4-SUBSTITUTED PYRROLO[2,3-B]PYRIDINE AS ERBB MODULATORS USEFUL FOR TREATING CANCER

Abstract

The present invention relates to certain 4-substituted 1H-pyrrolo[2,3-b]pyridine compounds of the formula (I) and pharmaceutically acceptable salts thereof. These compounds is useful in 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.

##STR00001##

Claims

1. A compound of the formula (I) ##STR00715## wherein ##STR00716## Z represents or A represents ##STR00717## ##STR00718## represents ##STR00719## B represents ##STR00720## ##STR00721## R.sub.1 represents —H, —R*, —CH.sub.2—R*, —CHR.sup.a—R*, —CR.sup.aR.sup.b—R*, —CH.sub.2CH.sub.2—R*, —CR.sup.aR.sup.b—CR.sup.cR.sup.d—R*, —CH═CH—R*, —CR.sup.a═CR.sup.b—R*, —CH.sub.2CH.sub.2CH.sub.2—R* or —CR.sup.aR.sup.b—CR.sup.cR.sup.d—CR.sup.eR.sup.f—R*; R.sup.a-R.sup.f represent independently of each other —H, —F, —Cl, —CH.sub.3, —OCH.sub.3, —CH.sub.2CH.sub.3, —CH.sub.2CH.sub.2CH.sub.3, —CH(CH.sub.3).sub.2, —CH.sub.2CH(CH.sub.3).sub.2, or -cyclo-C.sub.3H.sub.5; R* represents —H, —F, —Cl, —Br, —I, —OH, —CN, —NH.sub.2, —NHCH.sub.3, —NHC.sub.2H.sub.5, —NHC.sub.3H.sub.7, —NHCH(CH.sub.3).sub.2, —NHC(CH.sub.3).sub.3, —N(CH.sub.3).sub.2, —N(C.sub.2H.sub.5).sub.2, —N(C.sub.3H.sub.7).sub.2, —N[CH(CH.sub.3).sub.2].sub.2, —N[C(CH.sub.3).sub.3].sub.2, —NO.sub.2, —OCH.sub.3, —OC.sub.2H.sub.5, OC.sub.3H.sub.7, —OCH(CH.sub.3).sub.2, —OC(CH.sub.3).sub.3, —OC.sub.4H.sub.9, —O-cyclo-C.sub.3H.sub.5, —OCH.sub.2-cyclo-C.sub.3H.sub.5, —O—C.sub.2H.sub.4-cyclo-C.sub.3H.sub.5, —CHO, —COCH.sub.3, —COC.sub.2H.sub.5, —COC.sub.3H.sub.7, —COCH(CH.sub.3).sub.2, —COC(CH.sub.3).sub.3, —OOC—CH.sub.3, —OOC—C.sub.2H.sub.5, —OOC—C.sub.3H.sub.7, —OOC—CH(CH.sub.3).sub.2, —OOC-cyclo-C.sub.3H.sub.5, —OOC-cyclo-C.sub.3H.sub.5, —OCF.sub.3, —OC.sub.2F.sub.5, —NHSO.sub.2CH.sub.3, —NHSO.sub.2C.sub.2H.sub.5, —NHSO.sub.2C.sub.3H.sub.7, —NHSO.sub.2CH(CH.sub.3).sub.2, —NHSO.sub.2-cyclco-C.sub.3H.sub.5, —SOCH.sub.3, —SO.sub.2CH.sub.3, —SO.sub.2CF.sub.3, —SO.sub.2C.sub.2H.sub.5, —SO.sub.2CH.sub.2CF.sub.3, —SO.sub.2C.sub.3H.sub.7, —SO.sub.2CH(CH.sub.3).sub.2, —SO.sub.2-cyclco-C.sub.3H.sub.5, —SO(NH)CH.sub.3, —SO(NH)C.sub.2H.sub.5, —SO(NH)C.sub.3H.sub.7, —SO(NH)CH(CH.sub.3).sub.2, —SO(NH)-cyclco-C.sub.3H.sub.5, —SO(NCH.sub.3)CH.sub.3, —SO(NCH.sub.3)C.sub.2H.sub.5, —SO(NCH.sub.3)C.sub.3H.sub.7, —SO(NCH.sub.3)CH(CH.sub.3).sub.2, —SO(NCH.sub.3)-cyclco-C.sub.3H.sub.5, ##STR00722## R.sub.2 represents —H, —F, —Cl, —Br, —I, —OH, —CN, —CH.sub.3, —OCH.sub.3, —OC.sub.2H.sub.5, —OC.sub.3H.sub.7, —OCH(CH.sub.3).sub.2, —OC(CH.sub.3).sub.3, —OC.sub.4H.sub.9, —O-cyclo-C.sub.3H.sub.5, —OCH.sub.2-cyclo-C.sub.3H.sub.5, or —O—C.sub.2H.sub.4-cyclo-C.sub.3H.sub.5; R.sub.3 represents —H, —CH.sub.3, —C.sub.2H.sub.40H, —OC.sub.2H.sub.40H, —NR.sub.27R.sub.28, —CH.sub.2NR.sub.27R.sub.28, —CH.sub.2CH.sub.2NR.sub.27R.sub.28, —CH.sub.2CH.sub.2CH.sub.2NR.sub.27R.sub.28, —NHCOR.sub.27, —NHSO.sub.2R.sub.27, —OCH.sub.2NR.sub.27R.sub.28, —OCH.sub.2CH.sub.2NR.sub.27R.sub.28, —OCH.sub.2CH.sub.2CH.sub.2NR.sub.27R.sub.28, —NR.sub.29CH.sub.2NR.sub.27R.sub.28, —NR.sub.29CH.sub.2CH.sub.2NR.sub.27R.sub.28, —NR.sub.29CH.sub.2CH.sub.2CH.sub.2NR.sub.27R.sub.28, —CONR.sub.27R.sub.28, —CONHCH.sub.2NR.sub.27R.sub.28, —CONHCH.sub.2CH.sub.2NR.sub.27R.sub.28, —CONHCH.sub.2CH.sub.2CH.sub.2NR.sub.27R.sub.28, ##STR00723## ##STR00724## L is a bond, —CH.sub.2—, —CH(CH.sub.3)—, —CH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2CH.sub.2—, —CF.sub.2—, —CF.sub.2CH.sub.2—, —OCH.sub.2—, —OCH.sub.2CH.sub.2—, —OCH.sub.2CH.sub.2CH.sub.2—, —NHCH.sub.2—, —NHCH.sub.2CH.sub.2—, —NHCH.sub.2CH.sub.2CH.sub.2—, —N(CH.sub.3)CH.sub.2—, —N(CH.sub.3)CH.sub.2CH.sub.2—, —N(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2—, —NHCO—, —NHCOCH.sub.2—, —NHCOCH.sub.2CH.sub.2—, —CO—, —CH.sub.2CO—, —CH.sub.2CH.sub.2CO—, —COCH.sub.2—, —COCH.sub.2CH.sub.2—, —COCH.sub.2CO—, —COCH.sub.2CH.sub.2CO—, —CONH—, —CONHCH.sub.2—, —CONHCH.sub.2CH.sub.2—, —CONHCH.sub.2CH.sub.2CH.sub.2—, —OCO—, —SO.sub.2—, —CH.sub.2OCO— or —CH.sub.2CH.sub.2OCO—; R.sub.4 represents —H, —CH.sub.3, or —C.sub.2H.sub.5; R.sub.5 represents ##STR00725## R.sub.8-R.sub.11 represent independently of each other —H, —F, —Cl, —CN, —OCH.sub.3, —OC.sub.2H.sub.5, —OC.sub.3H.sub.7, —OCH(CH.sub.3).sub.2, —OC(CH.sub.3).sub.3, —OC.sub.4H.sub.9, —OCH.sub.2CH(CH.sub.3).sub.2, —OC.sub.2H.sub.4OCH.sub.3, —CH.sub.2OCH.sub.3, —CH.sub.3, —CF.sub.3, —C.sub.2H.sub.5, or —C.sub.3H.sub.7, or R.sub.8 and R.sub.9 or R.sub.9 and R.sub.10 form together —CH.sub.2—, —CH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2CH.sub.2CH.sub.2—, —CH.sub.2OCH.sub.2—, —CH.sub.2OCH.sub.2CH.sub.2—, —OCH.sub.2O—, or —OCH.sub.2CH.sub.2O—; R.sub.12-R.sub.16 represent independently of each other —H, —F, —Cl, —CN, —OCH.sub.3, —OC.sub.2H.sub.5, —OC.sub.3H.sub.7, —OCH(CH.sub.3).sub.2, —OC(CH.sub.3).sub.3, —OC.sub.4H.sub.9, —OCH.sub.2CH(CH.sub.3).sub.2, —OC.sub.2H.sub.4OCH.sub.3, —CH.sub.2OCH.sub.3, —CH.sub.3, —CF.sub.3, —C.sub.2H.sub.5, or —C.sub.3H.sub.7; R.sub.17-R.sub.21 represent independently of each other —H, —F, —Cl, —CN, —OCH.sub.3, —OC.sub.2H.sub.5, —OC.sub.3H.sub.7, —OCH(CH.sub.3).sub.2, —OC(CH.sub.3).sub.3, —OC.sub.4H.sub.9, —OCH.sub.2CH(CH.sub.3).sub.2, —OC.sub.2H.sub.4OCH.sub.3, —CH.sub.2OCH.sub.3, —CH.sub.3, —CF.sub.3, —C.sub.2H.sub.5, or —C.sub.3H.sub.7; R.sub.22 represents —H, —CH.sub.3, —CF.sub.3, —C.sub.2H.sub.5, —C.sub.3H.sub.7, —COCH.sub.3, —COC.sub.2H.sub.5, —SO.sub.2CH.sub.3, or —SO.sub.2C.sub.2H.sub.5; R.sub.23 represents —H, —CH.sub.3, —CF.sub.3, —C.sub.2H.sub.5, —C.sub.3H.sub.7, —CH.sub.2CH.sub.2OCH.sub.3, or —C.sub.4H.sub.9; R.sub.24 and R.sub.25 represent independently of each other —H, —CH.sub.3, —CF.sub.3, —C.sub.2H.sub.5, —C.sub.3H.sub.7, —CH.sub.2CH.sub.2OCH.sub.3, —CH(CH.sub.3).sub.2, —C.sub.4H.sub.9, -cyclo-C.sub.3H.sub.5, -cyclo-C.sub.4H.sub.7, -cyclo-C.sub.5H.sub.9, -cyclo-C.sub.6H.sub.11, ##STR00726## or R.sup.24 and R.sup.25 form together —CH.sub.2—, —CH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2CH.sub.2CH.sub.2—, —CH.sub.2OCH.sub.2—, or —CH.sub.2OCH.sub.2CH.sub.2—; L.sub.1 represents a bond, —CH.sub.2—, —CH.sub.2CH.sub.2—, or —CH.sub.2CH.sub.2CH.sub.2—; R.sub.26 represents —H, —CH.sub.3, —C.sub.2H.sub.5, —C.sub.3H.sub.7, —CH.sub.2CH.sub.2OCH.sub.3, —CH(CH.sub.3).sub.2, —C.sub.4H.sub.9, -cyclo-C.sub.3H.sub.5, -cyclo-C.sub.4H.sub.7, -cyclo-C.sub.5H.sub.9, -cyclo-C.sub.6H.sub.11, —C(CH.sub.3).sub.3, -Ph, or —CH.sub.2Ph; R.sub.27-R.sub.31 represent independently of each other —H, —F, —Cl, —OH, —CN, —NH.sub.2, —OCH.sub.3, —OC.sub.2H.sub.5, —OC.sub.3H.sub.7, —OCH(CH.sub.3).sub.2, —CH.sub.3, —CF.sub.3, —C.sub.2H.sub.5, —C.sub.3H.sub.7, —CH.sub.2CH.sub.2OCH.sub.3, —CH(CH.sub.3).sub.2, —C.sub.4H.sub.9, -cyclo-C.sub.3H.sub.5, -cyclo-C.sub.4H.sub.7, -cyclo-C.sub.5H.sub.9, or -cyclo-C.sub.6H.sub.11; R.sub.32, R.sub.37, R.sub.38, and R.sub.43 represent independently of each other —H, —CH.sub.3, —CF.sub.3, —C.sub.2H.sub.5, —C.sub.3H.sub.7, —CH(CH.sub.3).sub.2, -Ph, —CH.sub.2Ph, —COCH.sub.3, —COCF.sub.3, —COC.sub.2H.sub.5, —COCH(CH.sub.3).sub.2, —COC(CH.sub.3).sub.3, —COPh, —CO.sub.2CH.sub.3, —CO.sub.2C.sub.2H.sub.5, —CO.sub.2CH(CH.sub.3).sub.2, —CO.sub.2C(CH.sub.3).sub.3, —CO.sub.2Ph, —CO.sub.2CH.sub.2Ph, —SO.sub.2CH.sub.3, —SO.sub.2C.sub.2H.sub.5, —SO.sub.2CF.sub.3, or —SO.sub.2Ph; R.sub.33, R.sub.34, R.sub.35, and R.sub.36 represent independently of each other —H, —CH.sub.3, —CF.sub.3, —C.sub.2H.sub.5, —C.sub.3H.sub.7, —CH(CH.sub.3).sub.2, —CN, —NO.sub.2, —COCH.sub.3, —COC.sub.2H.sub.5, —COC.sub.3H.sub.7, —COCH(CH.sub.3).sub.2, —COC(CH.sub.3).sub.3, —COOH, —COOCH.sub.3, —COOC.sub.2H.sub.5, —COOC.sub.3H.sub.7, —COOCH(CH.sub.3).sub.2, or —COOC(CH.sub.3).sub.3; R.sub.39 represents —F, —Br, —Cl, or —I; R.sub.40, R.sub.41, and R.sub.42 represent independently of each other —H, —F, —Cl, —OH, —CN, —NH.sub.2, —CH.sub.3, —CF.sub.3, —C.sub.2H.sub.5, —C.sub.3H.sub.7, —CH(CH.sub.3).sub.2, —OCH.sub.3, —OC.sub.2H.sub.5, —OC.sub.3H.sub.7, —OCH(CH.sub.3).sub.2, —COCH.sub.3, —COCF.sub.3, —COC.sub.2H.sub.5, —COCH(CH.sub.3).sub.2, —NHCH.sub.3, —NHC.sub.2H.sub.5, —N(CH.sub.3).sub.2, —N(C.sub.2H.sub.5).sub.2, —NHCOCH.sub.3, —NHCOCF.sub.3, —NHCOC.sub.2H.sub.5, —NHCOCH(CH.sub.3).sub.2, —CO.sub.2H, —CO.sub.2CH.sub.3, —CO.sub.2C.sub.2H.sub.5, —CO.sub.2CH(CH.sub.3).sub.2, —CO.sub.2Ph, —CO.sub.2CH.sub.2Ph, —CONH.sub.2, —CONHCH.sub.3, —CONHC.sub.2H.sub.5, —CONHCH(CH.sub.3).sub.2, —CON(CH.sub.3).sub.2, —SO.sub.2CH.sub.3, —SO.sub.2C.sub.2H.sub.5, —SO.sub.2CF.sub.3, —SO.sub.2Ph, —SO.sub.2NH.sub.2, —SO.sub.2NHCH.sub.3, ##STR00727## or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of diastereomers, a tautomer, a hydrate, a solvate, or pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, wherein A represents ##STR00728## represents ##STR00729## B represents ##STR00730## and R.sub.8-R.sub.21 have the same meanings as defined in claim 1.

3. The compound according to claim 1 or 2, wherein A represents ##STR00731## represents ##STR00732## B represents ##STR00733## and R.sub.8-R.sub.11, and R.sub.16-R.sub.21 have the meanings as defined in claim 1.

4. The compound according to claim 1, wherein the compound has the formula (Ia) or (Ib): ##STR00734## wherein A represents ##STR00735## represents ##STR00736## B represents ##STR00737## and R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 have the same meanings as defined in claim 1.

5. The compound according to any one of claim 1-4, wherein Z represents ##STR00738## and is selected from ##STR00739## R.sub.1 represents —H, —CN, —C.sub.2H.sub.5, —OC.sub.2H.sub.5, —OCF.sub.3, —CH.sub.2OH, —COOH, —COOCH.sub.3, —COOCH.sub.2CH.sub.3, —COOCH(CH.sub.3).sub.2, —COOCH.sub.2CH.sub.2OCH.sub.3, —COO-cyclo-C.sub.3H.sub.5, —COO-cyclo-C.sub.4H.sub.7, —COO-cyclo-C.sub.5H.sub.9, —COO-cyclo-C.sub.6H.sub.11, —CONHCH(CH.sub.3).sub.2, —CONH-cyclo-C.sub.6H.sub.11, —CH.sub.2COOH, —CH.sub.2COOCH.sub.3, —CH.sub.2COOCH(CH.sub.3).sub.2, —CH.sub.2CONH(CH.sub.3), —CH.sub.2ON(CH.sub.3).sub.2, —NHCOCH.sub.3, —NHCOCH(CH.sub.3).sub.2, ##STR00740## ##STR00741## R.sub.2 represents —H, —Cl, —OCH.sub.3, —OC.sub.2H.sub.5, or —OCH(CH.sub.3).sub.2; B represents ##STR00742## R.sub.3 represents —H, —CH.sub.2N(CH.sub.3).sub.2, —CH.sub.2CH.sub.2N(CH.sub.3).sub.2, —OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, —OCH.sub.2CH.sub.2CH.sub.2N(CH.sub.3).sub.2, —CH.sub.2N(CH.sub.3).sub.2, —NHCOCH.sub.3, —NHSO.sub.2CH.sub.3, —N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2, —CONH-cyclo-C.sub.3H.sub.5, —CONH-cyclo-C.sub.6H.sub.11, —CONHCH.sub.2CH.sub.2N(CH.sub.3)CH.sub.2Ph, —CH.sub.2CH.sub.2OH, —OCH.sub.2CH.sub.2OH, ##STR00743## R.sub.5 represents ##STR00744## L is a bond, —CH.sub.2—, —OCH.sub.2CH.sub.2—, —CO—, —CONH—, —SO.sub.2—, or —CONHCH.sub.2CH.sub.2CH.sub.2—; and R.sub.32 represents —H, —CH.sub.3, —C.sub.2H.sub.5, —CH(CH.sub.3).sub.2, —CH.sub.2Ph, —COCH.sub.3, or —SO.sub.2C.sub.2H.sub.5.

