NZ728416B2 - 2-(morpholin-4-yl)-1,7-naphthyridines - Google Patents

Abstract

The present invention relates to substituted 2-(morpholin-4-yl)-1,7-naphthyridine compounds of general formula (I) or (lb), to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyperproliferative disease as a sole agent or in combination with other active ingredients. and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyperproliferative disease as a sole agent or in combination with other active ingredients.

Description

[Annotation] jennyp None set by jennyp ation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 2-(Morpholinyl)-1,7-naphthyridines Field of application of the ion The invention relates to substituted 2-(morpholinyl)-1,7-naphthyridine compounds, a process for their production and the use thereof.

BACKGROUND OF THE INVENTION The integrity of the genome of eukaryotic cells is secured by complex signaling pathways, referred to as the DNA damage response (DDR), and multiple DNA repair mechanisms. Upon recognizing DNA damage tion of the DDR pathways s in cell cycle arrest, suppression of general translation, induction of DNA repair, and, finally, in cell survival or cell death. Proteins that directly recognize aberrant DNA structures, such as the MREll-RadSO—Nbsl complex recognizing DNA double strand breaks by binding to double—stranded DNA ends, or RPA (replication protein A) binding to single stranded DNA, recruit and activate the most upstream kinases ofthe DDR pathway, ATM a-telangiectasia mutated), ATR (ATM-and elated, UniProtKB/Swiss- Prot Q13535), and DNA—PKcs (DNA—dependent protein kinase). Whereas ATM is primarily activated by DNA double strand , and DNA-PKcs is mainly involved in non-homologous end joining process of DNA repair, ATR responds to a broad spectrum of DNA , including double—strand breaks and lesions derived from interference with DNA replication. Major components of downstream ing of ATM include Cth and p53, whereas ATR signaling involves Chkl and cdc25. Knockout of the ATR gene in mice is embryonically lethal and ATR knockout cells develop chromosome breaks and undergo apoptosis [E.J. Brown, D. Baltimore: ATR tion leads to chromosomal fragmentation and early embryonic lethality. Genes Dev. 14, 397—402, 2000]. In st, ATM is not essential for cell survival although ATM knockout cells are hypersensitive to ionizing radiation and agents which cause DNA double—strand breaks.

ATR, which forms a complex with ATRIP (ATR-interacting protein, UniProtKB/Swiss-Prot ) is mainly activated by long stretches of single—stranded DNA which are generated by the [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp continuing DNA unwinding activity of helicases upon stalled replication. This replication stress with stalled replication forks may be induced by ultraviolet light, certain chemotherapeutic drugs, hydroxyurea, or nt oncogenic signaling resulting in increased replication tion or origin firing. Activation of ATR results in inhibition of the cell cycle in S or 62 phase via the Chk1-cdc25 pathway and in suppression of late origin firing. The cell gains time to resolve the replication stress and, eventually, to restart ation after the source of stress has been d. As the ATR pathway s cell survival after replication stress it potentially contributes to resistance to chemotherapy. Thus inhibition of ATR kinase activity could be useful for cancer treatment.

In oncogene—driven tumor cells (e.g. Ras mutation/upregulation, Myc lation, CyclinE overexpression) increased replication stress has been observed as compared to healthy normal cells. ATR suppression in Ras oncogene driven cells was reported to result in ntial tumor cell killing [0. Gilad, BY Nabet, et al.: Combining ATR suppression with oncogenic Ras synergistically ses genomic instability, g synthetic lethality or tumorigenesis in a dosage-dependent manner. Cancer Res. 70, 9693—9702, 2010].

Although ATM and ATR are principally activated by different types of DNA damage their signaling includes some cross-talk thus that they can, at least partially, tute for each others function.

This finding suggests some tumor-cell selectivity of pharmaceutical inhibition of ATR. A healthy normal cell, which has ATM and ATR pathways in parallel, arrests in 61 phase of the cell cycle upon induced DNA damage even in ce of an ATR inhibitor. In st, a tumor cell which most often deficient in ATM and/or p53 signaling relies on the ATR pathway and undergoes cell death in presence of an ATR inhibitor. This suggests that ATR inhibitors may be used for the treatment oftumors with ent ATM signaling and/or p53 function.

Details of DDR signaling and the functional role of ATM and ATR were recently reviewed in: E.

Fokas, R. Prevo et al.: Targeting ATR in DNA damage response and cancer therapeutics. Cancer Treatment Rev 40, 109-117, 2014. J.M. Wagner & S.H. Kaufmann: Prospects for the use of ATR inhibitors to treat cancer. Pharmaceuticals 3, 1311-1334, 2010. D. Woods & JJ. Tuchi: Chemotherapy induced DNA damage response. Cancer Biol. Thera. 14, 9, 2013. A. al & L. Zou: DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb. Perspect.

Biol. 5, a012716, 2013. M.K. Zeman & K.A. Cimprich: Causes and consequences of replication stress. Nat. Cell Biol. 16, 2-9, 2014.5. Llona-Minguez, A. Hoglund et al.: Chemical strategies for development of ATR inhibitors. Exp. Rev. Mol. Med. 16, e10, 2014.

Dme inhibitors of ATR kinase are known (J. Med. Chem. 2013, 56, 2125-2138; Exp. Rev. Mol.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Med. 16, e10, 2014; W02010054398A1; W02010071837A1; W02010073034A1; W02011143399A1; W02011143419A1; 143422A1; W02011143423A2; W02011143425A2; W02011143426A1; W02011154737A1; W02011163527A1; W02012138938A1; W02012178123A1; W02012178124A1; W02012178125A1; W02013049719A1; W02013049720A1; W02013049722A1; W02013049859A1; W02013071085A1; W02013071088A1; W02013071090A1; W02013071093A1; W02013071094A1; W02013152298A1; W02014062604A1; W02014089379A1; W02014143240).

WO 0058307 describe aryl fused 2,4-disubstituted nes as NK3 receptor ligands. However, no 1,7—naphthyridine compounds are exemplified.

WO 2006039718 be aryl nitrogen—containing bicyclic compounds for the laxis and treatment of protein kinase mediated diseases. However, no 1,7—naphthyridine compounds are exemplified.

WO 2008017461 and the Journal of Medicinal Chemistry 2011, 54(22), 7899-7910 describe 1,7- naphthyridine derivatives as p38 MAP kinase inhibitors. The 8—position of the 1,7—naphthyridine derivatives is substituted with a phenyl ring. No 1,7-naphthyridine compounds are exemplified, which are tuted with a heteroaryl group in the 8-position of the 1,7-naphthyridine.

There is a need for the development of ATR tors for treating diseases, in particular hyperproliferative diseases. The problem to be solved by the present ion is to provide further nds which inhibit ATR. It was found, singly, that 2-(Morpholin—4—y|)-1,7— naphthyridines of general formula (I) or (lb) inhibit ATR.

In accordance with a first aspect, the present invention covers compounds of l formula (I) o/Y 1 KrN/N/N R3\\l in which: [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp R1 represents a group selected from: ZI I2 n * tes the point of attachment of said group with the rest of the molecule; R2 represents en, halogen, -NR7R8, CN, C1-C6-alkyl, C1-C6-alkoxy, 3- to 10-membered heterocycloalkoxy, C2-Ce-alkenyl, C3-C5-cycloalkyl, 3- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkenyl, phenyl, heteroaryl, -(CO)OR7, -(CO)NR7R8, -(SOz)R9, -(SO)R9, -SR9, -(SOz)NR7R8, -NR7(SOz)R9, -((SO)=NR11)R1°, -N=(SO)R9R1°, -SiR1°R"R12, —(PO)(OR7)2, —(PO)(OR7)R10 or —(PO)(R1°)2, wherein each C1-C6-alkyl, C1-C5-alkoxy, 3- to 10-membered heterocycloalkoxy, C2-C5- alkenyl, C3—C6-cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl or heteroaryl is optionally substituted, one or more times, independently from each other, with n, OH, -NR7R8, C1-C6-alkyl optionally substituted one or more times with hydroxyl or phenyl, haloalkyl, C1—C6-alkoxy, C3-C5—cycloalkyl, 3- to 6—membered heterocycloalkyl, phenyl, R7, -(CO)NR7R8, O)R1°, -NR8(CO)OR7, -NR8(CO) NR7R8,-(SOz)R9,-(SO)R9,-SR9,-(SOZ)NR7R8,-NR7(SOZ)RB,-((SO)=NR11)R10, -N=(SO)R9R1°, -(PO)(OR7)2, —(PO)(OR7)R1°, —(PO)(R1°)2 or with a heteroaryl group which is optionally substituted, one or more times, with C1-C4—alkyl; wherein each 4- to 10—membered heterocycloalkenyl is ally substituted, one or more times, indepently from each other, with C1-C4-alkyl; R3, R4 represent, independently from each other, hydrogen or methyl; R7 R8 ent, independently from each other, en, C1—Ce-alkyl, C3-Ce-cycloalkyl or phenyl, which phenyl is optionally substituted, one or more times, with halogen; or R7 and R8 together represent a 4-, 5-, 6— or 7-membered cyclic amine group, which is ally substituted, one or more times, independently from each other, with a substituent selected from C1-C5-alkyl, C1-C5—haloalkyl, said 4—, 5-, 6— or 7-membered cyclic amine group optionally containing one further heteroatom selected from the group consisting of O, N and S; represents C1—C4-alkyl or phenyl, wherein each C1—C4-alkyl or phenyl is optionally substituted, one or more times, ndently from each other, with R13; R10 represents C1-C4-alkyl; or R9 and R10 together, in case of -N=(SO)R9R10 group, represent a 5- to 8-membered heterocycloalkyl group; R11 represents hydrogen, C1-C4-alkyl, R7, -(CO)NR7R8 or CN; R12 represents hydrogen or C1-C4-alkyl; R13 ents halogen, OH, -NR7R8, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6- haloalkoxy, C2-C6-alkenyl, C3-C6-cycloalkyl, -(CO)OR7 or -(CO)NR7R8; or a stereoisomer, a tautomer, an e, a hydrate, a solvate, or a salt thereof, or a mixture of same.

The present invention as claimed herein is described in the following items 1 to 25: 1. A compound of general formula (I) O R1 N N in which: R1 represents a group selected from: N N NH NH * * * , wherein * indicates the point of attachment of said group with the rest of the molecule; 83_1 (GHMatters) P105077.NZ R2 represents hydrogen, halogen, , CN, C1-C6-alkyl, C1-C6-alkoxy, 3- to 10-membered heterocycloalkoxy, C2-C6-alkenyl, C3-C6-cycloalkyl, 3- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkenyl, phenyl, heteroaryl, -(CO)OR7, -(CO)NR7R8, -(SO 9, -(SO)R9, -SR9, -(SO 7R8, -NR7(SO 9, -((SO)=NR11 )R 10 , -N=(SO)R9R10 , 2)R 2)NR 2)R -SiR 10 R11 R12 , –(PO)(OR7) 7)R10 or –(PO)(R10 ) 2, –(PO)(OR 2, wherein each C1-C6-alkyl, C1-C6-alkoxy, 3- to 10-membered heterocycloalkoxy, C2-C6- l, C3-C6-cycloalkyl, 3- to 10-membered cycloalkyl, phenyl or heteroaryl is optionally substituted, one or more times, ndently from each other, with halogen, OH, -NR7R8, C1-C6-alkyl optionally substituted with hydroxyl or phenyl, C1-C6- haloalkyl, C1-C6-alkoxy, C3-C6-cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, -(CO)OR 7, -(CO)NR7R8, -NR7(CO)R 10 , NR8(CO)OR 7, -NR8(CO) NR7R8, -(SO 9, -(SO)R9, -SR9, -(SO 7R8, O 9, -((SO)=NR11 )R 10 , -N=(SO)R9R10 , -(PO)(OR7) 7)R10 , 2)NR 2)R 2, OR –(PO)(R 10 ) 2 or with a heteroaryl group which is optionally substituted, one or more times, with C1-C4-alkyl; wherein each 4- to 10-membered heterocycloalkenyl is optionally substituted, one or more times, independently from each other, with C1-C4-alkyl; R3, R4 represent, independently from each other, hydrogen or methyl; R7, R8 represent, independently from each other, hydrogen, alkyl, C3-C6-cycloalkyl or phenyl, which phenyl is optionally substituted, one or more times, with halogen; or R7 and R8 together ent a 4-, 5-, 6- or 7-membered cyclic amine group, which is optionally substituted, one or more times, independently from each other, with a substituent selected from C1-C6-alkyl, C1-C6-haloalkyl, said 4-, 5-, 6- or 7-membered cyclic amine group optionally ning one further heteroatom selected from the group consisting of O, N and S; R9 ents C1-C4-alkyl or , wherein each alkyl or phenyl is optionally substituted, one or more times, independently from each other, with R13; R10 represents C1-C4-alkyl; or R9 and R10 together, in case of -N=(SO)R9R10 group, represent a 5- to 8-membered heterocycloalkyl group; R11 represents hydrogen, C1-C4-alkyl, -(CO)OR7, -(CO)NR7R8 or CN; 18225983_1 (GHMatters) P105077.NZ R12 represents hydrogen or C1-C4-alkyl; R13 represents halogen, OH, -NR7R8, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6- haloalkoxy, C2-C6-alkenyl, C3-C6-cycloalkyl, -(CO)OR7 or -(CO)NR7R8; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 2. The compound according to item 1, in which R1 represents a group selected from: N N NH NH * * * n * tes the point of attachment of said group with the rest of the molecule; R2 represents hydrogen, halogen, -NR7R8, CN, C1-C6-alkyl, C1-C6-alkoxy, 3- to 10-membered heterocycloalkoxy, C2-C6-alkenyl, C3-C6-cycloalkyl, 3- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkenyl, phenyl, heteroaryl, -(CO)OR7, -(CO)NR7R8, -(SO2)R9, -(SO)R9, -SR9, -(SO2)NR7R8, -NR7(SO2)R9, -((SO)=NR11)R10, -N=(SO)R9R10, -SiR10R11R12, –(PO)(OR7)2, –(PO)(OR7)R10 or –(PO)(R10)2, n each C1-C6-alkyl, C1-C6-alkoxy, 3- to bered heterocycloalkoxy, C2-C6- alkenyl, C3-C6-cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl or heteroaryl is optionally substituted, one or more times, independently from each other, with halogen, OH, -NR7R8, C1-C6-alkyl, 3- to 6-membered heterocycloalkyl, 4- to 6- membered heterocycloalkenyl , -(CO)OR7, R7R8, -NR7(CO)R10, -NR8(CO)OR7, -NR8(CO) NR7R8, -(SO2)R9, -(SO)R9, -SR9, -(SO2)NR7R8, O2)R9, -((SO)=NR11)R10, -N=(SO)R9R10, -(PO)(OR7)2,–(PO)(OR7)R10, R10)2 or with a heteroaryl group which is ally substituted, one or more times, with alkyl; wherein each 4- to 10-membered heterocycloalkenyl is ally substituted, one or more times, independently from each other, with C1-C4-alkyl; R3, R4 represent, independently from each other, hydrogen or methyl; R7, R8 represent, independently from each other, hydrogen or C1-C6-alkyl; or 18225983_1 (GHMatters) P105077.NZ R7 and R8 together represent a 4-, 5-, 6- or 7-membered cyclic amine group, which is ally substituted, one or more times, independently from each other, with a substituent selected from C1-C6-alkyl, C1-C6-haloalkyl, said 4-, 5-, 6- or 7-membered cyclic amine group optionally containing one r heteroatom selected from the group consisting of O, N and S; R9 represents C1-C4-alkyl or phenyl, n each C1-C4-alkyl or phenyl is ally tuted, one or more times, independently from each other, with R13; R10 represents C1-C4-alkyl; or R9 and R10 together, in case of -N=(SO)R9R10 group, represent a 5- to 8-membered heterocycloalkyl group; R11 represents hydrogen, C1-C4-alkyl, -(CO)OR7, -(CO)NR7R8 or CN; R12 represents hydrogen or C1-C4-alkyl; R13 represents halogen, OH, -NR7R8, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6- haloalkoxy, C2-C6-alkenyl, C3-C6-cycloalkyl, -(CO)OR7 or -(CO)NR7R8. 3. The compound according to item 1, which is ed from the group of: 4-[(2-(morpholinyl)[2H-pyrazolyl]-[1,7]¬naphthyridineyl]phenyl-N-ethoxycarbonyl- S-methylsulphoximide 4-[(2-(morpholinyl)(2H-pyrazolyl)-[1,7]naphthyridineyl]phenyl-S- methylsulphoximide 4-[6-(methylsulfonyl)pyridinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3,6-dihydro-2H-pyranyl)(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine 4-[4-(N,S-dimethylsulfonimidoyl)phenyl][morpholinyl](1H-pyrazolyl)-1,7- naphthyridine ethyl(methylsulfonyl)pyridinyl](morpholinyl)(1H-pyrazolyl)-1,7- naphthyridine 4-(4-methanesulphonylphenyl)(morpholinyl)(1H-pyrazolyl)-[1,7]-naphthyridine 4-(2-methanesulphonylphenyl)(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine hydrochloride 18225983_1 (GHMatters) P105077.NZ dimethyl {4-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]phenyl}phosphonate 4-isopropenyl(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine 2-(morpholinyl)phenyl(1H-pyrazolyl)-[1,7]naphthyridine 4-[4-(S-ethylsulfonimidoyl)phenyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 3-[(2-(morpholinyl)[2H-pyrazolyl]-[1,7]naphthyridineyl]phenyl-N-ethoxycarbonyl-S- sulphoximide 4-(1-methyl-1,2,3,6-tetrahydropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7- naphthyridine 4-(3-methanesulphonylphenyl)(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine 4-[5-methyl(methylsulfonyl)pyridinyl](morpholinyl)(1H-pyrazolyl)-1,7- naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(1,2,3,6-tetrahydropyridinyl)-1,7-naphthyridine 4-cyclopropyl(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine 3-[(2-(morpholinyl)(2H-pyrazolyl)-[1,7]naphthyridineyl]phenyl-S- methylsulphoximide 4-methyl(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine hydrochloride 4-[2-(methylsulfonyl)-1,3-thiazolyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyridin-2(1H)-one -[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyridin-2(1H)-one 4-[2-fluoro(methylsulfonyl)phenyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl){4-[S-(propanyl)sulfonimidoyl]phenyl}(1H-pyrazolyl)-1,7- naphthyridine ethanesulphonylphenyl)((R)methylmorpholinyl)(2H-pyrazolyl)- [1,7]naphthyridine 2-((R)methylmorpholinyl)phenyl(2H-pyrazolyl)-[1,7]naphthyridine ethanesulphonylphenyl)((R)methylmorpholinyl)(2H-pyrazolyl)- [1,7]naphthyridine 4-cyclopropyl((R)methylmorpholinyl)(1H-pyrazolyl)-[1,7]-naphthyridine 18225983_1 (GHMatters) P105077.NZ 4-[2-((R)methylmorpholinyl)(2H-pyrazolyl)-[1,7]naphthyridineyl]phenyl-S- methylsulphoximide 3-[2-((R)methylmorpholinyl)(2H-pyrazolyl)-[1,7]naphthyridineyl]phenyl-S- methylsulphoximide 4-methanesulphonyl(morpholinyl)[2-(tetrahydropyranyl)-2H-pyrazolyl]- [1,7]naphthyridine 2-[(3R)methylmorpholinyl](methylsulfonyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridinecarbonitrile 2-((R)methylmorpholinyl)(-2H-pyrazolyl]-[1,7]naphthyridinecarbonitrile holinyl(1H-pyrazolyl)-[1,7]naphthyridinecarboxamide 4-methanesulphonylmethylmorpholinyl(2H-pyrazolyl)-[1,7]naphthyridine [2-(morpholinyl)(2H-pyrazolyl)-[1,7]naphthyridineyl]methanol 4-(1-methanesulphonylcyclopropyl)(morpholinyl)(2H-pyrazolyl)-[1,7]naphthyridine 4-isopropoxy(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine 2-(morpholinyl)(propanyloxy)(1H-pyrrolyl)-1,7-naphthyridine 4-[3-(S-methylsulfonimidoyl)propoxy](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-ethoxy(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine oxy(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine 2-methyl{[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]oxy}propanol 2-(morpholinyl)(1H-pyrazolyl)(tetrahydrofuranylmethoxy)-1,7-naphthyridine 3-{[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]oxy}dihydrofuran-2(3H)-one 4-[(3-methyl-1,2-oxazolyl)methoxy](morpholinyl)(1H-pyrazolyl)-1,7- naphthyridine 4-[(5-methyl-1,2-oxazolyl)methoxy](morpholinyl)(1H-pyrazolyl)-1,7- naphthyridine 4-benzyloxy(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine ropoxy((R)methylmorpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine 18225983_1 (GHMatters) P105077.NZ tert-butyl [4-({2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin yl}oxy)butyl]carbamate 4-methoxy((R)methylmorpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine tert-butyl [3-({2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin yl}oxy)propyl]carbamate 2-({2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}oxy)ethanamine tert-butyl [2-({2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin )ethyl]carbamate 4-({2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}oxy)butan amine 2-[(3R,5S)-3,5-dimethylmorpholinyl]isopropoxy(1H-pyrazolyl)-1,7-naphthyridine 2-[(3R,5R)-3,5-dimethylmorpholinyl]isopropoxy(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(tetrahydro-2H-pyranyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine hydrochloride 4-chloromorpholinyl(1H-pyrazolyl)-[1,7]naphthyridine 2-[(3R)methylmorpholinyl](methylsulfanyl)(1H-pyrazolyl)-1,7-naphthyridine N-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}-1,4 4-oxathian- e 4-oxide 4-{[dimethyl(oxido)-6-sulfanylidene]amino}(morpholinyl)(1H-pyrazolyl)-1,7- yridine 2-[(3R)methylmorpholinyl](piperazinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-isopropoxy((S)methylmorpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine 2-(morpholinyl)(propanyloxy)(1H-pyrrolyl)-1,7-naphthyridine 4-(1-ethyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(1-methyl-1H-imidazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 2-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl]aniline 18225983_1 (GHMatters) P105077.NZ 4-(2,3-difluorophenyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 4-[2-methyl(methylsulfonyl)pyridinyl][(3R)methylmorpholinyl](1H-pyrazol yl)-1,7-naphthyridine 4-[2-fluoro(methylsulfonyl)phenyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-fluoro[2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl]aniline 4-(1-benzyl-1H-imidazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(2-fluorophenyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](2-methyl-1,3-thiazolyl)(1H-pyrazolyl)-1,7- naphthyridine 4-[4-methyl(methylsulfonyl)pyridinyl][(3R)methylmorpholinyl](1H-pyrazol yl)-1,7-naphthyridine 4-(1-cyclopropyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-[2-fluoro(piperazinyl)phenyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl][4-(methylsulfonyl)piperazinyl](1H-pyrazolyl)-1,7- naphthyridine N-(2,2-dimethylpropyl)-N-methyl[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- yridinamine (1-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}piperidin yl)methanol N-cyclopropyl-N-methyl[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin- 4-amine 4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)[(3R)methylmorpholinyl](1H-pyrazol- 1,7-naphthyridine N-(4-fluorophenyl)-N-methyl[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridinamine 18225983_1 (GHMatters) P105077.NZ 2-[(3R)methylmorpholinyl](6-methylpyridinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2-fluoropyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 4-(2-fluoromethylpyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](1-methyl-1H-pyrrolyl)(1H-pyrazolyl)-1,7- naphthyridine luoromethylpyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(2-fluoromethylpyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(6-fluoropyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 4-(6-methoxypyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(6-methoxymethylpyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(6-fluoromethylpyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl][1-methyl(trifluoromethyl)-1H-pyrazolyl](1H- pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](3-methylthienyl)(1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](5-methylthienyl)(1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](4-methylthienyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3-chlorothienyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](2-methylthienyl)(1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](1H-pyrazolyl)(1H-pyrrolo[2,3-b]pyridinyl)-1,7- yridine -dimethyl-1,2-oxazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(3-chloromethoxypyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- 18225983_1 (GHMatters) P105077.NZ naphthyridine 2-[(3R)methylmorpholinyl](1H-pyrazolyl)(tetrahydro-2H-pyranyl)-1,7- naphthyridine 4-(3,6-dihydro-2H-thiopyranyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](4-methylpiperidinyl)(1H-pyrazolyl)-1,7- naphthyridine ert-butyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](1-methyl-1H-pyrazolyl)(1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](3-methyl-1,2-oxazolyl)(1H-pyrazolyl)-1,7- naphthyridine 4-(1-ethylmethyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(1,4-dimethyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- yridine 4-[2-methyl(methylsulfanyl)pyridinyl][(3R)methylmorpholinyl](1H-pyrazol yl)-1,7-naphthyridine 4-[2-methyl(S-methylsulfonimidoyl)pyridinyl][(3R)methylmorpholinyl](1H- pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](1-propyl-1H-pyrazolyl)(1H-pyrazolyl)-1,7- naphthyridine 4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl)[(3R)methylmorpholinyl](1H-pyrazol- 5-yl)-1,7-naphthyridine 4-[1-ethyl(trifluoromethyl)-1H-pyrazolyl][(3R)methylmorpholinyl](1H-pyrazol- -yl)-1,7-naphthyridine methyl (3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}-1H- pyrrolecarboxylate 18225983_1 (GHMatters) P105077.NZ 2-[(3R)methylmorpholinyl](1H-pyrazolyl)(1,2-thiazolyl)-1,7-naphthyridine N,N-dimethyl{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin yl}aniline 4-(2,4-difluorophenyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 4-(1-isopropyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine ethyl methyl{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin yl}phosphinate 4-{[diethyl(oxido)-6-sulfanylidene]amino}[(3R)methylmorpholinyl](1H-pyrazol 7-naphthyridine isobutyl methyl{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin yl}phosphinate 2-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}propanol 3-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}pentanol 4-(5-chloropyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine -fluoro{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}aniline 4-[2-fluoro(methylsulfonyl)phenyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl][1-(oxetanyl)-1H-pyrazolyl](1H-pyrazolyl)-1,7- yridine 4-[2-fluoro(pyrrolidinyl)phenyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-[3-(methoxymethyl)methyl-1,2-oxazolyl][(3R)methylmorpholinyl](1H- pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](5-methyl-1,3,4-oxadiazolyl)(1H-pyrazolyl)-1,7- naphthyridine N-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}tetrahydro-1H- 14-thiophenimine 1-oxide 4-{[(4-fluorophenyl)(methyl)oxido-6-sulfanylidene]amino}[(3R)methylmorpholinyl] 18225983_1 ters) P105077.NZ (1H-pyrazolyl)-1,7-naphthyridine, mixture of 2 diastereoisomers 4-{[(2-fluorophenyl)(methyl)oxido-6-sulfanylidene]amino}[(3R)methylmorpholinyl] (1H-pyrazolyl)-1,7-naphthyridine, mixture of 2 diastereoisomers 4-{[(R)(2-fluorophenyl)(methyl)oxido-6-sulfanylidene]amino}[(3R)methylmorpholin yl](1H-pyrazolyl)-1,7-naphthyridine, diastereoisomer )(2-fluorophenyl)(methyl)oxido-6-sulfanylidene]amino}[(3R)methylmorpholinyl]- 8-(1H-pyrazolyl)-1,7-naphthyridine, diastereoisomer ethylphosphoryl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 4-(diethylphosphoryl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine ethyl isobutyl{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin yl}phosphinate 2-[(3R)methylmorpholinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1-isobutyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-[5-fluoro(methylsulfonyl)pyridinyl][(3R)methylmorpholinyl](1H-pyrazol yl)-1,7-naphthyridine 4-[(3R)methylmorpholinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](4-methyl-1H-pyrazolyl)(1H-pyrazolyl)-1,7- naphthyridine 4-[2-fluoro(methylsulfonyl)phenyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-[4-(isopropylsulfonyl)phenyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(6-fluoropyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 4-(1-ethyl-1H-imidazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 1-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}prolinamide 3-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}pyridinamine 18225983_1 ters) P105077.NZ 2-[(3R)methylmorpholinyl](1H-pyrazolyl)[1-(2,2,2-trifluoroethyl)-1H-pyrazol yl]-1,7-naphthyridine 1-methyl{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin yl}piperazinone 2-fluoroethyl)-1H-pyrazolyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-[1-(2-fluoroethyl)-1H-pyrazolyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 2-(3-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}-1H-pyrazol yl)ethanol yl(3-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}-1H- pyrazolyl)propanol 4-[(2R)methylmorpholinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(5-fluoropyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](6-methylpyridinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](3-methylpyridinyl)(1H-pyrazolyl)-1,7-naphthyridine N-(2-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin yl}phenyl)acetamide 3-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}pyridinol 2-(3-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin yl}phenyl)propanol 4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)(morpholinyl)(1H-pyrazolyl)-1,7- naphthyridine 4-[(2S)methylmorpholinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-[(trans)methylcyclopropyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- yridine 4-(difluoromethoxy)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 2-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]propanol 2-(morpholinyl)(3-oxaazabicyclo[3.2.1]octyl)(1H-pyrazolyl)-1,7-naphthyridine 18225983_1 (GHMatters) P105077.NZ 2-[(3R)methylmorpholinyl](1H-pyrazolyl)(pyrrolidinyl)-1,7-naphthyridine 4-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]piperazinone ethylphosphoryl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-[(trans)-2,5-dimethylpiperazinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-[(cis)-3,5-dimethylpiperazinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 1-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl](trifluoromethyl)azetidin methyl hydrogen {4-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridin yl]phenyl}phosphonate 4-(4-methylpiperazinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)[(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl]- 1,7-naphthyridine 4-(3-methoxymethylazetidinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)[(1S,4S)oxaazabicyclo[2.2.1]heptyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl][(methylsulfanyl)methyl](1H-pyrazolyl)-1,7- naphthyridine N,N-dimethyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyridinamine 4-(2-methylpyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 1-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}cyclohexanol 2-fluoro{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}aniline (methyl{4-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]phenyl}oxido-6- sulfanylidene)cyanamide l(methyl{4-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridin yl]phenyl}oxido-6-sulfanylidene)urea 3-({2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}oxy)propan amine 4-(4-cyclopropyl-1H-1,2,3-triazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- 83_1 (GHMatters) P105077.NZ naphthyridine 4-ethylsulfinyl(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)[propanylsulfinyl](1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl][3-(methylsulfonyl)propoxy](1H-pyrazolyl)-1,7- naphthyridine pholinyl)(phenylsulfonyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(propanylsulfonyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(ethylsulfonyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(phenylsulfinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(methylsulfinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl][1-oxidotetrahydro-2H-thiopyranyl](1H-pyrazolyl)- 1,7-naphthyridine 4-(1,1-dioxidotetrahydro-2H-thiopyranyl)[(3R)methylmorpholinyl](1H-pyrazol 7-naphthyridine 2-[(3R)methylmorpholinyl]-4,8-di(1H-pyrazolyl)-1,7-naphthyridine N,N-dimethyl(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinamine 2-(morpholinyl)(phenylsulfanyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)-N-(propanyl)(1H-pyrazolyl)-1,7-naphthyridinamine ylsulfanyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(propanylsulfanyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(1H-pyrrolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(1H-pyrrolyl)-1,7-naphthyridine 4-[(4-methoxyphenyl)sulfanyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(5-methyl-1H-pyrazolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 1-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyrrolidinone 4-(1,1-dioxido-1,2-thiazolidinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 1-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]piperidinone 18225983_1 (GHMatters) P105077.NZ 2-[(3R)methylmorpholinyl](2-methylpyridinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl][2-(propanyloxy)pyridinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(2-methoxypyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- yridine 2-(morpholinyl)(1H-pyrazolyl)(pyridinyl)-1,7-naphthyridine 4-[(4-methoxyphenyl)sulfanyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-[3-fluoro(morpholinyl)pyridinyl][(3R)methylmorpholinyl](1H-pyrazol yl)-1,7-naphthyridine 4-(6-fluoromethylpyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 3-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]-1,3-oxazinanone 3-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]-1,3-oxazolidinone 4-(3-methoxypyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(2,6-difluoropyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(5-chlorofluoropyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine luoropyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 4-(2-chloromethylpyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(5,6-dimethylpyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(5-fluoromethylpyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](5-methylthiophenyl)(1H-pyrazolyl)-1,7- naphthyridine ethoxythiophenyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- 18225983_1 (GHMatters) P105077.NZ naphthyridine 4-(2-chlorothiophenyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(isoquinolinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 4-(5-chlorothiophenyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](4-methylthiophenyl)(1H-pyrazolyl)-1,7- naphthyridine 4-(2,5-dimethylthiophenyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine )methylmorpholinyl](1H-pyrazolyl)(tetrahydro-2H-thiopyranyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](1-methyl-1,2,5,6-tetrahydropyridinyl)(1H-pyrazol yl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](1-methyl-1,2,3,6-tetrahydropyridinyl)(1H-pyrazol yl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl][1-methylpiperidinyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](1H-pyrazolyl)(1,2,3,6-tetrahydropyridinyl)-1,7- yridine 2-[(3R)methylmorpholinyl](1H-pyrazolyl)[1-(tetrahydro-2H-pyranyl)-1H- pyrazolyl]-1,7-naphthyridine 4-(4,6-difluoropyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](1-methyl-1H-pyrazolyl)(1H-pyrazolyl)-1,7- yridine 4-(1,3-dimethyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(1,5-dimethyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- 18225983_1 (GHMatters) P105077.NZ naphthyridine 2-[(3R)methylmorpholinyl](piperidinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](1H-pyrazolyl)[3-(trifluoromethyl)-1H-pyrazolyl]- 1,7-naphthyridine 4-(1-cyclobutyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- yridine 4-(1-cyclopropyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine )methylmorpholinyl][1-(propanyl)-1H-pyrazolyl](1H-pyrazolyl)-1,7- naphthyridine 4-[1-(difluoromethyl)-1H-pyrazolyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(1-tert-butyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](1H-pyrazolyl)(1,3,5-trimethyl-1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl][1-methyl(trifluoromethyl)-1H-pyrazolyl](1H- pyrazolyl)-1,7-naphthyridine 2-(4-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}-1H-pyrazol yl)ethanol 4-(1-ethyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- yridine 2-[(3R)methylmorpholinyl](1-methyl-1H-pyrrolyl)(1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl][1-(propanyl)-1H-pyrazolyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](1H-pyrazolyl)(1,2,5-trimethyl-1H-pyrrolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](1-phenyl-1H-pyrazolyl)(1H-pyrazolyl)-1,7- 18225983_1 (GHMatters) P105077.NZ naphthyridine 2-[(3R)methylmorpholinyl](3-methyl-1H-pyrazolyl)(1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinamine 2-[(3R)methylmorpholinyl][1-(2-methylpropyl)-1H-pyrazolyl](1H-pyrazolyl)- 1,7-naphthyridine 2-[(3R)methylmorpholinyl](1H-pyrazolyl)(1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](1,3-oxazolyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1,3-dimethyl-1H-pyrazolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1,5-dimethyl-1H-pyrazolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(1,3,5-trimethyl-1H-pyrazolyl)-1,7-naphthyridine 4-{[(2-methoxyethyl)(methyl)oxido-6-sulfanylidene]amino}[(3R)methylmorpholinyl]- pyrazolyl)-1,7-naphthyridine 4-{[(4-bromophenyl)(oxido)propanyl-6-sulfanylidene]amino}[(3R)methylmorpholin (1H-pyrazolyl)-1,7-naphthyridine 2-(methyl-N-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin yl}sulfonimidoyl)phenol 4-{[(4-bromophenyl)(methyl)oxido-6-sulfanylidene]amino}[(3R)methylmorpholinyl] (1H-pyrazolyl)-1,7-naphthyridine 4-{[tert-butyl(methyl)oxido-6-sulfanylidene]amino}[(3R)methylmorpholinyl](1H- pyrazolyl)-1,7-naphthyridine formic acid - N-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]-1,4 thian imine 4-oxide (1:1) N-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]hexahydro-14-thiopyran imine 1-oxide 3-methyl{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}butan- 2-ol 1-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}(tetrahydro- 2H-pyranyl)ethanol 18225983_1 (GHMatters) P105077.NZ 3,3-dimethyl{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin yl}butanol 2-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}hexanol 2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinecarboxamide 2-[(3R)methylmorpholinyl][1-(methylsulfonyl)cyclopropyl](1H-pyrazolyl)-1,7- naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(tetrahydro-2H-pyranylmethoxy)-1,7-naphthyridine N,N-dimethyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]benzamide {4-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]phenyl}(piperidin yl)methanone N,N-dimethyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]benzamide N-cyclopropyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]benzamide 4-(4-methylpyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1H-indolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1H-indolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 3-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]benzamide morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]benzamide N-methyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]benzamide 4-(3-fluorophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine hlorothiophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2-methoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)[2-(trifluoromethyl)phenyl]-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)[4-(trifluoromethyl)phenyl]-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)[3-(trifluoromethyl)phenyl]-1,7-naphthyridine hlorophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine N-{3-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]phenyl}acetamide 4-(3-methoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 18225983_1 (GHMatters) P105077.NZ 4-(3,5-dimethoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3-methylphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(4-methoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(furanylmethyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2,6-dimethyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]phenol 4-(2,3-dimethylphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine {3-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]phenyl}methanol 4-(4-fluorophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(4-methylphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(4-chlorophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2-fluoromethoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2-methylphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2,3-dimethoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine methyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]aniline N,N-dimethyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]aniline 2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridin yl]phenyl}methanesulfonamide N-{4-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridin nyl}methanesulfonamide N,N-dimethyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]benzamide 2-(morpholinyl)[(1E)-propenyl](1H-pyrazolyl)-1,7-naphthyridine 4-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]phenol 4-(2-fluorophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine {3-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]phenyl}(piperidin yl)methanone 2-(morpholinyl)[4-(propanyl)phenyl](1H-pyrazolyl)-1,7-naphthyridine N-cyclopropyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]benzamide 18225983_1 (GHMatters) P105077.NZ 4-(biphenylyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2,4-dimethoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2-chlorophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2,5-dimethylphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 3-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]aniline 2-(morpholinyl)(1H-pyrazolyl)[3-(1H-pyrazolyl)phenyl]-1,7-naphthyridine 3-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]phenol 4-(2-fluoromethoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(5-fluoromethoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2,4-difluorophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2,3-difluorophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2,6-dimethoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]aniline -dichlorophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine henylyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2-chloropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1-benzothiophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1-methyl-1H-pyrazolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(quinolinyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(pyridinyl)-1,7-naphthyridine 4-(2-methoxypyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(5-methylpyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(5-methoxypyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(quinolinyl)-1,7-naphthyridine 2-(morpholinyl)[1-(phenylsulfonyl)-1H-indolyl](1H-pyrazolyl)-1,7-naphthyridine 4-(2-chloropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 18225983_1 (GHMatters) P105077.NZ 4-(6-chloropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine {5-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]thiophenyl}methanol 4-(2-fluoropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(6-fluoropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2-chloromethylpyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2-methoxypyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(isoquinolinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3-chloropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3-fluoropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2,6-difluoropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1-methyl-1H-pyrazolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine tert-butyl oxy[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]-1H- indolecarboxylate 2-(morpholinyl)[6-(morpholinyl)pyridinyl](1H-pyrazolyl)-1,7-naphthyridine 4-(4-methylthiophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(thiophenyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(thiophenyl)-1,7-naphthyridine 4-(3-methylthiophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine hloromethylpyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(4-methoxypyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(5-chloromethoxypyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine utyl 5-methyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]-1H-indole- 1-carboxylate 4-(5-chlorofluoropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3,5-dimethyl-1,2-oxazolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(quinolinyl)-1,7-naphthyridine 4-(5-methylthiophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 18225983_1 (GHMatters) P105077.NZ 4-(6-ethoxypyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2-ethoxypyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(quinolinyl)-1,7-naphthyridine 4-(2-chlorothiophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 5-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyridinamine 2-(morpholinyl)(1H-pyrazolyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(6-methylpyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1-methyl-1H-pyrrolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine -[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyridinol 4-(5-chloropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3-chloromethoxypyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3-chlorothiophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(5-fluoropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-[2-(methylsulfanyl)pyrimidinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine N-cyclopropyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyrimidin amine 4-(isoquinolinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine N-methyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyridine carboxamide N-tert-butyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyridine carboxamide methylsulfanyl)pyridinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(1H-pyrrolo[2,3-b]pyridinyl)-1,7-naphthyridine 3-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyridinamine methyl 4-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]thiophene ylate 4-[2-methoxy(trifluoromethyl)pyridinyl](morpholinyl)(1H-pyrazolyl)-1,7- 18225983_1 (GHMatters) P105077.NZ naphthyridine pholinyl)[2-(propanyloxy)pyridinyl](1H-pyrazolyl)-1,7-naphthyridine 4-(5-chloroethoxypyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1-tert-butyl-1H-pyrazolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(piperidinyl)(1H-pyrazolyl)-1,7-naphthyridine 1-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]piperidinol N-methyl(morpholinyl)-N-phenyl(1H-pyrazolyl)-1,7-naphthyridinamine {1-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyrrolidinyl}methanol N-methyl(morpholinyl)-N-propyl(1H-pyrazolyl)-1,7-naphthyridinamine 4-(azepanyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine ethylpiperidinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(4-methylpiperidinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 1-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]piperidinecarboxamide 4-(2,5-dihydro-1H-pyrrolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3,4-dihydroquinolin-1(2H)-yl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3,4-dihydroisoquinolin-2(1H)-yl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1,3-dihydro-2H-isoindolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)[1,3,3-trimethylazabicyclo[3.2.1]octyl]-1,7- naphthyridine tert-butyl 1-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]-prolinate N-methyl-N-(2-methylpropyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinamine luorophenyl)-N-methyl(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinamine 4-(1,1-dioxidothiaazaspiro[3.3]heptyl)(morpholinyl)(1H-pyrazolyl)-1,7- naphthyridine 4-(3-fluoropiperidinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine N-(2-fluorophenyl)-N-methyl(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinamine 1-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]-prolinamide 18225983_1 (GHMatters) P105077.NZ {1-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]piperidinyl}methanol 4-(4-methoxypiperidinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine N-(4-fluorophenyl)-N-methyl(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinamine N-methyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]-prolinamide 4-[4-(ethylsulfonyl)piperazinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-[4-(methylsulfonyl)piperazinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine N-cyclopropyl-N-methyl(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinamine N-(2,2-dimethylpropyl)-N-methyl(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridin amine {1-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]piperidinyl}methanol. 4. The compound according to items 1 or 2 of general formula (Ib) O R1 N N (Ib) , in which R1 represents: * wherein * indicates the point of attachment of said group with the rest of the molecule; R2 represents hydrogen, halogen, -NR7R8, CN, C1-C6-alkyl, C1-C6-alkoxy, 3- to 10-membered heterocycloalkoxy, alkenyl, cycloalkyl, 3- to bered heterocycloalkyl, 4- to 10-membered heterocycloalkenyl, phenyl, heteroaryl, R7, -(CO)NR7R8, -(SO2)R9, -(SO)R9, -SR9, -(SO2)NR7R8, -NR7(SO2)R9, -((SO)=NR11)R10, -N=(SO)R9R10, 18225983_1 (GHMatters) P105077.NZ -SiR 10 R11 R12 , –(PO)(OR7) 7)R10 or –(PO)(R10 ) 2, –(PO)(OR 2, wherein each C1-C6-alkyl, C1-C6-alkoxy, 3- to 10-membered heterocycloalkoxy, C2-C6- alkenyl, C3-C6-cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl or heteroaryl is optionally substituted, one or more times, independently from each other, with halogen, OH, -NR7R8, C1-C6-alkyl optionally substituted with hydroxyl or phenyl, C1-C6- haloalkyl, C1-C6-alkoxy, cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, -(CO)OR 7, -(CO)NR7R8, -NR7(CO)R 10 , NR8(CO)OR 7, -NR8(CO) NR7R8, -(SO 9, -(SO)R9, -SR9, -(SO 7R8, -NR7(SO 9, -((SO)=NR11 )R 10 , -N=(SO)R9R10 , -(PO)(OR7) 7)R10 , 2)NR 2)R 2, –(PO)(OR –(PO)(R 10 ) 2 or with a heteroaryl group which is optionally substituted, one or more times, with alkyl; wherein each 4- to 10-membered cycloalkenyl is optionally substituted, one or more times, independently from each other, with C1-C4-alkyl; R3, R4 represent, independently from each other, hydrogen or methyl; R7, R8 represent, independently from each other, hydrogen, alkyl, C3-C6-cycloalkyl or phenyl, which phenyl is optionally substituted, one or more times, with halogen; or R7 and R8 together represent a 4-, 5-, 6- or 7-membered cyclic amine group, which is optionally substituted, one or more times, independently from each other, with a substituent ed from C1-C6-alkyl, C1-C6-haloalkyl, said 4-, 5-, 6- or 7-membered cyclic amine group optionally containing one further atom selected from the group consisting of O, N and S; R9 represents C1-C4-alkyl or phenyl, wherein each C1-C4-alkyl or phenyl is optionally substituted, one or more times, independently from each other, with R13; R10 represents alkyl; or R9 and R10 er, in case of -N=(SO)R9R10 group, represent a 5- to 8-membered heterocycloalkyl group; R11 represents hydrogen, C1-C4-alkyl, -(CO)OR7, -(CO)NR7R8 or CN; R12 represents hydrogen or C1-C4-alkyl; R13 represents n, OH, -NR7R8, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6- haloalkoxy, C2-C6-alkenyl, cycloalkyl, -(CO)OR7 or -(CO)NR7R8. 18225983_1 ters) P105077.NZ . The compound of general formula (Ib) according to item 4, in which R1 represents: wherein * indicates the point of attachment of said group with the rest of the molecule; R2 represents hydrogen, halogen, -NR7R8, CN, C1-C6-alkyl, C1-C4-alkoxy, 3- to 10-membered cycloalkoxy, C2-C4-alkenyl, C3-C6-cycloalkyl, 3- to bered heterocycloalkyl, 4- to 10-membered heterocycloalkenyl, phenyl, heteroaryl, -(CO)NR7R8, -(SO2)R9, 9, -SR9, )R9R10, –(PO)(OR7)2, –(PO)(OR7)R10, –(PO)(R10)2, wherein each C1-C6-alkyl, C1-C4-alkoxy, C3-C6-cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl or heteroaryl is optionally substituted, one or more times, independently from each other, with halogen, OH, amino, -NR7R8, C1-C4-alkyl optionally substituted with hydroxyl or phenyl, C1-C2-haloalkyl, C1-C3-alkoxy, C3-C6-cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, -(CO)OR7, -(CO)NR7R8, -NR7(CO)R10, O)OR7, -(SO2)R9, -SR9, -NR7(SO2)R9, -((SO)=NR11)R10, OR7)2, –(PO)(OR7)R10, or with a heteroaryl group; wherein each 4- to 10-membered heterocycloalkenyl is optionally tuted, one or more times, independently from each other, with methyl; R4 represents hydrogen or methyl; R7, R8 represent, independently from each other, hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl or phenyl, which phenyl is optionally tuted, one or more times, with halogen; R9 represents C1-C4-alkyl or phenyl, wherein each C1-C4-alkyl or phenyl is optionally tuted, one or more times, independently from each other, with R13; R10 represents C1-C4-alkyl; or 18225983_1 (GHMatters) P105077.NZ R9 and R10 together, in case of -N=(SO)R9R10 group, represent a 5- to 8-membered heterocycloalkyl group; R11 represents hydrogen, C1-C4-alkyl, -(CO)OR7, -(CO)NR7R8 or CN; R13 represents halogen, OH or C1-C6-alkoxy. 6. The compound of general formula (Ib) according to items 4 or 5, in which R1 represents: wherein * tes the point of attachment of said group with the rest of the molecule; R2 represents hydrogen, chloro, amino, amino, dimethylamino, methyl(propyl)amino, methyl(2-methylpropyl)amino, 2,2-dimethylpropyl(methyl)amino, cyclopropyl(methyl)amino, methyl(phenyl)amino, CN, methyl, ethyl, propanyl, 3- methylbutanyl, yl, hexanyl, 3,3-dimethylbutanyl, methoxy, ethoxy, propoxy, butoxy, 2-methyl-propanyloxy, propanyloxy, (2-oxotetrahydrofuranyl)oxy, propenyl, cyclopropyl, cyclohexyl, azetidinyl, pyrrolidinyl, 1,3-oxazolidinone, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, dinyl, piperazinyl, linyl, azepanyl, 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl, 3-oxo-piperazinyl, 2-oxo-1,3-oxazinanyl, 1-oxidotetrahydro-2H-thiopyranyl, 1,1-dioxidotetrahydro-2H-thiopyranyl, oxido-1,2-thiazolidinyl, ,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl, 3-oxaazabicyclo[3.2.1]octyl, 1,3,3-trimethylazabicyclo[3.2.1]octyl, (3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl, (1S,4S)oxaazabicyclo[2.2.1]heptyl, 1,1-dioxidothiaazaspiro[3.3]heptyl, 2,5-dihydro-1H-pyrrolyl, hydro-2H-pyranyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 3,6-dihydro-2H-thiopyranyl, phenyl, 1,3-dihydro-2H-isoindolyl, 3,4-dihydroquinolin- 1(2H)-yl, 3,4-dihydroisoquinolin-2(1H)-yl, pyrrolyl, pyrazolyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, zolyl, pyridinyl, pyrimidinyl, 2-oxo-1,2-dihydropyridin- 18225983_1 (GHMatters) P105077.NZ 4-yl, indolyl, benzothiophenyl, quinolinyl, isoquinolinyl, rolo[2,3-b]pyridinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, -(CO)NH2, methylsulfonyl, ethylsulfonyl, ylsulfonyl, phenylsulfonyl, methylsulfinyl, ethylsulfinyl, propanylsulfinyl, phenylsulfinyl, sulfanyl, ethylsulfanyl, propanylsulfanyl, phenylsulfanyl, -N=(SO)dimethyl, -N=(SO)diethyl, N CH 3 CH * S * 3 N CH 3 O N CH * 3 CH S S N 3 O O S O CH H3C H3C CH3 , , , , * * * N N N S S S O O O O , , wherein * indicates the point of attachment of said group with the rest of the molecule, –(PO)(O-methyl)2, –(PO)(O-ethyl)methyl, –(PO)(Omethylpropyl)methyl, –(PO)(O-ethyl)2-methylpropyl, –(PO)dimethyl, iethyl, wherein each methyl, ethyl, propanyl, 3-methylbutanyl, pentanyl, hexanyl, 3,3-dimethylbutanyl, methoxy, ethoxy, propoxy, 2-methyl-propanyloxy, butoxy, cyclopropyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 3-oxo-piperazinyl, phenyl, pyrrolyl, pyrazolyl, thiophenyl, olyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, indolyl, * * 3 N CH 3 N CH S S O O is optionally tuted, one or more times, independently from each other, with fluoro, chloro, bromo, OH, amino, -NH-cyclopropyl, dimethylamino, methyl, ethyl, propanyl, propanyl, 2-methylpropyl, tert-butyl, hydroxymethyl, 2-hydroxyethyl, 2-methylhydroxypropanyl, 2-hydroxypropanyl, benzyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, ymethyl, cyclopropyl, cyclobutyl , tetrahydrofuranyl, tetrahydropyranyl, 18225983_1 (GHMatters) P105077.NZ phenyl, -(CO)O-methyl, (CO)O-tert-butyl, -(CO)NH2, -(CO)NH-methyl, -(CO)NH-tert-butyl, -(CO)dimethylamino, -(CO)piperidinyl, -(CO)NH-cyclopropyl, -NH(CO)methyl, -NH(CO)O-tert-butyl, methylsulfonyl, ethylsulfonyl, propanylsulfonyl, phenylsulfonyl, methylsulfanyl, -(SO2)NR7R8, NH(SO2)methyl,-((SO)=NH)methyl, -((SO)=NH)ethyl, -((SO)=NH)propanyl, -((SO)=N-methyl)methyl, -((SO)=N-(CO)O-ethyl)methyl, -((SO)=N-(CN))methyl, -((SO)=N-(CO)NH-ethyl)methyl, –(PO)(O-methyl)2,–(PO)(OH)(O-methyl) or with furanyl, pyrazolyl, wherein each 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl is optionally substituted, one or more times, independently from each other, with methyl; R4 represents hydrogen or methyl. 7. The compound of l formula (Ib) according to any one of items 4 to 6, in which R1 represents: wherein * indicates the point of attachment of said group with the rest of the molecule; R2 represents 2,2-dimethylpropyl(methyl)amino, cyclopropyl(methyl)amino, methyl(phenyl)amino, 3-methylbutanyl, cyclopropyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, dinyl, piperazinyl, 5,6-dihydroimidazo[1,2-a]pyrazin- yl, 3,6-dihydro-2H-thiopyranyl, , pyrrolyl, lyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl or 6,7-dihydro-5H-pyrrolo[1,2- azolyl, wherein each 3-methylbutanyl, cyclopropyl, dinyl, piperazinyl, phenyl, pyrrolyl, pyrazolyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl or pyridinyl is optionally tuted, one or two or three times, independently from each other, with fluoro, , OH, amino, methyl, ethyl, propanyl, yl, tert-butyl, hydroxymethyl, benzyl, fluoroethyl, trifluoromethyl, methoxy, cyclopropyl, 18225983_1 (GHMatters) P105077.NZ -(CO)O-methyl, methylsulfonyl, sulfanyl, -((SO)=NH)methyl; R4 represents . 8. The compound of general formula (Ib) according to any one of items 4 to 7, in which R1 represents: wherein * indicates the point of ment of said group with the rest of the molecule; R2 represents ydro-2H-thiopyranyl, dinyl, 5,6-dihydroimidazo[1,2-a]pyrazin- 7(8H)-yl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, pyridinyl or 6,7-dihydro-5H-pyrrolo[1,2- a]imidazolyl, wherein each piperidinyl, phenyl, pyrrolyl, pyrazolyl, yl or pyridinyl is optionally substituted, one or two times, independently from each other, with fluoro, amino, , ethyl, propanyl, hydroxymethyl, methoxy, cyclopropyl, methylsulfonyl, methylsulfanyl, -((SO)=NH)methyl; R4 represents methyl. 9. The compound of general formula (Ib) according to any one of items 4 to 7, in which R1 represents: * , wherein * indicates the point of attachment of said group with the rest of the molecule; R2 represents 2,2-dimethylpropyl(methyl)amino, cyclopropyl(methyl)amino, methyl(phenyl)amino, 3-methylbutanyl, cyclopropyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, 5,6-dihydroimidazo[1,2- 18225983_1 (GHMatters) P105077.NZ a]pyrazin-7(8H)-yl, 3,6-dihydro-2H-thiopyranyl, phenyl, pyrrolyl, 1H-pyrazolyl, 1H- pyrazolyl, thiophenyl, thiophenyl, 1H-imidazolyl, 1,2-oxazolyl, 1,3-thiazol yl, pyridineyl, pyridineyl, 1H-pyrrolo[2,3-b]pyridinyl or 6,7-dihydro-5H- pyrrolo[1,2-a]imidazolyl, wherein each 3-methylbutanyl, ropyl, piperidinyl, piperazinyl, phenyl, pyrrolyl, 1H-pyrazolyl, 1H-pyrazolyl, thiophenyl, thiophenyl, dazol- -yl, 1,2-oxazolyl, 1,3-thiazolyl, pyridineyl or pyridineyl is ally substituted, one or two or three times, independently from each other, with fluoro, chloro, OH, amino, methyl, ethyl, propanyl, propanyl, tert-butyl, hydoxymethyl, , 2-fluoroethyl, trifluoromethyl, methoxy, cyclopropyl, -(CO)O-methyl, methylsulfonyl, methylsulfanyl or -((SO)=NH)methyl; R4 represents methyl.

. The compound of l formula (I) or (Ib) according to any one of items 1 to 9, which is 2-[(3R)methylmorpholinyl](1-methyl-1H-pyrazolyl)(1H-pyrazolyl)-1,7- naphthyridine, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 11. The compound of general a (I) or (Ib) according to any one of items 1 to 10 for use in the ent or laxis of a disease. 12. Use of the compound ing to any one of items 1 to 10 in the manufacture of a medicament for the treatment or prophylaxis of a disease. 13. A pharmaceutical composition comprising the compound according to any one of items 1 to and one or more pharmaceutically acceptable excipient(s). 14. The pharmaceutical composition according to item 13 for use in the treatment or prophylaxis of a hyperproliferative disease. 18225983_1 (GHMatters) P105077.NZ . A pharmaceutical combination comprising: - one or more active ient(s) selected from a compound according to any one of items 1 to 10, and - one or more active ingredient(s) selected from antihyperproliferative, cytostatic or cytotoxic substances for treatment of cancers. 16. A nd of general formula 8 O R1 N N in which R1, R3 and R4 are as defined for the compound of general formula (I) or(Ib) ing to any one of items 1 to 10. 17. Use of a compound according to any one of items 1 to 10 in the production of a medicament for the treatment and/or prophylaxis of a disease mediated by ATR kinase. 18. Use of a pharmaceutical composition according to item 13 in the production of a medicament for the ent and/or prophylaxis of a disease mediated by ATR kinase. 19. Use according to item 17 or 18, wherein the e mediated by ATR kinase is a hyperproliferative disease.

. A method for the ent or prophylaxis of a disease mediated by ATR kinase, comprising administering to a non-human mammal in need thereof an effective amount of: (i) a compound according to any one of items 1 to 10; or (ii) a pharmaceutical composition ing to item 13; or (iii) a pharmaceutical combination according to item 15. 21. The compound according to item 1 or 16, substantially as herein described with reference to any one of the Examples. 18225983_1 (GHMatters) P105077.NZ 5hh (The next page is page 6.) 22.The pharmaceutical composition according to item 13, substantially as herein described with reference to any one of the Examples. 23.The ceutical combination according to item 15, substantially as herein described with reference to any one of the Examples. 24.Use according to any one of items 12, 17 and 18, substantially as herein described with reference to any one of the Examples. 25.The method ing to item 20, substantially as herein described with reference to any one of the Examples.

The terms as mentioned in the present text have the following meanings: The term en atom", "halo-" or "Hal-" is to be understood as meaning a fluorine, chlorine, bromine or iodine atom.

The term -alkyl" is to be understood as meaning a linear or branched, ted, lent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl, 1- methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, methylbutyl, or 1,2-dimethylbutyl group, or an isomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms ("C1-C4-alkyl"), e.g. a , ethyl, propyl, butyl, iso-propyl, iso-butyl, tyl, tert-butyl group, more particularly 1, 2 or 3 carbon atoms 3-alkyl"), e.g. a methyl, ethyl, n-propyl or iso-propyl group.

The term "C1-C6-haloalkyl" is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "C1-C6-alkyl" is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in identically or differently, i.e. one halogen atom being independent from another. Particularly, said halogen atom is F. Said C1-C6- haloalkyl group is, for example, –CF3, -CHF2, -CH2F, -CF2CF3 or –CH2CF3.

The term "C1-C4-hydroxyalkyl" is to be understood as meaning a linear or branched, saturated, 18225983_1 (GHMatters) P105077.NZ ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp monovalent arbon group in which the term "C1—C4—alkyl" is defined supra, and in which one or more en atoms is replaced by a hydroxy group, e.g. a hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 1,3- dihydroxypropan-Z-yl, oxymethyI-propyl, 2-hydroxymethyI-propyl, 1-hydroxy methyl-propyl group.

The term "Cl—Ce-alkoxy" is to be understood as meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula —O-alkyl, in which the term "alkyl" is defined supra, e.g. a methoxy, ethoxy, n-propoxy, opoxy, n—butoxy, iso-butoxy, tert—butoxy, sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or an isomer thereof. Particularly, said "C1—C5-alkoxy" can contain 1, 2, 3, 4 or 5 carbon atoms, (a "C1—Cs—alkoxy"), preferably 1, 2, 3 or 4 carbon atoms ("C1-C4-alkoxy").

The term "Cl—Cg-haloalkoxy" is to be understood as meaning a linear or branched, ted, monovalent C1-C6-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom. Particularly, said halogen atom is F. Said haloalkoxy group is, for example, —OCF3, —OCHF2, -OCH2F, -OCF2CF3, or -OCH2CF3.

The term "C2—C6-alkenyl" is to be understood as meaning a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms or 2, 3 or 4 carbon atoms ("C2-C4-alkenyl), particularly 2 or 3 carbon atoms ("C2-C3- alkenyl"), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other. Said alkenyl group is, for example, a vinyl, allyl, methylvinyl, (Z)—2—methylvinyl, homoallyl, (E)—but- 2-enyl, (Z)-butenyl, (E)-butenyl, (Z)—butenyl, pent—4-enyl, (E)-pent-3—enyl, (Z)—pentenyl, (E)—pentenyl, ntenyl, (E)—pentenyl, (Z)-pentenyl, hexenyl, (E)-hex—4-enyl, (Z)- hex—4-enyl, (E)-hex-3—enyl, xenyl, (E)-hexenyl, (Z)-hex-2—enyl, (E)—hexenyl, (Z)-hex enyl, isopropenyl, 2—methylpropenyl, 1-methylprop-2—enyl, 2-methylpropenyl, (E) methylprop—l-enyl, (Z)—1-methylpropenyl, 3-methylbut—3-enyl, 2-methylbutenyl, 1- methylbut-3—enyl, 3-methylbut—2-enyl, methylbut-2—enyl, (Z)—2-methylbutenyl, (E)—1— methylbut-Z—enyl, (Z)—1-methy|butenyl, (E)-3—methylbutenyl, methylbut—1—enyl, (E)—2- methylbut-l—enyl, (Z)—2-methylbutenyl, methylbutenyl, (Z)methylbut—1-enyl, 1,1- dimethylprop—Z-enyl, 1-ethylpropenyl, 1-propylvinyl, 1—isopropylvinyl, 4—methylpentenyl, 3- methylpentenyl, 2—methylpentenyl, 1-methylpentenyl, 4-methylpentenyl, (E) methylpent—3—enyl, (Z)—3-methylpent-3—enyl, (E)—2-methy|pent-3—enyl, (Z)—2-methylpentenyl, [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (E)—1—methy|pent—3—enyl, methy|pent-3—enyl, (E)—4—methylpent—2-enyl, (Z)-4—methylpent—2— enyl, (E)methy|penteny|, (Z)methy|pentenyl, (E)methy|pent-2—enyl, (Z)—2- methylpent-Z-enyl, (E)methylpentenyl, (Z)methylpentenyl, methylpentenyl, (Z)methy|pentenyl, (E)methy|penteny|, (Z)methy|penteny|, (E)methylpent enyl, (Z)methylpentenyl, (E)methylpentenyl, (Z)methylpentenyl, 3-ethylbut enyl, 2-ethylbutenyl, 1-ethylbutenyl, ethy|butenyl, (Z)—3-ethy|buteny|, (E) ut-Z-enyl, (Z)ethylbutenyl, (E)ethylbutenyl, (Z)ethylbutenyl, (E)ethylbut- 1-enyl, (Z)ethy|but—1-eny|, 2—ethylbutenyl, (E)ethy|buteny|, (Z)-1—ethy|but—1-eny|, 2- propylprop—Z—enyl, 1—propylpropenyl, 2-isopropylprop—2-enyl, ropylprop-Z—enyl, (E)—2- propylprop-l—enyl, (Z)—2-propy|propeny|, (E)-1—propy|propeny|, (Z)propy|propeny|, (E)- 2-isopropylpropenyl, (Z)-2—isopropy|prop-l-enyl, (E)-1—isopropylprop-l—enyl, (Z)—1— isopropylprop-l-enyl, (E)-3,3-dimethy|prop-l-enyl, (Z)-3,3—dimethylprop-l—enyl, 1-(1,1- dimethylethyl)ethenyl, buta-1,3-dieny|, penta-1,4-dieny|, hexa-1,5—dieny|, or hexadienyl group. Particularly, said group is vinyl or a||y|.

The term "Cg—Clo-cycloalkyIII is to be understood as meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms ("C3-C10-cycloalkyl").

Said -cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, onyl or cyclodecyl, or a bicyclic hydrocarbon ring, e.g. a perhydropentalenylene or decalin ring. Particularly, said ring contains 3, 4, 5 or 6 carbon atoms ("C3-C5-cycloalkyl"), preferably cyclopropyl.

The term "3— to 10—membered heterocycloalkyl" is to be understood as meaning a saturated, monovalent, mono- or ic hydrocarbon ring which contains 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or more heteroatom—containing groups selected from C(=O), O, S, S(=O), S(=O)2, NR3, in which Ra ents a hydrogen atom, or a C1-C6-alkyl or haloalkyl group; it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, the nitrogen atom.

Particularly, said 3- to lO-membered heterocycloalkyl can contain 2, 3, 4, or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "3— to 6-membered heterocycloalkyl"), more ularly said heterocycloalkyl can contain 4 or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "5— to 6-membered heterocycloalkyl").

Drticularly, without being limited thereto, said heterocycloalkyl can be a 4-membered ring, such [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp as an azetidinyl, oxetanyl, or a 5—membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6—membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, zinyl, or trithianyl, or a 7-membered ring, such as a diazepanyl ring, for example. Optionally, said heterocycloalkyl can be benzo fused. Preferably, the 3- to 6-membered heterocycloalkyl is a tetrahydrofuranyl, tetrahydropyranyl or piperazinyl.

Said heterocycloalkyl can be bicyclic, such as, without being limited o, a 5,5-membered ring, e.g. a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6—membered bicyclic ring, e.g. a hexahydropyrrolo[1,2—a]pyrazin-2(1H)—yl ring.

As mentioned supra, said nitrogen atom-containing ring can be partially rated, Le. it can contain one or more double bonds, such as, without being limited thereto, a 2,5-dihydro-1H— pyrrolyl, 4H—[1,3,4]thiadiazinyl, hydrooxazolyl, or 4H—[1,4]thiazinyl ring, for example, or, it may be benzo-fused, such as, without being limited thereto, a oisoquinolinyl ring, for example.

The term "3— to 10—membered heterocycloalkoxy" of formula —O—heterocycloa|kyl, in which the term "heterocycloalkyl" is defined supra, is to be understood as meaning a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or more heteroatom-containing groups selected from C(=O), O, S, S(=O), S(=O)2, NRa, in which Ra represents a hydrogen atom, a C1-C6-alkyl or C1-C5-haloalkyl group and which is ted to the rest of the molecule via an oxygen atom, e.g. a pyrrolidineoxy, yd rofu y or tetra hyd ropyranoxy.

The term "4— to 10—membered heterocycloalkenyl" is to be understood as meaning an unsaturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or more heteroatom—containing groups selected from C(=O), O, S, S(=O), S(=O)2, NRa, in which R":1 represents a hydrogen atom, or a C1-C6-alkyl or C1-C6-haloalkyl group; it being possible for said heterocycloalkenyl group to be ed to the rest of the molecule via any one of the carbon atoms or, if present, the nitrogen atom. es of said heterocycloalkenyl may contain one or more double bonds, e.g. 4H—pyranyl, ZH-pyranyl, 3,6—dihydro—2H—pyran—4—yl, 3,6-dihydro-ZH-thiopyranyl, 6-tetrahydropyridinyl, 3H-diazirinyl, 2,5-dihydro-1H- pyrrolyl, [1,3]dioxolyl, 4H-[1,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5- dihydrothiophenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl, 4H-[1,4]thiazinyl or 5,6- Dhydroimidazo[1,2-a]pyrazin-7(8H)-y| group or it may be benzo fused.

[Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp ation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp The term "heteroaryl" is understood as meaning a monovalent, monocyclic— or lic , bicyclic— aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryIn group), 5 or 6 or 9 or 10 ring atoms (a "5- to 10-membered heteroaryI" group) or particularly 5 or 6 ring atoms ("5- to 6-membered heteroary III group), and which contains at least one heteroatom which may be identical or different, said atom being such as oxygen, nitrogen or sulfur, and in addition in each case can be benzocondensed. Particularly, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, lyl, isoxazolyl, isothiazolyl, oxadiazolyl, lyl, thiadiazolyl, thia-4H-pyrazolyl etc., and benzo tives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, zinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc., and benzo derivatives f; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, oxepinyl or 1H—pyrrolo[2,3-b]pyridinyl, etc. .

In general, and unless otherwise mentioned, the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof. Thus, for some illustrative non-restricting example, the term pyridinyl or pyridinylene es pyridinyl, pyridinylene, pyridinyl, pyridin-3—ylene, pyridinyl and pyridinylene; or the term thienyl or thienylene includes thienyl, thienylene, thienyl and thienylene.

The term ", as used throughout this text, e.g. in the context of the tion of "C1-C5-alkyl", "Cl-Ce-haloalkyl", "Cl-Ce-alkoxy", or "C1—C6-haloa|koxy" is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term "C1-C6" is to be interpreted as any sub-range comprised n, e.g. C1-C6, C2—C5, C3—C4, C1-C2, C1—C3, C1—C4, C1-C5; particularly C1-C2, C1-C3,C1—C4, C1—C5, C1- C6; more particularly C1-C4; in the case of "Cl-Ce-haloalkyl" or "Cl-Ce-haloalkoxy" even more particularly C1—C2.

Similarly, as used herein, the term "C2—C6", as used throughout this text, e.g. in the context of the definitions of "CZ—Ce-alkenyl" and —a|kynyll! is to be understood as meaning an alkenyl group or an l group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term "C2-C6" is to be interpreted as any sub-range comprised therein, e.g. C2-C6, C3-C5, C3—C4, C2-C3, C2-C4, C2—C5,- particularly C2—C3.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Further, as used herein, the term "C3—C5", as used throughout this text, e.g. in the context of the tion of "C3-C5-cycloalkyl", is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term "C3-C6" is to be interpreted as any sub-range comprised therein, e.g. C3-C6, C4-C5, C3-C5, C3-C4, C4-C6, C5-C5; particularly C3-C5.

Further, as used herein, the term "C2—C4", as used throughout this text, e.g. in the context of "C2-C4—alkenyIII - IS to be tood as g a alkenyl group having a finite number of carbon atoms of 2 to 4, i.e. 2, 3 or 4 carbon atoms. It is to be understood further that said term "C2—C4" is to be reted as any sub-range comprised therein, e.g. C2-C4, C2-C3, C3-C4.

The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the tution results in a stable compound. Combinations of substituents and/or variables are permissible only if such ations result in stable compounds.

The term "optionally substituted" means optional substitution with the specified groups, ls or moieties.

Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system.

As used herein, the term "one or more", e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning "one, two, three, four or five, particularly one, two, three or four, more particularly one, two or three, even more particularly one or two".

The invention also includes all le isotopic variations of a compound ofthe invention. An isotopic ion of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of es that can be incorporated into a compound ofthe invention include isotopes of hydrogen, carbon, nitrogen, , phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H um), 11C,13C, 14C, ISN, 170’ 180, 32p, 33p, 335, 34$, 355, 36S, 18F, 36G, 82Brl 123'! 124', 129' and 131', respectively. Certain isotopic variations of a compound of the invention, for example, those in Dhich one or more radioactive isotopes such as 3H or 14C are incorporated, are useful in drug [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp and/or substrate tissue distribution studies. ted and carbon—14, i.e., 14C, es are particularly preferred for their ease of preparation and ability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, sed in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of a compound of the invention can generally be prepared by conventional procedures known bya person d in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.

Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.

By "stable compound' or "stable ure" is meant a nd that is sufficiently robust to e isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The compounds of this invention may contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and reomeric es in the case of multiple asymmetric centres. In certain instances, try may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two tuted aromatic rings of the specified compounds.

The compounds of the present invention may contain sulphur atoms which are asymmetric, such as an asymmetric sulphoxide or sulphoximine group, of structure: ll *\S/* // \\ O o N for example, in which * indicates atoms to which the rest ofthe molecule can be bound.

Substituents on a ring may also be present in either cis or trans form. It is intended that all such urations (including enantiomers and diastereomers), are included within the scope of the [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp present invention.

Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures ofthe compounds of this invention are also included within the scope of the present invention. The cation and the separation of such materials can be accomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution ofthe racemic mixtures according to conventional ses, for example, by the formation of reoisomeric salts using an optically active acid or base or formation of covalent reomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then ted from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the tion ofthe enantiomers.

Suitable chiral HPLC columns are manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ among many others, all ely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of this invention can se be obtained by chiral syntheses utilizing optically active starting materials.

In order to limit different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

The present invention es all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. R— or S- isomers, or E- or Z-isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, ally chiral tography, for example.

Further, the compounds of the present invention may exist as tautomers. For example, any compound of the present ion which ns a pyrazole moiety as a heteroaryl group for example can exist as a 1H tautomer, or a 2H tautomer, or even a mixture in any amount of the two ers, or a triazole moiety for example can exist as a 1H er, a 2H tautomer, or a [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 4H tautomer, or even a mixture in any amount of said 1H, 2H and 4H tautomers, namely: 1H-tautomer tomer H N N \< \N \(/ \NHa \(/ \NJ NJ N H 1H-tautomer 2H-tautomer 4H-tautomer The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.

Further, the compounds of the present invention can exist as N—oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N—oxides.

The t invention also s to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, gs, salts, in particular pharmaceutically acceptable salts, and cipitates.

The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in ular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui—, di-, tri—, tetra—, penta- etc. solvates or hydrates, tively, are possible. The present invention includes all such hydrates or solvates.

Further, the compounds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a rion, or can exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any ceutically able organic or inorganic addition salt, customarily used in pharmacy. de term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp acid on salt of a compound of the present invention. For example, see S. M. Berge, et of.

"Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.

A suitable ceutically acceptable salt of the compounds of the present invention may be, for example, an acid—addition salt of a nd of the present ion bearing a nitrogen atom, in a chain or in a ring, for e, which is sufficiently basic, such as an acid—addition salt with an inorganic acid, such as hloric, romic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4—hydroxybenzoyl)—benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3—hydroxy—2—naphthoic, nicotinic, pamoic, pectinic, furic, 3—phenylpropionic, picric, pivalic, 2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic, dodecylsulfuric, ulfonic, benzenesulfonic, para—toluenesulfonic, methansulfonic, 2—naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D—gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.

Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for e a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically acceptable , for example a salt with N-methyl-glucamine, dimethyl—glucamine, ethyl—glucamine, lysine, ohexylamine, 1,6- hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, ydroxy—methyl—aminomethane, aminopropandiol, sovak-base, 1-amino—2,3,4-butantrio|. Additionally, basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides ; dialkyl sulfates like dimethyl, l, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, l halides like benzyl and phenethyl bromides and others.

Those d in the art will further recognise that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the riate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.

De present invention includes all possible salts of the compounds of the t invention as [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp single salts, or as any mixture of said salts, in any ratio.

Furthermore, the present invention includes all possible crystalline forms, or rphs, of the compounds of the present invention, either as single polymorphs, or as a mixture of more than one polymorphs, in any ratio.

When radicals in the nds ofthe present invention are tuted, the ls may be mono- or polysubstituted, unless specified otherwise. In the context of the present invention, all radicals which occur more than once are defined independently of one another. Substitution by one, two or three identical or different substituents is preferred.

In the t of the present invention, the term "treatment" or "treating" includes inhibition, retardation, checking, alleviating, attenuating, restricting, reducing, suppressing, ing or healing of a disease (the term "disease" includes but is not limited a condition, a disorder, an injury or a health problem), or the development, the course or the progression of such states and/or the symptoms of such states. The term "therapy" is tood here to be synonymous with the term "treatment".

The terms "prevention , prophylaxis" or "preclusion" are used synonymously in the t of the present invention and refer to the avoidance or reduction of the risk of contracting, experiencing, suffering from or having a e or a development or advancement of such states and/or the symptoms of such states.

The treatment or prevention of a disease may be partial or complete.

In another embodiment, the present invention covers compounds of general formula (I) O/\r 1 RN /N / N l R8 \ \ (l) in which: R1 ents a group selected from: [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ZI I2 wherein * indicates the point of attachment of said group with the rest of the molecule; R2 represents hydrogen, halogen, —NR7R8, CN, C1-C6—alkyl, C1—Ce-alkoxy, 3- to 10—membered heterocycloalkoxy, C2-C6-alkenyl, C3-C6-cycloalkyl, 3- to 10—membered heterocycloalkyl, 4- to 10-membered cycloalkenyl, phenyl, heteroaryl, -(CO)OR7, -(CO)NR7R8, -(SOz)R9, 9, -SR9, —(SOz)NR7R8, -N )R9, =N R11)R1°, -N=(SO)R9R1°, R"R12, —(PO)(OR7)2, —(PO)(OR7)R10 or —(PO)(R1°)2, n each C1—C6-alkyl, C1-C6-alkoxy, 3- to 10-membered heterocycloalkoxy, Cz—Ce-alkenyl, C3-C5—cycloalkyl, 3- to 10—membered heterocycloalkyl, phenyl or heteroaryl is optionally substituted, one or more times, independently from each other, with halogen, OH, —NR7R8, C1-C6-alkyl, 3- to 6-membered heterocycloalkyl, 4- to 6-membered heterocycloalkenyl, phenyl, —(CO)OR7, —(CO)NR7R8, -NR7(CO)R1°, -NR8(CO)OR7, —NR8(CO) NR7R8, -(SOZ)R9, —(SO)R9, -SR9, -(SOz)NR7R8, -NR7(SOZ)R9, -((SO)=NR")R1°, -N=(SO)R9R1°, OR7)2, —(PO)(OR7)R1°, —(PO)(R1°)2 or with a heteroaryl group which is optionally substituted, one or more times, with C1-C4-alkyl; wherein each 4- to 10—membered heterocycloalkenyl is optionally substituted, one or more times, indepently from each other, with C1—C4-alkyl; R3, R4 represent, independently from each other, hydrogen or methyl; R7, R8 ent, independently from each other, hydrogen or C1-C5-alkyl; or R7 and R8 together represent a 4-, 5-, 6- or 7-membered cyclic amine group, which is optionally substituted, one or more times, independently from each other, with a tuent selected from C1-C6-alkyl, haloalkyl, said 4—, 5—, 6- or 7—membered cyclic amine group ally containing one further heteroatom selected from the group consisting of O, N and S; R9 represents C1—C4-alkyl or phenyl, wherein each C1—C4-alkyl or phenyl is ally substituted, one or more times, independently from each other, with R13; do represents C1—C4-alkyl; or [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp R9 and R10 together, in case of —N=(SO)R9R10 group, ent a 5— t0 8—membered heterocycloalkyl group; R11 represents hydrogen, C1-C4-alkyl, -(CO)OR7, -(CO)NR7R8 or CN; R12 represents hydrogen or C1-C4-alkyl; R13 represents halogen, OH, -NR7R8, CN, N02, C1-C6—alkyl, C1—C5—haloalkyl, C1-C6—alkoxy, C1-C5—haloalkoxy, Cz-Ce—alkenyl, C3-C6-cycloalkyl, -(CO)OR7 or -(CO)NR7R8; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a e, or a salt thereof, or a mixture of same.

In accordance with another embodiment the present invention covers compounds of general formula (I), supra, in which: R1 represents a group selected from: H N / \ NH wherein * indicates the point of attachment of said group with the rest of the molecule; R2 represents hydrogen, fluoro, chloro, CN, C1-C4—alkyl, C1—C4—alkoxy, 3— to ered heterocycloalkoxy, C2-C4-alkenyl, C3-C6-cycloalkyl, 3- to 6-membered heterocycloalkyl, 4— to 6—membered cycloalkenyl, phenyl, 5— to ered heteroaryl, —(CO)NR7R8, R9, -SR9, -((SO)=NR")R1°, -N=(SO)R9R1°, wherein each C1-C4-alkyl, C1-C4-alkoxy, 3- to 6-membered heterocycloalkoxy, C2-C4-alkenyl, Cg-Ce-cycloalkyl, 3- to ered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, is optionally substituted, one or more times, ndently from each other, with fluoro, chloro, OH, -N R7R8, C1-C4—alkyl, 5—membered heterocycloalkyl, phenyl, —NR8(CO)OR7, -(SOZ)R9, -((SO)=N R")R1°, -(PO)(OR7)2 or with a 5- to 6-membered heteroaryl group which is optionally substituted, one or more times, with C1—C4-alkyl; wherein each 4— to ered heterocycloalkenyl is optionally substituted, one or more times, ndently from each other,with C1-C4-alkyl; D, R4 represent, independently from each other, hydrogen or methyl; [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp R7, R8 represent, independently from each other, hydrogen or C1—C4-alkyl; R9 represents C1—C4-alkyl; R10 represents alkyl; or R9 and R10 together, in case of —N=(SO)R9R10 group, ent a 6—membered heterocycloalkyl group; R11 represents hydrogen, alkyl, -(CO)OR7; or a stereoisomer, a tautomer, an N-oxide, a e, a solvate, or a salt thereof, or a mixture of same.

In accordance with another embodiment the present ion covers compounds of general formula (lb) O/YR R1 K/N /N / N ("0) in which R1, R2, R4, R7, R8, R9, R10, R", R12 and R13 are as defined for the compound of general formula (I) supra or infra.

In accordance with another embodiment the present invention covers compounds of general formula (lb), in which R1 represents: wherein * indicates the point of attachment of said group with the rest of the molecule; R2 represents hydrogen, fluoro, , CN, methyl, C1-C4-alkoxy, C2-C3—alkenyl, cyclopropyl, D 3- to 6-membered heterocycloalkyl, 4- to 6-membered heterocycloalkenyl, phenyl, [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp pyridinyl, thiazolyl, '(SOz)R9, —SR9, —((SO)=NR")R1°, —N=(SO)R9R1°, wherein each methyl, C1-C4-alkoxy, C2-C3—alkenyl, cyclopropyl, 3- to ered heterocycloalkyl, phenyl, pyridinyl or thiazolyl is optionally tuted, one or more times, independently from each other, with fluoro, chloro, OH, -NR7R8, methyl, 5-membered heterocycloalkyl, -NR8(CO)OR7, -(SOz)R9, -((SO)=NR")R1°, -(PO)(OR7)2, or with a group selected from: / o \ N I \ I —N O HSC HSC wherein * tes the point of attachment of said group with the rest of the molecule; wherein each 4- to 6—membered heterocycloalkenyl is optionally tuted, one or more times, with ; R4 represents hydrogen or ; R7, R8 represent, independently from each other, hydrogen or C1—C4-alkyl; R9 represents C1—C4-alkyl; R10 represents alkyl; or R9 and R10 together, in case of —N=(SO)R9R10 group, represent a 6—membered heterocycloalkyl group; R11 represents hydrogen, methyl, -(CO)OR7; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In accordance with another embodiment the present invention covers compounds of general formula (lb), in which R1 represents: [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp wherein * tes the point of attachment of said group with the rest of the molecule; R2 represents en, fluoro, , CN, methyl, cyclopropyl, C2-C3—alkenyl, C1—C4—alkoxy, 3- to 10—membered heterocycloalkyl, 4- to 10—membered heterocycloalkenyl, 5- to 10-membered heteroaryl, phenyl, —NR7R8, -N=(SO)R9R1°, -((SO)=NR")R1°, -(SOz)R9, -SR9, wherein each methyl, Cz-Cg-alkenyl, C1-C4-alkoxy, 3- to lO—membered heterocycloalkyl, - to 10-membered heteroaryl, phenyl is optionally substituted, one or more times, independently from each other, with , chloro, OH, -NR7R8, C1-C4—alkyl, cyclopropyl, C1—C6-haloalkyl, C1-C4-alkoxy, C1-C4-hydroxyalkyl, benzyl, 5- to 6— membered heterocycloalkyl, -N R8(CO)OR7, -(SOz)R9, -((SO)=NR")R1°, —(PO)(OR7)2 or with a group selected from: /P \ N \ I _N 0 HO HO 3 3 wherein * indicates the point of attachment of said group with the rest of the molecule; wherein each 4- to lO-membered heterocycloalkenyl is optionally substituted, one or more times, with methyl; R7 R8 represent, independently from each other, hydrogen, C1—C6—alkyl, cyclopropyl or optionally nated phenyl; R9 represents C1-C4-alkyl; R10 represents alkyl; or R9 and R10 together, in case of —N=(SO)R9R10 group, represent a 6-membered cycloalkyl group; in represents hydrogen, methyl, —(CO)OR7; [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp or a stereoisomer, a tautomer, an N—oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In accordance with another embodiment the present invention covers compounds of general a (lb), in which R1 represents: wherein * indicates the point of attachment of said group with the rest of the molecule; R2 represents CN, C1-C4—alkoxy, ‘(SOz)R9, —SR9, cyclopropyl, —NR7R8, —N=(SO)R9R1°, phenyl, - to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkenyl , n each C1-C4-alkoxy, phenyl, 5- to 10-membered heteroaryl, 3- to 10-membered cycloalkyl is optionally tuted, one or more times, independently from each other, with fluoro, chloro, -NR7R8, C1-C4-alkyl, ropyl, C1-C6-haloalkyl, C1-C4-alkoxy, C1-C4-hydroxyalkyl, benzyl, 5- to 6-membered heterocycloalkyl, -NR8(CO)OR7, -(SOz)R9, -((SO)=NR")R1°; R7, R8 represent, independently from each other, hydrogen, C1—C5-alkyl, cyclopropyl or optionally nated phenyl; R9 represents C1—C4-alkyl; R10 represents C1—C4-alkyl; or R9 and R10 together, in case of -N=(SO)R9R10 group, represent a 6—membered heterocycloalkyl group; R11 represents hydrogen; or a stereoisomer, a tautomer, an e, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In accordance with another embodiment the present invention covers compounds of general formula (lb), in which [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp R1 represents: wherein * indicates the point of attachment of said group with the rest of the molecule; R2 represents CN, methoxy, ethoxy, propoxy, butyloxy, isopropoxy, methylsulfanyl, cyclopropyl, —NR7R8, (4—oxido—1,4?\4-oxathian-4—ylidene)amino, phenyl, pyridinyl, thiazolyl, rolo[2,3-b]pyridinyl, pyrrolyl, thienyl, lyl, 1,2—oxazolyl, imidazolyl, tetrahydro—ZH—pyranyl, 3,6-dihydro-2H—thiopyranyl, piperidinyl, piperazinyl, ,6-dihydroimidazo[1,2-a]pyrazin-7(8H)—yl, methanesulphonyl, wherein each , propoxy, butyloxy, phenyl, pyridinyl, thiazolyl, pyrroly, thienyl, pyrazolyl, 1,2-oxazolyl, imidazolyl, piperidinyl or piperazinyl is optionally tuted, one or more times, independently from each other, with fluoro, , -NR7R8, methyl, ethyl, 2,2,—dimethylethyl, cyclopropyl, trifluoromethyl, methoxy, hydroxymethyl, benzyl, zinyl, -NR8(CO)OR7, methanesulphonyl, -((SOl=NR")R1°; R7, R8 represent, independently from each other, hydrogen, , 2,2-dimethylethyl, 2,2-dimethylpropyl, cyclopropyl or fluorophenyl; R10 represents methyl; R11 represents hydrogen; or a isomer, a tautomer, an N—oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In accordance with another embodiment the present invention covers compounds of general formula (lb), in which R1 represents: D wherein * tes the point of attachment of said group with the rest of the [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp molecule; R2 represents hydrogen, halogen, —NR7R8, CN, C1-C6—alkyl, C1—Ce-alkoxy, 3- to 10—membered heterocycloalkoxy, Cz-Ce-alkenyl, C3-C6-cycloalkyl, 3- to 10—membered heterocycloalkyl, 4- to 10-membered heterocycloalkenyl, phenyl, aryl, -(CO)OR7, -(CO)NR7R8, -(SOz)R9,-(SO)R9,-SR9,-(SOZ)NR7R8,-NR7(SOZ)R9,-((SO)=NR11)R1°,-N=(SO)R9R10, -SiR1°R"R12, —(PO)(OR7)2, —(PO)(OR7)R10 or —(PO)(R1°)2, wherein each C1-C6-alkyl, C1-C6-alkoxy, 3- to 10-membered heterocycloalkoxy, C2-C5-alkenyl, C3—C6-cycloalkyl, 3- to 10—membered heterocycloalkyl, phenyl or heteroaryl is ally substituted, one or more times, ndently from each other, with halogen, OH, , C1-C6—alkyl ally substituted with yl or phenyl, C1-C6-haloalkyl, C1-C6-alkoxy, C3-C6-cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, —(CO)OR7, -(CO)NR7R8, —NR7(CO)R1°, NR8(CO)OR7, -N R8(c0) NR7R8,-(SOZ)R9,-(SO)R9,-SR9,-(SOz)NR7R8,-NR7(SOZ)R9,-((SO)=NR11)R10, -N=(SO)R9R1°, —(PO)(OR7)2, —(PO)(OR7)R1°, —(PO)(R1°)2 or with a heteroaryl group which is optionally substituted, one or more times, with C1-C4-alkyl; wherein each 4- to 10-membered heterocycloalkenyl is optionally substituted, one or more times, indepently from each other, with C1-C4-alkyl; R3, R4 represent, independently from each other, hydrogen or methyl; R7, R8 represent, independently from each other, hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl or , which phenyl is ally substituted, one or more times, with halogen; or R7 and R8 together represent a 4-, 5-, 6- or 7-membered cyclic amine group, which is optionally substituted, one or more times, ndently from each other, with a substituent selected from C1-Ce-alkyl, C1-C5-haloalkyl, said 4-, 5-, 6- or 7-membered cyclic amine group optionally containing one further heteroatom selected from the group consisting of O, N and S; R9 ents C1-C4—alkyl or phenyl, wherein each C1-C4-alkyl or phenyl is optionally substituted, one or more times, independently from each other, with R13; R10 represents C1-C4-alkyl; or R9 and Riotogether, in case of -N=(SO)R9R10 group, represent a 5- to 8-membered heterocycloalkyl group; [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp R11 represents hydrogen, C1—C4-alkyl, —(CO)OR7, —(CO)NR7R8 or CN; R12 represents hydrogen or C1-C4-alkyl; R13 represents halogen, OH, , CN, N02, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6- haloalkoxy, C2-C5-alkenyl, C3-C5-cycloalkyl, -(CO)OR7 or -(CO)NR7R8.

In accordance with another embodiment the present invention covers compounds of general formula (lb), in which R1 represents: n * indicates the point of attachment of said group with the rest of the molecule; R2 represents hydrogen, n, —NR7R8, CN, C1-C6—alkyl, C1—Ce-alkoxy, 3- to 10—membered heterocycloalkoxy, C2-C6-alkenyl, C3-C6-cycloalkyl, 3- to 10—membered heterocycloalkyl, 4- to 10-membered heterocycloalkenyl, phenyl, aryl, -(CO)OR7, -(CO)NR7R8, -(SOz)R9,-(SO)R9,-SR9,-(SOZ)NR7R8,-NR7(SOZ)R9,-((SO)=NR11)R1°,-N=(SO)R9R10, trimethylsily, triethylsilyl, triisopropylsilyl, dimethylphenylsilyl, isopropyldimethylsilyl, tert- butyldiphenylsilyl, utyldimethylsilyl, —(PO)(OR7)2, —(PO)(OR7)R10 or —(PO)(R1°)2, n each C1—C6—alkyl, C1—C6-alkoxy, 3- to 10-membered heterocycloalkoxy, C2-C6-alkenyl, C3-C6-cycloalkyl, 3- to bered heterocycloalkyl, phenyl or heteroaryl is ally substituted, one or more times, independently from each other, with halogen, OH, -NR7R8, alkyl optionally substituted with hydroxyl or phenyl, C1—C5—haloalkyl, C1—C5—alkoxy, C3—Ce-cycloalkyl, 3— to 6-membered heterocycloalkyl, phenyl, -(CO)OR7, -(CO)NR7R8, -NR7(CO)R1°, NR8(CO)OR7, -N R8(CO) NR7R8, —(SOz)R9, —(SO)R9, —SR9, -(SOz)NR7R8, —NR7(SOz)R9, -((SO)=NR11)R1°, -N=(SO)R9R1°, -(PO)(OR7)2, —(PO)(OR7)R1°, —(PO)(R1°)2 or with a heteroaryl group which is optionally substituted, one or more times, with C1-C4-alkyl; wherein each 4- to 10-membered heterocycloalkenyl is ally substituted, one or more times, indepently from each other, with C1-C4-alkyl; R3, R4 represent, independently from each other, en or methyl; [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp R7, R8 represent, independently from each other, hydrogen, C1—C5—alkyl, Cg—Ce—cycloalkyl or phenyl, which phenyl is optionally substituted, one or more times, with halogen; or R7 and Rgtogether represent a 4-, 5—, 6- or 7-membered cyclic amine group, which is optionally substituted, one or more times, independently from each other, with a substituent selected from C1-C6-alkyl, C1-C6—haloalkyl, said 4-, 5-, 6- or 7-membered cyclic amine group optionally containing one further heteroatom selected from the group consisting of O, N and S; R9 represents C1—C4—alkyl or phenyl, wherein each C1—C4—alkyl or phenyl is optionally substituted, one or more times, independently from each other, with R13; R10 represents C1-C4-alkyl; or R9 and ether, in case of -N=(SO)R9R10 group, ent a 5- to ered heterocycloalkyl group; R11 represents hydrogen, C1—C4-alkyl, R7, -(CO)NR7R8 or CN; R12 represents hydrogen or C1-C4-alkyl; R13 represents halogen, OH, -NR7R8, CN, N02, C1-C5-alkyl, C1-C5-haloalkyl, C1-C5-alkoxy, C1-C5- haloalkoxy, C2-C6-alkenyl, C3-C6-cycloalkyl, -(CO)OR7 or -(CO)NR7R8.

In accordance with another embodiment the present invention covers compounds of general formula (lb), in which represents: wherein * tes the point of attachment of said group with the rest of the molecule; R2 represents hydrogen, halogen, —NR7R8, CN, C1-Ce-alkyl, C1-C4-alkoxy, 3- to bered heterocycloalkoxy, C2-C4-alkenyl, C3-C6-cycloalkyl, 3- to 10—membered cycloalkyl, 4- to 10—membered heterocycloalkenyl, phenyl, heteroaryl, —(CO)NR7R8, -(SOz)R9, -(SO)R9, [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp -SR9, —N=(SO)R9R1°, —(PO)(OR7)2, —(PO)(OR7)R1°, —(PO)(R1°)2, wherein each C1-C5-alkyl, C1-C4-alkoxy, C3-C6-cycloalkyl, 3- to lO-membered heterocycloalkyl, phenyl or heteroaryl is optionally substituted, one or more times, independently from each other, with halogen, OH, amino, -N R7R8, C1-C4-alkyl optionally substituted with hydroxyl or phenyl, haloalkyl, C1-C3-alkoxy, C3-C6-cycloalkyl, 3- to ered heterocycloalkyl, phenyl, -(CO)OR7, -(CO)NR7R8, -NR7(CO)R1°, O)OR7, -(SOz)R9, -SR9, -N R7(SOz)R9, —((SO)=NR11)R1°, -(PO)(OR7)2, —(PO)(OR7)R1°, or with a heteroaryl group; wherein each 4- to 10-membered heterocycloalkenyl is optionally substituted, one or more times, independently from each other, with methyl; R4 represents hydrogen or methyl; R7, R’3 represent, independently from each other, hydrogen, C1—C6-alkyl, C3-C6-cycloalkyl or phenyl, which phenyl is optionally substituted, one or more times, with n; R9 represents C1-C4-alkyl or phenyl, n each C1-C4-alkyl or phenyl is optionally substituted, one or more times, independently from each other, with R13; R10 represents C1-C4-alkyl; or R9 and R1°together, in case of -N=(SO)R9R10 group, represent a 5- to ered heterocycloalkyl group; R11 represents hydrogen, alkyl, R7, -(CO)NR7R8 or CN; RJ3 represents halogen, OH or C1-C6—alkoxy.

In accordance with another embodiment the present invention covers compounds of general formula (lb), in which R1 represents: D wherein * indicates the point of attachment of said group with the rest of the [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp molecule; represents hydrogen, chloro,—amino, propylamino, ylamino, methyl(propyl)amino, methyl(2-methylpropyl)amino, 2,2-dimethylpropyl(methy|)amino, cyclopropyl(methyl)amino, methyl(phenyl)amino, CN, methyl, ethyl, propan—Z-yl, 3-methylbutanyl, pentanyl, Z-yl, 3,3-dimethylbutanyl, methoxy, ethoxy, propoxy, butoxy, 2-methyI-propanyloxy, -Z-yloxy, (2-oxotetrahydrofuran—3-y|)oxy, yl, cyclopropyl, cyclohexyl, azetidinyI,-pyrro|idinyl, 2-oxo—1,3-oxazo|idin—Z—one, tetrahyd ro—ZH-pyranyl, yd ro-2H—thiopyran—4-yl, piperidinyl, zinyl, morpholinyl, azepanyl, 2-oxo-pyrrolidinyl, 2-oxo-piperidin—l-yl, 3—oxo—piperazinyl, 2—oxo-1,3—oxazinan—3-y|, otetrahydro—2H—thiopyranyl, 1,1-dioxidotetrahydro-2H-thiopyranyl, 1,1-dioxido-1,2-thiazo|idinyl, ,6—dihydroimidazo[1,2-a]pyrazin—7(8H)—yl, 3-oxa—8—azabicyclo[3.2.1]oct-8—y|, 1,3,3—trimethyIazabicyc|o[3.2.1]octy|, (3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol- (3H)—yl, )—2—oxa—5—azabicyclo[2.2.1]hept—5—yl, 1,1—dioxido—1—thia-6— azaspiro[3.3]heptyl7 2,5-dihydro-lH-pyrroI-l-yl, 3,6-dihydro-ZH-pyranyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 3,6-dihydro-2H-thiopyranyl, phenyl, 1,3-dihydro-ZH-isoindoI-Z-yl, 3,4-dihydroquinolin- 1(2H)-y|, 3,4-dihydroisoquinolin-2(1H)-y|, pyrrolyl, pyrazolyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, 2-oxo-1,2-dihydropyridin- 4-yl, indolyl, benzothiophenyl, quinolinyl, isoquinolinyl, 1H-pyrro|o[2,3-b]pyridinyl, 6,7-dihydro-5H-pyrro|o[1,2-a]imidazoI-3—yl, H2, methylsulfonyl, ethylsulfonyl, propan-Z-ylsulfonyl, phenylsulfonyl, methylsulfinyl, ethylsulfinyl, propan-Z—ylsulfinyl, phenylsulfinyl, methylsulfanyl, ethylsulfanyl, propan-Z-ylsulfanyl, phenylsulfanyl, -N=(SO)dimethyl, -N=(SO)diethyI, N (CH3 CH 0’ Z O 0’ 28 H 0 H30 CH3 ()0 [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp n * tes the point of attachment of said group with the rest of the molecule, —(PO)(O-methyl)2,~—(PO)(O-ethy|)methyl, —(PO)(Omethy|propyl)methyl, —(PO)(O-ethyl)2-methylpropyl, —(PO)dimethyl, —(PO)diethyl, wherein each methyl, ethyl, propan—2-yl, 3-methylbutanyl, pentanyl, hexan-Z-yl, 3,3-dimethylbutanyl, methoxy, ethoxy, propoxy, 2-methyl-propanyloxy, butoxy, cyclopropyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 3-oxo-piperazinyl, phenyl, yl, pyrazolyl, thiophenyl, imidazolyl, yl, thiazolyl, triazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, indolyl, * * CH3 | I N\\ ,CH3 N\\ J—CHs 0‘82 : 0’82 : is optionally tuted, one or more times, independently from each other, with fluoro, chloro, bromo, OH, amino, -NH—cyc|opropy|, dimethylamino, methyl, ethyl, propan—l-yl, propanyl, 2-methylpropyl, tert-butyl, hydroxymethyl, 2-hydroxyethyl, 2-methylhydroxypropanyl, 2-hydroxypropan—2-yl, benzyl, fluoroethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, methoxymethyl, cyclopropyl, cyclobutyl , tetrahydrofuranyl, tetrahydropyranyl, , -(CO)O-methyl, (CO)O—tert-butyl, -(CO)NH2, -(CO)NH-methyl, -(CO)NH-tert—butyl, -(CO)dimethylamino, -(CO)piperidin-1—yl, -(CO)NH-cyclopropy|, —NH(CO)methyl, —NH(CO)O—tert—butyl, methylsulfonyl, ethylsulfonyl, propan—Z-ylsulfonyl, phenylsulfonyl, methylsulfanyl, -(SOz)NR7R8, NH(SOz)methyl,-((SO)=NH)methyl, -((SO)=NH)ethy|, -((SO)=NH)propanyl, -((SO)=N-methyl)methyl, -((SO)=N-(CO)O-ethyl)methyl, -((SO)=N-(CN))methyl, -((SO)=N-(CO)NH-ethyl)methyl, —(PO)(O—methy|)z,—(PO)(OH)(O-methyl) or with furanyl or pyrazolyl, wherein each 1,2,5,6-tetrahydropyridin-3—yl, 1,2,3,6—tetrahydropyridin-4—yl is optionally substituted, one or more times, independently from each other, with methyl; R4 represents hydrogen or methyl.

In accordance with another embodiment the t invention covers nds of general armula (lb), in which ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp represents: wherein * indicates the point of attachment of said group with the rest of the molecule; ents methylpropyl(methy|)amino, cyclopropyl(methyl)amino, methyl(phenyl)amino, 3-methylbutan-2—yl, cyclopropyl, tetrahydro—ZH-pyranyl, tetrahydro-ZH—thiopyranyl, piperidinyl, piperazinyl, 5,6—dihydroimidazo[1,2-a]pyrazin- 7(8H)-yl, 3,6—dihydro-2H-thiopyranyl, phenyl, pyrrolyl, pyrazolyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, 1H—pyrrolo[2,3-b]pyridin-4—yl or hydro—5H—pyrrolo[1,2- a]imidazo|—3-yl, wherein each 3-methylbutan—2-yl, cyclopropyl, piperidinyl, piperazinyl, phenyl, pyrrolyl, pyrazolyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl or pyridinyl is optionally substituted, one or two or three times, ndently from each other, with fluoro, chloro, OH, amino, methyl, ethyl, propan-l-yl, propan-Z-yl, ter‘t-butyl, hydroxymethyl, benzyl, fluoroethyl, trifluoromethyl, methoxy, cyclopropyl, -(CO)O-methyl, methylsulfonyl, methylsulfanyl or =NH)methyl; R4 represents methyl.

In accordance with r embodiment the present invention covers compounds of general formula (lb), in which R1 represents: wherein * indicates the point of attachment of said group with the rest of the molecule; represents tetrahydro—2H-thiopyran-4—yl, piperidinyl, 5,6—dihydroimidazo[1,2—a]pyrazin- 7(8H)-yl, phenyl, pyrrolyl, pyrazolyl, yl, pyridinyl or 6,7-dihydro-5H-pyrrolo[1,2— a]imidazo|—3—yl, [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp wherein each piperidinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl or pyridinyl is ally substituted, one or two times, independently from each other, with fluoro, amino, methyl, ethyl, propan-Z-yl, hydroxymethyl, methoxy, cyclopropyl, methylsulfonyl, methylsulfanyl or -((SO)=NH)methyl; R4 represents methyl.

In another embodiment the present invention relates to compounds of formula (lb), in which R1 represents: wherein * indicates the point of attachment of said group with the rest of the molecule; R2 ents 2,2-dimethylpropyl(methyl)amino, cyclopropy|(methyl)amino, methyl(pheny|)amino, 3-methylbutan—2—yl, cyclopropyl, tetrahydro—ZH-pyranyl, ydro-ZH-thiopyranyl, piperidinyl, piperazin-l-yl, 5,6-dihydroimidazo[1,2- a]pyrazin-7(8H)—yl, 3,6—dihydro—ZH-thiopyran-4—yl, phenyl, pyrrol—2—yl, 1H—pyrazol-5—yl, 1H- Iyl, thiophen—Z-yl, thiophenyl, 1H-imidazolyl, 1,2-oxazolyl, 1,3-thiazoI yl, pyridine—3—yl, pyridineyl, 1H-pyrrolo[2,3-b]pyridin—4—yl or 6,7—dihydro—5H- pyrrolo[1,2-a]imidazol—3-yl, wherein each 3-methylbutan—2-yl, cyclopropyl, piperidin—4-yl, piperazin-l—yl, phenyl, pyrrol-Z-yl, azolyl, 1H-pyrazoIyl, en-Z-yl, thiophenyl, 1H-imidazol- 5—yl, or pyridine—4—yl is ally , 1,2—oxazol—5—yl, iazol-5—yl, pyridine—3-yl substituted, one or two or three times, independently from each other, with fluoro, chloro, OH, amino, methyl, ethyl, propan—l—yl, propan-2—yl, tert-butyl, hydoxymethyl, benzyl, 2-fluoroethyl, trifluoromethyl, methoxy, cyclopropyl, -(CO)O-methyl, methylsulfonyl, methylsulfanyl or -((SO)=NH)methyl; R4 represents methyl.

In another embodiment the present invention relates to compounds of formula (lb), in which R1 represents: [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp wherein * tes the point of attachment of said group with the rest of the molecule; R2 ents tetrahydro—2H-thiopyran-4—yl, piperidinyl, 5,6-dihydroimidazo[l,2-a]pyrazin- 7(8H)-yl, phenyl, pyrrol—2-yl, 1H—pyrazol—5-yl, 1H-pyrazol-4—yl, 1,2-oxazolyl, 1,3-thiazol- -yl, pyridine—3-yl, 6,7—dihydro—5H-pyrro|o[1,2-a]imidazoI—3-yl, wherein each piperidinyl, phenyl,pyrrolyl, lH-pyrazoI-S-yl, lH-pyrazoIyl, 1,2- oxazolyl, ne—3-yl is optionally substituted, one or two times, independently from each other, with fluoro, OH, amino, methyl, ethyl, propan—Z-yl, hydoxymethyl, 2-fluoroethyl, methoxy, ropyl, ethylsulfonyl, methylsulfanyl ,-((SO)=NH)methyl, R4 represents methyl.

In r embodiment the present invention relates to compounds of formula (lb), in which R1 represents: wherein * indicates the point of attachment of said group with the rest of the molecule; RZ represents phenyl, pyrazolyl, thiophenyl or pyridinyl, wherein each , pyrazolyl, thiophenyl or pyridinyl is optionally substituted, one or two times, independently from each other, with fluoro, chloro, amino, methyl, ethyl, propan-l-yl, propan—Z-yl, tert-butyl, benzyl, fluoroethyl, trifluoromethyl, methoxy, cyclopropyl, methylsulfonyl, methylsulfanyl, =NH)methyl, R4 ents methyl.

Danother embodiment the t invention relates to compounds of formula (lb), in which [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp R1 represents: n * indicates the point of attachment of said group with the rest of the molecule; R2 represents phenyl, 1H—pyrazol—4—yl, 1H—pyrazol-5—yl, thiophen-Z-yl, thiophen—3-yl or pyridineyl, pyridine—4-yl, wherein each phenyl, 1H-pyrazol-4—yl, 1H-pyrazolyl, thiophen—Z-yl, thiophen—3—yl, pyridine-3—yl or neyl,is optionally substituted, one or two times, independently from each other, with fluoro, chloro, amino, methyl, ethyl, -l-yl, propan-Z-yl, tert—butyl, benzyl, fluoroethyl, trifluoromethyl, methoxy, cyclopropyl, methylsulfonyl, methylsulfanyl, -((SO)=NH)methyl, R4 represents methyl.

