 x 100 ml_) and brine (2 x 100 ml_). 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 (30% EtOAc in pet ether). The obtained compound was further purified by triturated with n-pentane, filtered and dried to get Z3 (2.68 g, 56%) as off white solid. ¹ H NMR (400 MHz, DMSO -d ₆ ) d 11 .57 (s, 1 H), 8.24 (d, J = 2.0 Hz, 1 H), 7.67 (d, J = 1.6 Hz, 1 H), 7.46 (d, J = 7.6 Hz, 1 H), 7.35 (dd, J = 1.6 Hz, 7.6 Hz, 1 H), 7.19 (d, J = 2.0 Hz, 1 H), 6.19 (dd, J = 2.0 Hz, 16.8 Hz, 1 H), 6.01-5.94 (m, 1 H), 5.57 (dd, J = 2.4

Hz, 10.4 Hz, 1 H), 4.52 (s, 2H), 3.66-3.60 (m, 1 H), 3.20 (s, 3H), 2.20 (s, 3H), 1.11 (d, J = 6.0 Hz, 6H), 0.20 (s, 9H). MS (ES) C25H33N3O2S1 requires: 435, found: 436 (M+H) ⁺ .

Step 4: N-(5-(2-iodo-5-(isopropoxymethyl)-1 H-pyrrolor2.3-blpyridin-3-yl)-2- methylphenyl)-N-methylacrylamide (Z4)

Z4 (532mg, 1.08mmol, yellow solid) was prepared from Z3 following the general procedure reported in Preparative Example 1 Step 4. MS (ES) C22H24IN3O2 requires: 489, found: 490 (M+H) ⁺ .

Step 5: N-(5-(5-(isopropoxymethyl)-2-(1 -methyl-1 H-pyrazol-4-yl)-1H-pyrrolor2.3- blpvridin-3-vl)-2-methvlphenvl)-N-methvlacrvlamide 2,2,2-trifluoroacetate (Z5)

A mixture of N-(5-(2-iodo-5-(isopropoxymethyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2- methylphenyl)-N-methylacrylamide Z4 (60mg, 0.12mmol, 1.0eq.), K3PO4 (52mg, 0.24mmol, 2.0eq.), 1 -methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (33mg, 0.16mmol, 1.3eq.) and [1 ,T-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (10mg, 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 Z5 (10mg, 14%) as a pale yellow solid. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 12.02 (s, 1 H), 8.16 (d, J = 1.9 Hz, 1 H), 7.84 (s, 1 H), 7.70 (d, J = 1.9 Hz, 1 H), 7.60 (s, 1 H), 7.47 (d, J = 7.9 Hz, 1 H),

7.41 (dd, J = 1.9 Hz, J = 7.9 Hz, 1 H), 7.22 ( d, J = 1.9 Hz, 1 H), 6.18 (dd, J = 2.6 Hz, J = 16.9 Hz, 1 H), 6.03 (dd, J = 10.1 Hz, J = 16.9 Hz, 1 H), 5.59 (dd, J = 2.6 Hz, J = 10.1 Hz, 1 H), 4.50 (s, 2H), 3.79 (s, 3H), 3.65 (m, 1 H), 3.15 (s, 3H), 2.19 (s, 3H), 1.09 (d, J = 6.1 Hz, 6H). MS (ES) C ₂₆ H ₂₉ N ₅ O ₂ requires: 443, found: 444 (M+H) ⁺ .

The Examples in the following table were prepared according to the procedure described for Z5 (Example 170).

Example 172:

N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-1H- pyrrolor2.3-blpyridin-3-yl)-5-fluoro-2.6-dimethylphenyl)acry lamide 2,2,2- trifluoroacetate

A mixture of N-(3-(5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-2-iodo-4-methyl-1 H-pyrrolo[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 72 Step 1-7, K ₃ PO ₄ (43mg, 0.20mmol, 2.0eq.), 1 -methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (27mg, 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 AA1 (11 mg, 18%) as a white solid. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 12.10 (s, 1 H), 9.78 (s, 1 H), 7.91 (s, 1 H), 7.58 (s, 1 H), 7.34 (s, 1 H), 7.27 (br s, 1 H), 7.06 (d, J = 9.8 Hz, 1 H), 6.47 (dd, J = 10.2 Hz, J = 17.1 Hz, 1 H), 6.23 (dd, J = 1.9 Hz, J = 17.1 Hz, 1 H), 5.74 (dd, J = 1.9 Hz, J = 10.2 Hz, 1 H), 3.77 (s, 3H), 3.76 (s, 3H), 2.13 / 2.13 (s, 3H), 2.10 (s, 3H), 1.88 (s, 3H), 1.82 (s, 3H). MS (ES) C ₂₈ H ₂₈ FN ₇ 0 requires: 497, found: 498 (M+H) ⁺ .