6. The compound according to claim 1 selected from the group consisting of: N-(2-methyl-5-(2-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)acrylamide; N-(5-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; 1-(6-(2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; N-(5-(4-chloro-2-(4-(2-(dimethylamino)ethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(4-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(3-morpholinophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(3-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(2-(4-(4-acetylpiperazin-1-yl)phenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(4-(4-methylpiperazine-1-carbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(4-((dimethylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(4-(morpholine-4-carbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(4-(methylsulfonamido)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(4-(3-(dimethylamino)propoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(2-(4-acetamidophenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(3-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(4-(2-(dimethylamino)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-methoxy-2-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(2-(4-(4-acetylpiperazin-1-yl)phenyl)-4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-methoxy-2-(4-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-methoxy-2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-methoxy-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-ethoxy-2-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(3-(3-(dimethylamino)propoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(2-(3-((4-acetylpiperazin-1-yl)methyl)phenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(4-(3-(4-ethylpiperazin-1-yl)propoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(3-(3-(4-ethylpiperazin-1-yl)propoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(3-(morpholine-4-carbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(3-(2-(dimethylamino)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(4-(piperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(6-morpholinopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(2-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(2-morpholinopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; 1-(6-(4-chloro-2-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; N-(5-(4-chloro-2-(3-(4-methylpiperazine-1-carbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(2-(3-(4-acetylpiperazin-1-yl)phenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; 3-(3-(3-acrylamido-4-methylphenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(3-(pyrrolidin-1-yl)propyl)benzamide; 3-(3-(3-acrylamido-4-methylphenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(1-benzylpiperidin-4-yl)benzamide; 3-(3-(3-acrylamido-4-methylphenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-cyclopropylbenzamide; 3-(3-(3-acrylamido-4-methylphenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(3-(benzyl(methyl)amino)propyl)benzamide; N-(5-(2-(3-(4-acetylpiperazine-1-carbonyl)phenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(3-(2-methyl-2,7-diazaspiro[3.5]nonane-7-carbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; 3-(3-(3-acrylamido-4-methylphenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(3-(4-ethylpiperazin-1-yl)propyl)benzamide; 1-(6-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)prop-2-en-1-one; 1-(7-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroquinolin-1 (2H)-yl)prop-2-en-1-one; N-(5-(4-chloro-2-(2-morpholinopyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(3-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; 1-(7-(4-chloro-2-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroquinolin-1 (2H)-yl)prop-2-en-1-one; 1-(7-(4-chloro-2-(3-(2-(dimethylamino)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroquinolin-1 (2H)-yl)prop-2-en-1-one; 1-(7-(4-chloro-2-(6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroquinolin-1 (2H)-yl)prop-2-en-1-one; N-(5-(4-chloro-2-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(4-(4-ethylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(4-chloro-2-(4-(4-isopropylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; 1-(7-(4-chloro-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroquinolin-1 (2H)-yl)prop-2-en-1-one; 1-(7-(4-chloro-2-(4-(4-isopropylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroquinolin-1 (2H)-yl)prop-2-en-1-one; 1-(7-(4-chloro-2-(4-(2-(dimethylamino)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroquinolin-1 (2H)-yl)prop-2-en-1-one; 1-(7-(4-chloro-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroquinolin-1 (2H)-yl)prop-2-en-1-one; 1-(7-(4-chloro-2-(3-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroquinolin-1 (2H)-yl)prop-2-en-1-one; 1-(7-(4-chloro-2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroquinolin-1 (2H)-yl)prop-2-en-1-one; N-(5-(4-chloro-2-(4-(piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; 1-(6-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(2-(4-(4-acetylpiperazin-1-yl)phenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(4-((dimethylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(4-(4-isopropylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(4-(4-ethylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(3-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(4-(4-methylpiperazine-1-carbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(4-(2-(dimethylamino)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(4-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(4-(3-(dimethylamino)propoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; N-(5-(4-chloro-2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; 1-(6-(4-chloro-2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(4-(4-isopropylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)prop-2-en-1-one; N-(5-(4-chloro-2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(5-cyano-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; 3-(3-acrylamido-4-methylphenyl)-N-isopropyl-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; 1-(6-(4-chloro-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(4-(4-ethylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(4-((dimethylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)prop-2-en-1-one; 1-(6-(4-chloro-2-(3-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)prop-2-en-1-one; Isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; 1-(6-(4-ethoxy-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(2-(4-((dimethylamino)methyl)phenyl)-4-ethoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-ethoxy-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-ethoxy-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-ethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-ethoxy-2-(3-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 3-(3-acrylamido-4-methylphenyl)-N-cyclohexyl-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; 1-(6-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-methoxy-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-methoxy-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 3-(3-acrylamido-4-methylphenyl)-N-benzyl-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; N-(3-acetamidobenzyl)-3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; 1-(6-(4-isopropoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-methoxy-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 1-(6-(4-methoxy-2-(3-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one; 3-(3-acrylamido-4-methylphenyl)-N-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-N-(2-(pyridin-4-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; 3-(3-acrylamido-4-methylphenyl)-N-(4-fluorophenethyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; N-(2-methyl-5-(2-(2-morpholinopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)acrylamide; N-(2-methyl-5-(2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)acrylamide; 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-N-(3-sulfamoylbenzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-N-(pyridin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-N-(pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-N-((1-methylpiperidin-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; 3-(3-acrylamido-4-methylphenyl)-N-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; 3-(3-acrylamido-4-methylphenyl)-N-(2,4-difluorobenzyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; N-(4-acetamidobenzyl)-3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; 3-(3-acrylamido-4-methylphenyl)-N-(3-carbamoylbenzyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid; 2-Chloro-N-(5-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acetamide; (E)-N-(5-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)but-2-enamide; N-(5-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)ethenesulfonamide; (E)-N-(5-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)-4-(dimethylamino)but-2-enamide; Methyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; Ethyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; cyclobutyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; Cyclohexyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; Cyclopropyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; Cyclopentyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; 2-methoxyethyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; N-(5-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)propiolamide; oxetan-3-yl 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; (E)-N-(5-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)but-2-enamide; (E)-N-(5-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)-4-(dimethylamino)but-2-enamide; N-(5-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)-ethenesulfonamide; 2-chloro-N-(5-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acetamide; N-(5-(4-ethoxy-2-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; (E)-isopropyl 3-(3-(4-(dimethylamino)but-2-enamido)-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; N-(5-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,3-dimethylphenyl)acrylamide; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(4-((dimethylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; N-(5-(4-chloro-2-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,3-dimethylphenyl)acrylamide; 3-(3-acrylamido-4-methylphenyl)-2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; N-(5-(5-chloro-4-methyl-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-ethylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(2-(dimethylamino)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(2-(dimethylamino)ethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 2-(4-(4-acetylpiperazin-1-yl)phenyl)-3-(3-acrylamido-4-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-5-fluoro-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(2-morpholinopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(4-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(2-hydroxyethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(2-(4-methylpiperazin-1-yl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(3-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(6-morpholinopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-5-fluoro-4-methylphenyl)-2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(2-morpholinopyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-5-fluoro-4-methylphenyl)-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-isopropylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-5-fluoro-4-methylphenyl)-2-(4-((dimethylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(2-hydroxyethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-5-fluoro-4-methylphenyl)-2-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-5-fluoro-4-methylphenyl)-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-5-fluoro-4-methylphenyl)-2-(4-(2-(dimethylamino)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(3-(3-(dimethylamino)propoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 2-(3-(4-acetylpiperazin-1-yl)phenyl)-3-(3-acrylamido-4-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 2-(3-((4-acetylpiperazin-1-yl)methyl)phenyl)-3-(3-acrylamido-4-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(3-((dimethylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; N-(2-methyl-5-(2-(4-(4-methylpiperazin-1-yl)phenyl)-5-(trifluoromethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)acrylamide; 2-(3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid; isopropyl 2-(3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate; N-(5-(5-ethyl-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; isopropyl 3-(1-acryloylindolin-6-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; N-(5-(5-ethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(5-(2-(dimethylamino)-2-oxoethyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; methyl 2-(3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate; N-(2-methyl-5-(5-(2-(methylamino)-2-oxoethyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)acrylamide; oxetan-3-yl 2-(3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate; isopropyl 3-(3-acrylamido-4-methylphenyl)-4-methyl-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; N-(5-(5-(hydroxymethyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(5-isobutyramido-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; N-(5-(5-acetamido-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide; isopropyl 3-(5-acrylamido-2,4-dimethylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-(acrylamidomethyl)phenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-4-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(2-(dimethylamino)ethoxy)phenyl)-4-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-4-ethylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-2-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; isopropyl 3-(3-acrylamido-2-methylphenyl)-2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate, and isopropyl 3-(3-acrylamido-2-methylphenyl)-2-(4-(2-(dimethylamino)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of diastereomers, a tautomer, a hydrate, a solvate of the above mentioned compounds, or pharmaceutically acceptable salts thereof.

7. A compound according to any one of claims 1-6 as selective inhibitor of Exon 20 mutations of EGFR and Her2.

8. A compound according to any one of claims 1-6 for use as a medicament.

9. A compound according to any one of claims 1-6 for use in the treatment of cancer or for use in the treatment of cancer, wherein the cancer has an activating mutation of a receptor belonging to an ErbB family of receptors.

10. The compound for use according to claim 9, wherein the activating mutation of the receptor is an insertion within exon 20 of epidermal growth factor receptor (EGFR) or within exon 20 of human epidermal growth factor receptor (HER) or wherein the activating mutation of the receptor is selected from the group consisting of Her2 A775_G776insYVMA, EGFR D770_N771insSVD, EGFR H773_V774insNPH, EGFR V769_D770insASV, EGFR P772_H773insPR, EGFR T790M and EGFR T790ML858R.

11. The compound for use according to claim 9, wherein the cancer is selected from the group consisting of breast cancer, colon cancer, prostate cancer, lung cancer, gastric cancer, ovarian cancer, renal cancer, hepatocellular cancer, thyroid cancer, uterine cancer, esophagus cancer, squamous cell cancer, leukemia, lymphoma, osteosarcoma, melanoma, glioblastoma and neuroblastoma.

12. The compound for use according to any one of claims 9-11, wherein the cancer is non-small cell lung cancer or mamma carcinoma.

13. A compound according to claim 1-12 in combination with at least one anticancer drug for use in treatment of cancer.

14. A method for producing a compound of the formula (Ia-1), comprising: Step A1: performing a first cross coupling reaction of pyridine compound 1* with alkyne compound 2a* ##STR00745## to obtain a compound 3* ##STR00746## 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* ##STR00747## Step C1: performing a second cross coupling reaction of 4* with a compound 5* ##STR00748## in the presence of a second palladium catalyst, and a second base to obtain a compound 6* ##STR00749## Step D1: reducing nitro (NO.sub.2) group of the compound 6* to a primary amine (NH.sub.2) group to obtain a compound 7*; and Step E1: performing a coupling reaction of the compound 7* ##STR00750## with a compound HO—R.sub.5 or AG-R.sub.5 to obtain a product compound of the formula (Ia-1) ##STR00751## a method for producing a compound of the formula (Ia-1), comprising: Step A1: performing a first cross coupling reaction of pyridine compound 1* with alkyne compound 2a* ##STR00752## to obtain a compound 3* ##STR00753## in the presence of a first palladium catalyst, and a first base; Step D2: reducing nitro (NO.sub.2) group of the compound 3* to a primary amine (NH.sub.2) group to obtain a compound 10* ##STR00754## Step E2: performing a coupling reaction of the compound 10* with a compound HO—R.sub.5 or AG-R.sub.5 to obtain a compound 11* ##STR00755## Step B2: converting a trimethylsilyl group of the compound 11* to a halide like an iodide to obtain a compound 12* ##STR00756## and Step C2: performing a second cross coupling reaction of the compound 12* with a compound 5* in the presence of a second palladium catalyst, and a second base to obtain a product compound of the formula (Ia-1) ##STR00757## or a method for producing a compound of the formula (Ib), comprising: Step A3: i) performing a first cross coupling reaction of pyridine compound 1* ##STR00758## with alkyne compound 2b* ##STR00759## 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* ##STR00760## Step E3: performing a coupling reaction of the compound 3b* with a compound HO—R.sub.5 or AG-R.sub.5 to obtain a compound 11b* ##STR00761## Step B3: converting a trimethylsilyl group of the compound 11b* to a halide like an iodide to obtain a compound 12b* ##STR00762## and Step C3: performing a second cross coupling reaction of the compound 12b* with a compound 5* ##STR00763## in the presence of a second palladium catalyst, and a second base to obtain a product compound of the formula (Ib) ##STR00764## wherein A, B, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.4′, R.sub.5 and ##STR00765## have the same meanings as defined in the formula (I) of claim 1; X is a leaving group and represents Cl, Br, I, or OTf; AG is an activating group of carboxylic acid; PG is an amino protecting group; TMS is a trimethylsilyl group; 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.

15. An intermediate compound selected from the group consisting of the compounds 3*, 3b*, 4*, 7*, 10*, 11*, 11b*, 12* and 12b*: ##STR00766## ##STR00767## ##STR00768## ##STR00769## ##STR00770## ##STR00771## ##STR00772## ##STR00773## ##STR00774## wherein A, B, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.4′, R.sub.5, and ##STR00775## have the same meanings as defined in claim 1 and TMS is trimethyl silyl group.

Description

DESCRIPTION OF FIGURES

[0228] FIG. 1: core sequences of EGFR mutants EGFR D770_N771insSVD, EGFR H773_V774insNPH, EGFR V769_D770insASV, EGFR P772_H773insPR, EGFR T790M and EGFR T790ML858R and HER mutant Her2 INS8 INS YVMA.

[0229] FIG. 2 shows the hydrolysis of the acrylamide moiety of reference 1 in the presence of liver microsomes after 50 minutes.

PREPARATION OF COMPOUNDS

[0230] General Information:

[0231] 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. .sup.1H-NMR and .sup.13C-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 1.7 um, 2.1×50 mm. Flow: 0.5 ml/min. Eluents: A: H.sub.2O 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

[0232] ACN (acetonitrile); br (broad); CDCl.sub.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 (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate); HCl (hydrochloric acid); HOAc (acetic acid); H.sub.2O (water); K.sub.2CO.sub.3 (potassium carbonate); KOH (potassium hydroxide); MeOH (methanol); MS (mass spectrometry); Mwt (molecular weight); NaHCO.sub.3 (sodium hydrogencarbonate); NH.sub.3 (ammonia); NH.sub.4Cl (ammonium chloride); NIS (N-Iodosuccinimide); NMP (N-methyl-2-pyrrolidon); NMR (nuclear magnetic resonance); Pd(dppf)Cl.sub.2 ([1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II) complex with dichloromethane); iPrOH (iso-propanol); PyBroP (Bromotripyrrolidinophosphonium hexafluorophosphate); RP (reversed-phase); RT (room temperature); sat. aq. (saturated aqueous); SiO.sub.2 (silica gel); TFA (trifluoroacetic acid); THF (tetrahydrofurane).

PREPARATIVE EXAMPLES

Example 1

N-(5-(4-chloro-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (A1)

[0233] ##STR00314##

Step 1: 4-Chloro-3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (A1)

[0234] ##STR00315##

[0235] 4-Chloro-3-iodopyridine-2-amine (5.0 g, 19.0 mmol, 1.0 eq.), trimethyl((4-methyl-3-nitrophenyl)ethynyl)silane (5.7 g, 25.0 mmol, 1.25 eq.), 1,4-diazabicyclo[2.2.2]octane (3.6 g, 32.3 mmol, 1.7 eq.) and dichlorobis(triphenylphosphine)palladium(II) (1.4 g, 2.0 mmol, 0.1 eq.) in dry DMF (40 mL) under N.sub.2 atmosphere was splitted in three microwave vials. Each vial was heated in the microwave at 145° C. for 2 h. EtOAc (250 mL) was added and the organic phase was washed three times with aq. sat. NaHCO.sub.3-solution. The organic phase was dried over MgSO.sub.4 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 (3.9 g, 10.8 mmol, 57%) as a beige solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 0.11 (s, 9H), 2.58 (s, 3H), 7.12 (d, J=5.0 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 7.63 (d, J=7.9 Hz, 1H), 7.91 (s, 1H), 8.21 (d, J=5.0 Hz, 1H), 12.04 (s, 1H). MS (ES) C.sub.17H.sub.18ClN.sub.3O.sub.2Si requires: 359, found: 360 (M+H).sup.+.

Step 2: 5-(4-Chloro-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylaniline (A2)

[0236] ##STR00316##

[0237] A solution of 4-chloro-3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine A1 (5.6 g, 15.56 mmol, 1.0 eq.) and iron (4.3 g, 77.8 mmol, 5 eq.) in EtOH (100 mL) and aq. sat. NH.sub.4Cl-solution (10 mL) was stirred for 5 h 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. NaHCO.sub.3-solution. The organic phase was dried over MgSO.sub.4 and solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel (cHex/EtOAc=100:0 to 0:100) to yield the desired product A2 (5.0 g, 15.2 mmol, 97%) as a beige solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 0.10 (s, 9H), 2.10 (s, 3H), 4.76 (br s, 2H), 6.44 (d, J=7.4 Hz, 1H), 6.60 (s, 1H), 6.89 (d, J=7.4 Hz, 1H), 7.04 (d, J=5.1 Hz, 1H), 8.15 (d, J=5.1 Hz, 1H), 11.71 (s, 1H). MS (ES) C.sub.17H.sub.20ClN.sub.3Si requires: 329, found: 330 (M+H).sup.+.

Step 3: N-(5-(4-chloro-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide (A3)

[0238] ##STR00317##

[0239] A3 was prepared either by Procedure A or Procedure B:

[0240] Procedure A:

[0241] To a solution of A2 (2760 mg, 8.4 mmol, 1.0 eq.) and DIPEA (14.6 mL, 84.0 mmol, 10.0 eq.) in dry DCM (100 mL) at 0° C. was added slowly acrylolyl chloride (757 mg, 8.4 mmol, 1.0 eq.) in dry DCM (5 mL). The mixture was stirred for 5 min. The solution was diluted with EtOAc and washed twice with aq. sat. NaHCO.sub.3-solution. The organic phase was dried over MgSO.sub.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 (3070 mg, 8.0 mmol, 95%) as a white solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 0.11 (s, 9H), 2.28 (s, 3H), 5.72 (dd, J=2.1 Hz, J=10.2 Hz, 1H), 6.22 (dd, J=2.1 Hz, J=16.9 Hz, 1H), 6.55 (dd, J=10.2 Hz, J=16.9 Hz, 1H), 7.07 (m, 2H), 7.22 (d, J=7.7 Hz, 1H), 7.56 (s, 1H), 8.17 (d, J=5.0 Hz, 1H), 9.42 (s, 1H), 11.83 (s, 1H). MS (ES) C.sub.20H.sub.22ClN.sub.3OSi requires: 383, found: 384 (M+H).sup.+.

[0242] Procedure B:

[0243] To a solution of HATU (3460 mg, 9.1 mmol, 1.5 eq.) in DMF (10 mL) at 0° C. was added acrylic acid (655 mg, 9.1 mmol, 1.5 eq.) and DIPEA (1548 mg, 9.1 mmol, 2.0 eq.). The mixture was stirred for 15 min. Then A2 (2000 mg, 6.0 mmol, 1.0 eq.) was added and the mixture was stirred for 4 h at 0° C. The solution was diluted with EtOAc and washed twice with aq. sat. NaHCO.sub.3-solution. The organic phase was dried over MgSO.sub.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 (890 mg, 2.3 mmol, 39%) as a white solid. MS (ES) C.sub.20H.sub.22ClN.sub.3OSi requires: 383, found: 384 (M+H).sup.+.

Step 4: N-(5-(4-chloro-2-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide (A4)

[0244] ##STR00318##

[0245] N-(5-(4-chloro-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide A3 (890 mg, 2.32 mmol, 1.0 eq.) and N-iodosuccinimide (937 mg, 4.18 mmol, 1.8 eq.) were solved in dry dichloromethane (300 mL) and stirred for 15 h at RT. The organic phase was washed once with aq. sat. Na.sub.2S.sub.2O.sub.3-sol. and three times with aq. sat. NaHCO.sub.3-solution. The organic phase was dried over Na.sub.2SO.sub.4 and solvents were removed in vacuo yielding the desired product A4 (970 mg, 2.21 mmol, 95%) as a yellow solid. The crude was used without purification in the next step. MS (ES) C.sub.17H.sub.13ClIN.sub.3O requires: 437, found: 438 (M+H).sup.+.

Step 5: N-(5-(4-chloro-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (A5)

[0246] ##STR00319##

[0247] A mixture of N-(5-(4-chloro-2-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide A4 (40 mg, 0.09 mmol, 1.0 eq.), {4-[(4-methylpiperazin-1-yl)methyl]phenyl}boronic acid dihydrochloride (32 mg, 0.14 mmol, 1.5 eq.), and K.sub.3PO.sub.4 (38 mg, 0.18 mmol, 2.0 eq) in dioxane/H.sub.2O (3 mL/0.6 mL) was degassed with a stream of N.sub.2 for 5 min. [1,1′-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (8 mg, 0.01 mmol, 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. NaHCO.sub.3-solution. The organic phase was dried over MgSO.sub.4 and solvents were removed in vacuo. The crude was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound A5 (5 mg, 0.01 mmol, 8%) as a yellow powder. .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) δ 12.45 (s, 1H), 9.44 (s, 1H), 8.16 (dd, J=1.3 Hz, J=5.2 Hz, 1H), 7.52 (s, 1H), 7.44 (d, J=7.9 Hz, 2H), 7.25 (d, J=7.9 Hz, 2H), 7.20 (d, J=7.8 Hz, 1H), 7.10 (dd, J=1.3 Hz, J=5.2 Hz, 1H), 7.04 (d, J=7.8 Hz, 1H), 6.51 (dd, J=10.1 Hz, J=17.1 Hz, 1H), 6.17 (d, J=17.1 Hz, 1H), 5.70 (d, J=10.1 Hz, 1H), 3.58 (s, 2H), 3.01-2.89 (m, 4H), 2.74 (s, 3H), 2.65 (m, 2H), 2.31 (m, 2H), 2.25 (s, 3H). MS (ES) C.sub.29H.sub.30ClN.sub.5O requires: 500, found: 501 (M+H).sup.+.

[0248] The Examples in the following table were prepared according to the procedure described for A5 (Example 1).

TABLE-US-00002 Example Name Mwt [M + H].sup.+ 2 [00320] embedded image 485 486 3 [00321] 484 485 4 [00322] 458 459 5 [00323] 486 487 6 [00324] 472 473 7 [00325] 486 487 8 [00326] 513 514 9 [00327] 513 514 10 [00328] 444 445 11 [00329] 500 501 12 [00330] 480 481 13 [00331] 488 489 14 [00332] 444 445 15 [00333] 563 564 16 [00334] 499 500 17 [00335] embedded image 485 486 18 [00336] 474 475 19 [00337] 486 487 20 [00338] 488 489 21 [00339] 515 516 22 [00340] 527 528 23 [00341] 557 558 24 [00342] 389 390 25 [00343] 557 558 26 [00344] 486 487 27 [00345] 500 501 28 [00346] 474 475 29 [00347] 470 471 30 [00348] 473 474 31 [00349] 514 515 32 [00350] 473 474 33 [00351] embedded image 518 519 34 [00352] 534 535 35 [00353] 513 514 36 [00354] 474 475 37 [00355] 500 501 38 [00356] 500 501 38 [00357] 487 488 40 [00358] 499 500 41 [00359] 513 514 42 [00360] 503 504 43 [00361] 487 488

Example 44

N-(5-(4-chloro-2-(3-(4-methylpiperazine-1-carbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (B2)

[0249] ##STR00362##

Step 1: 3-(3-(3-acrylamido-4-methylphenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)benzoic acid (B1)

[0250] ##STR00363##

[0251] A mixture of N-(5-(4-chloro-2-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide A4 (500 mg, 1.14 mmol, 1.0 eq.), 3-carboxyphenylboronic acid (284 mg, 1.71 mmol, 1.5 eq.), and K.sub.3PO.sub.4 (483 mg, 2.28 mmol, 2.0 eq) in dioxane/H.sub.2O (15 mL/3 mL) was degassed with a stream of N.sub.2 for 5 min. [1,1′-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (93 mg, 0.11 mmol, 0.1 eq) was added and the reaction mixture heated to 130° C. for 2 h in the microwave oven. Solvents were removed and the crude was purified by flash chromatography on silica gel (DCM/MeOH=100:0 to 0:100) to yield the desired product B1 (200 mg, 0.46 mmol, 41%) as a beige solid. MS (ES) C.sub.24H.sub.18ClN.sub.3O.sub.3 requires: 431, found: 432 (M+H).sup.+.

