HYDROXAMAT COMPOUND, MANUFACTURING PROCESS FOR IT AND USE OF IT

Description

Technical field

[0001] The present invention relates to the field of pharmaceutical chemistry, and particularly relates to hydroxamate compounds, preparation method therefor, and application thereof.Background art

[0002] Janus Kinase (JAK) family is a group of non-receptor tyrosine kinase. Four members of the family have been found, including JAK1, JAK2, JAK3 and TYK2. Signal transducer and activator of transcription (STAT) is the direct substrate of JAK, and seven members have been found, including STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. Many cytokines and growth factors transmit signals through the JAK-STAT signal pathway. These cytokines and growth factors have corresponding receptors on the cell membrane, and these receptors do not have kinase activity by themselves but instead have JAK binding sites in the intracellular segment. The binding of the receptor to the ligand causes dimerization of the receptor molecules, making the JAK coupled to the receptor approach to each other and activated through the interaction of tyrosine residues phosphorylation. Activated JAK catalyzes the phosphorylation of the tyrosine residues of the receptor itself to form the corresponding STAT docking sites, so that STAT is allowed to couple with the receptor and activated by phosphorylation under the action JAK. After entering the nucleus in the form of dimer, STAT couples with the corresponding target gene promoter to activate the corresponding gene transcription and expression process. Although one kind of JAK can participate in the signal transduction processes of multiple cytokines, and one kind of cytokine signal pathway can also activate multiple JAKs, cytokines have certain selectivity for activated STAT molecules.

[0003] JAK-STAT signal pathway is closely related to autoimmune diseases and inflammatory diseases. Therefore, the JAK family has become a hot target for new drug research and development. Small molecular drugs that inhibit JAK1, JAK2 and JAK3 have been approved for the treatment of multiple related diseases, such as pan-JAK inhibitor tofacitinib and specifictinib, and JAK1 / JAK2 inhibitor baricitinib, which have been approved for the treatment of rheumatoid arthritis, and JAK1 / JAK2 inhibitor ruxolitinib, which has been approved for the treatment of bone marrow fibrosis. However, these drugs have been box-warned by the FDA of the United States because of the potential risk of infection and thrombosis, especially in the circumstances of high-dose and / or long-term uses. Such first generation of JAK inhibitors fail to achieve high selective inhibition of different subtypes of JAK kinase, which might be the reason for those substantial side effects. Therefore, the development of the next generation of JAK inhibitors focuses on high selectivity. WO2020 / 086616 discloses compounds that are useful in treating a TYK2-mediated disorder.

[0004] As a member of the JAK family, Tyrosine Kinase 2 (TYK2) is widely distributed in a variety of tissues and cells, and capable of coupling with receptors such as IFNAR1, IL10R2, EL12R- β1, and gp130, etc. It plays roles in coupled forms such as TYK2 / JAK1, TYK2 / JAK2, TYK2 / JAK1 / JAK2, to mediate signal pathways related to factors such as type I interferon, interleukin 10 (IL-10), IL-12, IL-23, etc. However, they do not participate in any cytokine response mediated by any other kinase. Although no TYK2 inhibitor has been approved for marketing yet, it is considered that TYK2 inhibitor might be a promising target with less side effects when providing the same efficacy, due to its unique molecular mechanism of action in diseases. By inhibiting the TYK2 signal pathway, TYK2 inhibitors might block the signal pathways induced by factors including type I interferon, IL-10, IL-12, IL-23, etc., and provide a positive effect on diseases including but not limited to those diseases closely related to these factors.Summary of the invention

[0005] The invention is set out in the appended set of claims 1-15.Problems to be solved by the invention:

[0006] Although several patent applications relating to TYK2 selective inhibitors have been published, due to the excellent prospects of TYK2 specific inhibitors in the treatment of inflammatory diseases, autoimmune diseases and cancers, there still is a need for new compounds. After continuous efforts, the inventors of this application have designed compounds represented by formula (I), formula (I') or formula (I"), which are found to exhibit excellent effects, better druggability, stronger drug efficacy and higher TYK2 kinase selectivity.Solutions to solve the problems:

[0007] Aiming to solve the above problems, the inventors of this application have carried out intensive researches and found that some particular hydroxamate compounds can achieve the desired purpose, thereby completing the invention.

[0008] The present invention relates to the following hydroxamate compounds.

[0009] Embodiments that the present invention seek to protect: A compound represented by formula (I), or a pharmaceutically acceptable salt thereof: wherein: X is CR a< ; Y is CH; R a< is hydrogen; R 0< is hydrogen; R 1< is selected from the group consisting of C 1-6 alkyl optionally substituted by from one to seven R 1a< groups; R 1a< is selected from the group consisting of deuterium, F and Cl; R 2< is selected from the group consisting of C 3-6 cycloalkyl-C(O)-, C 3-6 heterocyclyl-C(O)- wherein the C 3-6 heterocyclyl contains from one to two heteroatoms selected from N, O and S, phenyl, and 5-6 membered heteroaryl containing from one to two heteroatoms selected from N, O and S, wherein the C 3-6 cycloalkyl, C 3-6 heterocyclyl containing from one to two heteroatoms selected from N, O and S, phenyl, and 5-6 membered heteroaryl containing from one to two heteroatoms selected from N, O and S are respectively and optionally substituted by from one to two R 2a< groups; most preferably, R 2< is selected from the group consisting of C 3-6 cycloalkyl-C(O)-, C 3-6 heterocyclyl-C(O)- wherein the C 3-6 heterocyclyl contains from one to two heteroatoms selected from N, O and S, phenyl, and 5-6 membered heteroaryl containing from one to two heteroatoms selected from N and S, wherein the 5-6 membered heteroaryl containing from one to two heteroatoms selected from N and S is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl and pyrazolyl, wherein the C 3-6 cycloalkyl, C 3-6 heterocyclyl containing from one to two heteroatoms selected from N, O and S, phenyl, and 5-6 membered heteroaryl containing from one to two heteroatoms selected from N and S are respectively and optionally substituted by from one to two R 2a< groups; preferably, the C 3-6 heterocyclyl containing from one to two heteroatoms selected from N, O and S is azetidinyl; preferably, the heterocyclyl in the C 3-8 heterocyclyl-C(O)- or C 3-6 heterocyclyl-C(O)- is connected to -C(O)- through the heteroatom in the heterocyclic ring; preferably, the heteroatom is N atom; R 2a< is selected from the group consisting of deuterium, =O (oxo), F, Cl, Br, I, CN, OCF 3 , -NO 2 , -(CH 2 ) r -OR b< , -(CH 2 ) r -SR b< , -(CH 2 ) r -C(O)R b< , -(CH 2 ) r -C(O)OR b< , -(CH 2 ) r -NR b< R c< , -(CH 2 ) r -C(O)NR b< R c< , -(CH 2 ) r -NR b< C(O)R c< , -(CH 2 ) r -NR b< C(O)OR c< ,-NR b< C(O)NR c< R c< , -NR b< S(O) p R c< , -S(O) p R c< , -P(O)R b< R c< , C 1-6 alkyl optionally substituted by from one to three R d< groups, C 2-6 alkenyl optionally substituted by from one to three R d< groups, C 2-6 alkynyl optionally substituted by from one to three R d< groups, -(CH 2 ) r -3-10 membered carbocyclyl optionally substituted by from one to three R d< groups, and -(CH 2 ) r -5-10 membered heterocyclyl optionally substituted by from one to three R d< groups; wherein the heterocyclyl contains from one to four heteroatoms selected from O, N and S(O) p ; preferably R 2a< is selected from the group consisting of C 1-6 alkyl, halogen, C 1-6 alkoxy, C 3-6 cycloalkyl, cyano, halo C 1-6 alkyl, C 1-6 alkyl substituted by hydroxyl group, and C 1-6 alkyl-S(O) 2 -; R 3< is selected from the group consisting of phenyl, pyridinyl, 2-pyridinonyl and indazolyl, wherein the phenyl, pyridinyl, 2-pyridinonyl and indazolyl are optionally substituted by from one to three R 3a< groups; R 3a< is selected from the group consisting of F, Cl, Br, I, CN, -NO 2 , -OR b< , -SR b< ,-C(O)OR b< , -C(O)NR b< R c< , -NR b< C(O)R c< , -NR b< C(O)OR c< , -NR b< C(O)NR c< R c< , -NR b< S(O) 2 R c< , -S(O) 2 R c< , -S(O) 2 NR c< R c< , -P(O)R b< R c< , C 1-6 alkyl optionally substituted by from one to three R d< groups, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5-9 membered heteroaryl containing from one to three heteroatoms selected from N, O and S and optionally substituted by from one to three R d< groups, and 5-6 membered saturated heterocyclyl containing from one to two heteroatoms selected from N, O and S; R b< is selected from the group consisting of hydrogen, C 1-6 alkyl optionally substituted by from one to three R d< groups, and 4-6 membered saturated heterocyclyl containing from one to two oxygen atoms; R c< is selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-6 cycloalkyl; R d< is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I,-OCF 3 , -CF 3 , -(CH 2 ) r -CN, -NO 2 , -OR e< , -(CH 2 ) r -COR c< , -NR e< R e< , -NR e< C(O)OR c< , C 1 -C 6 alkyl, C 3-6 cycloalkyl, and -(CH 2 ) r -phenyl; R e< is hydrogen; p is 0, 1 or 2, and r is 0, 1, 2, 3 or 4.

[0010] According to a preferred embodiment, when: X is CR a< ; R a< is hydrogen; R 0< is hydrogen; R 1< is selected from the group consisting of methyl, ethyl, isopropyl, t-butyl, trideuterated methyl and 2,2,2-trifluoroethyl; R 2< is selected from the group consisting of cyclopropylcarbonyl, phenyl, pyrazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, wherein the cyclopropylcarbonyl, phenyl, pyrazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl are optionally substituted by from one to two R 2a< groups; R 2a< is selected from the group consisting of methyl, F, methoxy, cyclopropyl, cyano, -CF 3 , hydroxymethyl and methanesulfonyl; R 3< is selected from the group consisting of phenyl, pyridinyl, 2-pyridinonyl and indazolyl, wherein the phenyl, pyridinyl, 2-pyridinonyl and indazolyl are optionally substituted by from one to three R 3a< groups; R 3a< is selected from the group consisting of F, Cl, Br, I, CN, -OR b< , -C(O)NR b< R c< ,-NR b< S(O) 2 R c< , -S(O) 2 R c< , -S(O) 2 NR c< R c< , -P(O)R b< R c< , C 1-6 alkyl optionally substituted by from one to three R d< groups, C 2-6 alkynyl, C 3-6 cycloalkyl, 5-9 membered heteroaryl containing from one to three heteroatoms selected from N, O and S and optionally substituted by from one to three R d< groups, and 5-6 membered saturated heterocyclyl containing from one to two heteroatoms selected from N, O and S; R b< is selected from the group consisting of hydrogen; methyl, ethyl, and isopropyl, each optionally substituted by from one to three R d< groups; and R c< is selected from the group consisting of hydrogen, methyl and cyclopropyl; R d< is selected from the group consisting of deuterium, F, Cl, hydroxyl, methyl, cyclopropyl and isopropyl;

[0011] In some embodiments, when: X is CH; R 1< is selected from the group consisting of methyl, ethyl, isopropyl, t-butyl, trideuterated methyl and 2,2,2-trifluoroethyl; R 2a< is selected from the group consisting of methyl, F, methoxy, cyclopropyl, cyano, -CF 3 , hydroxymethyl and methanesulfonyl; R 3a< is selected from the group consisting of F, Cl, Br, I, CN, -OR b< , -C(O)NR b< R c< ,-NR b< S(O) 2 R c< , -S(O) 2 R c< , -S(O) 2 NR c< R c< , -P(O)R b< R c< , C 1 -C 3 alkyl optionally substituted by from one to three R d< groups, C 2-4 alkynyl, C 3-5 cycloalkyl, 5-9 membered heteroaryl containing from one to three heteroatoms selected from N, O and S and optionally substituted by R d< group, and 5-6 membered saturated heterocyclyl containing from one to two heteroatoms selected from N, O and S, wherein the 5-9 membered heteroaryl containing from one to three heteroatoms selected from N, O and S is selected from the group consisting of thiazolyl, benzimidazolyl, pyrazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl and pyrazinyl, wherein the 5-6 membered saturated heterocyclyl containing from one to two heteroatoms selected from N, O and S is selected from the group consisting of morpholinyl and piperidinyl; R b< is selected from the group consisting of hydrogen; methyl, ethyl, and isopropyl, each optionally substituted by from one to three R d< groups; and R c< is selected from the group consisting of hydrogen, methyl and cyclopropyl; R d< is selected from the group consisting of deuterium, F, Cl, hydroxyl, methyl, cyclopropyl and isopropyl.

[0012] In some preferred embodiments, R 2< is selected from the group consisting of

[0013] According to some of the above embodiments, R 3< is selected from the group consisting of:

[0014] Additionally, according to the above embodiments the present invention further provides a compound represented by formula (I") or a pharmaceutically acceptable salt thereof: wherein: X is CH; Y is CH; R 0< is hydrogen; R 1< is ethyl; R 2< is selected from the group consisting of pyridinyl, pyrimidinyl, -C(O)-C 3-6 cycloalkyl and -C(O)-C 3-6 heterocyclyl, wherein the C 3-6 heterocyclyl contains from one to two heteroatoms selected from N, O and S; wherein the C 3-6 cycloalkyl and C 3-6 heterocyclyl are respectively and optionally substituted by from one to three R 2a< groups;R 2a< is selected from the group consisting of C 1-6 alkyl, halogen, C 1-6 alkoxy, C 3-6 cycloalkyl, cyano, halo C 1-6 alkyl, C 1-6 alkyl substituted by hydroxyl group, and C 1-6 alkyl-S(O) 2 -; R 3< is phenyl optionally substituted by from one to three R 3a< groups; R 3a< is selected from the group consisting of -(CH 2 ) r -OR b< , -NR b< S(O) p R c< , F, Cl, C 1-6 alkyl, C 3-6 cycloalkyl, triazolyl, pyrazolyl, pyrimidinyl and pyrazinyl; wherein the C 1-6 alkyl, C 3-6 cycloalkyl, triazolyl, pyrazolyl, pyrimidinyl and pyrazinyl are, respectively and independently, optionally substituted by from one to three R d< groups. R b< is selected from the group consisting of hydrogen, C 1-6 alkyl optionally substituted by from one to three R d< groups, and 4-6 membered saturated heterocyclyl containing from one to two oxygen atoms; R c< is selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-6 cycloalkyl; R d< is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, OCF 3 , CF 3 , -(CH 2 ) r -CN, NO 2 , OR e< , -(CH 2 ) r -COR c< , -NR e< R e< , -NR e< C(O)OR c< , C 1 -C 6 alkyl, C 3-6 cycloalkyl, and -(CH 2 ) r -; R e< is hydrogen; p is 0, 1 or 2, and r is 0, 1, 2, 3 or 4.

[0015] The invention is further described by claims 7-12.