Example 173:

Isopropyl 4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-3-(4-methyl-3-(N- methylacrylamido)phenyl)-1H-pyrrolor2.3-blpyridine-5-carboxy late 2.2.2- triflu oroacetate (AB1)

A mixture of isopropyl 2-iodo-4-methyl-3-(4-methyl-3-(N-methylacrylamido)phenyl)-1 H- pyrrolo[2,3-b]pyridine-5-carboxylate (49mg, O.IOmmol, 1.0eq.), which was prepared according to the procedure for Example 172, K3PO4 (40mg, 0.20mmol, 2.0eq.), 1- methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (29mg, 0.1 mmol,

1.5eq.) and [1 ,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (12mg, 0.01 mmol, 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 AB1 (10mg, 20%) as a white solid. ¹ H NMR (400MHz, de-DMSO, 300K) d 12.31 (s, 1H), 8.59 (s, 1H), 7.55 (d, J = 2.7 Hz, 1 H), 7.48 (d, J = 8.9 Hz, 1 H), 7.38 - 7.23 (m, 3H), 6.18 (dd, J = 2.4 Hz, J = 16.9 Hz, 1H), 6.02 (m, 1 H), 5.57 (dd, J = 2.4 Hz, J = 10.3 Hz, 1H), 5.12 (septet, J = 6.2 Hz, 1H), 3.78 (s, 3H), 3.19 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H), 1.31 (d, J = 6.2 Hz, 6H). MS (ES) C^H^NsOs requires: 471, found: 472 (M+H) ⁺ .

Example 174:

N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-1H- pyrrolor2.3-blpyridin-3-yl)-2-methoxyphenyl)-N-methylacrylam ide 2,2,2- triflu oroacetate (AC9) Step 1: Tert-butyl (5-iodo-2-methoxyphenyl)carbamate (AC1)

Boc

Di-fe/f-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 AC1 (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, 1 H), 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 (AC2)

Boc

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 AC1 (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 AC2 (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 ₁₈ IN0 ₃ requires: 363, found: 308 (M-C H ₉ +H) ⁺ .

Step 3: Tert-butyl (2-methoxy-5-((trimethylsilyl)ethvnyl)phenyl)(methyl)carbama te

To a stirred solution of tert- butyl (5-iodo-2-methoxyphenyl)(methyl)carbamate AC2 (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 b/s(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 vacuo. The crude compound was purified by flash column chromatography (gradient elution of 15-20% ethyl acetate in pet ether) to obtain AC3 (3.7 g, 86%) as an off white solid. MS (ES) Ci8H ₂ 7N03Si requires: 333, found: 334 (M+H) ⁺ .

Step 4: Tert-butyl (5-(5-bromo-4-methyl-2-(trimethylsilyl)-1H-pyrrolor2.3-blpyr idin- 3-yl)-2-methoxyphenyl)(methyl)carbamate (AC4)

To a stirred solution of 5-bromo-3-iodo-4-methylpyridin-2-amine P1 (5.2 g, 16.6 mmol, 1 eq.), tert- butyl (2-methoxy-5-((trimethylsilyl)ethynyl)phenyl)(methyl)carbama te AC3 (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 AC4 (5.3 g, 61%) as a pale yellow solid. MS (ES) C ₂ 4H ₃₂ BrN ₃ 03Si requires: 519/517, found: 520/518 (M+H) ⁺ .

Step 5: 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 (AC5)

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 AC4 (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)CI ₂ 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 S0 ₄ , filtered and concentrated under reduced pressure to get crude compound. The crude compound was purified by flash column chromatography (gradient elution of 70% ethyl acetate in pet ether) to afford AC5 (4.3 g, 79%) as a pale yellow solid. ¹ H NMR (400 MHz, CDCIs) 5 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) CajHsgNsOsSi requires: 533, found: 534 (M+H) ⁺ .