Step 2: N-(5-(4-chloro-2-(3-(4-methylpiperazine-1-carbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (B2)

[0252] ##STR00364##

[0253] To a solution of B1 (10 mg, 0.02 mmol, 1.0 eq.) and HATU (18 mg, 0.05 mmol, 2.0 eq.) in DMF (2 mL) at 0° C. was added 1-methylpiperazine (4 mg, 0.03 mmol, 1.5 eq.) and DIPEA (20 uL, 0.11 mmol, 5.0 eq.). The mixture was stirred for 1 h. The reaction mixture was diluted with EtOAc, washed three times with aq. sat. NaHCO.sub.3-solution. The organic phase was dried over MgSO.sub.4 and solvents were removed in vacuo. The crude was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound B2 (3 mg, 0.003 mmol, 14%) as a yellow powder. .sup.1H NMR (400 MHz, MeOD, 300K) δ 8.17 (d, J=5.3 Hz, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.40 (m, 2H), 7.25 (d, J=7.7 Hz, 1H), 7.12 (m, 2H), 6.50 (dd, J=10.2 Hz, J=17.0 Hz, 1H), 6.35 (d, J=17.0 Hz, 1H), 5.80 (d, J=10.2 Hz, 1H), 3.54-2.80 (m, 8H), 2.95 (s, 3H), 2.32 (s, 3H). MS (ES) C.sub.29H.sub.28ClN.sub.5O.sub.2 requires: 513, found: 514 (M+H).sup.+.

[0254] The Examples in the following table were prepared according to the procedure described for B2 (Example 44).

TABLE-US-00003 Example Name Mwt [M + H].sup.+ 45 [00365] embedded image 512 513 46 [00366] 567 568 47 [00367] 541 542 48 [00368] 603 604 49 [00369] 470 471 50 [00370] 512 513 51 [00371] 591 592 52 [00372] 541 542 53 [00373] 553 554 54 [00374] 584 585

Example 55

1-(6-(4-Chloro-2-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one 2,2,2-trifluoroacetate (C5)

[0255] ##STR00375##

Step 1: Tert-butyl 6-(4-chloro-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indoline-1-carboxylate (C1)

[0256] ##STR00376##

[0257] C1 (1.0 g, 2.26 mmol, 76%, beige solid) was prepared from 4-chloro-3-iodopyridine-2-amine and tert-butyl 6-((trimethylsilyl)ethynyl)indoline-1-carboxylate following the general procedure reported in Preparative Example 1 Step 1. MS (ES) C.sub.23H.sub.28ClN.sub.3O.sub.2Si requires: 441, found: 442 (M+H).sup.+.

Step 2: 4-Chloro-3-(indolin-6-yl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (C2)

[0258] ##STR00377##

[0259] Tert-butyl 6-(4-chloro-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indoline-1-carboxylate C1 (1.0 g, 2.26 mmol) in 30% TFA in DCM (60 mL) at RT was stirred for 2 h. Evaporation of the solvents yielded the desired product C2 as beige solid, which was used in the next step without purification. MS (ES) C.sub.18H.sub.20ClN.sub.3Si requires: 341, found: 342 (M+H).sup.+.

Step 3: 1-(6-(4-Chloro-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one (C3)

[0260] ##STR00378##

[0261] C3 (50 mg, 0.13 mmol, 6%, beige solid) was prepared from C2 following the general procedure reported in Preparative Example 1 Step 3 Procedure A. MS (ES) C.sub.21H.sub.22ClN.sub.3OSi requires: 395, found: 396 (M+H).sup.+.

Step 4: 1-(6-(4-Chloro-2-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one (C4)

[0262] ##STR00379##

[0263] C4 (51 mg, 0.11 mmol, 84%, yellow solid) was prepared from C3 following the general procedure reported in Preparative Example 1 Step 4. MS (ES) C.sub.18H.sub.13ClIN.sub.3O requires: 448, found: 449 (M+H).sup.+.

Step 5: 1-(6-(4-chloro-2-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one 2,2,2-trifluoroacetate (C5)

[0264] ##STR00380##

[0265] C5 was prepared from C4 following the general procedure reported in Preparative Example 1 Step 5. The crude was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound C5 (10 mg, 0.01 mmol, 12%) as a yellow solid. .sup.1H NMR (400 MHz, d.sub.4-MeOD, 300K) δ 1.92 (m, 3H), 2.10 (d, J=13.6 Hz, 2H), 2.85 (m, 1H), 2.91 (s, 3H), 3.15 (m, 3H), 3.59 (d, J=10.3 Hz, 2H), 4.31 (t, J=8.5 Hz, 2H), 5.82 (d, J=10.6 Hz, 1H), 6.33 (d, J=16.8 Hz, 1H), 6.76 (dd, J=10.6 Hz, J=16.8 Hz, 1H), 7.05 (d, J=7.7 Hz, 1H), 7.10 (d, J=5.2 Hz, 1H), 7.30-7.19 (m, 3H), 7.46 (d, J=8.1 Hz, 2H), 7.71 (d, J=8.1 Hz, 1H), 8.12 (d, J=5.2 Hz, 1H), 8.25 (s, 1H). MS (ES) C.sub.30H.sub.29ClN.sub.4O requires: 496, found: 497 (M+H).sup.+.

[0266] The Examples in the following table were prepared according to the procedure described for C5 (Example 55).

TABLE-US-00004 Example Name Mwt [M + H].sup.+ 56 [00381] embedded image 497 498 57 [00382] 515 516 58 [00383] 525 526 59 [00384] 498 499 60 [00385] 511 512 61 [00386] 456 457 62 [00387] 525 526 63 [00388] 511 512 64 [00389] 512 513 65 [00390] 499 500 66 [00391] 525 526 67 [00392] 486 487 68 [00393] 498 499 69 [00394] 511 512 70 [00395] 498 499 71 [00396] 500 501

Example 72

N-(5-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (D5)

[0267] ##STR00397##

Step 1: 4-Methoxy-3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (D1)

[0268] ##STR00398##

[0269] D1 (3.50 g, 9.86 mmol, 38%, beige solid) was prepared from 3-iodo-4-methoxypyridin-2-amine and trimethyl((4-methyl-3-nitrophenyl)ethynyl)silane following the general procedure reported in Preparative Example 1 Step 1. MS (ES) C.sub.18H.sub.21N.sub.3O.sub.3Si requires: 355, found: 356 (M+H).sup.+.

Step 2: 5-(4-Methoxy-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylaniline (D2)

[0270] ##STR00399##

[0271] A solution of D1 (2.5 g, 7 mmol, 1 eq.) and iron (1.9 g, 35 mmol, 5 eq.) in EtOH (100 mL) and aq. sat. NH.sub.4Cl-solution (10 mL) was stirred for 5 h 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. NaHCO.sub.3-solution. The organic phase was dried over MgSO.sub.4 and solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel (cHex/EtOAc=100:0 to 0:100) to yield the desired product D2 (1.0 g, 3.1 mmol, 44%) as a beige solid. MS (ES) C.sub.18H.sub.23N.sub.3OSi requires: 325, found: 326 (M+H).sup.+.

Step 3: N-(5-(4-methoxy-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide (D3)

[0272] ##STR00400##

[0273] D3 (712 mg, 1.87 mmol, 40%, white solid) was prepared from D2 following the general procedure reported in Preparative Example 1 Step 3 Procedure A. MS (ES) C.sub.21H.sub.25N.sub.3O.sub.2Si requires: 379, found: 380 (M+H).sup.+.

Step 4: N-(5-(2-iodo-4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenylacrylamide (D4)

[0274] ##STR00401##

[0275] D4 (512 mg, 1.18 mmol, 66%, yellow solid) was prepared from D3 following the general procedure reported in Preparative Example 1 Step 4. MS (ES) C.sub.18H.sub.16IN.sub.3O.sub.2 requires: 433, found: 434 (M+H).sup.+.

Step 5: N-(5-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (D5)

[0276] ##STR00402##

[0277] D5 was prepared from D4 following the general procedure reported in Preparative Example 1 Step 5. The crude was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound D5 (2 mg, 0.01 mmol, 3%) as a yellow solid. .sup.1H NMR (400 MHz, d.sub.4-MeOD, 300K) δ 2.30 (s, 3H), 2.96 (s, 3H), 3.08 (m, 2H), 3.26 (m, 2H), 3.57 (m, 2H), 3.91 (m, 2H), 3.98 (s, 3H), 5.78 (dd, J=10.2 Hz, J=1.5 Hz, 1H), 6.34 (dd, J=17.0 Hz, J=1.5 Hz, 1H), 6.51 (dd, J=10.2 Hz, J=17.0 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 7.03 (d, J=6.7 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.38 (d, J=8.8 Hz, 2H), 7.46 (s, 1H), 8.22 (d, J=7.6 Hz, 1H). MS (ES) C.sub.29H.sub.31N.sub.5O.sub.2 requires: 481, found: 482 (M+H).sup.+.

[0278] The Examples in the following table were prepared according to the procedure described for D5 (Example 72).

TABLE-US-00005 Example Name Mwt [M + H].sup.+ 73 [00403] embedded image 480 481 74 [00404] 509 510 75 [00405] 482 483 76 [00406] 495 496 77 [00407] 495 496

Example 78

N-(2-methyl-5-(2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)acrylamide 2,2,2-trifluoroacetate (E1)

[0279] ##STR00408##

Step 1: 3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (E1)

[0280] ##STR00409##

[0281] 2-Amino-3-iodopyridine (5.65 g, 25.71 mmol, 1.2 eq.), trimethyl((4-methyl-3-nitrophenyl)ethynyl)silane (5.00 g, 21.43 mmol, 1.0 eq.), 1,4-diazabicyclo[2.2.2]octane (4.08 g, 32.3 mmol, 1.7 eq.) and dichlorobis(triphenylphosphine)palladium(II) (1.51 g, 2.14 mmol, 0.1 eq.) in dry DMF (40 mL) under N.sub.2 atmosphere was splitted in three microwave vials. Each vial was heated in the microwave at 145° C. for 2 h. EtOAc (250 mL) was added and the organic phase was washed three times with aq. sat. NaHCO.sub.3-solution. The organic phase was dried over MgSO.sub.4 and solvents were removed in vacuo. The crude product was purified by flash chromatography on silica gel (DCM/MeOH=100:0 to 10:1) to yield the desired product E1 (4.96 g, 10.25 mmol, 71%) as an orange solid. MS (ES) C.sub.17H.sub.19N.sub.3O.sub.2Si requires: 325, found: 326 (M+H).sup.+.

Step 2: 2-Methyl-5-(2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)aniline (E2)

[0282] ##STR00410##

[0283] A solution of 3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine E1 (4.96 g, 15.24 mmol, 1.0 eq.) and iron (8.51 g, 152.4 mmol, 10 eq.) in EtOH (100 mL) and aq. sat. NH.sub.4Cl-solution (20 mL) was stirred for 15 h 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. NaHCO.sub.3-solution. The organic phase was dried over MgSO.sub.4 and solvent was removed in vacuo. The crude product (3.04 g, 10.3 mmol, 68%, orange solid) was used without further purification in the next step. MS (ES) C.sub.17H.sub.21N.sub.3Si requires: 295, found: 296 (M+H).sup.+.

Step 3: N-(2-methyl-5-(2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenylacrylamide (E3)

[0284] ##STR00411##

[0285] To a solution of E2 (1000 mg, 3.38 mmol, 1.0 eq.) and DIPEA (2.96 mL, 16.92 mmol, 5.0 eq.) in dry DCM (100 mL) at 0° C. was added slowly acrylolyl chloride (306 mg, 3.38 mmol, 1.0 eq.) in dry DCM (5 mL). The mixture was stirred for 30 min. The solution was diluted with EtOAc and washed twice with aq. sat. NaHCO.sub.3-solution. The organic phase was dried over MgSO.sub.4 and solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel (cHex/EtOAc=100:0 to 1:2) to yield the desired product E3 (498 mg, 1.43 mmol, 42%) as a white solid. MS (ES) C.sub.20H.sub.23N.sub.3OSi requires: 349, found: 350 (M+H).sup.+.

Step 4: N-(5-(2-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide (E4)

[0286] ##STR00412##

[0287] N-(2-methyl-5-(2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)acrylamide E3 (497 mg, 1.42 mmol, 1.0 eq.) and N-iodosuccinimide (576 mg, 2.56 mmol, 1.8 eq.) were solved in dry dichloromethane (100 mL) and stirred for 15 h at RT. The organic phase was washed once with aq. sat. Na.sub.2S.sub.2O.sub.3-solution and three times with aq. sat. NaHCO.sub.3-solution. The organic phase was dried over Na.sub.2SO.sub.4 and solvents were removed in vacuo yielding the desired product E4 (337 mg, 0.84 mmol, 59%) as a yellow solid. The crude was used without purification in the next step. MS (ES) C.sub.17H.sub.14IN.sub.3O requires: 403, found: 404 (M+H).sup.+.

Step 5: N-(2-methyl-5-(2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)acrylamide 2,2,2-trifluoroacetate (E5)

[0288] ##STR00413##

[0289] A mixture of N-(5-(2-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide E4 (50 mg, 0.12 mmol, 1.0 eq.), 2-(4-methylpiperazino)pyridine-5-boronic acid pinacol ester (49 mg, 0.16 mmol, 1.3 eq.), and K.sub.3PO.sub.4 (53 mg, 0.24 mmol, 2.0 eq) in dioxane/H.sub.2O (3 mL/0.6 mL) was degassed with a stream of N.sub.2 for 5 min. [1,1′-Bis(diphenylphosphino)-ferrocene]palladium dichloride dichloromethane adduct (10 mg, 0.01 mmol, 0.1 eq) was added and the reaction mixture heated to 110° C. for 1 h in the microwave oven. The crude solution was directly purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound E5 (22 mg, 0.03 mmol, 23%) as a yellow powder. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 2.27 (s, 3H), 2.85 (s, 3H), 3.12 (m, 4H), 3.51 (d, J=11.3 Hz, 2H), 4.46 (d, J=12.3 Hz, 2H), 5.76 (d, J=10.3 Hz, 1H), 6.24 (d, J=17.0 Hz, 1H), 6.57 (dd, J=10.3 Hz, J=17.0 Hz, 1H), 6.99 (m, 2H), 7.12 (dd, J=4.7 Hz, J=7.9 Hz, 1H), 7.24 (d, J=7.9 Hz, 1H), 7.67 (s, 1H), 7.72 (dd, J=2.4 Hz, J=8.7 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H), 8.26 (d, J=4.7 Hz, 1H), 8.33 (d, J=2.4 Hz, 1H), 9.51 (s, 1H), 12.14 (s, 1H). MS (ES) C.sub.27H.sub.28N.sub.6O requires: 452, found: 453 (M+H).sup.+.

[0290] The Examples in the following table were prepared according to the procedure described for E5 (Example 78).

TABLE-US-00006 Example Name Mwt [M + H].sup.+ 79 [00414] embedded image 450 451 80 [00415] 439 440 81 [00416] 493 494 82 [00417] 452 453

Example 83

1-(6-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)prop-2-en-1-one 2,2,2-trifluoroacetate (F4)

[0291] ##STR00418##

Step 1: tert-butyl 6-(4-chloro-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (F1)

[0292] ##STR00419##

[0293] F1 (632 mg, 1.37 mmol, 40%, beige solid) was prepared from 4-chloro-3-iodopyridine-2-amine (867 mg, 3.41 mmol, 1.0 eq.) and tert-butyl 6-((trimethylsilyl)ethynyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (1.131 mg, 3.41 mmol, 1.0 eq.) following the general procedure reported in Preparative Example 1 Step 1. MS (ES) C.sub.23H.sub.28ClN.sub.3O.sub.3Si requires: 458, found: 459 (M+H).sup.+.

Step 2: tert-butyl 6-(4-chloro-2-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (F2)

[0294] ##STR00420##

[0295] Tert-butyl 6-(4-chloro-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate F1 (300 mg, 0.65 mmol) and N-iodosuccinimide (264 mg, 1.17 mmol, 1.8 eq.) were solved in dry dichloromethane (100 mL) and stirred for 5 h at RT. The organic phase was washed once with aq. sat. Na.sub.2S.sub.2O.sub.3-solution and three times with aq. sat. NaHCO.sub.3-solution. The organic phase was dried over Na.sub.2SO.sub.4 and solvents were removed in vacuo yielding the desired product F2 (341 mg, 0.65 mmol, 100%) as a brown solid. The crude was used without purification in the next step. MS (ES) C.sub.20H.sub.19ClIN.sub.3O.sub.3 requires: 511, found: 512 (M+H).sup.+.

Step 3: 6-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (F3)

[0296] ##STR00421##

[0297] A mixture of tert-butyl 6-(4-chloro-2-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate F2 (341 mg, 0.65 mmol, 1.0 eq.), 4-(4-methylpiperazin-1-yl)phenylboronic acid (186 mg, 0.85 mmol, 1.3 eq.), and K.sub.3PO.sub.4 (275 mg, 1.30 mmol, 2.0 eq) in dioxane/H.sub.2O (10 mL/1 mL) was degassed with a stream of N.sub.2 for 5 min. [1,1′-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (53 mg, 0.06 mmol, 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. NaHCO.sub.3-solution. The organic phase was dried over MgSO.sub.4 and solvents were removed in vacuo. The crude was solved in 30% TFA in DCM (60 mL) and stirred for 2 h at RT. Solvents were removed in vacuo. The crude product was purified by flash chromatography on silica gel (DCM/MeOH with 0.1% NEt.sub.3=100:0 to 5:1) to yield the desired product F3 (145 mg, 0.31 mmol, 49%) as a white solid. MS (ES) C.sub.26H.sub.26ClN.sub.5O requires: 459, found: 460 (M+H).sup.+.

Step 4: 1-(6-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)prop-2-en-1-one 2,2,2-trifluoroacetate (F4)

[0298] ##STR00422##

[0299] To a solution of F3 (29 mg, 0.063 mmol, 1.0 eq.) and DIPEA (110 uL, 0.63 mmol, 10.0 eq.) in dry DCM (4 mL) at 0° C. was added slowly acrylolyl chloride (5.1 mg, 0.057 mmol, 0.9 eq.) in dry DCM (5 mL). The mixture was stirred for 5 min. The solution was diluted with EtOAc and washed twice with aq. sat. NaHCO.sub.3-solution. The organic phase was dried over MgSO.sub.4 and solvent was removed in vacuo. The crude solution was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound F4 (24 mg, 0.03 mmol, 51%) as a yellow powder. .sup.1H NMR (400 MHz, d.sub.4-MeOH, 300K) δ 2.96 (s, 3H), 3.06 (m, 2H), 3.25 (m, 4H), 3.59 (m, 2H), 3.92 (m, 2H), 4.34 (m, 2H), 5.38 (d, J=10.4 Hz, 1H), 6.16 (dd, J=2.0 Hz, J=16.8 Hz, 1H), 6.36 (m, 1H), 6.98 (d, J=8.3 Hz, 1H), 7.02 (d, J=8.9 Hz, 2H), 7.12 (d, J=5.4 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 7.37 (d, J=8.9 Hz, 2H), 8.10 (d, J=5.4 Hz, 1H). MS (ES) C.sub.23H.sub.28ClN.sub.3O.sub.3Si requires: 513, found: 514 (M+H).sup.+.

[0300] The Examples in the following table were prepared according to the procedure described for F4 (Example 83).