In another embodiment the present invention relates to compounds of formula (lb), in which R1 represents: wherein * indicates the point of attachment of said group with the rest of the molecule; R2 ents phenyl, azolyl, 1H-pyrazol-5—yl or neyl, wherein each phenyl, 1H-pyrazol-4—yl, 1H-pyrazolyl or pyridineyl,is optionally substituted, one or two times, ndently from each other, with fluoro, amino, methyl, ethyl, propan-l—yl, propan—Z-yl, ter‘t—butyl, benzyl, fluoroethyl, trifluoromethyl, methoxy, cyclopropyl, methylsulfonyl, methylsulfanyl, -((SO)=NH)methyl, R4 represents methyl.

Danother embodiment the t invention relates to compounds of formula (I) or (lb), in [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp which R1 represents a group selected from I ZI \ I2 \NH / \NH wherein * indicates the point of attachment of said group with the rest of the molecule.

In another embodiment the present invention relates to compounds of a (I) or (lb), in which R1 represents a group selected from N N / _\ / \NH wherein * indicates the point of ment of said group with the rest of the molecule.

In another embodiment the present invention relates to compounds of a (I) or (lb), in which R1 represents wherein * indicates the point of attachment of said group with the rest of the le.

In another embodiment the present invention relates to compounds of a (I) or (lb), in which R2 represents hydrogen, fluoro, chloro, CN, C1-C4—alkyl, C1—C4—alkoxy, 3- to 6—membered heterocycloalkoxy, C2—C4-alkenyl, C3-C6-cycloalkyl, 3- to 6—membered cycloalkyl, 4- to 6- membered cycloalkenyl, phenyl, pyridinyl, thiazolyl, -(CO)NR7R8, -(SOZ)R9, -SR9, -((SO)=NR")R1°, -N=(SO)R9R1°, wherein each C1-C4-alkyl, C1-C4—alkoxy, 3- to 6-membered heterocycloalkoxy, C2-C4-alkenyl, cycloalkyl, 3- to 6—membered heterocycloalkyl, phenyl, pyridinyl or thiazolyl is optionally substituted, one or more times, independently from each other, with fluoro, chloro, OH, -N R7R8, C1-C4-alkyl, 5—membered cycloalkyl, phenyl, -N R8(CO)OR7, —(SOz)R9, —((SO)=NR")R1°, -(PO)(OR7)2 or a group selected from: [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp / P \ N —N \5 H30 H C wherein * indicates the point of attachment of said group with the rest of the molecule; wherein each 4- to 6-membered heterocycloalkenyl is optionally substituted, one or more times, with C1-C4-alkyl.

In another embodiment, the present ion s to compounds of formula (I) or (lb), in which R2 represents hydrogen, fluoro, chloro, CN, C1-C4—alkyl, C1—C4—alkoxy, 3— to 6—membered cycloalkoxy, Cz—Cg-alkenyl, C3-C6-cycloalkyl, 3- to 6-membered heterocycloalkyl, 4- to 6- membered heterocycloalkenyl, phenyl, pyridinyl, thiazolyl, —(CO)NR7R8, -(SOz)R9, —SR9, -((SO)=NR")R1°, -N=(SO)R9R1°, wherein each C1—C4-alkyl, alkoxy, 3- to 6 -membered heterocycloalkoxy, C2-C4- alkenyl, Cg-Ce—cycloalkyl, 3- to ered heterocycloalkyl, phenyl, pyridinyl or thiazolyl is optionally substituted, one or more times, independently from each other, with fluoro, chloro, OH, —NR7R8, alkyl, 5—membered heterocycloalkyl, phenyl, -NR8(CO)OR7, R9, -((SO)=NR")R1°, -(PO)(OR7)2 or a group selected from: / o \N I \ i —N O HSC HSC wherein * indicates the point of attachment of said group with the rest of the molecule; wherein each 4- to 6-membered heterocycloalkenyl is optionally substituted, one or more times, independently from each other, with C1-C4-alkyl.

In another embodiment the present invention s to compounds of general formula (I) or (lb), in which R2 ents hydrogen, halogen, -NR7R8, CN, alkyl, C1-C6-alkoxy, 3- to 10- membered heterocycloalkoxy, Cz-Ce-alkenyl, C3-C6-cycloalkyl, 3- to lO-membered heterocycloalkyl, 4- to 10-membered heterocycloalkenyl, phenyl, heteroaryl, -(CO)OR7, -(CO)NR7R8, -(SOZ)R9, -(SO)R9, -SR9, -(SOZ)N R7R8, -N R7(SOZ)R9, -((SO)=NR11)R1°, )R9R1°, -SiR1°R"R12, —(PO)(OR7)2, —(PO)(OR7)R10 or —(PO)(R1°)2, [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp wherein each C1—C6—alkyl, alkoxy, 3— to 10-membered heterocycloalkoxy, Cz—Ce—alkenyl, C3-C6-cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl or aryl is optionally substituted, one or more times, independently from each other, with halogen, OH, -NR7R8, C1-C5-alkyl optionally substituted with hydroxy or phenyl, C1- oalkyl, C1-C5-alkoxy, C3-C5-cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, -(CO)OR7, R7R8, -NR7(CO)R1°, -NR8(CO)OR7, -NR8(CO) NR7R8, -(SOz)R9, 9, -SR9, -(SOz)NR7R8, -NR7(SOZ)R9, -((SO)=NR11)R1°, -N=(SO)R9R1°, -(PO)(OR7)2, —(PO)(OR7)R1°, —(PO)(R1°)2 or with a heteroaryl group which is optionally substituted, one or more times, with C1—C4-alkyl; wherein each 4- to 10-membered heterocycloalkenyl is optionally substituted, one or more times, indepently from each other, with C1-C4-alkyl.

In another embodiment the present invention relates to compounds of a (I) or (lb), in which R2 represents CN, methoxy, ethoxy, propoxy, butyloxy, isopropoxy, methylsulfanyl, cyclopropyl, —NR7R8, (4—oxido—1,4?\4—oxathian—4—ylidene)amino, phenyl, pyridinyl, thiazolyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrrolyl, thienyl, pyrazolyl, 1,2-oxazolyl, imidazolyl, tetrahydro-ZH-pyranyl, 3,6-dihydro-2H-thiopyranyl, dinyl, piperazinyl, ,6-dihydroimidazo[1,2-a]pyrazin-7(8H)—yl, methanesulphonyl, -((SO)=NR")R1°, wherein each ethoxy, propoxy, butyloxy, phenyl, nyl, thiazolyl, pyrroly, l, pyrazolyl, 1,2-oxazolyl, imidazolyl, dinyl or piperazinyl is optionally substituted, one or more times, independently from each other, with , chloro, -NR7R8, methyl, ethyl, 2,2,-dimethylethyl, cyclopropyl, trifluoromethyl, methoxy, ymethyl, benzyl, piperazinyl, —NR8(CO)OR7, methanesulphonyl, S—methylsulfonimidoyl.

In another embodiment the present invention relates to nds of formula (I) or (lb), in which R2 represents hydrogen, chloro,—amino, propylamino, dimethylamino, methyl(propyl)amino, methyl(2—methylpropyl)amino, methylpropyl(methyl)amino, cyclopropyl(methyl)amino, methyl(phenyl)amino, CN, , ethyl, propan-Z-yl, 3-methylbutanyl, pentanyl, hexan-Z- yl, 3,3—dimethylbutan—2—yl, methoxy, ethoxy, propoxy, butoxy, 2—methyl—propan—1—yloxy, propan- 2-yloxy, (2-oxotetrahydrofuranyl)oxy, propenyl, cyclopropyl, cyclohexyl, azetidinyl,—pyrrolidinyl, 2—oxo—1,3—oxazolidin—2—one, tetrahydro—ZH-pyranyl, tetrahydro—2H—thiopyran—4-yl, piperidinyl, piperazinyl, linyl, azepanyl, 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl, 3-oxo—piperazin yl, 2-oxo-1,3-oxazinanyl, 1-oxidotetrahydro-2H-thiopyranyl, 1,1-dioxidotetrahydro-ZH- thiopyranyl, 1,1-dioxido-1,2-thiazolidin-Z-yl, 5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl, 3-oxa- Dazabicyclo[3.2.1]octy|, 1,3,3-trimethylazabicyclo[3.2.1]octyl, (3aR,6aS)-tetrahydro-1H- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp furo[3,4-c]pyrrol-5(3H)—yl, (15,4S)-2—oxa—5—azabicyclo[2.2.1]hept—5—yl, 1,1—dioxido—1—thia-6— azaspiro[3.3]heptyl; 2,5-dihydro-1H-pyrrolyl, 3,6-dihydro-ZH-pyran-4—yl, 1,2,5,6— ydropyridinyl, 1,2,3,6-tetrahydropyridinyl, hydro-2H-thiopyranyl, phenyl, 1,3-dihydro-2H-isoindoIyl, 3,4-dihydroquinolin-1(2H)-yl, hydroisoquinolin-2(1H)-yl, pyrrolyl, pyrazolyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, 2-oxo-1,2-dihydropyridin-4—yl, indolyl, benzothiophenyl, quinolinyl, isoquinolinyl, 1H- pyrrolo[2,3-b]pyridinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazo|y|, -(CO)NH2, methylsulfonyl, ethylsulfonyl, propan—Z-ylsulfonyl, phenylsulfonyl, methylsulfinyl, ethylsulfinyl, propan-Z- ylsulfinyl, phenylsulfinyl, methylsulfanyl, ethylsulfanyl, propan-Z—ylsulfanyl, sulfanyl, -N=(SO)dimethyl, -N=(SO)diethyl, wherein * indicates the point of ment of said group with the rest of the molecule, —(PO)(O-methyl)2;—(PO)(O-ethy|)methyl, —(PO)(Omethy|propyl)methyl, —(PO)(O-ethy|)2-methy|propyl, —(PO)dimethyl, —(PO)diethyl, wherein each methyl, ethyl, propan—Z-yl, 3-methylbutanyl, pentan-3—yl, Z-yl, 3,3-dimethylbutan—2-yl, methoxy, ethoxy, propoxy, yl—propan—1—yloxy, butoxy, cyclopropyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 3-oxo-piperazinyl, phenyl, pyrrolyl, pyrazolyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, indolyl, * * CH3 l I N\\ [CH3 N\\ CH3 o"8 o"8 is ally substituted, one or more times, independently from each other, with D fluoro, chloro, bromo, OH, amino, clopropyl, dimethylamino, methyl, [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ethyl, propan—l-yl, propan—2—yl, 2-methylpropyl, tert-butyl, hydroxymethyl, 2-hydroxyethyl, 2-methylhydroxypropanyl, 2-hydroxypropanyl, benzyl, ethyl, difluoromethyl, trifluoromethyl, y, , isopropoxy, methoxymethyl, cyclopropyl, cyclobutyl , tetrahydrofuranyl, tetrahydropyranyl, phenyl, -(CO)O-methyl, (CO)O-tert-butyl, -(CO)NH2, -(CO)NH-methyl, -(CO)NH-tert—buty|, -(CO)dimethylamino, -(CO)piperidiny|, -(CO)NH-cyc|opropyl, )methyl, -NH(CO)O-tert-butyl, methylsulfonyl, ethylsulfonyl, propan-Z-ylsulfonyl, phenylsulfonyl, sulfanyl, -(SOz)NR7R8, NH(SOz)methyI,-((SO)=NH)methyl, -((SO)=NH)ethy|, -((SO)=NH)propany|, -((SO)=N-methy|)methy|, -((SO)=N-(CO)O-ethy|)methy|, -((SO)=N-(CN))methy|, -((SO)=N-(CO)NH-ethyl)methyl, —(PO)(O—methy|)2,—(PO)(OH)(O-methy|) or with furanyl, pyrazolyl, wherein each 1,2,5,6-tetrahydropyridinyl, 1,2,3,6—tetrahydropyridin—4-yl is optionally substituted, one or more times, independently from each other, with methyl.

In another embodiment the present invention relates to compounds of formula (I) or (lb), in which R2 represents 2,2-dimethylpropyl(methyl)amino, cyclopropyl(methyl)amino, methyl(phenyl)amino, ylbutanyl, cyclopropyl, tetrahydro—ZH-pyranyl, tetrahydro-ZH-thiopyranyl, piperidinyl, piperazinyl, 5,6-dihydroimidazo[1,2-a]pyrazin- 7(8H)-y|, 3,6-dihydro-2H-thiopyranyl, phenyl, pyrrolyl, pyrazolyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, nyl, 1H—pyrrolo[2,3-b]pyridin-4—yl, 6,7-dihydro-5H—pyrro|o[1,2- a]imidazo|—3-yl, wherein each ylbutanyl, cyclopropyl, piperidinyl, piperazinyl, phenyl, yl, pyrazolyl, thiophenyl, imidazolyl, oxazolyl, lyl, pyridinyl, is optionally substituted, one or two or three times, independently from each other, with fluoro, chloro, OH, amino, methyl, ethyl, —1-yl, propan-Z-yl, utyl, hydroxymethyl, , fluoroethyl, trifluoromethyl, methoxy, cyclopropyl, -(CO)O-methyl, methylsulfonyl, methylsulfanyl, —((SO)=NH)methyl.

In another embodiment the present invention relates to compounds of formula (I) or (lb), in which R2 represents tetrahydro—2H-thiopyranyl, piperidinyl, 5,6—dihydroimidazo[1,2-a]pyrazin- 7(8H)—y|, phenyl, pyrrolyl, pyrazolyl, oxazolyl, pyridinyl, 6,7—dihydro—5H-pyrrolo[1,2— [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp a]imidazol—3—yl, wherein each piperidinyl, , pyrrolyl, pyrazolyl, oxazolyl, pyridinyl, is optionally substituted, one or two times, independentlyfrom each other, with fluoro, amino, methyl, ethyl, propanyl, hydroxymethyl, methoxy, cyclopropyl, methylsulfonyl, methylsulfanyl, -((SO)=NH)methyl.

In another ment the present invention relates to compounds of formula (I) or (lb), in which R2 ents 2,2-dimethylpropyl(methyl)amino, cyclopropyl(methyl)amino, methyl(phenyl)amino, ylbutan—2—yl, cyclopropyl, tetrahydro—ZH-pyranyl, tetrahydro-ZH-thiopyranyl, piperidinyl, zin-l-yl, 5,6-dihydroimidazo[1,2- a]pyrazin-7(8H)-yl, 3,6—dihydro—ZH-thiopyranyl, phenyl, pyrrol-Z—yl, 1H-pyrazol-5—yl, 1H- pyrazolyl, thiophen—Z-yl, thiophenyl, 1H-imidazolyl, 1,2-oxazolyl, 1,3-thiazol yl, pyridine-3—yl, pyridineyl, 1H-pyrrolo[2,3-b]pyridin-4—yl or 6,7—dihydro—5H- pyrrolo[1,2-a]imidazol—3-yl, wherein each 3-methylbutanyl, ropyl, piperidinyl, zin—l—yl, phenyl, pyrrol-Z-yl, 1H-pyrazolyl, 1H-pyrazolyl, thiophen—Z—yl, thiophenyl, 1H-imidazol- —yl, 1,2-oxazolyl, 1,3-thiazolyl, pyridine—3-yl or pyridine-4—yl is optionally substituted, one or two or three times, independently from each other, with fluoro, chloro, OH, amino, methyl, ethyl, propan—l-yl, propan-Z-yl, tert-butyl, hydoxymethyl, benzyl, 2-fluoroethyl, trifluoromethyl, y, ropyl, -(CO)O-methyl, methylsulfonyl, methylsulfanyl or -((SO)=NH)methyl.

In another ment the present invention relates to compounds of formula (I) or (lb), in which R2 represents tetrahydro—2H-thiopyran-4—yl, din—4-yl, 5,6—dihydroimidazo[1,2-a]pyrazin- 7(8H)-yl, phenyl, pyrrolyl, 1H—pyrazolyl, 1H-pyrazol-4—yl, 1,2-oxazolyl, 1,3-thiazol- —yl, pyridine—3—yl or 6,7—dihydro—5H-pyrrolo[1,2—a]imidazol—3-yl, wherein each piperidinyl, phenyl,pyrrolyl, 1H—pyrazolyl, azol-4—yl, azol-5—yl or pyridine-3—yl is optionally substituted, one or two times, independently from each other, with fluoro, OH, amino, methyl, ethyl, propan—Z-yl, hydoxymethyl, roethyl, methoxy, cyclopropyl, ethylsulfonyl, methylsulfanyl or -((SO)=NH)methyl.

In another embodiment the present invention relates to compounds of general formula (I) or (lb), in which R2 represents 5- to 6-membered heteroaryl, which is optionally substituted, one or two Dnes, independently from each other, with fluoro, chloro, methyl, ethyl, 2,2,-dimethylethyl, ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp cyclopropyl, trifluoromethyl, methoxy, benzyl or methanesulphonyl.

In another embodiment the present invention relates to compounds of formula (I) or (lb), in which R2 represents phenyl, pyrazolyl, thiophenyl or pyridinyl, wherein each , lyl, thiophenyl or pyridinyl is optionally substituted, one or two times, independently from each other, with fluoro, chloro, amino, methyl, ethyl, propan-l-yl, propan-Z-yl, tert—butyl, benzyl, fluoroethyl, trifluoromethyl, y, cyclopropyl, sulfonyl, methylsulfanyl or -((SO)=NH)methyl.

In another embodiment the present invention relates to compounds of formula (I) or (lb), in which R2 represents phenyl, 1H—pyrazol—4—yl, 1H—pyrazoI—5—yl, thiophen-Z—yl, thiophen—3-yl, pyridineyl or pyridineyl, wherein each phenyl, 1H—pyrazol—4—yl, 1H-pyrazol-5—yl, thiophen—Z-yl, thiophen—3—yl, pyridineyl or pyridineyl is optionally substituted, one or two times, independently from each other, with fluoro, chloro, amino, methyl, ethyl, propan-l-yl, propanyl, tert-butyl, benzyl, fluoroethyl, trifluoromethyl, methoxy, cyclopropyl, methylsulfonyl, methylsulfanyl or -((SO)=NH)methyl.

In r embodiment the present invention relates to nds of formula (I) or (lb), in which R2 represents phenyl, 1H—pyrazoI—4—yl, 1H—pyrazoI—5—yl or pyridine-3—yl, wherein each phenyl, 1H-pyrazoIyl, 1H-pyrazoIyl or pyridineyl is optionally tuted, one or two times, independently from each other, with fluoro, amino, methyl, ethyl, -l-yl, propan—2-yl, tert—butyl, benzyl, fluoroethyl, trifluoromethyl, methoxy, ropyl, methylsulfonyl, methylsulfanyl or -((SO)=NH)methyl.

In another embodiment the present invention relates to compounds of general formula (I) or (lb), in which R2 represents 5-membered aryl, which is optionally substituted, one or two times, ndently from each other, with chloro, methyl, ethyl, 2,2,-dimethylethyl, cyclopropyl, trifluoromethyl, benzyl, methanesulphonyl.

In another ment the present invention s to nds of general formula (I) or (lb), awhich R2 represents pyridinyl, thiazolyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, wherein each ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp pyridinyl, thiazolyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl is ally substituted, one or two times, independently from each other, with fluoro, chloro, methyl, ethyl, 2,2,-dimethylethyl, cyclopropyl, trifluoromethyl, methoxy, benzyl, methanesulphonyl.

In another embodiment the present invention relates to compounds of formula (I) or (lb), in which R2 represents a group Ho—)—R2a wherein * indicates the point of attachment of said group with the rest of the molecule; wherein R2a represents C1-C4-alkyl and R2b represents alkyl, cycloalkyl or a 5- to 6—membered heterocycloalkyl group, wherein each C1—C4—alkyl is ally substituted, independently from each other, one or more times, with fluoro, or R2a and R2b represent er a C3—C5—cycloalkyl group or a 5- to 6—membered heterocycloalkyl group.

In another embodiment the present ion s to compounds of a (I) or (lb), in which R2 represents a group Ho—)—R2a wherein * indicates the point of attachment of said group with the rest of the molecule; wherein R2a represents methyl and R2b represents C1-C4-alkyl, C3-Ce-cycloalkyl or a 5— to 6-membered heterocycloalkyl group or R2a and R2b represent together a C3-C6—cycloalkyl group or a 5- to 6—membered heterocycloalkyl group.

In another embodiment the present invention relates to compounds of formula (I), in which R3 represents methyl and R4 represents H.

In another embodiment the t invention relates to compounds of formula (I), in which R3 represents H and R4 represents methyl.

In another embodiment the present invention relates to compounds of formula (I), in which R3 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp represents H and R4 represents H.

In another embodiment the t invention relates to compounds of formula (I), in which R3 represents methyl and R4 represents methyl.

In another embodiment the t invention relates to compounds of formula (I) or (lb), in which R4 represents H or methyl.

In another ment the present invention relates to compounds of formula (I) or (lb), in which R4 represents H.

In a preferred ment the present invention relates to compounds of formula (I) or (lb), in which R4 represents .

In another preferred embodiment the present invention relates to nds of formula (I) or (lb), in which R4 represents methyl in the absolute configuration R.

In another embodiment the present invention s to compounds of formula (I) or (lb), in which R7represents en and R8 represents hydrogen.

In another embodiment the present invention relates to compounds of formula (I) or (lb), in which R7represents hydrogen and R8 represents C1-C4-alkyl.

In another embodiment the present invention relates to compounds of formula (I) or (lb), in which esents C1—C4-alkyl and R8 represents C1-C4-alkyl.

In r embodiment the present invention relates to compounds of formula (I) or (lb), in which R9 represents methyl, ethyl, propyl or phenyl optionally substituted with R13.

In another ment the present invention relates to compounds of formula (I) or (lb), in which R10 represents methyl, ethyl or propyl.

In r embodiment the present invention relates to compounds of formula (I) or (lb), in which R11 represents hydrogen, methyl, ethyl or —(CO)OR7.

In another embodiment the present invention relates to compounds of formula (I) or (lb), in which R12 represents hydrogen, methyl, ethyl or propyl.

In another embodiment the present ion s to compounds of formula (I) or (lb), in which R2 represents a —SiR1°R"R12 group, wherein R10, R11, R12 represent, independently from each [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp other, C1—C4—alkyl, phenyl or benzyl.

In another embodiment the present ion relates to compounds of formula (I) or (lb), in which R2 represents a R"R12 group selected from trimethylsily, triethylsilyl, triisopropylsilyl, dimethylphenylsilyl, isopropyldimethylsilyl, tert—butyldiphenylsilyl, tert-butyldimethylsilyl.

In another embodiment the present invention relates to compounds of formula (I) or (lb), in which R10, R", R12 represent, independently from each other, C1-C4-alkyl, phenyl or benzyl.

In another embodiment the present invention relates to compounds of a (I) or (lb), in which R10, R", R12 represent, independently from each other, methyl, ethyl, , isopropyl, tert- butyl, phenyl or benzyl.

In another ment the present ion relates to compounds of formula (I) or (lb), in which R10, R", R12 represent, independently from each other, methyl, ethyl, isopropyl, tert-butyl, or phenyl.

In r ment the present invention relates to compounds of formula (I) or (lb), in which R10, R11, R12 represent, independently from each other, methyl, ethyl, or phenyl.

In a further embodiment the invention s to compounds of formula (I) or (lb), according to any of the above-mentioned embodiments, in the form of or a stereoisomer, a tautomer, an N- oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

It is to be understood that the present ion relates to any sub-combination within any embodiment or aspect of the t invention of compounds of general formula (I) or (lb), supra.

More ularly still, the present invention covers the title compounds of general formula (I) or (lb), which are disclosed in the Example section of this text, infra.

In accordance with another aspect, the present invention covers methods of preparing compounds of the present ion, said methods comprising the steps as described below in the schemes 1 to 6 and/or the Experimental Section.

In particular, the present invention covers a method to prepare compounds of general formula 5, [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ,0 \ R \ \ O OH 4 5 characterized in that nds of general formula 4, in which R3 and R4 have the same meaning as defined for the compounds of general formula (I) or (lb) are reacted in an organic solvent at a temperature between -20°C and the boiling point of the solvent, preferably between -5°C and 30°C, using a strong base to obtain compounds of general formula (5).

The preparation of compounds of general formula 5 can be performed in an aprotic organic solvent, preferably in tetrahydrofuran or methylformamide. red strong bases which can be used for the preparation of compounds of general formula 5 are LiHMDS, KHMDS, NaHMDS or LDA.

In ular, the present invention covers a method to prepare compounds of general formula 8, H/N 3 R4 I O/\r R1 R3 N I —’ R/N/N/N 3 I H360 \ R \ \ O OH 7 8 characterized in that compounds of general formula 7, in which R1, R3 and R4 have the same meaning as defined for the compounds of general formula (I) or (lb) are reacted in an organic solvent at a temperature between -20°C and the boiling point ofthe solvent, preferably n - 5°C and 30°C, using a strong base to obtain compounds of general a (8).

The ation of compounds of general formula 8 can be performed in an aprotic organic solvent, preferably in tetrahydrofuran or N,N-dimethylformamide. red strong bases which can be used for the preparation of compounds of general formula 8 are LiHMDS, KHMDS, NaHMDS or LDA.

D accordance with a further aspect, the present invention covers intermediate compounds which [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp are useful in the preparation of compounds of the present invention of general formula (I) or (lb), particularly in the methods described herein. In particular, the present invention covers nds of general formula 5, in which R3 and R4 are as defined for the compound of general formula (I) or (Ib) supra.

In ance with a r aspect, the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of general formula (I) or (Ib), ularly in the methods bed herein. In particular, the t invention covers compounds of general formula 8, in which R1, R3 and R4 are as defined for the compound of general formula (I) or (Ib) supra.

In accordance with a further aspect, the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of general formula (I) or (Ib), particularly in the methods described herein. In particular, the t invention covers compounds of general formula 9, in which R3 and R4 are as defined for the compound of general formula (I) or (Ib) supra.

Daccordance with a further aspect, the present invention covers intermediate compounds which [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp are useful in the preparation of compounds of the present invention of general formula (I) or (lb), particularly in the s described herein. In particular, the t invention covers compounds of general formula 11, H/N /N / N R3 \ \l O=S=O in which R1, R3 and R4 are as defined for the compound of general formula (I) or (Ib) supra.

In accordance with a further aspect, the present invention covers ediate compounds which are useful in the preparation of compounds of the present invention of general a (I) or (lb), particularly in the methods described herein. In particular, the present invention covers nds of general formula 12, o/Y R1 lfi/N/N/N R \\l 12 in which R1, R3 and R4 are as defined for the compound of general formula (I) or (Ib), supra, and X is chloro, bromo or iodo.

In accordance with a r aspect, the present invention covers intermediate compounds which are useful in the preparation of nds of the present invention of general formula (I) or (lb), particularly in the methods described herein. In particular, the present invention covers compounds of general formula 15, [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp in which R1, R3 and R4 are as defined for the nd of general formula (I) or (lb) supra.

In accordance with a further aspect, the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of general formula (I) or (lb), particularly in the methods described herein. In particular, the present invention covers compounds of general formula 16, Cl—S=O in which R1, R3 and R4 are as defined for the compound of general formula (I) or (lb) supra.

In accordance with a further aspect, the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of l formula (lb), particularly in the methods bed herein. In particular, the present invention covers compounds of general formula 39, in which Y represents OH, -O-SOz-CF3, Cl, Br, I, SH or —SOZCI, preferably OH, -O-SOz-CF3 or Cl. d accordance with a further , the present ion covers intermediate compounds which [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp are useful in the preparation of compounds of the present invention of general formula (I) or (lb), particularly in the methods described herein. In particular, the present invention covers compounds of formula HSCHCHgH3 3 O¢S¢N O O (also referred to as 5—tetramethyl—(3-(N—(ethoxycarbonyl)—S—methy|sulfonimidoyl)phenyl)— 1,3,2-dioxaborolan).

In accordance with a further aspect, the t invention covers intermediate compounds which are useful in the preparation of compounds of the present ion of general formula (I) or (Ib), particularly in the methods described herein. In particular, the present invention covers nds of formula (also referred to as 4,4,5,5—tetramethyl-(4—(N—(ethoxycarbonyl)—S—methylsulfonimidoyl)phenyl)— dioxaborolane).

In accordance with yet another aspect, the present invention covers the use of the intermediate compounds of general formula 5, [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp in which R3 and R4 are as defined for the compound of general formula (I) or (lb) supra, for the preparation of a compound of general formula (I) or (lb) as defined supra.

In accordance with yet another aspect, the present invention covers the use of the intermediate compounds of general formula 8, in which R1, R3 and R4 are as defined for the compound of general formula (I) or (lb) supra, for the preparation of a compound of l formula (I) or (Ib) as defined supra.

In accordance with yet another aspect, the present invention covers the use of the intermediate compounds of general a 9, o’Nj/ m R \\l 9 in which R3 and R4 are as defined for the compound of general a (I) or (lb) supra, for the preparation of a compound of general formula (I) or (lb) as defined supra.

In accordance with yet another aspect, the present invention covers the use of the intermediate compounds of general formula 11, kW/N /N /, N R3 \. \tl o=s=o F4\F n [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp in which R1, R3 and R4 are as defined for the compound of general formula (I) or (lb) supra, for the preparation of a compound of l formula (I) or (Ib) as defined supra.

In accordance with yet another aspect, the present invention covers the use of the intermediate compounds of general formula 12, o/Y 1 l\I/N/N/N R \\l in which R1, R3 and R4 are as defined for the compound of general formula (I) or (lb), supra, and X is , bromo or iodo, for the preparation of a compound of general formula (I) or (lb) as defined supra.

In accordance with yet another aspect, the present ion covers the use of the intermediate compounds of general formula 15, in which R1, R3 and R4 are as defined for the compound of general formula (I) or (Ib) supra, for the preparation of a compound of general formula (I) or (Ib) as defined supra.

In ance with yet r aspect, the present ion covers the use of the intermediate compounds of general formula 16, O/Y R1 KrN /N/N 3 I R \ \ Cl—fi=O [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp in which R1, R3 and R4 are as defined for the compound of general formula (I) or (lb) supra, for the preparation of a compound of general formula (I) or (lb) as defined supra.

In accordance with yet another aspect, the t invention covers the use of the intermediate compounds of general formula 39, in which Y represents OH, -O—SOz-CF3, Cl, Br, I, SH or —SOZCI, preferably OH, —O-SOz—CF3 or CI for the preparation of a nd of general formula (I) or (lb) as defined supra.

The compounds of general formula (I) or (lb) according to the invention show a le spectrum of action which could not have been predicted. They are therefore suitable for use as medicaments for the treatment and/or prophylaxis of diseases in humans and animals.

In particular, said compounds of the present invention have surprisingly been found to effectively inhibit ATR kinase and may therefore be used for the treatment or prophylaxis of diseases mediated by ATR kinase, in particular hyperproliferative diseases.

The present invention relates to a method for using the nds and/or pharmaceutical compositions of the present invention, to treat diseases, in particular roliferative diseases.

Compounds can be ed to inhibit, block, , decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis. This method comprises administering to a mammal in need thereof, in particular a human, an amount of a compound of this invention which is effective to treat the disease. roliferative diseases include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumours, such as s of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their t metastases. Those diseases also include lymphomas, sarcomas, and leukaemias.

Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive Dbular oma, ductal carcinoma in situ, and Iobular carcinoma in situ.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp es of cancers ofthe respiratory tract include, but are not limited to small—cell and non— small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour. s of the male reproductive organs e, but are not limited to prostate and testicular cancer. Tumours ofthe female reproductive organs include, but are not limited to trial, al, ovarian, l, and vulvar cancer, as well as sarcoma of the uterus.

Tumours of the digestive tract include, but are not limited to anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.

Tumours of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, , urethral and human papillary renal cancers.

Eye cancers e, but are not limited to intraocular melanoma and retinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or t fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct oma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to eal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell. Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin’s lymphoma, cutaneous T- cell ma, Burkitt lymphoma, Hodgkin’s disease, and ma of the l nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

Leukemias e, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia. dese diseases have been well characterized in humans, but also exist with a similar etiology in [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp ed set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp ed set by jennyp other mammals, and can be d by stering compounds or pharmaceutical compositions of the present invention.

The present invention relates to the treatment of hyperproliferative diseases with deficient ATM sinaling and/or p53 function, in particular of lung carcinoma, in particular small-cell lung cancer, colorectal cancer, bladder cancer, lymphomas, gliomas, and ovarian cancer.

In particular, the present invention relates to the treatment of lung carcinoma, in particular small- cell lung cancer, colorectal cancer, bladder cancer, lymphomas, in particular diffuse large B—cell lymphoma (DLBC) and mantle cell lymphoma (MCL), prostate cancer, in particular castration— resistant prostate cancer, gliomas, and ovarian cancer The present invention further provides for the use of the nds of general formula (I) or (lb) and/or of the pharmaceutical compositions of the t invention for the production of a medicament for the treatment and/or prophylaxis of diseases, especially ofthe aforementioned diseases, in particular of a hyperproliferative disease.

A further subject matter of the present invention is the use of the compounds of l formula (I) or (lb) and/or of the pharmaceutical itions of the present invention in the manufacture of a medicament for the treatment and/or prophylaxis of disorders, in particular the disorders mentioned above.

The present invention furthermore relates to the nds of l formula (I) or (lb) for use in a method for the treatment and/or prophylaxis of a e, in particular of a hyper- proliferative disease.

The present invention further provides a method for treatment and/or prophylaxis of diseases, especially the aforementioned es, in particular of a hyperproliferative disease, using an effective amount of the compounds of general formula (I) or (lb) and/or of the pharmaceutical itions of the present invention.

The present invention further provides the compounds of general formula (I) or (lb) and/or ofthe pharmaceutical compositions of the present invention for use in the treatment and/or prophylaxis of diseases, especially of the aforementioned diseases, in particular of a hyperproliferative disease.The present invention further provides the compounds of general a (I) or (lb) and/or of the pharmaceutical compositions of the present invention for use in a method for Deatment and/or prophylaxis of the aforementioned diseases, in particular of a hyperproliferative [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp disease.

The present invention further provides a pharmaceutical composition comprising the nd of general a (I) or (lb), or a stereoisomer, a tautomer, an N—oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, with one or more excipient(s), in particular ceutically suitable excipients, which are inert and nontoxic. Conventional procedures for preparing such pharmaceutical itions in appropriate dosage forms can be utilized.

The present ion furthermore relates to pharmaceutical compositions, in particular medicaments, which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient, and to their use for the above mentioned es.

Pharmaceutically acceptable excipients are non—toxic, preferably they are xic and inert.

Pharmaceutically acceptable ents include, inter alia, 0 s and excipients (for example cellulose, microcrystalline cellulose, such as, for example, Avicel®, lactose, mannitol, starch, calcium phosphate such as, for example, Di- Cafos®), 0 ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), 0 bases for suppositories (for example hylene s, cacao butter, hard fat) 0 solvents (for example water, l, Isopropanol, glycerol, propylene glycol, medium chain—length triglycerides fatty oils, liquid polyethylene glycols, paraffins), 0 surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyle te, lecithin, phospholipids, fatty alcohols such as, for example, Lanette®, sorbitan fatty acid esters such as, for example, Span®, polyoxyethylene sorbitan fatty acid esters such as, for example, Tween®, polyoxyethylene fatty acid glycerides such as, for example, Cremophor®, polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers such as, for example, Pluronic®), 0 buffers and also acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, um ate, amol, triethanolamine) 0 isotonicity agents (for example glucose, sodium chloride), [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp adsorbents (for e highly-disperse silicas) viscosity-increasing , gel formers, thickeners and/or binders (for example polyvinylpyrrolidon, cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose—sodium, starch, carbomers, polyacrylic acids such as, for example, Carbopol®, alginates, gelatine), disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate such as, for example, Explotab®, cross- linked polyvinylpyrrolidon, croscarmellose-sodium such as, for example, l®), flow regulators, lubricants, glidant and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas such as, for example, Aerosil®), coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example nylpyrrolidones such as, for example, Kollidon®, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose e phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®), capsule materials (for example gelatine, hydroxypropylmethylcellulose), synthetic polymers (for example polylactides, ycolides, rylates, polymethacrylates such as, for example, Eudragit®, polyvinylpyrrolidones such as, for example, Kollidon®, polyvinyl alcohols, nyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers), plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate), penetration enhancers, stabilisers (for example antioxidants such as, for e, ic acid, yl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate), preservatives (for e parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), colourants (for example inorganic pigments such as, for example, iron , titanium 3O dioxide), flavourings, sweeteners, flavour— and/or odour-masking agents.

Further excipients and procedures are described in the following references, each of which is incorporated herein by reference: Powell, M.F. et al., "Compendium of ents for Parenteral armulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238—311; [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Strickley, R.G teral Formulations of Small Molecule Therapeutics ed in the United States (1999)-Part-1" PDA l of ceutical Science & Technology 1999, 53(6), 324—349; and Nema, S. et aI., "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical Science & Technology 1997, 51(4), 166-171.

The present invention furthermore relates to a pharmaceutical combination, in particular a medicament, comprising at least one compound ing to the invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of the above mentioned diseases.

The present ion further provides a pharmaceutical combination comprising: one or more active ingredients selected from a compound of general formula (I) or (lb), and one or more active ingredients selected from antihyperproliferative, cytostatic or cytotoxic substances for treatment of cancers.

The term "combination" in the present ion is used as known to persons skilled in the art and may be present as a fixed ation, a non-fixed combination or kit—of-parts.

A "fixed combination" in the present invention is used as known to persons skilled in the art and is defined as a combination n, for example, a first active ingredient and a second active ingredient are present together in one unit dosage or in a single . One example of a "fixed ation" is a pharmaceutical composition wherein a first active ingredient and a second active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical ation wherein a first active ingredient and a second active ingredient are present in one unit without being in admixture.

A non-fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a second active ingredient are present in more than one unit. One example of a non—fixed combination or kit-of-parts is a combination wherein the first active ingredient and the second active ingredient are present separately. The components of the non—fixed combination or kit—of—parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.

The compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination Duses no unacceptable adverse effects. The t invention relates also to such [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp pharmaceutical combinations. For e, the compounds of this invention can be combined with known chemotherapeutic agents and/or anti-cancer agents, e.g. anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof. Other indication agents include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, anti-metabolites, DNA-intercalating otics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, toposisomerase inhibitors, biological response modifiers, or anti-hormones.

For example, the compounds of the t invention can be combined with known antihyperproliferative, cytostatic or cytotoxic substances for treatment of cancers.

Examples of suitable antihyperproliferative, cytostatic or cytotoxic ation active ingredients include: hTNT, abarelix, abiraterone, bicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronic acid, tinoin, altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate,amrubicin, ine, anastrozole, ancestim, anethole dithiolethione, angiotensin II, antithrombin III, tant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, cin, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, taxel, cabozantinib, calcium folinate, calcium linate, capecitabine, capromab, latin, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib , crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, lomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, n alfa, epoetin beta, n zeta, eptaplatin, in, erlotinib, esomeprazole, estradiol, estramustine, etoposide, imus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, Eemtuzumab, Glucarpidase, im, GM-CSF, goserelin, granisetron, granulocyte colony [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, |—125 seeds, Iansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane , iomeprol, ipilimumab, irinotecan, ltraconazole, ixabepilone, Ianreotide, Iapatinib, lasocholine, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, sole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, Iomustine, Ionidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, lan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, atin, onitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, nedaplatin, nelarabine, neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, omacetaxine mepesuccinate, omeprazole, etron, oprelvekin, orgotein, orilotimod, oxaliplatin, oxycodone, holone, ozogamicine, p53 gene therapy, paclitaxel, palifermin, palladium—103 seed, palonosetron, pamidronic acid, panitumumab, pantoprazole, pazopanib, pegaspargase, oetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-Zb, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, afor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide—K, domide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, azole, propranolol, quinagolide, rabeprazole, momab, —223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib risedronic acid, rhenium-186 , regorafenib, etidronate, mab, romidepsin, romiplostim, romurtide, roniciclib samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, sipuleuceI-T, sizofiran, sobuzoxane, sodium idazole, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc- HYNlC—[Tyr3]—octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, olimus, teniposide, testosterone, osmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, Diostane, triptorelin, trametinib, famide, thrombopoietin, tryptophan, ubenimex, valatinib, [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, stat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

In a preferred embodiment the pharmaceutical ation of the present invention comprises a compound of general formula (I) or (lb), and one or more active ingredients selected from carboplatin and cisplatin.

Generally, the use of antihyperproliferative, cytostatic or cytotoxic combination active ingredients in ation with a compound or pharmaceutical composition of the present ion will serve to: (1) yield better cy in reducing the growth of a tumor or even ate the tumor as compared to administration of either agent alone, (2) provide for the administration of lesser amounts of the administered chemotherapeutic agents, (3) provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than ed with single agent herapies and certain other combined therapies, (4) provide for treating a broader spectrum of different cancer types in mammals, especially humans, (5) e for a higher response rate among treated patients, (6) provide for a longer survival time among treated patients compared to rd herapy ents, (7) provide a longer time for tumor progression, and/or (8) yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.

In on, the compounds of general formula (I) can also be used in combination with radiotherapy and/or surgical intervention.

In a further embodiment of the present invention, a compound of the present invention may be used to sensitize a cell to radiation. That is, treatment of a cell with a compound of the present Dvention prior to radiation treatment ofthe cell renders the cell more susceptible to DNA [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp damage and cell death than the cell would be in the absence of any treatment with a compound of the invention. In one aspect, the cell is treated with at least one compound of the invention.

Thus, the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the invention in combination with conventional radiation therapy.

The present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is d with one or more compounds of the invention prior to the treatment of the cell to cause or induce cell death. In one , after the cell is treated with one or more compounds of the invention, the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.

In another embodiment of the present invention, a cell is killed by treating the cell with at least one DNA damaging agent. That is, after treating a cell with one or more compounds of the invention to sensitize the cell to cell death, the cell is d with at least one DNA damaging agent to kill the cell. DNA damaging agents useful in the present invention include, but are not d to, chemotherapeutic agents (e.g., cisplatinum), ionizing radiation (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents.

In another ment, a cell is killed by treating the cell with at least one method to cause or induce DNA damage. Such s e, but are not limited to, activation of a cell signalling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signalling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage. By way of a non—limiting example, a DNA repair y in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an al accumulation of DNA damage in a cell.

In one aspect of the ion, a compound of the invention is administered to a cell prior to the radiation or other induction of DNA damage in the cell. In another aspect ofthe invention, a compound of the invention is administered to a cell concomitantly with the radiation or other induction of DNA damage in the cell. In yet another aspect of the invention, a nd of the invention is administered to a cell ately after radiation or other ion of DNA damage in the cell has begun.

In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo.

The compounds of general formula (I) or (lb) can act systemically and/or locally. For this purpose, Dey can be administered in a suitable manner, for example by the oral, parenteral, pulmonal, [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic route, or as an implant or stent.

The nds of general formula (I) or (lb) can be stered in administration forms suitable for these administration routes.

Suitable administration forms for oral administration are those which release the compounds of general formula (I) or (lb) in a rapid and/or modified manner, work according to the prior art and contain the compounds of general formula (I) or (lb) in lline and/or amorphous and/or dissolved form, for example tablets (uncoated or coated tablets, for e with enteric or retarded-dissolution or insoluble coatings which l the release of the compound of general formula (I) or (lb)), tablets or films/wafers which disintegrate rapidly in the oral cavity, films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, s, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished with nce of an tion step (for example by an intravenous, intraarterial, intracardial, intraspinal or intralumbal route) or with inclusion of an absorption (for example by an intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal route). Suitable administration forms for parenteral administration include injection and infusion formulations in the form of solutions, suspensions, ons, lyophilizates or sterile powders.

For the other administration routes, suitable examples are pharmaceutical forms for tion or inhalation medicaments (including powder inhalers, nebulizers), nasal drops, solutions or sprays; tablets, films/wafers or capsules for lingual, gual or buccal administration, wafers or capsules, suppositories, ear or eye preparations (for example eye baths, ocular insert, ear drops, ear powders, ear-rinses, ear tampons), l capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic sions, nts, creams, transdermal eutic systems (for example patches), milk, pastes, foams, dusting powders, implants, intrauterine coils, vaginal rings or stents.

The compounds of l formula (I) or (lb) can be converted to the administration forms mentioned. This can be done in a manner known per se, by mixing with pharmaceutically suitable excipients .

These excipients include carriers (for example microcrystalline cellulose, lactose, mannitol), Dlvents (e.g. liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp example sodium dodecylsulphate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants, for example ascorbic acid), dyes (e.g. inorganic pigments, for example iron oxides) and flavour and/or odour tants.

Pharmaceutically acceptable ents are non—toxic, preferably they are non-toxic and inert.

Pharmaceutically acceptable ents e, inter alia: fillers and excipients (for example cellulose, microcrystalline cellulose, such as, for e, Avicel®, lactose, mannitol, starch, calcium phosphate such as, for e, Di-Cafos®), 0 ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, hylene glycols), 0 bases for suppositories (for example polyethylene s, cacao butter, hard fat) 0 solvents (for example water, ethanol, lsopropanol, glycerol, ene , medium chain—length triglycerides fatty oils, liquid polyethylene glycols, paraffins), 0 surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyle sulphate, lecithin, phospholipids, fatty alcohols such as, for example, e®, sorbitan fatty acid esters such as, for e, Span®, polyoxyethylene sorbitan fatty acid esters such as, for example, Tween®, polyoxyethylene fatty acid glycerides such as, for example, Cremophor®, polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers such as, for example, Pluronic®), 0 buffers and also acids and bases (for example ates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine) 0 isotonicity agents (for e glucose, sodium chloride), 0 adsorbents (for example highly-disperse silicas) 0 viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidon, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, ers, polyacrylic acids such as, for example, Carbopol®, alginates, gelatine), 0 disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate such as, for example, Explotab®, cross- linked polyvinylpyrrolidon, croscarmellose-sodium such as, for example, AcDiSo|®), 0 flow regulators, lubricants, glidant and mould release agents (for example magnesium D stearate, stearic acid, talc, highly-disperse silicas such as, for example, Aerosil®), [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 0 coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones such as, for example, Kollidon®, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcel|u|ose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®), 0 capsule materials (for example gelatine, hydroxypropylmethylcellulose), 0 synthetic polymers (for example polylactides, polyglycolides, rylates, polymethacrylates such as, for example, Eudragit®, nylpyrrolidones such as, for example, on®, polyvinyl alcohols, polyvinyl acetates, hylene oxides, polyethylene glycols and their copolymers and blockcopolymers), 0 plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate), 0 penetration enhancers, 0 stabilisers (for e antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, ydroxyanisole, butylhydroxytoluene, propyl gallate), 0 preservatives (for example parabens, sorbic acid, thiomersal, konium chloride, exidine acetate, sodium benzoate), 0 colourants (for example inorganic pigments such as, for example, iron , titanium dioxide), 0 flavourings, sweeteners, flavour- and/or odour-masking agents.

The present invention further es medicaments which comprise at least one compound of l formula (I) or (lb), typically together with one or more inert, nontoxic, pharmaceutically suitable excipients, and the use thereof for the aforementioned purposes.

Based upon standard laboratory techniques known to evaluate compounds useful for the ent of hyperproliferative diseases by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in s, and by comparison of these results with the results of known active ingredients or medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can y be determined for treatment of each desired tion. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary Didely according to such considerations as the particular compound and dosage unit employed, ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be stered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and eral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will ably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered n one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily tion dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.

Of course the specific initial and continuing dosage n for each patient will vary according to the nature and severity of the ion as determined by the attending stician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug ations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.

In spite of this, it may be necessary to deviate from the amounts specified, specifically depending on body weight, administration route, individual our towards the active ingredient, type of formulation, and time or al of administration. For instance, less than the aforementioned minimum amount may be sufficient in some cases, while the upper limit mentioned has to be exceeded in other cases. In the case of administration of greater amounts, it may be advisable to divide them into several dual doses over the day.

The tages in the tests and examples which follow are, unless indicated otherwise, [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data for liquid/liquid solutions are based in each case on volume.

Syntheses of Compounds (Overview): The compounds of the present invention can be prepared as described in the following section.

The schemes and the ures described below illustrate general synthetic routes to the compounds of general formula (I) of the invention and are not intended to be limiting. It is clear to the person skilled in the art that the order of transformations as exemplified in the schemes can be modified in various ways. The order of ormations exemplified in the schemes is therefore not intended to be limiting. In addition, interconversion of any ofthe substituents can be ed before and/or after the exemplified transformations. These cations can be such as the uction of protecting groups, cleavage of protecting groups, exchange, reduction or oxidation of functional , halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in "Protective Groups in Organic Synthesis", 4th edition, Wiley 2006). Specific examples are described in the subsequent paragraphs. Further, it is le that two or more sive steps may be performed without work-up being performed n said steps, e.g. a "one—pot" reaction, as is well-known to the person d in the art.

The syntheses of the 2-(morpholin-4—yl)—1,7-naphthyridine derivatives according to the present invention are ably carried out according to the general synthetic sequence, shown in schemes 1—6.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp CI R1_B’ R1 /|N O—R H2N / Hsc H3C’O \ O O 3 6 KM 3 N CI Y R‘ R N R N /|N /|N H300, \ ,O \ 0 O 1 4 R R \\ \\ OH OH Scheme 1: Route for the preparation of compounds of general formula 8, wherein R1, R3 and R4 have the meaning as given for general formula (I), supra and R has the meaning as alkyl. In addition, the substituents R1 can bear a ting group and the interconversion of any of the substituents R1 can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups or cleavage of protecting groups. Appropriate protecting groups and their uction and cleavage are well-known to the person skilled in the art (see for e T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). ic examples are described in the subsequent Dragraphs.

[Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp ed set by jennyp The starting material methyl 3—amino-2—chloropyridine-4—carboxylate 3 (CAS No: 173435-41—1) is cially available or can be prepared according to a ture procedure (see Journal of Heterocyc/ic Chemistry, 38(1), 99-104; 2001).

Step 1 9 2 (Scheme 1) Amide formation In the first step (scheme 1), morpholine derivative 1 (which is commercially available or described in the literature) can be converted to the corresponding acetamide 2 using an acetylating agent.

The starting morpholine could either be used as a salt (e.g. HCI salt) or as the free amine.

For example the morpholine 1 can be acetylated using acetyl chloride in an organic solvent such as dichloromethane in the presence of a base such as K2C03. The acetylation can also be performed using acetic anhydride in ne. Alternatively, acetic acid, a base and an activating reagent generating an active ester in situ in an organic solvent can be used for the transformation.

For a review see: C.A.G.N. Montalbetti and V. Falque Tetrahedron 2005, 61, 10852 and references therein).

Step 3 9 4 (Scheme 1) Amidine formation Methyl 3-aminochloropyridinecarboxylate 3 is reacted with morpholine amide of furmula 2 in an amidine forming reaction to give nds of the l formula 4. Typically the reaction is performed with POC|3 neat or in an organic solvent at a temperature range n 0°C and the boiling point of the ed solvent. Preferably a halogenated solvent such as chloroform, DCE or DCM is used for the reaction.

Step 4 9 5 (Scheme 1) Naphthyridine formation The amidines of formula 4 can be converted to the corresponding 2-(morpholin-4—yl)-1,7- naphthyridines of formula 5. Typically the reaction is performed in an organic solvent at a temperature between -20°C and the boiling point of the selected solvent using a strong base.

Preferably LiHMDS, KHMDS, NaHMDS or LDA are used as base.

[Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Step 5 9 8 (Scheme 1) Palladium catalyzed reaction with boronic acids The chloronaphthyridines of formula 5 can be reacted with a boronic acid derivative Rl-B(OR)2 to give a compound of formula 8. The boronic acid derivative may be a boronic acid (R = —H) or an ester of the c acid, e.g. its isopropyl ester (R = —CH(CH3)2), preferably an ester d from pinacol in which the boronic acid intermediate forms a 2-aryl-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (R-R = —C(CH3)2-C(CH3)2—). The NH groups of the heterocycle R1 of the boronic acid derivatives may be masked by any suitable protecting group (see Green, Wuts, ctive groups in organic synthesis" 1999, John Wiley & Sons and references cited n). The ponding protective group may be removed at any suitable step of the synthesis. Preferably THP hydropyranyl), BOC (tertButoxycarbonyl) or PMB (para-Methoxybenzyl) are used as protective groups during the synthesis.

The coupling reaction is catalyzed by palladium catalysts, e.g. by Pd(0) catalysts like tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4], tris(dibenzylideneacetone)di-palladium(0) [Pd2(dba)3], or by Pd(||) catalysts like dichlorobis(triphenylphosphine)—palladium(||) [Pd(PPh3)2C|z], palladium(ll) e and triphenylphosphine or by [1,1'- bis(diphenylphosphino)ferrocene]palladium dichloride.

The on is preferably carried out in a mixture of a solvent like 1,2-dimethoxyethane, dioxane, DMF, DME, THF, or panol with water and in the presence of a base like potassium carbonate, sodium bicarbonate or potassium phosphate. (review: D.G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3- 527—30991—8 and references cited therein).

The reaction is performed at atures ranging from room temperature (i.e. approx. 20°C) to the boiling point of the respective solvent. Further on, the reaction can be performed at temperatures above the boiling point using pressure tubes and a microwave oven. The reaction is preferably completed after 1 to 36 hours of reaction time.

The steps for the synthesis sequence giving rise to naphthyridines of a 8 may be also interchanged using similar reaction conditions for each step as described above. For example: 3969798 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp o—R 4 R4 1 4 I R o/\rR R o oi R1—B\ o/\r R1 KKN /N / O_R / / N WN /N / (2: N 3 IN I —> 3 I —> R \ \ R3 R \ \ \ \ OH OH I 4 B\ R4 O/\rR CI O—R O/Y R1 N N N N / / / N —> I IN R3 R3 \ \ \ CI Cl 9 10 Scheme 2: Route for the preparation of nds of general formula 10 and 11, n R1, R3 and R4 have the meaning as given for l formula (I), supra and R has the meaning as alkyl. In addition, the substituents R1 can bear a protecting group and the onversion of any of the substituents R1 can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups or cleavage of protecting groups. Appropriate protecting groups and their introduction and cleavage are well—known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.

Step 8 -) 10 (Scheme 2) Transformation of hydroxy to chloro substituent In the next step, the hydroxy-naphthyridine of formula 8 is converted to the corresponding chloro-naphthyridine 10. This reaction is typically performed using POCI3 without any additional t. The reaction is typically carried out at elevated temperatures.

The steps for the sis sequence giving rise to yridines of formula 10 may also be nterchanged using similar reaction conditions for each step as described above. For example: [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp —)9910 Step 8 -) 11 (Scheme 2) Triflate ion The hydroxy—naphthyridine of the general a 8 can be converted to the corresponding triflate of formula 11. Typically the hydroxy-naphthyridine 8 is reacted with a triflating reagent such as for example N—Phenylbis(trifluoromethanesuIfonimide) with or without a base in an organic solvent such as for example dichloromethane.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp X=C|,Br,| O/YR 1 4 R 0/YR R1 KrN /N / IN N /N / N R3 \ \ R3 \ \I OH O N N N /N / —> / / N IN R3 \ \l R3 \ \ ,8 C'/ \\ H o Scheme 3: Route for the preparation of compounds of general formula 12, 13, 18, 19 and 20, wherein R1, R3, R4, R7, R8 and R9 have the meaning as given for general formula (I), supra and R" has the g as C1—C6-alkyl or 3- to 10-membered heterocycloalkyl. In addition, the substituents R1 can bear a protecting group and the onversion of any of the substituents R1 can be achieved before and/or after the exemplified transformations. These modifications can be Dch as the introduction of protecting groups or cleavage of protecting groups. Appropriate [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp protecting groups and their introduction and cleavage are well—known to the person d in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd n, Wiley 1999). Specific examples are described in the subsequent paragraphs.

Step 8 9 12 (Scheme 3) Conversion of hydroxy to halogen (F, Br, Cl, I) The transformation of y—naphthyridine 8 to a halogen compound of formula 12 can be performed (for n = CI) for example using chlorinating reagents such as trichlorophosphate with or without an organic solvent. Typically the reactions are performed at elevated atures. For n = Br reagents such as phosphorus tribromide or phosphorus oxytribromide can be used. For halogen = F see for example J. of Org. Chem, 2013, 78, 4184 — 4189. For halogen = | see for example Journal ofOrgan/c Chemistry, 2009, 74, 5111 — 5114 and references therein.

Step 8 9 13 (Scheme 3) sion of hydroxy to ethers Hydroxy-naphthyridines of formula 8 can be converted to the corresponding ether of general formula 13, in which R" is C1-C5-alkyl or 3- to 10-membered heterocycloalkyl. The reaction is performed using halides (preferably Cl, Br or I), tes, mesylates or triflates. This reaction is performed in a solvent such as for example acetonitrile, DMF or a 1:1 mixture of methanol and water. The reaction is performed in the presence of a base such as for example CsC03 or K2C03.

The reaction is med at temperatures ranging from room temperature to the boiling point of the respective solvent. Furthermore, the reaction can be performed at atures above the boiling point under pressure. The reaction is preferably completed after 1 to 16 hours.

Alternatively, the ether of general formula 13 can be synthesized via a Mitsunobu reaction from an alcohol in the presence ofa phosphine (such as for example triphenylphoshine) and an azodicarboxylate (e.g. diisopropyl azodicarboxylate) in a solvent such as for example THF.

Step 8 9 15 (Scheme 3) Conversion of hydroxy to thiol [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp For the conversion of y—naphthyridines of formula 8 to thiols of formula 15 for example Lawesson's t or diphosphorus pentasulfide in an organic t can be used. Typically these reactions are run at elevated temperatures.

Step 15 9 20 (Scheme 3) Conversion of thiol to sulfonamide Thiols of general formula 15 can be converted to the corresponding sulfonamides 20 via the intermediate sulfonylchlorides of formula 16 in analogy to ture procedures. For e see European J. of Medicinal Chemistry 2013, 60, 42—50 and references therein.

Step 15 9 17 (Scheme 3) Conversion of thiol to thioether Thiols of formula 15 can be ted to the corresponding hers 17. The reaction is performed using alkyl halides (preferably Cl, Br or I), tosylates, mesylates, or triflates. This reaction is performed in a solvent such as for example acetonitrile, DMF or a 1:1 mixture of methanol and water. The reaction is med in the presence ofa base such as for example CsC03 or K2C03. The reaction is med at temperatures g from room temperature to the boiling point of the respective solvent. Furthermore, the reaction can be performed at temperatures above the boiling point under pressure. The reaction is preferably completed after 1 to 16 hours.

Step 17 9 18 (Scheme 3) Conversion of thioether to sulfoxide Thioethers of formula 17 can be oxidized to the corresponding sulfoxides 18. Typically an oxidizing reagent in an organic solvent is used (for example 3-ch|oro-benzenecarboperoxoic acid in dichloromethane).

Step 17 9 19 (Scheme 3) Conversion of thioether to sulfone Thioethers of l formula 17 can be oxidized to the corresponding sulfoxides 19. Typically an oxidizing reagent in an organic solvent is used (for example 3-ch|oro-benzenecarboperoxoic acid Ddichloromethane).

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp O=S=O Fla/N‘ R7 F’i‘F 21 R4 1 11 4 or oArR O/T N N Kr JV / N / / 4 N —’ 3 | KrN /N / N r,l 3 | R \ \ 4 R4 O/\rR 1 R1 O/Y R N N /N / N / / N —> 3 I R3 \I R \ \ A 56 KKN /N / N R3 \ \I HEB/"\O Scheme 4: Route for the preparation of compounds of general formula 17, 19, 21, 23, 24, 26 and 27, wherein R1, R3, R4, R7, R8 and R9 have the meaning as given for general formula (I), supra. The Doup A represents Cz—Ce-alkenyl, cycloalkenyl or 4- to 10-membered heterocycloalkenyl and [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp the group D represents C2—C5—alkyl, cycloalkyl or 4— to 10—membered heterocycloalkyl. In addition, the substituents R1 can bear a protecting group and the interconversion of any of the substituents R1 can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups or cleavage of protecting groups. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in c Synthesis, 3rd edition, Wiley 1999). ic examples are described in the subsequent paragraphs.

Step 12 -) 17 (Scheme 4) Conversion to Thioether Halogen compounds of the general formula 12 can be converted to the corresponding thioethers of general formula 17 by nucleophilic substitution with thiols. Typically a base such as for example KOtBu, NaH, m carbonate, potassium carbonate in an organic solvent such as for example tert—butanol, DMSO or DMF are used. lly the reaction is performed at elevated temperature. See for example: Journal of Medicinal Chemistry, 2008 , 51, 3466 — 3479 and references therein.

Step 11 or 12 -) 21 (Scheme 4) C-N cross coupling reaction or nucleophilic tution Halogen compounds of general formula 12 or triflates of general formula 11 can be converted to the corresponding amines 21 bya C-N cross coupling reaction. Typically a metal catalyst, a ligand and a base in an organic solvent is used. For a recent review see for e: Chem. Soc. Rev., 2013, 42, 9283 or "Metal-Catalyzed Cross-Coupling Reactions (2 Volume Set)", 2004 by Armin de e (Editor), Francois Diederich r) and literature references therein.

Alternatively halogen nd of general formula 12 can be converted to the ponding amines 21 via a nucleophilic substitution reaction. Typically nucleophilic amines in ation with a base (for example triethylamine, Hijnig's base, potassium carbonate) in an organic solvent (for example iPrOH, DCM, DMSO, DMF) are used. See for example: Bioorganic and nal Chemistry Letters, 2011, 21, 5502 — 5505 and references therein.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp Step 11 or 12 -) 22 e 4) Hydrocarbonylation Halogen compounds of general formula 12 or triflates of general formula 11 can be converted to the corresponding esters 22 by a metal catalyzed ylation reaction. Typically carbonmonoxide and a ium catalyst with or without a ligand (for example: palladium acetate / 1,3-bis-(diphenylphosphino)propane; iphenylphosphine-pal|adium(||) chloride / - triphenylphosphine), an alcohol as nucleophile (for example: methanol, l) in an organic solvent (for example: DMF, methanol, ethanol) is used. See for example: Journal of Medicinal Chemistry, 2008, 51, 1649 — 1667 or Synthesis, 2001, 7, 1098 — 1109 and references therein.

Step 22 -) 23 (Scheme 4) Amide formation Esters of general formula 22 can be converted to the corresponding amides of general formula 23.

Typically an amine is reacted in combination with a base (as for example sodium hydroxide or magnesium methanolate) in a solvent (as for example methanol, isopropanol, water).

Alternatively the ester 22 can be reacted with an amine and n-butyllithium or trimethylaluminum in an organic solvent (such as for example THF, toluene) to form amides of formula 23. See for example Chem. Commun., 2008, 1100—1102 and references n. atively the ester of general a 22 can be hydrolyzed to the corresponding carboxylic acid (using for example KOH, water, methanol as ester hydrolysis conditions) and reacted further to the ponding amides 23 under classical amide coupling conditions. For a review for amide coupling conditions using the free carboxylic acid and an amine in combination with an activating agent see for example Chem. Soc. Rev., 2009, 38, 606—631 and references therein.

Step 11 or 12 -) 24 e 4) Nitrile formation Halogen comounds of general a 12 or triflates of general formula 11 can be ted to the corresponding nitriles 24. Typically a palladium catalyst and a ligand (such as for example 1,1'- bis—(diphenylphosphino)ferrocene / tris—(dibenzylideneacetone)dipalladium(0) ), zinc (ll) cyanide in t (such as for example N,N-dimethyl acetamide / water) is used. See for example Tetrahedron Letters, 2006, 47, 3303 — 3305 and references therein.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Step 11 or 12 -) 25 e 4) C-C cross coupling reaction Halogen comounds of general formula 12 or triflates of general formula 11 can be reacted with a boronic acid derivative A-B(OR)2 to give a compound of a 25. The group A represents C1-C5- alkyl, alkenyl, C3-C5-cycloalkyl, 3- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkenyl, phenyl, heteroaryl. The boronic acid derivative may be a boronic acid (R = —H) or an ester of the boronic acid, e.g. its isopropyl ester (R = —CH(CH3)2), preferably an ester derived from pinacol in which the boronic acid intermediate forms a 2—aryl- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (R-R = —C(CH3)2-C(CH3)2—). The group A of the c acid derivatives may be masked by any suitable ting group (see Green, Wuts, "Protective groups in organic sis" 1999, John Wiley & Sons). The ponding protective group may be removed at any suitable step of the synthesis.

The coupling reaction is catalyzed by ium catalysts, e.g. by Pd(0) catalysts like tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4], tris(dibenzylideneacetone)di-palladium(0) [Pd2(dba)3], or by Pd(||) catalysts like dichlorobis(triphenylphosphine)—palladium(|l) [Pd(PPh3)2C|z], palladium(ll) acetate and triphenylphosphine or by [1,1'- phenylphosphino)ferrocene]palladium dichloride.

The on is preferably carried out in a mixture of a solvent like 1,2-dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a base like potassium carbonate, sodium bicarbonate or potassium phosphate. (review: D.G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3- 527—30991—8 and references cited therein).

The reaction is performed at temperatures ranging from room temperature to the boiling point of the solvent. Further on, the reaction can be performed at temperatures above the boiling point under pressure. The reaction is preferably completed after 1 to 36 hours.

Step 25 -) 26 (Scheme 4) Hydrogenation of double bond Unsaturated derivatives of formula 25 (wherein the group A represents C2—C6-alkenyl, C5-C6- lkenyl, 4- to 10—membered heterocycloalkenyl). can be hydrogenated to the corresponding [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp saturated derivatives of general formula 26 (wherein the group D represents alkyl, C5—C5— cycloalkyl, 4- to 10-membered cycloalkyl). Typically hydrogen (at atmospheric or elevated pressure) is used in combination with a heterogeneous or homogeneous catalyst such as for example palladium on charcoal in an organic solvent such as ethyl acetate, methanol or acetic acid.

Step 12 -) 27 e 4) Dehalogenation reaction Halides of general formula 12 can be dehalogenated for example by a hydrogenation reaction to obtain naphthyridines of general formula 27. Typically hydrogen (at heric or elevated pressure), a base as for example triethylamine and a heterogeneous metal catalyst such as for example palladium on activated carbon in an organic solvent such as for example ethanol, ethyl acetate, acetic acid is used.

Step 11 or 12 -) 19 (Scheme 4) Sulfonylation reaction A halide of general formula 12 or a triflate of general formula 11 can be converted to the corresponding sulfone of l formula 19 by reaction with an alkyl sulfinic acid sodium salt or aryl sulfinic acid sodium salt with a base such as for example 4-(N,N-dimethlyamino)pyridine or pyridine in an organic solvent as for example N,N-dimethyI-formamide. Typically the reaction is performed at elevated temperature. The reaction can also be mediated by copper (see for example an Journal of Medicinal Chemistry, 2004 vol. 39, 735 — 744).

' / / IN _. H/N N / / N R \ \ R \ \ I R3 \ \ R9/ \0 9/3:\ _ R —o \NH RV "NR" 31 38 Scheme 5: Route for the preparation of compounds of l formula 38, wherein R1, R3, R4, R9 ad Rll have the g as given for general formula (I), supra. In on, the substituents Rl [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp can bear a protecting group and the onversion of any of the substituents R1 can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups or cleavage of protecting groups. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.

Step 18 -) 31 (Scheme 5) Sulfoximine formation Sulfoxide 18 is ted to the corresponding sulfoximine 31 in a two step procedure. Typically, the ide 18 is converted to a protected sulfoximine intermediate using a described procedure (Org. Lett, 2004, 6, 1305-1307 and references therein). Deprotection to the sulfoximine to 31 is performed using a base such as for example K2C03 in methanol. Additional options to convert the sulfoxide 18 to an ected sulfoximine 31 are the use of hydrazoic acid ed in situ (e.g.

ChemMedChem, 2013, 8, 1021) or the use of O-(mesitylenesulfonyl)hydroxylamine (MSH) (e.g. J.

Org. Chem, 1973, 38, 1239.

Step 31 -) 38 (Scheme 5) Functionalization of the sulfoximine nitrogen Functionalization of the nitrogen of sulfoximines of general formula 31 can be performed using previously described methods: N-unprotected sulfoximines of formula 31 may be reacted to give N-functionalized derivatives of formula 38. There are multiple methods for the preparation of N- functionalized sulfoximines by functionalization of the nitrogen of the imine group: - Alkylation: see for example: a) U. Liicking et al, US 2007/0232632; b) C.R. Johnson, J. Org. Chem. 1993, 58, 1922; c) C. Bolm et al, Synthesis 2009, 10, 1601.

— Reaction with nates: see for e: a) VJ. Bauer et al, J. Org. Chem. 1966, 31, 3440; b) C. R. Johnson et al, J. Am. Chem. Soc. 1970, 92, 6594; c) S. Allenmark et al, Acta Chem. Scand. Ser.

B 1983, 325; d) U. Lacking et al, U52007/0191393.

- Reaction with chloroformiates: see for example: a) P.B. Kirby et al, DE2129678; b) D.J. Cram et al, J. Am. Chem. Soc. 1974, 96, 2183; c) P. Stoss et al, Chem. Ber. 1978, 111, 1453; d) U. LUcking et al, W02005/37800.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp — Reaction with bromocyane: see for example: a) D.T. Sauer et al, Inorganic Chemistry 1972, 11, 238; b) C. Bolm et al, Org. Lett. 2007, 9, 2951; c) U. LCIcking et al, .

[Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 7/N\ I; Dheme 6: Route for the preparation of compounds of general formula 32, 33, 34, 35, 36 and 37, [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp wherein R1, R3, R4, R7, R8, R9, R10, R11 and R12 have the meaning as given for general formula (I), supra. In addition, the substituents R1 can bear a protecting group and the interconversion of any of the substituents R1 can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups or cleavage of protecting groups. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.

Step 11 9 32 e 6) A triflate of general a 11 can be converted to the corresponding amide 32 under palladium catalysis in analogy to literature procedures. For example see J. Am. Chem. 50c., 2009, 131, 16720 — 16734 and references therein.

Step 11 9 33 (Scheme 6) A triflate of general formula 11 can be ted to the corresponding sulfoximines 33 under ium catalysis in y to literature procedures. For example see USZOOl/144345.

Step 11 9 34 (Scheme 6) A triflate of general a 11 can be converted to the corresponding sililated compound 34 under palladium catalysis in analogy to literature procedures. For example see Org. Lett. 2007, 9, 3785—3788 and references therein.

Step 11 9 35 (Scheme 6) A te of general formula 11 can be converted to the phosphonate 35 under palladium catalysis in analogy to literature procedures. For example see U52008/9465 Step 11 9 36 (Scheme 6) A triflate of general formula 11 can be ted to the phosphinate 36 under palladium sis in analogy to literature procedures. For example see Adv. Synth. Cat, 2013, 355, 1361 — 1373 and references therein.

Step 11 9 37 (Scheme 6) atriflate of l formula 11 can be converted to the phosphine oxide 37 under palladium [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp catalysis in analogy to literature procedures. For example see /4648 EXPERIMENTAL SECTION The following table lists the abbreviations used in this aph, and in the examples section.

Boc tert-butyloxycarbonyl BuLi Butyllithium conc. concentrated DCE Dichloroethane DCM Dichloromethane DMAP N,N-Dimethylaminopyridine DME oxyethane DMF ylformamide DMSO Dimethyl sulfoxide EA Ethyl acetate EtOAc Ethyl acetate EtOH Ethanol HPLC, LC high performance liquid chromatography h hour LiHMDS Lithium bis(trimethylsilyl)amide KHMDS Potassium bis(trimethylsilyl)amide KOtBU Potassium tert-butoxide min minute LCMS, LC-MS, LC/MS Liquid chromatography—mass spectrometry LDA Lithium diisopropylamide MS mass spectroscopy NMR nuclear magnetic resonance NMO N-metylmorpholine-N-oxide NaHMDS Sodium bis(trimethylsilyl)amide PE Petrol ether Pd(dppf)Cl2 [1,1'-Bis-diphenylphosphino-ferrocene]palladium(||) ride Rac Racemate D Retardiation factor [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp Rt Retention time sat. ted rt, RT Room temperature TFA Trifluoroacetic acid THF Tetrahydrofuran TLC thin-layer chromatography al names were generated using ACD/Name Batch Version 12.01 or Autonom 2000.

All reagents, for which the synthesis is not described in the experimental part, are either commercially available or synthesized as bed in literature references.

Analflical s LC—MS Method 1: column: Ascentis Express C18, 2.7 um, 3 cm x 2.1 mm column temp.: 30 °C injection volume: 1 ul detection: MM-ES + APCI +DAD (254 nm) fragment.potential: 50 V mass range : 80-800 m/z mobile phase A: water / 0.1% formic acid mobile phase B: methanol /0.1% formic acid system time delay: 0.2 min gradient: time in min %A %B flow rate in mI/min 1.0 95 5 0 8 4.0 0 100 0.8 .0 i 0 100 0.8 6.0 i 95 5 0.8 6.5 ‘ 95 5 0.8 LC-MS Method 2: MS instrument type: Micromass Quatro Micro; HPLC instrument type: Agilent 1100 Series; UV DD; column: Chromolith Flash RP-18E 25-2 mm; mobile phase A: 0.0375% TFA in water, mobile [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp phase B: 0.01875% TFA in acetonitrile; gradient: 0.0 min 100% A 9 1.0 min 95% A 93.0 min 95% A 9 3.5 min 5% A 9 3.51 min 5% A 9 4.0 min 95% A; flow rate: 0.8 ml/min; column temp: 50 °C; UV detection: 220 nm & 254 nm.

LC-MS Method 3: System: MS (LBA639) Binary t Manager Sample Manager Organizer Column Manger ELSD Injection volume: 1 ul Column: Acquity UPLC BEH C18 1.7 50x2.1mm Eluent A1: H20 + 0,1%Vo|. HCOOH (99%) A2: H20+0,2%Vo|. NH3 (32%) B1: Acetonitril Flow rate: 0,8 ml/min Temperature: 60°C Eluent Gradient A1 + B1: 0-1.6 min 1-99% Bl; 1.6—2.0 min 99% B1 LC—MS Method 4: Instrument MS: Waters ZQ; Instrument HPLC: Waters UPLC Acquity; Column: Acquity BEH C18 (Waters), 50mm x 2.1mm, 1.7um; eluent A: water l% formic acid, eluent B: acetonitrile (Lichrosolv Merck); gradient: 0.0 min 99% A-1.6min 1% A-1.8 min 1%A - 1.81 min 99% A - 2.0min 99 % A; temperature: 60°C; flow: 0.8 mL/min; UV—Detection PDA 210—400nmnm — plus fixed wavelength 254 nm; MS ESI (+),Scan region 170-800 m/z Preparative HPLC Autopurifier: acidic conditions System: Waters rificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp nt: 0.00 — 0.50 min 5% B, 25 ml/min 0.51 — 5.50 min 10-100% B, 70 ml/min .51 — 6.50 min 100% B, 70 mL/min Autopurifier: basic conditions System Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD XBrigde C18 5 pm 100x 30 mm A = H20 + 0.2% Vol. NH3 (32%) Gradient: 0.00 — 0.50 min 5% B, 25mI/min 0.51 — 5.50 min 10-100% B, 70mI/min .51 — 6.50 min 100% B, 70mI/min Pre aration of Intermediates Intermediate-1 Step a: methylchloro[1-morpho|iny|eth-(E)-y|ideneamino]isonicotinate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp OWN—{ll \ / CH30 0 Under argon and at a temperature of 0°C, 2.44 ml (25.40 mmol) of phosphorus oxychloride were added to a solution of 2.17 ml (18.8 mmol) of N—acetylmorpholine in 12 ml of absolute dichloroethane. The yellow solution was stirred at room temperature for 30 min. 1.75 g (9.39 mmol) of methyl 3-amino—2-chloroisonicotinate were then added. The mixture was d at 80°C for 3 h. roethane was distilled off. t work-up, the residue was purified by column chromatography [Puriflash silica gel 60 (80 g, 30 um); ethyl acetate/methanol 1:1, (300 ml)]. In this manner, methyl 2-chloro[1-morpholinyleth-(E)-ylideneamino]isonicotinate was obtained in a yield of 2.5g (89% of theory) as a yellow oil. 1H NMR (400MHz, CDCla): 6 [ppm] = 1.79—1.84 (2H), 2.14 (3H), 3.66-67 (4H), 3.88-3.91(4H), 3.93 (3H), 7.77 (1H), 8.56 (2H).

Stepb: 8-chloro(morpholinyl)—[1,7]naphthyridinol o‘ ’ \ / \_/ — Under argon and at 0°C, 20.1 ml mol) of lithium bis(trimethylsilyl)amide were added dropwise to a solution of 2.0g (6.7 mmol) of methyl 2-chloro[1—morpholinyleth-(E)- ylideneamino]isonicotinate in 20 ml of dry N,N—dimethylformamide. The mixture was then stirred at room temperature for 3 h. For work-up, 2 ml of water were added and the mixture was concentrated. The residue was chromatographed [Puriflash silica gel 60 (80 g, 30 um), ethyl acetate/methanol 1:1 (500 ml)]. 1.16g (65% of theory) of 8-chloromorpholinyl- [1,7]naphthyridin-4—o| were isolated as a light-yellow solid. 1H NMR (400 MHZ, DMSO): 6 [ppm] = .65 (4H), 3.72-3.74 (4H), 6.62 (1H), 7.73 (1H), 7.98 (1H), 11.62 (1H).

Intermediate-2 2-(mo rpho|in-4—y|)[2-(tetrahyd ropyran-Z-yI)-ZH-pyrazo|y|]-[1,7]naphthyridin-4—o| [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under argon, 244 mg (0.30 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]dichloropal|adium(ll) complex with dichloromethane (1:1) and 650 mg (2.00 mmol) of caesium carbonate were added to a suspension of 556 mg (2.00 mmol) of 1-(tetrahydropyran-2—yl)—5—(4,4,5,5—tetramethyl— [1,3,2]dioxaborolaneyl)-1H-pyrazo|e and 266 mg (1.00 mmol) of romorpholinyl- [1,7]naphthyridin—4—ol in 4.0 ml of absolute 1,4—dioxane. The on e was stirred at 80°C for 16 h. The brown reaction solution was purified via column tography [silica gel 60 (30 g); ethyl acetate (200 ml)]. In this manner, 206 mg (54% of theory) of holinyl[2- (tetrahydropyran-Z-yl)-2H-pyrazolyl]-[1,7]naphthyridinol were isolated as a yellow oil. LCMS (method 1): m/z: [M+H]’r = 382.3, Rt = 3.0 min.

Intermediate-3 2-(mo rpho|iny|)[2-(tetrahyd ropyran-Z-yl)—2H—pyrazo|y|]-[1,7]naphthyridin-4—yl- trifluoromethanesulphonate Under argon, 25 pl (0.15 mmol) of diisopropylethylamine were added to a solution of 28 mg (0.07 mmol) of 2-morpholinyl-8—[2-(tetrahydropyran-Z—yl)-2H-pyrazolyl]-[1,7]naphthyridin ol and 39 mg (0.11 mmol) of N—phenylbis(trifluoromethanesulphonimide) in 3.0 ml of te dichloromethane. The reaction mixture was stirred at room temperature for 16h. The brown reaction solution was purified via column chromatography a gel 60 (12 g, 30 um); ethyl acetate (100 ml)]. 34 mg (88% of theory) of 2-morpholinyl-8—[2-(tetrahydropyranyl)—2H- pyrazolyl]-[1,7]naphthyridinyl trifluoromethanesulphonate were isolated as a yellow oil. 1H NMR (400MHz, com): 5 [ppm] = 1.48-1.52 (1H), 1.63-1.71 (2H), 2.04-2.10 (2H), 2.48-2.54 DH), 3.62-3.75 (4H), 3.80-3.83 (4H), 3.92 (1H), 6.04-6.06 (1H), 6.96 (1H), 7.10 (1H), 7.26 (1H), 7.61 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp (1H), 7.69 (1H), 8.53 (1H).

Intermediate-4 4,8-dich|oro(morpholin-4—yl)-[1,7]naphthyridine O/—\N / \ / \_/ — 3g (11.3 mmol) of 8—chloro—2—(morpholinyl)—[1,7]naphthyridin—4-ol were suspended in 10 ml (107 mmol) of phosphorus oxychloride, and the mixture was stirred at 95°C for 3 h. A clear brown solution was . For work-up, the mixture was, with ice-cooling, carefully adjusted to pH 8 using 5N sodium hydroxide solution. This aqueous phase was extracted three times with in each case 50 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then concentrated to dryness. The ing brown solid was triturated with 10 ml of methanol, filtered off and then dried. This gave 2.48g (77% of theory) of 4,8—dichlori (morpholin-4—yl)-[1,7]naphthyridine as a light-brown solid. LC-MS (method 1): m/z: [M+H]+ = 284.2, Rt = 3.53 min.

Intermediate-5 4-chloro(mo rpho|iny|)[2-(tetrahyd ropyrany|)-2H-pyrazo|y|]-[1,7]naphthyridine Under argon, 813 mg (0.7 mmol) of tetrakis(tripheny|phosphine)pal|adium(0) and 2.92 g (21.1 mmol) of potassium carbonate were added to a suspension of 2 g (7.04 mmol) of 4,8—dichloro—2-(morpholinyl)-[1,7]naphthyridine and 2.94g (10.56 mmol) of 1-(tetrahydro-2H- pyranyl)—3—(4,4,5,5—tetramethyl-1,3,2—dioxaborolan-2—yl)-1H-pyrazole in 30 ml of dimethoxyethane and 3 ml of water. The reaction mixture was stirred at 100°C for 2 h. For work- up, 20 ml of sodium bicarbonate solution were added to the mixture. The precipitated solid was filtered ohc and washed with 5ml of water. This gave 2g (71% of theory) of 4-chloro dwrpholin—4—yl)[2—(tetrahydropyran—2-yl)-2H—pyrazol—3—yl]—[1,7]naphthyridine as a yellow solid.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp LC—MS (method 1): m/z: [M+H]+ = 400.3, Rt = 3.62 min.

Intermediate-6 8-chloroisopropoxy—Z-(morpholinyl)-1,7-naphthyridine OmN \ / H30—< A suspension of 8—Chloro-2—(morpholinyl)—[1,7]naphthyridin—4-ol (2.66 g, 10 mmol), 2- iodopropane (2 ml, 20 mmol) and potassium carbonate (1.66 g, 12 mmol) in acetonitrile (100 ml) were d for 8 hours at 85°C. The reaction mixture was d to cool to ambient temperature, the solvent was distilled off under reduced pressure and the residue was dissolved in water (30 ml) and dichloromethane (50 ml). The layers were separated and the aqueous phase was extracted with dichloromethane (3x 30 ml). The combined organic phases were dried over sodium te and the solvent distilled ohc under reduced pressure.

The residue was crystallized from methanol (10 ml) and dried. The title compound was obtained in 2g as white solid. 1H-NMR (400 MHz, DMSO-d6): 6 [ppm]: 1.38 (6H), 3.67 - 3.82 (8H), 4.99 - 5.12 (1H), 6.83 (1H), 7.68 (1H), 7.99 (1H). ediate-7 Step 3: 1-((R)methy|morpholinyl)ethanone 12.8g (127 mmol) of (R)methylmorpholine and 52.7g (381 mmol) of potassium carbonate were suspended in 300 ml of dichloromethane, the mixture was stirred at room temperature for min, 19.9g (254 mmol) of acetyl chloride were added and the mixture was d at room temperature for 18 h. The conversion was monitored by NMR. For work—up, the precipitated solid was filtered off with suction and washed with 200 ml of romethane. The mother liquor was 'ncentrated to dryness. 17.19 g (95% of theory) of 1—[(R)—3-methy|morpholin-4—yl]ethanone were [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp isolated as a yellow oil. 1H NMR (400 MHz, CDCI3): 8 [ppm] = .35 (3H), 2.04-2.08 (3H), 2.98 (1/2H), 3.40-3.49 (2H), 3.53-3.60 (1H), 3.66-3.69 (1H), 3.79 (1/2H), 3.87 (1H), 4.24 (1/2H), 4.56 (1/2H).

Step b: methyl 2-ch|oro[1-((R)methy|morpholin-4—yl)eth-(E)-ylideneamino]isonicotinate MCI—'3 —N O\\/N\(/N \ / 9 O Under argon and at a temperature of 0°C, 17.1 ml (188 mmol) of phosphorus oxychloride were added to a solution of 9.00 g (62.8 mmol) of 1-[(R)methy|morpholinyl]ethanone in 78 ml of absolute 1,2-dichloroethane. The yellow solution was stirred at room temperature for 30 min. 11.7g (62.8 mmol) of methyl 3-aminochloroisonicotinate were then added. The mixture was stirred at 80°C for 1 h, at room temperature overnight and on the next day at 80°C for another h. The 1,2-dichloroethane was distilled off. For work-up, the mixture was taken up in 200 ml of dichloromethane and 100 ml of water, sodium carbonate was added slowly and a little at a time with vigorous stirring (pH = 9) and the mixture was extracted three times with in each case 250 ml of dichloromethane. The combined c phases were dried over sodium sulphate and then concentrated to dryness under d pressure. In this manner, methyl 2-chloro[1-((R) methylmorpholin-4—yl)eth-(E)—ylideneamino]isonicotinate was obtained in a yield of 19.5 g (100% of ) as a brown oil which was used without further cation in the next step. 1H NMR (400 MHz, CDCI3): 6 [ppm] = 1.37 (3H), 1.78 (3H), 3.35 (1H); 3.58 (1H), 3.72-3.75 (3H), 3.83 (3H), 3.95 (1H), 4.28 (1H), 7.52 (1H), 8.01 (1H). LC—MS (method 1): Rt=0.23 min; MS (ESI/APClpos) m/z = 312.2 [M+H]+.

Step c: 8—chloro((R)—3-methy|morpholin-4—yl)-[1,7]naphthyridin-4—ol CH —N [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under argon and at 0°C, a solution of 31.4g (187 mmol) of m bis(trimethylsilyl)amide dissolved in 250 ml of dry tetrahydrofuran was added dropwise over a period of 15 min to a solution of 19.5 g (62.8 mmol) of methyl 2-chloro[1-((R)methylmorpholinyl)eth-(E)- ylideneamino]isonicotinate in 600 ml of dry tetrahydrofuran. The e was then stirred at room temperature for 3 h. For work-up, 50 ml of water were carefully added and the mixture was concentrated to s under reduced pressure. The residue was taken up in 600 ml of saturated ammonium chloride on and extracted four times with in each case 200 ml of dichloromethane/isopropanol (4:1). The combined organic phases were dried over sodium sulphate, filtered and, under reduced pressure, concentrated to dryness. The residue was recrystallized from 250 ml of acetonitrile (7.56 g). The mother liquor was concentrated and the residue was recrystallized again from 125 ml of acetonitrile (3.65 g). 11.2g (64% of theory, lst fraction, clean) and 2.63 g (14% of , 2nd fraction, about 90% pure, concentrated mother liquor) of 8—ch|oro—2-((R)—3—methylmorpholin—4-yl)-[1,7]naphthyridin-4—o| were isolated as a yellow-orange solid. 1H NMR (400 MHz, DMSO—de): 6 [ppm] = 1.21 (3H), 3.18 (1H), 3.49 (1H), 3.65 (1H), 3.77 (1H), 3.98 (1H), 4.15 (1H), 4.41 (1H), 6.59 (1H), 7.72 (1H), 7.97 (1H), 11.59 (1H). LC-MS (method 1): Rt: 3.05 min; MS (ESl/APCIpos) m/z = 280.2 [M+H]+.

Intermediate-8 4,8-dich|oro-Z-[(3R)—3—methy|morphoIinyl]-1,7-naphthyridine CH3 ——N OHM 7N \ / 0.50 g (1.8 mmol) of ro-2—[(3R)—3-methylmorpholin-4—yl]-1,7-naphthyridin-4—o| were suspended in 1.6 ml (17 mmol) of phosphorus oxychloride, and the mixture was stirred at 95°C for 3 h. The reaction was cooled to room temperature and then placed in an ice bath. The reaction was carefully quenched by dropwise addition of NaOH (3N) until pH 9. The aqueous phase was extracted 3 times with . The organic layer was dried (silicon filter) and concentrated under reduced pressure. The crude mixture was then stirred with MeOH and filter. The solid was dried under d pressure at 40°C. The desired compound was obtained without further purification. 1H-NMR (300MHz, DMSO—de): 6 [ppm]: 1.25 (3H), 3.19 - 3.31 (1H), 3.50 (1H), 3.61 - 3.69 (1H), 3.74 - 3.81 (1H), 3.99 (1H), 4.29 (1H), 4.57 - 4.67 (1H), 7.77 - 7.81 (2H), 8.14 (1H). LC-MS d 3): m/z: [M+H]+= 299, R = 1.24 min.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Intermediate-9 )methy|morpholin-4—yl)[2-(tetrahydropyran-Z-yl)-2H—pyrazo|y|]-[1,7]naphthyridin- 4—ol Under argon, 146 mg (0.18 mmol) of [1,1’-bis(dipheny|phosphino)ferrocene]dichloropal|adium(||) complex with dichloromethane (1:1) and 2.33 g (7.15 mmol) of caesium carbonate were added to a suspension of 500 mg (1.79 mmol) of 8-chloro—2-((R)methy|morpholin—4-yl)- [1,7]naphthyridin-4—ol and 746 mg (2.68 mmol) of 1—(tetrahydropyran—2—yl)-5—(4,4,5,5- tetramethyI-[1,3,2]dioxaborolane-Z-yl)-1H-pyrazo|e in 7.5 ml of absolute 1,4—dioxane. The reaction mixture was stirred at 90°C for 16 h. The brown reaction solution was purified via column chromatography [silica gel 60 (30 g); ethyl acetate (200 ml)]. In this manner, 506 mg (72% of ) of 2-[(R)—3—methylmorpholin—4-yl)-8—[2—(tetrahydropyran-Z-yl)-2H-pyrazo|—3-y|]— [1,7]naphthyridinol were isolated as a yellow oil. LCMS (method 1): m/z: [M+H]+= 396.3, Rt = 3.11 min.

Intermediate-10 2-[(3R)—3-methy|morpholinyl][1-(tetrahydro-ZH-pyrany|)-1H-pyrazoly|]-1,7- naphthyridin-4—yl trifluoromethanesulfonate Under argon a on of 4.81 g (11.74 mmol) of 2-[(3R)methylmorpholinyl]—8-[1- Detrahydro—ZH-pyran—Z-yl)-1H—pyrazoI—S-yl]-1,7—naphthyridin-4—o|, 6.43 g (18 mmol) [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp N—Phenylbis(trifluoromethanesulfonimide) and 4.18 ml (24 mmol) N,N—Diisopropylethylamin in 100 ml absolute dichloromethane was stirred for 3 days at room temperature. The solvent was distilled off under reduced pressure and the residue was chromatographed twice [silica gel 60 (400 g); dichlormethane / methanol, 98 : 2/ ethyl e]. The title nd was obtained in 2.6 g (42 % of theory) as yellow solid. LC-MS (method 1): m/z: [M+H]+ = 528.2, Rt = 4.00 min.

Intermediate-11 Step a: 1-(($)methy|morpholinyl)ethanone 12.8g (127 mmol) of (5)methylmorpholine and 52.7g (381 mmol) of potassium carbonate were suspended in 300 ml dichloromethane, the mixture was stirred at room temperature for min, 19.9g (254 mmol) of acetyl chloride were added with ice bath cooling and the mixture was stirred at room temperature for 7 d. The potassium carbonate was ed off with suction and washed. With ice bath cooling, 43 ml (248 mmol) of N,N-diisopropylethylamine were added to the mother liquor, and the mixture was stirred at room temperature for 1 h. The solution was washed three times with in each case 200 ml of water, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. 9.39g (69% of theory) of 1-((5) methylmorpholinyl)ethanone were ed as a brown oil. 1H NMR (400MHz, : 6 [ppm] = 1.23-1.35 (3H), 2.04-2.08 (3H), 2.98 (1/2H), 3.40-3.49 (2H), .60 (1H), 3.66-3.69 (1H), 3.79 (1/2H), 3.87 (1H), 4.24 , 4.56 (1/2H).

Step b: methyl Z-ch|oro[1-(($)methy|morpho|inyl)eth-(E)-ylideneamino]isonicotinate .\CH3 _N O N l\/N\(’ \ / 9 o Under argon and at a temperature of 0°C, 18.3 ml of (197 mmol) of phosphorus oxychloride were aided to a solution of 9.39 g (65.6 mmol) of 1-((5)methy|morpholinyl)ethanone in 83 ml of [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp absolute 1,2—dichloroethane. The yellow on was stirred at room temperature for 30 min. 12.37 g (65.6 mmol) of methyl 3-aminochloroisonicotinate were then added. The mixture was stirred at 80°C for 5 h. The 1,2-dichloroethane was distilled off. For p, the mixture was taken up in 200 ml of dichloromethane and 100 ml of water, with vigorous stirring, by slowly , a little at a time, solid sodium carbonate, the pH was adjusted to pH = 9 and the mixture was then extracted three times with in each case 250 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then concentrated under reduced pressure.

In this manner, methyl 2-chloro—3-[1-((5)—3-methylmorpholinyl)eth-(E)- ylideneamino]isonicotinate was obtained in a yield of 19.2 g (94% of theory) as a brown oil which was reacted r without further purification. 1H NMR (400 MHz, CDCI3): 6 [ppm] = 1.37 (3H), 1.78 (3H), 3.35 (1H); 3.58 (1H), 3.72-3.75 (3H), 3.83 (3H), 3.95 (1H), 4.28 (1H), 7.52 (1H), 8.01 (1H).

LC-MS (method 1): Rt: 0.23 min; MS (ESI/APClpos) m/z = 312.2 [M+H]+.

Step c: 8-chloro(($)methylmorpholin-4—yl)-[1,7]naphthyridin-4—ol :CHS _N OWN x" \ / \_/ — Under argon at 0°C, 3 solution of 30.8 g (184 mmol) of m bis(trimethylsilyl)amide, dissolved in 250 ml of dry tetrahydrofuran, was added dropwise over a period of 15 min to a solution of 19.2 g (61.5 mmol) of methyl ro—3-[1-(5)methylmorpholiny|)eth-(E)- ylideneamino]isonicotinate in 600 ml of dry tetrahydrofuran. The mixture was then stirred at room temperature for 3 h. For work-up, 50 ml of water were carefully added and the mixture was concentrated under reduced pressure. The residue was taken up in 600ml of saturated ammonium chloride solution and extracted four times with in each case 200 ml of dichloromethane/isopropanol (4:1). The combined c phases were dried over sodium sulphate, filtered and, under reduced pressure, concentrated to dryness. The residue was recrystallized from 250 ml of acetonitrile (5.7 g). The mother liquor was trated and the residue was tallized again from 125 ml of acetonitrile (5.0 g). 10.7g (62% of theory, 1st fraction, clean) and 4.53 g (24% of theory, 2nd fraction, about 90% pure, concentrated mother liquor) of 8-chloro((S)methylmorpholinyl)-[1,7]naphthyridinol were isolated as a brown dud. 1H NMR (400 MHZ, DMSO-de): 5 [ppm] = 1.21 (3H), 3.18 (1H), 3.49 (1H), 3.65 (1H), 3.76 (1H), [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 3.98 (1H), 4.15 (1H), 4.40 (1H), 6.60 (1H), 7.72 (1H), 7.97 (1H), 11.6 (1H). LC-MS (method 1): Rt = 3.05 min; MS (ESI/APClpos) m/z = 280.2 [M+H]+.

Step cl: 2-(($)methy|morpholin-4—yl)—8-[2-(tetrahydropyran-Z-yl)—2H—pyrazo|y|]-[1,7]naphthyridin- 4-ol Under argon, 583 mg (0.75 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1) and 9.31 g (28.6 mmol) of m carbonate were added to a suspension of 2.00 g (7.15 mmol) of 8-chloro((5)methy|—morpholinyl)-[1,7]naphthyridin- 4-ol and 2.98 g (10.7 mmol) of 1-(tetrahydropyran-2H-pyran—2-yl)-1H-pyrazolboronic acid pinacol ester in 80 ml of absolute 1,4—dioxane. The reaction mixture was degassed three times and stirred at 85°C for 3 h. Since, according to LC/MS, conversion was incomplete and there was no further conversion (starting materia|2product about 40:60), another 2 g of 1-(tetrahydropyran- 2H-pyranyl)-1H-pyrazoleboronic acid pinacol ester, 200 mg of [1,1’- bis(dipheny|phosphino)ferrocene]dich|oropa||adium(|I) complex with dichloromethane (1:1) and 3 g of caesium carbonate were added to the reaction on and the mixture was stirred at 85°C for 1 h. The solvent was distilled off and 100 ml of ted um chloride solution were added to the e. The aqueous phase was extracted four times with in each case 100 ml of dichloromethane/isopropanol 4:1. The combined organic phases were dried over sodium sulphate and then concentrated to s under reduced pressure. The residue was chromatographed [silica gel 60 (2 x 80 g, 50 um); dichloromethane/methanol 96:4 to 90:10]. This gave 402 mg (13% of theory) of 2-((5)-3—methylmorpholin—4—yl)-8—[2—(tetrahydropyran—2-yl)-2H—pyrazol—3-yl]— [1,7]naphthyridino| as a brown solid. 1H NMR (400 MHz, DMSO-de): 6 [ppm] = 1.18 (3H), 1.44- 1.61(3H), 1.91-2.00 (2H), .40 (1H), 3.09—3.18(1H), 3.21-3.28 (1H), 3.45 (1H), 3.60-3.76 (3H), 3.91-4.02 (2H), 4.30 (1H), 6.09 (1H), 6.59 (1H), 6.91 (1H), 7.59 (1H), 7.77 (1H), 8.33 (1H), 11.46 (1H). LC-MS (method 1): Rt = 3.08 min; MS (ESl/APCIpos) m/z = 396.2 [M+H]*. dtermediate-lz ation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 8-chloro[(3R)methy|morpho|iny|](propanyloxy)-1,7—naphthyridine 2.96 g (21.5 mmol) of potassium carbonate were added to a on of 5 g (18 mmol) of 8—chloro- pholin—4-yl)-[1,7]naphthyridin-4—ol and 3.57 ml (36 mmol) of 2-iodopropane in 50 ml of dry acetonitrile. The suspension was stirred at 85°C for 2 h. The course of the reaction was monitored by LCMS. 100 ml of water were added to the mixture. The aqueous phase was extracted three times with in each case 50 ml ethyl acetate. The combined organic phases were dried over sodium sulphate and then concentrated to dryness. The residue was chromatographed [silica gel 60 (80 g, um); ethyl acetate (500 ml)]. 4 g (70% of ) of 8—chloro—2—[(3R)—3—methylmorpholin—4-yl]— 4-(propanyloxy)-1,7-naphthyridine were obtained as a beige solid. LC-MS (method 1): m/z: [M+H]+ = 322.2, R = 3.79 min.

Intermediate-13 Step 3: 4,8-dich|oro(morpholinyl)-[1,7]naphthyridine 3g (11.3 mmol) of 8—chloro—2—(morpholin-4—yl)—[1,7]naphthyridin—4-ol were suspended in 10 ml (107 mmol) of phosphorus oxychloride, and the mixture was stirred at 95°C for 3 h. A clear brown solution was formed. For work—up, the mixture was, with ice—cooling, carefully adjusted to pH 8 using 5N sodium hydroxide solution. This aqueous phase was extracted three times with in each case 50 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then concentrated to dryness. The ing brown solid was triturated with 10 ml of methanol, filtered off and then dried. This gave 2.48g (77% of theory) of chlori (morpholinyl)-[1,7]naphthyridine as a light-brown solid. LC-MS (method 1): m/z: D4+H1+ = 284.2, Rt = 3.53 min.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Step b: 4-chloro(mo rpho|iny|)[2-(tetrahyd ropyrany|)-2H-pyrazo|y|]-[1,7]naphthyridine Under argon, 813 mg (0.7 mmol) of tetrakis(tripheny|phosphine)pa||adium(0) and 2.92 g (21.1 mmol) of potassium ate were added to a suspension of 2 g (7.04 mmol) of 4,8—dichloro—2—(morpholin—4—yl)—[1,7]naphthyridine and 2.94g (10.56 mmol) of 1—(tetrahydro—2H— pyranyl)-3—(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H—pyrazole in 30 ml of dimethoxyethane and 3 ml of water. The reaction mixture was stirred at 100°C for 2 h. For work- up, 20 ml of sodium bicarbonate solution were added to the mixture. The precipitated solid was filtered off and washed with 5 ml of water. This gave 2 g (71% of theory) of 4-chloro (morpholin-4—yl)[2-(tetrahydropyran—2-yl)-2H—pyrazolyl]—[1,7]naphthyridine as a yellow solid.

LC—MS (method 1): m/z: [M+H]+ = 400.3, R = 3.62 min.

Intermediate-14 Step a: 1-[(3R,5$)-3,5-dimethy|morpholin-4—yl]ethanone H/N\n/CH3 CH3 0 (3R,5$)-3,5-Dimethylmorpholine (0.50 g, 4.3 mmol, 1 eq.) was solubilized in pyridine (8.6 mL, 0.11 mol, 25 eq.) and acetic anhydride (4.0 mL, 42 mmol, 10 eq.) was added. The on was d for 16 hours at room temperature. The reaction mixture was then concentrated under reduced pressure and the desired t was obtained in 95% yield (0.64 g). 1H NMR (400 MHz, DMSO- d5) 6 ppm: 1.22 (6H), 2.00 (3H), 3.44 (2H), 3.65 (2H), 4.00 (2H). LC—MS (Method 3): m/z: [M+H]+ = 158, Rt = 0.57 min.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Step b: methyl 2-chloro[(E)-{1-[(3R,5S)-3,5-dimethylmorpholin-4—yl]ethylidene}amino] isonicotinate ,5$)-3,5-Dimethylmorpholinyl]ethanone (0.54 g, 3.4 mmol, 2.3 eq.) was solubilized in DCE (2.7 mL) and the reaction mixture was cooled to 0°C. POC|3 (0.46 mL, 4.3 mmol, 3.3 eq.) was added slowly and the reaction was warmed up to rt. After 30 minutes, methyl o chloroisonicotinate (0.28 g, 1.5 mmol, 1 eq.) was added in one portion and the mixture was d at 80°C. After 6 hours, the reaction was cooled to room temperature and the solvent was removed under reduced re. The crude mixture was diluted with CH2C|2 and washed three times with sat. NaHC03. The organic phase was dried (MgSO4) and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (gradient: 100% hexane to 100% EtOAc). The desired product was obtained in 58% yield (0.28 g). 1H NMR (400 MHz, DMSO- de) 6 ppm: 1.29 (3H), 1.33 (3H), 1.77 (3H), 3.56 (2H), 3.72 (2H), 3.77 (3H), 4.06 - 4.24 (2H), 7.56 (1H), 8.01 (1H). LC-MS (Method 3): m/z: [M+H]+ = 326, Rt = 0.85 min.

Step c: 8-chloro-Z-[(3R,5S)—3,5-dimethylmorpholinyl]-4—isopropoxy-1,7-naphthyridine N /N |\N CH3 \ / HchO Methyl 2-ch|oro[(E)—{1-[(3R,5$)-3,5-dimethylmorpholin—4-yl]ethylidene}amino]isonicotinate (0.28 g, 0.86 mmol, 1 eq.) was solubilised in dry THF (6 mL) under inert atmosphere (Argon). The reaction mixture was cooled to 0°C and a solution of LiHMDS (1.0 M in THF, 2.5 mL, 2.6 mmol, 3 eq.) was added slowly. The on mixture was stirred for 16 h at room temperature. The reaction was quenched with H20 and concentrated under reduced re. The crude 8-chloro- 2-[(3R,5$)-3,5-dimethylmorpholiny|]—1,7-naphthyridin—4-ol (0.36 g) was used in the next step without further purification. CH3CN (10 mL) was added to 8-chloro—2-[(3R,5$)-3,5- [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp dimethylmorpholin—4—yl]—1,7—naphthyridin-4—ol (0.20 g, 0.68 mmol, 1 eq.). 2—lodopropane (0.13 mL, 1.4 mmol, 2 eq.) and K2C03 (0.14 g, 0.81 mmol, 1.2 eq.) were sequentially added to the suspension. The reaction mixture was stirred at 85°C for 16h. The reaction was cooled to room temperature and diluted with EtOAc and washed three times with H20. The c phase was dried (MgSO4) and concentrated under reduced pressure. The desired product was obtained without further purification in 60 % yield over two steps. 1H-NMR (400MHz, DMSO-de): 6 [ppm]: 1.31 (6H), 1.39 (6H), 3.64 (2H), 3.83 (2H), 4.54 (2H), 5.04 (1H), 6.66 (1H), 7.68 (1H), 7.97 (1H). LC- MS (Method 3): m/z: [M+H]+ = 336, Rt = 1.39 min.

Intermediate-15 Step a: 1-[(3R,5R)-3,5-dimethylmorpholinyl]ethanone O/YCHS Z\n/CHs 0H3 0 (3R,5R)-3,5—Dimethy|morpholine (0.50 g, 4.3 mmol, 1 eq.) was solubilized in pyridine (8.6 mL, 0.11 mmol, 25 eq.) and acetic anhydride (4.0 mL, 0.42 mmol, 10 eq.) was added. The reaction was stirred for 16 hours at room temperature. The on mixture was then concentrated under reduced pressure and the desired product was obtained in quantitative yield. 1H NMR (400 MHz, DMSO-de) 6 ppm: 1.26 (6H), 2.00 (3H), 3.43 - 3.59 (2H), 3.83 - 3.97 (4H). LC-MS (Method 3): m/z: [M+H]+ = 158, Rt = 0.56 min.

Step b: methyl ro[(E)-{1-[(3R,5R)-3,5-dimethylmorpholinyl]ethylidene}amino] isonicotinate . Ny/N \N : CH | CH3 03 / HC’O 1-[(3R,5R)-3,5-Dimethy|morpholinyl]ethanone (0.70 g, 4.4 mmol, 2.3 eq.) was solubilized in DCE (10 mL) and the reaction mixture was cooled to 0°C. POCI3 (0.59 mL, 6.4 mmol, 3.3 eq.) was added slowly and the reaction was warmed up to rt. After 30 minutes, methyl 3-amino nioroisonicotinate (0.36 g, 1.9 mmol, 1 eq.) was added in one n and the mixture was [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp stirred at rt. After 48 hours, the reaction was quenched with sat. NaHC03 and extracted three times with CH2C|2. The c phase was dried (MgSO4) and concentrated under d pressure. The crude mixture was purified by flash chromatography (gradient: 100% hexane to 100% . The desired product was ed in 18% yield (0.12 g). 1H NMR (400 MHz, DMSO- d5) 6 ppm: 1.26 (3H), 1.33 (3H), 1.79 (3H), 3.55 (2H), 3.77 (3H), 3.89 - 4.00 (4H), 7.54 - 7.58 (1H), 8.02 - 8.06 (1H).

