HEKKING KOEN F W (NL)
CALPE BLAISE (CH)
MÜLLER GERHARD (DE)
FABRITIUS CHARLES-HENRY (CH)
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CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 1049738-54-6
| CLAIMS 1. A compound of formula (I), optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof wherein X1 is selected from –N=, –CH= and –CF=; X2 is selected from –N=, –CH=, and –C(R1)=; each R2 is independently selected from hydrogen and R1; Y1 is selected from –S– and –O–; Y2 is selected from –N=, –CH=, –C(CH3)=, –CCl= and –CF=; Y3 is selected from –N=, –CH=, and –C(R1)=; A is selected from a monocyclic, bicyclic and tricyclic heterocyclyl, preferably from a monocyclic and bicyclic heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more R11 and furthermore optionally with one substituent selected from optionally substituted heterocyclyl, optionally substituted carbocyclyl, –C(O)‒heterocyclyl wherein said heterocyclyl is optionally substituted, –C(O)‒carbocyclyl wherein said carbocyclyl is optionally substituted, –C1‒ 6alkylene‒heterocyclyl wherein said –C1‒6alkylene and said heterocyclyl of –C1‒ 6alkylene‒heterocyclyl are independently optionally substituted, and –C1‒ 6alkylene‒carbocyclyl wherein said –C1‒6 alkylene and said carbocyclyl of –C1‒ 6alkylene‒carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyl, optionally substituted carbocyclyl, and optionally substituted C1‒6alkylene is independently selected from R11, wherein R11 is selected from –C1‒6alkyl, –C1‒6haloalkyl, –C1‒6alkoxy, ‒halogen, ‒CN, ‒NO2, oxo, ‒C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒C(O)NR*(C1‒ 4alkylene)S(O)2R*, ‒C(O)NR*(C1‒4alkylene)OR*, ‒C(O)NR*(C1‒4alkylene)NR*R*, ‒NR*R*, ‒N(R*)‒C(O)R*, ‒N(R*)‒C(O)‒OR*, ‒N(R*)‒C(O)‒NR*R*, ‒N(R*)‒ S(O)2R*, ‒OR*, ‒O‒C(O)R*, ‒O‒C(O)‒NR*R*, ‒SR*, ‒S(O)R*, ‒S(O)2R*, ‒S(O)2‒ NR*R*, ‒N(R*)‒S(O)2‒NR*R*, heterocyclyl which is optionally substituted with halogen or C1-6alkyl, and carbocyclyl which is optionally substituted with halogen or C1-6 alkyl; wherein each R* is independently selected from H, C1‒6 alkyl which is optionally substituted with halogen, heterocyclyl which is optionally substituted with halogen or C1-6 alkyl, and carbocyclyl which is optionally substituted with halogen or C1-6 alkyl; wherein any two R* connected to the same nitrogen atom can be optionally linked to form a heterocyclyl optionally substituted with one or more R11; R1 is selected from –(C1‒6alkyl which is optionally substituted with one or more halogen), C1‒6alkylene-OR*, C1‒6alkylene-NR*R*, ‒halogen, ‒CN, ‒NO2, oxo, ‒ C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒NR*R*, ‒N(R*)‒C(O)R*, ‒N(R*)‒C(O)‒OR*, ‒ N(R*)‒C(O)‒NR*R*, ‒N(R*)‒S(O)2R*, ‒OR*, ‒O‒C(O)R*, ‒O‒C(O)‒NR*R*, ‒ SR*, ‒S(O)R*, ‒S(O)2R*, and ‒S(O)2‒NR*R*, ‒N(R*)‒S(O)2‒NR*R*, heterocyclyl which is optionally substituted with halogen or C1-6alkyl, carbocyclyl which is optionally substituted with halogen or C1-6alkyl; wherein each R* is independently selected from H and C1‒6 alkyl which is optionally substituted with halogen; wherein any two R* connected to the same nitrogen atom can be optionally linked. 2. The compound according to claim 1, wherein said heterocyclyl has a carbonyl group or a heteroatom, preferably a nitrogen atom, at the ortho position to the position at which A is connected to the remaining structure of the compound of formula (I). 3. The compound according to claim 1 or 2, wherein said compound of formula (I) is a compound of formula (II) wherein X1 is selected from –N= and –CH=; X2 is selected from –N=, –CH=, and –C(R1)=; Y1 is selected from –S– and –O–; Y2 is selected from –N= and –CH; A is selected from a monocyclic, bicyclic and tricyclic heterocyclyl, preferably from a monocyclic and bicyclic heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more R11 and furthermore optionally with one substituent selected from optionally substituted heterocyclyl, optionally substituted carbocyclyl, –C(O)‒heterocyclyl wherein said heterocyclyl is optionally substituted, –C(O)‒carbocyclyl wherein said carbocyclyl is optionally substituted, –C1‒ 6alkylene‒heterocyclyl wherein said –C1‒6alkylene and said heterocyclyl of –C1‒ 6alkylene‒heterocyclyl are independently optionally substituted, and –C1‒ 6alkylene‒carbocyclyl wherein said –C1‒6 alkylene and said carbocyclyl of –C1‒ 6alkylene‒carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyl, optionally substituted carbocyclyl, and optionally substituted C1‒6alkylene is independently selected from R11, wherein R11 is selected from –C1‒6alkyl, –C1‒6haloalkyl, –C1‒6alkoxy, ‒halogen, ‒CN, ‒NO2, oxo, ‒C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒C(O)NR*(C1‒ 4alkylene)S(O)2R*, ‒C(O)NR*(C1‒4alkylene)OR*, ‒C(O)NR*(C1‒4alkylene)NR*R*, ‒NR*R*, ‒N(R*)‒C(O)R*, ‒N(R*)‒C(O)‒OR*, ‒N(R*)‒C(O)‒NR*R*, ‒N(R*)‒ S(O)2R*, ‒OR*, ‒O‒C(O)R*, ‒O‒C(O)‒NR*R*, ‒SR*, ‒S(O)R*, ‒S(O)2R*, ‒S(O)2‒ NR*R*, ‒N(R*)‒S(O)2‒NR*R*, heterocyclyl which is optionally substituted with halogen or C1-6alkyl, and carbocyclyl which is optionally substituted with halogen or C1-6 alkyl; wherein each R* is independently selected from H, C1‒6 alkyl which is optionally substituted with halogen, heterocyclyl which is optionally substituted with halogen or C1-6 alkyl, and carbocyclyl which is optionally substituted with halogen or C1-6 alkyl; wherein any two R* connected to the same nitrogen atom can be optionally linked to form a heterocyclyl optionally substituted with one or more R11; R1 is selected from –(C1‒6alkyl which is optionally substituted with one or more halogen), C1‒6alkylene-OR*, C1‒6alkylene-NR*R*, ‒halogen, ‒CN, ‒NO2, oxo, ‒ C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒NR*R*, ‒N(R*)‒C(O)R*, ‒N(R*)‒C(O)‒OR*, ‒ N(R*)‒C(O)‒NR*R*, ‒N(R*)‒S(O)2R*, ‒OR*, ‒O‒C(O)R*, ‒O‒C(O)‒NR*R*, ‒ SR*, ‒S(O)R*, ‒S(O)2R*, and ‒S(O)2‒NR*R*, ‒N(R*)‒S(O)2‒NR*R*, heterocyclyl which is optionally substituted with halogen or C1-6alkyl, carbocyclyl which is optionally substituted with halogen or C1-6alkyl; wherein each R* is independently selected from H and C1‒6 alkyl which is optionally substituted with halogen; wherein any two R* connected to the same nitrogen atom can be optionally linked; R21 is selected from hydrogen, halogen, C1‒2alkyl, C1‒2haloalkyl, –C1‒2alkoxy, –CN, – NO2, ‒C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒NR*R*, ‒N(R*)C(O)R*, ‒N(R*)C(O)OR*, ‒N(R*)C(O)NR*R*, ‒OR*, ‒OC(O)R* and ‒OC(O)NR*R*; wherein each R* is independently selected from H, C1‒2alkyl and C1‒2haloalkyl; R22 is selected from –(C1‒6alkyl which is optionally substituted with one or more halogen), C1‒6alkylene-OR*, C1‒6alkylene-NR*R*, ‒halogen, ‒CN, ‒NO2, oxo, ‒ C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒NR*R*, ‒N(R*)‒C(O)R*, ‒N(R*)‒C(O)‒OR*, ‒ N(R*)‒C(O)‒NR*R*, ‒N(R*)‒S(O)2R*, ‒OR*, ‒O‒C(O)R*, ‒O‒C(O)‒NR*R*, ‒ SR*, ‒S(O)R*, ‒S(O)2R*, and ‒S(O)2‒NR*R*, ‒N(R*)‒S(O)2‒NR*R*, heterocyclyl which is optionally substituted with halogen or C1-6alkyl, carbocyclyl which is optionally substituted with halogen or C1-6alkyl; wherein each R* is independently selected from H and C1‒6 alkyl which is optionally substituted with halogen; wherein any two R* connected to the same nitrogen atom can be optionally linked. 4. The compound according to claim 3, wherein R21 is hydrogen or methyl, preferably R21 is hydrogen, and/or wherein Y1 is –S–, and/or wherein Y2 is –CH=. 5. The compound according to any one of the preceding claims, wherein A is selected from a monocyclic or bicyclic heterocyclyl of any of the formula wherein Z1 is selected from –CH2–, –CH(RZ1)–, –NH–, –N(RZ1)– and –O–; Z2 is selected from –CH–, –C(RZ2)–, –N–; Z3 is selected from –CH–, –C(RZ3)–, –N–; Z4 is selected from –CH–, –C(RZ4)–, –N–; Z5 is selected from –CH2–, –CH(RZ5)–, –NH–, –N(RZ5)– and –O–; Z6 is selected from –CH–, –C(RZ6)–, –N–; Z7 is selected from –CH–, –C(RZ7)–, –N–; Z8 is selected from –CH–, –C(RZ8)–, –N–; Z9 is selected from –CH2–, –CH(RZ9)–, –NH–, –N(RZ9)– and –O–; and wherein RZ1, RZ2, RZ4, RZ5, RZ7 and RZ8 are independently selected from –C1‒6alkyl, –C1‒ 6haloalkyl, –C1‒6alkoxy, ‒halogen, ‒CN, ‒NO2, oxo, ‒C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒ NR*R*, ‒N(R*)C(O)R*, ‒N(R*)C(O)OR*, ‒N(R*)C(O)NR*R*, ‒N(R*)S(O)2R*, ‒OR*, ‒ OC(O)R*, ‒OC(O)NR*R*, ‒SR*, ‒S(O)R*, ‒S(O)2R*, ‒S(O)2NR*R*, ‒N(R*)S(O)2NR*R*, optionally substituted heterocyclyl, optionally substituted carbocyclyl, ‒C1‒6alkylene‒ heterocyclyl wherein said ‒C1‒6alkylene and said heterocyclyl are independently optionally substituted, and ‒C1‒6alkylene‒carbocyclyl wherein said ‒C1‒6 alkylene and said carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyl, optionally substituted carbocyclyl, and optionally substituted C1‒6alkylene is independently selected from –C1‒6alkyl, –C1‒ 6haloalkyl, –C1‒6alkoxy, ‒halogen, ‒CN, ‒NO2, oxo, ‒C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒ NR*R*, ‒N(R*)C(O)R*, ‒N(R*)C(O)OR*, ‒N(R*)C(O)NR*R*, ‒N(R*)S(O)2R*, ‒OR*, ‒ OC(O)R*, ‒OC(O)NR*R*, ‒SR*, ‒S(O)R*, ‒S(O)2R*, ‒S(O)2NR*R*, ‒N(R*)S(O)2NR*R*, wherein each R* is independently selected from H, C1‒6alkyl, –C1‒6haloalkyl, heterocyclyl which is optionally substituted with halogen or C1-6 alkyl, and carbocyclyl which is optionally substituted with halogen or C1-6 alkyl; wherein any two R* connected to the same nitrogen atom can be optionally linked; and wherein RZ1 and RZ2, as well as RZ4 and RZ5 as well as RZ7 and RZ8, can be optionally linked forming a 4-7 membered monocyclic heterocyclyl, wherein said formed 4-7 membered monocyclic heterocyclyl is optionally substituted by one or two –C1‒2alkyl, –C1‒2haloalkyl, ‒halogen; and RZ3, RZ6 and RZ9 are independently selected from –C1‒3alkyl, –C1‒3haloalkyl, –C1‒ 3alkoxy, ‒F, ‒Cl, ‒Br, ‒NO2, ‒NH2, ‒CN, phenyl and C3‒6cycloalkyl, wherein preferably RZ3, RZ6 and RZ9 are independently selected selected from –C1‒2alkyl, –C1‒2haloalkyl, – C1‒2alkoxy, ‒F, ‒Cl and C3‒4cycloalkyl, wherein further preferably RZ3, RZ6 and RZ9 is – CH3; Y5 is selected from –CH2–, –CH(RY5)–, –NH–, –N(RY5)– and –O; Y6 is selected from –CH–, –C(RY6)–, –N–; wherein RY5 and RY6 are independently selected from –C1‒3alkyl, –C1‒3haloalkyl, –C1‒ 3alkoxy, ‒F, ‒Cl, ‒Br, ‒NO2, ‒NH2, ‒CN, phenyl and C3‒6cycloalkyl, wherein preferably RY5 and RY6 are independently selected from –C1‒2alkyl, –C1‒2haloalkyl, –C1‒2alkoxy, ‒F, ‒Cl and C3‒4cycloalkyl, and wherein further preferably RY5 and RY6 are–CH3; R3 is selected from hydrogen, –C1‒6alkyl, –C1‒6haloalkyl, –C1‒6alkoxy, ‒halogen, ‒CN, ‒NO2, oxo, ‒C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒NR*R*, ‒N(R*)C(O)R*, ‒ N(R*)C(O)OR*, ‒N(R*)C(O)NR*R*, ‒N(R*)S(O)2R*, ‒OR*, ‒OC(O)R*, ‒OC(O)NR*R*, ‒ SR*, ‒S(O)R*, ‒S(O)2R*, ‒S(O)2NR*R*, ‒N(R*)S(O)2NR*R*, optionally substituted heterocyclyl, optionally substituted carbocyclyl, –C(O)‒heterocyclyl wherein said heterocyclyl is optionally substituted, –C(O)‒carbocyclyl wherein said carbocyclyl is optionally substituted, ‒C1‒6alkylene‒heterocyclyl wherein said ‒C1‒6alkylene and said heterocyclyl are independently optionally substituted, and ‒C1‒6alkylene‒carbocyclyl wherein said ‒C1‒6 alkylene and said carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyl, optionally substituted carbocyclyl, and optionally substituted C1‒6alkylene is independently selected from –C1‒6alkyl, –C1‒6haloalkyl, –C1‒6alkoxy, ‒halogen, ‒CN, ‒ NO2, oxo, ‒C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒C(O)NR*(C1‒4alkylene)S(O)2R*, ‒ C(O)NR*(C1‒4alkylene)OR*, ‒C(O)NR*(C1‒4alkylene)NR*R*, ‒NR*R*, ‒N(R*)C(O)R*, ‒ N(R*)C(O)OR*, ‒N(R*)C(O)NR*R*, ‒N(R*)S(O)2R*, ‒OR*, ‒OC(O)R*, ‒OC(O)NR*R*, ‒ SR*, ‒S(O)R*, ‒S(O)2R*, ‒S(O)2NR*R*, ‒N(R*)S(O)2NR*R*, wherein each R* is independently selected from H, C1‒6alkyl, –C1‒6haloalkyl, heterocyclyl which is optionally substituted with halogen or C1-6 alkyl, and carbocyclyl which is optionally substituted with halogen or C1-6 alkyl; wherein any two R* connected to the same nitrogen atom can be optionally linked to form a heterocyclyl optionally substituted with 1 to 4, preferably one or two, substituents independently selected from C1-4alkyl, C1-2haloalkyl, C1-4alkoxy, OH, halogen, ‒CN, ‒NO2, oxo, ‒NH2, NH(C1‒2alkyl), ‒N(C1‒2alkyl)2, ‒C1‒2alkylene‒NH2, ‒C1‒ 2alkylene‒NH(C1‒2alkyl), ‒C1‒2alkylene‒N(C1‒2alkyl)2, ‒C1‒2alkylene‒OH, ‒COOH, ‒ COO(C1‒2alkyl), ‒C(O)C1‒2alkyl, C3‒6cycloalkyl, monomeric heterocyclyl, bivalent bridging or fusing C1-3alkyl or C1-3alkoxy optionally substituted with one or two –F, bivalent spiro-forming C3-5alkyl or 3-5 membered heterocyclyl; and R4 is selected from hydrogen, –C1‒3alkyl, –C1‒3haloalkyl, –C1‒3alkoxy, ‒halogen, ‒CN, ‒NO2, oxo, ‒C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒NR*R*, ‒N(R*)C(O)R*, ‒OR*, ‒ OC(O)R*, ‒OC(O)NR*R*, ‒SR*, ‒S(O)R*, ‒S(O)2R*, wherein each R* is independently selected from H, C1‒2alkyl, –C1‒2haloalkyl, –C1‒2alkoxy, and wherein R3 and R4 can be optionally linked forming a C4-7cycloalkyl, wherein said formed C4-7cycloalkyl is optionally substituted by one or two –C1‒2alkyl, –C1‒2haloalkyl, ‒halogen. 6. The compound according to any one of the preceding claims, wherein A is selected from a monocyclic or bicyclic heterocyclyl of any of the formula wherein RZ11, RZ12, RZ14 and RZ15 are independently selected from hydrogen, –C1‒6alkyl, –C1‒6haloalkyl, –C1‒6alkoxy, ‒halogen, ‒CN, ‒NO2, oxo, ‒C(O)R*, ‒COOR*, ‒ C(O)NR*R*, ‒NR*R*, ‒N(R*)C(O)R*, ‒N(R*)C(O)OR*, ‒N(R*)C(O)NR*R*, ‒ N(R*)S(O)2R*, ‒OR*, ‒OC(O)R*, ‒OC(O)NR*R*, ‒SR*, ‒S(O)R*, ‒S(O)2R*, ‒ S(O)2NR*R*, ‒N(R*)S(O)2NR*R*, optionally substituted heterocyclyl, optionally substituted carbocyclyl, ‒C1‒6alkylene‒heterocyclyl wherein said ‒C1‒6alkylene and said heterocyclyl are independently optionally substituted, and ‒C1‒6alkylene‒carbocyclyl wherein said ‒C1‒6 alkylene and said carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyl, optionally substituted carbocyclyl, and optionally substituted C1‒6alkylene is independently selected from –C1‒6alkyl, –C1‒6haloalkyl, –C1‒6alkoxy, ‒halogen, ‒CN, ‒ NO2, oxo, ‒C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒NR*R*, ‒N(R*)C(O)R*, ‒N(R*)C(O)OR*, ‒ N(R*)C(O)NR*R*, ‒N(R*)S(O)2R*, ‒OR*, ‒OC(O)R*, ‒OC(O)NR*R*, ‒SR*, ‒S(O)R*, ‒ S(O)2R*, ‒S(O)2NR*R*, ‒N(R*)S(O)2NR*R*, wherein each R* is independently selected from H, C1‒6alkyl, –C1‒6haloalkyl, heterocyclyl which is optionally substituted with halogen or C1-6 alkyl, and carbocyclyl which is optionally substituted with halogen or C1-6 alkyl; wherein any two R* connected to the same nitrogen atom can be optionally linked; and wherein RZ11 and RZ12, as well as RZ14 and RZ15, can be optionally linked forming a 4-7 membered monocyclic heterocyclyl, wherein said formed 4-7 membered monocyclic heterocyclyl is optionally substituted by one or two –C1‒2alkyl, –C1‒2haloalkyl, ‒halogen; and RZ13 and RZ16 are independently selected from hydrogen, –C1‒2alkyl, –C1‒ 3haloalkyl, –C1‒2alkoxy, ‒F, ‒Cl, ‒Br, ‒NO2, ‒NH2, ‒CN, phenyl and C3‒6cycloalkyl, wherein preferably RZ13 and RZ16 are independently selected from hydrogen, –C1‒2alkyl, –C1‒2haloalkyl, –C1‒2alkoxy, ‒F, ‒Cl and C3‒4cycloalkyl, wherein further preferably RZ13 and RZ16 are independently selected from hydrogen and –CH3; and wherein again further preferably RZ13 and RZ16 are hydrogen; RY15 and RY16 are independently selected from hydrogen, –C1‒3alkyl, –C1‒ 3haloalkyl, –C1‒3alkoxy, ‒F, ‒Cl, ‒Br, ‒NO2, ‒NH2, ‒CN, phenyl and C3‒6cycloalkyl, wherein preferably RY15 and RY16 are independently selected from hydrogen, –C1‒2alkyl, –C1‒2haloalkyl, –C1‒2alkoxy, ‒F, ‒Cl and C3‒4cycloalkyl, and wherein further preferably RY15 and RY16 are independently selected from hydrogen and –CH3; R3 is selected from hydrogen, –C1‒6alkyl, –C1‒6haloalkyl, –C1‒6alkoxy, ‒halogen, ‒CN, ‒NO2, oxo, ‒C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒NR*R*, ‒N(R*)C(O)R*, ‒ N(R*)C(O)OR*, ‒N(R*)C(O)NR*R*, ‒N(R*)S(O)2R*, ‒OR*, ‒OC(O)R*, ‒OC(O)NR*R*, ‒ SR*, ‒S(O)R*, ‒S(O)2R*, ‒S(O)2NR*R*, ‒N(R*)S(O)2NR*R*, optionally substituted heterocyclyl, optionally substituted carbocyclyl, –C(O)‒heterocyclyl wherein said heterocyclyl is optionally substituted, –C(O)‒carbocyclyl wherein said carbocyclyl is optionally substituted ‒C1‒6alkylene‒heterocyclyl wherein said ‒C1‒6alkylene and said heterocyclyl are independently optionally substituted, and ‒C1‒6alkylene‒carbocyclyl wherein said ‒C1‒6 alkylene and said carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyl, optionally substituted carbocyclyl, and optionally substituted C1‒6alkylene is independently selected from –C1‒6alkyl, –C1‒6haloalkyl, –C1‒6alkoxy, ‒halogen, ‒CN, ‒ NO2, oxo, ‒C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒C(O)NR*(C1‒4alkylene)S(O)2R*, ‒ C(O)NR*(C1‒4alkylene)OR*, ‒C(O)NR*(C1‒4alkylene)NR*R*, ‒NR*R*, ‒N(R*)C(O)R*, ‒ N(R*)C(O)OR*, ‒N(R*)C(O)NR*R*, ‒N(R*)S(O)2R*, ‒OR*, ‒OC(O)R*, ‒OC(O)NR*R*, ‒ SR*, ‒S(O)R*, ‒S(O)2R*, ‒S(O)2NR*R*, ‒N(R*)S(O)2NR*R*, wherein each R* is independently selected from H, C1‒6alkyl, –C1‒6haloalkyl, heterocyclyl which is optionally substituted with halogen or C1-6 alkyl, and carbocyclyl which is optionally substituted with halogen or C1-6 alkyl; wherein any two R* connected to the same nitrogen atom can be optionally linked to form a heterocyclyl optionally substituted with 1 to 4, preferably one or two, substituents independently selected from C1-4alkyl, C1-2haloalkyl, C1-4alkoxy, OH, halogen, ‒CN, ‒NO2, oxo, ‒NH2, NH(C1‒2alkyl), ‒N(C1‒2alkyl)2, ‒C1‒2alkylene‒NH2, ‒C1‒ 2alkylene‒NH(C1‒2alkyl), ‒C1‒2alkylene‒N(C1‒2alkyl)2, ‒C1‒2alkylene‒OH, ‒COOH, ‒ COO(C1‒2alkyl), ‒C(O)C1‒2alkyl, C3‒6cycloalkyl, monomeric heterocyclyl, bivalent bridging or fusing C1-3alkyl or C1-3alkoxy optionally substituted with one or two –F, bivalent spiro-forming C3-5alkyl or 3-5 membered heterocyclyl; and R4 is selected from hydrogen, –C1‒3alkyl, –C1‒3haloalkyl, –C1‒3alkoxy, ‒halogen, ‒CN, ‒NO2, oxo, ‒C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒NR*R*, ‒N(R*)C(O)R*, ‒OR*, ‒ OC(O)R*, ‒OC(O)NR*R*, ‒SR*, ‒S(O)R*, ‒S(O)2R*, wherein each R* is independently selected from H, C1‒2alkyl, –C1‒2haloalkyl, –C1‒2alkoxy, and wherein R3 and R4 can be optionally linked forming a C4-7cycloalkyl, wherein said formed C4-7cycloalkyl is optionally substituted by one or two –C1‒2alkyl, –C1‒2haloalkyl, ‒halogen. 7. The compound according to any one of the preceding claims, wherein A is selected from a monocyclic or bicyclic heterocyclyl of any of the formula wherein RZ11, RZ12, RZ14 and RZ15 are independently selected from hydrogen, –C1‒6alkyl, –C1‒6haloalkyl, –C1‒6alkoxy, ‒halogen, ‒CN, ‒NO2, oxo, ‒C(O)R*, ‒COOR*, ‒ C(O)NR*R*, ‒NR*R*, ‒N(R*)C(O)R*, ‒N(R*)C(O)OR*, ‒N(R*)C(O)NR*R*, ‒ N(R*)S(O)2R*, ‒OR*, ‒OC(O)R*, ‒OC(O)NR*R*, ‒SR*, ‒S(O)R*, ‒S(O)2R*, ‒ S(O)2NR*R*, ‒N(R*)S(O)2NR*R*, optionally substituted heterocyclyl, optionally substituted carbocyclyl, ‒C1‒6alkylene‒heterocyclyl wherein said ‒C1‒6alkylene and said heterocyclyl are independently optionally substituted, and ‒C1‒6alkylene‒carbocyclyl wherein said ‒C1‒6 alkylene and said carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyl, optionally substituted carbocyclyl, and optionally substituted C1‒6alkylene is independently selected from –C1‒6alkyl, –C1‒6haloalkyl, –C1‒6alkoxy, ‒halogen, ‒CN, ‒ NO2, oxo, ‒C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒NR*R*, ‒N(R*)C(O)R*, ‒N(R*)C(O)OR*, ‒ N(R*)C(O)NR*R*, ‒N(R*)S(O)2R*, ‒OR*, ‒OC(O)R*, ‒OC(O)NR*R*, ‒SR*, ‒S(O)R*, ‒ S(O)2R*, ‒S(O)2NR*R*, ‒N(R*)S(O)2NR*R*, wherein each R* is independently selected from H, C1‒6alkyl, –C1‒6haloalkyl, heterocyclyl which is optionally substituted with halogen or C1-6 alkyl, and carbocyclyl which is optionally substituted with halogen or C1-6 alkyl; wherein any two R* connected to the same nitrogen atom can be optionally linked; and wherein RZ11 and RZ12, as well as RZ14 and RZ15, can be optionally linked forming a 4-7 membered monocyclic heterocyclyl, wherein said formed 4-7 membered monocyclic heterocyclyl is optionally substituted by one or two –C1‒2alkyl, –C1‒2haloalkyl, ‒halogen; and RY15 is selected from hydrogen, –C1‒3alkyl, –C1‒3haloalkyl, –C1‒3alkoxy, ‒F, ‒Cl, ‒Br, ‒NO2, ‒NH2, ‒CN, phenyl and C3‒6cycloalkyl, wherein preferably RY15 is selected from hydrogen, –C1‒2alkyl, –C1‒2haloalkyl, –C1‒2alkoxy, ‒F, ‒Cl and C3‒4cycloalkyl, and wherein further preferably RY15 is selected from hydrogen and –CH3; R3 is selected from hydrogen, –C1‒6alkyl, –C1‒6haloalkyl, –C1‒6alkoxy, ‒halogen, ‒CN, ‒NO2, oxo, ‒C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒NR*R*, ‒N(R*)C(O)R*, ‒ N(R*)C(O)OR*, ‒N(R*)C(O)NR*R*, ‒N(R*)S(O)2R*, ‒OR*, ‒OC(O)R*, ‒OC(O)NR*R*, ‒ SR*, ‒S(O)R*, ‒S(O)2R*, ‒S(O)2NR*R*, ‒N(R*)S(O)2NR*R*, optionally substituted heterocyclyl, optionally substituted carbocyclyl, –C(O)‒heterocyclyl wherein said heterocyclyl is optionally substituted, –C(O)‒carbocyclyl wherein said carbocyclyl is optionally substituted ‒C1‒6alkylene‒heterocyclyl wherein said ‒C1‒6alkylene and said heterocyclyl are independently optionally substituted, and ‒C1‒6alkylene‒carbocyclyl wherein said ‒C1‒6 alkylene and said carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyl, optionally substituted carbocyclyl, and optionally substituted C1‒6alkylene is independently selected from –C1‒6alkyl, –C1‒6haloalkyl, –C1‒6alkoxy, ‒halogen, ‒CN, ‒ NO2, oxo, ‒C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒C(O)NR*(C1‒4alkylene)S(O)2R*, ‒ C(O)NR*(C1‒4alkylene)OR*, ‒C(O)NR*(C1‒4alkylene)NR*R*, ‒NR*R*, ‒N(R*)C(O)R*, ‒ N(R*)C(O)OR*, ‒N(R*)C(O)NR*R*, ‒N(R*)S(O)2R*, ‒OR*, ‒OC(O)R*, ‒OC(O)NR*R*, ‒ SR*, ‒S(O)R*, ‒S(O)2R*, ‒S(O)2NR*R*, ‒N(R*)S(O)2NR*R*, wherein each R* is independently selected from H, C1‒6alkyl, –C1‒6haloalkyl, heterocyclyl which is optionally substituted with halogen or C1-6 alkyl, and carbocyclyl which is optionally substituted with halogen or C1-6 alkyl; wherein any two R* connected to the same nitrogen atom can be optionally linked to form a heterocyclyl optionally substituted with 1 to 4, preferably one or two, substituents independently selected from C1-4alkyl, C1-2haloalkyl, C1-4alkoxy, OH, halogen, ‒CN, ‒NO2, oxo, ‒NH2, NH(C1‒2alkyl), ‒N(C1‒2alkyl)2, ‒C1‒2alkylene‒NH2, ‒C1‒ 2alkylene‒NH(C1‒2alkyl), ‒C1‒2alkylene‒N(C1‒2alkyl)2, ‒C1‒2alkylene‒OH, ‒COOH, ‒ COO(C1‒2alkyl), ‒C(O)C1‒2alkyl, C3‒6cycloalkyl, monomeric heterocyclyl, bivalent bridging or fusing C1-3alkyl or C1-3alkoxy optionally substituted with one or two –F, bivalent spiro-forming C3-5alkyl or 3-5 membered heterocyclyl. 8. The compound according to any one of the claims 1 to 7, wherein A is selected from a monocyclic or bicyclic heterocyclyl of the formula wherein RZ11 is selected from hydrogen, –C1‒6alkyl, –C1‒6haloalkyl, –C1‒6alkoxy, ‒ halogen, optionally substituted mono- or bicyclic heterocyclyl, optionally substituted mono- or bicyclic carbocyclyl, ‒C1‒3alkylene‒(mono or bicyclic heterocyclyl) wherein said ‒C1‒3alkylene and said mono or bicyclic heterocyclyl are independently optionally substituted, and ‒C1‒3alkylene‒(mono- or bicyclic carbocyclyl) wherein said ‒C1‒3 alkylene and said mono- or bicyclic carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyls, optionally substituted carbocyclyls, and optionally substituted C1‒3alkylene is independently selected from –C1‒3alkyl, –C1‒3haloalkyl, –C1‒3alkoxy, ‒halogen, ‒CN, oxo, ‒C(O)R*, ‒ COOR*, ‒C(O)NR*R*, ‒NR*R*, ‒N(R*)C(O)R*, ‒N(R*)C(O)OR*, ‒OR*, ‒OC(O)R*, ‒ OC(O)NR*R*, ‒SR*, ‒S(O)R*, ‒S(O)2R*, ‒S(O)2NR*R*, ‒N(R*)S(O)2NR*R*, wherein each R* is independently selected from H, C1‒3alkyl, –C1‒2haloalkyl, heterocyclyl which is optionally substituted with halogen or C1-2alkyl, and carbocyclyl which is optionally substituted with halogen or C1-2alkyl; wherein any two R* connected to the same nitrogen atom can be optionally linked; and wherein RZ11 and RZ12 can be optionally linked forming a 4-7 membered monocyclic heterocyclyl, wherein said formed 4-7 membered monocyclic heterocyclyl is optionally substituted by one or two –C1‒2alkyl, –C1haloalkyl, ‒halogen; and RZ12 is selected from hydrogen, –C1‒6alkyl, –C1‒6haloalkyl, –C1‒6alkoxy, ‒ halogen, optionally substituted monocyclic heterocyclyl, optionally substituted monocyclic carbocyclyl, wherein the optional substituent of the optionally substituted monocyclic heterocyclyl and optionally substituted monocyclic carbocyclyl is independently selected from –C1‒2alkyl, –C1‒2haloalkyl, –C1‒2alkoxy, ‒halogen, and wherein RZ11 and RZ12 can be optionally linked forming a 4-7 membered monocyclic heterocyclyl, wherein said formed 4-7 membered monocyclic heterocyclyl is optionally substituted by one or two –C1‒2alkyl, –C1haloalkyl, ‒halogen. 