TABLE-US-00007 Example Name Mwt [M + H].sup.+ 84 [00423] embedded image 515 516 85 [00424] 541 542

Example 86

1-(7-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)prop-2-en-1-one 2,2,2-trifluoroacetate (G5)

[0301] ##STR00425##

Step 1: tert-butyl 7-(4-chloro-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (G1)

[0302] ##STR00426##

[0303] 4-Chloro-3-iodopyridine-2-amine (1175 mg, 4.6 mmol, 1.0 eq.), tert-butyl 7-((trimethylsilyl)ethynyl)-3,4-dihydroquinoline-1(2H)-carboxylate (1522 mg, 4.6 mmol, 1.0 eq.), 1,4-diazabicyclo[2.2.2]octane (876 mg, 7.8 mmol, 1.7 eq.) and dichlorobis(triphenylphosphine)palladium(II) (351 mg, 0.4 mmol, 0.1 eq.) in dry DMF (30 mL) under N2 atmosphere was splitted in three microwave vials. Each vial was heated in the microwave at 145° C. for 2 h. The 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 G1 (1010 mg, 2.2 mmol, 48%) as a beige solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 0.09 (s, 9H), 1.39 (s, 9H), 1.87 (m, 2H), 2.79 (7, J=6.5 Hz, 2H), 3.65 (m, 2H), 6.94 (dd, J=1.7 Hz, J=7.7 Hz, 1H), 7.06 (d, J=5.1 Hz, 1H), 7.09 (d, J=7.7 Hz, 1H), 7.61 (d, J=1.7 Hz, 1H), 8.17 (d, J=5.1 Hz, 1H), 11.82 (s, 1H). MS (ES) C.sub.24H.sub.30ClN.sub.3O.sub.2Si requires: 455, found: 456 (M+H).sup.+.

Step 2: 7-(4-chloro-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2,3,4-tetrahydroquinoline (G2)

[0304] ##STR00427##

[0305] Tert-butyl 7-(4-chloro-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroquinoline-1(2H)-carboxylate G1 (1.0 g, 2.19 mmol) in 50% TFA in DCM (20 mL) at RT was stirred for 2 h. Evaporation of the solvents yielded the desired product G2 as brown solid, which was used in the next step without purification. MS (ES) C.sub.19H.sub.22ClN.sub.3Si requires: 355, found: 356 (M+H).sup.+.

Step 3: 1-(7-(4-chloro-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroauinolin-1(2H)-yl)prop-2-en-1-one (G3)

[0306] ##STR00428##

[0307] To a solution of G2 (2.19 mmol, 1.0 eq.) and DIPEA (2.5 mL, 14.5 mmol, 5.0 eq.) in dry DCM (40 mL) at 0° C. was added slowly acrylolyl chloride (235 mg, 2.6 mmol, 1.0 eq.) in dry DCM (5 mL). The mixture was stirred for 10 min. The solution was diluted with EtOAc and washed twice with aq. sat. NaHCO.sub.3-solution. The organic phase was dried over MgSO.sub.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 G3 (581 mg, 1.42 mmol, 65%) as a white solid. MS (ES) C.sub.22H.sub.24ClN.sub.3OSi requires: 409, found: 410 (M+H).sup.+.

Step 4: 1-(7-(4-chloro-2-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)prop-2-en-1-one (G4)

[0308] ##STR00429##

[0309] 1-(7-(4-chloro-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)prop-2-en-1-one G3 (371 mg, 0.91 mmol, 1.0 eq.) and N-iodosuccinimide (366 mg, 1.63 mmol, 1.8 eq.) were solved in dry dichloromethane (300 mL) and stirred for 15 h at RT. The organic phase was washed once with aq. sat. Na.sub.2S.sub.2O.sub.3-solution and three times with aq. sat. NaHCO.sub.3-solution. The organic phase was dried over Na.sub.2SO.sub.4 and solvents were removed in vacuo yielding the desired product G4 as a yellow solid. The crude was used without purification in the next step. MS (ES) C.sub.19H.sub.15ClIN.sub.3O requires: 462, found: 463 (M+H).sup.+.

Step 5: 1-(7-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)prop-2-en-1-one 2,2,2-trifluoroacetate (G5)

[0310] ##STR00430##

[0311] A mixture of 1-(7-(4-chloro-2-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)prop-2-en-1-one G4 (50 mg, 0.10 mmol, 1.0 eq.), 4-(4-methylpiperazin-1-yl)phenylboronic acid (31 mg, 0.14 mmol, 1.5 eq.), and K.sub.3PO.sub.4 (38 mg, 0.18 mmol, 2.0 eq) in dioxane/H.sub.2O (3 mL/0.6 mL) was degassed with a stream of N.sub.2 for 5 min. [1,1′-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (8 mg, 0.01 mmol, 0.1 eq) was added and the reaction mixture heated to 130° C. for 2 h in the microwave oven. The crude reaction mixture was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound G5 (22 mg, 0.03 mmol, 30%) as a yellow powder. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 1.92 (q, J=6.5 Hz, 2H), 2.52 (m, 2H), 2.79 (t, J=6.5 Hz, 2H), 2.85 (s, 3H), 2.96 (t, J=12.2 Hz, 2H), 3.12 (m, 2H), 3.51 (d, J=12.2 Hz, 2H), 3.75 (m, 2H), 5.22 (dd, J=2.4 Hz, J=10.2 Hz, 1H), 6.03 (dd, J=2.4 Hz, J=16.7 Hz, 1H), 6.25 (dd, J=10.2 Hz, J=16.7 Hz, 1H), 6.88 (s, 1H), 6.99 (d, J=9.0 Hz, 2H), 7.12 (d, J=5.2 Hz, 1H), 7.21 (dd, J=1.6 Hz, J=7.6 Hz, 1H), 7.28 (d, J=7.6 Hz, 1H), 7.31 (d, J=9.0 Hz, 2H), 8.15 (d, J=5.2 Hz, 1H), 12.40 (s, 1H). MS (ES) C.sub.30H.sub.30ClN.sub.5O requires: 511, found: 512 (M+H).sup.+.

[0312] The Examples in the following table were prepared according to the procedure described for G5 (Example 86).

TABLE-US-00008 Example Name Mwt [M + H].sup.+ 87 [00431] embedded image 510 511 88 [00432] 500 501 89 [00433] 526 527 90 [00434] 526 527 91 [00435] 539 540 92 [00436] 500 501 93 [00437] 512 513 94 [00438] 526 527 95 [00439] 525 526

Example 96

N-(5-(4-chloro-2-(4-(piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (H2)

[0313] ##STR00440##

Step 1: tert-butyl 4-(4-(3-(3-acrylamido-4-methylphenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperazine-1-carboxylate (H1)

[0314] ##STR00441##

[0315] A mixture of N-(5-(4-chloro-2-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide A4 (100 mg, 0.22 mmol, 1.0 eq.), 4-(4-boc-piperazino)phenylboronic acid (105 mg, 0.34 mmol, 1.5 eq.), and K.sub.3PO.sub.4 (97 mg, 0.44 mmol, 2.0 eq) in dioxane/H.sub.2O (3 mL/0.6 mL) was degassed with a stream of N.sub.2 for 5 min. [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (19 mg, 0.02 mmol, 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. NaHCO.sub.3-solution. The organic phase was dried over MgSO.sub.4 and solvents were removed in vacuo. The crude product was purified by flash chromatography on silica gel (cHex/EtOAc=100:0 to 0:100) to yield the desired product H1 (41 mg, 0.07 mmol, 32%) as a beige solid. MS (ES) C.sub.32H.sub.34ClN.sub.5O.sub.3 requires: 571, found: 572 (M+H).sup.+.

Step 2: N-(5-(4-chloro-2-(4-(piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (H2)

[0316] ##STR00442##

[0317] Tert-butyl 4-(4-(3-(3-acrylamido-4-methylphenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)piperazine-1-carboxylate H1 (41 mg, 0.07 mmol) in 30% TFA in DCM (5 mL) at RT was stirred for 2 h. After evaporation of the solvents, the crude was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound H2 (18 mg, 0.02 mmol, 37%) as a yellow powder. .sup.1H NMR (400 MHz, d.sub.4-MeOH, 300K) δ 2.11 (s, 3H), 3.14 (m, 4H), 3.22 (m, 4H), 5.57 (dd, J=1.3 Hz, J=10.2 Hz, 1H), 6.13 (dd, J=1.3 Hz, J=16.9 Hz, 1H), 6.30 (dd, J=10.2 Hz, J=16.9 Hz, 1H), 6.75 (d, J=8.8 Hz, 2H), 6.90 (m, 2H), 7.03 (d, J=7.8 Hz, 1H), 7.23 (m, 3H), 7.89 (d, J=5.4 Hz, 1H). MS (ES) C.sub.27H.sub.26ClN.sub.5O requires: 471, found: 472 (M+H).sup.+.

Example 97

N-(5-(5-cyano-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-v1)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (I5)

[0318] ##STR00443##

Step 1: 3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (I1)

[0319] ##STR00444##

[0320] I1 (2.6 g, 7.43 mmol, 40%, yellow solid) was prepared from 6-amino-5-bromonicotinonitrile (3.6 g, 18.2 mmol, 1.00 eq.) and trimethyl((4-methyl-3-nitrophenyl)ethynyl)silane (4.5 g, 19.0 mmol, 1.05 eq.) following the general procedure reported in Preparative Example 1 Step 1. MS (ES) C.sub.18H.sub.18N.sub.4O.sub.2Si requires: 350, found: 351 (M+H).sup.+.

Step 2: 3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (12)

[0321] ##STR00445##

[0322] 3-(4-Methyl-3-nitrophenyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 11 (270 mg, 0.8 mmol, 1.0 eq.) and N-iodosuccinimide (208 mg, 0.96 mmol, 1.2 eq.) were solved in dry dichloromethane (40 mL) and stirred for 15 h at RT. The organic phase was washed once with aq. sat. Na.sub.2S.sub.2O.sub.3-solution and three times with aq. sat. NaHCO.sub.3-solution. The organic phase was dried over Na.sub.2SO.sub.4 and solvents were removed in vacuo yielding the desired product 12 (123 mg, 0.30 mmol, 38%) as a brown solid. The crude was used without purification in the next step. MS (ES) C.sub.15H.sub.9IN.sub.4O.sub.2 requires: 403, found: 404 (M+H).sup.+.

Step 3: 3-(4-methyl-3-nitrophenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (I3)

[0323] ##STR00446##

[0324] A mixture of 3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 12 (1.41 g, 3.5 mmol, 1.0 eq.), 4-(4-methylpiperazin-1-yl)phenylboronic acid (1.14 mg, 5.2 mmol, 1.5 eq.), and K.sub.3PO.sub.4 (1.47 g, 7.0 mmol, 2.0 eq) in dioxane/H.sub.2O (40 mL/4 mL) was degassed with a stream of N.sub.2 for 5 min. [1,1′-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (284 mg, 0.35 mmol, 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. NaHCO.sub.3-solution. The organic phase was dried over MgSO.sub.4 and solvents were removed in vacuo. The crude product was purified by flash chromatography on silica gel (DCM/MeOH with 0.1% NEt.sub.3=100:0 to 1:1) to yield the desired product 13 (500 mg, 1.10 mmol, 32%) as a yellow solid. MS (ES) C.sub.26H.sub.24N.sub.6O.sub.2 requires: 452, found: 453 (M+H).sup.+.

Step 4: 3-(3-amino-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (14)

[0325] ##STR00447##

[0326] 14 (93 mg, 0.22 mmol) was prepared from 13 following the general procedure reported in Preparative Example 1 Step 2. MS (ES) C.sub.18H.sub.18N.sub.4O.sub.2Si requires: 350, found: 351 (M+H).sup.+.

Step 5: N-(5-(5-cyano-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (I5)

[0327] ##STR00448##

[0328] To a solution of I4 (30 mg, 0.071 mmol, 1.0 eq.) and DIPEA (92 mg, 0.71 mmol, 10.0 eq.) in dry DCM (2 mL) at 0° C. was added slowly acrylolyl chloride (32 mg, 0.355 mmol, 5.0 eq.) in dry DCM (1 mL). The mixture was stirred for 5 min. The crude solution was directly purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound 16 (3 mg, 0.004 mmol, 5%) as a yellow powder. .sup.1H NMR (400 MHz, d.sub.4-MeOH, 300K) δ 2.31 (s, 3H), 2.95 (s, 3H), 3.30-3.48 (m, 8H), 5.79 (dd, J=1.6 Hz, J=10.2 Hz, 1H), 6.36 (dd, J=1.6 Hz, J=17.0 Hz, 1H), 6.52 (dd, J=10.2 Hz, J=17.0 Hz, 1H), 7.02 (d, J=9.0 Hz, 2H), 7.09 (d, J=8.1 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.50 (m, 3H), 8.23 (d, J=1.9 Hz, 1H), 8.51 (d, J=1.9 Hz, 1H). MS (ES) C.sub.29H.sub.28N.sub.6O requires: 476, found: 477 (M+H).sup.+.

Example 98

1-(6-(4-chloro-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)prop-2-en-1-one 2,2,2-trifluoroacetate (J4)

[0329] ##STR00449##

Step 1: 6-(4-chloro-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (J1)

[0330] ##STR00450##

[0331] Tert-butyl 6-(4-chloro-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate F1 (3489 mg, 7.62 mmol) in 30% TFA in DCM (20 mL) at RT was stirred for 2 h. Evaporation of the solvents yielded a brown solid, which was purified by flash chromatography on silica gel (DCM/MeOH=100:0 to 5:1) to yield the desired product J1 (2726 mg, 7.62 mmol, 100%) as a yellow solid. MS (ES) C.sub.18H.sub.20ClN.sub.3OSi requires: 357, found: 358 (M+H).sup.+.

Step 2: 1-(6-(4-chloro-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)prop-2-en-1-one (J2)

[0332] ##STR00451##

[0333] J2 (635 mg, 1.54 mmol, 55%, white solid) was prepared from J1 following the general procedure reported in Preparative Example 1 Step 3 Procedure A. MS (ES) C.sub.21H.sub.22ClN.sub.3O.sub.2Si requires: 411, found: 412 (M+H).sup.+.

Step 3: 1-(6-(4-chloro-2-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)prop-2-en-1-one (J3)

[0334] ##STR00452##

[0335] J3 (465 mg, 1.00 mmol, 100%, yellow solid) was prepared from J2 following the general procedure reported in Preparative Example 1 Step 4. MS (ES) C.sub.18H.sub.13ClN.sub.3O.sub.2 requires: 465, found: 466 (M+H).sup.+.

Step 4: 1-(6-(4-chloro-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)prop-2-en-1-one 2,2,2-trifluoroacetate (J4)

[0336] ##STR00453##

[0337] J4 (7.4 mg, 0.01 mmol, 9%, yellow solid) was prepared from J3 and 2-(4-methylpiperazino)pyridine-4-boronic acid pinacol ester following the general procedure reported in Preparative Example 1 Step 5. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 2.86 (s, 3H), 3.06 (m, 4H), 3.50 (d, J=10.3 Hz, 2H), 4.27-4.40 (m, 6H), 5.52 (d, J=10.6 Hz, 1H), 6.15 (dd, J=1.9 Hz, J=16.9 Hz, 1H), 6.59 (m, 1H), 6.66 (d, J=5.3 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 7.03 (s, 1H), 7.12 (d, J=7.6 Hz, 1H), 7.20 (d, J=5.1 Hz, 1H), 8.10 (d, J=5.3 Hz, 1H), 8.26 (d, J=5.1 Hz, 1H), 9.73 (s, 1H), 12.66 (s, 1H). MS (ES) C.sub.28H.sub.27ClN.sub.6O.sub.2 requires: 514, found: 515 (M+H).sup.+.

[0338] The Examples in the following table were prepared according to the procedure described for J4 (Example 98).

TABLE-US-00009 Example Name Mwt [M + H].sup.+ 99 [00454] embedded image 527 528 100 [00455] 527 528 101 [00456] 528 529 102 [00457] 472 473 103 [00458] 528 529

Example 104

1-(6-(4-ethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one 2,2,2-trifluoroacetate (K5)

[0339] ##STR00459##

Step 1: tert-butyl 6-(4-ethoxy-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indoline-1-carboxylate (K1)

[0340] ##STR00460##

[0341] K1 (3.74 g, 8.29 mmol, 73%, yellow solid) was prepared from 4-ethoxy-3-iodopyridin-2-amine and tert-butyl 6-((trimethylsilyl)ethynyl)indoline-1-carboxylate following the general procedure reported in Preparative Example 1 Step 1. MS (ES) C.sub.25H.sub.33N.sub.3O.sub.3Si requires: 451, found: 452 (M+H).sup.+.

Step 2: 4-ethoxy-3-(indolin-6-yl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (K2)

[0342] ##STR00461##

[0343] Tert-butyl 6-(4-ethoxy-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indoline-1-carboxylate K1 (1.5 g, 3.3 mmol) in 30% TFA in DCM (60 mL) at RT was stirred for 2 h. Evaporation of the solvents yielded a brown solid. To the crude was added aq. sat. NaHCO.sub.3-solution and the mixture were extracted three times with DCM. The organic phase was dried over MgSO.sub.4 and solvent was removed in vacuo. The desired product K2 which has an impurity of 4-ethoxy-3-(indolin-6-yl)-1H-pyrrolo[2,3-b]pyridine was used without further purification in the next step. MS (ES) C.sub.20H.sub.25N.sub.3OSi requires: 351, found: 352 (M+H).sup.+.

Step 3: 1-(6-(4-ethoxy-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one (K3)

[0344] ##STR00462##

[0345] K3 (371 mg, 0.91 mmol, 32%, white solid) was prepared from K2 following the general procedure reported in Preparative Example 1 Step 3 Procedure A. MS (ES) C.sub.23H.sub.2N.sub.3O.sub.2Si requires: 405 found: 406 (M+H).sup.+.

Step 4: 1-(6-(4-ethoxy-2-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one (K4)

[0346] ##STR00463##

[0347] K4 (380 mg, 0.83 mmol, yellow solid) was prepared from K3 following the general procedure reported in Preparative Example 1 Step 4. MS (ES) C.sub.20H.sub.18IN.sub.3O.sub.2 requires: 459, found: 460 (M+H).sup.+.

Step 5: 1-(6-(4-ethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one 2,2,2-trifluoroacetate (K5)

[0348] ##STR00464##

[0349] K5 (14 mg, 0.019 mmol, 17%, yellow solid) was prepared from K4 and 4-(4-methylpiperazin-1-yl)phenylboronic acid following the general procedure reported in Preparative Example 1 Step 5. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 1.09 (t, J=6.9 Hz, 3H), 2.85 (s, 3H), 2.97 (t, J=12.6 Hz, 2H), 3.12 (m, 2H), 3.21 (t, J=8.5 Hz, 2H), 3.51 (d, J=11.9 Hz, 2H), 3.91 (d, J=13.3 Hz, 2H), 4.11 (quart., J=6.9 Hz, 2H), 4.26 (t, J=8.5 Hz, 2H), 5.80 (d, J=10.3 Hz, 1H), 6.25 (d, J=16.5 Hz, 1H), 6.76 (m, 2H), 6.91 (d, J=7.6 Hz, 1H), 6.96 (d, J=8.5 Hz, 2H), 7.17 (d, J=7.6 Hz, 1H), 7.34 (d, J=8.5 Hz, 2H), 8.19 (d, J=6.0 Hz, 1H), 8.25 (s, 1H), 9.79 (s, 1H), 12.39 (s, 1H). MS (ES) C.sub.31H.sub.33N.sub.5O.sub.2 requires: 507, found: 508 (M+H).sup.+.

[0350] The Examples in the following table were prepared according to the procedure described for K5 (Example 104).

TABLE-US-00010 Example Name Mwt [M + H].sup.+ 105 [00465] embedded image 508 509 106 [00466] 466 467 107 [00467] 522 523 108 [00468] 521 522 109 [00469] 522 523

[0351] The Examples in the following table were prepared according to the procedure described for K5 (Example 104) using 4-methoxy-3-iodopyridin-2-amine as a starting material in the step 1.

TABLE-US-00011 Example Name Mwt [M + H].sup.+ 110 [00470] embedded image 493 494 111 [00471] 494 495 112 [00472] 508 509 113 [00473] 507 508 114 [00474] 508 509

Example 115

1-(6-(4-isopropoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)indolin-1-yl)prop-2-en-1-one 2,2,2-trifluoroacetate (L1)

[0352] ##STR00475##

[0353] L1 (15 mg, 0.2 mmol, yellow solid) was prepared according to the procedure described for K5 (Example 104) using 3-iodo-4-isopropoxypyridin-2-amine as a starting material in the step 1. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 1.13 (d, J=6.0 Hz, 6H), 2.85 (s, 3H), 3.00 (m, 2H), 3.12 (m, 2H), 3.22 (t, J=8.3 Hz, 2H), 3.50 (m, 2H), 3.92 (m, 2H), 4.27 (t, J=8.3 Hz, 2H), 4.85 (quint., J=6.0 Hz, 1H), 5.80 (d, J=10.3 Hz, 1H), 6.25 (d, J=16.6 Hz, 1H), 6.77 (d, J=10.3 Hz, J=16.6 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 6.94 (d, J=6.5 Hz, 1H), 6.98 (d, J=8.5 Hz, 2H), 7.18 (d, J=7.6 Hz, 1H), 7.35 (d, J=8.5 Hz, 2H), 8.27 (m, 2H), 10.02 (s, 1H), 12.81 (s, 1H). MS (ES) C.sub.32H.sub.35N.sub.5O.sub.2 requires: 521, found: 522 (M+H).sup.+.

Example 116

3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 2,2,2-trifluoroacetate (M3)

[0354] ##STR00476##

Step 1: 3-(4-methyl-3-nitrophenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid hydrochloric acid (M1)

[0355] ##STR00477##

[0356] A mixture of 3-(4-methyl-3-nitrophenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 13 (3.0 g, 6.6 mmol) in conc. aq. HCl-solution (50 mL) was heated for 3 h at 100° C. Solvent was removed in vacuo yielding the desired product M1 as a brown solid (3.1 g, 6.6 mmol). MS (ES) C.sub.26H.sub.25N.sub.5O.sub.4 requires: 471, found: 472 (M+H).sup.+.