Step c: 8-chloro[(3R,5R)-3,5-dimethylmorpholin-4—yllisopropoxy-1,7-naphthyridine o/YCH3 Cl K/N N / \N CHI I H3\ / H3C\r0 CH3 Methyl 2-ch|oro[(E)-{1-[(3R,5R)-3,5-dimethylmorpholiny|]ethy|idene}amino]isonicotinate (0.12 g, 0.36 mmol, 1 eq.) was solubilised in dry THF (2.5 mL) under inert atmosphere ). The reaction mixture was cooled to 0°C and a solution of LiHMDS (1.0 M in THF, 1.1 mL, 1.1 mmol, 3 eq.) was added slowly. The reaction mixture was stirred for 16 h at room temperature. The reaction was quenched with H20 and concentrated under reduced re The crude 8-chloro [(3R,5R)-3,5-dimethylmorpholinyl]-1,7-naphthyridino| (0.36 g) was used in the next step without further purification. CH3CN (6.8 mL) was added to 8-chloro[(3R,5R)-3,5- dimethylmorpholinyI]-1,7-naphthyridino| (0.14 g, 0.46 mmol, 1 eq.). 2-Iodopropane (0.10 mL, 0.90 mmol, 2 eq.) and K2C03 (74 mg, 0.55 mmol, 1.2 eq.) were sequentially added to the suspension. The reaction mixture was stirred at 85°C for 48 h. The reaction was cooled to room temperature and diluted with H20, extracted three times with CHZCIZ and washed with sat. NaCI.

The organic phase was dried (silicon filter) and concentrated under reduced pressure. The desired product was obtained without further purification in 52% yield over two steps (81 mg). 1H—NMR (400MHz, DMSO-de): 6 [ppm]: 1.26 (6H), 1.39 (6H), 3.58 - 3.64 (2H), 3.99 - 4.04 (2H), 4.17 - 4.25 (2H), 4.97 - 5.07 (1H), 6.85 (1H), 7.73 (1H), 8.06 (1H). LC—MS (Method 3): m/z: [M+H]+ = 336, Rt = 1.38min.

Intermediate-16 Step a: ation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1-bromo(methylsulfinyl)benzene To a solution of (3—bromophenyl)(methyl)sulfane (50.0 g, 0.246 mol) in CH3CN (500 mL) was added FeC|3 (1.2 g, 7.4 mmol) with stirring. After the addition, the mixture was stirred at room temperature for 10 min and then cooled to 0 °C. H5|05 (62.0 g, 0.272 mol) was added in portions and then the mixture was stirred at 0 °C for 1 h. TLC (PE: EA = 3: 1, Rf: 0.4) showed the most of starting material was consumed. The on mixture was quenched by the addition of saturated aqueous NH4CI (1.0 L) and extracted with EA (300 mL x 3). The combined organic layers were washed with brine, dried over NaZSO4, filtered and concentrated under reduced pressure to give 1-bromo(methylsulfinyl)benzene (55.0 g) as yellow oil, which was used directly in the next step without further purification.

Step b: 1-bromo( N-(ethoxycarbonyl)—S-methylsulfonimidoyl) H3C\ o "N To a sion of o-3—(methylsulfinyl)benzene (55.0 g, 0.251 mol), ethyl carbamate (45.0 g, 0.505 mol), MgO (40.3 g, 1.0 mol) and Rh2(OAc)4 (2.6 g, 7.6 mmol) in DCM (600 mL) was added Ph|(OAc)2 (122.0 g, 0.378 mol) carefully under N2. The mixture was stirred at room temperature for 5 days. TLC (PE: EA = 1: 1, Rf = 0.8) showed the most of starting material was consumed. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude compound, which was chromatographed on silica gel (PE: EA = 20: 1—5: 1) to give 1—bromo—3-(N- ycarbonyl)-S-methylsulfonimidoy|)benzene (55.0 g, 81.4% oftheory) as white solid. 1H NMR (400 MHz, CDCI3): 6 = 8.15 - 8.14 (1H), 7.94 - 7.92 (1H), 7.81 - 7.80 (1H), 7.51 - 7.47 (1H), 4.13 - 4.08 (2H), 3.32 (3H), 1.25 (3H).

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Step c: 4,4,5,5-tetramethyl-(3-(N-(ethoxycarbonyl)-S-methylsulfonimidoyl)phenyl)-1,3,2-dioxaborolane H30 CH3 H30 CH3 0‘ ,o To a solution of 1-bromo(N-(ethoxycarbonyl)-S-methylsulfonimidoyl)benzene (55.0 g, 0.18 mol) in anhydrous e (600 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (53.0 g, 0.209 mol), KOAc (35.3 g, 0.34 mol) and Pd(dppf)C|2 (4.0 g, 5.47 mmol ) under N2. After the addition, the e was stirred at 80 °C for 4 h. TLC (PE: EA = 1: 1, Rf = 0.6) showed the most of starting material was consumed. The mixture was ed and to the filtrate was added CH3COOH (20.0 g, 0.33 mol) and Pinacol (30.0 g, 0.253 mol). The resulting mixture was stirred at room temperature for 18 h. The mixture was concentrated and chromatographed on silica gel (PE: EA = 20: 1-5: 1) to give the crude, which was washed by PE/EA (100 mL x 2, PE: EA = 1: 10) to give 4,4,5,5-tetramethyl-(3—(N-(ethoxycarbonyl)—S-methylsulfonimidoyl) phenyl)—1,3,2- dioxaborolane (35.0 g, 55.2% of theory) as white solid. 1H NMR (400 MHz, MeOD-d4): 6 = 8.40 (1H), 8.09 - 8.07 (1H), 7.61 - 7.58 (1H), 4.13 - 4.07 (2H), 3.32 (3H), 1.35 (12H), 1.25 - 1.22 (3H). LC- MS method 2: (ES-API) m/z = 272.0 (M+H-82)+.

Intermediate-17 Step a: 1-bromo-4—(methylsulfinyl)benzene To a solution of (3—bromophenyl)(methyl)sulfane (100.0 g, 0.492 mol) in CH3CN (500 mL) was [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp added FeCI3 (2.4 g, 14.8 mmol) with ng. After the addition, the e was stirred at room temperature for 10 min and then cooled to 0 0C. H5|06 (124.2 g, 0.545 mol) was added in portions and the mixture was stirred at 0 0C for 1 h. TLC (PE : EA = 5 : 1, Rf = 0.2) showed the most of starting material was consumed. The reaction mixture was quenched by the addition of saturated aqueous NH4CI (1.0 L) and extracted with EA (300 mL x 4). The organic layers were washed with brine (300 mL), dried over Na2$O4 and concentrated. The residue was purified by tography on silica gel (PE/EA = 20: 1 N 5: 1) to give 1-bromo(methylsulfinyl)benzene (103.0 g, 95.5% of theory) as a white solid.

Step b 1-bromo-4—(N-(ethoxycarbonyl)-S-methy|sulfonimidoy|)benzene H3C\O o" \\ 0—\CH To a suspension of 1-bromo—4-(methylsulfinyl)benzene (100.0 g, 0.456 mol), ethyl carbamate (77.0 g, 0.864 mol), MgO (73.4 g, 1.821 mol) and Rh2(OAc)4 (4.7 g, 10.63 mmol) in DCM (1.5 L) was added Phl(OAc)2 (221.5 g, 0.688 mol) carefully under N2. The mixture was stirred at room temperature for 7 days. TLC (PE : EA = 1 : 1, Rf: 0.7) showed the most of starting material was consumed. The e was filtered and the filtrate was concentrated under reduced re.

The residue was purified by chromatography on silica gel (PE/EA = 20: 1 "' 5: 1) to give 1-bromo-4— (N-(ethoxycarbonyl)-S—methylsulfonimidoyl)benzene (95.0 g, 68.0% of theory) as a white solid. 1H NMR (400 MHz, CDCI3): 6 = 7.87 — 7.85 (2H), 7.76 — 7.74 (2H), 4.13 — 4.08 (2H), 3.30 (3H), 1.28 — 1.22 (3H).

Step c: 4,4,5,5-tetramethyl-(4—(N-(ethoxycarbonyl)-S-methylsulfonimidoyl)phenyl)-1,3,2-dioxaborolane ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Cl) CH3 on CH3 HSC\ O/ ‘ N OA\Ok To a on of 1—bromo-4—(N-(ethoxycarbonyI)-S-methylsulfonimidoyl)benzene (95.0 g, 0.310 mol) in anhydrous dioxane (1.5 L) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (95.0 g, 0.374 mol), KOAc (61.0 g, 0.622 mol) and Pd(dppf)C|2 (7.0 g, 9.57 mmol ) under N2. After the addition, the mixture was stirred at 80 0C for 18 h. The mixture was filtered and to the filtrate was added CH3COOH (18.0 g, 0.30 mol) and l (18.0 g, 0.152 mol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated and the residue was first purified by chromatography on silica gel (PE/EA = 20: 1 N 5: 1) and then washed by EA/PE (100 mL x 2, EA/PE = 1: 10) to give the title compound (87.0 g, 79.5% of theory) as a white solid. 1H NMR (400 MHz, MeOD-d4): 6 = 8.04 - 7.97 (4H), 4.13 - 4.06 (2H), 3.30 (3H), 1.36 (12H), 1.25 - 1.21 (3H). LC—MS method 2: (ES-API) m/z = 272.1 (M+H—82)+.

Intermediate-18 4—chloro[(3R)methylmorphoIiny|][1-(tetrahydro-2H-pyran-Z-y|)-1H-pyrazoly|]-1,7- naphthyridine Intermediate—8 (0.5 g, 1.7 mmol), 1-(tetrahydro-2H—pyran-2—yl)(4,4,5,5-tetramethyl—1,3,2- dioxaborolan—2-yl)-1H—pyrazole (0,47 g, 1.7 mmol) and PdC|2(PPh3)2 (0.12 g, 0,17 mmol) were solubilisend in DME (15 mL). Potassium carbonate (2.5 mL, 5,0 mmol, 2M aq. Solution) was added and the reaction was heated for 10 minutes under microwave irradiation at 130°C. The reaction mixture was dried by tion through a silicon filter and trated under reduced pressure. die crude material was purified by Flash column chromatography (Hexane\ethy| acetate). The [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp title compound was obtained in 45% yield (0.5 g). 1H—NMR (400MHz, DMSO-de): 6 [ppm]: 1.21 (dd, 3H), 1.40 - 1.64 (m, 3H), 1.90 - 2.03 (m, 2H), 2.30 - 2.39 (m, 1H), 3.15 - 3.28 (m, 2H), 3.41 - 3.52 (m, 1H), 3.57 - 3.78 (m, 3H), 3.92 - 3.99 (m, 1H), 4.12 (t, 1H), 4.44 - 4.54 (m, 1H), 5.99 - 6.09 (m, 1H), 6.92 (dd, 1H), 7.62 (s, 1H), 7.76 (d, 1H), 7.83 (d, 1H), 8.49 (d, 1H).

Preparation of the compounds of the present invention Example 1 4-[(2-(morpho|iny|)[2H-pyrazo|y|]-[1,7]naphthyridine-4—yl]phenyl-N-ethoxycarbonyl-S— methylsulphoximide Step a: 4—[(2-(morpho|iny|)[2-(tetrahyd ropyran-Z-yl)-2H—pyrazo|y|]-[1,7]naphthyridine-4— yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximide Under argon, 48 mg (0.06 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 761 mg (2.34 mmol) of caesium carbonate were added to a suspension of 300 mg (0.58 mmol) of 2-(morpholin-4—yl)—8-[2-(tetrahydropyran— 2-yl)-2H-pyrazolyl]—[1,7]naphthyridin—4-yl trifluoromethanesulphonate and 413 mg (1.17 mmol) of pinacol ester in 7.5 ml of absolute dioxane. The reaction mixture was d at 100°C for 3 h.

The mixture was chromatographed directly without p [silica gel 60 (25 g, 30 um); ethyl acetate (100 ml)]. This gave 280 mg (81% of theory) of 4-[(2—(morpholin-4—yl)—8-[2— (tetrahydropyranyl)-2H-pyrazolyl]-[1,7]naphthyridineyl]phenyl-N-ethoxycarbonyl Dethylsulphoximide as a yellow oil. LC-MS (method 1): m/z: [M+H]+ = 591.3, Rt = 3.43 min.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Step b: 4-[(2-(morpho|iny|)[2H-pyrazoIyl]-[1,7]naphthyridine-4—yl]pheny|—N—ethoxycarbonyl-S- methylsulphoximide ,S"N OVCHs o’\ \n’ CH3O 185 mg (0.31 mmol) of 4-[(2-(morpho|in—4—yl)-8—[2—(tetrahydropyran—2-yl)-2H—pyrazol—3-yl]— [1,7]naphthyridine-4—yl]phenyI—N-ethoxycarbonyl-S-methylsulphoximide were dissolved in 20 ml of l, and 4 ml of (8 mmol) of 2N hydrochloric acid were added. After 1 h, LCMS showed complete removal of the protective group. Ethanol was distilled off under reduced pressure and the residue that remained was adjusted to pH 7 using sodium onate solution. The aqueous phase was extracted three times with in each case 20 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then concentrated to dryness. This gave 158 mg (99% of theory) of 4-[(2-(Morpholiny|)-8—[2H-pyrazo|y|]—[1,7]—-naphthyridine yl]phenyI—N—ethoxycarbonyl—S—methylsulphoximide as a colourless solid. mp. 230—232°C. 1H NMR z, e): 6 [ppm]: 1.12-1.15 (3H), 3.56 (3H), 3.80 (8H), 3.91-4.00 (2H), 7.33-7.35 (1H), 7.42 (1H), 7.57 (1H), 7.65 (1H), 7.88—7.90 (2H), 8.15—8.17(2H), 8.35—8.36 (1H), 13.40 (1H). LC— MS (method 1): m/z: [M+H]+= 507.3, Rt: 2.93 min.

Example 2 4-[(2-(Morpholinyl)(2H—pyrazolyl)-[1,7]naphthyridine-4—yl]phenyl-S-methylsulphoximide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 158 mg (0.312 mmol) of 4-[(2—(morpho|inyl)—8—[-2H-pyrazolyl]-[1,7]naphthyridine yl]phenyl-N—ethoxycarbonyl-S—methylsulphoximide were suspended in 10 ml of sodium methoxide (33%), and the mixture was stirred at 60°C for 30 min. For p, 20 ml of water were added and the mixture was then extracted three times with in each case 20 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and concentrated. The solid formed was triturated with 5 ml of ol, ed off and dried. This gave 88 mg (65% of theory) of 4- [(2—(morpho|inyl)—8—(2H-pyrazolyl)—[1,7]naphthyridineyl]phenyl-S—methylsulphoximide as a yellow solid. mp. 271-273°C. 1H NMR (400 MHz, DMSO-de): 6 [ppm] = 3.17 (3H), 3.80 (8H), 4.35 (1H), 7.35-7.37 (1H), 7.42 (1H), 7.54 (1H), 7.65 (1H), 7.79-7.82 (2H), 8.12—8.14 (2H), 8.34-8.35 (1H), 13.40 (1H). LC-MS (method 1): m/z: [M+H]+ = 435.3, Rt = 2.62 min.

Example 3 methylsulfony|)pyridiny|](morpho|in-4—yl)—8—(1H-pyrazo|y|)-1,7-naphthyridine Step a: 4-[6-(methylsulfonyl)pyridinyl](morpho|iny|)[1-(tetrahyd ro-2H-pyranyl)—1H- pyrazoly|]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp Under argon, 16 mg (0.019 mmol) [1,1’-bis(dipheny|phosphino)ferrocene]dichloropal|adium(|l) were added to a mixture of 100 mg (0.20 mmol) 2-(morpholin-4—yl)[1-(tetrahydro-2H-pyran y|)—1H-pyrazo|y|]—1,7-naphthyridin-4—yl trifluoromethanesulfonate and 78 mg (0.39 mmol) [6- (methylsulfonyl)pyridinyl]boronic acid in 1.4 ml dioxane and 254 mg (0.78 mmol) caesium carbonate. The e was stirred at 110 °C for 4 hours. After cooling, the reaction mixture was diluted with ethyl acetate and an aqueous solution of sodium chloride. The mixture was extracted with ethyl acetate (2x) and the combined organic phases were filtered using a Whatman filter.

The organic phase was concentrated and the crude t (168 mg) was used without further purification.

Step b: 4-[6—(methylsu|fony|)pyridinyl](morphoIinyl)(1H-pyrazo|y|)-1,7-naphthyridine 0.37 ml (0.73 mmol) 2N aqueous solution of hydrogen chloride was added to a solution of 165 mg crude 4-[6—(methylsuIfonyl)pyridiny|](morpho|inyl)[1-(tetrahydro-2H-pyranyl)-1H- arazol-S-yl]-1,7-naphthyridine in 1.5 ml methanol and the reaction e was stirred at room [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp temperature for 1 hour. The e was basified by addition of an aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was ed by preperative HPLC (Autopurifier: acidic conditions) to give 9 mg (0.02 mmol) of the desired product. 1H-NMR (400 MHz, DMSO-d6): 6 [ppm] = 3.40 (3H), 3.82 (8H), 7.38 (1H), 7.43 (1H), 7.66 (1H), 7.70 (1H), 8.26 (1H), 8.36 (1H), 8.40 (1H), 9.01 (1H), 13.42 (1H).

Example 4 4-(3,6-dihyd r0-2H—pyran-4—yl)(morpholin-4—yl)(1H-pyrazolyl)-[1,7]naphthyridine Step a: 4—(3,6-dihyd ro-ZH—pyran-4—yl)(morpho|inyl)[2-(tetrahyd ropyran-Z-yl)-2H—pyrazo|y|]- [1,7]naphthyridine Under argon, 40 mg (0.05 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)Clz) and 635 mg (1.95 mmol) of caesium carbonate were added to a suspension of 250 mg (0.49 mmol) of 2-(morpholinyl)[2-(tetrahydropyran- 2-yl)-2H-pyrazolyl]—[1,7]naphthyridin—4-yl trifluoromethanesulphonate and 205 mg (0.97 mmol) of 3,6-dihydro-2H—pyranboronic acid and pinacol ester in 5.0 ml of absolute dioxane. The on mixture was d at 110°C for 4 h. The mixture was chromatographed directly without work-up [silica gel 60 (25 g, 30 um); ethyl e (100 ml)]. This gave 55 mg (25% of theory) of 4- (3,6—dihydro—2H-pyran—4-yl)(morpholinyl)-8—[2-(tetrahydropyranyl)—2H-pyrazolyl]— [1,7]naphthyridine as a yellow oil. LC-MS (method 1): m/z: = 448.4, Rt = 3.43 min.

Step b: -dihyd ro-ZH—pyran-4—yl)(morpholin-4—yl)—8-(1H-pyrazolyl)-[1,7]naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to 50 mg (0.11 mmol) of 4- (3,6—dihydro—2H-pyranyl)(morpho|iny|)[2-(tetrahydropyrany|)—2H-pyrazolyl]— [1,7]naphthyridine. After one hour of stirring at room temperature, the trifluoroacetic acid was distilled off and the residue was adjusted to pH 7 using sodium bicarbonate solution. The aqueous phase was ted three times with in each case 20 ml of romethane. The combined organic phases were dried over sodium sulphate and then concentrated to dryness. The residue was chromatographed [silica gel 60 (25 g, 30 um); ethyl acetate (100 ml)]. This gave 15 mg (37% of theory) of 4—(3,6-dihydro-ZH-pyranyl)—2-(morpho|in-4—y|)(1H-pyrazoI—3—yl)-[1,7]naphthyridine as a yellow solid. m.p. 5°C. 1H NMR (400 MHz, DMSO): 6 [ppm] = 3.76-3.78 (10H), 3.90-3.92 (2H), 4.29-4.31(2H), 5.99 (1H), 7.38 (2H), 7.61 (1H), 7.66—7.67 (1H), 8.35-8.36 (1H), 13.35 (1H). LC- MS (method 1): m/z: [M+H]+ = 364.3, R1 = 2.71 min. 4-[4-(N,S-dimethylsulfonimidoyl)phenyl][morpholinyl](1H-pyrazolyl)—1,7- naphthyridine Step 3: 4-[4-(N,S-dimethylsu|fonimidoyl)phenyl](morpho|in-4—yl)—8-[1-(tetrahydro-2H-pyranyl)—1H- pyrazolyl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 2-[Morpholinyl][4-(S-methylsulfonimidoyl)phenyl][1-(tetrahydro-2H-pyranyl)-1H- pyrazolyl]—1,7-naphthyridine (83 mg, 0.16 mmol, 1 eq.) was solubilized in THF (3 mL) and NaH (60% in mineral oil, 15 mg, 0.38 mmol, 2.4 eq). The reaction mixture was d for 30 minutes at rt and iodomethane (35 (AL, 0.56 mmol, 3.5 eq.) was added. The reaction was stirred for 16 hours at rt and then quenched by addition of H20. The aqueous phase was extracted 3 times with CH2CI2 and the organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC ) and the desired compound was ed in 63% yield (57 mg). 1H-NMR (400MHz, DMSO-de): 6 [ppm]: 1.40 - 1.66 (3H), 1.92 - 2.05 (2H), 2.34 - 2.45 (1H), 2.55 (3H), 3.22 (3H), 3.24 - 3.30 (1H), 3.72 (9H), 6.06 - 6.12 (1H), 6.94 (1H), 7.43 (1H), 7.52 (1H), 7.64 (1H), 7.85 (2H), 8.03 (2H), 8.39 (1H). LC-MS (Method 3): m/z: [M+H]+ = 533, Rt = Step b: 4-[4-(N,S-dimethylsulfonimidoy|)pheny|][morpho|iny|](1H-pyrazolyl)-1,7- naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 4-[4-(N,S-Dimethylsulfonimidoyl)phenyl][morpholinyl][1-(tetrahydro-2H-pyranyl)-1H- pyrazoIy|]-1,7-naphthyridine (57 mg, 0.11 mmol, 1 eq.) was solubilised in CH2C|2 (1.5 mL) and H20 (1.5 mL). Formic acid (1 mL) was added and the reaction mixture was stirred for 1h at rt. The mixture was neutralised with sat. NaHC03 and the aqueous phase was extracted 3 times with . The organic phase was dried (silicon filter) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (gradient from 100% Hex to 100% . The title compound was obtained in 70% yield (46 mg). 1H-NMR (400MHz, e): 6 [ppm]: 2.55 (3H), 3.22 (3H), 3.80 (8H), 7.38 (1H), 7.43 (1H), 7.57 (1H), 7.64 (1H), 7.84 (2H), 8.03 (2H), 8.35 (1H), 13.42 (1H). LC-MS (Method 3): m/z: [M+H]+ = 449, Rt = 0.91min.

Example 6 4—[4—methyl-6—(methylsu|fony|)pyridiny|](morpholin-4—yl)(1H-pyrazol-S-yl)-1,7- naphthyridine Step 3: 4—[4—methyl-6—(methylsu|fony|)pyridinyl](morpho|in-4—yl)[1—(tetrahyd ro-ZH-pyran-Z-yl)— 1H-pyrazolyl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under argon, 16 mg (0.019 mmol) [1,1’-bis(dipheny|phosphino)ferrocene]dichloropal|adium(||) were added to a mixture of 100 mg (0.20 mmol) 2-(morpholin—4—yl)-8—[1—(tetrahydro-2H-pyran yl)-1H-pyrazo|—5-y|]-1,7-naphthyridin-4—y| trifluoromethanesulfonate and 116 mg (0.39 mmol) 4- methyl-Z-(methylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-Z-yl)pyridine in 1.4 ml dioxane and 254 mg (0.78 mmol) caesium carbonate. The mixture was d at 130 0C for 10 minutes in a microwave oven. After cooling, the reaction mixture was diluted with DCM and filtered using a Whatman filter. The organic phase was concentrated and the crude product (164 mg) was used without further purification.

Step b: 4-[4-methyI(methylsu|fony|)pyridinyl](morpho|iny|)(1H-pyrazol-S-y|)-1,7- naphthyridine 0.31 ml (0.61 mmol) 2N s solution of en chloride was added to a solution of 164 mg Dude 4-[4-methyl(methylsulfonyl)pyridinyl](morpho|inyl )[1-(tetrahydro-2H-pyran [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp yl)—1H—pyrazo|—5-y|]—1,7—naphthyridine in 1.0 ml methanol and the reaction mixture was d at room temperature for 1 hour. The mixture was ed by addition of an aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were dried (NaZSO4), filtered and concentrated. The residue was purified by preperative HPLC (Autopurifier: basic conditions) to give 31 mg (0.07 mmol) of the d product. 1H-NMR (400 MHz, DMSO-d6): 5 [ppm] = 2.24 (3H), 3.37 (3H), 3.80 (8H), 7.00 (1H), 7.45 (1H), 7.65 (2H), 8.19 (1H), 8.30 (1H), 8.69 (1H), 13.44 (1H). 4—(4-methanesulphonylpheny|)(morpholin-4—yl)—8-(1H—pyrazo|y|)-[1,7]naphthyridine Step a: 4—(4—methanesulphonylphenyl)(morpholin-4—yl)—8-[2-(tetra yranyl)-2H—pyrazo|y|]- [1,7]naphthyridine Under argon, 25 mg (0.03 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)Clz) and 391 mg (1.2 mmol) of caesium carbonate were added to a suspension of 154 mg (0.3 mmol) of 2-(morpholiny|)-8—[2-(tetrahydropyran yl)—2H—pyrazo|—3-y|]—[1,7]naphthyridin—4—yltrifluoromethanesulphonate and 169 mg (0.6 mmol) of 4-methylsulphonylphenylboronic acid pinacol ester in 3.0 ml of absolute dioxane. The reaction mixture was stirred at 90°C for 2 h. The mixture was chromatographed ly without work-up [silica gel 60 (12 g, 30 um); ethyl acetate (100 ml)]. This gave 110 mg (71% of theory) of 4-(4- methanesulphonylphenyl)-2—(morpholin—4—yl)—8—[2-(tetrahydropyranyl)—2H-pyrazo|—3-y|]— [1,7]naphthyridine as a yellow foam. LC—MS (method 1): m/z: [M+H]+ = 520.3, Rt = 3.38 min.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp Step b: ethanesulphonylpheny|)(morpholin-4—yl)—8-(1H-pyrazo|y|)-[1,7]naphthyridine \ N 0’ ‘N / \ / \_/ — 0 \CH3 A drop of water and 2 ml of (26 mmol) of trifluoroacetic acid were added to 110 mg (0.21 mmol) of 4—(4-methanesu|phonylphenyl)(morpholiny|)[2-(tetrahydropyran-Z-yl)-2H-pyrazol—3-yl]— [1,7]naphthyridine. After 3 h, LCMS showed complete removal of the protective group. The trifluoroacetic acid was removed using a rotary evaporator and the residue that remained was adjusted to pH 7 using sodium bicarbonate solution. The aqueous phase was extracted three times with in each case 20 ml of dichloromethane. The ed organic phases were dried over sodium sulphate and then concentrated to dryness. 5 ml of methanol were added to the residue.

The resulting precipitated solid was filtered off using a frit and then dried. This gave 75 mg (81% of theory) of 4—(4-methanesu|phonylphenyI)(morpholin—4—yl)-8—(1H-pyrazol—3-yl)- [1,7]naphthyridine as a yellow solid. mp. 260-262°C. 1H NMR (400 MHz, DMSO, 6 ppm): 3.33 (3H), 3.80 (8H), 7.36 (1H), 7.40 (1H), 7.56 (1H), 7.67 (1H), 7.86 (2H), 8.14 (2H), 8.33 (1H), 13.40 (1H).

Example 8 4-(2-methanesulphonylphenyl)—2-(morpholin-4—yl)—8-(1H—pyrazo|y|)-[1,7]naphthyridine hydrochloride Step 3: 4-(2-methanesulphonylphenyl)—2-(morpholin-4—yl)—8-[2-(tetra hydropyran-Z-y|)-2H-pyrazo|y|]- [1,7]naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under argon, 30 mg (0.04 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]dich|oropalladium(||) complex with dichloromethane (1:1, Pd(dppf)C|2) and 482 mg (1.48 mmol) of m carbonate were added to a suspension of 190 mg (0.37 mmol) of 2-(morpholinyl)—8-[2-(tetrahydropyran- 2-yl)—2H-pyrazolyl]—[1,7]naphthyridin—4-yl trifluoromethanesulphonate and 148 mg (0.74 mmol) of anesulphonylphenylboronic acid in 2.0 ml of absolute dimethylformamide. The reaction mixture was stirred at 90°C for 2 h. The mixture was chromatographed directly without work-up [silica gel 60 (25 g, 30 um); chloroform/methanol 95:5 (100 ml)]. This gave 60 mg (31% of theory) of 4—(2-methanesulphonylphenyl)(morpholin—4—yl)-8—[2—(tetrahydropyran—2-yl)—2H—pyrazo|—3-yl]— [1,7]naphthyridine as a yellow oil. LC-MS (method 1): m/z: [M+H]*= 520.3, Rt = 2.92 min.

Step b: 4—(2-methanesulphonylphenyl)(morpholinyl)(1H—pyrazo|y|)-[1,7]naphthyridine A drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to 60 mg (0.12 mmol) of 4- (2-methanesulphonylphenyl)(morpholinyl)[2-(tetrahydropyranyl)-2H-pyrazo|yl]- [1,7]naphthyridine. After 10 min, the trifluoroacetic acid was distilled off and the residue was adjusted to pH 7 using sodium bicarbonate solution. The aqueous phase was extracted three times with in each case 20 ml of dichloromethane. The combined c phases were dried over Ddium te and then concentrated to dryness. The residue was chromatographed [silica gel [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 60 (12 g, 30 um); chloroform/methanol 95:5 (100 ml)]. This gave 20 mg (40% of theory) of 4—(2— methanesu|phonylphenyl)(morpholinyl)[2-(tetrahydropyranyl)-1H-pyrazolyl]- [1,7]naphthyridine as a yellow solid. LC-MS (method 1): m/z: [M+H]* = 436.2, Rt = 2.72 min.

Step c: 4—(2-methanesulphonylphenyl)—2-(morpholin-4—yl)—8-(1H—pyrazo|y|)-[1,7]naphthyridine hydrochloride mg (0.046 mmol) of ethanesu|phonylphenyl)(morpholin-4—yl)(1H—pyrazol—3-yl)- [1,7]naphthyridine were dissolved in 3 ml of 2—butanol, and 18 ul of trimethylchlorosilane were added. The mixture was stirred in the open vessel at room temperature for 1 h. The solid formed was filtered off with suction and dried. This gave 15 mg (69% of theory) of 4-(2-methane- nylphenyl)(morpho|in—4-yl)-8—(1H—pyrazoIyI)—[1,7]naphthyridine hydrochloride as a yellow solid. mp. 173-175°C. 1H NMR (400 MHz, CD3OD, 6 ppm): 3.05 (3H), 3.87—3.97 (8H), 7.36 (1H), 7.56-7.58 (1H), 7.72 (1H), 7.87 (1H), 7.89—7.95 (2H), 7.99 (1H), 8.19 (1H), 8.29 (1H), .31 (1H). LC-MS (method 1): m/z: [M+H]+ = 436.2, R1 = 2.72 min.

Example 9 dimethyl {4—[2-(morpholinyl)(1H-pyrazo|y|)-1,7-naphthyridin-4—yl]phenyl}phosphonate Step a: yl (4-{2-(morpholin-4—yl)—8-[1-(tetrahydro-ZH-pyran-Z-yl)-1H-pyrazo|yl]-1,7- naphthyridinyl}phenyl)phosphonate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp Under argon, 12 mg (0.015 mmol) bis(diphenylphosphino)ferrocene]dichloropalladium(ll) were added to a mixture of 75 mg (0.15 mmol) 2-(morpholin—4—yl)[1—(tetrahydro-2H-pyran yl)-1H-pyrazolyl]-1,7-naphthyridiny| oromethanesulfonate and 91 mg (0.29 mmo) dimethyl [4-(4,4,5,5—tetramethyl-1,3,2—dioxaborolan-2—y|)pheny|]phosphonate in 1.1 ml dioxane and 190 mg (0.58 mmol) caesium carbonate. The mixture was stirred at 110 0C for 150 minutes.

After cooling, the reaction mixture was diluted with ethyl acetate and an s solution of sodium chloride. The mixture was extracted with ethyl acetate (2x) and the combined organic phases were filtered using a Whatman . The organic phase was concentrated and the residue was purified by column chromatography (ethyl acetate) to give 53 mg (0.10 mmol) of the desired product.

Step b: dimethyl {4-[2-(morpholinyl)(1H-pyrazo|y|)-1,7-naphthyridin-4—yl]phenyl}phosphonate 9)] \O—CHB D11 ml (0.22 mmol) 2N aqueous solution of hydrogen chloride was added to a solution of 53 mg [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp dimethyl (4-{2—(morpholin—4—yl)—8—[1—(tetrahydro—2H—pyran—2—yl)—1H—pyrazol—5—yl]—1,7— naphthyridin—4-y|}phenyl)phosphonate in 0.4 ml methanol and the on mixture was stirred at room temperature for 1 hour. Aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated to give 38 mg (0.08 mmol) of the desired product. 1H-NMR (400 MHz, CDCI3): 5 [ppm] = 3.83 (4H), 3.87 (3H), 3.89 (3H), 3.98 (4H), 7.20 (1H), 7.39 (2H), 7.62 (2H), 7.78 (1H), 8.00 (1H), 8.04 (1H), 8.44 (1H).

Example 10 4—isopropenyl-Z-(morpholiny|)(1H—pyrazolyl)-[1,7]naphthyridine Step a: ropenyl-Z-(morpholiny|)[2-(tetrahydropyran-Z-yl)-2H—pyrazo|y|]- [1,7]naphthyridine ,—\ N / \ / O N \_/ — Under argon, 24 mg (29 umol) of [1,1'-bis(diphenylphosphino)ferrocene]dich|oropa||adium(||) complex with dichloromethane (1:1, Pd(dppf)C|2) and 286 mg (0.88 mmol) of caesium carbonate were added to a suspension of 150 mg (0.29 mmol) of 2-(morpholiny|)—8-[2-(tetrahydropyran- 2—yl)—2H-pyrazo|—3-y|]—[1,7]naphthyridin—4-yl trifluoromethanesulphonate and 483 mg (1.46 mmol) of tributylisopropenylstannane in 2.0 ml of absolute dioxane. The reaction mixture was stirred at 110°C for 16 h. 20 ml of water were added to the mixture. The aqueous phase was extracted three times with in each case 20 ml of romethane. The combined organic phases were dried over sodium sulphate and then trated to dryness. The e was chromatographed [silica gel 60 (12 g, 30 um); chloroform (100 ml)]. This gave 50 mg (42% of theory) of 4-isopropenyI (morpholin—4—yl)-8—[2—(tetrahydropyran—2—yl)—2H—pyrazol—3—y|]—[1,7]naphthyridine as a yellow oil.

LC-MS (method 1): m/z: [M+H]+ = 406.4, Rt = 3.58 min.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Step b: 4-isopropenyl-Z-(morpholiny|)(1H-pyrazolyl)—[1,7]naphthyridine \ / o’ ‘N / \ / \_/ — A drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to 50 mg (0.12 mmol) of 4- isopropenyI(morpholinyl)—8-[2-(tetrahydropyranyl)—2H-pyrazoly|]-[1,7]naphthyridine.

The mixture was allowed to stand at room temperature for one hour, the trifluoroacetic acid was then distilled off and the residue was adjusted to pH 7 using sodium bicarbonate on. The aqueous phase was extracted three times with in each case 20 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then concentrated to dryness. The e was chromatographed [silica gel 60 (12 g, 30 um); chloroform/methanol 95:5 (100 ml)].

This gave 30 mg (76% of theory) of 4-isopropenyI(morpholin-4—yl)(1H-pyrazo|—3-y|)— [1,7]naphthyridine as a yellow solid. mp 53—55°C. 1H NMR (400 MHZ, CDCI3, 8 ppm): 2.17 (3H), 3.70-3.73 (4H), 3.89-3.92 (4H), 5.12 (1H), 5.46 (1H), 7.02 (1H), 7.28 (1H), 7.53 (1H), 7.68 (1H), 8.39 (1H). LC-MS (method 1): m/z: [M+H]+ = 322.3, R1 = 2.85 min.

Example 11 2-(mo ny|)phenyl(1H—pyrazo|y|)-[1,7]naphthyridine Step a: 2-(mo rpho|inyl)—4-phenyl[2-(tetrahydropyran-Z-yl)-2H-pyrazo|y|]-[1,7]naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under argon, 74 mg (0.09 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]dich|oropa||adium(||) x with dichloromethane (1:1, Pd(dppf)C|2) and 391 mg (1.2 mmol) of caesium carbonate were added to a suspension of 154 mg (0.3 mmol) of 2—(morpho|iny|)-8—[2-(tetrahydropyran-Z- y|)—2H-pyrazo|—3-y|]-[1,7]naphthyridin—4—y| trifluoromethanesuIphonate and 245 mg (1.2 mmol) of phenylboronic acid pinacol ester in 6.0 ml of absolute dioxane. The reaction mixture was stirred at 90°C for 2 h. The mixture was chromatographed directly without work—up [silica gel 60 (12 g, um); ethyl e (100 m|)]. This gave 47 mg (36% of theory) of 2-(morpholin-4—yl)pheny|—8— [2—(tetrahydropyran—Z—yl)-2H—pyrazo|—3—yl]—[1,7]naphthyridine as a yellow oil. LC—MS (method 1): m/z: [M+H]+= 442.3, Rt = 3.81 min.

Step b: 2-(mo rpho|in-4—yl)—4—phenyI(1H-pyrazo|y|)-[1,7]naphthyridine A drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to 47 mg (0.11 mmol) of 2- (morpholin—4—yl)-4—pheny|—8—[2—(tetrahydropyran—Z—yl)—2H—pyrazol—3—yl]—[1,7]naphthyridine. After min, LCMS showed complete removal of the protective group. The trifluoroacetic acid was removed on a rotary evaporator and the residue that remained was adjusted to pH 7 using sodium bicarbonate solution. The aqueous phase was extracted three times with in each case U ml of dichloromethane. The combined c phases were dried over sodium sulphate and [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp then trated to dryness. 5ml of methanol were added to the residue. The resulting precipitated solid was filtered off using a frit and then dried. This gave 30 mg (75% of ) of 2- (morpholinyl)phenyl-8—(1H-pyrazoIyl)-[1,7]naphthyridine as a yellow solid. mp. 89-91°C. 1H NMR (400 MHz, CDCI3, 6 ppm): 3.74-3.76 (4H), 3.91-3.93 (4H), 7.14 (1H), 7.31 (1H), 7.41 (1H), 7.45-7.47 (2H), 7.50-7.55 (3H), 7.70 (1H), 8.35 (1H). LC-MS (method 1): m/z: [M+H]+=358.3, Rt = 3.16 min.

Example 12 4-[4-(S-ethylsulfonimidoyl)phenyl](morpholinyl)(1H-pyrazo|y|)-1,7-naphthyridine Step 3: 4-[4-(ethylsulfanyl)pheny|](morpho|iny|)[1-(tetrahyd ro-ZH-pyran-Z-yl)-1H-pyrazo|y|]- 1,7-naphthyridine Under argon, 24 mg (0.029 mmol) [1,1’-bis(dipheny|phosphino)ferrocene]dichloropal|adium(||) was added to a mixture of 150 mg (0.29 mmol) 2-(morpholin-4—yl)[1—(tetrahydro-2H-pyran y|)-1H-pyrazo|y|]-1,7-naphthyridin-4—yl trifluoromethanesulfonate and 106 mg (0.58 mmol) [4- (ethylsu|fany|)pheny|]boronic acid in 2.1 ml dioxane and 381 mg (1.17 mmol) caesium carbonate.

The e was d at 110 "C for 10 minutes. After cooling, the reaction mixture was diluted with ethyl acetate and an aqueous solution of sodium de. The mixture was extracted with ethyl acetate (2x) and the combined organic phases were filtered using a Whatman filter. The organic phase was concentrated and residue was purified by column chromatography (DCM / ethanol 0% - 30%) to give 150 mg (0.03 mmol) ofthe desired product, containing slight impurities, dat was used without further purifications.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Step b: N-[ethy|(4-{2-(morpholin-4—yl)[1-(tetrahyd ro-ZH-pyran-Z-yl)—1H-pyrazol-S-yl]-1,7— naphthyridinyl}phenyl)-7\4-sulfanylidene]-2,2,2-trif|uoroacetamide Under an atmosphere of argon, a solution of 49 mg (0.43 mmol) 2,2,2-trifluoroacetamide in 0.16 ml THF was added dropwise to a solution of 27 mg (0.29 mmol) sodium tert.-butoxide in 0.23 ml THF, so that the temperature of the mixture remained below 10 °C. Subsequently, a freshly prepared solution of 53 mg (0.19 mmol) 1,3-dibromo-5,5-dimethylhydantoin in 0.23 mL THF was added se to the stirred e, so that the temperature of the mixture remained below 10°C. Then the mixture was stirred for 10 minutes at 10 0C. Finally, a on of 145 mg (0.29 mmol) 4-[4—(ethylsuIfanyl)phenyl]—2-(morpho|in—4-yl)-8—[1-(tetrahydro-2H—pyran-2—yl)-1H-pyrazol- -yl]—1,7-naphthyridine in 0.23 ml THF was added dropwise to the stirred mixture, so that the temperature of the mixture remained below 10 °C. The mixture was stirred for 90 minutes at 10 °C and then at room temperature ght. The batch was d with 0.6 ml of toluene under cooling and an aqueous solution of 36 mg (0.29 mmol) sodium sulfite in 1.1 mL water was added so that the temperature of the mixture remained below 15 0C. The batch was extracted three times with ethyl acetate. The combined organic phases were washed with an aqueous solution of sodium chloride, filtered using a n filter and concentrated. The residue was purified by column tography on silica gel (ethyl acetate) to give 33 mg of the desired product. 1H—NMR (400 MHz, CDCI3): 5 [ppm] = 1.42 (3H), 1.61 (5H), 2.12 (2H), 2.59 (1H), 3.39 (2H), 3.48 (1H), 3.79 (6H), 3.98 (1H), 6.10 (1H), 7.00 (1H), 7.08 (1H), 7.37 (1H), 7.75 (3H), 7.97 (2H), 8.43 (1H).

Step c: fiM—(S-ethylsulfonimidoyl)phenyl](morpholin-4—yl)[1-(tetrahydro-ZH-pyran-Z-yl)-1H- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp pyrazoly|]-1,7-naphthyridine 33 mg (0.054 mmol) N—[ethyl(4—{2-(morpholin—4—yl)-8—[1—(tetrahydro-2H—pyran-2—yl)—1H-pyrazol-5— yl]-1,7-naphthyridin-4—yl}phenyl)-7\4-su|fany|idene]—2,2,2-trif|uoroacetamide was dissolved in 1.05 ml methanol. To this solution 0.37 ml water was added. The pH was adjusted to 10.5 by addition of an aqueous solution of potassium hydroxide (25%). 28 mg (0.046 mmol) Oxone® was added and the e was stirred at room temperature for 4 hours. Additional 28 mg (0.046 mmol) Oxone® was added. The pH was ed to 10.5 by addition of an aqueous solution of potassium hydroxide (25%). The batch was stirred at room temperature for 90 minutes. The pH was adjusted to 10.5 by addition of an s solution of potassium hydroxide (25%) and the batch was d at room temperature for 4 days. The batch was ed and the filtrate was adjusted to pH 6-7 by the addition of 1N aqueous hydrogen chloride solution. The mixture was diluted with aqueous sodium chloride solution and extracted with DCM (2x). The combined organic phases were washed with an aqueous solution of sodium sulfite (10%), filtered using a Whatman filter, and concentrated to give 25 mg crude product that was used without r purification.

Step d: 4-[4-(S-ethylsulfonimidoyl)phenyl](morpholin-4—yl)(1H-pyrazo|y|)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 0.05 ml (0.11 mmol) 2N aqueous solution of hydrogen chloride was added to a solution of 25 mg crude 4-[4-(S-ethylsuIfonimidoyl)phenyl]—2-(morpho|inyl)-8—[1-(tetrahydro-2H-pyranyl)-1H- pyrazol-5—yl]—1,7-naphthyridine in 0.22 ml methanol and the on mixture was stirred at room temperature for 1 hour. The mixture was basified by addition of an aqueous sodium bicarbonate solution and extracted with ethyl e (2x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preperative HPLC (Autopurifier: basic conditions) to give 5 mg (0.01 mmol) of the desired product. 1H-NMR (400 MHZ, DMSO-d6): 6 [ppm] = 1.15 (3H), 3.22 (2H), 3.81 (8H), 4.34 (1H), 7.36 (1H), 7.44 (1H), 7.56 (1H), 7.65 (1H), 7.81 (2H), 8.08 (2H), 8.35 (1H), 13.43 (1H).

Example 13 3-[(2-(morpho|iny|)[2H-pyrazo|y|]-[1,7]naphthyridine-4—yl]phenyl-N-ethoxycarbonyl-S— sulphoximide Step a: -(morpho|in-4—yl)[2-(tetrahyd ropyran-Z-yl)—2H—pyrazo|y|]-[1,7]naphthyridine-4— yl]phenyl-N-ethoxycarbonyl-S—methylsulphoximide [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under argon, 48 mg (0.06 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 761 mg (2.34 mmol) of caesium carbonate were added to a suspension of 300 mg (0.58 mmol) of 2—(morpholinyl)—8-[2-(tetrahydropyran- 2-y|)—2H-pyrazolyI]—[1,7]naphthyridin—4-yl trifluoromethanesulphonate and 413 mg (1.17 mmol) of pinacol ester in 7.5 ml of absolute dioxane. The reaction mixture was d at 100°C for 3 h.

The mixture was chromatographed ly without work-up [silica gel 60 (25 g, 30 um); ethyl acetate (100 ml)]. This gave 270 mg (78% of theory) of —(morpholin-4—yl)—8-[2- (tetrahydropyranyl)-2H-pyrazolyl]—[1,7]naphthyridineyl]phenyl-N-ethoxycarbonyl-5— methylsulphoximide as a yellow oil. LC—MS (method 1): m/Z: [M+H]+ = 591.3, Rt = 3.42 min.

Step b: 3-[(2-(morpho|iny|)[2H-pyrazo|y|]-[1,7]naphthyridine-4—yl]phenyl-N—ethoxycarbonyl-S— methylsulphoximide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 260 mg (0.44 mmol) of 3-[((morpholin—4-yl)[2-(tetrahydropyranyl)-2H-pyrazo|—3-y|]— [1,7]naphthyridine—4—yl]phenyl—N-ethoxycarbonyl—5-methylsulphoximide were dissolved in 10 ml of ethanol, and 5 ml of (10 mmol) of 2N hydrochloric acid were added. After 1 h, LCMS showed complete removal of the protective group. Ethanol was distilled off under reduced pressure and the residue that remained was adjusted to pH 7 using sodium bicarbonate solution. The aqueous phase was extracted three times with in each case 20 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then concentrated to dryness. The residue was chromatographed [silica gel 60 (25 g, 30 um); ethyl e (100 ml)]. This gave 160 mg (72% of theory) of (morpho|iny|)[2H-pyrazo|—3-y|]-[1,7]naphthyridineyl]phenyI-N- carbonyl—S—methylsulphoximide as a yellow solid. mp. 115—117°C. 1H NMR (400 MHz, e): 5[ppm] = 1.09-1.13 (3H), 3.57 (3H), 3.81 (8H), 3.98-4.00 (2H), 7.34-7.35 (1H), 7.42 (1H), 7.56 (1H), 7.65 (1H), 7.91-7.96 (1H), 7.98-7.99 (1H), 8.10-8.33 (2H), .34 (1H), 13.40 (1H). LC-MS (method 1): m/z: [M+H]+ = 507.3, Rt = 2.93 min.

Example 14 4-(1-methyl-1,2,3,6-tetra hyd ropyridiny|)(morpho|iny|)(1H-pyrazol-S-yl)-1,7- naphthyridine Step a: 4-(1-methyl-1,2,3,6-tetra hyd diny|)(morpho|iny|)[1-(tetrahyd ro-ZH-pyran-Z-y|)- 1H-pyrazolyl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under argon, 12 mg (0.015 mmol) [1,1’-bis(diphenylphosphino)ferrocene]dichloropal|adium(ll) was added to a e of 75 mg (0.15 mmol) 2—(morpholinyl)—8-[1-(tetrahydro—2H-pyran—2-yl)- 1H—pyrazol—5—yl]-1,7—naphthyridinyl trifluoromethanesulfonate and 65 mg (0.29 mmol) 1- methyl(4,4,5,5-tetramethyI—1,3,2-dioxaborolan-Z-yl)-1,2,3,6-tetrahydropyridine in 1.1 ml dioxane and 190 mg (0.58 mmol) caesium carbonate. The mixture was stirred at 110 0C for 150 minutes. After cooling, the on mixture was diluted with ethyl acetate and an aqueous solution of sodium chloride. The e was extracted with ethyl acetate (2x) and the combined organic phases were filtered using a Whatman filter. The organic phase was concentrated and the crude product (142 mg) was used t further purification.

Step b: 4—(1-methyl-1,2,3,6-tetra hyd ropyridiny|)(morpho|iny|)(1H-pyrazoly|)-1,7- naphthyridine 0.36 ml (0.71 mmol) 2N aqueous solution of hydrogen chloride was added to a solution of 142 mg crude ethyl-1,2,3,6-tetrahydropyridiny|)(morpholin-4—yl)[1-(tetrahydro-2H-pyran fll—1H-pyrazoI—5-yl]—1,7—naphthyridine in 1.4 ml methanol and the reaction mixture was stirred at [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp room temperature for 1 hour. The mixture was basified by addition of an aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were ed using a Whatman filter and concentrated. The residue was purified by preperative HPLC (Autopurifier: basic conditions) to give 22 mg (0.06 mmol) of the desired product. 1H-NMR (400 MHz, CDClg): 6 [ppm] = 2.51 (3H), 2.59 (2H), 2.78 (2H), 3.23 (2H), 3.76 (4H), 3.96 (4H), 5.89 (1H), 7.07 (1H), 7.31 (1H), 7.57 (1H), 7.73 (1H), 8.43 (1H), 12.99 (1H).

Example 15 4-(3-methanesulphonylphenyl)(morpholinyl)(1H-pyrazo|y|)-[1,7]naphthyridine Step 3: ethanesulphonylphenyl)—2-(morpholinyl)—8-[2-(tetra hydropyran-Z-y|)-2H-pyrazo|y|]- [1,7]naphthyridine fi—CHS Under argon, 24 mg (0.03 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 381 mg (1.17 mmol) of caesium carbonate were added to a suspension of 150 mg (0.29 mmol) of 2-(morpholinyl)[2-(tetrahydropyran- 2-yl)-2H-pyrazolyl]—[1,7]naphthyridinyl trifluoromethanesulphonate and 165 mg (0.58 mmol) of ethanesulphonylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane in 5.0 ml of absolute dioxane. The reaction mixture was stirred at 90°C for 16 h. The mixture was chromatographed ly without work—up a gel 60 (25 g, 30 um); chloroform/methanol 95:5 (100 ml)]. This gave 80 mg (53% of theory) of 4-(3-methanesulphonylphenyl)(morpholinyl)—8-[2- (tetrahydropyran-2—yl)-2H-pyrazolyl]—[1,7]naphthyridine as a yellow oil. LC-MS (method 1): m/z: [M+H]+ = 520.3, Rt = 3.33 min.

Step b: DB-methanesulphonylphenyl)(morpholinyl)—8-(1H-pyrazo|y|)-[1,7]naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp \ / 0’ ‘N / \ / \_/ — Sl—CH3 A drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to 80 mg (0.15 mmol) of 4- (3-methanesulphonylphenyl)-2—(morpholinyl)—8-[2-(tetrahydropyrany|)-2H-pyrazoly|]— [1,7]naphthyridine. After one hour of stirring at room temperature, the trifluoroacetic acid was distilled off and the residue was adjusted to pH 7 using sodium bicarbonate on. The aqueous phase was extracted three times with in each case 20 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then trated to dryness. The residue was chromatographed [silica gel 60 (12 g, 30 um); chloroform/methanol 90:10 (100 ml)]. This gave 30 mg (45% of theory) of 4-(3-methanesulphonylphenyl)-2—(morpholinyl)—8—(2H-pyrazol y|)-[1,7]naphthyridine as a yellow solid. mp 255-257°C. 1H NMR (400 MHz, DMSO, 6 ppm): 3.30 (3H), 3.81 (8H), 7.36 (1H), 7.43 (1H), 7.56 (1H), 7.64 (1H), 7.86-7.95 (2H), .13 (2H), 8.35 (1H), 13.41 (1H). LC-MS (method 1): m/z: [M+H]+ = 436.2, Rt = 2.80 min.

Example 16 ethyI(methylsulfonyl)pyridinyl](morpho|in-4—yl)(1H-pyrazol-S-y|)-1,7- naphthyridine Step 3: 4-[5-methyI(methylsulfonyl)pyridiny|](morpho|in-4—y|)[1-(tetrahydro-ZH-pyran-Z-yl)— 1H-pyrazolyl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under argon, 16 mg (0.019 mmol) [1,1’-bis(dipheny|phosphino)ferrocene]dichloropalladium(|l) were added to a mixture of 100 mg (0.20 mmol) 2-(morpholin-4—yl)[1—(tetrahydro-2H-pyran yl)-1H-pyrazo|yl]-1,7-naphthyridin-4—y| trifluoromethanesulfonate and 116 mg (0.39 mmol) 3- methyl(methylsulfonyl)-5—(4,4,5,5-tetramethyl—1,3,2—dioxaborolanyl)pyridine in 1.4 ml dioxane and 254 mg (0.78 mmol) caesium carbonate. The mixture was stirred at 130 0C for 10 minutes in a microwave oven. After cooling, the reaction mixture was diluted with DCM and filtered using a n filter. The organic phase was concentrated and the crude product (119 mg) was used without further purification.

Step b: 4-[5-methyl-6—(methylsulfonyl)pyridiny|](morpholin-4—yl)—8-(1H-pyrazoly|)-1,7- yridine 0.22 ml (0.45 mmol) 2N aqueous solution of hydrogen chloride was added to a on of 119 mg crude 4-[5-methyl(methylsuIfonyl)pyridinyI](morpholin-4—yl)[1-(tetrahydro-2H-pyran D—lH-pyrazoI-S-yl]-1,7-naphthyridine in 1.0 ml methanol and the reaction e was stirred at [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp room temperature for 1 hour. The mixture was basified by addition of an aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were dried 4), filtered and concentrated. The residue was purified by preperative HPLC (Autopurifier: basic conditions) to give 7 mg (0.016 mmol) of the desired product. 1H-NMR (400 MHz, DMSO-d6): 6 [ppm] = 2.73 (3H), 3.48 (3H), 3.81 (8H), 7.41 (2H), 7.66 (2H), 8.22 (1H), 8.35 (1H), 8.73 (1H), 13.44 (1H).

Example 17 2-(morpho|inyl)(1H-pyrazo|y|)(1,2,3,6-tetrahydropyridin-4—y|)-1,7-naphthyridine Step 3: 2-(mo rpho|iny|)[1-(tetrahyd ro-2H-pyran-2—yl)-1H-pyrazo|y|](1,2,3,6- ydropyridin-4—yl)-1,7-naphthyridine Under argon, 12 mg (0.015 mmol) [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(||) was added to a mixture of 75 mg (0.15 mmol) 2—(morpholinyl)—8-[1-(tetrahydro—2H-pyran—2-yl)- 1H—pyrazol-5—yl]-1,7-naphthyridinyl trifluoromethanesulfonate and 71 mg (0.29 mmol) 4- (4,4,5,5-tetramethyl—1,3,2-dioxaborolan—2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (1:1) in 1.1 ml dioxane and 285 mg (0.88 mmol) caesium carbonate. The mixture was stirred at 110 °C for 4 hours. After cooling, the reaction mixture was diluted with ethyl acetate and an aqueous solution of sodium chloride. The mixture was extracted with ethyl acetate (2x) and the ed organic phases were filtered using a Whatman filter. The organic phase was concentrated and residue was purified by ative HPLC (Autopurifier: basic conditions) to give 16 mg (0.04 mmol) of the desired t. 1H—NMR (400 MHz, CDCI3): 5 [ppm] = 1.76 (5H), 2.09 (2H), 2.52 (3H), 3.23 (2H), 3.47 (1H), 3.69 (5H), 3.83 (4H), 3.98 (1H), 5.93 (1H), 6.03 (1H), 6.95 (1H), 6.97 (1H), 7.64 (1H), 7.72 dH),8.43 (1H).

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp Step b: 2-(morpho|inyl)(1H-pyrazo|y|)(1,2,3,6-tetrahydropyridinyl)—1,7-naphthyridine 0.04 ml (0.08 mmol) 2N aqueous solution of hydrogen chloride was added to a solution of 16 mg (0.036 mmol) pholinyl)—8-[1-(tetrahydro—2H-pyran—2-yl)-1H—pyrazo|—5—y|](1,2,3,6- tetrahydropyridinyl)-1,7-naphthyridine in 0.17 ml methanol and the reaction mixture was stirred at room ature for 1 hour. The mixture was basified by addition of an aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated to give 11 mg (0.030 mmol) of the desired product. 1H—NMR (400 MHz, DMSO-d6): 5 [ppm] = 2.32 (2H), 2.98 (2H), 3.42 (2H), 3.67 (1H), 3.76 (8H), 5.90 (1H), 7.29 (1H), 7.36 (1H), 7.63 (1H), 7.67 (1H), 8.35 (1H), 13.30 (1H).

Example 18 4-cyclopropyl-Z-(morpholinyl)(1H—pyrazo|y|)-[1,7]naphthyridine Step a: 4-cyclopro pyl(morpholiny|)[2-(tetra hydropyrany|)-2H-pyrazo|y|]- [1,7]naphthyridine ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under argon, 80 mg (0.1 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)Clz) and 635 mg (2.0 mmol) of caesium carbonate were added to a suspension of 250 mg (0.49 mmol) of 2-(morpholinyl)[2-(tetrahydropyran- 2-yl)-2H-pyrazolyl]—[1,7]naphthyridin—4-yl trifluoromethanesulphonate and 84 mg (0.97 mmol) of 2-cyclopropyI-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane in 5 ml of absolute dioxane. The reaction mixture was stirred at 110°C for 4 h. The mixture was tographed directly without work-up [silica gel 60 (40 g, 30 um); chloroform/methanol (1:1, 100 ml)]. This gave 150 mg (76% of theory) of 4—cyclopropyl(morpholin—4-yl)[2-(tetrahydropyranyl)-2H—pyrazol—3-yl]— [1,7]naphthyridine as a yellow oil. LC—MS (method 1): m/z: [M+H]*= 406.3, Rt = 3.53 min.

Stepb: opropyl-Z-(morpholinyl)(1H—pyrazo|y|)-[1,7]naphthyridine \ N / \ / A drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to 150 mg (0.37 mmol) of 4-cyclopropyl(morpholinyl)[2-(tetrahydropyran-2—yl)-2H-pyrazoly|]—[1,7]naphthyridine.

After 1 h, LCMS showed complete removal of the protective group. The trifluoroacetic acid was distilled off under reduced pressure and the residue that remained was ed to pH 7 using sodium bicarbonate solution. The aqueous phase was extracted three times with in each case ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then concentrated to dryness. 5 ml of ol were added to the residue, resulting in the precipitation of a solid. The latter was filtered off and dried. This gave 30 mg (25% of theory) of 4- cyclopropyl-Z-(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine as a yellow solid. mp 211- 214°C. 1H NMR (400 MHz, DMSO): 6 [ppm] = 0.92-0.96 (2H), 1.10-1.14 (2H), 2.42-2.44 (1H), 3.72- 3.73 (4H), 3.77-3.78 (4H), 7.08 (1H), 7.36 (1H), 7.61 (1H), 7.99-8.00 (1H), 8.40-8.42 (1H), 13.34 (1H). LC-MS d 1): m/z: [M+H]+ = 322.3, Rt = 2.68 min.

Example 19 D[(2-(morpho|iny|)(2H—pyrazo|y|)-[1,7]naphthyridineyl]phenyl-S-methylsulphoximide [Annotation] jennyp None set by jennyp ation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 120 mg (0.24 mmol) of 3—[(2—(morpho|in—4—yl)-8—[2—(tetrahydropyran—2-yl)—2H—pyrazol—3-yl]— [1,7]naphthyridineyl]phenyI—N-ethoxycarbonyI-S-methylsuIphoximide were suspended in 8 ml of sodium methoxide (33%), and the e was stirred at 60°C for 30 min. For work—up, 20 ml of water were added and the mixture was then extracted three times with in each case 20 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and concentrated. This gave 100 mg (97% of theory) 3-[(2-(morpho|in-4—y|)(2H-pyrazo|—3-y|)- [1,7]naphthyridineyl]phenylmethylsulphoximide as a yellow solid. mp. 227-229°C. 1H NMR (400 MHz, CDCI3-d5): 8 [ppm] = 3.22 (3H), 3.79-3.81 (4H), 3.94-3.96 (4H), 7.20 (1H), 7.30-7.32 (1H), .36 (1H), 7.73-7.76 (3H), 8.18-8.20 (2H), 8.40-8.41 (1H). Lc-Ms (method 1): m/z: [M+H]+ = 435.3, Rt = 2.63 min.

Example 20 4-methyl(morpholinyl)(1H—pyrazo|y|)-[1,7]naphthyridine hydrochloride Step a: 4-methyl(morpho|iny|)[2-(tetrahyd ropyran-Z-yl)-2H—pyrazo|y|]-[1,7]naphthyridine O"N/\/N \_/— Under argon, 91 mg (0.11 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 241 mg (0.74 mmol) of caesium carbonate were added to a suspension of 190 mg (0.37 mmol) of 2—(morpholin-4—yl)—8—[2-(tetrahydropyran— [Annotation] jennyp None set by jennyp ation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 2—yl)—2H-pyrazol-3—yl]—[1,7]naphthyridin—4—yl trifluoromethanesulphonate and 44 mg (0.74 mmol) of methylboronic acid in 2.5 ml of absolute e. The reaction mixture was stirred at 90°C for 2 h. The mixture was chromatographed directly without work-up [silica gel 60 (40 g, 30 um); chloroform/methanol (95:5, 100 ml)]. This gave 120 mg (86% of theory) of 4-methyI (morpholinyl)-8—[2-(tetrahydropyranyl)-2H-pyrazoly|]-[1,7]naphthyridine as a yellow oil.

LC-MS (method 1): m/z: [M+H]+ = 380.3, Rt = 3.23 min.

Step b: 4-methyl(morpholinyl)(1H—pyrazo|y|)-[1,7]naphthyridine \ / o’ ‘N / \ / \_/ — A drop of water and 2 ml of (26 mmol) of trifluoroacetic acid were added to 120 mg (0.32 mmol) of 4-methyI(morpholin-4—yl)[2-(tetrahydropyran—2-yl)-2H—pyrazo|—3—y|]-[1,7]naphthyridine.

After 1 h, LCMS showed complete removal of the protective group. The trifluoroacetic acid was distilled off under reduced pressure and the e that remained was adjusted to pH 7 using sodium bicarbonate solution. The aqueous phase was extracted three times with in each case ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then concentrated to dryness. The residue was chromatographed [silica gel 60 (12 g, 30 um); chloroform (100 ml)]. This gave 45 mg (48% of theory) of 4—methyl-2—(morpholiny|)—8—(1H- pyrazoIyI)—[1,7]naphthyridine as a yellow solid. After brief exposure to air, this solid became oured. For this reason, the compound was converted into the corresponding hydrochloride.

LC-MS d 1): m/z: [M+H]+ = 296.3, Rt = 2.53 min.

Step c: 4-methyl(morpholinyl)(1H-pyrazo|y|)-[1,7]naphthyridine hydrochloride [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 45 mg (0.15 mmol) of 4-methyI(morpholiny|)(1H-pyrazoIyl)-[1,7]naphthyridine were dissolved in 4.0 ml of 2—butanol, and 58 (1| (0.46 mmol) of trimethylchlorosilane were added. The reaction solution was stirred at room temperature for 1 h. The precipitated solid was filtered off and then dried. This gave 45 mg (89% of theory) of 4—methyI—2—(morpholin—4—yl)—8—(1H-pyrazol-3— y|)-[1,7]naphthyridine hydrochloride as a yellow solid. mp 164-166°C. 1H NMR (400 MHz, DMSO, 6 ppm): 2.69 (3H), 3.81-3.86 (8H), 7.55 (1H), 7.82 (1H), .14 (2H), 8.38 (1H). LC-MS (method 1): m/z: [M+H]+ = 296.3, Rt = 2.51 min.

Example 21 4-[2-(methylsu|fony|)-1,3-thiazo|y|](morpholiny|)(1H-pyrazolyl)-1,7-naphthyridine Step a: 4-[2-(methylsu|fony|)-1,3-thiazol-4—yl]-2—(morpho|iny|)[1-(tetrahyd ro-ZH-pyran-Z-yl)-1H- pyrazol-S-yl]-1,7-naphthyridine Under argon, 16 mg (0.019 mmol) [1,1’-bis(diphenylphosphino)ferrocene]dichloropal|adium(|l) were added to a mixture of 100 mg (0.20 mmol) 2-(morpholin-4—yl)[1-(tetrahydro-2H-pyran d—lH-pyrazoI—S-yl]—1,7—naphthyridin—4—yl trifluoromethanesulfonate and 113 mg (0.39 mmol) 2- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (methylsulfonyl)-4—(4,4,5,5—tetramethyl—1,3,2—dioxaborolan—2-yl)—1,3—thiazole in 1.4 ml dioxane and 254 mg (0.78 mmol) caesium carbonate. The mixture was stirred at 110 °C for 2 hours. After cooling, the reaction mixture was diluted with ethyl acetate and an aqueous solution of sodium chloride. The mixture was extracted with ethyl acetate (2x) and the combined organic phases were ed using a Whatman . The organic phase was concentrated and the crude product (263 mg) was used without further purification.

Step b: methylsulfonyl)-1,3-thiazo|—4—yl](morpho|in-4—y|)(1H-pyrazo|y|)-1,7-naphthyridine 0.58 ml (1.15 mmol) 2N aqueous solution of hydrogen de was added to a solution of 263 mg crude 4-[2—(methylsulfonyl)-1,3-thiazolyl]—2—(morpho|inyl)[1-(tetrahydro-2H-pyran—2-yl)- 1H—pyrazol—5—yl]-1,7—naphthyridine in 2.3 ml methanol and the reaction mixture was d at room temperature for 1 hour. The mixture was basified by addition of an s sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated. The e was purified by preperative HPLC (Autopurifier: acidic conditions) to give 3 mg (0.007 mmol) of the desired product. 1H-NMR (400 MHz, DMSO-d6): 6 [ppm] = 3.61 (3H), 3.82 (8H), 7.41 (1H), 7.66 (1H), 7.82 (1H), 7.95 (1H), 8.41 (1H), 8.82 (1H), 13.42 (1H).

Example 22 4-[2-(morpholinyl)(1H-pyrazo|y|)-1,7-naphthyridin-4—yl]pyridin-2(1H)-one Step a: 4-(Z-methoxypyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A mixture of 2-(morpholin—4-yl)[1-(tetrahydro-2H—pyranyl)-1H-pyrazolyl]-1,7- yridin—4-yl trifluoromethanesulfonate (320 mg, 0.21 mmol), (2-methoxypyridin yl)boronic acid (94 mg, 0,62 mmol), iphenylphosphin)palladium(|l)ch|orid (14 mg, 0,021 mmol), Caesiumcarbonate (235 mg, 0,72 mmol) in Dioxane (4 ml) were heated in a sealed tube in the Microwave at 100° C for 30 minutes. A solution of conc. HCI (10 ml) was added and the reaction was stirred at ambient temperature for 16 hours and at 50°C for another 2 hours. The reaction mixture was filtered through a plug of Celite (1 cm). The Celite was washed with ethyl acetate (50 ml) and methanol (20 ml). The filtrate was dried over , the solvent was removed under reduced pressure. The title compound was obtained as crude product and used without further purification in the next step.

Step b: 4-[2-(morpholinyl)(1H-pyrazo|y|)-1,7-naphthyridin-4—yl]pyridin-2(1H)-one Crude 4-(2—methoxypyridin-4—yl)(morpholin—4-yl)(1H-pyrazolyl)-1,7-naphthyridine (1.882 g, purity ca. 10%) was added to a solution of concentrated HBr in acetic acid (2 ml) and acetic acid (15 ml) and stirred at 100°C for 2 hours. The reaction was cooled to ambient temperature, romethane (30 ml) and a saturated aqueous solution of NaHC03 (50 ml) was added. The ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp layers were separated and the aqueous phase was exctracted with dichloromethane (2 x 10 ml).

The combined organic layers were dried over NaZSO4. The solvent was removed under reduced re and the crude product (188 mg) was purified by HPLC chromatography (acidic conditions). The title compound was obtained in 1% yield (1.6 mg). 1H-NMR (400 MHz, DMSO): 6 [ppm] = 3.80 (8H), 6.33 (1H), 6.50 (1H), 7.41-7.66 (5H), 8.36 (1H), 11.89 (1H), 13.44 (1H).

Example 23 -[2-(morpholinyl)(1H-pyrazo|y|)-1,7-naphthyridin-4—yl]pyridin-2(1H)-one Step a: 4-(6-methoxypyridinyl)(morpholin-4—yl)(1H-pyrazol-S-yl)-1,7—naphthyridine A mixture of 2-(morpholin—4-yl)[1-(tetrahydro-2H—pyran-Z—yl)-1H-pyrazolyl]-1,7- naphthyridin—4-yl trifluoromethanesulfonate (605 mg, 0.39 mmol), (6-methoxypyridin yl)boronic acid (178 mg, 1.17 mmol), Bis(triphenylphosphin)pa||adium(||)chlorid (27 mg, 0,039 mmol), Caesiumcarbonate (443 mg, 1.36 mmol) in Dioxane (4 ml) were heated in a sealed tube in the Microwave at 100° C for 30 s. A solution of conc. HCI (10 ml) was added and the on was stirred at ambient temperature for 16 hours and at 50°C for another 2 hours. The reaction mixture was filtered through a plug of Celite (1 cm). The Celite was washed with ethyl acetate (50 ml) and methanol (20 ml). The filtrate was dried over NazSO4, the solvent was removed under reduced pressure. The title compound was obtained as crude product and used without further cation in the next step.

Step b: 5-[2-(morpholinyl)(1H-pyrazo|y|)-1,7-naphthyridin-4—yl]pyridin-2(1H)-one [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp Crude 4-(6—methoxypyridinyl)(morpholin-4—yl)(1H—pyrazol—5-yl)-1,7—naphthyridine (1.344 g, purity ca. 10%) was added to a solution of concentrated HBr in acetic acid (2 ml) and acetic acid (15 ml) and stirred at 100°C for 2 hours. The reaction was cooled to ambient temperature, dichloromethane (30 ml) and a saturated aqueous solution of NaHC03 (50 ml) was added. The layers were ted and the aqueous phase was exctracted with dichloromethane (2 x 10 ml). The combined organic layers were dried over Na2504. The t was d under reduced pressure and the crude product (188 mg) was purified by HPLC chromatography (acidic conditions). The title compound was obtained in 2% yield (2.3 mg). 1H-NMR (400 MHZ, DMSO): 6 [ppm] = 3.79 (8H), 6.51 (1H), 7.40 (1H), 7.48 (1H), 7.51 (1H), 7.64-7.70 (3H), 8.36 (1H), 12.10 (1H), 13.40 (1H).

Example 24 4-[2-fluoro-4—(methylsu|fony|)pheny|](morpholin-4—yl)—8-(1H-pyrazolyl)-1,7-naphthyridine Step 3: 4-[2-fluoro(methylsulfanyl)phenyl](morpholinyl)[1-(tetrahyd ro-2H-pyranyl)—1H- pyrazolyl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under argon, 24 mg (0.029 mmol) [1,1’-bis(dipheny|phosphino)ferrocene]dichloropal|adium(||) were added to a mixture of 150 mg (0.29 mmol) 2-(morpholin-4—yl)[1-(tetrahydro-2H-pyran y|)—1H-pyrazo|y|]-1,7-naphthyridin-4—yl oromethanesulfonate and 108 mg (0.58 mmol) [2- fluoro(methylsulfanyl)phenyl]boronic acid in 2.1 ml dioxane and 381 mg (1.17 mmol) caesium carbonate. The e was stirred at 110 "C for 2 hours. After cooling, the reaction mixture was diluted with ethyl acetat and washed with s sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography (hexane / ethyl acetate 20% - 70%) to give 126 mg (0.25 mmol) of the desired t.

Step b: 4-[2-fluoro-4—(methylsulfony|)phenyl](morpholin-4—yl)[1—(tetrahydro-ZH-pyran-Z-yl)-1H- pyrazolyl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under argon, 2 mg (0.006 mmol) tetrapropylammonium perruthenate (TPAP) and 14 mg (0.127 mmol) N-metylmorpholine-N-oxide (NMO) were added to a solution of 64 mg (0.127 mmol) 4-[2- fluoro(methylsulfanyl)phenyl](morpho|inyl)[1-(tetrahydro-2H-pyranyl)-1H-pyrazo| y|]-1,7-naphthyridine in 1.4 mL DCM and 1.4 mL acetonitrile at 0°C. The mixture was stirred for 4 hours at 0°C. Additional 14 mg (0.127 mmol) N-metylmorpholine-N-oxide (NMO) was added and the mixture was stirred at 0°C for 7 hours and then for 40 minutes at 10°C. Finally, the batch was concentrated to give 81 mg crude product that was used without further purification.

Step c: 4-[2-fluoro(methylsulfonyl)phenyl]-2—(morpholin-4—yl)—8-(1H-pyrazo|y|)-1,7-naphthyridine H30’ "0 0.17 ml (0.35 mmol) 2N aqueous solution of hydrogen chloride was added to a solution of 81 mg crude 4-[2—fluoro-4—(methylsulfonyl)phenyl]-2—(morpho|inyl)—8-[1-(tetrahydro-2H-pyran—2-yl)- 1H—pyrazoI—5—yl]-1,7—naphthyridine in 0.7 ml methanol and the reaction mixture was stirred at room temperature for 1 hour. The mixture was basified by addition of an s sodium bicarbonate on and extracted with ethyl acetate (2x). The combined organic phases were dried (NaZSO4), filtered and concentrated. The residue was purified by preperative HPLC urifier: acidic conditions) to give 18 mg (0.04 mmol) of the desired product. 1H-NMR (400 MHz, DMSO): 6 [ppm] = 3.40 (3H), 3.80 (8H), 7.20 (1H), 7.44 (1H), 7.70 (2H), 7.88 (1H), 8.00 (1H), 8.06 (1H), 8.33 (1H), 13.55 (1H).

Example 25 2-(morpho|iny|){4-[S-(propan-Z-yl)sulfonimidoyl]pheny|}(1H-pyrazolyl)-1,7- naphthyridine Dep a: [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 2-(morpholinyl)[4—(propan-Z-ylsulfanyl)phenyl][1—(tetrahydro-2H-pyran-Z-yl)-1H- pyrazolyl]-1,7-naphthyridine o N Under argon, 16 mg (0.019 mmol) [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(|l) was added to a mixture of 100 mg (0.20 mmol) 2-(morpholinyl)[1-(tetrahydro-2H-pyran yl)-1H-pyrazolyl]-1,7-naphthyridinyl trifluoromethanesulfonate and 76 mg (0.39 mmol) [4- (propan-Z-ylsulfanyl)phenyl]boronic acid in 1.4 ml dioxane and 253 mg (0.78 mmol) caesium carbonate. The mixture was stirred at 110 °C for 2 hours. After cooling, the reaction mixture was d with ethyl acetate and an aqueous solution of sodium chloride. The mixture was extracted with ethyl e (2x) and the combined organic phases were filtered using a Whatman filter.

The organic phase was concentrated and residue was purified by column tography (hexane / ethyl e 20% - 80%) to give 74 mg (0.14 mmol) of the desired product, containing slight impurities, that was used without further purifications.

Step b: 2,2,2-trifluoro-N-[(4—{2-(morpholin-4—yl)[1-(tetrahyd ro-ZH-pyran-Z-yl)—1H-pyrazolyl]-1,7- naphthyridin-4—yl}phenyl)(propan-Z-yl)-A4-sulfanylidenelacetamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under an atmosphere of argon, a solution of 39 mg (0.35 mmol) trifluoroacetamide in 0.13 ml THF was added dropwise to a solution of 22 mg (0.23 mmol) sodium tert.—butoxide in 0.19 ml THF, so that the temperature of the mixture remained below 10 °C. Subsequently, a freshly prepared solution of 43 mg (0.15 mmol) bromo-5,5-dimethylhydantoin in 0.19 ml THF was added dropwise to the stirred e, so that the temperature of the mixture remained below °C. Then the mixture was stirred for 10 minutes at 10 °C. Finally, a solution of 120 mg (0.23 mmol) 2-(morpholinyl)[4-(propanylsulfanyl)phenyl]—8—[1-(tetrahydro-2H-pyranyl)-1H- pyrazoIyl]—1,7-naphthyridine in 0.23 ml THF was added dropwise to the stirred mixture, so that the temperature of the mixture remained below 10 °C. The mixture was stirred for 80 minutes at "C and then at room ature overnight. The batch was diluted with 0.5 ml toluene under cooling and an s solution of 29 mg (0.23 mmol) sodium sulfite in 0.9 ml water was added so that the temperature of the mixture remained below 15 °C. The batch was extracted three times with ethyl acetate. The combined organic phases were washed with an aqueous solution of sodium chloride, filtered using a n filter and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate) to give 28 mg of the desired product containing slight ties.

Step c: 4-[4—(S-isopropylsulfonimicloyl)pheny|](morpholin-4—y|)[1-(tetrahydro-ZH-pyran-Z-yl)-1H- pyrazolyl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 28 mg (0.035 mmol) 2,2,2-trifluoro-N-[(4-{2-(morpho|in—4-yl)[1-(tetrahydro-2H-pyranyI)-1H- pyrazol-5—y|]—1,7-naphthyridin—4—y|}phenyl)(propan-Z-y|)—?\4—suIfanylidenejacetamide was dissolved in 0.87 ml methanol. To this solution 0.31 ml water was added. The pH was adjusted to 10.5 by addition of an aqueous solution of potassium hydroxide (25%). 23 mg (0.038 mmol) Oxoneg was added and the e was stirred at room temperature for 4 hours. Additional amount 23 mg (0.038 mmol) Oxone® was added. The pH was adjusted to 10.5 by addition of an aqueous solution of potassium ide (25%). The batch was stirred at room temperature for 90 minutes. The pH was adjusted to 10.5 by on of an s solution of potassium hydroxide (25%) and the batch was stirred at room temperature for 4 days. The batch was filtered and the filtrate was adjusted to pH 6-7 by the addition of 1N aqueous hydrogen chloride solution. The mixture was diluted with aqueous sodium chloride solution and extracted with DCM (2x). The combined organic phases were washed with an aqueous solution of sodium sulfite (10%), filtered using a Whatman filter, and trated to give 21 mg crude product that was used without further purification.

Step d: 2-(mo rpho|iny|){4-[S-(propan-Z-yl)sulfonimidoyl]pheny|}(1H-pyrazolyl)—1,7- naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 0.04 ml (0.11 mmol) 2N aqueous solution of hydrogen chloride was added to a solution of 21 mg crude 2-(morpholinyl){4—[S-(propany|)sulfonimidoyl]pheny|}[1-(tetrahydro-2H-pyran yl)—1H—pyrazo|—5-yl]—1,7—naphthyridine in 0.18 ml ol and the reaction mixture was stirred at room temperature for 1 hour. The mixture was basified by addition of an aqueous sodium bicarbonate solution and extracted with ethyl e (2x). The combined organic phases were filtered using a Whatman filter and concentrated. The e was purified by preperative HPLC (Autopurifier: basic conditions) to give 4 mg (0.01 mmol) of the desired product.1H-NMR (400 MHz, DMSO-d6): 6 [ppm] = 1.22 (6H), 3.35 (1H), 3.81 (8H), 4.30 (1H), 7.36 (1H), 7.44 (1H), 7.57 (1H), 7.65 (1H), 7.82 (2H), 8.05 (2H), 8.35 (1H), 13.43 (1H).

Example 26 4-(4-methanesulphonylpheny|)((R)methy|morphoIin-4—yl)—8-(2H-pyrazo|y|)- [1,7]naphthyridine Step a: 4-(4-methanesulphonylphenyI)((R)methy|morpholin-4—yl)—8-[2-(tetrahydropyran-Z-yl)-2H— pyrazolyl]-[1,7]naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under argon, 120 mg (227 umol) of 2—((R)-3—methy|morpholin—4—yl)-8—[2—(tetrahydropyran—2-yl)- 2H-pyrazoI-3—y|]-[1,7]naphthyridinyl trifluoromethanesulphonate, 76 mg (0.38 mmol) of 4- (methanesulphonyl)phenylboronic acid, 18 mg (22.7 umol) of [1,1’—bis(diphenylphosphino)- ferrocene]dichloropalladium(ll) x dichloromethane and 296 mg (0.91 mmol) of caesium carbonate were weighed out and dissolved in 1.5 ml of absolute 1,4-dioxane. The mixture was degassed three times and stirred at 90°C for 2 h. The course of the on was monitored by LC/MS. Since conversion was incomplete, another 52 mg of hanesu|phony|)pheny|boronic acid, 18 mg of [1,1’—bis(diphenylphosphino)ferrocene]dich|oropalladium(|l) x dichloromethane and 296mg of m carbonate were added to the reaction solution and the mixture was stirred at 90°C for h. Under reduced re, the mixture was concentrated to dryness. The residue was chromatographed [silica gel 60 (40 g, 50 um); dichloromethane/methanol 98:2 to 95:5]. 79 mg (65% of ) of 4—(4-methanesu|phonylphenyl)((R)methy|morpholiny|)—8-[2- hydropyran-Z-yl)-2H—pyrazolyl]—[1,7]naphthyridine were obtained as a yellow solid. 1H NMR (400MHz, CDCI3): 6 [ppm] = 1.34 (3H), 1.48-1.74 (3H), 2.08-2.11 (2H), 2.56 (1H), 3.19 (3H), 3.34 (1H), 3.46 (1H), 3.59 (1H), 3.71-3.84 (3H), 3.94 (1H), 4.02-4.24 (2H), 4.44 (1H), 6.08 (1H), 6.98 (1H), 7.01 (1H), 7.69—7.72 (3H), 8.14 (2H), 8.40 (1H). LC—MS (method 1): R: 3.46 min; MS (ESl/APClpos) m/z = 534.3 [M+H]+.

Step b: 4-(4-methanesulphonylphenyl)—2-((R)-3—methy|morphoIinyl)(2H-pyrazo|y|)- [1,7]naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 79 mg (0.15 mmol) of 4—(4-methanesulphonylphenyl)-2—((R)—3-methy|morpholin-4—yl)—8—[2— (tetrahydropyran-Z-yl)-2H—pyrazolyl]—[1,7]naphthyridine were dissolved in 5 ml of methanol, 1 ml of 2N hydrochloric acid (2 mmol) was added and the mixture was stirred at room temperature for 1 h. After 1 h, LC/MS showed complete removal of the protective group. The methanol was removed under reduced pressure and the residue was adjusted to pH = 7 using saturated sodium onate on. The aqueous phase was ted five times with in each case 10 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and concentrated to s under reduced pressure. The residue was washed twice with in each case 4 ml of methanol, filtered off and dried. This gave 44 mg (66% of theory) of 4-(4- methanesu|phonylphenyl)((R)methylmorpholiny|)(2H-pyrazoly|)-[1,7]naphthyridine as a yellow solid. 1H NMR (400MHz, DMSO—de): 6 [ppm] = 1.31 (3H), 3.33 (3H), 3.32-3.40 (1H), 3.57 (1H), 3.72 (1H), 3.83 (1H), 4.05 (1H), 4.24 (1H), 4.66 (1H), 7.35 (1H), 7.43 (1H), 7.50 (1H), 7.61 (1H), 7.87 (2H), 8.13 (2H), 8.33 (1H), 13.4 (1H). LC—MS (method 1): Rt = 2.88 min; MS (ESI/APCIpos) m/z = 450.2 [M+H]+.

Example 27 2-((R)methy|morpho|in-4—yl)phenyl(2H-pyrazo|y|)-[1,7]naphthyridine Step a: 2-((R)methy|morpholin-4—yl)-4—phenyl[2-(tetra hyd ropyran-Z-yl)—2H—pyrazo|y|]- [1,7]naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 0‘ :N Under argon, 120 mg (227 umol) of 2—((R)methy|morpholin—4—yl)[2—(tetrahydropyran—2-yl)- 2H—pyrazoI-3—y|]-[1,7]naphthyridinyl trifluoromethanesulphonate, 46 mg (0.38 mmol) of benzeneboronic acid, 18 mg (0.0227 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]— dichloropalladium(|l) x dichloromethane and 296 mg (0.91 mmol) of caesium carbonate were weighed out and dissolved in 1.5 ml of absolute 1,4-dioxane. The e was degassed three times and stirred at 90°C for 1 h. The course of the reaction was monitored by LC/MS. The e was concentrated to dryness under reduced pressure. The e was chromatographed [silica gel 60 (40 g, 50 um); dichloromethane/methanol 98:2 to 95:5]. This gave 90 mg (87% of theory) of 2-((R)methy|morpholinyI)—4-phenyl[2-(tetrahydropyran-2—yl)-2H-pyrazo|—3-y|]- [1,7]naphthyridine as a yellow solid. 1H NMR (400 MHz, CDCI3): 6 [ppm] = 1.33 (3H), 1.48—1.51 (1H), 1.62-1.77 (2H), 2.07-2.10 (2H), 2.56 (1H), 3.32 (1H), 3.46 (1H), 3.58 (1H), 3.69-3.83 (2H), 3.94—3.98 (1H), 4.03—4.52 (3H), 6.05 (1H), 6.97 (1H), 7.02 (1H), 7.47—7.56 (6H), 7.71 (1H), 8.38 (1H).

LC-MS (method 1): Rt = 3.89 min; MS (ESl/APCIpos) m/z = 456.3 .

Step b: 2-((R)methy|morpholinyl)—4-phenyl(2H-pyrazo|y|)-[1,7]naphthyridine \ /N CH3 _N o’ (N / \ / \_/ — 90 mg (0.20 mmol) of methy|morpholinyl)pheny|—8-[2-(tetrahydropyranyl)-2H— Drazolyl]—[1,7]naphthyridine were dissolved in 5 ml of methanol, 1 ml of 2N hydrochloric acid [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (2 mmol) was added and the mixture was stirred at room temperature for 1 h. After 1 h, LC/MS showed complete removal of the protective group. The methanol was removed under reduced pressure and the residue was adjusted to pH = 7 using saturated sodium onate solution.

The s phase was extracted five times with in each case 10 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then, under reduced pressure, concentrated to dryness. The residue was chromatographed twice [silica gel 60 (25 g, 30 um); romethane/methanol 96:4]. This gave 52 mg (71% of theory) of 2—((R)methy|morpho|in- 4-yl)pheny|—8-(2H-pyrazol-3—yl)-[1,7]naphthyridine as an orange solid. 1H NMR (400 MHz, CDCI3): 6 [ppm] = 1.46 (3H), 3.57 (1H), 3.72 (1H), 3.84-3.94 (2H), 4.04 (1H), 4.17 (1H), 4.46 (1H), 7.14 (1H), 7.32 (1H), 7.43 (1H), 7.47-7.58 (5H), 7.72 (1H), 8.38 (1H). 13CNMR (101 MHz, : 6[ppm] = 13.6, 40.6, 48.6, 66.7, 71.1, 106.3, 113.5, 117.8, 126.9, 120.8, 129.0, 129.2, 137.2, 140.1, 140.4, 140.5, 143.0 144.7, 149.9, 156.8. LC-MS (method 1): Rt = 3.32 min; MS (ESl/APClpos) m/z = 372.2 [M+H]+.

Example 28 4—(3-methanesulphonylphenyl)—2-((R)methy|morpholin-4—yl)-8—(2H—pyrazo|y|)- [1,7]naphthyridine Step a: 4-(3-methanesulphonylphenyl)—2-((R)methy|morpholin-4—yl)-8—[2-(tetrahydropyran-Z-y|)-2H- pyrazolyl]-[1,7]naphthyridine Under argon, 120 mg (227 umol) of 2—((R)methylmorpholin—4—yl)[2—(tetrahydropyran—2-yl)- azol-3—yl]—[1,7]naphthyridine-4—yl trifluoromethanesulphonate, 76 mg (0.38 mmol) of 3- (methanesu|phonyl)phenylboronic acid, 18 mg (22.7 (.lmol) of [1,1’-bis(diphenylphosphino)- ferrocene]dichloropalladium(|l) x dichloromethane and 296 mg (0.91 mmol) of caesium carbonate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp were weighed out and dissolved in 1.5 ml of absolute 1,4-dioxane. The mixture was degassed three times and stirred at 90°C for 90 min. The course of the reaction was monitored by LC/MS.

Under reduced re, the mixture was concentrated to s. The residue was chromatographed [silica gel 60 (25 g, 30 um); dichloromethane/methanol 98:2]. This gave 72 mg (60% of ) of 4-(3-methanesulphonylphenyl)((R)methylmorpholinyl)[2- (tetrahydropyranyl)-2H-pyrazo|y|]—[1,7]naphthyridine as a yellow solid. 1H NMR (400MHz, com): 6 [ppm] = 1.32-1.37 (3H), 1.49-1.69 (1H), 1.69 (2H), 2.09 (2H), 2.55 (1H), 2.68 (3H), 3.27- 3.39 (1H), 3.47 (1H), 3.59 (1H); 3.77 (2H), 3.94-4.48 (4H), 6.10 (1H), 6.93-6.95 (1H), 7.02-7.08 (1H), 7.20-7.25 (1H), 7.42 (1H), .79 (3H), 8.32-8.35 (2H). Lc-Ms (method 1): R.=3.43 min; MS (ESI/APClpos) m/z = 534.3 [M+H]+.

Step b: 4-(3-methanesulphonylphenyl)((R)methy|morpholinyl)(2H—pyrazo|y|)- [1,7]naphthyridine 72 mg (0.13 mmol) of 4-(3-methanesu|phonylphenyl)((R)methylmorpholinyl)—8-[2- (tetrahydropyran-2—yl)—2H—pyrazo|—3—yl]—[1,7]naphthyridine were dissolved in 5 ml of ol, 1 ml of 2N hydrochloric acid (2 mmol) was added and the mixture was stirred at room temperature for 1 h. After 1 h, LC/MS showed te removal of the protective group. The methanol was removed under d pressure and the residue was adjusted to pH = 7 using saturated sodium bicarbonate solution. The aqueous phase was extracted five times with in each case 10 ml of dichloromethane. The ed organic phases were dried over sodium sulphate and then, under reduced pressure, concentrated to dryness. The residue was chromatographed twice [silica gel 60 (25g, 30 um); dichloromethane/methanol 96:4]. This gave 37 mg (61% of theory) of 4-(3-methanesulphonylphenyl)((R)methylmorpholinyl)(2H-pyrazolyl)- [1,7]naphthyridine as an orange solid. 1H NMR (400 MHz, CDCI3): 6 [ppm] = 1.46 (3H), 2.66 (3H), D58 (1H), 3.72 (1H), 3.83-3.92 (2H), 4.04-4.20 (2H), 4.39 (1H), 6.91 (1H), 7.33-7.37 (2H), 7.42 (1H), [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp .80 (3H), 8.33 (2H). LC—MS (method 1): Rt = 2.80 min; MS (ESl/APCIpos) m/z = 450.2 [M+H]+.

Example 29 4—cyclopropyl-Z-((R)methy|morpho|iny|)(1H—pyrazol-3—yl)-[1,7]-naphthyridine Step a: 4-cyclopro pyl-Z-((R)methy|morpho|iny|)[2-(tetrahyd ropyran-2—yl)-2H—pyrazo|y|]- aphthyridin Under argon, 82 mg (0.1 mmol) of [1,1’-bis(dipheny|phosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)Cl2) and 652 mg (2.0 mmol) of caesium carbonate were added to a suspension of 264 mg (0.5 mmol) of 2—[(3R)methy|morpholin-4—yl]—8-[1— (tetrahydro-2H-pyran—2-yl)-1H—pyrazoly|]-[1,7]naphthyridin-4—y| trifluoromethanesulphonate and 86 mg (1 mmol) of 2-cyclopropyI—4,4,5,5-tetramethyl—[1,3,2]dioxaborolane in 5 ml of absolute e. The reaction mixture was stirred at 110°C for 4 h. Without work-up, the mixture was chromatographed directly Flash, silica gel 60 (25 g, 30 um); ethyl acetate (100 ml)]. This gave 100 mg (48% of theory) of 4-cyclopropyl((R)—3-methy|morpholin-4—yl)-8—[2-(tetrahydropyran y|)—2H-pyrazoly|]—[1,7]naphthyridine as a yellow solid. 13C NMR (101 MHz, CDCIg-de): 6 [ppm] = 6.9, 7.0, 12.5, 13.5, 22.8, 25.0, 30.0, 39.4, 39.7, 47.1, 47.7, 66.9, 67.0, 67.6, 71.1, 84.8, 108.8, 110.2, 116.6, 128.0, 128.1, 138.5, 138.6, 139.0, 139.1, 140.3, 141.7, 148.2, 149.6, 156.6, 156.7.

Step b: 4—cyclopro pyl-Z-((R)methy|morpho|in-4—y|)(1H—pyrazolyl)-[1,7]-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 100 mg (0.24 mmol) of 4-cyc|opropy|-2—((R)methy|morpholin-4—yl)[2—(tetrahydropyran—Z-yl)- 2H—pyrazol—3—yl]—[1,7]naphthyridine were dissolved in 5 ml of methanol, and 1 ml (2 mmol) of 2N hloric acid was added. After 1 h, LCMS showed complete removal of the protective group.

The ol was distilled off under reduced pressure and the residue that remained was adjusted to pH 7 using sodium bicarbonate solution. The aqueous phase was extracted three times with in each case 20 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then trated to dryness. The residue was chromatographed [Puri- Flash, silica gel 60 (12 g, 30 um); ethyl acetate (100 ml)]. This gave 70 mg (88% of theory) of 4- cyclopropyI—2—((R)-3—methy|morpholin—4—yl)(1H—pyrazo|—3-y|)-[1,7]naphthyridine as a yellow solid. mp. C. 1H NMR (400 MHz, CDCI3): 8 [ppm] = 0.78-0.82 (2H), 1.14-1.17 (2H), 1.38-1.40 (3H), 2.24—2.28 (1H), 3.46-3.52 (1H), 3.64-3.71(1H), 3.80—3.96 (3H), 4.11—4.15(1H), 4.37-4.39 (1H), 6.86 (1H), .26 (1H), 7.68-7.69 (1H), 7.81-7.83 (1H), 8.44-8.45 (1H).

Example 30 4-[2-((R)methy|morpho|in-4—yl)—8-(2H—pyrazoly|)-[1,7]naphthyridineyl]phenyl-S— methylsulphoximide Step 3: 4-[2-((R)methy|morpho|in-4—yl)—8-[2-(tetrahydropyranyl)-2H—pyrazo|—3-yl]- [1,7]naphthyridine-4—yl]phenyl-N-ethoxycarbonyl-S—methylsulphoximide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under argon, 48 mg (0.06 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with romethane (1:1, Pd(dppf)C|2) and 761 mg (2.34 mmol) of caesium carbonate were added to a suspension of 308 mg (0.58 mmol) of 2—((R)—3-methylmorpholin-4—yl)—8—[2— (tetrahydropyran-Z-yl)-2H-pyrazolyl]—[1,7]naphthyridin—4-yl trifluoromethanesulphonate and 413 mg (1.17 mmol) of pinacol ester in 7.5 ml of absolute dioxane. The reaction mixture was stirred at 90°C for 2 h. The mixture was chromatographed ly without work-up [silica gel 60 (25 g, 30 um); ethyl acetate (100 ml)]. This gave 245 mg (69% of theory) of (morpho|in—4—yl)— 8-[2—(tetrahydropyran-Z-yl)-2H-pyrazolyl]-[1,7]naphthyridineyl]phenyl-N-ethoxycarbonyI-S- methylsulphoximide as a yellow foam. LC-MS (method 1): m/z: [M+H]+ = 605.3, R1 = 3.52 min.

Step b: 4—[2-((R)methy|morpho|iny|)[2-(tetrahyd ropyran-Z-yl)-2H-pyrazo|y|]- [1,7]naphthyridineyl]phenyl-N—ethoxycarbonyl-(S)-methylsu|phoximide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 240 mg (0.40 mmol) of 4-[2—((R)—3-methylmorpholin-4—yl)—8—[2-(tetrahydropyran-2—yl)-2H-pyrazol- 3-y|]-[1,7]naphthyridineyl]phenyl-N-ethoxycarbonyl-5—methylsu|phoximide were dissolved in ml of ethanol, and 4 ml of (8 mmol) of 2N hydrochloric acid were added. After 1 h, LCMS showed complete removal of the protective group. Ethanol was distilled ohc under reduced pressure and the residue that ed was adjusted to pH 7 using sodium bicarbonate on.

The s phase was extracted three times with in each case 20 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then concentrated to dryness.

This gave 200 mg (97% of theory) of 2—((R)methylmorpholin-4—yl)(1H-pyrazol—3-yl)- [1,7]naphthyridine—4—carbonitrile as a yellow solid. LC—MS (method 1): m/z: [M+H]+=521.3, Rt = 3.00 min.

Step c: 4-[2-((R)methy|morpho|iny|)(2H—pyrazolyl)—[1,7]naphthyridineyl]phenyl-S- methylsulphoximide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp 170 mg (0.33 mmol) of 4—[2—((R)-3—methylmorpholin—4—yl)—8-(2H—pyrazol—3—y|)-[1,7]naphthyridine— 4-yl]phenyl-S—methylsulphoximide were suspended in 5 ml of sodium ide (33%), and the mixture was stirred at 60°C for 30 min. For work-up, 20 ml of water were added and the mixture was then extracted three times with in each case 20 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and concentrated. The solid formed was triturated with 5 ml of methanol, filtered ofic and dried. This gave 88 mg (57% of theory) of 4-[2- ((R)—3-methylmorpho|inyl)—8—(2H—pyrazol-3—y|)—[1,7]naphthyridineyl]phenyI-$— methylsulphoximide as a yellow solid. mp. 233-236°C. 1H NMR (400 MHz, DMSO-de): 6 [ppm] = 1.30-1.32 (3H), 3.17 (3H), 3.54 (1H), 3.55-3.57 (1H), 3.70-3.73 (1H), 3.81-3.84 (1H), 4.22- 4.25 (1H), 4.35 (1H), 7.35-7.36 (1H), 7.42 (1H), 7.48 (1H), 7.65 (1H), 7.80-7.82 (2H), 8.12-8.14 (2H), .34 (1H), 13.40 (1H). LC—MS (method 1): m/z: [M+H]+ = 449.3, Rt = 2.69 min.

Example 31 3-[2—((R)methy|morpho|in-4—y|)(2H-pyrazolyl)-[1,7]naphthyridine-4—yl]phenyl-S— methylsulphoximide Step a: 3-[2—((R)methy|morpho|in-4—yl)—8-[2-(tetrahydropyranyl)-2H-pyrazo|—3-yl]- [1,7]naphthyridine-4—yl]phenyl-N—ethoxycarbonyl-S—methylsulphoximide Under argon, 48 mg (0.06 mmol) of bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 761 mg (2.34 mmol) of caesium ate were added to a suspension of 308 mg (0.58 mmol) of 2-((R)methylmorpholinyl)[2- Gtrahydropyran-2—yl)-2H-pyrazolyI]—[1,7]naphthyridin—4-yl trifluoromethanesulphonate and [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp 413 mg (1.17 mmol) of pinacol ester in 7.5 ml of absolute dioxane. The reaction mixture was stirred at 90°C for 2 h. The mixture was chromatographed directly without work-up [silica gel 60 (25g, 30 um); ethyl acetate (100 ml)]. This gave 289 mg (82% of theory) of 3-[2-((R) methylmorpholinyl)—8—[2-(tetrahydropyran-Z-yl)-2H-pyrazolyl]-[1,7]naphthyridine yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximide as a yellow oil. LC-MS (method 1): m/z: [M+H]+ = 605.3, Rt = 3.56 min.

Step b: 4-[2-((R)methy|morpho|iny|)[2-(tetrahydropyranyl)—2H—pyrazo|y|]- [1,7]naphthyridine-4—yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximide 280 mg (0.46 mmol) of 3-[2-((R)—3-methy|morpholiny|)[2-(tetrahydropyran-Z-yl)-2H-pyrazol- 3-y|]-[1,7]naphthyridineyl]phenyl-N-ethoxycarbonyl-$-methylsu|phoximide were dissolved in ml of ethanol, and 4 ml of (10 mmol) of 2N hloric acid were added. After 1 h, LCMS showed complete removal of the protective group. Ethanol was distilled off under reduced re and the residue that remained was ed to pH 7 using sodium bicarbonate solution.

The aqueous phase was extracted three times with in each case 20 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then concentrated to s. The residue was chromatographed [silica gel 60 (25 g, 30 um); ethyl acetate (100 ml)]. This gave 220 mg (91% of theory) of 2-((R)methylmorpholinyl)-8—(1H-pyrazol-3—yl)-[1,7]naphthyridine- 4-carbonitrile as a yellow solid. LC-MS (method 1): m/z: [M+H]+ = 521.3, R1 = 3.04 min.

Step c: 3-[2—((R)methy|morpho|in-4—y|)(2H-pyrazolyl)—[1,7]naphthyridineyl]phenyl-S— Dethylsulphoximide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 210 mg (0.40 mmol) of 4-[2—((R)—3-methy|morpholin-4—yl)—8—[2—(tetrahydropyran—2—yl)-2H—pyrazol— 3-yl]—[1,7]naphthyridineyl]phenyl-N-ethoxycarbonyl-5—methylsulphoximide were suspended in ml of sodium methoxide (33%), and the mixture was stirred at 60°C for 30 min. For work—up, ml of water were added and the mixture was then ted three times with in each case ml of dichloromethane. The ed organic phases were dried over sodium sulphate and concentrated. This gave 165 mg (91% of theory) of 3-[2-((R)—3-methylmorpholinyl)(2H— pyrazolyl)-[1,7]naphthyridineyl]phenyl-S-methylsulphoximide as a yellow solid. mp. 79- 81°C. 1H NMR (400 MHz, DMSO-de): 6 [ppm] = 1.30-1.32 (3H), 3.18 (3H), 3.57-3.58 (1H), .75 (1H), 3.82-3.85 (1H), 4.03-4.06 (1H), 4.21-4.24 (1H), 4.34 (1H), 4.67-4.68 (1H), 7.35-7.36 (1H), 7.42 (1H), 7.48 (1H), 7.65 (1H), 7.80-7.82 (2H), 8.12-8.14 (2H), 8.33-8.34 (1H), 13.40 (1H). LC-MS (method 1): m/z: [M+H]+ = 449.3, Rt = 2.69 min.

Example 32 4-methanesulphonyl(morpho|iny|)[2-(tetrahyd ropyran-Z-yl)-2H—pyrazo|y|]- [1,7]naphthyridine Step a: anesulphonyl(morpho|iny|)[2-(tetrahyd ropyran-Z-yl)-2H—pyrazo|y|]- [1,7]naphthyridine [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 500 mg (1.25 mmol) of 4-chloro-Z-(morpholinyl)[2-(tetrahydropyran-Z-yll-ZH- pyrazolyl]—[1,7]naphthyridine, 140 mg (1.38 mmol) of sodium methanesulphinate, 45 mg (0.13 mmol) of copper(ll) trifluoromethanesulphonate and 29 mg (0.25 mmol) of (t)-trans-1,2- diaminocyclohexane in 5 ml of yl sulphoxide was stirred at 100°C for 16 h. 20 ml of water were added to the reaction mixture. The ing precipitated solid was filtered off. The solid was purified by column chromatography [Purl-Flash, silica gel 60 (40 g, 30 um), dichloromethane/methanol 1:1 (300 ml)]. In this manner, 4-methanesuIphonyI—Z—(morpholin y|)-8—[2-(tetrahydropyran-Z-y|)—2H-pyrazolyl]—[1,7]naphthyridine was obtained as a yellow solid in a yield of 300 mg (54% of theory). LC—MS (method 1): m/z: [M+H]+ = 444.3, Rt = 3.24 min.

Step b: 4-methanesulphonyl(morpholin-4—yl)[2-(tetrahyd ropyran-Z-yl)—2H—pyrazolyl]- [1,7]naphthyridine 300 mg (0.67 mmol) of 4-methanesulphonyI(morpholinyl)[2-(tetrahydropyran-Z-yl)-2H- pyrazoIyI]—[1,7]naphthyridine were dissolved in 5 ml of methanol, and 1 ml (4 mmol) of 2N hydrochloric acid was added. After 1 h, LCMS showed te removal of the protective group.

Methanol was distilled off under reduced pressure and the residue that remained was adjusted to pH 7 using sodium onate solution. The aqueous phase was extracted three times with in Dch case 20 ml of dichloromethane. The combined organic phases were dried over sodium [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp sulphate and then concentrated to s. The solid residue was triturated with 5ml of methanol, filtered off and dried. This gave 146 mg (60% of theory) of 4-methanesulphonyI olinyl)[2-(tetrahydropyranyl)-2H-pyrazolyl]-[1,7]naphthyridine as a yellow solid. mp. 271-273°C. 1H NMR (400 MHz, DMSO, 6 ppm): 3.48 (3H), 3.80 (8H), 7.35 (1H), 7.65 (1H), 7.93 (1H), .16 (1H), 8.49-8.50 (1H), 13.43 (1H). Lc-Ms (method 1): m/z: [M+H]+=360.2, Rt = 2.78 min.

Example 33 2-[(3R)methy|morpho|in-4—yl]-4—(methylsulfonyl)(1H-pyrazolyl)-1,7-naphthyridine Step a: 2-[(3R)—3-methy|morpholin-4—yl]-4—(methylsulfonyl)[1—(tetra hyd ro-ZH-pyranyl)-1H-pyrazo|— 1,7-naphthyridine 4-ChIoro[(3R)methylmorpholin-4—yl][1—(tetrahydro-2H-pyranyl)—1H-pyrazo|y|]—1,7- naphthyridine (50 mg, 0.12 mmol, 1 eq.) was solubilised in DMF (4 mL). Methanesulfinic acid sodium salt (25 mg, 0.24 mmol, 2 eq.) and DMAP (1.5 mg, 0.012 mmol, 0.1 eq.) were added. The reaction was stirred for 16h at 120°C. After cooling to rt, the reaction mixture was concentrated under reduced pressure and the crude was purified by flash column chromatography (gradient 100% hexane to 100% EtOAc). The desired product was obtained in 74% yield (46 mg). lH—NMR (400MHz, DMSO-de): 6 [ppm]: 1.24 (3H), 1.39 - 1.65 (3H), 1.89 - 2.03 (2H), 2.34 - 2.43 (1H), 3.20 - 3.29 (1H), 3.41 - 3.54 (5H), 3.58 - 3.73 (2H), 3.77 (1H), 3.94 - 4.01 (1H), 4.12 (1H), 4.45 - 4.56 (1H), .97 - 6.08 (1H), 6.89 (1H), 7.64 (1H), 7.84 (1H), 8.19 (1H), 8.54 (1H). LC-MS (Method 3): m/z: [M+H]+ = 458, R1 = 1.01 min.