[0016] The compounds represented by Formula I or Formula I' or Formula I" in the present invention include the following exemplary compounds: Compound #Structurenomenclature1* 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-oxo-1-(thiazol-2-yl)-1,2-dihydropyridin-3-yl)amino)nicotinamide2 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicoti namide3* 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)amino)nicotinamide4 6-((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicoti namide5* N-methoxy-6-(((2-methoxy pyridin-3-yl)amino)-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicoti namide6* 6-(cyclopropylcarboxamido)-N-methoxy-4-((4-methoxy-2-(N-methyl methanesulfonamido)phenyl)amino)nicoti namide7* 6-(cyclopropylcarboxamido)-N-methoxy-4-((6-methoxy-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide8* 6-((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((6-methoxy-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide9* N-methoxy-4-((6-methoxy-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)-6-((2-methoxy pyridin-3-yl)amino)nicotinamide10 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-(N-methyl methanesulfonamido)-4-(trifluoromethyl)phenyl)amino)nicotinamide11* 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)-4-(trifluoromethyl)phenyl)amino)nicotinamide12 6-(cyclopropylcarboxamido)-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide13 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide14 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide15* 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((4-fluorophenyl)amino)-N-methoxy nicotinamide16 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy-6-((5-methoxy pyridin-2-yl)amino)nicotinamide17* 6-((4-fluorophenyl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide18 4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy-6-((5-methoxy pyridin-2-yl)amino)nicotinamide19 4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide20 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((5-methoxy pyridin-2-yl)amino)nicotinamide21 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy nicotinamide22 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((6-fluoropyridin-2-yl)amino)nicotinamide23* 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-isopropoxy nicotinamide24* 4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(((6-fluoropyridin-2-yl)amino)-N-isopropoxy nicotinamide25* 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide26* 6-(cyclopropylcarboxamido)-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide27* 6-((5-cyclopropyl pyridin-2-yl)amino)-N-ethoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicoti namide28* 6-(cyclopropylcarboxamido)-N-methoxy-4-((1-methyl-1H-indazol-6-yl)amino)nicotinamide29 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)nicotinamide30* 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)nicotinamide31* 4-((3-cyano-2-methoxy phenyl)amino)-6-(cyclopropylcarboxamido)-N-methoxy nicotinamide32* 6-(cyclopropylcarboxamido)-4-((3-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide33* 6-(cyclopropylcarboxamido)-N-methoxy-4-((3-methyl-2-(N-methyl methanesulfonamido)phenyl)amino)nicoti namide34* 6-(cyclopropylcarboxamido)-4-((2-(N, N-dimethyl aminosulfonyl)phenyl)amino)-N-methoxy nicotinamide35* 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide36 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide37* 4-((2-(N, N-dimethyl aminosulfonyl)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide38 4-((3-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide39* 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-(oxetan-3-yloxy)phenyl)amino)nicotinamide40* 6-(((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(oxetan-3-yloxy)phenyl)amino)nicotinamide41 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)nicotinamide42 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)nicotinamide43 6-((5-cyano pyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicoti namide44 6-((5-fluoro-4-methyl pyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicoti namide45 6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicoti namide46 4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide47 4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide48* 4-((2-cyano-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6-(cyclopropylcarboxamido)-N-methoxy nicotinamide49* 4-((2-cyano-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide50* 6-(cyclopropylcarboxamido)-N-methoxy-4-((3-(1-methyl-1H-pyrazol-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinamide51* 6-((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((3-(1-methyl-1H-pyrazol-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinamide52* 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide53* 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)pyridazine-3-carboxamide54* 6-(cyclopropylcarboxamido)-4-((2-(difluoromethoxy)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-N-methoxy nicotinamide55* 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(5-methyl-1, 2, 4-oxadiazol-3-yl)phenyl)amino)nicotinamide56 6-(cyclopropylcarboxamido)-N-methoxy-4-((4-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide57 4-((3-carbamoyl-2-methoxy phenyl)amino)-6-(cyclopropylcarboxamido)-N-methoxy nicotinamide58 6-((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((4-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide59* 6-(cyclopropylcarboxamido)-N-methoxy-4-((6-methyl-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide60 6-(((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((6-methyl-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide61 4-((4-(cyclopropyl methoxy)-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide62 4-((4-(cyclopropyl methoxy)-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide63 6-(cyclopropylcarboxamido)-4-((4-(cyclopropyl methoxy)-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide64* 6-((4-fluorophenyl)amino)-N-methoxy-4-((6-methyl-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide65* 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-N-methyl-4-((2-(N-methyl methanesulfonamido)phenyl)amino) nicotinamide66* 6-((4, 6-dimethyl pyrimidin-2-yl)amino)-N-ethoxy-4-((4-methyl-2-(N-methyl cyclopropylsulfonamido)phenyl)amino) nicotinamide67* 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy-2-methyl nicotinamide68 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-(methoxy-d3)nicotinamide69 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl)phenyl)amino)-nicotinamide70 6-(cyclopropylcarboxamido)-4-((4-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide71* (control) 6-(cyclopropylcarboxamido)-N-ethyl-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide72* N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6-((4-(methanesulfonyl)phenyl)amino)nicotinamide73* 6-(cyclopropylcarboxamido)-4-((2-(dimethyl phosphoryl)phenyl)amino)-N-methoxy nicotinamide74* 4-((2-(dimethyl phosphoryl)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide75* 4-((3-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(cyclopropylcarboxamido)-N-methoxy nicotinamide76* 4-((3-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide77* 4-((3-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide78* 4-((3-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy-6-((2-methoxy pyridin-3-yl)amino)nicotinamide79 4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(cyclopropylcarboxamido)-N-methoxy nicotinamide80 4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide81 6-(cyclopropylcarboxamido)-N-methoxy-4-((4-methyl-2-(N-methyl methanesulfonamido)phenyl)amino) nicotinamide82* 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-(N-methyl methanesulfonamido)-3-(trifluoromethyl)phenyl)amino)nicotinamide83* 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)-3-(trifluoromethyl)phenyl)amino)nicotinamide84* 6-((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)-3-(trifluoromethyl)phenyl)amino)nicotinamide85* 6-(cyclopropylcarboxamido)-4-((3-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide86* 4-((3-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(6-fluoropyridin-2-yl)-N-methoxy nicotinamide87* 6-(cyclopropylcarboxamido)-N-methoxy-4-((3-(1-methyl-1H-pyrazol-4-yl)-2-(N-methyl methanesulfonamido)phenyl)amino) nicotinamide88* 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((3-(1-methyl-1H-pyrazol-4-yl)-2-(N-methyl methanesulfonamido)phenyl)amino) nicotinamide89* 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methanesulfonyl)phenyl)amino) nicotinamide90 6-(cyclopropylcarboxamido)-N-ethoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino) nicotinamide91* N-(t-butoxy)-6-(cyclopropylcarboxamido)-4-((2-(N-methyl methanesulfonamido)phenyl)amino) nicotinamide92* N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-(trifluoromethyl)pyridin-2-yl)amino)nicotinamide93* (control) 6-(cyclopropylcarboxamido)-4-((2-(dimethyl phosphoryl)phenyl)amino)nicotinamide94* (S)-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(2, 2-dimethyl cyclopropyl-1-carboxamido)-N-methoxy nicotinamide95 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((5-fluoropyridin-2-yl)amino)nicotinamide96* 4-((4-cyclopropyl-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-(pyridin-2-ylamino)nicotinamide97 6-(cyclopropylcarboxamido)-4-((4-cyclopropyl-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy nicotinamide98 4-((4-cyclopropyl-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy nicotinamide99* 4-((4-cyclopropyl-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((5-fluoro-4-methyl pyridin-2-yl)amino)nicotinamide100* (control) 6-((5-fluoropyridin-2-yl)amino)-N-methyl-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide101 N-methoxy-6-(((5-methoxy pyridin-2-yl)amino)-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide102 N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-methyl pyridin-2-yl)amino)nicotinamide103* 6-((4-cyano phenyl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide104* 6-((4-fluorophenyl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino) nicotinamide105* (S)-6-(2, 2-dimethyl cyclopropyl-1-carboxamido)-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino) nicotinamide106 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((4-methyl-2-(N-methyl methanesulfonamido)phenyl)amino) nicotinamide107* N-methoxy-4-((4-methyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-methyl pyridin-2-yl)amino)nicotinamide108 N-methoxy-6-(((5-methoxy pyridin-2-yl)amino)-4-((4-methyl-2-(N-methyl methanesulfonamido)phenyl)amino) nicotinamide109 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((6-methyl-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide110 4-((6-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-fluoro-4-methyl pyridin-2-yl)amino)-N-methoxy nicotinamide111 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-cyano pyridin-2-yl)amino)-N-methoxy nicotinamide112 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-methoxy nicotinamide113 4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((4-methoxy phenyl) amino)nicotinamide114 4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((5-cyano pyridin-2-yl)amino)nicotinamide115 4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy nicotinamide116 4-((2-(cyclopropyl sulfonamido)phenyl)amino)-N-ethoxy-6-((6-fluoropyridin-2-yl)amino)nicotinamide117* N-ethoxy-6-(((6-fluoropyridin-2-yl)amino)-2-((2-(methyl sulfonamido)phenyl)amino)nicotinamide118 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethoxy)nicotinamide119 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-(2,2,2-trifluoroethoxy)nicotinamide120* 6-(cyclopropylcarboxamido)-4-((4-cyclopropyl-5-methyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy nicotinamide121* 4-((4-cyclopropyl-5-methyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy nicotinamide122* 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((5-(hydroxymethyl)pyridin-2-yl)amino)nicotinamide123 * 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((4, 6-dimethyl pyrimidin-2-yl)amino)-N-ethoxy nicotinamide124* 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-(pyrimidin-2-ylamino)nicotinamide125 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((5-fluoro-4-methyl pyridin-2-yl)amino)nicotinamide126 6-((5-cyano pyridin-2-yl)amino)-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy nicotinamide127 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino) nicotinamide128 4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((5-fluoropyridin-2-yl)amino)nicotinamide129 4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((6-fluoropyridin-2-yl)amino)nicotinamide130 N-ethoxy-6-(((5-fluoropyridin-2-yl)amino)-4-((2-(N-methyl methanesulfonamido)-4-morpholinophenyl)amino)nicotinamide131 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((4-methoxy-2-(N-methyl methanesulfonamido)phenyl)amino) nicotinamide132 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((2-(N-methyl methanesulfonamido)-4-(piperidin-1-yl)phenyl)amino)nicotinamide133 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((4-methyl-2-(N-methyl methanesulfonamido)phenyl)amino) nicotinamide134 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((2-(N-methyl methanesulfonamido)-4-morpholinophenyl)amino)nicotinamide135* N-ethoxy-6-(((1-methyl-1H-pyrazol-5-yl)amino)-4-((2-(N-methyl methanesulfonamido)-4-morpholinophenyl)amino)nicotinamide136 N-ethoxy-4-((2-(N-methyl methanesulfonamido)-4-morpholinophenyl)amino)-6-(pyrazin-2-ylamino)nicotinamide137* N-ethoxy-6-(((1-methyl-1H-pyrazol-3-yl)amino)-4-((2-(N-methyl methanesulfonamido)-4-morpholinophenyl)amino)nicotinamide138 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-(pyridin-2-ylamino)nicotinamide139 6-(cyclopropylcarboxamido)-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy nicotinamide140* 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((1-methyl-1H-pyrazol-4-ylamino)nicotinamide141 N-ethoxy-4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(5-methoxy pyridin-2-ylamino)nicotinamide142 6-(5-cyano pyridin-2-ylamino)-N-ethoxy-4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino) nicotinamide143 N-ethoxy-4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(6-fluoropyridin-2-ylamino)nicotinamide144 N-ethoxy-4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(5-fluoropyridin-2-ylamino)nicotinamide145 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-(pyrazin-2-ylamino)nicotinamide146 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((6-methyl pyridin-2-yl)amino)nicotinamide147* 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((4-methyl pyridin-2-yl)amino)nicotinamide148* 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((6-methyl pyridin-3-yl)amino)nicotinamide149* 4-((5-chloro-4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy nicotinamide150* 4-((5-chloro-4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(cyclopropylcarboxamido)-N-ethoxy nicotinamide151 4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-(pyridazin-3-ylamino)nicotinamide152* 4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-cyclopropyl pyridin-2-yl)amino)-N-ethoxy nicotinamide153 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-(pyridazin-3-ylamino)nicotinamide154 6-((5-cyclopropyl pyridin-2-yl)amino)-N-ethoxy-4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)nicoti namide155 6-((5-cyclopropyl pyridin-2-yl)amino)-N-ethoxy-4-((4-methoxy-2-(N-methyl methanesulfonamido)phenyl)amino)nicoti namide156 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((5-methyl thiazol-2-yl)amino)nicotinamide157 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((4-methyl thiazol-2-yl)amino)nicotinamide158* 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-(thiazol-2-ylamino)nicotinamide159 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((6-methyl pyridazin-3-yl)amino)nicotinamide160 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((1-methyl-1H-pyrazol-3-yl)amino)nicotinamide161* 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((1-methyl-1H-pyrazol-5-yl)amino)nicotinamide162 N-ethoxy-4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(pyridin-2-ylamino)nicotinamide163* N-ethoxy-4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(pyrimidin-2-ylamino)nicotinamide164* 6-((4, 6-dimethyl pyrimidin-2-yl)amino)-N-ethoxy-4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino) nicotinamide165* N-ethoxy-4-((4-methyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((4-methyl thiazol-2-yl)amino)nicotinamide166 6-(cyclopropylcarboxamido)-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl)phenyl)amino)nicotinamide167 4-((4-cyclopropyl-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-(pyrazin-2-ylamino)nicotinamide168* 4-((4-cyclopropyl-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((1-methyl-1H-pyrazol-5-yl)amino)nicotinamide169* 4-((4-cyclopropyl-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-(pyrimidin-2-ylamino)nicotinamide170 4-((4-cyclopropyl-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((4-methyl thiazol-2-yl)amino)nicotinamide171 4-((4-cyclopropyl-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((1-methyl-1H-pyrazol-3-yl)amino)nicotinamide172* N-ethoxy-4-((4-methoxy-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(5-methyl thiazol-2-ylamino)nicotinamide173 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((2-(N-methyl cyclopropyl sulfonamido)phenyl)amino)nicotinamide174 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((4-methoxy-2-(N-methyl cyclopropylsulfonamido)phenyl)amino) nicotinamide175 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((4-methyl-2-(N-methyl cyclopropylsulfonamido)phenyl)amino) nicotinamide176 4-((4-cyclopropyl-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((6-methyl pyridazin-3-yl)amino)nicotinamide177 4-((4-cyano-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy nicotinamide178 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((4-isopropoxy-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide179 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((2-methoxy pyrimidin-4-yl)amino)nicotinamide180 6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((4-ethyl-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide181 6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((4-ethoxy-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide182 6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((4-ethynyl-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino) nicotinamide183 6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((4-fluoro-2-(N-methyl cyclopropylsulfonamido)phenyl)amino) nicotinamide184* 6-((4, 6-dimethyl pyrimidin-2-yl)amino)-N-ethoxy-4-((4-methyl-2-(N-methyl cyclopropylsulfonamido)phenyl)amino) nicotinamide185 4-((4-cyclopropyl-2-(N-methyl ethyl sulfonamido)phenyl)amino)-6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy nicotinamide186 6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((6-methyl-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide187 4-((4-chloro-2-(N-methyl ethyl sulfonamido)phenyl)amino)-6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxynicotinamide188 4-((4-cyclopropyl-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((2-methoxy pyrimidin-4-yl)amino)nicotinamide189 4-((4-cyclopropyl-2-(N-methyl cyclopropylsulfonamido)phenyl)amino)-6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy nicotinamide190 4-((4-cyclopropyl-2-(N-methyl cyclopropylsulfonamido)phenyl)amino)-N-ethoxy-6-(pyrimidin-4-ylamino)nicotinamide195* 4-((4-cyclopropyl-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(3, 3-difluoroazetidin-1-ylcarboxamido)-N-ethoxy nicotinamide196* 4-((5-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy nicotinamide197 6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((3-fluoro-4-methyl-2-(N-methyl methanesulfonamido)phenyl)amino) nicotinamide198 4-((4-chloro-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy nicotinamide199* 4-((4-chloro-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((2-methyl pyrimidin-4-yl)amino)nicotinamide200 4-((4-chloro-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((2-methoxy pyrimidin-4-yl)amino)nicotinamide202 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((2-(N-methyl methanesulfonamido)-4-(trifluoromethyl)phenyl)amino)nicotinamide204 4-((3-(1-cyclopropyl-1H-1, 2, 4-triazol-3-yl)-5-fluoro-2-methoxy phenyl)amino)-6-((2, 6-dimethyl pyridin-4-yl)amino)-N-ethyl nicotinamide291* 4-((4-bromo-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy nicotinamide194 4-((4-cyclopropyl-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((2-methyl pyrimidin-4-yl)amino)nicotinamide292* 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((4-fluoro-2-(N-methyl ethyl sulfonamido)phenyl)amino)nicotinamide293* 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((2-methoxy pyrimidin-4-yl)amino)nicotinamide192 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((2-methyl pyrimidin-4-yl)amino)nicotinamide193 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((4-ethyl-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide203 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((4-methyl-2-(N-methyl ethyl sulfonamido)phenyl)amino)nicotinamide230 N-ethoxy-4-((5-fluoro-4-isopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(pyrimidin-4-ylamino)nicotinamide229 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((5-fluoro-4-isopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide201 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((4-isopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide294* N-ethoxy-4-((4-isopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((2-methoxy pyridin-4-yl)amino)nicotinamide191 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((5-fluoro-4-methyl-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide295* N-ethoxy-4-((4-ethynyl-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((2-methoxy pyrimidin-4-yl)amino)nicotinamide205 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1, 2, 4-triazol-3-yl)-5-fluoro-2-methoxy phenyl)amino)-N-ethyl nicotinamide206* 4-((4-cyclopropyl-2-(oxetan-3-yloxy)phenyl)amino)-6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy nicotinamide207 6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-4-(1-methyl-1H-pyrazol-5-yl)phenyl)amino)nicotinamide208 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((3-(5-fluoropyrimidin-2-yl)-2-methoxy phenyl)amino)nicotinamide209 6-(cyclopropylcarboxamido)-N-ethoxy-4-((3-(5-fluoropyrimidin-2-yl)-2-methoxy phenyl)amino)nicotinamide210 6-(cyclopropylcarboxamido)-N-ethoxy-4-((5-fluoro-3-(5-fluoropyrimidin-2-yl)-2-methoxy phenyl)amino)nicotinamide211 6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((5-fluoro-3-(5-fluoropyrimidin-2-yl)-2-methoxy phenyl)amino)nicotinamide212 6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide213 6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(5-methyl pyrazin-2-yl)phenyl)amino)nicotinamide214 6-(((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((5-fluoro-2-methoxy-3-(5-methyl pyrazin-2-yl)phenyl)amino)nicotinamide215 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((5-fluoro-2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide216* 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((5-fluoro-6-methyl pyridin-2-yl)amino)nicotinamide217 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((6-methyl pyridin-2-yl)amino)nicotinamide218 4-((3-(5-chloropyrimidin-2-yl)-2-methoxy phenyl)amino)-6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy nicotinamide219 4-((3-(5-chloropyrimidin-2-yl)-2-methoxy phenyl)amino)-6-(cyclopropylcarboxamido)-N-ethoxy nicotinamide220 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((6-(trifluoromethyl)pyridin-2-yl)amino)nicotinamide221* 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(((2, 6-dimethyl pyridin-4-yl)amino)-N-ethoxy nicotinamide222 N-ethoxy-4-((2-methoxy-4-(1-methyl-1H-pyrazol-5-yl)phenyl)amino)-6-((6-methyl pyridin-2-yl)amino)nicotinamide223 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((6-fluoro-2-methyl pyridin-3-yl)amino)nicotinamide224 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((6-methyl pyridin-2-yl)amino)nicotinamide225 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((5-fluoro-2-methoxy-3-(5-methyl pyrimidin-2-yl)phenyl)amino)nicotinamide226 6-(cyclopropylcarboxamido)-N-ethoxy-4-((5-fluoro-2-(methylamino)-3-(5-methyl pyrimidin-2-yl)phenyl)amino)nicotinamide227* N-ethoxy-6-((6-fluoro-2-methyl pyridin-3-yl)amino)-4-((5-fluoro-4-isopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide228* 6-((3, 5-difluoropyridin-2-yl)amino)-N-ethoxy-4-((5-fluoro-4-isopropyl-2-(N-methyl methanesulfonamido)phenyl)amino) nicotinamide231* N-ethyl-4-((5-fluoro-2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)-6-((6-fluoro-2-methyl pyridin-3-yl)amino)nicotinamide232* 4-((4-cyclopropyl-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((6-fluoro-2-methyl pyridin-3-yl)amino)nicotinamide233* N-ethoxy-6-((6-fluoro-2-methyl pyridin-3-yl)amino)-4-((5-fluoro-3-(5-fluoropyrimidin-2-yl)-2-methoxy phenyl)amino)nicotinamide234 6-((3, 5-difluoropyridin-2-yl)amino)-N-ethoxy-4-((5-fluoro-3-(5-fluoropyrimidin-2-yl)-2-methoxy phenyl)amino)nicotinamide235 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((6-fluoro-5-methyl pyridin-3-yl)amino)nicotinamide236 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((5-fluoropyridin-3-yl)amino)nicotinamide237 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((6-fluoropyridin-3-yl)amino)nicotinamide238 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(5-methyl pyrimidin-2-yl)phenyl)amino)nicotinamide239 6-(cyclopropylcarboxamido)-N-ethoxy-4-((2-methoxy-3-(5-methyl pyrimidin-2-yl)phenyl)amino)nicotinamide240 N-ethoxy-4-((2-methoxy-3-(5-methyl pyrimidin-2-yl)phenyl)amino)-6-((2-methyl pyrimidin-4-yl)amino)nicotinamide241* 6-((3, 5-difluoropyridin-2-yl)amino)-N-ethoxy-4-((3-(5-fluoropyrimidin-2-yl)-2-methoxy phenyl)amino)nicotinamide242 6-((3, 5-difluoropyridin-2-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide243 N-ethoxy-4-((3-(5-fluoropyrimidin-2-yl)-2-methoxy phenyl)amino)-6-((2-methyl pyrimidin-4-yl)amino)nicotinamide244 4-((3-(1-cyclopropyl-1H-1, 2, 4-triazol-3-yl)-5-fluoro-2-methoxy phenyl)amino)-6-((3, 5-difluoropyridin-2-yl)amino)-N-ethoxy nicotinamide245 4-((3-(1-cyclopropyl-1H-1, 2, 4-triazol-3-yl)-5-fluoro-2-methoxy phenyl)amino)-N-ethoxy-6-((2-methyl pyrimidin-4-yl)amino)nicotinamide246* 4-((4-cyclopropyl-5-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((3, 5-difluoropyridin-2-yl)amino)-N-ethoxy nicotinamide247* 6-(2, 2-difluorocyclopropyl-1-carboxamido)-N-ethoxy-4-((3-(5-fluoropyrimidin-2-yl)-2-methoxy phenyl)amino)nicotinamide248 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrazin-2-yl)phenyl)amino)nicotinamide249* N-ethoxy-4-((2-methoxy-3-(5-methyl pyrazin-2-yl)phenyl)amino)-6-((6-(trifluoromethyl)pyridin-3-yl)amino)nicotinamide250* N-ethoxy-4-((2-methoxy-3-(5-methyl pyrazin-2-yl)phenyl)amino)-6-((5-(trifluoromethyl)pyridin-3-yl)amino)nicotinamide251* N-ethoxy-6-((6-fluoro-5-methyl pyridin-3-yl)amino)-4-((2-methoxy-3-(5-methyl pyrazin-2-yl)phenyl)amino)nicotinamide252* 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((3-(5-isopropyl pyrazin-2-yl)-2-methoxy phenyl)amino)nicotinamide253* control 4-((3-(5-fluoropyrimidin-2-yl)-2-methoxy phenyl)amino)-N-(methyl-d3)-6-(pyridin-2-ylamino)nicotinamide254* 6-(2, 2-difluorocyclopropyl-1-carboxamido)-N-ethoxy-4-((2-methoxy-3-(5-methyl pyrazin-2-yl)phenyl)amino)nicotinamide255* 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((3-(5-fluoropyridin-2-yl)-2-methoxy phenyl)amino)nicotinamide256* N-ethoxy-4-((3-(5-fluoropyrimidin-2-yl)-2-methoxy phenyl)amino)-6-(pyrimidin-2-ylamino)nicotinamide257* N-ethoxy-4-((3-(5-fluoropyrimidin-2-yl)-2-methoxy phenyl)amino)-6-((5-fluoropyrimidin-2-yl)amino)nicotinamide258 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((5-fluoro-2-methoxy-3-(pyrazin-2-yl)phenyl)amino)nicotinamide259* N-methoxy-4-((5-fluoro-2-methoxy-3-(5-methyl pyrazin-2-yl)phenyl)amino)-6-((6-fluoro-2-methyl pyridin-3-yl)amino)nicotinamide260* 4-((3-(5-chloropyrimidin-2-yl)-2-methoxy phenyl)amino)-6-(2, 2-difluorocyclopropyl-1-carboxamido)-N-ethoxy nicotinamide261* 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((5-fluoro-3-(5-isopropyl pyrazin-2-yl)-2-methoxy phenyl)amino)nicotinamide262* 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((3-(5-fluoropyrimidin-2-yl)-2-methoxy phenyl)amino)pyridazine-3-carboxamide263* 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)pyridazine-3-carboxamide264* 4-((3-(5-chloropyrimidin-2-yl)-2-methoxy phenyl)amino)-N-ethoxy-6-(pyrimidin-2-ylamino)nicotinamide265* N-ethoxy-6-((6-fluoro-5-methyl pyridin-3-yl)amino)-4-((3-(5-fluoropyrimidin-2-yl)-2-methoxy phenyl)amino)nicotinamide266* N-ethoxy-4-((3-(5-fluoropyrimidin-2-yl)-2-methoxy phenyl)amino)-6-((6-(trifluoromethyl)pyridin-3-yl)amino)nicotinamide267* N-ethoxy-4-((3-(5-fluoropyrimidin-2-yl)-2-methoxy phenyl)amino)-6-((5-(trifluoromethyl)pyridin-3-yl)amino)nicotinamide268 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl)phenyl)amino)nicotinamide269* 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((3-(6-fluoropyridin-3-yl)-2-methoxy phenyl)amino)nicotinamide270* 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((5-fluoro-2-methoxy-3-(5-methyl pyrimidin-2-yl)phenyl)amino)pyridazine-3-carboxamide271* 6-((3, 5-difluoropyridin-2-yl)amino)-N-ethoxy-4-((5-fluoro-2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide272* 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((5-fluoro-2-(methoxy-d3)-3-(5-methyl pyrazin-2-yl)phenyl)amino)nicotinamide273 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((3-(5-fluoropyrimidin-2-yl)-2-(methoxy-d3)phenyl)amino)nicotinamide274* N-ethoxy-4-((2-methoxy-3-(5-methyl pyrimidin-2-yl)phenyl)amino)-6-(pyrimidin-2-ylamino)nicotinamide275* N-ethoxy-4-((2-methoxy-3-(5-methyl pyrimidin-2-yl)phenyl)amino)-6-(pyrimidin-2-ylamino)pyridazine-3-carboxamide276* 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(5-methyl pyrimidin-2-yl)phenyl)amino)pyridazine-3-carboxamide277 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(2, 2-difluorocyclopropyl-1-carboxamido)-N-ethoxy nicotinamide278* 6-[(3, 5-difluoropyridin-2-yl)amino]-N-ethoxy-4-((5-fluoro-3-(5-fluoropyrimidin-2-yl)-2-methoxy phenyl)amino)pyridine-3-carboxamide279 6-((2, 6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((2-(methoxy-d3)-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide280* 6-(2, 2-difluorocyclopropyl-1-carboxamido)-N-ethoxy-4-((5-fluoro-3-(5-fluoropyrimidin-2-yl)-2-methoxy phenyl)amino)nicotinamide281* 6-(2, 2-difluorocyclopropyl-1-carboxamido)-N-ethoxy-4-((5-fluoro-4-isopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide282* 6-(2, 2-difluorocyclopropyl-1-carboxamido)-N-ethoxy-4-((2-methoxy-3-(5-methyl pyrimidin-2-yl)phenyl)amino)nicotinamide283* 6-(2, 2-difluorocyclopropyl-1-carboxamido)-N-ethoxy-4-((5-fluoro-2-methoxy-3-(5-methyl pyrimidin-2-yl)phenyl)amino)nicotinamide284* 6-(2, 2-difluorocyclopropyl-1-carboxamido)-N-ethoxy-4-((5-fluoro-2-methoxy-3-(5-methyl pyrazin-2-yl)phenyl)amino)nicotinamide285* 6-(2, 2-difluorocyclopropyl-1-carboxamido)-N-ethoxy-4-((5-fluoro-2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide286* 6-(2, 2-difluorocyclopropyl-1-carboxamido)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamideNB: An asterisk (*) indicates that the compound is not part of the present invention

[0017] The invention is further described by claims 14 and 15.

[0018] As used herein, the term "pharmaceutically acceptable salt of compound represented by Formula (I) or Formula (I') or Formula (I") is exemplified by those organic acid addition salt formed from organic acids that form pharmaceutically acceptable anions.

[0019] The pharmaceutically acceptable salt can be obtained by using standard procedures well known in the art, for example, by reacting sufficient amounts of basic compound with suitable acid providing pharmaceutically acceptable anion.Preparation method:

[0020] Herein also disclosed is a method for preparing the compound of the present invention. The preparation of compound represented by Formula (I) or Formula (I') or Formula (I") of the present invention can be accomplished by following exemplary methods and Examples, which, however, should not be recognized in any way as a limitation to the scope of the present invention. The compound of the present invention can also be synthesized through those synthesis technologies known to those skilled in the art, or through those synthesis technologies known to those skilled in the art in combination with the preparation method described in the present invention. Conventional separation technologies known in the art can be adapted to obtain the products of each step of reaction, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents needed for the reactions can be synthesized according to the conventional synthesis process described in the literature (such as, Scifinder), or are commercially available.

[0021] Compound represented by Formula (I) or Formula (I') or Formula (I") of the present invention can be synthesized according to a scheme described in the following preparation method: 1) reacting a starting material A1 with hydroxylamine having different substituents in oxygen atom (i.e., ) via condensation reaction, to result in A2; 2) reacting A2 with (hetero)aryl amines containing functional groups (i.e. R 2< -NH 2 ) via substitution reaction in the presence of a base, to result in A3; 3) reacting A3 with amides or aromatic amines having different functional groups (i.e. R 3< -NH 2 ) via Buchwald coupling reaction, to result in the target compound A4: wherein X Y R 0< , R 1< , R 2< and R 3< are as defined above;

[0022] The present invention further provides a pharmaceutical composition, comprising the compound or a pharmaceutically acceptable salt thereof as described above, and optionally comprising, a pharmaceutical acceptable carrier and / or adjuvant and / or diluent.

[0023] In some embodiments, the pharmaceutical composition may further comprise other drugs for treating and / or preventing a related disease mediated by TYK2.

[0024] Method for preparing a pharmaceutical composition comprising a certain amount of active ingredient is known in the art, or obvious to those skilled in the art in light of the disclosure of the present invention. As described in such as REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, E.W., ed., Mack Publishing Company, 19th ed.(1995), method for preparing the pharmaceutical composition comprises the incorporation of suitable pharmaceutical excipient(s), carrier(s), diluent(s), etc.

[0025] The present invention further provides a pharmaceutical formulation comprising the compound or a pharmaceutically acceptable salt thereof as described above, along with a pharmaceutical acceptable carrier and / or adjuvant and / or diluent.

[0026] In another aspect, the present invention further provides use of the compound or pharmaceutically acceptable salt thereof or the pharmaceutical composition or the pharmaceutical formulation as described above in the preparation of a medicament for treating and / or preventing a related disease mediated by TYK2.

[0027] In another aspect, the present invention further provides a compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition or the pharmaceutical formulation as described above, for use in treating and / or preventing a related disease mediated by TYK2.

[0028] In another aspect, the present invention further provides a method for treating and / or preventing a related disease mediated by TYK2, comprising administering a therapeutically and / or preventively effective amount of the compound or pharmaceutically acceptable salt thereof or the pharmaceutical composition or the pharmaceutical formulation as decribed above to a subject in need thereof.

[0029] In some embodiments, the disease includes inflammatory disease, autoimmune disease and cancer.

[0030] In the present invention, "treat", "treating", or "treatment" generally refers to obtaining the desired pharmacological and / or physiological effects, which may be preventive in sense of completely or partially preventing the disease or its symptoms, or may be therapeutic in sense of partially or completely stabilizing or curing of the disease and / or the adverse effects caused by the disease. The term "treat", "treating", or "treatment" used herein encompasses any treatment of the disease in the patient, including: (a) preventing the occurrence of disease or its symptoms in patient who is susceptible to the disease but has not been diagnosed; (b) arresting symptoms of the disease, i.e., stopping its progress; or (c) alleviating symptoms of the disease, i.e., degenerating the disease or its symptom.

[0031] In the present invention, "subject" refers to vertebrates. In some embodiments, vertebrates refer to mammals. Mammals include, but are not limited to, livestock (such as, cattle), pets (such as, cats, dogs, and horses), primates, mice and rats. In some embodiments, mammals refer to humans.

[0032] In the present invention, the expression "effective amount" refers to the amount that can effectively achieve the desired therapeutic or preventive effect in terms of both dose and time. The expression "therapeutically effective amount" of the substance / molecule of the present invention may vary according to factors such as the disease status, age, sex and weight of the individual, and the ability of the substance / molecule to trigger the desired response in the individual. The therapeutically effective amount also encompasses the amount that the therapeutically beneficial effect of the substance / molecule outweighs any toxic or harmful consequences. The expression "preventively effective amount" refers to the amount that can effectively achieve the desired preventive effect in terms of both dose and time. Usually, but not necessarily, since the preventive dose is used for the subjects before the onset of the disease or at the early stage of the disease, preventively effective amount will be lower than the therapeutically effective amount. In the case of cancer, the therapeutically effective amount of the drug can lead to the outcomes such as reducing the number of cancer cells; reducing tumor volume; inhibiting (i.e. slowing down to some extent, preferably arresting) the infiltration of cancer cells into the surrounding organs; inhibiting (i.e. slowing down to some extent, preferably arresting) tumor metastasis; inhibiting tumor growth to some extent; and / or alleviating one or more symptoms related to cancer to some extent.Definitions of terms:

[0033] According to the conventional practice in the field, used in the structural formula herein is used to indicate the bond by which the moiety or substituent is connected to the parent or main structure.

[0034] The symbol "-" (dash) is used to indicate the connection point of the substitution, except that appears between two letters or symbols. For example, -CONH 2 is connected by the carbon atom.

[0035] In various parts of the present description, the substituents of the compounds disclosed in the present invention are described in accordance to the type or scope of the group. It should be noted that, the present invention encompasses each and every independent sub-group of individual members within the type and scope of these groups. For example, the term "C 1-6 alkyl" particularly encompasses independent disclosure of groups such as methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl, or particularly encompasses independent disclosure of sub-groups such as "C 1-4 alkyl" and "C 1-3 alkyl".

[0036] As used herein, the term "alkyl" refers to branched and linear saturated aliphatic hydrocarbyl having specified number of carbon atoms. For example, "C 1-6 alkyl" refers to C 1 , C 2 , C 3 , C 4 , C 5 and C 6 . In addition, for example, the expression "C 1-6 alkyl" refers to alkyls having from one to six carbon atoms. Alkyl may be unsubstituted or substituted by replacing one or more of its hydrogen atoms with another chemical group. Example of alkyl includes, but is not limited to, methyl, ethyl, propyl (such as, n-propyl and isopropyl), butyl ( such as, n-butyl, isobutyl, t-butyl), pentyl (such as, n-pentyl, isopentyl, neopentyl), etc.

[0037] As used herein, the term "alkoxy" refers to any above described alkyl (such as, C 1-6 alkyl, C 1 - 4 alkyl, C 1-3 alkyl, and the like) which is connected to rest of the molecule through the oxygen atom (-O-).

[0038] As used herein, the term "halo C 1-6 alkyl" or "halo C 1-6 alkoxy" refers to an alkyl or alkoxy wherein one or more (such as, two, or three) hydrogen atom is replaced by halogen atom, such as, fluoro, chloro, bromo, wherein the alkyl and alkoxy are respectively as defined above. In some embodiments, the halogen atom in the term "halo C 1-6 alkyl" is preferably fluoro, such as the term "halo C 1-6 alkyl" may be -CF 3 , - CHF 2 , -CH 2 F, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , etc. In some embodiments, the halogen atom in the term "halo C 1-6 alkoxy" is preferably fluoro, such as the term "halo C 1-6 alkoxy" may be -OCF 3 , -OCHF 2 , -OCH 2 F, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , etc.

[0039] As used herein, the term "C 1-6 alkyl substituted by hydroxyl group" refers to an alkyl wherein one hydrogen atom is replaced by hydroxyl, wherein the alkyl is as defined above. For example, the term "C 1-6 alkyl substituted by hydroxyl group" may be hydroxymethyl.

[0040] As used herein, the term "alkenyl" means to include straight- or branched hydrocarbon chain having one or more carbon-carbon double bond positioned at any stable point along the chain. For example, "C 2-6 alkenyl" means to include C 2 , C 3 , C 4 , C 5 and C 6 . Example of alkenyl includes, but is not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, etc.

[0041] As used herein, the term "alkynyl" means to include straight- or branched hydrocarbon chain having one or more carbon-carbon triple bond positioned at any stable point along the chain. For example, "C 2-6 alkynyl" means to include C 2 , C 3 , C 4 , C 5 and C 6 alkynyl. Example of alkynyl includes, but is not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.

[0042] It can be understood by those skilled in the art that, when term "CO 2 " is used herein, it refers to the group "''.

[0043] As used herein, the expression "substituted by" means the replacement of one or more hydrogen on particular atom or group with specified substituent group, provided that the normal valence of the particular atom or group is not exceeded.

[0044] As used herein, the term "cycloalkyl" refers to cyclic alkyl, including monocyclic, bicyclic or multicyclic system. C 3-7 cycloalkyl means to include C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl. Example of cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. As used herein, the term "carbocyclyl" or "carbocyclyl" residue refers to any stable 3-membered, 4-membered, 5-membered, 6-membered or 7-membered monocyclic or bicyclic ring, or 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered bicyclic or tricyclic ring, wherein any ring may be a saturated, partially unsaturated, unsaturated or aromatic ring. Example of such carbocyclyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptenyl, cycloheptyl, adamantyl, cyclooctyl, phenyl, naphthyl, etc. According to the above description, the definition of carbocycle also encompasses bridged rings, such as [2,2,2] dicyclooctane. Unless stated otherwise, preferred carbocyclyl is cyclopropyl, cyclobutyl, cyclopentyl, or phenyl. Bridged ring may be formed when one or more carbon atoms are connected to two other non-adjacent carbon atoms. The preferred bridge has one or two carbon atoms. It should be noted that the bridge always converts monocyclic ring into bicyclic ring. When a ring is further bridged, the substituent for the ring may also exist on the bridge.

[0045] As used herein, the term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbyl having from 6 to 12 carbon atoms in the ring, such as phenyl and naphthyl, each of which can be substituted.

[0046] As used herein, the term "heterocyclyl", "heterocycloalkyl" and "heterocyclylic" are interchangeable and refers respectively to substituted and unsubstituted 3-7 membered monocyclic group, 7-11 membered bicyclic group, and 10- 15-membered tricyclic group, wherein at least one ring has at least one heteroatom (O, S or N), the ring containing heteroatom preferably has one, two, or three heteroatoms selected from the group consisting of O, S and N. Each ring containing heteroatom of the group may have one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms, provided that each ring contains 4 or less heteroatoms in total, and further provided that the ring has at least one carbon atom. Nitrogen and sulfur atom in the ring may be optionally oxidized, and nitrogen atom may optionally be quaternized. The ring fused to accomplish bicyclic and tricyclic ring may contain merely carbon atom and may be saturated, partially saturated or completely unsaturated. Heterocyclic group may be connected through any available nitrogen or carbon atom. The terms "heterocyclyl", "heterocycloalkyl" and "heterocyclic" used herein all encompass "heteroaryl" as defined as follows.

[0047] Exemplary monocyclic heterocycly includes, in addition to the heteroaryl described below, azetidinyl, oxetanyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, 1-pyridinonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, 1, 3-dioxalanyl, etc. Exemplary bicyclic heterocycly includes quinuclidinyl. Further monocyclic heterocyclyl includes:

[0048] As used herein, the term "saturated heterocyclyl" refers to the monocyclic, bicyclic, or tricyclic group as described above is completely saturated. The term "heterocyclyl" is as defined above. For example, saturated heterocyclyl may be morpholinyl (such as, ), piperidinyl (such as, ), piperazinyl( etc.

[0049] As used herein, the term "heteroaryl" refers to, substituted or unsubstituted, aromatic 5-membered or 6-membered monocyclic group, 9-membered or 10-membered bicyclic group, or 11-14-membered tricyclic group, containing at least one heteroatom (O, N and S) in at least one ring, wherein the heteroatom-containing ring preferably may contain one or two or three heteroatoms selected from the group consisting of O, N and S. Each heteroatom-containing ring of heteroaryl may contain 1 or 2 oxygen or sulfur atoms, and / or from 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring contains at least one carbon atom. The ring fused to accomplish bicyclic and tricyclic ring may contain merely carbon atom and may be saturated, partially saturated or completely unsaturated. Nitrogen and sulfur atoms may optionally be oxidized, and nitrogen atom may be quaternized. Bicyclic or tricyclic heteroaryl must include at least one complete aromatic ring, but the other one or more fused rings may be aromatic or non-aromatic. Heteroaryl may be connected through any available nitrogen or carbon atom of any ring. The other ring(s), when selected from cycloalkyl or heterocyclyl, may be optionally substituted by =O (oxo), provided that the valence permits.