9. The compound according to any one of the claims 1 to 7, wherein A is selected from a monocyclic or bicyclic heterocyclyl of the formula wherein RZ14 is selected from hydrogen, –C1‒6alkyl, –C1‒6haloalkyl, –C1‒6alkoxy, ‒ halogen, optionally substituted mono- or bicyclic heterocyclyl, optionally substituted mono- or bicyclic carbocyclyl, ‒C1‒3alkylene‒(mono or bicyclic heterocyclyl) wherein said ‒C1‒3alkylene and said mono or bicyclic heterocyclyl are independently optionally substituted, and ‒C1‒3alkylene‒(mono- or bicyclic carbocyclyl) wherein said ‒C1‒3 alkylene and said mono- or bicyclic carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyls, optionally substituted carbocyclyls, and optionally substituted C1‒3alkylene is independently selected from –C1‒3alkyl, –C1‒3haloalkyl, –C1‒3alkoxy, ‒halogen, ‒CN, oxo, ‒C(O)R*, ‒ COOR*, ‒C(O)NR*R*, ‒NR*R*, ‒N(R*)C(O)R*, ‒N(R*)C(O)OR*, ‒OR*, ‒OC(O)R*, ‒ OC(O)NR*R*, ‒SR*, ‒S(O)R*, ‒S(O)2R*, ‒S(O)2NR*R*, ‒N(R*)S(O)2NR*R*, wherein each R* is independently selected from H, C1‒3alkyl, –C1‒2haloalkyl, heterocyclyl which is optionally substituted with halogen or C1-2alkyl, and carbocyclyl which is optionally substituted with halogen or C1-2alkyl; wherein any two R* connected to the same nitrogen atom can be optionally linked; and wherein RZ14 and RZ15 can be optionally linked forming a 4-7 membered monocyclic heterocyclyl, wherein said formed 4-7 membered monocyclic heterocyclyl is optionally substituted by one or two –C1‒2alkyl, –C1haloalkyl, ‒halogen; and RZ15 are independently selected from hydrogen, –C1‒6alkyl, –C1‒6haloalkyl, –C1‒ 6alkoxy, ‒halogen, optionally substituted monocyclic heterocyclyl, optionally substituted monocyclic carbocyclyl, wherein the optional substituent of the optionally substituted monocyclic heterocyclyl and optionally substituted monocyclic carbocyclyl is independently selected from –C1‒2alkyl, –C1‒2haloalkyl, –C1‒2alkoxy, ‒halogen, and wherein RZ11 and RZ12 can be optionally linked forming a 4-7 membered monocyclic heterocyclyl, wherein said formed 4-7 membered monocyclic heterocyclyl is optionally substituted by one or two –C1‒2alkyl, –C1haloalkyl, ‒halogen. 10. The compound according to any one of the claims 1 to 7, wherein A is selected from a monocyclic or bicyclic heterocyclyl of any of the formula wherein RY15 is selected from hydrogen, –C1‒3alkyl, –C1‒3haloalkyl, –C1‒3alkoxy, ‒F, ‒Cl, ‒Br, ‒NO2, ‒NH2, ‒CN, phenyl and C3‒6cycloalkyl, wherein preferably RY15 is selected from hydrogen, –C1‒2alkyl, –C1‒2haloalkyl, –C1‒2alkoxy, ‒F, ‒Cl and C3‒4cycloalkyl, and wherein further preferably RY15 is selected from hydrogen and –CH3; R3 is selected from hydrogen, –C1‒6alkyl, –C1‒6haloalkyl, –C1‒6alkoxy, ‒halogen, ‒CN, ‒NO2, oxo, ‒C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒NR*R*, ‒N(R*)C(O)R*, ‒ N(R*)C(O)OR*, ‒N(R*)C(O)NR*R*, ‒N(R*)S(O)2R*, ‒OR*, ‒OC(O)R*, ‒OC(O)NR*R*, ‒ SR*, ‒S(O)R*, ‒S(O)2R*, ‒S(O)2NR*R*, ‒N(R*)S(O)2NR*R*, optionally substituted heterocyclyl, optionally substituted carbocyclyl, –C(O)‒heterocyclyl wherein said heterocyclyl is optionally substituted, –C(O)‒carbocyclyl wherein said carbocyclyl is optionally substituted ‒C1‒6alkylene‒heterocyclyl wherein said ‒C1‒6alkylene and said heterocyclyl are independently optionally substituted, and ‒C1‒6alkylene‒carbocyclyl wherein said ‒C1‒6 alkylene and said carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyl, optionally substituted carbocyclyl, and optionally substituted C1‒6alkylene is independently selected from –C1‒6alkyl, –C1‒6haloalkyl, –C1‒6alkoxy, ‒halogen, ‒CN, ‒ NO2, oxo, ‒C(O)R*, ‒COOR*, ‒C(O)NR*R*, ‒C(O)NR*(C1‒4alkylene)S(O)2R*, ‒ C(O)NR*(C1‒4alkylene)OR*, ‒C(O)NR*(C1‒4alkylene)NR*R*, ‒NR*R*, ‒N(R*)C(O)R*, ‒ N(R*)C(O)OR*, ‒N(R*)C(O)NR*R*, ‒N(R*)S(O)2R*, ‒OR*, ‒OC(O)R*, ‒OC(O)NR*R*, ‒ SR*, ‒S(O)R*, ‒S(O)2R*, ‒S(O)2NR*R*, ‒N(R*)S(O)2NR*R*, wherein each R* is independently selected from H, C1‒6alkyl, –C1‒6haloalkyl, heterocyclyl which is optionally substituted with halogen or C1-6 alkyl, and carbocyclyl which is optionally substituted with halogen or C1-6 alkyl; wherein any two R* connected to the same nitrogen atom can be optionally linked to form a heterocyclyl optionally substituted with 1 to 4, preferably one or two, substituents independently selected from C1-4alkyl, C1-2haloalkyl, C1-4alkoxy, OH, halogen, ‒CN, ‒NO2, oxo, ‒NH2, NH(C1‒2alkyl), ‒N(C1‒2alkyl)2, ‒C1‒2alkylene‒NH2, ‒C1‒ 2alkylene‒NH(C1‒2alkyl), ‒C1‒2alkylene‒N(C1‒2alkyl)2, ‒C1‒2alkylene‒OH, ‒COOH, ‒ COO(C1‒2alkyl), ‒C(O)C1‒2alkyl, C3‒6cycloalkyl, monomeric heterocyclyl, bivalent bridging or fusing C1-3alkyl or C1-3alkoxy optionally substituted with one or two –F, bivalent spiro-forming C3-5alkyl or 3-5 membered heterocyclyl; 11. A pharmaceutical composition comprising: a compound having the formula (I) as defined in any of claims 1 to 10, optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s). 12. A compound having the formula (I) as defined in any of claims 1 to 10, preferably a therapeutically effective amount of said compound, optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, or the pharmaceutical composition of claim 11, wherein the compound or pharmaceutical composition is for use in the treatment, amelioration or prevention of cancer, Alzheimer, Parkinson, Down syndrome, Metabolic syndrome, Diabetes and/or osteoarthritis. 13. A compound for use according to claim 11, a pharmaceutical composition for use according to claim 10, wherein the disease is cancer. 14. A compound for use according to claim 12 or 13, a pharmaceutical composition for use according to claim 12 or 13, wherein the cancer is selected from pancreatic cancer, lung cancer, ovarian cancer, uterine cancer, sarcoma, bloodborne cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, ovarian cancer, gastric cancer, head cancer, neck cancer and glioblastoma. 15. A therapeutically effective amount of a compound having the formula (I) as defined in any of claims 1 to 10, optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, or a pharmaceutical composition of claim 11, and a second therapeutic agent, wherein the second therapeutic agent is preferably selected from chemotherapeutics, anti- angiogenics, radiation, targeted therapy, CDK4/6 inhibitors, mTOR inhibitors and EGFR inhibitors, for use in a method of treating, ameliorating or preventing cancer. |
Specific examples and very preferred compounds and embodiments of the present invention are any of the compounds 00001 to 00284. Thus, in a very further preferred embodiment, said compound of formula (I) is a compound selected from any one of the compounds 00001 to 00284. Pharmaceutically acceptable salts etc. The scope of the invention embraces all pharmaceutically acceptable salt forms of the compounds of formula (I) which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate salts; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate salts. Preferred pharmaceutically acceptable salts of the compounds of formula (I) include a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, and a phosphate salt. A particularly preferred pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride salt. Accordingly, it is preferred that the compound of formula (I), including any one of the specific compounds of formula (I) described herein, is in the form of a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, or a phosphate salt, and it is particularly preferred that the compound of formula (I) is in the form of a hydrochloride salt. Furthermore, the compounds of formula (I) may exist in the form of different isomers, in particular stereoisomers (including, e.g., geometric isomers (or cis/trans isomers), enantiomers and diastereomers) or tautomers. All such isomers of the compounds of formula (I) are contemplated as being part of the present invention, either in admixture or in pure or substantially pure form. As for stereoisomers, the invention embraces the isolated optical isomers of the compounds according to the invention as well as any mixtures thereof (including, in particular, racemic mixtures/racemates). The racemates can be resolved by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. The individual optical isomers can also be obtained from the racemates via salt formation with an optically active acid followed by crystallization. The present invention further encompasses any tautomers of the compounds provided herein. The scope of the invention also embraces compounds of formula (I), in which one or more atoms are replaced by a specific isotope of the corresponding atom. For example, the invention encompasses compounds of formula (I), in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e., 2 H; also referred to as "D"). Accordingly, the invention also embraces compounds of formula (I) which are enriched in deuterium. Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol-% hydrogen-1 ( 1 H) and about 0.0156 mol-% deuterium ( 2 H or D). The content of deuterium in one or more hydrogen positions in the compounds of formula (I) can be increased using deuteration techniques known in the art. For example, a compound of formula (I) or a reactant or precursor to be used in the synthesis of the compound of formula (I) can be subjected to an H/D exchange reaction using, e.g., heavy water (D 2 O). Further suitable deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861-5868, 2014. The content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy. Unless specifically indicated otherwise, it is preferred that the compound of formula (I) is not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or 1 H hydrogen atoms in the compounds of formula (I) is preferred. The present invention also embraces compounds of formula (I), in which one or more atoms are replaced by a positron-emitting isotope of the corresponding atom, such as, e.g., 18 F, 11 C, 13 N, 15 O, 76 Br, 77 Br, 120 I and/or 124 I. Such compounds can be used as tracers or imaging probes in positron emission tomography (PET). The invention thus includes (i) compounds of formula (I), in which one or more fluorine atoms (or, e.g., all fluorine atoms) are replaced by 18 F atoms, (ii) compounds of formula (I), in which one or more carbon atoms (or, e.g., all carbon atoms) are replaced by 11 C atoms, (iii) compounds of formula (I), in which one or more nitrogen atoms (or, e.g., all nitrogen atoms) are replaced by 13 N atoms, (iv) compounds of formula (I), in which one or more oxygen atoms (or, e.g., all oxygen atoms) are replaced by 15 O atoms, (v) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by 76 Br atoms, (vi) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by 77 Br atoms, (vii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by 120 I atoms, and (viii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by 124 I atoms. In general, it is preferred that none of the atoms in the compounds of formula (I) are replaced by specific isotopes. Cancer The tumor to be treated can be a solid tumor or a non-solid tumor. Within the context of the present invention, the expression “non-solid tumors” stands for tumors that affect hematopoietic structures including components of the immune system. Examples of non-solid tumors include leukemias, multiple myelomas and lymphomas. These tumor cells generally appear in the bone marrow and peripheral circulation. Within the context of the present invention, the expression "solid tumors" stands for primary tumors and/or metastases (wherever located) other than tumors that affect hematopoietic structures, e.g. brain and other central nervous system tumors (e.g. tumors of the meninges, brain, spinal cord, cranial nerves and other parts of the central nervous system, e.g. glioblastomas or medulla blastomas); head and/or neck cancer; breast tumors; circulatory system tumors (e.g. heart, mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissue); excretory system tumors (e.g. kidney, renal pelvis, ureter, bladder, other and unspecified urinary organs); gastrointestinal tract tumors (e.g. oesophagus, stomach, small intestine, colon, colorectal, rectosigmoid junction, rectum, anus and anal canal), tumors involving the liver and intrahepatic bile ducts, gall bladder, other and unspecified parts of biliary tract, pancreas); head and neck; oral cavity (lip, tongue, gum, floor of mouth, palate, and other parts of mouth, parotid gland, and other parts of the salivary glands, tonsil, oropharynx, nasopharynx, pyriform sinus, hypopharynx, and other sites in the lip, oral cavity and pharynx); reproductive system tumors (e.g. vulva, vagina, Cervix uteri, Corpus uteri, uterus, ovary, and other sites associated with female genital organs, placenta, penis, prostate, testis, and other sites associated with male genital organs); respiratory tract tumors (e.g. nasal cavity and middle ear, accessory sinuses, larynx, trachea, bronchus and lung, e.g. small cell lung cancer or non-small cell lung cancer); skeletal system tumors (e.g. bone and articular cartilage of limbs, bone articular cartilage and other sites); skin tumors (e.g. malignant melanoma of the skin, non-melanoma skin cancer, basal cell carcinoma of skin, squamous cell carcinoma of skin, mesothelioma, Kaposi's sarcoma); and tumors involving other tissues including peripheral nerves and autonomic nervous system, connective and soft tissue, retroperitoneum and peritoneum, eye and adnexa, thyroid, adrenal gland and other endocrine glands and related structures, secondary and unspecified malignant neoplasm of lymph nodes, secondary malignant neoplasm of respiratory and digestive systems and secondary malignant neoplasm of other sites. As such, the cancer may be a B-cell proliferative cancer, leukemia, lymphoma, breast cancer or myeloma. In a further embodiment, the tumor may be adrenocortical carcinoma, astrocytoma, basal cell carcinoma, carcinoid, cardiac, cholangiocarcinoma, chordoma, chronic myeloproliferative neoplasms, craniopharyngioma, ductal carcinoma in situ, ependymoma, intraocular melanoma, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, glioma, histiocytosis, leukemia {e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell leukemia, myelogenous leukemia, myeloid leukemia), lymphoma (e.g., Burkitt lymphoma [non-Hodgkin lymphoma], cutaneous T-cell lymphoma, Hodgkin lymphoma, mycosis fungoides, Sezary syndrome, AIDS-related lymphoma, follicular lymphoma, diffuse large B-cell lymphoma), melanoma, merkel cell carcinoma, mesothelioma, myeloma (e.g., multiple myeloma), myelodysplastic syndrome, papillomatosis, paraganglioma, pheochromacytoma, pleuropulmonary blastoma, retinoblastoma, sarcoma (e.g., Ewing sarcoma, Kaposi sarcoma, osteosarcoma, rhabdomyosarcoma, uterine sarcoma, vascular sarcoma), Wilms' tumor, and/or cancer of the adrenal cortex, anus, appendix, bile duct, bladder, bone, brain, breast, bronchus, central nervous system, cervix, colon, endometrium, esophagus, eye, fallopian tube, gall bladder, gastrointestinal tract, germ cell, head and neck, heart, intestine, kidney (e.g., Wilms' tumor), larynx, liver, lung (e.g., non-small cell lung cancer, small cell lung cancer), mouth, nasal cavity, oral cavity, ovary, pancreas, rectum, skin, stomach, testes, throat, thyroid, penis, pharynx, peritoneum, pituitary, prostate, rectum, salivary gland, ureter, urethra, uterus, vagina, vulva, or acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer (NSCLC), oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, s)movioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, or Wilms' tumor. Preferably, the tumor to be treated is treatment-resistant and preferably drug-resistant. Within the context of the present invention the term “treatment-resistant tumor” means the ability of tumor cells to survive and grow despite anti-cancer therapies and includes for example radiotherapy and medication intake. The term “drug-resistant tumor” means that such an anti-cancer therapy is based on medication intake. It is known that hypoxia is an environmental selection pressure that contributes to the development of therapy resistance. Thus, due to the inhibition of DYRK1B by the compounds of the present invention, the micro- environment within the tumor can be significantly improved by selectively targeting hypoxic cancer cells. Consequently, the compounds according to the present invention allow overcoming therapy resistance since the remaining tumor comprises well-oxygenated and proliferating cancer cells which may be conventionally treated. Preferably, the tumor to be treated comprises hypoxic tumor cells and/or glycolytic cancer cells. Most of the cancer cells feature increased glycolysis as a metabolic strategy. Further, also the presence of oncogenes or loss of tumor suppressor genes lead to the activation of HIF and thereby to a glycolytic phenotype. Moreover, HIF can be activated through genetic and metabolic alterations in key metabolic genes. Thus, by inhibiting DYRK1B by the compounds of the present invention, tumors comprising hypoxic tumor cells and/or glycolytic cancer cells can be effectively treated. Preferably, the tumor comprises dormant, slow cycling or quiescent cancer cells. Dormant, slow cycling or quiescent cancer cells are known to reside in hypoxic area. Moreover, quiescence can also be induced by nutrient deprivation, ROS, drug treatment and other tumor microenvironmental effects. DYRK1B is upregulated by these stresses and can cause cells to enter a state of reversible quiescence through phosphorylation of cyclin-dependent kinase inhibitor p27 on serine 10. Quiescence promotes cells survival under unfavourable conditions and by inhibiting DYRK1B, the compounds of the present invention are therefore particularly useful to drive cells out of quiescence, which leads to cell death under harsh microenvironmental conditions and/or resensitize them to treatment targeting cycling cancer cells. In addition, dormant cancer cells are known to be often the seed of metastasis. Therefore, by inhibiting DYRK1B, the compounds of the present invention are particularly useful in the treatment of metastasis. It is believed that the compounds of the present invention are particularly useful in the treatment of quiescent cancer cells as a result of hypoxia. The tumour may also be a tumour wherein AR is expressed, or in cancers in which there is activation of CBP and/or p300 function. The cancers that can be treated include those which express AR or are otherwise associated with AR, those that harbour loss of function mutations in CBP or p300 and those which have activated CBP and/or p300. Cancers that may be treated include, but are not restricted to, prostate cancer, breast cancer, bladder cancer, lung cancer, lymphoma and leukaemia. The prostate cancer may be, for instance, castration-resistant prostate cancer (CRPC). The lung cancer may be, for instance, non-small cell lung cancer or small cell lung cancer. Within the present invention, “inhibiting” involves specific binding. By specific binding is meant a particular interaction between one binding partner and another binding partner, for example a compound of the present invention and a target such as DYRK1B and/or DYRK1A. Interactions between one binding partner and another binding partner may be mediated by one or more, typically more than one, non-covalent bonds. An exemplary way of characterising specific binding is by a specific binding curve. Such binding may be analysed using methods well known in the art, such as e.g. BIACORE. In a preferred embodiment, the compounds of the present invention show inhibition of DYRK1B and/or DYRK1A to a higher extent than expected by the skilled person. The inhibition may be expressed as IC 50 , i.e. the concentration necessary to inhibit activity to 50%. In a preferred embodiment of the present invention, the compounds have an IC 50 value of 12.500 nM or less, preferably 10.000 nM or less, more preferably 7.500 and even more preferably 5.000 nM or less. The IC 50 value may be determined using methods such as those described in the examples. As such, a suitable method comprises the steps of incubating strep- DYRK1B (e.g. at 0.5nM) and DYRKtide (e.g. at 50µM) in kinase buffer, following compound dispensing (e.g. 1µl),e.g. 2µl of ATP (final concentration e.g. 100µM) and incubating, preferably at room temperature. After that, a detection reagent such as ADP-Glo™ can be dispensed and incubated, preferably at room temperature. Finally, Kinase Detection Reagent can be dispensed and the solution be incubated before measuring. Preferably, the tumor comprises tumor stem cells. Within the context of the present invention, a “tumor stem cell” means a cell which has self-replication capacity and cancer forming ability in combination and which is resistant to anti-cancer agents and/or radiation therapy and which is a causative cell of cancer recurrence. Tumor stem cells often reside in a hypoxic niche. By inhibiting DYRK1B by the compounds of the present invention, the number of tumor stem cells can be significantly reduced or even the birth of tumor stem cells can be avoided. In particular leukemic cancer stem cells are very hypoxic and can be effectively treated by the compounds of the present invention. In another embodiment of the present invention, the growth of the tumor associated with the overexpression of dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B) can be inhibited by the compound of the present invention. Amplification of the DYRK1B occurs in many different cancers including pancreatic cancer, ovarian cancer and non-small cell lung cancer. In these cancers, DYRK1B gene may act as a potential driver oncogene, that is, as a proto-oncogene having a genetic mutation that is considered to cause a mutation specific to cancer cells and to become a main cause of cancer development. Thus, the patients can be stratified on the basis of having this amplification and then specifically be treated with the compounds of the present invention. An amplification of DYRK1B has, e.g., been found in Pancreatic cancer, Lung cancer, Ovarian cancer and Uterine cancer. Furthermore, cancers where DYRK1A/B is described as a target include sarcoma, leukemia, breast cancer, colon cancer, prostate cancer, pancreatic cancer, ovarian cancer and glioblastoma. Other diseases The present invention furthermore relates to the use of the compounds of formula I as a therapeutically active substance, and in particular for use in the treatment of disorders wherein hypoxic cells are involved. It has been surprisingly found by the present inventors that by inhibiting DYRK1A and/or DYRK1B, the compounds of the present invention are useful in the treatment of neurodegenerative diseases. Said compounds are particularly useful in the amelioration, treatment or control of Down's syndrome, Autism spectrum disorder, Alzheimer's disease, Down syndrome, Parkinson, Metabolic syndrome, Diabetes, and/or Osteoarthritis. Thus, present invention furthermore relates to a method of treating, ameliorating or preventing cancer, Alzheimer, Parkinson, Down syndrome, Metabolic syndrome, Diabetes and/or osteoarthritis, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the formula (I) as defined herein, optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, or a pharmaceutical composition comprising a compound having the formula (I) as defined herein, optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s). Formulation, dosage forms etc. As detailed above, the compounds provided herein may be administered as compounds per se or may be formulated as medicaments, e.g. as pharmaceutical composition or combination. The medicaments/pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and/or solubility enhancers, or any combination thereof. In particular, the pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., poly(ethylene glycol), including poly(ethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da, ethylene glycol, propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate, phospholipids, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, cyclodextrins, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β- cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β- cyclodextrin, carboxyalkyl thioethers, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, vinyl acetate copolymers, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof. The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof. The pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in "Remington: The Science and Practice of Pharmacy", Pharmaceutical Press, 22 nd edition. The pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and ovula. Dosage forms for nasal administration can be administered via inhalation and insufflation, for example by a metered inhaler. Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems. The compounds of formula (I) or the above described pharmaceutical compositions comprising a compound of formula (I) may be administered to a subject by any convenient route of administration, whether systemically/peripherally or at the site of desired action, including but not limited to one or more of: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using injection techniques or infusion techniques, and including, for example, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal by, e.g., implant of a depot, for example, subcutaneously or intramuscularly), pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (including intravitreal or intracameral), rectal, and vaginal. If said compounds or pharmaceutical compositions are administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracardially, intracranially, intramuscularly or subcutaneously administering the compounds or pharmaceutical compositions, and/or by using infusion techniques. For parenteral administration, the compounds are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. Said compounds or pharmaceutical compositions can also be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled- release applications. Alternatively, said compounds or pharmaceutical compositions can be administered in the form of a suppository or pessary, or it may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of the present invention may also be dermally or transdermally administered, for example, by the use of a skin patch. Said compounds or pharmaceutical compositions may also be administered by sustained release systems. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained-release matrices include, e.g., polylactides (see, e.g., US 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman, U. et al., Biopolymers 22:547-556 (1983)), poly(2-hydroxyethyl methacrylate) (R. Langer et al., J. Biomed. Mater. Res.15:167- 277 (1981), and R. Langer, Chem. Tech.12:98-105 (1982)), ethylene vinyl acetate (R. Langer et al., Id.) or poly-D-(-)-3-hydroxybutyric acid (EP133988). Sustained-release pharmaceutical compositions also include liposomally entrapped compounds. Liposomes containing a compound of the present invention can be prepared by methods known in the art, such as, e.g., the methods described in any one of: DE3218121; Epstein et al., Proc. Natl. Acad. Sci. (USA) 82:3688-3692 (1985); Hwang et al., Proc. Natl. Acad. Sci. (USA) 77:4030-4034 (1980); EP0052322; EP0036676; EP088046; EP0143949; EP0142641; JP 83-118008; US 4,485,045; US 4,544,545; and EP0102324. Said compounds or pharmaceutical compositions may also be administered by the pulmonary route, rectal routes, or the ocular route. For ophthalmic use, they can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum. It is also envisaged to prepare dry powder formulations of the compounds of formula (I) for pulmonary administration, particularly inhalation. Such dry powders may be prepared by spray drying under conditions which result in a substantially amorphous glassy or a substantially crystalline bioactive powder. Accordingly, dry powders of the compounds of the present invention can be made according to the emulsification/spray drying process disclosed in WO 99/16419 or WO 01/85136. Spray drying of solution formulations of the compounds of the present invention can be carried out, e.g., as described generally in the "Spray Drying Handbook", 5th ed., K. Masters, John Wiley & Sons, Inc., NY (1991), and in WO 97/41833 or WO 03/053411. For topical application to the skin, said compounds or pharmaceutical compositions can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol and water. The present invention thus relates to the compounds or the pharmaceutical compositions provided herein, wherein the corresponding compound or pharmaceutical composition is to be administered by any one of: an oral route; topical route, including by transdermal, intranasal, ocular, buccal, or sublingual route; parenteral route using injection techniques or infusion techniques, including by subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral, or intracranial route; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ophthalmic route, including by intravitreal, or intracameral route; rectal route; or vaginal route. Particularly preferred routes of administration of the compounds or pharmaceutical compositions of the present invention are oral forms of administration. Typically, a physician will determine the dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy. A proposed, yet non-limiting dose of the compounds according to the invention for administration to a human (of approximately 70 kg body weight) may be 0.05 to 2000 mg, preferably 0.1 mg to 1000 mg, of the active ingredient per unit dose. The unit dose may be administered, e.g., 1, 2, 3 or more times per day. The unit dose may also be administered 1 to 7 times per week, e.g., with one, two or more administration(s) per day. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient/subject as well as the severity of the condition to be treated. The precise dose and also the route of administration will ultimately be at the discretion of the attendant physician. The compounds of formula (I) can be used in combination with other therapeutic agents, including in particular other anticancer agents. When a compound of the invention is used in combination with a second therapeutic agent active against the same disease, the dose of each compound may differ from that when the compound is used alone. The combination of a compound of the present invention with a second therapeutic agent may comprise the administration of the second therapeutic agent simultaneously/concomitantly or sequentially/separately with the compound of the invention. Selected other aspects of the invention In addition, the present invention provides a pharmaceutical composition comprising a compound having the formula (I) as defined in any of claims 1 to 14, optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s). The present invention further provides a compound having the formula (I) as defined herein, optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, or the pharmaceutical composition as defined herein, wherein the compound or pharmaceutical composition is for use in the treatment, amelioration or prevention of cancer, Alzheimer, Parkinson, Down syndrome, Metabolic syndrome, Diabetes and/or osteoarthritis. A method of treating, ameliorating or preventing cancer, Alzheimer, Parkinson, Down syndrome, Metabolic syndrome, Diabetes and/or osteoarthritis is also described herein. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound having the formula (I) as defined herein, optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, or a pharmaceutical composition as described herein. In addition, a method of treating, ameliorating or preventing cancer is also provided. The method comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the formula (I) as defined herein, optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, or a pharmaceutical composition as described herein, wherein the method further comprises administering to the patient in need thereof a second therapeutic agent. Combination therapies The present invention furthermore relates to the use of a compound of formula (I) according to the present invention in combination with a second therapeutic agent. It has been found that DYRK1B is essential for cancer cell survival in the context of tumor hypoxia. When functionally inhibited, DYRK1B produces synthetic lethality in hypoxic cancer cells in a tumor. Thus, by successfully inhibiting DYRK1B, a hypoxic environment can be reduced or avoided which allows a successful conventional treatment of a tumor both subsequently or in parallel. Preferably, the second therapeutic agent is an anticancer drug. The anticancer drug to be administered in combination with a compound of formula (I) according to the present invention is preferably selected from chemotherapeutics, anti-angiogenics, radiation, and targeted therapy such as by CDK4/6 inhibitors, mTOR inhibitors or EGFR inhibitors. Thus, the present invention furthermore relates to a method of treating, ameliorating or preventing cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the formula (I) as defined herein, optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, or a pharmaceutical composition comprising a compound having the formula (I) as defined herein, optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s), wherein the method further comprises administering to the patient in need thereof a second therapeutic agent, wherein the second therapeutic agent is preferably selected from chemotherapeutics, anti-angiogenics, radiation, targeted therapy, CDK4/6 inhibitors, mTOR inhibitors and EGFR inhibitors. Chemotherapeutics include a tumor angiogenesis inhibitor (for example, a protease inhibitor, an epidermal growth factor receptor kinase inhibitor, or a vascular endothelial growth factor receptor kinase inhibitor); a cytotoxic drug (for example, an antimetabolite, such as purine and pyrimidine analogue antimetabolites); and an antimitotic agent (for example, a microtubule stabilizing drug or an antimitotic alkaloid); a platinum coordination complex; an anti-tumor antibiotic. A platinum coordination complex which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, or triplatin tetranitrate. A cytotoxic drug which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, an antimetabolite, including folic acid analogue antimetabolites (such as aminopterin, methotrexate, pemetrexed, or raltitrexed), purine analogue antimetabolites (such as cladribine, clofarabine, fludarabine, 6- mercaptopurine (including its prodrug form azathioprine), pentostatin, or 6-thioguanine), and pyrimidine analogue antimetabolites (such as cytarabine, decitabine, 5-fluorouracil (including its prodrug forms capecitabine and tegafur), floxuridine, gemcitabine, enocitabine, or sapacitabine). An antimitotic agent which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, a taxane (such as docetaxel, larotaxel, ortataxel, paclitaxel/taxol, or tesetaxel), a Vinca alkaloid (such as vinblastine, vincristine, vinflunine, vindesine, or vinorelbine), an epothilone (such as epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, or epothilone F) or an epothilone B analogue (such as ixabepilone/azaepothilone B). The term "anti-angiogenic inhibitor" stands for a substance that inhibits the growth of new blood vessels. It is known that the clinical resistance to anti-angiogenic inhibitors is quite likely due to tumor cells utilizing an alternative method for obtaining a vasculature. Further, anti-angiogenic therapy is known to induce hypoxia and thereby contribute to drug resistance. Interestingly, it could be shown that the inhibition of DYRK1B inhibits the resistance to anti- angiogenic therapy. Thus, a combination medicament comprising a compound of formula (I) and an anti-angiogenic inhibitor prevents or at least diminishes the danger of a medicament resistance and allows a long-term treatment against the tumor. Preferably, the anti-angiogenic inhibitor is selected from the group consisting of bevacizumab, erlotinib, lapatanib, sunitinib, pazopanib, imatinib, dasatanib, nilotinib, bortezomib, ibrutinib, semaxinib, vatalinib, sorafenib, leflunomide, canertinib, axitinib, nintedanib, regorafenib, pazobanib, cabozantinib, vandetanib, ziv-aflibercept, thalidomide, IMC-1C11, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylme thyl)amino]-3- pyridinecarboxamide (AMG 706), 3-(4-bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidine-1-yl- butyl)-ureido]-isothiazole-4-carboxylic acid amide (CP-547,632), pazopanib (GW-786034), N- (4-(3-amino-1H-indazol-4-yl)phenyl)-N′-(2-fluoro-5-methylp henyl)urea (ABT-869), and cediranib (AXD-2171), most preferably of bevacizumab, ziv-aflibercept, sorafenib, sunitinib, axitinib, nintedanib, regorafenib, pazobanib, cabozantinib, vandetanib, and thalidomide. Specific examples where a combination with anti-angiogenic inhibitors may be particularly useful include renal carcinoma, colon cancer, glioblastoma and hepatocellular carcinoma. The compounds of formula (I) can also be administered in combination with physical therapy, such as radiotherapy. Radiotherapy may commence before, after, or simultaneously with administration of the compounds of the invention. For example, radiotherapy may commence 1-10 minutes, 1-10 hours or 24-72 hours after administration of the compounds. Yet, these time frames are not to be construed as limiting. The subject is exposed to radiation, preferably gamma radiation, whereby the radiation may be provided in a single dose or in multiple doses that are administered over several hours, days and/or weeks. Gamma radiation may be delivered according to standard radiotherapeutic protocols using standard dosages and regimens. Specific examples where a combination with radiation therapy may be particularly useful include lung cancer, colorectal cancer, ovarian cancer, uterine cancer, cervical cancer and other gynecological malignancies, head cancer, neck cancer and gastric cancer. Many cancers are known to involve BRAF, MEK, ERK and/or EGFR expression. Thus, within the present invention the second therapeutic agent to be administered in combination with a compound of this invention, may be an inhibitor of BRAF, MEK, ERK, EGFR, CDK4/6 and mTOR. In particular not limiting embodiments: i) said BRAFi is vemurafenib, dabrafenib, encorafenib, LGX818, PLX4720, TAK- 632, MLN2480, SB590885, XL281, BMS-908662, PLX3603, RO5185426, GSK2118436 or RAF265, ii) said MEKi is AZD6244, trametinib, selumetinib, cobimetinib, binimetinib, MEK162, RO5126766, GDC-0623, PD 0325901, CI-1040, PD-035901, hypothemycin or TAK-733, iii) said ERKi is ulixertinib, corynoxeine, SCH772984, XMD8-92, FR 180204, GDC- 0994, ERK5-IN-1, DEL-22379, BIX 02189, ERK inhibitor (CAS No. 1049738-54-6), ERK inhibitor III (CAS No.331656-92-9), GDC-0994, honokiol, LY3214996, CC-90003, deltonin, VRT752271, TIC10, astragaloside IV, XMD8-92, VX-11e, mogrol, or VTX11e, and/or iv) said EGFRi is cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, necitumumab, osimertinib, afatinib, AP26113, EGFR inhibitor (CAS No. 879127-07-8), EGFR/ErbB- 2/ErbB-4 Inhibitor (CAS No.881001-19-0), EGFR/ErbB-2 Inhibitor (CAS No.179248- 61-4), EGFR inhibitor II (BIBX 1382,CAS No. 196612-93-8), EGFR inhibitor III (CAS No. 733009-42-2), EGFR/ErbB-2/ErbB-4 Inhibitor II (CAS No. 944341-54-2) or PKCβII/EGFR Inhibitor (CAS No.145915-60-2). v) said CDK4/6i is ribociclib, palbociclib or abemaciclib. vi) said mTORi is dactosilib, rapamycin, sirolimus, tmsirolimus, everolimus or ridaforolimus. It is also envisaged that the second therapeutic agent administered in combination with a compound of the invention may be an immunotherapy agent, more particular immuno- oncology agent, such as, e.g. an agent targeting CD52, PD-L1, CTLA4, CD20, or PD-1. Agents that may be used in combination with a compound of the present invention include, for example, alemtuzumab, atezolizumab, ipilimumab, nivolumab, ofatumumab, pembrolizumab, rituximab. The second therapeutic agent may also be selected from: an alkylating agent (for example, a nitrogen mustard or a nitrosourea); an endocrine agent (for example, an adrenocorticosteroid, an androgen, an anti- androgen, an estrogen, an anti-estrogen, an aromatase inhibitor, a gonadotropin-releasing hormone agonist, or a somatostatin analogue); or a compound that targets an enzyme or receptor that is overexpressed and/or otherwise involved in a specific metabolic pathway that is misregulated in the tumor cell (for example, ATP and GTP phosphodiesterase inhibitors, histone deacetylase inhibitors, protein kinase inhibitors (such as serine, threonine and tyrosine kinase inhibitors (for example, Abelson protein tyrosine kinase)) and the various growth factors, their receptors and corresponding kinase inhibitors (such as epidermal growth factor receptor (EGFR) kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, fibroblast growth factor inhibitors, insulin- like growth factor receptor inhibitors and platelet-derived growth factor receptor kinase inhibitors)); methionine, aminopeptidase inhibitors, proteasome inhibitors, cyclooxygenase inhibitors (for example, cyclooxygenase-1 or cyclooxygenase-2 inhibitors), topoisomerase inhibitors (for example, topoisomerase I inhibitors or topoisomerase II inhibitors), and poly ADP ribose polymerase inhibitors (PARP inhibitors). An alkylating agent which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, a nitrogen mustard (such as cyclophosphamide, mechlorethamine (chlormethine), uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, or trofosfamide), a nitrosourea (such as carmustine, streptozocin, fotemustine, lomustine, nimustine, prednimustine, ranimustine, or semustine), an alkyl sulfonate (such as busulfan, mannosulfan, or treosulfan), an aziridine (such as hexamethylmelamine (altretamine), triethylenemelamine, ThioTEPA (N,N'N'- triethylenethiophosphoramide), carboquone, or triaziquone), a hydrazine (such as procarbazine), a triazene (such as dacarbazine), or an imidazotetrazines (such as temozolomide). An anti-tumor antibiotic which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, an anthracycline (such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, or zorubicin), an anthracenedione (such as mitoxantrone, or pixantrone) or an anti-tumor antibiotic isolated from Streptomyces (such as actinomycin (including actinomycin D), bleomycin, mitomycin (including mitomycin C), or plicamycin). A tyrosine kinase inhibitor which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, afatinib, acalabrutinib, alectinib, apatinib, axitinib, bosutinib, cabozantinib, canertinib, crenolanib, cediranib, crizotinib, damnacanthal, dasatinib, entospletinib, entrectinib, erlotinib, foretinib, fostamatinib, gilteritinib, glesatinib, gefitinib, ibrutinib, icotinib, imatinib, linafanib, lapatinib, lestaurtinib, motesanib, mubritinib, nintedanib, nilotinib, ONT-380, pazopanib, quizartinib, regorafenib, rociletinib, radotinib, savolitinib, sitravatinib, semaxanib, sorafenib, sunitinib, savolitinib, sitravatinibg, T790M, tesevatinib, V600E, vatalanib, vemurafenib or vandetanib. A topoisomerase-inhibitor which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, a topoisomerase I inhibitor (such as irinotecan, topotecan, camptothecin, belotecan, rubitecan, or lamellarin D) or a topoisomerase II inhibitor (such as amsacrine, etoposide, etoposide phosphate, teniposide, or doxorubicin). A PARP inhibitor which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, BMN-673, olaparib, rucaparib, veliparib, CEP 9722, MK 4827, BGB-290, or 3-aminobenzamide. Further anticancer drugs may also be used in combination with a compound of the present invention. The anticancer drugs may comprise biological or chemical molecules, like TNF-related apoptosis-inducing ligand (TRAIL), tamoxifen, amsacrine, bexarotene, estramustine, irofulven, trabectedin, cetuximab, panitumumab, tositumomab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, alvocidib, seliciclib, aminolevulinic acid, methyl aminolevulinate, efaproxiral, porfimer sodium, talaporfin, temoporfin, verteporfin, alitretinoin, tretinoin, anagrelide, arsenic trioxide, atrasentan, bortezomib, carmofur, celecoxib, demecolcine, elesclomol, elsamitrucin, etoglucid, lonidamine, lucanthone, masoprocol, mitobronitol, mitoguazone, mitotane, oblimersen, omacetaxine, sitimagene, ceradenovec, tegafur, testolactone, tiazofurine, tipifarnib, vorinostat, or iniparib. Also biological drugs, like antibodies, antibody fragments, antibody constructs (for example, single-chain constructs), and/or modified antibodies (like CDR-grafted antibodies, humanized antibodies, "full humanized" antibodies, etc.) directed against cancer or tumor markers/factors/cytokines involved in proliferative diseases can be employed in co-therapy approaches with the compounds of the invention. Antibodies may, for example, be immuno- oncology antibodies, such as ado-trastuzumab, alemtuzumab, atezolizumab, avelumab, bevacizumab, blinatumomab, brentuximab, capromab, cetuximab, ipilimumab, necitumumab, nivolumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, trastuzumab, or rituximab. The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation. The individual components of such combinations may be administered either sequentially or simultaneously/concomitantly in separate or combined pharmaceutical formulations by any convenient route. When administration is sequential, either the compound of the present invention (i.e., the compound of formula (I) or a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof) or the second therapeutic agent may be administered first. When administration is simultaneous, the combination may be administered either in the same pharmaceutical composition or in different pharmaceutical compositions. When combined in the same formulation, it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately, they may be provided in any convenient formulation. The present invention thus relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, or a pharmaceutical composition comprising any of the aforementioned entities in combination with a pharmaceutically acceptable excipient, for use in the treatment or prevention of cancer, wherein the compound or the pharmaceutical composition is to be administered in combination with an anticancer drug and/or in combination with radiotherapy. Monotherapy Yet, the compounds of formula (I) can also be used in monotherapy, particularly in the monotherapeutic treatment or prevention of cancer (i.e., without administering any other anticancer agents until the treatment with the compound(s) of formula (I) is terminated). Accordingly, the invention also relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, or a pharmaceutical composition comprising any of the aforementioned entities in combination with a pharmaceutically acceptable excipient, for use in the monotherapeutic treatment or prevention of cancer. The subject or patient, such as the subject in need of treatment or prevention, may be an animal (e.g., a non-human animal), a vertebrate animal, a mammal, a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), a murine (e.g., a mouse), a canine (e.g., a dog), a feline (e.g., a cat), a porcine (e.g., a pig), an equine (e.g., a horse), a primate, a simian (e.g., a monkey or ape), a monkey (e.g., a marmoset, a baboon), an ape (e.g., a gorilla, chimpanzee, orang-utan, gibbon), or