Step b: 2-[(3R)—3-methy|morpholin-4—yl]-4—(methylsulfonyl)(1H-pyrazoly|)-1,7-naphthyridine ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 2-[(3R)Methylmorpholiny|](methylsulfonyl)[1-(tetrahydro-2H-pyranyl)—1H-pyrazol yl]—1,7-naphthyridine (38 mg, 0.084 mmol, 1 eq.) was solubilised in CHZCIZ (1.5 mL) and H20 (1 mL). Formic acid was added (1 mL) and the reaction was stirred for 2h at rt. The mixture was then quenched with sat. NaHCOs and the aqueous phase was extracted three times with CHzClz. The organic phase was dried (silicon filter) and concentrated under d pressure. The crude e was purified by flash column chromatography (gradient from 100% hex to 100% EtOAc to EtOAc/EtOH 28/2). The d compound was obtained in 85% yield. 1H-NMR (400MHz, DMSO- d5): 6 [ppm]: 1.32 (3H), 3.36 - 3.46 (1H), 3.49 (3H), 3.57 (1H), 3.71 (1H), 3.84 (1H), 4.06 (1H), 4.17 (1H), 4.57 - 4.66 (1H), 7.37 (1H), 7.63 - 7.66 (1H), 7.88 (1H), 8.14 (1H), 8.49 (1H), 13.46 (1H). LC- MS (Method 3): m/z: [M+H]+ = 374, R1 = 0.81 min.

Example 34 2-(morpho|inyl)(1H-pyrazo|y|)-[1,7]naphthyridinecarbonitrile Step a: 2-(mo rpho|iny|)[2-(tetrahyd ropyran-Z-yl)-2H—pyrazo|y|]-[1,7]naphthyridine carbonitrile Under argon, 34 mg (0.029 mmol) of tetrakis(triphenylphosphine)palladium(0) were added to a suspension of 500 mg (0.97 mmol) of 2—(morpholinyl)—8-[2-(tetrahydropyran-Z-yl)—2H-pyrazol D—[1,7]naphthyridin—4-y| trifluoromethanesuIphonate and 43 mg (0.37 mmol) of zinc cyanide in [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ml of absolute dimethylformamide. The reaction mixture was stirred at 130°C for 1 h. 30 ml of sodium bicarbonate solution were added to the mixture. The aqueous phase was ted three times with in each case 40 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then concentrated to dryness. The residue was triturated with 10 ml of ethyl e, filtered off and then dried. This gave 260 mg (68% of theory) of 2-(morpholinyI)[2- (tetrahydropyran-Z-yl)-2H-pyrazo|y|]—[1,7]naphthyridinecarbonitrile as a colourless solid. LC- MS (method 1): m/z: [M+H]+ = 391.3, R1 = 3.44 min.

Step b: pho|in-4—yl)(1H-pyrazo|y|)-[1,7]naphthyridine-4—carbonitrile \ N A drop of water and 2 ml (26 mmol) of trifluoroacetic acid were added to 100 mg (0.26 mmol) of 2-(morpholin—4-yl)[2-(tetrahydropyran-Z-yl)-2H-pyrazo|y|]—[1,7]naphthyridinecarbonitrile.

After 16 h, LCMS showed complete removal of the protective group. The trifluoroacetic acid was distilled off under reduced pressure and the e that remained was ed to pH 7 using sodium bicarbonate solution. The aqueous phase was extracted three times with in each case ml of dichloromethane. The combined organic phases were dried over sodium te and then concentrated to dryness. The residue was triturated with 5 ml of form, filtered off and then dried. This gave 30 mg (38% of theory) of 2-morpholinyI(1H—pyrazoI—3-y|)- [1,7]naphthyridine—4—carbonitrile as a yellow solid. mp. 256—258°C. 1H NMR (400MHz, DMSO): 6 [ppm] = 3.79 (8H), 7.36 (1H), 7.65-7.66 (1H), 7.68-7.69 (1H), 8.28 (1H), 8.49-8.51 (1H), 13.42 (1H). LC-MS (method 1): m/z: [M+H]’r = 306.1, R1 = 2.93 min.

Example 35 2-((R)methy|morpho|iny|)(-2H-pyrazo|y|]-[1,7]naphthyridinecarbonitrile Step a: D((R)methylmorpholin-4—yl)[2-(tetrahyd ropyran-Z-yl)-2H—pyrazo|y|]-[1,7]naphthyridine- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 4-carbonitrile Under argon, 4mg (0.004 mmol) of tetrakis(triphenylphosphine)palladium(0) were added to a sion of 60 mg (0.114 mmol) of 2—((R)—3—methylmorpholin—4—yl)-8—[2—(tetrahydropyran—Z—yl)— 2H-pyrazol-3—yl]—[1,7]naphthyridinyl oromethanesulphonate and 14 mg (0.114 mmol) of zinc cyanide in 2 ml of absolute dimethylformamide. The reaction mixture was stirred at 100°C for min. For work-up, a mixture of 25 ml of water and 25 ml of 50 percent strength ammonia solution was added to the mixture. The precipitated solid was filtered off with n and washed with 10 ml of water. The solid was then dried under reduced pressure. 35 mg (76% of theory) of 2methylmorpholinyl)[2-(tetrahydropyranyl)-2H-pyrazoly|]-[1,7]naphthyridine carbonitrile were obtained as a yellow solid. LC-MS (method 1): m/z: [M+H]+ = 405.3, R1 = 3.53 min.

Step b: methy|morpho|iny|)(-2H-pyrazo|y|]-[1,7]naphthyridinecarbonitrile 1 ml (2 mmol) of 2N hydrochloric acid was added to a solution of 35 mg (0.087 mmol) of 2—((R) methylmorpholinyl)—8-[2-(tetrahydropyran-Z—yl)-2H-pyrazolyl]—[1,7]naphthyridine carbonitrile in 2 ml of methanol. The solution was stirred at 50°C for 18 h. After 18 h, LCMS showed complete removal of the protective group. Methanol was distilled off under reduced Eressure and the residue that remained was adjusted to pH 7 using sodium onate solution.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp A solid precipitated out; this was separated off and washed with 10 ml of water. The solid was then dried under reduced pressure. This gave 18 mg (58% of theory) of 2-((R)methy|morpho|in- 4-yl)(-2H-pyrazo|yl]-[1,7]naphthyridinecarbonitrile as a yellow solid. LC-MS (method 1): m/z: [M+H]+ = 321.2, Rt = 3.08 min.

Example 36 holinyl(1H—pyrazolyl)—[1,7]naphthyridinecarboxamide Step a: Z-morpholinyl[2-(tetrahyd ropyran-Z-yl)-2H—pyrazolyl]-[1,7]naphthyridine carboxamide 47 mg (0.85 mmol) of potassium hydroxide in a drop of water were added to a suspension of 300 mg (0.77 mmol) of 2-(morpholin—4-yl)-8—[2—(tetrahydropyranyl)-2H-pyrazo|—3-y|]- [1,7]naphthyridine-4—carbonitrile in 15 ml of isopropanol, and the mixture was stirred at 70°C for 6h. The solvent was distilled off and the residue was used without further purification for protective group removal. This gave holinyl—8—[2-(tetrahydropyrany|)—2H-pyrazo|—3- y|]—[1,7]naphthyridine—4-carboxamide as a yellow solid in a yield of 314 mg (100% of theory). LC- MS (method 1): m/z: [M+H]+ = 409.3, Rt = 2.62 min.

Step b: Z-morpholinyl(1H—pyrazolyl)—[1,7]naphthyridinecarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp \ /N o’ ‘N / \ / \_/ — A drop of water and 1 ml (13 mmol) of oroacetic acid were added to 95 mg (0.23 mmol) of 2- (morpholin-4—yl)[2—(tetrahydropyran—2-yl)-2H—pyrazo|—3-y|]—[1,7]naphthyridine-4—carboxamide.

After 2 h, LCMS showed complete removal of the protective group. The trifluoroacetic acid was distilled off under d pressure and the residue that remained was adjusted to pH 7 using sodium bicarbonate solution. The precipitated solid was filtered ofic with suction and dried. The product was chromatographed [silica gel 60 (12 g, 30 um); form/methanol (1:1, 300 ml)].

This gave 20 mg (25% of theory) of 2—(morpholiny|)—8-(1H—pyrazoI-3—yl)—[1,7]naphthyridine carboxamide as a yellow solid. m.p.282-285°C.1H NMR (400 MHz, DMSO, 6 ppm): 3.79 (8H), 7.36 (1H), 7.61 (2H), 7.83—7.84 (1H), 7.89 (1H), 8.23 (1H), 8.37—8.39 (1H), 13.36 (1H).

Example 37 4-methanesulphonylmethyl-Z-morpholinyl(2H—pyrazo|y|)-[1,7]naphthyridine Step 3: potassium 2-(morpholiny|)[1-(tetrahydro-ZH—pyran-Z-yl)-1H-pyrazo|y|]-1,7- naphthyridine-4—carboxylate 3.3 g (8.45 mmol) of 2—(morpholin-4—yl)—8—[2-(tetrahydropyran—2—yl)—2H—pyrazo|—3—yl]—[1,7]— naphthyridinecarbonitrile were ded in 33 ml of 2-methoxyethanol, 1.4g (25.4 mmol) of Utassium hydroxide in 772 pl of water were added and the mixture was stirred at 150°C for 7 h. ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Since conversion was still incomplete, the mixture was d at 130°C for a further 14 h. For work-up, most of the t was removed. The residue was triturated with 10 ml of panol and 50 ml of diethyl ether. The resulting precipitated yellow solid was filtered off and dried under reduced pressure. This gave 2.74 g (72% of theory) of potassium 2-(morpholinyl)—8-[1- (tetrahydro-2H-pyranyl)-1H-pyrazoly|]-1,7-naphthyridinecarboxylate as a yellow solid. LC- MS (method 1): m/z: [M+H]+ = 410.3, Rt = 3.03 min.

Step b: methyl 2-(morpholiny|)[2-(tetrahydropyran-Z-y|)-2H-pyrazolyl]-[1,7]naphthyridine carboxylate 630 mg (1.41 mmol) of potassium 2—(morpholin—4-yl)-8—[1-(tetrahydro-2H—pyran—2—yl)-1H—pyrazo|— -yl]—[1,7]naphthyridinecarboxylate were suspended in 10 ml of tetrahydrofuran, 459 mg (1.41 mmol) of caesium ate and 102 pl (1.69 mmol) of methyl iodide were added and the mixture was stirred at 80°C for 32 h. For work—up, most of the solvent was d. 20 ml of water were added to the residue, and the mixture was extracted three times with in each case ml of chloroform. The combined organic phases were dried over sodium sulphate and then concentrated to dryness. This gave 405 mg (68% of theory) of methyl 2-(morpholinyI)—8-[2- (tetrahydropyranyl)—2H-pyrazolyl]—[1,7]naphthyridinecarboxylate as a yellow solid. LC-MS (method 1): m/z: [M+H]+ = 424.4, Rt = 3.50 min.

Step c: {2-(morpholin-4—yl)—8-[1-(tetrahyd ro-ZH-pyran-Z-y|)-1H-pyrazo|y|]-1,7-naphthyridine-4— y|}methano| ation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp At 0°C and under an atmosphere of argon, 178 mg (4.68 mmol) of lithium aluminium hydride were added to a solution of 660 mg (1.56 mmol) of methyl 2-(morpholinyl)—8-[2- (tetrahydropyran—Z-yl)—2H—pyrazol-3—y|]-[1,7]naphthyridine—4-carboxylate in 16 ml of absolute ydrofuran, and the mixture was stirred at 0°C for 30 min. With ice-cooling, 20 ml of saturated ammonium chloride solution were added to the reaction mixture, and the mixture was then extracted three times with in each case 30 ml of chloroform. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. This gave 570 mg (93% of theory) of {2-(morpholinyl)[1-(tetrahydro-ZH-pyran-Z-yl)-1H-pyrazolyl]-1,7- naphthyridineyl}methanol as a crude product. The latter consisted of two compounds.

According to 1H NMR um, this crude product contained 30% of {2-(morpholinyl)—8—[1- (tetrahydro-ZH-pyran—Z-yl)-1H—pyrazoI—S-yl]-1,7—naphthyridine-4—y|}methano| and 70% of a compound having 2 extra mass units. It was not possible to separate the two products by chromatography, and therefore they were used as crude product in the next step. LC-MS (method 1): m/z: [M+H]+ = 396.3, Rt = 2.95 min.

Step d: 2-(mo ny|)[2-(tetrahyd ropyran-Z-yl)-2H—pyrazo|y|]-[1,7]naphthyridineylmethyl methanesulphonate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under argon and at 10°C, 56 ul (0.72 mmol) of methanesulphonyl chloride were added dropwise to a solution of 260mg (0.66 mmol) of {2-(morpholin—4-yl)[1-(tetrahydro-2H—pyranyl)-1H- pyrazolyl]—1,7-naphthyridine—4-yl}methanol and 119 pl (0.86 mmol) of ylamine in 10 ml of absolute tetrahydrofuran, and the mixture was stirred at 10°C for 1 h. The precipitated solid was filtered off and the filtrate was concentrated under reduced pressure. This gave 311 mg (100% of theory) of 2-(morpholinyl)[2-(tetrahydropyrany|)-2H-pyrazolyl]-[1,7]naphthyridine ylmethyl methanesulphonate as a brown solid. This crude product was used t further purification for the next sis. LC-MS (method 1): m/z: [M+H]+ = 474.3, Rt = 3.24 min.

Step e: 4-methanesulphonylmethyl-Z-(morpholinyl-)8-[2-(tetrahyd ropyranyl)-2H-pyrazolyl]- [1,7]naphthyridine Sodium methylsulphinate was added a little at a time to a on of 311 mg (0.66 mmol) of 2- (morpholin—4—yl)[2—(tetrahydropyran—2-yl)-2H—pyrazol—3—yl]-[1,7]naphthyridine—4—ylmethyl methanesulphonate in 10 ml of absolute dimethyl sulphoxide, and the mixture was then stirred at dO‘T for 20 min. The mixture was diluted with 10 ml of water and then extracted three times [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp with in each case 10 ml of dichloromethane. The combined c solutions were dried over sodium sulphate and then trated under reduced pressure. The e was chromatographed [Puri-Flash, silica gel 60 (25 g, 30 um); dichloromethane/methanol 95:5]. This gave 80 mg (27% of theory) of 4-methanesulphonylmethyl-Z-(morpholinyl-)8-[2- (tetrahydropyran-Z-yl)-2H-pyrazolyl]-[1,7]naphthyridine as a yellow solid. LC-MS (method 1): m/z: [M+H]+= 458.3, R1 = 2.89 min.

Step f: 4-methanesulphonylmethyl-Z-morpholinyl(2H—pyrazo|y|)-[1,7]naphthyridine mg (0.07 mmol) of 4-methanesulphonylmethyl(morpholiny|-)8-[2—(tetrahydropyran—Z-yl)- 2H-pyrazol—3—yI]-[1,7]naphthyridine were dissolved in 1 ml of methanol, and 0.5 ml (1 mmol) of 2N hydrochloric acid was added. After 1 h, LCMS showed complete removal of the protective group. Methanol was distilled off under reduced pressure and the residue that remained was adjusted to pH 7 using sodium onate solution. The resulting precipitated solid was filtered off and dried under reduced pressure. This gave 24 mg (98% of theory) of 4- methanesu|phonylmethyl-Z-morpholin—4-yl(2H-pyrazo|—3-yl)-[1,7]naphthyridine as a yellow solid. mp. 272-274°C. 1H NMR (400 MHz, DMSO): 6 [ppm] = 3.10 (3H), 3.74-3.81 (8H), 5.00 (2H), 7.36 (1H), 7.64 (2H), 7.94 (1H), 8.40 (3H), 13.31 (1H).

Example 38 [2-(morpholin-4—yl)(2H—pyrazo|y|)-[1,7]naphthyridine-4—yl]methanol [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 50 mg (0.126 mmol) of [2-(morpholin—4-y|)[1-(tetrahydro-2H-pyrany|)-1H-pyrazo|yl]-1,7- naphthyridine—4-yl}methanol were dissolved in 1 ml of methanol, and 0.5 ml (1 mmol) of 2N hydrochloric acid was added. After 1 h, LCMS showed complete removal of the protective group.

Methanol was distilled off under reduced pressure and the residue that remained was adjusted to pH 7 using sodium bicarbonate solution. The aqueous phase was extracted three times with in each case 10 ml of dichloromethane. The combined organic phases were dried over sodium te and concentrated under reduced pressure. The residue was purified using a Flashmaster chromatography [silica gel 60 (25 g, 30 um); dichloromethane/methanol 95:5]. This gave 20 mg (51% of theory) of rpholinyl)(2H-pyrazo|—3-yl)-[1,7]—naphthyridineyl]methanol as a yellow solid. 1H NMR (400 MHz, DMSO): 6 [ppm] =3.81 (8H), 4.95 (2H), 7.47-7.48 (1H), 7.68 (1H), 7.89-7.92 (2H), 8.35-8.36 (1H), 13.31 (1H). LC-MS (method 1): m/z: [M+H]+ = 312.2, R = 2.31 min.

Example 39 4-(1-methanesulphonylcyclopropyl)(morpholinyl)(2H—pyrazo|y|)-[1,7]naphthyridine Step 3: ethanesulphonylcyclopropyl)(morpholin-4—yl)[2-(tetrahyd ropyran-Z-yl)—2H—pyrazo|- 3-yl)-[1,7]naphthyridine I 0 D0 pl of 50 percent strength sodium hydroxide solution were added to a solution of 150 mg [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (0.328 mmol) of 4—methanesu|phonylmethyl—2—(morpholin-4—yl)—8—[2—(tetrahydropyran—Z—yl)—2H— pyrazolyl]—[1,7]naphthyridine, 28 ul (0.319 mmol) of bromoethane and 10 mg (0.032 mmol) of tetrabutylammonium bromide in 960 pl of absolute tetrahydrofuran, and the mixture was then stirred at room temperature for 1 h. The colour of the suspension changed from dark-green to rown. Another 28 ul (0.319 mmol) of 1,2-dibromoethane, 10 mg (0.032 mmol) of tetrabutylammonium bromide and 330 pl of 50 percent strength sodium hydroxide solution were added, and the mixture was stirred at 60°C for 3 h. The mixture was diluted with 10 ml of water and then extracted three times with in each case 10 ml of dichloromethane. The ed organic phases were dried over sodium te and concentrated under reduced pressure. The residue was purified twice by column chromatography on a Flashmaster [silica gel 60 (2 x25 g, 30 um), dichloromethane/methanol 95:5]. This gave 23 mg (15% of theory) of 4—(1—methanesuIphonylcyclopropyl)—2-(morpho|iny|)—8—[2- (tetrahydropyran-Z-yl)-2H-pyrazoly|)—[1,7]naphthyridine as a yellow solid. The solid, which was , was used without further purification for the next step. LC—MS (method 1): m/z: [M+H]+ = 484.2, Rt = 2.75 min.

Step b: 4—(1—methanesulphonylcyclopropyl)—2-(morpho|iny|)-8—(2H-pyrazo|y|)-[1,7]naphthyridine 0.5 ml of (1 mmol) of 2N hydrochloric acid was added to a solution of 23 mg (0.048 mmol) of 4-(1- methanesu|phonylcyclopropyl)—2-(morpho|in-4—yl)[2—(tetrahydropyran—Z—yl)-2H—pyrazo|—3—yl)]— [1,7]naphthyridine in 1 ml of methanol. The solution was stirred at 50°C for 18 h. After 18 h, LCMS showed complete removal of the protective group. Methanol was distilled off under reduced pressure and the residue that remained was ed to pH 7 using sodium bicarbonate solution.

The aqueous phase was extracted three times with in each case 10 ml of dichloromethane. The ed organic phases were dried over sodium sulphate and concentrated under reduced flessure. This gave 18 mg (85% of theory) of 4—(1—methanesulphonylcyclopropyl)—2—(morpholin [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp yl)—8—(2H—pyrazol-3—y|)—[1,7]—naphthyridine as a yellow solid. mp. 220—234°C. 1H NMR (400 MHZ, DMSO): 6 [ppm] =1.39-2.09 (4H), 3.06 (3H), 3.79-3.80 (8H), 7.36 (1H), 7.61 (1H), 7.82-7.88 (2H), 8.39-8.41(1H), 13.36 (1H). LC-MS (method 1): m/z: [M+H]+ = , R. = 2.21 min.

Example 40 ropoxy—2-(morpholin-4—yl)(1H-pyrazo|y|)-[1,7]naphthyridine Step a: 4-isopropoxy(morpholin-4—yl)[2-(tetra hydropyran-Z-yl)—2H—pyrazolyl]-[1,7]naphthyridin 44 mg (0.31 mmol) of ium carbonate were added to a solution of 100 mg (0.26 mmol) of 2— (morpholin-4—yl)[2-(tetrahydropyranyl)-2H-pyrazo|y|]-[1,7]naphthyridino| and 45 mg (0.26 mmol) of iodopropane in 6 ml of dry acetonitrile (MeCN). The suspension was stirred at 85°C for 7 h. The course of the reaction was monitored by LCMS. The solvent was removed and the e that remained was chromatographed [silica gel 60 (12 g, 30 pm); ethyl acetate (100 ml)].

This gave 90 mg (81% of theory) of 4-isopropoxy(morpholinyl)(1H-pyrazo|—3-y|)- [1,7]naphthyridine as a yellow oil. LC—MS (method 1): m/z: [M+H]*= 424.3, Rt = 3.66 min.

Step b: 4—isopropoxy—2-(morpholin-4—yl)(1H-pyrazo|y|)-[1,7]naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to 80 mg (0.19 mmol) of 4- isopropoxy-Z—(morpholiny|)—8-(1H-pyrazoIyI)-[1,7]naphthyridine. After 10 min, LCMS showed complete removal of the protective group. The trifluoroacetic acid was d under reduced pressure and the residue that remained was adjusted to pH 7 using sodium bicarbonate solution.

The aqueous phase was ted three times with in each case 20 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then concentrated to dryness. The e was chromatographed [silica gel 60 (12 g, 30 um); ethyl acetate (100 ml)]. This gave 40 mg (59% of theory) of 4—isopropoxy(morpholin—4-yl)-8—(1H-pyrazo|y|)—[1,7]naphthyridine as a yellow foam. m.p. C. 1H NMR (400 MHz, CDCI3, 6 ppm): 1.48 (6H), 3.64-3.67 (4H), 3.89-3.92 (4H), 4.75—4.78 (1H), 6.37 (1H), 7.23 (1H), 7.67 (1H), 7.71 (1H), 8.38 (1H). LC-MS (method 1): m/z: [M+H]+ = 340.3, Rt = 2.95 min.

Example 41 2-(mo rpholin-4—yl)-4—(propanyloxy)(1H-pyrro|y|)-1,7-naphthyridine Step a: tert-butyl 2-[2-(morpho|in-4—yl)-4—(propan-Z-yloxy)-1,7-naphthyridiny|]-1H-pyrrole carboxylate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under argon, 20 mg (0.024 mmol) [1,1’-bis(dipheny|phosphino)ferrocene]dichloropal|adium(||) were added to a mixture of 75 mg (0.24 mmol) 8—chloro(morpholin-4—yl)(propanyloxy)- 1,7—naphthyridine and 57 mg (0.27 mmol) [1—(tert-butoxycarbonyl)-1H-pyrrolyl]boronic acid in 2 ml acetonitrile and 2 ml 2M s solution of potassium carbonate. The e was stirred in a microwave oven at 130 °C for 10 s. After g, DCM was added and the mixture was filtered using a Whatman filter. The organic phase was concentrated and the residue was purified by HPLC separation (Autopurifier: basic conditions) to give 35 mg (0.08 mmol) of the desired product. 1H-NMR (400 MHz, DMSO-d6): 6 [ppm] = 0.92 (9H), 1.37 (6H), 3.52 (4H), 3.63 (4H), 5.05 (1H), 6.29 (1H), 6.39 (1H), 6.76 (1H), 7.37 (1H), 7.63 (1H), 8.20 (1H).

Step b: 2-(mo rpholin-4—yl)-4—(propanyloxy)—8-(1H-pyrro|y|)-1,7-naphthyridine 7 ul (0.096 mmol) TFA were added to a solution of 9 mg (0.020 mmol) tert-butyl 2-[2-(morpholin- 4-yl)(propany|oxy)-1,7-naphthyridin-S-yl]-1H-pyrro|ecarboxylate in 2 ml DCM and the reaction mixture was stirred at room temperature for 150 minutes. Additional 7 (4] (0.096 mmol) TFA was added and the reaction mixture was stirred overnight. Additional 23 ul (0.32 mmol) TFA Das added and the reaction mixture was stirred for 8 hours. The e was basified by addition [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp of aqueous sodium bicarbonate solution and extracted with DCM (2x). The ed organic phases were filtered using a Whatman filter and concentrated to give 9 mg (0.027 mmol) of the desired product. 1H-NMR (400 MHz, CDCls): 5 [ppm] = 1.50 (6H), 3.70 (4H), 3.96 (4H), 4.80 (1H), 6.41 (2H), 7.03 (1H), 7.48 (1H), 7.61 (1H), 8.31 (1H), 11.53 (1H).

Example 42 4-[3-(S-methylsulfonimidoyl)propoxy](morpholin-4—yl)(1H-pyrazolyl)-1,7-naphthyridine Step a: 2,2,2—trifluoro-N-[(3-hydroxypropyl)(methyl)oxido-Ae-sulfanylidene]acetamide \\ z/N HOWS\ A mixture of 1.00 g (2.83 mmol) N—[{3-[(benzyloxy)methoxy]propy|}(methyl)oxido-?\6- sulfanylidene]—2,2,2—trifluoroacetamide and 0.75 g palladium on al (10%) in 100 ml ethanol was stirred under a hydrogen atmosphere for 90 minutes at 80°C. 0.50 g palladium on charcoal (10%) are added and the mixture is stirred for additional 3 hours under a hydrogen atmosphere at 80°C. After cooling, the reaction e was filtered and the filtrate was concentrated to give 0.61 g of the d product that was used without further purification. 1H—NMR (400 MHZ, : 6 [ppm] = 2.18 (2H), 3.41 (3H), 3.61 (1H), 3.72 (1H), 3.86 (2H).

Step b: 2,2,2-trifluoro-N-{methyl[3-({2-(morpholinyl)[1-(tetrahyd ro-2H-pyran-Z-yl)-1H-pyrazol y|]-1,7-naphthyridin-4—y|}oxy)propyl]oxido-Ae-sulfanylidene}acetamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 26 ul (0.13 mmol) diisopropyl azodicarboxylate in 0.1 ml THF was added dropwise to a mixture of 50 mg (0.13 mmol) 2-(morpholin-4—yl)[1—(tetrahydro-2H-pyrany|)—1H-pyrazo|—5- yl]—1,7-naphthyridin-4—o|, 28 mg crude 2,2,2-trifluoro-N-[(3—hydroxypropyl)(methyl)oxido-}\6- sulfanylidene]acetamide and 34 mg (0.13 mmol) triphenylphosphine in 0.5 ml THF and the batch was stirred at room ature for 6 hours. 94 mg (0.36 mmol) triphenylphosphine and 71 ul (0.36 mmol) ropyl azodicarboxylate were added and the mixture was stirred at room temperature overnight. Finally, 34 mg (0.13 mmol) triphenylphosphine and 26 ul (0.13 mmol) diisopropyl azodicarboxylate were added and the mixture was stirred for 6 hours before it was concentrated. The residue was purified by column chromatography on silica gel (DCM to DCM / ethanol 15%) to give 34 mg of the product with approximately 70% purity.

Step c: 4-[3-(S-methylsulfonimidoyl)propoxy](morpholin-4—yl)—8-[1-(tetrahydro-ZH-pyran-Z-yl)—1H- pyrazolyl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ,—\ N o / \ / \_/ — HC/S\" 3 NH 39 mg (0.29 mmol) potassium carbonate was added to a solution of 34 mg 2,2,2-trifluoro-N- {methyl[3—({2—(morpholin-4—yl)—8—[1—(tetrahydro—ZH-pyran—Z-yl)—1H—pyrazol—S—yl]—1,7—naphthyridin— 4-yl}oxy)propyl]oxido-7\6-sulfanylidene}acetamide (purity approximately 70%) in 1.2 ml methanol and the reaction mixture was stirred at room temperature for 90 minutes. Aqueous sodium chloride on was added and the mixture was extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated to give 27 mg of the desired product with a purity of approximately 66%.

Step d: 4-[3-(S-methylsulfonimidoyl)propoxy](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 0.06 ml (0.12 mmol) 2N s solution of hydrogen chloride was added to a on of 27 mg 4-[3—(S-methylsulfonimidoyl)propoxy]—2—(morpholiny|)—8-[1-(tetrahydro—ZH-pyran—Z-yl)-1H— pyrazolyl]—1,7-naphthyridine y approximately 66%) in 0.25 ml methanol and the reaction [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp mixture was stirred at room ature for 1 hour. The mixture was basified by addition of an aqueous sodium bicarbonate solution and extracted with ethyl e (2x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preperative HPLC (Autopurifier: acidic conditions) to give 3 mg (0.007 mmol) of the desired product. 1H-NMR (400 MHz, DMSO-d6): 6 [ppm] = 2.32 (2H), 2.99 (3H), 3.31 (2H), 3.75 (4H), 3.80 (4H), 4.41 (2H), 6.90 (1H), 7.38 (1H), 7.62 (1H), 7.81 (1H), 8.35 (1H), 13.37 (1H). e 43 4-ethoxy(morpholin-4—yl)(1H—pyrazolyl)-[1,7]naphthyridine Step a: 4—eth oxy(morpholiny|)[2-(tetrahydropyran-Z-yl)-2H—pyrazo|y|]-[1,7]naphthyridine 44 mg (0.31 mmol) of ium carbonate were added to a solution of 100 mg (0.26 mmol) of 2- (morpholinyl)[2-(tetrahydropyranyl)-2H-pyrazoly|]-[1,7]naphthyridinol and 21 ul (0.26 mmol) of iodoethane in 6 ml of dry acetonitrile . The suspension was stirred at 85°C for 2 h. The course of the reaction was monitored by LCMS. The solvent was removed and the residue that remained was reacted further without purification. LC—MS (method 1): m/z: [M+H]+ = 410.3, Rt = 3.53 min.

Step b: 4—eth oxy(morpholin-4—yl)-8—(1H—pyrazo|y|)-[1,7]naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp One drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to 107 mg (0.26 mmol) of 4-ethoxy(morpholin-4—yl)[2—(tetrahydropyran—2-yl)-2H—pyrazo|—3—yl]-[1,7]naphthyridine.

After 1 h, LCMS showed complete removal of the protective group. The trifluoroacetic acid was removed under reduced pressure and the residue that remained was adjusted to pH 7 using sodium bicarbonate solution. The aqueous phase was extracted three times with in each case ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then concentrated to dryness. 5 ml of methanol were added to the e. The ing precipitated solid was filtered off and then dried. This gave 25 mg (29% of theory) of 4-ethoxy (morpholin-4—yl)-8—(1H-pyrazol—3-yl)-[1,7]naphthyridine as a yellow solid. mp. 173-175°C. 1H NMR (400 MHz, CDCI3, 6 ppm): .61 (3H), 3.70—3.72 (4H), 3.92-3.95 (4H), .27 (2H), 6.41 (1H), 7.25 (2H), 7.70 (1H), 7.75 (1H), 8.42 (1H). LC-MS (method 1): m/z: [M+H]+ = 326.3, R1 = 2.81 min.

Example 44 4-methoxy(morpholin-4—y|)(1H-pyrazo|y|)-[1,7]naphthyridine Step 3: 4—methoxy(morpholin-4—yl)[2-(tetra hyd ny|)-2H-pyrazolyl]-[1,7]naphthyridine o’ ‘N / \ / \_/ — D mg (0.31 mmol) of potassium carbonate were added to a solution of 100 mg (0.26 mmol) of 2- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (morpholin—4—yl)-8—[2—(tetrahydropyran—2—yl)—2H—pyrazol—3—yl]-[1,7]naphthyridin—4—ol and 32 ul (0.26 mmol) of methyl iodide in 6 ml of dry acetonitrile. The suspension was stirred at 85°C for 2 h. The course of the reaction was monitored by LCMS. The solvent was removed and the residue that remained was reacted further without purification. LC-MS d 1): m/z: [M+H]+= 396.3, R1 = 3.33 min.

Step b: 4—methoxy(morpholin-4—yl)(1H-pyrazo|y|)-[1,7]naphthyridine A drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to 103 mg (0.26 mmol) of 4-methoxy-2—(morpholiny|)[2-(tetrahydropyrany|)-2H—pyrazo|—3-y|]—[1,7]naphthyridine.

After 10 min, LCMS showed complete removal of the protective group. The trifluoroacetic acid was removed under reduced re and the residue that ed was adjusted to pH 7 using sodium bicarbonate solution. The aqueous phase was extracted three times with in each case 20 ml of dichloromethane. The combined organic phases were dried over sodium te and then concentrated to s. The residue was triturated with 5 ml of methanol. The resulting precipitated solid was filtered off and then dried. This gave 30 mg (35% of theory) of 4-methoxy- 2-(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine as a yellow solid. mp 234-235°C. 1H NMR (400 MHz, CDCI3, 6 ppm): 3.67-3.69 (4H), 3.91-3.93 (4H), 4.01 (3H), 6.36 (1H), 7.25 (1H), 7.68 (2H), 8.40 (1H). LC-MS (method 1): m/z: [M+H]’r = 312.3, R1 = 2.60 min.

Example 45 2-methyl{[2-(morpholin-4—yl)—8-(1H-pyrazo|y|)-1,7-naphthyridin-4—yl]oxy}propano| Step a: 2-methyl({2-(morpho|inyl)[1-(tetrahyd ro-ZH-pyran-Z-yl)-1H-pyrazo|y|]-1,7- naphthyridin-4—yl}oxy)propano| [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 87 mg (0.63 mmol) potassium carbonate was added to a mixture of 60 mg (0.16 mmol) 2- (morpholin-4—yl)[1—(tetrahydro-2H-pyran-Z-yl)—1H-pyrazo|y|]—1,7-naphthyridin—4-ol and 102 mg (0.94 mmol) 1-chloromethylpropan-Z-ol in 5.0 ml ethanol and 0.5 ml water and the mixture was stirred at 70°C for 20 hours. 51 mg (0.47 mmol) 1-chloro—2-methylpropan-2—ol and 44 mg (0.32 mmol) potassium carbonate were added and the mixture was stirred for additional 24 hours at 70°C. After cooling, the on mixture was diluted with water and extracted with DCM (2x).

The combined organic phases were dried (MgSO4), filtered and concentrated. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 17 mg (0.04 mmol) of the desired product.

Step b: 2-methyl-1—{[2-(morpholinyl)(1H-pyrazo|y|)-1,7-naphthyridinyl]oxy}propano| S Example 47 3-{[2-(morpholin-4—yl)(1H-pyrazo|y|)-1,7-naphthyridinyl]oxy}dihydrofuran-2(3H)-one [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A mixture of 2-(morpholinyl)[1-(tetrahydro-2H-pyranyl)-1H-pyrazolyl]-1,7- naphthyridinol (242 mg, 0.40 mmol), 3-bromodihydrofuran-2(3H)-one (99 mg, 0.60 mmol) and Caesiumcarbonate (169 mg, 0.52 mmol) in DMF (2 ml) was heated in a sealed tube in the microwave at 100°C for one hour. The reaction mixture was allowed to cool to ambient temperature, a solution of concentrated aqueous HCI (0.49 ml) was added and the reaction was stirred at this temperature for two hours. The solvent was ated under reduced pressure, the residue was taken up in dichloromethane (10 ml) and water (10 ml). The layers were separated and the aqueous layer was ted with dichloromethane (2x10ml). The combined organic layers were dried over NaZSO4 and the solvent was removed under reduced re. The crude product was purified by HPLC chromatography (acidic conditions). The title compound was obtained in 4% yield (7 mg). 1H-NMR (400 MHz, DMSO): 6 [ppm] = 2.91-2.95 (1H), 3.67-3.80 (9H), 4.36 (1H), 4.55 (1H), 5.80 (1H), 7.08 (1H), 7.36 (1H), 7.61 (1H), 7.70 (1H), 8.34 (1H), 13.33 (1H).

Example 48 4-[(3-methyl-1,2-oxazo|yl)methoxy](morpholin-4—yl)(1H-pyrazolyl)—1,7-naphthyridine A e of 2-(morpholin—4-yl)[1-(tetrahydro-2H-pyranyl)-1H-pyrazolyl]-1,7-naphthy- ol (283 mg, 0.47 mmol), 5-(bromomethyl)methyl-1,2-oxazole (123 mg, 0.70 mmol) and [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Caesiumcarbonate (197 mg, 0.61 mmol) in DMF (1.78 ml) was heated in a sealed tube in the microwave at 100°C for one hour. The on mixture was allowed to cool to ambient temperature, a solution of concentrated aqueous HCI (0.7 ml) was added and the reaction was d at this temperature for two hours. The solvent was ated under d pressure, the residue was taken up in dichloromethane (10 ml) and water (10 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (2x10ml). The combined organic layers were dried over Na2504 and the solvent was removed under reduced pressure. The crude product was purified by HPLC chromatography (acidic conditions). The title compound was obtained in 3 % yield (6 mg). 1H-NMR (400 MHz, DMSO): 6 [ppm] = 2.27 (3H), 3.76 (8H), 5.57 (2H), 6.65 (1H), 7.06 (1H), 7.36 (1H), 7.61 (1H), 7.69 (1H), 8.32 (1H), 13.35 (1H).

Example 49 4-[(5-methyl-1,2-oxazolyl)methoxy](morpholin-4—yl)(1H-pyrazo|y|)-1,7-naphthyridine A mixture of 2-(morpholin—4-yl)[1-(tetrahydro-2H-pyrany|)-1H-pyrazolyl]-1,7- naphthyridin—4—ol (264 mg, 0.35 mmol), momethyl)-5—methyl—1,2—oxazole (91 mg, 0.51 mmol) and mcarbonate (147 mg, 0.45 mmol) in DMF (1.32 ml) was heated in a sealed tube in the microwave at 100°C for one hour. The reaction mixture was allowed to cool to ambient temperature, a on of concentrated aqueous HCI (0.51 ml) was added and the reaction was stirred at this temperature for two hours. The solvent was evaporated under reduced pressure, the residue was taken up in dichloromethane (10 ml) and water (10 ml). The layers were separated and the aqueous layer was ted with dichloromethane (2x10ml). The combined organic layers were dried over NaZSO4 and the solvent was removed under reduced pressure. The crude product was purified by HPLC chromatography (acidic conditions). The title compound was obtained in 10 mg yield. 1H-NMR (400 MHz, DMSO): 6 [ppm] = 2.46 (3H), 3.77 (8H), 5.49 (2H), 6.52 DH), 7.09 (1H), 7.39 (1H), 7.62 (1H), 7.72 (1H), 8.34 (1H), 13.38 (1H).

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 50 4-benzyloxy-Z-(morpholin-4—yl)(1H-pyrazo|y|)-[1,7]naphthyridine Step 3: yloxy(morpholin-4—y|)[2-(tetrahydropyran-Z-yl)—2H—pyrazolyl]-[1,7]naphthyridine 44 mg (0.31 mmol) of potassium carbonate were added to a solution of 100 mg (0.26 mmol) of 2- (morpholin-4—yl)[2-(tetrahydropyran—2-yl)-2H-pyrazo|—3-y|]—[1,7]naphthyridinol, 31 ul (0.26 mmol) of benzyl bromide and 4mg (0.024 mmol) of potassium iodide in 6ml of dry acetonitrile (MeCN). The suspension was stirred at 85°C for 2 h. The course of the on was monitored by LCMS. The solvent was removed and the residue that remained was chromatographed [silica gel 60 (12 g, 30 um); ethyl acetate (100 ml)]. This gave 90 mg (73% of theory) of 4-benzyloxy(morpholin—4-yl)-8—[2—(tetrahydropyranyl)-2H-pyrazo|—3-yl]— [1,7]naphthyridine as a yellow oil. LC-MS (method 1): m/z: [M+H]+= 472.3, R = 3.86 min.

Step b: 4—benzyloxy-Z-(morpholin-4—yl)(1H-pyrazo|y|)-[1,7]naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp N/N\/ o \_/ — A drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to 90 mg (0.19 mmol) of 4- benzyloxy-2—(morpholinyl)[2-(tetrahydropyrany|)—2H-pyrazolyl]—[1,7]naphthyridine.

After 10 min, LCMS showed complete removal of the protective group. The trifluoroacetic acid was removed under d pressure and the residue that remained was adjusted to pH 7 using sodium bicarbonate solution. The aqueous phase was extracted three times with in each case ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then concentrated to dryness. 5ml of methanol were added to the residue. The ing precipitated solid was filtered off and then dried. This gave 40 mg (54% of theory) of 4-benzyloxy- 2—(morpholin—4—yl)—8—(1H—pyrazol—3-y|)—[1,7]naphthyridine as a yellow solid. mp. 217—219°C. 1H NMR z, CDCI3, 6 ppm): 3.69-3.71 (t, 4H), 3.92-3.94 (t, 4H), 5.29 (s, 2H), 6.52 (s, 1H), 7.41—7.51 (m, 6H), 7.70 (d, 1H), 7.79 (d, 1H), 8.42 (d, 1H). LC-MS (method 1): m/z: [M+H]+= 388.3, Rt = 3.23 min.

Example 51 ropoxy-Z-((R)methy|mo rpho|iny|)(1H-pyrazo|y|)-[1,7] naphthyridine Step a: 4—isopropoxy—Z-((R)—3-methy|mo rpho|iny|)[2-(tetrahyd ropyrany|)-2H-pyrazoly|]- [1,7]naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 84 mg (0.61 mmol) of potassium ate were added to a solution of 200 mg (0.51 mmol) of 2—[(R)—3-methylmorpholin-4—yl)—8—[2-(tetrahydropyran—2—yl)—2H—pyrazol-3—yl]—[1,7]naphthyridin—4- o| and 101 pl (1.01 mmol) of iodopropane in 4 ml of dry acetonitrile. The suspension was stirred at 85°C for 3 h. The course of the reaction was monitored by LCMS. The solvent was removed and the residue that remained was chromatographed a gel 60 (25 g, 30 um); ethyl acetate (100 ml)]. This gave 60 mg (27% of theory) of 4—isopropoxy-2—((R)—3-methylmorpholin-4—yl)—8—[2— (tetrahydropyran-Z-yl)-2H-pyrazo|—3-y|]—[1,7]naphthyridine as a yellow oil. LCMS (method 1): m/z: [M+H]+ = 438.4, Rt = 3.73 min.

Step b: 4-isopropoxy—Z-((R)methy|mo rpho|iny|)(1H-pyrazo|y|)-[1,7]naphthyridine 80 mg (0.18 mmol) of 4-isopropoxy-2—((R)methy|morpholin-4—yl)[2—(tetrahydropyran—2-yl)- 2H—pyrazol—3—yl]—[1,7]naphthyridine were ved in 2 ml of methanol, and 2 ml (4 mmol) of 2N hydrochloric acid were added. After 1 h, LCMS showed complete removal of the protective group. l was distilled off under reduced pressure and the residue that remained was adjusted to pH 7 using sodium bicarbonate solution. The aqueous phase was extracted three times with in each case 20 ml of dichloromethane. The combined organic phases were dried over sodium ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp sulphate and then concentrated to dryness. The e was chromatographed [silica gel 60 (25 g, um); ethyl acetate (100 ml)]. This gave 45 mg (70% of theory) of 4-isopropoxy((R) methylmorpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine as a yellow solid. m.p. C. 1H NMR (400 MHz, CDCI3): 6 [ppm] = 1.38-1.41 (3H), 1.47-1.49 (6H), .51 (1H), 3.65-3.72 (1H), 3.81-3.91 (3H), 4.01-4.15 (1H), 4.30-4.33 (1H), 4,744.79 (1H), 6.37 (1H), 7.22 (1H), 7.67-7.68 (1H), .72 (1H), 8.36-8.37 (1H). LC-MS (method 1): m/z: [M+H]+ = 354.4, Rt = 2.92 min.

Example 52 tert—butyl [4-({2-[(3R)methylmorpholinyl](1H-pyrazo|yl)-1,7-naphthyridin yl}oxy)butyl]carba mate Step a: tert—butyl [4-({2-[(3R)methylmorpholiny|][1-(tetrahydro-ZH-pyran-Z-yl)-1H-pyrazol yl]-1,7-naphthyridin-4—y|}oxy)butyl]carbamate 2-[(3R)methy|morpholinyl]—8—[1-(tetrahydro-2H-pyranyl)-1H-pyrazo|y|]-1,7-naphthyri- din—4—ol (0.41 g, 1.0 mmol, 1 eq.) was lized in DMF (12 mL). 4—(Boc—amino)buty| bromide (0.53 g, 2.1 mmol, 2 eq.) and K2C03 (0.72 g, 5.2 mmol, 5 eq.) were added to the mixture. The reaction was stirred at rt for 16 hours. The suspension was diluted with EtOAc and filtered. The organic phase was concentrated under reduced pressure and the crude material purified by flash chromatography (gradient Hex/EtOAc 9/1 to 100% EtOAc). The desired product was obtained in 87% yield (0.52 g). 1H-NMR (400MHz, DMSO-de): 6 [ppm]: 1.14 - 1.24 (3H), 1.38 (9H), 1.41 - 1.69 DH), 1.80 - 1.90 (2H), 1.99 (2H), 2.30 - 2.42 (1H), 3.03 (2H), 3.10 - 3.29 (2H), 3.40 - 3.52 (1H), 3.73 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (3H), 3.91 - 3.99 (1H), 4.12 (1H), 4.27 (2H), 4.45 - 4.58 (1H), 6.01 - 6.13 (1H), 6.75 (1H), 6.84 - 6.95 (2H), 7.60 (1H), 7.75 (1H), 8.35 (1H). LC-MS (Method 3): m/z: [M+H]+ = 567, Rt = 1.31 min.

Step b: tert-butyl [4-({2-[(3R)methylmorpholinyl](1H-pyrazo|yl)-1,7-naphthyridin yl}oxy)butyl]carba mate 0 0 Tert-butyl [4-({2-[(3R)methylmorpholinyl][1-(tetrahydro-2H-pyranyl)-1H-pyrazol—5-yl]— 1,7-naphthyridinyl}oxy)butyl]carbamate (20 mg, 0.035 mmol, 1 eq.) was solubilized in CH2C|2 (0.5 mL) and water (0.5 mL). Acetic acid (0.12 mL, 1.8 mmol, 50 eq.) was added. After 2 hours, formic acid (0.10 mL, 2.6 mmol, 75 eq.) was added and the on was stirred at rt for 1 hour.

The reaction mixture was neutralised by addition of sat. NaHC03 and the aqueous phase was extracted 3 times with CHZCIZ. The organic phase was dried (silicon filter) and trated under reduced pressure. The crude mixture was purified by flash column chromatography (gradient 1/1 Hex/EtOAc to 100% EtOAc to 9/1 EtOAc/MeOH). The desired product was obtained in 68% yield (12 mg). 1H-NMR (400MHz, DMSO-de): 6 [ppm]: 1.20 - 1.30 (4H), 1.37 (9H), 1.57 - 1.67 (2H), 1.80 - 1.89 (2H), 3.03 (2H), 3.56 (1H), 3.71 (1H), 3.83 (1H), 4.05 (1H), 4.15 (1H), 4.27 (2H), 4.56 - 4.65 (1H), 6.81 (1H), 6.89 (1H), 7.37 (1H), 7.60 (1H), 7.71 (1H), 8.32 (1H), 13.37 (1H). LC-MS d 3): m/z: [M+H]+ = 483, R1 = 0.98 min.

Example 53 4-methoxy-Z-((R)methy|morpho|iny|)(1H-pyrazolyl)—[1,7]naphthyridine Step a: [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 8-chloro-4—methoxy-Z-((R)methy|morpholin-4—y|)-[1,7]naphthyridine 320 mg (2.32 mmol) of potassium carbonate were added to a on of 540 mg (1.93 mmol) of 8—chloro-2—((R)—3-methylmorpholin-4—y|)—[1,7]naphthyridin—4-ol and 144 pl (2.32 mmol) of iodomethane in 10 ml of acetonitrile. The suspension was stirred at 80°C for 5 h. For work-up, ml of water were added to the e. The aqueous phase was extracted three times with in each case 30 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then concentrated to dryness. The crude product was separated by column chromatography [Puri-Flash, silica gel 60 (25 g, 30 um); ethyl acetate (200 ml)]. This gave 270 mg (48%) of 8—chloromethoxy((R)methylmorpholinyl)-[1,7]naphthyridine as a yellow oil.

LCMS (method 1): m/z: [M+H]+= 294.3, Rt = 3.43 min.

Step b: 4-methoxy((R)methy|morpho|iny|)[2-(tetrahyd ropyran-Z-yl)—2H—pyrazo|y|]- [1,7]naphthyridine Under argon, 145 mg (0.18 mmol) of bis(diphenylphosphino)ferrocene]dichloropalladium(||) complex with dichloromethane (1:1) and 1.15 g (3.54 mmol) of caesium carbonate were added to a suspension of 260 mg (0.89 mmol) of 8—ch|oro-4—methoxy—2-((R)—3—methylmorpholin—4-yl)- [1,7]naphthyridine and 369 mg (1.33 mmol) of 1—(tetrahydropyranyl)—5-(4,4,5,5-tetramethy|— ]dioxaborolane—2-yl)-1H—pyrazole in 12 ml of absolute 1,4-dioxane. The reaction mixture was stirred at 95°C for 6h. The brown reaction solution was purified via column chromatography ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [silica gel 60 (30 g); ethyl acetate (200 ml)]. In this manner, 360 mg (99% of theory) of 4—methoxy— 2-((R)methylmorpholinyl)[2-(tetrahydropyrany|)-2H-pyrazolyI]-[1,7]naphthyridine were ed as a yellow solid. LCMS (method 1): m/z: [M+H]+ = 410.3, R1 = 3.46 min.

Step c: 4-methoxy-Z-((R)methy|morpho|iny|)(1H-pyrazolyl)-[1,7]naphthyridine 360 mg (0.88 mmol) of 4-isopropoxy((R)methy|morpholinyl)[2—(tetrahydropyran—2-yl)- 2H—pyrazol—3—yl]—[1,7]naphthyridine were dissolved in 10 ml of methanol, and 2 ml (4 mmol) of 2N hydrochloric acid were added. After 1 h, LCMS showed complete removal of the protective group.

The methanol was distilled off under reduced pressure and the residue that ed was adjusted to pH 7 using sodium bicarbonate on. The aqueous phase was ted three times with in each case 20 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then concentrated to dryness. 5 ml of ethyl acetate were added to the residue. The resulting precipitated solid was filtered off and dried. This gave 120 mg (42% of theory) of 4—methoxy((R)methy|morpholinyl)(1H-pyrazo|—3-y|)-[1,7]naphthyridine and 100 mg (35% oftheory) of slightly inated t as a beige solid. mp. 193-195°C. 1H NMR (400 MHz, DMSO): 6 [ppm] = 1.27-1.29 (3H), 3.31-3.32 (1H), 3.56—3.57 (1H), 3.70-3.73 (1H), 3.82- 3.85 (1H), 3.85-4.06 (1H), 4.04 (3H), 4.15-4.17 (1H), 4.61-4.63 (1H), 6.82 (1H), 7.37 (1H), 7.61 (1H), 7.70-7.71(1H), 8.32-8.33 (1H), 13.36 (1H).

Example 54 tert—butyl [3-({2-[(3R)methylmorpholinyl](1H-pyrazo|yl)-1,7-naphthyridin y|}oxy)propyl]carba mate Step a: tert—butyl [3-({2-[(3R)methylmorpholiny|][1-(tetrahydro-ZH-pyran-Z-yl)-1H-pyrazol y|]-1,7-naphthyridin-4—y|}oxy)propyl]carba mate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp HN O CH3 oHC3 CH3 )—3—Methylmorpholin—4—yl]—8-[1—(tetrahydro—2H—pyranyl)—1H-pyrazol—5-yl]—1,7—naphthyri- dinol (0.37 g, 0.93 mmol, 1 eq.) was solubilized in DMF (6 mL). N-Bocchloropropylamine (0.36 g, 1.9 mmol, 2 eq.) and K2C03 (0.64 g, 4.7 mmol, 5 eq.) were added to the mixture. The reaction was stirred at 120°C for 16 hours. After cooling to rt, the mixture was filtered, the solid was washed with CH2C|2 and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography (gradient 100% Hexane to 100% . The desired product was obtained in 70% yield (0.36 g). 1H-NMR (400MHz, DMSO-de): 6 [ppm]: 1.13 - 1.23 (3H), 1.36 (9H), 1.40 - 1.64 (3H), 1.89 - 2.04 (4H), 2.30 - 2.41 (1H), 3.10 - 3.29 (4H), 3.40 - 3.51 (1H), 3.57 - 3.79 (3H), 3.92 - 3.99 (1H), 4.07 - 4.17 (1H), 4.27 (2H), 4.45 - 4.58 (1H), 6.01 - 6.13 (1H), 6.71 - 6.77 (1H), 6.88 — 6.98 (2H), 7.60 (1H), 7.77 (1H), 8.36 (1H). LC-MS (Method 3): m/z: [M+H]+ = 553 Rt = 1.23 min.

Step b: tert-butyl -[(3R)methy|morpholin-4—yl](1H-pyrazo|yl)-1,7-naphthyridin-4— y|}oxy)propyl]carba mate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Tert—butyl [3—({2—[(3R)—3-methylmorpholin-4—yl]—8—[1—(tetrahydro—2H-pyran—2-yl)—1H—pyrazo|—5—yl]— 1,7-naphthyridiny|}oxy)propy|]carbamate (20 mg, 0.036 mmol, 1 eq.) was solubilized in CH2C|2 (0.5 mL) and water (0.5 mL). Formic acid (0.10 mL, 2.7 mmol, 75 eq.) was added and the reaction was stirred at rt for 1 hour. The reaction mixture was neutralised by addition of sat. NaHC03 and the aqueous phase was extracted 3 times with CH2C|2. The organic phase was dried (silicon filter) and concentrated under reduced re. The desired product was obtained without further purification in 86% yield (15 mg). 1H—NMR (400MHz, DMSO-de): 6 [ppm]: 1.26 (3H), 1.36 (9H), 1.93 - 2.02 (2H), 3.18 (2H), 3.25 - 3.30 (1H), 3.55 (1H), 3.70 (1H), 3.82 (1H), 4.05 (1H), 4.15 (1H), 4.27 (2H), 4.55 - 4.63 (1H), 6.80 (1H), 6.95 (1H), 7.37 (1H), 7.61 (1H), 7.73 (1H), 8.33 (1H), 13.37 (1H).

LC-MS (Method 3): m/z: [M+H]+ = 469, R = 0.96min.

Example 55 2-({2-[(3R)methy|morpholin-4—yl](1H-pyrazol-S-yl)-1,7-naphthyridiny|}oxy)ethanamine Tert—butyl [2—({2-[(3R)—3-methy|morpho|in-4—y|][1-(tetrahydro-2H-pyran—2-yl)-1H—pyrazo|—5—y|]— 1,7—naphthyridin-4—yl}oxy)ethyl]carbamate (0.36 g, 0.67 mmol, 1 eq.) was solubilised in CH2Cl2 (4.3 mL) and trifluoroacetic acid (2.6 mL, 33 mmol, 50 eq.) was added. The reaction was stirred for 16h at rt and quenched with sat NaHC03. The aqueous phase was extracted 3 times with EtOAc and the c phase was washed with H20 and sat. NaCI. The organic phase was dried (silicon filter) and concentrated under d pressure. The crude material was purified by flash column chromatography (gradient hex/EtOAc :7/3 to 100% EtOAc to EtOAc/EtOH:9/1). The combined fractions were concentrated and EtOH was added. The suspension was filtered and the solid was dried under reduced pressure. The d t was ed in 11% yield (26 mg). 1H-NMR z, DMSO-de): 6 [ppm]: 1.26 (3H), 3.24 - 3.31 (1H), 3.55 (1H), 3.67 - 3.78 (3H), 3.83 (1H), 4.05 (1H), 4.17 (1H), 4.32 - 4.41 (3H), 4.57 - 4.67 (1H), 6.85 (1H), 7.37 (1H), 7.60 (1H), 7.75 (1H), 8.33 (1H), 9.77 (1H), 13.37 (1H).

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 56 tert-butyl [2-({2-[(3R)methy|morpholiny|](1H-pyrazo|yl)-1,7-naphthyridin-4— y|}oxy)ethyl]carbamate Step 3: tert-butyl [2-({2-[(3R)methy|morpholiny|][1-(tetrahydro-2H-pyran-Z-yl)-1H-pyrazo| y|]-1,7-naphthyridiny|}oxy)ethy|]carbamate 2—[(3R)Methylmorpholin-4—yl]—8-[1—(tetrahydro-2H-pyranyl)—1H-pyrazoly|]—1,7- naphthyridin—4-ol (0.40 g, 1.0 mmol, 1 eq.) was solubilised in DMF (10 mL). K2C03 (0.70 g, 5.0 mmol, 2 eq.) and tert—butyl (2—bromoethyl)carbamate (0.45 g, 2.0 mmol, 2 eq.) were sequentially added. The reaction was d for 16 hours at rt. The reaction was then diluted with EtOAc and the sion was filtered. The filtrate was concentrated under reduced pressure and purified ny flash column chromatography (gradient Hex/EtOAc: 8/2 to hex/EtOAc 1/9). The desired product was obtained in 84% yield (0.46 g). 1H—NMR (400MHz, e): 6 [ppm]: 1.19 (3H), 1.32 - 1.49 (11H), 1.49 — 1.64 (1H), 1.89 - 2.04 (2H), 2.30 - 2.40 (1H), 3.10 - 3.30 (2H), 3.40 - 3.51 (3H), 3.73 (3H), 3.90 - 3.99 (1H), 4.09 - 4.18 (1H), 4.19 - 4.23 (2H), 4.47 - 4.59 (1H), 6.01 - 6.13 (1H), 6.78 (1H), 6.92 (1H), 7.21 (1H), 7.60 (1H), 7.88 (1H), 8.34 (1H). LC-MS (Method 3): m/z: [M+H]* = 539, Rt = 1.23 min.

Step b: tert-butyl [2-({2-[(3R)methy|morpholiny|](1H-pyrazo|yl)-1,7-naphthyridin-4— y|}oxy)ethyl]carbamate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp Tert—butyl [2-({2-[(3R)—3-methy|morpholiny|][1-(tetrahydro-2H-pyranyl)-1H-pyrazo|—5-y|]— 1,7—naphthyridin-4—yl}oxy)ethy|]carbamate (0.10 g, 0.19 mmol, 1 eq.) was lsed in CH2Cl2 (1.2 mL) and trifluoroacetic acid (0.29 mL, 3.7 mmol, 20 eq.) was added. The reaction was stirred for 1 h at rt and quenched with sat NaHCOs. The suspension was filtered and the solid was purified by flash column chromatography (gradient from OAc: 1/1 to 100% EtOAc to 100% EtOH).The desired product was obtained in 28% yield (24 mg). 1H-NMR (400MHz, DMSO-de): 6 [ppm]: 1.26 (3H), 1.39 (9H), 3.24 - 3.30 (1H), 3.46 (2H), 3.52 — 3.62 (1H), 3.70 (1H), 3.82 (1H), 3.99 - 4.09 (1H), 4.17 (1H), 4.22 (2H), 4.61 (1H), 6.84 (1H), 7.21 (1H), 7.37 (1H), 7.60 (1H), 7.83 (1H), 8.31 (1H), 13.36 (1H).

Example 57 4—({2-[(3R)methy|morpholin-4—yl](1H-pyrazo|y|)-1,7-naphthyridiny|}oxy)butan amine Tert—butyl [4—({2-[(3R)methylmorpholin-4—yl]—8—[1-(tetrahydro—2H-pyran—2-yl)—1H—pyrazo|—5-y|]— [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp 1,7—naphthyridin-4—yl}oxy)butyl]carbamate (0.10 g, 0.18 mmol, 1 eq.) was solubilsed in CHZClz (1.1 mL) and TFA (0.27 mL, 3.5 mmol, 20 eq.) was added. The reaction was stirred at rt for 30 min and ed with sat. . The suspension was filtered and the solid was dried under reduced pressure. The desired product was obtained without further purification in quantitative yield. 1H- NMR (400MHz, DMSO-de): 5 [ppm]: 1H-NMR (400MHz, DMSO-de): 6 [ppm]: 1.27 (3H), 1.73 - 1.84 (2H), 1.88 - 1.98 (2H), 2.86 - 2.95 (2H), 3.56 (1H), 3.71 (1H), 3.84 (1H), 4.02 - 4.10 (1H), 4.15 (1H), 4.30 (2H), 4.61 (1H), 6.82 (1H), 7.37 (1H), 7.57 (1H), 7.61 (2H), 7.71 (1H), 8.33 (1H), 13.36 (1H).

Example 58 2-[(3R,5S)-3,5-dimethy|morpholinyl]isopropoxy—8-(1H-pyrazo|y|)-1,7-naphthyridine ro-2—[(3R,5$)—3,5—dimethylmorpholin-4—yl]—4-isopropoxy-1,7—naphthyridine (0.10 g, 0.28 mmol, 1 eq.) was solubilised in DME (3 mL). 1-(2-Tetrahydropyranyl)-1H-pyrazoleboronic acid pinacol ester (0.24 g, 0.84 mmol, 3 eq.), K2C03 (0.11 g, 0.84 mmol, 3 eq.), bis(triphenylphosphin)pa|ladium(|l)chloride (20 mg, 0.030 mmol, 0.1 eq.) and H20 (1.5 mL) were added sequentially. The reaction was heated under ave irradiation at 130°C for 10 min.

The crude reaction mixture was ed through a silicon filter and concentrated under reduced pressure. The crude mixture was ed by preparative HPLC (H20(HCOOH)/CH3CN : 50:50 to :70). The purified product was concentrated under reduced pressure, solubilised in CHZCIZ and washed two times with sat. NaHCOs. The organic phase was dried (MgSO4) and concentrated under reduced pressure. The desired product was obtained as a solid in 54 % yield (56 mg). 1H- NMR (400MHz, DMSO-de): 6 [ppm]: 1.37 (6H), 1.41 (6H), 3.69 (2H), 3.88 (2H), 4.50 (2H), 5.07 (1H), 6.70 (1H), 7.36 (1H), 7.60 (1H), 7.69 (1H), 8.29 (1H), 13.38 (1H).

Example 59 2-[(3R,5R)-3,5-dimethylmorpholinyl]isopropoxy(1H-pyrazo|y|)-1,7-naphthyridine [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 8-Chloro[(3R,5R)—3,5-dimethylmorpholinyl]—4-isopropoxy-1,7—naphthyridine (40 mg, 0.12 mmol, 1 eq.) ,1-(2—tetrahydropyranyl)—1H-pyrazo|eboronic acid pinacol ester (50 mg, 0.18 mmol, 1.5 eq.), K2C03 (2 M in H20, 0,18 mL, 0.36 mmol, 3 eq.) and ipheny|phosphin)palladium(ll)chloride (8.5 mg, 0.011 mmol, 0.1 eq.) were added sequentially to DME (1.1 mL). The reaction was heated under microwave irradiation at 130°C for 10min. The reaction mixture was filtered through a silicon filter and concentrated under reduced pressure. The crude mixture was purified by preparative HPLC (H20(HCOOH)/CH3CN : 48:52 to 68:32). The desired product was obtained in 20% yield (9.8 mg). lH-NMR (400MHz, DMSO—de): 6 [ppm]: 1.26 (6H), 1.41 (6H), 3.67 (2H), 4.11 (2H), 4.22 — 4.31 (2H), 4.99 - 5.09 (1H), 6.83 (1H), 7.44 (1H), 7.61 (1H), 7.73 (1H), 8.36 (1H), 13.28 - 13.56 (1H).

Example 60 2-(mo ny|)(1H-pyrazo|y|)(tetrahyd ro-ZH—pyranyl)—1,7-naphthyridine \ N 75 mg (0.20 mmol) of -dihydro-2H-pyran-4—yl)-2—(morpho|inyl)(1H—pyrazolyl)—1,7— naphthyridine were dissolved in 50 ml of methanol, 50 mg of palladium/carbon (10 percent) were added and the mixture was hydrogenated at 2 bar at room ature for 3 h. The reaction solution was then filtered through celite and concentrated under reduced pressure. The residue was triturated with methanol, the solid was filtered off and dried under reduced pressure. This Dve 2-(morpholin—4—y|)(1H—pyrazoI—5-yl)-4—(tetrahydr0-2H-pyran-4—yl)—1,7-naphthyridine in a [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp ed set by jennyp yield of 30 mg (40% of theory). mp. 303-304°C. 1H NMR z, DMSO-ds): 6 [ppm] = 1.76 (2H), 1.89 (2H), 3.53 (1H), 3.63 (2H), 3.77 (8H), 4.01 (2H), 7.36 (2H), 7.61 (1H), 7.88 (1H), 8.38 (1H), 13.33 (1H).

Example 61 2-(morpho|in-4—yl)(1H—pyrazolyl)-[1,7]naphthyridine hydrochloride Step a: 2-(mo rpho|iny|)[2-(tetrahyd ropyran-Z-yl)-2H—pyrazo|y|]-[1,7]naphthyridine O/\N/N\/ Under argon, 40 mg (0.05 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with romethane (1:1, Pd(dppf)Cl2) and 635 mg (1.95 mmol) of caesium carbonate were added to a suspension of 250 mg (0.49 mmol) of 2-(morpholiny|)—8-[2-(tetrahydropyran- 2-yl)—2H-pyrazo|—3-y|]—[1,7]naphthyridin—4-yl trifluoromethanesulphonate and 205 mg (0.97 mmol) 3,6—dihydro—2H-pyran—4-boronic acid pinacol ester in 5.0 ml of absolute dioxane. The reaction e was stirred at 110°C for 4 h. The mixture was chromatographed directly without work-up [silica gel 60 (25 g, 30 um); ethyl acetate (100 ml)]. This gave 30 mg (17% of theory) of 2- (morpholin—4—yl)[2—(tetrahydropyran—2-yl)-2H—pyrazo|—3—y|]—[1,7]naphthyridine as a colourless oil. LC-MS (method 1): m/z: [M+H]+ = 366.3, Rt = 3.09 min.

Step b: 2-(morpho|in-4—yl)(1H—pyrazoly|)-[1,7]naphthyridine o’ ‘N / \ / \_/ — A drop of water and 0.5 ml (6.5 mmol) of trifluoroacetic acid were added to 30 mg (0.08 mmol) of fi(morpholin—4—yl)-8—[2—(tetrahydropyranyl)—2H—pyrazo|—3-yl]—[1,7]naphthyridine. After 1h, ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp LCMS showed complete removal of the tive group. The trifluoroacetic acid was distilled off under reduced pressure and the residue that remained was adjusted to pH7 using sodium bicarbonate solution. The aqueous phase was extracted three times with in each case 20 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then concentrated to dryness. The residue was chromatographed [silica gel 60 (12 g, 30pm); chloroform (100 ml)]. This gave 20 mg (87% of theory) of 2-(morpholiny|)(1H—pyrazol—3-yl)- [1,7]naphthyridine as a yellow solid. Since the latter was still impure, the corresponding hydrochloride was prepared. LC-MS (method 1): m/z: [M+H]+ = 282.3, Rt = 2.42 min.

Step c: 2-(morpho|inyl)(1H—pyrazolyl)-[1,7]naphthyridine hydrochloride \;N HCI o’ ‘N / \ / \_/ — mg (0.07 mmol) of 2-(morpholinyl)(1H-pyrazol-3—yl)-[1,7]naphthyridine were dissolved in 3.0 ml of 2—butanol and 28 )1] (0.21 mmol) of hylchlorosilane were added. The on solution was stirred at room temperature for 1 h. The precipitated solid was filtered off and then dried. This gave 17 mg (75% of theory) of 2-(morpholin—4—y|)(1H-pyrazol—3-yl)- [1,7]naphthyridine hydrochloride as a yellow solid. mp. 151-153°C. 1H NMR z, DMSO): 6 [ppm] = 3.80-3.85 (8H), 7.61-7.62 (1H), 7.89-7.91 (1H), 8.11-8.13 (2H), 8.33-8.34 (1H), 8.41-8.43 (1H).

Example 62 4-chloromorpho|iny|(1H-pyrazolyl)-[1,7]naphthyridine Step 3: methyl —b utoxyca rbonylamino-Z-chloroisonicotinate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp H30 CH3 o=<— H30/ 0 Under argon and at room temperature, 1.92 g (8.7 mmol) of di-tert-butyl dicarbonate and 244 mg (2 mmol) of thylaminopyridine were added to a solution of 1.49 g (8 mmol) of methyl 3- aminochloroisonicotinate in 20 ml of dry tetrahydrofuran. The mixture was stirred at room temperature for 16 h. For work-up, the reaction mixture was adjusted to pH 7 using 2N hydrochloric acid. The resulting precipitated solid was filtered off with suction and washed with ml of water. In this manner, methyl —butoxycarbonylamino-2—chloroisonicotinate was obtained in a yield of 1.2 g (52% of theory) as a colourless solid. This solid was a mixture of the product and the double Boc protected compound. The mixture was used for the next step without further purification.

Step b: 1-(3-aminochloropyridiny|)morpholinyl-propane-1,3-dione H2N\/ Under argon and at room temperature, 6.76 ml (6.76 mmol) of lithium bis(trimethylsilyl)amide were added se to a solution of 484 pl (4.19 mmol) of ylmorpholine and 1.2 g (4.2 mmol) of methyl 3-tert-butoxycarbonylamino-2—chloroisonicotinate in 10 ml of dry tetrahydrofuran. The mixture was stirred at room temperature for 6 h. For work—up, the reaction mixture was adjusted to pH=1 using 2N hydrochloric acid and stirred at room temperature for 16 h. LC-MS showed complete removal of the protective group. The mixture was ted three times with in each case 50 ml of dichloromethane. The combined organic phases were dried with sodium sulphate and then concentrated to dryness. In this manner, minochloropyridin yl)—3—morpholinyl—propane—1,3-dione was obtained in a yield of 680 mg (57% of theory) as a [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp yellow solid. 1H NMR (400 MHz, CDCI3): 6 [ppm] = 3.49—3.52 (2H), 3.64—3.74 (6H), 4.08 (s, 2H), 6.73 (s, 2H), 7.57 (d, 1H), 7.75 (d, 1H).

Step c: 1-{3-amino[2-(4-methoxybenzyl)-2H-pyrazolyl]pyridiny|}(morpholinyl)propane- 1,3-dione Under argon, 207 mg (0.66 mmol) of 1-(4-methoxybenzyl)—5-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolane—Z—yl)-1H—pyrazo|e, 195 mg (0.6 mmol) of caesium carbonate, 95 mg (0.33 mmol) of 1-(3-aminochIoropyridiny|)morpho|inylpropane-1,3-dione and 20 mg (0.02 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1) in 2.5 ml of e were stirred in a microwave vessel at 100°C for 2 h.

Without work—up, the e was purified by column chromatography [Puriflash silica gel 60 (25 g, 30 um); ethyl acetate/methanol 1:1, (200 ml)]. In this , 1-{3-amino[2-(4- methoxybenzyl)-2H—pyrazol—3—yl]pyridin—4—yl}—3—(morpholin—4—yl)propane—1,3—dione was obtained in a yield of 38 mg (26% of theory) as a light-yellow oil. 1H NMR (400 MHz, CDCI3): 8 [ppm] = 3.48- 3.51 (2H), 3.64-3.68 (6H), 4.09 (2H), 5.37 (2H), 6.43 (2H), 6.55 (1H), 6.69-6.73 (2H), 6.95-6.97 (2H), 7.58-7.62 (2H), 8.09 (1H).

Step d: 4-chloromorpholinyl(1H-pyrazolyl)-[1,7]naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp o’ ‘N / \ / \_/ — Under argon, 45 mg (0.1 mmol) of 1-{3-amino—2-[2-(4-methoxybenzyl)-2H—pyrazo|—3-yl]pyridin yl}—3—(morpholin-4—yl)propane—1,3-dione and 500 pl (5.36 mmol) of orus oxychloride were stirred at 120°C for 3 h. Without work—up, the residue was purified by column chromatography [Puriflash silica gel 60 (12 g, 30 um); ethyl e/methanol 1:1, (100 ml)]. In this manner, 4— morpholin-4—yl(1H—pyrazolyl)-[1,7]naphthyridine was obtained in a yield of 25 mg (79% of theory) as a yellow solid. 1H NMR (400 MHZ, DMSO): 5 [ppm] = 3.69-3.79 (8H), 7.36 (1H), 7.64 (1H), 7.78 (1H), 7.85 (1H), 8.45 (1H). LCMS (method 1): m/z: [M+H]+ = 316.3, Rt = 3.0 min.

Example 63 2-[(3R)methy|morpho|iny|](methylsuIfanyl)(1H-pyrazolyl)—1,7-naphthyridine 4—Chloro-2—[(3R)methylmorpholin-4—yl]—8-[1—(tetrahydro-2H-pyranyl)—1H-pyrazolyl]—1,7- naphthyridine (50 mg, 0.12 mmol, 1 eq.) was solubilised in DMF (3 mL). Sodium methanethiolate (8.5 mg, 0.12 mmol, 1 eq.) was added and the reaction was stirred at 50°C for 2h. Sat. NH4CI was added to the mixture and the aqueous phase was extracted 3 times with CH2Cl2. The organic phase was dried (silicon filter) and concentrated under reduced pressure. The crude mixture was purified by ative HPLC (HzO(HCOOH)/CH3CN : 56:44 to 36:64). The desired t was obtained in 75% yield. 1H-NMR (400MHz, DMSO-de): 6 [ppm]: 1.28 (3H), 2.69 (3H), 3.34 (1H), 3.56 (1H), 3.71 (1H), 3.83 (1H), 4.05 (1H), 4.17 (1H), 4.61 - 4.68 (1H), 7.08 (1H), 7.37 (1H), 7.61 (1H), 7.66 (1H), 8.36 (1H), 13.36 (br. s, 1H).

Dample 64 [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp N-{2-[(3R)methy|morpholiny|](1H-pyrazol-S-y|)-1,7-naphthyridin-4—yl}-1,4A4-oxathian imine 4—oxide Step 3: N-(Z-[(3R)methylmorpholinyl]{1-[(2R)—tetrahydro-ZH-pyranyl]-1H-pyrazoly|}-1,7- naphthyridin-4—yl)-1,4A4-oxathianimine 4—oxide Under argon, 8 mg (0.014 mmol) 4,5—bis(diphenylphosphino)—9,9-dimethylxanthene and 7 mg (0.007 mmol) ibenzy|ideneacetone)dipal|adium(0) were added to a mixture of 75 mg (0.142 mmol) 2—[(3R)—3—methylmorpho|in—4-yl]-8—[1—(tetrahydro-ZH—pyran-Z—yl)-1H-pyrazol-5—y|]—1,7- yridin—4-yl trifluoromethanesulfonate, 25 mg (0.19 mmol) 1,47x4-oxathian-4—imine 4—oxide and 69 mg (0.21 mmol) caesium carbonate in 0.67 ml toluene. The mixture was stirred at 110 °C for 3 hours. After cooling, the reaction mixture was diluted with ethyl acetate /THF and washed with an aqueous solution of sodium chloride. The organic phase was filtered using a Whatman filter and concentrated to give 113 mg crude product that was used without further purification.

Step b: N-{2-[(3R)methy|morpholiny|](1H-pyrazol-S-y|)-1,7-naphthyridin-4—yl}-1,4A4-oxathian imine 4—oxide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 0.25 ml (0.51 mmol) 2N aqueous solution of hydrogen chloride was added to a solution of 113 mg crude N-(2—[(3R)methylmorpholin—4-yl]—8-{1—[(2R)-tetrahydro—2H-pyranyl]—1H-pyrazoI—5-yl}- 1,7—naphthyridinyl)—1,4?\4-oxathian—4—imine 4—oxide in 1.0 ml ol and the reaction e was stirred at room temperature for 1 hour. The mixture was basified by addition of an aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was ed by preparative HPLC (Autopurifier: basic ions) to give 23 mg (0.05 mmol) of the desired product. 1H-NMR (400 MHz, CDCI3): 6 [ppm] = 1.43 (3H), 3.43 (2H), 3.51 (1H), 3.61 (2H), 3.70 (1H), 3.85 (1H), 3.92 (2H), 4.14 (3H), 4.30 (2H), 4.38 (1H), 6.97 (1H), 7.26 (1H), 7.72 (1H), 7.89 (1H), 8.43 (1H).

Example 65 4-{[dimethyl(oxido)-A6-sulfanylidenelamino}(morpholin-4—yl)-8—(1H-pyrazoly|)-1,7- naphthyridine Step 3: 4-{[dimethyl(oxido)-A6-sulfanylidene]amino}(morpholinyl)[1-(tetrahydro-ZH-pyran-Z- y|)-1H-pyrazolyl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under argon, 11 mg (0.019 mmol) 4,5-bis(diphenylphosphino)—9,9-dimethylxanthene and 9 mg (0.010 mmol) tris(dibenzylideneacetone)dipal|adium(0) were added to a e of 100 mg (0.20 mmol) 2-(morpholinyl)[1-(tetrahydro-2H—pyran-Z—yl)-1H-pyrazoIyl]-1,7-naphthyridinyl trifluoromethanesulfonate, 24 mg (0.26 mmol) S,S-dimethy|sulfoximin and 95 mg (0.29 mmol) caesium carbonate in 0.92 ml toluene. The mixture was stirred at 110 °C for 3 hours. After cooling, the reaction mixture was diluted with ethyl acetate / THF and washed with an aqueous solution of sodium chloride. The organic phase was filtered using a Whatman filter and concentrated to give 136 mg crude product that was used without further purification.

Step b: 4-{[dimethyl(oxido)—7\6-sulfanylidene]amino}(morpho|in-4—y|)(1H-pyrazolyl)—1,7- naphthyridine 0.34 ml (0.68 mmol) 2N aqueous solution of hydrogen chloride was added to a solution of 135 mg crude 4-{[dimethyl(oxido)-7\6-sulfanylidene]amino}(morpholinyl)-8—[1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazo|—5-y|]-1,7-naphthyridine in 1.4 ml methanol and the reaction mixture was stirred at room temperature for 1 hour. The mixture was ed by addition of an aqueous sodium bicarbonate solution and extracted with ethyl e (2x). The combined organic phases were DIered using a Whatman filter and concentrated. The residue was purified by preperative HPLC ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp (Autopurifier: acidic conditions) to give 23 mg (0.06 mmol) of the desired product. 1H-NMR (400 MHz, CDCI3): 6 [ppm] = 3.39 (6H), 3.70 (4H), 3.94 (4H), 6.93 (1H), 7.25 (1H), 7.72 (1H), 7.82 (1H), 8.43 (1H).

Example 66 2-[(3R)—3-methy|morpholin-4—yl]-4—(piperaziny|)(1H-pyrazolyl)-1,7-naphthyridine Step a: 2-[(3R)methy|morpho|in-4—yl]-4—(piperazinyl)[1-(tetra ZH-pyran-Z-yl)-1H-pyrazo|- 1,7-naphthyridine Under argon, a mixture of 75 mg (0.14 mmol) 2-[(3R)-3—methy|morpholin—4-yl]-8—[1-(tetrahydro- 2H—pyran-2—yl)-1H-pyrazoI-S-yl]-1,7-naphthyridin—4-yl trifluoromethanesuIfonate, and 42 mg (0.48 mmol) piperazine in 0.21 ml acetonitrile was stirred at 70°C for 90 minutes. After cooling, the reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium chloride. The organic phase was filtered using a Whatman filter and concentrated to give 91 mg crude product that was used without further purification.

Step b: 2-[(3R)—3-methy|morpholin-4—yl]-4—(piperazinyl)(1H-pyrazo|y|)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp 0.30 ml (0.60 mmol) 2N aqueous solution of hydrogen chloride was added to a solution of 120 mg crude 2—[(3R)methylmorpholinyl]—4-(piperazin—l-yl)[1-(tetrahydro-2H-pyranyl)-1H- pyrazolyl]—1,7-naphthyridine in 1.2 ml methanol and the reaction mixture was stirred at room temperature for 1 hour. The mixture was basified by on of an aqueous sodium bicarbonate solution and extracted with ethyl e (2x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 27 mg (0.07 mmol) of the desired product. 1H-NMR (400 MHz, CDCI3): 6 [ppm] = 1.44 (3H), 3.21 (8H), 3.54 (1H), 3.73 (1H), 3.87 (1H), 3.95 (2H), 4.18 (1H), 4.40 (1H), 6.56 (1H), 7.27 (1H), 7.57 (1H), 7.71 (1H), 8.40 (1H).

Example 67 ropoxy—2-(($)methy|morpholin-4—yl)(1H—pyrazo|y|)-[1,7]naphthyridine Step a: 4-isopropoxy(($)methy|morpho|iny|)[2-(tetrahyd ropyranyl)-2H-pyrazo|y|]- [1,7]naphthyridine 96 mg (0.69 mmol) of potassium carbonate were added to a solution of 380 mg (0.58 mmol) of 2- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp ed set by jennyp 3-methylmorpholin-4—yl]—8—(2—tetrahydropyran-2—y|pyrazol—3—yl)-1,7—naphthyridin-4—ol and 0.12 ml (1.15 mmol) of 2-iodopropane in 20 ml of acetonitrile. The suspension was stirred in a microwave vessel at 70°C for 16 h. Under reduced pressure, the mixture was concentrated to dryness. The residue was taken up in 50 ml of water and extracted four times with in each case 50 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then, under reduced pressure, concentrated to dryness. The residue was tographed [silica gel 60 (40 g, 50 um); ethyl e 100%]. 139 mg (55% of theory) of 4-isopropoxy—2-((5) methylmorpholinyl)[2-(tetrahydropyranyl)-2H-pyrazolyI]-[1,7]naphthyridine were obtained as a beige solid. 1H NMR (400 MHz, CDCI3): 6 [ppm] = 1.30 (3H), 1.48 (m, 1H), 1.49 (6H), 1.56-1.77 (2H), 2.02-2.10 (2H), 2.52 (1H), 3.27 (1H), 3.44 (1H), 3.57 (1H); 3.70-3.82 (2H), .16 (3H), 4.35 (1H), 4.78 (1H), 6.02 (1H), 6.32 (1H); 6.94 (1H), 7.67 (1H), 7.78 (1H), 6.39 (1H). LC-MS (method 1): Rt: 3.75 min; MS (ESI/APCIpos) m/z = 438.3 [M+H]+.

Step b: 4-isopropoxy(($)methy|morpholin-4—yl)(1H—pyrazo|y|)-[1,7]naphthyridine 127 mg (0.29 mmol) of (35)—4—[4-isopropoxy—8—(2-tetrahydropyran—Z-ylpyrazol—3—yl)—1,7— naphthyridin—2-yl]methylmorpholine were dissolved in 10 ml of methanol, 1.5 ml of 2N hydrochloric acid (3 mmol) were added and the mixture was stirred at room temperature for 1 h.

After 1h, the LC/MS showed complete removal of the protective group. The methanol was removed under reduced pressure. Saturated sodium bicarbonate solution (pH = 7) was added to the residue. The aqueous phase was extracted five times with in each case 10 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then, under reduced pressure, concentrated to dryness. This gave 89 mg (87% of theory) of 4—isopropoxy -methylmorpho|iny|)(1H-pyrazoIy|)-[1,7]naphthyridine as a yellow solid. 1H NMR (400MHz, CDCI3): 6 [ppm] = 1.41 (3H), 1.50 (6H), 3.50 (1H), 3.70 (1H), 3.85 (1H), 3.90 (1H), 3.92 DH), 4.15 (1H), 4.34 (1H), 4.80 (1H), 6.39 (1H), 7.24 (1H), 7.69 (1H), 7.73 (1H), 8.39 (1H), 13.18 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (1H). l3CNMR (101 MHZ, CDCI3): 6 [ppm] = 13.4, 21.6, 21.7, 40.8, 48.9, 66.8, 71.0, 71.7, 91.9, 105.7, 114.3, 123.4, 139.9, 140.0, 140.8, 143.2, 143.9, 158.9, 161.0. LC-MS (method 1): R1 = 2.90 min; MS (ESI/APClpos) m/z = 354.3 [M+H]*.

Example 68 2-(mo rpholinyl)(propanyloxy)—8—(1H-pyrro|y|)-1,7-naphthyridine Under argon, 13 mg (0.016 mmol) [1,1’-bis(diphenylphosphino)ferrocene]dichloropal|adium(ll) were added to a mixture of 50 mg (0.16 mmol) 8—chloro(morpholin—4—yl)(propan-2—yloxy)— 1,7—naphthyridine and 34 mg (0.18 mmol) 3—(4,4,5,5—tetramethyl-1,3,2—dioxaborolan-Z-yl)—1H- pyrrole in 1.5 ml acetonitrile and 1.5 ml 2M aqueous solution of ium carbonate. The mixture was stirred in a at 130 "C in a microwave oven for 10 minutes. After g, DCM was added and the mixture was filtered using a Whatman filter. The organic phase was concentrated and the residue was purified by preparative HPLC separation (Autopurifier: acidic conditions) to give 5 mg (0.01 mmol) of the desired product. 1H—NMR (400 MHz, 6): 5 [ppm] = 1.38 (6H), 3.67 (4H), 3.78 (4H), 5.02 (1H), 6.78 (2H), 6.98 (1H), 7.44 (1H), 8.07 (1H), 8.17 (1H), 10.94 (1H).

Example 69 4-(1-ethyl-1H-pyrazo|yl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine Step 3: 4-(1-ethyl-1H-pyrazol-S-yl)[(3R)methylmorpholinyl][1-(tetrahydro-2H-pyran-2—yl)—1H— pyrazol-5—yl]-1,7-naphthyridine ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A suspension of 100 mg (0.19 mmol) of )methylmorpholin-4—yl]—8—[1-(tetrahydro-2H- pyranyl)—1H-pyrazolyl]-1,7-naphthyridin-4—yl trifluoromethanesulfonate, 53 mg (0.38 mmol) (1-ethyl-1H—pyrazol-5—yl)boronic acid, 15 mg (0.02 mmol) of [1,1’- bis(dipheny|phosphino)ferrocene]dich|oropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 65 mg (0.47 mmol) of potassium carbonate in 2 ml MeCN and 1 ml water was degased with argon. Under argon, the reaction mixture was stirred at 130°C for 10 min in a microwave reactor. After cooling the reaction mixture was diluted with saturated s sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-(1-ethyl-1H-pyrazo|y|)[(3R)methylmorpholiny|](1H-pyrazolyl)—1,7- naphthyridine A solution of 104 mg of crude 4-(1—ethyI-1H—pyrazoI—S—yl)[(3R)methylmorpholiny|]—8-[1- hydro-2H-pyran—2-yl)-1H—pyrazolyl]—1,7—naphthyridine from step a in 2 ml of methanol and 0.2 ml of 2N hydrochloric acid was stirred for 1 h at room temperature. The reaction mixture was diluted with saturated s sodium chloride solution and extracted with ethyl acetate (2x). The combined organic phases were dried over magnesium sulphate and then concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give Dmg (0.03 mmol) of the desired product.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400MHz, DMSO—d6): 6 [ppm] = 1.22 (3H), 1.30 (3H), 3.35 - 3.40 (1H), 3.58 (1H), 3.72 (1H), 3.82 (1H), 3.99 (2H), 4.03 - 4.09 (1H), 4.23 (1H), 4.64 (1H), 6.55 (1H), 7.19 (1H), 7.44 (1H), 7.58 (1H), 7.65 (1H), 7.70 (1H), 8.35 (1H), 13.45 (1H).

Example 70 4—(1-methyl-1H-imidazolyl)[(3R)methylmorpholin-4—yl](1H-pyrazol-5—yl)-1,7- naphthyridine Step a: ethyl-1H-imidazo|y|)[(3R)methy|morpho|in-4—yl][1-(tetrahydro-2H-pyran-2—yl)- 1H-pyrazol-S-yl]-1,7-naphthyridine A sion of 100 mg (0.19 mmol) of 2-[(3R)methy|morpholinyl]—8—[1-(tetrahydro-2H- Z-yl)—1H—pyrazol—5-y|]—1,7—naphthyridin—4—yl trifluoromethanesulfonate, 79 mg (0.38 mmol) y|—5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)—1H-imidazo|e, 15 mg (0.02 mmol) of [1,1’—bis(diphenylphosphino)ferrocene]dich|oropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 65 mg (0.47 mmol) of potassium carbonate in 2 ml MeCN and 1 ml water was degased with argon. Under argon, the reaction mixture was stirred at 130°C for 10 min in a microwave reactor. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then trated to give the crude product that was used without further purification in the next step.

Step b: 4—(1-methyl-1H-imidazolyl)[(3R)methylmorpholin-4—yl](1H-pyrazol-5—yl)-1,7- naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 99 mg of crude 4-(1-methyl-1H-imidazol-5—yl)[(3R)methy|morpholiny|]—8-[1- (tetrahydro—2H-pyran—2-yl)-1H—pyrazoI—5-yl]-1,7—naphthyridine from step a in 2 ml of methanol and 0.2 ml of 2N hydrochloric acid was stirred for 1 h at room temperature. The reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combined organic phases were dried over magnesium te and then concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic ions) to give 5 mg (0.01 mmol) of the desired product. lH-NMR z, DMSO-d6): 6 [ppm] = 1.30 (3H), 3.50 - 3.65 (4H), 3.72 (1H), 3.83 (1H), 4.06 (1H), 4.23 (1H), 4.54 - 4.71 (1H), 7.24 (1H), 7.43 (2H), 7.51 (1H), 7.65 (1H), 7.93 (1H), 8.36 (1H), 13.43 (1H).

Example 71 2-{2-[(3R)methy|morpholinyl](1H-pyrazo|y|)-1,7-naphthyridiny|]aniline Step a: 2-{2-[(3R)methylmorpholinyl][1-(tetrahyd ro-2H-pyranyl)—1H-pyrazoly|]-1,7- naphthyridinyl}aniline A suspension of 100 mg (0.19 mmol) of 2-[(3R)methy|morpho|inyl]—8—[1-(tetrahydro-2H- -yl)—1H-pyrazolyl]-1,7-naphthyridin-4—yl trifluoromethanesulfonate, 52 mg (0.38 mmol) [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (2—aminophenyl)boronic acid, 15 mg (0.02 mmol) of bis(diphenylphosphino)ferrocene]— dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 247 mg (0.76 mmol) of caesium carbonate in 1.4 ml of dixoane was degased with argon. Under argon, the reaction mixture was stirred at 110°C for 2 h. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The ded organic phases were ed using a Whatman filter and then concentrated to give the crude t that was used without further purification in the next step.

Step b: 2-{2-[(3R)—3-methy|morpholin-4—yl](1H-pyrazo|y|)-1,7-naphthyridinyl]aniline A solution of 163 mg of crude 2—{2-[(3R)—3-methylmorpholin-4—y|]—8—[1-(tetrahydro—2H-pyran—2—yl)— 1H-pyrazol-5—yl]-1,7-naphthyridiny|}ani|ine from step a in 7.8 ml of methanol and 0.35 ml of 2N hydrochloric acid was stirred for 90 min at room temperature. The reaction mixture was treated with 2 ml of a saturated aqueous sodium bicarboante solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 17 mg (0.04 mmol) of the desired product. 1H-NMR z, DMSO-d6): 6 [ppm] = 1.31 (3H), 3.45 - 3.64 (1H), 3.71 (1H), 3.82 (1H), 3.91 - 4.12 (1H), 4.21 (1H), 4.61 (1H), 4.84 (2H), 6.70 (1H), 6.82 (1H), 7.02 (1H), 7.08 - 7.27 (2H), 7.35 (1H), 7.44 (1H), 7.64 (1H), 8.28 (1H), 13.28 (1H). e 72 4—(2,3-difluorophenyl)[(3R)methylmorpholin-4—yl](1H-pyrazo|yl)-1,7-naphthyridine Step 3: 4—(2,3-difluoropheny|)[(3R)methylmorpholin-4—yl][1-(tetrahydro-ZH-pyran-Z-yl)—1H- Drazol-S-yl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A suspension of 100 mg (0.19 mmol) of 2—[(3R)-3—methy|morpholin—4—yl]—8—[1—(tetrahydro—2H— pyran-Z-yl)-1H-pyrazol-S-yl]—1,7-naphthyridinyl trifluoromethanesulfonate, 60 mg (0.38 mmol) (2,3—difluoropheny|)boronic acid, 15 mg (0.02 mmol) of [1,1’—bis(diphenylphosphino)ferrocene]— dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 247 mg (0.76 mmol) of m carbonate in 1.4 ml of dixoane was degased with argon. Under argon, the reaction mixture was d at 110°C for 2 h. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride on and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without r purification in the next step.

Step b: 4-(2,3-dif|uorophenyl)—2-[(3R)methylmorphoIin-4—yl](1H-pyrazo|y|)-1,7-naphthyridine A solution of 133 mg of crude 4-(2,3-difluorophenyl)[(3R)methylmorpholinyl]—8-[1- (tetrahydro-2H-pyran—2-yl)-1H-pyrazolyl]—1,7-naphthyridine from step a in 6.1 ml of ol and 0.27 ml of 2N hydrochloric acid was d for 90 min at room ature. The reaction mixture was treated with 2 ml of a saturated aqueous sodium bicarboante solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic anditions) to give 20 mg (0.05 mmol) ofthe desired product.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400MHz, DMSO-d6): 6 [ppm] = 1.31 (3H), 3.39 (1H), 3.58 (1H), 3.72 (1H), 3.83 (1H), 4.05 (1H), 4.23 (1H), 4.64 (1H), 7.22 (1H), 7.35 - 7.52 (3H), 7.52 - 7.75 (4H), 8.33 (1H), 13.09 (1H).

Example 73 4-[2-methyl(methylsulfonyl)pyridinyl][(3R)methylmorpho|inyl](1H-pyrazol 7-naphthyridine Step a: 4-[2-methyl(methylsulfonyl)pyridinyl][(3R)methy|morpho|in-4—yl][1-(tetrahydro- 2H-pyranyl)-1H-pyrazoly|]-1,7-naphthyridine A suspension of 75 mg (0.14 mmol) of 2-[(3R)methy|morpholinyl]—8-[1-(tetrahydro-2H- pyran-Z-yl)-1H-pyrazol-S-yl]—1,7-naphthyridinyl trifluoromethanesulfonate, 84 mg (0.28 mmol) 2-methyl(methylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine, 12 mg (0.014 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 185 mg (0.57 mmol) of caesium carbonate in 1.0 ml of e was degased with argon. Under argon, the reaction e was stirred at 110°C for 2 h.

After cooling the on mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4—[2-methyl(methylsulfonyl)pyridinyl][(3R)methylmorpho|inyl](1H-pyrazol yl)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp A on of 152 mg of crude 4-[2—methyl—6-(methylsulfonyl)pyridin—3-yl]—2-[(3R) methylmorpholiny|][1-(tetrahydro—2H-pyranyl)-1H-pyrazo|—5-yl]-1,7-naphthyridine from step a in 1.3 ml of methanol and 0.3 ml of 2N hydrochloric acid was stirred for 1 h at room temperature. The reaction e was treated with 2 ml of a saturated aqueous sodium bicarboante solution and extracted with ethyl acetate (2x). The combined organic phases were ed using a Whatman filter and then concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 36 mg (0.08 mmol) of the desired product. 1H—NMR (400MHz, DMSO-d6): 6 [ppm] = 1.29 (3H), 2.36 (3H), 3.33 — 3.44 (4H), 3.46 — 3.63 (1H), 3.66 - 3.76 (1H), 3.76 - 3.88 (1H), 4.04 (1H), 4.21 (1H), 4.55 - 4.64 (1H), 6.99 (1H), 7.43 (1H), 7.51 - 7.61 (1H), 7.64 (1H), 7.97 - 8.15 (2H), 8.29 (1H), 13.41 (1H).

Example 74 4-[2-fluoro-4—(methylsulfonyl)phenyl]-2—[(3R)methy|morphoIin-4—yl](1H-pyrazol-S-y|)-1,7- naphthyridine Step 3: 4-[2-fluoro(methylsulfanyl)pheny|][(3R)methy|morpho|iny|][1-(tetrahyd ro-ZH- pyran-Z-yl)-1H-pyrazo|—5-y|]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp A suspension of 150 mg (0.28 mmol) of 2-[(3R)methy|morpholiny|][1-(tetrahydro-2H- Z-yl)—1H-pyrazoly|]—1,7-naphthyridin—4—yl trifluoromethanesulfonate, 106 mg (0.57 mmol) oro(methylsulfanyl)phenyl]boronic acid, 23 mg (0.028 mmol) of [1,1’- bis(diphenylphosphino)ferrocene]dich|oropa||adium(|I) complex with dichloromethane (1:1, Pd(dppf)C|2) and 371 mg (1.14 mmol) of m carbonate in 2.0 ml of dixoane was degased with argon. Under argon, the reaction e was stirred at 110°C for 150 min. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated. The residue was purified by flash chromatography (gradient Hex/EtOAc 9/1 to 100% EtOAc) to give 96 mg (0.18 mmol) of the desired product. 1H—NMR (400MHz, DMSO-d6): 6 [ppm] = 1.21 (3H), 1.35 — 1.56 (3H), 1.87 - 2.08 (2H), 2.29 - 2.43 (1H), 2.58 (3H), 3.08 - 3.26 (2H), 3.39 - 3.58 (1H), 3.58 - 3.66 (1H), 3.66 - 3.79 (2H), 3.95 (1H), 4.16 (1H), 4.47 - 4.58 ( 1H), 6.10 ( 1H), 6.94 ( 1H), 7.23 (1H), 7.26 - 7.32 (1H), 7.35 ( 1H), 7.43 ( 1H), 7.48 (1H), 7.62 (1H), 8.34( 1H).

Step b: 4-[2—fluoro-4—(methylsulfony|)phenyl]-2—[(3R)methy|morpho|iny|][1-(tetrahydro-ZH- pyran-Z-yl)-1H-pyrazo|yl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 2.7 mg (0.009 mmol) TPAP and 20.7 mg (0.18 mmol) 4-methylmorpholine N-oxide were added to a stirred solution of 92 mg (0.18 mmol) of luoro(methylsulfanyl)phenyl]—2-[(3R) methylmorpholinyl]—8—[1-(tetrahydro—2H-pyrany|)-1H-pyrazol—5-y|]-1,7—naphthyridine in 2 ml DCM and 2 ml MeCN at 0°. After 4 h, additional 2.7 mg (0.009 mmol) TPAP was added and the ice bath removed. After 14 h at Rt, additional 2.7 mg (0.009 mmol) TPAP and 20.7 mg (0.18 mmol) 4- methylmorpholine N—oxide were added and the mixture was stirred at room temperatue. After 18 h at Rt, onal 2.7 mg (0.009 mmol) TPAP and 20.7 mg (0.18 mmol) 4—methylmorpholine N- oxide were added and the mixture was stirred at room temperatue. After 16h at Rt, additional 2.7 mg (0.009 mmol) TPAP and 20.7 mg (0.18 mmol) 4-methylmorpholine N—oxide were added and the mixture was stirred at room temperatue. The reaction was ed using a Whatman filter and concentrated to give the crude product that was used without r purification in the next step.

Step c: 4-[2-fluoro-4—(methylsulfony|)pheny|]-2—[(3R)-3—methy|morphoIiny|](1H-pyrazol-S-y|)-1,7- naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 134 mg of crude 4—[2-fluoro—4-(methylsulfonyl)phenyl]—2-[(3R)—3-methylmorpholin-4— [1-(tetrahydro-2H-pyrany|)-1H-pyrazo|—5—y|]-1,7-naphthyridine from step b in 5.4 ml of methanol and 0.25 ml of 2N hydrochloric acid was stirred for 90 min at room temperature. The reaction mixture was treated with 10 ml of a saturated aqueous sodium bicarboante solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 23 mg (0.05 mmol) of the desired t. 1H-NMR (400MHz, DMSO-d6): 6 [ppm] = 1.30 (3H), 3.33 - 3.42 (4H), 3.50 - 3.61 (1H), 3.66 - 3.76 (1H), 3.81 (1H), 3.95 - 4.09 (1H), 4.21 (1H), 4.54 -4.71 (1H), 7.15 (1H), 7.42 (1H), 7.56 - 7.70 (2H), 7.87 (1H), 7.98 (1H), 8.03 (1H), 8.31 (1H), 13.40 (1H).

Example 75 ro-Z-[Z-[(3R)—3-methylmorpho|inyl](1H-pyrazo|y|)-1,7-naphthyridinyl]aniline Step 3: 4-fluoro-Z-{Z-[(3R)—3-methylmorpholin-4—yl][1-(tetrahyd ro-ZH-pyran-Z-yl)-1H-pyrazolyl]- 1,7-naphthyridin-4—yl}aniline A suspension of 100 mg (0.19 mmol) of 2-[(3R)methy|morpho|iny|][1-(tetrahydro-2H- pyranyl)—1H-pyrazoly|]-1,7-naphthyridin-4—yl trifluoromethanesulfonate, 58 mg (0.38 mmol) (2-aminofluorophenyl)boronic acid, 15 mg (0.019 mmol) of [1,1’- bis(dipheny|phosphino)ferrocene]dichloropalladium(ll) x with dichloromethane (1:1, Pd(dppf)C|2) and 65 mg (0.47 mmol) of potassium carbonate in 2.0 ml of MeCN and 1.0 ml water was degased with argon. Under argon, the reaction mixture was stirred at 130°C for 10 s in a microwave reactor. After cooling the reaction mixture was diluted with saturated aqueous sodium de solution and extracted with ethyl acetate (2x). The combinded organic phases were ed using a Whatman filter and then concentrated to give the crude product that was [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp used t further cation in the next step.

Step b: 4-fluoro-Z-[Z-[(3R)—3-methylmorpho|in-4—yl](1H-pyrazo|y|)-1,7-naphthyridin-4—yl]aniline A solution of 59 mg of crude 4-fluoro—2-{2-[(3R)-3—methy|morpholin—4-yl]—8-[1—(tetrahydro—2H— pyranyl)-1H-pyrazolyl]-1,7-naphthyridinyl}aniline from step a in 3.0 ml of methanol and 0.12 ml of 2N hydrochloric acid was stirred for 3 h at room temperature. The on mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to dryness. The e was purified by preparative HPLC (Autopurifier: basic conditions) to give 22 mg (0.05 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 5 [ppm]: 1.31 (3H), 3.57 (1H), 3.65 - 3.76 (1H), 3.76 - 3.88 (1H), 4.05 (1H), 4.22 (1H), 4.62 (1H), 4.74 (2H), 6.81 (1H), 6.94 (1H), 7.07 (1H), 7.14 (1H), 7.39 (1H), 7.44 (1H), 7.59 - 7.73 (m, 1H), 8.29 (1H), 13.42 (1H). e 76 4—(1-benzyl-1H-imiclazo|y|)[(3R)methy|morpholin-4—yl](1H-pyrazo|y|)-1,7- naphthyridine Step a: 4—(1-benzyl-1H-imidazo|y|)[(3R)methy|morpholin-4—yl][1-(tetrahyd ro-2H-pyranyl)— 1H-pyrazoly|]-1,7-naphthyridine [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A suspension of 100 mg (0.19 mmol) of 2—[(3R)methy|morpholin—4—yl]—8—[1—(tetrahydro-2H- pyran-Z-yl)-1H-pyrazoIy|]-1,7-naphthyridinyl trifluoromethanesulfonate, 53 mg (0.19 mmol) 1—benzy|—5—(4,4,5,5-tetramethyl-1,3,2—dioxaborolanyl)—1H-imidazole, 15 mg (0.019 mmol) of [1,1’—bis(diphenylphosphino)ferrocene]dich|oropalladium(l|) complex with dichloromethane (1:1, Pd(dppf)C|2) and 247 mg (0.76 mmol) of cesium carbonate was degased with argon. Under argon, the reaction mixture was stirred at 110°C for 90 s. After cooling the reaction mixture was d with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x).

The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude t that was used without further purification in the next step.

Step b: 4-(1-benzyl-1H-imidazo|y|)[(3R)methylmorpholinyl](1H-pyrazo|y|)-1,7- naphthyridine A solution of 170 mg of crude 4—(1-benzyl-1H—imidazol—5—yl)-2—[(3R)—3-methy|morpholin-4—yl]—8—[1— (tetrahydro-2H-pyran—2-yl)-1H-pyrazoly|]-1,7-naphthyridine from step a in 3.0 ml of methanol and 0.32 ml of 2N hydrochloric acid was stirred for 3 h at room temperature. The reaction e was diluted with saturated aqueous sodium chloride solution and extracted with ethyl Detate (2x). The combined c phases were filtered using a Whatman filter and then [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp concentrated to s. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 5 mg (0.01 mmol) of the desired t. 1H-NMR (400MHz, 6): 6 [ppm]= 1.17 (3H), 3.22 (1H), 3.51 (1H), 3.65 (1H), 3.76 (1H), 3.90 - 4.07 (2H), 4.32 (1H), 5.24 (2H), 6.86 (2H), 7.11 - 7.24 (4H), 7.26 (1H), 7.34 (1H), 7.38 (1H), 7.63 (1H), 8.13 (1H), 8.29 ( 1H), 13.40 (1H). e 77 4—(2—fluorophenyl)[(3R)—3—methylmorpholin-4—yl]-8—(1H-pyrazol-5—yl)-1,7—naphthyridine Step a: 4—(2-fluorophenyl)[(3R)—3—methylmorpholinyl]-8—[1-(tetrahydro-ZH-pyranyl)-1H-pyrazol- -y|]-1,7-naphthyridine A suspension of 100 mg (0.19 mmol) of 2-[(3R)methy|morpho|in-4—yl]—8-[1—(tetrahydro-2H- pyranyl)—1H-pyrazoI—S-yl]-1,7—naphthyridin-4—y| trifluoromethanesulfonate, 53 mg (0.38 mmol) (2-fluorophenyl)boronic acid, 15 mg (0.02 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]— dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 247 mg (0.76 mmol) of caesium carbonate in 1.4 ml of dixoane was degased with argon. Under argon, the reaction mixture was stirred at 110°C for 2 h. After cooling the on mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-(2-fluorophenyl)[(3R)—3—methylmorpholin-4—yl]-8—(1H-pyrazol-5—yl)-1,7—naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp A solution of 126 mg of 4—(2—fluorophenyl)-2—[(3R)methy|morpholin-4—yl]—8-[1—(tetrahydro-2H- pyranyl)-1H-pyrazoly|]-1,7-naphthyridine from step a in 6 ml of methanol and 0.27 ml of 2N hydrochloric acid was d for 90 min at room temperature. The reaction mixture was treated with 2 ml of a saturated s sodium bicarboante solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to dryness. The residue was purified by preparative HPLC urifier: basic conditions) to give 16 mg (0.04 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm] = 1.31 (3H), 3.39 (1H), 3.58 (1H), 3.64 - 3.77 (1H), 3.82 (1H), 4.05 (1H), 4.23 (1H), 4.65 (1H), 7.15 (1H), 7.39 - 7.69 (7H), 8.32 (1H), 13.33 (1H).