[0050] Exemplary monocyclic heteroaryl comprises pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, pyridinonyl, 2-pyridinonyl (such as, ), etc. It is noted that, in the present invention, pyridinone has the structure of and 2-pyridinone has the structure of

[0051] Exemplary bicyclic heteroaryl comprises indolyl, benzothiazolyl, benzimidazolyl, benzo-1,3-dioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzofuryl, indolizinyl, benzopyranyl, chromonyl, coumarinyl, benzopyranyl, quinoxalinyl, indazolyl, pyrrolopyrimidinyl, furanopyridinyl, dihydroisoindolyl, tetrahydroquinolinyl, etc.

[0052] Exemplary tricyclic heteroaryl comprises carbazolyl, benzoindolyl, phenanthrolinyl, acridinyl, etc.

[0053] In compounds represented by formula (I) or formula (I') or formula (I"), preferred heteroaryl comprises, such as: and may optionally be substituted on any available carbon or nitrogen atom.

[0054] Unless otherwise specified, when reference is made to the definitely named aryl (such as, phenyl), cycloalkyl (such as, cyclohexyl), heterocyclyl (such as, pyrrolidinyl, piperidyl, morpholinyl) or heteroaryl (such as, imidazolyl, pyrazolyl, triazolyl), such reference refers to the corresponding ring containing 0-3, preferably 0-2, substituents, wherein the substituent may be, as appropriate, selected from the substituents which are described above for aryl, cycloalkyl, heterocyclyl and / or heteroaryl .

[0055] As used herein, the term "carbocyclyl" or "carbocyclic" refers to saturated or unsaturated monocyclic or bicyclic ring, wherein all atoms of all rings are carbon atoms. That is, such terms comprise cycloalkyl and aryl ring. Monocyclic carbocyclyl generally contains from three to six carbon atoms, more generally 5 or 6 carbon atoms. Bicyclic carbocyclyl contains from seven to twelve carbon atoms arranged as, e.g., [4, 5], [5, 5], or [6, 6] bicyclic system, or contains 9 or 10 carbon atoms arranged as [5, 6] or [6, 6] bicyclic system. Example of monocyclic and bicyclic carbocyclyl comprises cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl and naphthyl. Carbocyclyl may be substituted, in which circumstance, the substituent may be selected from the substituents which are described above for cycloalkyl and aryl.

[0056] As used herein, the term "heteroatom" comprises oxygen atom, sulfur atom, and nitrogen atom.

[0057] When a ring or group is preceded by term "unsaturated", as used herein, the ring or group may be completely unsaturated or partially unsaturated.

[0058] From all above descriptions, it is obvious to those skilled in the art that, any group named by compounded name, such as "C 3-10 cycloalkyl-C(O)-", should be interpreted as being constructed by the constituents from which the group is derived, i.e., constructed from carbonyl substituted by C 3-10 cycloalkyl, wherein cycloalkyl is as above defined. Any other compounded name should be similarly interpreted accordingly.

[0059] As used herein, the term "optionally" means the circumstance that follows may be present or not. For example, "C 1-6 alkyl optionally substituted by from one to three R d< groups", means that, the C 1-6 alkyl may be substituted by from one to three R d< groups, or not. Any other circumstance should be similarly interpreted accordingly.

[0060] Throughout the description, any group and its substituent may be selected by those skilled in the art to provide stable part and compound, as well as compounds useful as pharmaceutically acceptable compound, and / or intermediate useful for preparing pharmaceutically acceptable compounds.Effect of the invention:

[0061] The hydroxamate compound represented by formula (I), formula (I') and formula (I") of the present invention exhibits good TYK2 inhibition effect and can be used as drug for the treatment and / or prevention of diseases related to such effect.Detailed description of embodiments

[0062] It should be understood that the terms used herein are intended to describe the specific embodiments and are not intended to limit. In addition, although any method, device and material similar to or equivalent to those described herein can be used to implement or test the present invention, the preferred method, device and material are now described.

[0063] The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR is measured with Bruker ASCENA-400 nuclear magnetic instrument. The measured solvents used include deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD). The internal standard is tetramethylsilane (TMS), and the chemical shift is given in 10 -6< (ppm).

[0064] Thermofisher ESQ (ESI) mass spectrometer was used for reaction monitoring and MS determination.

[0065] HPLC was determined by using the Thermo U3000 DAD high pressure liquid chromatograph (GL Sciences ODS-HL HP 3µm 3.0*100mm column).

[0066] Thin layer chromatography was performed on Qingdao Ocean GF254 silica gel plate, and the silica gel plate used for thin layer chromatography (TLC) are of 0.15-0.2mm, and the high-performance thin layer chromatography preparation plate used for thin layer chromatography separation and purification products are of 0.9-1.0mm. The column chromatography was performed with Qingdao Ocean 200~300 mesh silica gel as the carrier, and the elution system includes A: dichloromethane and methanol system; and B: petroleum ether and ethyl acetate system, the ratio of solvent in volume is adjusted according to the polarity of the compound. The medium pressure preparation liquid phase is purified by using biotage isera one preparation liquid phase.

[0067] In the following Examples, unless otherwise specified, all reaction raw materials are available from manufacturers such as Saen Chemical Technology (Shanghai) Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Nanjing Yaoshi Technology Co., Ltd., Jiangsu Aikang Biomedical Research and Development Co., Ltd., and Shanghai Bide Pharmaceutical Technology Co., Ltd.Intermediate int-1 4,6-dichloro-N-methoxy nicotinamide

[0068] 1) 4,6-dichloronicotinic acid (int-1a, 1.92g, 10mmol) was dissolved in dichloromethane (30ml) in a 100ml two-necked flask. The mixture was cooled to 0°C~5°C with ice-water bath, added with catalytic amount of DMF(0.1ml) dropwise followed by carefully adding oxalyl chloride (1.52g, 12mmol) dropwise, and then stirred at room temperature for 30 min. Upon indication of completed reaction by TLC, the reaction mixture was concentrated at 40°C under reduced pressure, the resulting crude material was added to dichloromethane (20ml), concentrated under reduced pressure, and used directly in next reaction. 2) The methoxy amine in form of hydrochloride salt (1.25g, 15mmol) was added to ethyl acetate / water mixture (40ml) (5:1), added with potassium carbonate (4.14g, 30mmol), and stirred at room temperature for 10 min. The reaction mixture was added with the previously obtained crude material, which was dissolved in dichloromethane (10ml) and carefully added dropwise. After the addition, the mixture was stirred at room temperature overnight. After phase separation, the organic phase was concentrated and then purified by column chromatography (petroleum ether / ethyl acetate=2:1) to provide the desired product 4,6-dichloro-N-methoxy nicotinamide (int-1, 2.0g, 9 mmol, 90.5% yield for 2 steps). MS Calcd: 221; MS Found: 222 ([M+H] +< ). Intermediate int-2 4,6-dichloro-N-ethoxy nicotinamide

[0069]

[0070] Step 1:1) 4,6-dichloronicotinic acid (int-1a, 1.92g, 10mmol) was dissolved in dichloromethane (30ml) in a 100ml two-necked flask. The mixture was cooled to 0°C~5°C with ice-water bath, added with catalytic amount of DMF(0.1ml) dropwise followed by carefully adding oxalyl chloride (1.52g, 12mmol) dropwise, and stirred at room temperature for 30 min. Upon indication of completed reaction by TLC, the reaction mixture was concentrated at 40°C under reduced pressure. The resulting crude product was added to dichloromethane (20ml) and further concentrated under reduced pressure.

[0071] 2) The ethoxy amine in form of hydrochloride salt (1.426g, 15mmol) was added to ethyl acetate / water mixture (40ml) (5:1), added with potassium carbonate (4.14g, 30mmol), and stirred at room temperature for 10 min. The reaction mixture was added with the previously obtained crude material, which was dissolved in dichloromethane (10ml) and carefully added dropwise. After the addition, the mixture was stirred at room temperature overnight. After phase separation, the organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate=2:1) to provide 4,6-dichloro-N-ethoxy nicotinamide (int-2 , 1.6g, 6.8mmol, 68.3% yield). MS Calcd: 234; MS Found: 235 ([M+H] +< ).Example 1 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-oxo-1-(thiazol-2-yl)-1,2-dihydropyridin-3-yl)amino)nicotinamide

[0072]

[0073] Step 1: To a 50ml reaction flask was added 3-amino-2-hydroxyl pyridine (1-a, 440mg, 4.0mmol) dissolved in dichloromethane (10ml), followed by benzyl chloroformate (750.60mg, 4.4mmol) which was dissolved in dichloromethane (5ml) and carefully added to the reaction flask dropwise at 0°C~5°C. The reaction mixture was stirred at room temperature for 3h. Upon indication of completed reaction by TLC, the reaction mixture was washed respectively with water (10 ml x 1) and brine (10 ml x 1), dried over anhydrous sodium sulfate and concentrated to provide crude material, which was purified by column chromatography to provide the desired product benzyl 2-oxo-1,2-dihydropyridine-3-carbamate (1-b, 850mg, 87% yield). MS Calcd:244; MS Found: 245 ([M+H] +< ).

[0074] Step 2: Benzyl 2-oxo-1,2-dihydropyridine-3-carbamate (1-b, 600mg, 2.46mmol), 2-bromothiazole (524.2mg, 3.20mmol), CuI(93.7mg, 0.492mmol), N,N'-dimethyl ethylene diamine (86.74mg, 0.987mmol) and potassium carbonate (679mg, 4.92mmol) were suspended in dioxane (20ml). After atmosphere replacement with nitrogen three times, the mixture was heated to 115°C to react for 5h. Upon indication of completed reaction by TLC, the reaction mixture was concentrated, added with 20 ml of water, and extracted with ethyl acetate (10ml x 3). The combined ethyl acetate layers were dried over anhydrous sodium sulfate, filtered by suction, and concentrated to obtain a crude material, which was purified by column chromatography (PE:EA =4:1) to provide benzyl (2-oxo-1-(thiazol-2-yl)-1,2-dihydropyridin-3-yl)carbamate (1-c, 525mg, 1.60mmol, 66% yield). MS Calcd: 327; MS Found: 328 ([M+H] +< ).

[0075] Step 3: Benzyl (2-oxo-1-(thiazol-2-yl)-1,2-dihydropyridin-3-yl)carbamate (1-c, 500mg, 1.53mmol) was dissolved in glacial acetic acid (10ml) in a 50 ml reaction flask, added with 40% hydrogen bromide aqueous solution (0.5ml), heated to 90°C to react for 3h. Upon indication of completed reaction by TLC, the reaction mixture was added with water and ethyl acetate, adjusted to pH 7~8 with sodium carbonate, and then extracted with ethyl acetate (10ml x 3). The combined ethyl acetate layers were dried over anhydrous sodium sulfate, filtered by suction, and concentrated to obtain a crude material, which was purified by column chromatography to provide 3-amino-1-(thiazol-2-yl)pyridin-2(1H)-one (1-d, 206mg, 1.07mmol, 70% yield). MS Calcd: 193; MS Found: 194 ([M+H] +< ).

[0076] Step 4: 3-amino-1-(thiazol-2-yl)pyridin-2(1H)-one (1-d, 150mg, 0.78mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 169.4mg, 0.78mmol) were added to 5ml of anhydrous N,N-dimethylacetamide, added at room temperature with a solution of LiHMDS in tetrahydrofuran(2.34ml, 2.34mmol), and stirred at room temperature for 2h. Upon indication of completed reaction by TLC, the reaction mixture was adjusted to pH 5 by aqueous hydrochloride (1N), and extracted with ethyl acetate (10ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography to provide 6-chloro-N-methoxy-4-((2-oxo-1-(thiazol-2-yl)-1,2-dihydropyridin-3-yl)amino)nicotinamide (1-e, 200mg, 0.53mmol, 68% yield). MS Calcd: 377; MS Found: 378 ([M+H] +< ).

[0077] Step 5: 6-chloro-N-methoxy-4-((2-oxo-1-(thiazol-2-yl)-1,2-dihydropyridin-3-yl)amino)nicotinamide (1-e, 100mg, 0.26mmol), cyclopropylcarboxamide (24.8mg, 0.292mmol), cesium carbonate (256.80mg, 0.80mmol), XantPhos(30mg, 0.04mmol) and Pd 2 (dba) 3 (24mg, 0.026mmol) were added to anhydrous dioxane (5ml) and the mixture was evacuated to vacuum. After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 100°C, stirred for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-oxo-1-(thiazol-2-yl)-1,2-dihydropyridin-3-yl)amino)nicotinamide (1, 15mg, 0.035mmol, 13.5% yield). MS Calcd: 426; MS Found: 427 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.92 (s, 1H), 10.98 (s, 1H), 10.56 (s, 1H), 8.49-8.47 (dd, J 1 =1.2 Hz, J 2 =7.2 Hz, 1H), 8.42 (s, 1H), 8.27 (s, 1H), 7.83-7.82(d, J = 3.2 Hz, 1H), 7.73-7.72(d, J = 4 Hz, 1H), 7.52-7.50 (t, J = 8.0 Hz, 1H), 6.71-6.67-7.50 (t, J= 16 Hz, 1H), 3.74 (s, 3H), 1.98-1.95 (m, 1H), 0.85-0.82 (m, 4H).Example 2 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide

[0078]

[0079] Step 1: 1-fluoro-2-nitrobenzene (2-a, 1.0g, 9.16mmol) dissolved in acetonitrile (30ml) was added to a 100ml reaction flask followed by cesium carbonate (5.95g, 18.32mmol) and N-methyl methanesulfonamide (1.227g, 8.702mmol) The reaction mixture was stirred at room temperature overnight. Upon indication of completed reaction by TLC, the reaction mixture was washed respectively with water (30 ml x 1) and brine (30 ml x 1), dried over anhydrous sodium sulfate, and concentrated to obtain a crude material, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3:1) to provide the product N-methyl-N-(2-nitrophenyl) methanesulfonamide (2-b, 1.2g, 73.6% yield). MS Calcd:230; MS Found: 231([M+H] +< ).

[0080] Step 2: N-methyl-N-(2-nitrophenyl) methanesulfonamide (2-b, 460mg, 2mmol) and 10% palladium on carbon (46mg) were added to methanol (15ml), followed by atmosphere replacement by hydrogen three times, and stirred under hydrogen atmosphere at room temperature overnight. The reaction mixture was filtered by suction, and the filtrate was concentrated under reduced pressure to provide N-(2-amino phenyl)-N-methyl methanesulfonamide (2 -c, 350mg, 1.75mmol, 87.5% yield), which was used directly in the next reaction without further purification. MS Calcd: 200; MS Found: 201 ([M+H] +< ). Step 3: N-(2-amino phenyl)-N-methyl methanesulfonamide (2 -c, 200mg, 1mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 218mg, 1mmol) were added to 5ml of anhydrous N,N-dimethylacetamide, added at room temperature with a solution of LiHMDS in tetrahydrofuran (3ml, 3mmol), and stirred at room temperature for 2h. Upon indication of completed reaction by TLC, the reaction mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (30 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography to provide 6-chloro-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (2-d, 150mg, 0.39mmol, 39% yield). MS Calcd: 384; MS Found: 385 ([M+H] +< ).

[0081] Step 4: 6-chloro-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (2-d, 39mg, 0.1mmol), cyclopropylcarboxamide (9.4mg, 0.11mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(15mg, 0.02mmol) and Pd 2 (dba) 3 (10mg, 0.01mmol) were added to anhydrous dioxane (5ml) and the mixture was evacuated to vacuum. After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 100°C, and stirred for 5h. After filtration by suction, the filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (2, 10 mg, 0.023mmol, 23.1% yield). MS Calcd: 433; MS Found: 434 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.82 (s, 1H), 10.81 (s, 1H), 10.05 (s, 1H), 8.33 (s, 1H), 7.92 (s, 1H), 7.58-7.53 (m, 1H), 7.50-7.48 (m, 1H), 7.42-7.24 (m, 1H), 7.23-7.20 (m, 1H), 3.88 (s, 3H), 3.14 (s, 3H), 3.10(s, 3H), 1.97-1.94 (m, 1H), 0.77-0.76 (m, 4H).Example 3 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)amino)nicotinamide

[0082]

[0083] Step 1: To a 100ml flask were added 1-bromo-2-methoxy-3-nitrobenzene(3-a, 1g, 4.32mmol), iron powder (1.21g, 21.6mmol) and glacial acetic acid (20ml). The mixture was heated to 85°C with stirring for 3h. When TLC indicated a completed reaction, the reaction mixture was allowed to cool down to room temperature, added with ethyl acetate and water, and then filtered through diatomaceous earth. The filtrate was subjected to phase separation, and the aqueous phase was extracted with ethyl acetate until no product remained in the aqueous phase. The organic phases were combined and washed with saturated sodium carbonate solution (50 ml x 3), then washed with saturated brine once, dried over anhydrous sodium sulfate, and filtered by suction. The filtrate was concentrated under reduced pressure to provide 3-bromo-2-methoxy aniline (3-b, 750mg, 3.73mmol, 86.37% yield), which was used directly in the next reaction without further purification. MS Calcd: 202; MS Found: 203 ([M+H] +< ).

[0084] Step 2: 3-bromo-2-methoxy aniline(3-b , 402mg, 2mmol), sodium carbonate (318mg, 3mmol), bis(pinacolato)diboron (609.6g, 2.4mmol) and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (II) (146.2mg, 0.2mmol) were added to anhydrous dioxane (10ml). The reaction mixture was evacuated to vacuum. After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 90°C, stirred for 3h, and then filtered by suction. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=3:1) to provide 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3-c, 210 mg, 0.84mmol, 42.2% yield). MS Calcd: 249; MS Found: 250 ([M+H] +< ).

[0085] Step 3: 2-bromo-1H-benzo[d]imidazole (3-c, 392mg, 2mmol) dissolved in acetonitrile (15ml)was added to a 100ml reaction flask followed by cesium carbonate (975mg, 3mmol), iodomethane (312.4mg, 2.2mmol). The reaction mixture was stirred at room temperature overnight. Upon indication of completed reaction by TLC, the reaction mixture was added with water and ethyl acetate, extracted with ethyl acetate (30 ml x 2). The organic phase was washed with brine (30 ml x 1), dried over anhydrous sodium sulfate, and concentrated to provide a crude material, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=4:1) to provide 2-bromo-1-methyl-1H-benzo[d]imidazole (3-d, 400mg, 1.90mmol, 95.2% yield). MS Calcd:210; MS Found: 211([M+H] +< ).

[0086] Step 4: 2-bromo-1-methyl-1H-benzo[d]imidazole (3-d, 176.4mg, 0.84mmol), sodium carbonate (178mg, 1.68mmol), 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(33067-c, 210 mg, 0.84mmol) and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (II) (61.4mg, 0.084mmol) were added to anhydrous dioxane (15ml) and the mixture was evacuated to vacuum. After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 90°C, stirred for 3h, and filtered by suction. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=2:1) to provide 2-methoxy-3-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline (3-e, 105 mg, 0.41mmol, 49.4% yield). MS Calcd: 253; MS Found: 254([M+H] +< ).

[0087] Step 5: 2-methoxy-3-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline (3-e, 105 mg, 0.41mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 90mg, 0.41mmol) were added to 5ml of anhydrous N,N-dimethylacetamide followed by the addition of a solution of LiHMDS in tetrahydrofuran (1.23ml, 1.23mmol) at room temperature, and stirred at room temperature for 2h. Upon indication of completed reaction by TLC, the reaction mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (30 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography to provide 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)amino)nicotinamide (3-f, 70mg, 0.16mmol, 39% yield). MS Calcd: 437; MS Found:438 ([M+H] +< ).

[0088] Step 6: 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)amino)nicotinamide (3-f, 70mg, 0.16mmol), cyclopropylcarboxamide (21.51mg, 0.19mmol), cesium carbonate (156mg, 0.48mmol), XantPhos(18mg, 0.032mmol) and Pd 2 (dba) 3 (16.5mg, 0.016mmol) were added to anhydrous dioxane (5ml) and the mixture was evacuated to vacuum. After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 100°C, stirred for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)amino)nicotinamide (3, 10mg, 0.02mmol, 10.8% yield). MS Calcd: 486; MS Found: 487 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.88 (s, 1H), 10.85 (s, 1H), 10.18 (s, 1H), 8.38 (s, 1H), 8.05 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.8 Hz, 2H), 7.37 - 7.24 (m, 4H)., 3.73 (s, 3H), 3.66 (s, 3H), 3.40(s, 3H), 2.33-2.31 (m, 1H), 0.85-0.79 (m, 4H).Example 4 6-((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide

[0089]

[0090] Step 1: 6-chloro-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (2-d, 67mg, 0.17mmol), 5-fluoro-2-aminopyridine (21.51mg, 0.19mmol), cesium carbonate (166.7mg, 0.51mmol), XantPhos(18.6mg, 0.034mmol) and Pd 2 (dba) 3 (16.6mg, 0.017mmol) were added to anhydrous dioxane (5ml) and the mixture was evacuated to vacuum. After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 100°C, stirred for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide 6-((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (4 , 17 mg, 0.037 mmol, 21.7% yield). MS Calcd: 460; MS Found: 461 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.71 (s, 1H), 10.09 (s, 1H), 9.84 (s, 1H), 8.30 (s, 1H), 8.15-8.14 (d, J = 2.8 Hz, 1H), 7.67-7.61 (m, 4H), 7.55 (dd, J= 8.0, 2.0 Hz, 1H), 7.50-7.46 (m, 1H), 7.20-7.19 (m, 1H), 3.72 (s, 3H), 3.16 (s, 3H), 3.14 (s, 3H).Example 5 N-methoxy-6-(((2-methoxy pyridin-3-yl)amino)-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide

[0091]

[0092] Step 1: 6-chloro-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (2-d, 60mg, 0.16mmol), 2-methoxy-3-aminopyridine (19.4mg, 0.16mmol), cesium carbonate (152mg, 0.47mmol), XantPhos(17.53mg, 0.032mmol) and Pd 2 (dba) 3 (15.6mg, 0.016mmol) were added to anhydrous dioxane (5ml) and the mixture was evacuated to vacuum. After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 100°C, stirred for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: N-methoxy-6-(((2-methoxy pyridin-3-yl)amino)-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (5, 15 mg, 0.032mmol, 20.5% yield). MS Calcd: 472; MS Found: 473 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.68 (s, 1H), 9.93 (s, 1H), 8.58 (s, 1H), 8.50-8.48 (m, 1H), 8.33 (s, 1H), 7.73-7.72 (m, 1H), 7.56-7.53 (m, 2H), 7.44-7.40 (m, 1H), 7.21-7.17 (m, 1H), 6.95-6.91 (m, 1H), 6.85-6.84 (m, 1H), 3.91 (s, 3H), 3.71 (s, 3H), 3.16 (s, 3H), 3.14 (s, 3H).Example 6 6-(cyclopropylcarboxamido)-N-methoxy-4-((4-methoxy-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide

[0093]

[0094] Step 1: 3-fluoro-4-nitrophenol (6-a, 628mg, 4mmol) dissolved in acetonitrile (30ml) was added to a 100ml reaction flask followed by cesium carbonate (1.95g, 6mmol) and iodomethane (624.8mg, 4.4mmol). The reaction mixture was stirred at room temperature overnight. Upon indication of completed reaction by TLC, the reaction mixture was added with water and ethyl acetate, extracted with ethyl acetate (30 ml x 2). The organic phase was washed with brine (30 ml x 1), dried over anhydrous sodium sulfate, and concentrated to provide a crude material, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3:1) to provide 2-fluoro-4-methoxy-1-nitrobenzene(6-b, 650mg, 3.82mmol, 95% yield). MS Calcd:157; MS Found: 158([M+H] +< ).

[0095] Step 2: 2-fluoro-4-methoxy-1-nitrobenzene (6-b, 600g, 3.5mmol) dissolved in dichloromethane (30ml)was added to a 100ml reaction flask followed by cesium carbonate (1.70g, 5.25mmol) and N-methyl methanesulfonamide (412mg, 3.85mmol). The reaction mixture was stirred at room temperature overnight. Upon indication of completed reaction by TLC, the reaction mixture was washed respectively with water (30 ml x 1) and brine (30 ml x 1), dried over anhydrous sodium sulfate, and concentrated to provide a crude material, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3:1) to provide N-(5-methoxy-2-nitrophenyl)-N-methyl methanesulfonamide (6-c, 520mg, 2mmol, 57.1% yield). MS Calcd: 260; MS Found: 261([M+H] +< ).

[0096] Step 3: N-(5-methoxy-2-nitrophenyl)-N-methyl methanesulfonamide (6-c, 520mg, 2mmol) and palladium on carbon (46mg) were added to methanol (20ml), followed by atmosphere replacement by hydrogen three times, and stirred under hydrogen atmosphere at room temperature overnight, and filtered by suction. The filtrate was concentrated under reduced pressure to provide N-(2-amino phenyl)-N-methyl methanesulfonamide (6-d, 440mg, 1.87mmol, 93.47% yield), which was used directly in the next reaction without further purification. MS Calcd: 230; MS Found: 231 ([M+H] +< )

[0097] Step 4: N-(2-amino-5-methoxy phenyl)-N-methyl methanesulfonamide (6-d, 230mg, 1mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 218mg, 1mmol) were added to 5ml of anhydrous N,N-dimethylacetamide. The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (3ml, 3mmol), and stirred at room temperature for 2h. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (30 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography to provide 6-chloro-N-methoxy-4-((4-methoxy-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (6-e, 200mg, 0.483mmol, 48.3% yield). MS Calcd: 414; MS Found:415 ([M+H] +< ).

[0098] Step 5: 6-chloro-N-methoxy-4-((4-methoxy-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (6-e, 100mg, 0.24mmol), cyclopropylcarboxamide (20.4mg, 0.24mmol), cesium carbonate (234mg, 0.72mmol), XantPhos(27.74mg, 0.048mmol) and Pd 2 (dba) 3 (23.4mg, 0.024mmol) were added to anhydrous dioxane (5ml) and the mixture was evacuated to vacuum. After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 100°C, stirred for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide 6-(cyclopropylcarboxamido)-N-methoxy-4-((4-methoxy-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (6, 15 mg, 0.032mmol, 13.3% yield). MS Calcd: 463; MS Found: 464 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.72 (s, 1H), 10.70 (s, 1H), 9.70 (s, 1H), 8.30 (s, 1H), 7.62 (s, 1H), 7.51 (s, 1H), 7.35-7.33 (m, 1H), 7.14 (s, 1H), 3.81 (s, 3H), 3.71 (s, 3H), 3.11 (s, 3H), 3.09 (s, 3H), 1.98-2.01 (m, 1H), 0.75-0.73 (m, 4H).Example 7 6-(cyclopropylcarboxamido)-N-methoxy-4-((6-methoxy-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide

[0099]

[0100] Step 1: 6-chloro-5-nitropyridin-2-ol (7-a, 696mg, 4mmol) dissolved in acetonitrile (30ml) was added to a 100ml reaction flask followed by cesium carbonate (1.95g, 6mmol) and iodomethane (624.8mg, 4.4mmol). The reaction mixture was stirred at room temperature overnight. Upon indication of completed reaction by TLC, the reaction mixture was added with water and ethyl acetate, extracted with ethyl acetate (30 ml x 2). The organic phase was washed with brine (30 ml x 1), dried over anhydrous sodium sulfate, and concentrated to provide a crude material, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3:1) to provide 2-chloro-6-methoxy-3-nitropyridine (7-b, 700mg, 3.72mmol, 93% yield). MS Calcd:188; MS Found: 189([M+H] +< ).

[0101] Step 2: 2-chloro-6-methoxy-3-nitropyridine (7-b, 600g, 3.19mmol) dissolved in dichloromethane (30ml) was added to a 100ml reaction flask followed by cesium carbonate (1.57g, 4.78mmol) and N-methyl methanesulfonamide (379mg, 3.51mmol). The reaction mixture was stirred at room temperature overnight. Upon indication of completed reaction by TLC, the reaction mixture was washed respectively with water (30 ml x 1) and brine (30 ml x 1), dried over anhydrous sodium sulfate, and concentrated to provide a crude material, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3:1) to provide N-(6-methoxy-3-nitropyridin-2-yl)-N-methyl methanesulfonamide (7-c, 550mg, 2.10mmol, 65.8% yield). MS Calcd: 261; MS Found: 262([M+H] +< ).