Step 6: 5-(5-(1.5-Dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(trimethylsil yl)-1H- pyrrolor2.3-blpyridin-3-yl)-2-methoxy-N-methylaniline (AC6)

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 AC5 (4.3 g, 8.05 mmol, 1 eq.) in DCM (40 ml_) was added TFA (6.1 ml_, 80.5 mmol, 10.0 eq.) 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 S0 ₄ , filtered and concentrated under reduced pressure to give AC6 (3.2 g, 91 %) as an off white solid. MS (ES) C ₂₄ H _3i N ₅ OSi requires: 433, found: 434 (M+H) ⁺ .

Step 7: N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(trimethyl silyl)-1H- pyrrolor2.3-blpyridin-3-yl)-2-methoxyphenyl)-N-methylacrylam ide (AC8) To a stirred solution 5-(5-(1,5-dimethyl-1/-/-pyrazol-4-yl)-4-methyl-2-(trimethyls ilyl)-1/-/- pyrrolo[2,3-b]pyridin-3-yl)-2-methoxy-/V-methylaniline AC6 (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. NaHCOs (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 AC7 (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, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.14-5.96 (m, 2H), 5.50 (dd, J = 2.4 Hz, 10.0 Hz, 1H), 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 8: N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-2-iodo-4-methyl-1H-py rrolor2.3- blpyridin-3-yl)-2-methoxyphenyl)-N-methylacrylamide (AC8)

AC8 (512mg, 0.95mmol, yellow solid) was prepared from AC7 following the general procedure reported in Preparative Example 1 Step 4. MS (ES) C24H24IN5O2 requires: 541, found: 542 (M+H) ⁺ .

Step 9: N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(1 -methyl-1 H-pyrazol-4- yl)-1H-pyrrolor2.3-blpyridin-3-yl)-2-methoxyphenyl)-N-methyl acrylamide 2,2,2- trifluoroacetate (AC9) 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-methoxyphenyl)-N-methylacrylamide AC8 (50mg, 0.1 mmol, 1.0eq.), K ₃ PO ₄ (39mg, 0.2mmol, 2.0eq.), 1-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 H-pyrazole (29mg, 0.1 mmol, 1.5eq.) and [1 ,1'-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 AC9 (15mg, 28%) as an yellow solid. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 12.18 (s, 1H), 7.95 (s, 1 H), 7.64 (d, J = 15.3 Hz, 1H), 7.41 (br s, 1H), 7.36 (s, 1H), 7.35 - 7.23 (m, 3H), 6.10 (d, J = 8.0 Hz, 1 H), 6.02 (m, 1H), 5.50 (m, 1H), 3.88 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.15 (s, 3H), 2.13 (s, 3H), 1.98 (s, 3H). MS (ES) C ₂₈ H ₂₉ N ₇ O ₂ requires: 495, found: 496 (M+H) ⁺ .

The Examples in the following table were prepared according to the procedure described for AC9 (Example 174).

Example 176:

N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-ethyl-2-(1 -methyl-1 H-pyrazol-4-yl)-1H- pyrrolor2.3-blpyridin-3-yl)-2-methylphenyl)-N-methylacrylami de 2,2,2- trifluoroacetate (AD1) 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 72 Step 1 -7, K3PO4 (55mg, 0.26mmol, 2.0eq.), 1 -methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (35mg, 0.17mmol, 1.3eq.) and [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (11 mg, 0.01 mmol, 0.1 eq.) 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 AD1 (10mg, 12%) as a yellow solid. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 12.07 (s, 1 H), 7.86 (s, 1 H), 7.60 (s, 0.5H), 7.51 (s, 0.5H), 7.47 (m, 1 H), 7.37 (t, J = 8.8 Hz, 1 H), 7.34 - 7.27 (m, 2.5H), 7.20 (s, 0.5H), 6.16 (dd, J = 4.4 Hz, J = 16.8 Hz, 1 H), 6.03 (dd, J = 10.1 Hz, J = 16.8 Hz, 0.5H), 5.90 (dd, J = 10.1 Hz, J = 16.8 Hz, 0.5 H), 5.55 (t, J = 10.1 Hz, 1 H), 3.78 (s, 3H), 3.77 (s, 3H), 3.19 (s, 1.5H), 3.14 (s, 1.5H), 2.38 (m, 2H), 2.23 (s, 3H), 2.09 (s, 3H), 0.62 (t, J = 7.5 Hz, 1.5H), 0.60 (t, J =7.5Hz, 1.5H). MS (ES) C29H31N7O requires: 493, found: 494 (M+H) ⁺ .