a human. In the context of this invention, it is particularly envisaged that animals are to be treated which are economically, agronomically or scientifically important. Scientifically important organisms include, but are not limited to, mice, rats, and rabbits. Lower organisms such as, e.g., fruit flies like Drosophila melagonaster and nematodes like Caenorhabditis elegans may also be used in scientific approaches. Non-limiting examples of agronomically important animals are sheep, cattle and pigs, while, for example, cats and dogs may be considered as economically important animals. Preferably, the subject/patient is a mammal; more preferably, the subject/patient is a human or a non-human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orang-utan, a gibbon, a sheep, cattle, or a pig); most preferably, the subject/patient is a human. The term "treatment" of a disorder or disease as used herein (e.g., "treatment" of cancer) is well known in the art. "Treatment" of a disorder or disease implies that a disorder or disease is suspected or has been diagnosed in a patient/subject. A patient/subject suspected of suffering from a disorder or disease typically shows specific clinical and/or pathological symptoms which a skilled person can easily attribute to a specific pathological condition (i.e., diagnose a disorder or disease). The "treatment" of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease (e.g., no deterioration of symptoms) or a delay in the progression of the disorder or disease (in case the halt in progression is of a transient nature only). The "treatment" of a disorder or disease may also lead to a partial response (e.g., amelioration of symptoms) or complete response (e.g., disappearance of symptoms) of the subject/patient suffering from the disorder or disease. Accordingly, the "treatment" of a disorder or disease may also refer to an amelioration of the disorder or disease, which may, e.g., lead to a halt in the progression of the disorder or disease or a delay in the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It is to be understood that a subject/patient may experience a broad range of responses to a treatment (such as the exemplary responses as described herein above). The treatment of a disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief). The "amelioration" of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease or a delay in the progression of the disorder or disease. The term "prevention" of a disorder or disease as used herein (e.g., "prevention" of cancer) is also well known in the art. For example, a patient/subject suspected of being prone to suffer from a disorder or disease may particularly benefit from a prevention of the disorder or disease. The subject/patient may have a susceptibility or predisposition for a disorder or disease, including but not limited to hereditary predisposition. Such a predisposition can be determined by standard methods or assays, using, e.g., genetic markers or phenotypic indicators. It is to be understood that a disorder or disease to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the patient/subject (for example, the patient/subject does not show any clinical or pathological symptoms). Thus, the term "prevention" comprises the use of a compound of the present invention before any clinical and/or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician. It is to be understood that the present invention specifically relates to each and every combination of features and embodiments described herein, including any combination of general and/or preferred features/embodiments. In particular, the invention specifically relates to each combination of meanings (including general and/or preferred meanings) for the various groups and variables comprised in formula (I). In this specification, a number of documents including patent applications and scientific literature are cited. The disclosure of these documents, while not considered relevant for the patentability of this invention, is herewith incorporated by reference in its entirety. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference. The present invention may be better understood with reference to the following examples. These examples are intended to be representative of specific embodiments of the invention, and are not intended as limiting the scope of the invention. EXAMPLES Some general routes towards the desired derivatives are depicted in the schemes below. Scheme 1
Friedel-Crafts amination of a suitable bicyclic heteroaromatic building block 1 with a bromo acetyl bromide 2 afforded bromoketone 3. Reductive amination of a suitable aldehyde 4 with hydroxylamine followed by elimination, gave nitrile 5, which was subsequently converted into the corresponding thioamide 6. Finally, coupling of 3 and 6 through Hantzsch thiazole formation afforded the desired targets (I). Scheme 2 Alternatively, a suitable N-protected bromoketone 7 was coupled to one of two isomeric imidazole thioamides 8 (Z 1 or Z 2 = N), affording thiazole 9. Subsequent N-alkylation followed by deprotection afforded the desired targets (I). Scheme 3
Alternatively, a suitable N-protected bromoketone 7 was coupled to N-protected pyridinone thioamide 11 followed by ester saponification, affording carboxylic acid containing thiazole 12. Amide coupling with the appropriated amine gave 13, which was subsequently deprotected, affording the desired targets (I). General experimental methods LCMS methods: Method A: Apparatus: Agilent 1260; Bin. Pump: G1312B, degasser; autosampler, ColCom, DAD: Agilent G1315D, 220-320 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-800, ELSD Alltech 3300 gas flow 1.5 mL/min, gas temp: 40 °C; column: Waters XSelect TM C18, 30x2.1 mm, 3.5µ, Temp: 35 ºC, Flow: 1 mL/min, Gradient: t 0 = 5% A, t 1.6min = 98% A, t 3min = 98% A, Posttime: 1.3 min, Eluent A: 0.1% formic acid in acetonitrile, Eluent B: 0.1% formic acid in water. Method B: Apparatus: Agilent 1260; Bin. Pump: G1312B, degasser; autosampler, ColCom, DAD: Agilent G1315D, 220-320 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-800, ELSD Alltech 3300 gas flow 1.5 mL/min, gas temp: 40 °C; column: Waters XSelect TM C18, 50x2.1 mm, 3.5µ,Temp: 35 ºC, Flow: 0.8 mL/min, Gradient: t 0 = 5% A, t 3.5min = 98% A, t 6min = 98% A, Posttime: 2 min; Eluent A: 0.1% formic acid in acetonitrile, Eluent B: 0.1% formic acid in water. Method C: Apparatus: Agilent 1260; Bin. Pump: G1312B, degasser; autosampler, ColCom, DAD: Agilent G1315C, 220-320 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-800; column: Waters XSelect TM CSH C18, 30x2.1 mm, 3.5µ,Temp: 25 ºC, Flow: 1 mL/min, Gradient: t 0 = 5% A, t 1.6min = 98% A, t 3min = 98% A, Posttime: 1.3 min, Eluent A: 95% acetonitrile + 5% 10 mM ammoniumbicarbonate in water in acetonitrile, Eluent B: 10 mM ammoniumbicarbonate in water (pH=9.5). Method D: Apparatus: Agilent 1260; Bin. Pump: G1312B, degasser; autosampler, ColCom, DAD: Agilent G1315C, 220-320 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-800; column: Waters XSelect TM CSH C18, 50x2.1 mm, 3.5µ, Temp: 25 ºC, Flow: 0.8 mL/min, Gradient: t 0 = 5% A, t 3.5min = 98% A, t 6min = 98% A, Posttime: 2 min, Eluent A: 95% acetonitrile + 5% 10 mM ammoniumbicarbonate in water in acetonitrile, Eluent B: 10 mM ammoniumbicarbonate in water (pH=9.5). Method E: Apparatus: Waters IClass; Bin. Pump: UPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210-320 nm, SQD: ACQ-SQD2 ESI, pos/neg 100-800; ELSD: gas pressure 40 psi, drift tube temp: 50 °C; column: Waters XSelect CSH C18, 50x2.1mm, 2.5μm,Temp: 25 ºC, Flow: 0.6 mL/min, Gradient: t 0 = 5% A, t 2.0min = 98% A, t 2.7min = 98% A, Posttime: 0.3 min, Eluent A: acetonitrile, Eluent B: 10 mM ammoniumbicarbonate in water (pH=9.5). Method F: Apparatus: Waters IClass; Bin. Pump: UPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210-320 nm, SQD: ACQ-SQD2 ESI, pos/neg 100-800; ELSD: gas pressure 40 psi, drift tube temp: 50 °C; column: Acquity Shield RP18, 50x2.1mm, 1.7μm, Temp: 25 ºC, Flow: 0.5 mL/min, Gradient: t 0 = 5% A, t 2.0min = 98% A, t 2.7min = 98% A, Posttime: 0.3 min, Eluent A: 0.1% formic acid in acetonitrile, Eluent B: 0.1% formic acid in water. Method G: Apparatus: Waters IClass; Bin. Pump: UPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210-320 nm, MS: QDA ESI, pos/neg 100-800; column: Waters XSelect CSH C18, 50x2.1mm, 2.5μm, Temp: 40 ºC, Flow: 0.6 mL/min, Gradient: t 0 = 5% A, t 2.0min = 98% A, t 2.7min = 98% A, Posttime: 0.3 min, Eluent A: 0.1% formic acid in acetonitrile, Eluent B: 0.1% formic acid in water. Method H: Apparatus: Waters IClass; Bin. Pump: UPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210-320 nm, SQD: ACQ-SQD2 ESI, pos/neg 100-800; ELSD: gas pressure 40 psi, drift tube temp: 50 °C; column: Acquity Shield RP18, 50x2.1mm, 1.7μm, Temp: 25 ºC, Flow: 0.5 mL/min, Gradient: t 0 = 5% A, t 2.0min = 98% A, t 2.7min = 98% A, Posttime: 0.3 min, Eluent A: acetonitrile, Eluent B: 10 mM ammoniumbicarbonate in water (pH=9.5). SFC methods: Method A: Apparatus: Waters Acquity UPC2: Waters ACQ-ccBSM Binary Pump; Waters ACQ- CCM Convergence Manager; Waters ACQ-SM Sample Manager - Fixed Loop; Waters ACQ- CM Column Manager - 30S; Waters ACQ-PDA Photodiode Array Detector; Waters ACQ-ISM Make Up Pump, Waters Acquity QDa MS Detector; Column: Chiralpak IC (100x4.6mm 5µM); Column temp: 35 ºC; Flow: 2.5 mL/min; ABPR: 170 bar; Eluent A: CO 2 , Eluent B: methanol + 20mM ammonia; Gradient: t 0 = 5% B, t 5min = 50% A, t 6min = 50% B, Posttime: 0.5 min; Detection: PDA (210–320 nM). Reversed phase chromatography methods: Method A: Instrument type: Reveleris™ preparative MPLC; Column: Phenomenex LUNA C18 (150x25 mm, 10μ); Flow: 40 mL/min; Column temp: room temperature; Eluent A: 0.1% (v/v) formic acid in water, Eluent B: 0.1% (v/v) formic acid in acetonitrile; Gradient: t=0 min 5% B, t=1 min 5% B, t=2 min 30% B, t=17 min 70% B, t=18 min 100% B, t=23 min 100% B; Detection UV: 220/254 nm. Appropriate fractions combined, concentrated and lyophilised from acetonitrile/water. Method B: Instrument type: Reveleris™ preparative MPLC; Column: Waters XSelect CSH C18 (145x25 mm, 10μ); Flow: 40 mL/min; Column temp: room temperature; Eluent A: 10 mM ammoniumbicarbonate in water pH = 9.0); Eluent B: 99% acetonitrile + 1% 10 mM ammoniumbicarbonate in water; Gradient: t=0 min 5% B, t=1 min 5% B, t=2 min 30% B, t=17 min 70% B, t=18 min 100% B, t=23 min 100% B; Detection UV: 220/254 nm. Appropriate fractions combined, concentrated and lyophilized from acetonitrile/water. Preparative HPLC methods: Method A: HPLC instrument: Agilent Technologies 1200 preparative LC; MS instrument: Agilent Technologies G6130B Quadrupole; Column: Waters XSelect CSH (C18, 150x19mm, 10µ); Flow: 25 mL/min; Column temp: RT; Eluent A: 0.1% formic acid in acetonitrile; Eluent B: 0.1% formic acid in water; lin. gradient: t=0 min 5% A, t=2.5 min 5% A, t=11 min 40% A, t=13 min 100% A, t=17 min 100% A; Detection: DAD (220-320 nm); Detection: MSD (ESI pos/neg) mass range: 100 – 800; Fraction collection based on MS and DAD. Appropriate fractions combined, concentrated and lyophilised from acetonitrile/water. Method B: HPLC instrument: Agilent Technologies 1200 preparative LC; MS instrument: Agilent Technologies G6130B Quadrupole; Column: Waters XSelect CSH (C18, 150x19mm, 10µ); Flow: 25 mL/min; Column temp: RT; Eluent A: 100% acetonitrile; Eluent B: 10mM ammonium bicarbonate in water pH=9.0; lin. gradient: t=0 min 20% A, t=2.5 min 20% A, t=11 min 60% A, t=13 min 100% A, t=17 min 100% A; Detection: DAD (220-320 nm); Detection: MSD (ESI pos/neg) mass range: 100 – 800; Fraction collection based on MS and DAD. Appropriate fractions combined, concentrated and lyophilised from acetonitrile/water. Preparative SFC methods: Method A: Apparatus: Waters Prep 100 SFC UV/MS directed system; Waters 2998 Photodiode Array (PDA) Detector; Waters Acquity QDa MS detector; Waters 2767 Sample Manager; Column: Phenomenex Lux Amylose-1 (250x21mm, 5µm); Column temp: 35 °C; Flow: 70 mL/min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in Methanol; Linear gradient: t=0 min 10% B, t=5 min 50% B; t=7.5 min 50% B; Detection: PDA (210-400 nm); Fraction collection based on PDA TIC. Appropriate fractions combined, concentrated and lyophilized from acetonitrile/water. Method B: Apparatus: Waters Prep 100 SFC UV/MS directed system; Waters 2998 Photodiode Array (PDA) Detector; Waters Acquity QDa MS detector; Waters 2767 Sample Manager; Column: Diacel Chiralpak IC for SFC (250x20 mm, 5 μm); Column temp: 35°C; Flow: 70 ml/min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in Methanol; Isocratic method: 50% B for 15 min; Detection: PDA (210-400 nm); Fraction collection: PDA TIC. Appropriate fractions combined, concentrated and lyophilized from acetonitrile/water. Method C: Apparatus: Waters Prep 100 SFC UV/MS directed system; Waters 2998 Photodiode Array (PDA) Detector; Waters Acquity QDa MS detector; Waters 2767 Sample Manager; Column: Phenomenex Lux Cellulose-1 (250x21.2 mm, 5µm); Column temp: 35°C; Flow: 70 ml/min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in Methanol; Linear gradient: t=0 min 30% B, t=6.5 min 50% B, t=8 min 50% B; Detection: PDA (210-400 nm); Fraction collection: PDA TIC. Appropriate fractions combined, concentrated and lyophilized from acetonitrile/water. Starting materials Standard reagents and solvents were obtained at highest commercial purity and used as such, specific reagents purchased are described below.
Synthetic procedures for key intermediates Intermediate 1: synthesis of 2-chloro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one A suspension of AlCl 3 (11.3 g, 85 mmol) in dichloromethane (200 mL) under N 2 atmosphere was stirred at room temperature for 5 min, after which 7-azaindole (2.0 g, 16.9 mmol) was added. After stirring for 1.5h, the mixture was cooled to 0 °C and a solution of chloroacetyl chloride (6.74 mL, 85 mmol) in dichloromethane (50 mL) was slowly added. The reaction was allowed to warm to room temperature and stirred for 18h. Next, MeOH (60 mL) was added, the mixture was stirred for 4h, Na 2 SO 4 .10H 2 O (11 g) was added and stirring was continued for 30 min. The solids were isolated by filtration and resuspended in aq. sat. NaHCO 3 (50 mL) and dichloromethane (200 mL). After filtration the remaining solids were stirred in 2-propanol/water (1/1), filtered off and dried in vacuo, affording 2-chloro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethan- 1-one (quant. yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.68 (s, 1H), 8.59 (s, 1H), 8.46 (d, J = 7.9 Hz, 1H), 8.36 (d, J = 4.7 Hz, 1H), 7.29 (dd, J = 7.9, 4.7 Hz, 1H), 4.93 (s, 2H); LCMS (method C): t R 1.64 min, MS (ESI) 195.1 (M+H) + . Intermediate 2: synthesis of 2-bromo-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one To a suspension of 3-acetyl-7(1H)-azaindole (3.92 g, 24.47 mmol) in 33% hydrobromic acid in acetic acid (64.3 mL, 367 mmol) was slowly added bromine (1.320 mL, 25.7 mmol). The reaction mixture was stirred at 60 °C for 2h, cooled to room temperature and poured in ice- water (200 mL). The resulting suspension was stirred for 20 min, the solids were isolated by filtration, resuspended in water (100 mL) and the resulting suspension neutralized with aq. sat. Na 2 CO 3 . The remaining solids were isolated by filtration, washed with water, triturated with 2- propanol (25 mL) and dried in a vacuo stove at 45 °C for 16h, yielding 2-bromo-1-(1H- pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (4.44 g, 76%) as a beige solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.69 (s, 1H), 8.64 (d, J = 2.9 Hz, 1H), 8.45 (d, J = 7.8 Hz, 1H), 8.36 (d, J = 4.8 Hz, 1H), 7.29 (dd, J = 7.8, 4.8 Hz, 1H), 4.70 (s, 2H); LCMS (method C): t R 1.69 min, MS (ESI) 238.9/240.9 (M+H) + . Intermediate 3: synthesis of 2-bromo-1-(1H-pyrazolo[3,4-b]pyridin-3-yl)ethan-1-one This compound was prepared using procedures analogous to Intermediate 2. 1 H NMR (400 MHz, DMSO-d6): δ 14.68 (s, 1H), 8.67 (dd, J = 4.5, 1.6 Hz, 1H), 8.55 (dd, J = 8.1, 1.6 Hz, 1H), 7.45 (dd, J = 8.1, 4.5 Hz, 1H), 4.93 (s, 2H); LCMS (method A): t R 1.69 min, MS (ESI) 239.9/241.9 (M+H) + . Intermediate 4: synthesis of 2-bromo-1-(6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1- one To a solution of 6-methyl-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.89 mmol) in dichloromethane (10 mL) under N 2 atmosphere was added aluminium trichloride (757 mg, 5.67 mmol). After stirring at 40 °C for 3 min, a solution of bromoacetyl bromide (0.165 mL, 1.89 mmol) in dichloromethane (2 mL) was slowly added and the reaction was stirred at 40 °C for 1h. The resulting mixture was cooled to 0 °C and quenched with ice/water. The precipitated solids were isolated by filtration, washed with 2-propanol and purified by flash chromatography (silicagel, 1% to 10% methanol in dichloromethane), affording 2-bromo-1-(6-methyl-1H-pyrrolo[2,3- b]pyridin-3-yl)ethan-1-one (291 mg, 61%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.49 (s, 1H), 8.53 (d, J = 3.1 Hz, 1H), 8.32 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 4.68 (s, 2H), 2.55 (s, 3H); LCMS (method C): t R 1.75 min, MS (ESI) 253.0/255.0 (M+H) + The following intermediates were prepared using procedures analogous to Intermediate 4:
Intermediate 15: synthesis of tert-butyl 3-(2-bromoacetyl)-1H-pyrrolo[2,3-b]pyridine-1- carboxylate A mixture of 2-bromo-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (Intermediate 2, 1.0 g, 4.18 mmol), di-tert-butyl dicarbonate (1.19 g, 5.44 mmol), 2,6-lutidine (0.59 mL, 5.02 mmol) and 4- dimethylaminopyridine (0.026 g, 0.21 mmol) in tetrahydrofuran (10 mL) and acetonitrile (10 mL) was stirred at room temperature for 45 min. Next, the volatiles were removed in vacuo, the residue was dissolved in EtOAc (70 mL), the resulting solution was washed with 0.1N aq. HCl (3 x 30 mL), dried over Na 2 SO 4 and concentrated. The residue was purified by flash chromatography (silicagel, 5% to 50% EtOAc in heptane), affording tert-butyl 3-(2- bromoacetyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (1.18 g, 83%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.90 (s, 1H), 8.62 – 8.42 (m, 2H), 7.45 (dd, J = 7.8, 4.9 Hz, 1H), 4.90 (s, 2H), 1.66 (s, 9H); LCMS (method C): t R 1.84 min, MS (ESI) 382.0/384.0 (M+H) + . Intermediate 16: synthesis of 2-oxo-1,2-dihydropyridine-3-carbothioamide To a solution of 1,2-dihydro-2-oxopyridine-3-carbonitrile (0.50 g, 4.16 mmol) in pyridine (4 mL) were added triethylamine (0.637 mL, 4.58 mmol) followed by ammonium sulfide (20% in water, 1.56 mL, 4.58 mmol). The reaction mixture was heated in a sealed vial to 50 °C for 3h followed by stirring at room temperature for 3 d. The volatiles were removed in vacuo and the remaining solids were stirred with water (10 mL), isolated by filtration, washed with water and dried on the filter, affording 2-oxo-1,2-dihydropyridine-3-carbothioamide (439 mg, 68%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.67 (s, 1H), 11.34 (s, 1H), 10.04 (s, 1H), 8.95 (dd, J = 7.5, 2.2 Hz, 1H), 7.80 (d, J = 6.1 Hz, 1H), 6.55 (dd, J = 7.4, 6.2 Hz, 1H); LCMS (method C): t R 0.75 min, MS (ESI) 153.1 (M-H)-. Intermediate 17: synthesis of 2-bromo-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazole A suspension of 2-bromo-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (Intermediate 2, 3.0 g, 12.6 mmol) and sodium thiocyanate (1.12 g, 13.8 mmol) in ethanol (20 mL) was stirred at 80 °C for 3 h. Next, the mixture was cooled to room temperature, water (6 mL) was added and stirring was continued for 30 min. The resulting precipitate was isolated by filtration, washed with 1:1 EtOH/water and dried in a vacuum stove at 45 °C, affording 1-(1H-pyrrolo[2,3- b]pyridin-3-yl)-2-thiocyanatoethan-1-one (2.49 g, 91%) as a beige solid. LCMS (method C): t R 1.70 min, MS (ESI) 218.0 (M+H) + . A suspension of 1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2- thiocyanatoethan-1-one (2.48 g, 11.4 mmol) and hydrobromic acid (33% in acetic acid, 18.0 mL, 103 mmol) in dichloromethane (40 mL) was stirred at 45 °C for 4 h. The mixture was cooled to room temperature and neutralized with sat. aq. Na 2 CO 3 (75 mL). Additional water (75 mL) was added and the resulting solids were isolated by filtration. The crude product was suspended in warm MeOH (100 mL) and cooled to room temperature while stirring. The remaining solids were isolated by filtration, washed with MeOH and dried in vacuo, affording 2-bromo-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazole (1.62 g, 49%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.01 (s, 1H), 8.42 (d, J = 7.9 Hz, 1H), 8.30 (d, J = 4.7 Hz, 1H), 8.02 (s, 1H), 7.90 (s, 1H), 7.20 (dd, J = 8.0, 4.7 Hz, 1H); LCMS (method C): t R 1.94 min, MS (ESI) 279.9/281.9 (M+H) + . Intermediate 18: synthesis of 2-bromo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazolo[3,4-b]pyridin-3-yl)ethan-1-one To a cooled (0 °C) solution of 3-iodo-1H-pyrazolo[3,4-b]pyridine (25.2 g, 103 mmol) in N,N- dimethylformamide (500 mL) were added cesium carbonate (36.9 g, 113 mmol) and SEM-Cl (20.1 mL, 113 mmol). The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was filtered,. the filtrate was concentrated in vacuo and the residue was partitioned between water (250 mL) and EtOAc (250 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2x250 mL). The combined organic layers were washed with water (2x250 mL) and brine (2x250 mL), dried over Na 2 SO 4 and concentrated. The crude product was purified by flash chromatography (silicagel, 0% -> 20% EtOAc in n-heptane), affording 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4- b]pyridine (28.8 g, 77 mmol, 75%). LCMS (method C): t R 2.30 min, MS (ESI) 376.1 (M-H)-. To a solution of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4- b]pyridine (28.8 g, 77 mmol) in N,N-dimethylformamide (500 mL) was added tributyl(1-ethoxyvinyl)tin (30 mL, 89 mmol). The mixture was degassed with Argon for 30 min, after which bis(triphenylphosphine)palladium(II) dichloride (5.19 g, 7.39 mmol) was added and the mixture was heated to 100 °C overnight. The reaction mixture was cooled to room temperature and aqueous HCl (1M, 6 mL, 6.0 mmol) was added and the resulting mixture was stirred at room temperature for 2 h. The volume was reduced to ~50 mL in vacuo and the remainder was partitioned between EtOAc (250 mL) and water (200 mL). After standing overnight, aq. KF (50g/100 mL, 600 mL) was added, the resulting mixture was stirred vigorously for 30 min, filtered to remove remaining solids, and the layers were separated. The aqueous layer was extracted with EtOAc (2x250 mL), the combined organic layers were washed with water (2x300 mL) and brine (2x300 mL), dried (Na 2SO4) and concentrated. The residue was purified by flash chromatography (silicagel, 0% to 20% EtOAc in n-heptane), giving 1-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-3-y l)ethan-1-one (19.4 g, 87%). 1 H NMR (400 MHz, DMSO): δ 8.81 (dd, J = 4.5, 1.6 Hz, 1H), 8.69 (dd, J = 8.1, 1.6 Hz, 1H), 7.59 (dd, J = 8.1, 4.5 Hz, 1H), 6.01 (s, 2H), 3.86 – 3.72 (m, 2H), 2.77 (s, 3H), 1.02 – 0.90 (m, 2H), - 0.05 (s, 9H); ); LCMS (method C): t R 2.22 min, MS (ESI) 292.1 (M-H)-.To a solution of 1-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-3-y l)ethan-1-one (266 mg, 0.913 mmol) in chloroform (10 mL) were added sodium hydrogen carbonate (115 mg, 1.37 mmol) and a solution of bromine (0.056 mL, 1.10 mmol) in chloroform (0.6 mL). The resulting mixture was heated to 50 °C for 1.5h, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silicagel, 0% to 30% EtOAc in n-heptane), yielding 2-bromo-1-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-3-y l)ethan-1-one (247 mg, 68%) as a colourless oil. 1 H NMR (400 MHz, CDCl 3 ): δ 8.72 – 8.67 (m, 2H), 7.42 (dd, J = 8.0, 4.6 Hz, 1H), 6.00 (s, 2H), 4.79 (s, 2H), 3.78 – 3.73 (m, 2H), 1.04 – 0.95 (m, 2H), -0.01 (s, 9H); LCMS (method C): t R 2.34 min, MS (ESI) 372.0 (M+H) + . The following intermediates were prepared using procedures analogous to Intermediate 18:
Intermediate 27: synthesis of 1-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-5- methyl-1H-imidazole-2-carbothioamide To a solution of 5-methyl-1H-imidazole-2-carbonitrile (5 g, 46.7 mmol) and 4- (bromomethyl)tetrahydro-2H-thiopyran 1,1-dioxide (12.7 g, 56.0 mmol) in acetonitrile (260 mL) was added potassium carbonate (7.74 g, 56.0 mmol) and the resulting mixture was stirred at reflux temperature overnight. After filtration, the solution was concentrated in vacuo, the residue was partitioned between water and dichloromethane, the layers were separated and the aqueous layer was extracted with 2x dichloromethane. The combined organic layers were dried (Na 2 SO 4 ) and concentrated and the residue was purified by preparative SFC (method B), yielding 1-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-5-methyl -1H-imidazole-2- carbonitrile (3.48 g, 29%) as the pure regioisomer. 1 H NMR (400 MHz, DMSO): δ 7.02 (s, 1H), 4.06 (d, J = 7.6 Hz, 2H), 3.19 – 3.01 (m, 4H), 2.28 (s, 3H), 2.11 (m, 1H), 1.83 (d, J = 13.5 Hz, 2H), 1.79 – 1.66 (m, 2H). SFC (method A): t R 4.92 min, MS (ESI) 254.0 (M+H) + . A suspension of 1-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-5-methyl -1H-imidazole-2-carbonitrile (3.48 g, 13.8 mmol) in pyridine (45 mL) and triethylamine (4.8 mL, 34.5 mmol) was degassed with Argon for 5 min. Ammonium sulfide (20% in water, 7.1 mL, 20.7 mmol) was added and the mixture was stirred at 40 °C overnight. The volatiles were removed in vacuo and the resulting solids were stirred in diethyl ether for 2h. The product was collected by filtration, washed with diethyl ether and dried in air, affording 1-((1,1-dioxidotetrahydro-2H-thiopyran-4- yl)methyl)-5-methyl-1H-imidazole-2-carbothioamide (3.98 g, 100%) as a beige solid. 1 H NMR (400 MHz, DMSO): δ 9.62 (s, 1H), 9.41 (s, 1H), 6.84 (s, 1H), 4.72 (s, 2H), 3.13 – 2.95 (m, 4H), 2.24 (s, 3H), 2.17 – 2.06 (m, 1H), 1.78 – 1.67 (m, 4H). LCMS (method C): t R 1.55 min, MS (ESI) 288.0 (M+H) + . The following intermediate was prepared using procedures analogous to Intermediate 27: Synthetic procedures for final products Example 1: synthesis of 2-(1H-imidazol-4-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazo le (001) A mixture of 2-chloro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (Intermediate 1, 100 mg, 0.51 mmol) and 1H-imidazole-4-carbothioamide (65.3 mg, 0.51 mmol) in ethanol (5 mL) was heated in a sealed vial to 125 °C for 2 d. The resulting suspension was cooled to room temperature and concentrated in vacuo. The crude product was purified by reversed phase chromatography (method B) to afford 2-(1H-imidazol-4-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (57 mg, 42%) as a white foam. 1 H NMR (400 MHz, DMSO-d6): δ 12.56 (s, 1H), 11.93 – 11.84 (m, 1H), 8.59 (dd, J = 8.1, 1.6 Hz, 1H), 8.28 (dd, J = 4.8, 1.6 Hz, 1H), 8.00 (s, 1H), 7.82 (s, 1H), 7.79 (s, 1H), 7.70 (s, 1H), 7.18 (dd, J = 7.9, 4.7 Hz, 1H); LCMS (method D): t R 2.47 min, 98%, MS (ESI) 268.1 (M+H) + . The following compounds were prepared using procedures analogous to Example 1, using the appropriate intermediates and starting materials: Example 2: synthesis of 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-1,2,4-oxad iazole (017) A mixture of 2-bromo-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (Intermediate 2, 74.1 mg, 0.31 mmol) and 1,2,4-oxadiazole-3-carbothioamide (40 mg, 0.31 mmol) in acetonitrile (3 mL) was heated in a sealed vial to 50 °C overnight. The resulting suspension was cooled to room temperature and concentrated in vacuo. The crude product was purified by reversed phase chromatography (method B) to afford 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-1,2,4- oxadiazole (37 mg, 44%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.07 (s, 1H), 9.88 (s, 1H), 8.58 (dd, J = 7.9, 1.6 Hz, 1H), 8.32 (dd, J = 4.7, 1.6 Hz, 1H), 8.28 (s, 1H), 8.15 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 8.0, 4.6 Hz, 1H); LCMS (method D): t R 3.03 min, 95%, MS (ESI) 270.0 (M+H) + . The following compounds were prepared using procedures analogous to Example 2, using the appropriate intermediates and starting materials: Example 3: synthesis of 2-(1H-imidazol-4-yl)-5-methyl-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (038) To a solution of 7-azaindole (200 mg, 1.69 mmol) in dichloromethane (10 mL) under N 2 atmosphere was added aluminium trichloride (677 mg, 5.08 mmol). After heating for 3 min to 40 °C, a solution of 2-bromopropanoyl bromide (0.213 mL, 2.03 mmol) in dichloromethane (2 mL) was slowly added. Stirring was continued 40 °C for 2h, after which the mixture was cooled to 0 °C. Water was added, the resulting suspension was stirred at 20 min upon warming to room temperature and the resulting precipitate was isolated by filtration, washed with water and dried on the filter. The crude product was purified by flash chromatography (silicagel, 0.5% to 10% methanol in dichloromethane), affording 2-bromo-1-(1H-pyrrolo[2,3-b]pyridin-3- yl)propan-1-one (236 mg, 55%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.69 (s, 1H), 8.67 (d, J = 2.7 Hz, 1H), 8.48 (dd, J = 7.9, 1.7 Hz, 1H), 8.36 (dd, J = 4.7, 1.7 Hz, 1H), 7.29 (dd, J = 7.9, 4.7 Hz, 1H), 5.68 (q, J = 6.6 Hz, 1H), 1.78 (d, J = 6.6 Hz, 3H); LCMS (method C): t R 1.77 min, 100%, MS (ESI) 252.9/254.9 (M+H) + . A mixture of 2-bromo-1-(1H-pyrrolo[2,3- b]pyridin-3-yl)propan-1-one (40 mg, 0.16 mmol) and 1H-imidazole-4-carbothioamide (26.1 mg, 0.21 mmol) in ethanol (3 mL) was heated in a sealed vial to 80 °C for 16h. The mixture was cooled to room temperature, the resulting solids were isolated by filtration and washed with ethanol. The remaining material was purified by reversed phase chromatography (method B) to afford 2-(1H-imidazol-4-yl)-5-methyl-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (23 mg, 52%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.51 (s, 1H), 11.90 (s, 1H), 8.54 (dd, J = 8.0, 1.7 Hz, 1H), 8.28 (dd, J = 4.6, 1.7 Hz, 1H), 7.79 – 7.70 (m, 3H), 7.14 (dd, J = 7.9, 4.6 Hz, 1H), 2.56 (s, 3H); LCMS (method D): t R 2.47 min, 99%, MS (ESI) 282.1 (M+H) + . The following compounds were prepared using procedures analogous to Example 3, using the appropriate intermediates and starting materials: Example 4: synthesis of 5-chloro-2-(1H-imidazol-4-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (044) To a solution of 2-(1H-imidazol-4-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazo le (001, 26.8 mg, 0.10 mmol) in N,N-dimethylformamide (dry) (1.5 mL) was added N-chlorosuccinimide (15.5 mg, 0.12 mmol) and the reaction was stirred at room temperature for 4 d. Next the mixture was partitioned between water (5 mL) and dichloromethane (5 mL), the layers were separated and the organic layer was concentrated. The resulting material was purified by preparative HPLC (method A), affording 5-chloro-2-(1H-imidazol-4-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (3.5 mg, 12%) as a tan solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.72 (s, 1H), 12.12 (s, 1H), 8.69 (dd, J = 7.9, 1.7 Hz, 1H), 8.31 (dd, J = 4.6, 1.6 Hz, 1H), 8.13 (s, 1H), 7.94 (s, 1H), 7.82 (s, 1H), 7.20 (dd, J = 8.0, 4.7 Hz, 1H); LCMS (method D): t R 2.70 min, 99%, MS (ESI) 302.0/304.0 (M+H) + . Example 5: synthesis of 5-(1H-imidazol-4-yl)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2,4 - thiadiazole (045) To a solution of 3-bromo-5-chloro-1,2,4-thiadiazole (260 mg, 1.30 mmol) in N,N- dimethylformamide (3.5 mL), were added copper(I) iodide (24.8 mg, 0.13 mmol) and cesium fluoride (495 mg, 3.26 mmol). The reaction mixture was purged with Argon for 10 min, after which 1-(oxan-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imi dazole (399 mg, 1.43 mmol) and tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.065 mmol) were added and the reaction mixture was heated in a sealed vial to 90 °C for 16 h. Subsequently, the reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted 5x with EtOAc. The combined organic layers were washed with brine and concentrated in vacuo. The resulting material was purified using reversed phase chromatography (method B), yielding 3-bromo-5-(1H-imidazol-5-yl)- 1,2,4-thiadiazole (77 mg, 26%). LCMS (method C): t R 1.62 min, 98%, MS (ESI) 230.9/232.9 (M+H) + . To a solution of 3-bromo-5-(1H-imidazol-5-yl)-1,2,4-thiadiazole (40 mg, 0.17 mmol) in N,N-dimethylformamide (4 mL) were added 1H-pyrrolo[2,3-b]pyridine-3-boronic acid pinacol ester (46.5 mg, 0.19 mmol) and potassium phosphate (tribasic monohydrate, 94 mg, 0.41 mmol). The reaction mixture was purged with Argon for 10 min, after which tetrakis(triphenylphosphine)palladium(0) (20.0 mg, 0.017 mmol) was added and the reaction mixture was heated in a Biotage microwave to 120 °C for 15 min. The reaction mixture was partitioned between EtOAc and water, the layers were separated and the aqueous layer was extracted 5x with EtOAc. The combined organic layers were concentrated in vacuo and the resulting material was purified by reversed phase chromatography (method B), affording 5- (1H-imidazol-4-yl)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2,4-t hiadiazole (2.0 mg, 4%) as a pink solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.70 – 8.64 (m, 2H), 8.36 (dd, J = 4.6, 1.7 Hz, 1H), 8.30 (s, 1H), 8.06 (t, J = 1.5 Hz, 1H), 7.31 – 7.23 (m, 2H); LCMS (method D): t R 2.75 min, 90%, MS (ESI) 269.1 (M+H) + . Example 6: synthesis of 4-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5- methyloxazole (046) A solution of 5-methyl-1,3-oxazole-4-carbonitrile (126 mg, 1.17 mmol) in pyridine (4 mL) was purged with Argon 10 min, after which. triethylamine (0.244 mL, 1.75 mmol) and ammonium sulfide (20% in water, 0.596 mL, 1.75 mmol) were added and the resulting solution was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted 2x with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to afford 5-methyloxazole-4-carbothioamide (160 mg, 97%). LCMS (method C): t R 1.28 min, 100%, MS (ESI) 143.0 (M+H) + . A mixture of 2-bromo-1-(1H- pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (Intermediate 2, 50.4 mg, 0.21 mmol) and 5- methyloxazole-4-carbothioamide (30 mg, 0.21 mmol) in acetonitrile (2 mL) was heated in a sealed vial to 50 °C overnight. The resulting suspension was cooled to room temperature and concentrated in vacuo. The crude product was purified by reversed phase chromatography (method B) to afford 4-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5-methylox azole (53 mg, 88%) as a light-purple solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.98 (s, 1H), 8.55 (dd, J = 8.0, 1.6 Hz, 1H), 8.43 (s, 1H), 8.29 (dd, J = 4.6, 1.5 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.89 (s, 1H), 7.20 (dd, J = 7.9, 4.6 Hz, 1H), 2.84 (s, 3H); LCMS (method D): t R 3.36 min, 98%, MS (ESI) 283.0 (M+H) + . The following compounds were prepared using procedures analogous to Example 6, using the appropriate intermediates and starting materials:
Example 7: synthesis of 2-(5-methyl-1H-imidazol-4-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (058) O Br O N ) p N y H ri 2 d O in H e . S N 1 , H 1 C 1 l 0 , A °C c 2 O S N N N H N NH H NH NH 2 ) p (N yr H id 4 i ) n 2 e, 5 E 0 t3 ° N C H2N Me N S , CN, 50 °C N H 058 To a suspension of 5-methyl-1H-imidazole-4-carbaldehyde (1 g, 9.1 mmol) in pyridine (2.5 mL) was added hydroxylamine hydrochloride (0.694 g, 9.99 mmol) and the mixture was stirred at room temperature for 30 min, resulting in a thick slurry. The temperature was raised to 85 °C, acetic anhydride (1.71 mL, 18.2 mmol) was added carefully and the resulting solution was heated further to 110 °C for 1 h. Subsequently, the mixture was cooled to room temperature, diluted with EtOAc and washed with sat. aq. NaHCO 3 . The aqueous phase was extracted 4x with EtOAc and the combined organic layers were washed with water and brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The resulting gel was triturated with diethyl ether, affording 5-methyl-1H-imidazole-4-carbonitrile (584 mg, 60%). 1 H NMR (400 MHz, DMSO-d6): δ 12.82 (s, 1H), 7.74 (s, 1H), 2.32 (s, 3H).5-Methyl-1H-imidazole-4-carbonitrile (250 mg, 2.34 mmol) was dissolved in pyridine (2 mL), after which triethylamine (0.455 mL, 3.27 mmol) and ammonium sulfide (1.11 mL, 3.27 mmol) were added and the reaction was stirred at room temperature overnight. The volatiles were removed in vacuo, the residue was taken up in EtOAc and washed 2x with water and with brine. The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo to afford 5-methyl-1H-imidazole-4-carbothioamide (204 mg, 62%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.41 (s, 1H), 9.05 (s, 1H), 8.83 (s, 1H), 7.57 (s, 1H), 2.61 (s, 3H). A mixture of 2-bromo-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1- one (Intermediate 2, 85 mg, 0.35 mmol) and 5-methyl-1H-imidazole-4-carbothioamide (50 mg, 0.35 mmol) in acetonitrile (2 mL) was heated in a sealed vial to 50 °C overnight. The resulting suspension was cooled to room temperature and concentrated in vacuo. The crude product was purified by reversed phase chromatography (method B) to afford 2-(5-methyl-1H-imidazol- 4-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazole (63 mg, 63%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.35 (s, 1H), 11.90 (s, 1H), 8.56 (dd, J = 8.0, 1.6 Hz, 1H), 8.28 (dd, J = 4.5, 1.7 Hz, 1H), 8.00 (d, J = 2.6 Hz, 1H), 7.66 – 7.61 (m, 2H), 7.18 (dd, J = 7.9, 4.7 Hz, 1H), 2.69 (s, 3H); LCMS (method D): t R 2.60 min, 98%, MS (ESI) 282.1 (M+H) + . The following compounds were prepared using procedures analogous to Example 7, using the appropriate intermediates and starting materials: Example 8: synthesis of 2-(1-methyl-1H-1,2,3-triazol-4-yl)-4-(1H-pyrrolo[2,3-b]pyrid in-3- yl)thiazole (064) This compound was prepared using procedures analogous to Example 7, but instead purified by preparative HPLC (method A), affording 2-(1-methyl-1H-1,2,3-triazol-4-yl)-4-(1H- pyrrolo[2,3-b]pyridin-3-yl)thiazole (41 mg, 59%) as a white solid. 1 H NMR (400 MHz, DMSO- d6): δ 11.97 (s, 1H), 8.79 (s, 1H), 8.61 (dd, J = 7.9, 1.6 Hz, 1H), 8.30 (dd, J = 4.7, 1.6 Hz, 1H), 8.05 (d, J = 2.5 Hz, 1H), 7.90 (s, 1H), 7.19 (dd, J = 7.9, 4.6 Hz, 1H), 4.16 (s, 3H); LCMS (method D): t R 2.88 min, 100%, MS (ESI) 283.0 (M+H) + . The following compounds were prepared using procedures analogous to Example 8, using the appropriate intermediates and starting materials:
Example 9: synthesis of 2-(5-methyl-1H-imidazol-2-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (069) A solution of 4-methylimidazole (1.0 g, 12.2 mmol) in tetrahydrofuran (10 mL) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.536 g, 13.4 mmol) in tetrahydrofuran (10 mL). After stirring at room temperature for 1h, the mixture was cooled to 0 °C and a solution of 2-(trimethylsilyl)ethoxymethyl chloride (2.27 mL, 12.8 mmol) in tetrahydrofuran (dry) (3 mL) was added dropwise. Stirring was continued at room temperature for 1.5h, after which the reaction was quenched with water (5 mL). Most of the THF was removed in vacuo and diethyl ether (70 mL) was added. The mixture was washed with water (25 mL) and brine (25 mL), the organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (silicagel, 0% to 5% methanol in dichloromethane), affording SEM-protected 4-methylimidazole as a ~1:1 mixture of two regioisomers (1.95 g, 75%). LCMS (method A): t R 1.49/1.53 min, 91%, MS (ESI) 213.1 (M+H) + . A solution of 4/5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (regioisomeric mixture, 1.0 g, 4.71 mmol) in tetrahydrofuran (20 mL) under Ar atmosphere was cooled to -78 °C and n-butyllithium (2.5M in hexane, 1.88 mL, 4.71 mmol) was added dropwise. After stirring for 20 min, a solution of N,N-dimethylformamide (0.364 mL, 4.71 mmol) in tetrahydrofuran (2 mL) was added. The resulting mixture was stirred at -78 °C for 15 min followed by stirring at room temperature for 2 days. The reaction mixture was partitioned between aq. sat. NH 4 Cl (30 mL) and diethyl ether (30 mL). The layers were separated and the aqueous layer was extracted with Et 2 O (30 mL). The combined organic layers were washed with aq. sat. NH 4 Cl (30 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (silicagel, 5% to 50% EtOAc in heptane), affording 4/5-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbaldehyde as a ~1:1 mixture of regioisomers (474 mg, 42%). LCMS (method C): t R 2.02/2.04 min, 100%, MS (ESI) 241.1 (M+H) + . To a solution of 4/5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole -2-carbaldehyde (regioisomeric mixture, 0.47 g, 1.96 mmol) in pyridine (5 mL) was added hydroxylamine hydrochloride (0.149 g, 2.15 mmol) and the mixture was stirred at room temperature for 1h. The temperature was raised to 85 °C acetic anhydride (0.367 mL, 3.91 mmol) was added, the temperature was increased further to 110 °C and stirring was continued for 16h. Next , the pyridine was removed in vacuo, MeOH (5 mL) and aq. 2M HCl (5 mL) were added and the resulting mixture was stirred at 60 °C for 5 min and subsequently at 40 °C for 18h. The volatiles were removed in vacuo, the residue was partitioned between aq. sat. NaHCO 3 and EtOAc, the layers were separated, the organic layer washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash chromatography (silicagel, 10% to 40% EtOAc in heptane), affording the SEM-deprotected nitrile as a white solid. This was dissolved in pyridine (4 mL), triethylamine (0.38 mL, 2.76 mmol) was added, the solution was purged with Ar for 3 min and ammonium sulfide (20% in water, 0.941 mL, 2.76 mmol) was added. The reaction was stirred at 40 °C for 16h, cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (silicagel, 1% to 10% ammonia/MeOH in dichloromethane), affording 4-methyl-1H-imidazole-2-carbothioamide (160 mg, 62% over 2 steps) as a light beige solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.43 (s, 1H), 9.50 (s, 1H), 9.25 (s, 1H), 7.11 – 6.68 (m, 1H), 2.18 (s, 3H); LCMS (method C): t R 0.58 min, 100%, MS (ESI) 142.1 (M+H) + . A mixture of 2-bromo-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1- one (Intermediate 2, 40 mg, 0.17 mmol) and 4-m ethyl-1H-imidazole-2-carbothioamide (28 mg, 0.20 mmol) in ethanol (3 mL) was heated in a sealed vial to 80 °C for 3.5h. The volatiles were removed in vacuo and the residue was purified by reversed phase chromatography (method B), affording 2-(5-methyl-1H-imidazol-2-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (11 mg, 23%) as an off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.11 (s, 2H), 8.74 (dd, J = 7.8, 1.6 Hz, 1H), 8.29 (dd, J = 4.6, 1.6 Hz, 1H), 8.05 (s, 1H), 7.79 (s, 1H), 7.19 (dd, J = 7.9, 4.6 Hz, 1H), 6.91 (s, 1H), 2.24 (s, 3H); LCMS (method D): t R 2.90 min, 99%, MS (ESI) 282.0 (M+H) + . The following compounds were prepared using procedures analogous to Example 9, using the appropriate intermediates and starting materials:
Example 10: synthesis of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(5,6,7,8- tetrahydroimidazo[1,5-a]pyrazin-3-yl)thiazole (077) N O N 1) p NH2OH.HCl, Ac2O S N nBuLi, yridine, 110 °C N DMF H N then HCl, MeOH H 2 N N N O THF N O N 2) p (N yr H id 4 i ) n 2 e S , , 5 E 0 t3 ° N C O O O O O Br S N S N N N N N H N HCl/dioxane N N N N N H O N NH MeCN, 50 °C O H 077 Preparation of tert-butyl 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5,6- dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate was performed using procedures analogous to Example 9. To a solution of tert-butyl 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5,6- dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (25 mg, 0.059 mmol) in 1,4-dioxane (2 mL) was added hydrogen chloride (4M in 1,4-dioxane, 0.59 mL, 2.37 mmol) and the mixture was stirred at room temperature for 3 d. The volatiles were removed in vacuo and the residue was purified by reversed phase chromatography (method B), affording 4-(1H-pyrrolo[2,3-b]pyridin- 3-yl)-2-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)thiazo le (17 mg, 89%) as an off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.99 (s, 1H), 8.51 (dd, J = 7.9, 1.6 Hz, 1H), 8.30 (dd, J = 4.6, 1.6 Hz, 1H), 8.09 (s, 1H), 7.82 (s, 1H), 7.20 (dd, J = 7.9, 4.7 Hz, 1H), 6.85 (s, 1H), 4.50 (t, J = 5.6 Hz, 2H), 3.97 (s, 2H), 3.15 (t, J = 5.6 Hz, 2H), 2.66 (d, J = 8.3 Hz, 1H); LCMS (method H): t R 1.08 min, 98%, MS (ESI) 323.0 (M+H) + . Example 11: synthesis of 2-(1-methyl-1H-imidazol-2-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (078) To a solution of tert-butyl 3-(2-bromoacetyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate 15, 250 mg, 0.74 mmol), in acetonitrile (4 mL) were added 1H-imidazole-2- carbothioamide (94 mg, 0.74 mmol) and sodium hydrogencarbonate (61.9 mg, 0.74 mmol) and the mixture was heated to 60 °C for 18h. The reaction mixture was cooled to room temperature and water (2 mL) was added. The resulting suspension was stirred 1h, after which the solids were collected by filtration, washed with water, followed by diethyl ether and dried in a vacuum oven at 40 °C, yielding tert-butyl 3-(2-(1H-imidazol-2-yl)thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridi ne- 1-carboxylate (235 mg, 87%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 13.13 (s, 1H), 8.89 (dd, J = 7.9, 1.7 Hz, 1H), 8.49 (dd, J = 4.8, 1.7 Hz, 1H), 8.39 (s, 1H), 8.20 (s, 1H), 7.42 (dd, J = 8.0, 4.7 Hz, 1H), 7.38 – 7.06 (m, 2H), 1.66 (s, 9H); LCMS (method C): t R 1.95 min, 97%, MS (ESI) 368.1 (M+H) + . To a solution of tert-butyl 3-(2-(1H-imidazol- 2-yl)thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (25 mg, 0.068 mmol) in N,N- dimethylformamide (3 mL) was added sodium hydride (60% dispersion in mineral oil (3.0 mg, 0.075 mmol) at room temperature. After 5 min, iodomethane (6.4 µL, 0.10 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was partitioned between water and dichloromethane, the layers were separated using a phase separator and the organic phase was concentrated in vacuo, yielding the crude Boc-protected product. This was dissolved in 1,4-dioxane (4 mL) and hydrogen chloride (4.0M in dioxane, 0.066 mL, 0.26 mmol) was added. The resulting mixture was heated to 50 °C for 18h, after which the volatiles were removed in vacuo. The crude product was purified by reversed phase chromatography (method B) to afford 2-(1-methyl-1H-imidazol-2-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (12 mg, 81%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.99 (s, 1H), 8.53 (dd, J = 7.9, 1.6 Hz, 1H), 8.30 (dd, J = 4.6, 1.6 Hz, 1H), 8.09 (s, 1H), 7.88 (s, 1H), 7.42 (d, J = 1.0 Hz, 1H), 7.20 (dd, J = 7.9, 4.7 Hz, 1H), 7.06 (d, J = 1.0 Hz, 1H), 4.21 (s, 3H); LCMS (method D): t R 2.75 min, 100%, MS (ESI) 282.0 (M+H) + . The following compounds were prepared using procedures analogous to Example 11, using the appropriate intermediates and starting materials:
Example 12: synthesis of 2-(4-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol - 2-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazole (099) and 2-(5-methyl-1-((tetrahydro-2H- pyran-4-yl)methyl)-1H-imidazol-2-yl)-4-(1H-pyrrolo[2,3-b]pyr idin-3-yl)thiazole (100) A mixture of tert-butyl 3-(2-bromoacetyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate 15, 100 mg, 0.30 mmol), 4-methyl-1H-imidazole-2-carbothioamide (43.7 mg, 0.31 mmol) and sodium hydrogen carbonate (27.2 mg, 0.324 mmol) in acetonitrile (4 mL) was stirred at 50 °C for 18h. The resulting mixture was concentrated in vacuo and the residue was purified by flash chromatography (silicagel, 0.5% to 5% MeOH in dichloromethane), affording tert-butyl 3-(2-(5- methyl-1H-imidazol-2-yl)thiazol-4-yl)-1H-pyrrolo[2,3-b]pyrid ine-1-carboxylate (102 mg, 79%) as a white solid. LCMS (method C): t R 1.99 min, 95%, MS (ESI) 382.1 (M+H) + . A mixture of tert-butyl 3-(2-(5-methyl-1H-imidazol-2-yl)thiazol-4-yl)-1H-pyrrolo[2,3 -b]pyridine-1-carboxylate (50 mg, 0.13 mmol), 4-(iodomethyl)tetrahydro-2H-pyran (44.4 mg, 0.20 mmol) and potassium carbonate (54.3 mg, 0.39 mmol) in N,N-dimethylformamide (4 mL) was stirred at 65 °C for 16h. The volatiles were removed in vacuo, the residue was dissolved in EtOAc (25 mL), washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash chromatography (silicagel, 5% to 100% EtOAc in heptane), yielding two regioisomers as separated product. The first eluting isomer (23 mg, 0.048 mmol) was dissolved in in 1,4- dioxane (2 mL), hydrogen chloride (4N in dioxane, 0.4 mL, 1.6 mmol) was added and the reaction mixture was heated to 40 °C overnight. The resulting mixture was concentrated, the resulting material purified by SCX-cartridge (eluted with 2.5N NH 3 /MeOH) and the resulting material was lyophilized from acetonitrile/water. The product was identified by 2D-NMR as 2- (4-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-2 -yl)-4-(1H-pyrrolo[2,3-b]pyridin- 3-yl)thiazole (099, 15 mg, 31%). 1 H NMR (400 MHz, DMSO-d6): δ 11.98 (s, 1H), 8.50 (dd, J = 8.1, 1.6 Hz, 1H), 8.30 (dd, J = 4.7, 1.6 Hz, 1H), 8.00 (s, 1H), 7.86 (s, 1H), 7.21 – 7.13 (m, 2H), 4.55 (d, J = 7.3 Hz, 2H), 3.87 – 3.78 (m, 2H), 3.22 (td, J = 11.6, 2.2 Hz, 2H), 2.16 (m, 4H), 1.52 – 1.42 (m, 2H), 1.42 – 1.28 (m, 2H); LCMS (method D): t R 3.28 min, 99%, MS (ESI) 380.1 (M+H) + . The second eluting isomer (13 mg, 0.027 mmol) was dissolved in in 1,4-dioxane (1.5 mL), hydrogen chloride (4N in dioxane, 0.2 mL, 0.8 mmol) was added and the reaction mixture was heated to 40 °C overnight. The resulting mixture was concentrated, the resulting material purified by SCX-cartridge (eluted with 2.5N NH 3 /MeOH) and the resulting material was lyophilized from acetonitrile/water. The product was identified by 2D-NMR as 2-(5-methyl-1- ((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-2-yl)-4-(1H-p yrrolo[2,3-b]pyridin-3-yl)thiazole (100, 3.3 mg, 7%). 1 H NMR (400 MHz, DMSO-d6): δ 11.98 (s, 1H), 8.51 (dd, J = 8.0, 1.6 Hz, 1H), 8.31 (dd, J = 4.7, 1.6 Hz, 1H), 8.00 (s, 1H), 7.84 (s, 1H), 7.19 (dd, J = 7.9, 4.7 Hz, 1H), 6.88 (d, J = 1.0 Hz, 1H), 4.57 (d, J = 7.5 Hz, 2H), 3.80 (dt, J = 11.4, 3.2 Hz, 2H), 3.24 – 3.14 (m, 3H), 2.30 (s, 3H), 2.24 – 2.09 (m, 1H), 1.46 – 1.32 (m, 4H); LCMS (method D): t R 3.26 min, 100%, MS (ESI) 380.1 (M+H) + . The following compound was prepared using procedures analogous to Example 12, using the appropriate intermediates and starting materials: Example 13: synthesis of 2-(5-phenyl-1H-imidazol-4-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (111) A solution of bromine (1.61 mL, 31.2 mmol) in acetic acid (40 mL) was added dropwise to a stirring solution of 1H-imidazole-4-carbaldehyde (2 g, 20.8 mmol) and sodium acetate (18.8 g, 229 mmol) in acetic acid (40 mL. The resulting mixture was stirred at room temperature for 20h, after which the volatiles were removed in vacuo. The residue was partitioned between diethyl ether and water, the layers were separated and the aqueous layer was extracted 2x with diethyl ether. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo to afford 5-bromo-1H-imidazole-4-carbaldehyde (1.9 g, 52%). LCMS (method A): t R 0.74 min, 88%, MS (ESI) 174.9/176.9 (M+H) + . 5-bromo-1H- imidazole-4-carbaldehyde (1.4 g, 8.00 mmol) was suspended in pyridine (10 mL) and hydroxylamine hydrochloride (0.61 g, 8.80 mmol) was added. The mixture was stirred at room temperature for 0.5 h, after which the temperature was raised to 85 °C and acetic anhydride (1.51 mL, 16.0 mmol) was added. The resulting mixture was heated to 110 °C for 3 h, cooled to room temperature and concentrated in vacuo. The resulting oil was diluted with EtOAc and washed with aq. sat. NaHCO 3 . The aqueous phase was extracted 4x with EtOAc, the combined organic layers were washed with water and brine, dried over Na 2 SO 4 , filtered and concentrated, and the resulting sticky solid was triturated overnight in diethyl ether. The resulting material was dissolved in N,N-dimethylformamide (40 mL), cooled to 0 °C and sodium hydride (60% dispersion in mineral oil, 240 mg, 6.01 mmol) was added. After 20 min of stirring SEM-Cl (1.45 mL, 8.20 mmol) was and the resulting mixture was stirred at room temperature overnight for 20 h. The resulting mixture was diluted with water and extracted 3x with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (silicagel, 0% to 35% EtOAc in heptane), affording 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5- carbonitrile (~2:1 regioisomeric mixture, 0.9 g, 37%) as a colorless oil. 1 H NMR (400 MHz, chloroform-d): δ 7.70 (s, 0.35H), 7.63 (s, 0.65H), 5.36 (s, 1.3H), 5.31 (s, 0.7H), 3.63 – 3.51 (m, 2H), 0.99 – 0.87 (m, 2H), 0.01 (s, 9H). Regioisomers could be separated by multiple flash chromatography steps (silicagel, 0% -> 30% EtOAc in heptane). A solution of 4-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbonitrile (single regioisomer, 57 mg, 0.189 mmol), phenylboronic acid (25.3 mg, 0.21 mmol) and potassium carbonate (78 mg, 0.57 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was purged with Ar for 5 min, after which tetrakis(triphenylphosphine)palladium(0) (10.9 mg, 9.43 µmol) was added and the reaction was heated in a sealed vial to 100 °C overnight. The resulting mixture was cooled to room temperature and diluted with water. The resulting mixture was extracted 3x with EtOAc, the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash chromatography (silicagel, 0% to 30% EtOAc in heptane), affording 4-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5 -carbonitrile (50.5 mg, 89%) as a beige solid. 1 H NMR (400 MHz, chloroform-d): δ 8.11 – 7.97 (m, 2H), 7.76 (s, 1H), 7.56 – 7.33 (m, 3H), 5.42 (s, 2H), 3.69 – 3.55 (m, 2H), 1.04 – 0.91 (m, 2H), 0.01 (s, 9H). To a solution of 4-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5 -carbonitrile (50 mg, 0.17 mmol) and triethylamine (0.035 mL, 0.25 mmol) in pyridine (2 mL) was added a solution of ammonium sulfide (20% in water, 0.085 mL, 0.25 mmol) was added and the resulting mixture was stirred at room temperature overnight. Additional ammonium sulfide (20% in water, 0.085 mL, 0.25 mmol) was added and stirring was continued at room temperature for 3 d. The resulting mixture was concentrated in vacuo and the residue was partitioned between water and EtOAc. The layers were separated and the organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo to afford 4-phenyl- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbothi oamide (54 mg, 97%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1H), 9.75 (s, 1H), 7.90 (s, 1H), 7.75 – 7.71 (m, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.25 (t, J = 7.4 Hz, 1H), 5.55 (s, 2H), 3.52 – 3.44 (m, 2H), 0.88 – 0.82 (m, 2H), -0.02 (s, 9H). To a solution of 4-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-imidazole-5-carbothioamide (50 mg, 0.15 mmol) in acetonitrile (3 mL) was added 2-bromo- 1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (36 mg, 0.15 mmol) and the reaction mixture was stirred at 50 °C overnight. The volatiles were removed in vacuo, the residue was suspended in dichloromethane (5 mL), ethanol (0.1 mL, 1.7 mmol) and trifluoroacetic acid (1 mL, 13 mmol) were added and the reaction was stirred at room temperature for overnight. The reaction mixture was concentrated and the residue was purified by preparative LCMS (method B), followed by additional purification by reversed phase chromatography (method B), affording 2- (5-phenyl-1H-imidazol-4-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl )thiazole (7.3 mg, 14%) as an off- white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.85 (s, 1H), 11.84 (s, 1H), 8.31 (d, J = 7.9 Hz, 1H), 8.25 (dd, J = 4.7, 1.6 Hz, 1H), 8.06 (d, J = 7.6 Hz, 2H), 7.91 (s, 1H), 7.86 (s, 1H), 7.73 (s, 1H), 7.56 – 7.42 (m, 3H), 7.08 (dd, J = 8.0, 4.7 Hz, 1H); LCMS (method D): t R 3.23 min, 99%, MS (ESI) 344.1 (M+H) + . The following compound was prepared using procedures analogous to Example 13, using the appropriate intermediates and starting materials: Example 14: synthesis of 2-(5-isopropyl-1H-imidazol-4-yl)-4-(1H-pyrrolo[2,3-b]pyridin -3- yl)thiazole (113) To a stirring mixture of ethyl isocyanoacetate (1.94 mL, 17.7 mmol) in tetrahydrofuran (15 mL) were added isobutyric anhydride (3.23 mL, 19.5 mmol) and 1,8-diazabicyclo[5.4.0]undec-7- ene (2.91 mL, 19.5 mmol) and the reaction mixture was stirred at room temperature overnight. Next, the volatiles were removed in vacuo, the residue was dissolved in EtOAc and washed subsequently with 10% aq. Na 2 CO 3 , 10% aq. citric acid and brine. The organic layer was dried over Na 2 SO 4 , filtered and concentrated. The resulting material was purified by flash chromatography (silicagel, 0% to 30% EtOAc in heptane), affording ethyl 5-isopropyloxazole- 4-carboxylate (2 g, 62%). 1 H NMR (400 MHz, chloroform-d): δ 7.75 (s, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.81 (h, J = 7.0 Hz, 1H), 1.40 (t, J = 7.1 Hz, 3H), 1.30 (d, J = 7.0 Hz, 6H). A solution of ethyl 5-isopropyloxazole-4-carboxylate (1.7 g, 9.3 mmol) in formamide (3 mL, 75 mmol) was heated to 165 °C overnight in a sealed vial. The reaction mixture was cooled to room temperature and partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted 3x with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (silicagel, 0% to 5% MeOH in dichloromethane), affording ethyl 5-isopropyl- 1H-imidazole-4-carboxylate (840 mg, 50%). 1 H NMR (400 MHz, chloroform-d): δ 10.09 (s, 1H), 7.59 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.71 (br s, 1H), 1.37 (t, J = 7.2 Hz, 3H), 1.30 (d, J = 7.0 Hz, 6H). A solution of ethyl 5-isopropyl-1H-imidazole-4-carboxylate (840 mg, 4.61 mmol) in tetrahydrofuran (20 mL) was cooled to 0 °C and lithium aluminum hydride (2.4M in THF, 1.92 mL, 4.61 mmol) was added. The resulting mixture was stirred at 0 °C for 1 h and subsequently at room temperature overnight. Next, the mixture cooled again to 0 °C and quenched with Na 2 SO 4 .10H 2 0 until no more gas formation was observed. After stirring at room temperature for 1 h, the solids were removed by filtration, washed 3x with THF and the filtrate was concentrated in vacuo to afford a yellow oil, which solidified upon standing. This material was dissolved in acetone (40 mL), manganese dioxide (88 wt%, 3.19 g, 32.3 mmol) was added and the mixture was stirred at room temperature overnight. Next, the mixture was filtered through a pad of Celite, the filter cake was rinsed 3x with acetone and the filtrate was concentrated in vacuo, affording 5-isopropyl-1H-imidazole-4-carbaldehyde (530 mg, 83%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.77 (s, 1H), 9.81 (s, 1H), 7.76 (s, 1H), 3.61 – 3.47 (m, 1H), 1.23 (d, J = 7.0 Hz, 6H). 5-Isopropyl-1H-imidazole-4-carbaldehyde (530 mg, 3.84 mmol) was dissolved in pyridine (5 mL) and hydroxylamine hydrochloride (293 mg, 4.22 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, after which the temperature was raised to 85 °C, acetic anhydride (0.72 mL, 7.67 mmol) was added and the reaction mixture was heated further to 110 °C for 3 h. Next, the volatiles were removed in vacuo, the residue was partitioned between EtOAc and sat. aq. NaHCO 3 , the layers were separated and the aqueous layer was extracted 2x with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo to give 5- isopropyl-1H-imidazole-4-carbonitrile (485 mg, 94%) a yellow solid, which was used without further purification. 5-Isopropyl-1H-imidazole-4-carbonitrile (300 mg, 2.22 mmol) was dissolved in pyridine (10 mL), triethylamine (0.46 mL, 3.33 mmol) and ammonium sulfide (20% in water, 1.13 mL, 3.33 mmol) were added and the reaction mixture was stirred at room temperature overnight. Additional ammonium sulfide (20% in water, 1.13 mL, 3.33 mmol) was added and stirring was continued for 3 d. Next, the volatiles were removed in vacuo and the residue was partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted 2x with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated and the residue was purified by flash chromatography (silicagel, 0% to 5% MeOH in dichloromethane), affording 5-isopropyl-1H- imidazole-4-carbothioamide (337 mg, 72%) as an off-white solid. 1 H NMR (400 MHz, DMSO- d6): δ 12.37 (s, 1H), 9.08 (s, 1H), 8.87 (s, 1H), 7.58 (s, 1H), 4.68 – 4.54 (m, 1H), 1.19 (d, J = 7.0 Hz, 6H). A mixture of 2-bromo-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (Intermediate 2, 56.5 mg, 0.24 mmol) and 5-isopropyl-1H-imidazole-4-carbothioamide (50 mg, 0.24 mmol) in acetonitrile (3 mL) was heated in a sealed vial to 50 °C overnight. The volatiles were removed in vacuo and the residue was purified by reversed phase chromatography (method B), affording 2-(5-isopropyl-1H-imidazol-4-yl)-4-(1H-pyrrolo[2,3-b]pyridin -3-yl)thiazole (53 mg, 73%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.37 (s, 1H), 11.90 (s, 1H), 8.53 (d, J = 7.8 Hz, 1H), 8.28 (dd, J = 4.7, 1.6 Hz, 1H), 7.98 (s, 1H), 7.68 – 7.61 (m, 2H), 7.18 (dd, J = 7.9, 4.7 Hz, 1H), 4.19 – 4.02 (m, 1H), 1.35 (d, J = 7.0 Hz, 6H); LCMS (method D): t R 2.82 min, 99%, MS (ESI) 310.1 (M+H) + . Example 15: synthesis of 2-(5-isopropyl-1H-1,2,3-triazol-4-yl)-4-(1H-pyrrolo[2,3- b]pyridin-3-yl)thiazole (114) A solution of 2-bromo-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazole (Intermediate 17, 900 mg, 3.21 mmol) in acetonitrile (20 mL) and tetrahydrofuran (20 mL) was cooled to 0 °C, after which di- tert-butyl dicarbonate (912 mg, 4.18 mmol), 2,6-lutidine (0.45 mL, 3.86 mmol) and DMAP (39.2 mg, 0.32 mmol) were added. The reaction mixture was stirred at room temperature for 16 h, concentrated in vacuo and the residue purified by flash chromatography (silicagel, 5% to 50% EtOAc in heptane), affording tert-butyl 3-(2-bromothiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1- carboxylate (895 mg, 73%) as a white foam. LCMS (method C): t R 2.26 min, 99%, MS (ESI) 380.0/382.0 (M+H) + . A solution of tert-butyl 3-(2-bromothiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine- 1-carboxylate (100 mg, 0.263 mmol) in tetrahydrofuran (4 mL) was purged with Ar for 10 min, after which 3-methyl-1-butyne (108 µL, 1.05 mmol), DABCO (59 mg, 0.53 mmol), bis(triphenylphosphine)palladium(II) dichloride (9.2 mg, 13 µmol) and copper(I) iodide (10 mg, 53 µmol) were added. The reaction mixture was heated to 60 °C overnight, cooled to room temperature and filtered over Celite. The filter cake was washed with THF, the combined filtrates were concentrated and the residue was purified by flash chromatography (silicagel, 0% to 30% EtOAc in heptane), affording tert-butyl 3-(2-(3-methylbut-1-yn-1-yl)thiazol-4-yl)-1H- pyrrolo[2,3-b]pyridine-1-carboxylate (63 mg, 61%). 1 H NMR (400 MHz, DMSO-d6): δ 8.59 (dd, J = 7.9, 1.7 Hz, 1H), 8.48 (dd, J = 4.7, 1.7 Hz, 1H), 8.30 (s, 1H), 8.26 (s, 1H), 7.42 (dd, J = 8.0, 4.7 Hz, 1H), 3.00 – 2.91 (m, 1H), 1.65 (s, 9H), 1.27 (d, J = 6.9 Hz, 6H); LCMS (method C): t R 2.40 min, 99%, MS (ESI) 368.1 (M+H) + . To a solution of tert-butyl 3-(2-(3-methylbut-1-yn-1- yl)thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (20 mg, 0.054 mmol) in N,N- dimethylformamide (2 mL) was added sodium azide (4.3 mg, 0.065 mmol) and the resulting mixture was heated to 95 °C overnight. The reaction mixture was cooled to room temperature and water was added. The mixture was extracted 5x with EtOAc, the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by reversed phase chromatography (method B), to afford 2-(5-isopropyl-1H-1,2,3- triazol-4-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazole (19 mg, 40%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 15.33 (br s, 1H), 11.97 (s, 1H), 8.54 (dd, J = 7.8, 1.6 Hz, 1H), 8.30 (dd, J = 4.6, 1.6 Hz, 1H), 8.04 (d, J = 2.5 Hz, 1H), 7.87 (s, 1H), 7.21 (dd, J = 7.9, 4.7 Hz, 1H), 3.92 (m, 1H), 1.41 (d, J = 7.0 Hz, 6H); LCMS (method D): t R 2.90 min, 99%, MS (ESI) 311.0 (M+H) + . Example 16: synthesis of 2-(4,5-dihydro-1H-imidazol-2-yl)-4-(1H-pyrrolo[2,3-b]pyridin -3- yl)thiazole (115) A solution of 2-bromo-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazole (Intermediate 17, 100 mg, 0.36 mmol) in N,N-dimethylacetamide (2 mL) was purged with Ar for 5 min, after which copper(I) cyanide (48 mg, 0.54 mmol) and sodium cyanide (26 mg, 0.54 mmol) were added. The reaction mixture was heated in a sealed vial to 150 °C for 16 h. The resulting mixture was cooled to room temperature, poured in water (13 mL), stirred for 30 min and the resulting solids were isolated by filtration and dried in air. This afforded 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazole-2- carbonitrile (62 mg, 70%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.14 (s, 1H), 8.50 (d, J = 7.8 Hz, 1H), 8.44 (s, 1H), 8.33 (br s, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 7.9, 4.3 Hz, 1H). A mixture of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazole-2-carbonitrile (60 mg, 0.27 mmol) and ethylenediamine (0.089 mL, 1.33 mmol) in ethanol (2 mL) was heated to 80 °C for 4 d. The resulting mixture was concentrated in vacuo and the residue was purified by flash chromatography (silicagel, 0.5% to 10% MeOH in dichloromethane), followed by reversed phase chromatography (method B), affording 2-(4,5-dihydro-1H-imidazol-2-yl)-4-(1H- pyrrolo[2,3-b]pyridin-3-yl)thiazole (8 mg, 11%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.96 (s, 1H), 8.69 (dd, J = 7.9, 1.6 Hz, 1H), 8.29 (dd, J = 4.6, 1.6 Hz, 1H), 8.06 (s, 1H), 7.99 (s, 1H), 7.24 (s, 1H), 7.18 (dd, J = 8.0, 4.6 Hz, 1H), 3.86 (t, J = 9.9 Hz, 2H), 3.50 (t, J = 9.9 Hz, 2H); LCMS (method E): t R 0.96 min, 98%, MS (ESI) 270.0 (M+H) + . The following compound was prepared using procedures analogous to Example 16 using the appropriate intermediates and starting materials: Example 17: synthesis of 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-4-methyl-5 - propylpyridin-2(1H)-one (117) and 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-4,5- diethylpyridin-2(1H)-one (118)
A solution of hexan-3-one (2 g, 20.0 mmol), 2-cyanoacetamide (1.68 g, 20.0 mmol), ammonium acetate (0.15 g, 2.0 mmol) and acetic acid (0.231 mL, 3.99 mmol) in toluene (30 mL) was heated to reflux under Dean stark conditions for 2 d. The reaction mixture was cooled to room temperature and EtOAc (50 mL) was added. The resulting mixture was washed with sat. aq. NaHCO 3 (30 mL) and brine (20 mL), dried over Na 2 SO 4 and concentrated, affording 2-cyano-3-ethylhex-2-enamide (E/Z mixture, 2.59 g, 78%) as a yellow oil, which solidified over time. 1 H NMR (400 MHz, chloroform-d): δ 6.11 (br s, 1H), 5.58 (br s, 1H), 2.86 – 2.73 (m, 2H), 2.59 – 2.47 (m, 2H), 1.68 – 1.47 (m, 2H), 1.19 (t, J = 7.6 Hz, 1.5H), 1.13 (t, J = 7.5 Hz, 1.5H), 1.02 (t, J = 7.0 Hz, 1.5H), 0.98 (t, J = 7.1 Hz, 1.5H). A solution of 2-cyano-3-ethylhex-2-enamide (E/Z mixture, 1.70 g, 10.2 mmol), dimethylformamide diethyl acetal (1.93 mL, 11.3 mmol) in toluene (25 mL) was stirred at 60 °C for 2 h. Next, the volatiles were removed in vacuo and the residue was co-evaporated with toluene, affording 2-cyano-N-((dimethylamino)methylene)- 3-ethylhex-2-enamide (E/Z mixture, 2.17 g, 96%) as an orange/brown oil. LCMS (method C): t R 1.91 min, 97%, MS (ESI) 222.1 (M+H) + . A solution of 2-cyano-N- ((dimethylamino)methylene)-3-ethylhex-2-enamide (E/Z mixture, 2.15 g, 9.72 mmol) in tetrahydrofuran (40 mL) was heated to 50 °C, after which potassium tert-butoxide (1.0M in THF, 10.7 mL, 10.7 mmol) was added. The mixture was heated further to 60 °C for 1h, after which additional potassium tert-butoxide (1.0M in THF, 0.97 mL, 0.97 mmol) was added and heating was continued stirring for 45 min. The reaction was cooled to room temperature, sat. aq. NH 4 Cl (100 mL) was added and the mixture was extracted 2x with EtOAc. The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash chromatography (silicagel, 1% to 4% MeOH in dichloromethane), affording a mixture of 4,5-diethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile and 4-methyl-2-oxo-5-propyl-1,2-dihydropyridine-3-carbonitrile (1.19 g, 60%) as a beige solid. To a solution of a mixture of 4,5-diethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile and 4-methyl- 2-oxo-5-propyl-1,2-dihydropyridine-3-carbonitrile (829 mg, 4.70 mmol) in pyridine (15 mL) were added triethylamine (2.6 mL, 18.8 mmol) and ammonium sulfide (20% in water, 4.42 mL, 18.8 mmol) and the reaction mixture was heated to 50 °C overnight. The mixture was cooled to room temperature and concentrated in vacuo. EtOAc (150 mL) was added and the resulting mixture was washed with water and brine, dried (Na 2 SO 4 ), filtered, the solids washed extensively with warm MeOH and all combined filtrates were concentrated. The residue was purified by flash chromatography (silicagel, 0.5% to 10% MeOH in dichloromethane), yielding 80 mg of a mixture of two isomeric thioamides. The isomers were separated by preparative SFC (method A), affording 4-methyl-2-oxo-5-propyl-1,2-dihydropyridine-3-carbothioamide (42 mg, 4%), 1 H NMR (400 MHz, DMSO-d6): δ 11.37 (br s, 1H), 9.84 (s, 1H), 9.36 (s, 1H), 7.08 (s, 1H), 2.47 – 2.39 (m, 2H), 1.99 (s, 3H), 1.58 – 1.45 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H) and 4,5- diethyl-2-oxo-1,2-dihydropyridine-3-carbothioamide (17 mg, 2%), 1 H NMR (400 MHz, DMSO- d6): δ 11.41 (br s, 1H), 9.89 – 9.81 (m, 1H), 9.38 (s, 1H), 7.03 (s, 1H), 2.56 – 2.51 (m, 3H), 2.38 (q, J = 7.4 Hz, 2H), 1.19 – 1.05 (m, 6H). Both thioamides were reacted separately according to procedures analogous to Example 2, affording 3-(4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazol-2-yl)-4-methyl-5-propylpyridin-2(1H)-one (117) and 3-(4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazol-2-yl)-4,5-diethylpyridin-2(1H)-one (118) as white solids. 117: 1 H NMR (400 MHz, DMSO-d6): δ 12.04 (s, 1H), 11.90 (s, 1H), 8.50 (d, J = 7.3 Hz, 1H), 8.29 (d, J = 4.5 Hz, 1H), 7.94 (s, 1H), 7.88 (s, 1H), 7.40 (s, 1H), 7.18 (dd, J = 8.0, 4.7 Hz, 1H), 3.30 – 3.20 (m, 2H), 2.16 (s, 3H), 1.73 – 1.58 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H); LCMS (method E): t R 1.28 min, 98%, MS (ESI) 351.0 (M+H) + ; 118: 1 H NMR (400 MHz, DMSO-d6): δ 12.08 (s, 1H), 11.89 (s, 1H), 8.51 (dd, J = 7.9, 1.6 Hz, 1H), 8.29 (dd, J = 4.5, 1.6 Hz, 1H), 7.96 (s, 1H), 7.89 (s, 1H), 7.33 (s, 1H), 7.19 (dd, J = 7.9, 4.6 Hz, 1H), 3.30 (m, 2H) 2.57 (q, J = 7.4 Hz, 2H), 1.28 (t, J = 7.3 Hz, 3H), 1.18 (t, J = 7.4 Hz, 3H); LCMS (method D): t R 3.00 min, 99%, MS (ESI) 351.0 (M+H) + . Example 18: synthesis of 4-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5,6- dimethylpyridazin-3(2H)-one (119)