Step 2: 3-(3-amino-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (M2)

[0357] ##STR00478##

[0358] A mixture of 3-(4-methyl-3-nitrophenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid M1 (3.0 g, 6.6 mmol, 1.0 eq.) and iron (1.8 g, 31.8 mmol, 5 eq.) in EtOH (100 mL) and sat. aq. NH.sub.4Cl-solution (20 mL) was heated for 15 h at 80° C. Solvents were removed in vacuo and the crude was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound M2 (1.7 g, 4.0 mmol, 60%) as a yellow powder. MS (ES) C.sub.26H.sub.27N.sub.5O.sub.2 requires: 441, found: 442 (M+H).sup.+.

Step 3: 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 2,2,2-trifluoroacetate (M3)

[0359] ##STR00479##

[0360] To a solution of 3-(3-amino-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid M2 (580 mg, 1.31 mmol, 1.0 eq.) and DIPEA (2.3 mL, 13.1 mmol, 10 eq.) in dry THF (10 ml) at 0° C. was added slowly acryloyl chloride (0.11 mL, 1.31 mmol, 1.0 eq.) in dry THF (1 mL). After 10 min a drop of water was added and solvents were removed in vacuo. The crude was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound M3 (170 mg, 0.34 mmol, 26%) as a yellow powder. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 2.27 (s, 3H), 2.85 (s, 3H), 3.01 (t, J=12.5 Hz, 2H), 3.13 (m, 2H), 3.51 (d, J=12.0 Hz, 2H), 3.93 (d, J=13.3 Hz, 2H), 5.74 (dd, J=10.1 Hz, J=2.0 Hz, 1H), 6.22 (dd, J=17.1 Hz, J=2.0 Hz, 1H), 6.56 (dd, J=17.1 Hz, J=10.1 Hz, 1H), 7.03 (m, 3H), 7.27 (d, J=7.9 Hz, 1H), 7.47 (d, J=6.4 Hz, 2H), 7.60 (s, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H), 9.55 (s, 1H), 9.72 (br s, 1H), 12.41 (s, 1H), 12.86 (br s, 1H). MS (ES) C.sub.29H.sub.29N5O.sub.3 requires: 495, found: 496 (M+H).sup.+.

Example 117

isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 2,2,2-trifluoroacetate (N3)

[0361] ##STR00480##

Step 1: isoproyl 3-(4-methyl-3-nitrophenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (N1)

[0362] ##STR00481##

[0363] A mixture of 3-(4-methyl-3-nitrophenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 13 (100 mg, 0.2 mmol) and conc. H.sub.2SO.sub.4 (1 mL) in isopropyl alcohol (2 mL) was heated for 48 h at 80° C. After cooling to RT, EtOAc and sat. aq. NaHCO.sub.3-solution was added. The aq. phase was extracted with EtOAc (3×) and the combined organic phase was dried over MgSO.sub.4. Evaporation of solvents yielded the crude product of N1 (28 mg, 0.05 mmol, 27%) as a yellow solid. The crude was used in the next step without further purification. MS (ES) C.sub.29H.sub.31N.sub.5O.sub.4 requires: 513, found: 514 (M+H).sup.+.

Step 2: isopropyl 3-(3-amino-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (N2)

[0364] ##STR00482##

[0365] Isopropyl 3-(4-methyl-3-nitrophenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate N1 (28 mg, 0.05 mmol, 1.0 eq.) and iron (15 mg, 0.3 mmol, 5 eq.) in EtOH (5 mL) and sat. aq. NH.sub.4Cl-solution (1 mL) was heated for 3 h at 80° C. Sat. aq. NaHCO.sub.3-solution was added and the aq. phase was extracted with DCM (3×). The organic phase was dried over MgSO.sub.4 and solvents were removed in vacuo. The crude product was purified by flash chromatography on silica gel (DCM/MeOH with 0.1% NEt.sub.3=100:0 to 1:1) to yield the desired product N2 (25 mg, 0.05 mmol, 94%) as a brown solid. MS (ES) C.sub.29H.sub.33N.sub.5O.sub.2 requires: 483, found: 484 (M+H).sup.+.

Step 3: isoproyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 2,2,2-trifluoroacetate (N3)

[0366] ##STR00483##

[0367] N3 (2 mg, 0.003 mmol, 4%, yellow solid) was prepared from N2 following the general procedure reported in Preparative Example 98 Step 3. The crude product was purified reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound N3 as a yellow solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 1.31 (d, J=6.2 Hz, 6H), 2.26 (s, 3H), 2.85 (s, 3H), 2.98 (t, J=13.0 Hz, 2H), 3.10 (m, 2H), 3.50 (d, J=12.0 Hz, 2H), 3.92 (d, J=13.0 Hz, 2H), 5.14 (quint., J=6.2 Hz, 1H), 5.72 (dd, J=10.2 Hz, J=2.0 Hz, 1H), 6.21 (dd, J=17.1 Hz, J=2.0 Hz, 1H), 6.55 (dd, J=10.2 Hz, J=17.1 Hz, 1H), 6.99 (d, J=8.6 Hz, 2H), 7.25 (d, J=7.9 Hz, 1H), 7.45 (d, J=8.6 Hz, 2H), 7.64 (s, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.79 (d, J=2.0 Hz, 1H), 9.50 (s, 1H), 9.58 (br. s, 1H), 12.43 (s, 1H). MS (ES) C.sub.32H.sub.35N.sub.5O.sub.3 requires: 537 found: 538 (M+H).sup.+.

Example 118

3-(3-acrylamido-4-methylphenyl)-N-benzyl-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 2,2,2-trifluoroacetate (O1)

[0368] ##STR00484##

[0369] A solution of 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid M3 (30 mg, 0.06 mmol, 1.0 eq.), DIPEA (0.1 mL, 0.60 mmol, 10 eq.) and HATU (46 mg, 0.12 mmol, 2.0 eq.) in dry DMF (1 mL) was stirred for 5 min at 0° C. Then benzyl amine (13 mg, 0.12 mmol, 2.0 eq.) was added and the mixture was stirred for 30 min at 0° C. Sat. aq. NaHCO.sub.3-solution was added and the mixture was extracted with EtOAc. The combined organic phase was dried over MgSO.sub.4 and and solvents were removed in vacuo. The crude was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound O1 (10 mg, 0.01 mmol, 21%) as a yellow powder. .sup.1H NMR (400 MHz, d.sub.4-MeOH, 300K) δ 2.30 (s, 3H), 2.97 (s, 3H), 3.07 (t, J=12.4 Hz, 2H), 3.26 (m, 2H), 3.61 (d, J=12.4 Hz, 2H), 3.93 (d, J=13.7 Hz, 2H), 4.59 (s, 2H), 5.77 (dd, J=10.2 Hz, J=1.7 Hz, 1H), 6.32 (dd, J=17.0 Hz, J=1.7 Hz, 1H), 6.50 (dd, J=10.2 Hz, J=17.0 Hz, 1H), 7.01 (d, J=8.9 Hz, 2H), 7.12 (d, J=8.1 Hz, 1H), 7.20-7.37 (m, 6H), 7.50 (d, J=8.9 Hz, 2H), 7.54 (s, 1H), 8.48 (d, J=2.1 Hz, 1H), 8.75 (d, J=2.1 Hz, 1H). MS (ES) C.sub.36H.sub.36N.sub.6O.sub.2 requires: 584 found: 585 (M+H).sup.+.

[0370] The Examples in the following table were prepared according to the procedure described for 01 (Example 118).

TABLE-US-00012 Example Name Mwt [M + H].sup.+ 119 [00485] embedded image 536 537 120 [00486] 576 577 121 [00487] 641 642 122 [00488] 696 670 123 [00489] 599 600 124 [00490] 616 617 125 [00491] 624 625 126 [00492] 663 664 127 [00493] 585 586 128 [00494] 585 586 129 [00495] 605 606 130 [00496] 589 590 131 [00497] 620 621 132 [00498] 641 642 133 [00499] 627 628

Example 134

Methyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 2,2,2-trifluoroacetate (P1)

[0371] ##STR00500##

[0372] A solution of 3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid M3 (40 mg, 0.08 mmol, 1.0 eq.), DMAP (5 mg, 0.04 mmol, 0.5 eq.), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (17 mg, 0.09 mmol, 1.1 eq.) and dry methanol (7 mg, 0.2 mmol, 2.5 eq.) in DCM (2 mL) was stirred for 15 h at RT. The crude solution was directly purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound P1 (20 mg, 0.03 mmol, 34%) as a yellow powder. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 2.26 (s, 3H), 2.84 (s, 3H), 2.98 (t, J=12.0 Hz, 2H), 3.11 (m, 2H), 3.50 (t, J=12.0 Hz, 2H), 3.84 (s, 3H), 3.92 (d, J=13.3 Hz, 2H), 5.72 (dd, J=10.2 Hz, J=2.0 Hz, 1H), 6.21 (dd, J=17.0 Hz, J=2.0 Hz, 1H), 6.54 (dd, J=17.0 Hz, J=10.2 Hz, 1H), 6.99 (d, J=9.0 Hz, 2H), 7.02 (m, 1H), 7.26 (d, J=7.9 Hz, 1H), 7.44 (d, J=9.0 Hz, 2H), 7.58 (s, 1H), 8.26 (d, J=2.1 Hz, 1H), 8.80 (d, J=2.1 Hz, 1H), 9.52 (s, 1H), 9.72 (s, 1H), 12.45 (s, 1H). MS (ES) C.sub.30H.sub.31N.sub.5O.sub.3 requires: 509 found: 510 (M+H).sup.+.

[0373] The Examples in the following table were prepared according to the procedure described for P1 (Example 134).

TABLE-US-00013 Example Name Mwt [M + H].sup.+ 135 [00501] embedded image 523 524 136 [00502] 549 550 137 [00503] 577 578 138 [00504] 535 536 139 [00505] 563 564 140 [00506] 553 554 141 [00507] 551 552

Example 142

(E)-N-(5-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)but-2-enamide 2,2,2-trifluoroacetate (Q2)

[0374] ##STR00508##

Step 1: 5-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylaniline (Q1)

[0375] ##STR00509##

[0376] Q1 was prepared from 4-chloro-3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine A1 following the procedure reported in Preparative Example 97 Step 2-4. MS (ES) C.sub.25H.sub.26ClN.sub.5 requires: 431 found: 432 (M+H).sup.+.

Step 2: (E)-N-(5-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)but-2-enamide 2,2,2-trifluoroacetate (Q2)

[0377] ##STR00510##

[0378] To a solution of Q1 (20 mg, 0.05 mmol, 1.0 eq.) and DIPEA (60 mg, 0.46 mmol, 10.0 eq.) in dry THF (2 mL) at 0° C. was added slowly crotonoyl chloride (5 mg, 0.05 mmol, 1.1 eq.) in dry THF (0.5 mL). The mixture was stirred for 10 min. The solution was diluted with EtOAc and washed twice with aq. sat. NaHCO.sub.3-solution. The organic phase was dried over MgSO.sub.4 and solvent was removed in vacuo. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound Q2 (13 mg, 0.02 mmol, 36%) as a yellow powder. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 1.82 (dd, J=7.0 Hz, J=1.7 Hz, 3H), 2.23 (s, 3H), 2.82 (s, 3H), 2.95 (t, J=12.4 Hz, 2H), 3.07 (m, 2H), 3.43 (m, 2H), 3.90 (d, J=13.3 Hz, 2H), 6.21 (d, J=15.2 Hz, 1H), 6.70 (dq, J=7.0 Hz, J=15.2 Hz, 1H), 6.92 (d, J=9.0 Hz, 2H), 7.00 (dd, J=7.5 Hz, J=1.8 Hz, 1H), 7.06 (d, J=5.2 Hz, 1H), 7.18 (d, J=7.9 Hz, 1H), 7.35 (d, J=9.0 Hz, 2H), 7.52 (s, 1H), 8.12 (d, J=5.2 Hz, 1H), 9.21 (s, 1H), 9.69 (s, 1H), 12.30 (s, 1H). MS (ES) C.sub.29H.sub.30ClN.sub.5O requires: 500, found: 501 (M+H).sup.+.

Example 143

(E)-N-(5-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)-4-(dimethylamino)but-2-enamide 2,2,2-trifluoroacetate (R1)

[0379] ##STR00511##

[0380] To a solution of trans-4-dimethylaminocrotonic acid hydrochlorid (46 mg, 0.28 mmol, 3 eq.) and a drop of dry DMF in dry DCM (1 mL) at 0° C. was added slowly oxalyl chloride (20 uL, 0.23 mmol, 2.5 eq.) in dry DCM (0.2 mL). After 1 h this mixture was added to a solution of Q1 (40 mg, 0.09 mmol, 1.0 eq.) in dry DCM (1 mL) and dry NMP (1 mL). The mixture was stirred for 10 min. The solution was diluted with DCM and washed twice with aq. sat. NaHCO.sub.3-solution. The organic phase was dried over MgSO.sub.4 and solvent was removed in vacuo. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound R1 (26 mg, 0.03 mmol, 33%) as a yellow powder. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 2.28 (s, 3H), 2.80 (s, 6H), 2.84 (s, 3H), 2.97 (t, J=12.6 Hz, 2H), 3.09 (m, 2H), 3.48 (m, 2H), 3.93 (m, 2H), 6.57 (d, J=15.4 Hz, 1H), 6.68 (dt, J=7.0 Hz, J=15.4 Hz, 1H), 6.94 (d, J=9.0 Hz, 2H), 7.05 (d, J=7.7 Hz, 1H), 7.08 (d, J=5.2 Hz, 1H), 7.23 (d, J=7.7 Hz, 1H), 7.36 (d, J=9.0 Hz, 2H), 7.56 (s, 1H), 8.14 (d, J=5.2 Hz, 1H), 9.65 (s, 1H), 9.74 (s, 1H), 12.34 (s, 1H). MS (ES) C.sub.31H.sub.35ClN.sub.6O requires: 543, found: 544 (M+H).sup.+.

Example 144

N-(5-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)propiolamide 2,2,2-trifluoroacetate (S1)

[0381] ##STR00512##

[0382] To a solution of Q1 (70 mg, 0.16 mmol, 1.0 eq.) and DIPEA (0.28 mL, 1.62 mmol, 10.0 eq.) in dry THF (2 mL) at 0° C. was added slowly 3-(trimethylsilyl)propioloyl chloride (29 mg, 0.18 mmol, 1.1 eq.) in dry THF (0.5 mL). The mixture was stirred for 10 min. Then K.sub.2CO.sub.3 (223 mg, 1.62 mmol, 10 eq.) was added and the solution was stirred for 30 min at at 0° C. The mixture was directly purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound S1 (30 mg, 0.04 mmol, 26%) as a yellow powder. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 2.25 (s, 3H), 2.85 (s, 3H), 2.98 (t, J=12.4 Hz, 2H), 3.10 (m, 2H), 3.48 (d, J=12.0 Hz, 2H), 3.92 (d, J=13.3 Hz, 2H), 4.32 (s, 1H), 6.93 (d, J=8.8 Hz, 2H), 7.08 (m, 2H), 7.23 (d, J=7.8 Hz, 1H), 7.31 (s, 1H), 7.35 (d, J=8.8 Hz, 2H), 8.14 (d, J=5.2 Hz, 1H), 9.78 (s, 1H), 10.23 (s, 1H), 12.35 (s, 1H). MS (ES) C.sub.28H.sub.26ClN.sub.5O requires: 483, found: 484 (M+H).sup.+.

Example 145

N-(5-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)ethenesulfonamide 2,2,2-trifluoroacetate (T1)

[0383] ##STR00513##

[0384] To a solution of Q1 (25 mg, 0.06 mmol, 1.0 eq.) and triethylamine (0.10 mL, 0.58 mmol, 10.0 eq.) in dry THF (2 mL) at −10° C. was added slowly 2-chloroethanesulfonyl chloride (10 mg, 0.06 mmol, 1.1 eq.) in dry THF (0.5 mL). After 2 h stirring at −10° C., the mixture was directly purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound T1 (18 mg, 0.02 mmol, 40%) as a yellow powder. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 2.32 (s, 3H), 2.82 (s, 3H), 2.95 (m, 2H), 3.08 (m, 2H), 3.42 (m, 2H), 3.90 (m, 2H), 5.79 (d, J=9.8 Hz, 1H), 5.80 (d, J=16.4 Hz, 1H), 6.64 (dd, J=9.8 Hz, J=16.4 Hz, 1H), 6.91 (d, J=9.0 Hz, 2H), 7.07 (d, J=5.2 Hz, 1H), 7.08 (d, J=1.8 Hz, 1H), 7.13 (d, J=1.8 Hz, 1H), 7.21 (d, J=7.7 Hz, 1H), 7.27 (d, J=9.0 Hz, 2H), 8.12 (d, J=5.2 Hz, 1H), 9.22 (s, 1H), 9.85 (s, 1H), 12.33 (s, 1H). MS (ES) C.sub.27H.sub.28ClN.sub.5O.sub.2S requires: 522, found: 523 (M+H).sup.+.

Example 146

2-chloro-N-(5-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acetamide 2,2,2-trifluoroacetate (U1)

[0385] ##STR00514##

[0386] To a solution of Q1 (30 mg, 0.07 mmol, 1.0 eq.) and DIPEA (0.12 mL, 0.69 mmol, 10.0 eq.) in dry THF (2 mL) at 0° C. was added slowly chloroacetyl chloride (39 mg, 0.35 mmol, 5.0 eq.) in dry THF (0.5 mL). The mixture was stirred for 10 min. Then sat. aq. NaHCO.sub.3-solution was added and the aq. phase was extracted with DCM. The combined organic phase was dried over MgSO.sub.4 and solvents were removed in vacuo. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound U1 (13 mg, 0.02 mmol, 25%) as a yellow powder. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 2.25 (s, 3H), 2.81 (s, 3H), 2.96 (t, J=12.6 Hz, 2H), 3.08 (m, 2H), 3.46 (d, J=12.0 Hz, 2H), 3.90 (d, J=13.2 Hz, 2H), 4.26 (s, 2H), 6.91 (d, J=8.9 Hz, 2H), 7.04 (d, J=7.6 Hz, 1H), 7.07 (d, J=5.2 Hz, 1H), 7.20 (d, J=7.6 Hz, 1H), 7.34 (d, J=8.9 Hz, 2H), 7.43 (s, 1H), 8.12 (d, J=5.2 Hz, 1H), 9.62 (s, 1H), 9.73 (s, 1H), 12.32 (s, 1H). MS (ES) C.sub.27H.sub.27Cl.sub.2N.sub.5O requires: 507, found: 508 (M+H).sup.+.

Example 147

N-(5-(4-ethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (V1)

[0387] ##STR00515##

[0388] V1 was prepared from 3-iodo-4-ethoxypyridin-2-amine, trimethyl((4-methyl-3-nitrophenyl)ethynyl)silane and 4-(1-methyl-4-piperidyl)phenylboronic acid pinacol Ester following the general procedure reported in Preparative Example 72 Step 1-5. MS (ES) C.sub.31H.sub.34N.sub.4O.sub.2 requires: 494, found: 495 (M+H).sup.+.

Example 148

(E)-isoproyl 3-(3-(4-(dimethylamino)but-2-enamido)-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 2,2,2-trifluoroacetate (W1)

[0389] ##STR00516##

[0390] To a solution of trans-4-dimethylaminocrotonic acid hydrochlorid (30 mg, 0.18 mmol, 3.5 eq.) and a drop of dry DMF in dry THF (1 mL) at 0° C. was added slowly oxalyl chloride (14 uL, 0.16 mmol, 3.0 eq.) in dry THF (0.2 mL). After 90 min the mixture was added to a solution of N2 (25 mg, 0.05 mmol, 1.0 eq.) in dry NMP (1 mL). The mixture was stirred for 10 min. The solution was diluted with DCM and washed twice with aq. sat. NaHCO.sub.3-solution. The organic phase was dried over MgSO.sub.4 and solvent was removed in vacuo. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound W1 (13 mg, 0.01 mmol, 28%) as a yellow powder. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 1.34 (d, J=6.3 Hz, 6H), 2.29 (s, 3H), 2.81 (s, 6H), 2.86 (s, 3H), 3.04 (m, 2H), 3.13 (m, 2H), 3.43 (m, 2H), 3.90 (m, 2H), 3.94 (d, J=7.0 Hz, 2H), 5.16 (sept., J=6.3 Hz, 1H), 6.62 (d, J=15.4 Hz, 1H), 6.73 (dt, J=15.4 Hz, J=7.0 Hz, 1H), 7.02 (m, 3H), 7.27 (d, J=7.9 Hz, 1H), 7.47 (d, J=8.9 Hz, 2H), 7.67 (s, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.82 (d, J=2.0 Hz, 1H), 9.75 (s, 1H), 10.02 (s, 1H), 12.47 (s, 1H). MS (ES) C.sub.35H.sub.42N.sub.6O.sub.3 requires: 594, found: 595 (M+H).sup.+.