[0102] Step 3: N-(6-methoxy-3-nitropyridin-2-yl)-N-methyl methanesulfonamide (7-c, 550mg, 2.1mmol) and palladium on carbon (46mg) were added to methanol(20ml), followed by atmosphere replacement by hydrogen three times, and stirred under hydrogen atmosphere at room temperature overnight, and filtered by suction. The filtrate was concentrated under reduced pressure to provide N-(3-amino-6-methoxy pyridin-2-yl)-N-methyl methanesulfonamide (7-d, 450mg, 1.95mmol, 92.76% yield), which was used directly in the next reaction without further purification. MS Calcd: 231; MS Found: 232 ([M+H] +< ).

[0103] Step 4: N-(3-amino-6-methoxy pyridin-2-yl)-N-methyl methanesulfonamide (7-d, 231mg, 1mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 218mg, 1mmol), were added to 5ml of anhydrous N,N-dimethylacetamide. The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (3ml, 3mmol), and stirred at room temperature for 2h. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (30 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography to provide 6-chloro-N-methoxy-4-((6-methoxy-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (7-e, 210mg, 0.506mmol, 50.6% yield). MS Calcd: 415; MS Found:416 ([M+H] +< ).

[0104] Step 5: 6-chloro-N-methoxy-4-((6-methoxy-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (7-e, 100mg, 0.24mmol), cyclopropylcarboxamide (20.4mg, 0.24mmol), cesium carbonate (234mg, 0.72mmol), XantPhos(27.74mg, 0.048mmol) and Pd 2 (dba) 3 (23.4mg, 0.024mmol) were added to anhydrous dioxane (5ml) and the mixture was evacuated to vacuum. After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 100°C, stirred for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-N-methoxy-4-((6-methoxy-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (7, 16 mg, 0.034mmol, 14.3% yield). MS Calcd: 464; MS Found: 465 ([M+H] +< ).

[0105] 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.79 (s, 1H), 10.76 (s, 1H), 9.78 (s, 1H), 8.34 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.58 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.71 (s, 3H), 3.18 (s, 3H), 3.11 (s, 3H), 1.98-2.01 (m, 1H), 0.76-0.74 (m, 4H).Example 8 6-((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((6-methoxy-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide

[0106]

[0107] Step 1: 6-chloro-N-methoxy-4-((6-methoxy-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (7-e, 50mg, 0.12mmol), 5-fluoropyridin-2-ylamine (14.87mg, 0.13mmol), cesium carbonate (117mg, 0.36mmol), XantPhos(13.9mg, 0.024mmol) and Pd 2 (dba) 3 (11mg, 0.012mmol) were added to anhydrous dioxane (5ml) and the mixture was evacuated to vacuum. After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 100°C, stirred for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((6-methoxy-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (8, 8 mg, 0.016mmol, 13.6% yield). MS Calcd: 491; MS Found: 492 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.68 (s, 1H), 9.79 (s, 1H), 9.76 (s, 1H), 8.30 (s, 1H), 8.12 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.68-7.67 (m, 2H), 7.24 (s, 1H), 7.03 (d, J = 8.8 Hz, 1H), 3.89 (s, 3H), 3.71 (s, 3H), 3.21 (s, 3H), 3.13 (s, 3H).Example 9 N-methoxy-4-((6-methoxy-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)-6-((2-methoxy pyridin-3-yl)amino)nicotinamide

[0108]

[0109] Step 1: 6-chloro-N-methoxy-4-((6-methoxy-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (7-e, 50mg, 0.12mmol), 2-methoxy pyridin-3-amine (16.12mg, 0.13mmol), cesium carbonate (117mg, 0.36mmol), XantPhos(13.9mg, 0.024mmol) and Pd 2 (dba) 3 (11mg, 0.012mmol) were added to anhydrous dioxane (5ml) and the mixture was evacuated to vacuum. After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 100°C, stirred for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: N-methoxy-4-((6-methoxy-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)-6-((2-methoxy pyridin-3-yl)amino)nicotinamide (9 , 8 mg, 0.016mmol, 13.6% yield). MS Calcd: 503; MS Found: 504 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.65 (s, 1H), 9.59(s, 1H)8.52 (dd, J = 8.0, 1.6 Hz, 1H), 8.43 (s, 1H), 8.24(s, 1H)7.88 (d, J = 8.8 Hz, 1H), 7.71 (dd, J = 4.8, 2.0 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.92 (dd, J = 8.0, 4.8 Hz, 1H), 6.44 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.71 (s, 3H), 3.21(s, 3H), 3.12(s, 3H).Example 10 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-(N-methyl methanesulfonamido)-4-(trifluoromethyl)phenyl)amino)nicotinamide

[0110]

[0111] Step 1: 2-fluoro-1-nitro-4-(trifluoromethyl)benzene (10-a, 418mg, 2mmol)dissolved in DMF(20ml) was added to a 100ml reaction flask followed by 60% sodium hydride (120°Cg, 3mmol) and N-methyl methanesulfonamide (261.6mg, 2.4mmol). The mixture was stirred at 50°C for 2h. Upon indication of completed reaction by TLC, the reaction mixture was added with water (40ml) / ethyl acetate (30ml), and subjected to phase separation. The organic phase was washed with water (30 ml x 1) and brine (30 ml x 1), dried over anhydrous sodium sulfate, and concentrated to provide a crude material, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3:1) to provide the product N-methyl-N-(2-nitro-5-(trifluoromethyl)phenyl) methanesulfonamide(10-b, 420mg, 70.4% yield). MS Calcd:298; MS Found: 299([M+H] +< ).

[0112] Step 2: N-methyl-N-(2-nitro-5-(trifluoromethyl)phenyl) methanesulfonamide (10-b, 400mg, 1.34mmol) and palladium on carbon (40mg) were added to methanol(15ml), followed by atmosphere replacement by hydrogen three times, stirred under hydrogen atmosphere at room temperature overnight, and filtered by suction. The filtrate was concentrated under reduced pressure to provide N-(2-amino-5-(trifluoromethyl)phenyl)-N-methyl methanesulfonamide (10-c, 350mg, 1.31mmol, 97.4% yield), which was used directly in the next reaction without further purification. MS Calcd: 268; MS Found: 269 ([M+H] +< ).

[0113] Step 3: N-(2-amino-5-(trifluoromethyl)phenyl)-N-methyl methanesulfonamide (10-c, 350mg, 1.31mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 285.6mg, 1.31mmol) were added to 5ml of anhydrous N,N-dimethylacetamide. The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (4ml, 3.93mmol), and stirred at room temperature for 2h. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (30 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography to provide 6-chloro-N-methoxy-4-((2-(N-methyl methanesulfonamido)-4-(trifluoromethyl)phenyl)amino)nicotinamide (10-d, 110mg, 0.24mmol, 18.6% yield). MS Calcd: 452; MS Found: 453 ([M+H] +< ).

[0114] Step 4: 6-chloro-N-methoxy-4-((2-(N-methyl methanesulfonamido)-4-(trifluoromethyl)phenyl)amino)nicotinamide (10-d, 60mg, 0.13mmol), cyclopropylcarboxamide (12.4mg, 0.15mmol), cesium carbonate (126.7mg, 0.39mmol), XantPhos(11mg, 0.02mmol) and Pd 2 (dba) 3 (10mg, 0.01mmol) were added to anhydrous dioxane (5ml) and the mixture was evacuated to vacuum. After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 120°C, stirred for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-(N-methyl methanesulfonamido)-4-(trifluoromethyl)phenyl)amino)nicotinamide (10, 8 mg, 0.016mmol, 12.3% yield).

[0115] MS Calcd: 501; MS Found: 502 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.91 (s, 1H), 10.93 (s, 1H), 10.37 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.77 - 7.70 (m, 2H), 3.92 (s, 3H), 3.22 (s, 3H), 3.20 (s, 3H), 1.99(m, 1H), 0.85-0.79(m, 4H).Example 11 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)-4-(trifluoromethyl)phenyl)amino)nicotinamide

[0116]

[0117] Step 1: 6-chloro-N-methoxy-4-((2-(N-methyl methanesulfonamido)-4-(trifluoromethyl)phenyl)amino)nicotinamide (10-d, 50mg, 0.11mmol), 6-fluoro-2-aminopyridine (10.4mg, 0.12mmol), cesium carbonate (108.2mg, 0.33mmol), XantPhos(11mg, 0.02mmol) and Pd 2 (dba) 3 (10mg, 0.01mmol) were added to anhydrous dioxane (5ml) and the mixture was evacuated to vacuum. After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 120°C, stirred for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)-4-(trifluoromethyl)phenyl)amino)nicotinamide (11, 15 mg, 0.028mmol, 25.8% yield). MS Calcd: 528; MS Found: 529 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.84 (s, 1H), 10.46 (s, 1H), 10.16 (s, 1H), 8.38 (s, 1H), 7.92-7.89 (m, 3H), 7.83 (dd, J = 16.4, 8.0 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 6.61 (dd, J = 8.0, 2.4 Hz, 1H), 3.71(s, 3H), 3.22 (s, 3H), 3.13 (s, 3H).Example 12 6-(cyclopropylcarboxamido)-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide

[0118]

[0119] Step 1: To N-methyl methanesulfonamide (0.6 g, 5.5 mmol) dissolved in 10 mL of N,N-dimethyl formamide was added sodium hydride (0.29g, 7.5 mmol) portionwise. The reaction mixture was heated up to 55°C with continuous stirring for 2 hours, added with 4-bromo-2-fluoro-1-nitrobenzene (12-a, 1.1 g, 5.0 mmol), followed by further stirring at the temperature for 2 hours. Upon indication of completed reaction by TLC, the reaction mixture was added with water (40 mL), extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA:PE=1:5) to provide N-(5-bromo-2-nitrophenyl)-N-methyl methanesulfonamide (12-b, 1.6 g, 5.17 mmol, 94% yield), as a pale yellow solid. MS Calcd: 307.95; MS Found: 307.00 ([M-H] -< ).

[0120] Step 2: N-(5-bromo-2-nitrophenyl)-N-methyl methanesulfonamide (12-b, 1.6 g, 5.17 mmol), cyclopropyl boronic acid (0.53 g, 6.2 mmol), potassium phosphate (5.27 g, 15.6 mmol) and Pd(dppf)Cl 2 (0.38g, 0.52 mmol) were sequentially added to 30 mL of solution of dioxane / water (5 / 1). The atmosphere of the mixture was evacuated and replaced with nitrogen three times followed by stirring at 110°C for 6 hours. Upon indication of completed reaction by TLC, the reaction mixture was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA:PE=1:1) to provide N-(5-cyclopropyl-2-nitrophenyl)-N-methyl methanesulfonamide (12-c, 1.1 g, 0.4 mmol, 77.3% yield), as a yellow solid. MS Calcd: 270.07; MS Found: 271.13 ([M+H] +< ).

[0121] Step 3: N-(5-cyclopropyl-2-nitrophenyl)-N-methyl methanesulfonamide (12-c, 1 g, 3.7mmol), ammonium chloride (0.98 g, 18 mmol) and iron powder (0.62 g, 11.1 mmol) were sequentially added to 10 mL of mixed solvent of water and ethanol (1:4), and stirred under reflux for 6 hours. Upon TLC indicating a completed reaction, the mixture was filtered by suction, and concentrated. The residue was separated and purified by silica gel column chromatography to provide N-(2-amino-5-cyclopropyl phenyl)-N-methyl methanesulfonamide (12-d, 0.72 g, 2.98 mmol, 80.7% yield), as a colorless oil. MS Calcd: 240.09; MS Found: 241.22 ([M+H] +< ).

[0122] Step 4: N-(2-amino-5-cyclopropyl phenyl)-N-methyl methanesulfonamide (12-d, 165.8 mg, 0.69 mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 150 mg, 0.69 mmol) were added to 10 ml of anhydrous N,N-dimethylacetamide. The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (2.0 ml, 2.0 mmol), and stirred at room temperature for 3 hours. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (20 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (12-e, 250 mg, 0.59 mmol, 85.6% yield), as a tan oil. MS Calcd: 424.10; MS Found: 425.29 ([M+H] +< ).

[0123] Step 5: 6-chloro-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (12-e, 127 mg, 0.3 mmol), cyclopropylcarboxamide (28 mg, 0.33mmol), cesium carbonate (293 mg, 0.9 mmol), XantPhos(34.7mg, 0.06mmol) and Pd 2 (dba) 3 (28.4mg, 0.03 mmol) were added to anhydrous dioxane (5 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 6 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (12, 40mg, 0.085mmol, 28.2% yield). MS Calcd: 473.17; MS Found: 472.36 ([M-H] -< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.76 (s, 1H), 10.74(s, 1H), 9.789(s, 1H), 8.30 (s, 1H), 7.82(s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 8.4, 2.0 Hz, 1H), 3.71(s, 3H), 3.12(s, 3H), 3.07(s, 3H), 1.98 - 1.93 (m, 2H), 1.00-0.95(m, 2H)0.77-0.70 (m, 6H).Example 13 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide

[0124]

[0125] Step 1: 6-chloro-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (12-e, 127 mg, 0.3 mmol), 5-fluoropyridin-2-ylamine (28 mg, 0.33mmol), cesium carbonate (293 mg, 0.9 mmol), XantPhos (34.7mg, 0.06mmol) and Pd 2 (dba) 3 (28.4mg, 0.03 mmol) were added to anhydrous dioxane (5 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 6 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide (13, 50mg, 0.085mmol, 33.3% yield). MS Calcd: 500.17; MS Found: 501.36 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.67 (s, 1H), 9.92(s, 1H), 9.78(s, 1H), 8.27 (s, 1H), 8.15(d, J = 7.2 Hz, 1H), 7.67-7.64(m, 2H), 7.50 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.16 (dd, J = 8.4, 2.0 Hz, 1H), 3.70 (s, 3H), 3.14 (s, 3H)3.10 (s, 3H), 2.01-1.97 (m, 1H), 1.01-0.97 (m, 2H), 0.74-0.70 (m, 2H).Example 14 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide

[0126]

[0127] Step 1: 6-chloro-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (12-e, 127 mg, 0.3 mmol), 6-fluoropyridin-2-ylamine (28 mg, 0.33mmol), cesium carbonate (293 mg, 0.9 mmol), XantPhos(34.7mg, 0.06mmol) and Pd 2 (dba) 3 (28.4mg, 0.03 mmol) were added to anhydrous dioxane (5 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 6 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide (14, 45mg, 0.085mmol, 30% yield). MS Calcd: 500.17; MS Found: 501.36 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.69 (s, 1H), 9.96(s, 1H), 9.93(s, 1H), 8.30 (s, 1H), 7.79 (dd, J = 16.8, 8.4 Hz, 1H), 7.76(s, 1H), 7.54-7.48 (m, 1H), 7.46-7.44 (m, 1H), 7.28 (s, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.56-6.54 (m, 1H), 3.70 (s, 3H), 3.14 (s, 3H)3.07 (s, 3H), 2.01-1.97 (m, 1H), 1.01-0.97 (m, 2H), 0.74-0.70 (m, 2H).Example 15 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((4-fluorophenyl)amino)-N-methoxy nicotinamide

[0128]

[0129] Step 1: 6-chloro-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (15-e, 100 mg, 0.24 mmol), 4-fluoroaniline (31.5 mg, 0.28mmol), cesium carbonate (230 mg, 0.71 mmol), XantPhos(27.3mg, 0.047mmol) and Pd 2 (dba) 3 (23.08mg, 0.023 mmol) were added to anhydrous dioxane (5 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 6 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((4-fluorophenyl)amino)-N-methoxy nicotinamide (15, 40mg, 0.08mmol, 33.3% yield). MS Calcd: 499.17; MS Found: 500.16 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.60 (s, 1H), 9.67(s, 1H), 9.04(s, 1H), 8.22 (s, 1H), 7.59-7.57(m, 2H), 7.37 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.12-7.05 (m, 3H), 6.28 (s, 1H), 3.77 (s, 3H), 3.14 (s, 3H)3.10 (s, 3H), 2.01-1.97 (m, 1H), 1.01-0.97 (m, 2H), 0.74-0.70 (m, 2H).Example 16 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy-6-((5-methoxy pyridin-2-yl)amino)nicotinamide

[0130]

[0131] Step 1: 6-chloro-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (12-e, 80 mg, 0.189 mmol), 5-methoxy pyridin-2-ylamine (25.8 mg, 0.208mmol), cesium carbonate (184.3 mg, 0.567 mmol), XantPhos(21.97mg, 0.038mmol) and Pd 2 (dba) 3 (18.58mg, 0.019 mmol) were added to anhydrous dioxane (5 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 6 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy-6-((5-methoxy pyridin-2-yl)amino)nicotinamide (16, 25mg, 0.049mmol, 25.8% yield). MS Calcd: 512.18; MS Found: 513.22 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.61 (s, 1H), 9.90 (s, 1H), 9.51(s, 1H), 8.25 (s, 1H), 7.87 (d, J = 2.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.47-7.44 (m, 2H), 7.35 (dd, J = 8.8, 2.8 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.15-7.13 (m, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 3.14 (s, 3H), 3.10 (s, 3H), 2.01-1.97 (m, 1H), 1.01-0.97(m, 2H), 0.74-0.70 (m, 2H).Example 17 6-((4-fluorophenyl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide

[0132]

[0133] Step 1: N-methyl methanesulfonamide (0.48 g, 4.4 mmol) was dissolved in 10 mL of N,N-dimethyl formamide, added with sodium hydride (0.24g, 6 mmol) portionwise. After that, the reaction mixture was heated to 55°C with continuous stirring for 2 hours, added with 2-chloro-3-nitropyridine (17-a, 0.632 g, 4.0 mmol), followed by further stirring at the temperature for 2 hours. Upon indication of completed reaction by TLC, the reaction mixture was added with water (40 mL), and extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA:PE=1:5) to provide N-methyl-N-(3-nitropyridin-2-yl) methanesulfonamide (17-b, 572 mg, 2.48 mmol, 61.9% yield), as a pale yellow solid. MS Calcd: 231.07; MS Found: 230.20 ([M-H] -< ).

[0134] Step 2: N-methyl-N-(3-nitropyridin-2-yl) methanesulfonamide (17-b, 572mg, 2.48mmol), ammonium chloride (0.67 g, 12.4 mmol) and iron powder (0.42 g, 7.44mmol) were sequentially added to 10 mL of mixed solvent of water and ethanol (1:4), and stirred under reflux for 6 hours. Upon indication of completed reaction by TLC, the reaction mixture was filtered by suction. The filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography to provide N-(3-aminopyridin-2-yl)-N-methyl methanesulfonamide (17-c, 0.41 g, 2.19 mmol, 88.4% yield), as a colorless oil. MS Calcd: 201.06; MS Found: 202.06 ([M+H] +< ).

[0135] Step 3: N-(3-aminopyridin-2-yl)-N-methyl methanesulfonamide (17-c, 150 mg, 0.80 mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 174.8 mg, 0.80 mmol) were added to 5 ml of anhydrous N,N-dimethylacetamide. The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (2.4 ml, 2.4 mmol), and stirred at room temperature for 3 hours. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (20 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-N-methoxy-4-((2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (17-d, 180 mg, 0.467 mmol, 58.4% yield). MS Calcd: 385.06; MS Found: 386.22 ([M+H] +< ). Step 4: 6-chloro-N-methoxy-4-((2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (17-d, 53 mg, 0.13 mmol), 4-fluoroaniline (18.4 mg, 0.16mmol), cesium carbonate (135mg, 0.41 mmol), XantPhos(16.2mg, 0.028mmol) and Pd 2 (dba) 3 (13.7mg, 0.014 mmol) were added to anhydrous dioxane (5 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 6 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-((4-fluorophenyl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (17, 15mg, 0.032mmol, 25% yield). MS Calcd: 460.13; MS Found: 459.2 ([M-H] -< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.67 (s, 1H), 9.99(s, 1H), 9.13(s, 1H), 8.27 (s, 1H), 8.24 (dd, J = 8.4, 1.6 Hz, 1H), 8.02 (dd, J = 7.2, 1.6 Hz, 1H), 7.61-7.57 (m, 2H), 7.48 (dd, J = 8.4, 4.8 Hz, 1H), 7.12-7.09 (m, 2H), 6.44 (s, 1H), 3.71 (s, 3H), 3.20 (s, 3H), 3.15 (s, 3H).Example 18 4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy-6-((5-methoxy pyridin-2-yl)amino)nicotinamide

[0136]

[0137] Step 1: N-methyl methanesulfonamide (0.6 g, 5.5 mmol) dissolved in 10 mL of N,N-dimethyl formamide was added with sodium hydride (0.29g, 7.5 mmol) portionwise. After that, the reaction mixture was heated to 55°C with continuous stirring for 2 hours, added with 4-bromo-2-fluoro-1-nitrobenzene (18-a, 1.1 g, 5.0 mmol), followed by further stirring at the temperature for 2 hours. Upon indication of completed reaction by TLC, the reaction mixture was added with water (40 mL), extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA:PE=1:5) to provide N-(5-bromo-2-nitrophenyl)-N-methyl methanesulfonamide (18-b, 1.6 g, 5.17 mmol, 94% yield), as a pale yellow solid. MS Calcd: 307.95; MS Found: 307.00 ([M-H] -< ).

[0138] Step 2: N-(5-bromo-2-nitrophenyl)-N-methyl methanesulfonamide (18-b, 0.45 g, 1.46 mmol), ethynyl trimethylsilane (0.43g, 4.38 mmol), cuprous (I) iodide (23.04mg, 0.15 mmol) and Pd(dppf)Cl 2 (109.7mg, 0.15 mmol) were sequentially added to 5ml of triethylamine. The atmosphere of the mixture was evacuated and replaced with nitrogen three times, followed by stirring at 60°C for 4 hours. Upon indication of completed reaction by TLC, the mixture was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA:PE=1:1) to provide N-methyl-N-(2-nitro-5-((trimethylsilyl)ethynyl)phenyl) methanesulfonamide(18-c, 0.375g, 1.07mmol, 73.2% yield), as a yellow solid. MS Calcd: 326.08; MS Found: 327.10 ([M+H] -< ).

[0139] Step 3: N-methyl-N-(2-nitro-5-((trimethylsilyl)ethynyl)phenyl) methanesulfonamide (18-c, 0.3375 g, 1.07mmol), ammonium chloride (0.322g, 5.75 mmol) and iron powder (0.62 g, 11.1 mmol) were sequentially added to 10 mL of mixed solvent of water and ethanol (1:4), stirred under reflux for 6 hours. Upon indication of completed reaction by TLC, the reaction mixture was filtered by suction. The filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography to provide N-(2-amino-5-((trimethylsilyl)ethynyl)phenyl)-N-methyl methanesulfonamide (18-d, 0.307 g, 1.03 mmol, 96.2% yield), as a colorless oil. MS Calcd: 296.09; MS Found: 297.22 ([M+H] +< ).

[0140] Step 4: N-(2-amino-5-((trimethylsilyl)ethynyl)phenyl)-N-methyl methanesulfonamide (18-d, 307 mg, 1.03 mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 224.5 mg, 1.03 mmol) were added to 10 ml of anhydrous N,N-dimethylacetamide. The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (3.1 ml, 3.09 mmol), and stirred at room temperature for 3 hours. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (20 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (18-e, 197mg, 0.48 mmol, 46.8% yield), as a tan oil. MS Calcd: 408.10; MS Found: 409.29 ([M+H] +< ).

[0141] Step 5: 6-chloro-4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (18-e, 100 mg, 0.245 mmol), 5-methoxy pyridin-2-ylamine (33.43 mg, 0.27mmol), cesium carbonate (239 mg, 0.74 mmol), XantPhos(28.9mg, 0.05mmol) and Pd 2 (dba) 3 (24.45mg, 0.025 mmol) were added to anhydrous dioxane (5 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 6 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy-6-((5-methoxy pyridin-2-yl)amino)nicotinamide (18, 10mg, 0.02mmol, 8.2% yield). MS Calcd: 496.15; MS Found: 497.20 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.71 (s, 1H), 10.32 (s, 1H), 9.67 (s, 1H), 8.31 (s, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.87 (m, 1H), 7.66-7.64 (m, 2H), 7.59-7.54 (m, 2H), 7.37 (dd, J = 8.8, 2.8 Hz, 1H), 4.23 (s, 1H), 3.79 (s, 3H), 3.71 (s, 3H), 3.18 (s, 6H).Example 19 4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide

[0142]

[0143] Step 1: 6-chloro-4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (18-e, 90 mg, 0.22 mmol), 6-fluoropyridin-2-ylamine (27.13 mg, 0.24mmol), cesium carbonate (215 mg, 0.66 mmol), XantPhos(25.4mg, 0.04mmol) and Pd 2 (dba) 3 (21.5mg, 0.022 mmol) were added to anhydrous dioxane (5 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 6 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide (19, 5mg, 0.01mmol, 4.7% yield). MS Calcd: 484.13; MS Found: 485.20 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.78 (s, 1H), 10.30(s, 1H), 10.08 (s, 1H), 8.35 (s, 1H), 7.84-7.78 (m, 1H), 7.70-7.66 (m, 1H), 7.47-7.45 (m, 2H), 7.40-7.29 (m, 2H), 6.58 (d, J = 8.0 Hz 1H), 4.21 (s, 1H), 3.71 (s, 3H), 3.17 (s, 3H), 3.16 (s, 3H).Example 20 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((5-methoxy pyridin-2-yl)amino)nicotinamide

[0144]

[0145] Step 1:N-(2-amino-5-cyclopropyl phenyl)-N-methyl methanesulfonamide (18-b, 240 mg, 1.0mmol) and 4,6-dichloro-N-ethoxy nicotinamide (int-2, 234 mg, 1.0 mmol) were added to 10 ml of anhydrous N,N-dimethylacetamide. The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (3 ml, 3.0 mmol), and stirred at room temperature for 3 hours. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (20 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy nicotinamide (20-a, 325mg, 0.74 mmol, 74.2% yield). MS Calcd: 438; MS Found: 439 ([M+H] +< ).

[0146] Step 2: 6-chloro-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy nicotinamide (33169-c, 87 mg, 0.2 mmol), 5-methoxy pyridin-2-ylamine (29.76 mg, 0.24mmol), cesium carbonate (215 mg, 0.66 mmol), XantPhos(25.4mg, 0.04mmol) and Pd 2 (dba) 3 (21.5mg, 0.022 mmol) were added to anhydrous dioxane (5 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 6 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((5-methoxy pyridin-2-yl)amino)nicotinamide (20, 20mg, 0.038mmol, 19% yield). MS Calcd: 526.20; MS Found: 527.20 ([M+H] -< ).

[0147] 1< H NMR (400 MHz, DMSO-d 6 ) : δ 9.86 (s, 1H), 9.50(s, 1H), 8.27 (s, 1H), 7.87 (d, J = 3.2 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.46-7.44 (m, 2H), 7.36 (dd, J = 8.8, 3.2 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.14 (d, J =8.4Hz, 1H), 3.93 (q, J = 7.2 Hz, 2H), 3.77 (s, 3H), 3.18 - 3.08 (m, 7H), 2.01-1.95 (m, 1H), 1.227 (t, J = 7.2 Hz, 3H), 1.01-0.96 (m, 2H), 0.74-0.70 (m, 2H).Example 21 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((2,6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy nicotinamide

[0148]

[0149] Step 1: 6-chloro-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy nicotinamide (20-a, 87 mg, 0.2 mmol), 2,6-dimethyl pyrimidin-4-ylamine (29.7 mg, 0.24mmol), cesium carbonate (215 mg, 0.66 mmol), XantPhos(25.4mg, 0.04mmol) and Pd 2 (dba) 3 (21.5mg, 0.022 mmol) were added to anhydrous dioxane (5 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 6 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((2,6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy nicotinamide (21, 25mg, 0.047mmol, 23.8% yield). MS Calcd: 525.20; MS Found: 526.20 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.59 (s, 1H), 9.99(s, 1H), 9.85 (s, 1H), 8.32 (s, 1H), 7.82(s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.11 (dd, J = 8.4, 2.0 Hz, 1H), 7.04 (s, 1H), 3.94 (q, J = 7.2 Hz, 2H), 3.13 (s, 3H), 3.09 (s, 3H), 2.3 1 (s, 3H), 2.26 (s, 3H), 1.98-1.94 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H), 0.99-0.95 (m, 2H), 0.72-0.698 (m.2H).Example 22 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((6-fluoropyridin-2-yl)amino)nicotinamide

[0150]

[0151] Step 1: 6-chloro-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy nicotinamide (20-a, 87 mg, 0.2 mmol), 6-fluoropyridin-2-ylamine (26.9 mg, 0.24mmol), cesium carbonate (215 mg, 0.66 mmol), XantPhos(25.4mg, 0.04mmol) and Pd 2 (dba) 3 (21.5mg, 0.022 mmol) were added to anhydrous dioxane (5 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 6 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-ethoxy-6-((6-fluoropyridin-2-yl)amino)nicotinamide (22, 20mg, 0.039mmol, 19.4% yield). MS Calcd: 514.18; MS Found: 515.20 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.10 (s, 1H), 9.94 (s, 1H), 9.85 (s, 1H), 8.38 (s, 1H), 7.78 (dd, J = 16.4, 8.4 Hz, 1H), 7.51-7.44 (m, 3H), 7.27 (d, J = 2.0 Hz, 1H), 7.09-7.06 (m, 1H), 6.64 (dd, J = 8.0, 2.8 Hz, 1H), 3.93 (q, J = 7.2 Hz, 2H), 3.13 (s, 3H), 3.07 (s, 3H), 1.96-1.94 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H), 1.00-0.95 (m, 2H), 0.72-0.698 (m.2H).Example 23 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-isopropoxy nicotinamide

[0152]

[0153] Step 1:1) 4,6-dichloronicotinic acid(23-a, 288mg, 1.5mmol) dissolved in dichloromethane (10ml) was added to a 50ml two-necked flask, the reaction mixture was cooled with ice-water bath to 0°C~5°C, added with catalytic amount of DMF(0.1ml) dropwise followed by carefully adding oxalyl chloride (229mg, 1.8mmol) dropwise, stirred at room temperature for 30min. Upon indication of completed reaction by TLC, the reaction mixture was concentrated at 40°C under reduced pressure, and the resulting crude product was added to dichloromethane (20ml) and further concentrated under reduced pressure.