A solution of 2-chloro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (Intermediate 1, 500 mg, 2.57 mmol) and ethyl 3-amino-3-thioxopropanoate (378 mg, 2.57 mmol) in ethanol (10 mL) was heated to reflux for 2 h. The volatiles were removed in vacuo, the residue was dissolved in EtOAc (75 mL) and washed with sat. aq. NaHCO 3 (25 mL). The aqueous layer was extracted with EtOAc (30 mL), the combined organic layers were washed with brine (25 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silicagel, 10% to 100% EtOAc in heptane) affording ethyl 2-(4-(1H- pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)acetate (270 mg, 37%) as a light brown solid. LCMS (method C): t R 1.89 min, 99%, MS (ESI) 288.1 (M+H) + . A solution of ethyl 2-(4-(1H-pyrrolo[2,3- b]pyridin-3-yl)thiazol-2-yl)acetate (265 mg, 0.92 mmol) and hydrazine monohydrate (0.67 mL, 13.8 mmol) in ethanol (5 mL) was heated to 50 °C for 18h. The mixture was cooled to 0 °C, the resulting precipitate was isolated by filtration, washed with cold EtOH and dried in vacuo at 40 °C, affording 2-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)acetohydraz ide (210 mg, 83%) as a white solid. LCMS (method C): t R 1.55 min, 99%, MS (ESI) 274.1 (M+H) + . A solution of 2-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)acetohydraz ide (50 mg, 0.18 mmol) and 2,3- butanedione (0.032 mL, 0.37 mmol) in ethanol (2 mL) was heated in a sealed vial to 50 °C for 1.5 h. The mixture was cooled to 0 °C, the resulting precipitate was isolated by filtration, washed with cold EtOH and dried in vacuo at 40 °C, affording 2-(4-(1H-pyrrolo[2,3-b]pyridin- 3-yl)thiazol-2-yl)-N'-(3-oxobutan-2-ylidene)acetohydrazide (62 mg, 99%) as a light yellow solid. LCMS (method C): t R 1.79 min, 99%, MS (ESI) 342.1 (M+H) + . A solution of 2-(4-(1H- pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-N'-(3-oxobutan-2-yl idene)acetohydrazide (20 mg, 0.059 mmol) in acetic acid (0.5 mL) was heated to 125 °C for 2 h. The mixture was cooled to room temperature, the resulting precipitate was isolated by filtration, washed with acetic acid, water and EtOAc and lyophilized from acetonitrile/water, affording 4-(4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazol-2-yl)-5,6-dimethylpyridazin-3(2H)-one (11 mg, 58%) as a green solid. 1 H NMR (400 MHz, DMSO-d6): δ 13.28 (s, 1H), 11.99 (s, 1H), 8.57 (d, J = 7.8 Hz, 1H), 8.30 (d, J = 4.6 Hz, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.25 – 7.15 (m, 1H), 2.91 (s, 3H), 2.41 (s, 3H); LCMS (method B): t R 2.56 min, 100%, MS (ESI) 324.1 (M+H) + . The following compound was prepared using procedures analogous to Example 18 using the appropriate intermediates and starting materials: Example 19: synthesis of 5-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-6-oxo-1,6- dihydropyridine-3-carboxylic acid hydrochloride (121) A suspension of methyl 5-bromo-6-oxo-1,6-dihydropyridine-3-carboxylate (2 g, 8.62 mmol) in N,N-dimethylformamide (10 mL) under Ar atmosphere was cooled to 0 °C and sodium hydride (60% oil dispersion, 0.45 g, 11.2 mmol) was added. Stirring at was continued 0 °C for 10 min followed by addition of (2-(chloromethoxy)ethyl)trimethylsilane (1.75 mL, 9.91 mmol) and the reaction mixture was stirred at 0 °C for 4 h. The resulting mixture was diluted with EtOAc, quenched with water and the layers were separated. The aqueous layer was extracted 5x with EtOAc, the combined organic layers were washed with brine and concentrated. The residue was purified by flash chromatography (silicagel, 50% to 100% EtOAc in heptane), yielding methyl 5-bromo-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihyd ropyridine-3-carboxylate (1.4 g, 44%). LCMS (method C): t R 2.21 min, 98%, MS (ESI) 362.0/364.0 (M+H) + . A solution of methyl 5-bromo-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihyd ropyridine-3- carboxylate (300 mg, 5.02 mmol) in N,N-dimethylformamide (20 mL) was purged with for 5 min. Next, zinc cyanide (590 mg, 5.02 mmol) and tetrakis(triphenylphosphine)palladium(0) (581 mg, 0.50 mmol) were added and the reaction mixture was heated to 100 °C in a sealed vial overnight. The mixture was cooled room temperature and diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted 4x with EtOAc. Subsequently, the aqueous layer was basified to pH~10 using solid Na 2 CO 3 and extracted 2x with EtOAc. The combined organic layers were dried over Na 2 SO 4 , filtered, concentrated and the residue was coevaporated 3x with dichloromethane. The resulting solids were purified by flash chromatography (silicagel, 0% to 100% EtOAc in heptane), affording methyl 5-cyano-6-oxo-1- ((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-car boxylate (1.28 g, 83%). 1 H NMR (400 MHz, chloroform-d): δ 8.53 (d, J = 2.5 Hz, 1H), 8.34 (d, J = 2.5 Hz, 1H), 5.40 (s, 2H), 3.89 (s, 3H), 3.74 – 3.59 (m, 2H), 1.02 – 0.89 (m, 2H), 0.00 (s, 9H); LCMS (method C): t R 2.10 min, 99%, MS (ESI) 309.1 (M+H) + . A solution of methyl 5-cyano-6-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carboxy late (0.663 g, 2.15 mmol) in pyridine (20 mL) was flushed with Ar for 5 min, after which triethylamine (0.45 mL, 3.22 mmol) and ammonium sulfide (20% in water, 1.47 mL, 4.30 mmol) were added. The reaction mixture was flushed with Ar for an additional 2 min and the reaction mixture was heated in to 50 °C in a sealed vial overnight. The volatiles were removed in vacuo and coevaporated 2x with dichloromethane, affording methyl 5-carbamothioyl-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)- 1,6-dihydropyridine-3-carboxylate (730 mg, 99%) as a yellow solid. LCMS (method C): t R 2.11 min, 97%, MS (ESI) 343.1 (M+H) + . To a suspension of methyl 5-carbamothioyl-6-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carboxy late (240 mg, 0.70 mmol) in acetonitrile (6 mL) were added 2 tert-butyl 3-(2-bromoacetyl)-1H-pyrrolo[2,3-b]pyridine-1- carboxylate (Intermediate 15, 238 mg, 0.70 mmol) and sodium hydrogen carbonate (58.9 mg, 0.701 mmol) and the reaction mixture was heated to 50 °C for 3 h. After cooling to room temperature, the solids were removed by filtration, washed extensively with acetonitrile and the combined filtrates were concentrated in vacuo, affording tert-butyl 3-(2-(5- (methoxycarbonyl)-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl) -1,2-dihydropyridin-3-yl)thiazol-4- yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (177 mg, 43%). 1 H NMR (400 MHz, DMSO-d6): δ 8.99 (d, J = 2.5 Hz, 1H), 8.73 (d, J = 2.6 Hz, 1H), 8.68 (dd, J = 8.0, 1.7 Hz, 1H), 8.49 (dd, J = 4.8, 1.7 Hz, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 7.45 (dd, J = 7.9, 4.7 Hz, 1H), 5.56 (s, 2H), 3.90 (s, 3H), 3.74 – 3.64 (m, 2H), 1.67 (s, 9H), 0.95 – 0.87 (m, 2H), -0.03 (s, 9H); LCMS (method C): t R 2.53 min, 94%, MS (ESI) 583.1 (M+H) + . To a solution of tert-butyl 3-(2-(5-(methoxycarbonyl)- 2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydropyridi n-3-yl)thiazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-1-carboxylate (177 mg, 0.304 mmol) in tetrahydrofuran (1 mL) was added a solution of lithium hydroxide monohydrate (25.5 mg, 0.607 mmol) in water (1 mL) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and water, and the resulting precipitate was isolated by filtration, washed with diethyl ether and dried in vacuo at 40 °C to afford 5-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-6-oxo-1-(( 2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carboxy lic acid (96 mg, 67%) as a white solid. To a suspension of 5-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-6-oxo-1-(( 2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carboxy lic acid (30 mg, 0.064 mmol) in dichloromethane (0.5 mL) under N 2 atmosphere was added trifluoroacetic acid (0.49 mL, 6.40 mmol) and the reaction was stirred at room temperature for 1 h. The volatiles were removed in vacuo and the residue was coevaporated 2x with dichloromethane. Subsequently, the material was dissolved in dichloromethane (2 mL), hydrogen chloride (1M in diethyl ether, 2.0 mL, 2 mmol) was added, the mixture was stirred vigorously for 20 min and the volatiles were removed in vacuo. This procedure was repeated once, affording 5-(4-(1H-pyrrolo[2,3-b]pyridin- 3-yl)thiazol-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid hydrochloride (24 mg, 99%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.93 (m, 1H), 12.24 (s, 1H), 9.00 (d, J = 2.5 Hz, 1H), 8.73 – 8.67 (m, 1H), 8.36 (dd, J = 5.0, 1.5 Hz, 1H), 8.25 – 8.19 (m, 1H), 8.18 – 8.13 (m, 1H), 8.00 (s, 1H), 7.32 (dd, J = 7.9, 4.9 Hz, 1H); LCMS (method D): t R 2.07 min, 97%, MS (ESI) 339.1 (M+H) + . Example 20: synthesis of methyl 5-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-6-oxo- 1,6-dihydropyridine-3-carboxylate hydrochloride (122) To a suspension of methyl 5-carbamothioyl-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1 ,6- dihydropyridine-3-carboxylate (from Example 19; 84 mg, 0.25 mmol) in acetonitrile (1.5 mL) under Ar atmosphere were added 2-bromo-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (Intermediate 2, 59 mg, 0.25 mmol) and sodium hydrogen carbonate (31 mg, 0.37 mmol) and the reaction was heated to 50 °C overnight. After cooling to room temperature, the solids were removed by filtration, washed extensively with acetonitrile and the combined filtrates were concentrated in vacuo, affording methyl 5-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-6-oxo- 1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-c arboxylate (35.4 mg, 30%). LCMS (method C), t R 2.28 min, 98%, MS (ESI) 483.1 (M+H) + . To a suspension of methyl 5-(4-(1H- pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-6-oxo-1-((2-(trimet hylsilyl)ethoxy)methyl)-1,6- dihydropyridine-3-carboxylate (35 mg, 0.073 mmol) in dichloromethane (0.5 mL) under Ar atmosphere was added trifluoroacetic acid (0.56 mL, 7.25 mmol) and the reaction was stirred at room temperature for 2 h. The volatiles were removed in vacuo and the residue coevaporated 2x with dichloromethane. The resulting solids were suspended in a mixture of dichloromethane (2 mL) and acetonitrile (2 mL), hydrogen chloride (1M in diethyl ether, 2 mL, 2 mmol) was added, the mixture was stirred vigorously for 20 min and the volatiles were removed in vacuo. This procedure was repeated once, affording methyl 5-(4-(1H-pyrrolo[2,3- b]pyridin-3-yl)thiazol-2-yl)-6-oxo-1,6-dihydropyridine-3-car boxylate hydrochloride (15.5 mg, 54%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 13.00 (s, 1H), 12.15 (s, 1H), 9.00 (d, J = 2.5 Hz, 1H), 8.67 (d, J = 7.9 Hz, 1H), 8.35 (d, J = 4.7 Hz, 1H), 8.30 – 8.24 (m, 1H), 8.14 (d, J = 2.5 Hz, 1H), 7.99 (s, 1H), 7.30 (dd, J = 7.9, 4.8 Hz, 1H), 3.88 (s, 3H); LCMS (method D): t R 2.69 min, 98%, MS (ESI) 353.1 (M+H) + . Example 21: synthesis of 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5-(piperid ine- 1-carbonyl)pyridin-2(1H)-one (123) To a solution of 5-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-6-oxo-1-(( 2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carboxy lic acid (from Example 19; 50 mg, 0.11 mmol) and piperidine (0.021 mL, 0.213 mmol) in N,N-dimethylformamide (1.5 mL) were added diisopropylethylamine (0.056 mL, 0.320 mmol) and HATU (44.6 mg, 0.12 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DMSO (1.5 mL) and directly purified by reversed phase chromatography (method B) to afford 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5-(piperid ine-1-carbonyl)-1-((2- (trimethylsilyl)ethoxy)methyl)pyridin-2(1H)-one (44 mg, 77%) as an off-white solid. LCMS (method C): t R 2.22 min, 100%, MS (ESI) 536.2 (M+H) + . To a suspension of 3-(4-(1H- pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5-(piperidine-1-car bonyl)-1-((2- (trimethylsilyl)ethoxy)methyl)pyridin-2(1H)-one (44 mg, 0.083 mmol) in dichloromethane (1 mL) was added TFA (0.64 mL, 8.3 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and coevaporated with dichloromethane. The residue was purified by reversed phase chromatography (method B), to afford 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5-(piperid ine-1-carbonyl)pyridin-2(1H)- one (24.2 mg, 72%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.70 (br s, 1H), 11.94 (d, J = 2.7 Hz, 1H), 8.66 (d, J = 2.6 Hz, 1H), 8.61 (dd, J = 8.0, 1.6 Hz, 1H), 8.29 (dd, J = 4.6, 1.6 Hz, 1H), 8.10 (d, J = 2.6 Hz, 1H), 7.92 (s, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.19 (dd, J = 7.9, 4.6 Hz, 1H), 3.61 – 3.50 (m, 4H), 1.72 – 1.64 (m, 2H), 1.63 – 1.54 (m, 4H); LCMS (method D): t R 2.97 min, 96%, MS (ESI) 406.1 (M+H) + . The following compounds were prepared using procedures analogous to Example 21, using the appropriate intermediates and starting materials:
Example 22: synthesis of 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5- (morpholinomethyl)pyridin-2(1H)-one (203)
O O OH N S MeNHOMe.HCl S O CDMT, NMM N N N N N O O THF N O O N N H H Si Si O H N O S morpholine S DIBALH NaBH(OAc)3 N N N N - T 78 HF °C N O O MS 4A N O O N DCM N H H Si Si N O S TFA N DCM NH N O N H 203 To a solution of 5-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-6-oxo-1-(( 2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carboxy lic acid (from Example 19; 50 mg, 0.11 mmol) in tetrahydrofuran (1.5 mL) under N 2 atmosphere were added 2-chloro-4,6- dimethoxy-1,3,5-triazine (22.5 mg, 0.13 mmol) and N-methylmorpholine (0.035 mL, 0.32 mmol) and the mixture was stirred at room temperature for 30 min. Subsequently, N,O- dimethylhydroxylamine hydrochloride (11.5 mg, 0.12 mmol) was added and stirring was continued overnight. The resulting mixture was diluted with DMSO and directly purified by reversed phase chromatography (method B), affording 5-(4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazol-2-yl)-N-methoxy-N-methyl-6-oxo-1-((2-(trimethylsi lyl)ethoxy)methyl)-1,6- dihydropyridine-3-carboxamide (24 mg, 44%). LCMS (method C): t R 2.16 min, 100%, MS (ESI) 512.2 (M+H) + . A solution of 5-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-N-methoxy- N- methyl-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydr opyridine-3-carboxamide (44 mg, 0.086 mmol) in tetrahydrofuran (1.5 mL) under Ar atmosphere was cooled to -78 °C. Subsequently, DIBALH (1M in hexane, 0.30 mL, 0.30 mmol) was added dropwise and stirring was continued at -78 °C for 5 h. The reaction was quenched at -78 °C with sat. aq. NH 4 Cl, diluted with EtOAc and the resulting mixture was warmed to room temperature and stirred for 30 min. The layers were separated and the aqueous layer was extracted 4x with EtOAc and 3x with dichloromethane. The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated, affording crude 5-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-6-oxo-1-(( 2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carbald ehyde, which was used further without purification. LCMS (method C): t R 2.18 min, 75%, MS (ESI) 453.1 (M+H) + . To a suspension of crude 5-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-6-oxo-1-(( 2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carbald ehyde (38.9 mg, 0.086 mmol) dichloromethane (1 mL) were added morpholine (0.015 mL, 0.17 mmol) and activated 4Å molsieves (dried at 110 °C before use; 430 mg, 0.086 mmol) and the reaction mixture was stirred at room temperature for 20 min. Subsequently, sodium triacetoxyborohydride (29.2 mg, 0.14 mmol) was added and stirring was continued overnight. The mixture was diluted with dichloromethane, quenched with sat. aq. NaHCO 3 , stirred for 30 min and filtered. The layers were separated and the aqueous layer was extracted 3x with dichloromethane and 2x with EtOAc. Subsequently, the aqueous layer was basified till pH~11 using Na 2 CO 3 and extracted with dichloromethane and EtOAc. The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated and the residue was purified by reversed phase chromatography (method B), affording 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5-(morphol inomethyl)-1- ((2-(trimethylsilyl)ethoxy)methyl)pyridin-2(1H)-one (10 mg, 22% over 2 steps) as an off-white solid. LCMS (method C): t R 2.12 min, 99%, MS (ESI) 524.2 (M+H) + . To a suspension of 3-(4- (1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5-(morpholinome thyl)-1-((2- (trimethylsilyl)ethoxy)methyl)pyridin-2(1H)-one (10 mg, 0.019 mmol) in dichloromethane (0.5 mL) under N 2 atmosphere was added trifluoroacetic acid (0.15 mL, 1.91 mmol) and the reaction was stirred at room temperature for 5 h. The volatiles were removed in vacuo and the residue was purified by reversed phase chromatography (method B), affording 3-(4-(1H-pyrrolo[2,3- b]pyridin-3-yl)thiazol-2-yl)-5-(morpholinomethyl)pyridin-2(1 H)-one (4.6 mg, 60%) as an off- white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.37 (s, 1H), 11.93 (d, J = 2.7 Hz, 1H), 8.64 (d, J = 2.6 Hz, 1H), 8.60 (dd, J = 7.9, 1.7 Hz, 1H), 8.29 (dd, J = 4.7, 1.6 Hz, 1H), 8.08 (d, J = 2.6 Hz, 1H), 7.88 (s, 1H), 7.52 (s, 1H), 7.20 (dd, J = 7.9, 4.6 Hz, 1H), 3.60 (t, J = 4.6 Hz, 4H), 3.42 – 3.39 (m. 2H), 2.45 – 2.40 (m, 4H); LCMS (method D): t R 2.74 min, 98%, MS (ESI) 394.1 (M+H) + . The following compound was prepared using procedures analogous to Example 22 using the appropriate intermediates and starting materials:
Example 23: synthesis of 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5- (morpholinomethyl)pyridin-2(1H)-one (205) A suspension of O-benzylhydroxylamine hydrochloride (1.5 g, 9.40 mmol) in pyridine (5 mL) was stirred at room temperature for 2 h. Next, the mixture was cooled to 0 °C, ethyl chloroformate (0.90 mL, 9.40 mmol) was slowly added and the resulting mixture was stirred for 60 min at 0 °C and 2 d at room temperature. The volatiles were removed in vacuo, the residue was dissolved in EtOAc (60 mL), the resulting solution was washed sequentially with 1M aq. HCl, sat. aq. NaHCO 3 and brine, dried over Na 2 SO 4 , filtered off and concentrated under reduced pressure. The residue was purified by flash chromatography (silicagel, 5% to 50% EtOAc in heptane), affording ethyl (benzyloxy)carbamate (1.23 g, 67%) as a clear oil. LCMS (method C): t R 1.83 min, 99%, MS (ESI) 196.2 (M+H) + . To a solution of ethyl (benzyloxy)carbamate (0.60 g, 3.07 mmol) and 4-bromobutyronitril (0.37 mL, 3.69 mmol) in acetonitrile (20 mL) was added potassium carbonate (2.12 g, 15.4 mmol) and the reaction mixture was heated to reflux for 16 h. The mixture was cooled to room temperature, the solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silicagel, 10% to 50% EtOAc in heptane), affording ethyl (benzyloxy)(3-cyanopropyl)carbamate (0.76 g, 94%) as a colourless oil. LCMS (method C): t R 1.99 min, 100%, MS (ESI) 263.2 (M+H) + . A solution of ethyl (benzyloxy)(3- cyanopropyl)carbamate (0.20 g, 0.76 mmol) in tetrahydrofuran (5 mL) was cooled to -78 °C, lithium bis(trimethylsilyl)amide (1M in THF, 1.6 mL, 1.6 mmol) was added and the reaction was stirred at -78 °C for 1.5 h. The reaction was quenched by addition of 10% aq. HOAc (5 mL), the resulting mixture was warmed to room temperature and EtOAc (50 mL) was added. The resulting solution was washed with water and brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (silicagel, 5% to 50% EtOAc in heptane), affording 1-(benzyloxy)-2-oxopyrrolidine-3-carbonitrile (129 mg, 78%) as a colourless oil. 1 H NMR (400 MHz, chloroform-d): δ 7.47 – 7.36 (m, 5H), 5.07 – 4.98 (m, 2H), 3.44 (dd, J = 9.5, 8.3 Hz, 1H), 3.33 – 3.22 (m, 2H), 2.44 – 2.32 (m, 1H), 2.27 – 2.13 (m, 1H); LCMS (method C): t R 1.74 min, 100%, MS (ESI) 217.2 (M+H) + . To a solution of 1-(benzyloxy)- 2-oxopyrrolidine-3-carbonitrile (120 mg, 0.56 mmol) and triethylamine (0.25 mL, 1.78 mmol) in pyridine (2 mL) was added ammonium sulfide (20% in water, 0.27 mL, 0.78 mmol) and the reaction was stirred at room temperature overnight. The volatiles were removed in vacuo, the residue was dissolved in EtOAc (50 mL), the resulting solution was washed with water (20 mL) and brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (silicagel, 10% to 70% EtOAc in heptane), affording 1- (benzyloxy)-2-oxopyrrolidine-3-carbothioamide (79 mg, 57%) as a yellow oil. LCMS (method C): t R 1.75 min, 99%, MS (ESI) 251.1 (M+H) + . A mixture of 2-chloro-1-(1H-pyrrolo[2,3-b]pyridin- 3-yl)ethan-1-one (75 mg, 0.31 mmol) and 1-(benzyloxy)-2-oxopyrrolidine-3-carbothioamide (77 mg, 0.31 mmol) in ethanol (4 mL) in a closed pressure vial was heated in an oil bath of 125 °C for 2 d. The resulting mixture was cooled to room temperature and the volatiles were removed in vacuo. The residue was purified by flash chromatography (silicagel, 0.5% to 10% MeOH in dichloromethane) and the resulting material was purified further by reversed phase chromatography (method B), affording 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2- yl)pyrrolidin-2-one (11 mg, 13%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.88 (s, 1H), 8.49 (dd, J = 8.1, 1.6 Hz, 1H), 8.27 (dd, J = 4.7, 1.6 Hz, 1H), 8.01 (s, 1H), 7.96 (s, 1H), 7.76 (s, 1H), 7.17 (dd, J = 7.9, 4.6 Hz, 1H), 4.07 (t, J = 8.9 Hz, 1H), 3.47 – 3.34 (m, 2H), 2.69 – 2.53 (m, 2H); LCMS (method D): t R 2.48 min, 100%, MS (ESI) 285.1 (M+H) + . The following compound was prepared using procedures analogous to Example 23 using the appropriate intermediates and starting materials: Example 24: synthesis of 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5- (hydroxymethyl)pyridin-2(1H)-one (207) To a cooled (-5 °C) solution of 6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-5-(4-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl )thiazol-2-yl)-1,6-dihydropyridine-3- carboxylic acid (from Example 19, 0.100 g, 0.167 mmol) in tetrahydrofuran (1 mL) under Argon atmosphere were added triethylamine (0.028 ml, 0.200 mmol) and ethyl chloroformate (0.019 mL, 0.200 mmol). Stirring was continued at -5 °C for 1h, after which the mixture was filtered and transferred into a cooled (0 °C) solution of cerium chloride heptahydrate (0.093 g, 0.250 mmol) in methanol (0.5 mL). The resulting solution was stirred for 10 min, after which sodium borohydride (9.48 mg, 0.250 mmol) was added portionwise and the resulting mixture was allowed to warm to room temperature overnight. The reaction mixture was quenched with an aqueous saturated solution of NH 4 Cl and diluted with EtOAc. Layers were separated and the aqueous layer was extracted with EtOAc and DCM. The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated. The crude material was purified by preparative HPLC (method B), resulting in 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5-(hydroxy methyl)-1- ((2-(trimethylsilyl)ethoxy)methyl)pyridin-2(1H)-one (26 mg, 27%). This intermediate was dissolved in dichloromethane (1.5 mL), trifluoracetic acid (0.44 mL, 5.6 mmol) was added and the mixture was stirred at room temperature for 4h. Next, the volatiles were removed in vacuo and the residue was coevaporated twice with dichloromethane. The resulting material was suspended in tetrahydrofuran (1 mL) and water (0.25 mL) and 1M aq. NaOH (0.168 mL, 0.168 mmol) was added. Stirring was continued overnight at room temperature, after which additional tetrahydrofuran (1 mL), water (0.25 mL) and 1M aq. NaOH (0.336 mL, 0.336 mmol) were added. The mixture was heated to 35 °C for 5h, diluted with tetrahydrofuran and concentrated in vacuo. The resulting solids were purified by preparative HPLC (method B), affording 3-(4- (1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5-(hydroxymethy l)pyridin-2(1H)-one (8 mg, 44%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.29 (s, 1H), 11.93 (s, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.63 (dd, J = 8.0, 1.6 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.88 (s, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.20 (dd, J = 7.9, 4.7 Hz, 1H), 5.27 (t, J = 5.8 Hz, 1H), 4.42 (d, J = 5.6 Hz, 2H); LCMS (method D): t R 2.56 min, 98%, MS (ESI) 325.1 (M+H) + . Example 25: synthesis of 5-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-1-methyl-6 - oxo-1,6-dihydropyridine-3-carboxylic acid (208) To a suspension of methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (2.5 g, 10.2 mmol) in N,N-dimethylformamide (40 ml) was added zinc cyanide (1.19 g, 10.2 mmol) and the mixture was degassed with Argon for 5 min. Next, tetrakis(triphenylphosphine)palladium(0) (1.17 g, 1.02 mmol) was added and the reaction mixture was heated to 100 °C overnight. The reaction mixture was cooled to room temperature and the resulting solids were isolated by filtration, washed with 70 mL MeCN and dried under vacuum at 40 °C. The mother liquor was diluted with 60 mL water, cooled in an ice bath for 1 h, and the resulting solids were isolated by filtration, washed with 30 mL water and dried under vacuum at 40 °C. The combined solids were triturated with 60 mL methanol and the remaining solids were dried under vacuum at 40 °C, affording methyl 5-cyano-1-methyl-6-oxo-1,6- dihydropyridine-3-carboxylate (1.21 g, 6.30 mmol, 62%) as a white solid. LCMS (method C): t R 1.15 min, 100%, MS (ESI) 193.1 (M+H) + . To a suspension of methyl 5-cyano-1-methyl-6- oxo-1,6-dihydropyridine-3-carboxylate (2.15 g, 11.2 mmol) in pyridine (30 mL) was added triethylamine (3.12 ml, 22.4 mmol) and the mixture was degassed with Argon for 5 min. Next, ammonium sulfide (20 wt% in H 2 O, 7.62 ml, 22.4 mmol) was added, the vial was sealed and the reaction mixture was heated to 50 °C overnight. The reaction mixture was concentrated in vacuo and to the residue were again added pyridine (15 mL) and triethylamine (3.12 ml, 22.4 mmol). The mixture was degassed with Argon for 5 min, ammonium sulfide (20 wt% in H 2 