Example 149

isoproyl 3-(3-acrylamido-4-methylphenyl)-2-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 2,2,2-trifluoroacetate (AA1)

[0391] ##STR00517##

[0392] AA1 was prepared following the procedure reported in Preparative Example 97 and 117. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AA1 as a yellow solid. .sup.1H-NMR (400 MHz, d.sub.6-DMSO, 300K) δ 1.34 (d, J=6.2 Hz, 6H), 1.82 (q, J=13.2 Hz, 2H), 2.05 (d, J=13.2 Hz, 2H), 2.28 (s, 3H), 2.82 (m, 4H), 3.08 (q, J=12.0 Hz, 2H), 5.15 (septet, J=6.2 Hz, 1H), 5.75 (dd, J=2.0 Hz, J=10.2 Hz, 1H), 6.21 (dd, J=2.0 Hz, J=17.0 Hz, 1H), 6.58 (dd, J=10.2 Hz, J=17.0 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 7.27 (m, 3H), 7.54 (d, J=8.1 Hz, 2H), 7.66 (s, 1H), 8.40 (d, J=1.9 Hz, 1H), 8.85 (d, J=1.9 Hz, 1H), 9.41 (br s, 1H), 9.53 (s, 1H), 12.56 (s, 1H). MS (ES) C.sub.33H.sub.36N.sub.4O.sub.3 requires: 536 found: 537 (M+H).sup.+.

[0393] The Example in the following table was prepared according to the procedure described for AA1 (Example 149).

TABLE-US-00014 Example Name Mwt [M + H].sup.+ 151 [00518] embedded image 496 497

Example 150

N-(5-(4-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,3-dimethylphenyl)acrylamide 2,2,2-trifluoroacetate (AB1)

[0394] ##STR00519##

[0395] AB1 was prepared was prepared from 4-chloro-3-iodopyridine-2-amine and ((3,4-dimethyl-5-nitrophenyl)ethynyl)trimethylsilane following the general procedure reported in Preparative Example 1. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AB1 as a yellow solid. .sup.1H-NMR (400 MHz, d.sub.6-DMSO, 300K) δ 2.14 (s, 3H), 2.26 (s, 3H), 2.84 (s, 3H), 2.87 (m, 2H), 3.01 (m, 2H), 3.12 (m, 2H), 3.91 (m, 2H), 5.70 (dd, J=2.0 Hz, J=10.1, 1H), 6.18 (dd, J=2.0 Hz, J=17.2 Hz, 1H), 6.52 (dd, J=10.1 Hz, J=17.2 Hz, 1H), 6.93 (d, J=8.7 Hz, 2H), 7.0 (s, 1H), 7.05 (d, J=5.2 Hz, 1H), 7.26 (s, 1H), 7.41 (d, J=8.7 Hz, 2H), 8.12 (d, J=5.2 Hz, 1H), 9.54 (s, 1H), 9.81 (br s, 1H), 12.28 (s, 1H). MS (ES) C.sub.29H.sub.30ClN.sub.5O requires: 500 found: 501 (M+H).sup.+.

[0396] The Example in the following table was prepared according to the procedure described for AB1 (Example 150).

TABLE-US-00015 Example Name Mwt [M + H].sup.+ 152 [00520] embedded image 499 500

Example 153

3-(3-acrylamido-4-methylphenyl)-2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 2,2,2-trifluoroacetate (AC1)

[0397] ##STR00521##

[0398] AC1 was prepared was prepared following the general procedure reported in Preparative Example 97 and 116. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AC1 as a yellow solid. .sup.1H-NMR (400 MHz, d.sub.6-DMSO, 300K) δ 2.27 (s, 3H), 2.83 (s, 3H), 2.84 (s, 3H), 2.94 (s, 3H), 3.23 (m, 2H), 3.66 (m, 2H), 5.74 (dd, J=2.1 Hz, J=10.2 Hz, 1H), 6.22 (d, J=2.1 Hz, J=17.1 Hz, 1H), 6.55 (dd, J=10.2 Hz, 17.1 Hz, 1H), 6.79 (d, J=9.1 Hz, 2H), 7.04 (d, J=7.9 Hz, 1H), 7.28 (d, J=7.9 Hz, 1H), 7.44 (d, J=9.1 Hz, 2H), 7.58 (s, 1H), 8.23 (d, J=2.0 Hz, 1H), 8.79 (d, J=2.0 Hz, 1H), 9.34 (br s, 1H), 9.56 (s, 1H), 12.34 (s, 1H), 12.81 (br s, 1H). MS (ES) C.sub.29H.sub.31N.sub.5O.sub.3 requires: 497 found: 498 (M+H).sup.+.

Example 154

isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 2,2,2-trifluoroacetate (AD1)

[0399] ##STR00522##

[0400] AD1 (8 mg, 0.01 mmol, 26%) was prepared from AC1 and isopropanol following the general procedure reported in Preparative Example 98 Step 3. The crude product was purified reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AD1 as a yellow solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 1.33 (d, J=6.3 Hz, 6H), 2.28 (s, 3H), 2.80 (s, 6H), 2.95 (s, 3H), 3.19 (m, 2H), 3.68 (t, J=7.4 Hz, 2H), 5.15 (septet, J=6.3 Hz, 1H), 5.75 (dd, J=1.9 Hz, J=10.0 Hz, 1H), 6.23 (dd, J=1.9 Hz, J=17.0 Hz, 1H), 6.57 (dd, J=10.0 Hz, J=17.0 Hz, 1H), 6.79 (d, J=8.8 Hz, 2H), 7.03 (d, J=7.8 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.44 (d, J=8.8 Hz, 2H), 7.63 (s, 1H), 8.29 (d, J=2.0 Hz, 1H), 8.79 (d, J=2.0 Hz, 1H), 9.55 (s, 1H), 9.75 (br s, 1H), 12.39 (s, 1H). (ES) C.sub.32H.sub.37N.sub.5O.sub.3 requires: 539, found: 540 (M+H).sup.+.

Example 155

N-(5-(5-chloro-4-methyl-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenylacrylamide 2,2,2-trifluoroacetate (AE1)

[0401] ##STR00523##

[0402] AE1 was prepared was prepared from 3-bromo-5-chloro-4-methylpyridin-2-amine and trimethyl((4-methyl-3-nitrophenyl)ethynyl)silane following the general procedure reported in Preparative Example 1. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AE1 as a yellow solid. .sup.1H-NMR (400 MHz, d.sub.6-DMSO, 300K) δ 2.07 (s, 3H), 2.28 (s, 3H), 2.82/2.83 (s, 3H), 2.94 (t, J=12.6 Hz, 2H), 3.08 (m, 2H), 3.45 (m, 2H), 3.88 (d, J 13.2 Hz, 2H), 5.71 (dd, J=2.0 Hz, J=10.1 Hz, 1H), 6.20 (dd, J=2.0 Hz, J=17.1 Hz, 1H), 6.52 (dd, J=10.1 Hz, J=17.1 Hz, 1H), 6.90 (d, J=8.8 Hz, 2H), 7.02 (d, J=7.8 Hz, 1H), 7.24 (d, 7.8 Hz, 1H), 7.34 (d, J=8.8 Hz, 2H), 7.56 (s, 1H), 8.14 (s, 1H), 9.46 (s, 1H), 9.54 (br s, 1H), 12.09 (s, 1H). MS (ES) C.sub.29H.sub.30ClN.sub.5O requires: 500 found: 501 (M+H).sup.+.

Example 156

isoproyl 3-(3-acrylamido-4-methylphenyl)-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 2,2,2-trifluoroacetate (AF5)

[0403] ##STR00524##

Step 1: Isoproyl 3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (AF1)

[0404] ##STR00525##

[0405] Isopropyl 6-amino-5-iodonicotinate (11.4 g, 37.2 mmol, 1.0 eq.), trimethyl((4-methyl-3-nitrophenyl)ethynyl)silane (8.7 g, 37.2 mmol, 1.0 eq.), 1,4-diazabicyclo[2.2.2]octane (7.1 g, 63.2 mmol, 1.7 eq.) and dichlorobis(triphenylphosphine)palladium(II) (2.6 g, 3.7 mmol, 0.1 eq.) in dry DMF (120 mL) under N.sub.2 atmosphere was splitted in six microwave vials. Each vial was heated at 145° C. for 5 h. The solvent was removed in vacuo and the crude product was purified by flash chromatography on silica gel (cHex/EtOAc=100:0 to 1:1) to yield the desired product AF1 (7.1 g, 17.3 mmol, 46%) as a beige solid. .sup.1H-NMR (400 MHz, d.sub.6-DMSO, 300K) δ 0.23 (s, 9H), 1.33 (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=1.9 Hz, J=7.8 Hz, 1H), 7.97 (d, J=1.9 Hz, 1H), 8.25 (d, J=1.9 Hz, 1H), 8.88 (d, J=1.9 Hz, 1H), 12.17 (s, 1H). MS (ES) C.sub.21H.sub.25N.sub.3O.sub.4Si requires: 411, found: 412 (M+H).sup.+.

Step 2: Isopropyl 3-(3-amino-4-methylphenyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (AF2)

[0406] ##STR00526##

[0407] A solution of isopropyl 3-(4-methyl-3-nitrophenyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate AF1 (7.1 g, 17.3 mmol, 1.0 eq.) and iron (2 g, 36.4 mmol, 2.1 eq.) in EtOH (360 mL) and aq. sat. NH.sub.4Cl-solution (36 mL) was stirred for 8 h at 80° C. The solution was filtered through a pad of Celite®. Solvents were removed in vacuo. The crude product was purified by flash chromatography on silica gel (cHex/EtOAc=100:0 to 0:100) to yield the desired product AF2 (5.4 g, 14.2 mmol, 82%) as a beige solid. MS (ES) C.sub.21H.sub.27N.sub.3O.sub.2Si requires: 381, found: 382 (M+H).sup.+.

Step 3: Isoproyl 3-(3-acrylamido-4-methylphenyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (AF3)

[0408] ##STR00527##

[0409] To a solution of AF2 (5.4 g, 14.2 mmol, 1.0 eq.) and DIPEA (24.7 mL, 141.7 mmol, 10.0 eq.) in dry THF (200 mL) at −78° C. was added acrylolyl chloride (1.53 g, 17.0 mmol, 1.2 eq.) in dry THF (20 mL). The mixture was stirred for 20 min at −40° C. and then a few drops of water were added. 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 AF3 (6.2 g, 14.2 mmol, quant.) as a yellow solid. MS (ES) C.sub.24H.sub.29N.sub.3O.sub.3Si requires: 435, found: 436 (M+H).sup.+.

Step 4: Isopropyl 3-(3-acrylamido-4-methylphenyl)-2-iodo-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (AF4)

[0410] ##STR00528##

[0411] Isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate AF3 (6.2 g, 14.2 mmol, 1.0 eq.) and N-iodosuccinimide (4.2 g, 18.5 mmol, 1.3 eq.) were solved in dry dichloromethane (700 mL) and stirred for 15 h at RT. The organic phase was washed once with aq. sat. Na.sub.2S2O.sub.3-solution and twice with aq. sat. NaHCO.sub.3-solution. The organic phase was dried over Na.sub.2SO.sub.4 and solvents were removed in vacuo. The crude was stirred in DCM (30 mL) for 1 h at RT, the precipitate was filtered off and dried in vacuo yielding desired product AF4 (3.9 g, 8.0 mmol, 56%) as a beige solid. The crude was used without purification in the next step. .sup.1H-NMR (400 MHz, d.sub.6-DMSO, 300K) δ 1.33 (d, J=6.2 Hz, 6H), 2.31 (s, 3H), 5.16 (septet, J=6.2 Hz, 1H), 5.77 (dd, J=2.2 Hz, J=10.1 Hz, 1H), 6.27 (dd, J=2.2 Hz, 17.0 Hz, 1H), 6.60 (dd, J=10.1 Hz, J=17.0 Hz, 1H), 7.32 (J=1.8 Hz, J=7.8 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.78 (s, 1H), 8.43 (d, J=2.0 Hz, 1H), 8.79 (d, J=2.0 Hz, 1H), 9.57 (s, 1H), 12.84 (s, 1H). MS (ES) C.sub.21H.sub.20IN.sub.3O.sub.3 requires: 489, found: 490 (M+H).sup.+.

Step 5: Isopropyl 3-(3-acrylamido-4-methylphenyl)-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 2,2,2-trifluoroacetate (AF5)

[0412] ##STR00529##

[0413] A mixture of isopropyl 3-(3-acrylamido-4-methylphenyl)-2-iodo-1H-pyrrolo[2,3-b]pyridine-5-carboxylate AF4 (30 mg, 0.06 mmol, 1.0 eq.), 2-(4-methylpiperazino)pyridine-4-boronic acid pinacol ester (24 mg, 0.08 mmol, 1.3 eq.) and K.sub.3PO.sub.4 (26 mg, 0.12 mmol, 2.0 eq.) in dioxane/H.sub.2O (5 mL, 10/1) was degassed with a stream of N.sub.2 for 5 min. [1,1′-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (5 mg, 0.006 mmol, 0.1 eq.) was added and the reaction mixture heated to 130° C. for 2 h under N.sub.2 atmosphere in the microwave oven. The reaction mixture was diluted with EtOAc, washed three times with aq. sat. NaHCO.sub.3-solution. The organic phase was dried over MgSO.sub.4 and solvents were removed in vacuo. The crude was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AF5 (8 mg, 0.01 mmol, 17%) as a yellow powder. .sup.1H-NMR (400 MHz, d.sub.6-DMSO, 300K) δ 1.34 (d, J=6.2 Hz, 6H), 2.31 (s, 3H), 2.85 (s, 3H), 3.07 (m, 2H), 3.13 (m, 2H), 3.50 (d, J=11.7 Hz, 2H), 4.35 (d, J=13.8 Hz, 2H), 5.17 (septet, J=6.2 Hz, 1H), 5.76 (dd, J=2.1 Hz, J=10.2 Hz, 1H), 6.23 (dd, J=2.1 Hz, J=17.1 Hz, 1H), 6.56 (dd, J=10.2 Hz, J=17.1 Hz, 1H), 6.78 (dd, J=1.3 Hz, J=5.3 Hz, 1H), 7.10 (dd, J=1.8 Hz, J=7.8 Hz, 1H), 7.16 (s, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.64 (s, 1H), 8.10 (d, J=5.3 Hz, 1H), 8.38 (d, J=2.0 Hz, 1H), 8.91 (d, J=2.0 Hz, 1H), 9.58 (s, 1H), 9.78 (br s, 1H), 12.75 (s, 1H). MS (ES) C.sub.31H.sub.34N.sub.6O.sub.3 requires: 538, found: 539 (M+H).sup.+.

[0414] The Example in the following table was prepared according to the procedure described for AF5 (Example 156).

TABLE-US-00016 Example Name Mwt [M + H].sup.+ 157 [00530] embedded image 551 552 158 [00531] 552 553 159 [00532] 526 527 160 [00533] 551 552 161 [00534] 510 511 162 [00535] 565 566 163 [00536] 538 539 164 [00537] 555 556 166 [00538] 525 526 167 [00539] 601 602 168 [00540] 483 484 169 [00541] 544 545 170 [00542] 552 553 171 [00543] 525 526 173 [00544] 526 527 175 [00545] embedded image 539 540 176 [00546] 565 566 178 [00547] 499 500 181 [00548] 551 552 183 [00549] 540 541 184 [00550] 615 616 185 [00551] 565 566 186 [00552] 579 580 187 [00553] 496 497

Example 165

isoproyl 3-(3-acrylamido-5-fluoro-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 2,2,2-trifluoroacetate (AG1)

[0415] ##STR00554##

[0416] AG1 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 156. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AG1 as a yellow solid. .sup.1H-NMR (400 MHz, d.sub.6-DMSO, 300K) δ 1.34 (d, J=6.2 Hz, 6H), 2.18 (s, 3H), 2.85/2.87 (s, 3H), 3.02 (t, J=12.4 Hz, 2H), 3.14 (q, J=12.4 Hz, 2H), 3.51 (m, 2H), 3.96 (d, J=13.3 Hz, 2H), 5.17 (septet, J=6.2 Hz, 1H), 5.87 (dd, J=2.0 Hz, J=10.2 Hz, 1H), 6.25 (dd, J=2.0 Hz, J=17.1 Hz, 1H), 6.57 (dd, J=10.2 Hz, J=17.1 Hz, 1H), 6.87 (d, J=10.4 Hz, 1H), 7.05 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 7.54 (s, 1H), 8.38 (d, J=2.0 Hz, 1H), 8.83 (d, J=2.0 Hz, 1H), 9.64 (br s, 1H), 9.72 (s, 1H), 12.53 (s, 1H). MS (ES) C.sub.32H.sub.34FN.sub.5O.sub.3 requires: 555 found: 556 (M+H).sup.+.

[0417] The Example in the following table was prepared according to the procedure described for AG1 (Example 165).

TABLE-US-00017 Example Name Mwt [M + H].sup.+ 172 [00555] embedded image 557 558 174 [00556] 556 557 177 [00557] 514 515 179 [00558] 554 555 180 [00559] 556 557 182 [00560] 544 545

Example 188

N-(2-methyl-5-(2-(4-(4-methylpiperazin-1-yl)phenyl)-5-(trifluoromethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)acrylamide 2,2,2-trifluoroacetate (AH1)

[0418] ##STR00561##

[0419] AH1 was prepared from 3-bromo-5-(trifluoromethoxy)pyridin-2-amine and trimethyl((4-methyl-3-nitrophenyl)ethynyl)silane following the general procedure reported in Preparative Example 1. The crude product was purified by reverse phase RP-HPLC (column: 018), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AH1 as a yellow solid. .sup.1H-NMR (400 MHz, d.sub.6-DMSO, 300K) δ 2.26 (s, 3H), 2.86/2.87 (s, 3H), 3.00 (t, J=12.8 Hz, 2H), 3.13 (m, 2H), 3.52 (d, J=12.0 Hz, 2H), 3.96 (d, J=13.3 Hz, 2H), 5.75 (dd, J=2.0 Hz, J=10.0 Hz, 1H), 6.25 (dd, J=2.0 Hz, J=17.1 Hz, 1H), 6.57 (dd, J=10.0 Hz, J=17.1 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 7.02 (d, J=9.0 Hz, 2H), 7.23 (d, J=7.8 Hz, 1H), 7.46 (d, J=9.0 Hz, 2H), 7.63 (s, 1H), 7.78 (d, J=1.9 Hz, 1H), 8.29 (d, J=1.9 Hz, 1H), 9.51 (s, 1H), 9.66 (br s, 1H), 12.36 (s, 1H). MS (ES) C.sub.29H.sub.28F.sub.3N.sub.5O.sub.2 requires: 535 found: 536 (M+H).sup.+.

Example 189

2-(3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid 2,2,2-trifluoroacetate (AI2)

[0420] ##STR00562##

Step 1: tert-butyl 2-(3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate 2,2,2-trifluoroacetate (AI1)

[0421] ##STR00563##

[0422] AI1 was prepared from tert-butyl 2-(6-amino-5-bromopyridin-3-yl)acetate and trimethyl((4-methyl-3-nitrophenyl)ethynyl)silane following the general procedure reported in Preparative Example 1. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AI1 as a yellow solid. MS (ES) C.sub.34H.sub.39N.sub.5O.sub.3 requires: 565 found: 566 (M+H).sup.+.

Step 2: 2-(3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid 2,2,2-trifluoroacetate (AI2)

[0423] ##STR00564##

[0424] A solution of AI1 (245 mg, 0.31 mmol) and TFA (2.5 mL) in DCM (7.5 mL) was stirred for 3 h at RT. Solvents were removed in vacuo. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AI2 (172 mg, 0.23 mmol, 74%) as a yellow solid. .sup.1H-NMR (400 MHz, d.sub.6-DMSO, 300K) δ 2.26 (s, 3H), 2.86/2.87 (s, 3H), 2.98 (t, J=12.1 Hz, 2H), 3.13 (m, 2H), 3.52 (m, 2H), 3.65 (s, 2H), 3.92 (d, J=13.3 Hz, 2H), 5.73 (dd, J=2.0 Hz, J=10.2 Hz, 1H), 6.22 (dd, J=2.0 Hz, J=17.1 Hz, 1H), 6.55 (dd, J=10.2 Hz, J=17.1 Hz, 1H), 6.99 (m, 3H), 7.24 (d, J=7.9 Hz, 1H), 7.45 (d, J=8.9 Hz, 2H), 7.56 (s, 1H), 7.67 (d, J=2.1 Hz, 1H), 8.11 (d, J=2.1 Hz, 1H), 9.50 (s, 1H), 9.60 (br s, 1H), 11.95 (s, 1H), 12.30 (br s, 1H). MS (ES) C.sub.30H.sub.31N.sub.5O.sub.3 requires: 509 found: 510 (M+H).sup.+.