[0154] 2) Hydrochloride salt of isoproxylamine (200.7g, 1.8mmol) was added to a mixture of ethyl acetate / water (40ml) (5:1), added with potassium carbonate (828mg, 6mmol), and stirred at room temperature for 10 min. To which was carefully added the crude material from the previous step dissolved in dichloromethane (5ml) dropwise, followed by stirring at room temperature overnight. After phase separation, the organic phase was concentrated, purified by column chromatography (petroleum ether / ethyl acetate=2:1) to provide the desired product 4,6-dichloro-N-isopropoxy nicotinamide (23-b, 350mg, 1.42mmol, 94.8% yield). MS Calcd: 248; MS Found: 249 ([M+H] +< ).

[0155] Step 2: N-(2-amino-5-cyclopropyl phenyl)-N-methyl methanesulfonamide (23-b, 120 mg, 0.5mmol) and 4,6-dichloro-N-isopropoxy nicotinamide (123 mg, 0.5 mmol) were added to 5 ml of anhydrous N,N-dimethylacetamide. The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (1.5 ml, 1.5 mmol), and stirred at room temperature for 3 hours. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (20 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-isopropoxy nicotinamide (23-c, 170mg, 0.37 mmol, 75.2% yield), as a tan oil. MS Calcd: 452; MS Found: 453 ([M+H] +< ).

[0156] Step 3: 6-chloro-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-isopropoxy nicotinamide (23-c, 71 mg, 0.16 mmol), 6-fluoropyridin-2-ylamine (21.18 mg, 0.19mmol), cesium carbonate (153 mg, 0.47 mmol), XantPhos(18.5mg, 0.03mmol) and Pd 2 (dba) 3 (15.2mg, 0.015 mmol) were added to anhydrous dioxane (5 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 6 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-isopropoxy nicotinamide (23, 15mg, 0.028mmol, 17.8% yield). MS Calcd: 528; MS Found: 529 ([M+H] +< ). 1H NMR (400 MHz, DMSO-d 6 ) : δ 11.10 (s, 1H), 9.94(s, 1H), 9.85 (s, 1H), 8.33 (s, 1H), 7.78 (dd, J = 16.4, 8.4 Hz, 1H), 7.50-7.47 (m, 3H), 7.28 (s, 1H), 7.08 (dd, J = 8.4, 2.0 Hz, 1H), 6.55 (dd, J = 8.0, 2.8 Hz, 1H), 4.14 (q, J = 7.0 Hz, 1H), 3.14 (s, 3H), 3.07 (s, 3H), 1.98-1.96 (m, 1H), 1.22 (d, J = 7.0 Hz, 6H), 0.99-0.95 (m, 2H), 0.72-0.69 (m.2H).Example 24 4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(((6-fluoropyridin-2-yl)amino)-N-isopropoxy nicotinamide

[0157]

[0158] Step 1: N-(2-amino-5-((trimethylsilyl)ethynyl)phenyl)-N-methyl methanesulfonamide (226 mg, 0.76 mmol) and 4,6-dichloro-N-isopropoxy nicotinamide (23-b, 187mg, 0.76 mmol) were added to 5 ml of anhydrous N,N-dimethylacetamide. The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (2.3 ml, 2.28 mmol), and stirred at room temperature for 3 hours. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (20 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-isopropoxy nicotinamide (24-a, 130mg, 0.298 mmol, 39.2% yield), as a tan oil.

[0159] MS Calcd: 436.10; MS Found: 437.29 ([M+H] +< ).

[0160] Step 2: 6-chloro-4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-isopropoxy nicotinamide (24-a, 130mg, 0.298 mmol), 6-fluoropyridin-2-ylamine (40.11 mg, 0.36mmol), cesium carbonate (290.6 mg, 0.89 mmol), XantPhos(34.7mg, 0.06mmol) and Pd 2 (dba) 3 (28.41mg, 0.03 mmol) were added to anhydrous dioxane (5 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 6 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((4-ethynyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(((6-fluoropyridin-2-yl)amino)-N-isopropoxy nicotinamide (24, 17.2mg, 0.033mmol, 11.2% yield). MS Calcd: 512.16; MS Found: 513.20 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.52 (s, 1H), 10.24(s, 1H), 10.05 (s, 1H), 8.35 (s, 1H), 7.82 (dd, J = 16.8, 8.0 Hz, 1H), 7.77 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.48-7.46 (m, 2H), 6.59 (dd, J = 8.0, 2.4 Hz, 1H), 4.23 (s, 1H), 4.17-4.11 (m, 1H), 3.19 (s, 3H), 3.17 (s, 3H), 1.22 (d, 3H), 1.21(s, 3H).Example 25 6-((2,6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide

[0161]

[0162] Step 1: 2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)aniline (203 mg, 1.0mmol) and 4,6-dichloro-N-ethoxy nicotinamide (int-2, 234 mg, 1.0 mmol) were added to 10 ml of anhydrous N,N-dimethylacetamide. The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (3 ml, 3.0 mmol), and stirred at room temperature for 3 hours. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (20 ml × 3). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (25-a, 320mg, 0.80 mmol, 80% yield). MS Calcd: 401; MS Found: 402 ([M+H] +< ).

[0163] Step 2: 6-chloro-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (25-a, 120 mg, 0.3 mmol), 2,6-dimethyl pyrimidin-4-ylamine (40.59 mg, 0.33mmol), cesium carbonate (292.5 mg, 0.9mmol), XantPhos(34.68mg, 0.06mmol) and Pd 2 (dba) 3 (27.47mg, 0.03 mmol) were added to anhydrous dioxane (5 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 6 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(((2,6-dimethyl pyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (25, 6mg, 0.012mmol, 4% yield). MS Calcd: 488.23; MS Found: 489.20 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.70 (s, 1H), 10.23 (s, 1H), 10.08 (s, 1H), 8.38 (s, 1H), 8.17-8.16 (m, 2H), 7.92 (s, 1H), 7.44 (dd, J = 8.0, 1.2 Hz, 1H), 7.38 (dd, J = 8.0, 1.6 Hz, 1H), 7.19(t, J = 8.0 Hz, 1H), 7.07 (s, 1H), 3.96 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.61 (s, 3H), 2.37 (s, 3H), 2.27 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H).Example 26 6-(cyclopropylcarboxamido)-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide

[0164]

[0165] Step 1: 6-chloro-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (25-a, 120 mg, 0.3 mmol), cyclopropylcarboxamide (25.5 mg, 0.3mmol), cesium carbonate (292.5 mg, 0.9mmol), XantPhos(34.68mg, 0.06mmol) and Pd 2 (dba) 3 (27.47mg, 0.03 mmol) were added to anhydrous dioxane (5 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 6 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (26, 40mg, 0.088mmol, 29.5% yield). MS Calcd: 450.20; MS Found: 451.20([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.76 (s, 1H), 10.79 (s, 1H), 10.14 (s, 1H), 8.38 (s, 1H), 8.16 (s, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.36 (dd, J = 8.0, 1.6 Hz, 1H), 7.27 (dd, J = 8.0, 1.6 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 3.96 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.58 (s, 3H), 1.98-1.97 (m, 1H), 1.24-1.21 (t, J = 7.2 Hz, 3H), 0.78-0.75 (m, 2H), 0.64-0.58 (m, 2H).Example 27 6-((5-cyclopropyl pyridin-2-yl)amino)-N-ethoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide

[0166]

[0167] Step 1: N-(2-amino phenyl)-N-methyl methanesulfonamide (2-c, 201mg, 1mmol) and 4,6-dichloro-N-ethoxy nicotinamide (int-2, 236mg, 1mmol) were added to 10ml of anhydrous N,N-dimethylacetamide. The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (3ml, 3mmol), and stirred at room temperature for 2h. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (30ml×3). The combined organic layers were dried, concentrated and then purified by column chromatography to provide 6-chloro-N-ethoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (27-a, 380mg, 0.76mmol, 76% yield).

[0168] Step 2: 6-chloro-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (27-a, 92 mg, 0.185 mmol), 5-cyclopropyl pyridin-2-ylamine (24.8 mg, 0.185mmol, Tetrahedron Letters 2017, 58, 1681), cesium carbonate (175.5 mg, 0.54mmol), XantPhos(20.81mg, 0.036mmol) and Pd 2 (dba) 3 (17.5mg, 0.018 mmol) were added to anhydrous dioxane (5 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 6 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-((5-cyclopropyl pyridin-2-yl)amino)-N-ethoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (27, 20mg, 0.04mmol, 21.7% yield). MS Calcd: 496.19.20; MS Found: 497.20([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.57 (s, 1H), 10.06(s, 1H), 9.65 (s, 1H), 8.30 (s, 1H), 8.00-7.99 (m, 1H), 7.73-7.68 (m, 1H), 7.63 (dd, J = 8.4, 1.6 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.48-7.44 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 3.96 (q, J = 7.2 Hz, 2H), 3.15 (s, 3H), 3.13 (s, 3H), 1.89-1.83 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H), 0.92-0.91 (m, 2H), 0.65-0.61 (m, 2H).Example 28 6-(cyclopropylcarboxamido)-N-methoxy-4-((1-methyl-1H-indazol-6-yl)amino)nicotinamide

[0169]

[0170] Step 1: To a two-necked flask were sequentially added 1-methyl-6-amino-1H-indazole (28-a, 147mg, 1mmol), 4,6-dichloro-N-methoxy nicotinamide (int-1, 218mg, 1mmol), and anhydrous tetrahydrofuran (5ml). The mixture was added with a solution of LiHMDS in tetrahydrofuran (3ml, 1mol / L) at room temperature, with continuous stirring at room temperature for 2h. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (30mL x 3). The organic layers were combined, dried and concentrated, followed by purification by column chromatography to provide 6-chloro-N-methoxy-4-((1-methyl-1H-indazol-6-yl)amino)nicotinamide (28-b, 142mg, 0.39mmol, 43% yield). MS Calcd: 331; MS Found: 332([M+H] +< ).

[0171] Step 2: 6-chloro-N-methoxy-4-((1-methyl-1H-indazol-6-yl)amino)nicotinamide (28-b, 33mg, 0.1mmol), cyclopropylcarboxamide (9.4mg, 0.11mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(15mg, 0.02mmol) and Pd 2 (dba) 3 (10mg, 0.01mmol) were added to anhydrous dioxane (5ml). The atmosphere of the mixture was replaced by nitrogen three times. The reaction mixture was heated to 125°C with stirring for 8h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-N-methoxy-4-((1-methyl-1H-indazol-6-yl)amino)nicotinamide (28, 12mg, 0.032mmol, 32% yield). MS Calcd: 380; MS Found: 381([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.83 (s, 1H), 10.74 (s, 1H), 10.07 (s, 1H), 8.37 (s, 1H), 8.03 (s, 1H), 8.00 (d, J = 1.2 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.52 (s, 1H), 7.03 (dd, J = 8.4, 2.0 Hz, 1H), 3.99 (s, 3H), 3.74 (s, 3H), 1.99-1.93 (m, 1H), 0.77 - 0.60 (m, 4H).Example 29 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)nicotinamide

[0172]

[0173] Step 1: To a 100mL flask were sequentially added 1-(2-hydroxyl-3-nitrophenyl)ethan-1-one (29-a, 1g, 5.5mmol), iodomethane (1g, 7mmol), anhydrous potassium carbonate (1g, 7.2mmol) and N,N-dimethyl formamide (5mL), and stirred at room temperature. Upon indication of completed reaction by TLC, the reaction mixture was added with 20mL of water for dilution of the mother liquid, and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, followed by solvent removed by rotary evaporation to provide 1-(2-methoxy-3-nitrophenyl)ethan-1-one (29-b, 1.03g, 5.28mmol, 96% yield). MS Calcd: 195; MS Found: 196([M+H] +< ).

[0174] Step 2: Into a flask was weighted 1-(2-methoxy-3-nitrophenyl)ethan-1-one (29-b, 1.03g, 5.28mmol), added with 2mL of DMF-DMA and stirred at 90 °C. Upon indication of completed reaction by TLC, DMF-DMA was directly removed by rotary evaporation to provide 3-(dimethylamino)-1-(2-methoxy-3-nitrophenyl)prop-2-en-1-one (29-c), which was used directly in the next reaction without further purification, adding small amount of ethanol to prepare a ready-use stock solution. MS Calcd: 250; MS Found: 251([M+H] +< ).

[0175] Step 3: Into a flask was added hydrazine monohydrate(0.5mL), added in ice bath with 5mL of ethanol and 1mL of acetic acid and stirred for 5minutes, followed by adding stock solution from the previous Step 2, and stirred at room temperature. Upon indication of completed reaction by TLC, the mixture was subjected to rotary evaporation to remove solvent, washed with small amount of water, and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, followed by solvent removed by rotary evaporation to provide 3-(2-methoxy-3-nitrophenyl)-1H-pyrazole (29-d, 1.07g, 4.88mmol, 92% yield). MS Calcd: 219; MS Found: 220([M+H] +< ).

[0176] Step 4: To a flask was added 3-(2-methoxy-3-nitrophenyl)-1H-pyrazole (29-d, 1.05g, 4.82mmol), followed by sequential addition of N,N-dimethyl formamide (5mL), anhydrous potassium carbonate (2g, 14.4mmol) and iodomethane (2g, 14.1mmol), with stirring at room temperature. Upon indication of completed reaction by TLC, the reaction mixture was added with small amount of water for dilution of the mother liquid, and extracted with ethyl acetate (30mL x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (30mL x 3), dried over anhydrous sodium sulfate, followed by solvent removed by rotary evaporation to provide 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-pyrazole (29-e, 1.07g, 4.59mmol, 95% yield). MS Calcd: 233; MS Found: 234([M+H] +< ).

[0177] Step 5: To 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-pyrazole (29-e, 1.07g, 4.59mmol), were sequentially added iron powder (1.8g, 32mmol), saturated ammonium chloride aqueous solution (6mL) and methanol (6mL). After the addition, the reaction mixture was heated to 100°C and stirred. When the reaction was completed, the mother liquid was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, followed by solvent removed by rotary evaporation to provide 2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)aniline (29-f, 580mg, 2.86mmol, 62% yield). MS Calcd: 203; MS Found: 204([M+H] +< ).

[0178] Step 6: To a two-necked flask were sequentially added 2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)aniline (29-f, 203mg, 1mmol), 4,6-dichloro-N-methoxy nicotinamide (218mg, 1mmol), and 5ml of anhydrous tetrahydrofuran as solvent, followed by addition at room temperature of a solution of LiHMDS in tetrahydrofuran (3ml, 1mol / L), with continuous stirring at room temperature for 2h. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (30mLx3). The combined organic layers were dried, concentrated, and purified by column chromatography to provide 6-chloro-N-methoxy-4-(2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)nicotinamide 29-g, 138mg, 0.36mmol, 36% yield). MS Calcd: 387; MS Found: 388([M+H] +< ).

[0179] Step 7: 6-chloro-N-methoxy-4-(2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)nicotinamide (29-g, 39mg, 0.1mmol), cyclopropylcarboxamide (9.4mg, 0.11mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(15mg, 0.02mmol) and Pd 2 (dba) 3 (10mg, 0.01mmol) were added to anhydrous dioxane (5ml). After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 120°C with stirring for 8h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-N-methoxy-4-(2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)nicotinamide (29, 14mg, 0.033mmol, 32% yield). MS Calcd: 436; MS Found: 437 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.88 (s, 1H), 10.82 (s, 1H), 10.17 (s, 1H), 8.37 (s, 1H), 8.08 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.61 (dd, J = 8.0, 1.6 Hz, 1H), 7.36 (dd, J = 8.0, 1.6 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 3.91 (s, 3H), 3.73 (s, 3H), 3.59 (s, 3H), 2.01 - 1.93 (m, 1H), 0.81 - 0.75 (m, 4H).Example 30 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)nicotinamide

[0180]

[0181] Step 1: 6-chloro-N-methoxy-4-(2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)nicotinamide (29-g, 38.7mg, 0.1mmol), 6-fluoropyridin-2-ylamine (12.2mg, 0.11mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(15mg, 0.02mmol) and Pd 2 (dba) 3 (10mg, 0.01mmol) were added to anhydrous dioxane (5ml). After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 120°C with stirring for 8h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(((6-fluoropyridin-2-yl)amino)-N-methoxy-4-(2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)nicotinamide (30, 11.8mg, 0.025mmol, 25% yield). MS Calcd: 463; MS Found: 464([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.81 (s, 1H), 10.27 (s, 1H), 10.07 (s, 1H), 8.36 (s, 1H), 7.86 - 7.79 (m, 2H), 7.78 (d, J = 2.4 Hz, 1H), 7.60 (dd, J = 8.0, 1.6 Hz, 1H), 7.56 (dd, J = 8.0, 1.6 Hz, 1H), 7.49 (dd, J = 8.0, 2.4 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.58 (dd, J = 7.8, 2.4 Hz, 1H), 3.91 (s, 3H), 3.74 (s, 3H), 3.62 (s, 3H).Example 31 4-((3-cyano-2-methoxy phenyl)amino)-6-(cyclopropylcarboxamido)-N-methoxy nicotinamide

[0182]

[0183] Step 1: To a 100mL flask were sequentially added methyl 2-hydroxyl-3-nitrobenzoate (31-a, 3g, 15mmol), iodomethane (2.8g, 20mmol), anhydrous potassium carbonate (3g, 21.7mmol) and N,N-dimethyl formamide (5mL), followed by stirring at room temperature. Upon indication of completed reaction by TLC, the reaction mixture was added with water (20mL) for dilution of the mother liquid, and extracted with ethyl acetate (30mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, followed by solvent removed by rotary evaporation to provide methyl 2-methoxy-3-nitrobenzoate (31-b, 2.9g, 13.7mmol, 91.3% yield). MS Calcd: 211; MS Found: 212([M+H] +< ).

[0184] Step 2: To methyl 2-methoxy-3-nitrobenzoate(31-b , 2.9g, 13.7mmol) were sequentially added 10mL of methanol, 2ml of water and sodium hydroxide (2g, 40mmol). The reaction mixture was stirred at room temperature. Upon indication of completed reaction by TLC, the reaction mixture was added with small amount of water for dilution of the mother liquid. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, causing a large amount of solid to precipitate, which was filtered by suction and dried to provide 2-methoxy-3-nitrobenzoic acid(31-c, 2.55g, 12.9mmol, 94.5% yield). MS Calcd: 197; MS Found: 198([M+H] +< ).

[0185] Step 3: Into N,N-dimethyl formamide (10mL) was added 2-methoxy-3-nitrobenzoic acid(31-b , 2.55g, 12.9mmol). After total dissolution, Boc-hydrazide (2.6g, 20mmol), HATU(7.6g, 20mmol) were added and stirred at 45°C overnight. Upon indication of completed reaction by TLC, the reaction mixture was washed with small amount of water, and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to provide t-butyl 2-(2-methoxy-3-nitrobenzoyl)hydrazine-1-carboxylate (31-d , 2.31g, 7.43mmol, 57.6% yield). MS Calcd: 311; MS Found: 312([M+H] +< ).

[0186] Step 4: To dichloromethane (6mL) was added t-butyl 2-(2-methoxy-3-nitrobenzoyl) hydrazine-1-carboxylate (31-d, 2.3g, 7.43mmol), followed by adding trifluoroacetic acid (3ml) dropwise in ice bath. The reaction was allowed to warm back to room temperature and stirred. Upon indication of completed reaction by TLC, solvent was directly removed by rotary evaporation to provide 2-methoxy-3-nitrobenzohydrazide (31-e, 1.56g, 7.4mmol, 99% yield). MS Calcd: 211; MS Found: 212([M+H] +< ).

[0187] Step 5: To trimethyl orthoformate (3mL) was added 2-methoxy-3-nitrobenzohydrazide (31-e, 0.63g, 3mmol), heated to 105°C under nitrogen atmosphere and stirred. Upon indication of completed reaction by TLC, the mixture was subjected to rotary evaporation to remove solvent, washed with small amount of water(30 mL x 3), and extracted with ethyl acetate (30mL x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (30mL x 3), dried over anhydrous sodium sulfate to provide 2-(2-methoxy-3-nitrophenyl)-1,3,4-oxadiazole (31-f, 521mg, 2.36mmol, 78.7% yield). MS Calcd: 221; MS Found: 222([M+H] +< ).

[0188] Step 6: To 2-(2-methoxy-3-nitrophenyl)-1,3,4-oxadiazole(31-f , 300mg, 1.35mmol), were added palladium on carbon (20mg) and 5mL of methanol, allowed to react at room temperature under hydrogen atmosphere. When the reaction was completed, the mother liquid was filtered, and subjected to rotary evaporation to provide 2-methoxy-3-(1,3,4-oxadiazol-2-yl)aniline (31-g, 223mg, 1.16mmol, 86% yield). MS Calcd: 191; MS Found: 192([M+H] +< ).

[0189] Step 7: To a two-necked flask were sequentially added 2-methoxy-3-(1,3,4-oxadiazol-2-yl)aniline (31-g, 191mg, 1mmol), 4,6-dichloro-N-methoxy nicotinamide (int-1, 218mg, 1mmol), and 5ml of anhydrous tetrahydrofuran as solvent, followed by adding a solution of LiHMDS in tetrahydrofuran (3ml, 3mmol) at room temperature and with continuous stirring at room temperature for 2h. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (30ml x 3). The combined organic layers were dried, concentrated, and purified by column chromatography to provide 6-chloro-4-((3-cyano-2-methoxy phenyl)amino)-N-methoxy nicotinamide (31-h, 156mg, 0.47mmol, 47% yield). MS Calcd: 332; MS Found: 333([M+H] +< ).

[0190] Step 8: 6-chloro-4-((3-cyano-2-methoxy phenyl)amino)-N-methoxy nicotinamide (31-h, 33mg, 0.1mmol), cyclopropylcarboxamide (9.4mg, 0.11mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(15mg, 0.02mmol) and Pd 2 (dba) 3 (10mg, 0.01mmol) were added to anhydrous dioxane (5ml). After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 120°C with stirring for 8h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((3-cyano-2-methoxy phenyl)amino)-6-(cyclopropylcarboxamido)-N-methoxy nicotinamide (31, 8mg, 0.021mmol, 21% yield). MS Calcd: 381; MS Found: 382([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.92 (s, 1H), 10.88 (s, 1H), 10.19 (s, 1H), 8.40 (s, 1H), 7.96 (s, 1H), 7.75 (dd, J = 8.0, 1.6 Hz, 1H), 7.54 (dd, J = 7.8, 1.6 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 3.91 (s, 3H), 3.73 (s, 3H), 2.05 - 1.91 (m, 1H), 0.81 - 0.73 (m, 4H).Example 32 6-(cyclopropylcarboxamido)-4-((3-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide

[0191]

[0192] Step 1: 1,2-difluoro-3-nitrobenzene(32-a , 0.48g, 3mmol) was dissolved in acetonitrile (10ml), to which were sequentially added cesium carbonate (2.98g, 9mmol), N-methyl methanesulfonamide (0.36g, 3.3mmol). The reaction mixture was stirred at room temperature overnight. Upon indication of completed reaction by TLC, the mother liquid was washed respectively with water (30ml x 3) and saturated sodium chloride aqueous solution (30 ml x 3), dried over anhydrous sodium sulfate, and concentrated to provide a crude material, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3:1) to provide N-(2-fluoro-6-nitrophenyl)-N-methyl methanesulfonamide (32-b, 0.42g, 1.69mmol, 56.6% yield). MS Calcd:248; MS Found: 249([M+H] +< ).

[0193] Step 2: N-(2-fluoro-6-nitrophenyl)-N-methyl methanesulfonamide (32-b, 420mg, 1.69mmol) and palladium on carbon (15mg) were added to methanol(5ml). After atmosphere replacement by hydrogen three times, the reaction mixture was stirred at room temperature overnight, and filtered by suction. The filtrate was concentrated under reduced pressure to provide N-(2-amino-6-fluorophenyl)-N-methyl methanesulfonamide (32-c, 288mg, 1.32mmol, 78% yield). MS Calcd: 218; MS Found: 219([M+H] +< ).

[0194] Step 3: N-(2-amino-6-fluorophenyl)-N-methyl methanesulfonamide (32-c, 218mg, 1mmol) and 4,6-dichloro-N-methoxy nicotinamide (218mg, 1mmol) were added to anhydrous tetrahydrofuran (5ml), to which was slowly added a solution of LiHMDS in tetrahydrofuran (3ml, 3mmol), and stirred at room temperature for 2h. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (30ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography to provide 6-chloro-4-((3-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (32-d, 185mg, 0.46mmol, 46% yield). MS Calcd: 402; MS Found: 403([M+H] +< ).

[0195] Step 4: 6-chloro-4-((3-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (32-d, 40mg, 0.1mmol), cyclopropylcarboxamide (9.4mg, 0.11mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(15mg, 0.02mmol) and Pd 2 (dba) 3 (10mg, 0.01mmol) were added to anhydrous dioxane (5ml). After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 125°C with stirring for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography to provide the title compound: (cyclopropylcarboxamido)-4-((3-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (32, 16mg, 0.36mmol, 36% yield). MS Calcd: 451; MS Found: 452([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.87 (s, 1H), 10.87 (s, 1H), 10.17 (s, 1H), 8.40 (s, 1H), 8.38 (s, 1H), 8.24 - 8.23 (m, 1H), 8.05 - 8.03 (m, 1H), 7.36 - 7.31 (m, 1H), 3.72 (s, 3H), 3.16 (s, 3H), 3.14 (s, 3H), 2.06 - 1.90 (m, 1H), 0.82 - 0.73 (m, 4H).Example 33 6-(cyclopropylcarboxamido)-N-methoxy-4-((3-methyl-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide

[0196]

[0197] Step 1: 2-fluoro-1-methyl-3-nitrobenzene(33-a , 0.46mg, 3mmol) was dissolved in acetonitrile (10ml), to which were sequentially added cesium carbonate (2.97g, 9mmol), N-methyl methanesulfonamide (0.36g, 3.3mmol). The reaction mixture was stirred at room temperature overnight. Upon indication of completed reaction by TLC, the mother liquid was washed respectively with water (30ml x 3) and saturated sodium chloride aqueous solution (30ml x 3), dried over anhydrous sodium sulfate, and concentrated to provide a crude material, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3: 1) to provide N-methyl-N-(2-methyl-6-nitrophenyl) methanesulfonamide(33-b , 399mg, 1.63mmol, 54% yield). MS Calcd:244; MS Found: 245([M+H] +< ).

[0198] Step 2: N-methyl-N-(2-methyl-6-nitrophenyl) methanesulfonamide(33-b , 399mg, 1.63mmol) and palladium on carbon (15mg) were added to methanol(5ml). After atmosphere replacement with hydrogen three times, the reaction was stirred at room temperature overnight, and filtered by suction. The filtrate was concentrated under reduced pressure to provide N-(2-amino-6-methyl phenyl)-N-methyl methanesulfonamide (33-c, 280mg, 1.30mmol, 80% yield). MS Calcd: 214; MS Found: 215([M+H] +< ).