O, 7.62 ml, 22.4 mmol) was added, the vial was sealed and the reaction mixture was again heated to 50 °C overnight. The reaction mixture was concentrated in vacuo and the residue was triturated with 60 mL methanol/water (1/1). After filtration, the solids were washed with Et 2 O and dried under vacuum at 40 °C to afford methyl 5-carbamothioyl-1-methyl-6-oxo-1,6- dihydropyridine-3-carboxylate (2.18 g, 9.64 mmol, 86%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.86 (br s, 1H), 10.24 (br s, 1H), 9.31 (s, 1H), 8.89 (s, 1H), 3.85 (s, 3H), 3.64 (s, 3H); LCMS (method C): t R 1.52 min, 98%, MS (ESI) 227.1 (M+H) + . A mixture of 2-bromo- 1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (Intermediate 2, 1.15 g, 4.81 mmol) and methyl 5- carbamothioyl-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxyla te (1.25 g, 5.53 mmol) in acetonitrile (120 mL) was stirred at 50 °C overnight. The mixture was cooled to room temperature, and the resulting precipitate was isolated by filtration. The resulting solids were triturated with water and sat. aq. NaHCO 3 , washed with water and Et 2 O/MeOH (9/1), and dried under reduced pressure, yielding methyl 5-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-1- methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (2.0 g, 93%) as a brown solid, which was used as such in the next step. LCMS (method C): t R 1.80 min, 96%, MS (ESI) 367.1 (M+H) + . To a suspension of methyl 5-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-1-methyl-6 -oxo-1,6- dihydropyridine-3-carboxylate (1 g, 2.73 mmol) in tetrahydrofuran (12 mL) under Argon atmosphere were added dichloromethane (2 mL), N,N-diisopropylethylamine (0.57 mL, 3.28 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.407 mL, 2.29 mmol) and the reaction was stirred overnight. Additional N,N-diisopropylethylamine (0.57 mL, 3.28 mmol) and 2- (trimethylsilyl)ethoxymethyl chloride (0.407 mL, 2.29 mmol) were added and stirring was continued for 5h. Next, the mixture was diluted with dichloromethane and quenched with sat. aq. NaHCO 3 . The layers were separated and the aqueous layer was extracted 3x with EtOAc. The combined organic layers were dried (Na 2 SO 4 ), concentrated and the residue was purified by flash chromatography (silicagel, 0% to 100% EtOAc in heptane), affording methyl 1-methyl- 6-oxo-5-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[ 2,3-b]pyridin-3-yl)thiazol-2-yl)-1,6- dihydropyridine-3-carboxylate (808 mg, 60%). LCMS (method C): t R 2.35 min, 100%, MS (ESI) 497.1 (M+H) + . A mixture of methyl 1-methyl-6-oxo-5-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-1,6-dihydropyrid ine-3-carboxylate (708 mg, 1.43 mmol) and lithium hydroxide monohydrate (299 mg, 7.13 mmol) in tetrahydrofuran (30 mL) and water (4 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and 0.1M aq. HCl. The layers were separated and the organic layer was washed with brine, dried (Na 2 SO 4 ) and concentrated, affording 1- methyl-6-oxo-5-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-p yrrolo[2,3-b]pyridin-3-yl)thiazol-2- yl)-1,6-dihydropyridine-3-carboxylic acid (625 mg, 91%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 13.20 (s, 1H), 9.02 (d, J = 2.5 Hz, 1H), 8.74 (d, J = 2.5 Hz, 1H), 8.60 (dd, J = 8.0, 1.6 Hz, 1H), 8.37 (dd, J = 4.6, 1.6 Hz, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.31 (dd, J = 7.9, 4.7 Hz, 1H), 5.73 (s, 2H), 3.73 (s, 3H), 3.61 – 3.53 (m, 2H), 0.89 – 0.81 (m, 2H), -0.09 (s, 9H). LCMS (method C): t R 1.76 min, 99%, MS (ESI) 483.1 (M+H) + . To a solution of this SEM-protected carboxylic acid (35 mg, 0.073 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.167 mL, 2.18 mmol) and the reaction was stirred at 30 °C overnight. The solvents were removed in vacuo and the residue was redissolved in 2-propanol (3 mL). Ethylenediamine (0.194 mL, 2.90 mmol) was added, the mixture was stirred at 40 °C for 7h and allowed to warm to room temperature over 2d. Additional ethylenediamine (0.146 mL, 2.18 mmol) was added stirring was continued at 40 °C overnight. The volatiles were removed in vacuo and the residue was purified by preparative HPLC (method A), affording 5-(4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazol-2-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbox ylic acid (5.9 mg, 23%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 13.23 (br s, 1H), 11.96 (d, J = 2.7 Hz, 1H), 9.01 (d, J = 2.5 Hz, 1H), 8.70 (d, J = 2.5 Hz, 1H), 8.58 (dd, J = 8.0, 1.6 Hz, 1H), 8.30 (dd, J = 4.8, 1.6 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.95 (s, 1H), 7.22 (dd, J = 7.9, 4.6 Hz, 1H), 3.72 (s, 3H); LCMS (method B): t R 2.66 min, 99%, MS (ESI) 353.0 (M+H) + . Example 26: synthesis of 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-1-methyl-5 - (1,4-oxazepane-4-carbonyl)pyridin-2(1H)-one (209) To a solution of 1-methyl-6-oxo-5-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H -pyrrolo[2,3- b]pyridin-3-yl)thiazol-2-yl)-1,6-dihydropyridine-3-carboxyli c acid (from Example 25, 27 mg, 0.056 mmol) in N,N-dimethylformamide (1.5 mL) were added homomorpholine monochloride (15.9 mg, 0.12 mmol), N,N-diisopropylethylamine (0.04 mL, 0.23) and HATU (24.1 mg, 0.064 mmol) and the reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo, and the residue was used directly in the deprotection step. To a solution of this crude 1-methyl-5-(1,4-oxazepane-4-carbonyl)-3-(4-(1-((2-(trimethyl silyl)ethoxy)methyl)- 1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)pyridin-2(1H)-one in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL, 26.0 mmol) and the reaction was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was taken up in 2-propanol (4 mL). Ethylenediamine (2 mL, 29.6 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by preparative HPLC (method B), affording 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-1- methyl-5-(1,4-oxazepane-4-carbonyl)pyridin-2(1H)-one (14 mg, 57%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.96 (s, 1H), 8.69 (d, J = 2.5 Hz, 1H), 8.60 (dd, J = 8.0, 1.6 Hz, 1H), 8.32 – 8.26 (m, 2H), 8.11 (s, 1H), 7.95 (s, 1H), 7.20 (dd, J = 8.0, 4.6 Hz, 1H), 3.81 – 3.64 (m, 11H), 1.91 m, 2H); LCMS (method E): t R 1.23 min, 100%, MS (ESI) 436.2 (M+H) + . The following compounds were prepared using procedures analogous to Example 26, using the appropriate intermediates and starting materials:
Example 27: synthesis of 2-(1-ethyl-4-methyl-1H-imidazol-2-yl)-4-(1H-pyrazolo[3,4- b]pyridin-3-yl)thiazole (255) and 2-(1-ethyl-5-methyl-1H-imidazol-2-yl)-4-(1H- pyrazolo[3,4-b]pyridin-3-yl)thiazole (256) A solution of di-tert-butyl dicarbonate (0.411 mL, 1.77 mmol) in tetrahydrofuran (40 mL) was added to 2-(4-methyl-1H-imidazol-2-yl)-4-(1H-pyrazolo[3,4-b]pyridin-3 -yl)thiazole (072, 617 mg, 2.185 mmol). After 5 min, 4-dimethylaminopyridine (26.7 mg, 0.22 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, the residue was dissolved in EtOAc, washed with water and brine, dried (Na 2 SO 4 ) and concentrated to give tert-butyl 3-(2-(5-methyl-1H-imidazol-2-yl)thiazol-4-yl)-1H- pyrazolo[3,4-b]pyridine-1-carboxylate (743 mg, 89%) as a white solid. LCMS (method C): t R 1.85 min, 99%, MS (ESI) 383.1 (M+H) + . To a solution of tert-butyl 3-(2-(4-methyl-1H-imidazol- 2-yl)thiazol-4-yl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (125 mg, 0.33 mmol) and ethyl iodide (0.081 mL, 0.98 mmol) in N,N-dimethylformamide (4 mL) under Argon atmosphere was added potassium carbonate (136 mg, 0.98 mmol) and the reaction was stirred at room temperature overnight. The reactions were concentrated in vacuo and the residue was purified by flash chromatography (silicagel, 0 to 60% EtOAc in n-heptane, followed by 0 to 2% MeOH in dichloromethane). Further purification by preparative SFC (method A) resulting in complete separation of the regioisomers. Both isomers were separately dissolved in dichloromethane (4 mL) and trifluoracetic acid (1 mL) was added. After stirring for 2h, the volatiles were removed in vacuo, and the product was isolated by SCX. Lyophilization from water/acetonitrile afforded the regioisomeric products as white solids. 2-(1-ethyl-4-methyl-1H-imidazol-2-yl)-4-(1H- pyrazolo[3,4-b]pyridin-3-yl)thiazole (255): 1 H NMR (400 MHz, DMSO-d6): δ 13.88 (s, 1H), 8.64 – 8.56 (m, 2H), 8.16 (s, 1H), 7.34 (dd, J = 8.0, 4.5 Hz, 1H), 7.23 (s, 1H), 4.66 (q, J = 7.1 Hz, 2H), 2.17 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H); LCMS (method E): t R 1.36 min, 99%, MS (ESI) 311.2 (M+H) + .2-(1-ethyl-5-methyl-1H-imidazol-2-yl)-4-(1H-pyrazolo[ 3,4-b]pyridin-3-yl)thiazole (256): 1 H NMR (400 MHz, DMSO-d6): δ 13.87 (s, 1H), 8.65 – 8.57 (m, 2H), 8.14 (s, 1H), 7.35 (dd, J = 8.0, 4.4 Hz, 1H), 6.89 (d, J = 1.1 Hz, 1H), 4.66 (q, J = 7.2 Hz, 2H), 2.32 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H); LCMS (method E): t R 1.35 min, 99%, MS (ESI) 311.2 (M+H) + . The following compounds were prepared using procedures analogous to Example 27, using the appropriate intermediates and starting materials: 259 260 261 262
Example 28: synthesis of 2-(5-methyl-1H-imidazol-2-yl)-4-(5-nitro-1H-pyrazolo[3,4- b]pyridin-3-yl)thiazole (265) To a solution of 2-bromo-1-(5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-p yrazolo[3,4- b]pyridin-3-yl)ethan-1-one (Intermediate 18, 188 mg, 0.453 mmol) and 4-methyl-1H-imidazole- 2-carbothioamide (from Example 9, 70.3 mg, 0.50 mmol) in acetonitrile (4 mL) was added sodium hydrogen carbonate (36.1 mg, 0.43 mmol) and the reaction was heated to 50 °C overnight. The volatiles were removed in vacuo and the residue was purified by flash chromatography (silicagel, 0% to 20% EtOAc in n-heptane), giving 2-(5-methyl-1H-imidazol-2- yl)-4-(5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyraz olo[3,4-b]pyridin-3-yl)thiazole (165 mg, 80%). LCMS (method D): t R 2.32 min, 91%, MS (ESI) 458.1 (M+H) + . To a solution of 2-(5- methyl-1H-imidazol-2-yl)-4-(5-nitro-1-((2-(trimethylsilyl)et hoxy)methyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)thiazole (25 mg, 0.055 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL, 13.0 mmol) was added and the resulting mixture was stirred at room temperature for 3h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (method B), affording 2-(5-methyl-1H-imidazol-2-yl)-4-(5-nitro-1H- pyrazolo[3,4-b]pyridin-3-yl)thiazole (14 mg, 78%) a white solid. 1 H NMR (400 MHz, DMSO-d6, tautomers observed): δ 14.59 (s, 1H), 13.11 (d, J = 9.9 Hz, 1H), 9.63 (dd, J = 23.1, 2.5 Hz, 1H), 9.38 (t, J = 3.1 Hz, 1H), 8.27 (d, J = 4.7 Hz, 1H), 7.17 (s, 0.5H), 6.84 (s, 0.5H), 2.33 (s, 1.5H), 2.21 (s, 1.5H); LCMS (method D): t R 2.86 min, 100%, MS (ESI) 328.0 (M+H) + The following compounds were prepared using procedures analogous to Example 28, using the appropriate intermediates and starting materials:
Example 29: synthesis of 4-((2-(4-(6-amino-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl )-5- methyl-1H-imidazol-1-yl)methyl)tetrahydro-2H-thiopyran 1,1-dioxide (277) 2-(3-(2-(1-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl) -5-methyl-1H-imidazol-2- yl)thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindoline-1 ,3-dione was prepared from 2-(3-(2- bromoacetyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindoline-1,3-d ione (Intermediate 14) and 1-((1,1- dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-5-methyl-1H-imid azole-2-carbothioamide (Intermediate 27) following the procedures from Example 28. LCMS (method C): t R 1.91 min, MS (ESI) 573.1 (M+H) + . To a solution of 2-(3-(2-(1-((1,1-dioxidotetrahydro-2H-thiopyran-4- yl)methyl)-5-methyl-1H-imidazol-2-yl)thiazol-4-yl)-1H-pyrrol o[2,3-b]pyridin-6-yl)isoindoline- 1,3-dione (86 mg, 0.15 mmol) in tetrahydrofuran (5 mL) was added hydrazine monohydrate (0.042 mL, 0.85 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was filtered, the filtrated was concentrated in vacuo and the residue was purified by reversed phase chromatography (method B), affording 4-((2-(4-(6-amino-1H-pyrrolo[2,3- b]pyridin-3-yl)thiazol-2-yl)-5-methyl-1H-imidazol-1-yl)methy l)tetrahydro-2H-thiopyran 1,1- dioxide (31 mg, 47%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.13 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.47 (d, J = 2.5 Hz, 1H), 6.88 (s, 1H), 6.38 (d, J = 8.5 Hz, 1H), 5.74 (s, 2H), 4.62 (d, J = 7.5 Hz, 2H), 3.20 – 3.05 (m, 2H), 3.05 – 2.96 (m, 2H), 2.33 – 2.20 (m, 4H), 1.89 – 1.75 (m, 4H); LCMS (method G): t R 0.78 min, 100%, MS (ESI) 443.2 (M+H) + Example 30: synthesis of -((2-(4-(1H-pyrazolo[3,4-b]pyridin-3-yl)thiazol-2-yl)-5-meth yl- 1H-imidazol-1-yl)methyl)tetrahydrothiophene 1,1-dioxide (pure enantiomers, 278/279) The enantiomers of racemic 3-((5-methyl-2-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazolo[3,4-b]pyridin-3-yl)thiazol-2-yl)-1H-imidazol-1-yl)m ethyl)tetrahydrothiophene 1,1- dioxide (from Example 28, 177 mg, 0.33 mmol) were separated by preparative SFC (method C). The first eluting isomer (59.7 mg, 0.11 mmol) was dissolved dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added and the reaction was stirred at room temperature overnight. After concentration in vacuo, the residue was redissolved in methanol (5 mL), ethylenediamine (0.074 mL, 1.10 mmol) was added and the mixture was heated to 40 °C for 2h. The volatiles were removed in vacuo and the residue was purified by reversed phase chromatography (method B), affording 3-((2-(4-(1H-pyrazolo[3,4-b]pyridin-3-yl)thiazol-2-yl)-5- methyl-1H-imidazol-1-yl)methyl)tetrahydrothiophene 1,1-dioxide (isomer 1, 278, 35 mg, 77%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 13.90 (s, 1H), 8.64 – 8.56 (m, 2H), 8.18 (s, 1H), 7.38 – 7.31 (m, 1H), 6.94 (s, 1H), 4.83 – 4.68 (m, 2H), 3.20 (ddd, J = 12.0, 7.5, 2.9 Hz, 2H), 3.10 – 2.96 (m, 3H), 2.33 (s, 3H), 2.15 – 2.03 (m, 1H), 2.02 – 1.88 (m, 1H); LCMS (method E): t R 1.17 min, 100%, MS (ESI) 415.2 (M+H) + . The second eluting isomer (49.7 mg, 0.091 mmol) was dissolved dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added and the reaction was stirred at room temperature overnight. After concentration in vacuo, the residue was redissolved in methanol (5 mL), ethylenediamine (0.074 mL, 1.10 mmol) was added and the mixture was heated to 40 °C for 2h. The volatiles were removed in vacuo and the residue was purified by reversed phase chromatography (method B), affording 3-((2-(4-(1H- pyrazolo[3,4-b]pyridin-3-yl)thiazol-2-yl)-5-methyl-1H-imidaz ol-1- yl)methyl)tetrahydrothiophene 1,1-dioxide (isomer 2, 279, 28 mg, 74%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 13.89 (s, 1H), 8.64 – 8.57 (m, 2H), 8.18 (s, 1H), 7.38 – 7.30 (m, 1H), 6.94 (s, 1H), 4.83 – 4.67 (m, 2H), 3.20 (ddd, J = 12.3, 7.7, 3.0 Hz, 2H), 3.11 – 2.96 (m, 3H), 2.33 (s, 3H), 2.14 – 2.03 (m, 1H), 2.02 – 1.88 (m, 1H); LCMS (method E): t R 1.17 min, 100%, MS (ESI) 415.2 (M+H) + . Example 31: synthesis of 3-(2-(5-methyl-1H-imidazol-2-yl)thiazol-4-yl)-1H-pyrazolo[3, 4- b]pyridin-5-amine (280) Iron (15.3 mg, 0.27 mmol) and ammonium chloride (14.6 mg, 0.27 mmol) were taken up in water (2 mL) and a solution of 2-(5-methyl-1H-imidazol-2-yl)-4-(5-nitro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-3-y l)thiazole (from Example 28, 25 mg, 0.055 mmol) in a mixture of methanol (1 mL) and tetrahydrofuran (1 mL) was added. The resulting suspension was stirred at 70 °C for 3h and was allowed to cool to room temperature overnight. The mixture was extracted with EtOAc (3x 3 mL), the combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated to give 3-(2-(5-methyl-1H-imidazol-2-yl)thiazol-4-yl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyrid in-5-amine (23 mg, 98%) as a yellow glass. LCMS (method C): t R 2.05 min, MS (ESI) 428.2 (M+H) + . SEM-deprotection was carried out as described in Example 28, affording 3-(2-(5-methyl-1H-imidazol-2-yl)thiazol-4-yl)- 1H-pyrazolo[3,4-b]pyridin-5-amine (2.0 mg, 14%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6, tautomers observed): δ 13.36 (br s, 1H), 12.87 (br s, 1H), 8.12 (d, J = 2.6 Hz, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.07 (br s, 0.5H), 6.82 (br s, 0.5H), 5.03 (s, 2H), 2.25 (s, 3H); LCMS (method E): t R 0.97 min, 95%, MS (ESI) 298.2 (M+H) + . Example 32: synthesis of 4-((2-(4-(5-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)thiazol-2-y l)- 5-methyl-1H-imidazol-1-yl)methyl)tetrahydro-2H-thiopyran 1,1-dioxide (281) 4-((5-Methyl-2-(4-(5-nitro-1-((2-(trimethylsilyl)ethoxy)meth yl)-1H-pyrazolo[3,4-b]pyridin-3- yl)thiazol-2-yl)-1H-imidazol-1-yl)methyl)tetrahydro-2H-thiop yran 1,1-dioxide was prepared from the appropriate intermediates, following procedures described in Example 28. Subsequent nitro-reduction was performed analogeous to Example 31, giving 4-((2-(4-(5- amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b ]pyridin-3-yl)thiazol-2-yl)-5- methyl-1H-imidazol-1-yl)methyl)tetrahydro-2H-thiopyran 1,1-dioxide (30 mg, 100%). LCMS (method C): t R 2.06 min, MS (ESI) 574.1 (M+H) + . SEM-deprotection was carried out following the procedures from Example 30. The crude product was purified by reversed phase chromatography (method B), affording 4-((2-(4-(5-amino-1H-pyrazolo[3,4-b]pyridin-3- yl)thiazol-2-yl)-5-methyl-1H-imidazol-1-yl)methyl)tetrahydro -2H-thiopyran 1,1-dioxide (4.8 mg, 21%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 13.40 (s, 1H), 8.12 (d, J = 2.5 Hz, 1H), 7.95 (s, 1H), 7.62 (d, J = 2.6 Hz, 1H), 6.92 (s, 1H), 5.14 (s, 2H), 4.66 (d, J = 7.4 Hz, 2H), 3.15 – 2.85 (m, 4H), 2.32 (s, 3H), 2.29 – 2.14 (m, 1H), 1.89 (d, J = 13.6 Hz, 2H), 1.83 – 1.65 (m, 2H); LCMS (method B): t R 2.18 min, 96%, MS (ESI) 444.1 (M+H) + Example 33: synthesis of N-(3-(2-(5-methyl-1H-imidazol-2-yl)thiazol-4-yl)-1H- pyrazolo[3,4-b]pyridin-5-yl)acetamide (282) To a cooled (0 °C) solution of 3-(2-(5-methyl-1H-imidazol-2-yl)thiazol-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-a mine (from Example 31, 72 mg, 0.17 mmol) in tetrahydrofuran (2 mL) was added acetic anhydride (0.016 mL, 0.17 mmol). The reaction mixture was allowed to warm to room temperature overnight and concentrated in vacuo, giving crude N-(3-(2-(5-methyl-1H-imidazol-2-yl)thiazol-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-y l)acetamide (75 mg, 95%), which was used as such in the next step. LCMS (method C): t R 2.07 min, MS (ESI) 470.1 (M+H) + . SEM-deprotection was carried out as described in Example 28, affording N-(3-(2-(5-methyl- 1H-imidazol-2-yl)thiazol-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-y l)acetamide (29 mg, 54%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6, tautomers observed): δ 13.82 (s, 1H), 12.92 (s, 1H), 10.19 (s, 1H), 8.82 (s, 1H), 8.66 (s, 1H), 8.04 (s, 1H), 7.08 (s, 0.5H), 6.85 (s, 0.5H), 2.25 (s, 3H), 2.11 (s, 3H); LCMS (method E): t R 1.01 min, 98%, MS (ESI) 340.2 (M+H) + . Example 34: synthesis of 3-(4-(5-amino-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-1- methyl-5-(1,4-oxazepane-4-carbonyl)pyridin-2(1H)-one (283) 1-Methyl-3-(4-(5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol- 2-yl)-5-(1,4-oxazepane-4-carbonyl)pyridin-2(1H)-one was prepared following the procedures from Examples 25 and 26. 1-Methyl-3-(4-(5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5-(1,4-oxazepane-4- carbonyl)pyridin-2(1H)-one (54 mg, 0.088 mmol) was converted to 3-(4-(5-amino-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-1- methyl-5-(1,4-oxazepane-4-carbonyl)pyridin-2(1H)-one (19 mg, 48%) analogous to the procedure in Example 31. 1 H NMR (400 MHz, DMSO-d6): δ 11.42 (d, J = 2.9 Hz, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 2.7 Hz, 1H), 7.79 (d, J = 2.5 Hz, 1H), 7.74 (d, J = 2.5 Hz, 1H), 7.69 (s, 1H), 4.82 (br, 2H), 3.73 (m, 8H), 3.68 (s, 4H), 1.90 (dd, J = 7.8, 4.1 Hz, 2H); LCMS (method E): t R 1.01 min, 99%, MS (ESI) 451.2 (M+H) + . Example 35: synthesis of 3-(4-(5-(aminomethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol- 2- yl)-1-methyl-5-(morpholine-4-carbonyl)pyridin-2(1H)-one (284)
3-(2-(1-Methyl-5-(morpholine-4-carbonyl)-2-oxo-1,2-dihydropy ridin-3-yl)thiazol-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-c arbonitrile was prepared following the procedures from Examples 25 and 26. To a suspension of 3-(2-(1-methyl-5-(morpholine- 4-carbonyl)-2-oxo-1,2-dihydropyridin-3-yl)thiazol-4-yl)-1-(( 2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridine-5-carbonitrile (35.9 mg, 0.062 mmol) in ethanol (1.5 mL) were added aqueous ammonium hydroxide (35%, 0.25 mL, 6.22 mmol) and 1,4-dioxane (0.5 mL). Subsequently, Raney®-Nickel (activated catalyst, 50% in water, 0.25 mL, 0.062 mmol) was added and the reaction was stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The reaction mixture was diluted with EtOH and was filtered through Celite. The Celite pad was rinsed with EtOH and dioxane and the combined filtrates were concentrated in vacuo, affording crude 3-(4-(5-(aminomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-1-methyl-5-(morphol ine-4-carbonyl)pyridin-2(1H)-one, which was used directly in the next step. LCMS (method C): t R 2.16 min, MS (ESI) 581.2 (M+H) + . SEM-deprotection was carried out following the procedures from Example 30. The crude product was purified by preparative HPLC (method A), affording 3-(4-(5-(aminomethyl)- 1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-1-methyl-5-(morp holine-4-carbonyl)pyridin-2(1H)- one (11 mg, 36%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.96 (s, 1H), 8.72 (d, J = 2.5 Hz, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.31 (dd, J = 6.2, 2.5 Hz, 3H), 8.13 (s, 1H), 7.93 (s, 1H), 4.05 (s, 2H), 3.68 (s, 3H), 3.65 (m, 8H); LCMS (method E): t R 0.99 min, 97%, MS (ESI) 451.2 (M+H) + . DYRK1B PROTEIN PRODUCTION Insect cells Sf9 (Merck-Millipore 71104-3) were grown in a flask under constant agitation at 28 °C in Sf-900 II SFM medium. For protein expression, 300 mL of Sf9 cells (~2*10 6 /mL) were transduced with 3 mL of N-strep-DYRK1B bacculovirus and grown for 3 days. Finally, cells were collected by centrifugation, washed with PBS and lysed in 40 mL NP buffer (50 mM NaH 2 PO 4 , 300 mM NaCl, pH8) supplemented with 1% Igepal CA-630. The lysate was filtered through a 0.45µm filter and loaded on a Strep-Tactin Superflow Plus Cartridge 5 mL column (Qiagen, Cat. No.30060) using a peristaltic pump (5mL/min). Purification steps were carried out according to manufacturer instructions (Strep-tag Protein Handbook). For buffer exchange and concentration, the eluate was loaded on an Amicon Ultra-1530kd filter (Merck-Milipore UFC903008) and centrifuged 15 min at 5000g. After discarding the flow through, the column was refilled with kinase storage buffer (50mM Tris pH 7.5, 150mM NaCl, 0.5mM EDTA, 0.02% Triton-X, 2mM DTT) and centrifuged again for 15 min at 5000g. Concentrated DYRK1B solution was collected and mixed with 25% glycerol, aliquoted and stored at -80 °C. IC 50 DETERMINATION OF DYRK1B INHIBITORS 11 concentrations (3 fold dilutions) of screening compounds in kinase reaction buffer (50mM HEPES pH 7.5, 20 mM MgCl 2 ,0.01% Triton X-100, were dispensed in white 384 well plates (3572, Corning, NY, USA) (2 µL/well). Next, 2 µL of ATP diluted in kinase reaction buffer (final concentration 100µM) was added to the wells. Finally, the kinase reaction was started by adding 2 µL of a mix of N-strep-DYRK1B (0.5nM) and DYRKtide (50µM) (Lucerna-Chem AG, D96-58) diluted in kinase reaction buffer supplemented with 0.1% DTT. The plate was briefly centrifuged after each steps and the kinase reaction was incubated for 30 min at room temperature. Next, 6 µL of ADP-Glo™ reagent was dispensed and incubated for 40 min at room temperature. Finally, 12 µL of Kinase Detection Reagent was dispensed and incubated for 30 min before measuring the plate on a Tecan infinite M1000pro plate reader (Luminescence mode). For IC50 determination, background (DMSO controls without kinase) were subtracted and the values were normalized to DMSO. Curve fitting was performed with Graphpad Prism software using a 4PL fit (constrain set to top constant equal to 100, bottom constant equal to 0). Legend IC50: A < 10 nM < B < 100 nM < C < 1 µM < D