Example 190

isopropyl 2-(3-(3-acrylamido-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate 2,2,2-trifluoroacetate (AJ1)

[0425] ##STR00565##

[0426] AD1 (2 mg, 0.003 mmol, 26%) was prepared from AI2 and isopropanol following the general procedure reported in Preparative Example 134. The crude product was purified reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AD1 as a yellow solid. .sup.1H NMR (400 MHz, d.sub.4-MeOD, 300K) δ 1.22 (d, J=6.3 Hz, 6H), 2.30 (s, 3H), 2.98 (s, 3H), 3.07 (m, 2H), 3.27 (m, 2H), 3.60 (m, 2H), 3.73 (s, 2H), 3.93 (m, 2H), 4.98 (septet, J=6.3 Hz, 1H), 5.79 (dd, J=1.7 Hz, 10.0 Hz, 1H), 6.35 (dd, J=1.7 Hz, J=17.0 Hz, 1H), 6.51 (dd, J=10.0 Hz, J=17.0 Hz, 1H), 7.01 (d, J=9.0 Hz, 2H), 7.09 (d, J=7.9 Hz, 1H), 7.23 (d, J=7.9 Hz, 1H), 7.50 (m, 3H), 7.91 (d, J=1.9 Hz, 1H), 8.13 (d, J=1.9 Hz, 1H). MS (ES) C.sub.33H.sub.37N.sub.5O.sub.3 requires: 551 found: 552 (M+H).sup.+.

[0427] The Examples in the following table were prepared according to the procedure described for AJ1 (Example 190).

TABLE-US-00018 Example Name Mwt [M + H].sup.+ 196 [00566] embedded image 523 524 198 [00567] 565 566

Example 191

N-(5-(5-ethyl-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (AK1)

[0428] ##STR00568##

[0429] AK1 was prepared from 3-bromo-5-ethylpyridin-2-amine and trimethyl((4-methyl-3-nitrophenyl)ethynyl)silane following the general procedure reported in Preparative Example 1. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AK1 as a yellow solid. .sup.1H-NMR (400 MHz, d.sub.6-DMSO, 300K) δ 1.23 (t, J=7.6 Hz, 3H), 2.27 (s, 3H), 2.69 (q, J=7.6 Hz, 2H), 2.86/2.87 (s, 3H), 3.00 (t, J=12.7 Hz, 2H), 3.14 (m, 2H), 3.51 (m, 2H), 3.93 (d, J=13.5 Hz, 2H), 5.75 (dd, J=2.0 Hz, J=10.0 Hz, 1H), 6.24 (dd, J=2.0 Hz, J=17.0 Hz, 1H), 6.57 (dd, J=10.0 Hz, J=17.0 Hz, 1H), 7.00 (m, 3H), 7.23 (d, J=7.7 Hz, 1H), 7.44 (d, J=7.0 Hz, 2H), 7.61 (s, 1H), 7.68 (d, J=2.0 Hz, 1H), 8.13 (d, J=2.0 Hz, 1H), 9.51 (s, 1H), 9.70 (br s, 1H), 11.90 (s, 1H). MS (ES) C.sub.30H.sub.33N.sub.5O requires: 479 found: 480 (M+H).sup.+.

Example 192

isoproyl 3-(1-acryloylindolin-6-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 2,2,2-trifluoroacetate (AL1)

[0430] ##STR00569##

[0431] AL1 was prepared from isopropyl 6-amino-5-iodonicotinate and tert-butyl 6-((trimethylsilyl)ethynyl)indoline-1-carboxylate following the general procedure reported in Preparative Example 104. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AL1 as a yellow solid. .sup.1H NMR (400 MHz, d.sub.4-MeOD, 300K) δ 1.30 (d, J=6.1 Hz, 6H), 2.84 (s, 3H), 2.98 (t, J=12.6 Hz, 2H), 3.10 (m, 2H), 3.23 (m, 2H), 3.48 (d, J=12.0 Hz, 2H), 3.92 (d, J=13.4 Hz, 2H), 4.27 (m, 2H), 5.13 (septet, J=6.1 Hz, 1H), 5.79 (d, J=10.2 Hz, 1H), 6.24 (d, J=16.6 Hz, 1H), 6.74 (dd, J=10.2 Hz, J=16.6 Hz, 1H), 6.98 (m, 3H), 7.29 (d, J=7.7 Hz, 1H), 7.44 (d, J=8.7 Hz, 2H), 8.21 (s, 1H), 8.25 (s, 1H), 8.80 (d, J=2.0 Hz, 1H), 9.65 (br s, 1H), 12.44 (s, 1H). MS (ES) C.sub.33H.sub.35N.sub.5O.sub.3 requires: 549 found: 550 (M+H).sup.+.

Example 193

N-(5-(5-ethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (AM1)

[0432] ##STR00570##

[0433] AM1 was prepared from 3-bromo-5-ethoxypyridin-2-amine and trimethyl((4-methyl-3-nitrophenyl)ethynyl)silane following the general procedure reported in Preparative Example 1. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AM1 as a yellow solid. .sup.1H NMR (400 MHz, d.sub.4-MeOD, 300K) δ 1.32 (t, J=7.0 Hz, 3H), 2.24 (s, 3H), 2.84 (s, 3H), 2.97 (t, J=12.6 Hz, 2H), 3.12 (m, 2H), 3.50 (d, J=12.0 Hz, 2H), 3.88 (d, J=13.4 Hz, 2H), 4.05 (q, J=7.0 Hz, 2H), 5.72 (dd, J=2.0 Hz, J=10.1 Hz, 1H), 6.22 (dd, J=2.0 Hz, J=17.1 Hz, 1H), 6.55 (dd, J=10.1 Hz, J=17.1 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 6.98 (d, J=9.0 Hz, 2H), 7.18 (d, J=8.0 Hz, 1H), 7.42 (m, 3H), 7.62 (s, 1H), 7.96 (d, J=2.7 Hz, 1H), 9.49 (s, 1H), 9.73 (br s, 1H), 11.79 (s, 1H). MS (ES) C.sub.30H.sub.33N.sub.5O.sub.2 requires: 495 found: 496 (M+H).sup.+.

Example 194

N-(5-(5-(2-(dimethylamino)-2-oxoethyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (AN1)

[0434] ##STR00571##

[0435] AN1 (2 mg, 0.003 mmol, 26%) was prepared from A12 and dimethylamine following the general procedure reported in Preparative Example Example 118. The crude product was purified reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AN1 as a yellow solid. .sup.1H NMR (400 MHz, d.sub.4-MeOD, 300K) δ 2.26 (s, 3H), 2.81 (s, 3H), 2.86 (s, 3H), 2.99 (t, J=12.6 Hz, 2H), 3.04 (s, 3H), 3.13 (m, 2H), 3.51 (m, 2H), 3.76 (s, 2H), 3.92 (d, J=13.3 Hz, 2H), 5.74 (dd, J=2.0 Hz, J=10.1 Hz, 1H), 6.22 (dd, J=2.0 Hz, J=17.0 Hz, 1H), 6.55 (dd, J=10.1 Hz, J=17.0 Hz, 1H), 6.99 (m, 3H), 7.23 (d, J=7.8 Hz, 1H), 7.43 (d, J=8.9 Hz, 2H), 7.57 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 8.08 (d, J=2.0 Hz, 1H), 9.50 (s, 1H), 9.65 (br s, 1H), 11.93 (s, 1H). MS (ES) C.sub.32H.sub.36N.sub.6O.sub.2 requires: 536 found: 537 (M+H).sup.+.

[0436] The Example in the following table was prepared according to the procedure described for AN1 (Example 194).

TABLE-US-00019 Example Name Mwt [M + H].sup.+ 196 [00572] embedded image 522 523

Example 198

isoproyl 3-(3-acrylamido-4-methylphenyl)-4-methyl-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 2,2,2-trifluoroacetate (AO1)

[0437] ##STR00573##

[0438] AO1 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. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AO1 as a yellow solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 1.32 (d, J=6.2 Hz, 6H), 2.27 (s, 3H), 2.30 (s, 3H), 2.84/2.85 (s, 3H), 2.96 (t, J=12.8 Hz, 2H), 3.08 (m, 2H), 3.49 (m, 2H), 3.90 (d, J=13.4 Hz, 2H), 5.12 (septet, J=6.2 Hz, 1H), 5.73 (dd, J=2.0 Hz, J=10.1 Hz, 1H), 6.20 (dd, J=2.0 Hz, J=17.0 Hz, 1H), 6.55 (dd, J=10.1 Hz, J=17.0 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 7.05 (d, J=7.9 Hz, 1H), 7.26 (d, J=7.9 Hz, 1H), 7.36 (d, J=9.0 Hz, 2H), 7.58 (s, 1H), 8.60 (s, 1H), 9.49 (s, 1H), 9.59 (br s, 1H), 12.28 (s, 1H). MS (ES) C.sub.33H.sub.37N.sub.5O.sub.3 requires: 551 found: 552 (M+H).sup.+.

[0439] The Examples in the following table were prepared according to the procedure described for AO1 (Example 198).

TABLE-US-00020 Example Name Mwt [M + H].sup.+ 204 [00574] embedded image 553 554 205 [00575] 540 541

Example 199

N-(5-(5-(hydroxymethyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (AP3)

[0440] ##STR00576##

Step 1: methyl 3-(3-amino-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 2,2,2-trifluoroacetate (AP1)

[0441] ##STR00577##

[0442] To a solution of 3-(3-amino-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid M2 (800 mg, 1.8 mmol, 1.0 eq.) in dry methanol (12 mL) was added thionyl chloride (0.4 mL). The mixture was stirred at 70° C. for 15 h. Solvent were removed and the crude was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AP1 (306 mg, 0.45 mmol, 25%) as a yellow powder. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 2.15 (s, 3H), 2.84 (s, 3H), 2.98 (t, J=12.6 Hz, 2H), 3.11 (m, 2H), 3.49 (d, J=11.8 Hz, 2H), 3.84 (s, 3H), 3.91 (d, J=13.2 Hz, 2H), 6.61 (m, 1H), 6.86 (s, 1H), 6.99 (d, J=9.0 Hz, 2H), 7.06 (d, J=7.6 Hz, 1H), 7.45 (d, J=9.0 Hz, 2H), 8.23 (d, J=2.1 Hz, 1H), 8.80 (d, J=2.1 Hz, 1H), 9.70 (br s, 1H), 12.39 (s, 1H). MS (ES) C.sub.27H.sub.29N.sub.5O.sub.2 requires: 455, found: 456 (M+H).sup.+.

Step 2: (3-(3-amino-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol (AP2)

[0443] ##STR00578##

[0444] To a solution of AP1 (306 mg, 0.45 mmol, 1.0 eq.) in dry THF (24 mL) at 0° C. was added LiAlH.sub.4-solution (1M, 1.34 mL, 1.34 mmol, 3.0 eq.). The mixture was stirred 2 h at 0° C. and 0.5 h at RT. The mixture was cooled to 0° C. and again LiAlH.sub.4-solution (1M, 0.45 mL, 0.45 mmol, 1.0 eq.) was added. After 1 h aq. sat. NaHCO.sub.3-solution was carefully added and then EtOAc was added. The precipitate was filtered off and dried in vacuo yielding the title compound AP2 (25 mg, 0.06 mmol, 13%) as a beige powder. MS (ES) C.sub.26H.sub.29N50 requires: 427, found: 428 (M+H).sup.+.

Step 3: N-(5-(5-(hydroxymethyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (AP3)

[0445] ##STR00579##

[0446] To a solution of AP2 (25 mg, 0.06 mmol, 1.0 eq.), DIPEA (30 uL, 0.18 mmol, 3.0 eq.) and HATU (34 mg, 0.09 mmol, 1.5 eq.) in dry DMF (1.5 mL) at 0° C. was added a solution of acrylic acid (4 mg, 0.06 mmol, 1.0 eq.) in dry DMF (0.5 mL). The mixture was stirred for 1 h at 0° C. The mixture was diluted with EtOAc and then was washed with with aq. sat. NaHCO.sub.3-solution and brine. The organic phase was dried over MgSO.sub.4 and solvents were removed in vacuo. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AP3 (3 mg, 0.004 mmol, 73%) as a yellow solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 2.24 (s, 3H), 2.84 (s, 3H), 2.97 (t, J=12.6 Hz, 2H), 3.13 (m, 2H), 3.48 (m, 2H), 3.90 (d, J=13.4 Hz, 2H), 4.54 (s, 2H), 5.72 (dd, J=2.0 Hz, J=10.1 Hz, 1H), 6.20 (dd, J=2.0 Hz, J=17.1 Hz, 1H), 6.53 (dd, J=10.1 Hz, J=17.1 Hz, 1H), 6.97 (m, 3H), 6.22 (d, J=7.8 Hz, 1H), 7.43 (d, J=8.9 Hz, 2H), 7.56 (s, 1H), 7.73 (d, J=2.0 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 9.50 (s, 1H), 9.65 (br s, 1H), 11.93 (s, 1H). MS (ES) C.sub.29H.sub.31N.sub.5O.sub.2 requires: 481 found: 482 (M+H).sup.+.

Example 200

N-(5-(5-isobutyramido-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (AQ5)

[0447] ##STR00580##

Step 1: tert-butyl (2-methyl-5-(2-(4-(4-methylpiperazin-1-yl)phenyl)-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)carbamate (AQ1)

[0448] ##STR00581##

[0449] AQ1 was prepared from 3-iodo-5-nitropyridin-2-amine and tert-butyl (2-methyl-5-((trimethylsilyl)ethynyl)phenyl)carbamate following the general procedure reported in Preparative Example 1. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AQ1 as an orange solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 1.42 (s, 9H), 2.24 (s, 3H), 2.84 (s, 3H), 3.00 (m, 2H), 3.11 (m, 2H), 3.48 (m, 2H), 3.94 (d, J=13.2 Hz, 2H), 6.95 (dd, J=1.8 Hz, J=7.7 Hz, 1H), 7.01 (d, J=8.9 Hz, 2H), 7.20 (d, J=7.7 Hz, 1H), 7.44 (m, 1H), 7.46 (d, J=8.9 Hz, 2H), 8.47 (d, J=2.4 Hz, 1H), 8.61 (s, 1H), 9.09 (d, J=2.4 Hz, 1H), 9.75 (br s, 1H), 12.83 (s, 1H). MS (ES) C.sub.30H.sub.34N.sub.6O.sub.4 requires: 542 found: 543 (M+H).sup.+.

Step 2: tert-butyl (5-(5-amino-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)carbamate (AQ2)

[0450] ##STR00582##

[0451] A solution of tert-butyl (2-methyl-5-(2-(4-(4-methylpiperazin-1-yl)phenyl)-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)carbamate AQ1 (40 mg, 0.05 mmol, 1.0 eq.) and iron (15 mg, 0.26 mmol, 5.0 eq.) in EtOH (1 mL) and aq. sat. NH.sub.4Cl-solution (0.1 mL) was stirred for 3 h at 80° C. The solution was filtered through a pad of Celite®. Solvents were removed in vacuo. The crude was solved in DCM and was washed twice with aq. sat. NaHCO.sub.3-solution and once with brine. The organic phase was dried over MgSO.sub.4 and solvents were removed in vacuo yielding the desired product AQ2 (23 mg, 0.04 mmol, 85%) as a beige solid. MS (ES) C.sub.30H.sub.36N.sub.6O.sub.2 requires: 512, found: 513 (M+H).sup.+.

Step 3: tert-butyl (5-(5-isobutyramido-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)carbamate (AQ3)

[0452] ##STR00583##

[0453] To a solution of AQ2 (20 mg, 0.04 mmol, 1.0 eq.) and DIPEA (17 uL, 0.10 mmol, 2.50 eq.) in dry DCM (1 mL) at 0° C. was added isobutyryl chloride (4 mg, 0.04 mmol, 1.0 eq.) in dry DCM (0.5 mL). The mixture was stirred for 1 h at 0° C. and 1 h at RT. The mixture was diluted with DCM and then was washed with with aq. sat. NaHCO.sub.3-solution and brine. The organic phase was dried over MgSO.sub.4 and solvents were removed in vacuo. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AQ3 (20 mg, 0.02 mmol, 63%) as a yellow solid. MS (ES) C.sub.34H.sub.42N.sub.6O.sub.3 requires: 582, found: 583 (M+H).sup.+.

Step 4: N-(3-(3-amino-4-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isobutyramide (AQ4)

[0454] ##STR00584##

[0455] A solution of AQ3 (19 mg, 0.02 mmol) and TFA (1 mL) in DCM (4 mL) was stirred for 0.5 h at RT. Solvents were removed in vacuo yielding the title compound AQ4 (23 mg, 0.03 mmol, quant.) as a yellow solid. MS (ES) C.sub.29H.sub.34N.sub.6O requires: 482, found: 483 (M+H).sup.+.

Step 5: N-(5-(5-isobutyramido-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylphenyl)acrylamide 2,2,2-trifluoroacetate (AQ5)

[0456] ##STR00585##

[0457] To a solution of AQ4 (23 mg, 0.03 mmol, 1.0 eq.) and DIPEA (47.4 uL, 0.28 mmol, 10.0 eq.) in dry DCM (2 mL) at −78° C. was added acrylolyl chloride (3 mg, 0.03 mmol, 1.0 eq.) in dry DCM (0.5 mL). The mixture was stirred for 15 min at −78° C. and then 15 min at 0° C. Again acrylolyl chloride (3 mg, 0.03 mmol, 1.0 eq.) in dry DCM (0.5 mL) was added. After 15 min a few drops of water were added and the mixture was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AQ5 (4 mg, 0.005 mmol, 19%) as a yellow solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 1.10 (d, J=6.8 Hz, 6H), 2.27 (s, 3H), 2.58 (septet, J=6.8 Hz, 1H), 2.85/2.86 (s, 3H), 2.98 (t, J=13.0 Hz, 2H), 3.13 (m, 2H), 3.51 (d, J=12.1 Hz, 2H), 3.91 (d, J=13.3 Hz, 2H), 5.73 (dd, J=2.0 Hz, J=10.2 Hz, 1H), 6.20 (dd, J=2.0 Hz, J=17.0 Hz, 1H), 6.55 (dd, J=10.2 Hz, J=17.0 Hz, 1H), 6.98 (d, J=9.0 Hz, 2H), 7.00 (m, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.43 (d, J=9.0 Hz, 2H), 7.53 (s, 1H), 8.06 (d, J=2.3 Hz, 1H), 8.36 (d, J=2.3 Hz, 1H), 9.51 (s, 1H), 9.67 (br s, 1H), 9.82 (s, 1H), 11.87 (s, 1H). MS (ES) C.sub.33H.sub.36N.sub.6O.sub.2 requires: 536 found: 537 (M+H).sup.+.

[0458] The Example in the following table was prepared according to the procedure described for AQ5 (Example 200).

TABLE-US-00021 Example Name Mwt [M + H].sup.+ 201 [00586] embedded image 508 509

Example 202

isoproyl 3-(5-acrylamido-2,4-dimethylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 2,2,2-trifluoroacetate (AR1)

[0459] ##STR00587##

[0460] AR1 was prepared from isopropyl 6-amino-5-iodonicotinate and ((2,4-dimethyl-5-nitrophenyl)ethynyl)trimethylsilane following the general procedure reported in Preparative Example 1. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AR1 as a yellow solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 1.31 (d, J=6.2 Hz, 3H), 1.32 (d, J=6.2 Hz, 3H), 1.86 (s, 3H), 2.29 (s, 3H), 2.86/2.87 (s, 3H), 2.99 (t, J=12.8 Hz, 2H), 3.10 (m, 2H), 3.50 (d, J=12.1 Hz, 2H), 3.95 (d, J=13.6 Hz, 2H), 5.15 (septet, J=6.2 Hz, 1H), 5.73 (dd, J=2.0 Hz, J=10.0 Hz, 1H), 6.20 (dd, J=2.0 Hz, J=17.0 Hz, 1H), 6.54 (dd, J=10.0 Hz, J=17.0 Hz, 1H), 7.00 (d, J=8.6 Hz, 2H), 7.22 (s, 1H), 7.43 (d, J=8.6 Hz, 2H), 7.46 (s, 1H), 7.96 (d, J=2.1 Hz, 1H), 8.81 (d, J=2.1 Hz, 1H), 9.51 (s, 1H), 9.68 (br s, 1H), 12.51 (s, 1H). MS (ES) C.sub.33H.sub.37N.sub.5O.sub.3 requires: 551 found: 552 (M+H).sup.+.

Example 203

isopropyl 3-(3-(acrylamidomethyl)phenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 2,2,2-trifluoroacetate (AS1)

[0461] ##STR00588##

[0462] AS1 was prepared from isopropyl 6-amino-5-iodonicotinate and tert-butyl 3-((trimethylsilyl)ethynyl)benzylcarbamate following the general procedure reported in Preparative Example 83. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AS1 as a yellow solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 1.34 (d, J=6.2 Hz, 6H), 2.87/2.88 (s, 3H), 3.00 (t, J=12.6 Hz, 2H), 3.13 (m, 2H), 3.51 (m, 2H), 3.94 (d, J=13.5 Hz, 2H), 4.39 (d, J=5.8 Hz, 2H), 5.16 (septet, J=6.2 Hz, 1H), 5.61 (dd, J=2.2 Hz, J=10.2 Hz, 1H), 6.11 (dd, J=2.2 Hz, J=17.0 Hz, 1H), 6.26 (dd, J=10.2 Hz, J=17.0 Hz, 1H), 7.00 (d, J=9.2 Hz, 2H), 7.23 (d, J=7.6 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.34 (s, 1H), 7.42 (m, 3H), 8.24 (d, J=2.1 Hz, 1H), 8.64 (t, J=5.8 Hz, 1H), 8.83 (d, J=2.1 Hz, 1H), 9.66 (br s, 1H), 12.51 (s, 1H). MS (ES) C.sub.32H.sub.35N.sub.5O.sub.3 requires: 537 found: 538 (M+H).sup.+.