[0199] Step 3: N-(2-amino-6-methyl phenyl)-N-methyl methanesulfonamide (33-c, 214mg, 1mmol) and 4,6-dichloro-N-methoxy nicotinamide (218mg, 1mmol) were added to anhydrous tetrahydrofuran (5ml), to which was slowly added a solution of LiHMDS in tetrahydrofuran (3ml, 1mol / L), and stirred at room temperature for 2h. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (30ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography to provide 6-chloro-N-methoxy-4-((3-methyl-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (33-d, 128mg, 0.32mmol, 32% yield). MS Calcd: 398; S Found: 399([M+H] +< ).

[0200] Step 4: 6-chloro-N-methoxy-4-((3-methyl-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (33-d, 40mg, 0.1mmol), cyclopropylcarboxamide (9.4mg, 0.11mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(15mg, 0.02mmol) and Pd 2 (dba) 3 (10mg, 0.01mmol) were added to anhydrous dioxane (5ml). After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 125 °C with stirring for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography to provide 6-(cyclopropylcarboxamido)-N-methoxy-4-((3-methyl-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (33, 6mg, 0.013mmol, 13% yield). MS Calcd: 447; MS Found: 448([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.89 (s, 1H), 10.80 (s, 1H), 9.97 (s, 1H), 8.36 (s, 1H), 7.90 (s, 1H), 7.32 - 7.27 (m, 2H), 7.15 - 7.09 (m, 1H), 3.73 (s, 3H), 3.13 (s, 3H), 3.07 (s, 3H), 2.35 (s, 3H), 2.06 - 1.90 (m, 1H), 0.78 - 0.72 (m, 4H).Example 34 6-(cyclopropylcarboxamido)-4-((2-(N,N-dimethylaminosulfonyl)phenyl)amino)-N-methoxy nicotinamide

[0201]

[0202] Step 1: 2-amino-N,N-dimethyl benzenesulfonamide(34-a , 200mg, 1mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 218mg, 1mmol) were added to 5ml of anhydrous tetrahydrofuran, to which was slowly added a solution of LiHMDS in tetrahydrofuran (3ml, 1mol / L), and stirred at room temperature for 2h. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (30ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography to provide 6-chloro-4-((2-(N,N-dimethylaminosulfonyl)phenyl)amino)-N-methoxy nicotinamide (34-b, 178mg, 0.46mmol, 46% yield). MS Calcd: 384; MS Found: 385([M+H] +< ).

[0203] Step 2: 6-chloro-4-((2-(N,N-dimethylaminosulfonyl)phenyl)amino)-N-methoxy nicotinamide (34-b, 38mg, 0.1mmol), cyclopropylcarboxamide (9.4mg, 0.11mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(15mg, 0.02mmol) and Pd 2 (dba) 3 (10mg, 0.01mmol) were added to anhydrous dioxane (5ml). After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 125°C with stirring for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography to provide the title compound: (cyclopropylcarboxamido)-4-((2-(N,N-dimethylaminosulfonyl)phenyl)amino)-N-methoxy nicotinamide (34, 7mg, 0.016mmol, 16% yield). MS Calcd: 433; MS Found:434([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.83 (s, 1H), 10.87 (s, 1H), 10.27 (s, 1H), 8.38 (s, 1H), 7.97 (s, 1H), 7.84 (dd, J = 8.0, 1.6 Hz, 1H), 7.70 - 7.60 (m, 2H), 7.37 - 7.30 (m, 1H), 3.72 (s, 3H), 2.62 (s, 6H), 2.00 - 1.92 (m, 1H), 0.79 - 0.73 (m, 4H).Example 35 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide

[0204]

[0205] Step 1: 2-chloro-3-nitropyridine (35-a, 0.474g, 3mmol) was dissolved in acetonitrile (10ml), to which were sequentially added cesium carbonate (2.97g, 9mmol), N-methyl methanesulfonamide (0.36g, 3.3mmol). The reaction mixture was stirred at room temperature overnight. Upon indication of completed reaction by TLC, the mother liquid was washed respectively with water (30ml x 3) and saturated sodium chloride aqueous solution (30ml x 3), dried over anhydrous sodium sulfate, and concentrated to provide a crude material, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3:1) to provide N-methyl-N-(3-nitropyridin-2-yl) methanesulfonamide(35-b , 366mg, 1.58mmol, 53% yield). MS Calcd: 231; MS Found: 232([M+H] +< ).

[0206] Step 2: N-methyl-N-(3-nitropyridin-2-yl) methanesulfonamide(35-b , 366mg, 1.58mmol) and palladium on carbon (15mg) were added to methanol(5ml). After atmosphere replacement with hydrogen three times, the reaction mixture was stirred at room temperature overnight, and filtered by suction. The filtrate was concentrated under reduced pressure to provide N-(3-aminopyridin-2-yl)-N-methyl methanesulfonamide (35-c, 274mg, 1.37mmol, 86% yield). MS Calcd: 201; MS Found: 202([M+H] +< ).

[0207] Step 3: N-(3-aminopyridin-2-yl)-N-methyl methanesulfonamide (35-c, 201mg, 1mmol) and 4,6-dichloro-N-methoxy nicotinamide (218mg, 1mmol) were added to anhydrous tetrahydrofuran (5ml), to which was slowly added a solution of LiHMDS in tetrahydrofuran (3ml, 1mol / L), and stirred at room temperature for 2h. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (30ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography to provide 6-chloro-N-methoxy-4-((2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (35-d, 172mg, 0.45mmol, 45% yield). MS Calcd: 385; MS Found: 386 ([M+H] +< ).

[0208] Step 4: 6-chloro-N-methoxy-4-((2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (35-d, 39mg, 0.1mmol), cyclopropylcarboxamide (9.4mg, 0.11mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(15mg, 0.02mmol) and Pd 2 (dba) 3 (10mg, 0.01mmol) were added to anhydrous dioxane (5ml). After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 125°C with stirring for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography to provide the title compound: 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (35, 13mg, 0.029mmol, 29% yield). MS Calcd: 434; MS Found: 435([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.85 (s, 1H), 10.86 (s, 1H), 10.15 (s, 1H), 8.39 (s, 1H), 8.26 (dd, J = 4.8, 1.6 Hz, 1H), 7.98 - 7.95 (m, 1H), 7.95 (s, 1H), 7.48 (dd, J = 8.0, 1.6 Hz, 1H), 3.73 (s, 3H), 3.18 (s, 3H), 3.14 (s, 3H), 2.01 - 1.92 (m, 1H), 0.82 - 0.74 (m, 4H).Example 36 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide

[0209]

[0210] Step 1: 6-chloro-N-methoxy-4-((2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (35-d, 39mg, 0.1mmol), 6-fluoropyridin-2-ylamine (13.2mg, 0.11mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(15mg, 0.02mmol) and Pd 2 (dba) 3 (10mg, 0.01mmol) were added to anhydrous dioxane (5ml). After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 125°C with stirring for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography to provide the title compound: 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (36, 15mg, 0.032mmol, 32% yield). MS Calcd: 461; MS Found: 462([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.79 (s, 1H), 10.23 (s, 1H), 10.09 (s, 1H), 8.37 (s, 1H), 8.25 (dd, J = 4.6, 1.6 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.86 - 7.77 (m, 1H), 7.70 (s, 1H), 7.49 - 7.44 (m, 2H), 6.61 - 6.56 (m, 1H), 3.73 (s, 3H), 3.21 (s, 3H), 3.16 (s, 3H).Example 37 4-((2-(N,N-dimethylaminosulfonyl)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide

[0211]

[0212] Step 1: 6-chloro-4-((2-(N,N-dimethylaminosulfonyl)phenyl)amino)-N-methoxy nicotinamide (34-b, 39mg, 0.1mmol), 6-fluoropyridin-2-ylamine (13.2mg, 0.11mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(15mg, 0.02mmol) and Pd 2 (dba) 3 (10mg, 0.01mmol) were added to anhydrous dioxane (5ml). After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 125 °C with stirring for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography to provide the title compound: 4-((2-(N,N-dimethylaminosulfonyl)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide (37, 13mg, 0.028mmol, 28% yield). MS Calcd: 460; MS Found: 461([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.75 (s, 1H), 10.24 (s, 1H), 10.03 (s, 1H), 8.35 (s, 1H), 7.88 - 7.84 (m, 1H), 7.84 - 7.78 (m, 1H), 7.78 - 7.73 (m, 1H), 7.73 - 7.65 (m, 1H), 7.63 (s, 1H), 7.47 - 7.43 (m, 1H), 7.39 - 7.31 (m, 1H), 6.55 (dd, J = 7.8, 2.4 Hz, 1H), 3.72 (s, 3H), 2.65 - 2.61 (s, 6H).Example 38 4-((3-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide

[0213]

[0214] Step 1: 6-chloro-4-((3-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (32-d, 40mg, 0.1mmol), 6-fluoropyridin-2-ylamine (13.2mg, 0.11mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(15mg, 0.02mmol) and Pd 2 (dba) 3 (10mg, 0.01mmol) were added to anhydrous dioxane (5ml). After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 125°C with stirring for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography to provide the title compound: 4-((3-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide (38, 18mg, 0.037mmol, 37% yield). MS Calcd: 478; MS Found: 479([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.81 (s, 1H), 10.25 (s, 1H), 10.11 (s, 1H), 8.37 (s, 1H), 7.86 - 7.78 (m, 1H), 7.77 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.09 (t, J = 9.2 Hz, 1H), 6.59 (dd, J = 8.0, 2.4 Hz, 1H), 3.73 (s, 3H), 3.19 (s, 3H), 3.16 (s, 3H).Example 39 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-(oxetan-3-yloxy)phenyl)amino)nicotinamide

[0215]

[0216] Step 1: 1-fluoro-2-nitrobenzene(39-a , 0.42g, 3mmol) was dissolved in acetonitrile (10ml), to which were sequentially added cesium carbonate (2.97g, 9mmol) and oxetan-3-ylmethanol (0.3g, 3.3mmol). The reaction mixture was stirred at room temperature overnight. Upon indication of completed reaction by TLC, the mother liquid was washed respectively with water (30ml x 3) and saturated sodium chloride aqueous solution (30ml x 3), dried over anhydrous sodium sulfate, and concentrated to provide a crude material, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3:1) to provide 3-(2-nitrophenoxy)oxetane(39-b , 341mg, 1.74mmol, 58% yield). MS Calcd: 195; MS Found: 196([M+H] +< ).

[0217] Step 2: 3-(2-nitrophenoxy) oxetane(39-b , 341mg, 1.74mmol), palladium on carbon (15mg) were added to methanol(5ml). After atmosphere replacement with hydrogen three times, the reaction mixture was stirred at room temperature overnight, and filtered by suction. The filtrate was concentrated under reduced pressure to provide 2-(oxetan-3-yloxy) aniline (39-c, 247mg, 1.49mmol, 50% yield). MS Calcd: 165; MS Found: 166([M+H] +< ).

[0218] Step 3: 2-(oxetan-3-yloxy) aniline(39-c , 165mg, 1mmol) and 4,6-dichloro-N-methoxy nicotinamide (218mg, 1mmol) were added to anhydrous tetrahydrofuran (5ml), to which was slowly added a solution of LiHMDS in tetrahydrofuran (3ml, 1mol / L), and stirred at room temperature for 2h. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (30ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography to provide 6-chloro-N-methoxy-4-((2-(oxetan-3-yloxy)phenyl)amino)nicotinamide (39-d, 135mg, 0.39mmol, 39% yield). MS Calcd: 349; MS Found: 350([M+H] +< ).

[0219] Step 4: 6-chloro-N-methoxy-4-((2-(oxetan-3-yloxy)phenyl)amino)nicotinamide (39-d, 35mg, 0.1mmol), cyclopropylcarboxamide (9.4mg, 0.11mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(15mg, 0.02mmol) and Pd 2 (dba) 3 (10mg, 0.01mmol) were added to anhydrous dioxane (5ml). After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 125°C with stirring for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography to provide the title compound: 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-(oxetan-3-yloxy)phenyl)amino)nicotinamide (39, 13mg, 0.032mmol, 32% yield). MS Calcd: 398; MS Found:399([M+H] +< ). 1< H NMR (400 MHz, Chloroform-d)δ10.00 (s, 1H), 8.84 (s, 1H), 8.31 (s, 1H), 7.98 (s, 1H), 7.48 - 7.42 (m, 1H), 7.10 - 7.02 (m, 2H), 6.52 - 6.44 (m, 1H), 5.26 - 5.17 (m, 1H), 4.98 - 4.89 (m, 2H), 4.84 - 4.75 (m, 2H), 3.92 (s, 3H), 1.46 - 1.38 (m, 1H), 0.92 - 0.72 (m, 4H).Example 40 6-(((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(oxetan-3-yloxy)phenyl)amino)nicotinamide

[0220]

[0221] Step 1: 6-chloro-N-methoxy-4-((2-(oxetan-3-yloxy)phenyl)amino)nicotinamide (39-d, 35mg, 0.1mmol), 6-fluoropyridin-2-ylamine (13.2mg, 0.11mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(15mg, 0.02mmol) and Pd 2 (dba) 3 (10mg, 0.01mmol) were added to anhydrous dioxane (5ml). After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 125°C with stirring for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography to provide the title compound: 6-(((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(oxetan-3-yloxy)phenyl)amino)nicotinamide (40, 12mg, 0.028mmol, 28% yield). MS Calcd: 425; MS Found: 426 ([M+H] +< ). 1< H NMR (400 MHz, Chloroform-d)δ10.07 (s, 1H), 8.36 (s, 1H), 7.84 - 7.71 (m, 1H), 7.71 - 7.62 (m, 1H), 7.62 - 7.51 (m, 1H), 7.17 - 7.09 (m, 2H), 7.09 - 6.99 (m, 1H), 6.56 - 6.47 (m, 1H), 6.44 (dd, J = 8.0, 2.4 Hz, 1H), 5.28 - 5.20 (m, 1H), 5.00 - 4.90 (m, 2H), 4.87 - 4.74 (m, 2H), 3.93 (s, 3H).Example 41 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)nicotinamide

[0222]

[0223] Step 1: To a 50mL flask were added 2-bromo-6-nitrophenol(41-a , 1.09g, 5mmol), pyrazole (0.68g, 10mmol), cuprous (I) iodide (0.095g, 0.5mmol), L-proline (0.115g, 1mmol), anhydrous potassium carbonate (1.38g, 10mmol), and DMSO(10mL), heated to 100°C with stirring for about 20h. Upon TLC indicating a substantially completed reaction, the mother liquid was filtered through diatomaceous earth. The filtrate was adjusted with 1N aqueous hydrochloride to pH 4, causing a large amount of solid to precipitate, which was filtered by suction to provide 2-nitro-6-(1H-pyrazol-1-yl)phenol (41-b, 460mg, 2.24mmol, 49% yield). MS Calcd: 205; MS Found: 206 ([M+H] +< ).

[0224] Step 2: To a 100mL flask were sequentially added 2-nitro-6-(1H-pyrazol-1-yl)phenol (41-b, 460mg, 2.24mmol), iodomethane (0.416g, 3mmol), anhydrous potassium carbonate (0.618g, 4.448mmol) and N,N-dimethyl formamide (5mL), and stirred at room temperature. Upon indication of completed reaction by TLC, the reaction mixture was added with water (20mL) for dilution of the mother liquid, and extracted with ethyl acetate (20ml x 3). The combined organic phases were washed with saturated brine (20ml x 3), dried over anhydrous sodium sulfate, followed by solvent removed by rotary evaporation to provide 1-(2-methoxy-3-nitrophenyl)-1H-pyrazole (41-c, 455mg, 2.07mmol, 93% yield). MS Calcd: 219; MS Found: 220 ([M+H] +< ).

[0225] Step 3: To 1-(2-methoxy-3-nitrophenyl)-1H-pyrazole (41-c, 455mg, 2.07mmol) were added iron powder (0.56g, 10mmol), saturated ammonium chloride aqueous solution (6mL) and methanol (6mL). After the addition, the reaction mixture was heated to 100°C and stirred. When the reaction was completed, the mother liquid was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (20ml x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (20ml x 3), dried over anhydrous sodium sulfate, followed by solvent removed by rotary evaporation to provide 2-methoxy-3-(1H-pyrazol-1-yl)aniline (41-d, 204mg, 1.08mmol, 52% yield). MS Calcd: 189; MS Found: 190 ([M+H] +< ).

[0226] Step 4: To a two-necked flask were sequentially added 2-methoxy-3-(1H-pyrazol-1-yl)aniline (41-d, 0.189g, 1mmol), 4,6-dichloro-N-methoxy nicotinamide (218mg, 1mmol), and 5ml of anhydrous tetrahydrofuran as solvent. To which was added at room temperature with a solution of LiHMDS in tetrahydrofuran (3ml, 1mol / L) and with continuous stirring at room temperature for 2h. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (30ml x 3). The combined organic layers were dried, concentrated, and purified by column chromatography to provide 6-chloro-N-methoxy-4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)nicotinamide (41-e, 198mg, 0.53mmol, 53% yield). MS Calcd; 373; MS Found: 374 ([M+H] +< ).

[0227] Step 5: 6-chloro-N-methoxy-4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)nicotinamide (41-e, 37.3mg, 0.1mmol), cyclopropylcarboxamide (9.4mg, 0.11mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(15mg, 0.02mmol) and Pd 2 (dba) 3 (10mg, 0.01mmol) were added to anhydrous dioxane (5ml). After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 120 °C with stirring for 8h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)nicotinamide (41, 12mg, 0.028mmol, 28% yield). MS Calcd: 422; MS Found: 423([M+H] +< ). 1< H NMR (400 MHz, Chloroform-d)δ10.28 (s, 1H), 8.97 (s, 1H), 8.37 (s, 1H), 8.16 (s, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.53 - 7.43 (m, 2H), 7.35 - 7.26 (m, 1H), 6.48 - 6.46 (m, 1H), 3.92 (s, 3H), 3.51 (s, 3H), 1.46 - 1.37 (m, 1H), 0.95 - 0.83 (m, 4H).Example 42 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)nicotinamide

[0228]

[0229] Step 1: 6-chloro-N-methoxy-4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)nicotinamide (41-e, 37mg, 0.1mmol), 6-fluoropyridin-2-ylamine (13.2mg, 0.11mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(15mg, 0.02mmol) and Pd 2 (dba) 3 (10mg, 0.01mmol) were added to anhydrous dioxane (5ml). After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 120°C with stirring for 8h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)nicotinamide (42, 13mg, 0.029mmol, 29% yield). MS Calcd: 449; MS Found: 450([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.83 (s, 1H), 10.34 (s, 1H), 10.11 (s, 1H), 8.38 (s, 1H), 8.23 (d, J = 2.4 Hz, 1H), 7.87 - 7.79 (m, 2H), 7.78 - 7.77 (m, 1H), 7.68 - 7.62 (m, 1H), 7.54 - 7.47 (m, 1H), 7.38 (dd, J = 8.0, 1.6 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 6.62 - 6.54 (m, 2H), 3.74 (s, 3H), 3.47 (s, 3H).Example 43 6-((5-cyano pyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide

[0230]

[0231] Step 1: 6-chloro-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (2-d, 117mg, 0.3mmol), 6-aminonicotinonitrile (42mg, 0.35mmol), cesium carbonate (390mg, 3.6mmol), XantPhos(29mg, 0.06mmol) and Pd 2 (dba) 3 (54mg, 0.06mmol) were added to anhydrous dioxane (5ml) and the mixture was evacuated to vacuum. After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 125°C with stirring for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-((5-cyano pyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (43, 32mg, 0.068mmol, 20.5% yield). MS Calcd: 467; MS Found: 468 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.78 (s, 1H), 10.37 (s, 1H), 10.09 (s, 1H), 8.63 - 8.58 (m, 1H), 8.35 (s, 1H), 8.04 (d, J = 7.2 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.73 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 3.72 (s, 3H), 3.16 (s, 3H), 3.13 (s, 3H).Example 44 6-((5-fluoro-4-methyl pyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide

[0232]

[0233] Step 1: 6-chloro-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (2-d, 117mg, 0.3mmol), 5-fluoro-4-methyl pyridin-2-ylamine (44mg, 0.35mmol), cesium carbonate (390mg, 3.6mmol), XantPhos(29mg, 0.06mmol) and Pd 2 (dba) 3 (54mg, 0.06mmol) were added to anhydrous dioxane (5ml) and the mixture was evacuated to vacuum. After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 125°C with stirring for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-((5-fluoro-4-methyl pyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (44, 26mg, 0.055mmol, 16.5% yield). MS Calcd: 474; MS Found: 475 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.67 (s, 1H), 10.07 (s, 1H), 9.71 (s, 1H), 8.30 (s, 1H), 8.03 (s, 1H), 7.66 - 7.57 (m, 2H), 7.56 - 7.51 (m, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 3.71 (s, 3H), 3.15 (s, 3H), 3.13 (s, 3H), 2.23 (s, 3H).Example 45 6-(((2,6-dimethyl pyrimidin-4-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide

[0234]

[0235] Step 1: 6-chloro-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (2-d, 117mg, 0.3mmol), 2,6-dimethyl pyrimidin-4-ylamine (43mg, 0.35mmol), cesium carbonate (390mg, 1.2mmol), XantPhos(29mg, 0.06mmol) and Pd 2 (dba) 3 (54mg, 0.06mmol) were added to anhydrous dioxane (5ml) and the mixture was evacuated to vacuum. After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 125°C with stirring for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(((2,6-dimethyl pyrimidin-4-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (45, 20mg, 0.042mmol, 12.7% yield). MS Calcd: 471; MS Found: 472 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.75 (s, 1H), 10.11 (s, 1H), 10.05 (s, 1H), 8.34 (s, 1H), 8.00 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 7.06 (s, 1H), 3.72 (s, 3H), 3.16 (s, 3H), 3.13 (s, 3H), 2.35 (s, 3H), 2.27 (s, 3H).Example 46 4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide

[0236]

[0237] Step 1: To a 100ml reaction flask was added 4-chloro-2-fluoro-1-nitrobenzene(46-a , 0.53g, 3.00mmol) dissolved in acetonitrile (30ml), followed by cesium carbonate (2g, 6.1mmol), N-methyl methanesulfonamide (0.56g, 4mmol). The reaction mixture was stirred at room temperature overnight. Upon indication of completed reaction by TLC, the reaction mixture was washed respectively with water (30ml x 3) and saturated sodium chloride aqueous solution (30ml x 3), dried over anhydrous sodium sulfate, and concentrated to provide a crude material, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3:1) to provide the product N-(5-chloro-2-nitrophenyl)-N-methyl methanesulfonamide (46-b, 0.63g, 81.1% yield). MS Calcd:264; MS Found: 265([M+H] +< ).

[0238] Step 2: N-(5-chloro-2-nitrophenyl)-N-methyl methanesulfonamide (46-b, 600mg, 2.3mmol) and iron powder (672mg, 12mmol) were added to methanol (3ml) and saturated ammonium chloride aqueous solution (3ml). The reaction mixture was refluxed at 100°C with stirring for 8h, filtered by suction. The filtrate was extracted with ethyl acetate (30ml x 3). The organic layers were combined, dried, and concentrated under reduced pressure to provide N-(2-amino-5-chloro phenyl)-N-methyl methanesulfonamide (46-c, 328mg, 1.4mmol, 60.9% yield), which was used directly in the next reaction without further purification. MS Calcd: 234; MS Found: 235 ([M+H] +< ).

[0239] Step 3: N-(2-amino-5-chloro phenyl)-N-methyl methanesulfonamide (46-c, 234mg, 1mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 218mg, 1mmol) were added to 5ml of tetrahydrofuran. The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (3ml, 1mol / L), and stirred at room temperature for 2h. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (30 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography to provide 6-chloro-4-((4-chloro-2-((N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (46-d, 156mg, 0.37mmol, 37% yield). MS Calcd: 418; MS Found: 419 ([M+H] +< ).

[0240] Step 4: 6-chloro-4-((4-chloro-2-((N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (46-d, 75mg, 0.18mmol), 5-fluoropyridin-2-ylamine (28mg, 0.25mmol), cesium carbonate (195mg, 0.6mmol), XantPhos(20mg, 0.04mmol) and Pd 2 (dba) 3 (37mg, 0.04mmol) were added to anhydrous dioxane (5ml) and the mixture was evacuated to vacuum. After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 125°C with stirring for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide (46, 20mg, 0.04mmol, 22.4% yield). MS Calcd: 494; MS Found: 495 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.75 (s, 1H), 10.15 (s, 1H), 9.85 (s, 1H), 8.32 (s, 1H), 8.24 - 8.19 (m, 1H), 8.00 (s, 1H), 7.88 - 7.85 (m, 1H), 7.83 - 7.79 (m, 1H), 7.21 (s, 1H), 7.12 - 7.08 (m, 1H), 7.02 (s, 1H), 3.71 (s, 3H), 3.17 (s, 3H), 3.13 (s, 3H).Example 47 4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide

[0241]

[0242] Step 4: 6-chloro-4-((4-chloro-2-((N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (46-d, 75mg, 0.18mmol), 6-fluoropyridin-2-ylamine (28mg, 0.25mmol), cesium carbonate (195mg, 0.6mmol), XantPhos(20mg, 0.04mmol) and Pd 2 (dba) 3 (37mg, 0.04mmol) were added to anhydrous dioxane (5ml) and the mixture was evacuated to vacuum. After atmosphere replacement with nitrogen three times, the reaction mixture was heated to 125°C with stirring for 5h, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide (47, 13mg, 0.026mmol, 14.6% yield). MS Calcd: 494; MS Found: 495 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.80 (s, 1H), 10.24 (s, 1H), 10.09 (s, 1H), 8.36 (s, 1H), 7.85 - 7.74 (m, 2H), 7.53 - 7.36 (m, 3H), 7.09 (t, J = 9.2 Hz, 1H), 6.58 (dd, J = 9.2, 2.4 Hz, 1H), 3.73 (s, 3H), 3.16 (s, 3H), 3.13 (s, 3H).Example 48 4-((2-cyano-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6-(cyclopropylcarboxamido)-N-methoxy nicotinamide

[0243]

[0244] Step 1: 2-bromo-6-nitrobenzonitrile(48-a , 500mg, 2.20mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (458mg, 2.20mmol), Pd(dppf)Cl 2 (36mg, 0.044mmol) and sodium carbonate (700mg, 6.60mmol) were dissolved in a mixed solvent of water and dioxane (2ml / 8mL), heated to 100°C for 3h. The reaction mixture was concentrated, added with 10ml of water, and extracted with ethyl acetate (10ml). The combined ethyl acetate layers were dried over anhydrous sodium sulfate, filtered by suction, and concentrated to obtain a crude material, which was purified by column chromatography (PE:EA =4:1) to provide 2-(1-methyl-1H-pyrazol-4-yl)-6-nitrobenzonitrile (48-b, 421mg, 1.85mmol, 84% yield), as ayellow solid. MS Calcd: 228; MS Found: 229 ([M+H] +< ).

[0245] Step 2: To methanol(20ml) were added 2-(1-methyl-1H-pyrazol-4-yl)-6-nitrobenzonitrile (48-b, 400mg, 1.75mmol) and palladium on carbon (40mg). After atmosphere replacement by hydrogen three times, the reaction mixture was stirred under hydrogen atmosphere at room temperature overnight, and filtered by suction. The filtrate was concentrated under reduced pressure to provide 2-amino-6-(1-methyl-1H-pyrazol-4-yl) benzonitrile(48-c , 330mg, 1.67mmol, 90% yield), as a grey oil, which was used directly in the next reaction without further purification. MS Calcd: 198; MS Found: 199 ([M+H] +< ).

[0246] Step 3: To 5ml of anhydrous tetrahydrofuran were added 2-amino-6-(1-methyl-1H-pyrazol-4-yl) benzonitrile(48-c , 200mg, 1.01mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 223.2mg, 1.01mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (2ml, 2.02mmol), and stirred at room temperature for 2 hours. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10ml). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-4-((2-cyano-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-N-methoxy nicotinamide (48-d, 120°Cg, 0.31mmol, 30% yield), as a white solid. MS Calcd: 382; MS Found: 383 ([M+H] +< ).