Example 78 2-[(3R)—3-methylmorpholin-4—yl](2-methyl-1,3-thiazoly|)(1H-pyrazolyl)-1,7- naphthyridine Step 3: 2-[(3R)—3-methylmorpholin-4—yl](2-methyl-1,3-thiazo|y|)[1-(tetrahyd ro-Z H-pyran-Z-yl)- 1H-pyrazo|y|]-1,7-naphthyridine A suspension of 100 mg (0.19 mmol) of 2-[(3R)methy|morpho|iny|][1-(tetrahydro-2H- -yl)—1H-pyrazolyl]-1,7-naphthyridin-4—yl trifluoromethanesulfonate, 85 mg (0.38 mmol) [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 2—methy|—5—(4,4,5,5—tetramethyl—1,3,2—dioxaborolan-Z—yl)—1,3-thiazo|e, 15 mg (0.019 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]dich|oropalladium(ll) complex with dichloromethane (1:1, Pd(dppf)C|2) and 105 mg (0.76 mmol) of potassium carbonate in 2.0 ml of MeCN and 1.0 ml water was degased with argon. Under argon, the reaction e was stirred at 130°C for 10 minutes in a microwave reactor. After cooling the reaction e was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without r purification in the next step.

Step b: 2-[(3R)methy|morpho|inyl](2-methy|-1,3-thiazo|y|)(1H-pyrazo|y|)-1,7- naphthyridine A solution of 183 mg of crude 2-[(3R)—3-methy|morpho|in-4—yl]-4—(2-methy|-1,3-thiazolyl)—8—[1- (tetrahydro—2H-pyran—2-yl)-1H—pyrazoI—5—yl]-1,7—naphthyridine from step a in 1.8 ml of methanol and 0.44 ml of 2N hydrochloric acid was stirred for 1 h at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then trated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 14 mg (0.04 mmol) ofthe desired product. 1H—NMR (400MHz, DMSO-d6): 6 [ppm]: 1.30 (3H), 2.79 (3H), 3.57 (1H), 3.71 (1H), 3.83 (1H), 4.05 (1H), 4.21 (1H), 4.56 - 4.71 (1H), 7.40 (1H), 7.55 (1H), 7.65 (1H), 7.73 (1H), 8.07 (1H), 8.39 (1H), 13.41 (1H).

Example 79 4—[4—methyl-6—(methylsulfonyl)pyridinyl][(3R)—3-methy|morpho|inyl](1H-pyrazol d-lfl-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp Step 3: 4-[4-methyI(methylsulfonyl)pyridinyl][(3R)methy|morpho|inyl][1-(tetrahydro- 2H-pyranyl)-1H-pyrazoly|]-1,7-naphthyridine A suspension of 75 mg (0.14 mmol) of 2—[(3R)methylmorpholin-4—yl]—8—[1—(tetrahydro-2H- pyran-Z-yl)-1H-pyrazo|yl]-1,7-naphthyridin-4—yl trifluoromethanesulfonate, 84 mg (0.28 mmol) 4-methyI-2—(methylsulfonyl)—5—(4,4,5,5—tetramethy|-1,3,2—dioxaborolan-2—y|)pyridine, 11 mg (0.014 mmol) of [1,1’-bis(dipheny|phosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 185 mg (0.56 mmol) of caesium carbonate in 1.0 ml of dixoane was degased with argon. Under argon, the on mixture was stirred at 110°C for 2 h.

After cooling the reaction mixture was diluted with saturated aqueous sodium chloride on and extracted with ethyl acetate (2x). The ded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-[4—methyl-6—(methylsulfonyl)pyridin-3—yl][(3R)methy|morpho|inyl](1H-pyrazo|—5- yl)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 152 mg of 4-[4-methyl-6—(methylsu|fony|)pyridin-3—yl]—2-[(3R)—3-methylmorpho|in y|]—8—[1-(tetrahydro-2H-pyran—2-yl)-1H—pyrazo|—5—y|]-1,7—naphthyridine from step a in 1.3 ml of ol and 0.32 ml of 2N hydrochloric acid was stirred for 60 min at room temperature. The on mixture was treated with 2 ml of a saturated aqueous sodium bicarboante solution and ted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 33 mg (0.07 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 8 [ppm] = 1.30 (3H), 2.23 (3H), 3.35 (4H), 3.57 (1H), 3.65 - 3.76 (1H), 3.76 — 3.89 (1H), 4.04 (1H), 4.14 — 4.32 (1H), 4.60 (1H), 6.98 (1H), 7.43 (1H), 7.57 (1H), 7.64 (1H), 8.17 (1H), 8.28 (1H), 8.68 (1H), 13.41(1H).

Example 80 4-(1-cyclopropyl-lH-pyrazoI-S-yl)[(3R)methy|morpholin-4—yl](1H-pyrazoIyl)-1,7- naphthyridine Step 3: 4-(1-cyclopropyl-1H-pyrazoIyl)[(3R)methy|morpho|in-4—yl][1-(tetrahydro-ZH-pyran-Z- yl)-1H-pyrazolyl]-1,7-naphthyridine ation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A suspension of 100 mg (0.19 mmol) of 2—[(3R)-3—methy|morpholin—4—yl]—8—[1—(tetrahydro—2H— pyranyl)-1H-pyrazol-S-yl]—1,7-naphthyridinyl trifluoromethanesulfonate, 57 mg (0.38 mmol) (l-cyclopropyl-1H-pyrazolyl)boronic acid, 15 mg (0.019 mmol) of [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 247 mg (0.76 mmol) of caesium carbonate in 1.4 ml of dixoane was degased with argon. Under argon, the reaction mixture was stirred at 110°C for 1 h. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude t that was used without further purification in the next step.

Step b: 4—(1-cyclopropyl-1H-pyrazol-S-yl)[(3R)methy|morpholin-4—yl](1H-pyrazolyl)-1,7- naphthyridine A solution of 96 mg of crude 4-(1-cyclopropyl-1H-pyrazo|—5-yl)[(3R)methylmorpholin-4—yl]—8- [1—(tetrahydro—2H—pyran-2—yl)—1H-pyrazol—5-yl]—1,7—naphthyridine from step a in 5.0 ml of ol and 0.20 ml of 2N hydrochloric acid was stirred for 3 h at room temperature. The reaction mixture was treated with 2 ml of a saturated aqueous sodium bicarboante solution and extracted with ethyl acetate (2x). The ed organic phases were filtered using a Whatman filter and then concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 6 mg (0.02 mmol) of the d t. 1H-NMR (400MHz, DMSO-d6): 6 [ppm] = 0.74 - 0.83 (2H), 0.91 - 1.02 (2H), 1.30 (3H), 3.39 (1H), 3.52 - 3.64 (2H), 3.73 (1H), 3.83 (1H), 4.06 (1H), 4.23 (1H), 4.60 - 4.71 (1H), 6.59 (1H), 7.28 (1H), 7.43 (1H), 7.53 - 7.79 (3H), 8.36 (1H), 13.01 (1H). nample 81 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 4-[2-fluoro-4—(piperazin-l—yl)pheny|][(3R)methy|morpho|iny|](1H-pyrazol-S-y|)-1,7- naphthyridine Step 3: 4-[2-fluoro(piperazin-l-yl)phenyl][(3R)methylmorpho|iny|][1-(tetrahydro-ZH- Z-yl)-1H-pyrazo|y|]-1,7-naphthyridine A suspension of 100 mg (0.19 mmol) of 2-[(3R)methy|morpholinyl]—8—[1-(tetrahydro-2H- pyran-Z-yl)-1H-pyrazo|y|]-1,7-naphthyridinyl trifluoromethanesulfonate, 85 mg (0.38 mmol) oro(piperazin-l-yl)pheny|]boronic acid, 15 mg (0.019 mmol) of [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(|I) complex with dichloromethane (1:1, Pd(dppf)C|2) and 65 mg (0.47 mmol) of potassium carbonate in 2.0 ml of MeCN and 1.0 ml water was degased with argon. Under argon, the reaction mixture was stirred at 130°C for 10 minutes in a microwave reactor. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride on and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-[2-fluoro-4—(piperazin-l—yl)phenyl][(3R)—3-methylmorpho|iny|](1H-pyrazol-S-yl)—1,7- naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp A solution of 106 mg of crude 4-[2-fluoro(piperazin-1—yl)phenyl]—2-[(3R)methy|morpholin y|]—8—[1-(tetrahydro—2H—pyran—2—yl)-1H—pyrazol—5—yl]-1,7—naphthyridine from step a in 3.0 ml of ol and 0.38 ml of 2N hydrochloric acid was stirred for 1 h at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then trated to s. The residue was purified by preparative HPLC (Autopurifier: acidic conditions) to give 20 mg (0.04 mmol) ofthe desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]= 1.29 (3H), 2.78 - 3.01 (m, 4H), 3.20 - 3.43 (m, 5H), 3.57 (1H), 3.72 (1H), 3.82 (1H), 4.04 (1H), 4.20 (1H), 4.62 (1H), 6.81 - 7.03 (2H), 7.25 (1H), 7.30 - 7.49 (3H), 7.65 (1H), 8.25 (1H), 8.32 (1H).

Example 82 2-[(3R)—3-methylmorpholin-4—yl]-4—[4—(methylsulfonyl)piperazin-1—yl](1H-pyrazolyl)—1,7- naphthyridine Step 3: 2-[(3R)—3-methylmorpholin-4—yl][4-(methylsulfonyl)piperazin-1—yl][1—(tetrahyd ro-ZH- pyran-Z-yl)-1H-pyrazolyl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp l 3 A mixture of 150 mg (0.28 mmol) of 2-[(3R)methylmorpholin-4—yl]—8—[1-(tetrahydro-2H-pyran yl)—1H-pyrazolyl]-1,7-naphthyridin-4—y| trifluoromethanesulfonate and 159 mg (0.97 mmol) 1- (methylsulfonyl)piperazine in 0.42 ml of MeCN was stirred at 70°C for 8 h under argon. After cooling the reaction mixture was diluted with ethyl acetate and THF and washed with saturated aqueous sodium chloride solution. The organic phase was ed using a Whatman filter and then trated to give the crude product that was used without r purification in the next step.

Step b: 2-[(3R)—3-methy|morpholin-4—yl][4—(methylsulfonyl)piperaziny|](1H-pyrazolyl)—1,7- naphthyridine O fi—CH3 A solution of 267 mg of crude 2-[(3R)—3-methylmorpholinyl]—4—[4-(methylsulfonyl)piperazin-l- yl]-8—[1-(tetrahydro-2H-pyran-Z-yl)-1H-pyrazol-5—yl]-1,7-naphthyridine from step a in 2.3 ml of methanol and 0.57 ml of 2N hydrochloric acid was stirred for 1 h at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted Dith ethyl e / THF (1:1) (2x). The combined organic phases were filtered using a Whatman [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp filter and then concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 55 mg (0.12 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]= 1.27 (3H), 3.00 (3H), 3.18 - 3.31 (5H), 3.38 - 3.49 (4H), 3.55 (1H), 3.70 (1H), 3.83 (1H), 4.05 (1H), 4.13 (1H), 4.53 - 4.64 (1H), 6.84 (1H), 7.35 (1H), 7.53 - 7.71 (2H), 8.33 (1H), 13.21 (1H).

Example 83 N-(2,2-dimethylpropyl)—N-methyl[(3R)-3—methylmorpholin-4—yl]-8—(1H-pyrazol-5—yl)-1,7— naphthyridinamine Step a: N-(2,2-dimethylpropyl)—N-methyl-2—[(3R)methy|morpho|inyl][1-(tetrahyd ro-ZH-pyran-Z- y|)-1H-pyrazo|y|]-1,7-naphthyridinamine HSC CH3 A mixture of 150 mg (0.28 mmol) of 2—[(3R)-3—methy|morpho|in—4—yl][1—(tetrahydro-2H-pyran y|)-1H-pyrazo|y|]-1,7-naphthyridin-4—y| trifluoromethanesulfonate and 98 mg (0.97 mmol) N,2,2—trimethy|propan—l-amine in 0.42 ml of MeCN was stirred at 70°C for 7 h under argon. After cooling the reaction e was diluted with ethyl acetate and THF and washed with saturated aqueous sodium de solution. The organic phase was filtered using a Whatman filter and then concentrated to give the crude product that was used t r purification in the next step.

Step b: N-(2,2-dimethylpropyl)—N-methyl[(3R)-3—methylmorpholin-4—yl]-8—(1H-pyrazolyl)-1,7— naphthyridin-4—amine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp H30 CH3 A solution of 205 mg of crude N-(2,2—dimethy|propyl)—N—methy|—2-[(3R)—3—methy|morpho|in—4-y|]- 8-[1—(tetrahydro-2H-pyranyl)-1H-pyrazoIyI]—1,7-naphthyridin—4-amine from step a in 2.0 ml of methanol and 0.50 ml of 2N hydrochloric acid was stirred for 1 h at room temperature. The on mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate / THF (1:1) (2x). The combined organic phases were ed using a Whatman filter and then concentrated to dryness. The residue was purified by ative HPLC (Autopurifier: basic conditions) to give 47 mg (0.12 mmol) of the desired t. 1H—NMR (400MHz, DMSO-d6): 6 [ppm]: 0.90 (9H), 1.23 (3H), 3.09 (3H), 3.16 - 3.31 (2H), 3.36 — 3.42 (1H), 3.56 (1H), 3.63 - 3.78 (1H), 3.82 (1H), 3.92 - 4.18 (2H), 4.49 - 4.61 (1H), 6.99 (1H), 7.34 (1H), 7.60 (1H), 7.73 (1H), 8.30 (1H), 13.36 (1H).

Example 84 (1-{2-[(3R)methylmorpholin-4—yl](1H-pyrazolyl)-1,7-naphthyridin-4—yl}piperidin-4— yl)methano| Step a: (1-{2-[(3R)methylmorpholin-4—yl][1-(tetrahyd ro-ZH-pyranyl)—1H-pyrazolyl]-1,7- naphthyridin-4—yl}piperidin-4—yl)methano| [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A mixture of 150 mg (0.28 mmol) of )methylmorpholinyl]-8—[1-(tetrahydro-2H-pyran -pyrazolyl]-1,7-naphthyridinyl trifluoromethanesulfonate and 111 mg (0.97 mmol) piperidinylmethanol in 0.42 ml of MeCN was stirred at 70°C for 3 h under argon. After cooling the reaction mixture was diluted with ethyl acetate and THF and washed with saturated aqueous sodium de solution. The organic phase was filtered using a Whatman filter and then trated to give the crude product that was used t further purification in the next step.

Step b: (1-{2-[(3R)methy|morpholinyl](1H-pyrazol-S-yl)-1,7-naphthyridiny|}piperidin yl)methano| A solution of 345 mg of crude (1-{2-[(3R)methylmorpholin-4—yl][1—(tetrahydro-2H-pyran yl)-1H-pyrazolyl]-1,7-naphthyridin-4—yl}piperidinyl)methanol from step a in 3.2 ml of methanol and 0.81 ml of 2N hydrochloric acid was stirred for 1 h at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate / THF (1:1) (2x). The combined organic phases were filtered using a Whatman [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp filter and then concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 37 mg (0.09 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]= 1.26 (3H), 1.38 - 1.55 (2H), 1.55 - 1.71 (1H), 1.76 - 1.96 (2H), 2.71 - 2.93 (2H), 3.22 - 3.31 (1H), 3.36 - 3.43 (2H), 3.43 - 3.61 (3H), 3.70 (1H), 3.82 (1H), 4.03 (1H), 4.11 (1H), 4.51 - 4.62 (2H), 6.74 (1H), 7.34 (1H), 7.56 (1H), 7.61 (1H), 8.31 (1H), 13.33 (1H).

Example 85 N-cyclopropyl-N-methyl-Z-[(3R)—3—methy|morphoIin-4—yl](1H-pyrazo|y|)-1,7-naphthyridin- 4-amine Step a: N-cyclopropyl-N-methyl[(3R)-3—methylmorpho|iny|][1-(tetrahyd ro-ZH-pyran-Z-yl)—1H- pyrazol-S-yl]-1,7—naphthyridinamine A mixture of 150 mg (0.28 mmol) of 2—[(3R)-3—methy|morpho|in-4—yl][1—(tetrahydro-2H—pyran-2— -pyrazo|y|]-1,7-naphthyridin-4—y| oromethanesu|fonate and 69 mg (0.97 mmol) N- methylcyclopropanamine in 0.42 ml of MeCN was stirred at 70°C for 7 h under argon. After cooling the reaction mixture was diluted with ethyl acetate and THF and washed with saturated aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: N-cyclopropyl-N-methyl-Z-[(3R)—3—methy|morphoIin-4—y|](1H-pyrazo|y|)-1,7-naphthyridin- 4-amine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 188 mg of crude opropyl-N-methyl[(3R)methylmorpholinyI]—8-[1- (tetrahydro—2H-pyran—2-yl)-1H—pyrazol—5—yl]-1,7—naphthyridin-4—amine from step a in 1.9 ml of methanol and 0.48 ml of 2N hydrochloric acid was stirred for 1 h at room ature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate / THF (1:1) (2x). The combined c phases were filtered using a Whatman filter and then concentrated to dryness. The e was purified by preparative HPLC (Autopurifier: basic conditions) to give 45 mg (0.12 mmol) of the desired product. 1H—NMR (400MHz, DMSO-d6): 6 [ppm]: 0.34 — 0.56 (2H), 0.75 — 0.89 (2H), 1.27 (3H), 2.78 — 2.89 (1H), 3.08 (3H), 3.23 - 3.32 (1H), 3.56 (1H), 3.66 - 3.76 (1H), 3.83 (1H), 3.99 - 4.14 (2H), 4.46 - 4.58 (1H), 6.86 (1H), 7.33 (1H), 7.60 (1H), 7.65 (1H), 8.25 (1H), 13.36 (1H).

Example 86 4—(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-y|)[(3R)methy|morphoIinyl](1H-pyrazo|—5- yl)-1,7-naphthyridine Step a: 4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-y|)[(3R)methy|morphoIinyl][1-(tetrahydro- 2H-pyran-Z-yl)-1H-pyrazol-S-yl]-1,7-naphthyridine "mixture of 150 mg (0.28 mmol) of 2—[(3R)-3—methy|morpho|in—4—yl][1—(tetrahydro—2H—pyran-2— [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp y|)—1H—pyrazo|—5-yl]—1,7—naphthyridin—4—yl trifluoromethanesulfonate and 119 mg (0.97 mmol) ,6,7,8—tetrahydroimidazo[1,2-a]pyrazine in 0.42 ml of MeCN was stirred at 70°C for 48 h under argon. After cooling the reaction mixture was diluted with ethyl acetate and THF and washed with saturated aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and then concentrated to give the crude t that was used without further purification in the next step.

Step b: 4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-y|)[(3R)methy|morphoIinyl](1H-pyrazol yl)-1,7-naphthyridine A solution of 106 mg of crude 4-(5,6—dihydroimidazo[1,2-a]pyrazin-7(8H)—yl)[(3R) morpholin—4—yl]—8—[1—(tetrahydro—2H-pyran—2-yl)—1H—pyrazol—5-yl]—1,7—naphthyridine from step a in 5.0 ml of methanol and 0.21 ml of 2N hydrochloric acid was stirred for 1 h at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and ted with ethyl acetate / THF (1:1) (2x). The combined organic phases were filtered using a Whatman filter and then trated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic ions) to give 6 mg (0.01 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.28 (3H), 3.55 (1H), 3.61 - 3.75 (3H), 3.83 (1H), 4.05 (1H), 4.19 (1H), 4.25 - 4.36 (2H), 4.41 - 4.52 (2H), 4.62 (1H), 6.91 (1H), 6.96 (1H), 7.22 (1H), 7.36 (1H), 7.62 (1H), 7.68 (1H), 8.33 (1H), 13.38 (1H).

Example 87 N-(4-fluorophenyl)-N-methyl-2—[(3R)methylmorpholin-4—yl](1H-pyrazolyl)—1,7- naphthyridinamine Dep a: ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp ation] jennyp Unmarked set by jennyp N-(4-f|uorophenyl)-N-methyI[(3R)-3—methy|morpho|inyl][1-(tetrahydro-ZH-pyran-Z-y|)- 1H-pyrazo|y|]-1,7-naphthyridin-4—amine A mixture of 150 mg (0.28 mmol) of 2-[(3R)methy|morpho|in-4—yl]—8—[1-(tetrahydro-2H-pyran y|)—1H-pyrazo|—5-y|]—1,7—naphthyridin—4—y| trifluoromethanesulfonate and 121 mg (0.97 mmol) 4— f|uoro-N-methy|ani|ine in 0.42 ml of MeCN was stirred at 70°C for 3 h under argon. After cooling the reaction mixture was diluted with ethyl e and THF and washed with saturated aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and then trated to give the crude product that was used without further purification in the next step.

Step b: N-(4-fluorophenyl)-N-methyl[(3R)methylmorpho|inyl](1H-pyrazolyl)-1,7- naphthyridinamine A solution of 273 mg of crude N—(4—fluorophenyll—N-methy|—2—[(3R)—3-methylmorpholin-4—yl]—8—[1— (tetrahydro-2H-pyran—2-yl)-1H-pyrazoly|]-1,7-naphthyridinamine from step a in 2.5 ml of methanol and 0.63 ml of 2N hydrochloric acid was stirred for 1 h at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted Dith ethyl acetate / THF (1:1) (2x). The combined organic phases were filtered using a Whatman [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp filter and then concentrated to s. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 54 mg (0.13 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]= 1.30 (3H), 3.45 (3H), 3.58 (1H), 3.73 (1H), 3.84 (1H), 4.06 (1H), 4.16 (1H), 4.54 - 4.66 (1H), 6.95 - 7.02 (2H), 7.03 - 7.15 (4H), 7.36 (1H), 7.62 (1H), 8.08 (1H), 13.26 (1H).

Example 88 )—3-methy|morpholin-4—yl](6-methy|pyridinyl)—8-(1H-pyrazolyl)-1,7-naphthyridine Intermediate—10 (0.10 g, 0.19 mmol) was solubilised in dioxane (1 ml). 2-MethyI pyridinylboronic acid (52 mg, 0.38 mmol) was added in one portion followed by addition of caesium carbonate (0.25 g, 0.76 mmol) and PdCl2(dppf) in complex with dichloromethane (31 mg, 0.038 mmol). The reaction was heated for 4 hours in a sealed tube at 110°C. The reaction was then cooled to rt and filtered. The solid was washed with ethyl e and the filtrate was concentrated under reduced pressure. The crude material was purified by preparative HPLC nitriIe/water/formic acid mixture). The combined fractions were concentrated under reduced pressure, solubilised in dichloromethane and 3N hydrochloric acid was added. The mixture was stirred overnight at rt and then quenched with a saturated aqueous solution of sodium en carbonate. The aqueous phase was extracted three times with dichloromethane. The organic phase was dried, filtered and trated under reduced pressure. The title compound was obtained in 53% yield (39 mg). 1H-NMR (400MHz, DMSO-de): 6 [ppm]: 1.29 (d, 3H), 2.59 (s, 3H), 3.35 - 3.42 (m, 1H), 3.56 (t, 1H), 3.71 (d, 1H), 3.82 (d, 1H), 4.05 (d, 1H), 4.23 (d, 1H), 4.61 - 4.71 (m, 1H), 7.38 (d, 1H), 7.43 (s, 1H), 7.47 (d, 2H), 7.63 (s, 1H), 7.92 (dd, 1H), 8.32 (d, 1H), 8.64 (d, 1H), 13.43 (s, 1H).

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp ed set by jennyp Example 89 4-(2-fluoropyridinyl)[(3R)methy|morpho|iny|](1H-pyrazo|y|)-1,7-naphthyridine Intermediate—10 (0.25 g, 0.47 mmol) was solubilised in dioxane (2.5 ml). (2—Fluoropyridin yl)boronic acid (0.20 g, 1.4 mmol) was added in one portion followed by addition of caesium carbonate (0.62 g, 1.90 mmol) and PdC|2(dppf) in complex with dichloromethane (77 mg, 0.094 mmol). The reaction was heated for 4 hours in a sealed tube at 110°C. The reaction was then cooled to rt and filtered. The solid was washed with dichloromethane and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (hexane/ethyl acetate/ethanol mixture). The combined ons were concentrated under reduced pressure, solubilised in methanol (3 ml) and 3N hydrochloric acid (10 ml) was added. The mixture was stirred for 2 hours rt and then ed with a 3M sodium hydroxide solution. The suspension was ed and washed with water. The solid was dried under reduced pressure at 60°C. The title compound was obtained in 90% yield (109 mg). 1H-NMR (400MHz, DMSO-ds): 6 [ppm]: 1.30 (d, 3H), 3.29 - 3.41 (m, 1H), 3.51 - 3.61 (m, 1H), 3.67 - 3.75 (m, 1H), 3.78 - 3.86 (m, 1H), 4.00 - 4.09 (m, 1H), 4.17 - 4.26 (m, 1H), 4.59 - 4.68 (m, 1H), 7.17 (dd, 1H), 7.43 (s, 1H), 7.58 - 7.68 (m, 3H), 8.14 - 8.22 (m, 1H), 8.32 (d, 1H), 8.44 - 8.48 (m, 1H), 13.43 (br. s, 1H).

Example 90 4-(2-fluoro-4—methylpyridiny|)[(3R)methylmorpholinyl](1H-pyrazolyl)—1,7- naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ediate-10 (0.10 g, 0.19 mmol) was solubilised in dioxane (1 ml). (2-Fluoromethylpyridin- 3-yl)boronic acid (61 mg, 0.38 mmol) was added in one portion followed by addition of caesium carbonate (0.25 g, 0.76 mmol) and dppf) in x with dichloromethane (31 mg, 0.038 mmol). The reaction was heated for 4 hours in a sealed tube at 110°C. The reaction was then cooled to rt and filtered. The filtrate was concentrated under reduced pressure. The crude material was purified by preparative HPLC (acetonitriIe/water/formic acid mixture). The combined fractions were concentrated under reduced pressure, solubilised in dichloromethane and washed with a saturated solution of sodium hydrogen carbonate. The organic phase was dried (silicon filter) and concentrated under reduced re. The title compound was obtained in 47% yield (36 mg). 1H-NMR (400MHz, FORM-d): 6 [ppm]: 1.47 (dd, 3H), 2.16 (d, 3H), 3.58 (td, 1H), 3.70 - 3.78 (m, 1H), 3.90 — 3.95 (m, 2H), 4.01 - 4.09 (m, 1H), 4.19 (dd, 1H), 4.37 - 4.46 (m, 1H), 6.94 (d, 1H), 7.13 (d, 1H), 7.26 (d, 1H), 7.32 - 7.35 (m, 1H), 7.74 (d, 1H), 8.27 (d, 1H), 8.37 (d, 1H).

Example 91 2-[(3R)—3-methy|morpholin-4—yl]-4—(1-methyl-1H-pyrrol-Z-y|)(1H-pyrazolyl)—1,7- naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Intermediate—10 (0.10 g, 0.19 mmol yl—2—(4,4,5,5-tetramethyl-1,3,2—dioxaborolan—Z—yI)—1H— e (79 mg, 0.38 mmol), aq. ium carbonate (0.29 ml, 2 M) and PdC|2(PPh3)2 (13 mg, 0.019 mmol) were solubilised in dimethoxyethane (5 ml). The reaction mixture was stirred for 10 s at 130°C under microwave irradiation. After cooling to rt, the reaction e was dried by filtration and the filtrate was concentrated under reduced pressure. The crude material was purified by preparative HPLC (acetonitriIe/water/formic acid mixture). The combined fractions were concentrated under reduced pressure, solubilised in romethane and washed with a saturated solution of sodium hydrogen carbonate. The organic phase was dried (silicon filter) and concentrated under reduced pressure. The title compound was obtained in 53% yield (39 mg). 1H—NMR (400MHz, DMSO-de): 6 [ppm]: 1.29 (d, 3H), 3.28 — 3.39 (m, 1H), 3.52 - 3.62 (m, 4H), 3.68 — 3.76 (m, 1H), 3.78 - 3.86 (m, 1H), 4.00 - 4.09 (m, 1H), 4.18 - 4.26 (m, 1H), 4.59 - 4.68 (m, 1H), 6.22 - 6.28 (m, 1H), 6.35 (dd, 1H), 7.07 (dd, 1H), 7.41 (s, 2H), 7.48 (d, 1H), 7.64 (br. s, 1H), 8.34 (d, 1H), 13.41 (br. s, 1H).

Example 92 4-(6-fluoromethylpyridiny|)[(3R)methy|morpholin-4—yl](1H-pyrazolyl)—1,7- naphthyridine Intermediate—10 (0.075 g, 0.14 mmol) was solubilised in dioxane (3.2 ml). (6-Fluoro methylpyridin—3-yl)boronic acid (44 mg, 0.28 mmol) was added in one portion followed by addition of caesium carbonate (0.19 g, 0.59 mmol) and PdC|2(dppf) in complex with dichloromethane (11 mg, 0.014 mmol). The reaction was heated for 4 hours in a sealed tube at 110°C. The reaction was then cooled to rt and filtered. The filtrate was concentrated under dduced pressure. The crude material was ed by flash column chromatography [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (hexane/ethyl acetate mixture). The combined ons were concentrated under reduced pressure, solubilised in methanol (1.5 ml) and 3N hydrochloric acid (1.6 ml) was added. The mixture was stirred overnight at rt and then ed with a 3M sodium hydroxide solution. The suspension was filtered and washed with water. The solid was purified by preparative HPLC (acetonitrile/water/formic acid e). The title compound was obtained in 20% yield (11 mg). 1H—NMR (400MHz, DMSO-de): 6 [ppm]: 1.30 (dd, 3H), 2.12 (s, 3H), 3.36 — 3.39 (m, 1H), 3.52 — 3.63 (m, 1H), 3.68 - 3.76 (m, 1H), 3.78 - 3.85 (m, 1H), 4.01 - 4.09 (m, 1H), 4.18 - 4.27 (m, 1H), 4.57 - 4.66 (m, 1H), 7.00 (dd, 1H), 7.33 (s, 1H), 7.40 — 7.45 (m, 1H), 7.51 (d, 1H), 7.65 (d, 1H), 8.17 (d, 1H), 8.29 (d, 1H), 13.42 (br. s, 1H).

Example 93 4-(2-fluoromethylpyridiny|)[(3R)methy|morpholin-4—yl](1H-pyrazolyl)—1,7- naphthyridine Intermediate—10 (0.075 g, 0.14 mmol) was solubilised in dioxane (3.2 ml) under argon. (2-Fluoro- 6—methylpyridin-3—yl)boronic acid (44 mg, 0.28 mmol) was added in one portion followed by addition of caesium ate (0.19 g, 0.59 mmol) and PdC|2(dppf) in complex with romethane (11 mg, 0.014 mmol). The reaction was heated for 4 hours in a sealed tube at 110°C. The reaction was then cooled to rt and ed. The filtrate was concentrated under d re. The crude material was purified by flash column chromatography (hexane/ethyl acetate mixture). The combined fractions were concentrated under reduced pressure, solubilised in methanol (1 ml) and 3N hydrochloric acid (1 ml) was added. The mixture was stirred overnight at rt and then basified with a 3M sodium hydroxide solution. The aspension was filtered and washed with water. The solid was purified by preparative HPLC [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (acetonitrile/water/formic acid mixture). The title compound was obtained in 54% yield (19 mg). 1H—NMR (400MHz, DMSO-de): 6 [ppm]: 1.30 (d, 3H), 2.56 (s, 3H), 3.36 - 3.40 (m, 1H), 3.52 — 3.61 (m, 1H), 3.67 - 3.75 (m, 1H), 3.79 - 3.86 (m, 1H), 4.00 - 4.07 (m, 1H), 4.17 - 4.24 (m, 1H), 4.58 - 4.66 (m, 1H), 7.18 (dd, 1H), 7.41 (d, 1H), 7.46 (dd, 1H), 7.58 (s, 1H), 7.65 (d, 1H), 8.04 (dd, 1H), 8.32 (d, 1H), 13.41 (br. s, 1H). e 94 4-(6-fluoropyridinyl)[(3R)methy|morpho|iny|](1H-pyrazo|y|)-1,7-naphthyridine Intermediate—10 (0.075 g, 0.14 mmol) was solubilised in dioxane (3.2 ml) under argon. (6- F|uoropyridiny|)boronic acid (40 mg, 0.28 mmol) was added in one portion followed by addition of caesium ate (0.19 g, 0.59 mmol) and PdC|2(dppf) in complex with dichloromethane (11 mg, 0.014 mmol). The reaction was heated for 4 hours in a sealed tube at 110°C. The reaction was then cooled to rt and filtered. The filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (hexane/ethyl acetate mixture). The combined fractions were concentrated under reduced re, solubilised in methanol (1.4 ml) and 3N hydrochloric acid (1.4 ml) was added. The mixture was stirred overnight at rt and then basified with a 3M sodium hydroxide solution. The suspension was ed and washed with water. The solid was purified by preparative HPLC (acetonitriIe/water/formic acid mixture). The title compound was ed in 10% yield (5 mg). 1H-NMR (400MHz, DMSO-de): 6 [ppm]: 1.30 (d, 3H), 3.35 - 3.41 (m, 1H), 3.52 - 3.61 (m, 1H), 3.67 - 3.75 (m, 1H), 3.79 - 3.86 (m, 1H), 4.01 - 4.09 (m, 1H), 4.19 - 4.28 (m, 1H), 4.62 - 4.71 (m, 1H), 7.37 (d, 1H), 7.39 - 7.46 (m, 2H), 7.55 (s, 1H), 7.62 - 7.68 (m, 1H), 8.21 - 8.29 (m, 1H), 8.34 (d, 1H), 8.48 D, 1H), 13.43 (br. s, 1H).

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 95 4-(6-methoxypyridinyl)[(3R)methylmorpholin-4—y|](1H-pyrazolyl)-1,7- naphthyridine Iuoropyridinyl)[(3R)methy|morpholinyl]—8-(1H-pyrazo|—5-y|)-1,7-naphthyridine (10 mg, 0.026 mmol) was solubilised in methanol (3 ml) and the mixture was stirred overnight at 50°C. Sodium methoxide was then added to the mixture (7.1 mg, 0.13 mmol) and the reaction was stirred for onal 18 hours at 50°C. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude al was purified by preparative HPLC (acetonitrile/water/formic acid mixture) and the title compound was obtained in 59% yield (6.3 mg). lH-NMR (400MHz, DMSO-de): 6 [ppm]: 1.30 (d, 3H), 3.34 - 3.40 (m, 1H), 3.50 - 3.62 (m, 1H), 3.68 - 3.75 (m, 1H), 3.79 - 3.86 (m, 1H), 3.96 (s, 3H), 4.01 - 4.09 (m, 1H), 4.19 — 4.28 (m, 1H), 4.61 — 4.71 (m, 1H), 7.04 (d, 1H), 7.42 (d, 2H), 7.47 (s, 1H), 7.64 (br. s, 1H), 7.96 (dd, 1H), 8.33 (d, 1H), 8.40 (d, 1H), 13.41 (br. s, 1H).

Example 96 4—(6-methoxy—5-methylpyridinyl)[(3R)methylmorpholin-4—y|](1H-pyrazolyl)-1,7— naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 4—(6—fluoro—5—methylpyridin-3—yl)[(3R)—3-methylmorpholinyl]—8—(1H—pyrazol-5—yI)-1,7- naphthyridine (13 mg, 0.031 mmol) was solubilised in methanol (3 ml) and the mixture was stirred overnight at 50°C. Sodium methoxide was then added to the mixture (8.3 mg, 0.16 mmol) and the on was stirred for additional 18 hours at 50°C. Sodium methoxide was again added (8.3 mg, 0.16 mmol) and the on was d for 24 hours at 50°C. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude material was purified by preparative HPLC (acetonitrile/water/formic acid mixture) and the title nd was obtained in 93% yield (12 mg). 1H-NMR (400MHz, DMSO-de): 6 [ppm]: 1.30 (dd, 3H), 2.04 (s, 3H), 3.34 - 3.40 (m, 1H), 3.52 - 3.63 (m, 1H), 3.68 - 3.76 (m, 1H), 3.77 - 3.85 (m, 1H), 3.89 - 3.96 (m, 3H), 4.00 - 4.08 (m, 1H), 4.17 - 4.26 (m, 1H), 4.56 - 4.67 (m, 1H), 6.91 (s, 1H), 7.00 - 7.06 (m, 1H), 7.39 - 7.47 (m, 2H), 7.64 (br. s, 1H), 8.07 (s, 1H), 8.29 (d, 1H), 13.41 (br. s, 1H).

Example 97 4-(6-fluoro-Z-methylpyridiny|)[(3R)methy|morpholin-4—yl](1H-pyrazolyl)—1,7- naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Intermediate-10 (0.075 g, 0.14 mmol) was solubilised in dioxane (3.2 ml) under argon. (6-Fluoro- 2-methylpyridinyl)boronic acid (44 mg, 0.28 mmol) was added in one portion ed by addition of caesium carbonate (0.19 g, 0.59 mmol) and PdC|2(dppf) in complex with romethane (11 mg, 0.014 mmol). The reaction was heated for 4 hours in a sealed tube at 110°C. The reaction was then cooled to rt and filtered. The filtrate was concentrated under d pressure. The crude material was purified by preparative HPLC (acetonitriIe/water/formic acid mixture) followed by flash column chromatography (hexane/ethyl acetate mixture). The title compound was obtained in 68% yield (41 mg). 1H-NMR (400MHz, DMSO-ds): 6 [ppm]: 1.29 (t, 3H), 2.21 (d, 3H), 3.28 - 3.39 (m, 1H), 3.52 - 3.62 (m, 1H), 3.68 - 3.76 (m, 1H), 3.77 - 3.85 (m, 1H), 4.00 - 4.08 (m, 1H), 4.17 - 4.27 (m, 1H), 4.56 - 4.66 (m, 1H), 7.02 (dd, 1H), 7.21 (dd, 1H), 7.44 (br. s., 1H), 7.51 (d, 1H), 7.64 (br. s., 1H), 7.94 (t, 1H), 8.29 (d, 1H), 13.43 (br. s, 1H).

Example 98 2-[(3R)—3-methy|morpholin-4—yl][1-methy|—3-(trifluoromethyl)-1H-pyrazo|—5-yl](1H-pyrazol- -yl)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ediate—18 (0.060 g, 0.14 mmol) was solubilised in dioxane (3.3 ml) under argon. [1-Methyl- 3-(trifluoromethyl)-1H-pyrazo|—5-yl]boronic acid (56 mg, 0.28 mmol) was added in one portion followed by addition of caesium carbonate (0.19 g, 0.58 mmol) and PdC|2(dppf) in complex with dichloromethane (11 mg, 0.014 mmol). The reaction was heated for 4 hours in a sealed tube at 110°C. The reaction was then cooled to rt and filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (hexane/ethyl acetate mixture) ed by ative TLC (hexane/MTBE mixture). The combined fractions were concentrated under reduced pressure, lised in ol (1 ml) and 3N hydrochloric acid (2 ml) was added. The mixture was stirred overnight at rt and then basified with a 3M sodium hydroxide solution. The suspension was filtered and washed with water. The solid was dried under reduced pressure at 60°C. The title compound was obtained in 6% yield (4 mg). 1H-NMR (400MHz, DMSO-de): 6 [ppm]: 1.30 (d, 3H), 3.36 - 3.42 (m, 1H), 3.52 - 3.62 (m, 1H), 3.68 - 3.75 (m, 1H), 3.79 - 3.87 (m, 4H), 4.01 - 4.09 (m, 1H), 4.19 - 4.27 (m, 1H), 4.59 - 4.68 (m, 1H), 7.13 (s, 1H), 7.25 (d, 1H), 7.43 (br. s, 1H), 7.65 (br. s, 1H), 7.72 (s, 1H), 8.36 (d, 1H), 13.45 (br. s, 1H). e 99 2-[(3R)—3-methy|morpholin-4—yl](3-methy|—2-thienyl)(1H-pyrazo|y|)-1,7-naphthyridine [Annotation] jennyp None set by jennyp ation] jennyp ionNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Intermediate—10 (0.075 g, 0.14 mmol), (3-methylthiophenyl)boronic acid (40 mg, 0.28 mmol), aq. potassium carbonate (0.21 ml, 2 M) and PdC|2(PPh3)2 (10 mg, 0.019 mmol) were solubilised in dimethoxyethane (4 ml). The reaction mixture was stirred for 10 minutes at 130°C under microwave ation. After cooling to rt, the on mixture was dried by filtration and the filtrate was concentrated under reduced pressure. The crude material was ed by preparative HPLC (acetonitriIe/water/formic acid mixture). The combined fractions were concentrated under reduced pressure, solubilised in methanol (2 ml) and 3M hydrochloric acid (2 ml) was added. The reaction was stirred overnight at rt and then basified with a 3M sodium hydroxide solution. The suspension was filtered and washed with water. The solid was dried under reduced pressure at 60°C. The title compound was obtained in 66% yield (38 mg). lH-NMR (400MHz, DMSO-de): 6 [ppm]: 1.29 (d, 3H), 2.09 (s, 3H), 3.28 - 3.39 (m, 1H), 3.51 - 3.62 (m, 1H), 3.67 — 3.75 (m, 1H), 3.78 - 3.85 (m, 1H), 3.99 - 4.08 (m, 1H), 4.15 — 4.25 (m, 1H), 4.58 — 4.67 (m, 1H), 7.16 (d, 1H), 7.32 (d, 1H), 7.41 (d, 1H), 7.46 (s, 1H), 7.64 (d, 1H), 7.73 (d, 1H), 8.34 (d, 1H), 13.35 (br. s, 1H).

Example 100 2-[(3R)—3-methy|morpholin-4—yl]-4—(5-methy|—2-thienyl)-8—(1H-pyrazo|yl)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Intermediate—10 (0.075 g, 0.14 mmol), (5-methylthiophen-Z-yl)boronic acid (40 mg, 0.28 mmol), aq. ium carbonate (0.21 ml, 2 M) and PdC|2(PPh3)z (10 mg, 0.019 mmol) were solubilised in dimethoxyethane (4 ml). The reaction mixture was stirred for 10 s at 130°C under microwave irradiation. After cooling to rt, the reaction mixture was dried by filtration and the filtrate was concentrated under reduced pressure. The crude material was purified by preparative HPLC (acetonitrile/water/formic acid mixture). The combined fractions were concentrated under reduced pressure, solubilised in methanol (2 ml) and 3M hydrochloric acid (2 ml) was added. The on was stirred overnight at rt and then basified with a 3M sodium hydroxide solution. The suspension was filtered and washed with water. The solid was dried under reduced pressure at 60°C. The title compound was obtained in 67% yield (39 mg). lH—NMR (400MHz, DMSO-de): 6 [ppm]: 1.28 (d, 3H), 2.57 (d, 3H), 3.28 - 3.39 (m, 1H), 3.51 - 3.61 (m, 1H), 3.67 - 3.75 (m, 1H), 3.78 - 3.85 (m, 1H), 4.00 - 4.08 (m, 1H), 4.15 - 4.23 (m, 1H), 4.58 - 4.67 (m, 1H), 7.02 (dd, 1H), 7.34 — 7.45 (m, 3H), 7.63 (s, 1H), 7.86 (d, 1H), 8.38 (d, 1H), 13.40 (br. s, 1H).

Example 101 2-[(3R)—3-methy|morpholinyl]-4—(4—methy|—3-thieny|)(1H-pyrazo|yl)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ediate—10 (0.075 g, 0.14 mmol), (4-methylthiophen—3-y|)boronic acid (40 mg, 0.28 mmol), aq. potassium carbonate (0.21 ml, 2 M) and PdC|2(PPh3)2 (10 mg, 0.019 mmol) were solubilised in dimethoxyethane (4 ml). The on mixture was stirred for 10 s at 130°C under microwave irradiation. After cooling to rt, the reaction mixture was dried by filtration and the filtrate was concentrated under reduced pressure. The crude material was purified by preparative HPLC (acetonitriIe/water/formic acid mixture). The combined ons were concentrated under reduced pressure, solubilised in dichloromethane (2 ml) and 3M hydrochloric acid (2 ml) was added. The reaction was stirred overnight at rt and then basified with a 3M sodium hydroxide solution and ted three times with dichloromethane. The organic phase was dried (silicon filter) and concentrated under reduced pressure. The title compound was obtained in 76% yield (45 mg). 1H—NMR (400MHz, s): 6 [ppm]: 1.29 (d, 3H), 2.03 (d, 3H), 3.33 (s, 1H), 3.51 - 3.62 (m, 1H), 3.67 - 3.75 (m, 1H), 3.77 - 3.84 (m, 1H), 4.00 - 4.08 (m, 1H), 4.17 - 4.26 (m, 1H), 4.57 - 4.67 (m, 1H), 7.17 (d, 1H), 7.37 — 7.47 (m, 3H), 7.64 (d, 1H), 7.68 (d, 1H), 8.31 (d, 1H), 13.40 (br. s, 1H).

Example 102 4-(3-chloro-Z-thienyl)[(3R)methylmorphoIiny|](1H-pyrazo|y|)-1,7-naphthyridine Intermediate—10 (0.075 g, 0.14 mmol), (3-chlorothiophenyl)boronic acid (46 mg, 0.28 mmol), aq. potassium carbonate (0.21 ml, 2 M) and PdC|2(PPh3)2 (10 mg, 0.019 mmol) were solubilised in dimethoxyethane (4 ml). The reaction mixture was stirred for 10 minutes at 130°C under ave irradiation. After g to rt, the reaction mixture was dried by filtration and the filtrate was concentrated under reduced pressure. The crude material was purified by preparative HPLC (acetonitriIe/water/ammonium hydroxyde). The combined fractions were concentrated under reduced pressure, solubilised in methanol (2 ml) and 3M hydrochloric acid (2 ml) was [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp added. The reaction was stirred overnight at rt and then basified with a 3M sodium hydroxide on. The suspension was ed and washed with water. The solid was dried under reduced pressure at 60°C. The title compound was obtained in 4% yield (2 mg). 1H—NMR (400MHz, e): 6 [ppm]: 1.29 (d, 3H), 3.34 - 3.39 (m, 1H), 3.52 - 3.62 (m, 1H), 3.68 - 3.75 (m, 1H), 3.78 - 3.85 (m, 1H), 3.99 - 4.08 (m, 1H), 4.16 - 4.25 (m, 1H), 4.58 - 4.67 (m, 1H), 7.28 (d, 1H), 7.35 (d, 1H), 7.40 (s, 1H), 7.58 (s, 1H), 7.65 (s, 1H), 7.98 (d, 1H), 8.36 (d, 1H), 13.41 (br. s, 1H).

Example 103 2-[(3R)—3-methy|morpholin-4—yl](2-methy|thienyl)(1H-pyrazo|y|)-1,7-naphthyridine Intermediate—10 (0.10 g, 0.19 mmol), ylthiopheneboronic acid pinacol ester (85 mg, 0.38 mmol), aq. potassium carbonate (0.28 ml, 2 M) and PdC|2(PPh3)2 (13 mg, 0.019 mmol) were solubilised in dimethoxyethane (5 ml). The reaction mixture was stirred for 10 minutes at 130°C under microwave irradiation. After g to rt, the reaction mixture was dried by filtration and the filtrate was concentrated under d re. The crude material was purified by preparative HPLC (acetonitriIe/water/formic acid mixture). The combined fractions were concentrated under reduced re, solubilised in methanol (2 ml) and concentrated hydrochloric acid (1.5 ml) was added. The reaction was stirred overnight at rt and then basified with a saturated solution of sodium hydrogen carbonate and extracted three times with dichloromethane. The organic phase was dried (silicon filter) and concentrated under reduced pressure. The title compound was obtained in 48% yield (37 mg). 1H-NMR (400MHz, DMSO-de): 6 [ppm]: 1.28 (d, 3H), 2.32 (s, 3H), 3.34 - 3.38 (m, 1H), 3.51 - 3.62 (m, 1H), 3.66 - 3.75 (m, 1H), 3.79 (d, 1H), 4.00 - 4.08 (m, 1H), 4.16 - 4.25 (m, 1H), 4.57 - 4.66 (m, D4), 7.12 (d, 1H), 7.23 (d, 1H), 7.40 (d, 2H), 7.53 (d, 1H), 7.63 (br. s., 1H), 8.31 (d, 1H), 13.41 (br. s, [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp 1H).

Example 104 2-[(3R)methylmorpholinyl](1H-pyrazolyl)-4—(1H-pyrrolo[2,3-b]pyridin-4—yl)-1,7- naphthyridine Intermediate—10 (0.075 g, 0.14 mmol), 4—(4,4,5,5—tetramethyl-1,3,2—dioxaborolan-Z-yI)-1h- pyrrolo[2,3—b]pyridine (69 mg, 0.28 mmol), aq. potassium ate (0.21 ml, 2 M) and PdC|2(PPh3)2 (10 mg, 0.019 mmol) were solubilised in dimethoxyethane (4 ml). The reaction mixture was stirred for 10 s at 130°C under microwave irradiation. After cooling to rt, the reaction mixture was diluted with water and extracted with dichloromethane and the ethyl acetate. The combined organic phases were dried on filter) and concentrated under reduced pressure. The crude material was purified by ative HPLC (acetonitrile/water/formic acid).

The combined fractions were concentrated under reduced pressure, solubilised in methanol (2 ml) and concentrated hydrochloric acid (1.5 ml) was added. The reaction was stirred overnight at rt and then basified with a saturated solution of sodium en carbonate and extracted three times with dichloromethane. The organic phase was dried (silicon filter) and concentrated under reduced pressure. The title compound was obtained in 71% yield (43 mg). 1H-NMR (400MHz, DMSO-de): 6 [ppm]: 1.31 (d, 3H), 3.35 - 3.42 (m, 1H), 3.57 (t, 1H), 3.72 (d, 1H), 3.81 (d, 1H), 4.05 (d, 1H), 4.22 (d, 1H), 4.58 - 4.67 (m, 1H), 6.13 - 6.18 (m, 1H), 7.22 (t, 2H), 7.46 (s, 1H), 7.54 (s, 2H), 7.63 - 7.67 (m, 1H), 8.26 (d, 1H), 8.40 (d, 1H), 11.96 (br. s, 1H), 13.44 (br. s, 1H).

Example 105 D(3,5-dimethyl-1,2-oxazo|yl)[(3R)methy|morpholin-4—yl](1H-pyrazol-S-y|)-1,7- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp naphthyridine Intermediate-10 (0.075 g, 0.14 mmol), methylisoxazoleboronic acid (40 mg, 0.28 mmol), aq. potassium carbonate (0.21 ml, 2 M) and PdCIz(PPh3)2 (10 mg, 0.019 mmol) were lised in dimethoxyethane (4 ml). The reaction mixture was stirred for 10 minutes at 130°C under microwave irradiation. After g to rt, the reaction mixture was diluted with water and filtered. The solid was purified by preparative HPLC (acetonitriIe/water/formic acid). The combined fractions were concentrated under reduced pressure, solubilised in methanol (2 ml) and concentrated hydrochloric acid (1.5 ml) was added. The reaction was stirred overnight at rt and then basified with a saturated on of sodium hydrogen ate and extracted three times with dichloromethane. The organic phase was dried (silicon filter) and concentrated under reduced pressure. The title nd was obtained in 42% yield (24 mg). 1H-NMR (400MHz, DMSO-de): 6 [ppm]: 1.29 (d, 3H), 2.12 (s, 3H), 2.32 (s, 3H), 3.35 - 3.40 (m, 1H), 3.57 (t, 1H), 3.72 (d, 1H), 3.82 (d, 1H), 4.05 (d, 1H), 4.22 (d, 1H), 4.61 (d, 1H), 7.21 - 7.28 (m, 1H), 7.42 (s, 1H), 7.52 (s, 1H), 7.62 - 7.67 (m, 1H), 8.33 (d, 1H), 13.43 (br. s, 1H).

Example 106 4-(3—chloro-Z-methoxypyridinyl)—2-[(3R)methy|morpholiny|](1H-pyrazoIy|)-1,7- naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Intermediate—10 (0.075 g, 0.14 mmol), 3-chloro—2-methoxypyridineboronic acid (53 mg, 0.28 mmol), aq. ium ate (0.21 ml, 2 M) and PdC|2(PPh3)2 (10 mg, 0.019 mmol) were solubilised in dimethoxyethane (4 ml). The reaction mixture was stirred for 10 minutes at 130°C under microwave irradiation. After cooling to rt, the reaction mixture was diluted with water and filtered. The solid was purified by preparative HPLC (acetonitriIe/water/formic acid). The ed fractions were concentrated under reduced pressure, solubilised in ol (2 ml) and concentrated hloric acid (1.5 ml) was added. The reaction was stirred 2 hours at rt and then basified with a saturated on of sodium hydrogen carbonate and extracted three times with dichloromethane. The organic phase was dried (silicon filter) and concentrated under reduced pressure. The title compound was obtained in 22% yield (14 mg). 1H-NMR (400MHz, DMSO-de): 5 [ppm]: 1.25 - 1.33 (m, 3H), 3.34 - 3.40 (m, 1H), 3.52 - 3.61 (m, 1H), 3.67 - 3.74 (m, 1H), 3.78 - 3.85 (m, 1H), 4.04 (s, 4H), 4.16 - 4.24 (m, 1H), 4.55 - 4.64 (m, 1H), 7.01 - 7.06 (m, 1H), 7.18 (d, 1H), 7.42 (s, 1H), 7.51 - 7.55 (m, 1H), 7.61 - 7.67 (m, 1H), 8.25 - 8.34 (m, 2H), 13.42 (br. s, 1H).

Example 107 2-[(3R)—3-methy|morpholiny|](1H-pyrazol-S-yl)—4—(tetrahyd ro-ZH-pyran-4—yl)-1,7- naphthyridine [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ediate—18 (0.10 g, 0.22 mmol) and hydro—2H-pyran—4-boronic acid pinacolester (95 mg, 0.43 mmol) were solubilised in dioxane (5 ml). Caesium carbonate (0.28 g, 0.87 mmol) and PdCl2(dppf) in complex with dichloromethane (18 mg, 0.021 mmol) were added sequentially. The reaction was heated for 4 hours in a sealed tube at 110°C. 3,6-Dihydro-2H-pyran—4-boronic acid pinacolester (53 mg, 0.22 mmol) was added and the reaction was stirred for 48 hours at 110°C.

The reaction was then cooled to rt, diluted with water and extracted with ethyl acetate. The organic phase was dried ), filtered and concentrated under reduced pressure. The crude mixture was solubilised in dichloromethane (6 ml) and 1M hydrochloric acid (1.2 ml) was added.

The reaction was stirred overnight and basified using a saturated solution of sodium hydrogen carbonate. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated under reduced re.The crude al (42 mg) was solubilised in methanol (2 ml) and was hydrogenated in an autoclave (10.5 bar) at rt for 18 hours using 10% Pd/C (20 mg). The reaction mixture was filtered through Celite ® and concentrated under reduced pressure. The crude material was purified by flash chromatography (hexane/ethyl acetate mixture) and the title compound was obtained in 10% yield (11 mg). 1H-NMR (400MHz, DMSO-de): d [ppm]: 1.26 (d, 3H), 1.73 - 1.81 (m, 2H), 1.89 (qd, 2H), 3.33-3.35 (m, 1H), 3.50 - 3.58 (m, 2H), 3.59 - 3.67 (m, 2H), 3.70 - 3.75 (m, 1H), 3.79 - 3.84 (m, 1H), 3.96 - 4.09 (m, 3H), 4.19 (d, 1H), 4.60 - 4.70 (m, 1H), 7.31 (s, 1H), 7.37 (s, 1H), 7.60 (s, 1H), 7.89 (d, 1H), 8.37 (d, 1H), 13.36 (br. s., 1H).

Example 108 4—(3,6-dihyd ro-ZH-thiopyranyl)[(3R)methylmorpholin-4—yl](1H-pyrazolyl)—1,7- naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp ation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Intermediate—10 (0.30 g, 0.53 mmol), 2—(3,6-dihydro-ZH—thiopyran—4-yl)—4,4,5,5-tetramethyl—1,3,2- dioxaborolane (0.25 g, 1.1 mmol), aq. potassium carbonate (0.85 ml, 2 M) and PdC|2(PPh3)2 (40 mg, 0.056 mmol) were solubilised in dimethoxyethane (12 ml). The on mixture was stirred for 10 minutes at 130°C under microwave irradiation. After cooling to rt, the reaction mixture was dried by filtration and the filtrate was concentrated under reduced pressure. The crude material was purified by preparative HPLC (acetonitrile/water/formic acid mixture). The combined fractions were concentrated under reduced pressure, solubilised in romethane and washed with a saturated solution of sodium hydrogen carbonate. The organic phase was dried (silicon filter) and trated under reduced pressure. The title compound was obtained in 45% yield (100 mg). 1H-NMR (400MHz, DMSO-de): 6 [ppm]: 1.27 (d, 3H), 2.56 - 2.62 (m, 2H), 2.93 (t, 2H), 3.26 - 3.32 (m, 1H), 3.36 - 3.40 (m, 2H), 3.55 (td, 1H), 3.70 (dd, 1H), 3.81 (d, 1H), 4.00 - 4.08 (m, 1H), 4.18 (d, 1H), 4.57 - 4.64 (m, 1H), 6.00 - 6.04 (m, 1H), 7.30 (s, 1H), 7.38 (br. s., 1H), 7.58 (d, 1H), 7.62 (br. s., 1H), 8.34 (d, 1H), 13.38 (br. s., 1H).

Example 109 2-[(3R)methy|morpho|in-4—yl]-4—(4—methy|piperidiny|)(1H-pyrazoly|)-1,7- naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Intermediate-10 (0.075 g, 0.14 mmol) was solubilised in N-methylpyrrolidone (2 ml) and 4- methylpiperidine (0.061, 51 mg, 0.50 mmol) was added. The reaction mixture was stirred at 70°C overnight. The mixture was cooled to rt, d with ethyl acetate and washed with a half saturated solution of sodium chloride. The organic phase was dried (silicon filter) and concentrated under reduced pressure. The crude material was ed by preparative HPLC 1H- NMR (400MHz, e): 6 [ppm]: 0.98 (d, 3H), 1.21 (d, 4H), 1.35 - 1.49 (m, 2H), 1.49 - 1.63 (m, 1H), 1.75 (d, 2H), 2.69 - 2.82 (m, 2H), 3.19 - 3.28 (m, 1H), 3.39 - 3.50 (m, 3H), 3.65 (dd, 1H), 3.77 (d, 1H), 4.03 - 4.10 (m, 1H), 4.52 (dd, 1H), 6.69 (s, 1H), 7.30 (s, 1H), 7.51 (d, 1H), 7.56 (s, 1H), 8.26 (d, 1H), 13.31 (br. s., 1H).

Example 110 4-(1-tert-b H-pyrazo|y|)[(3R)methylmorpholin-4—yl](1H-pyrazolyl)-1,7- naphthyridine Intermediate-10 (0.1 g, 0.19 mmol), l-tert-butyl-lH-pyrazoleboronic acid pinacol ester (95 mg, 0.0.38 mmol), aq. ium carbonate (0.81 ml, 2 M) and PdC|2(PPh3)2 (13 mg, 0.019 mmol) were Dlubilised in dimethoxyethane (7 ml). The reaction mixture was stirred for 10 minutes at 130°C [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp under ave irradiation. After cooling to rt, the reaction mixture was diluted with dichloromethane and dried by filtration and the filtrate was concentrated under reduced pressure. The crude material was ed by preparative HPLC nitrile/water/formic acid mixture). The ed fractions were concentrated under d pressure, solubilised in methanol (2 ml) and concentrated hloric acid (1 ml) was added. The mixture was stirred for 2 hours at rt and then quenched with a saturated aqueous solution of sodium hydrogen carbonate. The aqueous phase was extracted three times with dichloromethane. The c phase was dried (silicon filter) and concentrated under reduced pressure. The title compound was obtained in 18% yield (15 mg). 1H—NMR (400MHz, DMSO-de): 6 [ppm]: 1.21 — 1.31 (m, 3H), 1.38 (s, 9H), 3.35 - 3.41 (m, 1H), 3.52 - 3.63 (m, 1H), 3.67 - 3.76 (m, 1H), 3.77 - 3.85 (m, 1H), 4.00 - 4.10 (m, 1H), 4.17 - 4.27 (m, 1H), 4.56 - 4.65 (m, 1H), 6.34 — 6.40 (m, 1H), 6.96 (t, 1H), 7.44 (s, 1H), 7.59 — 7.68 (m, 3H), 8.30 — 8.35 (m, 1H), 13.44 (br. s, 1H).

Example 111 2-[(3R)—3-methylmorpholin-4—yl]-4—(1-methy|—1H-pyrazol-S-yl)(1H-pyrazolyl)—1,7- naphthyridine Intermediate—10 (0.5 g, 0.95 mmol), 1—methyl-5—(4,4,5,5—tetramethyl-1,3,2—dioxaborolan-Z-yI)-1H- pyrazole (415 mg, 1.9 mmol), aq. potassium carbonate (1.4 ml, 2 M) and PdC|2(PPh3)2 (67 mg, 0.094 mmol) were solubilised in oxyethane (60 ml). The reaction mixture was stirred for 20 minutes at 130°C under microwave irradiation. After cooling to rt, the reaction mixture was filtered through a silicon filter and concentrated under reduced pressure. The crude material was purified by flash column chromatography (hexane/ethyl acetate/ethanol mixture). The desired fractions were concentrated under reduced pressure and solubilised in conc. sulphuric acid (5 ml).

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp The mixture was stirred for 3h at rt. The mixture was then poured into ice and basified using solid sodium hydrogen carbonate. The suspension was filtered and the solid was stirred with ethanol at 40°C, filtered and dried under d pressure. The title compound was obtained in 78% yield (0.28 g). lH-NMR (400MHz, DMSO-de): 5 [ppm]: 1.30 (d, 3H), 3.30 - 3.40 (m, 1H), 3.51 - 3.62 (m, 1H), 3.68 - 3.77 (m, 4H), 3.79 - 3.86 (m, 1H), 4.01 - 4.09 (m, 1H), 4.18 - 4.28 (m, 1H), 4.60 - 4.69 (m, 1H), 6.59 (d, 1H), 7.27 (d, 1H), 7.42 (s, 1H), 7.60 (s, 1H), 7.63 - 7.69 (m, 2H), 8.35 (d, 1H), 13.42 (br. s, 1H).

Example 112 2-[(3R)—3-methylmorpholin-4—yl](3-methy|-1,2-oxazo|y|)(1H-pyrazolyl)-1,7- naphthyridine Step 3: 2-[(3R)—3-methylmorpholin-4—yl](3-methy|-1,2-oxazo|y|)[1-(tetrahyd ro-2H-pyranyl)— w1H-pyrazol-S-yl]-1,7-naphthyridine A sion of 100 mg (0.19 mmol) of 2—[(3R)-3—methylmorpholin—4—yl]—8—[1—(tetrahydro—2H— Z-yl)-1H-pyrazoI-S-yl]-1,7-naphthyridiny| trifluoromethanesulfonate, 79 mg (0.38 mmol) 3—methyl—5—(4,4,5,5-tetramethyl—1,3,2—dioxaborolan-Z—yl)—1,2-oxazole, 15 mg (0.019 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]dichloropal|adium(||) complex with dichloromethane (1:1, Pd(dppf)C|2) and 65 mg (0.47 mmol) of potassium ate in 2.0 ml of MeCN and 1.0 ml water was degased with argon. Under argon, the reaction mixture was stirred at 130°C for 10 minutes in a microwave reactor. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a n filter and then concentrated to give the crude product that was used t further purification in the next step.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp Step b: )—3-methylmorpholin-4—yl](3-methyl-1,2-oxazo|y|)(1H-pyrazo|y|)-1,7- naphthyridine A solution of 160 mg of crude 2-[(3R)methy|morpholinyl](3-methyI-1,2-oxazo|—5-y|)[1- (tetrahydro—ZH—pyran—Z—yl)—1H—pyrazol—5—yl]-1,7—naphthyridine from step a in 6.7 ml of methanol and 0.35 ml of 2N hydrochloric acid was stirred for 1 h at room temperature. The reaction mixture was diluted with a saturated s sodium chloride soltuion and extracted with ethyl acetate (2x). The combined organic phases were dried (MgSO4), filtered and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 4 mg (0.01 mmol) of the d product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.30 (3H), 2.40 (3H), 3.37 (1H), 3.51-3.64 (1H), 3.73 (1H), 3.84 (1H), 4.00-4.11 (1H), 4.23 (1H), 4.58-4.72 (1H), 7.22 (1H), 7.36—7.44 (1H), 7.59-7.67 (1H), 7.79 (1H), 7.92 (1H), 8.43 (1H),13.36-13.48 (1H).

Example 113 4-(1-ethyImethyl-1H-pyrazolyl)[(3R)methy|morpholin-4—y|](1H-pyrazoly|)-1,7- naphthyridine Step 3: 4—(1-ethylmethyl-1H-pyrazolyl)[(3R)methylmorpholinyl][1-(tetrahyd ro-ZH- pyran-Z-yl)—1H-pyrazolyl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp A suspension of 100 mg (0.19 mmol) of 2—[(3R)-3—methy|morpholin—4—yl]—8—[1—(tetrahydro—2H— pyran-Z-yl)-1H-pyrazol-S-yl]—1,7-naphthyridinyl trifluoromethanesulfonate, 90 mg (0.38 mmol) 1—ethyl-3—methyl-5—(4,4,5,5—tetramethyl—1,3,2—dioxaborolan-Z—yl)—1H-pyrazole, 15 mg (0.019 mmol) of [1,1’-bis(dipheny|phosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, f)C|2) and 65 mg (0.47 mmol) of potassium carbonate in 2.0 ml of MeCN and 1.0 ml water was degased with argon. Under argon, the reaction mixture was stirred at 130°C for 10 minutes in a microwave reactor. After cooling the on mixture was diluted with saturated aqueous sodium de solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-(1-ethylmethyl-1H-pyrazolyl)[(3R)methy|morpholiny|](1H-pyrazolyl)-1,7- naphthyridine A solution of 127 mg of crude 4-(1—ethyImethyl-1H—pyrazoI-5—yl)[(3R)—3-methylmorpholin y|]-8—[1-(tetrahydro-2H-pyran-Z-yl)-1H-pyrazo|—5—y|]-1,7-naphthyridine from step a in 2.5 ml of methanol and 0.26 ml of 2N hydrochloric acid was stirred for 90 minutes at room temperature.

The on e was diluted with a saturated aqueous sodium bicarbonate solution and atracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp filter and concentrated to dryness. The residue was purified by ative HPLC (Autopurifier: basic conditions) to give 18 mg (0.04 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]= 1.20 (3H), 1.29 (3H), 2.28 (3H), 3.51 - 3.63 (1H), 3.72 (1H), 3.82 (1H), 3.89 (2H), 4.05 (1H), 4.22 (1H), 4.63 (1H), 6.33 (1H), 7.24 (1H), 7.43 (1H), 7.54 (1H), 7.64 (1H), 8.35 (1H), 13.44 (1H).

Example 114 -dimethyl-1H-pyrazo|y|)[(3R)—3-methy|morpholin-4—y|](1H-pyrazolyl)—1,7- naphthyridine Step a: 4—(1,4-dimethyl-1H-pyrazo|y|)[(3R)methy|morpholin-4—y|][1-(tetrahyd ro-ZH-pyran-Z- -pyrazolyl]-1,7-naphthyridine A suspension of 100 mg (0.19 mmol) of 2—[(3R)methy|morpholin-4—yl]—8-[1—(tetrahydro-2H- pyranyl)-1H-pyrazoIyl]-1,7-naphthyridinyl trifluoromethanesulfonate, 53 mg (0.38 mmol) 1(1,4-dimethyl-1H-pyrazol-5—yl)boronic acid, 15 mg (0.019 mmol) of [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 65 mg (0.47 mmol) of potassium carbonate in 2.0 ml of MeCN and 1.0 ml water was degased with argon. Under argon, the reaction mixture was d at 130°C for 10 minutes in a microwave reactor. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further cation in the next step.

Step b: 4—(1,4-dimethyl-1H-pyrazo|y|)[(3R)methy|morpholin-4—y|](1H-pyrazolyl)—1,7- daphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 102 mg of crude 4-(1,4-dimethyl-lH-pyrazol—5-yl)[(3R)methy|morpholin-4—yl]—8- [1—(tetrahydro-2H-pyranyl)—1H-pyrazoly|]—1,7-naphthyridine from step a in 4.2 ml of methanol and 0.22 ml of 2N hydrochloric acid was stirred for 1 hour at room temperature. The reaction mixture was diluted with saturated aqueous chloride solution and extracted with ethyl acetate (2x). The ed organic phases were dried (MgSO4), filtered and trated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 12 mg (0.03 mmol) of the desired product. lH-NMR (400MHz, DMSO-d6): 8 [ppm]: 1.30 (3H), 1.88 (3H), 3.49 - 3.69 (4H), 3.69 - 3.76 (1H), 3.82 (1H), 4.06 (1H), 4.25 (1H), 4.64 ( 1H), 7.05 (1H), 7.44( 1H), 7.50 (1H), 7.58 (1H), 7.65 (1H), 8.35 (1H), 13.44 (1H).

Example 115 4-[2-methyl(methylsulfanyl)pyridinyl][(3R)methylmorpholin-4—yl](1H-pyrazo|y|)- 1,7-naphthyridine Step 3: 4—[2-methyl-6—(methylsulfanyl)pyridinyl][(3R)methylmorpho|inyl][1-(tetrahydro- ZH-pyran-Z-yl)-1H-pyrazolyl]-1,7-naphthyridine D suspension of 75 mg (0.14 mmol) of 2—[(3R)methy|morpholin-4—yI][1—(tetrahydro-2H- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp pyran—2-yl)—1H—pyrazoI—5-y|]—1,7—naphthyridin—4—yl trifluoromethanesulfonate, 26 mg (0.14 mmol) [2-methyl(methy|su|fanyl)pyridinyl]boronic acid, 11 mg (0.014 mmol) of [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 49 mg (0.36 mmol) of potassium carbonate in 3.0 ml of MeCN and 1.0 ml water was degased with argon. Under argon, the reaction mixture was stirred at 130°C for 10 minutes in a ave reactor. After g the reaction mixture was diluted with saturated aqueous sodium chloride on and ted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then trated to give the crude product that was used without further purification in the next step.

Step b: 4-[2-methyl(methylsulfanyl)pyridinyl][(3R)methylmorpho|iny|](1H-pyrazol-S-y|)- 1,7-naphthyridine A solution of 119 mg of crude 4—[2-methyI—6-(methylsulfanyl)pyridin—3-yl]—2-[(3R) methylmorpholinyl][1-(tetrahydro—2H-pyranyl)-1H-pyrazo|—5-y|]-1,7—naphthyridine from step a in 5.5 ml of methanol and 0.23 ml of 2N hydrochloric acid was stirred for 1 hour at room temperature. The reaction mixture was diluted with saturated aqueous chloride solution and extracted with ethyl acetate (2x). The combined organic phases were dried (MgSO4), filtered and concentrated to dryness. The residue was ed by ative HPLC (Autopurifier: basic conditions) to give 15 mg (0.04 mmol) ofthe desired product. 1H—NMR (400MHz, DMSO-d6): 6 [ppm]: 1.30 (3H), 2.24 (3H), 2.55 — 2.63 (3H), 3.49 — 3.64 (1H), 3.72 (1H), 3.82 (1H), 3.98 - 4.13 (1H), 4.22 (1H), 4.61 (1H), 7.05 (1H), 7.32 (1H), 7.37 - 7.53 (2H), 7.53 — 7.70 (2H), 8.30 (1H), 13.42 (1H).

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp e 116 4-[2-methyl(S-methylsulfonimidoyl)pyridinyl][(3R)—3-methylmorpholiny|](1H- pyrazol-S-yI)-1,7-naphthyridine Step 3: 4-[2-methyl(methylsulfanyl)pyridinyl][(3R)methylmorpho|inyl][1-(tetrahydro- 2H-pyranyl)-1H-pyrazoly|]-1,7-naphthyridine A suspension of 250 mg (0.47 mmol) of 2-[(3R)methy|morpholiny|][1-(tetrahydro-2H- pyranyl)-1H-pyrazoly|]-1,7-naphthyridinyl trifluoromethanesulfonate, 87 mg (0.47 mmol) [2-methyl(methy|sulfany|)pyridinyl]boronic acid, 38 mg (0.047 mmol) of [1,1’- bis(diphenylphosphino)ferrocene]dich|oropa||adium(|I) complex with romethane (1:1, Pd(dppf)C|2) and 164 mg (1.19 mmol) of potassium carbonate in 10.0 ml of MeCN and 3.3 ml water was degased with argon. Under argon, the reaction e was stirred at 130°C for 10 minutes in a microwave reactor. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride solution and ted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated. The residue was purified by column chromatography (gradient from 100% Hex to 100% EtOAc) to give 170 mg (0.33 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.15 - 1.35 (3H), 1.46 (2H), 1.52 - 1.69 (1H), 1.88 - 2.07 (2H), 2.25 (3H), 2.30 — 2.45 ( 1H), 2.56 — 2.64 (3H), 3.14 - 3.29 (2H), 3.39 - 3.55 (1H), 3.58 - 3.68 (1H), 3.68 - 3.82 (2H), 3.97 (1H), 4.18 (1H), 4.52 (1H), 6.08 - 6.22 (1H), 6.93 - 7.06 (1H), 7.10 (1H), 7.32 (1H), 7.37 - 7.48 (1H), 7.56 - 7.68 (2H), 8.33 (1H).

Step b: 2,2,2-trifluoro-N-[methyl(6-methyl{2-[(3R)methy|morpholinyl][1-(tetrahyd ro-ZH- pyran-Z-yl)-1H-pyrazo|—5-yl]-1,7-naphthyridinyl}pyridin-Z-yl)-A4-sulfanylidene]acetamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under an atmosphere of argon, a on of 43 mg (0.38 mmol) trifluoroacetamide in 0.20 ml THF was added dropwise to a solution of 24 mg (0.25 mmol) sodium tert.-butoxide in 0.25 ml THF, so that the temperature of the mixture remained below 10 0C. Subsequently, a freshly prepared solution of 47 mg (0.16 mmol) 1,3-dibromo-5,5-dimethylhydantoin in 0.25 ml THF was added dropwise to the stirred mixture, so that the temperature of the mixture remained below °C. Then the mixture was stirred for 10 minutes at 10 "C. y, a solution of 130 mg (0.25 mmol) 4—[2—methyl—6—(methylsulfanyl)pyridin—3—yl]—2—[(3R)—3-methylmorpholin-4—yl]—8—[1— (tetrahydro-2H-pyran—2-yl)-1H-pyrazolyl]—1,7-naphthyridine in 0.8 ml THF was added dropwise to the stirred mixture, so that the temperature of the mixture remained below 10 "C. The mixture was stirred for 3 hours at 10 °C and then at room temperature overnight. The batch was diluted with 1.0 ml toluene under cooling and an aqueous solution of 32 mg (0.25 mmol) sodium sulfite in 0.9 ml water was added so that the temperature of the mixture remained below 15 0C. The batch was extracted three times with ethyl acetate. The combined c phases were washed with an aqueous solution of sodium de, filtered using a Whatman filter and trated. The residue was purified by column chromatography on silica gel (ethyl acetate) to give 28 mg of the d product containing slight impurities.

Step c: 4-[2-methyl(S-methylsulfonimidoyl)pyridinyl][(3R)methy|morpholinyl][1- (tetrahyd ro-ZH-pyran-Z-yl)-1H-pyrazo|yl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp ed set by jennyp 28 mg (0.045 mmol) 2,2,2-trifluoro-N-[methyl(6-methyl—5-{2-[(3R)methy|morpholinyl]—8-[1- (tetrahydro—ZH-pyran—Z-yl)-1H—pyrazo|—5-y|]-1,7—naphthyridin-4—y|}pyridin—Z—yl)-}\4— su|fany|idene]acetamide was dissolved in 0.87 ml methanol. To this solution 0.31 ml water was added. The pH was adjusted to 10.5 by addition of an aqueous solution of potassium ide (25%). 23 mg (0.038 mmol) Oxone® was added and the mixture was stirred at room temperature for 5 hours. Additional amount 23 mg (0.038 mmol) Oxones was added. The pH was adjusted to .5 by addition of an aqueous solution of potassium hydroxide (25%). The batch was stirred at room temperature for 3 hours. The batch was ed and the filtrate was adjusted to pH 6-7 by the addition of 1N aqueous hydrogen chloride solution. The mixture was diluted with aqueous sodium chloride solution and ted with DCM (2x). The combined organic phases were washed with an aqueous solution of sodium sulfite (10%), filtered using a Whatman filter, and concentrated to give 10 mg crude product that was used without further purification.

Step d: 4-[2-methyI(S-methylsulfonimidoyl)pyridiny|][(3R)methy|morpholinyl](1H- pyrazolyl)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A on of 10 mg of crude 4-[2-methy|(S-methylsulfonimidoyl)pyridinyl]—2-[(3R) morpholin-4—yl]—8-[1—(tetrahydro—2H-pyranyl)—1H-pyrazol—5-y|]—1,7-naphthyridine from step c in 1.0 ml of methanol and 0.02 ml of 2N hydrochloric acid was stirred for 2 hour at room temperature. The reaction e was diluted with saturated aqueous sodium bicarbonate solution and ted with ethyl acetate (2x). The combined organic phases were dried (MgSO4), filtered and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: acidic conditions) to give 2 mg (0.004 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.23 - 1.40 (3H), 2.22 - 2.41 (3H), 3.25 (3H), 3.38 (1H), 3.46 — 3.65 (1H), 3.72 (1H), 3.82 (1H), 4.05 (1H), 4.13 - 4.32 (1H), 4.53 (1H), 4.62 (1H), 6.91 - 7.11 (1H), 7.46 (1H), 7.58 (1H), 7.66 (1H), 7.99 - 8.17 (2H), 8.31 (1H).

Example 117 2-[(3R)—3-methy|morpholin-4—yl](1-propyl-1H-pyrazo|y|)(1H-pyrazolyl)-1,7- naphthyridine Step 3: 2-[(3R)—3-methy|morpholin-4—yl]-4—(1-propyl-1H-pyrazo|y|)[1-(tetrahyd ro-ZH-pyran-Z-yl)— 1H-pyrazolyl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A suspension of 75 mg (0.14 mmol) of 2—[(3R)-3—methy|morpholin—4—yl]—8—[1—(tetrahydro—2H— 2-yl)-1H-pyrazol-S-yl]—1,7-naphthyridinyl trifluoromethanesulfonate, 34 mg (0.14 mmol) 1-propyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole, 11 mg (0.014 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dich|oropalladium(ll) complex with dichloromethane (1:1, Pd(dppf)C|2) and 49 mg (0.36 mmol) of potassium carbonate in 3.0 ml of MeCN and 1.0 ml water was degased with argon. Under argon, the reaction mixture was stirred at 130°C for 10 minutes in a microwave reactor. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride on and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a n filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 2-[(3R)—3-methy|morpho|inyl](1-propyl-1H-pyrazo|y|)(1H-pyrazolyl)-1,7- naphthyridine A solution of 110 mg of crude 2-[(3R)—3—methylmorpholinyI]—4—(1-propyl—1H-pyrazoI-5—yl)—8—[1- (tetrahydro-2H-pyran—2-yl)-1H—pyrazoI-S-yl]-1,7-naphthyridine from step a in 5.4 ml of methanol and 0.23 ml of 2N hloric acid was stirred for 1 hour at room temperature. The reaction mixture was diluted with saturated aqueous chloride solution and extracted with ethyl e (2x). The ed organic phases were dried (MgSO4), filtered and trated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 11 mg (0.03 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 8 [ppm]: 0.64 (3H), 1.29 (3H), 1.63 (2H), 3.34 (1H), 3.59 (1H), 3.73 (1H), 3.82 (1H), 3.89 - 4.02 (2H), 4.02 - 4.12 (1H), 4.23 (1H), 4.63 (1H), 6.55 (1H), 7.21 (1H), 7.44 (1H), 7.57 (1H), 7.60 - 7.74 (2H), 8.35 (1H), 13.43 (1H).

Example 118 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazo|y|)[(3R)methy|morpholinyl](1H-pyrazo|—5- yl)-1,7-naphthyridine Step 3: 4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazo|y|)[(3R)methy|morpholin-4—yl][1— (tetra hyd ro-ZH-pyranyl)-1H-pyrazo|y|]-1,7-naphthyridine A suspension of 100 mg (0.19 mmol) of 2-[(3R)methy|morpholinyl]—8—[1-(tetrahydro-2H- pyran-Z-yl)—1H-pyrazol—5-yl]—1,7—naphthyridin—4—yl trif|uoromethanesulfonate, 57 mg (0.38 mmol) 6,7-dihydro-5H-pyrrolo[1,2-a]imidazoIylboronic acid, 15 mg (0.019 mmol) of [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(|I) complex with dichloromethane (1:1, Pd(dppf)C|2) and 65 mg (0.47 mmol) of potassium carbonate in 2.0 ml of MeCN and 1.0 ml water was d with argon. Under argon, the reaction mixture was stirred at 130°C for 10 minutes in a microwave reactor. After g the reaction e was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded c phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazo|y|)[(3R)methy|morpholin-4—yl](1H-pyrazo|—5- yl)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 166 mg of crude —dihydro—5H-pyrrolo[1,2—a]imidazol—3—yl)—2—[(3R)-3— methylmorpholiny|][1-(tetrahydro-2H-pyranyl)-1H-pyrazo|y|]-1,7-naphthyridine from step a in 3.2 ml of methanol and 0.34 ml of 2N hydrochloric acid was d for 90 minutes at room temperature. The reaction mixture was diluted with ted aqueous chloride solution and extracted with ethyl acetate (2x). The combined organic phases were dried (MgSO4), filtered and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 1 mg (0.002 mmol) of the d product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.19 - 1.42 (3H), 2.54 - 2.71 (2H), 2.81 - 3.00 (2H), 3.58 (1H), 3.73 (1H), 3.84 (1H), 3.97 -4.15 (3H), 4.21 (1H), 4.63 (1H), 7.29 - 7.51 (3H), 7.64 (1H), 7.78 (1H), 8.37 (1H), 13.42 (1H).

Example 119 4—[1-ethyl(trifluoromethyl)—1H-pyrazolyl][(3R)methy|morpholin-4—yl](1H-pyrazo|—5- y|)-1,7-naphthyridine Step 3: 4-[1—ethyI(trifluoromethy|)-1H-pyrazol-S-y|][(3R)methy|morpho|in-4—yl][1- (tetra hyd ro-ZH-pyranyl)-1H-pyrazo|y|]-1,7-naphthyridine A sion of 75 mg (0.14 mmol) of 2-[(3R)methy|morpholiny|][1-(tetrahydro-2H- pyran—2-yl)—1H—pyrazol—5-y|]—1,7—naphthyridin—4—yl trifluoromethanesulfonate, 30 mg (0.14 mmol) [1-ethyI(trifluoromethyl)-1H-pyrazo|y|]boronic acid, 11 mg (0.014 mmol) of [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 49 mg (0.36 mmol) of potassium carbonate in 3.0 ml of MeCN and 1.0 ml water was degased with argon. Under argon, the reaction e was stirred at 130°C for 10 minutes in a microwave reactor. After cooling the on mixture was diluted with saturated aqueous Ddium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-[1-ethyl(trifluoromethyl)-1H-pyrazo|yl][(3R)methy|morpholinyl](1H-pyrazol yl)-1,7-naphthyridine A solution of 118 mg of crude 4-[1-ethyl(trifluoromethyl)-1H—pyrazolyl][(3R) methylmorpholin—4—yl]—8—[1—(tetrahydro—2H-pyran—2-yl)—1H—pyrazol—5—y|]—1,7—naphthyridine from step a in 5.2 ml of methanol and 0.22 ml of 2N hydrochloric acid was stirred for 1 hour at room temperature. The reaction mixture was diluted with saturated aqueous de solution and extracted with ethyl acetate (2x). The combined organic phases were dried ), filtered and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 1 mg (0.002 mmol) ofthe desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.11 - 1.38 (6H), 3.36 (1H), 3.58 (1H), 3.72 (1H), 3.83 (1H), 4.07 (3H), 4.24 (1H), 4.64 (1H), 7.10 (1H), 7.17 (1H), 7.36 — 7.48 (1H), 7.66 (1H), 7.72 (1H), 8.36 (1H), 13.40 (1H).

Example 120 methyl 5-{2-[(3R)methy|morpho|iny|](1H-pyrazolyl)-1,7-naphthyridin-4—y|}-1H- e-Z-carboxylate Step 3: -butyl 2-methyl 5-{2-[(3R)methy|morpholinyl][1-(tetrahydro-2H-pyranyl)—1H- pyrazol-S-yI]-1,7-naphthyridiny|}-1H-pyrroIe-1,2-dicarboxylate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A suspension of 75 mg (0.14 mmol) of 2-[(3R)methy|morpholin-4—yl]—8—[1-(tetrahydro-2H- pyranyl)-1H-pyrazo|y|]-1,7-naphthyridin-4—yl trifluoromethanesulfonate, 38 mg (0.14 mmol) [1—(tert-butoxycarbonyl)(methoxycarbony|)-1H-pyrro|—2-yl]boronic acid, 11 mg (0.014 mmol) of [1,1’—bis(diphenylphosphino)ferrocene]dich|oropalladium(|l) complex with romethane (1:1, Pd(dppf)C|2) and 49 mg (0.36 mmol) of potassium carbonate in 3.0 ml of MeCN and 1.0 ml water was degased with argon. Under argon, the on mixture was stirred at 130°C for 10 minutes in a microwave reactor. After g the on mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: methyl 5-{2-[(3R)methy|morpho|iny|](1H-pyrazolyl)-1,7-naphthyridiny|}-1H- pyrrole-Z-ca ate A solution of 115 mg of crude 1-tert-butyl 2—methyl 5-{2-[(3R)methylmorpholinyl]—8—[1- Detrahydro—ZH-pyran—Z-yl)-1H—pyrazoI—S-yl]-1,7—naphthyridiny|}—1H-pyrrole-1,2-dicarboxylate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp from step a in 5.5 ml of methanol and 0.23 ml of 2N hydrochloric acid was stirred for 1 hour at room ature. The reaction mixture was diluted with saturated aqueous chloride solution and extracted with ethyl acetate (2x). The combined organic phases were dried (MgSO4), filtered and concentrated to s. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 5 mg (0.01 mmol) of the desired product. 1H-NMR (400MHz, 6): 6 [ppm]: 1.32 (3H), 3.36 - 3.44 (1H), 3.52 - 3.65 (1H), 3.72 (1H), 3.78 - 3.93 (4H), 3.99 —4.16 (1H), 4.24 (1H), 4.66 (1H), 6.72 (1H), 7.03 (1H), 7.39 (1H), 7.49 - 7.59 (1H), 7.59 - 7.70 (1H), 7.84 (1H), 8.38 (1H), 12.60 (1H), 13.40 (1H). e 121 2-[(3R)—3-methy|morpholin-4—yl](1H-pyrazolyl)-4—(1,2-thiazolyl)-1,7-naphthyridine Step 3: 2-[(3R)—3-methy|morpholin-4—yl][1-(tetrahydro-ZH-pyran-Z-yl)-1H-pyrazo|y|](1,2-thiazo|— -yl)-1,7-naphthyridine A sion of 100 mg (0.19 mmol) of 2—[(3R)-3—methy|morpho|in—4—yl]—8-[1—(tetrahydro—2H— pyranyl)-1H-pyrazolyl]—1,7-naphthyridinyl trifluoromethanesulfonate, 80 mg (0.38 mmol) —(4,4,5,5—tetramethyl—1,3,2—dioxaborolan-2—yl)—1,2-thiazole, 15 mg (0.019 mmol) of [1,1’— bis(diphenylphosphino)ferrocene]dichloropalladium(||) complex with dichloromethane (1:1, Pd(dppf)Clz) and 247 mg (0.76 mmol) of ceasium carbonate in 1.3 ml of dioxane was degased with argon. Under argon, the reaction mixture was stirred at 110°C for 2 hours. After cooling the reaction mixture was d with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used t further purification in the next step.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Step b: 2-[(3R)—3-methy|morpholin-4—yl](1H-pyrazolyl)—4—(1,2-thiazolyl)—1,7-naphthyridine A solution of 155 mg of crude 2-[(3R)—3-methylmorpholiny|]—8—[1-(tetrahydro-ZH-pyran—Z-yl)- 1H—pyrazol—5—yl]—4—(1,2-thiazol—5-yl)-1,7—naphthyridine from step a in 1.5 ml of methanol and 0.39 ml of 2N hydrochloric acid was stirred for 1 hour at room temperature. The reaction mixture was diluted with saturated aqueous sodium onate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 5 mg (0.01 mmol) of the d product. lH-NMR (400MHz, DMSO-d6): 8 [ppm]: 1.31 (3H), 3.40 (1H), 3.57 (1H), 3.72 (1H), 3.83 (1H), 4.05 (1H), 4.17 - 4.34 (1H), 4.59 - 4.83 (1H), 7.41 (1H), 7.57 - 7.75 (3H), 7.89 (1H), 8.40 (1H), 8.80 (1H), 13.39 (1H).

Example 122 N,N-dimethyl-Z-{Z-[(3R)—3-methy|morpholinyl](1H-pyrazo|—5-y|)-1,7-naphthyridin-4— y|}aniline Step 3: methyl-Z-{Z-[(3R)methy|morpho|inyl][1-(tetrahydro-ZH-pyran-Z-y|)-1H-pyrazol yl]-1,7-naphthyridin-4—y|}aniline ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A suspension of 100 mg (0.19 mmol) of 2—[(3R)-3—methy|morpholin—4—yl]—8—[1—(tetrahydro—2H— pyranyl)-1H-pyrazol-S-yl]—1,7—naphthyridin-4—yl trifluoromethanesulfonate, 63 mg (0.38 mmol) [2-(dimethylamino)phenyl]boronic acid, 15 mg (0.019 mmol) of [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) x with dichloromethane (1:1, Pd(dppf)C|2) and 247 mg (0.76 mmol) of ceasium carbonate in 1.4 ml of dioxane was degased with argon. Under argon, the reaction mixture was stirred at 110°C for 2 hours. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further cation in the next step.

Step b: N,N-dimethyl-2—{2—[(3R)—3—methy|morpholinyl]-8—(1H-pyrazo|y|)-1,7-naphthyridin-4— y|}aniline A solution of 180 mg of crude N,N-dimethyI{2-[(3R)—3-methylmorpholinyl][1-(tetrahydro- 2H-pyranyl)—1H-pyrazolyl]-1,7-naphthyridinyl}aniline from step a in 1.7 ml of methanol and 0.42 ml of 2N hydrochloric acid was d for 1 hour at room ature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and ted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 40 mg (0.10 mmol) ofthe desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.28 (3H), 2.45 (6H), 3.60 (1H), 3.70- 3.78 (1H), 3.78 — 3.86 (1H), 3.97 - 4.12 (1H), 4.21 (1H), 4.59 (1H), 7.03 - 7.19 (2H), 7.19 - 7.29 (2H), 7.36 - 7.54 (3H), 7.64 (1H), 8.25 (1H), 13.40 (1H).

Dample 123 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 4-(2,4-difluorophenyl)—2-[(3R)methylmorpholiny|](1H-pyrazo|yl)-1,7-naphthyridine Step 3: 4-(2,4-difluoropheny|)[(3R)methylmorpholinyI][1-(tetrahydro-2H-pyranyl)-1H- pyrazolyl]-1,7-naphthyridine A suspension of 100 mg (0.19 mmol) of 2-[(3R)methylmorpholinyl]—8—[1-(tetrahydro-2H- pyran-Z-yl)—1H—pyrazol—5-yl]—1,7—naphthyridin—4—yl trifluoromethanesulfonate, 60 mg (0.38 mmol) (2,4—difluorophenyl)boronic acid, 15 mg (0.019 mmol) of [1,1’-bis(dipheny|phosphino)ferrocene]— ropalladium(l|) complex with dichloromethane (1:1, Pd(dppf)C|2) and 247 mg (0.76 mmol) of ceasium carbonate in 1.4 ml of dioxane was degased with argon. Under argon, the reaction mixture was stirred at 110°C for 90 minutes. After g the reaction mixture was diluted with saturated aqueous sodium chloride solution and ted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without r purification in the next step.

Step b: 4-(2,4-difluorophenyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine dsolution of 126mg of crude 4—(2,4-difluorophenyl)[(3R)—3-methylmorpholin-4—yl]—8—[1— [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp hydro—ZH—pyran—Z—yl)—1H—pyrazol—5—yl]-1,7—naphthyridine from step a in 5.7 ml of methanol and 0.26 ml of 2N hydrochloric acid was stirred for 90 minutes at room temperature. The on mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a n filter and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 12 mg (0.03 mmol) ofthe d product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.30 (3H), 3.38 (1H), 3.57 (1H), 3.68 - 3.75 (1H), 3.82 (1H), 4.05 (1H), 4.22 (1H), 4.64 (1H), 7.17 (1H), 7.31 - 7.38 (1H), 7.42 (1H), 7.49 - 7.58 (2H), 7.60 - 7.70 (2H), 8.32 (1H), 13.18 (1H).

Example 124 4—(1-isopropyl-1H-pyrazo|y|)[(3R)—3-methylmorpholin-4—yl](1H-pyrazolyl)-1,7- naphthyridine Step 3: 4—(1—isopropyl-1H-pyrazo|y|)[(3R)methylmorpholin-4—yl][1-(tetrahydro-ZH-pyran-Z- y|)-1H-pyrazolyl]-1,7-naphthyridine A suspension of 100 mg (0.19 mmol) of 2-[(3R)methy|morpholinyl]—8—[1-(tetrahydro-2H- pyran—2-yl)—1H—pyrazol—5-y|]—1,7—naphthyridin—4—yl trifluoromethanesulfonate, 58 mg (0.38 mmol) (1-isopropyI-1H-pyrazo|—5-y|)boronic acid, 15 mg (0.019 mmol) of [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(|I) complex with dichloromethane (1:1, Pd(dppf)C|2) and 247 mg (0.76 mmol) of ceasium carbonate in 2.0 ml of dioxane was degased with argon. Under argon, the reaction mixture was stirred at 110°C for 60 minutes. After cooling the reaction e was d with saturated aqueous sodium de solution and extracted with ethyl acetate (2x). The combinded organic phases were ed using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next a... ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Step b: 4-(1-isopropyl-1H-pyrazo|y|)[(3R)methylmorpholiny|](1H-pyrazolyl)-1,7- naphthyridine A solution of 126 mg of crude 4-(1-isopropyl-1H-pyrazol—5-yl)-2—[(3R)methylmorpholin-4—yl]—8— [1-(tetrahydro-2H-pyranyl)—1H-pyrazolyl]-1,7-naphthyridine from step a in 4.0 ml of methanol and 0.20 ml of 2N hydrochloric acid was stirred for 60 minutes at room temperature.

The reaction mixture was diluted with saturated s sodium bicarbonate solution and extracted with ethyl e (2x). The combined organic phases were filtered using a Whatman filter and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: acidic conditions) to give 14 mg (0.03 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 8 [ppm]: 1.32 (9H), 3.59 (1H), 3.72 (1H), 3.82 (1H), 4.06 (1H), 4.13 - 4.31 (2H), 4.52 - 4.74 (1H), 6.51 (1H), 7.14 (1H), 7.43 (1H), 7.54 (1H), 7.66 (1H), 7.71 (1H), 8.35 (1H), 13.43 (1H).

Example 125 ethyl methy|{2-[(3R)—3-methy|morpho|in-4—y|](1H-pyrazo|y|)-1,7-naphthyridin-4— yl}phosphinate Step 3: ethyl methyl{2-[(3R)methylmorpholin-4—yl][1-(tetrahydro-ZH-pyran-Z-yl)-1H-pyrazoI-S-yl]- 1,7-naphthyridin-4—y|}phosphinate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A mixture of 250 mg (0.47 mmol) of 2—[(3R)-3—methylmorpholin—4—yl][1—(tetrahydro—2H—pyran-2— yl)-1H-pyrazo|yl]-1,7-naphthyridiny| oromethanesulfonate, 53 mg (0.47 mmol) ethyl methylphosphinate, 2 mg (0.009 mmol) ium(||) acetate, 6mg (0.01 mmol) of 1,1’— bis(diphenylphosphino)ferrocene and 0.11 ml (0.62 mmol) of ethyldiisopropylamine in 2.1 ml of DMF and 0.24 ml 1,2—dimethoxyethane was degased with argon. Under argon, the reaction mixture was stirred at room ature for 10 minutes and then at 110°C overnight. After g the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium de solution. The aqueous phase was saturated with solid sodium chloride and extracted with a mixture of THF and ethyl acetet (1:1). The combined organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used t further purification in the next step.

Step b: ethyl methyl{2—[(3R)—3-methy|morpho|iny|](1H-pyrazo|y|)-1,7-naphthyridin-4— y|}phosphinate A solution of 310 mg of crude ethyl methyl{2-[(3R)methy|morpho|inyl]—8—[1-(tetrahydro-2H- pyranyl)—1H-pyrazoIyl]-1,7-naphthyridin-4—yl}phosphinate from step a in 2.9 ml of methanol and 0.75 ml of 2N hydrochloric acid was stirred for 60 minutes at room temperature. The Daction mixture was diluted with saturated s sodium bicarbonate solution and extracted [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp with ethyl acetate (2x). The combined organic phases were filtered using a n filter and concentrated to dryness. The e was purified by preparative HPLC (Autopurifier: basic conditions) to give 15 mg of an nt salt of the desired product. The material was taken up in 13 ml of ethyl acetate and 2 ml of saturated aqueous sodium chloride solution and the mixture was stirred for 15 minutes. The e was filtered using a Whatman filter and concentrated to give 8 mg (0.02 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.18 - 1.28 (3H), 1.28 - 1.37 (3H), 1.81 - 1.97 (3H), 3.58 (1H), 3.72 (1H), 3.85 (1H), 3.88 - 3.98 (1H), 4.00 —4.12 (2H), 4.12 - 4.21 (1H), 4.60 (1H), 7.37 (1H), 7.65 (1H), 7.80 (1H), 8.11 (1H), 8.33 - 8.51 (1H), 13.45 (1H).

Example 126 4—{[diethy|(oxido)-A5-sulfanylidene]amino}-2—[(3R)—3-methylmorpholinyl]-8—(1H-pyrazolyl)— 1,7-naphthyridine Step 3: 4—{[diethyl(oxido)—A6-sulfanylidene]amino}-2—[(3R)methylmorpholin-4—yl][1-(tetrahydro- ZH-pyran-Z-yl)-1H-pyrazolyl]-1,7—naphthyridine Under argon, 8 mg (0.014 mmol) 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and 7 mg (0.007 mmol) tris(dibenzylideneacetone)dipal|adium(0) were added to a mixture of 75 mg (0.142 mmol) 2-[(3R)-3—methy|morpholinyl][1-(tetrahydro-2H-pyranyl)-1H-pyrazo|—5-yl]-1,7- naphthyridin—4-yl trifluoromethanesuIfonate, 22 mg (0.19 mmol) (S-ethylsuIfonimidoyl)ethane and 69 mg (0.21 mmol) caesium carbonate in 0.67 ml e. The mixture was stirred at 110 °C for 3 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with an aqueous on of sodium chloride. The organic phase was filtered using a Whatman filter and Dncentrated to give the crude product that was used without further purification. ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Step b: 4-{[diethyl(oxido)-7\5-sulfanylidene]amino}[(3R)methylmorpholin-4—yl](1H-pyrazoIy|)- 1,7-naphthyridine 0.14 ml (0.29 mmol) 2N aqueous solution of hydrogen chloride was added to a solution of 71 mg crude 4—{[diethyl(oxido)-?\6—sulfanylidene]amino}-2—[(3R)—3-methylmorpholin-4—yl]—8-[1— (tetrahydro-2H-pyran—2-yl)-1H—pyrazolyl]—1,7-naphthyridine in 3.2 ml methanol and the reaction mixture was d at room temperature for 1 hour. The mixture was basified by on of an aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 25 mg (0.06 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 5 [ppm]: 1.25 (3H), 1.29 - 1.40 (6H), 3.20 - 3.31 (1H), 3.48 - 3.67 (5H), 3.71 (1H), 3.83 (1H), 3.94 - 4.14 (2H), 4.39 (1H), 6.84 (s, 1H), 7.34 (1H), 7.60 (1H), 7.88 (1H), 8.29 (1H), 13.35 (1H).

Example 127 yl methy|{2-[(3R)methy|morphoIin-4—yl](1H-pyrazo|y|)-1,7-naphthyridin y|}phosphinate Step 3: isobutyl methy|{2-[(3R)methylmorpho|in-4—yl][1-(tetrahydro-ZH-pyran-Z-y|)-1H-pyrazol y|]-1,7-naphthyridin-4—y|}phosphinate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A e of 100 mg (0.19 mmol) of 2—[(3R)methy|morpholin-4—yl]-8—[1—(tetrahydro-2H-pyran-Z- -pyrazo|—5-yl]-1,7-naphthyridin-4—y| trifluoromethanesulfonate, 26 mg (0.19 mmol) methylphosphonic acid isobutylester, 1 mg (0.004 mmol) palladium(||) acetate, 2 mg (0.004 mmol) of 1,1’—bis(diphenylphosphino)ferrocene and 0.01 ml (0.25 mmol) of ethyldiisopropylamine in 0.9 ml of DMF and 0.1 ml 1,2-dimethoxyethane was d with argon. Under argon, the reaction mixture was stirred at room temperature for 10 minutes and then at 110°C overnight.

After cooling the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The aqueous phase was saturated with solid sodium chloride and extracted with a e of THF and ethyl acetet (1:1). The combined organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: isobutyl methy|{2-[(3R)—3-methy|morphoIin-4—yl](1H-pyrazo|y|)-1,7-naphthyridin y|}phosphinate A solution of 135 mg of crude yl methyl{2-[(3R)—3—methylmorpholin—4-yl]-8—[1-(tetrahydro- D-I—pyran-Z—yl)-1H-pyrazol-S-yl]-1,7-naphthyridin—4-yl}phosphinate from step a in 1.2 ml of [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp methanol and 0.3 ml of 2N hydrochloric acid was stirred for 60 minutes at room ature.

The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined c phases were filtered using a Whatman filter and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 26 mg (0.06 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 0.88 (6H), 1.31 (3H), 1.90 (3H), 3.30- 3.45 (1H), 3.52 - 3.64 (2H), 3.72 (1H), 3.76 - 3.91 (2H), 4.07 (1H), 4.11 - 4.27 (2H), 4.47 - 4.71 (1H), 7.37 (1H), 7.64 (1H), 7.79 (1H), 8.10 (1H), 8.44 (1H), 13.41 (1H).

Example 128 2-{2-[(3R)methy|morpholiny|](1H-pyrazol-S-yl)-1,7-naphthyridiny|}propano| Step 3: methyl 2-[(3R)methylmorpholinyl][1-(tetrahydro-ZH-pyranyl)-1H-pyrazoly|]-1,7- naphthyridinecarboxylate In an autoclave, a mixture of 2527 mg (4.79 mmol) of 2-[(3R)methy|morpho|iny|]—8-[1- (tetrahydro—2H-pyran—2—yl)-1H—pyrazol—5—yl]-1,7—naphthyridin-4—y| oromethanesulfonate, 203 mg (0.48 mmol) 1,3-bis(diphenylphosphino)propane, 108 mg (0.48 mmol) palladium(|l) acetate and 1.3 ml triethylamine (9.6 mmol) in 34 ml of DMF and 18 ml of methanol was purged with carbon monoxide at room temperature. The autoclave was pressured with carbonmonoxide to 16.5 bar and the mixture was stirred at room temperature for 30 minutes. The autoclave was depressurized and then pressured with carbon monoxide to 20.9 bar. The e was stirred at 80°C for 20 hours. The autoclave was depressurized and after cooling, the mixture was d with water and extracted with ethyl acetate (2x). The combined c phases were dried (NaZSO4), filtered and concentrated. The residue was purified by column chromatography (gradient from 100% Hex to 100% EtOAc) to give 1537 mg (3.51 mmol) of the desired product. n—NMR (400MHz, DMSO—d6): 6 [ppm]= 1.22 (3H), 1.35 — 1.52 (2H), 1.52 — 1.72 (1H), 1.82 — 2.05 [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (2H), 2.28 - 2.45 (1H), 3.14 - 3.31 (2H), 3.43 - 3.57 (1H), 3.57 - 3.85 (3H), 3.91 - 4.05 (4H), 4.12 (1H), 4.40 - 4.61 (1H), 5.90 - 6.18 (1H), 6.89 (1H), 7.59 - 7.68 (1H), 7.86 (1H), 8.19 (1H), 8.47 (1H).

Step b: 2-{2-[(3R)-3—methy|morpholinyl][1-(tetrahyd ro-ZH-pyranyl)-1H-pyrazolyl]-1,7- naphthyridin-4—yl}propano| 0.23 ml (0.69 mmol) of a 3.0 M solution of methylmagnesium bromide in diethylether was added dropwise to a d solution of 100 mg (0.23 mmol) methyl 2—[(3R)-3—methylmorpholin—4—yl]—8— [1—(tetrahydro-ZH-pyran-Z-yl)-1H-pyrazo|yl]-1,7-naphthyridinecarboxylate in 3.8 ml of THF at 0°C. The mixture was stirred at 0°C for 30 minutes and then the icebath was removed and the e was stirred at room temperature for 150 s. The mixture was diluted with a ted aqueous solution of ammonium chloride and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step c: 2-{2-[(3R)methy|morpholinyl](1H-pyrazo|y|)-1,7-naphthyridiny|}propano| A solution of 91 mg of crude 2-{2-[(3R)methylmorpholiny|]—8-[1-(tetrahydro—2H-pyran—2-yl)- 1H—pyrazol-5—yl]-1,7-naphthyridinyl}propan-2—ol from step b in 1.8 ml of methanol and 0.21 ml of 2N hydrochloric acid was stirred for 3 hours at room temperature. The reaction mixture was diluted with saturated aqueous sodium de solution and extracted with ethyl acetate (2x).

Die ed organic phases were dried (MgSO4), filtered and concentrated to dryness. The [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 14 mg (0.04 mmol) of the desired product. 1H-NMR (400MHz, 6): 6 [ppm]= 1.28 (3H), 1.69 (6H), 3.57 (1H), 3.72 (1H), 3.84 (1H), 4.06 (1H), 4.09 - 4.18 (1H), 4.58 (1H), 5.59 (1H), 7.35 (1H), 7.42 (1H), 7.61 (1H), 8.26 - 8.38 (2H), 13.35 (1H).

Example 129 3-{2-[(3R)methy|morpholinyl](1H-pyrazo|y|)-1,7-naphthyridiny|}pentano| Step a: 3-{2-[(3R)methy|morpholinyl][1—(tetrahyd ro-ZH-pyran-Z-yl)-1H-pyrazo|—5-yl]-1,7- naphthyridin-4—yl}pentanol 0.46 ml (1.37 mmol) of a 3.0 M solution of ethylmagnesium bromide in diethylether was added dropwise to a stirred solution of 200 mg (0.46 mmol) methyl )methy|morpholin-4—yl]—8- [1—(tetrahydro-ZH-pyran-Z-yl)—1H-pyrazoly|]—1,7-naphthyridine—4—carboxylate in 7.7 ml of THF at 0°C. The mixture was d at 0°C for 30 minutes and then the icebath was removed and the mixture was stirred at room temperature for 150 s. The mixture was diluted with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 3-{2-[(3R)methy|morpholinyl](1H-pyrazo|y|)-1,7-naphthyridin-4—y|}pentano| [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 211 mg of crude 3-{2-[(3R)methylmorpholinyl]—8-[1-(tetrahydro-2H-pyranyl)- 1H-pyrazo|—5-yl]-1,7-naphthyridiny|}pentanol from step a in 5.0 ml of methanol and 0.45 ml of 2N hydrochloric acid was stirred for 3 hours at room temperature. The reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x).