Example 206

isopropyl 3-(3-acrylamido-4-ethylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 2,2,2-trifluoroacetate (AT1)

[0463] ##STR00589##

[0464] AT1 was prepared from isopropyl 6-amino-5-iodonicotinate and ((4-ethyl-3-nitrophenyl)ethynyl)trimethylsilane following the general procedure reported in Preparative Example 1. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AT1 as a yellow solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 1.18 (t, J=7.5 Hz, 3H), 1.34 (d, J=6.3 Hz, 6H), 2.67 (q, J=7.5 Hz, 2H), 2.87 (s, 3H), 3.01 (t, J=12.6 Hz, 2H), 3.11 (m, 2H), 3.54 (m, 2H), 3.96 (d, J=13.4 Hz, 2H), 5.17 (septet, J=6.3 Hz, 1H), 5.76 (d, J=10.2 Hz, 1H), 6.24 (d, J=17.1 Hz, 1H), 6.58 (dd, J=10.2 Hz, J=17.1 Hz, 1H), 7.02 (d, J=8.5 Hz, 2H), 7.08 (d, J=7.8 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.46 (d, J=8.5 Hz, 2H), 7.61 (s, 1H), 8.38 (d, J=2.0 Hz, 1H), 8.82 (d, J=2.0 Hz, 1H), 9.95 (s, 1H), 9.69 (br s, 1H), 12.49 (s, 1H). MS (ES) C.sub.32H.sub.37N.sub.5O.sub.3 requires: 551 found: 552 (M+H).sup.+.

Example 207

isopropyl 3-(3-acrylamido-2-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 2,2,2-trifluoroacetate (AU1)

[0465] ##STR00590##

[0466] AU1 was prepared from isopropyl 6-amino-5-iodonicotinate and trimethyl((2-methyl-3-nitrophenyl)ethynyl)silane following the general procedure reported in Preparative Example 1. The crude product was purified by reverse phase RP-HPLC (column: C18), using H.sub.2O (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to yield the title compound AU1 as a yellow solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) δ 1.31 (d, J=6.2 Hz, 6H), 1.88 (s, 3H), 2.85 (s, 3H), 2.98 (t, J=12.6 Hz, 2H), 3.10 (m, 2H), 3.50 (m, 2H), 3.93 (d, J=13.4 Hz, 2H), 5.14 (septet, J=6.2 Hz, 1H), 5.75 (dd, J=2.0 Hz, J=10.1 Hz, 1H), 6.26 (dd, J=2.0 Hz, J=17.0 Hz, 1H), 6.55 (dd, J=10.1 Hz, J=17.0 Hz, 1H), 6.98 (d, J=9.0 Hz, 2H), 7.10 (d, J=7.8 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.39 (d, J=9.0 Hz, 2H), 7.61 (d, J=7.8 Hz, 1H), 7.88 (d, J=2.0 Hz, 1H), 8.81 (d, J=2.0 Hz, 1H), 9.58 (s, 1H), 9.68 (br s, 1H), 12.52 (s, 1H). MS (ES) C.sub.32H.sub.35N.sub.5O.sub.3 requires: 537 found: 538 (M+H).sup.+.

[0467] The Examples in the following table were prepared according to the procedure described for AU1 (Example 207).

TABLE-US-00022 Example Name Mwt [M + H].sup.+ 208 [00591] embedded image 539 540 209 [00592] 526 527

Biological Assays

[0468] The exemplified compounds described herein were tested for activity and were found to have an IC.sub.50 value less than 10 uM, particularly less than 500 nM, in one of the following assays:

[0469] 1. Measurement of HER2 INS YVMA Kinase Activity

[0470] This protocol describes how the Lance Kinase Activity Assay was performed to determine IC.sub.50 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.

[0471] 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-US-00023 TABLE 2 Reagents, stock concentrations and final assay concentrations for Her2 INS YVMA. Stock Working Final assay Reagents concentration concentration concentration Supplier ULight ™-Poly GT 10 μM 250 nM 100 nM PerkinElmer substrate Eu-Anti-PT66 3125 nM 4 nM 2 nM PerkinElmer Antibody (AB) Her2 ins YVMA 41.83 μM 2.5 nM 1 nM DPF ATP 100 mM 8 μM 1.6 μM Sigma

[0472] 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 μl.

[0473] For every sample, 8 μl of kinase-substrate mix was transferred into a suitable assay plate (e.g. Corning #3673). Compound was added via pintool transfer (10 nl/well) using a Biomek FX robot (BeckmanCoulter). Reaction was started by addition of 2 μl ATP working solution and mixed using variomag teleshaker (Thermo Fischer Scientific). After 1 h incubation at room temperature the reaction was stopped with 10 μl detection mix containing the Eu-labeled phosphospecific antibody and 10 mM 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 ULight-substrate and Eu-AB, respectively) with an Envision spectrophotometer (Perkin Elmer, Waltham, Mass., USA) with 50 μs delay and 300 μs integration time. IC.sub.50 values were determined from the sigmoidal dose response curves with the software Quattro Workflow (Quattro GmbH, Munich, Germany).

[0474] 2. Measurement of Cellular Activity

[0475] 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 24 h in humidified chambers at 37° C. and 5% CO.sub.2, compounds in DMSO are added at different concentrations. Cells are further incubated for 72 h at 37° C. and 5% CO.sub.2. Cells treated with the compound vehicle DMSO are used as positive controls and cells treated with 10 μM 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 IC.sub.50-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.

[0476] Table 3 shows activity data in the biochemical Her2 Exon 20 INSYVMA Lance assay and cellular Her2 Exon 20 INSYVMA Ba/F3 CellTiter-Glo and EGFR Exon 20 INSNPH Ba/F3 CellTiter-Glo assays. Inhibition is indicated as IC.sub.50 [nM] (“−”=not measured). Compounds having an activity designated as “A” provided an IC.sub.50≤100 nM; compounds having an activity designated as “B” provided an 100 nM<IC.sub.50≤500 nM; compounds having an activity designated as “C” provided an 500 nM<IC.sub.50≤1000 nM; compounds having an activity designated as “D” provided an 1000 nM<IC.sub.50≤10000 nM; and compounds having an activity designated as “E” provided an IC.sub.50>10000 nM.

TABLE-US-00024 TABLE 3 Her2 Her2 EGFR Exon 20 Exon 20 Exon 20 INSYVMA INSYVMA INSNPH Lance Ba/F3 CTG Ba/F3 CTG Example IC.sub.50/[nM] IC.sub.50/[nM] IC.sub.50/[nM] 1 A B A 2 A A A 3 A A A 4 A B B 5 A B B 6 C C C 7 C C D 8 A B B 9 A B B 10 A A A 11 A B B 12 B B B 13 A B B 14 B C C 15 B B B 16 A B B 17 A B B 18 A B A 19 B C C 20 A C C 21 B C C 22 B C D 23 A B B 24 B C C 25 A B B 26 A B B 27 C D D 28 A B B 29 A C C 30 B D C 31 B D D 32 B C C 33 D D D 34 D D D 35 B C C 36 C D D 37 A B B 38 A A A 39 B C D 40 A A A 41 A A A 42 A B B 43 A A A 44 B D D 45 E D D 46 D D D 47 A D D 48 A B B 49 C C D 50 E D D 51 B C C 52 B D D 53 A D D 54 B D D 55 A C C 56 A B B 57 A B C 58 A D D 59 A B B 60 A B B 61 A B B 62 A B B 63 A B B 64 A B B 65 A B C 66 A B C 67 A B B 68 A C D 69 A B B 70 A B C 71 A B C 72 A A A 73 A A A 74 A C B 75 A B A 76 A B B 77 A B B 78 B B C 79 A B B 80 C D D 81 D D D 82 D D D 83 A B B 84 A B B 85 A B B 86 A C C 87 A C C 88 A D D 89 A B B 90 A C D 91 A C C 92 A C D 93 B C D 94 A D D 95 A D D 96 A B B 97 A B A 98 A B B 99 A B B 100 A B C 101 A B B 102 A B B 103 A B B 104 A B B 105 A B B 106 A B B 107 A B B 108 A B B 109 A B B 110 A B B 111 A A A 112 A C C 113 A A A 114 — — — 115 A B B 116 A E E 117 A A A 118 A B B 119 A B B 120 A B B 121 A E E 122 A D D 123 C D D 124 B B C 125 D D D 126 B E E 127 A D D 128 A D D 129 C E E 130 B E E 131 B C D 132 C E E 133 B E E 134 A B B 135 A B B 136 A B B 137 B C C 138 A B B 139 B C C 140 A B B 141 A C C 142 C D D 143 A B B 144 A D D 145 A C C 146 A B B 147 A C C 148 A B C 149 A B B 150 A C B 151 A B B 152 A B B 153 A E E 154 A B B 155 A C B 156 A B B 157 A B B 158 A B B 159 A B B 160 A B B 161 A B B 162 A D C 163 A C C 164 A B B 165 A B B 166 C D D 167 B C C 168 B C C 169 A C B 170 A B B 171 D D D 172 A B B 173 E D D 174 A C B 175 B D D 176 A B B 177 A B B 178 B D C 179 A B B 180 A B B 181 A C C 182 A B B 183 A B B 184 C D D 185 D D D 186 B D D 187 A B B 188 A B B 189 A E E 190 A B B 191 A B B 192 A B C 193 A A B 194 A D D 195 A B B 196 A A D 197 A D B 198 A A A 199 A C B 200 A B B 201 A D D 202 D D D 203 D D D 204 A A A 205 A B A 206 — — — 207 — — — 208 — — — 209 — — —

[0477] Table 4 shows activity data in the biochemical EGFR T790ML858R Lance and EGFR wt Lance assays and the cellular H1975 CellTiter-G, H1781 CellTiter-G and A431 CellTiter-G1 assays. Inhibition is indicated as 1M.sub.50 [nM] (“−”=not measured). Compounds having an activity designated as “A” provided an IC.sub.50≤100 nM; compounds having an activity designated as “B” provided an 100 nM<IC.sub.50≤500 nM; compounds having an activity designated as “C” provided an 500 nM<IC.sub.50≤1000 nM; compounds having an activity designated as “D” provided an 1000 nM<IC.sub.50≤100000 nM; and compounds having an activity designated as “E” provided an IC.sub.50>10000 nM.

TABLE-US-00025 TABLE 4 EGFR T790M EGFR L858R wt H1975 H1781 A431 Lance Lance CTG CTG CTG IC.sub.50 IC.sub.50 IC.sub.50 IC.sub.50 IC.sub.50 Example [nM] [nM] [nM] [nM] [nM] 1 A A A B B 2 A A A B B 3 A A A B B 4 A A A B B 5 A A A E E 6 A A B — — 7 A B B — — 8 A A A B B 9 A A A — — 10 A A A B C 11 A A A C B 12 A A A — — 13 A A A B B 14 A A B — — 15 A A A C B 16 A A A C C 17 A A A B B 18 A A A B B 19 A A B — D 20 A A A — — 21 A A A — — 22 A B B — — 23 A A A B B 24 A B B — — 25 A A A C B 26 A A A C B 27 A B B — — 28 A A A B B 29 A A A — — 30 A A B — — 31 A C B — — 32 A A A — — 33 B C B — — 34 B D C — — 35 A A A — — 36 A A B — D 37 A A A — B 38 A A A — B 39 A A B — D 40 A A A — B 41 A A A — B 42 A A A — B 43 A A A — B 44 A B B — — 45 B D D — — 46 A C D — — 47 A A A — C 48 A A A B B 49 A B B — — 50 B D C — — 51 A A A — — 52 A B B — — 53 A A B — — 54 A A B — D 55 A A A D D 56 A A A C C 57 A A B D D 58 A A B D D 59 A A A B B 60 A A B C C 61 A A A C B 62 A A A — C 63 A A A — C 64 A A A — C 65 A A A — C 66 A A B — D 67 A A B — D 68 A A B — D 69 A A A — C 70 A A B — C 71 A A B — C 72 A A A B B 73 A A A B B 74 A A A — C 75 A A A B B 76 A A A C C 77 A A A B B 78 A A A C B 79 A A A C B 80 A B B — D 81 A B D — D 82 A B C — D 83 A A B D D 84 A A B — C 85 A A B — C 86 A A B D D 87 A A B — D 88 A A B — D 89 A A B — C 90 A A B — D 91 A A B — D 92 A A C — D 93 A A C — D 94 A A B — D 95 A A C — D 96 A A A B B 97 A A A — B 98 A A B — C 99 A A B — D 100 A A B — D 101 A A B — D 102 A A B — D 103 A A B — C 104 A A A — C 105 A A A — B 106 A A A — C 107 A A A — C 108 A A A — C 109 A A A — C 110 A A A — C 111 A A A — B 112 A A B — D 113 A A A — B 114 — — — — — 115 A A A — C 116 A A E — E 117 A A A — B 118 A A C — C 119 A A C — C 120 A A B — B 121 B A E — E 122 A A D — D 123 A A E — D 124 A A C — C 125 B A B — D 126 A A E — E 127 A A D — D 128 A A D — D 129 B B E — E 130 B A E — E 131 C A D — D 132 B A E — E 133 B A E — E 134 A A B — D 135 A A A — D 136 A A B — D 137 A A B — D 138 A A A — D 139 A A B — D 140 A A B — D 141 A A B — D 142 A A B — D 143 A A B — D 144 A A D — D 145 A A B — D 146 A A A — B 147 A A A — — 148 A A C — D 149 A A B — D 150 A A A — C 151 A A B — D 152 A A A — C 153 A A E — E 154 A A B — D 155 A A A — D 156 A A C — D 157 A A B — D 158 A A B — D 159 A A B — D 160 A A B — D 161 A A B — D 162 A A D — D 163 A A C — D 164 A A B — D 165 A A B — D 166 B A D — D 167 A A C — D 168 B A D — D 169 A A D — D 170 A A B — D 171 C A D — D 172 A A B — D 173 D C D — D 174 A A C — D 175 B A D — D 176 A A B — D 177 A A B — D 178 B A D — D 179 A A B — D 180 A A C — D 181 A A C — D 182 A A B — D 183 A A B — D 184 B A D — E 185 C A D — E 186 B A D — D 187 A A B — D 188 A A B — D 189 A A E — E 190 A A B — D 191 A A A — D 192 A A D — D 193 A A B — D 194 A A D — D 195 A A B — D 196 A A D — D 197 A A C — D 198 A A B — C 199 A A B — D 200 A A D — D 201 A A D — D 202 B A D — E 203 C B D — D 204 A A B — D 205 A A B — D 206 — — — — — 207 — — — — — 208 — — — — — 209 — — — — —

[0478] 3. Metabolic Stability

[0479] There are two major groups of enzyme reactions catalyzed by drug metabolizing enzymes, the so called Phase I and Phase II reactions. The basic processes in phase I reactions are oxidation, reduction and/or hydrolysis mostly catalyzed by the cytochrome P450 (CYP) family of enzymes. Exploring the metabolic stability of reference 1 we have observed as a major metabolite the hydrolysis of the acrylamide moiety in the presence of mouse liver microsomes with and without the cofactor NADPH. FIG. 2 shows the hydrolysis of the acrylamide moiety of reference 1 in the presence of mouse liver microsomes after 50 minutes.

[0480] The following procedures describe the determination of the in vitro Phase I metabolic stability of test compounds using liver microsomes by measuring compound depletion over time. Test compound at the concentration of 3 μM was incubated with the liver microsomes from the mouse species and the experiment was performed without NADPH. The depletion of the test compounds was measured over time up to 50 minutes at 37° C. by LC-MS/MS. Different compounds were tested under these conditions for microsomal stability (see Table 5). Prevention of hydrolysis of the acrylamide moiety was achieved either by the introduction of substituents like a methyl group (as in Example 1) next to the acrylamide moiety or by modifying the secondary acrylamide of reference 1 to a tertiary acrylamide (like Example 55).

TABLE-US-00026 TABLE 5 Stability without cofactor NADPH in mouse liver microsomes Stability in presence of mouse liver microsomes without cofactor NADPH Example Structure [% remaining after 50 min] Reference 1 [00593] embedded image 33 Reference 2 [00594] 48 1 [00595] >99 2 [00596] >99 3 [00597] >99 4 [00598] >99 5 [00599] >99 6 [00600] >99 7 [00601] >99 8 [00602] >99 9 [00603] >99 10 [00604] >99 11 [00605] >99 12 [00606] >99 13 [00607] 95 14 [00608] 68 15 [00609] >99 16 [00610] >99 17 [00611] 90 18 [00612] 90 19 [00613] embedded image >99 20 [00614] >99 21 [00615] 93 22 [00616] >99 23 [00617] >99 24 [00618] >99 25 [00619] >99 26 [00620] >99 27 [00621] >99 28 [00622] >99 29 [00623] >99 30 [00624] >99 31 [00625] >99 32 [00626] >99 36 [00627] >99 37 [00628] >99 38 [00629] >99 39 [00630] >99 40 [00631] >99 41 [00632] >99 42 [00633] embedded image >99 43 [00634] >99 55 [00635] >99 56 [00636] >99 57 [00637] >99 58 [00638] >99 59 [00639] >99 60 [00640] >99 61 [00641] >99 62 [00642] >99 63 [00643] >99 64 [00644] >99 65 [00645] >99 66 [00646] >99 67 [00647] >99 68 [00648] >99 69 [00649] 98 70 [00650] >99 71 [00651] >99 72 [00652] >99 73 [00653] embedded image 99 74 [00654] 90 75 [00655] >99 76 [00656] >99 77 [00657] >99 78 [00658] >99 79 [00659] >99 80 [00660] >99 81 [00661] 80 82 [00662] 97 83 [00663] >99 84 [00664] 94 85 [00665] >99 86 [00666] >99 88 [00667] >99 91 [00668] >99 92 [00669] >99 93 [00670] >99 95 [00671] >99 96 [00672] 92 97 [00673] embedded image >99 98 [00674] >99 99 [00675] >99 100 [00676] >99 104 [00677] 89 108 [00678] 86 109 [00679] 77 110 [00680] 93 111 [00681] 90 112 [00682] 79 113 [00683] 96 115 [00684] >99 116 [00685] 92 117 [00686] 100 119 [00687] >99 120 [00688] >99 134 [00689] >99 135 [00690] 95 138 [00691] >99 146 [00692] embedded image 9 147 [00693] 94 154 [00694] >99 155 [00695] >99 157 [00696] >99 158 [00697] >99 159 [00698] >99 160 [00699] >99 161 [00700] >99 164 [00701] >99 165 [00702] >99 170 [00703] >99 172 [00704] >99 176 [00705] >99 177 [00706] >99 179 [00707] >99 182 [00708] >99 187 [00709] >99

[0481] 4. SAR

[0482] The structure activity relationship (SAR) of the compounds of the present invention as represented by the Formula (Ia and Ib) shows covalent inhibitor as cellular potent mutant-selective ErbB inhibitors. The covalent binding mode, obtained for example through the introduction of an acrylic moiety, is crucial for improved biochemical and cellular activity. The direct comparison of examples from this invention having a acryl moiety for the covalent binding with corresponding molecules having a propionic moiety are showing the improved cellular activities for the covalent binder.

##STR00710##

[0483] Table 6 shows comparison of covalent inhibitors with the corresponding reversible analogues. In all cases the covalent inhibitor shows improved cellular activities compared to the reversible analogues.

TABLE-US-00027 TABLE 6 Comparison covalent inhibitors with corresponding reversible one. Her2 Exon 20 EGFR Her2 INSYVM Exon 20 Exon 20 A INSNPH INSYVMA Ba/F3 Ba/F3 Lance CTG CTG Binding IC.sub.50 IC.sub.50 IC.sub.50 Mode Structure [nM] [nM] [nM] Covalent [00711] embedded image 5 64 35 Reversibel [00712] 916 754 1311 Covalent [00713] 13 208 200 Reversibel [00714] 4023 2391 2344

TABLE-US-00028 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

4-SUBSTITUTED PYRROLO[2,3-B]PYRIDINE AS ERBB MODULATORS USEFUL FOR TREATING CANCER

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Cpc classification

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C07F7/0814

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A61K31/4545

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A61K31/4709

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A61K31/5377

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A61K45/06

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A61K31/496

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A61K31/506

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Classification Explorer

A61K31/437

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A61K31/538

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A61P35/00

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C07D471/04

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International classification

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A61K31/496

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A61K31/437

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Classification Explorer

A61K31/4545

HUMAN NECESSITIES

Classification Explorer

A61K31/4709

HUMAN NECESSITIES

Classification Explorer

A61K31/506

HUMAN NECESSITIES

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A61K31/5377

HUMAN NECESSITIES

Classification Explorer

A61K31/538

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A61K45/06

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C07D471/04

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Abstract

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Description