[0247] Step 4: 6-chloro-4-((2-cyano-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-N-methoxy nicotinamide (48-d, 50mg, 0.13mmol), cyclopropylcarboxamide (22mg, 0.26mmol), cesium carbonate (127mg, 0.39mmol), XantPhos(30mg, 0.04mmol) and Pd 2 (dba) 3 (24mg, 0.026mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide 4-((2-cyano-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6-(cyclopropylcarboxamido)-N-methoxy nicotinamide (48, 10mg, 0.023mmol, 18% yield), as a yellow solid. MS Calcd: 431; MS Found: 432 ([M+H] +< ). 1H NMR (400 MHz, DMSO-d 6 ) : δ 11.87 (s, 1H), 10.89 (s, 1H), 10.46 (s, 1H), 8.44 (s, 1H), 8.26 (s, 1H), 7.95-7.95 (m, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.45-7.42 (m, 2H), 3.92 (s, 3H), 3.73 (s, 3H), 1.98-1.95 (m, 1H), 0.78-0.75 (m, 2H), 0.65-0.62(m, 2H).Example 49 4-((2-cyano-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide

[0248]

[0249] Step 1: 6-chloro-4-((2-cyano-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-N-methoxy nicotinamide (48-d, 50mg, 0.13mmol), 5-fluoropyridin-2-ylamine (29mg, 0.26mmol), cesium carbonate (127mg, 0.39mmol), XantPhos(30mg, 0.04mmol) and Pd 2 (dba) 3 (24mg, 0.026mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((2-cyano-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide (49, 13mg, 0.028mmol, 22% yield). MS Calcd: 458; MS Found: 459 ([M+H] +< ). 1H NMR (400 MHz, DMSO-d 6 ) : δ 11.85 (s, 1H), 10.51 (s, 1H), 9.94 (s, 1H), 8.40 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.96 (s, 1H), 7.75-7.64 (m, 4H), 7.53-7.55 (d, J = 8.0 Hz, 1H), 7.42-7.41 (d, J=7.8 Hz, 1H), 3.93 (s, 3H), 3.73 (s, 3H).Example 50 6-(cyclopropylcarboxamido)-N-methoxy-4-((3-(1-methyl-1H-pyrazol-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinamide

[0250]

[0251] Step 1: 1-(2-hydroxyl-3-nitrophenyl)ethan-1-one (50-a, 2g, 11mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate(2.7g, 11mmol) and potassium carbonate (4.6g, 33mmol) were added to DMF(50ml). The reaction mixture was heated to 80°C with stirring for 2 hours. Upon indication of completed reaction by TLC, the reaction mixture was poured into 250ml of water, extracted with ethyl acetate (100ml). The extracted ethyl acetate organic layer was washed with water, dried over anhydrous sodium sulfate, filtered by suction, concentrated under reduced pressure to provide a brown oil (50-b, 2.9g, 10.4mmol, 94% yield).

[0252] Step 2: 1-(3-nitro-2-(2,2,2-trifluoroethoxy)phenyl)ethan-1-one (50-b, 2.9g, 10.4mmol), was added to DMF-DMA(20ml). The mixture was heated to 80°C with stirring for 30 minutes. Upon indication of completed reaction by TLC, the reaction mixture was directly concentrated, with residual solvent removed with toluene, to provide 2-(dimethylamino)-1-(3-nitro-2-(2,2,2-trifluoroethoxy)phenyl)ethan-1-one (50-c, 2.8g, 8.7mmol), as a brown oil, which was used directly in the next reaction.

[0253] Step 3: To ethanol was added 2-(dimethylamino)-1-(3-nitro-2-(2,2,2-trifluoroethoxy)phenyl)ethan-1-one (50-c, 2.8g, 8.7mmol). The mixture was cooled to 0°C, and added with hydrazine hydrate dropwise. Upon the addition was completed, the reaction mixture was heated to 80°C with stirring for 1 hour. Upon indication of completed reaction by TLC, the reaction mixture was concentrated under reduced pressure, poured into DCM (50ml) to cause a solid precipitation, followed by filtration. The filtrate was concentrated and purified by column chromatography (EA: PE=2: 1) to provide 3-(3-nitro-2-(2,2,2-trifluoroethoxy)phenyl)-1H-pyrazole (50-d, 700mg, 2.32mmol, 27% yield), as a yellow oil. MS Calcd: 301; MS Found: 302 ([M+H] +< ). Step 4: 3-(3-nitro-2-(2,2,2-trifluoroethoxy)phenyl)-1H-pyrazole (50-a, 700mg, 2.32mmol) and potassium carbonate (0.97g, 6.96mmol) were added to DMF(20ml), to which was added at room temperature iodomethane (329mg, 2.32mmol) and stirred overnight. Upon indication of completed reaction by TLC, the reaction mixture was poured into 30ml of water, and extracted with ethyl acetate (15ml). The organic layers were dried over anhydrous sodium sulfate, filtered by suction, concentrated and then purified by column chromatography (EA: PE=1:2) to provide 1-methyl-3-(3-nitro-2-(2,2,2-trifluoroethoxy)phenyl)-1H-pyrazole (50-e, 620mg, 2.05mmol, 88% yield). MS Calcd: 301; MS Found: 302 ([M+H] +< ).

[0254] Step 5: 1-methyl-3-(3-nitro-2-(2,2,2-trifluoroethoxy)phenyl)-1H-pyrazole (50-e, 620mg, 2.05mmol) and palladium on carbon (100mg) were added to methanol(20ml). After atmosphere replacement by hydrogen three times, the reaction mixture was stirred under hydrogen atmosphere at room temperature overnight, and filtered by suction. The filtrate was concentrated under reduced pressure to provide 3-(1-methyl-1H-pyrazol-3-yl)-2-(2,2,2-trifluoroethoxy) aniline(50-f , 530mg, 1.96mmol, 95% yield), which was used directly in the next reaction without further purification. MS Calcd: 271; MS Found: 272 ([M+H] +< ).

[0255] Step 6: 3-(1-methyl-1H-pyrazol-3-yl)-2-(2,2,2-trifluoroethoxy) aniline(50-f , 200mg, 0.74mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 149mg, 0.74mmol) were added to 2ml of anhydrous tetrahydrofuran. The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (1.5ml, 1.48mmol), and stirred at room temperature for 2 hours. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10ml). The combined organic layers were dried, concentrated and then purified by column chromatography (petroleum ether:ethyl acetate =1:2) to provide 6-chloro-N-methoxy-4-((3-(1-methyl-1H-pyrazol-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinamide (50-g, 120°Cg, 0.26mmol, 35% yield). MS Calcd: 455; MS Found: 456 ([M+H] +< ).

[0256] Step 7: 6-chloro-N-methoxy-4-((3-(1-methyl-1H-pyrazol-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinamide (50-g, 50mg, 0.11mmol), cyclopropylcarboxamide (19mg, 0.22mmol), cesium carbonate (107mg, 0.33mmol), XantPhos(20mg, 0.03mmol) and Pd 2 (dba) 3 (25mg, 0.027mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-N-methoxy-4-((3-(1-methyl-1H-pyrazol-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinamide (50, 15mg, 0.03mmol, 27% yield). MS Calcd: 504; MS Found: 505 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.81 (s, 1H), 10.78 (s, 1H), 9.97 (s, 1H), 8.36 (s, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.61-7.58 (m, 1H), 7.39-7.24 (m, 2H), 6.64 (s, 1H), 4.29-4.25(m, 2H), 3.91 (s, 3H), 3.71 (s, 3H), 1.97-1.94 (m, 1H), 0.77-0.74 (m, 4H).Example 51 6-((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((3-(1-methyl-1H-pyrazol-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinamide

[0257]

[0258] Step 1: 6-chloro-N-methoxy-4-((3-(1-methyl-1H-pyrazol-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinamide (50-g, 50mg, 0.11mmol), 5-fluoropyridin-2-ylamine (25mg, 0.22mmol), cesium carbonate (107mg, 0.33mmol), XantPhos(20mg, 0.03mmol) and Pd 2 (dba) 3 (25mg, 0.027mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((3-(1-methyl-1H-pyrazol-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinamide (51, 12mg, 0.02mmol, 21% yield). MS Calcd: 531; MS Found: 532 ([M+H] +< ). 1H NMR (400 MHz, DMSO-d 6 ) : δ 11.70 (s, 1H), 9.97 (s, 1H), 9.84 (s, 1H), 8.34 (s, 1H), 8.09 (d, J = 3.2, 1H), 7.80 (s, 1H), 7.67-7.48 (m, 6H), 6.65 (s, 1H), 4.30-4.28 (m, 2H), 3.91 (s, 3H), 3.71 (s, 3H).Example 52 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide

[0259]

[0260] Step 1: Diethyl 3-oxaglutarate (52-a, 7.6g, 37.6mmol), 4-acetamidobenzenesulfonyl azide (9g, 37.6mmol), and triethylamine (3.8g, 37.6mmol) were added to acetonitrile (100ml) and stirred at room temperature for 1 hour, followed by filtration. The filter cake was washed with diethyl ether, and the filtrate was concentrated. The residue was slurried with diethyl ether:petroleum ether (1:1), and filtered by suction. The filtrate was concentrated to provide diethyl 2-diazo-3-oxaglutarate (52-b, 9.2g), which was used directly in the next reaction without further purification.

[0261] Step 2: Diethyl 2-diazo-3-oxaglutarate (52-b, 7.2g, 32mmol) and triphenylphosphine (8.4g, 32mmol) was added to diethyl ether (100ml) and stirred at room temperature for 48 hours. The reaction mixture was concentrated, and added with mixed solvent of acetic acid and water (100ml: 10ml), heated to 120°C with stirring for 9 hours, and then concentrated directly. The residue was added to sodium bicarbonate aqueous solution (2N, 200ml), andwashed with ethyl acetate (100ml). The aqueous layer was adjusted to pH 3, and further extracted with ethyl acetate (200ml). The organic layers were dried, filtered by suction, and concentrated to obtain ethyl 4,6-dihydroxyl pyridazine-3-carboxylate, which was used directly in the next reaction without further purification. (52-c, 3.6g, 19.5mmol, 61% yield). MS Calcd: 184; MS Found: 183 ([M-H] -< ).

[0262] Step 3: To phosphorus oxychloride (50ml) was added ethyl 4,6-dihydroxyl pyridazine-3-carboxylate (52-c, 3.6g, 19.5mmol), heated to 100°C with stirring for 3 hours, and concentrated under reduced pressure. The residue was poured into 50ml of water, and extracted with ethyl acetate (20ml ), The organic layer was dried, filtered by suction, and concentrated. The residue was purified by column chromatography (ethyl acetate:petroleum ether=1:4) to provide ethyl 4,6-dichloropyridazine-3-carboxylate (52-d, 2.8g, 12.7mmol, 65% yield), which was used directly in the next reaction without further purification.

[0263] Step 4: To a mixed solvent of tetrahydrofuran and water (40ml:10ml) was added ethyl 4,6-dichloropyridazine-3-carboxylate (52-d, 2.8g, 12.7mmol), followed by lithium hydroxide (914mg, 38.1mmol), and stirred at room temperature for 2 hours. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and concentrated under reduced pressure. The residue was washed with a mixture of methanol and dichloromethane, and filtered by suction. The filtrate was concentrated under reduced pressure to provide 4,6-dichloropyridazine-3-carboxylic acid (52-e, 1.8g, 9.3mmol, 73% yield).

[0264] Step 5: To dichloromethane(20ml) was added 4,6-dichloropyridazine-3-carboxylic acid (52-e, 1.8g, 9.3mmol), followed by catalytic amount of DMF. The reaction mixture was cooled to 0°C, and slowly added with oxalyl chloride dropwise. Upon the addition was completed, the reaction mixture was heated to room temperature slowly, stirred for 2 hours, and concentrated under reduced pressure. The residue was dissolved in 5ml of ethyl acetate, and added slowly to a solution of methoxy amine (900mg, 18mmol) and potassium carbonate (3.7g, 27mmol) in mixed solvent of water and ethyl acetate, and stirred at room temperature overnight, added with ethyl acetate (50ml). After phase separation, the organic layer was dried and concentrated, and the residue was purified by column chromatography (ethyl acetate:petroleum ether=1:2) to provide 4,6-dichloro-N-methoxy pyridazine-3-carboxamide (52-f, 1.3g, 5.8mmol, 62% yield). MS Calcd: 221; MS Found: 220 ([M-H] -< ).

[0265] Step 6: To 5ml of anhydrous tetrahydrofuran was added 4,6-dichloro-N-methoxy pyridazine-3-carboxamide (52-f, 300mg, 1.35mmol) and 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (275.2mg, 1.35mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (2.7ml, 2.7mmol), and stirred at room temperature for 2 hours. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10ml). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:2) to provide 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide(52-g , 150mg, 0.39mmol, 29% yield). MS Calcd: 389; MS Found: 390 ([M-H] -< ).

[0266] Step 7: 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide(52-g , 50mg, 0.13mmol), cyclopropylcarboxamide (22mg, 0.26mmol), cesium carbonate (127mg, 0.39mmol), XantPhos(30mg, 0.04mmol) and Pd 2 (dba) 3 (24mg, 0.026mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (52, 13mg, 0.03mmol, 23% yield). MS Calcd: 438; MS Found: 439 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d6)δ11.64 (s, 1H), 11.34 (s, 1H), 10.53 (s, 1H), 8.57 (s, 1H), 8.56 (s, 1H), 7.63 (ddd, J = 12.8, 8.0, 1.6 Hz, 2H), 7.33 (t, J = 8.0 Hz, 1H), 3.95 (s, 6H), 3.94 (s, 3H), 2.06 - 1.93 (m, 1H), 0.78-0.74 (m, 4H).Example 53 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)pyridazine-3-carboxamide

[0267]

[0268] Step 1: To 5ml of anhydrous tetrahydrofuran were added 4,6-dichloro-N-methoxy pyridazine-3-carboxamide (52-f, 260mg, 1.18mmol) and 2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)aniline (252mg, 1.18mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (2.5ml, 2.4mmol), and stirred at room temperature for 2 hours. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10ml). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (53-a, 124mg, 0.32mmol, 27% yield), as a white solid. MS Calcd: 388; MS Found: 389 ([M+H] +< ).

[0269] Step 2: 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (53-a, 50mg, 0.13mmol), cyclopropylcarboxamide (22mg, 0.26mmol), cesium carbonate (127mg, 0.39mmol), XantPhos(30mg, 0.04mmol) and Pd 2 (dba) 3 (24mg, 0.026mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (53, 8mg, 0.018mmol, 14% yield). MS Calcd: 437; MS Found: 438 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d6)δ11.33 (s, 1H), 10.65 (s, 1H), 10.52 (s, 1H), 8.19 (s, 1H), 7.93 (d, J = 4.5 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.30 - 7.16 (m, 2H), 3.90 (s, 3H), 3.76 (s, 3H), 3.60 (s, 3H), 2.06 - 1.93 (m, 1H), 0.78-0.74 (m, 4H)Example 54 6-(cyclopropylcarboxamido)-4-((2-(difluoromethoxy)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-N-methoxy nicotinamide

[0270]

[0271] Step 1: 2-bromo-6-nitrophenol (54-a, 900mg, 4.17mmol), 2-chloro-2,2-difluoro acetic acid (812mg, 6.25mmol), and potassium carbonate (2.3g, 16.7mmol) were added to DMF(15ml). The reaction mixture was heated to 100°C, and stirred for 3 hours. Upon indication of completed reaction by TLC, the reaction mixture was cooled to room temperature, poured into 50ml of water, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the organic layer was filtered by suction, concentrated, purified by column chromatography (ethyl acetate:petroleum ether=1:60) to provide the target compound 1-bromo-2-(difluoromethoxy)-3-nitrobenzene. (54-b, 530mg, 1.98mmol, 47% yield).

[0272] Step 2: 1-bromo-2-(difluoromethoxy)-3-nitrobenzene (54-b, 500mg, 1.87mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (389mg, 1.87mmol), Pd(dppf)Cl 2 (20mg, 0.02mmol) and sodium carbonate (594mg, 5.61mmol) were dissolved in a mixed solvent of water and dioxane (2ml / 8mL), heated to 100°C to react for 3h. The reaction mixture was concentrated, added with water (10ml), and extracted with ethyl acetate (10ml). The combined ethyl acetate layers were dried over anhydrous sodium sulfate, filtered by suction, and concentrated to obtain a crude material, which was purified by column chromatography (PE:EA =3:1) to provide 4-(2-(difluoromethoxy)-3-nitrophenyl)-1-methyl-1H-pyrazole (54-c, 420mg, 1.56mmol, 83% yield), as a yellow solid. MS Calcd: 269; MS Found: 270 ([M+H] +< ).

[0273] Step 3: To methanol (20ml) were added 4-(2-(difluoromethoxy)-3-nitrophenyl)-1-methyl-1H-pyrazole (54-c, 420mg, 1.56mmol) and palladium on carbon (40mg). After atmosphere replacement by hydrogen three times, the reaction mixture was stirred under hydrogen atmosphere at room temperature overnight, and filtered by suction. The filtrate was concentrated under reduced pressure to provide 2-(difluoromethoxy)-3-(1-methyl-1H-pyrazol-4-yl)aniline (54-d, 360mg, 1.50mmol, 95% yield), as a grey oil, which was used directly in the next reaction without further purification. MS Calcd: 239; MS Found: 240 ([M+H] +< ).

[0274] Step 4: To 5ml of anhydrous tetrahydrofuran were added 4,6-dichloro-N-methoxy nicotinamide (int-1, 332mg, 1.50mmol) and 2-(difluoromethoxy)-3-(1-methyl-1H-pyrazol-4-yl)aniline (54-d, 360mg, 1.50mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (3ml, 3mmol), and stirred at room temperature for 2 hours. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10ml). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-4-((2-(difluoromethoxy)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-N-methoxy nicotinamide (54-e, 210mg, 0.49mmol, 33% yield), as a white solid. MS Calcd: 423; MS Found: 424 ([M+H] +< ).

[0275] Step 5: 6-chloro-4-((2-(difluoromethoxy)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-N-methoxy nicotinamide (54-e, 50mg, 0.12mmol), cyclopropylcarboxamide (22mg, 0.26mmol), cesium carbonate (127mg, 0.36mmol), XantPhos(30mg, 0.04mmol) and Pd 2 (dba) 3 (24mg, 0.024mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-4-((2-(difluoromethoxy)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-N-methoxy nicotinamide (54, 9mg, 0.02mmol, 16.7% yield). MS Calcd: 472; MS Found: 473 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.83 (s, 1H), 10.79 (s, 1H), 10.01 (s, 1H), 8.36 (s, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.85 (s, 1H), 7.45-7.43 (m, 1H), 7.34-7.32 (m, 2H), 6.95-6.59 (m, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 1.98-1.95 (m, 1H), 0.76-0.74 (m, 4H).Example 55 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(5-methyl-1, 2,4-oxadiazol-3-yl)phenyl)amino)nicotinamide

[0276]

[0277] Step 1: 2-hydroxyl-3-nitrobenzonitrile (55-a, 1.2g, 7.3mmol), iodomethane (3.1g, 22mmol) and potassium carbonate (5.9g, 43mmol) were added to DMF, and stirred at room temperature overnight. The reaction mixture was poured into 150ml of water, filtered by suction, solid was washed with water, and dried to provide 2-methoxy-3-nitrobenzonitrile (55-b, 800mg, 4.5mmol, 62% yield).

[0278] Step 2: To methanol(20ml) were added 2-methoxy-3-nitrobenzonitrile(55-b, 800mg, 4.5mmol) and palladium on carbon (40mg). After atmosphere replacement by hydrogen three times, the reaction mixture was stirred under hydrogen atmosphere at room temperature overnight, and filtered by suction. The filtrate was concentrated under reduced pressure to provide 3-amino-2-methoxy benzonitrile (55-c, 630mg, 4.2mmol, 93% yield), which was used directly in the next reaction without further purification. MS Calcd: 148; MS Found: 149 ([M+H] +< ).

[0279] Step 3: To 5ml of anhydrous tetrahydrofuran were added 4,6-dichloro-N-methoxy nicotinamide (int-1, 332mg, 1.50mmol) and 3-amino-2-methoxy benzonitrile (55-c, 230mg, 1.55mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (3ml, 3mmol), and stirred at room temperature for 2 hours. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10ml). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-4-((3-cyano-2-methoxy phenyl)amino)-N-methoxy nicotinamide (55-d, 152mg, 0.46mmol, 29% yield). MS Calcd: 332; MS Found: 333 ([M+H] +< ).

[0280] Step 4: 6-chloro-4-((3-cyano-2-methoxy phenyl)amino)-N-methoxy nicotinamide (55-d, 52mg, 0.16mmol), cyclopropylcarboxamide (27mg, 0.32mmol), cesium carbonate (156mg, 0.48mmol), XantPhos(30mg, 0.04mmol) and Pd 2 (dba) 3 (24mg, 0.024mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide 4-((3-cyano-2-methoxy phenyl)amino)-6-(cyclopropylcarboxamido)-N-methoxy nicotinamide (55-e, 15mg, 0.04mmol, 25% yield). MS Calcd: 381; MS Found: 382 ([M+H] +< ).

[0281] Step 5: To a mixed solvent of ethanol and water (1ml: 2ml) were added 4-((3-cyano-2-methoxy phenyl)amino)-6-(cyclopropylcarboxamido)-N-methoxy nicotinamide (55-e, 30mg, 0.08mmol) and freed hydroxylamine (11mg, 0.32mmol). The reaction mixture was heated to 90°C with stirring for 6 hours, and concentrated under reduced pressure. The residue was purified by high performance preparative thin layer chromatography ( methanol: dichloromethane=1:10) to provide 6-(cyclopropylcarboxamido)-4-((3-(N-hydroxyaminocarboxamido)-2-methoxy phenyl)amino)-N-methoxy nicotinamide (55-f, 9mg, 0.02mmol, 13% yield). MS Calcd: 414; MS Found: 413 ([M-H] -< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.86 (s, 1H), 10.82 (s, 1H), 10.12 (s, 1H), 9.53 (s, 1H), 8.36 (s, 1H), 8.07 (s, 1H), 7.44 (dd, J=4, 5.6, 1H), 7.15-7.12 (m, 2H), 5.76 (s, 2H), 3.73 (s, 3H), 3.70 (s, 3H), 1.99-1.96 (m, 1H), 0.78-0.77 (m, 4H).

[0282] Step 6: To 1,4-dioxane were added 6-(cyclopropylcarboxamido)-4-((3-(N-hydroxyaminocarboxamido)-2-methoxy phenyl)amino)-N-methoxy nicotinamide (55-f, 20mg, 0.05mmol), acetic anhydride (5mg, 0.05mmol), heated to 90°C with stirring for 5 hours, and concentrated under reduced pressure. The residue was purified by high performance preparative thin layer chromatography ( methanol: dichloromethane=1:30) to provide 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(5-methyl-1, 2,4-oxadiazol-3-yl)phenyl)amino)nicotinamide (55, 9mg, 0.02mmol, 40% yield), as a white solid. MS Calcd: 438; MS Found: 439 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.86 (s, 1H), 10.83 (s, 1H), 10.30 (s, 1H), 8.40 (s, 1H), 8.07 (s, 1H), 7.65-7.60 (m, 2H), 7.33 (dd, J = 8.0, 4.0 Hz, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 2.68 (s, 3H), 2.00-1.96 (m, 1H), 0.78-0.74 (m, 4H).Example 56 6-(cyclopropylcarboxamido)-N-methoxy-4-((4-(N-methyl sulfonamido)pyridin-3-yl)amino)nicotinamide

[0283]

[0284] Step 1: To DMF were added 4-chloro-3-nitropyridine (56-a, 1g, 6.3mmol), N-methyl methanesulfonamide (680mg, 6.3mmol) and potassium carbonate (2.6g, 19mmol). The reaction mixture was heated to 80°C with stirring for 2 hours. When TLC indicated that all starting material was depleted, the reaction mixture was cooled to room temperature, poured into 100ml of water to cause a solid precipitation, which was filtered by suction to provide N-methyl-N-(3-nitropyridin-4-yl) methanesulfonamide (56-b, 920mg, 3.98mmol, 63% yield). MS Calcd: 231; MS Found: 232 ([M-H] -< ).

[0285] Step 2: To methanol(20ml) were added N-methyl-N-(3-nitropyridin-4-yl) methanesulfonamide (56-b, 920mg, 3.98mmol) and palladium on carbon (100mg). After atmosphere replacement by hydrogen three times, the reaction mixture was stirred under hydrogen atmosphere at room temperature overnight, and filtered by suction. The filtrate was concentrated under reduced pressure to provide N-(3-aminopyridin-4-yl)-N-methyl methanesulfonamide (56-c, 730mg, 3.6mmol, 90% yield), which was used directly in the next reaction without further purification. MS Calcd: 201; MS Found: 202 ([M+H] +< ).

[0286] Step 3: To 2.5ml of anhydrous tetrahydrofuran were added 4,6-dichloro-N-methoxy nicotinamide (int-1, 230mg, 1.14mmol) and N-(3-aminopyridin-4-yl)-N-methyl methanesulfonamide (56-c, 230mg, 1.14mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (2.5ml, 2.5mmol), and stirred at room temperature for 2 hours. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10ml). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-N-methoxy-4-((4-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (56-d, 125mg, 0.32mmol, 28% yield). MS Calcd: 385; MS Found: 386 ([M+H] +< ).

[0287] Step 4: 6-chloro-N-methoxy-4-((4-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (56-d, 50mg, 0.13mmol), cyclopropylcarboxamide (22mg, 0.26mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(20mg, 0.03mmol) and Pd 2 (dba) 3 (19mg, 0.02mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-N-methoxy-4-((4-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (56, 12mg, 0.03mmol, 23% yield). MS Calcd: 434; MS Found: 435 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.86 (s, 1H), 10.84 (s, 1H), 9.99 (s, 1H), 8.72 (s, 1H), 8.43 (d, J = 5.2, 1H), 8.36 (s, 1H), 7.84 (s, 1H), 7.63 (d, J = 5.2, 1H), 3.72 (s, 3H), 3.16 (s, 6H), 1.99-1.94 (m, 1H), 0.77-0.6 (m, 4H).Example 57 4-((3-carbamoyl-2-methoxy phenyl)amino)-6-(cyclopropylcarboxamido)-N-methoxy nicotinamide

[0288]

[0289] Step 1: 4-((3-cyano-2-methoxy phenyl)amino)-6-(cyclopropylcarboxamido)-N-methoxy nicotinamide (55-e, 20mg, 0.05mmol) and potassium carbonate (14mg, 0.1mmol) were added to a mixed solvent of water and ethanol. The reaction mixture was heated to 80°C with stirring for 2 hours, and concentrated under reduced pressure. The residue was purified by high performance preparative thin layer chromatography ( methanol: dichloromethane=1:20) to provide the title compound: 4-((3-carbamoyl-2-methoxy phenyl)amino)-6-(cyclopropylcarboxamido)-N-methoxy nicotinamide (57, 8mg, 0.02mmol, 40% yield). MS Calcd: 399; MS Found: 400 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.84 (s, 1H), 10.82 (s, 1H), 10.13 (s, 1H), 8.37 (s, 1H), 8.03 (s, 1H), 7.74 (s, 1H), 7.52-7.49 (m, 2H), 7.32-7.30 (dd, J = 8.0, 1.6 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 3.70 (s, 6H), 1.99-1.94 (m, 1H), 0.78-0.76 (m, 4H).Example 58 6-((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((4-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide

[0290]

[0291] Step 1: 6-chloro-N-methoxy-4-((4-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (56-d, 50mg, 0.13mmol), 5-fluoropyridin-2-ylamine (30mg, 0.26mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(20mg, 0.03mmol) and Pd 2 (dba) 3 (19mg, 0.02mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((4-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (58, 9mg, 0.02mmol, 15% yield). MS Calcd: 461; MS Found: 462 ([M+H] +< ). 1H NMR (400 MHz, DMSO-d 6 ) : δ 11.86 (s, 1H), 9.98 (s, 1H), 9.86 (s, 1H), 8.83 (s, 1H), 8.44 (d, J = 5.2 Hz, 1H), 8.33 (s, 1H), 8.08 (d, J = 3.2 Hz, 1H), 7.78-7.77 (m, 1H), 7.64-7.61 (m, 2H), 7.39 (s, 1H), 3.72 (s, 3H), 3.20 (s, 3H), 3.19 (s, 3H).Example 59 6-(cyclopropylcarboxamido)-N-methoxy-4-((6-methyl-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide

[0292]

[0293] Step 1: To DMF were added 2-chloro-6-methyl-3-nitropyridine (59-a, 1g, 5.8mmol), N-methyl methanesulfonamide (630mg, 5.8mmol) and potassium carbonate (2.4g, 17.4mmol). The mixture was heated to 80°C with stirring for 2 hours. When TLC indicated that all starting material was depleted, the reaction mixture was cooled to room temperature, poured into 100ml of water to cause solid precipitation, which was filtered by suction to provide N-methyl-N-(6-methyl-3-nitropyridin-2-yl) methanesulfonamide (59-b, 965mg, 3.9mmol, 67% yield). MS Calcd: 245; MS Found: 246 ([M-H] -< ).