Example 177:

N-(3-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-1H- pyrrolor2.3-blpyridin-3-yl)-2.6-dimethylphenyl)-N-methylacry lamide 2.2.2- triflu oroacetate (AE1)

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.), 1 -methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (35mg, 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 AE1 (15mg, 19%) as a pale yellow solid. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 11.98 (s, 1 H), 7.89 (s, 1 H), 7.56 (s, 0.5H), 7.48 (s, 0.5H), 7.33 - 7.23 (m, 3H), 7.20 (s, 0.5H), 7.16 (s, 0.5H), 6.17 (dd, J = 2.3 Hz, J = 16.9 Hz, 0.5H), 6.16 (dd, J = 2.3 Hz, J = 16.9 Hz, 0.5H), 5.96 (dd, J = 10.3 Hz, J = 16.9 Hz, 0.5 H), 5.84 (dd, J = 10.3 Hz, J = 16.9 Hz, 0.5 H), 5.53 (dd, J = 10.3 Hz, 1 H), 3.77 (s, 1.5H), 3.76 (s, 1.5H), 3.75 (s, 3H), 3.14 (s, 1.5H), 3.10 (s, 1.5H), 2.20 (s, 3H), 2.10 (s, 1.5H), 2.08 (s, 1.5H), 1.83 (s, 1.5H), 1.80 (s, 1.5H), 1.79 (s, 1.5H), 1.76 (s, 1.5H). MS (ES) C29H31N7O requires: 493, found: 494 (M+H) ⁺ .

Example 178:

N-(5-(5-(1.5-dimethyl-1H-pyrazol-4-yl)-4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-1H- pyrrolor2.3-blpyridin-3-yl)-3-methoxy-2-methylphenyl)acrylam ide 2,2,2- trifluoroacetate (AF1)

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 (55mg, O.IOmmol, 1.0eq.), which was prepared according to the procedure Example 72 Step 1-7, K ₃ PO ₄ (43mg, 0.20mmol, 2.0eq.), 1 -methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (25mg, 0.13mmol, 1.3eq.) and [1 ,T-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 purification (C18 column, water + 0.1 % TFA/ACN + 0.1 % TFA). The desired fractions were combined and lyophilized to yield the title compound AF1 (11 mg, 7%) as a pale yellow solid. ¹ H NMR (400MHz, d ₆ -DMSO, 300K) d 12.17 (s, 1 H), 9.60 (s, 1 H), 7.94 (s, 1 H), 7.80 (s, 1 H), 7.45 (s, 1 H), 7.36 (s, 1 H), 7.12 (br s, 1 H), 6.82 (s, 1 H), 6.50 (dd, J = 10.1 Hz, J = 17.1 Hz, 1 H), 6.20 (dd, J = 2.2 Hz, 17.1 Hz, 1 H), 5.71 (dd, J = 2.2 Hz, J = 10.1 Hz, 1 H), 3.78 (s, 3H), 3.77 (s, 3H), 3.75 (s, 3H), 2.12 (s, 3H), 2.11 (s, 3H), 1.99 (s, 3H). MS (ES) C28H29N7O2 requires: 495, found: 496 (M+H) ⁺ . Biological Assays

The exemplified compounds described herein were tested for activity and were found to have an IC50 value less than 10 mM, particularly less than 500 nM, in one of the following assays: 1. Measurement of HE R2 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 pi 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 IC ₅₀ £ 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 < 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, E 46-750) Lance and EGFR wt Lance assays. Inhibition is indicated as IC50 not measured). Compounds having an activity designated as ”A” provided 50nM; compounds having an activity designated as ”B” provided an 50n 100nM; compounds having an activity designated as ”C” provided an 100 500nM; compounds having an activity designated as ”D” provided an 500n 1000nM; compounds having an activity designated as ”E” provided an 1000 £ IOOOOhM; and compounds having an activity designated as ”F” provided a OOnM. 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 38, 53 to 59, 61 to 64, 68 to 69, 71 , 73 to 86, 88 to 103, 106, 108 to 111 , 114 to 117, 119 to 120, 124 to 128 and 133 to 142 show similar activity in comparison to compounds 1 to 37, 39 to 52, 60, 65 to 67, 70, 72, 87, 104 to 105, 107, 112 to 113, 118, 121 to 123, 129 to 132 and 143 to 178 so that compounds 1 to 37, 39 to 52, 60, 65 to 67, 70, 72, 87, 104 to 105, 107, 112 to 113, 118, 121 to 123, 129 to 132 and 143 to 178 are regarded as selected representative examples of all 178 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