The combined organic phases were dried (MgSO4), filtered and concentrated to dryness. The e was purified by preparative HPLC (Autopurifier: acidic conditions) to give 6 mg (0.02 mmol) of the d product. lH-NMR (400MHz, DMSO-d6): 6 [ppm]: 0.66 (6H), 1.26 (3H), 1.84 - 2.07 (2H), 2.17 (2H), 3.59 (1H), 3.75 (1H), 3.84 (1H), 3.99 - 4.15 (2H), 4.51 (1H), 5.17 (1H), 7.35 (1H), 7.53 (1H), 7.61 (1H), 8.11 (1H), 8.31 (1H), 13.34 (1H). e 130 4—(5-chloropyridiny|)[(3R)methy|morpholin-4—yl](1H-pyrazolyl)-1,7-naphthyridine Step a: 4—(5-chloropyridiny|)[(3R)methy|morpholin-4—yl][1-(tetrahydro-2H-pyranyl)-1H- pyrazoly|]-1,7-naphthyridine A suspension of 75 mg (0.14 mmol) of 2-[(3R)methy|morpholin-4—yI][1—(tetrahydro-2H- pyran-Z-yl)-1H-pyrazol—5-yl]-1,7-naphthyridin-4—yl trifluoromethanesulfonate, 45 mg (0.28 mmol) D-chloropyridinyl)boronic acid, 11 mg (0.014 mmol) of [1,1’- ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 185 mg (0.57 mmol) of caesium carbonate in 1.0 ml of dioxane was degased with argon. Under argon, the reaction mixture was stirred at 110°C for 90 minutes. After cooling the reaction mixture was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-(5-chloropyridiny|)[(3R)—3-methy|morpholiny|](1H-pyrazo|y|)-1,7-naphthyridine A solution of 120 mg of crude 4-(5-chIoropyridinyl)[(3R)—3-methylmorpholinyl]—8-[1- (tetrahydro-2H-pyranyl)-1H-pyrazo|y|]-1,7-naphthyridine from step a in 5.0 ml of methanol and 0.24 ml of 2N hydrochloric acid was stirred for 2 hour at room temperature. The reaction mixture was d with ted aqueous sodium onate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 8 mg (0.02 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.31 (3H), 3.36 - 3.41 (1H), 3.57 (1H), 3.72 (1H), 3.84 (1H), 4.06 (1H), 4.25 (1H), 4.55 - 4.77 (1H), 7.38 (1H), 7.43 (1H), 7.59 (1H), 7.66 (1H), 8.26 (1H), 8.35 (1H), 8.75 (1H), 8.83 (1H), 13.34 (1H). e 131 ro-Z-{Z-[(3R)—3-methylmorphoIin-4—yl](1H-pyrazo|y|)-1,7-naphthyridin-4—y|}aniline Step 3: -fluoro{2-[(3R)—3-methylmorpho|iny|][1—(tetrahyd ro-ZH-pyran-Z-yl)-1H-pyrazo|—5-y|]- ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1,7-naphthyridiny|}ani|ine A suspension of 100 mg (0.19 mmol) of )methylmorpholin-4—yl]—8—[1—(tetrahydro-2H- pyran-Z-yl)-1H-pyrazol-S-yl]—1,7-naphthyridin-4—yl trifluoromethanesulfonate, 90 mg (0.38 mmol) —fluoro-2—(4,4,5,5-tetramethyl—1,3,2—dioxaborolan-Z-yl)aniline, 15 mg (0.019 mmol) of [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(|I) complex with dichloromethane (1:1, Pd(dppf)Clz) and 65 mg (0.47 mmol) of potassium carbonate in 2.0 ml of acetonitrile and 1.0 ml water was degased with argon. Under argon, the reaction mixture was stirred at 130°C for 10 minutes in a microwave oven. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude t that was used without further purification in the next step.

Step b: 5-fluoro-Z-{Z-[(3R)methy|morphoIinyl](1H-pyrazo|y|)-1,7-naphthyridiny|}aniline A solution of 147 mg of crude 5-fluoro{2—[(3R)methylmorpholin—4—yl]—8—[1—(tetrahydro—2H- pyran-Z-yl)-1H-pyrazoI-S-yl]-1,7-naphthyridinyl}aniline from step a in 5.8 ml of methanol and d30 ml of 2N hydrochloric acid was stirred for 60 minutes at room temperature. The reaction [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp mixture was diluted with saturated aqueous sodium bicarbonate on and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated to dryness. The residue was purified by preparative HPLC urifier: acidic conditions) to give 14 mg (0.03 mmol) ofthe desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.31 (3H), 3.48 - 3.65 (1H), 3.66 - 3.77 (1H), 3.82 (1H), 4.05 (1H), 4.15 - 4.30 (1H), 4.50 - 4.73 (1H), 5.20 (2H), 6.37 - 6.54 (1H), 6.58 (1H), 7.04 (1H), 7.14 (1H), 7.35 (1H), 7.44 (1H), 7.64 (1H), 8.28 (1H), 13.41 (1H).

Example 132 4—[2—fluoro-3—(methylsulfonyl)phenyl]-2—[(3R)methy|morpho|in-4—yl](1H-pyrazol-S-y|)-1,7- naphthyridine Step a: 4—[2-fluoro(methylsulfonyl)phenyl][(3R)methy|morpho|iny|][1-(tetrahydro-ZH- pyran-Z-yl)-1H-pyrazoly|]-1,7-naphthyridine A suspension of 100 mg (0.19 mmol) of 2-[(3R)methy|morpholin-4—yl]—8—[1-(tetrahydro-2H- pyranyl)-1H-pyrazolyl]—1,7-naphthyridin-4—yl trifluoromethanesulfonate, 57 mg (0.19 mmol) 2-[2—fluoro-3—(methylsulfonyl)phenyl]-4,4,5,5-tetramethyl—1,3,2-dioxaborolane, 15 mg (0.019 mmol) of [1,1’—bis(dipheny|phosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 247 mg (0.76 mmol) of caesium carbonate in 2.0 ml of dioxane was degased with argon. Under argon, the reaction mixture was stirred at 110°C for 90 s. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride on and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then trated to give the crude product that was used without further purification in the next step.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Step b: 4-[2-fluoro(methylsulfonyl)phenyl][(3R)—3-methylmorpholin-4—yl](1H-pyrazoly|)-1,7- naphthyridine A solution of 105 mg of crude 4—[2-fluoro(methylsuIfonyl)phenyl]—2-[(3R)—3-methylmorpholin y|]-8—[1-(tetrahydro-2H-pyran—2-yl)-1H—pyrazo|-5—y|]-1,7-naphthyridine from step a in 3.0 ml of methanol and 0.19 ml of 2N hydrochloric acid was stirred for 3 hours at room temperature. The reaction mixture was d with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated to s. The residue was purified by preparative HPLC (Autopurifier: acidic conditions) to give 14 mg (0.03 mmol) ofthe desired product. 1H-NMR (400MHz, 6): 6 [ppm]: 1.32 (3H), 3.36 - 3.44 (4H), 3.58 (1H), 3.72 (1H), 3.83 (1H), 4.05 (1H), 4.23 (1H), 4.65 (1H), 7.18 (1H), 7.44 (1H), 7.52 — 7.82 (3H), 7.90 — 8.02 (1H), 8.02 — 8.16 (1H), 8.34 (1H), 13.43 (1H).

Example 133 2-[(3R)—3-methylmorpholin-4—yl][1-(oxetanyl)—1 H-pyrazo|y|](1H-pyrazolyl)—1,7- naphthyridine Step 3: 2-[(3R)methylmorpholinyl][1-(oxetany|)-1H-pyrazo|y|][1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazo|y|]-1,7-naphthyridine ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp A suspension of 100 mg (0.19 mmol) of 2-[(3R)methylmorpholinyl]—8—[1-(tetrahydro-2H- pyranyl)—1H-pyrazoly|]-1,7-naphthyridin-4—yl trifluoromethanesulfonate, 94 mg (0.38 mmol) 1-(oxetanyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan—Z-yl)-1H—pyrazole, 15 mg (0.019 mmol) of [1,1’-bis(dipheny|phosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, f)C|2) and 65 mg (0.47 mmol) of potassium carbonate in 2.0 ml of acetonitrile and 1.0 ml water was degased with argon. Under argon, the reaction mixture was stirred at 130°C for 10 minutes in a microwave oven. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 2-[(3R)methy|morpholinyl]-4—[1-(oxetany|)-1H-pyrazo|y|](1H-pyrazoIy|)-1,7- yridine A solution of 119 mg of crude 2-[(3R)-3—methylmorpholinyl][1-(oxetanyl)-1H-pyrazol—5-yl]— 8—[1—(tetrahydro-2H—pyran-Z—yl)-1H-pyrazoI-S—yl]—1,7-naphthyridine from step a in 3.0 ml of methanol and 0.24 ml of 2N hydrochloric acid was stirred for 60 minutes at room temperature.

The reaction mixture was d with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman Der and concentrated to dryness. The e was ed by preparative HPLC (Autopurifier: ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp acidic conditions) to give 11 mg (0.03 mmol) of the d product. 1H-NMR (400MHz, DMSO-d6): 8 [ppm]: 1.19 - 1.39 (3H), 3.57 (1H), 3.72 (1H), 3.83 (1H), 4.06 (1H), 4.21 (1H), 4.62 (1H), 4.73 (2H), 5.00 (2H), 5.25 - 5.44 (1H), 6.65 (1H), 7.09 (1H), 7.43 (1H), 7.48 (1H), 7.58 - 7.71 (1H), 7.88 (1H), 8.26 - 8.40 (1H), 13.45 (1H).

Example 134 4-[2-fluoro(pyrrolidinyl)phenyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine Step 3: 4-[2-fluoro-4—(pyrrolidinyl)phenyl][(3R)methy|morpholinyl][1—(tetrahydro-2H- pyran-Z-yl)-1H-pyrazo|yl]-1,7-naphthyridine A suspension of 100 mg (0.19 mmol) of )methy|morpho|in-4—yl]—8-[1—(tetrahydro-2H- Z-yl)-1H-pyrazoly|]-1,7-naphthyridin-4—yl trifluoromethanesulfonate, 79 mg (0.38 mmol) [2—fluoro-4—(pyrrolidin—1—yl)phenyl]boronic acid, 15 mg (0.019 mmol) of [1,1’- bis(dipheny|phosphino)ferrocene]dichloropalladium(|I) x with dichloromethane (1:1, Pd(dppf)C|2) and 247 mg (0.76 mmol) of caesium carbonate in 1.4 ml of dioxane was degased with argon. Under argon, the reaction mixture was stirred at 110°C for 2 hours. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: D[2-fluoro(pyrro|idinyl)pheny|][(3R)methylmorpholinyl](1H-pyrazoly|)-1,7- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp naphthyridine A on of 180 mg of crude 4-[2-fluoro(pyrrolidin-1—yl)phenyl]—2-[(3R)methy|morpholin y|]—8—[1-(tetrahydro—2H—pyran—Z—yl)-1H—pyrazo|—5—y|]-1,7—naphthyridine from step a in 1.5 ml of ol and 0.38 ml of 2N hydrochloric acid was stirred for 1 hours at room temperature. The reaction mixture was diluted with saturated s sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: acidic conditions) to give 44 mg (0.10 mmol) ofthe desired product. 1H—NMR (400MHz, DMSO-d6): 6 [ppm]: 1.30 (3H), 1.96 — 2.07 (4H), 3.27 — 3.33 (4H), 3.58 (1H), 3.72 (1H), 3.82 (1H), 4.05 (1H), 4.14 - 4.25 (1H), 4.56 - 4.70 (1H), 6.47 - 6.58 (2H), 7.24 - 7.48 (4H), 7.64 (1H), 8.31 (1H), 13.41 (1H).

Example 135 4-[3-(methoxymethyl)methyl-1,2-oxazo|y|][(3R)methylmorpholin-4—yl](1H-pyrazol- -yl)-1,7-naphthyridine Step a: 4—[3-(methoxymethyl)—5-methyl-1,2-oxazolyl][(3R)methylmorpholin-4—yl]-8—[1- (tetrahyd ro-ZH-pyran-Z-yl)-1H-pyrazo|y|]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A suspension of 75 mg (0.14 mmol) of 2-[(3R)methylmorpholinyl]—8—[1-(tetrahydro-2H- pyranyl)—1H-pyrazo|y|]-1,7-naphthyridin-4—yl trifluoromethanesulfonate, 24 mg (0.14 mmol) [3-(methoxymethyl)-5—methyl—1,2-oxazolyl]boronic acid, 11 mg (0.014 mmol) of [1,1’- pheny|phosphino)ferrocene]dich|oropal|adium(|I) complex with dichloromethane (1:1, Pd(dppf)C|2) and 49 mg (0.36 mmol) of potassium carbonate in 3.0 ml of acetonitrile and 1.0 ml water was degased with argon. Under argon, the reaction mixture was d at 130°C for 10 minutes in a ave oven. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl e (2x). The combinded organic phases were filtered using a n filter and then concentrated to give the crude product that was used t further purification in the next step.

Step b: 4-[3-(methoxymethyl)—5-methyl-1,2-oxazo|y|][(3R)methylmorpholin-4—yl](1H-pyrazol- 5-yl)-1,7-naphthyridine A solution of 111 mg of crude 4-[3-(methoxymethyl)methyl-1,2-oxazolyl]—2-[(3R) methylmorpholinyl]—8-[1-(tetrahydro-2H-pyranyI)-1H-pyrazoly|]-1,7-naphthyridine from step a in 3.0 ml of methanol and 0.22 ml of 2N hydrochloric acid was stirred for 60 minutes at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were dried (MgSO4), Dered and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp basic conditions) to give 11 mg (0.02 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 8 [ppm]: 1.25 - 1.36 (3H), 2.34 (3H), 3.09 (3H), 3.37 (1H), 3.59 (1H), 3.73 (1H), 3.83 (1H), 4.07 (1H), 4.20 (1H), 4.37 (1H), 4.50 (1H), 4.54 - 4.64 (1H), 7.29 (1H), 7.41 (1H), 7.55 (1H), 7.65 (1H), 8.34 (1H), 13.14 (1H).

Example 136 )—3-methylmorpholin-4—yl](5-methyl-1,3,4—oxadiazolyl)(1H-pyrazolyl)-1,7- yridine Step a: 2-[(3R)methylmorpholinyl][1-(tetrahydro-2H-pyran-Z-yl)-1H-pyrazol-S-yl]-1,7- naphthyridine-4—carbohyd razide 0.06 ml (1.14 mmol) hydrazine hydrate was added to a solution of 50 mg (0.11 mmol) of methyl 2— [(3R)methylmorpholinyl]—8—[1-(tetrahydro-2H-pyran—2-y|)-1H—pyrazo|—5-y|]—1,7- naphthyridine—4—carboxylate in 2 ml of ethanol and the mixture was stirred at 100 °C for 5 hours.

The mixture was concentrated to give the crude product that was used without further purification in the next step.

Step b: 2-[(3R)—3-methylmorpholin-4—yl](5-methyl-1,3,4—oxadiazolyl)[1-(tetrahyd ro-ZH-pyran-Z- yl)-1H-pyrazolyl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 0.03 ml (0.34 mmol) trifluoroacetic acid was added to a solution of crude 2—[(3R)-3— methylmorpholinyl][1-(tetrahydro—2H-pyranyl)-1H-pyrazo|yl]—1,7-naphthyridine-4— carbohydrazide from step a in 1.5 ml of trimethyl orthoacetate. The mixture was stirred at 95°C for 60 minutes. After cooling the reaction e was concentrated to give the crude product that was used without further purification in the next step.

Step c: 2-[(3R)—3-methy|morpholin-4—yl](5-methy|-1,3,4—oxadiazo|y|)(1H-pyrazolyl)—1,7- naphthyridine o \IN A solution of 47 mg of crude )methylmorpholinyl](5-methyl-1,3,4-oxadiazolyl) [1-(tetrahydro-2H-pyranyl)-1H-pyrazolyl]-1,7-naphthyridine from step b in 3.0 ml of ol and 0.10 ml of 2N hydrochloric acid was stirred for 60 minutes at room temperature.

The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were dried (MgSO4), filtered and concentrated to dryness. The residue was ed by preparative HPLC (Autopurifier: basic ions) to give 5 mg (0.01 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 8 [ppm]: 1.31 (3H), 2.63 - 2.82 (3H), 3.37 - 3.46 (1H), 3.59 (1H), 3.74 (1H), 3.85 (1H), 4.08 (1H), 4.21 (1H), 4.65 (1H), 7.40 (1H), 7.66 (1H), 7.96 (1H), 8.49 (1H), 8.62 DH), 13.45 (1H).

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 137 N-{2-[(3R)—3-methylmorpho|inyl](1H-pyrazo|y|)-1,7-naphthyridinyl}tetrahydro-1H- 1A4-thiophenimine 1-oxide Step a: N-{2—[(3R)—3-methylmorpholinyl][1-(tetrahydro-2H-pyran-Z-y|)-1H-pyrazol-S-yl]-1,7- naphthyridinyl}tetrahydro-1H-1A4-thiophenimine 1-oxide Under argon, 8 mg (0.014 mmol) 4,5—bis(diphenylphosphino)-9,9-dimethylxanthene and 7 mg (0.007 mmol) tris(dibenzylideneacetone)dipalladium(0) were added to a mixture of 75 mg (0.142 mmol) 2-[(3R)-3—methy|morpholin—4-yl][1-(tetrahydro-2H-pyranyl)-1H-pyrazolyl]-1,7- naphthyridin—4—yl trifluoromethanesulfonate, 22 mg (0.19 mmol) ydro-lH—1A4—thiophen-l— imine 1-oxide and 69 mg (0.21 mmol) caesium carbonate in 0.67 ml toluene. The mixture was stirred at 110 °C for 3 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium chloride. The organic phase was filtered using a Whatman filter and concentrated to give the crude product that was used without r cation.

Step b: N-{2-[(3R)—3-methylmorpho|inyl](1H-pyrazo|y|)-1,7-naphthyridinyl}tetrahydro-1H- 1A4-thiophenimine 1-oxide [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 0.15 ml (0.29 mmol) 2N aqueous solution of hydrogen chloride was added to a on of 72 mg crude N-{2-[(3R)-3—methy|morpholin—4-yl][1-(tetrahydro-2H—pyranyl)-1H-pyrazo|—5-y|]-1,7- naphthyridin—4-yl}tetrahydro—1H-1A4-thiophen—1—imine e in 3.3 ml methanol and the reaction mixture was stirred at room temperature for 1 hour. The mixture was basified by addition of an s sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC (Autopurifier: basic ions) to give 26 mg (0.06 mmol) of the desired product. lH-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.26 (3H), 2.07 - 2.24 (2H), 2.24 - 2.37 (2H), 3.18 - 3.30 (1H), 3.44 — 3.69 (5H), 3.72 (1H), 3.83 (1H), 3.95 - 4.13 (2H), 4.44 (1H), 6.67 (1H), 7.35 (1H), 7.60 (1H), 7.89 (1H), 8.29 (1H), 13.36 (1H).

Example 138 4-{[(4-f|uorophenyl)(methy|)oxido-A5-sulfanylidene]amino}[(3R)methy|morpholin-4—yl] (1H-pyrazolyl)-1,7-naphthyridine, mixture of 2 diastereoisomers Step 3: 4—{[(4-f|uorophenyl)(methyl)oxido-Ae-sulfanylidene]amino}[(3R)methylmorpholin-4—yl] [1-(tetrahydro-2H-pyran-2—yl)—1H-pyrazo|y|]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under argon, 8 mg (0.014 mmol) 4,5—bis(diphenylphosphino)-9,9-dimethylxanthene and 7 mg (0.007 mmol) tris(dibenzylideneacetone)dipalladium(0) were added to a mixture of 75 mg (0.142 mmol) 2-[(3R)-3—methylmorpholin—4-yl][1-(tetrahydro-2H—pyranyl)-1H-pyrazolyl]-1,7- naphthyridin—4-yl trifluoromethanesulfonate, 32 mg (0.19 mmol) l-fluoro—4-(S- methylsulfonimidoyl)benzene and 69 mg (0.21 mmol) caesium ate in 0.67 ml toluene. The mixture was stirred at 110 °C for 3 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with an aqueous on of sodium de. The organic phase was filtered using a Whatman filter and concentrated to give the crude product that was used without further purification.

Step b: 4-{[(4-fluorophenyl)(methyl)oxido-A6-sulfanylidene]amino}[(3R)—3-methylmorpholin-4—yl] (1H-pyrazolyl)-1,7-naphthyridine, e of 2 diastereoisomers [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 0.23 ml (0.29 mmol) 2N aqueous solution of hydrogen chloride was added to a on of 125 mg crude 4-{[(4-fluorophenyl)(methyl)oxido-Ae-sulfanylidene]amino}[(3R)methylmorpholin yl][1-(tetrahydro-2H-pyranyl)-1H-pyrazoly|]-1,7-naphthyridine in 5.1 ml methanol and the reaction e was d at room temperature for 90 minutes. The mixture was ed by on of an aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 24 mg (0.05 mmol) of the desired product as a mixture of 2 stereoisomers. lH-NMR (400MHz, DMSO-d6): 6 [ppm]: 0.82 (3H), 1.16 (3H), 3.00 - 3.17 (2H), 3.41 - 3.55 (2H), 3.55 - 3.67 (2H), 3.67 — 3.78 (8H), 3.78 - 3.92 (2H), 3.98 (3H), 4.14 (1H), 6.44 (1H), 6.56 (1H), 7.28 (2H), 7.49 (4H), 7.56 (2H), 7.92 - 8.17 (6H), 8.33 (2H), 13.29 (2H).

Example 139 4-{[(2-f|uorophenyl)(methy|)oxido-Ae-sulfanylidenehmino}[(3R)methy|morpholin-4—yl] (1H-pyrazolyl)-1,7-naphthyridine, mixture of 2 diastereoisomers Step 3: 4—{[(2-fluorophenyl)(methyl)oxido-Ae-sulfanylidene]amino}[(3R)methylmorpholin-4—yl] [1-(tetrahydro-ZH-pyran-Z-yl)—1H-pyrazo|y|]-1,7-naphthyridine Under argon, 8 mg (0.014 mmol) s(diphenylphosphino)-9,9-dimethylxanthene and 7 mg (0.007 mmol) tris(dibenzylideneacetone)dipal|adium(0) were added to a mixture of 75 mg (0.142 mmol) 2—[(3R)-3—methy|morpholin—4-yl][1-(tetrahydro-2H—pyran-2—yl)-1H-pyrazo|—5-y|]-1,7- naphthyridin—4-yl trifluoromethanesulfonate, 32 mg (0.19 mmol) 1-fluoro—2-(S- methylsulfonimidoyl)benzene and 69 mg (0.21 mmol) caesium carbonate in 0.67 ml toluene. The Dixture was stirred at 110 °C for 3 hours. After cooling, the reaction e was diluted with [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ethyl acetate and washed with an aqueous solution of sodium chloride. The organic phase was filtered using a Whatman filter and concentrated to give the crude product that was used without further purification.

Step b: 4-{[(2-fluorophenyl)(methyl)oxido-Ae-sulfanylidene]amino}[(3R)methylmorpholin-4—yl] (1H-pyrazolyl)-1,7-naphthyridine, mixture of 2 diastereoisomers 0.20 ml (0.29 mmol) 2N aqueous solution of hydrogen chloride was added to a on of 110 mg crude 4—{[(2-fluorophenyl)(methyl)oxido-Ae—sulfanylidene]amino}[(3R)—3-methylmorpholin y|][1-(tetrahydro-2H-pyranyl)-1H-pyrazo|—5—y|]-1,7-naphthyridine in 4.5 ml methanol and the reaction mixture was stirred at room temperature for 90 s. The mixture was basified by addition of an aqueous sodium onate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 28 mg (0.06 mmol) of the desired product as a mixture of 2 stereoisomers. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 0.82 (3H), 1.15 (3H), 2.99 - 3.17 (2H), 3.46 (2H), 3.57 (1H), 3.60 — 3.67 (1H), 3.71 (2H), 3.74 — 3.92 (8H), 3.92 — 4.06 (3H), 4.12 (1H), 6.47 (1H), 6.52 (1H), 7.27 (2H), 7.38 - 7.54 (4H), 7.56 (2H), 7.73 - 7.84 (2H), 7.91 - 7.96 (2H), 8.11 (1H), 8.11(1H), 8.27 - 8.34 (2H), 13.28 (2H).

Examples 140 and 141 -fluorophenyl)(methyl)oxido-Ae-sulfanylidene]amino}[(3R)methylmorpholin-4—yl] (1H-pyrazolyl)-1,7-naphthyridine, diastereoisomer 1 4—{[(2-fluorophenyl)(methyl)oxido-Ae-sulfanylidene]amino}[(3R)methylmorpholin-4—yl] [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp razoIyl)-1,7-naphthyridine, diasteroisomer 2 The mixture of 2 steroisomers from example 139 was separated into the single stereoisomers using preparative chiral HPLC: System: Labomatic Pump HD-5000, Labomatic SP-3000, Labocord 5000, Labomatic Labcol Vario 4000, Gilson GX—241 Column: Chiralpak IA 5 pm 250 x 30 mm t: EtOH / Methanol /diethylamine 50:50:0.1 (v/v/V) Flow: 35 mL/min Temperature: RT mg / 3 mL DCM/MeOH Injection: 5 x 0.6 mL Detection: UV 254 nm Retention time in min purity in % yield Example 140 7.4 — 7.9 93 6 mg Stereoisomer 1 (0.01 mmol) Example 141 6 mg isomer 2 (0.01 mmol) Example 142 4-(dimethylphosphoryl)-2—[(3R)—3-methy|morphoIiny|](1H-pyrazoI-S-y|)-1,7-naphthyridine Step 3: 4-(dimethylphosphoryl)[(3R)methy|morpho|iny|][1-(tetrahydro-ZH-pyran-Z-yI)-1H- pyrazoly|]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A mixture of 150 mg (0.28 mmol) of )methy|morpholin-4—y|][1-(tetrahydro-2H-pyran-Z- y|)—1H-pyrazol—5-y|]—1,7—naphthyridin—4—yl trifluoromethanesulfonate, 35 mg (0.32 mmol) dimethylphosphinoxide, 33 mg (0.028 mmol tetrakis(triphenylphosphine)pa||adium(0) and 0.06 ml (0.43 mmol) of triethylamine in 0.9 ml of acetonitrile was degased with argon. Under argon, the reaction mixture was stirred at 90°C for 3 hours. After cooling the reaction mixture was diluted with ethyl acetate and washed with aqueous chloride on. The organic phase was filtered using a n filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: ethylphosphoryl)[(3R)methy|morphoIin-4—yl](1H-pyrazolyl)-1,7-naphthyridine A solution of 210 mg of crude 4-(dimethylphosphoryl)[(3R)methylmorpholinyI]—8-[1- (tetrahydro—ZH-pyran—Z-yl)-1H—pyrazol—5—yl]-1,7—naphthyridine from step a in 2.1 ml of methanol and 0.53 ml of 2N hydrochloric acid was stirred for 10 minutes at room ature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated to s. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 13 mg (0.04 mmol) ofthe desired t. 1H—NMR (400MHz, DMSO-d6): 6 [ppm]= 1.30 (3H), 1.94 (3H), 1.90 (3H), 3.36 — 3.43 (1H), 3.57 (1H), 3.72 (1H), 3.85 (1H), 4.07 (1H), 4.18 (1H), 4.55 - 4.71 (1H), 7.37 (1H), 7.54 - 7.74 (2H), 8.32 - D51 (2H), 13.40 (1H).

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp e 143 4-(diethylphosphoryl)[(3R)methylmorpho|iny|](1H-pyrazo|y|)-1,7-naphthyridine Step a: 4-(diethylphosphoryl)[(3R)—3-methylmorpho|iny|][1-(tetrahydro-ZH-pyran-Z-yl)—1H- pyrazoly|]-1,7-naphthyridine A mixture of 150 mg (0.28 mmol) of 2—[(3R)-3—methylmorpholin—4—yl][1—(tetrahydro-2H—pyran-Z— yl)-1H-pyrazolyl]-1,7-naphthyridinyl trifluoromethanesulfonate, 32 mg (0.28 mmol) diethylphosphane oxide, 1.3 mg (0.006 mmol) palladium(|l) acetate, 3.5 mg (0.006 mmol) of 1,1’— phenylphosphino)ferrocene and 0.06 ml (0.37 mmol) of ethyldiisopropylamine in 1.2 ml of DMF and 0.14 ml 1,2—dimethoxyethane was degased with argon. Under argon, the reaction mixture was d at room temperature for 10 minutes and then at 110°C ght. After cooling the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The aqueous phase was saturated with solid sodium chloride and extracted with a mixture of THF and ethyl acetet (1:1). The combined organic phases were ed using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-(diethylphosphoryl)—2-[(3R)methylmorpho|iny|](1H-pyrazo|y|)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 190 mg of crude 4—(diethylphosphoryl)-2—[(3R)—3-methylmorpholiny|]—8-[1— (tetrahydro-2H-pyranyl)-1H-pyrazoly|]-1,7-naphthyridine from step a in 1.8 ml of methanol and 0.45 ml of 2N hydrochloric acid was stirred for 60 minutes at room temperature. The reaction mixture was diluted with saturated aqueous sodium onate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and trated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 25 mg (0.06 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 0.89 - 1.12 (6H), 1.18 - 1.35 (3H), 2.09 - 2.31 (4H), 3.59 (1H), 3.74 (1H), 3.84 (1H), 4.07 (1H), 4.18 (1H), 4.62 (1H), 7.37 (1H), 7.54 - 7.81 (2H), 8.39 (1H), 8.50 (1H), 13.40 (1H). e 144 ethyl isobutyl{2-[(3R)methy|morpholin-4—yl](1H-pyrazo|yl)-1,7-naphthyridin-4— sphinate Step a: ethyl isobutyl{2-[(3R)methylmorpholin-4—yl][1-(tetrahydro-ZH-pyran-Z-yl)-1H-pyrazo| y|]-1,7-naphthyridin-4—y|}phosphinate A mixture of 250 mg (0.47 mmol) of 2-[(3R)methy|morpholin-4—yl][1-(tetrahydro-2H-pyran yl)—1H-pyrazo|—5-y|]-1,7-naphthyridin-4—yl trifluoromethanesulfonate, 71 mg (0.47 mmol) ethyl (2- methylpropyl)phosphinate, 2.1 mg (0.009 mmol) palladium(|l) acetate, 5.8 mg (0.01 mmol) of 1,1'—bis(diphenylphosphino)ferrocene and 0.11 ml (0.62 mmol) of iisopropylamine in 2.1 ml of DMF and 0.24 ml 1,2-dimethoxyethane was degased with argon. Under argon, the reaction mixture was stirred at room ature for 10 minutes and then at 110°C overnight. After cooling the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ddium bicarbonate solution and saturated aqueous sodium chloride solution. The aqueous phase [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp was saturated with solid sodium chloride and extracted with a mixture of THF and ethyl acetet (1:1). The combined organic phases were filtered using a n filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: ethyl isobutyl{2-[(3R)methy|morpholin-4—yl](1H-pyrazo|yl)-1,7-naphthyridin-4— y|}phosphinate A solution of 456 mg of crude ethyl isobutyl{2-[(3R)methylmorpholinyl]—8-[1-(tetrahydro-2H- pyranyl)—1H-pyrazoI-S-yl]—1,7-naphthyridin—4—yl}phosphinate from step a in 3.9 ml of methanol and 1.0 ml of 2N hloric acid was stirred for 60 minutes at room ature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The ed organic phases were filtered using a n filter and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 29 mg (0.07 mmol) ofthe desired t. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 0.79 - 0.96 (3H), 1.03 (3H), 1.13 - 1.42 (6H), 1.90 - 2.19 (4H), 3.59 (1H), 3.73 (1H), 3.79 - 3.93 (2H), 3.97 — 4.27 (3H), 4.42 — 4.72 (1H), 7.38 (1H), 7.64 (1H), 7.81 (1H), 8.10 (1H), 8.45 (1H), 13.42 (1H).

Example 145 2-[(3R)—3-methy|morpholin-4—yl]-4—(morpholinyl)(1H-pyrazoly|)-1,7-naphthyridine Step a: 2-[(3R)—3-methy|morpholin-4—yl]-4—(morpholinyl)[1-(tetrahydro-ZH-pyranyl)-1H-pyrazo|— -y|]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A mixture of 50 mg (0.095 mmol) of 2—[(3R)-3—methy|morpholin—4—yl][1—(tetrahydro-2H-pyran y|)-1H-pyrazolyl]-1,7-naphthyridin-4—yl trifluoromethanesulfonate and 28 mg (0.32 mmol) morpholine in 0.14 ml of MeCN was stirred at 70°C for 150 minutes under argon. After cooling the reaction mixture was diluted with ethyl e and THF and washed with saturated aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and then trated to give the crude product that was used without further purification in the next step.

Step b: 2-[(3R)—3-methy|morpholin-4—yl]-4—(morpholin-4—yl)(1H-pyrazoly|)-1,7-naphthyridine A solution of 45 mg of crude 2—[(3R)—3-methylmorpho|in—4—yl]-4—(morpho|in—4-y|)—8—[1—(tetrahydro— 2H-pyrany|)-1H-pyrazoIyI]-1,7-naphthyridinel from step a in 0.45 ml of methanol and 0.11 ml of 2N hydrochloric acid was stirred for 1 h at room temperature. The reaction e was diluted with ted aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were ed using a Whatman filter and then concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 16 mg (0.04 mmol) of the desired product. 1H-NMR z, DMSO-d6): 8 [ppm]: 1.25 (3H), 3.07 - 3.23 (4H), 3.54 (1H), 3.69 (1H), 3.77 - D91 (5H), 3.98 - 4.07 (1H), 4.11 (1H), 4.57 (1H), 6.77 (1H), 7.33 (1H), 7.59 (1H), 7.63 (1H), 8.29 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (1H),13.33 (1H).

Example 146 sobutyl-1H-pyrazo|y|)[(3R)—3-methylmorphoIin-4—yl](1H-pyrazoly|)-1,7- naphthyridine Step 3: 4-(1-isobutyl-1H-pyrazo|y|)[(3R)—3-methylmorpho|iny|][1-(tetrahyd ro-ZH-pyran-Z-yl)- 1H-pyrazolyl]-1,7-naphthyridine A suspension of 75 mg (0.14 mmol) of )methy|morpholin-4—yl]—8—[1—(tetrahydro-2H- pyran-Z-yl)-1H-pyrazo|y|]-1,7-naphthyridin-4—yl trifluoromethanesulfonate, 36 mg (0.14 mmol) 1—isobutyl-5—(4,4,5,5—tetramethyl-1,3,2—dioxaborolan-Z—yl)—1H-pyrazole, 11mg (0.019 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]dich|oropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 49 mg (0.36 mmol) of potassium carbonate in 3.0 ml of acetonitrile and 1.0 ml water was degased with argon. Under argon, the reaction mixture was stirred at 130°C for 10 minutes in a microwave oven. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were ed using a n filter and then concentrated to give the crude product that was used without r purification in the next step.

Step b: 4-(1-isobutyI-1H-pyrazo|y|)[(3R)—3-methy|morphoIiny|](1H-pyrazol-S-yI)-1,7- naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 105 mg of crude sobutyl-1H-pyrazo|—5—yl)[(3R)methylmorpholinyI]—8-[1- (tetrahydro—2H-pyran—2-yl)-1H—pyrazoI—5-yl]-1,7—naphthyridine from step a in 3.0 ml of methanol and 0.21 ml of 2N hydrochloric acid was stirred for 60 minutes at room temperature. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The e was purified by preparative HPLC (Autopurifier: acidic conditions) to give 8 mg (0.02 mmol) of the desired t. lH-NMR (400MHz, DMSO-d6): 8 [ppm]: 0.64 (6H), 1.16 - 1.36 (3H), 1.82 - 2.04 (1H), 3.50 - 3.67 (1H), 3.69 - 3.96 (4H), 3.98 - 4.14 (1H), 4.23 (1H), 4.62 (1H), 6.56 (1H), 7.23 (1H), 7.44 (1H), 7.57 (1H), 7.65 (1H), 7.71 (1H), 8.36 (1H), 13.43 ( 1H).

Example 147 4—[5-fluoro(methylsulfonyl)pyridinyl][(3R)methylmorpho|in-4—yl](1H-pyrazolyl)- 1,7-naphthyridine Step a: 4—[5-fluoro(methylsulfonyl)pyridinyl][(3R)methylmorpholin-4—yl][1-(tetrahyd ro- ZH-pyran-Z-yl)-1H-pyrazolyl]-1,7-naphthyridine ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp A suspension of 75 mg (0.14 mmol) of 2—[(3R)-3—methy|morpholin—4—yl]—8—[1—(tetrahydro—2H— pyranyl)-1H-pyrazol-S-yl]—1,7-naphthyridinyl trifluoromethanesulfonate, 86 mg (0.28 mmol) 3-fluoro(methylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine, 12 mg (0.014 mmol) of [1,1’-bis(dipheny|phosphino)ferrocene]dichloropalladium(|l) complex with romethane (1:1, Pd(dppf)C|2) and 185 mg (0.57 mmol) of caesium carbonate in 1.0 ml of dioxane was degased with argon. Under argon, the reaction mixture was stirred at 110°C for 2 hours. After cooling the reaction mixture was diluted with ted aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: luoro(methylsulfonyl)pyridinyl][(3R)methy|morpho|in-4—yl](1H-pyrazolyl)- 1,7-naphthyridine /S\\=O A solution of 118 mg of crude 4—[5—fluoro—6—(methylsulfonyl)pyridin—3—yl]—2—[(3R)-3— methylmorpholiny|][1-(tetrahydro—2H-pyrany|)-1H-pyrazoI-S-y|]-1,7-naphthyridine from step a in 1.0 ml of methanol and 0.25 ml of 2N hydrochloric acid was stirred for 1 hours at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated to dryness. The residue was ed by preparative HPLC (Autopurifier: acidic conditions) to give 1 mg (0.002 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 8 [ppm]: 1.27- 1.33 (3H), 3.45 - 3.63 (5H), 3.71 (1H), 3.83 (1H), 4.05 (1H), 4.23 (1H), 4.65 (1H), 7.33 - 7.54 (2H), 7.64 (2H), 8.34 (1H), 8.43 (1H), 8.80 (1H), 13.42 (1H).

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 148 4-[(3R)—3-methylmorpholinyl](morpholin-4—yl)—8-(1H-pyrazolyl)—1,7-naphthyridine Step 3: 4-[(3R)—3-methylmorpholin-4—yl](morpholin-4—yl)—8-[1-(tetrahydro-2H-pyranyl)-1H-pyrazol- -yl]-1,7-naphthyridine A mixture of 150 mg (0.29 mmol) of 2-(morpholin—4-yl)-8—[1-(tetrahydro-2H-pyranyl)-1H- pyrazol-S—yl]—1,7-naphthyridin—4—yl trifluoromethanesulfonate and 100 mg (0.99 mmol) — methylmorpholine in 0.43 ml of MeCN was stirred at 70°C overnight under argon. After cooling the reaction mixture was diluted with ethyl acetate and washed with saturated s sodium chloride solution. The c phase was filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-[(3R)methylmorpholin-4—yl](morpholin-4—yl)—8-(1H-pyrazolyl)—1,7-naphthyridine A solution of 190 mg of crude 4-[(3R)—3—methylmorpholin-4—yl]—2—(morpho|in-4—yl)—8—[1— (tetrahydro-2H-pyran—2-yl)-1H-pyrazoly|]-1,7-naphthyridine from step a in 1.9 ml of methanol and 0.47 ml of 2N hydrochloric acid was stirred for 1 h at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with Dhyl acetate (2x). The ed c phases were ed using a Whatman filter and then [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 18 mg (0.05 mmol) ofthe desired product. 1H-NMR (400MHz, 6): 6 [ppm]= 0.93 (3H), 2.82 (1H), 3.38 - 3.47 (1H), 3.54 (1H), 3.65 - 3.86 (10H), 3.91 (1H), 3.98 (1H), 6.96 (1H), 7.36 (1H), 7.61 (1H), 7.71 (1H), 8.33 (1H), 13.35 (1H).

Example 149 2-[(3R)methy|morpholin-4—yl]-4—(4—methyl-1H-pyrazol-S-yl)(1H-pyrazolyl)-1,7- naphthyridine Step a: 2-[(3R)—3-methy|morpho|in-4—yl](4-methy|-1H-pyrazo|y|)[1-(tetrahyd ro-ZH-pyran-Z-yl)— 1H-pyrazolyl]-1,7-naphthyridine A suspension of 100 mg (0.19 mmol) of 2—[(3R)methy|morpho|in—4—yl]—8-[1—(tetrahydro-2H- pyran-Z-yl)-1H-pyrazoIyl]-1,7-naphthyridin-4—y| trifluoromethanesulfonate, 48 mg (0.38 mmol) 1—isobutyl—5—(4,4,5,5—tetramethyl-1,3,2—dioxaborolan-Z—yl)—1H-pyrazole, 15 mg (0.019 mmol) of [1,1’-bis(diphenylphosphino)ferrocene]dich|oropa||adium(||) complex with romethane (1:1, Pd(dppf)C|2) and 65 mg (0.47 mmol) of ium carbonate in 2.0 ml of acetonitrile and 1.0 ml water was degased with argon. Under argon, the reaction mixture was stirred at 130°C for 10 minutes in a microwave oven. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were ed using a n filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 2-[(3R)methylmorpholinyl](4-methyl-1H-pyrazolyl)(1H-pyrazolyl)—1,7- naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 111 mg of crude 2-[(3R)methy|morpholinyl]-4—(4-methyl-1H-pyrazoIyl)—8-[1- (tetrahydro—2H-pyran—2-yl)-1H—pyrazoI—5-yl]-1,7—naphthyridine from step a in 5.0 ml of ol and 0.24 ml of 2N hloric acid was stirred for 60 minutes at room temperature. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: acidic conditions) to give 12 mg (0.03 mmol) of the d t. lH-NMR (400MHz, DMSO-d6): 8 [ppm]: 1.30 (3H), 2.07 (3H), 3.59 (1H), 3.73 (1H), 3.83 (1H), 4.06 (1H), 4.20 (1H), 4.62 (1H), 7.25 — 7.52 (2H), 7.64 (2H), 7.76 (1H), 8.34 (1H), 13.11 (1H), 13.41 (1H).

Example 150 4—[2—fluoro(methylsulfonyl)phenyl]-Z-[(3R)—3-methy|morphoIin-4—yl](1H-pyrazoly|)-1,7- naphthyridine Step a: 4—[2-fluoro(methylsulfonyl)phenyl][(3R)methy|morpho|iny|][1-(tetrahydro-ZH- pyran-Z-yl)-1H-pyrazolyl]-1,7-naphthyridine A suspension of 100 mg (0.19 mmol) of 2-[(3R)methy|morpho|in-4—yl]—8-[1-(tetrahydro-2H- Dranyl)—1H-pyrazolyl]-1,7-naphthyridin-4—yl trifluoromethanesulfonate, 83 mg (0.38 mmol) ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [2—fluoro—5—(methylsulfonyl)phenyl]boronic acid, 15 mg (0.019 mmol) of [1,1’— phenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (1:1, Pd(dppf)C|2) and 65 mg (0.47 mmol) of potassium carbonate in 2.0 ml of acetonitrile and 1.0 ml water was degased with argon. Under argon, the reaction mixture was stirred at 130°C for 10 minutes in a microwave oven. After cooling the reaction mixture was diluted with saturated s sodium chloride solution and extracted with ethyl acetate (2x). The ded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4—[2-fluoro(methylsulfonyl)phenyl][(3R)methy|morphoIin-4—yl](1H-pyrazol-S-yl)—1,7— naphthyridine A solution of 83 mg of crude 4-[2-fluoro(methylsulfonyl)phenyl]—2-[(3R)—3-methylmorpholin yl]—8—[1-(tetrahydro—2H—pyran—Z—yl)-1H—pyrazol—5—y|]-1,7—naphthyridine from step a in 3.0 ml of methanol and 0.15 ml of 2N hydrochloric acid was stirred for 3 hours at room temperature. The reaction mixture was d with ethyl acetate and washed with aqueous sodium chloride solution. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The residue was purified by preparative HPLC urifier: acidic conditions) to give 29 mg (0.06 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.32 (3H), 3.37 (1H), 3.35 (3H), 3.58 (1H), 3.72 (1H), 4.05 (1H), 4.21 (1H), 4.65 (1H), 7.17 (1H), 7.45 (1H), 7.65 (2H), 7.77 (1H), 8.07 - 8.28 (2H), 8.33 (1H), 13.45 (1H).

Example 151 dM—(isopropylsulfonyl)phenyl][(3R)methylmorpholin-4—y|](1H-pyrazolyl)—1,7- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp naphthyridine 4-[4—(isopropylsu |fonyl)phenyI]—2-[(3R)—3-methy|morpho| inyl]-8—(1H-pyrazo|—5-y| )—1,7- naphthyridine was isolated as a side product in minor amounts in the preparation of example 25. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.25 (6H), 3.55 (1H), 3.81 (8H), 7.38 (1H), 7.44 (1H), 7.59 (1H), 7.65 (1H), 7.74- 7.94 (2H), 7.95 - 8.15 (2H), 8.35 (1H), 13.43 (1H).

Example 152 luoropyridin-Z-yl)[(3R)methy|morpho|in-4—yl](1H-pyrazoly|)-1,7-naphthyridine Step a: 4—(6-fluoropyridin-Z-yl)[(3R)methy|morpho|in-4—yl][1-(tetrahyd ro-2H-pyranyl)—1H- pyrazolyl]-1,7-naphthyridine A suspension of 100 mg (0.19 mmol) of 2—[(3R)methy|morpholin-4—yl]-8—[1—(tetrahydro-2H- Z-yl)-1H-pyrazo|—5-yl]-1,7-naphthyridin-4—yl trifluoromethanesulfonate, 53 mg (0.38 mmol) (6—fluoropyridinyl)boronic acid, 15 mg (0.019 mmol) of [1,1’- bis(dipheny|phosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, "(dppfmlz) and 247 mg (0.76 mmol) of caesium carbonate in 1.4 ml of dioxane was degased with [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp argon. Under argon, the reaction mixture was stirred at 110°C for 2 hours. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride solution and ted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-(6-fluoropyridinyl)[(3R)methy|morpholiny|](1H-pyrazo|y|)-1,7-naphthyridine A solution of 92 mg of crude 4—(6—fluoropyridin—2—yl)-2—[(3R)—3-methylmorpholin-4—yl]—8-[1— hydro-2H-pyranyl)-1H-pyrazoly|]-1,7-naphthyridine from step a in 3.0 ml of methanol and 0.19 ml of 2N hydrochloric acid was stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium chloride on. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 12 mg (0.03 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.31 (3H), 3.35 - 3.42 (1H), 3.58 (1H), 3.73 (1H), 3.84 (1H), 4.06 (1H), 4.16 - 4.29 (1H), 4.59 - 4.75 (1H), 7.37 - 7.46 (2H), 7.59 - 7.67 (2H), 7.72 (1H), 7.82 (1H), 8.26 (1H), 8.36 (1H), 13.43 (1H).

Example 153 thyl-1H-imidazol-4—yl)[(3R)—3-methy|morpholiny|](1H-pyrazoly|)-1,7- naphthyridine Step 3: 4-(1-ethyI-1H-imidazol-4—yl)[(3R)methy|morpholiny|][1-(tetrahydro-2H-pyranyl)- 1H-pyrazolyl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A suspension of 100 mg (0.19 mmol) of )methy|morpholin-4—yl]—8—[1-(tetrahydro-2H- pyran-Z-yl)—1H-pyrazol—5-yl]—1,7—naphthyridin-4—yl trifluoromethanesulfonate, 83 mg (0.38 mmol) 1-ethyl(4,4,5,5-tetramethy|—1,3,2-dioxaborolan-Z-yl)-1H-imidazo|e, 15 mg (0.019 mmol) of [1,1’—bis(diphenylphosphino)ferrocene]dich|oropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 65 mg (0.47 mmol) of potassium carbonate in 2.0 ml of acetonitrile and 1.0 ml water was degased with argon. Under argon, the reaction mixture was stirred at 130°C for 10 minutes in a microwave oven. After cooling the reaction e was diluted with saturated aqueous sodium chloride solution and ted with ethyl acetate (2x). The combinded organic phases were filtered using a n filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-(1-ethyl-1H-imidazol-4—yl)—2-[(3R)—3-methy|morpholiny|](1H-pyrazolyl)—1,7- naphthyridine A solution of 130 mg of crude 4-(1—ethyl-1H—imidazoI—4—yl)[(3R)—3-methylmorpholin-4—yl]—8—[1— (tetrahydro-2H-pyran—2-yl)-1H—pyrazoI-S-yl]-1,7-naphthyridine from step a in 3.0 ml of methanol and 0.28 ml of 2N hydrochloric acid was stirred for 1 hour at room temperature. The reaction [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp mixture was diluted with ethyl acetate and washed with aqueous sodium de solution. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 12 mg (0.03 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.29 (3H), 1.46 (3H), 3.51 - 3.64 (1H), 3.74 (1H), 3.85 (1H), 3.99 - 4.26 (4H), 4.62 (1H), 7.38 (1H), 7.51 - 7.73 (2H), 7.88 - 8.00 (1H), 8.09 (1H), 8.36 (1H), 8.61 (1H), 13.38 (1H).

Example 154 1-{2-[(3R)methylmorpholinyl](1H-pyrazo|y|)-1,7-naphthyridiny|}prolinamide Step a: 1-{2-[(3R)methylmorpholinyl][1-(tetrahyd ro-2H-pyranyl)—1H-pyrazolyl]-1,7- naphthyridinyl}prolinamide A mixture of 150 mg (0.28 mmol) of )methy|morpholin—4—yl][1—(tetrahydro-2H-pyran y|)-1H-pyrazoly|]-1,7-naphthyridin-4—yl trifluoromethanesulfonate and 110 mg (0.97 mmol) prolinamide in 0.42 ml of MeCN was d at 70°C for 3 hours under argon. After cooling the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic phase was ed using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 1-{2—[(3R)methylmorpholinyl](1H-pyrazo|y|)-1,7-naphthyridin-4—yl}prolinamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp A solution of 233 mg of crude (3R)methylmorpholiny|][1-(tetrahydro-2H-pyran—2-yl)- 1H-pyrazo|—5-yl]-1,7-naphthyridin-4—y|}pro|inamide from step a in 2.2 ml of methanol and 0.55 ml of 2N hydrochloric acid was stirred for 1 h at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to dryness. The e was purified by preparative HPLC (Autopurifier: basic conditions) to give 18 mg (0.05 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.16 - 1.32 (3H), 1.82 - 2.10 (3H), 2.28 - 2.36 (1H), 3.24 (1H), 3.45 - 3.61 (1H), 3.68 (2H), 3.82 (1H), 4.01 — 4.21 (3H), 4.26 - 4.52 (2H), 6.20 (1H), 7.16 (1H), 7.31 (1H), 7.58 (1H), 7.66 (1H), 7.87 (1H), 8.21 (1H), 13.36 (1H).

Example 155 3-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}pyridinamine Step 3: 3-{2-[(3R)methy|morpholinyl][1-(tetrahyd ro-ZH-pyran-Z-yl)-1H-pyrazolyl]-1,7- naphthyridin-4—yl}pyridin-Z-amine A suspension of 100 mg (0.19 mmol) of 2—[(3R)-3—methy|morpho|in—4—yl]—8-[1—(tetrahydro—2H- pyranyl)-1H-pyrazolyl]—1,7-naphthyridin-4—yl trif|uoromethanesulfonate, 42 mg (0.19 mmol) d(4,4,5,5—tetramethyl—1,3,2—dioxaborolan-Z-yl)pyridin—2—amine, 15 mg (0.019 mmol) of [1,1’— [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp bis(diphenylphosphino)ferrocene]dichloropalladium(l|) complex with dichloromethane (1:1, f)C|2) and 247 mg (0.76 mmol) of m carbonate in 1.5 ml of dioxane was degased with argon. Under argon, the reaction mixture was stirred at 110°C for 90 minutes. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 3-{2-[(3R)methy|morpholiny|](1H-pyrazo|y|)-1,7-naphthyridin-4—y|}pyridinamine A solution of 76 mg of crude 3—{2-[(3R)—3-methylmorpholin-4—yl]—8—[1-(tetrahydro—2H-pyran—2—yl)— 1H-pyrazo|—5—yl]-1,7-naphthyridiny|}pyridinamine from step a in 3.0 ml of methanol and 0.16 ml of 2N hydrochloric acid was stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate and washed with s sodium chloride on. The organic phase was dried (MgSO4), filtered and trated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 7 mg (0.02 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.31 (3H), 3.57 (1H), 3.71 (1H), 3.82 (1H), 4.06 (1H), 4.21 (1H), 4.57 - 4.67 (1H), 5.71 (2H), 6.72 (1H), 7.12 (1H), 7.29 - 7.54 (3H), 7.64 (1H), 8.11 (1H), 8.29 (1H), 13.42 (1H).

Example 156 2-[(3R)—3-methy|morpho|inyl](1H-pyrazolyl)—4-[1-(2,2,2-trifluoroethyl)-1H-pyrazo|y|]- 1,7-naphthyridine Step 3: 2-[(3R)—3-methy|morpholin-4—yl][1—(tetrahydro-ZH-pyrany|)-1H-pyrazo|y|][1-(2,2,2- Dfluoroethyl)-1H-pyrazolyl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A suspension of 100 mg (0.19 mmol) of 2-[(3R)methylmorpholinyl]—8—[1-(tetrahydro-2H- pyranyl)—1H-pyrazoly|]-1,7-naphthyridin-4—yl trifluoromethanesulfonate, 74 mg (0.38 mmol) [1-(2,2,2-trifluoroethy|)-1H-pyrazolyl]boronic acid, 15 mg (0.019 mmol) of [1,1’- bis(dipheny|phosphino)ferrocene]dich|oropal|adium(|I) complex with dichloromethane (1:1, f)C|2) and 247 mg (0.76 mmol) of caesium carbonate in 2.0 ml of dioxane was degased with argon. Under argon, the reaction mixture was stirred at 110°C for 1 hour. After g the reaction mixture was diluted with ted aqueous sodium chloride solution and ted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 2-[(3R)methy|morpholinyl](1H-pyrazolyl)—4—[1—(2,2,2-trifluoroethyl)-1H-pyrazo|y|]- 1,7-naphthyridine A solution of 107 mg of crude 2-[(3R)methylmorpholinyl][1-(tetrahydro-2H-pyran—2-yl)- 1H-pyrazoIyI][1-(2,2,2-trif|uoroethy|)-1H-pyrazo|—5-yl]-1,7-naphthyridine from step a in 3.0 ml of methanol and 0.20 ml of 2N hydrochloric acid was stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The c phase was dried (MgSO4), filtered and concentrated to Dyness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 7 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp mg (0.02 mmol) of the desired product. 1H-NMR (400MHz, CDCI3): 6 [ppm]: 1.48 (3H), 3.61 (1H), 3.68 - 3.81(1H), 3.81 - 4.00 (2H), 4.05 (1H), 4.20 (1H), 4.50 (1H), 4.89 (2H), 6.79 (1H), 7.33 (1H), 7.42 (1H), 7.67 - 7.79 (2H), 8.08 (1H), 8.47 (1H).

Example 157 1-methyl{2-[(3R)—3-methylmorpholin-4—yl](1H-pyrazolyl)-1,7-naphthyridin yl}piperazin-Z-one Step a: 1-methyl{2-[(3R)methylmorpholinyl][1-(tetrahydro-ZH-pyran-Z-yl)-1H-pyrazol-S-yl]- 1,7-naphthyridin-4—yl}piperazin-Z-one 04;: A mixture of 150 mg (0.29 mmol) of 2—(morpholin—4—yl)—8—[1—(tetrahydro-2H—pyran—2—yI)—1H— pyrazoly|]-1,7-naphthyridiny| trifluoromethanesulfonate, 150 mg (0.99 mmol) 1- methylpiperazin-2—one hloride and 0.28 ml (1.99 mmol) of triethylamine in 0.43 ml of MeCN was stirred at 70°C overnight under argon. After cooling the reaction mixture was d with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic phase was ed using a n filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 1-methyl{2-[(3R)—3-methylmorpholin-4—yl](1H-pyrazolyl)-1,7-naphthyridin yl}piperazin-Z-one [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 207 mg of crude 1-methyI{2-[(3R)methy|morpho|in-4—yl][1-(tetrahydro-2H- pyranyl)-1H-pyrazol—5-y|]-1,7—naphthyridin-4—yl}piperazinone from step a in 2.0 ml of methanol and 0.50 ml of 2N hydrochloric acid was stirred for 1 h at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined c phases were filtered using a Whatman filter and then concentrated to dryness. The residue was purified by preparative HPLC urifier: basic conditions) to give 11 mg (0.03 mmol) ofthe desired product. 1H—NMR (400MHz, DMSO-d6): 6 [ppm]: 2.96 (3H), 3.49 (2H), 3.61 (2H), 3.76 (8H), 3.86 (2H), 6.84 (1H), 7.35 (1H), 7.47 - 7.75 (2H), 8.33 (1H), 13.36 (1H).

Example 158 and 159 4-[1-(2-fluoroethyl)-1H-pyrazolyl][(3R)methylmorpholin-4—y|](1H-pyrazolyl)-1,7- naphthyridine 4-[1-(2-fluoroethyl)-1H-pyrazolyl][(3R)methy|morpholin-4—y|](1H-pyrazolyl)-1,7- naphthyridine Step 3: 2-[(3R)—3-methylmorpholin-4—yl]-4—(1H-pyrazolyl)[1-(tetrahydro-ZH-pyrany|)-1H-pyrazol- -yl]-1,7-naphthyridine nsion of 200 mg (0.38 mmol) of 2-[(3R)methy|morpho|in-4—yl][1—(tetrahydro-2H- [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp pyran—Z-yl)—1H—pyrazoI—5-y|]—1,7—naphthyridin—4—yl trifluoromethanesulfonate, 136 mg (0.76 mmol) -(5,5-dimethy|—1,3,2-dioxaborinan-Z-yl)—1H-pyrazole, 31 mg (0.038 mmol) of [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 131 mg (0.95 mmol) of potassium carbonate in 3.9 ml of acetonitrile and 2.0 ml water was degased with argon. Under argon, the reaction mixture was stirred at 130°C for 10 minutes in a microwave oven. After cooling the reaction mixture was diluted with saturated aqueous sodium de solution and extracted with ethyl acetate (2x). The combinded organic phases were ed using a Whatman filter and then concentrated to give the crude product that was purified by column chromatography on silica gel (hexane / ethylacetate 40% to ethyl acetate) to give 134 mg of the desired product containing slight impurities.

Step b: 4-[1-(2-fluoroethyl)—1H-pyrazolyl][(3R)—3-methy|morpho|iny|][1-(tetrahydro-ZH- pyran-Z-yl)-1H-pyrazo|—5-y|]-1,7-naphthyridine 4-[1-(2-fluoroethyl)—1H-pyrazol-S-yl][(3R)methy|morpho|iny|][1-(tetrahydro-ZH- pyran-Z-yl)-1H-pyrazo|—5-y|]-1,7-naphthyridine A mixture of 45 mg (0.10 mmol) 2-[(3R)—3-methylmorpholiny|](1H-pyrazolyl)—8-[1- (tetrahydro—ZH-pyran—Z-yl)-1H—pyrazoI—S-yl]-1,7—naphthyridine from step a, 35 mg (0.20 mmol) of 1-fluoroiodoethane and 66 mg (0.20 mmol) of m ate in 1.0 ml DMF was stirred at 50°C for 3 hours. After cooling, the mixture was diluted with ethyl e and washed with aqueous sodium chloride solution and aqueous sodium bicarbonate solution. The organic phase was filtered using a Whatman filter and concentrated to dryness to give a mixture of the crude products 4—[1—(2-fluoroethyl)—1H-pyrazo|—3-y|]—2-[(3R)—3—methy|morpholin—4-yl]-8—[1-(tetrahydro- 2H—pyran-Z—yl)-1H-pyrazo|—5-y|]-1,7-naphthyridine and 4-[1-(2—fluoroethyl)-1H—pyrazo|—5—y|]—2- [(3R)—3-methylmorpholinyl]—8-[1-(tetrahydro—ZH-pyran—2-y|)-1H—pyrazo|—5-y|]—1,7—naphthyridine Dat was used without further purification.

[Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Step c: 2-fluoroethyl)—1H-pyrazolyl][(3R)methy|morpholinyl](1H-pyrazolyl)—1,7- naphthyridine 4-[1-(2-fluomethyl)-1H-pyrazolyl][(3R)methy|morpholinyl](1H-pyrazolyl)—1,7- naphthyridine A on of 55 mg of a crude misture of 4-[1-(2-fluoroethyl)-1H—pyrazol—3-yl][(3R) methylmorpholiny|][1-(tetrahydro—2H-pyrany|)-1H-pyrazol—5-yl]-1,7-naphthyridine and 4- fluoroethyl)-1H—pyrazol-5—yl]—2-[(3R)—3-methylmorpholinyl][1-(tetrahydro—2H-pyran yl)—1H-pyrazo|yl]-1,7-naphthyridine from step b in 0.5 ml of methanol and 0.13 ml of 2N hydrochloric acid was stirred for 1 hour at room temperature. The reaction mixture was diluted with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2x). The combined c phases were filtered using a Whatman filter and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 12 mg (0.03 mmol) of 4—[1-(2-fluoroethyl)—1H-pyrazolyl]—2-[(3R)—3—methylmorpholin—4-yl]—8—(1H-pyrazol yl)-1,7-naphthyridine (example 158) and 2 mg (0.005 mmol) of 4—[1-(2-fluoroethyl)—1H-pyrazol yl]—2—[(3R)—3—methylmorpholin—4—yl]-8—(1H-pyrazoly|)—1,7-naphthyridine (example 159).

Example 158 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.21 - 1.37 3H), 3.59 (1H), 3.74 (1H), 3.85 (1H), 4.07 (1H), 4.22 (1H), 4.59 (1H), 4.62 - 4.72 (2H), 4.83 (1H), 4.95 (1H), 7.03 (1H), 7.40 (1H), 7.64 (2H), 7.84 - 8.13 (1H), 8.39 (1H), 8.47 - 8.58 (1H), 13.40 (1H).

Example 159 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.29 (3H), 3.58 (1H), 3.72 (1H), 3.82 (1H), 4.06 (1H), 4.21 UH), 4.25 — 4.39 (2H), 4.53 — 4.68 (2H), 4.72 (1H), 6.60 (1H), 7.23 (1H), 7.42 (1H), 7.53 (1H), 7.65 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp (1H), 7.77 (1H), 8.29 — 8.36 (1H), 13.32 (1H).

Example 160 2-(3-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridiny|}-1H-pyrazol yl)ethano| Step a: 2-[(3R)—3-methylmorpholin-4—yl]-4—{1-[2-(tetrahyd pyranyloxy)ethy|]-1H-pyrazo|y|} [1-(tetrahydro-2H-pyran-2—yl)—1H-pyrazol-S-yl]-1,7-naphthyridine A mixture of 45 mg (0.10 mmol) 2-[(3R)—3-methylmorpholiny|]—4—(1H-pyrazoIyl)—8-[1- (tetrahydro—2H-pyran—2-yl)-1H—pyrazoI—5—yl]-1,7—naphthyridine, 25 mg (0.12 mmol) of 2-(2- thoxy)tetrahydro-ZH-pyran and 39 mg (0.12 mmol) of caesium carbonate in 0.2 ml DMF was stirred at 70°C for 7 hours. After cooling, the mixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated to dryness to give a mixture of the crude products that was used without further purification.

Step b: 2-(3-{2-[(3R)methylmorpholin-4—yl](1H-pyrazo|y|)-1,7-naphthyridiny|}-1H-pyrazol yl)ethano| [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 52 mg crude 2-[(3R)methylmorpholiny|]—4-{1-[2-(tetrahydro-2H-pyran ethy|]—1H-pyrazoly|}—8—[1-(tetrahydro-2H—pyran—2—yl)-1H—pyrazo|—5—yl]-1,7—naphthyridine from step a in 0.8 ml of methanol and 0.21 ml of 2N hydrochloric acid was stirred for 90 s at room temperature. The reaction mixture was diluted with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate and THF (2x). The combined organic phases were filtered using a Whatman filter and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 11 mg (0.03 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 8 [ppm]: 1.29 (3H), 3.35-3.41(1H), 3.53-3.63 (1H), .79 (1H), 3.85 (3H), 4.00-4.10(1H), 4.17—4.24 (1H), 4.31 (2H), 4.63-4.73 (1H), 5.00 (1H), 6.98 (1H), 7.40 (1H), 7.62 (2H),7.94 (1H), 8.38 (1H), 8.56 (1H), 13.41 (1H).

Example 161 2-methyl(3—{2-[(3R)methy|morpholin-4—yl](1H-pyrazo|y|)-1,7-naphthyridin-4—y|}-1H- pyrazol-l—yl)propano| Step a: 2-methyl(3—{2-[(3R)methy|morpholin-4—yl][1—(tetrahydro-ZH-pyran-Z-yl)—1H-pyrazol y|]-1,7-naphthyridiny|}-1H-pyrazolyl)propan-Z-ol [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp In a closed vessel under argon, a mixture of 50 mg (0.11 mmol) 2-[(3R)methylmorpholinyl]— pyrazoI—5-yl)—8—[1-(tetrahydro-2H—pyran—2—yl)-1H—pyrazol-5—y|]-1,7-naphthyridine, 16 mg (0.22 mmol) of 2,2-dimethyloxirane and 23 mg (0.17 mmol) of potassium ate in 0.5 ml DMF was stirred at 130°C in a microwave oven for 10 minutes. After cooling, 31 mg (0.29 mmol) of 2,2- yloxirane was added and the mixture was stirred at 130°C in a microwave oven for 10 minutes.After cooling, the mixture was diluted with ethyl acetate and washed with water. The organic phase was filtered using a Whatman filter and concentrated to dryness to give a mixture of the crude products that was used without further purification.

Step b: yl(3-{2-[(3R)methy|morpholin-4—yl](1H-pyrazo|y|)-1,7-naphthyridin-4—y|}-1H- pyrazolyl)propano| A on of 30 mg crude 2—methyl—1—(3-{2—[(3R)methylmorpholin—4—yl]—8—[1—(tetrahydro-2H- pyran-Z-yl)-1H-pyrazo|yl]-1,7-naphthyridiny|}-1H-pyrazoly|)propan—2-ol from step a in 1.5 ml of methanol and 0.06 ml of 2N hydrochloric acid was stirred for 90 minutes at room temperature. The reaction mixture was diluted with an aqueous solution of sodium bicarbonate dd extracted with ethyl acetate and THF (2x). The combined c phases were filtered using a [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Whatman filter and concentrated to s. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 8 mg (0.02 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]= 1.17 (6H), 1.30 (3H), 3.50 - 3.67 (1H), 3.74 (1H), 3.85 (1H), 3.99 - 4.15 (1H), 4.15 -4.40 (3H), 4.68 (1H), 4.81 (1H), 7.00 (1H), 7.40 ( 1H), 7.54 - 7.70 (2H), 7.89 (1H), 8.37 (1H), 8.56 (1H), 13.40 (1H).

Example 162 4-[(2R)methy|morpholinyl](morpholinyl)(1H-pyrazolyl)—1,7-naphthyridine Step a: 4-[(2R)—2-methy|morpho|inyl](morpholinyl)[1—(tetrahydro-ZH-pyranyl)-1H-pyrazo|— -yl]-1,7-naphthyridine A mixture of 150 mg (0.29 mmol) of 2-(morpholiny|)[1-(tetrahydro-2H-pyranyl)-1H- ly|]-1,7-naphthyridiny| trifluoromethanesulfonate, 103 mg (1.02 mmol) (2R) methylmorpholine hydrochloride and 0.14 ml (1.02 mmol) hylamine in 0.5 ml of MeCN was stirred at 70°C overnight under argon. After cooling the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic phase was filtered using a n filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4—[(2R)—2-methylmorpholin-4—yl](morpholin-4—yl)—8-(1H-pyrazolyl)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 178 mg of crude 4-[(2R)methylmorpho|iny|]—2—(morpho|in-4—y|)—8-[1- (tetrahydro-2H-pyran—2-yl)-1H—pyrazoIyl]-1,7-naphthyridine from step a in 8.6 ml of methanol and 0.38 ml of 2N hydrochloric acid was d for 90 s at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and ted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 64 mg (0.17 mmol) ofthe desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.16 (3H), 2.57 - 2.69 (1H), 2.87 (1H), 3.32 - 3.41 (2H), 3.71 (4H), 3.77 (4H), 3.81 - 3.97 (3H), 6.81 (1H), 7.33 (1H), 7.59 (1H), 7.63 (1H), 8.31 (1H), 13.32 (1H).

Example 163 4-(5-fluoropyridinyl)[(3R)methy|morpholiny|](1H-pyrazo|y|)-1,7-naphthyridine Step a: 4-(5-fluoropyridin-Z-yl)[(3R)methy|morpholin-4—yl][1-(tetrahyd ro-ZH-pyran-Z-yl)—1H- pyrazolyl]-1,7-naphthyridine A suspension of 100 mg (0.19 mmol) of 2-[(3R)methy|morpho|iny|][1-(tetrahydro-2Hyl)—1H—pyrazol—5-yl]—1,7—naphthyridin—4—yl trifluoromethanesulfonate, 53mg (0.38 mmol) [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp ed set by jennyp (5—fluoropyridin-2—yl)boronic acid, 15 mg (0.019 mmol) of [1,1’— bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, f)C|2) and 247 mg (0.76 mmol) of caesium carbonate in 1.4 ml of dioxane was degased with argon. Under argon, the reaction e was stirred at 110°C for 150 minutes. After cooling the on mixture was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-(5-fluoropyridin-Z-yl)[(3R)methy|morpholinyl](1H-pyrazo|y|)-1,7-naphthyridine A solution of 106 mg of crude luoropyridin—2—yl)-2—[(3R)—3-methylmorpholin—4—yl]—8—[1— (tetrahydro-2H-pyranyl)-1H-pyrazolyl]—1,7-naphthyridine from step a in 3.0 ml of methanol and 0.22 ml of 2N hydrochloric acid was stirred for 2 hour at room temperature. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 3 mg (0.01 mmol) of the desired product. 1H-NMR (400MHz, CDCI3): 6 [ppm]: 1.26 - 1.39 (3H), 3.53 - 3.65 (2H), 3.73 (1H), 3.84 (1H), 4.06 (1H), 4.24 (1H), 4.67 (1H), 7.42 (1H), 7.44 - 7.53 (1H), 7.60 (1H), 7.62 - 7.67 (1H), 7.68 - 7.74 (1H), 7.87 - 8.13 (2H), 8.28 — 8.44 (1H), 8.84 (1H), 13.20 (1H).

Example 164 2-[(3R)—3-methy|morpholin-4—y|](6-methy|pyridin-Z-yl)—8-(1H-pyrazolyl)-1,7-naphthyridine map a: ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 2-[(3R)methy|morpho|inyl]-4—(6-methy|pyridinyl)[1-(tetrahyd ro-ZH-pyran-Z-y|)-1H- pyrazolyl]-1,7-naphthyridine A suspension of 100 mg (0.19 mmol) of 2—[(3R)methylmorpholin-4—yl]—8—[1—(tetrahydro-2H- pyranyl)-1H-pyrazol-S-yl]—1,7-naphthyridin-4—yl trifluoromethanesulfonate, 52 mg (0.38 mmol) (6—methylpyridinyl)boronic acid, 15 mg (0.019 mmol) of [1,1’- bis(dipheny|phosphino)ferrocene]dichloropalladium(|l) x with romethane (1:1, Pd(dppf)C|2) and 247 mg (0.76 mmol) of caesium carbonate in 1.4 ml of dioxane was d with argon. Under argon, the reaction mixture was stirred at 110°C for 2 hours. After cooling the reaction e was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude t that was used without further purification in the next step.

Step b: 2-[(3R)methy|morpho|iny|](6-methylpyridin-Z-yl)(1H-pyrazoIyl)-1,7-naphthyridine A solution of 113 mg of crude 2-[(3R)methylmorpholin-4—yl](6-methylpyridin-Z-yI)—8-[1- (tetrahydro—ZH-pyran—Z-yl)-1H—pyrazol—5—yl]-1,7—naphthyridine from step a in 5.4 ml of methanol and 0.24 ml of 2N hydrochloric acid was stirred for 2 hour at room temperature. The reaction dixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp organic phase was filtered using a Whatman filter and trated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 4 mg (0.01 mmol) of the desired product. 1H-NMR (400MHz, CDCI3): 6 [ppm]: 1.30 (3H), 2.57 - 2.63 (3H), 3.53 - 3.64 (1H), 3.73 (1H), 3.80 - 3.89 (1H), 4.06 (1H), 4.22 (1H), 4.66 (1H), 7.44 (2H), 7.55 (1H), 7.58 - 7.68 (2H), 7.72 (1H), 7.93 (1H), 8.33 (1H), 13.42 (1H).

Example 165 2-[(3R)—3-methy|morpholin-4—yl](3-methy|pyridin-Z-y|)(1H-pyrazolyl)-1,7-naphthyridine Step 3: 2-[(3R)—3-methy|morpholin-4—yl](3-methy|pyridiny|)[1-(tetrahyd ro-ZH-pyran-Z-yl)—1H- pyrazol-S-yl]-1,7-naphthyridine A suspension of 100 mg (0.19 mmol) of 2-[(3R)methy|morpholiny|][1-(tetrahydro-2H- pyran—2-yl)—1H—pyrazo|—5-y|]—1,7—naphthyridin—4—yl trifluoromethanesulfonate, 52 mg (0.38 mmol) hylpyridinyl)boronic acid, 15 mg (0.019 mmol) of [1,1’- bis(diphenylphosphino)ferrocene]dichloropal|adium(||) complex with dichloromethane (1:1, Pd(dppf)C|2) and 247 mg (0.76 mmol) of caesium carbonate in 1.4 ml of e was degased with argon. Under argon, the reaction e was d at 110°C for 2 hours. After cooling the reaction mixture was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 2-[(3R)—3-methy|morpholin-4—yl](3-methy|pyridin-Z-y|)(1H-pyrazolyl)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp ation] jennyp Unmarked set by jennyp A solution of 113 mg of crude 2-[(3R)methy|morpholin-4—yl](3—methy|pyridiny|)—8-[1- (tetrahydro-2H-pyran—2-yl)-1H—pyrazoI—5-yl]-1,7—naphthyridine from step a in 4.3 ml of methanol and 0.19 ml of 2N hydrochloric acid was stirred for 2 hour at room temperature. The reaction e was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 4 mg (0.01 mmol) of the desired product. 1H-NMR (400MHz, CDCI3): 6 [ppm]: 1.29 (d, 3H), 2.13 (s, 3H), 3.57 (d, 1H), 3.67 - 3.79 (m, 1H), 3.79 — 3.90 (m, 1H), 4.05 (d, 1H), 4.15 — 4.30 (m, 2H), 4.61 (1H), 6.96 (1H), 7.38 - 7.57 (3H), 7.65 (1H), 7.89 (1H), 8.27 (1H), 8.59 (1H), 13.43 (1H).

Example 166 N-(2-{2-[(3R)methylmorpholin-4—yl](1H-pyrazo|yl)-1,7-naphthyridin y|}phenyl)acetamide Step 3: N-(2-{2-[(3R)methylmorpholinyl][1-(tetrahyd ro-ZH-pyra ny|)-1H-pyrazolyl]-1,7- naphthyridin-4—yl}phenyl)acetamide fisuspension of 100 mg (0.19 mmol) of 2—[(3R)methy|morpho|in—4—yl]—8-[1—(tetrahydro—2H- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp pyran—2-yl)—1H—pyrazol—5-yl]—1,7—naphthyridin—4—yl trifluoromethanesulfonate, 68 mg (0.38 mmol) (2-acetamidophenyl)boronic acid, 15 mg (0.019 mmol) of bis(diphenylphosphino)ferrocene]— dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 247 mg (0.76 mmol) of caesium carbonate in 1.4 ml of dioxane was degased with argon. Under argon, the reaction mixture was stirred at 110°C for 7 hours. After cooling the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The organic phase was ed using a Whatman filter and then concentrated to give the crude product that was used without further cation in the next step.

Step b: N-(2-{2-[(3R)methylmorpholin-4—yl](1H-pyrazo|yl)-1,7-naphthyridin yl}phenyl)acetamide A solution of 164 mg of crude N—(2—{2—[(3R)-3—methy|morpholin—4—yl]—8—[1—(tetrahydro—2H—pyran-2— yl)-1H-pyrazo|yl]-1,7-naphthyridinyl}pheny|)acetamide from step a in 1.5 ml of methanol and 0.37 ml of 2N hydrochloric acid was stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl e and washed with aqueous sodium chloride solution. The c phase was filtered using a Whatman filter and concentrated to s. The residue was ed by preparative HPLC (Autopurifier: basic conditions) to give 11 mg (0.03 mmol) of the desired product. 1H-NMR (400MHz, CDCI3): 6 [ppm]: 1.32 (3H), 1.71 (3H), 3.50 - 3.64 (1H), 3.64 - 3.78 (1H), 3.78 - 3.92 (1H), 4.07 (1H), 4.23 (1H), 4.59 (1H), 7.02 (1H), 7.20 - 7.47 (4H), 7.47 - 7.60 (1H), 7.65 (1H), 7.74 (1H), 8.24 (1H), 9.16 (1H), 12.82 (1H).

Example 167 3-{2-[(3R)methy|morpholinyl](1H-pyrazo|y|)-1,7-naphthyridin-4—y|}pyridino| map a: [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 3-{2-[(3R)methy|morpholinyl][1—(tetrahyd ro-ZH-pyran-Z-yl)-1H-pyrazo|—5-yl]-1,7- naphthyridinyl}pyridinol A suspension of 100 mg (0.19 mmol) of 2—[(3R)methylmorpholin-4—yl]—8—[1—(tetrahydro-2H- pyranyl)-1H-pyrazolyl]—1,7-naphthyridin-4—yl oromethanesulfonate, 53 mg (0.38 mmol) (2—hydroxypyridin-3—yl)boronic acid, 15 mg (0.019 mmol) of [1,1’- bis(dipheny|phosphino)ferrocene]dichloropalladium(|l) complex with romethane (1:1, Pd(dppf)C|2) and 247 mg (0.76 mmol) of caesium carbonate in 1.4 ml of dioxane was degased with argon. Under argon, the reaction e was stirred at 110°C for 2 hours. After cooling the reaction mixture was diluted aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combined c phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 3-{2-[(3R)—3-methy|morpholinyl](1H-pyrazo|y|)-1,7-naphthyridin-4—y|}pyridino| A solution of 96 mg of crude 3—{2-[(3R)—3-methylmorpho|inyl]—8-[1-(tetrahydro—2H-pyran—2-yl)- 1H-pyrazol-5—yl]-1,7-naphthyridinyl}pyridin-2—ol from step a in 5.1 ml of methanol and 0.20 ml of 2N hydrochloric acid was stirred for 3 hours at room temperature. The reaction mixture was diluted with aqueous sodium chloride solution and ted with ethyl acetate (2x). The dmbined organic phases were filtered using a n filter and concentrated to dryness. The [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp residue was purified by preparative HPLC urifier: basic conditions) to give 2 mg (0.005 mmol) of the d product. 1H-NMR (400MHz, CDCI3): 6 [ppm]= 1.30 (3H), 3.57 (1H), 3.71 (1H), 3.82 (1H), 4.04 (1H), 4.18 (1H), 4.62 (1H), 6.39 (1H), 7.27 (1H), 7.40 (2H), 7.50 - 7.75 (3H), 8.28 (1H), 12.05 (1H), 13.39 (1H).

Example 168 2-(3-{2-[(3R)methylmorpholin-4—yl]-8—(1H-pyrazolyl)-1,7-naphthyridinyl}phenyl)propan- 2-ol Step a: 2-(3-{2-[(3R)methylmorpholin-4—yl][1-(tetrahyd ro-ZH-pyran-Z-yl)-1H-pyrazolyl]-1,7- naphthyridin-4—yl}phenyl)propan-Z-ol A suspension of 100 mg (0.19 mmol) of 2-[(3R)methy|morpholiny|][1-(tetrahydro-2H- pyran—Z-yl)—1H—pyrazo|—5-y|]—1,7—naphthyridin—4—yl trifluoromethanesulfonate, 53 mg (0.38 mmol) (2-hydroxypyridinyl)boronic acid, 15 mg (0.019 mmol) of [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 247 mg (0.76 mmol) of caesium carbonate in 1.4 ml of dioxane was degased with argon. Under argon, the reaction e was stirred at 110°C for 2 hours. After g the reaction mixture was diluted aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 2-(3-{2-[(3R)methylmorpholin-4—yl](1H-pyrazolyl)-1,7-naphthyridin-4—yl}phenyl)propan- 2-ol [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp A solution of 96 mg of crude 2-(3-{2-[(3R)—3-methy|morpholin-4—yl][1—(tetrahydro-2H-pyran yl)—1H-pyrazoly|]-1,7-naphthyridin-4—y|}pheny|)propan—2-ol from step a in 5.1 ml of methanol and 0.20 ml of 2N hydrochloric acid was stirred for 3 hours at room temperature. The reaction mixture was diluted with aqueous sodium chloride solution and ted with ethyl acetate (2x).

The combined organic phases were filtered using a Whatman filter and concentrated to dryness.

The residue was purified by preparative HPLC (Autopurifier: basic ions) to give 2 mg (0.005 mmol) of the desired product. 1H—NMR (400MHz, CDCI3): 6 [ppm]: 1.30 (3H), 3.57 (1H), 3.71 (1H), 3.82 (1H), 4.04 (1H), 4.18 (1H), 4.62 (1H), 6.39 (1H), 7.27 (1H), 7.40 (2H), 7.50 - 7.75 (3H), 8.28 (1H), 12.05 (1H), 13.39 (1H).

Example 169 4—(5,6-dihydroimidazo[1,2—a]pyrazin-7(8H)-yl)(morpholinyl)(1H-pyrazoly|)-1,7- naphthyridine Step 3: 4-(5,6-dihyd roimidazo[1,2-a]pyrazin-7(8H)—y|)-2—(morpholinyl)—8-[1—(tetra hyd ro-ZH-pyran-Z- yl)-1H-pyrazolyl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A mixture of 150 mg (0.29 mmol) of 2—(m0rpholin—4—yl)—8—[1—(tetrahydro-2H—pyran—2—yI)—1H— pyrazolyl]-1,7-naphthyridinyl trifluoromethanesulfonate and 122 mg (0.99 mmol) 5,6,7,8— tetrahydroimidazo[1,2-a]pyrazine in 0.4 ml of MeCN was stirred at 70°C for 90 s under argon. After cooling the reaction e was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: -dihydroimidazo[1,2-a]pyrazin-7(8H)—yl)(morpholin-4—yl)(1H-pyrazolyl)-1,7- yridine A solution of 200 mg of crude 4—(5,6—dihydroimidazo[1,2—a]pyrazin—7(8H)—y|)—2-(morpholin—4—y|)-8— [1-(tetrahydro-2H-pyranyl)-1H-pyrazolyl]—1,7-naphthyridine from step a in 1.9 ml of methanol and 0.47 ml of 2N hydrochloric acid was stirred for 1 hour at room temperature. The reaction mixture was diluted with saturated s sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to dryness. The residue was purified by preparative HPLC urifier: basic conditions) to give 5 mg (0.01 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 3.66 (2H), 3.72 - 3.87 (8H), 4.27 - 4.40 (2H), 4.47 (2H), 6.85 - 7.05 (2H), 7.23 (1H), 7.36 (1H), 7.62 (1H), 7.68 (1H), 8.34 (1H), 13.37 (1H).

Example 170 4—[(ZS)methylmorpho|in-4—yl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine Step a: D[(ZS)methylmorpho|in-4—yl](morpholinyl)[1-(tetrahydro-ZH-pyranyl)-1H-pyrazo|— [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp -y|]-1,7-naphthyridine A mixture of 150 mg (0.29 mmol) of 2-(morpholin—4-y|)[1-(tetrahydro-2H-pyranyI)-1H- pyrazol-5—y|]—1,7-naphthyridin—4—yl oromethanesulfonate and 103 mg (1.02 mmol) (ZS) morpholine in 0.5 ml of MeCN was stirred at 70°C overnight under argon. After cooling the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-[(2$)—2-methylmorpholin-4—yl](morpho|in-4—y|)(1H-pyrazolyl)-1,7-naphthyridine A solution of 146 mg of crude 4-[(25)—2-methylmorpholinyl]—2—(morpholin-4—yl)—8—[1— (tetrahydro-2H-pyran—2-yl)-1H—pyrazoly|]-1,7-naphthyridine from step a in 7.0 ml of methanol and 0.31 ml of 2N hydrochloric acid was d for 90 s at room temperature. The reaction mixture was diluted with saturated aqueous sodium onate solution and extracted with ethyl acetate (2x). The combined organic phases were ed using a Whatman filter and then concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 62 mg (0.16 mmol) ofthe desired product. 1H-NMR (400MHz, DMSO-d6): 8 [ppm]: 1.16 (3H), 2.57 - 2.69 (1H), 2.87 (1H), 3.32 - 3.41 (2H), D71 (4H), 3.77 (4H), 3.81 - 3.97 (3H), 6.81 (1H), 7.33 (1H), 7.59 (1H), 7.63 (1H), 8.31 (1H), 13.32 [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (1H).

Example 171 4-[(trans)—2-methylcyclopropyl][(3R)—3-methylmorpholin-4—yl](1H-pyrazolyl)—1,7- naphthyridine Step 3: 4-[(trans)—2-methylcyclopropyl][(3R)methylmorpholinyl][1-(tetrahyd ro-ZH-pyra n-Z- yl)-1H-pyrazolyl]-1,7-naphthyridine A suspension of 100 mg (0.19 mmol) of 2-[(3R)methy|morpholinyl]—8—[1-(tetrahydro-2H- pyranyl)—1H-pyrazoly|]-1,7-naphthyridin-4—yl trifluoromethanesulfonate, 69 mg (0.38 mmol) 1-methyl-cyc|opropy|boronic ester, 15 mg (0.019 mmol) of [1,1’- bis(diphenylphosphino)ferrocene]dich|oropa||adium(|I) x with dichloromethane (1:1, Pd(dppf)C|2) and 65 mg (0.47 mmol) of potassium carbonate in 2.0 ml of acetonitrile and 1.0 ml water was degased with argon. Under argon, the reaction mixture was stirred at 130°C for 10 minutes in a microwave oven. After cooling the reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded organic phases were ed using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-[(trans)—2-methylcyclopropyl][(3R)—3-methy|morpholin-4—yI](1H-pyrazoly|)-1,7- naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 113 mg of crude 4-[(trans)methy|cyclopropyl][(3R)methylmorpholin-4—yl]—8— [1—(tetrahydr0—2H—pyran—2—yl)—1H—pyrazol—5-y|]—1,7—naphthyridine from step a in 3.0 ml of methanol and 0.26 ml of 2N hydrochloric acid was stirred for 3 hours at room temperature. The reaction e was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combined organic phases were dried (MgSO4), filtered and concentrated to dryness. The e was ed by preparative HPLC (Autopurifier: basic conditions) to give 8mg (0.02 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 0.86 - 0.94 (1H), 1.19 - 1.28 (5H), 1.28 - 1.34 (3H), 2.14 - 2.24 (1H), 3.22 - 3.32 (1H), 3.54 (1H), 3.69 (1H), 3.81 (1H), 4.03 (1H), 4.09 - 4.24 (1H), 4.49 - 4.77 (1H), 7.00 (1H), 7.37 (1H), 7.61 (1H), 7.93 (1H), 8.41 (1H), 13.38 (1H).

Example 172 4-(difluoromethoxy)[(3R)methy|morpholin-4—yl](1H-pyrazol-S-y|)-1,7-naphthyridine Step 3: 4-(difluoromethoxy)—2-[(3R)—3-methy|morpholin-4—y|][1-(tetrahyd ro-Z H-pyran-Z-y|)-1H- pyrazolyl]-1,7-naphthyridine A mixture of 100 mg (0.25 mmol) of 2-[(3R)methy|morpholin-4—yl]—8—[1-(tetrahydro-2H-pyran y|)—1H-pyrazoly|]-1,7-naphthyridin-4—0I, 66 mg (0.51 mmol) chlorodifluoroacetic acid and 42 mg (0.30 mmol) of potassium carbonate in 0.9 ml of DMF and 0.9 ml water was degased with argon.

Dwder argon, the reaction mixture was stirred at 120°C for 90 minutes. After cooling the reaction [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp mixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and then concentrated to give the crude product that was used without r purification in the next step.

Step b: 4-(difluoromethoxy)—2-[(3R)methylmorpholin-4—yl](1H-pyrazolyl)-1,7-naphthyridine A solution of 71 mg of crude 4-(difluoromethoxy)[(3R)methylmorpholiny|]—8-[1- (tetrahydro—2H-pyran—2-yl)-1H—pyrazoI—S-yl]-1,7—naphthyridine from step a in 0.7 ml of methanol and 0.18 ml of 2N hydrochloric acid was stirred for 1 hour at room temperature. The reaction mixture was diluted with aqueous onate solution and extracted with ethyl acetate (2x). The ed c phases were filtered using a Whatman filter and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 7 mg (0.02 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.29 (3H), 3.56 (1H), 3.66 - 3.79 (1H), 3.84 (1H), 4.05 (1H), 4.15 (d, 1H), 4.58 (1H), 7.16 (1H), 7.39 (1H), 7.62 (1H), 7.66 - 7.74 (2H), 8.40 (1H), 13.40 (1H).

Example 173 2-[2-(morpholinyl)(1H-pyrazo|y|)-1,7-naphthyridin-4—yl]propan-Z-ol Step 3: 2-{2-(morpholin-4—yl)—8-[1-(tetrahyd pyra n-Z-yl)-1H-pyrazo|y|]-1,7-naphthyridin-4— yl}propanol ation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 0.24 ml (0.71 mmol) of a 3.0 M solution of methylmagnesium bromide in diethylether was added dropwise to a stirred solution of 100 mg (0.24 mmol) methyl 2-(morpholin—4-yl)-8—[1-(tetrahydro- 2H—pyran-2—yl)-1H-pyrazolyl]-1,7-naphthyridinecarboxylate in 4.0 ml of THF at 0°C. The mixture was d at 0°C for 30 minutes and then the icebath was removed and the mixture was stirred at room temperature overnight. The mixture was diluted with a ted aqueous solution of ammonium chloride and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to give the crude product that was used without further cation in the next step.

Step b: 2-[2-(morpholinyl)(1H-pyrazo|y|)-1,7-naphthyridin-4—yl]propan-Z-ol A solution of 80 mg of crude 2-{2-(morpholinyl)[1-(tetrahydro-2H-pyranyl)-1H-pyrazol yl]-1,7-naphthyridin-4—yl}propanol from step a in 2.0 ml of methanol and 0.19 ml of 2N hydrochloric acid was stirred for 1 hour at room temperature. The reaction mixture was diluted with saturated aqueous sodium onate solution and extracted with ethyl e (2x). The combined organic phases were dried (MgSO4), filtered and concentrated to dryness to give 34 mg (0.09 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.69 (6H), 3.73 (4H), 3.77 - 3.93 (4H), 5.60 (1H), 7.35 (1H), 7.46 (1H), 7.61 (1H), 8.28 - 8.45 (2H), 13.35 (1H).

Dample 174 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp 2-(mo rpho|inyl)(3-oxaazabicyclo[3.2.1]octy|)(1H-pyrazo|yl)-1,7-naphthyridine Step 3: 2-(mo rpho|inyl)(3-oxaazabicyclo[3.2.1]octy|)[1-(tetrahyd ro-2H-pyranyl)-1H- pyrazolyl]-1,7-naphthyridine A mixture of 150 mg (0.29 mmol) of pholin—4—yl)-8—[1—(tetrahydro-2H—pyran—2—yI)—1H— pyrazoly|]-1,7-naphthyridiny| trif|uoromethanesulfonate, 153 mg (1.02 mmol) 3-oxa-8— azabicyclo[3.2.1]octane hydrochloride (1:1) and 0.14 ml (1,02 mmol) triethylamine in 0.5 ml of MeCN was d at 70°C for 72 hours under argon. After cooling the reaction mixture was diluted with DCM and washed with saturated aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 2-(mo rpho|inyl)(3-oxaazabicyclo[3.2.1]octy|)(1H-pyrazo|yl)-1,7-naphthyridine A solution of 152 mg of crude 2—(morpholin-4—yl)—4—(3-oxa—8—azabicyclo[3.2.1]oct-8—y|)—8—[1— (tetrahydro-2H-pyran—2-yl)-1H-pyrazoly|]-1,7-naphthyridine from step a in 7.2 ml of methanol and 0.32 ml of 2N hydrochloric acid was stirred overnight at room temperature. The reaction mixture was diluted with ted aqueous sodium bicarbonate solution and extracted with Dhyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp concentrated to dryness. The residue was purified by ative HPLC (Autopurifier: basic conditions) to give 12 mg (0.03 mmol) ofthe desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]= 1.92 (3H), 3.58 - 3.72 (6H), 3.72 - 3.86 (4H), 3.94 (2H), 4.15 (2H), 6.70 (1H), 7.34 (1H), 7.60 (1H), 7.71 (1H), 8.31 (1H), 13.34 (1H).

Example 175 2-[(3R)methy|morpholin-4—yl](1H-pyrazoly|)(pyrro|idinyl)—1,7-naphthyridine Step a: 2-[(3R)methy|morpho|in-4—yl]-4—(pyrro|idinyl)-8—[1-(tetra hydro-ZH-pyran-Z-yl)-1H-pyrazo|— 5-yl]-1,7-naphthyridine A mixture of 75 mg (0.14 mmol) of 2—[(3R)methylmorpholin-4—y|][1—(tetrahydro-2H-pyran yl)-1H-pyrazo|y|]-1,7-naphthyridin-4—yl trifluoromethanesulfonate and 35 mg (0.50 mmol) pyrrolidine in 0.21 ml of MeCN was stirred at 70°C for 90 minutes under argon. After cooling the reaction e was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic phase was ed using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 2-[(3R)—3-methylmorpholin-4—yl](1H-pyrazoIyl)(pyrrolidinyl)-1,7-naphthyridine Dsolution of 10 mg of crude 2—[(3R)—3—methy|morpholin—4—yl]—4—(pyrro|idin—1-yl)—8—[1—(tetrahydro— [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 2H—pyran—Z—yl)—1H—pyrazo|—5—yl]—1,7—naphthyridine from step a in 0.5 ml of ol and 0.02 ml of 2N hydrochloric acid was stirred overnight at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 2 mg (0.005 mmol) of the desired product. 1H-NMR (400MHz, CDCI3): 6 [ppm] = 1.47 (3H), 2.20 (4H), 3.55 (1H), 3.66 - 3.94 (7H), 4.04 (1H), 4.16 - 4.37 (2H), 5.75 (1H), 7.12 (1H), 7.77 (1H), 7.90 (1H), 8.53 (1H). e 176 4—[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridin-4—yl]piperazin-Z-one Step a: 4—{2-(morpholin-4—y|)[1-(tetrahyd ro-ZH-pyrany|)-1H-pyrazol-S-yl]-1,7-naphthyridin-4— y|}piperazinone O N A mixture of 150 mg (0.29 mmol) of 2-(morpholin—4-yl)-8—[1-(tetrahydro-2H-pyranyI)-1H- pyrazol-5—yl]—1,7-naphthyridin—4—yl oromethanesulfonate and 99 mg (0.99 mmol) zin-Z- one in 0.4 ml of MeCN was stirred at 70°C for 3 hours under argon. After cooling the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The c phase was filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-[2-(morpholinyl)(1H-pyrazoly|)-1,7-naphthyridin-4—yl]piperazin-Z-one [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp A solution of 182 mg of crude 4-{2—(morpholin—4-yl)-8—[1-(tetrahydro-2H—pyran—2—yl)-1H-pyrazol- -y|]—1,7-naphthyridin—4-yl}piperazinone from step a in 1.8 ml of methanol and 0.45 ml of 2N hydrochloric acid was d for 1 hour at room temperature. The reaction mixture was diluted with ted aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to dryness.

The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 32 mg (0.08 mmol) of the desired product. 1H—NMR (400MHz, DMSO-d6): 6 [ppm]: 3.39 - 3.45 (2H), 3.45 - 3.55 (2H), 3.64 - 3.88 (10H), 6.84 (1H), 7.35 (1H), 7.63 (2H), 8.11 (1H), 8.32 (1H), 13.36 (1H).

Example 177 4-(dimethylphosphoryl)—2-(morpholin-4—yl)(1H-pyrazolyl)-1,7-naphthyridine Step 3: 4-(dimethylphosphoryl)—2-(morpholin-4—yl)[1—(tetrahyd ro-ZH-pyran-Z-yl)-1H-pyrazolyl]- 1,7-naphthyridine A mixture of 150 mg (0.29 mmol) of pholin—4-yl)[1-(tetrahydro-2H—pyranyl)-1H- pyrazoly|]—1,7-naphthyridin—4—yl trifluoromethanesulfonate, 36 mg (0.33 mmol) dimethylphosphinoxide, 34 mg (0.029 mmol tetrakis(triphenylphosphine)pa||adium(0) and 0.06 ml (0.44 mmol) of triethylamine in 0.9 ml of acetonitrile was degased with argon. Under argon, [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp the reaction mixture was stirred at 90°C for 3 hours. After cooling the reaction mixture was diluted with ethyl acetate and washed with aqueous chloride solution. The organic phase was filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-(dimethylphosphoryl)(morpho|iny|)(1H-pyrazolyl)-1,7-naphthyridine A solution of 210 mg of crude 4—(dimethylphosphoryl)—2-(morpholin—4—yl)—8-[1—(tetrahydro—2H— pyranyl)-1H-pyrazo|—5-yl]-1,7-naphthyridine from step a in 2.2 ml of methanol and 0.55 ml of 2N hydrochloric acid was stirred for 1 hour at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated to dryness. The e was purified by ative HPLC (Autopurifier: basic conditions) to give 21 mg (0.06 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.88 (3H), 1.92 (3H), 3.78 (8H), 7.35 (1H), 7.55 - 7.79 (2H), 8.33 - 8.51 (2H), 13.37 (1H). e 178 4-[(trans)-2,5-dimethylpiperaziny|](morpholiny|)(1H-pyrazo|y|)-1,7-naphthyridine Step a: 4-[(trans)-2,5-dimethy|piperaziny|](morpholinyl)[1-(tetrahydro-2H-pyranyl)-1H- pyrazoly|]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp A mixture of 150 mg (0.29 mmol) of 2-(morpholin—4-yl)-8—[1-(tetrahydro-ZH—pyran-Z—yI)-1H- pyrazoly|]—1,7-naphthyridin—4-yl trifluoromethanesuIfonate and 113 mg (0.99 mmol) (trans)- 2,5—dimethy|piperazine in 0.4 ml of MeCN was stirred at 70°C for 3 hours under argon. After cooling the reaction mixture was diluted with ethyl e and washed with ted aqueous sodium chloride solution. The organic phase was filtered using a n filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-[(trans)-2,5-dimethy|piperazin-l—yl]-2—(morpholin-4—yl)—8-(1H-pyrazo|y|)-1,7-naphthyridine A solution of 117 mg of crude 4-[(trans)-2,5-dimethylpiperazin-l-yl]—2-(morpholiny|)[1- (tetrahydro—ZH-pyran—Z—yl)—1H—pyrazol—5—yl]-1,7—naphthyridine from step a in 1.1 ml of methanol and 0.28 ml of 2N hydrochloric acid was stirred for 1 hour at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 3 mg (0.008 mmol) ofthe desired product.

D-NMR z, DMSO-d6): 6 [ppm]: 0.81 - 0.95 (3H), 0.95 - 1.06 (3H), 2.24 - 2.40 (1H), 2.63 - [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 2.75 (1H), 3.02 - 3.21 (4H), 3.67 - 3.77 (4H), 3.77 - 3.85 (4H), 7.12 (1H), 7.36 (1H), 7.62 (1H), 7.79 (1H), 8.24 (1H), 8.36 (1H).

Example 179 4-[(cis)-3,5-dimethylpiperazinyl](morpho|inyl)(1H-pyrazolyl)-1,7-naphthyridine Step a: 4-[(cis)-3,5-dimethylpiperazinyl](morpholinyl)[1-(tetrahyd pyran-Z-yl)—1H- pyrazolyl]-1,7-naphthyridine A mixture of 150 mg (0.29 mmol) of 2-(morpholin—4-y|)[1-(tetrahydro-2H—pyranyl)-1H- pyrazoly|]—1,7-naphthyridin—4-y| trifluoromethanesulfonate and 113 mg (0.99 mmol) (cis)—2,6- dimethylpiperazine in 0.4 ml of MeCN was stirred at 70°C for 90 minutes under argon. After cooling the reaction mixture was diluted with ethyl acetate and washed with saturated s sodium chloride solution. The organic phase was filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-[(cis)-3,5-dimethy|piperazinyl](morpho|inyl)(1H-pyrazo|y|)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 189 mg of crude 4—[(cis)—3,5—dimethylpiperazin-l—yl]—2—(morpholin-4—yl)—8—[1— (tetrahydro-2H-pyranyl)-1H-pyrazoly|]-1,7-naphthyridine from step a in 1.8 ml of methanol and 0.46 ml of 2N hydrochloric acid was stirred for 1 hour at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to dryness. The residue was purified by preparative HPLC urifier: basic conditions) to give 51 mg (0.13 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.03 (6H), 2.30 - 2.42 (2H), 2.94 - 3.16 (2H), 3.35 (2H), 3.63 - 3.74 (4H), 3.74 - 3.87 (4H), 6.75 (1H), 7.34 (1H), 7.59 (2H), 8.28 - 8.35 (1H), 13.33 (1H).

Example 180 morpholinyl)(1H-pyrazoly|)-1,7-naphthyridin-4—yl](trifluoromethy|)azetidinol Step 3: 1-{2-(morpholin-4—yl)—8-[1-(tetrahyd pyra ny|)-1H-pyrazo|y|]-1,7-naphthyridin-4—y|} (trifluoromethy|)azetidino| A mixture of 150 mg (0.29 mmol) of 2-(morpholinyl)-8—[1-(tetrahydro-2H-pyranyl)-1H- ly|]-1,7-naphthyridiny| trifluoromethanesulfonate, 182 mg (1.02 mmol) 3- (trifluoromethyl)azetidinol hydrochloride (1:1) and 0.14 ml (1.02 mmol) trimethylamine in 0.5 ml of MeCN was stirred at 70°C for 90 minutes under argon. After cooling the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic phase was ed using a Whatman filter and then trated to give the crude product that was used without further purification in the next step.

Step b: 1-[2-(morpholinyl)(1H-pyrazo|y|)-1,7-naphthyridiny|](trif|uoromethyl)azetidinol [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 156 mg of crude morpholin—4-yl)-8—[1-(tetrahydro-2H—pyran-2—yl)-1H-pyrazo|— -yl]—1,7-naphthyridin—4-yl}-3—(trif|uoromethyl)azetidin-3—o| from step a in 7.0 ml of methanol and 0.31 ml of 2N hydrochloric acid was stirred for 90 minutes at room temperature. The reaction mixture was d with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a n filter and then concentrated to dryness. The residue was purified by ative HPLC urifier: basic conditions) to give 6 mg (0.02 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 3.53 - 3.71 (4H), 3.71 - 3.84 (4H), 4.30 (2H), 4.64 (2H), 6.23 (1H), 7.30 (1H), 7.47 (1H), 7.54 - 7.68 (2H), 8.22 (1H), 13.33 (1H).

Example 181 methyl hydrogen {4-[2—(morphoIiny|)(1H-pyrazoIyl)-1,7-naphthyridin-4— yl]phenyl}phosphonate A mixture of 33 mg (0.07 mmol) of dimethyl {4—[2—(morpholinyl)—8—(1H—pyrazol-5—yl)—1,7- naphthyridin—4-yl]phenyl}phosphonate and 0.14 ml (0.28 mmol) aqueous 2N sodium hydroxide dlution in 0.14 ml of MeOH was stirred at 70°C for 4 hours. The pH was adjusted to 6 by the [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp addition of aqueous sodium onate solution and the mixture was extracted with THF (3x).

The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC (Autopurifier: acidic conditions) to give 1 mg (0.002 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 3.56-3.63 (8H), 3.80 (3H), 7.40 (1H), 7.41 (1H), 7.52 (1H), 7.65 (1H), 7.69 (2H), 7.89 (3H), 8.33 (1H) Example 182 ethylpiperazinyl)(morphoIin-4—yl)(1H-pyrazo|y|)-1,7-naphthyridine Step a: 4-(4-methylpiperazinyl)(morpho|iny|)[1-(tetrahydro-ZH-pyran-Z-yl)-1H-pyrazo|y|]- 1,7-naphthyridine A mixture of 150 mg (0.29 mmol) of 2-(morpholin—4-y|)[1-(tetrahydro-2H-pyranyl)-1H- pyrazol-S—yl]—1,7-naphthyridin—4—yl trifluoromethanesulfonate and 100 mg (0.99 mmol) 1— methylpiperazine in 0.4 ml of MeCN was d at 70°C for 90 minutes under argon. After cooling the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The c phase was filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 2-(mo n-4—yl)(1H-pyrazolyl)-4—[(3aR,GaS)-tetrahyd ro-1H-furo[3,4—c]pyrro|—5(3H)-yl]- 1,7-naphthyridine [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 204 mg of crude 2-(morpholin—4-y|)[(3aR,6aS)—tetrahydro-1H-furo[3,4-c]pyrrol- (3H)-y|][1—(tetrahydro-2H—pyran-2—y|)-1H-pyrazo|yl]—1,7-naphthyridine from step a in 2.0 ml of ol and 0.51 ml of 2N hydrochloric acid was stirred for 1 hour at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate on and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 7 mg (0.02 mmol) of the desired product. 1H—NMR (400MHz, DMSO-d6): 6 [ppm]: 2.30 (3H), 2.61 (4H), 3.18 (4H), 3.62 - 3.75 (4H), 3.78 (4H), 6.81 (1H), 7.35 (1H), 7.53 - 7.69 (2H), 8.32 (1H), 13.35 (1H).

Example 183 2-(mo ny|)(1H-pyrazoly|)[(3aR,6aS)-tetrahyd ro-1H-furo[3,4—c]pyrrol-5(3H)-y|]- 1,7-naphthyridine Step a: 2-(mo rpho|in-4—yl)-4—[(3aR,GaS)-tetrahyd ro-1H-furo[3,4—c]pyrro|-5(3H)-y|][1-(tetrahyd ro-ZH- pyran-Z-yl)-1H-pyrazoly|]-1,7-naphthyridine é mixture of 150 mg (0.29 mmol) of 2-(m0rpholin—4—yl)-8—[1—(tetrahydro-2H—pyran-2—yI)—1H- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp pyrazol-5—yl]—1,7-naphthyridin—4—yl trifluoromethanesulfonate, 153 mg (1.00 mmol) (3aR,6aS)— dro-1H-furo[3,4-c]pyrro|e hydrochloride and 0.14 ml (1.00 mol) of triethylamine in 0.4 ml of MeCN was stirred at 70°C for 3 hours under argon. After cooling the reaction mixture was diluted with ethyl acetate and washed with ted aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and then concentrated to give the crude product that was used without r purification in the next step.

Step b: 4-(4-methylpiperazinyl)(morphoIin-4—yl)(1H-pyrazo|y|)-1,7-naphthyridine A solution of 176 mg of crude 2—(morpholin—4—yl)-4—[(3aR,6aS)—tetrahydro—1H—furo[3,4—c]pyrrol— (3H)-yl][1-(tetrahydro-2H-pyrany|)-1H-pyrazolyl]-1,7-naphthyridine from step a in 8.2 ml of methanol and 0.37 ml of 2N hydrochloric acid was stirred for 1 hour at room temperature. The reaction e was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to dryness. The e was purified by preparative HPLC (Autopurifier: basic conditions) to give 13 mg (0.03 mmol) ofthe desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 2.30 (3H), 2.61 (4H), 3.18 (4H), 3.62 - 3.75 (4H), 3.78 (4H), 6.81 (1H), 7.35 (1H), 7.53 - 7.69 (2H), 8.32 (1H), 13.35 (1H). e 184 4-(3-methoxy—3-methylazetidiny|)(morpholin-4—yl)(1H-pyrazolyl)—1,7-naphthyridine Step 3: 4-(3-methoxymethylazetidiny|)(morpholin-4—yl)—8-[1-(tetrahyd ro-ZH-pyran-Z-yl)—1H- pyrazolyl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A mixture of 150 mg (0.29 mmol) of pholin—4-yl)-8—[1-(tetrahydro-2H—pyran-2—yl)-1H- pyrazoly|]—1,7-naphthyridin—4-y| trifluoromethanesulfonate, 137 mg (0.99 mmol) 3-methoxy azetidine hydrochloride and 0.28 ml (1.99 mmol) trimethylamine in 0.4 ml of MeCN was stirred at 70°C for 90 minutes under argon. After cooling the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium de solution. The organic phase was filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 4-(3-methoxy—3-methylazetidiny|)(morpholin-4—yl)(1H-pyrazolyl)—1,7-naphthyridine A solution of 225 mg of crude 4-(3-methoxymethylazetidinyl)(morpholinyl)[1- (tetrahydro-2H-pyranyl)-1H-pyrazolyl]-1,7-naphthyridine from step a in 2.3 ml of methanol and 0.56 ml of 2N hydrochloric acid was stirred for 1 hour at room ature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a n filter and then concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: basic conditions) to give 3 mg (0.01 mmol) of the desired product.

D-NMR (400MHz, DMSO-d6): 5 [ppm]: 1.52 (3H), 3.25 (3H), 3.59 - 3.71 (4H), 3.71 - 3.85 (4H), [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 4.17 (2H), 4.27 (2H), 6.11 (1H), 7.31 (1H), 7.59 (1H), 7.65 (1H), 8.22 (1H), 13.36 (1H).

Example 185 2-(morpho|in-4—yl)-4—[(1$,4S)—2—oxaazabicyclo[2.2.1]heptyl](1H-pyrazoly|)-1,7- yridine Step 3: 2-(mo rpho|inyl)[(1S,4S)oxaazabicyc|o[2.2.1]heptyl][1-(tetrahyd ro-ZH-pyran-Z- yl)-1H-pyrazolyl]-1,7-naphthyridine A mixture of 150 mg (0.29 mmol) of 2-(morpholinyl)-8—[1-(tetrahydro-2H-pyranyl)-1H- pyrazoly|]-1,7-naphthyridiny| trifluoromethanesulfonate, 139 mg (1.00 mmol) (15,4S)oxa- -azabicyclo[2.2.1]heptane hydrochloride and 0.14 ml (1.02 mmol) trimethylamine in 0.4 ml of MeCN was stirred at 70°C ght under argon. After cooling the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium de solution. The c phase was filtered using a Whatman filter and then concentrated to give the crude product that was used without further purification in the next step.

Step b: 2-(mo rpho|inyl)[(1$,4S)—2-oxaazabicyclo[2.2.1]heptyl](1H-pyrazolyl)-1,7- naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A solution of 172 mg of crude 2—(morpholin—4—yl)—4-[(15,4S)-2—oxa—5—azabicyclo[2.2.1]hept—5—y|]—8— [1-(tetrahydro-2H-pyranyl)-1H-pyrazo|y|]-1,7-naphthyridine from step a in 8.3 ml of methanol and 0.37 ml of 2N hloric acid was stirred for 90 minutes at room temperature.

The reaction mixture was diluted with saturated aqueous sodium onate solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and then concentrated to dryness. The e was purified by preparative HPLC (Autopurifier: basic conditions) to give 39 mg (0.10 mmol) of the d product. 1H-NMR (400MHz, 6): 6 [ppm]: 1.91 (1H), 2.03 (1H), 3.38 (1H), 3.56 - 3.72 (4H), 3.72 - 3.86 (5H), 3.89 - 4.14 (2H), 4.64 (1H), 4.78 (1H), 6.44 (1H), 7.29 (1H), 7.58 (1H), 7.70 (1H), 8.20 (1H), 13.32 (1H).

Example 186 2-[(3R)—3-methy|morpho|in-4—yl]-4—[(methylsulfanyl)methy|](1H-pyrazolyl)—1,7- naphthyridine Step 3: 2-[(3R)—3-methylmorpholinyl](1-{[2-(trimethylsilyl)ethoxy]methy|}-1H-pyrazolyl)-1,7- naphthyridin-4—ol A suspension of 2310 mg (8.3 mmol) of 8-chloro(3-methylmorpholinyl)-1,7-naphthyridin-4— ol, 3000 mg (12.4 mmol) (1-{[2-(trimethy|si|y|)ethoxy]methyl}-1H-pyrazo|—5-yl)boronic acid, 1348 mg (1.7 mmol) of [1,1’—bis(diphenylphosphino)ferrocene]dichloropalladium(|l) complex with dichloromethane (1:1, Pd(dppf)C|2) and 4251 mg (13.0 mmol) of m carbonate in 69 ml of dioxane was degased with argon. Under argon, the reaction mixture was stirred at 110°C for 1 hour. After cooling the reaction mixture was diluted with agqueous sodium chloride solution and extracted with ethyl acetate (3x). The combined organic phases were filtered using a Whatman filter and then trated. The residue was purified by column tography (gradient from 100% Hex to 100% EtOAc) to give 1710 mg (3.9 mmol) of the desired product. 1H—NMR (400MHz, DMSO-d6): 6 [ppm]: -0.35 — -0.27 (9H), 0.47 — 0.61 (2H), 1.18 (3H), 3.06 — 3.29 DH), 3.46 (1H), 3.63 (1H), 3.74 (1H), 3.95 (2H), 4.32 (1H), 5.81 (1H), 5.88 (1H), 6.59 (1H), 6.98 (1H), ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 7.63 (1H), 7.78 (1H), 8.32 (1H), 11.49 (1H).

Step b: 2-[(3R)—3-methy|morpholin-4—yl](1-{[2-(trimethylsi|y|)ethoxy]methy|}-1H-pyrazoly|)-1,7- naphthyridinyl trifluoromethanesulfonate A mixture of 1710 mg (3.9 mmol) 2-[(3R)-3—methylmorpholin—4-yl]—8—(1-{[2- (trimethylsi|y|)ethoxy]methy|}—1H-pyrazo|yl)-1,7-naphthyridin-4—ol, 1549 mg (4.3 mmol) 1,1,1- trifluoro-N-phenyI-N—[(trifluoromethy|)su|fonyl]methanesulfonamide and 1.35 ml (7.7 mmol) of N,N—diisopropyethylamin in 22 ml of DCM was stirred at room temperature for 2 hours. The e was concentrated and the residue was purified by column chromatography (gradient from 100% Hex to hexane / EtOAc 50%) to give 1870 mg (3.3 mmol) of the desired product. 1H—NMR (400MHz, DMSO-d6): 6 [ppm]: -0.37 (9H), 0.43 — 0.64 (2H), 1.23 (3H), 3.13 - 3.30 (3H), 3.49 (1H), 3.64 (1H), 3.79 (1H), 3.96 - 4.03 (1H), 4.14 (1H), 4.48 (1H), 5.82 (1H), 5.89 (1H), 7.05 (1H), 7.64 (1H), 7.68 (1H), 7.76 (1H), 8.54 (1H).

Step c: methyl 2-[(3R)methylmorpholin-4—yl](1-{[2-(trimethylsilyl)ethoxy]methy|}-1H-pyrazol y|)-1,7-naphthyridine-4—carboxylate D an autoclave, a e of 1800 mg (3.14 mmol) of 2—[(3R)—3—methylmorpholin—4—yl]—8—(1—{[2— [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (trimethylsilyl)ethoxy]methyl}—1H-pyrazol—5-yl)—1,7—naphthyridin—4—yl trifluoromethanesulfonate, 133 mg (0.31 mmol) 1,3-bis(diphenylphosphino)propane, 70 mg (0.31 mmol) palladium(||) acetate and 0.9 ml triethylamine (6.3 mmol) in 22 ml of DMF and 12 ml of methanol was purged with carbon monoxide at room temperature. The autoclave was pressured with carbonmonoxide to 13.7 bar and the mixture was stirred at room temperature for 30 minutes. The autoclave was depressurized and then pressured with carbon monoxide to 16.1 bar. The mixture was stirred at 80°C for 24 hours. The autoclave was depressurized and after cooling, the mixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The organic phase was dried (Na2$O4), filtered and concentrated. The residue was ed by column chromatography (gradient from 100% Hex to 100% EtOAc) to give 720 mg (1.49 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: -0.48 - -0.30 (9H), 0.42 - 0.61 (2H), 1.22 (3H), 3.20 (3H), 3.48 (1H), 3.54 - 3.68 (1H), 3.75 (1H), 3.88 - 4.05 (4H), 4.10 (1H), 4.50 (1H), 5.78 (1H), 5.85 (1H), 6.96 (1H), 7.66 (1H), 7.87 (1H), 8.19 (1H), 8.46 (1H).

Step d: {2-[(3R)methy|morphoIin-4—yl](1-{[2-(trimethy|si|y|)ethoxy]methy|}-1H-pyrazolyl)—1,7- naphthyridinyl}methanol 3.0 ml (3.00 mmol) of a 1M on of DIBAL in e was added to a on of 720 mg (1.49 mmol) of methyl 2-[(3R)—3-methylmorpholiny|]—8—(1-{[2—(trimethylsi|y|)ethoxy]methy|}-1H- pyrazoIyl)—1,7-naphthyridinecarboxylate in 17 ml of dry THF at room ature and the e was stirred at 70 °C for 4 hours. After cooling, the mixture was diluted with 25 ml of a saturated solution of ammonium chloride and stirred at room temperature ght. The e was diluted with ethyl acetate and filtered using a Whatman filter. The organic phase was concentrated and the residue was purified by column chromatography (gradient from 100% Hex to 100% EtOAc) to give 405 mg (0.89 mmol) ofthe desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: -0.37 - -0.25 (9H), 0.39 - 0.62 (2H), 1.13 - 1.31 (3H), 3.12 - uzs (3H), 3.48 (1H), 3.63 (1H), 3.77 (1H), 3.98 (1H), 4.11 (1H), 4.47 (1H), 4.93 (2H), 5.65 (1H), 5.80 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (1H), 5.86 (1H), 6.96 (1H), 7.45 (1H), 7.64 (1H), 7.72 (1H), 8.38 (1H).

Step e: oromethyl)—2-[(3R)—3—methylmorpho|in-4—yl](1-{[2-(trimethy|si|y|)ethoxy]methyl}-1H- pyrazo|y|)-1,7-naphthyridine and 4-(chloromethyl)—2-[(3R)—3—methylmorpholinyl](1H-pyrazo|y|)-1,7-naphthyridine 0.05 ml (0.66 mmol) thiony chloride was added to a stirred solution of {2-[(3R) methylmorpholin-4—yl]—8-(1—{[2—(trimethy|si|yl)ethoxy]methy|}-1H—pyrazoI—S—yl)-1,7—naphthyridin- 4-yl}methanol in 33 ml of dry DMF at 0 °C. The mixture was stirred at 5 °C for 1 hour. Toluene was added and the mixture was concentrated to give a crude mixture of 4—(chloromethyl)-2—[(3R) methylmorpholinyl]-8—(1-{[2—(trimethy|si|y|)ethoxy]methyl}-1H—pyrazol-5—y|)-1,7-naphthyridine and 4-(chloromethyl)—2-[(3R)—3—methy|morpho|inyl]-8—(1H-pyrazo|y|)—1,7-naphthyridine.

Step f: 2-[(3R)—3-methylmorpholiny|][(methylsulfanyl)methyl](1—{[2- (trimethylsilyl)ethoxy]methy|}-1H-pyrazoly|)-1,7-naphthyridine and 2-[(3R)methylmorpholinyl][(methylsulfanyl)methyl](1H-pyrazolyl)—1,7- yridine 0.56 ml (1.71 mmol) of an aqueous solution of sodium methanethiolate (21%) was added to 184 Dg of a crude mixture of 4-(chloromethyl)—2-[(3R)—3—methy|morpho|in—4-yl]—8—(1—{[2- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (trimethylsilyl)ethoxy]methy|}—1H-pyrazol—5-yl)—1,7—naphthyridine and 4—(chloromethyl)—2—[(3R)-3— methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine from step e in 4.3 ml of acetone at roomtemperature. The e was stirred at room temperature for 150 minutes before it was diluted with ethyl acetate and washed with an aqueous solution of sodium chloride. The c phase was filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC urifier: basic conditions) to give 33 mg (0.07 mmol) 2-[(3R) methylmorpholinyl][(methylsulfanyl)methyl]—8-(1-{[2-(trimethylsi|yl)ethoxy]methyI}-1H- pyrazolyl)—1,7-naphthyridine and 32 mg (0.09 mmol) of 2-[(3R)methylmorpholin-4—yl]—4- [(methylsulfanyl)methyI](1H—pyrazoI—5-yl)-1,7—naphthyridine. )methylmorpholin-4—y|][(methylsulfanyl)methyl]—8-(1—{[2- (trimethylsi|y|)ethoxy]methyl}—1H-pyrazo|—5-yl)-1,7-naphthyridine: 1H—NMR (400MHz, DMSO-d6): 6 [ppm]: -0.14 — 0.02 (9H), 0.86 (2H), 1.24 (3H), 2.02 (3H), 3.26 (1H), 3.53 (1H), 3.60 (2H), 3.64 - 3.73 (1H), 3.77 (1H), 3.91 - 4.05 (1H), 4.10 (2H), 4.18 (1H), 4.53 (1H), 5.50 (2H), 7.17 (1H), 7.39 (1H), 7.81 (1H), 7.95 (1H), 8.35 (1H). 2-[(3R)methylmorpholiny|][(methylsulfanyl)methyl]—8-(1H-pyrazolyl)-1,7- yridine: 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.20 - 1.36 (3H), 2.02 (3H), 3.32 (1H), 3.52 - 3.67 (1H), 3.73 (1H), 3.84 (1H), 3.96 - 4.23 (4H), 4.55 (1H), 7.38 (1H), 7.47 (1H), 7.62 (1H), 7.83 (1H), 8.37 (1H), 13.38 (1H).

Example 187 N,N-dimethyl-S-[2-(morpholinyl)(1H-pyrazol-S-yl)-1,7-naphthyridin-4—yl]pyridin-Z-amine Example 187 was prepared using Automated Medicinal Chemistry (see es 346-437).

However, initial purity was not sufficient for testing and therefore the sample had to be purified Da second preparative HPLC (Autopurifier: basic conditions) to give 1 mg (0.002 mmol) of the [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp desired product. 1H-NMR z, DMSO-d6): 6 [ppm]: 3.13 (6H), 3.80 (8H), 6.83 (1H), 7.31 - 7.49 (2H), 7.53 (1H), 7.64 (1H), 7.77 (1H), 8.18 - 8.39 (2H), 13.42 (1H).

Example 188 4-(2-methylpyridin-4—yl)—2-(morpholiny|)(1H-pyrazoly|)-1,7-naphthyridine e 187 was prepared using Automated Medicinal Chemistry (see examples 346—437).

However, initial purity was not sufficient for testing and therefore the sample had to be purified by a second ative HPLC urifier: basic conditions) to give 0.7 mg (0.002 mmol) of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]= 2.60 (3H), 3.80 (8H), 7.40 (2H), 7.43 (1H), 7.48 (1H), 7.54 (1H), 7.65 (1H), 8.34 (1H), 8.64 (1H), 13.44 (1H).

Example 189 1-{2-[(3R)methy|morpholinyl](1H-pyrazo|y|)-1,7-naphthyridiny|}cyclohexano| Step a: 1-{2-[(3R)methy|morpholinyl](1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazo|y|)-1,7- naphthyridin-4—yl}cyclohexanol D23 ml (0.12 mmol) ofa solution of 0.5M pentamethylenebis(magnesium bromide) in THF was [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp added to a on of 56 mg (0.12 mmol) methyl )—3—methylmorpholin—4-yl]—8-(1-{[2— (trimethylsilyl)ethoxy]methyl}-1H-pyrazolyl)-1,7-naphthyridinecarboxylate in 3.0 ml of THF at 0°C under argon. The mixture was stirred at 0°C for 30 minutes and then 1 hour at room temperature. Additional 0.12 ml (0.06 mmol) of the solution of 0.5M pentamethylenebis(magnesium bromide) in THF was added and the mixture was d for 150 minutes at room temperature. The mixture was diluted with aqueous ammonium chloride solution and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by column chromatography (gradient from 100% Hex hexane / EtOAc 50%) to give 26 mg (0.05 mmol) the desired product.

Step b: 1-{2—[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin-4—yl}cyclohexanol 0.04 ml (0.08 mmol) ofa 2N aqueous hydrogen chloride solution was added to a solution of 20 mg (0.038 mmol) of 1-{2-[(3R)methylmorpholin-4—yl]—8-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrazolyl)-1,7-naphthyridinyl}cyclohexanol from step a in 0.4 ml of dioxane. The mixture was stirred at room temperature for 7 hours. The mixture was diluted with s sodium de solution and extracted with ethyl acetat (2x) and DCM (1x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC urifier: basic conditions) to give 4 mg (0.01 mmol)of the desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.25 (3H), 1.41 - 1.57 (2H), 1.57 - 1.68 (1H), 1.70 - 1.84 (1H), 1.96 - 2.11 (2H), 3.31 (1H), 3.56 (1H), 3.71 (1H), 3.82 (1H), 4.05 (1H), 4.12 (1H), 4.53 (1H), 4.89 - 5.01 (2H), 5.09 - 5.29 (1H), 5.61 (1H), 5.77 (1H), 7.36 (1H), 7.49 (1H), 7.60 (1H), 7.77 (1H), 8.34 (1H), 13.36 (1H). e 190 -fluoro-Z-{Z-[(3R)—3-methylmorpholin-4—yl](1H-pyrazolyl)-1,7-naphthyridin-4—yl}aniline Dep a: [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 2-fluoro{2-[(3R)methylmorpho|iny|][1—(tetrahyd ro-ZH-pyran-Z-yl)-1H-pyrazo|—5-y|]- 1,7-naphthyridin-4—yl}aniline A suspension of 100 mg (0.19 mmol) of 2—[(3R)methylmorpholin—4—yl]—8—[1—(tetrahydro—2H- pyran-Z-yl)-1H-pyrazol-S-yl]—1,7-naphthyridin-4—yl trifluoromethanesulfonate, 90 mg (0.38 mmol) Z—fluoro-6—(4,4,5,5—tetramethyl—1,3,2—dioxaborolan-Z-yl)aniline, 15 mg (0.019 mmol) of [1,1’— phenylphosphino)ferrocene]dichloropalladium(|l) x with dichloromethane (1:1, Pd(dppf)C|2) and 65 mg (0.47 mmol) of potassium carbonate in 2.0 ml of acetonitrile and 1.0 ml water was degased with argon. Under argon, the reaction mixture was stirred at 130°C for 10 minutes in a microwave oven. After cooling the on mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2x). The combinded c phases were filtered using a Whatman filter and then concentrated to give the crude product that was used t further purification in the next step.

Step b: Z-fluoro{2-[(3R)methylmorphoIinyl](1H-pyrazo|y|)-1,7-naphthyridiny|}aniline A solution of 156 mg of crude 2-fluoro{2-[(3R)methylmorpholinyl]—8—[1-(tetrahydro-2H- pyran—Z-yl)—1H—pyrazoI—S-yl]—1,7—naphthyridin—4—yl}ani|ine from step a in 5.8 ml of methanol and 0.30 ml of 2N hydrochloric acid was stirred for 90 minutes at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated to dryness. The residue was purified by preparative HPLC (Autopurifier: acidic conditions) to give 2 mg (0.005 mmol) ofthe desired product. 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 1.22 - 1.40 (3H), 3.51 - 3.64 (1H), 3.71 (1H), 3.82 (1H), 4.05 (1H), 4.21 (1H), 4.54 - 4.70 (1H), 4.89 (2H), 6.62 - 6.76 (1H), 6.90 (1H), 6.97 - 7.26 (2H), 7.39 (1H), 7.44 (1H), 7.55 - 7.74 (1H), 8.28 (1H), 13.42 (1H).

Example 191 (methy|{4-[2-(morpholin-4—yl)(1H-pyrazo|yl)-1,7-naphthyridin-4—yl]phenyl}oxido-N5- sulfanylidene)cyanamide Step 3: 4—[4—(methylsulfonimidoyl)phenyl](morpho|in-4—yl)—8-{1-[(2)—tetrahydro-2H-pyranyl]-1H- pyrazoly|}-1,7-naphthyridine 4-[(2—(Morpholinyl)—8-[2-(tetrahydropyran-2—yl)-2H-pyrazo|—3-yl]—[1,7]naphthyridine yl]phenyI-N-ethoxycarbonyl-S—methylsulphoximide (1.00 g, 1.52 mmol) was solubilised in a solution of NaOMe (30% solution in MeOH, 25 mL). the reaction was stirred at 60°C for 3h. The reaction mixture was concentrated under reduced pressure and diluted with DCM and H20. The aqueous phase was extracted two times with DCM. The ed organic phases were washed with brine, dried (silicon filter) and concentrated under d re. The titled compound was obtain in tative yield without further purification. lH-NMR (400MHz, DMSO-de): 6 [ppm]: 1.40 - 1.66 (m, 3H), 1.99 (br. s., 2H), 2.30 — 2.47 (m, 1H), 3.17 (s, 3H), 3.22 — 3.30 (m, 1H), 3.72 (s, 8H), 4.35 (s, 1H), 5.75 (s, 1H), 6.06 — 6.12 (m, 1H), 6.93 (d, 1H), 7.41 (d, 1H), 7.50 (s, 1H), 7.64 (d, 1H), 7.82 (d, 2H), 8.13 (d, 2H), 8.38 (d, 1H).

Step b: ation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (methy|{4-[2-(morpholinyl)—8-(1H-pyrazo|yl)-1,7-naphthyridinyl]pheny|}oxido-}i.6- sulfanylidene)cyanamide \ l\lH K/N /N \ / .s. // 4-[4—(Methylsulfonimidoyl)pheny|](morpholin—4-yl)-8—{1-[(2)-tetrahydro—2H-pyran—2-yl]—1H— pyrazoly|}—1,7-naphthyridine (200 mg, 0.39 mmol) was solubilised in DCM (6 mL). DMAP (51 mg, 0,42 mmol) and BrCN (82 mg, 0.77 mmol, 3M solution) were added sequentially. The reaction was stirred at rt for 16h. The reaction mixture was concentrated under reduced pressure and diluted with MeOH. The suspension was filtered, washed with MeOH and dried under reduced pressure. The crude solid (74 mg) was then solubilized in DCM (2 mL) and 3M HCI (1.5 mL) was added. The reaction was stirred for 1h at rt. The reaction was quenched by addition of sat. bicarbonate and the solid was filtered and dried. The title compound was obtained without further purification in (60 mg). 1H-NMR z, DMSO-de): 6 [ppm]: 3.76 - 3.85 (m, 11H), 7.33 (d, 1H), 7.43 (br. s, 1H), 7.60 - 7.68 (m, 2H), 8.00 (d, 2H), 8.26 (d, 2H), 8.36 (d, 1H), 13.42 (br. s, 1H).

Example 192 1-ethyl(methy|{4-[2-(morpholinyl)(1H-pyrazo|y|)-1,7-naphthyridiny|]pheny|}oxido- ke-sulfanylidene)urea Step 3: (methy|{4-[2-(morpholiny|)(1H-pyrazo|yl)-1,7-naphthyridinyl]pheny|}oxido-}i.6- sulfanylidene)cyanamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 4-[4—(Methylsulfonimidoyl)phenyl]—2-(morpholin—4-yl)-8—{1—[(2)-tetrahydro—2H-pyran—2-yl]—1H— pyrazolyl}—1,7-naphthyridine (100 mg, 0.19 mmol) was solubilised in DCM (6 mL). Triethylamine (39 mg, 0.39 mmol) and ethyl isocyanate (27 mg, 0. 39 mmol) were added. The on was stirred for 16h at rt and triethylamine (195 mg, 3.89 mmol) and ethyl isocyanate (135 mg, 1.95 mmol) were added. The reaction was stirred for 16h at rt and concentrated under reduced pressure. The crude material was solubilized in DMF (6 mL) and triethylamine (195 mg, 3.89 mmol) and ethyl isocyanate (135 mg, 1.95 mmol) were added. The reaction was stirred for 48h at 60°C. The reaction was diluted with water and extracted with DCM. The organic phase was dried (silicon filter) and concentrated under d pressure. The crude material was purified by flash chromatography (100% Hexane to 100% AcOEt to 20% MeOH). The titled compound was obtained in 78% yield (93 mg). 1H-NMR (400MHz, DMSO—de): 5 [ppm]= 0.99 (t, 3H), 1.40 - 1.66 (m, 3H), 1.99 (s, 2H), 2.34 - 2.45 (m, 1H), 2.90 - 3.04 (m, 2H), 3.23 - 3.29 (m, 1H), 3.45 (s, 3H), 3.72 (s, 9H), 6.09 (dd, 1H), 6.94 (d, 1H), 7.00 (t, 1H), 7.41 (d, 1H), 7.53 (s, 1H), 7.64 (d, 1H), 7.87 (d, 2H), 8.11 (d, 2H), 8.39 (d, 1H).

Step b: 1-ethyl(methyl{4—[2-(morpholin-4—yl)(1H-pyrazolyl)-1,7-naphthyridiny|]phenyl}oxido- ke-sulfanylidenewrea ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (Methy|{4-[2—(morpholinyl)—8—(1H-pyrazo|y|)—1,7-naphthyridin—4-y|]pheny|}oxido-7t6- su|fany|idene)cyanamide (93 mg, 46 mmol) was solubilized in DCM (3 mL) and 3M HCI (2 mL) was added. The reaction was stirred 16h at rt and then quenched with sat NaHCO3. The aqueous phase was extracted with DCM and the organic phase was dried (silicon filter) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (100% Hexane to 100% AcOEt to 20% MeOH) and the titled compound was obtained in 85% yield (68 mg). lH-NMR (400MHz, DMSO—de): 5 [ppm]: 0.99 (t, 3H), 2.90 — 3.03 (m, 2H), 3.45 (s, 3H), 3.80 (s, 8H), 7.00 (t, 1H), 7.35 (d, 1H), 7.43 (br. s, 1H), 7.57 (s, 1H), 7.65 (br. s, 1H), 7.86 (d, 2H), 8.11 (d, 2H), 8.35 (d, 1H), 13.37 - 13.47 (m, 1H). e 193 3-({2-[(3R)methy|morpholinyl](1H-pyrazo|y|)-1,7-naphthyridiny|}oxy)propan amine Tert-butyl [3-({2-[(3R)methylmorpholiny|][1-(tetrahydro-2H-pyranyl)-1H-pyrazo|—5-y|]— 1,7-naphthyridinyl}oxy)propyl]carbamate (80 mg, 0.15 mmol) was solubilised in DCM (2 mL) and TFA (0,22 mL, 2.9 mmol) was added. The reaction was stirred 2h at rt and quenched with sat.

DHcog. The s phase was extracted with DCM and the organic phase was dried (silicon ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp filter) and concentrated under reduced pressure.

The crude material was purified by preparative HPLC (ACN/HZO/formic acid system). The titled compound was obtained in 18% yield (10 mg). lH-NMR (400MHz, DMSO-de): 5 [ppm]= 1.27 (d, 3H), 2.11 (quin, 2H), 2.99 (t, 2H), 3.30 (dt, 1H), 3.56 (dt, 1H), 3.72 (dd, 1H), 3.83 (d, 1H), 4.05 (dd, 1H), 4.15 (d, 1H), 4.36 (t, 2H), 4.56 - 4.64 (m, 1H), 6.82 (s, 1H), 7.36 (d, 1H), 7.61 (d, 1H), 7.75 (d, 1H), 8.30 - 8.41 (m, 2H).

Example 194 4-(4-cyclopropyl-1H-1,2,3-triazo|y|)[(3R)methy|morphoIin-4—yl](1H-pyrazolyl)-1,7- naphthyridine Step a: 4-(cyclopropylethynyl)[(3R)methylmorpholin-4—y|]{1-[tetrahyd ro-2H-pyranyl]-1H- pyrazoly|}-1,7-naphthyridine 2-[(3R)methylmorpholin-4—yl]—8-{1—[tetrahydro—2H-pyranyl]—1H-pyrazol—5-y|}—1,7- yridin—4-yl trifluoromethanesulfonate (150 mg, 284 umol), copper(|) iodide (5.53 mg, 98 % purity, 28.4 umol) and triethylamine (790 pl, 5.7 mmol) were dissolved in acetonitrile (4.0 mL).

The reaction mixture was degassed with Argon. Ethynylcyclopropane (74 pl, 98 % purity, 850 umol) and : Bis(tripheny|phosphin)palladium(|l)chlorid (8.15 mg, 98 % purity, 11.4 umol) were added sequentially and the reaction was stirred for 16h at 45°C. The reaction was then filtered and concentrated under reduced pressure. The e was dissolved in DCM and water and the aqueous phase was extracted 3x with DCM. The combined organic layers were dried (silicone filter) and trated under reduced pressure. The crude material was purified by flash column chromatography tOAc mixture) and the title nd was obtained in 87% yield (110 mg). 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 0.90 - 0.98 (m, 2H), 1.01 - 1.08 (m, 2H), 1.15 - 1.22 (m, Di), 1.39 - 1.50 (m, 2H), 1.52 - 1.65 (m, 1H), 1.72 - 1.81 (m, 1H), 1.94 - 2.01 (m, 2H), 2.31 - 2.39 (m, [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp 1H), 3.11 - 3.30 (m, 2H), 3.40 - 3.51 (m, 1H), 3.56 - 3.64 (m, 1H), 3.65 - 3.77 (m, 2H), 3.90 - 3.98 (m, 1H), 4.07 - 4.16 (m, 1H), 4.42 - 4.53 (m, 1H), 6.07 (ddd, 1H), 6.92 (dd, 1H), 7.53 (d, 1H), 7.62 (d, 1H), 7.80 (d, 1H), 8.44 (d, 1H).

Step b: 4—(4-cyclopropyl-lH-1,2,3-triazo|y|)[(3R)methy|morphoIiny|](1H-pyrazol-5—yl)-1,7— naphthyridine 4—(cyclopropylethynyl)—2-[(3R)—3-methy|morpholinyl]—8—{1-[(2R)—tetrahydro-2H-pyranyl]—1H- pyrazolyl}—1,7—naphthyridine (70.0 mg, 158 umol) was solubilised in tert. l (1.8 mL) and water (1.8 mL). Sodium azide (10.3 mg, 158 umol) was added and the e was strirred for 5 min. at rt. Copper(|l) sulphate hydrate (19.7 mg, 78.9 umol) and (+)-sodium L-ascorbate (15.6 mg, 78.9 umol) were added and the mixture was strirred for 16h at 100°C.

The reaction was then cooled to rt, diluted with DCM and washed with H20. The organic phase was dried and concentrated under reduced pressure. The crude material was purified by preparative HPLC (HZO/CAN/formic acid mixture). The title compound was obtained in 1% yield (1 mg). 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 0.82 - 0.89 (m, 2H), 0.94 - 1.00 (m, 2H), 1.22 - 1.29 (m, 1H), 1.31 (d, 3H), 1.89 — 1.99 (m, 1H), 3.52 - 3.65 (m, 2H), 3.71 — 3.77 (m, 1H), 3.81 — 3.86 (m, 1H), 4.07 (dd, 1H), 4.17 - 4.24 (m, 1H), 4.56 - 4.64 (m, 1H), 7.42 (s, 1H), 7.61 (s, 1H), 7.65 (s, 1H), 7.77 (d, 1H), 8.37 (d, 1H), 13.44 (br. 5., 1H).

[Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp The following compounds of Table 1 were prepared according to Scheme 3 and in analogy to example 54.

Table 1 Structure 1H-NMR (400MHz, DMSO—d6): d [ppm]: 1.12 (t, 3H), 2.86 - 2.97 (m, 1H), 3.23 - 3.29 (m, 1H), 3.81 (s, 8H), 7.41 (s, 1H), 7.61 - 7.68 (m, 2H), 7.74 (s, 1H), 8.41 (d, 1H), 13.43 (s, 1H). 4—ethylsulfinyl—2—(morpholin—4—yl)—8—(1H—pyrazo|—5—y|)—1,7—naphthyridine 1H—NMR (400MHz, DMSO—d6): cl [ppm]: 0.94 (cl, 3H), 1.40 (d, 3H), 3.18 — 3.27 (m, 1H), 3.81 (cl, 8H), 7.41(s, 1H), 7.63 — 7.71 (m, 3H), 8.41 (cl, 1H), 13.45 (s, 1H). pholiny|)[propan-Z-ylsulfinyl](1H-pyrazoIyl)-1,7- yridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.27 (d, 3H), 2.25 - 2.35 (m, 2H), 3.07 (s, 3H), 3.28-3.34 (m, 1H), 3.37 - 3.45 (m, 2H), 3.56 (td,1H), 3.71 (dd, 1H), 3.83 (d, 1H), 4.05 (dd, 1H), 4.16 (d, 1H), 4.40 (t, 2H), 4.56 - 4.65 (m, 1H), 6.83 (s, 1H), 7.37 (s, 1H), 7.61 (s, 1H), 7.82 (d, 1H), 8.34 (d, 1H), 13.36 (br. s., 1H). 2—[(3R)—3-methy|morpholin—4-y|]-4—[3—( methylsulfonyl)propoxy]—8—(1H— pyrazol—S—yl)-1,7—naphthyridine 1H-NMR (400MHz, DMSO—d6): d [ppm]: 3.83 (s, 8H), 7.35 (br. s., 1H), 7.54 (t, 3H), 7.62 (br. s., 1H), 7.71 (d, 1H), 7.89 - 7.95 (m, 2H), 8.07 (s, 1H), 8.30 (d, 1H), 13.38 (br. s, 1H). 2—(morpholin—4—yl)—4—(phenylsulfonyl)—8—(1H—pyrazol—S—yl)—1,7— naphthyridine [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp ed set by jennyp 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.25 (d, 6H), 3.69 (spt, 1H), 3.80 (br. 5., 8H), 7.37 (br. s, 1H), 7.64 (br. s, 1H), 7.90 (s, 1H), 8.15 (d, 1H), 8.48 (d, 1H), 13.46 (br. s, 1H). 2-(morpholin—4—yI)—4-( propa n—2—ylsulfonyI)—8—(1H—pyrazoI—5—yI)—1,7— naphthyridine 1H-NMR (400MHz, DMSO—d6): d [ppm]: 1.19 (t, 3H), 3.56 (q, 2H), 3.80 (s, 8H), 7.37 (br. s, 1H), 7.64 (br. 5, 1H), 7.91 (br. s, 1H), 8.14 (d, 1H), 8.49 (d, 1H), 13.44 (br. s, 1H). 4-(ethylsulfonyI)—2—(morpholin-4—yI)—8—(1H—pyrazol-5—y|)—1,7-naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 3.83 (s, 8H), 7.30 (br. s, 1H), 7.60 - 7.69 (m, 3H), 7.72 - 7.77 (m, 1H), 7.99 (d, 1H), 8.12 - 8.17 (m, 2H), 8.21 (s, 1H), 8.37 (d, 1H), 13.40 (br. s, 1H). 2-(morpholiny|)(phenylsulfinyl)(1H-pyrazoly|)-l,7- naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 2.93 (s, 3H), 3.80 (s, 8H), 7.39 (d, 1H), 7.61 (d, 1H), 7.65 (d, 1H), 7.82 (s, 1H), 8.41 (d, 1H), 13.42 (br. s, 1H). 4—(methylsuIfiny|)—2—(morpholin—4—yl)—8—(1H—pyrazoI—S—yI)—1,7— naphthyridine 1H-NMR (400MHz, DMSO—d6): d [ppm]: 1.20 - 1.32 (m, 3H), 1.79 - 1.88 (m, 1H), 2.55 - 2.65 (m, 1H), 2.83 - 2.97 (m, 1H), 2.97 - 3.10 (m, 2H), 3.17 - 3.30 (m, 1H), 3.29 - 3.38 (m, 2H), 3.44 - 3.62 (m, 2H), 3.64 - 3.75 (m, 2H), 3.77 - 3.85 (m, 1H), 3.99 -4.08 (m, 1H), 4.14 - 4.24 (m, 1H), 4.56 -4.70 (m, 1H), 7.29 - 7.41 (m, 2H), 7.58 - 7.88 (m, 2H), 8.31 - 8.41 (m, 1H), 13.37 (br. s, 1H). 2—[(3R)—3-methylmorpho|inyl]—4-[1-oxidotetrahydro-ZH-thiopyran-4—y|]- 8—(1H—pyrazoI—5—yI)—1,7—naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.20 — 1.31 (m, 3H), 2.11 - 2.21 (m, 1H), 2.25 - 2.40 (m, 1H), 2.96 - 3.04 (m, 1H), 3.14 - 3.24 (m, 1H), 3.26 - 3.37 (m, 2H), 3.43 - 3.60 (m, 3H), 3.65 - 3.74 (m, 1H), 3.77 - 3.85 (m, 1H), 3.96 - 4.08 (m, 2H), 4.14 - 4.26 (m, 1H), 4.56 - 4.71 (m, 1H), 5.79 (t, 1H), 7.31 - 7.42 (m, 2H), 7.58 - 7.91 (m, 2H), 8.38 (dd, 1H), 13.32 - 13.43 (m, 1H). 4—(1,1—dioxidotetrahydro—2H—thiopyran-4—y|)—2—[(3R)-3—methy|morpholin—4— yl]—8—(1H—pyrazoI—S—yl)—1,7—naphthyridine The following compounds of Table 2 were ed ing to Scheme 4 and in analogy to examples 63, 70, 85 and 107.

Table 2 Structure 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.29 (d, 3H), 3.38 (dd, 1H), 3.59 (dt, 1H), 3.73 (dd, 1H), 3.84 (d, 1H), 4.06 (dd, 1H), 4.21 (d, 1H), 4.62 -4.71 (m, 1H), 7.00 (br. s, 1H), 7.39 (d, 1H), 7.63 (s, 2H), 7.99 (br. s, 1H), 8.38 (d, 1H), 8.49 - 8.57 (m, 1H), 12.95 - 13.63 (m, 2H). )—3—methy|morpholin—4-yl]—4,8—di(1H—pyrazo|—S—y|)—1,7-naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 2.97 (s, 6H), 3.70 (t, 4H), 3.78 (t, 4H), 6.68 (s, 1H), 7.33 (d, 1H), 7.68 (d, 1H), 8.18 (s, 1H), 8.29 (d, 1H), 13.07 - 13.60 (m, 1H).

N,N—dimethyl—2—(morpholin—4-yI)—8—(1H-pyrazoI—S-yl)—1,7—naphthyridin-4— amine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 3.50 - 3.59 (m, 4H), 3.69 - 3.77 (m, 4H), 7.00 (s, 1H), 7.36 (d, 1H), 7.46 - 7.59 (m, 5H), 7.63 (d, 1H), 7.76 (d, 1H),8.38(d,1H). 2—(morpholin—4—yl)—4—(phenylsulfa ny|)—8—(1H—pyrazoI—S—yI)—1,7— naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.27 (d, 6H), 3.59 - 3.67 (m, 4H), 3.73 - 3.82 (m, 4H), 3.90 - 4.01 (m, 1H), 6.24 (s, 1H), 6.69 (d, 1H), 7.30 (s, 1H), 7.58 (s, 1H), 7.98 (d, 1H), 8.25 (d, 1H), 13.38 (br. s., 1H). 2-(morpholiny|)-N-(propany|)-8—(1H-pyrazoIy|)-1,7-naphthyridin- 4—amine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H—NMR z, DMSO—d6): d [ppm]: 1.38 (t, 3H), 3.27 (q, 2H), 3.74-3.8 (m, 8H), 7.21 (s, 1H), 7.37 (br. s., 1H), 7.61 (s, 1H), 7.67 (d, 1H), 8.36 (d, 1H), 13.37 (br. s., 1H). 4—(ethylsulfanyl)—2—(morpholin—4—yI)—8—(1H—pyrazol—5—yI)—1,7-naphthyridine 1H—NMR z, DMSO—d6): d [ppm]: 1.40 (d, 6H), 3.74-3.80 (m, 8H), 4.02 (spt, 1H), 7.32 (s, 1H), 7.36 (br. s., 1H), 7.62 (br. s, 1H), 7.70 (d, 1H), 8.36 (d, 1H), 13.36 (br. s., 1H). 2-(morpholin—4—y|)—4—(propan—Z—ylsulfany|)—8—(1H-pyrazoI—S—yI)—1,7— naphthyridine 1H—NMR z, DMSO—d6): d [ppm]: 3.73 - 3.86 (m, 8H), 6.29 - 6.36 (m, 1H), 6.68 - 6.74 (m, 1H), 7.11 - 7.17 (m, 1H), 7.37 (d, 1H), 7.45 (5, 1H), 7.63 (d, 1H), 8.01 (d, 1H), 8.38 (d, 1H), 11.66 (br. s, 1H), 13.36 (br. s, 1H). 2-(morpholin-4—yI)—8-(1H—pyrazoI-S—yI)—4-(1H—pyrroI-2—yI)—1,7- naphthyridine 1H-NMR (400MHz, DMSO-d6): d [ppm]: 3.71 - 3.87 (m, 8H), 6.53 - 6.58 (m, 1H), 6.97 - 7.01 (m, 1H), 7.33 - 7.43 (m, 3H), 7.62 (br. s, 1H), 7.97 (d, 1H), 8.35 (d, 1H), 11.37 (br. s, 1H), 13.37 (br. s, 1H). 2—(morpholin—4—yI)—8—(1H—pyrazoI—S—yI)—4—(1H—pyrroI—3—yI)—1,7— naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 3.49 (t, 4H), 3.71 (t, 4H), 3.83 (s, 3H), 6.71 (s, 1H), 7.10 - 7.16 (m, 2H), 7.36 (br. s, 1H), 7.56 - 7.65 (m, 3H), 7.79 (d, 1H), 8.40 (d, 1H), 13.39 (br. s, 1H). 4—[(4-methoxypheny|)sulfa ny|]—2—(morpholin—4-y|)—8—(1H-pyrazol—S-y|)—1,7- naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 2.35 (s, 3H), 3.79 (d, 8H), 6.74 (s, 1H), 7.38 (br. s., 1H), 7.63 (d, 2H), 8.38 (d, 1H), 8.57 (d, 1H), 13.06 (br. s., 1H),13.37(br.s,1H). 4—(5—methyI—1H—pyrazoI—3—yI)—2—(morpholin—4—yI)—8-(1H—pyrazoI—5—yI)—1,7— naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 2.25 (q, 2H), 2.55 (d, 2H), 3.77 (dd, 8H), 3.92 (t, 2H), 7.38 (s, 1H), 7.48 (d, 1H), 7.55 (s, 1H), 7.62 (s, 1H), 8.33 (d,1H),13.39(s,1H). 1—[2-(morpholin—4-yl)—8-(1H-pyrazoI—5-yl)—1,7—naphthyridin—4—yl]pyrrolidin— 2—one ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp 1H—NMR (400MHz, DMSO—d6): d [ppm]: 2.54 - 2.58 (m, 2H), 3.57 (t, 2H), 3.71 - 3.86 (m, 8H), 4.00 (t, 2H), 7.37 (d, 1H), 7.54 (s, 1H), 7.63 (d, 1H), 7.94 (d, 1H), 8.38 (d, 1H), 13.34 (br. s, 1H). 4—(1,1—dioxido—1,2—thiazolidin-2—yl)—2—(morpholin—4—yI)—8—(1H—pyrazoI—5—yl)— 1,7-naphthyridine 1H—NMR(400MHz, DMSO—d6): d [ppm]: 1.86 - 2.05 (m, 4H), 2.36 - 2.65 (m, 2H), 3.45 - 3.54 (m, 1H), 3.71 - 3.84 (m, 9H), 7.36 - 7.43 (m, 2H), 7.59 - 7.64 (m, 2H), 8.34 (d, 1H), 13.34 - 13.42 (m, 1H). 1-[2—(morpholin—4—yl)-8—(1H—pyrazoI—S—yl)-1,7—naphthyridinyl]piperidin— 2-one 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.30 (t, 3H), 2.25 (d, 3H), 3.34 - 3.40 (m, 1H), 3.52 - 3.63 (m, 1H), 3.67 - 3.76 (m, 1H), 3.78 - 3.85 (m, 1H), 4.00 - 4.09 (m, 1H), 4.17 - 4.27 (m, 1H), 4.57 - 4.67 (m, 1H), 6.93 - 6.99 (m, 1H), 7.38 - 7.46 (m, 2H), 7.49 (d, 1H), 7.64 (br. s, 1H), 7.72 (dd, 1H), 8.29 (d, 1H), 8.64 (dd, 1H), 13.42 (br. s, 1H). 2-[(3R)—3—methy|morpho|in—4-y|]-4—(2—methy|pyridin-3—yl)—8-(1H—pyrazo|-5— y|)—1,7—naphthyridine 1H-NMR(400MHz, 6): d [ppm]: 1.13 (dd, 6H), 1.26 - 1.34 (m, 3H), 3.33 - 3.39 (m, 1H), 3.57 (dt, 1H), 3.71 (dd, 1H), 3.82 (br. d, 1H), 4.04 (dd, 1H), 4.22 (d, 1H), 4.57 -4.65 (m, 1H), 5.34 (spt, 1H), 7.12 (d, 1H), 7.17 (dd, 1H), 7.41 (br. s, 1H), 7.45 (br. s, 1H), 7.64 (br. s, 1H), 7.81 (dd, 1H), 8.28 (s, 1H), 8.34 (dd, 1H), 13.38 (br. s, 1H). 2—[(3R)—3—methy|morpho|in—4—y|]—4—[2—(propan—Z—yloxy)pyridin—3—y|]—8-(1H— pyrazoI—S-y|)-1,7—naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.30 (d, 3H), 3.34 (dt, 1H), 3.56 (dt,1H),3.67 - 3.74 (m, 1H), 3.80 (s, 4H), 4.03 (d, 1H), 4.16 - 4.23 (m, 1H), 4.58 - 4.66 (m, 1H), 7.06 (d, 1H), 7.22 (dd, 1H), 7.44 (d, 2H), 7.63 (br. s, 1H), 7.82 (dd, 1H), 8.28 (d, 1H), 8.37 (dd, 1H), 13.39 (s, 1H). 4-(2—methoxypyridin-3—y|)—2—[(3 R)—3—methy|morpholin—4—yl]-8—(1H—pyrazo|— -yl)—1,7—naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 3.79 (s, 8H), 7.34 -7.45 (m, 2H), 7.52 - 7.68 (m, 4H), 8.34 (d, 1H), 8.79 (dd, 2H), 13.42 (s, 1H). 2-(morpholin—4—yI)—8-(1H—pyrazoI—S—yI)—4-(pyridinyl)—1,7—naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.13 (d, 3H), 3.13 - 3.25 (m, 1H), 3.43 - 3.53 (m, 1H), 3.57 - 3.65 (m, 1H), 3.71 - 3.78 (m, 1H), 3.78 - 3.86 (m, 4H), 3.95 — 4.01 (m, 1H), 4.08 — 4.17 (m, 1H), 6.63 (s, 1H), 7.09 - 7.16 (m, 2H), 7.36 (s, 1H), 7.56 - 7.63 (m, 3H), 7.78 (d, 1H), 8.39 (d, 1H), 13.38 (br. s, 1H). 4—[(4—methoxyphenyl)suIfanyl]-2—[(3R)—3-methy|morpholin—4—yI]—8—(1H— I—S-y|)—1,7—naphthyridine 1H—NMR z, 6): d [ppm]: 1.30 (d, 3H), 3.33 - 3.40 (m, 1H), 3.41 - 3.49 (m, 4H), 3.52 - 3.61 (m, 1H), 3.67 - 3.78 (m, 5H), 3.79 - 3.85 (m, 1H), 3.99 - 4.08 (m, 1H), 4.16 - 4.25 (m, 1H), 4.57 -4.68 (m, 1H), 7.04 (t, 1H), 7.21 (dd, 1H), 7.42 (br. s, 1H), 7.52 - 7.68 (m, 2H), 8.20 (d, 1H), 8.33 (d, 1H), 13.40 (br. 5, 1H). 4—[3—fluoro-2—(morpholin—4—y|)pyridin—4—y|]—2—[(3R)-3—methylmorpholin—4— yl]-8—(1H—pyrazoI—5—yl)-1,7—naphthyridine 1H—NMR (400MHz, DMSO—d6): 0) [ppm]: 2.12 (s, 3H), 3.79 (s, 8H), 7.01 (d, 1H), 7.33 (s, 1H), 7.42 (d, 1H), 7.55 (s, 1H), 7.65 (d, 1H), 8.16 (s, 1H), 8.30 (d, 1H), 13.39 (br. s, 1H). 4-(6-f|uoromethylpyridiny|)(morpholiny|)(1H-pyrazoIy|)- 1,7—naphthyridine 1H—NMR(400MHz, DMSO—d6): d [ppm]= 3.77 (d, 8H), 4.20 (br. 5., 2H), 4.61 (br. s., 2H), 7.31 - 7.42 (m, 1H), 7.64 (br. 5., 3H), 8.36 (br. s., 1H), 13.30 - 13.48 (m, 1H) 3—[2—(morpholin—4—yl)—8—(1H—pyrazoI—5—yl)—1,7—naphthyridin—4—yI]—1,3- oxazinan—Z-one 1H-NMR (400MHz, DMSO—d6): d [ppm]: 2.14 - 2.32 (m, 2H), 3.72 - 3.83 (m, 9H), 4.41 - 4.60 (m, 2H), 7.37 (s, 1H), 7.54 (d, 1H), 7.62 - 7.66 (m, 1H), 7.73 (s, 1H), 8.37 (d, 1H), 13.27 - 13.54 (m, 1H). 3-[2—(morpholin—4—yl)-8—(1H—pyrazoI—S—y|)-1,7—naphthyridinyI]—1,3— oxazolidin—Z—one 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.30 (d, 3H), 3.34 - 3.39 (m, 1H), 3.51 - 3.61 (m, 1H), 3.67 - 3.74 (m, 1H), 3.78 - 3.86 (m, 4H), 3.99 - 4.07 (m, 1H), 4.16 - 4.24 (m, 1H), 4.57 - 4.66 (m, 1H), 7.04 (d, 1H), 7.38 - 7.48 (m, 3H), 7.64 (br. s, 1H), 8.27 (d, 1H), 8.41 (d, 1H), 8.60 (s, 1H), 13.40 (br. s, 1H). 4—(3—methoxypyridin—4—yI)—2—[(3R)—3—methy|morpholin—4—yI]—8—(1H—pyrazo|— -yl)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H—NMR (400MHz, DMSO-d6): d [ppm]: 1.30 (d, 3H), 3.30 - 3.41 (m, 1H), 3.52 - 3.61 (m, 1H), 3.68 - 3.74 (m, 1H), 3.80 - 3.85 (m, 1H), 4.01 —4.08 (m, 1H), 4.16 — 4.24 (m, 1H), 4.57 — 4.66 (m, 1H), 7.25 (dd, 1H), 7.39 — 7.48 (m, 2H), 7.62 - 7.67 (m, 2H), 8.32 (d, 1H), 8.38 (q, 1H). 4—(2,6—difluoropyridin—3—yI)—2-[(3R)—3—methy|morpholin—4-yII—8—(1H— I—S—y|)—1,7—naphthyridine 1H—NMR (400MHz, 6): d [ppm]: 1.31 (d, 3H), 3.37 - 3.41 (m, 1H), 3.52 - 3.62 (m, 1H), 3.67 - 3.75 (m, 1H), 3.79 - 3.87 (m, 1H), 4.01 - 4.09 (m, 1H), 4.17 - 4.26 (m, 1H), 4.56 - 4.67 (m, 1H), 7.25 (dd, 1H), 7.41 (br. s, 1H), 7.62 - 7.70 (m, 2H), 8.33 (d, 1H), 8.40 (dd, 1H), 8.55 (br. s, 1H). 4-(5—chIoro-Z—fluoropyridin—3-yl)—2—[(3R)—3—methy|morpholin-4—y|]—8—(1H— pyrazoI—S—yl)—1,7—naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.30 (d, 3H), 3.34 - 3.42 (m, 1H), 3.51 - 3.62 (m, 1H), 3.67 - 3.76 (m, 1H), 3.81 (s, 1H), 4.00 -4.09 (m, 1H), 4.17 - 4.26 (m, 1H), 4.58 - 4.67 (m, 1H), 7.17 (dd, 1H), 7.43 (s, 1H), 7.60 - 7.72 (m, 3H), 8.33 (d, 1H), 8.66 (dd, 1H), 8.83 (d, 1H), 13.44 (br. s., 1H). 4—(3—fluoropyridin—4-y|)—2—[(3R)—3—methy|morpholin—4—y|]—8—(1H—pyrazoI—S— y|)-1,7-naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.29 (t, 3H), 2.59 (s, 3H), 3.28 - 3.39 (m, 1H), 3.51 - 3.62 (m, 1H), 3.67 - 3.75 (m, 1H), 3.77 - 3.86 (m, 1H), 4.00 - 4.08 (m, 1H), 4.16 - 4.25 (m, 1H), 4.55 - 4.64 (m, 1H), 7.03 (dd, 1H), 7.42 (br. s., 1H), 7.48 - 7.56 (m, 2H), 7.65 (s, 1H), 7.90 (d, 1H), 8.30 (d, 1H), 13.42 (br. s, 1H). 4—(2—chIoro—6-methylpyridin-3—y|)—2—[(3R)—3—methy|morpholin-4—y|]—8—(1H— pyrazoI—S—y|)—1,7—naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.30 (d, 3H), 2.37 (s, 3H), 2.54 (s, 3H), 3.28 - 3.40 (m, 1H), 3.50 - 3.62 (m, 1H), 3.66 -3.76 (m, 1H), 3.78 - 3.87 (m, 1H), 4.00 -4.09 (m, 1H), 4.18 -4.27 (m, 1H), 4.60 -4.71 (m, 1H), 7.36 - 7.49 (m, 3H), 7.63 (s, 1H), 7.77 (d, 1H), 8.33 (d, 1H), 8.45 (d, 1H), 13.43 (5,1H). 4-(5,6—dimethylpyridin—3—y|)—2-[(3R)—3—methy|morpholin—4—yl]-8—(1H— pyrazoI—S—y|)—1,7—naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.30 (d, 3H), 2.57 (d, 3H), 3.29 - 3.40 (m, 1H), 3.50 - 3.62 (m, 1H), 3.66 - 3.76 (m, 1H), 3.78 - 3.87 (m, 1H), 4.01 — 4.09 (m, 1H), 4.19 — 4.28 (m, 1H), 4.61 — 4.71 (m, 1H), 7.42 (d, 2H), 7.54 (s, 1H), 7.64 (br. s., 1H), 7.97 (dd, 1H), 8.34 (d, 1H), 8.52 (s, 1H), 13.43 (br. s, 1H). 4—(5—f|uoro-6—methylpyridin—3-yI)—2—[(3R)—3—methylmorpholin—4—yI]—8—(1H— pyrazoI—S-y|)—1,7—naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.29 (d, 3H), 2.56 (d, 3H), 3.28 - 3.39 (m, 1H), 3.51 - 3.61 (m, 1H), 3.67 - 3.75 (m, 1H), 3.78 - 3.86 (m, 1H), 4.00 - 4.08 (m, 1H), 4.16 - 4.24 (m, 1H), 4.59 - 4.69 (m, 1H), 7.18 (t, 1H), 7.36 - 7.45 (m, 2H), 7.60 - 7.70 (m, 3H), 8.35 (d, 1H), 13.41 (br. s., 1H). )—3—methy|morpho|in—4-yl]—4—(5—methylthiophen—3—yI)(1H—pyrazol— —yl)—1,7—naphthyridine 1H-NMR (400MHz, DMSO—d6): d [ppm]: 1.28 (d, 3H), 3.27 - 3.38 (m, 1H), 3.52 - 3.61 (m, 1H), 3.68 - 3.75 (m, 1H), 3.78 - 3.85 (m, 4H), 4.00 - 4.07 (m, 1H), 4.10 - 4.19 (m, 1H), 4.55 - 4.63 (m, 1H), 7.27 (d, 1H), 7.36 - 7.44 (m, 2H), 7.50 (d, 1H), 7.63 (d, 1H), 7.79 (d, 1H), 8.34 (d, 1H), 13.32 (br. s, 1H). 4-(3-methoxythiophenyl)—2-[(3R)methy|morpholinyl](1H- pyrazoI—S—y|)—1,7—naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.29 (d, 3H), 3.29 - 3.39 (m, 1H), 3.52 - 3.62 (m, 1H), 3.68 - 3.74 (m, 1H), 3.78 - 3.85 (m, 1H), 4.01 -4.07 (m, 1H), 4.17 - 4.25 (m, 1H), 4.57 - 4.66 (m, 1H), 7.22 (d, 1H), 7.27 (d, 1H), 7.42 (br. s, 1H), 7.50 (br. s, 1H), 7.61 - 7.66 (m, 1H), 7.74 (d, 1H), 8.34 (d, 1H), 13.42 (br. s, 1H). 4—(2—chIorothiophen-3—yI)—2—[(3 R)—3—methy|morpholin—4—y|]-8—(1H—pyrazol— —yl)—1,7—naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.32 (dd, 3H), 3.34 - 3.42 (m, 1H), 3.53 - 3.63 (m, 1H), 3.68 - 3.76 (m, 1H), 3.77 - 3.84 (m, 1H), 4.04 (d, 1H), 4.24 (d, 1H), 4.60 - 4.70 (m, 1H), 6.81 - 6.87 (m, 1H), 7.37 - 7.42 (m, 1H), 7.46 - 7.51 (m, 1H), 7.63 - 7.68 (m, 2H), 7.69 - 7.80 (m, 2H), 8.19 (d, 1H), 8.26 - 8.33 (m, 1H), 8.57 (d, 1H), 9.52 (5, 1H), 13.44 (br. s, 1H). 4—(isoquinolin—4—y|)—2—[(3R)—3—methy|morpholin—4—y|]—8—(1H-pyrazoI—S—yl)— 1,7-naphthyridine ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.28 (d, 3H), 3.35 - 3.39 (m, 1H), 3.50 - 3.61 (m, 1H), 3.67 - 3.75 (m, 1H), 3.77 - 3.86 (m, 1H), 4.00 - 4.08 (m, 1H), 4.16 - 4.24 (m, 1H), 4.60 - 4.68 (m, 1H), 7.36 (d, 1H), 7.40 (s, 1H), 7.46 (d, 1H), 7.49 (s, 1H), 7.61 - 7.65 (m, 1H), 7.79 (d, 1H), 8.38 (d, 1H), 13.42 (br. s, 1H). 4—(5—ch|orothiophen-2—yI)—2—[(3R)—3—methy|morpholin—4—y|]-8—(1H—pyrazol— —yl)—1,7—naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.29 (d, 3H), 2.34 (d, 3H), 3.35 - 3.41 (m, 1H), 3.52 - 3.62 (m, 1H), 3.69 - 3.75 (m, 1H), 3.80 - 3.87 (m, 1H), 4.01 - 4.09 (m, 1H), 4.16 - 4.24 (m, 1H), 4.60 - 4.68 (m, 1H), 7.39 - 7.43 (m, 2H), 7.46 (s, 2H), 7.64 (s, 1H), 7.87 (d, 1H), 8.39 (d, 1H), 13.42 (br. s, 1H). 2-[(3R)—3—methy|morpho|in—4-yl]—4—(4—methylthiophen—Z—yI)(1H—pyrazol— —yl)—1,7—naphthyridine 1H-NMR (400MHz, DMSO—d6): d [ppm]: 1.28 (d, 3H), 2.25 (s, 3H), 2.54 (s, 3H), 3.24- 3.31 (m, 1H), 3.52 - 3.63 (m, 1H), 3.68 - 3.74 (m, 1H), 3.77 - 3.84 (m, 1H), 3.99 -4.09 (m, 1H), 4.16 -4.25 (m, 1H), 4.55 -4.67 (m, 1H), 6.79 - 6.84 (m, 1H), 7.28 (d, 1H), 7.36 (s, 1H), 7.42 (s, 1H), 7.63 (s, 1H), 8.32 (d, 1H), 13.41 (br. s, 1H). 4—(2,5—dimethylthiophen—3—yl)—2—[(3R)—3—methy|morpholin—4—y|]—8—(1H— pyrazoI-S-y|)—1,7-naphthyridine 1H—NMR (400MHz, 6): 0) [ppm]: 1.22 - 1.36 (m, 3H), 1.86 - 2.03 (m, 2H), 2.11 (t, 2H), 2.63 — 2.78 (m, 2H), 2.95 — 3.08 (m, 2H), 3.22 — 3.32 (m, 1H), 3.36 - 3.44 (m, 1H), 3.57 (td, 1H), 3.71 (dd, 1H), 3.82 (d, 1H), 3.99 - 4.12 (m, 1H), 4.20 (d, 1H), 4.59 - 4.71 (m, 1H), 7.30 (s, 1H), 7.36 (d, 1H), 7.62 (d, 1H), 7.85 (d, 1H), 8.37 (d, 1H), 13.34 (br. s., 1H). 2—[(3R)—3-methy|morpho|in—4—y|]—8—(1H-pyrazoI—S—yl)—4—(tetrahydro—2H— thiopyran-4—yI)—1,7—naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.27 (d, 3H), 2.33 (s, 3H), 2.36 (m, 2H), 2.60 (t, 2H), 3.16 (br. s., 2H), 3.25 - 3.32 (m, 1H), 3.55 (td, 1H), 3.66 - 3.73 (m, 1H), 3.77 - 3.86 (m, 1H), 4.03 (dd, 1H), 4.14- 4.21 (m, 1H), 4.57 - 4.68 (m, 1H), 5.90 (dt, 1H), 7.30 (s, 1H), 7.38 (br. s., 1H), 7.62 (d, 2H), 8.34 (d, 1H), 13.38 (br. s., 1H). 2-[(3R)—3—methy|morpho|in—4-y|]-4—(1—methyI—1,2,5,6—tetrahydropyridin-3— y|)—8—(1H—pyrazoI—S—yl)—1,7—naphthyridine [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H—NMR (400MHz, METHANOL—d4): d [ppm]: 1.38 (d, 3H), 2.49 (s, 3H), 2.57 - 2.63 (m, 2H), 2.83 (t, 2H), 3.20 - 3.26 (m, 2H), 3.40 - 3.51 (m, 1H), 3.64 — 3.73 (m, 1H), 3.79 — 3.92 (m, 2H), 4.06 — 4.17 (m, 2H), 4.53 — 4.63 (m, 1H), 5.86 - 5.91 (m, 1H), 7.26 (s, 1H), 7.32 (s, 1H), 7.64 - 7.68 (m, 1H), 7.71 (d, 1H), 8.32 (d, 1H). 2—[(3R)—3—methy|morpho|in—4-y|]—4—(1—methyI—1,2,3,6—tetrahydropyridin—4— y|)-8—(1H-pyrazoI—5-y|)-1,7—naphthyridine 1H-NMR (400MHz, DMSO—d6): d [ppm]: 1.27 (dd, 3H), 1.62 (td, 1H), 1.71 - 1.81 (m, 2H), 1.88 (d, 1H), 1.99 - 2.09 (m, 1H), 2.18 (td, 1H), 2.24 (d, 3H), 2.79 - 2.92 (m, 2H), 3.24 - 3.31 (m, 1H), 3.41 - 3.51 (m, 1H), 3.57 (td,1H), 3.72 (dd, 1H), 3.83 (d, 1H), 4.05 (dd, 1H), 4.16 (d, 1H), 4.57 - 4.65 (m, 1H), 7.32 - 7.38 (m, 2H), 7.62 (d, 1H), 7.79 (d, 1H), 8.38 (d, 1H), 13.33 (br. s., 1H). 2-[(3R)—3—methy|morpho|in—4-y|]-4—[1—methy|piperidin—3—yI](1H—pyrazol— —yl)—1,7—naphthyridine 1H-NMR (400MHz, DMSO-d6): d [ppm]: 1.21 - 1.30 (m, 4H), 2.34 - 2.40 (m, 1H), 2.41 - 2.48 (m, 1H), 2.97 - 3.02 (m, 1H), 3.25 - 3.31 (m, 1H), 3.40 - 3.46 (m, 2H), 3.50 - 3.60 (m, 1H), 3.66 - 3.74 (m, 1H), 3.78 - 3.85 (m, 1H), 3.99 - 4.07 (m, 1H), 4.12 - 4.21 (m, 1H), 4.56 - 4.64 (m, 1H), 5.86 - 5.93 (m, 1H), 7.27 (d, 1H), 7.38 (s, 1H), 7.58 - 7.68 (m, 2H), 8.33 (d, 1H), 13.38 (br. s, 1H). )—3-methy|morpho|in-4—y|]-8—(1H—pyrazoI-5—y|)-4—(1,2,3,6- tetrahydropyridin—4-yl)—1,7—naphthyridine 1H-NMR (400MHz, DMSO—d6): d [ppm]: 1.29 (d, 3H), 1.64 - 1.93 (m, 2H), 2.04 - 2.19 (m, 2H), 3.19 - 3.27 (m, 2H), 3.36 - 3.43 (m, 1H), 3.53 - 3.64 (m, 1H), 3.68 - 3.77 (m, 1H), 3.78 - 3.90 (m, 3H), 4.02 -4.10 (m, 1H), 4.10 - 4.18 (m, 1H), 4.19 -4.29 (m, 1H), 4.56 -4.68 (m, 1H), 6.54 (d, 1H), 7.16 (d, 1H), 7.45 (br. s., 1H), 7.56 (s, 1H), 7.64- 7.68 (m, 1H), 7.74 (d, 1H), 8.35 (d, 1H), 13.45 (br. s., 1H). 2-[(3R)—3—methy|morpho|in—4—yI]—8—(1H-pyrazoI—S—yI)—4—[1—(tetrahydro—2H— pyran—4—yl)-1H—pyrazoI—3—yl]—1,7-naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.30 (s, 3H), 3.34 -3.41 (m, 1H), 3.51 - 3.63 (m, 1H), 3.68 - 3.75 (m, 1H), 3.80 - 3.87 (m, 1H), 4.01 - 4.09 (m, 1H), 4.17 - 4.26 (m, 1H), 4.59 - 4.67 (m, 1H), 7.21 - 7.27 (m, 1H), 7.43 (s, 1H), 7.60 (dd, 1H), 7.65 (d, 2H), 8.32 (d, 1H), 8.51 (d, 1H), 13.44 (br. s, 1H). 4—(4,6—difluoropyridin—3—yI)—2—[(3R)—3—methy|morpholin—4—yl]—8—(1H— pyrazoI-S-y|)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.29 (d, 3H), 3.30 - 3.38 (m, 1H) 3.52 - 3.62 (m, 1H), 3.72 (dd, 1H), 3.80 - 3.87 (m, 1H), 3.97 (s, 3H), 4.06 (dd, 1H), 4.21 (d, 1H), 4.65 (d, 1H), 7.40 (s, 1H), 7.45 (s, 1H), 7.63 (s, 1H), 7.84 (d, 1H), 7.98 (s, 1H), 8.31 - 8.40 (m,2H), 13.41 (br. s., 1H). 2—[(3R)—3-methy|morpho|in—4—yl]—4—(1—methyI—1H-pyrazoI—4—y|)-8—(1H- pyrazoI—S—y|)—1,7—naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.28 (d, 3H), 2.17 (s, 3H), 3.27 - 3.40 (m,1H), 3.53 - 3.63 (m, 1H), 3.72 (dd, 1H), 3.83 (d, 1H), 3.89 (s, 3H), 4.01 - 4.09 (m, 1H), 4.19 (d, 1H), 4.60 (d, 1H), 7.34 (s, 1H), 7.41 (s, 1H), 7.52 (d, 1H), 7.63 (5, 1H), 8.01 (s, 1H), 8.34 (d, 1H), 13.41 (br. s., 1H). 4-(1,3—dimethyl—1H-pyrazoI—4—yI)—2—[(3R)—3—methylmorpholin-4—y|]—8—(1H— pyrazoI—S—yl)—1,7—naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.29 (d, 3H), 2.27 (s, 3H), 3.29 - 3.33 (m, 1H), 3.58 (td, 1H), 3.72 (dd, 1H), 3.83 (d, 1H), 3.87 (s, 3H), 4.05 (dd, 1H), 4.19 (d, 1H), 4.60 (d, 1H), 7.30 (s, 1H), 7.42 (br. s., 1H), 7.49 (d, 1H), 7.64 (br. s., 1H), 7.65 (s, 1H), 8.33 (d, 1H), 13.41 (br. s., 1H). 4—(1,5—dimethyl—1H—pyrazoI—4—yI)—2—[(3R)—3—methylmorpholin—4—y|]—8—(1H— pyrazoI-S-yl)-1,7-naphthyridine 1H—NMR (400MHz, CHLOROFORM—d): d [ppm]: 1.38 - 1.46 (m, 4H), 1.77 - 1.87 (m, 2H), 1.96 - 2.06 (m, 2H), 2.94 (t, 2H), 3.27 - 3.39 (m, 2H), 3.53 (td, 1H),3.72(td,1H),3.82 - 4.05 (m, 3H), 4.18 (dd, 1H), 4.36 - 4.47 (m, 1H), 7.12 (s, 1H), 7.28 (d, 1H), 7.61 (d, 1H), 7.71 (d, 1H), 8.43 - 8.49 (m, 1H). 2—[(3R)—3—methy|morpho|in—4-y|]—4—(piperidin—4—yl)—8—(1H—pyrazoI—S—yl)—1,7— naphthyridine 1H—NMR z, DMSO—d6): d [ppm]: 1.28 (d, 3H), 3.36 - 3.44 (m, 1H), 3.58 (td, 1H), 3.72 (dd, 1H), 3.82 (d, 1H), 4.05 (dd, 1H), 4.18 (d, 1H), 4.56 (d, 1H), 7.27 (d, 1H), 7.41 (s, 1H), 7.44 (s, 1H), 7.64 - 7.66 (m, 1H), 8.33 (s, 2H),13.41(br.s.,1H),14.11(br.s.,1H). 2-[(3R)—3—methy|morpho|in—4-y|]—8—(1H—pyrazoI—5-y|)—4—[3— (trifluoromethyI)—1H—pyrazoI—4-yl]—1,7—naphthyridine 1H—NMR (400MHz, CHLOROFORM—d): d [ppm]: 1.46 (d, 3H), 1.90 - 2.03 (m, 2H), 2.56 - 2.72 (m, 4H), 3.57 (td, 1H), 3.74 (td, 1H), 3.86 - 3.98 (m, 2H), 4.04 (dd, 1H), 4.20 (dd, 1H), 4.46 (dd, 1H), 4.91 (dd, 1H), 7.16 (s, 1H), 7.32 (d, 1H), 7.73 (d, 1H), 7.74 (d, 1H), 7.80 (s, 1H), 7.85 (s, 1H), 8.46 (d, 1H). 4—(1—cyclobutyI—1H—pyrazoI—4—yI)—2—[(3R)—3—methylmorpholin—4—yl]—8—(1H— pyrazoI-S-yl)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H—NMR (400MHz, 6): d [ppm]: 1.00 - 1.08 (m, 2H), 1.14 - 1.20 (m, 2H), 1.28 (d, 3H), 3.34 (s, 1H), 3.51 -3.61 (m, 1H), 3.68 -3.75 (m, 1H), 3.80 — 3.89 (m, 2H), 4.02 — 4.08 (m, 1H), 4.16 — 4.23 (m, 1H), 4.60 — 4.69 (m, 1H), 7.39 (s, 1H), 7.45 (s, 1H), 7.63 (d, 1H), 7.83 (d, 1H), 7.97 (d, 1H), 8.36 (d, 1H), 8.41 (s, 1H), 13.38 (br. s, 1H). 4—(1—cyclopropyI—1H-pyrazoI—4-yI)—2—[(3R)—3—methylmorpholin—4—y|]—8-(1H— pyrazoI—S-y|)—1,7—naphthyridine 1H-NMR z, DMSO—d6): 6 [ppm]: 1.29 (d,3H), 1.52 (d, 6H), 3.29 - 3.39 (m, 1H), 3.52 - 3.62 (m, 1H), 3.68 - 3.76 (m, 1H), 3.80 - 3.87 (m, 1H), 4.01 - 4.09 (m, 1H), 4.16 - 4.24 (m, 1H), 4.57 - 4.69 (m, 2H), 7.39 (s, 1H), 7.45 (s, 1H), 7.62 (s, 1H), 7.85 (d, 1H), 7.98 (s, 1H), 8.34 - 8.41 (m, 2H), 13.38(br.s,1H). 2—[(3R)—3—methy|morpho|in—4-yl]—4—[1—(propan—2—yI)—1H—pyrazoI—4—y|]—8— (1H—pyrazoI-S—y|)—1,7-naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.29 (d, 3H), 3.29 - 3.40 (m, 1H), 3.51 - 3.61 (m, 1H), 3.68 - 3.75 (m, 1H), 3.81 - 3.87 (m, 1H), 4.02 -4.08 (m, 1H), 4.19 - 4.26 (m, 1H), 4.62 - 4.70 (m, 1H), 7.40 (s, 1H), 7.57 (s, 1H), 7.64 (s, 1H), 7.74 (d, 1H), 7.88 (t, 1H), 8.33 (s, 1H), 8.38 (d, 1H), 8.85 (s, 1H), 13.41 (br. s, 1H). 4—[1-(difluoromethyl)—1H—pyrazol-4—y|]-2—[(3R)methy|morpholiny|]—8— (1H—pyrazoI—S—y|)—1,7—naphthyridine 1H-NMR (400MHz, DMSO—d6): d [ppm]: 1.30 (d, 3H), 1.63 (s, 9H), 3.34 - 3.39 (m, 1H), 3.58 (td, 1H), 3.73 (dd, 1H), 3.85 (d, 1H), 4.07 (dd, 1H), 4.21 (d, 1H), 4.67 (d, 1H), 7.40 (br. s., 1H), 7.46 (s, 1H), 7.63 (s, 1H), 7.86 (d, 1H), 7.99 (s, 1H), 8.38 (d, 1H), 8.41 (s, 1H), 13.39 (br. s., 1H). 4—(1—tert-butyI—lH—pyrazoI—4-yl)-2—[(3R)—3-methy|morpholin—4-y|]—8—(1H- pyrazoI—S—yl)—1,7—naphthyridine 1H—NMR z, DMSO—d6): d [ppm]: 1.28 (d, 3H), 2.02 (d, 3H), 2.12 (d, 3H), 3.27 - 3.33 (m, 1H), 3.51 - 3.65 (m, 1H), 3.69 -3.76 (m, 1H), 3.78 (s, 3H), 3.79 - 3.85 (m, 1H), 4.00 - 4.11 (m, 1H), 4.20 (d, 1H), 4.53 - 4.67 (m, 1H), 7.25 (d, 1H), 7.31 (d, 1H), 7.42 (s, 1H), 7.63 (s, 1H), 8.31 (d, 1H), 13.41 (br. s., 1H). 2-[(3R)—3—methy|morpho|in—4-y|]-8—(1H-pyrazoI—S-y|)-4—(1,3,5-trimethyl- 1H—pyrazol—4—yI)—1,7—naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H—NMR (400MHz, DMSO-d6): d [ppm]: 1.27 (d, 3H), 3.28 -3.38 (m, 1H), 3.58 (td, 1H), 3.72 (dd, 1H), 3.82 (d, 1H), 4.02 - 4.11 (m, 4H), 4.17 (d, 1H), 4.50 - 4.59 (m, 1H), 7.32 (d, 1H), 7.41 (br. 5., 1H), 7.44 (s, 1H), 7.63 (br. s., 1H), 8.28 (s, 1H), 8.34 (d, 1H), 13.41 (br. s., 1H). 2—[(3R)—3-methy|morpho|in—4—y|]-4—[1—methyI—3-(trifluoromethyI)—1H— pyrazoI—4—y|]—8—(1H—pyrazo|—5—y|)—1,7—naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.29 (d, 3H), 3.34 - 3.40 (m, 1H), 3.58 (td,1H),3.69 - 3.75 (m, 1H), 3.80 - 3.87 (m, 3H), 4.06 (dd, 1H), 4.21 (d, 1H), 4.27 (t, 2H), 4.65 (d, 1H), 5.00 (br. s., 1H), 7.39 (s, 1H), 7.45 (s, 1H), 7.64 (d, 1H), 7.86 (d, 1H), 8.01 (s, 1H), 8.34 (s, 1H), 8.37 (d, 1H), 13.37 (br. ., 1H). 2-(4—{2—[(3R)-3—methy|morpholin—4—y|]—8-(1H—pyrazoI—S—yI)—1,7— naphthyridin—4—y|}—1H—pyrazol—1—y|)ethanol 1H-NMR (400MHz, DMSO—d6): d [ppm]: 1.29 (d, 3H), 1.48 (t, 3H), 3.33 - 3.40 (m, 1H), 3.53 - 3.62 (m, 1H), 3.69 - 3.76 (m, 1H), 3.80 - 3.88 (m, 1H), 4.02 - 4.10 (m, 1H), 4.17 - 4.23 (m, 1H), 4.26 (q, 2H), 4.61 -4.70 (m, 1H), 7.40 (s, 1H), 7.46 (s, 1H), 7.63 (s, 1H), 7.85 (d, 1H), 7.99 (s, 1H), 8.35 - 8.40 (m, 2H), 13.39 (br. s, 1H). 4—(1—ethyI—1H—pyrazoI—4—yI)—2—[(3R)—3—methy|morpholin—4—yl]—8—(1H— pyrazoI-S-y|)—1,7-naphthyridine 1H—NMR (400MHz, DMSO—d6): 0) [ppm]: 1.27 (d, 3H), 3.25 - 3.32 (m, 1H), 3.52 — 3.61 (m, 1H), 3.68 — 3.77 (m, 4H), 3.81 (s, 1H), 4.01 - 4.08 (m, 1H), 4.14 - 4.21 (m, 1H), 4.57 - 4.66 (m, 1H), 6.51 (dd, 1H), 6.94 (t, 1H), 7.31 (s, 1H), 7.34 (t, 1H), 7.38 (d, 1H), 7.62 (d, 1H), 7.97 (d, 1H), 8.34 (d, 1H), 13.12 (br. s, 1H). 2—[(3R)—3-methy|morpho|in—4—y|]—4—(1—methyI—1H-pyrroI—3—yl)-8—(1H— pyrazoI—S—yl)—1,7—naphthyridine 1H—NMR (400MHz, DMSO—d6): 0) [ppm]: 1.29 (d, 3H), 1.52 (d, 6H), 3.27 - 3.42 (m, 1H), 3.57 (td, 1H), 3.73 (dd, 1H), 3.84 (d, 1H), 4.06 (dd, 1H), 4.21 (d, 1H), 4.56 - 4.72 (m, 2H), 7.40 (s, 1H), 7.46 (s, 1H), 7.64 (d, 1H), 7.86 (d, 1H), 7.99(s,1H),8.35 - 8.42 (m, 2H), 13.40 (br. 5., 1H). 2—[(3R)—3—methy|morpho|in—4-yl]—4—[1—(propan—2—yI)—1H—pyrazoI—3—y|]—8— (1H—pyrazoI-S—y|)—1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.27 (d, 3H), 2.18 (s, 3H), 2.26 (s, 3H), 3.26 - 3.32 (m, 1H), 3.49 (s, 3H), 3.51 - 3.62 (m, 1H), 3.72 (dd, 1H), 3.82 (d, 1H), 4.05 (dd, 1H), 4.16 (d, 1H), 4.51 - 4.60 (m, 1H), 6.00 (d, 1H), 7.16 (s, 1H), 7.39 (s, 1H), 7.60 - 7.66 (m, 2H), 8.30 (d, 1H), 13.38 (br. 5., 1H). )—3—methy|morpho|in—4-y|]—8—(1H—pyrazoI—S-y|)—4—(1,2,5—trimethyl— 1H—pyrroI—3-yI)—1,7-naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.32 (d, 3H), 3.36 - 3.43 (m, 1H), 3.59 (td, 1H), 3.74 (dd, 1H), 3.86 (d, 1H), 4.08 (dd, 1H), 4.24 (d, 1H), 4.69 (d, 1H), 7.35 - 7.45 (m, 2H), 7.54 - 7.62 (m, 3H), 7.65 (s, 1H), 7.94 (d, 1H), 7.99 (dd, 2H), 8.32 (s, 1H), 8.40 (d, 1H), 9.10 (s, 1H), 13.43 (br. s., 1H). )—3—methy|morpho|in—4-y|]—4—(1—phenyI—1H—pyrazoI—4-yI)—8—(1H— pyrazoI—S—y|)—1,7—naphthyridine 1H-NMR (400MHz, DMSO—d6): d [ppm]: 1.29 (d, 3H), 2.26 (br. s., 3H), 3.58 (td, 1H), 3.28 - 3.39 (m, 1H), 3.72 (dd, 1H), 3.83 (d, 1H), 4.06 (dd, 1H), 4.19 (d, 1H), 4.61 (d, 1H), 7.34 (s, 1H), 7.42 (br. 5., 1H), 7.51 (d, 1H), 7.63 (s, 1H), 7.69 - 7.87 (m, 1H), 8.34 (d, 1H), 13.02 (br. s., 1H), 13.41 (br. s., 1H). 2—[(3R)—3—methy|morpho|in—4—yl]—4—(3—methy|—1H—pyrazoI—4—yI)—8—(1H— pyrazoI-S-y|)—1,7-naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.23 (d, 3H), 3.24 (td, 1H), 3.55 (td, 1H), 3.70 (dd, 1H), 3.81 (d, 1H), 3.92 (d, 1H), 4.03 (dd, 1H), 4.34 (dd, 1H), 6.36 (s, 1H), 6.73 (s, 2H), 7.30 (s, 1H), 7.58 (s, 1H), 7.83 (d, 1H), 8.24 (d, 1H), 13.40 (br. s.,1H). 2—[(3R)—3—methy|morpho|in—4-y|]—8—(1H—pyrazoI—S-yl)—1,7—naphthyridin-4— amine 1H—NMR (400MHz, CHLOROFORM—d): d [ppm]: 1.01 (d,6H), 1.46 (d,3H), 2.33 (dt,1H),3.51 - 3.61 (m, 1H), 3.72 (td, 1H), 3.84 - 3.90 (m, 1H), 3.90 - 3.97 (m, 1H), 3.99 - 4.08 (m, 3H), 4.18 (dd, 1H), 4.42 - 4.50 (m, 1H), 7.15 (s, 1H), 7.31 (d, 1H), 7.69 (d, 1H), 7.71 - 7.75 (m, 2H), 7.81 (s, 1H), 8.44 (d, 1H). 2—[(3R)—3—methy|morpho|in—4-y|]—4—[1—(2-methylpropyI)—1H-pyrazoI—4—y|]—8— (1H—pyrazol-5—yl)—1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H—NMR z, DMSO—d6): d [ppm]: 1.29 (d, 3H), 3.30 - 3.38 (m, 1H), 3.53 - 3.62 (m, 1H), 3.73 (dd, 1H), 3.84 (d, 1H), 4.03 - 4.09 (m, 1H), 4.21 (d, 1H), 4.66 (d, 1H), 7.41 (s, 1H), 7.47 (s, 1H), 7.63 (s, 1H), 7.84 (d, 1H), 8.03 (s, 1H), 8.37 (d, 2H), 13.37 (br. s., 1H), 13.41 (br. s., 1H). )—3-methy|morpho|in—4—y|]-4—(1H—pyrazoI—4—y|)-8—(1H—pyrazoI—5—y|)- 1,7—naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 1.31 (d, 3H), 3.40 - 3.44 (m, 1H), 3.55 - 3.64 (m, 1H), 3.71 - 3.77 (m, 1H), 3.82 - 3.87 (m, 1H), 4.03 - 4.11 (m, 1H), 4.19 - 4.25 (m, 1H), 4.62 - 4.69 (m, 1H), 7.40 (br. s., 1H), 7.64 (br. s., 1H), 7.68 (d, 1H), 8.00 (s, 1H), 8.47 (d, 1H), 8.49 (d, 1H), 8.82 (d, 1H), 13.44 (br. s., 1H). 2-[(3R)—3—methy|morpho|in—4-y|]—4—(1,3-oxazol—2—yI)-8—(1H—pyrazoI—5—y|)- 1,7—naphthyridine 1H-NMR (400MHz, DMSO—d6): d [ppm]: 2.16 (s, 3H), 3.72 -3.84 (m, 8H), 3.88 (s, 3H), 7.35 - 7.43 (m, 2H), 7.50 (d, 1H), 7.63 (br. s., 1H), 8.00 (s, 1H), 8.34 (d, 1H), 13.40 (br. s., 1H). 4—(1,3—dimethyl—1H—pyrazoI—4—yI)—2—(morpholin—4—yI)—8—(1H—pyrazoI—5—yl)— 1,7-naphthyridine 1H—NMR (400MHz, 6): d [ppm]: 2.25 (s, 3H), 3.71 -3.82 (m, 8H), 3.86 (s, 3H),7.35 (5,1H), 7.40(br. s., 1H), 7.48 (d, 1H), 7.64(s, 2H), 8.33 (d,1H),13.40(br.s.,1H). 4-(1,5—dimethyl—1H-pyrazoI—4-yl)-2—(morpho|in—4—yI)-8—(1H—pyrazoI—5-yl)- 1,7—naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 2.00 (s, 3H), 2.10 (s, 3H), 3.71 - 3.86 (m, 11H), 7.24 (d, 1H), 7.36 (s, 1H), 7.41 (br. s., 1H), 7.64 (s, 1H), 8.32 (d, 1H). 2—(morpholin—4—yI)—8-(1H—pyrazoI—S—yI)—4-(1,3,5—trimethyl—1H—pyrazoI—4—yl)— 1,7-naphthyridine The following compounds of Table 3 were prepared according to Scheme 6 and in analogy to e 126.

Table 3 Structure [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400MHz, DMSO-d6): d [ppm]: 1.25 (d, 3H), 3.23 - 3.29 (m, 1H), 3.30 (s, 3H), 3.35 - 3.41 (m, 1H), 3.43 (d, 2H), 3.56 (td, 1H), 3.67 - 3.74 (m, 1H), 3.78 — 3.92 (m, 5H), 3.95 — 4.08 (m, 2H), 4.34 — 4.47 (m, 1H), 6.81 (d, 1H), 7.35 (s, 1H), 7.60 (s, 1H), 7.87 (d, 1H), 8.29 (d, 1H), 13.36 (br. s., 1H). 4—{[(2—methoxyethyl)(methyl)oxido—?»6-suIfanylidene]amino}—2—[(3R)-3— methylmorpholin-4—y|]—8—(1H—pyrazoI-S—yI)—1,7-naphthyridine lH—NMR (400MHz, DMSO—d6): d [ppm]: 0.94 (dd, 3H), 1.31 (dd, 3H), 1.48 (q, 3H), 3.03 - 3.15 (m, 1H), 3.41 -3.52 (m, 1H), 3.53 - 3.92 (m, 4H), 3.93 - 4.10 (m, 2H), 6.45 (d, 1H), 7.26 - 7.32 (m, 1H), 7.58 (s, 1H), 7.79 (t, 2H), 7.84 - 7.91 (m, 2H), 8.06 (q, 1H), 8.36 (d, 1H), 13.29 (br. s, 1H). 4—{[(4—bromophenyl)(oxido)propan—2—yI-?L5—suIfanylidene]amino}—2— [(3R)—3—methy|morpho|in—4—y|]—8—(1H—pyrazoI—S—yI)—1,7—naphthyridine 1H—NMR (400MHz, DMSO—d6): d [ppm]: 0.80 - 1.18 (m, 3H), 3.61 - 3.66 (m, 1H ), 3.69 (s, 4H), 3.72 -3.89 (m, 2H), 3.93 -4.04 (m, 2H), 4.05 -4.13 (m, 1H), 6.42 (d, 1H), 6.83 - 6.94 (m, 1H), 6.96 - 7.05 (m, 1H), 7.24 - 7.30 (m, 1H ), 7.40 - 7.50 (m, 1H), 7.56 (s, 1H), 7.91 - 8.00 (m, 2H), 8.26 -8.30 (m, 1H), 11.28 (br. s, 1H). 2—(methyl—N—{Z-[(3R)—3-methy|morpholin—4—yl]-8—(1H—pyrazol—5—y|)-1,7— naphthyridin—4—y|}sulfonimidoyl)phenol 1H-NMR (400MHz, DMSO-d6): d [ppm]: 0.81 (d, 1H), 1.17 (d, 2H), 3.06 - 3.18 (m, 1H), 3.42 - 3.54 (m, 1H), 3.55 - 3.67 (m, 1H), 3.68 - 3.79 (m, 4H), 3.81 - 3.92 (m, 1H), 3.93 -4.03 (m, 1H), 4.09 - 4.18 (m, 1H), 6.49 (d, 1H), 7.29 (d, 1H), 7.57 (s, 1H), 7.84 - 7.90 (m, 2H), 7.91 - 7.99 (m, 2H), 8.03 (dd, 1H), 8.34 (dd, 1H), 13.31 (br. s, 1H). 4—{[(4—bromophenyl)(methyl)oxido—K6-suIfanylidene]amino}—2—[(3R)-3— methylmorpholin-4—y|]—8—(1H—pyrazoI-S—yI)—1,7-naphthyridine lH—NMR (400MHz, DMSO—d6): d [ppm]: 1.22 - 1.29 (m, 3H), 1.55 (d, 9H), 3.25 - 3.30 (m, 1H), 3.32 (s, 3H), 3.52 - 3.62 (m, 1H), 3.72 (dd, 1H), 3.80 - 3.86 (m, 1H), 3.94 - 4.09 (m, 2H), 4.33 - 4.48 (m, 1H), 6.83 - 6.93 (m, 1H), 7.29 - 7.37 (m, 1H), 7.60 (d, 1H), 7.84 (d, 1H), 8.29 (d, 1H), 13.15 - 13.44 (m, 1H). 4—{[tert—butyl(methyl)oxido—7L6—sulfa nylidene]amino}—2—[(3R)—3— methylmorpholinyl]-8—(1H-pyrazol-S-y|)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400MHz, DMSO-d6): d [ppm]: 3.59 - 3.67 (m, 6H), 3.77 - 3.86 (m, 6H), 3.96 (t, 2H), 4.13 - 4.20 (m, 2H), 6.84 (s, 1H), 7.35 (d, 1H), 7.61 (d, 1H), 7.98 (d, 1H), 8.17 (s, 1H), 8.33 (d, 1H). formic acid — N—[2—(morpholin—4—yl)—8—(1H—pyrazoI—5—yl)—1,7- naphthyridin—4—y|]—1,4?»4—oxathian—4—imine 4—oxide (1:1) lH—NMR (400MHz, DMSO—d6): d [ppm]: 1.55 - 1.75 (m, 2H), 1.85 - 2.07 (m, 4H), 3.42 - 3.53 (m, 2H), 3.62 (t, 4H), 3.71 (d, 2H), 3.76 - 3.84 (m, 4H), 6.82 (s, 1H), 7.36 (s, 1H), 7.60 (s, 1H), 7.95 (d, 1H), 8.32 (d, 1H), 13.37 (5,1H).

N-[2—(morpholin—4-yl)—8—(1H-pyrazol—5-y|)—1,7—naphthyridin-4— yl]hexahydro—1K4—thiopyran—1—imine 1—oxide Example 281 3-methyl{2-[(3R)methy|morphoIin-4—yl](1H-pyrazolyl)-1,7-naphthyridinyl}butan Step a: 2-[(3R)—3-methy|morpho|inyl]{1-[(2R)-tetrahyd ro-ZH-pyrany|]-1H-pyrazol-S-y|}-1,7- naphthyridine-4—carboxylic acid Methyl 2—[(3R)—3-methylmorpho|in-4—yl]—8-{1—[(2R)—tetrahydro—2H—pyran—2—yl]—1H—pyrazoI—5—yl}— 1,7-naphthyridinecarboxylate (1.10 g, 2.51 mmol) was solubilized in THF (11 mL) and ol (5 mL9). NaOH solution (2.8 ml, 1.0 M, 2.8 mmol) was added and the mixture was stirred for 10 min at rt. The solvent was removed under reduced pressure and the aqueous phase was acidified to pH 5 using 1M HCI. The aquoueous solution was lised and the title compound was obtained without further purification in 99% yield (1.10 g). 1H-NMR (400MHz, DMSO-d6): d [ppm]: 1.18 (dd, 3H), 1.37 - 1.49 (m, 2H), 1.51 - 1.64 (m, 1H), 1.88 - 2.03 (m, 2H), 2.29 - 2.40 (m, 1H), 3.09 - 3.19 (m, 1H), 3.19 - 3.28 (m, 1H), 3.41 - 3.51 (m, 1H), D58 - 3.65 (m, 1H), 3.66 - 3.78 (m, 2H), 3.89 - 4.00 (m, 1H), 4.06 (t, 1H), 4.36 - 4.51 (m, 1H), 5.92 - ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 6.08 (m, 1H), 6.84 (dd, 1H), 7.48 (d, 1H), 7.60 (s, 1H), 8.32 (d, 1H), 8.46 - 8.53 (m, 1H).

Step b: N-methoxy-N-methyl[(3R)methy|morpholiny|]{1-[(2R)-tetrahydro-ZH-pyran-Z-yll-lH- pyrazol-S-y|}-1,7-naphthyridinecarboxamide N-methoxymethanamine hydrochloride (1:1) (861 mg, 8.83 mmol) was solubilized in DMF (20 mL).

N,N—Diisopropylethylamin (3.1 ml, 18 mmol) and HATU (2.52 g, 6.62 mmol) were added and the mixture stirred for 10 min at rt. 2-[(3R)—3-Methylmorpholin-4—yl]—8—{1-[(2R)-tetrahydro-2H-pyran- 2-yl]—1H-pyrazo|yl}—1,7-naphthyridine—4—carboxylic acid (1.10 g, 85 % purity, 2.21 mmol) was then added and the mixture stirred 16h at rt. N,N-Diisopropylethylamin (3.1 ml, 18 mmol) and HATU (2.52 g, 6.62 mmol) were added again and the reaction stirred for 16h at rt.Water was added and the mixture was stirred for 10 min. The aqueous phase was extracted with EtOAc and the combined c layers were washed with half sat. NaCl-solution. The organic layer was dried over a silicone filter and concentrated under reduced pressure. The crude al was purified by flash column chromatograpy ( from Ac: 0-100% to 100% EtOAc to EtOAc/EtOH: 0—20%) and the title compound was obtained in quantitative yield. 1H-NMR z, DMSO-d6): d [ppm]: 1.19 - 1.25 (m, 3H), 1.41 - 1.54 (m, 2H), 1.54 - 1.66 (m, 1H), 1.92 — 1.99 (m, 2H), 2.69 (s, 2H), 3.15 - 3.32 (m, 2H), 3.42 (br. 5., 3H), 3.50 (br. 5., 3H), 3.60 - 3.72 (m, 2H), 3.72 - 3.80 (m, 1H), 3.93 - 4.01 (m, 1H), 4.12 - 4.22 (m, 1H), 4.46 - 4.57 (m, 1H), 6.04 - 6.17 (m, 1H), 6.97 (dd, 1H), 7.44 (d, 1H), 7.58 - 7.67 (m, 2H), 8.41 (d, 1H).

Step c: 1-(2-[(3R)methy|morpholiny|]{1-[(2R)—tetrahyd ro-2H-pyran-Z-yl]-1H-pyrazoly|}-1,7- naphthyridin-4—y|)ethanone ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp N—methoxy—N—methyl—2-[(3R)—3—methy|morpho|in—4-yl]—8—{1-[(2R)—tetrahydr0—2H-pyranyl]—1H- pyrazolyl}—1,7-naphthyridinecarboxamide (710 mg, 1.52 mmol) was solubilized in THF and cooled to 0°C. Methylmagnesium bromide (1.5 ml, 3.0 M, 4.6 mmol)was added dropwise and the on was stirred at 0°C for 30 min. and 1.5 h at rt. Methylmagnesium bromide (1.5 ml, 3.0 M, 4.6 mmol) was added again and the reaction was stirred for 16h. The reaction was quenched with sat. NH4C| and extracted with DCM. The organic phase was filtred and concentrated under reduced pressure. The title compound was used without further purification. 1H-NMR (400MHz, DMSO-d6): d [ppm]: 1.23 (dd, 3H), 1.40 - 1.48 (m, 2H), 1.53 — 1.64 (m, 1H), 1.95 — 2.00 (m, 1H), 2.32 - 2.40 (m, 1H), 2.69 (s, 3H), 2.78 (s, 2H), 3.19 — 3.30 (m, 2H), 3.64 — 3.73 (m, 2H), 3.75 - 3.81 (m, 1H), 3.95 - 4.02 (m, 1H), 4.14 - 4.21 (m, 1H), 4.55 - 4.63 (m, 1H), 5.97 — 6.07 (m, 1H), 6.88 (dd, 1H), 7.63 (t, 1H), 7.85 (d, 1H), 7.95 (d, 1H), 8.42 (d, 1H).

Step cl: yl{2-[(3R)methy|morphoIin-4—yl](1H-pyrazoly|)-1,7-naphthyridin-4—yl}butan 1-(2—[(3R)methylmorpholin—4-yl]{1—[(2R)-tetrahydro—2H-pyranyl]-1H-pyrazo|—5-y|}-1,7— naphthyridin—4-yl)ethanone (33.0 mg, 78.3 umol) was solubilized in THF (2.0 mL) and the mixture was cooled to 0°C. Chloro(propanyl)magnesium (120 pl, 2.0 M, 230 umol) was added dropwise.

The mixture was stirred at 0°C 0.5h and 1.5h at rt. The reaction mixture was quenched with water and of 3M aq. HCI (0.5 mL) was added. The mixture was stirred for 16h at rt. The reaction was quenched with NaHC03 and extracted with DCM. The c phase was dried over a ne filter and concentrated under reduced pressure. The crude material was purified by preparative HPLC [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (ACN/HZO/NH4OH mixture) and the title compound was obtained in 27% yield (9 mg). 1H-NMR (400MHz, DMSO-d6): 6 [ppm]: 0.75 - 0.89 (m, 6H), 1.26 (d, 3H), 1.63 (d, 3H), 3.59 (t, 1H), 3.71 - 3.78 (m, 1H), 3.80 - 3.88 (m, 1H), 4.03 - 4.16 (m, 2H), 4.50 - 4.60 (m, 1H), 5.39 (d, 1H), 7.35 (s, 1H), 7.43 (s, 1H), 7.60 (s, 1H), 8.27 - 8.32 (m, 2H), 13.34 (br. s., 1H).

Example 282 1-{2-[(3R)methy|morpholinyl](1H-pyrazo|y|)-1,7-naphthyridiny|}(tetrahydro-ZH- 4—yl)ethano| 1—(2—[(3R)—3—methylmorpholin—4—yl]-8—{1—[(2R)—tetrahydro—2H-pyran—2-yl]—1H—pyrazol—5-yI}-1,7— naphthyridin—4-yl)ethanone (33.0 mg, 78.3 umol) was solubilized in THF (2.0 mL) and the e was cooled to 0°C. Chloro(tetrahydro—2H-pyran—4-yl)magnesium (1.4 ml, 0.50 M, 710 umol) was added dropwise. The mixture was stirred at 0°C 0.5h and 1.5h at rt. The mixture was cooled to 0°C and ch|oro(tetrahydro—2H-pyran—4-yl)magnesium (1.4 ml, 0.50 M, 710 umol) was again added. The reaction was stirred at 0°C for 30 min and 45 at rt. The reaction mnixture was quenched with water and of 3M aq. HCl (0.5 mL) was added. The mixture was stirred for 72h at rt. The reaction was quenched with NaHC03 and extracted with DCM. The organic phase was dried over a silicone filter and concentrated under reduced pressure. The crude material was purified by preparative HPLC (ACN/HZO/NH4OH mixture) and the title compound was obtained in 23% yield (25 mg). 1H-NMR (400MHz, DMSO-d6): d [ppm]: 1.25 (d, 4H),1.34 - 1.45 (m, 2H), 1.45 - 1.56 (m, 1H), 1.64 - 1.68 (m, 3H), 2.24 - 2.35 (m, 1H), 3.06 - 3.24 (m, 2H), 3.26 - 3.32 (m, 1H), 3.57 (t, 1H), 3.69 - 3.90 (m, 5H), 4.02 - 4.14 (m, 2H), 4.48 - 4.58 (m, 1H), 5.48 (d, 1H), 7.33 (br. s., 1H), 7.45 (d, 1H), 7.60 (s, 1H), 8.24 - 8.34 (m, 2H), 13.33 (br. s., 1H).

Example 283 3,3-dimethyl{2-[(3R)methy|morpho|in-4—yl](1H-pyrazo|y|)-1,7-naphthyridin-4— y|}butano| [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (3R)-3—methylmorpholin—4-yl]{1—[(2R)-tetrahydro—2H-pyranyl]-1H-pyrazo|—5-yl}-1,7— naphthyridin—4-yl)ethanone (33.0 mg, 78.3 umol) was solubilized in THF (2.0 mL) and the e was cooled to 0°C. tert-butyl(chloro)magnesium (710 pl, 1.0 M, 710 umol) was added dropwise. The mixture was stirred at 0°C 0.5h and 1.5h at rt. The reaction mixture was quenched with water and of 3M aq. HCI (0.5 mL) was added. The mixture was stirred for 72h at rt. The on was quenched with NaHC03 and extracted with DCM. The organic phase was dried over a silicone filter and concentrated under reduced pressure. The crude material was purified by preparative HPLC (ACN/HzO/NH4OH e) and the title compound was obtained in 24% yield (25 mg). 1H—NMR (400MHz, DMSO-d6): d [ppm]: 0.94 (s, 9H), 1.14 - 1.30 (m, 3H), 1.70 (s, 3H), 3.19 — 3.31 (m, 1H), 3.58 (t, 1H), 3.67 - 3.75 (m, 1H), 3.75 - 3.86 (m, 1H), 3.98 - 4.17 (m, 2H), 4.53 (br. s., 1H), .59 (s, 1H), 7.10 (br. s., 1H), 7.31 (br. s., 1H), 7.58 (s, 1H), 8.26 (d, 1H), 8.92 (br. s., 1H), 13.30 (br. s., 1H).

Example 284 2-{2-[(3R)methy|morpholiny|](1H-pyrazo|y|)-1,7-naphthyridiny|}hexano| 1-(2—[(3R)-3—methylmorpholin—4-yl]{1—[(2R)-tetrahydro—2H-pyranyl]-1H-pyrazo|—5-yl}-1,7— naphthyridin—4-yl)ethanone (33.0 mg, 78.3 umol) was solubilized in THF (2.0 mL) and the mixture was cooled to 0°C. Butyl(chloro)magnesium (360 pl, 2.0 M, 710 umol) was added dropwise. The mixture was stirred at 0°C 0.5h and 1.5h at rt. The reaction mixture was quenched with water and [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp of 3M aq. HCI (0.5 mL) was added. The mixture was stirred for 72h at rt. The reaction was quenched with NaHC03 and extracted with DCM. The organic phase was dried over a silicone filter and concentrated under reduced pressure. The crude material was purified by preparative HPLC (ACN/HZO/NH4OH mixture) and the title nd was ed in 7% yield (7 mg). 1H-NMR z, DMSO-d6): d [ppm]: 0.77 (td, 3H), 0.97 - 1.08 (m, 1H), 1.12 - 1.22 (m,3H), 1.27 (d, 4H), 1.68 (d, 3H), 1.87 - 2.00 (m, 1H), 2.02 - 2.14 (m, 1H), 3.58 (t, 1H), 3.73 (d, 1H), 3.84 (d, 1H), 4.01 - 4.16 (m, 2H), 4.55 (d, 1H), 5.47 (d, 1H), 7.35 (s, 1H), 7.47 (d, 1H), 7.61 (s, 1H), 8.22 (dd, 1H), 8.32 (d, 1H), 13.35 (br. s., 1H).

Example 285 2-[(3R)methylmorpholinyl](1H-pyrazol-3—yl)-1,7-naphthyridinecarboxamide Step 3 2-((R)methy|morpho|inyl)[2-(tetrahyd ropyran-Z-yl)-2H—pyrazo|y|]-[1,7]naphthyridine- 4-carboxamide 2-((R)methylmorpholinyl)—8-(1H-pyrazol-5—yl)-1,7-naphthyridinecarbonitrile (1.5g, 3.882 mmol) were suspended in 2—methoxyethanol (15 ml). Then KOH (0.653 g, 11.645 mmol) in water (367 (1|) were added and the reaction was stirred at 150°C for 7 hours and at 130°C for 14 hours.

The solvent was removed by lation under d pressure and the residue was crystallized from a mixture of isopropanol (5 ml) and diethylether (25 ml). The title compound was obtained by filtration as a yellow solid in 6% yield (95 mg). LC—MS (method 1): m/z: [M+H]" = 423.2, R1 = 3.01 min.

Step b 2-[(3R)—3-methy|morpho|inyl](1H-pyrazol-3—yl)-1,7-naphthyridinecarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp \ IN 074] N / \ / \_/ — To 2-((R)methylmorpholinyl)—8—[2-(tetrahydropyranyl)-2H-pyrazolyl]-[1,7]naphthy- ridine—4-carb0xamide (95 mg, 0.22 mmol) was added a drop of water and trifluoroacetic acid (1 ml, 13 mmol). After 2 hours LCMS indicated the complete removal of the protective group. The trifluoroacetic acid was removed under reduced pressure and the residue was adjusted to pH 7 by addition of aq. NaHC03 solution. The s layer was extracted with a mixture of romethane / isopropanol (10 :1, 5 x). The combined organic layers were dried over sodium sulfate and the solvent was evaporated. The residue was purified in a flashmaster chromatography (25 g of silica gel 60, 30 uM) with chloroform / methanol 90 :10 as eluent. The title nd was obtained in 19% yield (14 mg) as a yellow solid. Melting point: 145—147 0C. 1H-NMR (400 MHz, c0300): 6 [ppm] 1.41 (m, 3H), 3.49-3.52 (m, 1H), 3.65-3.71 (m, 1H), 3.82—3.91 (m, 2H), .18 (m, 2H), 4.60-4.61 (m, 1H), 7.34 (s, 1H), 7.56 (s, 1H), 7.67 (s, 1H), 7.86—7.87 (m, 1H), 8.37-8.38 (m, 1H). LC—MS (method 1): m/z: [M+H]+ = 339.2, Rt = 2.23 min. e 286 2-[(3R)—3-methy|morpholinyl]-4—[1—(methylsulfonyl)cyclopropyl](1H-pyrazolyl)-1,7- naphthyridine Step a {2-((R)methylmorpho|inyl)[2-(tetrahyd ropyran-Z-yl)—2 H-pyrazoly|]- [1,7]naphthyridiney|}methanol O\_/N To a solution of methyl((R)—3-Methy|morpholinyl)[2-(tetrahydropyranyl)-2H-pyrazol D—[IJ]naphthyridine—4-carboxylate (190.5 mg, 0.435 mmol) in absolute THF (19 ml) was added ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp diisobutylaluminium hydride solution (1M in toluene, 871 pl, 0.871 mmol) under argon at ambient temperature and the reaction was stirred for 1.5 hours at 80°C. The reaction mixture was cooled with ice, a saturated aqueous ammonium chloride solution (20 ml) was added and the aqueous layer was extracted with ethyl acetate (3 x 30 ml). The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified in a Flashmaster chromatography (silica gel 60, 30 (1M) using form / methanol 98 : 2 as eluent.

The title compound was obtained in 66 % yield (118 mg). LC-MS (method 1): m/z: [M+H]+ = 410.3, Rt = 3.07 min.

Step b {2-[(3 R)methy|morphoIinyl][1-(tetrahydro-2H-pyran-Z-y|)-1H-pyrazoly|]-1,7- naphthyridinyl}methyl methanesulfonate O\_/N To a solution of {2-((R)Methylmorpholinyl)[2-(tetrahydropyranyl)-2H-pyrazolyl]— [1,7]naphthyridineyl}methanol (118 mg, 0.288 mmol) and hylamine (52 ul, 0.375 mmol) in absolute THF (5 ml) was added dropwise under argon at 0°C methansulfonyl chloride (25 ul, 0.317 mmol) and the reaction was allowed to stir for one hour at 0°C. With intervals of two hours additional methansulfonyl chloride (3 x 25 pl, 0.317 mmol) were added and the reaction was allowed to stir for another 16 hours at ambient temperature. After addition of another portion of methansulfonyl chloride (25 ul, 0.317 mmol) the reaction was stirred at 40°C for two hours. The reaction mixture was filtered and the te was evaporated. The title nd was obtained in tative yield (219 mg) and used without r purification in the next step. LC-MS (method 1): m/z: [M+H]+ = 488.2, Rt = 3.32 min.

Step c )—3-methy|morpholinyl][(methylsulfonyl)methyl][1-(tetrahyd pyran-Z-yl)- 1H-pyrazolyl]-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp To a solution of {2-[(3R)methylmorpholinyl][1-(tetrahydro-2H-pyranyl)-1H-pyrazol yl]-1,7-naphthyridinyl}methyl methanesulfonate (219 mg, 0.45 mmol) in absolute DMSO (2 ml) was added nwise sodium methylsulfinate (161 mg, 1.572 mmol) and the reaction was allowed to stir at 120°C for 20 minutes. The reaction was diluted with water (10 ml) and extracted with dichloromethane (3 x 10 ml).The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by Puri—Flash chromatography (25 g of silica gel 60, 30 um) using dichloromethane / methanol 95 : 5 as eluent.

The title compound was obtained in 40% yield (84 mg) as a yellow solid. LC-MS d 1): m/z: [M+H]+ = 472.3, Rt = 3.06 min.

Step d 2-[(3R)methy|morpholinyl][1—(methylsulfonyl)cyclopropyl]-8—[1—(tetrahydro-ZH-pyran-Z- y|)-1H-pyrazol-5—yl]-1,7-naphthyridine To a solution of 2-[(3R)methylmorpho|in-4—y|]—4-[(methylsulfonyl)methyl][1—(tetrahydro-2H- pyranyl)-1H-pyrazolyl]-1,7-naphthyridine (84 mg, 0.178 mmol), 1,2—dibromoethane (15 ul, 0.178 mmol) and tetrabutylammoniumbromide (6 mg, 0.018 mmol) in absolute THF (1.68 ml) was added a NaOH solution (50% in water, 185 pi) and the reaction was stirred at t temperature for one hour. The suspension d its color to dark green / dark brown.

Additional 1,2-dibromoethane (15 ul, 0.178 mmol), tetrabutylammoniumbromide (6 mg, 0.018 mmol) and NaOH on (50% in water, 185 pl) were added and the reaction was stirred at 60°C [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp for 5 hours. The reaction was diluted with water (10 ml) and extracted with dichloromethane (3 x ml). The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure. The e was purified in a Flashmaster chromatography (25 g of silica gel 60, 30 um) using dichloromethane / methanol 95 : 5 as eluent. The title compound was obtained in 28% yield (25 mg) as yellow solid. The product was used in the next step without further purification. LC-MS (method 1): m/z: [M+H]+ = 498.3, Rt = 3.27 min.

Step e 2-[(3R)methy|morpho|inyl][1-(methylsulfonyl)cyclopropyl](1H-pyrazolyl)-1,7- naphthyridine To a on of 2-[(3R)methylmorpholinyl][1-(methylsulfonyl)cyclopropyl]—8-[1- (tetrahydro—ZH-pyran—Z-yl)—1H—pyrazo|—5—yl]-1,7—naphthyridine (25 mg, 0.05 mmol) in methanol (2 ml) was added HCI (2N in water). The reaction was stirred for 18 hours at 50°C. The LCMS indicated te l of the protective group. Methanol was removed under reduced pressure and the pH value of the e was adjusted to seven by addition of aqueous NaHC03 solution. The aqueous layer was extracted with dichloromethane (3 x 10 ml). The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure. The title compound was obtained in 73% yield (16 mg) as a yellow solid. g point: 240—248 0C. 1H-NMR (400 MHz, CDCI3): 6 [ppm] =0.06-0.09 (m, 3H), 89 (m, 1H), 1.22-1.53 (m, 1H), 1.97-2.36 (m, 2H), 2.86 (s, 3H), 3.51-3.58 (m, 1H), 3.67-3.75 (m, 1H), 3.83-3.88 (m, 1H), 3.91-3,95 (m, 1H), 3.98-4.03 (m, 1H), 4.16-4.20 (m, 1H), 4.39-4.46 (m, 1H), 7.32 (s, 1H), 7.45 (s, 1H), 7.71 (s, 1H), 7.82—7.83 (m, 1H), 8.48-8.49 (m, 1H). Lc-Ms (method 1): m/z: [M+H]+ = 414.2, R. = 2.65 min. e 287 2-(mo rpholinyl)(1H-pyrazo|y|)(tetrahyd ro-2H-pyranylmethoxy)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A e of 2-(morpholinyl)-8—[1-(tetrahydro—2H-pyranyl)-1H-pyrazo|—5-yl]—1,7- naphthyridinol (75 mg, 0.1 mmol), 4-(bromomethyl)tetrahydro-2H-pyran (26.4 mg, 147.5 umol) and cesiumcarbonate (41.6 mg, 127.8 uM) in DMF (0.6 ml) was heated in a microwave r at 100°C for one hour. The reaction mixture was cooled to ambient temperature and conc. HCI (0.13 ml) was added slowly (gas evolution). The reaction was stirred at ambient temperature for 14 hours. The t was evaporated and the residue was extracted with dichloromethane (10 ml) and water (10 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 10 ml). The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure. The title compound was obtained after HPLC separation in 3 % yield (1 mg). 1H-NMR (400 MHz, CD2CI2, selected peaks): 6 [ppm] = 1.86 (m, 2H), 3.52 (m, 2H), 3.64 (m, 1H), 3.77 (m, 4H), 3.95 (m, 4H), 4.07 (m, 4H), 6.51 (s, 1H), 7.26 (d, 1H), 7.67 (d, 1H), 7.79 (d, 1H), 8.42 (d, 1H).

Example 288 N,N-dimethyl[2-(morpholinyl)(1H-pyrazol-S-yl)-1,7-naphthyridin-4—yl]benzamide HSC'N‘CHS To a solution of [3-(dimethylcarbamoyl)phenyl]boronic acid (530 pl, 0.57 M, 300 umol) in 0.52 mL DVIF was added 2-(morpholinyl)-8—[2-(tetrahydropyranyl)-2H-pyrazolyl]- [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [1,7]naphthyridin—4—yI—trifluoromethanesulphonate (1.0 ml, 0.15 M, 150 umol; ediate—3) in 1 mL DMF, aqueous sodium carbonate solution (200 pl, 2.3 M, 450 umol) and 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium(|l) (400 pl, 0.038 M in DMF, 15 umol). The reaction mixture was shaked at 90°C for 12 h.

To the crude reaction mixture aqueous hydrochloric acid (240 pl, 1.9 M, 470 umol) was added and the corresponding mixture was shaked over night at room temperature.

The reaction mixture was purified by ative HPLC to give 22 mg of the product as solid material.

LC—MS Method 4: Rt = 0.75 min; MS (ESIpos) m/z = 429 [M+H]*.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp The following examples (Table 4) were prepared in y to example 288: Table 4 Retention Example Structure time [min] {4-[2-(morpholin—4-yl)-8—(1H- lyl)-1,7-naphthyridin l)methanone naphthyridinyl]benzamide naphthyridinyl]benzamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example Structure |)-1,7-naphthyridine 3-[2-(morpholin—4-y|)(1H- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp Retention Example Stru ctu re time [min] yrazoI-S-yl)-1,7-naphthyrid in |]benzamide N-methy|—3-[2-(morpho|in—4-y|) (1H-pyrazoIy|)—1,7- naphthyridin-4—yl]benzamide 4-(3-fluorophenyI)(morpho|in- 4-yl)-8—(1H-pyrazo|—5-y|)-1,7- naphthyridine 4-(5-ch|orothiophenyl)—2- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure time |)-1,7-naphthyridine 2-(morpholin-4—yl)—8—(1H—pyrazo|— 2-(morpholin-4—yl)—8-(1H—pyrazo|— 2—(morpholin—4—yl)—8—(1H—pyrazol— [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure time 4-y|)(1H-pyrazo|y| )-1,7- naphthyridine N-{3—[2—(morpho|inyl)—8—(1H- pyrazoI—S-yI)-1,7—naphthyridin-4— |)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure time [min] 4-y|)(1H-pyrazo|y| )-1,7- naphthyridine |)-1,7-naphthyridine ation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure time |)-1,7-naphthyridine {3-[2—(morpholin—4-y|)-8—(1H- pyrazoI—S-yI)-1,7—naphthyridin-4— A -(4-f|uorophenyI)(morpho|in- -y|)-8—(1H-pyrazoly|)-1,7- naphthyridine naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure time A -(2-methy|pheny|)(morpho|in- 4-y|)(1H-pyrazo|y|)-1,7- naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp Example Structure time [min] N,N-dimethy|—3-[2-(morpho|in naphthyridinyl]aniline naphthyridin—4—yl]aniline N-{2-[2-(morpho|iny|)(1H- pyrazol—S—yI)-1,7—naphthyridin-4— yl]phenyl}methanesuIfonamide N-{4-[2—(morpho|inyl)-8—(1H- pyrazoI-S-yl)-1,7-naphthyridin I]phenyl}methanesuIfonamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure naphthyridinyl]benzamide A -[2-(morpho|in—4-y|)(1H- 4-yl)-8—(1H-pyrazo|—5-y|)-1,7- naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure time [min] {3-[2-(morpholin—4-y|)(1H- pyrazoly|)-1,7-naphthyrid in |]pheny|}(piperidin |)methanone opropy|[2-(morpho|in naphthyridinyl]benzamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention e Structure time |)-1,7—naphthyridine A -(2-ch|orophenyI)(morpho|in- 4-yl)-8—(1H-pyrazo|—5-y|)—1,7- naphthyridine 4-(2,5—dimethylphenyI)—2— [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure time [min] 3-[2-(morpholin—4-y|)(1H- pyrazoI-S-yl)-1,7-naphthyridin |]ani|ine 2-(morpholin-4—yl)—8—(1H—pyrazo|— -y|)[3-(1H-pyrazoI morpholiny|)(1H- pyrazol—S—yl)-1,7—naphthyridin-4— A -(2-f|uoromethoxyphenyl) [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example ure time 4-(5-fluoro-Z-methoxyphenyI) (morpholiny|)(1H-pyrazo|—5- |)-1,7-naphthyridine |)-1,7-naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp Retention Example Structure time [min] 2-[2-(morpholin—4-yl)-8—(1H- pyrazolyl)-1,7-naphthyrid in |]ani|ine The examples in the following table (Table 5) were prepared in analogy to this procedure: To 2—5 eq of boronic acid derivative were added 0.15 mmol 2-(morpholin-4—yl)[1-(tetrahydro- 2H—pyran—Z—yl)—1H—pyrazol-S—yl]—1,7-naphthyridin—4-yl trifluoromethanesulfonate (0.25 M in NMP, 600 uL), 30 umol 1,1'-BIS(D|PHENYLPHOSPH|NO)FERROCENE]DICHLOROPALLADIUMUI) (0.04 M in NMP, 750 uL) and 0.45 mmol potassium carbonate (1 M in water, 450 uL) and the e was heated in a microwave oven at 110°C for 5 hours. After cooling, 0.9 mmol HCl (2M in water, 450 uL) were added and the mixture was heated in a microwave oven for 10 hours at 50°C. After g, the mixture was ed, washed with NMP and subjected to preparative HPLC to yield the target product.

LC-MS Method 4 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Table 5 Retention Example Structure time |)-1,7—naphthyridine 4-(1-benzothiophenyl)—2- (morpholinyI)—8—(1H-pyrazoI-5— 2-(morpholinyl)-8—(1H-pyrazo|— —yl )—4—(quino|in—5—y| )-1,7— naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure time [min] pholinyl)-8—(1H-pyrazo|— -yl )(pyridiny| )-1,7- naphthyridine A -(2-methoxypyridin-4—yl)—2- morpholinyl)—8—(1H-pyrazoI A —(5—methylpyridin—3-yI)—2— morpholinyl)—8—(1H-pyrazoI A —(5—methoxypyridin-3—yl)—2— linyl)—8—(1H-pyrazoI 2-(morpholinyl)-8—(1H—pyrazo|— -yl )(quino|iny| )-1,7- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure time [min] 2-(morpholiny|)[1- phenylsulfony|)-1H-indo|—2-y|] razoIy|)—1,7- naphthyridine {5-[2-(morpholin—4-y|)-8—(1H- A -(2-f| uoropyridin—3-yI)—2— morpholinyl)—8—(1H-pyrazoI [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp Retention Example Structure time A -(2-ch|oromethylpyridinyl)— 2-(morpholin-4—yl)—8—(1H—pyrazo|— -y|)-1,7—naphthyridine A —(2—methoxypyridin-3—yl)—2— morpholinyl)—8—(1H-pyrazoI A uinolin—4—yI)(morpho|in— 4-y|)(1H-pyrazo|—5-y|)-1,7- naphthyridine 4-(3-chloropyrid iny|) (morpholinyl)—8—(1H-pyrazoI |)-1,7—naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure time 4-(2,6-dif|uoropyridinyI) A -(1-methyl-1H—pyrazoI-4—yl) morpholinyI)—8-(1H-pyrazoI-5— ert-butyl 5-methoxy-2—[2— morpholinyl)—8—(1H-pyrazoI indoIe—l—carboxylate 2-(morpholin-4—yI)[6- olinyl)pyridinyl]—8— 1H-pyrazoIyl)—1,7- naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention e Structure time 2-(morpholinyl)-8—(1H-pyrazo|— -yl)(thiophenyI)-1,7- naphthyridine 2-(morpholinyl)-8—(1H-pyrazo|— -yl)-4—(thiophen—3-y|)—1,7— naphthyridine morpholin-4—yl)—8—(1H—pyrazol—5— 4-(2-chIoromethylpyridinyl)- 2—(morpholin—4—yl)—8—(1H—pyrazol— -y|)-1,7—naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure time 4-(5-chIoro-Z-methoxypyridin |)(morpho|iny|)-8—(1H- utyl 5-methyI[2- (morpholinyI)—8-(1H-pyrazoI-5— indoIe—l—carboxylate A -(5-ch|orof|uoropyridinyl)— 2-(morpholinyl)—8—(1H-pyrazo|— -y|)-1,7—naphthyridine A dimethyI—1,2-oxazol—4-y|)-2— (morpholinyI)(1H-pyrazoI |)-1,7—naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure time [min] pholinyl)-8—(1H-pyrazo|— -yl )(quino|iny| )-1,7- yridine A -(2-ethoxypyridin—3-y|)—2— (morpholinyl)—8—(1H-pyrazoI 2-(morpholin-4—yl)—8—(1H—pyrazo|— -yl )(quino|in—6-y| )-1,7— naphthyridine ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure time 4-(2-chlorothiophenyl)—2- -[2-(morpholiny|)(1H- pyrazol-S-yl)-1,7-naphthyridin 2-(morpholin-4—y|)(1H—pyrazo|— 3-yl)-8—(1H-pyrazo|y|)—1,7- naphthyridine A -(1-methyl-1H—pyrro|—2—y|)—2- morpholinyl)—8—(1H-pyrazoI [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure time [min] -[2-(morpholiny|)(1H- pyrazoI-S-yl )-1,7-naphthyridin hloro-Z—methoxypyridin-4— y|)(morpho|in—4-y|)(1H- pyrazol—5—yl)-1,7—naphthyridine A -(3-ch|orothiophen-2—yl)—2— (morpholinyl)—8—(1H-pyrazoI A -(5-f| uoropyridin—3-yI)—2— morpholinyl)—8—(1H-pyrazoI ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp Retention Example Structure time 4-[2-(methylsulfanyl)pyrimidin-S- N-cyc|opropyI-S-[Z-(morpholin |)(1H-pyrazoly|)-1,7- 4-(isoquinolin-S-yI)(morpho|in- 4—yl)—8—(1H—pyrazol—5-yl)—1,7— naphthyridine N-methyI-S-[Z-(morpholin—4-y|)-8— 1H-pyrazolyI)—1,7- naphthyridinyl]pyridine carboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure time [min] 4-[5-(methylsu|fany|)pyridiny|]— 2-(morpholin-4—yl)—8-(1H—pyrazo|— 1,7—naphthyridine 2—(morpholin—4—yl)—8—(1H—pyrazol— -yl )(1H-pyrro|o[2,3-b] pyridin- -y|)-1,7—naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure time [min] pholiny|)[2-(propan-2— |oxy)pyridin-3—yl](1H—pyrazol— N 5-y|)-1,7—naphthyridine A -(5-chloroethoxypyridiny|)— 2-(morpholinyl)—8-(1H—pyrazo|— -y|)-1,7—naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example Structure time [min] 4-(1-tert—butyl-1H-pyrazol—4-yl) (morpholinyl)(1H-pyrazol //N yl)-1,7-naphthyridine 0.85 The examples in the following table (Table 6) were prepared in analogy to this procedure: To 2—5 eq of amine derivative were added 0.15 mmol pholinyl)-8—[1-(tetrahydro-2H— pyran-Z-yl)-1H-pyrazo|—5-yl]-1,7-naphthyridin-4—yl trifluoromethanesulfonate (0.25 M in NMP, 600 uL) and the mixture was heated at 70°C overnight. After cooling, 1.5 mmol HCI (2M in water, 750 uL) were added and the mixture was heated ght at 50°C. After cooling, the mixture was subjected to preparative HPLC to yield the target product.

LC—MS Method 4 Table 6 Retention Example Structure time 2-(morpholiny|)(piperidin 0.83 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Structure time [min] 1-[2-(morpholiny|)(1H- pyrazoI-S-yl naphthyridin {1-[2—(morpholin—4—yl)—8—(1H- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp Retention Example Structure A -(4-m ethyl piperidin-l-yl )—2- morpholinyI)—8-(1H-pyrazoI-5— yl)-1,7-naphthyridine A-(3I4-dihydroquinolin—1(2H)-y|)- 2-(morpholinyl)—8-(1H-pyrazo|— -y|)-1,7—naphthyridine [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure time 4-(3,4-dihydroisoquino|in—2(1H)- yl)(morpho|iny|)(1H- pyrazoI-S-yl)-1,7-naphthyridine 4-(1,3-dihydro-2H-isoindoI—2-yl) 2-(morpholin-4—yl)—8—(1H—pyrazo|— -yl)[1,3,3-trimethy|—6— tert-butyl 1-[2—(morpholin—4-yI)-8— lH-pyrazoI-S-yI)—1,7- naphthyridinyI]-pro|inate ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure time [min] |)-1,7—naphthyridine A -(3-f| uoropiperidin-l-yl )—2— morpholinyl)—8—(1H-pyrazoI 1-[2-(morpholin—4-yI)(1H- pyrazoI-S-yl)-1,7-naphthyridin |]-pro|inamide ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example ure time {1-[2-(morpholin—4-y|)(1H- yrazoI-S-yl )-1,7-naphthyridin A -(4-methoxypiperidin-l-yI) (morpholinyl)—8-(1H-pyrazoI |)-1,7—naphthyridine N-methyI[2-(morpho|iny|) (1H-pyrazoIy|)-1,7- naphthyridin-4—yI]—pro|inamide -[4-(ethy|su|fonyl)piperazinyl]— 2-(morpholinyl)—8—(1H-pyrazo|— [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Retention Example Structure time [min] 4-[4-(methylsu|fony|)piperazin N-cyclopropyI—N—methyl—Z— morpholinyl)—8—(1H-pyrazoI —dimethylpropy|)—N—methyl— 2-(morpholinyl)(1H-pyrazo|— -yl )-1,7—naphthyridinamine {1-[2-(morpholiny|)(1H- pyrazoI-S-yl)-1,7-naphthyridin l]piperidinyl}methanol The title compounds described in the example section were tested in ed biological assays one or more times. When tested more than once, data are reported as either average values or as median , wherein -the average value, also referred to as the arithmetic mean value, represents the sum of the [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp values obtained divided by the number of times tested, and -the median value represents the middle number of the group of values when ranked in ing or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.

Expression of ATR/ATRIP in HEK 293-6E cells: The cDNAs encoding the protein sequences of full-length human ATR ce (Q13535) with an N-terminally fused Flag tag as well as the full-length human ATRIP (Q8WXE1) were optimized for expression in eukaryotic cells and synthesized by the t Technology at Life Technologies.

Both cDNAs also encoded att—site sequences at the 5'and 3’ ends for subcloning into the following destination vectors using the Gateway Technology: pD-MamA (an in-house derivate ofthe vector pEAK from EdgeBioSystems but with a human CMV promotor) which provides a N-terminal fusion of a GST-tag to the integrated gene of interest; pD-MamB (an in-house derivative of p'l'l'5 from NRCC, Y. Durocher) which provides a N—terminal fusion of a STREP II —tag to the integrated gene.

The cDNAs of ATR and ATR-DN were cloned into pD-MamA and the ATRIP—FL into pD—MamB.

The cDNA sequence of codon-optimized ATR including a GST tag is bed in SEQ ID No. 1 of the attached sequence listing, its corresponding protein sequence in SEQ ID No.3.

The cDNA sequence of codon-optimized ATRIP including a STREP II tag is bed in SEQ ID No. 2, its corresponding protein sequence in SEQ ID No.4.

Coexpression of ATR and ATRIP by transient transfection in HEK293-6E cells: For transient transfection of HEK293-6E suspension cells a Biostat Cultibag ctor with 5 L culture volume (starting ) in a 20 L culture bag was used. The cells were ed in F17 Medium (Gibco, Invitrogen, Cat# 05-0092DK) with the ing supplements Pluronic F68 (10 mL/L of 10% solution, Gibco # 24040), Gluta—Max (20ml of 100x solution/L, L—Alanyl-Glutamine (200mM, ogen ), G418 (final concentration 25ug/ml, PAA #P02-012). The applied culture conditions were 37°C, rocking rate18 rpm, pH 7.0, p02 55 %. At the day of transfection the cell culture had reached a cell y of 1.6 x 106 cells/mL and a viability of 99 %. For preparation athe transfection solution to 500 mL F17 medium (without the supplements) 4 mg of the ATR [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp encoding plasmid, 1 mg of the ATRIP encoding plasmid and 10 mg PEI (Polyethylenimin, linear, Polysciences # 23966, as 1 mg/mL stock solution) were subsequently added, carefully mixed and incubated at room temperature for 15 min. This transfection solution was then added to the 5 L cell culture in the culture bag. This cell culture was incubated for 5 h and afterwards 5 L of F17 medium with the mentioned supplements were added and the rocking rate increased to 19 rpm. 48 h after transfection the cells were harvested by fugation (30 min., 1000g, 15 °C) and the cell pellets stored at —80 °C.

Purification: Purification of the ATR (Flag-Tag)/ATR|P(Strep-Tag) complex was achieved by affinity chromatography using anti-FLAG-resin (Sigma, #A220).

Cells were harvested by centrifugation g) and lysed in buffer A (50mM Tris—HCI pH 7,5; 150mM NaCl, 5% Glycerol, 1mM Na3VO4, 1mM NaF, 10mM erophosphate, 1% Tween 20; 0,1% NP40; Complete with EDTA) for 1h at 4°C. The supernatant (20.000xg) was than bound to Flag—Agarose and eluted after several washing steps using Buffer B (50mM Tris-HCI pH7.4; 150mM NaCl; 10% Glycerin, ZOOug/ml Flag Peptides from Sigma, #F3290). Elution fractions were aliquoted and shock frozen using liquid nitrogen. The final concentration of ATR in the final preparation was 250ug/ml ated densitrometrically using BSA as a standard in a sie stained gel. The yield of copurified ATRIP was far below a 1:1 ratio ed to ATR but was essential for ATR activity.

Tracer A: 3',6'-bis(dimethylamino)—N-(4-{[2-(1H-indo|y|)(morpholinyl)pyrimidin-4—yl]amino}butyl)— 3-oxo-3H-spiro[2-benzofuran-1,9'-xanthene]carboxamide Step a: tert-butyl (4-{[2-(1H-indo|y|)(morpholin-4—yl)pyrimidin-4—yl]amino}butyl)carbamate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp The starting material 4-[4-chloro(morpholinyl)pyrimidinyl]—1H-indole was synthesized according to the literature (W02008/125833). A solution of 4—[4—ch|oro—6—(morpho|in y|)pyrimidiny|]-1H-indo|e (980 mg, 3.11 mmol), diisopropylethylamine (805 mg, 1.09 ml, 6.23 mmol) and N—BOC—1,4—diaminobutane (879 mg, 4.67 mmol) in 1—methyI—2—pyrrolidinone (24.5 ml) was stirred overnight at 150°C. The mixture was allowed to cool to ambient temperature. Ethyl e (50 ml) and brine (50 ml) were added, the layers were separated and the organic layer was washed with brine (3x 50 ml). The organic layer was dried over sodium sulphate and the t was removed under reduced pressure. The title compound was obtained as crude mixture (purity 40%, 2.37g) and used without further purification in the next step.

Step b: N-[Z-(lH-indolyl)(morpholinyl)pyrimiclinyl]butane-1,4-diamine x N / HN I N N/\/\/NH2 Tert—butyl (4—{[2-(1H—indol-4—yl)(morpholin—4—yl)pyrimidin-4—yl]amino}butyl)carbamate (2.37 g, 2.03 mmol) was dissolved in HCI / dioxane (4M, 20 ml) and stirred at t temperature for 10 minutes. Ethyl e (50 ml) and water (50 ml) were added and the phases separated. By addition of aqueous NaOH (2N, 50 ml) the pH of the aqueous layer was basified and extracted with ethyl acetate (2 x 50 ml). The combined organic layers were dried over sodium sulphate and the solvent was removed under reduced pressure. The title compound was obtained in 77% yield (770 mg) and used without further purification in the next step.

Dep c: [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 3',6'-bis(dimethylamino)-N-(4-{[2-(1H-indo|y|)(morpholinyl)pyrimidinyl]amino}buty|)— 3-oxo-3H-spiro[2-benzofuran-1,9'-xanthene]carboxamide 3',6'-bis(dimethylamino)-N-(4-{[2-(1H-indolyl)(morpholinyl)pyrimidinyl]amino}butyl)- 3-oxo-3H-spiro[2-benzofuran-1,9'-xanthene]carboxamide Isomer 2 1H-indolyl)-6—(morpho|iny|)pyrimidin—4-yl]butane-1,4-diamine (70 mg, 0.14 mmol) was dissolved in DMF (3 mL). DIPEA (74 ul, 0.43 mmol, 3 eq.) and a mixture of commercially ble -carboxytetramethylrhodamine N-succinimidyl ester and 6-carboxytetramethylrhodamine N- succinimidyl ester (75 mg, 0.14 mmol, 1 eq.) were added sequentially. The e was stirred for minutes at ambient temperature and concentrated under reduced pressure. The two title compounds were separated by preparative HPLC (H20(NH4OH)/CH3CN: 85:15 to 45:55).

Isomer 1 was obtained in 22 % yield (25 mg). 1H-NMR (300 MHz, DMSO—de): 6 [ppm]: 1.56 (4H), 2.92 (12H), 3.49 (4H), 3.69 (4H), 5.53 (1H), 6.48 (6H), 6.74 (1H), 7.06 (1H), 7.33 (2H), 7.43 (1H), 7.63 (1H), 8.03 (2H), 8.15 (1H), 8.71 (1H), 1H).

Isomer 2 was obtained in 34 % yield (31 mg). 1H-NMR (400 MHz, DMSO-de): 6 [ppm]: 1.67 (4H), n93 (12H), 3.38 (4H), 3.52 (4H), 3.71 (4H), 5.58 (1H), 6.47 (6H), 6.80 (1H), 7.09 (1H), 7.28 (1H), 7.36 (2H), 7.44 (1H), 8.02 (1H), 8.22 (1H), 8.44 (1H), 8.83 (1H).

Isomer 2 was used as ligand for the ATR binding assay which is described infra.

Tracer B: bis(dimethylamino)-N-[4-({2-[(3R)methy|morpholin-4—yl](1H-pyrazolyl)-1,7- naphthyridin-4—yl}oxy)butyl]oxo-3H-spiro[2-benzofuran-1,9'-xanthene]carboxamide Step a: tert—butyl [4-({2-[(3R)—3-methylmorpholiny|][1-(tetrahydro-ZH-pyran-Z-yl)-1H-pyrazo|—5- yl]-1,7-naphthyridiny|}oxy)butyl]carbamate 2-[(3R)Methylmorpholinyl]—8-[1-(tetrahydro-2H-pyrany|)-1H-pyrazolyl]-1,7-naphthy- ridinol (0.41 g, 1.0 mmol, 1 eq.) was solubilized in DMF (12 mL). -amino)buty| bromide (0.53 g, 2.1 mmol, 2 eq.) and K2C03 (0.72 g, 5.2 mmol, 5 eq.) were added to the mixture. The reaction was stirred at ambient temperature for 16 hours. The sion was diluted with EtOAc and filtered. The organic phase was concentrated under reduced pressure and the crude material purified by flash chromatography (gradient Hex/EtOAc 9/1 to 100% EtOAc). The desired product was obtained in 87% yield (0.52 g). 1H—NMR (400MHz, DMSO—de): 6 [ppm]: 1.14 — 1.24 (m, 3H), 1.38 (s, 9H), 1.41 - 1.69 (m, 5H), 1.80 - 1.90 (m, 2H), 1.99 (s, 2H), 2.30 - 2.42 (m, 1H), 3.03 (q, 2H), 3.10 - 3.29 (m, 2H), 3.40 - 3.52 (m, 1H), 3.73 (d, 3H), 3.91 - 3.99 (m, 1H), 4.12 (t, 1H), 4.27 (t, 2H), 4.45 - 4.58 (m, 1H), 6.01 - 6.13 (m, 1H), 6.75 (d, 1H), 6.84 - 6.95 (m, 2H), 7.60 (s, 1H), 7.75 (d, 1H), 8.35 (d, 1H). LC-MS (Method A): m/z: [M+H]+ = 567, Rt = 1.31 min.

[Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Step b: 4-({2-[(3R)methy|morpholin-4—yl](1H-pyrazolyl)-1,7-naphthyridin-4—y|}oxy)butan amine 4-({2-[(3R)-3—methylmorpholin—4-y|](1H-pyrazoIyl)-1,7-naphthyridin-4—yl}oxy)butanamine (0.10 g, 0.18 mmol, 1 eq.) was solubilized in CH2C|2 (1.1 mL) and TFA was added (0.27 mL, 3.5 mmol, 20 eq.). The reaction was stirred at ambient temperature for 30 minutes. The mixture was then quenched with saturated NaHC03 solution and the suspension was filtered. The solid was dried under reduced pressure and the desired compound was obtained without r purification in quantitative yield. 1H-NMR (400MHz, DMSO-de): 6 [ppm]: 1.27 (d, 3H), 1.73 — 1.84 (m, 2H), 1.88 - 1.97 (m, 2H), 2.92 (s, 2H), 3.49 — 3.61 (m, 1H), 3.65 - 3.74 (m, 1H), 3.80 - 3.87 (m, 1H), 4.02 - 4.09 (m, 1H), 4.11 - 4.19 (m, 1H), 4.30 (s, 2H), 4.56 - 4.65 (m, 1H), 6.82 (s, 1H), 7.34 - 7.40 (m, 1H), 7.50 - 7.65 (m, 4H), 7.71 (d, 1H), 8.33 (d, 1H), 13.31 — 13.41 (m, 1H).

Step c: 3',6'-bis(dimethylamino)-N-[4—({2-[(3R)methy|morpholin-4—yl](1H-pyrazolyl)-1,7- naphthyridin-4—yl}oxy)buty|]-3—oxo-3H-spiro[2-benzofuran-1,9'-xanthene]carboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp 4—({2—[(3R)—3—Methylmorpholin—4—yl]-8—(1H-pyrazolyl)—1,7-naphthyridin—4—yl}oxy)butan-1—amine (18 mg, 0.047 mmol, 1 eq.) was solubilized in DMF (1mL). DIPEA (25 (AL, 0.14 mmol, 3 eq.) and a e of commercially available 5—carboxytetramethylrhodamine N—succinimidyl ester and 6— ytetramethylrhodamine N-succinimidyl ester (25 mg, 0.047 mmol, 1 eq.) were added sequentially. The reaction was stirred for 15 minutes at ambient temperature and concentrated under reduced pressure. The crude product was purified by preparative HPLC (HZO(NH4OH)/CH3CN : 85:15 to 45:55) and the desired compound was obtained in 49% yield (18 mg). 1H-NMR (400MHz, DMSO-de): 6 [ppm]: 1.26 (d, 3H), 1.79 - 1.88 (m, 2H), 1.92 - 2.02 (m, 2H), 2.94 (s, 12H), 3.46 (q, 2H), 3.52 - 3.60 (m, 1H), 3.67 - 3.73 (m, 1H), 3.82 (d, 1H), 4.01 - 4.07 (m, 1H), 4.12 - 4.19 (m, 1H), 4.34 (t, 2H), 4.56 - 4.64 (m, 1H), 6.44 - 6.53 (m, 6H), 6.83 (s, 1H), 7.32 (d, 1H), 7.37 (br. s., 1H), 7.61 (s, 1H), 7.73 (d, 1H), 8.24 (dd, 1H), 8.32 (d, 1H), 8.46 (s, 1H), 8.88 (t, 1H), 13.36 (br. s., 1H). 1. Binding assay ATR To determine of binding activity of the test compounds, full-length human ATR protein was expressed and purified er with ATRIP as described above. Furthermore, a fluorescently ed compound (either tracer A or B as described above) was used as a tracer molecule.

Detection of the binding event ofthe tracer was achieved by time—resolved fluorescence energy [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp transfer (TR—FRET). We used an anti—GST—Terbium antibody (CisBio) that binds to the GST—tag at the N-terminus of ATR-kinase. Excitation of Terbium with 337 nm light results in emission of fluorescent light with 545 nm. In case a tetrameric complex has formed (antiGST—Tb + GST-ATR + Strp2-ATRIP + tracer), part of the energy will be transferred from the m to the fluorophore that itself emits light of 570 nm. Displacement of the fluorescent tracer by a test compound leads to a reduction of the TR-FRET-signal.

For the assay 50 hi of a 100-fold concentrated solution ofthe test compound in DMSO was pipetted into a black low volume 384we|| iter plate (MTP, Greiner Bio—One, Frickenhausen, Germany). To prepare the ATR—working solution, ATR/ATRIP stock on was diluted in assay buffer [50mM HEPES (pH 7.0), 10mM MgCI2, 1mM DTT, 0.01% (w/v) lgepal, 0.01% (w/v) BSA] to 4.2nM protein tration (concentration may vary from lot to lot of protein preparation).

AntiGST-Tb antibody was diluted to 4.2 nM. The ATR-working solution was incubated for 30 min at 22°C prior to sing to pre-form the complex of antiGST-Tb + GST-ATR + ATRIP. Then, 3 ul of the ATR—working solution were added to the test compound and the mixture was incubated for 10 min at 22°C to allow pre-binding of the test compounds to ATR/ATRIP. Then, 2 ul of a 100 nM solution of either tracer A or B in assay buffer were added to the ATR-working solution. The resulting mixture was incubated for 30 min at 22°C. The measurement of the TR-FRET signal was performed in a standard HTRF-compatible MTP reader instrument (e.g. BMG tar) by ing the fluorescence emissions at 545 nm and 570 nm after excitation at 337-350 nm. The ratio between emission at 570 nm d by emission at 545 nm was calculated to give the well ratio. The experimental data (well ratios) were normalised by the following way: positive control contained ATR-working solution plus either tracer A or B solution (= 0 % inhibition), the negative control contained all components except GST-ATR/ATRIP (= 100 % inhibition). y the nds were tested on the same MTP in 11 different trations in the range of 20 (AM to 0.1 nM (20 (AM, 5.9 uM, 1.7 uM, 0.51 (AM, 0.15 uM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1 nM). The dilution series were prepared separately before the assay on the level of the 100 fold concentrated solutions in DMSO by serial 1:3.4 dilutions in duplicate values for each concentration. ICSO values were calculated by a 4 parameter fit using standard software (GraphPad prism or equivalent).

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Table 7: ATR binding e No ATR binding (tracer A) ATR binding (tracer B) ICSO [M] |C50 [M] 3,68 E—8 2,39 E-8 9,52 E—8 3,83 E-8 ,69 E—8 3,87 E-8 1,10 E-7 7,51 E-8 26 1,56 E-8 6,36 E-9 27 1,72 E-8 1,09 E-8 28 1,76 E-8 8,40 E-9 29 2,15 E-8 9,23 E-9 2,28 E-8 9,48 E-9 , 31 8,66 E-8 4,51 E-8 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example No ATR binding (tracer A) ATR binding (tracer B) IC50 [M] ICSO [M] 32 8,47 E—8 3,67 E—8 33 1,98 E-8 1,03 E-8 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example No ATR binding r A) ATR binding (tracer B) IC50 [M] ICSO [M] 64 2,74 E-8 65 3,35 E-7 2,76 E-7 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp Example No ATR binding (tracer A) ATR binding (tracer B) IC50 [M] ICSO [M] 96 1,27 E—8 97 1,39 E-8 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp Example No ATR binding (tracer A) ATR binding (tracer B) IC50 [M] ICSO [M] 128 3.26 E—8 129 3.53 E-8 ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example No ATR binding (tracer A) ATR binding (tracer B) IC50 [M] ICSO [M] 160 3.72 E—8 161 6.26 E-8 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp Example No ATR binding (tracer A) ATR binding (tracer B) IC50 [M] ICSO [M] 192 1.15 E—7 193 2.45 E-7 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example No ATR binding r A) ATR binding (tracer B) IC50 [M] ICSO [M] 224 5.21 E—8 225 4.47 E-7 [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example No ATR binding (tracer A) ATR binding (tracer B) IC50 [M] ICSO [M] 257 5.88 E-8 258 7.66 E-9 ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example No ATR binding (tracer A) ATR binding (tracer B) IC50 [M] ICSO [M] 289 2.99 E—6 290 1.19 E-6 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example No ATR binding (tracer A) ATR binding (tracer B) IC50 [M] ICSO [M] 322 8.09 E—8 324 7.77 E-8 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp e No ATR binding (tracer A) ATR binding (tracer B) IC50 [M] ICSO [M] 355 4.84 E-7 356 7.95 E-8 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example No ATR binding (tracer A) ATR binding (tracer B) IC50 [M] ICSO [M] 387 2.18 E—7 388 7.91 E-8 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example No ATR binding (tracer A) ATR binding (tracer B) IC50 [M] ICSO [M] 420 6.02 E—7 421 1.79 E-6 427 1.12 E-7 428 6.98 E-8 429 4.48 E-8 430 6.13 E-8 431 3.47 E-8 432 2.04 E-6 433 4.16 E—8 434 3.18 E—8 435 6.51 E—8 436 2.40 E—8 437 1.18 E—7 2. ATR activity assay ATR kinase phosphorylates a biotinylated peptide derived from Rad17 (sequence: biotin-PEGZ- ASELPASQPQPFS-amide, produced by Biosyntan GmbH, Berlin). The assay measures the amount of phosphorylated peptide by time-resolved fluorescence (TR-FRET). Streptavidin-XL665 (Cisbio, reference #6105AXLB), an anti—Rad17—phospho—serine 645 specific antibody (available from either lmgenex/Biomol reference 386A, or from Lifespan, reference 3028) and antiRabbit-IgG-Europium (Perkin Elmer, reference #AD0083) are employed to ically detect phosphorylated biotin—peptide, but not non-phosphorylated peptide. tion of Europium with 337 nm light results in emission of fluorescent light with 620 nm. In case a tetrameric detection complex has formed, part of the energy will be transferred to the Streptavidin-XL665 fluorophor that itself emits light of 665 nm. Unphosphorylated peptide does not give rise to light on at 665nm, because no FRET-competent ion complex can be formed.

[Annotation] jennyp None set by jennyp ation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp For the assay 50 n| of a 100—fold concentrated solution of the test compound in DMSO was ed into a black low volume 384we|l microtiter plate (MTP, Greiner Bio-One, Frickenhausen, Germany). To prepare the ATR-working solution, ATR/ATRIP stock solution (expression and purification: see above) was diluted in assay buffer [50mM HEPES (pH 7.0), 10mM MgClZ, 1mM dithiothreitol (D'l'l'), 0.01% (w(v) lgepal, 0.2% (w/v) bovine gamma in (BGG)] to 10nM protein tration (concentration may vary from lot to lot of protein preparation). A substrate working solution was prepared by diluting the biotinylated Rad17 e to 0.5uM together with ATP to ZOuM in assay buffer. A etection working solution was prepared containing 50mM Hepes pH 7.0, 0.15 % (w/v) bovine serum albumin (BSA), 150mM EDTA, 200nM Streptavidin- XL665, 2.5nM anti phospho Rad17-pS645 (lMG-6386A) and 1.5 nM anti-Rabbit-lgG-Eu. The amount of the antibodies is dependent on the batch used and was optimized by variation the activity of the batch. All solutions were kept at 20°C. First, 2.5 ul of ATR-working solution were dispensed into the wells of the MTP containing the test compounds. After 10 s pre- incubation to allow binding of the compounds to ATR, 2.5 ul of substrate working solution was dispensed to the wells. After 180 minutes, 5 ul of stop/detection solution were dispensed into the wells. The resulting mixture was incubated for 60 min at 20°C. The measurement of the TR—FRET signal was performed in a standard HTRF-compatible MTP reader instruments (e.g. BMG Pherastar or Perkin Elmer ViewLux) by recording the fluorescence emissions at 620 nm and 665 nm after excitation at 0 nm. The ratio between emission at 665 nm divided by emission at 620 nm was calculated to give the well ratio. The experimental data (well ratios) were normalised by the following way: positive control was ed of ATR-working solution + substrate on (= 0 % inhibition), the negative control ns the same reagents, but ATR—working solution is replaced by assay buffer (= 100 % inhibition). Usually the compounds were tested on the same MTP in 11 different concentrations in the range of 20 (AM to 0.1 nM (20 uM, 5.9 uM, 1.7 uM, 0.51 (AM, 0.15 (AM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1 nM) The dilution series were prepared separately before the assay on the level ofthe 100 fold concentrated ons in DMSO by serial 1:3.4 dilutions in duplicate values for each concentration. leo values were calculated by a 4 parameter fit using with standard software (GraphPad prism or equivalent). 3. Proliferation assay Human tumour cells (Table 8) were originally obtained from the American Type Culture Collection (ATCC), the Deutsche ng von Mikroorganismen und Zellkulturen (DSMZ, German Collection of Microorganisms and Cell Cultures), or Epo GmbH Berlin.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Adherently g cells (HeLa, HeLa—MaTu—ADR, HT—144, Lovo, HT—29, NCI—H460, DU145, CacoZ, B16F10) were plated out in a y of 1500—4000 cells/measurement point, depending on the rate of growth of the cell line, in a 96-well multititre plate in 200 pl ofgrowth medium (DMEM/HAMS F12, 2 mM L-glutamine, 10% foetal calf serum). After 24 hours, the cells of one plate (zero plate) were dyed with crystal violet (see below), whereas the medium of the other plates was ed with fresh culture medium (200 pl) to which the test substances were added in various concentrations (0 (AM, and also in the range of 0001—10 (1M; the final concentration of the solvent dimethyl sulphoxide was 0.1 or 0.5%). The cells were incubated for 4 days in the presence of the test substances. Cell proliferation was determined by staining the cells with crystal violet: the cells were fixed at room ature for 15 min by adding 20 uI/measurement point of an 11% strength glutaraldehyde solution. After washing the fixed cells three times with water, the plates were dried at room temperature. The cells were stained by adding 100 uI/measurement point of a 0.1% strength crystal violet solution (pH adjusted to pH 3 by adding acetic acid). After washing the cells three times with water, the plates were dried at room temperature. The dye was ved by adding 100 uI/measurement point of a 10% strength acetic acid solution. Absorbance was determined etrically at a wavelength of 595 nm. The percentage change in cell growth was calculated by normalizing the measured values to the ance values ofthe zero plate (=0%) and the absorbance of the ted (0 uM) cells (=100%). The leo values were determined by means of a four parameter fit.

Cells growing in suspension (GRANTA-519,Jeko-1) were plated out in a cell density of 2000—4000 cells/measurement point, depending on the rate of growth of the cell line, in a black-walled, clear-bottom 96-well multititre plate in 100 pl of growth medium (DMEM/HAMS F12, 2 mM L- glutamine, 10% foetal calf serum). After 24 hours, cell y was determined in one plate (zero plate) by adding 60 uI/measurement point of CTG solution (Promega Cell Titer-Glo solution (catalogue numbers G755B and G756B)), uent incubation for 2 min followed by 10 min shaking (in the dark) and measurement of luminescence (VICTOR V, Perkin Elmer).

For the test plates, the test substances were prepared in s concentrations (0 (AM, and also in the range of 10 (AM; the final concentration of the solvent dimethyl sulphoxide was 0.1 or 0.5%) as 3x concentrated solutions in fresh growth medium. Aliquots of 50 ul each were added to the cell suspensions and the cells were incubated for 4 days in the presence ofthe test substances. Subsequently, cell density was determined using CTG solution as described above and leo values were calculated by means of a four parameter fit. ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp The substances were investigated in the following cell lines, which, by way of example, represent the ied indications (Table 8).

Table 8: List of the cell lines igated in the proliferation assays.

Tumour indication Cell line Source Cervical cancer HeLa DSMZ ACC-57 HeLa-MaTu-ADR (multi-drug Epo GmbH ant) Colon & colorectal cancer Lovo DSMZ ACC-SOO HT29 DSMZ ACC-299 Caco-2 DSMZ ACC-169 Lymphoma, mantle cell GRANTA—519 DSMZ ACC—342 Jeko-l DSMZ ACC-553 Melanoma, malignant HT-144 ATCC HTB-63 B16F10 ATCC CRL-6475 Prostate cancer (hormone DU 145 DSMZ ACC-261 independent) The results ofthe proliferation assays demonstrate the efficacy of test compounds in the human tumour cells investigated. These data suggest a possible use of the test nds in the tumour types investigated.

Table 9: Inhibition of proliferation of HeLa, HeLa-MaTu-ADR, NCI-H460, DU 145, Caco—Z and B16F10 cells by compounds according to the present ion, determined as described above.

All ICSO (inhibitory concentration at 50% of maximal effect) values are indicated in M, "n.t." means that the compounds have not been tested in the respective assay. n©©©©© Example Number tion of HeLa cell proliferation Inhibition of HeLa-MaTu-ADR cell proliferation Inhibition of NCl-H460 cell eration Inhibition of DU145 cell proliferation Inhibition of Caco-2 cell proliferation [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ®: Inhibition of BlSFlO cell proliferation Table 9: Inhibition of proliferation 6,41 E-7 3,68 E-7 2,19 E-6 2,98 E-6 1,02 E—6 1,59 E-6 5,95 E-6 2,98 E-6 2,98 E-6 > 3,00 E-6 5,28 E-7 8,17 E-7 1,72 E-6 > 3,00 E-6 3,65 E-6 > 1,00 E—6 2,43 E-7 2,91 E-7 5,77 E-7 1,58 E-6 > 3,00 E-6 2,93 E—7 3,25 E-7 2,89 E-6 1,37 E-6 > 3,00 E-6 > 3,00 E-6 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp 1,08 E—6 > 3,00 E-6 2,82 E—6 > 3,00 E-6 > 1,00 E-5 1,80 E-6 3,91 E—7 8,95 E-7 2,93 E-6 > 3,00 E-6 6,32 E-6 > 3,00 E-6 > 3,00 E-6 1,31 E-7 2,18 E—5 > 3,00 E-6 2,19 E—6 8,76 E-7 2,98 E-6 1,8-1E7 1,7-9E6 5,9-0E8 7,4-8E7 6,-31E7 2,0—3E7 >1,0—0E6 >1,0—0E6 >1,0—0E6 >1,0-0E6 2,7-1E7 76 9,68 E-7 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 77 2,54 E-7 9,37 E-8 6,56 E-7 8,68 E-7 1,06 E-6 8,17 E—8 1,04 E-7 2,86 E-7 4,98 E-7 91 1,08 E—7 97 2,52 E-7 103 3,74 E—7 109 2,98 E-7 110 2,06 E—7 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 111 1,56 E—7 2,26 E—7 6,50 E-8 1,10 E-7 2,37 E-7 7,11 E—7 117 2,25 E—7 118 1,71 E—7 135 1,82 E—6 136 5,75 E-7 1,53 E-7 1,46 E-7 5,49 E-7 7,79 E-7 144 > 3,00 E—6 [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ,22 E—7 9,06 E-8 3,05 E-8 4,92 E-7 6,73 E—7 1,90 E-6 2,05 E-6 2,91 E—7 1,44 E—7 8,69 E-7 [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 197 1,01 E—6 > 3,00 E—6 5,16 E—7 1,29 E—7 > 3,00 E—6 2,96 E—6 3,20 E-7 2,44 E-7 7,08 E-7 > 1,00 E-6 203 9,98 E-7 204 5,68 E—7 2,19 E—7 6,52 E-7 1,24 E-6 1,70 E-6 > 3.00 E-6 > 3.00 E-6 218 3,00 E-7 3,03 E-7 3,34 E-7 > 1,00 E-6 > 1,00 E-6 228 2,25 E—7 5,94 E-7 2,33 E-7 3,13 E-7 6,37 E-7 2,60 E-6 234 1,21 E-6 235 9,50 E—7 242 8,11 E—7 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 243 3,60 E-7 250 1,16 E—7 251 8,00 E—7 259 4,97 E-7 266 1,54 E-7 272 6,48 E—7 281 2,59 E-7 282 1,18 E—6 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp 283 1,46 E-7 7,56 E-8 4,86 E-8 5,29 E-7 5,86 E-7 296 2,74 E-6 298 2,44 E—6 310 > 3,00 E—6 318 2,00 E-6 325 9,99 E-7 334 > 3,00 E-6 335 2,96 E—6 ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 348 6,13 E—7 9,40 E-7 3,99 E—7 5,18 E-7 8,22 E-7 349 > 3,00 E—6 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 4. Phospho-HZAX assay Phospho-Ser139 Histone H2AX (also known as ?H2AX, tKB/Swiss-Prot P16104) represents an ar early marker for DNA damage response. In particular, H2AX gets phosphorylated by ATR upon DNA replication stress. HT-29 human colorectal adenoadenocarcinoma cells, originally obtained from the DSMZ, were plated out in a density of 12000 cells/measurement point a black- walled, clear—bottom 96-well multititre plate in 100 pl of growth medium (DMEM/HAMS F12, 2 mM L-glutamine, 10% foetal calf serum). After 24 hours, the test substances were added in various concentrations (0 uM, and also in the range of 0001—10 uM in quadruplicates; the final tration of the solvent dimethyl sulphoxide was 0.1%) followed by addition of a hydroxyurea solution to achieve a finale concentration of 2.5 mM and a final assay volume of 200 uL. One control plate was left ted and further processed in parallel. The cells were incubated for 30 min at 37°C. uently,the growth medium was carefully evaporated and the cells were fixed with 50 uL/well of ice-cold methanol for 15 min. The cells were washed once with 100 uL/well of PBS, followed by incubation with 50 uL/well of blocking buffer (Liqor, 000) for 1 h at room temperature. Subsequently, the cells were incubated with 50 uL/well of anti- phospho-HZAX (Ser 139) antibody (Merck Millipore, clone JBW301, 05-636) diluted 1:500 in blocking buffer for 1 h at room temperature (or over night at 4°C). The cells were washed three time with 100 uL/well of PBS, followed by incubation with 50 uL/well of a 1:500 diluted solution of Alexa Fluor 488 conjugated donkey anti-mouse lgG antibody (Life Technologies, A-21202) in TBST for 1 h at room temperature and ted from light. After the cells were washed three time with 100 uL/well of PBS, the wells were filled with 100 uL of PBS and fluorescence was determined using an Acumen laser scanning cytometer ('I'I'P Labtech). The tage change in y urea induced phospho-H2AX content was calculated by normalizing the measured values to the fluorescence values of ted l wells (=0%) and the fluorescence of the hydroxy urea control wells without test compounds (0 uM, =100%). The |C5o values were determined by means of a four parameter fit.

. Caco-Z Permeation Assay Caco—2 cells (purchased from DSMZ Braunschweig, Germany) were seeded at a density of 4.5 x 104 cell per well on 24 well insert plates, 0.4 um pore size, and grown for 15 days in DMEM medium supplemented with 10% fetal bovine serum, 1% GlutaMAX (100x, GIBCO), 100 U/ml llin, 100ug/ml streptomycin (GIBCO) and 1% non essential amino acids (100 x). Cells were maintained at 370C in a humified 5% C02 here. Medium was changed every 2-3 day.

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp Before running the permeation assay, the culture medium was replaced by a FCS—free hepes— carbonate transport puffer (pH 7.2) For ment of monolayer integrity the transepithelial electrical resistance (TEER) was measured. Test compounds were predissolved in DMSO and added either to the apical or basolateral compartment in final concentration of 2 uM. Before and after 2h incubation at 370C samples were taken from both compartments. Analysis of compound content was done after precipitation with methanol by LC/MS/MS analysis. bility (Papp) was calculated in the apical to basolateral (A 9 B) and basolateral to apical (B 9 A) directions.

The apparent permeability was calculated using following equation: Papp = (Vr/P0)(1/S)(P2/t) Where Vr is the volume of medium in the receiver chamber, P0 is the measured peak area of the test drug in the donor chamber at t=0, S the surface area ofthe yer, P2 is the measured peak area of the test drug in the acceptor chamber after 2h of incubation, and t is the tion time. The efflux ratio basolateral (B) to apical (A) was calculated by dividing the Papp B-A by the Papp A-B. In addition the compound recovery was calculated. As assay control reference compounds were analyzed in parallel.

Claims (25)

1. A compound of l formula (I) O R1 N N 5 in which: R1 represents a group selected from: N N NH NH * * * , wherein * indicates the point of attachment of said group with the rest of the molecule; R2 represents en, halogen, -NR7R8, CN, C1-C6-alkyl, C1-C6-alkoxy, 3- to 10-membered 10 heterocycloalkoxy, C2-C6-alkenyl, C3-C6-cycloalkyl, 3- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkenyl, phenyl, heteroaryl, R7, R7R8, -(SO2)R9, 9, -SR9, -(SO2)NR7R8, -NR7(SO2)R9, -((SO)=NR11)R10, -N=(SO)R9R10, -SiR10R11R12, –(PO)(OR7)2, –(PO)(OR7)R10 or –(PO)(R10)2, wherein each C1-C6-alkyl, C1-C6-alkoxy, 3- to 10-membered heterocycloalkoxy, C2-C6- 15 alkenyl, C3-C6-cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl or heteroaryl is optionally substituted, one or more times, independently from each other, with halogen, OH, -NR7R8, C1-C6-alkyl optionally substituted with hydroxyl or phenyl, C1-C6- haloalkyl, C1-C6-alkoxy, C3-C6-cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, -(CO)OR7, R7R8, -NR7(CO)R10, NR8(CO)OR7, -NR8(CO) NR7R8, -(SO2)R9, -(SO)R9, -SR9, 20 -(SO2)NR7R8, O2)R9, -((SO)=NR11)R10, -N=(SO)R9R10, -(PO)(OR7)2, –(PO)(OR7)R10, –(PO)(R10)2 or with a heteroaryl group which is optionally substituted, one or more times, with C1-C4-alkyl; 18225983_1 (GHMatters) P105077.NZ n each 4- to 10-membered heterocycloalkenyl is optionally substituted, one or more times, independently from each other, with C1-C4-alkyl; R3, R4 represent, independently from each other, hydrogen or methyl; R7, R8 represent, independently from each other, hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl or 5 phenyl, which phenyl is optionally substituted, one or more times, with halogen; or R7 and R8 together represent a 4-, 5-, 6- or 7-membered cyclic amine group, which is optionally substituted, one or more times, independently from each other, with a substituent selected from alkyl, C1-C6-haloalkyl, said 4-, 5-, 6- or ered cyclic amine group optionally containing one further atom selected from the group consisting of O, N 10 and S; R9 ents C1-C4-alkyl or phenyl, wherein each C1-C4-alkyl or phenyl is optionally substituted, one or more times, independently from each other, with R13; R10 represents C1-C4-alkyl; or R9 and R10 together, in case of -N=(SO)R9R10 group, represent a 5- to 8-membered 15 heterocycloalkyl group; R11 represents hydrogen, C1-C4-alkyl, R7, -(CO)NR7R8 or CN; R12 represents hydrogen or C1-C4-alkyl; R13 represents halogen, OH, -NR7R8, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6- koxy, C2-C6-alkenyl, cycloalkyl, -(CO)OR7 or -(CO)NR7R8; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

2. The compound according to claim 1, in which R1 represents a group selected from: N N NH NH 25 * * * 18225983_1 (GHMatters) P105077.NZ wherein * indicates the point of attachment of said group with the rest of the molecule; R2 represents hydrogen, halogen, -NR7R8, CN, C1-C6-alkyl, alkoxy, 3- to 10-membered heterocycloalkoxy, C2-C6-alkenyl, C3-C6-cycloalkyl, 3- to 10-membered heterocycloalkyl, 5 4- to 10-membered heterocycloalkenyl, phenyl, heteroaryl, -(CO)OR7, -(CO)NR7R8, -(SO 9, -(SO)R9, -SR9, -(SO 7R8, -NR7(SO 9, -((SO)=NR11 )R 10 , -N=(SO)R9R10 , 2)R 2)NR 2)R -SiR 10 R11 R12 , –(PO)(OR7) 7)R10 or –(PO)(R10 ) 2, –(PO)(OR 2, wherein each C1-C6-alkyl, C1-C6-alkoxy, 3- to 10-membered heterocycloalkoxy, C2-C6- alkenyl, C3-C6-cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl or heteroaryl is 10 optionally substituted, one or more times, independently from each other, with halogen, OH, -NR7R8, C1-C6-alkyl, 3- to 6-membered heterocycloalkyl, 4- to 6- membered heterocycloalkenyl , -(CO)OR7, -(CO)NR7R8, -NR7(CO)R 10 , -NR8(CO)OR 7, -NR8(CO) NR7R8, -(SO 9, -(SO)R9, -SR9, -(SO 7R8, -NR7(SO 9, 2)R 2)NR 2)R -((SO)=NR 11 )R 10 , -N=(SO)R9R10 , -(PO)(OR7) 7)R10 , –(PO)(R10 ) 2,–(PO)(OR 2 or with a 15 heteroaryl group which is optionally substituted, one or more times, with C1-C4-alkyl; wherein each 4- to 10-membered heterocycloalkenyl is optionally substituted, one or more times, ndently from each other, with C1-C4-alkyl; R3, R4 represent, ndently from each other, hydrogen or ; R7, R8 represent, independently from each other, hydrogen or C1-C6-alkyl; or 20 R7 and R8 together represent a 4-, 5-, 6- or 7-membered cyclic amine group, which is optionally tuted, one or more times, independently from each other, with a substituent ed from C1-C6-alkyl, C1-C6-haloalkyl, said 4-, 5-, 6- or 7-membered cyclic amine group optionally containing one r atom selected from the group consisting of O, N and S; 25 R9 represents C1-C4-alkyl or phenyl, wherein each C1-C4-alkyl or phenyl is optionally substituted, one or more times, independently from each other, with R13; R10 represents C1-C4-alkyl; or R9 and R10 together, in case of -N=(SO)R9R10 group, represent a 5- to 8-membered heterocycloalkyl group; 30 R11 represents hydrogen, C1-C4-alkyl, R7, -(CO)NR7R8 or CN; 18225983_1 (GHMatters) P105077.NZ R12 represents hydrogen or C1-C4-alkyl; R13 represents halogen, OH, -NR7R8, CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6- haloalkoxy, C2-C6-alkenyl, C3-C6-cycloalkyl, -(CO)OR7 or -(CO)NR7R8. 5 3. The compound according to claim 1, which is selected from the group of: 4-[(2-(morpholinyl)[2H-pyrazolyl]-[1,7]¬naphthyridineyl]phenyl-N-ethoxycarbonyl- S-methylsulphoximide 4-[(2-(morpholinyl)(2H-pyrazolyl)-[1,7]naphthyridineyl]phenyl-S- sulphoximide 10 4-[6-(methylsulfonyl)pyridinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3,6-dihydro-2H-pyranyl)(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine 4-[4-(N,S-dimethylsulfonimidoyl)phenyl][morpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-[4-methyl(methylsulfonyl)pyridinyl](morpholinyl)(1H-pyrazolyl)-1,7- 15 naphthyridine 4-(4-methanesulphonylphenyl)(morpholinyl)(1H-pyrazolyl)-[1,7]-naphthyridine 4-(2-methanesulphonylphenyl)(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine hydrochloride dimethyl (morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]phenyl}phosphonate 20 4-isopropenyl(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine pholinyl)phenyl(1H-pyrazolyl)-[1,7]naphthyridine 4-[4-(S-ethylsulfonimidoyl)phenyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 3-[(2-(morpholinyl)[2H-pyrazolyl]-[1,7]naphthyridineyl]phenyl-N-ethoxycarbonyl-S- methylsulphoximide 25 ethyl-1,2,3,6-tetrahydropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7- naphthyridine 4-(3-methanesulphonylphenyl)(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine 4-[5-methyl(methylsulfonyl)pyridinyl](morpholinyl)(1H-pyrazolyl)-1,7- naphthyridine 18225983_1 (GHMatters) P105077.NZ 2-(morpholinyl)(1H-pyrazolyl)(1,2,3,6-tetrahydropyridinyl)-1,7-naphthyridine 4-cyclopropyl(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine 3-[(2-(morpholinyl)(2H-pyrazolyl)-[1,7]naphthyridineyl]phenyl-S- methylsulphoximide 5 yl(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine hydrochloride 4-[2-(methylsulfonyl)-1,3-thiazolyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyridin-2(1H)-one 5-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyridin-2(1H)-one 4-[2-fluoro(methylsulfonyl)phenyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 10 2-(morpholinyl){4-[S-(propanyl)sulfonimidoyl]phenyl}(1H-pyrazolyl)-1,7- naphthyridine 4-(4-methanesulphonylphenyl)((R)methylmorpholinyl)(2H-pyrazolyl)- [1,7]naphthyridine 2-((R)methylmorpholinyl)phenyl(2H-pyrazolyl)-[1,7]naphthyridine 15 4-(3-methanesulphonylphenyl)((R)methylmorpholinyl)(2H-pyrazolyl)- [1,7]naphthyridine 4-cyclopropyl((R)methylmorpholinyl)(1H-pyrazolyl)-[1,7]-naphthyridine (R)methylmorpholinyl)(2H-pyrazolyl)-[1,7]naphthyridineyl]phenyl-S- methylsulphoximide 20 3-[2-((R)methylmorpholinyl)(2H-pyrazolyl)-[1,7]naphthyridineyl]phenyl-S- methylsulphoximide 4-methanesulphonyl(morpholinyl)[2-(tetrahydropyranyl)-2H-pyrazolyl]- [1,7]naphthyridine 2-[(3R)methylmorpholinyl](methylsulfonyl)(1H-pyrazolyl)-1,7-naphthyridine 25 pholinyl)(1H-pyrazolyl)-[1,7]naphthyridinecarbonitrile 2-((R)methylmorpholinyl)(-2H-pyrazolyl]-[1,7]naphthyridinecarbonitrile 2-morpholinyl(1H-pyrazolyl)-[1,7]naphthyridinecarboxamide 4-methanesulphonylmethylmorpholinyl(2H-pyrazolyl)-[1,7]naphthyridine 18225983_1 (GHMatters) P105077.NZ rpholinyl)(2H-pyrazolyl)-[1,7]naphthyridineyl]methanol 4-(1-methanesulphonylcyclopropyl)(morpholinyl)(2H-pyrazolyl)-[1,7]naphthyridine 4-isopropoxy(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine pholinyl)(propanyloxy)(1H-pyrrolyl)-1,7-naphthyridine 5 4-[3-(S-methylsulfonimidoyl)propoxy](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-ethoxy(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine 4-methoxy(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine 2-methyl{[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]oxy}propanol 2-(morpholinyl)(1H-pyrazolyl)(tetrahydrofuranylmethoxy)-1,7-naphthyridine 10 3-{[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]oxy}dihydrofuran-2(3H)-one 4-[(3-methyl-1,2-oxazolyl)methoxy](morpholinyl)(1H-pyrazolyl)-1,7- naphthyridine 4-[(5-methyl-1,2-oxazolyl)methoxy](morpholinyl)(1H-pyrazolyl)-1,7- naphthyridine 15 4-benzyloxy(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine ropoxy((R)methylmorpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine tert-butyl [4-({2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin yl}oxy)butyl]carbamate 4-methoxy((R)methylmorpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine 20 tert-butyl [3-({2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin yl}oxy)propyl]carbamate 2-({2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}oxy)ethanamine tert-butyl [2-({2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin yl}oxy)ethyl]carbamate 25 4-({2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}oxy)butan amine 2-[(3R,5S)-3,5-dimethylmorpholinyl]isopropoxy(1H-pyrazolyl)-1,7-naphthyridine 2-[(3R,5R)-3,5-dimethylmorpholinyl]isopropoxy(1H-pyrazolyl)-1,7-naphthyridine 18225983_1 (GHMatters) P105077.NZ 2-(morpholinyl)(1H-pyrazolyl)(tetrahydro-2H-pyranyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine hydrochloride 4-chloromorpholinyl(1H-pyrazolyl)-[1,7]naphthyridine 2-[(3R)methylmorpholinyl](methylsulfanyl)(1H-pyrazolyl)-1,7-naphthyridine 5 N-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}-1,4 4-oxathian- 4-imine 4-oxide 4-{[dimethyl(oxido)-6-sulfanylidene]amino}(morpholinyl)(1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](piperazinyl)(1H-pyrazolyl)-1,7-naphthyridine 10 4-isopropoxy((S)methylmorpholinyl)(1H-pyrazolyl)-[1,7]naphthyridine 2-(morpholinyl)(propanyloxy)(1H-pyrrolyl)-1,7-naphthyridine 4-(1-ethyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(1-methyl-1H-imidazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- 15 naphthyridine 2-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl]aniline 4-(2,3-difluorophenyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 4-[2-methyl(methylsulfonyl)pyridinyl][(3R)methylmorpholinyl](1H-pyrazol yl)-1,7-naphthyridine 20 luoro(methylsulfonyl)phenyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-fluoro[2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl]aniline 4-(1-benzyl-1H-imidazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- yridine 25 4-(2-fluorophenyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine )methylmorpholinyl](2-methyl-1,3-thiazolyl)(1H-pyrazolyl)-1,7- naphthyridine 4-[4-methyl(methylsulfonyl)pyridinyl][(3R)methylmorpholinyl](1H-pyrazol 18225983_1 (GHMatters) P105077.NZ yl)-1,7-naphthyridine 4-(1-cyclopropyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-[2-fluoro(piperazinyl)phenyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- 5 naphthyridine 2-[(3R)methylmorpholinyl][4-(methylsulfonyl)piperazinyl](1H-pyrazolyl)-1,7- naphthyridine -dimethylpropyl)-N-methyl[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridinamine 10 (1-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}piperidin yl)methanol opropyl-N-methyl[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin- 4-amine 4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)[(3R)methylmorpholinyl](1H-pyrazol- 15 1,7-naphthyridine N-(4-fluorophenyl)-N-methyl[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridinamine 2-[(3R)methylmorpholinyl](6-methylpyridinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2-fluoropyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 20 4-(2-fluoromethylpyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](1-methyl-1H-pyrrolyl)(1H-pyrazolyl)-1,7- naphthyridine 4-(6-fluoromethylpyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- 25 naphthyridine 4-(2-fluoromethylpyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(6-fluoropyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 4-(6-methoxypyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- 18225983_1 (GHMatters) P105077.NZ naphthyridine 4-(6-methoxymethylpyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- yridine 4-(6-fluoromethylpyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- 5 naphthyridine )methylmorpholinyl][1-methyl(trifluoromethyl)-1H-pyrazolyl](1H- pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](3-methylthienyl)(1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](5-methylthienyl)(1H-pyrazolyl)-1,7-naphthyridine 10 2-[(3R)methylmorpholinyl](4-methylthienyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3-chlorothienyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](2-methylthienyl)(1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](1H-pyrazolyl)(1H-pyrrolo[2,3-b]pyridinyl)-1,7- naphthyridine 15 4-(3,5-dimethyl-1,2-oxazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(3-chloromethoxypyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine )methylmorpholinyl](1H-pyrazolyl)(tetrahydro-2H-pyranyl)-1,7- 20 naphthyridine 4-(3,6-dihydro-2H-thiopyranyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](4-methylpiperidinyl)(1H-pyrazolyl)-1,7- naphthyridine 25 4-(1-tert-butyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](1-methyl-1H-pyrazolyl)(1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](3-methyl-1,2-oxazolyl)(1H-pyrazolyl)-1,7- 18225983_1 (GHMatters) P105077.NZ naphthyridine 4-(1-ethylmethyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(1,4-dimethyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- 5 yridine ethyl(methylsulfanyl)pyridinyl][(3R)methylmorpholinyl](1H-pyrazol yl)-1,7-naphthyridine 4-[2-methyl(S-methylsulfonimidoyl)pyridinyl][(3R)methylmorpholinyl](1H- pyrazolyl)-1,7-naphthyridine 10 2-[(3R)methylmorpholinyl](1-propyl-1H-pyrazolyl)(1H-pyrazolyl)-1,7- naphthyridine 4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl)[(3R)methylmorpholinyl](1H-pyrazol- 5-yl)-1,7-naphthyridine 4-[1-ethyl(trifluoromethyl)-1H-pyrazolyl][(3R)methylmorpholinyl](1H-pyrazol- 15 5-yl)-1,7-naphthyridine methyl 5-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}-1H- pyrrolecarboxylate )methylmorpholinyl](1H-pyrazolyl)(1,2-thiazolyl)-1,7-naphthyridine N,N-dimethyl{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin 20 yl}aniline 4-(2,4-difluorophenyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 4-(1-isopropyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine ethyl methyl{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin 25 yl}phosphinate 4-{[diethyl(oxido)-6-sulfanylidene]amino}[(3R)methylmorpholinyl](1H-pyrazol yl)-1,7-naphthyridine isobutyl methyl{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin yl}phosphinate 18225983_1 (GHMatters) P105077.NZ (3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}propanol 3-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}pentanol 4-(5-chloropyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 5-fluoro{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}aniline 5 4-[2-fluoro(methylsulfonyl)phenyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl][1-(oxetanyl)-1H-pyrazolyl](1H-pyrazolyl)-1,7- naphthyridine 4-[2-fluoro(pyrrolidinyl)phenyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- 10 naphthyridine 4-[3-(methoxymethyl)methyl-1,2-oxazolyl][(3R)methylmorpholinyl](1H- pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](5-methyl-1,3,4-oxadiazolyl)(1H-pyrazolyl)-1,7- naphthyridine 15 N-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}tetrahydro-1H- 14-thiophenimine 1-oxide 4-{[(4-fluorophenyl)(methyl)oxido-6-sulfanylidene]amino}[(3R)methylmorpholinyl] (1H-pyrazolyl)-1,7-naphthyridine, mixture of 2 diastereoisomers 4-{[(2-fluorophenyl)(methyl)oxido-6-sulfanylidene]amino}[(3R)methylmorpholinyl] 20 (1H-pyrazolyl)-1,7-naphthyridine, mixture of 2 reoisomers 4-{[(R)(2-fluorophenyl)(methyl)oxido-6-sulfanylidene]amino}[(3R)methylmorpholin yl](1H-pyrazolyl)-1,7-naphthyridine, diastereoisomer 4-{[(S)(2-fluorophenyl)(methyl)oxido-6-sulfanylidene]amino}[(3R)methylmorpholinyl]- 8-(1H-pyrazolyl)-1,7-naphthyridine, diastereoisomer 25 4-(dimethylphosphoryl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 4-(diethylphosphoryl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine ethyl isobutyl{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin yl}phosphinate 2-[(3R)methylmorpholinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 18225983_1 (GHMatters) P105077.NZ 4-(1-isobutyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-[5-fluoro(methylsulfonyl)pyridinyl][(3R)methylmorpholinyl](1H-pyrazol yl)-1,7-naphthyridine 5 )methylmorpholinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](4-methyl-1H-pyrazolyl)(1H-pyrazolyl)-1,7- naphthyridine luoro(methylsulfonyl)phenyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 10 4-[4-(isopropylsulfonyl)phenyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(6-fluoropyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 4-(1-ethyl-1H-imidazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 15 1-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}prolinamide 3-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}pyridinamine 2-[(3R)methylmorpholinyl](1H-pyrazolyl)[1-(2,2,2-trifluoroethyl)-1H-pyrazol yl]-1,7-naphthyridine 1-methyl{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin 20 yl}piperazinone 4-[1-(2-fluoroethyl)-1H-pyrazolyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-[1-(2-fluoroethyl)-1H-pyrazolyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 25 2-(3-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}-1H-pyrazol yl)ethanol 2-methyl(3-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}-1H- lyl)propanol 4-[(2R)methylmorpholinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 18225983_1 (GHMatters) P105077.NZ 4-(5-fluoropyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](6-methylpyridinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](3-methylpyridinyl)(1H-pyrazolyl)-1,7-naphthyridine N-(2-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin 5 yl}phenyl)acetamide 3-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}pyridinol 2-(3-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin yl}phenyl)propanol 4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)(morpholinyl)(1H-pyrazolyl)-1,7- 10 naphthyridine 4-[(2S)methylmorpholinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-[(trans)methylcyclopropyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(difluoromethoxy)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 15 2-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]propanol 2-(morpholinyl)(3-oxaazabicyclo[3.2.1]octyl)(1H-pyrazolyl)-1,7-naphthyridine )methylmorpholinyl](1H-pyrazolyl)(pyrrolidinyl)-1,7-naphthyridine 4-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]piperazinone 4-(dimethylphosphoryl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 20 4-[(trans)-2,5-dimethylpiperazinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-[(cis)-3,5-dimethylpiperazinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 1-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl](trifluoromethyl)azetidin methyl hydrogen {4-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridin 25 yl]phenyl}phosphonate 4-(4-methylpiperazinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine pholinyl)(1H-pyrazolyl)[(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl]- 1,7-naphthyridine 18225983_1 (GHMatters) P105077.NZ 4-(3-methoxymethylazetidinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)[(1S,4S)oxaazabicyclo[2.2.1]heptyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl][(methylsulfanyl)methyl](1H-pyrazolyl)-1,7- 5 naphthyridine N,N-dimethyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyridinamine 4-(2-methylpyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine (3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}cyclohexanol 2-fluoro{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}aniline 10 (methyl{4-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]phenyl}oxido-6- sulfanylidene)cyanamide 1-ethyl(methyl{4-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridin yl]phenyl}oxido-6-sulfanylidene)urea 3-({2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}oxy)propan 15 amine 4-(4-cyclopropyl-1H-1,2,3-triazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine lsulfinyl(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)[propanylsulfinyl](1H-pyrazolyl)-1,7-naphthyridine 20 2-[(3R)methylmorpholinyl][3-(methylsulfonyl)propoxy](1H-pyrazolyl)-1,7- naphthyridine 2-(morpholinyl)(phenylsulfonyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(propanylsulfonyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(ethylsulfonyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 25 2-(morpholinyl)(phenylsulfinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(methylsulfinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl][1-oxidotetrahydro-2H-thiopyranyl](1H-pyrazolyl)- 1,7-naphthyridine 83_1 (GHMatters) P105077.NZ 4-(1,1-dioxidotetrahydro-2H-thiopyranyl)[(3R)methylmorpholinyl](1H-pyrazol yl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl]-4,8-di(1H-pyrazolyl)-1,7-naphthyridine N,N-dimethyl(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinamine 5 2-(morpholinyl)(phenylsulfanyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)-N-(propanyl)(1H-pyrazolyl)-1,7-naphthyridinamine 4-(ethylsulfanyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(propanylsulfanyl)(1H-pyrazolyl)-1,7-naphthyridine pholinyl)(1H-pyrazolyl)(1H-pyrrolyl)-1,7-naphthyridine 10 2-(morpholinyl)(1H-pyrazolyl)(1H-pyrrolyl)-1,7-naphthyridine 4-[(4-methoxyphenyl)sulfanyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(5-methyl-1H-pyrazolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 1-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyrrolidinone 4-(1,1-dioxido-1,2-thiazolidinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 15 morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]piperidinone 2-[(3R)methylmorpholinyl](2-methylpyridinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl][2-(propanyloxy)pyridinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(2-methoxypyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- 20 naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(pyridinyl)-1,7-naphthyridine 4-[(4-methoxyphenyl)sulfanyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-[3-fluoro(morpholinyl)pyridinyl][(3R)methylmorpholinyl](1H-pyrazol 25 yl)-1,7-naphthyridine 4-(6-fluoromethylpyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 3-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]-1,3-oxazinanone 83_1 (GHMatters) P105077.NZ 3-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]-1,3-oxazolidinone 4-(3-methoxypyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(2,6-difluoropyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- 5 naphthyridine 4-(5-chlorofluoropyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(3-fluoropyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine 4-(2-chloromethylpyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- 10 naphthyridine 4-(5,6-dimethylpyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(5-fluoromethylpyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 15 2-[(3R)methylmorpholinyl](5-methylthiophenyl)(1H-pyrazolyl)-1,7- naphthyridine 4-(3-methoxythiophenyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(2-chlorothiophenyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- 20 naphthyridine 4-(isoquinolinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridine hlorothiophenyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](4-methylthiophenyl)(1H-pyrazolyl)-1,7- 25 naphthyridine 4-(2,5-dimethylthiophenyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine )methylmorpholinyl](1H-pyrazolyl)(tetrahydro-2H-thiopyranyl)-1,7- naphthyridine 18225983_1 ters) P105077.NZ 2-[(3R)methylmorpholinyl](1-methyl-1,2,5,6-tetrahydropyridinyl)(1H-pyrazol yl)-1,7-naphthyridine 2-[(3R)methylmorpholinyl](1-methyl-1,2,3,6-tetrahydropyridinyl)(1H-pyrazol yl)-1,7-naphthyridine 5 2-[(3R)methylmorpholinyl][1-methylpiperidinyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](1H-pyrazolyl)(1,2,3,6-tetrahydropyridinyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](1H-pyrazolyl)[1-(tetrahydro-2H-pyranyl)-1H- 10 pyrazolyl]-1,7-naphthyridine 4-(4,6-difluoropyridinyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine )methylmorpholinyl](1-methyl-1H-pyrazolyl)(1H-pyrazolyl)-1,7- naphthyridine 15 4-(1,3-dimethyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine -dimethyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](piperidinyl)(1H-pyrazolyl)-1,7-naphthyridine 20 2-[(3R)methylmorpholinyl](1H-pyrazolyl)[3-(trifluoromethyl)-1H-pyrazolyl]- 1,7-naphthyridine 4-(1-cyclobutyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 4-(1-cyclopropyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- 25 naphthyridine 2-[(3R)methylmorpholinyl][1-(propanyl)-1H-pyrazolyl](1H-pyrazolyl)-1,7- naphthyridine difluoromethyl)-1H-pyrazolyl][(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- naphthyridine 18225983_1 (GHMatters) P105077.NZ 4-(1-tert-butyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- yridine )methylmorpholinyl](1H-pyrazolyl)(1,3,5-trimethyl-1H-pyrazolyl)-1,7- naphthyridine 5 2-[(3R)methylmorpholinyl][1-methyl(trifluoromethyl)-1H-pyrazolyl](1H- pyrazolyl)-1,7-naphthyridine 2-(4-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}-1H-pyrazol yl)ethanol 4-(1-ethyl-1H-pyrazolyl)[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7- 10 naphthyridine 2-[(3R)methylmorpholinyl](1-methyl-1H-pyrrolyl)(1H-pyrazolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl][1-(propanyl)-1H-pyrazolyl](1H-pyrazolyl)-1,7- naphthyridine 15 2-[(3R)methylmorpholinyl](1H-pyrazolyl)(1,2,5-trimethyl-1H-pyrrolyl)-1,7- naphthyridine 2-[(3R)methylmorpholinyl](1-phenyl-1H-pyrazolyl)(1H-pyrazolyl)-1,7- yridine 2-[(3R)methylmorpholinyl](3-methyl-1H-pyrazolyl)(1H-pyrazolyl)-1,7- 20 naphthyridine 2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinamine 2-[(3R)methylmorpholinyl][1-(2-methylpropyl)-1H-pyrazolyl](1H-pyrazolyl)- 1,7-naphthyridine 2-[(3R)methylmorpholinyl](1H-pyrazolyl)(1H-pyrazolyl)-1,7-naphthyridine 25 2-[(3R)methylmorpholinyl](1,3-oxazolyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1,3-dimethyl-1H-pyrazolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1,5-dimethyl-1H-pyrazolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(1,3,5-trimethyl-1H-pyrazolyl)-1,7-naphthyridine 4-{[(2-methoxyethyl)(methyl)oxido-6-sulfanylidene]amino}[(3R)methylmorpholinyl]- 18225983_1 (GHMatters) P105077.NZ 8-(1H-pyrazolyl)-1,7-naphthyridine 4-{[(4-bromophenyl)(oxido)propanyl-6-sulfanylidene]amino}[(3R)methylmorpholin yl](1H-pyrazolyl)-1,7-naphthyridine 2-(methyl-N-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin 5 yl}sulfonimidoyl)phenol 4-{[(4-bromophenyl)(methyl)oxido-6-sulfanylidene]amino}[(3R)methylmorpholinyl] (1H-pyrazolyl)-1,7-naphthyridine 4-{[tert-butyl(methyl)oxido-6-sulfanylidene]amino}[(3R)methylmorpholinyl](1H- pyrazolyl)-1,7-naphthyridine 10 formic acid - N-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]-1,4 4-oxathian imine 4-oxide (1:1) morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]hexahydro-14-thiopyran imine 1-oxide 3-methyl{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}butan- 15 2-ol 1-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}(tetrahydro- 2H-pyranyl)ethanol 3,3-dimethyl{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridin yl}butanol 20 2-{2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinyl}hexanol 2-[(3R)methylmorpholinyl](1H-pyrazolyl)-1,7-naphthyridinecarboxamide 2-[(3R)methylmorpholinyl][1-(methylsulfonyl)cyclopropyl](1H-pyrazolyl)-1,7- naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(tetrahydro-2H-pyranylmethoxy)-1,7-naphthyridine 25 N,N-dimethyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]benzamide {4-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]phenyl}(piperidin yl)methanone methyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]benzamide N-cyclopropyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]benzamide 83_1 (GHMatters) P105077.NZ 4-(4-methylpyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1H-indolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1H-indolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 3-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]benzamide 5 4-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]benzamide N-methyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]benzamide 4-(3-fluorophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(5-chlorothiophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2-methoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 10 2-(morpholinyl)(1H-pyrazolyl)[2-(trifluoromethyl)phenyl]-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)[4-(trifluoromethyl)phenyl]-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)[3-(trifluoromethyl)phenyl]-1,7-naphthyridine 4-(3-chlorophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine N-{3-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]phenyl}acetamide 15 4-(3-methoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3,5-dimethoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3-methylphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(4-methoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine anylmethyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 20 methyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]phenol 4-(2,3-dimethylphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine {3-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]phenyl}methanol 4-(4-fluorophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(4-methylphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 25 4-(4-chlorophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2-fluoromethoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 18225983_1 (GHMatters) P105077.NZ 4-(2-methylphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2,3-dimethoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine N,N-dimethyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]aniline N,N-dimethyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]aniline 5 N-{2-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridin yl]phenyl}methanesulfonamide 2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridin yl]phenyl}methanesulfonamide N,N-dimethyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]benzamide 10 2-(morpholinyl)[(1E)-propenyl](1H-pyrazolyl)-1,7-naphthyridine 4-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]phenol 4-(2-fluorophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine {3-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]phenyl}(piperidin yl)methanone 15 pholinyl)[4-(propanyl)phenyl](1H-pyrazolyl)-1,7-naphthyridine N-cyclopropyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]benzamide 4-(biphenylyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2,4-dimethoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2-chlorophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 20 4-(2,5-dimethylphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 3-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]aniline 2-(morpholinyl)(1H-pyrazolyl)[3-(1H-pyrazolyl)phenyl]-1,7-naphthyridine 3-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]phenol 4-(2-fluoromethoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 25 4-(5-fluoromethoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2,4-difluorophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2,3-difluorophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 83_1 (GHMatters) P105077.NZ 4-(2,6-dimethoxyphenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]aniline -dichlorophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine henylyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 5 4-(2-chloropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1-benzothiophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1-methyl-1H-pyrazolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(quinolinyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(pyridinyl)-1,7-naphthyridine 10 4-(2-methoxypyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(5-methylpyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(5-methoxypyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(quinolinyl)-1,7-naphthyridine 2-(morpholinyl)[1-(phenylsulfonyl)-1H-indolyl](1H-pyrazolyl)-1,7-naphthyridine 15 4-(2-chloropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(6-chloropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine {5-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]thiophenyl}methanol 4-(2-fluoropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(6-fluoropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 20 4-(2-chloromethylpyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2-methoxypyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(isoquinolinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3-chloropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3-fluoropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 25 4-(2,6-difluoropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1-methyl-1H-pyrazolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 18225983_1 (GHMatters) P105077.NZ tert-butyl 5-methoxy[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]-1H- indolecarboxylate 2-(morpholinyl)[6-(morpholinyl)pyridinyl](1H-pyrazolyl)-1,7-naphthyridine 4-(4-methylthiophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 5 2-(morpholinyl)(1H-pyrazolyl)(thiophenyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(thiophenyl)-1,7-naphthyridine 4-(3-methylthiophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2-chloromethylpyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(4-methoxypyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 10 hloromethoxypyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine tert-butyl 5-methyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]-1H-indole- 1-carboxylate 4-(5-chlorofluoropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3,5-dimethyl-1,2-oxazolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 15 2-(morpholinyl)(1H-pyrazolyl)(quinolinyl)-1,7-naphthyridine 4-(5-methylthiophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine thoxypyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(2-ethoxypyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(quinolinyl)-1,7-naphthyridine 20 4-(2-chlorothiophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 5-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyridinamine 2-(morpholinyl)(1H-pyrazolyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(6-methylpyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1-methyl-1H-pyrrolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 25 5-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyridinol hloropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3-chloromethoxypyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 18225983_1 (GHMatters) P105077.NZ 4-(3-chlorothiophenyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(5-fluoropyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine methylsulfanyl)pyrimidinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine N-cyclopropyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyrimidin 5 amine 4-(isoquinolinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine N-methyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyridine carboxamide N-tert-butyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyridine 10 carboxamide 4-[5-(methylsulfanyl)pyridinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)(1H-pyrrolo[2,3-b]pyridinyl)-1,7-naphthyridine

3. -[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyridinamine methyl 4-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]thiophene 15 carboxylate 4-[2-methoxy(trifluoromethyl)pyridinyl](morpholinyl)(1H-pyrazolyl)-1,7- naphthyridine 2-(morpholinyl)[2-(propanyloxy)pyridinyl](1H-pyrazolyl)-1,7-naphthyridine 4-(5-chloroethoxypyridinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 20 4-(1-tert-butyl-1H-pyrazolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(piperidinyl)(1H-pyrazolyl)-1,7-naphthyridine 1-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]piperidinol N-methyl(morpholinyl)-N-phenyl(1H-pyrazolyl)-1,7-naphthyridinamine {1-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]pyrrolidinyl}methanol 25 N-methyl(morpholinyl)-N-propyl(1H-pyrazolyl)-1,7-naphthyridinamine panyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3-methylpiperidinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 18225983_1 (GHMatters) P105077.NZ 4-(4-methylpiperidinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 1-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]piperidinecarboxamide 4-(2,5-dihydro-1H-pyrrolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(3,4-dihydroquinolin-1(2H)-yl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 5 4-(3,4-dihydroisoquinolin-2(1H)-yl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-(1,3-dihydro-2H-isoindolyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 2-(morpholinyl)(1H-pyrazolyl)[1,3,3-trimethylazabicyclo[3.2.1]octyl]-1,7- naphthyridine utyl morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]-prolinate 10 N-methyl-N-(2-methylpropyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinamine N-(3-fluorophenyl)-N-methyl(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinamine 4-(1,1-dioxidothiaazaspiro[3.3]heptyl)(morpholinyl)(1H-pyrazolyl)-1,7- naphthyridine 4-(3-fluoropiperidinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 15 N-(2-fluorophenyl)-N-methyl(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinamine 1-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]-prolinamide {1-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]piperidinyl}methanol 4-(4-methoxypiperidinyl)(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine N-(4-fluorophenyl)-N-methyl(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinamine 20 N-methyl[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]-prolinamide 4-[4-(ethylsulfonyl)piperazinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine 4-[4-(methylsulfonyl)piperazinyl](morpholinyl)(1H-pyrazolyl)-1,7-naphthyridine N-cyclopropyl-N-methyl(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinamine N-(2,2-dimethylpropyl)-N-methyl(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridin 25 amine {1-[2-(morpholinyl)(1H-pyrazolyl)-1,7-naphthyridinyl]piperidinyl}methanol. 18225983_1 (GHMatters) P105077.NZ

4. The compound according to claims 1 or 2 of general formula (Ib) O R1 N N (Ib) , in which R1 represents: 5 wherein * indicates the point of attachment of said group with the rest of the molecule; R2 represents hydrogen, halogen, -NR7R8, CN, C1-C6-alkyl, C1-C6-alkoxy, 3- to 10-membered heterocycloalkoxy, C2-C6-alkenyl, C3-C6-cycloalkyl, 3- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkenyl, phenyl, aryl, -(CO)OR7, -(CO)NR7R8, 10 R9, -(SO)R9, -SR9, -(SO2)NR7R8, -NR7(SO2)R9, -((SO)=NR11)R10, -N=(SO)R9R10, -SiR10R11R12, –(PO)(OR7)2, –(PO)(OR7)R10 or –(PO)(R10)2, wherein each C1-C6-alkyl, alkoxy, 3- to 10-membered heterocycloalkoxy, C2-C6- l, C3-C6-cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl or heteroaryl is optionally substituted, one or more times, independently from each other, with 15 halogen, OH, -NR7R8, C1-C6-alkyl optionally substituted with hydroxyl or phenyl, C1-C6- haloalkyl, alkoxy, C3-C6-cycloalkyl, 3- to 6-membered heterocycloalkyl, , -(CO)OR7, -(CO)NR7R8, -NR7(CO)R10, NR8(CO)OR7, -NR8(CO) NR7R8, -(SO2)R9, -(SO)R9, -SR9, -(SO2)NR7R8, -NR7(SO2)R9, -((SO)=NR11)R10, -N=(SO)R9R10, -(PO)(OR7)2, –(PO)(OR7)R10, –(PO)(R10)2 or with a heteroaryl group which is ally substituted, one or more 20 times, with C1-C4-alkyl; wherein each 4- to 10-membered heterocycloalkenyl is optionally substituted, one or more times, independently from each other, with C1-C4-alkyl; R3, R4 represent, independently from each other, en or ; 18225983_1 (GHMatters) P105077.NZ R7, R8 represent, independently from each other, hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl or phenyl, which phenyl is optionally substituted, one or more times, with halogen; or R7 and R8 together represent a 4-, 5-, 6- or 7-membered cyclic amine group, which is ally substituted, one or more times, independently from each other, with a substituent 5 ed from alkyl, C1-C6-haloalkyl, said 4-, 5-, 6- or 7-membered cyclic amine group optionally containing one further heteroatom selected from the group consisting of O, N and S; R9 represents C1-C4-alkyl or phenyl, wherein each C1-C4-alkyl or phenyl is optionally substituted, one or more times, independently from each other, with R13; 10 R10 represents C1-C4-alkyl; or R9 and R10 er, in case of -N=(SO)R9R10 group, represent a 5- to 8-membered heterocycloalkyl group; R11 represents hydrogen, C1-C4-alkyl, -(CO)OR7, -(CO)NR7R8 or CN; R12 represents en or C1-C4-alkyl; 15 R13 represents halogen, OH, , CN, NO2, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6- haloalkoxy, C2-C6-alkenyl, C3-C6-cycloalkyl, -(CO)OR7 or -(CO)NR7R8.

5. The compound of general formula (Ib) according to claim 4, in which R1 represents: 20 * wherein * indicates the point of attachment of said group with the rest of the molecule; R2 represents hydrogen, halogen, -NR7R8, CN, C1-C6-alkyl, alkoxy, 3- to 10-membered heterocycloalkoxy, C2-C4-alkenyl, C3-C6-cycloalkyl, 3- to 10-membered heterocycloalkyl, 25 4- to 10-membered heterocycloalkenyl, phenyl, heteroaryl, -(CO)NR7R8, -(SO2)R9, -(SO)R9, -SR9, -N=(SO)R9R10, –(PO)(OR7)2, –(PO)(OR7)R10, –(PO)(R10)2, 83_1 (GHMatters) P105077.NZ wherein each C1-C6-alkyl, C1-C4-alkoxy, C3-C6-cycloalkyl, 3- to 10-membered cycloalkyl, phenyl or heteroaryl is optionally substituted, one or more times, ndently from each other, with n, OH, amino, -NR7R8, 5 C1-C4-alkyl optionally substituted with hydroxyl or phenyl, C1-C2-haloalkyl, C1-C3-alkoxy, C3-C6-cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, -(CO)OR7, -(CO)NR7R8, -NR7(CO)R10, -NR8(CO)OR7, -(SO2)R9, -SR9, -NR7(SO2)R9, -((SO)=NR11)R10, OR7)2, –(PO)(OR7)R10, or with a heteroaryl group; 10 wherein each 4- to 10-membered heterocycloalkenyl is optionally substituted, one or more times, independently from each other, with ; R4 represents hydrogen or methyl; R7, R8 represent, independently from each other, hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl or phenyl, which phenyl is optionally substituted, one or more times, with halogen; 15 R9 represents C1-C4-alkyl or phenyl, wherein each C1-C4-alkyl or phenyl is optionally substituted, one or more times, ndently from each other, with R13; R10 represents C1-C4-alkyl; or R9 and R10 together, in case of -N=(SO)R9R10 group, represent a 5- to 8-membered heterocycloalkyl group; 20 R11 represents hydrogen, C1-C4-alkyl, -(CO)OR7, -(CO)NR7R8 or CN; R13 represents halogen, OH or C1-C6-alkoxy.

6. The compound of general formula (Ib) according to claims 4 or 5, in which R1 represents: 25 * wherein * indicates the point of ment of said group with the rest of the molecule; 18225983_1 (GHMatters) P105077.NZ R2 represents hydrogen, chloro, amino, propylamino, dimethylamino, methyl(propyl)amino, methyl(2-methylpropyl)amino, methylpropyl(methyl)amino, ropyl(methyl)amino, methyl(phenyl)amino, CN, methyl, ethyl, yl, 3- methylbutanyl, pentanyl, hexanyl, 3,3-dimethylbutanyl, methoxy, ethoxy, 5 propoxy, , 2-methyl-propanyloxy, propanyloxy, (2-oxotetrahydrofuranyl)oxy, propenyl, cyclopropyl, cyclohexyl, azetidinyl, pyrrolidinyl, 2-oxo-1,3-oxazolidinone, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl, 3-oxo-piperazinyl, 1,3-oxazinanyl, 1-oxidotetrahydro-2H-thiopyranyl, 10 oxidotetrahydro-2H-thiopyranyl, 1,1-dioxido-1,2-thiazolidinyl, 5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl, 3-oxaazabicyclo[3.2.1]octyl, 1,3,3-trimethylazabicyclo[3.2.1]octyl, (3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl, (1S,4S)oxaazabicyclo[2.2.1]heptyl, 1,1-dioxidothiaazaspiro[3.3]heptyl, 15 2,5-dihydro-1H-pyrrolyl, 3,6-dihydro-2H-pyranyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 3,6-dihydro-2H-thiopyranyl, phenyl, 1,3-dihydro-2H-isoindolyl, 3,4-dihydroquinolin- 1(2H)-yl, 3,4-dihydroisoquinolin-2(1H)-yl, pyrrolyl, pyrazolyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, 2-oxo-1,2-dihydropyridin- 20 4-yl, indolyl, benzothiophenyl, quinolinyl, isoquinolinyl, 1H-pyrrolo[2,3-b]pyridinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, -(CO)NH2, methylsulfonyl, ethylsulfonyl, propanylsulfonyl, phenylsulfonyl, methylsulfinyl, ethylsulfinyl, propanylsulfinyl, phenylsulfinyl, methylsulfanyl, ethylsulfanyl, ylsulfanyl, phenylsulfanyl, -N=(SO)dimethyl, -N=(SO)diethyl, N CH 3 CH * S * 3 CH3 O CH * N N 3 N CH S S 3 O O S O CH H3C H3C CH3 25 , , , , * * * N N N S S S O O O O , , wherein * indicates the point of attachment of said group with the rest of the le, 18225983_1 (GHMatters) P105077.NZ –(PO)(O-methyl)2, –(PO)(O-ethyl)methyl, –(PO)(Omethylpropyl)methyl, –(PO)(O-ethyl)2-methylpropyl, –(PO)dimethyl, –(PO)diethyl, wherein each methyl, ethyl, propanyl, 3-methylbutanyl, pentanyl, hexanyl, 3,3-dimethylbutanyl, methoxy, ethoxy, propoxy, 2-methyl-propanyloxy, butoxy, 5 cyclopropyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, zinyl, morpholinyl, 3-oxo-piperazinyl, phenyl, pyrrolyl, pyrazolyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, lyl, oxadiazolyl, pyridinyl, pyrimidinyl, indolyl, * * 3 N CH3 N CH S S O O 10 is optionally substituted, one or more times, independently from each other, with fluoro, chloro, bromo, OH, amino, -NH-cyclopropyl, dimethylamino, , ethyl, propanyl, propanyl, 2-methylpropyl, tert-butyl, hydroxymethyl, 2-hydroxyethyl, 2-methylhydroxypropanyl, 2-hydroxypropanyl, , fluoroethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, poxy, 15 methoxymethyl, cyclopropyl, cyclobutyl , ydrofuranyl, tetrahydropyranyl, phenyl, -(CO)O-methyl, (CO)O-tert-butyl, -(CO)NH2, H-methyl, -(CO)NH-tert-butyl, -(CO)dimethylamino, -(CO)piperidinyl, -(CO)NH-cyclopropyl, -NH(CO)methyl, -NH(CO)O-tert-butyl, methylsulfonyl, ethylsulfonyl, propanylsulfonyl, sulfonyl, methylsulfanyl, -(SO2)NR7R8, 20 NH(SO2)methyl,-((SO)=NH)methyl, -((SO)=NH)ethyl, -((SO)=NH)propanyl, -((SO)=N-methyl)methyl, -((SO)=N-(CO)O-ethyl)methyl, -((SO)=N-(CN))methyl, -((SO)=N-(CO)NH-ethyl)methyl, –(PO)(O-methyl)2,–(PO)(OH)(O-methyl) or with furanyl, lyl, wherein each 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl is 25 ally substituted, one or more times, independently from each other, with methyl; R4 represents hydrogen or methyl.

7. The compound of general formula (Ib) according to any one of claims 4 to 6, in which 18225983_1 (GHMatters) P105077.NZ R1 represents: wherein * indicates the point of attachment of said group with the rest of the 5 R2 represents 2,2-dimethylpropyl(methyl)amino, cyclopropyl(methyl)amino, methyl(phenyl)amino, 3-methylbutanyl, cyclopropyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, 5,6-dihydroimidazo[1,2-a]pyrazin- 7(8H)-yl, 3,6-dihydro-2H-thiopyranyl, phenyl, pyrrolyl, pyrazolyl, thiophenyl, imidazolyl, yl, thiazolyl, pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl or 6,7-dihydro-5H-pyrrolo[1,2- 10 a]imidazolyl, wherein each 3-methylbutanyl, cyclopropyl, piperidinyl, piperazinyl, phenyl, pyrrolyl, pyrazolyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl or pyridinyl is optionally substituted, one or two or three times, independently from each other, with fluoro, chloro, OH, amino, methyl, ethyl, propanyl, propanyl, tert-butyl, 15 ymethyl, benzyl, fluoroethyl, oromethyl, methoxy, cyclopropyl, -(CO)O-methyl, methylsulfonyl, methylsulfanyl, -((SO)=NH)methyl; R4 represents methyl.

8. The compound of general formula (Ib) according to any one of claims 4 to 7, in which 20 R1 represents: wherein * indicates the point of ment of said group with the rest of the molecule; R2 represents tetrahydro-2H-thiopyranyl, piperidinyl, 5,6-dihydroimidazo[1,2-a]pyrazin- 25 7(8H)-yl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, nyl or 6,7-dihydro-5H-pyrrolo[1,2- azolyl, 18225983_1 (GHMatters) P105077.NZ wherein each piperidinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl or pyridinyl is optionally substituted, one or two times, independently from each other, with fluoro, amino, , ethyl, propanyl, hydroxymethyl, methoxy, cyclopropyl, sulfonyl, methylsulfanyl, -((SO)=NH)methyl; 5 R4 represents methyl.

9. The compound of general formula (Ib) according to any one of claims 4 to 7, in which R1 represents: * , 10 wherein * tes the point of attachment of said group with the rest of the molecule; R2 ents 2,2-dimethylpropyl(methyl)amino, cyclopropyl(methyl)amino, methyl(phenyl)amino, 3-methylbutanyl, ropyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, hydroimidazo[1,2- 15 a]pyrazin-7(8H)-yl, 3,6-dihydro-2H-thiopyranyl, phenyl, pyrrolyl, 1H-pyrazolyl, 1H- pyrazolyl, enyl, thiophenyl, 1H-imidazolyl, azolyl, 1,3-thiazol yl, pyridineyl, pyridineyl, 1H-pyrrolo[2,3-b]pyridinyl or 6,7-dihydro-5H- pyrrolo[1,2-a]imidazolyl, wherein each 3-methylbutanyl, cyclopropyl, piperidinyl, piperazinyl, phenyl, 20 pyrrolyl, 1H-pyrazolyl, 1H-pyrazolyl, thiophenyl, thiophenyl, 1H-imidazol- 5-yl, 1,2-oxazolyl, 1,3-thiazolyl, pyridineyl or pyridineyl is optionally substituted, one or two or three times, ndently from each other, with fluoro, chloro, OH, amino, methyl, ethyl, propanyl, propanyl, tert-butyl, hydoxymethyl, benzyl, 2-fluoroethyl, trifluoromethyl, methoxy, cyclopropyl, 25 -(CO)O-methyl, methylsulfonyl, methylsulfanyl or =NH)methyl; R4 represents methyl.

10. The compound of general formula (I) or (Ib) according to any one of claims 1 to 9, which is 2-[(3R)methylmorpholinyl](1-methyl-1H-pyrazolyl)(1H-pyrazolyl)-1,7- 18225983_1 (GHMatters) P105077.NZ naphthyridine, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a e of same.

11. The compound of general formula (I) or (Ib) according to any one of claims 1 to 10 for use in 5 the treatment or prophylaxis of a disease.

12. Use of the nd according to any one of claims 1 to 10 in the manufacture of a medicament for the treatment or prophylaxis of a disease. 10

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 and one or more pharmaceutically acceptable excipient(s).

14. The pharmaceutical composition according to claim 13 for use in the treatment or prophylaxis of a hyperproliferative disease.

15. A pharmaceutical combination sing: - one or more active ingredient(s) ed from a compound according to any one of claims 1 to 10, and - one or more active ingredient(s) selected from antihyperproliferative, cytostatic or 20 cytotoxic substances for treatment of cancers.

16. A compound of general a 8 O R1 N N in which R1, R3 and R4 are as defined for the compound of general formula (I) or(Ib) 25 according to any one of claims 1 to 10. 18225983_1 (GHMatters) P105077.NZ

17. Use of a compound according to any one of claims 1 to 10 in the production of a medicament for the treatment and/or prophylaxis of a disease mediated by ATR kinase. 5

18. Use of a pharmaceutical composition according to claim 13 in the tion of a medicament for the treatment and/or prophylaxis of a disease mediated by ATR kinase.

19. Use according to claim 17 or 18, wherein the disease mediated by ATR kinase is a hyperproliferative disease.

20. A method for the treatment or prophylaxis of a disease mediated by ATR kinase, comprising administering to a non-human mammal in need thereof an ive amount of: (i) a compound according to any one of claims 1 to 10; or (ii) a pharmaceutical composition according to claim 13; or (iii) a pharmaceutical ation according to claim 15.

21. The compound ing to claim 1 or 16, substantially as herein described with reference to any one of the Examples.

22. The pharmaceutical composition according to claim 13, substantially as herein described with 20 reference to any one of the Examples.

23. The ceutical ation according to claim 15, substantially as herein described with reference to any one of the Examples. 25

24. Use according to any one of claims 12, 17 and 18, substantially as herein described with reference to any one of the Examples.

25. The method according to claim 20, substantially as herein described with reference to any one of the Examples. 18225983_1 (GHMatters) P105077.NZ eolf‐seql.txt