[0294] Step 2: To methanol(20ml) were added N-methyl-N-(6-methyl-3-nitropyridin-2-yl) methanesulfonamide (59-b, 965mg, 3.9mmol) and palladium on carbon (100mg). After atmosphere replacement by hydrogen three times, the reaction mixture was stirred under hydrogen atmosphere at room temperature overnight, and filtered by suction. The filtrate was concentrated under reduced pressure to provide N-(3-amino-6-methyl pyridin-2-yl)-N-methyl methanesulfonamide (59-c, 753mg, 3.5mmol, 89% yield), which was used directly in the next reaction without further purification. MS Calcd: 215; MS Found: 216 ([M+H] +< ).

[0295] Step 4: To 2.5ml of anhydrous tetrahydrofuran were added N-(3-amino-6-methyl pyridin-2-yl)-N-methyl methanesulfonamide (59-c, 253mg, 1.17mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 230mg, 1.14mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (2.5ml, 2.5mmol), and stirred at room temperature for 2 hours. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10ml). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-N-methoxy-4-((6-methyl-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (59-d, 138mg, 0.36mmol, 29% yield). MS Calcd: 399; MS Found: 400 ([M+H] +< ).

[0296] Step 5: 6-chloro-N-methoxy-4-((6-methyl-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (59-d, 50mg, 0.13mmol), cyclopropylcarboxamide (22mg, 0.26mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(20mg, 0.03mmol) and Pd 2 (dba) 3 (19mg, 0.02mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-N-methoxy-4-((6-methyl-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (59, 18mg, 0.04mmol, 31% yield). MS Calcd: 448; MS Found: 449 ([M+H] +< ). 1H NMR (400 MHz, DMSO-d 6 ) : δ 11.81 (s, 1H), 10.82 (s, 1H), 10.01 (s, 1H), 8.35 (s, 1H), 7.84-7.82 (m, 2H), 7.34-7.32 (d, J = 8.4 Hz, 1H), 3.71 (s, 3H), 3.17 (s, 3H), 3.10 (s, 3H), 2.47 (s, 3H), 1.97-1.95 (m, 1H), 0.78-0.76 (m, 4H).Example 60 6-(((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((6-methyl-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide

[0297]

[0298] Step 1: 6-chloro-N-methoxy-4-((6-methyl-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (59-d, 50mg, 0.13mmol), 5-fluoropyridin-2-ylamine (30mg, 0.26mmol), cesium carbonate (130mg, 0.4mmol), XantPhos(20mg, 0.03mmol) and Pd 2 (dba) 3 (19mg, 0.02mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((6-methyl-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (60, 13mg, 0.03mmol, 23% yield). MS Calcd: 475; MS Found: 476 ([M+H] +< ). 1H NMR (400 MHz, DMSO-d 6 ) : δ 11.72 (s, 1H), 10.06 (s, 1H), 9.86 (s, 1H), 8.32 (s, 1H), 8.18 (s, 1H), 7.96-7.94 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 5.2 Hz, 2H), 7.55 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 3.71 (s, 3H), 3.21 (s, 3H), 3.12 (s, 3H), 2.49 (s, 3H).Example 61 4-((4-(cyclopropyl methoxy)-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide

[0299]

[0300] Step 1: To DMF were added 3-fluoro-4-nitrophenol(61-a, 1g, 6.3mmol), (bromo methyl)cyclopropane(850mg, 6.3mmol), and potassium carbonate (2.6g, 18.9mmol). The reaction mixture was heated to 90°C with stirring for 5 hours, followed by cooling to room temperature, added with water, and extracted with ethyl acetate. The organic layer was washed with water (30ml), dried over anhydrous sodium sulfate and filtered by suction, and concentrated under reduced pressure to provide 4-(cyclopropyl methoxy)-2-fluoro-1-nitrobenzene (61-b, 1.1g, 5.2mmol, 83% yield). MS Calcd: 211; MS Found: 212 ([M+H] +< ).

[0301] Step 2: To DMF were added 4-(cyclopropyl methoxy)-2-fluoro-1-nitrobenzene (61-b, 1.1g, 5.2mmol), N-methyl methanesulfonamide (630mg, 5.8mmol) and potassium carbonate (2.2g, 15.6mmol). The mixture was heated to 80°C with stirring for 2 hours. When TLC indicated that all starting material was depleted, the reaction mixture was cooled to room temperature, poured into 100ml of water, extracted with ethyl acetate (100ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered by suction, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:petroleum ether=1:4) to provide N-(5-(cyclopropyl methoxy)-2-nitrophenyl)-N-methyl methanesulfonamide (61-c, 862mg, 2.9mmol, 56% yield). MS Calcd: 300; MS Found: 301 ([M-H] -< ).

[0302] Step 3: To methanol(20ml) were added N-(5-(cyclopropyl methoxy)-2-nitrophenyl)-N-methyl methanesulfonamide (61-c, 862mg, 2.9mmol) and palladium on carbon (100mg). After atmosphere replacement by hydrogen three times, the mixture was stirred under hydrogen atmosphere at room temperature overnight, and filtered by suction. The filtrate was concentrated under reduced pressure to provide N-(2-amino-5-(cyclopropyl methoxy)phenyl)-N-methyl methanesulfonamide (61-d, 731mg, 2.7mmol, 93% yield), which was used directly in the next reaction without further purification. MS Calcd: 270; MS Found: 271 ([M+H] +< ).

[0303] Step 4: To 2.5ml of anhydrous tetrahydrofuran were added N-(2-amino-5-(cyclopropyl methoxy)phenyl)-N-methyl methanesulfonamide (61-d, 261mg, 0.96mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 200mg, 1mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (2ml, 2mmol), and stirred at room temperature for 2 hours. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10ml). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:2) to provide 6-chloro-4-((4-(cyclopropyl methoxy)-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (61-e, 185mg, 0.41mmol, 43% yield). MS Calcd: 454; MS Found: 455 ([M+H] +< ).

[0304] Step 5: 6-chloro-4-((4-(cyclopropyl methoxy)-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (61-e, 50mg, 0.11mmol), 5-fluoropyridin-2-ylamine (19mg, 0.22mmol), cesium carbonate (107mg, 0.33mmol), XantPhos(20mg, 0.03mmol) and Pd 2 (dba) 3 (19mg, 0.02mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide 4-((4-(cyclopropyl methoxy)-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide (61, 16mg, 0.03mmol, 27% yield), as a white solid. MS Calcd: 530; MS Found: 531 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.62 (s, 1H), 9.72 (s, 1H), 9.71 (s, 1H), 8.26 (s, 1H), 8.12 (d, J = 2.8 Hz, 1H), 7.66-7.60 (m, 2H), 7.43 (d, J = 8.8 Hz, 1H), 7.29 (s, 1H), 7.13 (d, J = 2.4 Hz, 1H), 7.08 (dd, J = 8.8, 2.8 Hz, 1H), 3.88 (d, J = 7.2 Hz, 2H), 3.70 (s, 3H), 3.12 (s, 3H), 3.08 (s, 3H), 1.24-1.23 (m, 1H), 0.61-0.57 (m, 2H), 0.37-0.33 (m, 2H).Example 62 4-((4-(cyclopropyl methoxy)-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide

[0305]

[0306] Step 1: 6-chloro-4-((4-(cyclopropyl methoxy)-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (61-e, 50mg, 0.11mmol), 6-fluoropyridin-2-ylamine (19mg, 0.22mmol), cesium carbonate (107mg, 0.33mmol), XantPhos(20mg, 0.03mmol) and Pd 2 (dba) 3 (19mg, 0.02mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((4-(cyclopropyl methoxy)-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide (62, 13mg, 0.024mmol, 22% yield). MS Calcd: 530; MS Found: 531 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.66 (s, 1H), 9.90 (s, 1H), 9.71 (s, 1H), 8.27 (s, 1H), 7.79-7.76 (m, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.29 (s, 1H), 7.15 (d, J = 2.8 Hz, 1H), 7.00 (dd, J = 8.8, 2.8 Hz, 1H), 6.54 (dd, J = 8.0, 2.8 Hz, 1H), 3.865 (d, J=7.2, 2H), 3.72 (s, 3H), 3.14 (s, 3H), 3.07 (s, 3H), 1.26-1.23 (m, 1H), 0.61-0.57 (m, 2H), 0.37-0.33 (m, 2H).Example 63 6-(cyclopropylcarboxamido)-4-((4-(cyclopropyl methoxy)-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide

[0307]

[0308] Step 1: 6-chloro-4-((4-(cyclopropyl methoxy)-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (61-e, 50mg, 0.11mmol), cyclopropylcarboxamide (19mg, 0.22mmol), cesium carbonate (107mg, 0.33mmol), XantPhos(20mg, 0.03mmol) and Pd 2 (dba) 3 (19mg, 0.02mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide 6-(cyclopropylcarboxamido)-4-((4-(cyclopropyl methoxy)-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (63, 15mg, 0.029mmol, 26% yield), as a white solid. MS Calcd: 503; MS Found: 504 ([M+H] +< ). 1H NMR (400 MHz, DMSO-d 6 ) : δ 11.71 (s, 1H), 10.69 (s, 1H), 9.68 (s, 1H), 8.28 (s, 1H), 7.59 (s, 1H), 7.319 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 2.8, 1H), 6.98 (dd, J = 8.8, 2.8 Hz, 1H), 3.86 (d, J = 7.2 Hz, 2H), 3.70 (s, 3H), 3.09 (s, 3H), 3.05 (s, 3H), 1.97-1.96 (m, 1H), 1.23-1.17 (m, 1H), 0.75-0.72 (m, 4H), 0.35-0.34 (m, 2H), 0.28-0.27 (m, 2H).Example 64 6-((4-fluorophenyl)amino)-N-methoxy-4-((6-methyl-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide

[0309]

[0310] Step 1: 6-chloro-N-methoxy-4-((6-methyl-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (59-d, 50mg, 0.13mmol), 4-fluoroaniline(30mg, 0.26mmol), cesium carbonate (130mg, 0.4mmol), Xantphos(20mg, 0.03mmol) and Pd 2 (dba) 3 (19mg, 0.02mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-((4-fluorophenyl)amino)-N-methoxy-4-((6-methyl-2-(N-methyl methanesulfonamido)pyridin-3-yl)amino)nicotinamide (64, 16mg, 0.03mmol, 23% yield). MS Calcd: 474; MS Found: 475 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.65 (s, 1H), 9.82 (s, 1H), 9.08 (s, 1H), 8.26 (s, 1H), 7.90-7.88 (d, J=8.0, 1H), 7.59 (d, J 1 =4.0, J 2 =8.0, 2H), 7.36-7.34 (d, J=8.0, 1H), 7.11-7.07 (t, J=8.0, 2H), 6.29 (m, 1H), 3.71 (s, 3H), 3.20 (s, 3H), 3.12 (s, 3H), 2.48 (s, 3H)Example 65 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-N-methyl-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide

[0311]

[0312] Step 1: To dichloromethane (20ml) was added 4,6-dichloronicotinic acid(65-a, 1g, 5.2mmol), followed by catalytic amount of DMF. The mixture was cooled to 0°C, and slowly added with oxalyl chloride (0.7ml, 7.8mmol) dropwise. Upon the addition was completed, the reaction mixture was heated to room temperature slowly and stirred for 2 hours, then concentrated under reduced pressure. The residue was dissolved in 5ml of ethyl acetate, and added slowly to aqueous solution of dimethyl hydroxylamine hydrochloride (1.5g, 16mmol) and potassium carbonate (3.7g, 27mmol) in mixed solvent of water and ethyl acetate. The mixture was stirred at room temperature overnight, added with ethyl acetate (50ml), and subjected to phase separation. The organic layer was dried and concentrated, and the residue was purified by column chromatography (ethyl acetate:petroleum ether=1:2) to provide 4,6-dichloro-N-methoxy-N-methyl nicotinamide (65-b, 800mg, 3.4mmol, 65% yield). MS Calcd: 234; MS Found: 235 ([M+H] +< ).

[0313] Step 2: To 5ml of anhydrous tetrahydrofuran were added 4,6-dichloro-N-methoxy-N-methyl nicotinamide (65-b, 200mg, 0.9mmol) and N-(2-amino phenyl)-N-methyl methanesulfonamide (220mg, 1.1mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (1.8ml, 1.8mmol), and stirred at room temperature for 2 hours. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (petroleum ether:ethyl acetate =1:2) to provide 6-chloro-N-methoxy-N-methyl-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (65-c, 160mg, 0.4mmol, 44% yield). MS Calcd: 398; MS Found: 399 ([M+H] +< ).

[0314] Step 3: 6-chloro-N-methoxy-N-methyl-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (65-c, 100mg, 0.25mmol), 6-fluoropyridin-2-ylamine (56mg, 0.5mmol), cesium carbonate (240mg, 0.75mmol), Xantphos(60mg, 0.08mmol) and Pd 2 (dba) 3 (50mg, 0.05mmol) were added to anhydrous dioxane (3ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-N-methyl-4-((2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (65, 30mg, 0.06mmol, 24% yield). MS Calcd: 474; MS Found: 475 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 10.01 (brs, 1H), 8.86 (s, 1H), 8.30 (s, 1H), 7.80-7.78 (d, J=8.0, 1H), 7.78-7.51 (m, 4H), 7.41-7.37 (m, 1H), 7.20-7.18 (m, 1H), 6.56-6.54 (d, J=8.0, 1H), 3.61 (s, 3H), 3.29 (s, 3H), 3.14 (s, 3H), 3.10 (s, 3H)Example 66 6-((4,6-dimethyl pyrimidin-2-yl)amino)-N-ethoxy-4-((4-methyl-2-(N-methyl cyclopropylsulfonamido)phenyl)amino)nicotinamide

[0315]

[0316] Step 1: To a 100ml reaction flask was added 2-fluoro-4-methyl-1-nitrobenzene(66-a, 465g, 3mmol) dissolved in N,N-dimethyl formamide (30ml), followed by potassium carbonate (1.24g, 9mmol) and cyclopropanesulfonamide (400mg, 3.3mmol). The mixture was heated to 90°C with stirring for 3h. Upon indication of completed reaction by TLC, the reaction mixture was washed respectively with water (30 ml x 1) and brine (30 ml x 1), dried over anhydrous sodium sulfate, and concentrated to provide a crude material, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3:1) to provide the product N-(5-methyl-2-nitrophenyl) cyclopropylsulfonamide (66-b, 695mg, 90% yield). MS Calcd:256.05; MS Found: 257.10 ([M+H] +< )

[0317] Step 2: To a 100ml reaction flask was added N-(5-methyl-2-nitrophenyl) cyclopropylsulfonamide (66-b, 690mg, 2.72mmol) dissolved in N,N-dimethyl formamide (30ml), followed by sodium hydride (163.2mg, 60%, 4.08mmol) and iodomethane (463mg, 3.26mmol). The reaction mixture was stirred at room temperature for 3h. Upon indication of completed reaction by TLC, the reaction mixture was added with water and ethyl acetate, extracted with ethyl acetate (30 ml x 2). The organic phase was washed with brine (30 ml x 1), dried over anhydrous sodium sulfate, and concentrated to obtain N-(5-methyl-2-nitrophenyl)-N-methyl cyclopropylsulfonamide (66-c, 761mg, 2.72mmol, 100% yield). MS Calcd: 270.09; MS Found: 271.22 ([M+H] +< ).

[0318] Step 3: N-(5-methyl-2-nitrophenyl)-N-methyl cyclopropylsulfonamide (66-c, 761mg, 2.72mmol), ammonium chloride (1.46g, 27.2 mmol) and iron powder (0.76 g, 13.6 mmol) were sequentially added to 10 mL of mixed solvent of water and ethanol (1:4), stirred under reflux for 3 hours. Upon indication of completed reaction by TLC, the reaction mixture was filtered by suction. The filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography to provide N-(2-amino-5-methyl phenyl)-N-methyl cyclopropylsulfonamide (66-d, 0.47 g, 1.96mmol, 72% yield). MS Calcd: 240.09; MS Found: 241.22 ([M+H] +< ).

[0319] Step 4: To 10 ml of anhydrous N,N-dimethylacetamide were added N-(2-amino-5-methyl phenyl)-N-methyl cyclopropylsulfonamide (66-d, 125mg, 0.5 mmol) and 4,6-dichloro-N-ethoxy nicotinamide (int-2, 117 mg, 0.5 mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (1.5 ml, 1.5 mmol), and stirred at room temperature for 3 hours. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (20 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-N-ethoxy-4-((4-methyl-2-(N-methyl cyclopropylsulfonamido)phenyl)amino)nicotinamide (66-e, 187mg, 0.43 mmol, 85.2% yield). MS Calcd: 438.10; MS Found: 439.29 ([M+H] +< ).

[0320] Step 5: 6-chloro-N-ethoxy-4-((4-methyl-2-(N-methyl cyclopropylsulfonamido)phenyl)amino)nicotinamide (66-e, 132mg, 0.3 mmol), 4,6-dimethyl pyrimidin-2-ylamine (40.6mg, 0.33mmol), cesium carbonate (292.5 mg, 0.9 mmol), Xant-Phos(34.68mg, 0.06mmol) and Pd 2 (dba) 3 (27.5mg, 0.03 mmol) were added to anhydrous dioxane (5 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 6 hours, and filtered by suction. The filtrate was concentrated and purified by preparative TLC (MeOH:DCM=1:20) to provide the title compound: 6-((4,6-dimethyl pyrimidin-2-yl)amino)-N-ethoxy-4-((4-methyl-2-(N-methyl cyclopropylsulfonamido)phenyl)amino)nicotinamide (66, 30mg, 0.057mmol, 19.2% yield). MS Calcd: 525.21; MS Found: 526.20 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.60 (s, 1H), 9.97 (s, 1H), 9.60 (s, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 8.0, 2.0 Hz, 1H), 6.72 (s, 1H), 3.93 (q, J= 7.2 Hz, 2H), 3.14 (s, 3H), 2.81-2.77 (m, 1H), 2.34 (s, 3H), 2.25 (s, 6H), 1.22 (t, J= 7.2 Hz, 3H), 1.02-0.98 (m, 2H), 0.88 - 0.82 (m, 2H).Example 67 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy-2-methyl nicotinamide

[0321]

[0322] Step 1: To dichloromethane (20ml) was added 4,6-dichloro-2-methyl nicotinic acid (67- a, 1g, 4.8mmol), followed by catalytic amount of DMF. The mixture was cooled to 0°C, and slowly added with oxalyl chloride (0.7ml, 7.8mmol) dropwise. Upon the addition was completed, the reaction mixture was heated to room temperature slowly and stirred for 2 hours, and concentrated under reduced pressure. The residue was dissolved in 5ml of ethyl acetate, and added slowly to solution of methoxy amine hydrochloride (1.2g, 16mmol) and potassium carbonate (3.7g, 27mmol) in a mixed solvent of water and ethyl acetate. The mixture was stirred at room temperature overnight, added with ethyl acetate (50ml), and subjected to phase separation. The organic layer was dried and concentrated, and the residue was purified by column chromatography (ethyl acetate:petroleum ether=1:2) to provide the title compound: 4,6-dichloro-N-methoxy-2-methyl nicotinamide (67-b, 750mg, 3.2mmol, 66% yield).

[0323] MS Calcd: 234; MS Found: 235 ([M+H] +< ).

[0324] Step 2: To 5ml of anhydrous tetrahydrofuran were added 4,6-dichloro-N-methoxy-2-methyl nicotinamide (67-b, 200mg, 0.9mmol) and N-(2-amino-5-cyclopropyl phenyl)-N-methyl methanesulfonamide (264mg, 1.1mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (1.8ml, 1.8mmol), and stirred at room temperature for 2 hours. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (petroleum ether:ethyl acetate =1:2) to provide 6-chloro-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy-2-methyl nicotinamide (67-c, 187mg, 0.43mmol, 48% yield), MS Calcd: 438; MS Found: 439 ([M+H] +< ).

[0325] Step 3: 6-chloro-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy-2-methyl nicotinamide (67-c, 60mg, 0.14mmol), 6-fluoropyridin-2-ylamine (31mg, 0.28mmol), cesium carbonate (137mg, 0.42mmol), XantPhos(30mg, 0.04mmol) and Pd 2 (dba) 3 (30mg, 0.03mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy-2-methyl nicotinamide (67, 25mg, 0.05mmol, 36% yield). MS Calcd: 514; MS Found: 515 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.60 (s, 1H), 9.79 (s, 1H), 7.76 (d, J=8.0, 1H), 7.74 (s, 1H), 7.48 (d, J=8.0, 1H), 7.44-7.40 (m, 2H), 7.28 (d, J=4.0, 1H), 7.08 (d, J=8.0, 1H), 6.50 (d, J=8.0, 1H), 3.73 (s, 3H), 3.13 (s, 3H), 3.10 (s, 3H), 2.35 (s, 3H), 1.96-1.93 (m, 1H), 0.98-0.96 (m, 2H), 0.70-0.68 (m, 2H)Example 68 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-(methoxy-d3)nicotinamide

[0326]

[0327] Step 1: To dichloromethane (20ml) was added 4,6-dichloronicotinic acid (68-a, 1g, 5.2mmol), followed by catalytic amount of DMF. The mixture was cooled to 0°C, and slowly added with oxalyl chloride (0.7ml, 7.8mmol) dropwise. Upon the addition was completed, the reaction mixture was heated to room temperature slowly and stirred for 2 hours, and concentrated under reduced pressure. The residue was dissolved in 5ml of ethyl acetate, and added slowly to aqueous solution of hydroxylamine hydrochloride (1g, 16mmol) and potassium carbonate (3.7g, 27mmol) in mixed solvent of water and ethyl acetate. The mixture was stirred at room temperature overnight, added with ethyl acetate (50ml), and subjected to phase separation. After adjusting with aqueous hydrochloride to pH 5, the organic layer was dried and concentrated. The residue was purified by column chromatography (ethyl acetate:petroleum ether=1:2) to provide 4,6-dichloro-N-hydroxyl nicotinamide (68-b, 455mg, 2.2mmol, 42% yield). MS Calcd: 206; MS Found: 205 ([M-H] -< ).

[0328] Step 2: To a mixed solvent of water and ethanol (1ml / 5ml) were added 4,6-dichloro-N-hydroxyl nicotinamide (68-b, 455mg, 2.2mmol) and sodium hydroxide (264mg, 6.6mmol). The mixture was added at room temperature with deuterated iodomethane (319mg, 2.2mmol), and stirred at room temperature for 4 hours. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (petroleum ether:ethyl acetate =1:2) to provide 4,6-dichloro-N-(methoxy-d3)nicotinamide (68-c, 160mg, 0.72mmol, 33% yield). MS Calcd: 223; MS Found: 224 ([M+H] +< ).

[0329] Step 2: To 5ml of anhydrous tetrahydrofuran were added 4,6-dichloro-N-(methoxy-d3)nicotinamide (68-c, 160mg, 0.72mmol) and N-(2-amino-5-cyclopropyl phenyl)-N-methyl methanesulfonamide (180mg, 0.72mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (1.5ml, 1.5mmol), and stirred at room temperature for 2 hours. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (petroleum ether:ethyl acetate =1:2) to provide 6-chloro-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-(methoxy-d3)nicotinamide (68-d, 110mg, 0.26mmol, 36% yield)MS Calcd: 427; MS Found: 428 ([M+H] +< ).

[0330] Step 3: 6-chloro-4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-(methoxy-d3)nicotinamide (68-d, 110mg, 0.26mmol), 6-fluoropyridin-2-ylamine (58mg, 0.52mmol), cesium carbonate (254mg, 0.78mmol), XantPhos(60mg, 0.08mmol) and Pd 2 (dba) 3 (60mg, 0.06mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((4-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-(methoxy-d3)nicotinamide (68, 30mg, 0.06mmol, 23% yield). MS Calcd: 503; MS Found: 504 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.69 (s, 1H), 9.97(s, 1H), 9.93 (s, 1H), 8.30 (s, 1H), 7.82-7.76 (m, 1H), 7.54 (s, 1H), 7.49 (d, J=8.0, 1H), 7.45 (d, J=4.0, 1H), 6.55 (d, J=4.0, 1H)7.28 (s, 1H), 7.09-7.07 (d, J=8, 1H)3.13 (s, 3H), 3.10 (s, 3H), 2.00-1.96 (m, 1H), 1.01-0.97 (m, 2H), 0.70-0.68 (m, 2H)Example 69 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-nicotinamide

[0331]

[0332] Step 1: To 50 mL of N,N-dimethyl formamide were sequentially added 3-nitrosalicylic acid (69-a, 5.0 g, 27 mmol) and potassium carbonate (10.0 g, 36 mmol), followed by iodomethane (5.0 mL, 80 mmol). The mixture was heated to 60°C and stirred overnight. Upon indication of completed reaction by TLC, the reaction mixture was added with 60 mL of water, and extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1: 4) to provide methyl 2-methoxy-3-nitrobenzoate (69-b, 4.2 g, 19.9 mmol, 74% yield).

[0333] Step 2: methyl 2-methoxy-3-nitrobenzoate (69-b, 3.7 g, 17.3 mmol) was dissolved in methanol solution of ammonia (7 N, 83 mL), followed by adding high concentration ammonia water (35 mL), and stirred at room temperature overnight. Upon indication of completed reaction by TLC, the reaction mixture was concentrated. The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1: 5) to provide 2-methoxy-3-nitrobenzamide (69-c, 3.0 g, 15.3 mmol, 88% yield). MS Calcd: 196.16; MS Found: 196.74 ([M+H] +< ).

[0334] Step 3: 2-methoxy-3-nitrobenzamide (69-c, 3.0 g, 15.3 mmol) was suspended in DMF-DMA (20 mL). The mixture was heated to 95°C with stirring for 30 minutes until the reaction mixture was clear. The mixture was concentrated under reduced pressure to remove volatiles, followed by adding 20 mL of ethanol for dissolution. To the flask in ice bath were sequentially added 63 mL of ethanol, 15 mL of acetic acid and hydrazine hydrate (7.4 mL, 152 mmol). The mixture was stirred at room temperature overnight. Upon indication of completed reaction by TLC, organic solvent was removed and water (100 mL) was added to cause solid to precipitate, which was filtered by suction to provide 3-(2-methoxy-3-nitrobenzene)-1-H-1,2,4-triazole (69-d, 2.31 g, 10.5 mmol, 68% yield).

[0335] MS Calcd: 220.19; MS Found: 243.09 ([M+Na +< ] +< ).

[0336] Step 4: 3-(2-methoxy-3-nitrobenzene)-1-H-1,2,4-triazole (69-d, 2.2 g, 10.1 mmol) and potassium carbonate (4.2 g, 30 mmol) were sequentially added to 20 mL of N,N-dimethyl formamide, followed by adding iodomethane (0.86 mL, 13.6 mmol). The mixture was stirred at room temperature overnight. Upon indication of completed reaction by TLC, the reaction mixture was added with 20 ml of water, and extracted with ethyl acetate (20 mL x 3). Combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether=2:1) to provide 3-(2-methoxy-3-nitrobenzene)-1-methyl-1-H-1,2,4-triazole (69-e, 1.5 g, 6.4 mmol 63% yield).

[0337] Step 5: To methanol(20ml) were added 3-(2-methoxy-3-nitrobenzene)-1-methyl-1-H-1,2,4-triazole (69-e, 0.53 g, 2.2 mmol) and palladium on carbon (100mg). After atmosphere replacement by hydrogen three times, the mixture was stirred under hydrogen atmosphere at room temperature overnight. Upon indication of completed reaction by TLC, the mixture was filtered by suction. The filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate) to provide 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (69-f, 330mg, 1.6mmol, 74% yield). MS Calcd: 204.23; MS Found: 205.23 ([M+H] +< )

[0338] Step 6: To 5ml of anhydrous tetrahydrofuran were added 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (69-f, 150 mg, 0.7 mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 140 mg, 0.63 mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (2.5 ml, 2.5 mmol), and stirred at room temperature for 2 hours. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (DCM: MeOH =1: 10) to provide 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)nicotinamide (69-g, 100 mg, 0.25 mmol, 37% yield).

[0339] MS Calcd: 388.11; MS Found: 389.23 ([M+H] +< ).

[0340] Step 7: 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)nicotinamide (69-g, 100 mg, 0.25 mmol), cyclopropylcarboxamide (22mg, 0.26mmol), cesium carbonate (127mg, 0.39mmol), XantPhos(30mg, 0.04mmol) and Pd 2 (dba) 3 (24mg, 0.026mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 3 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-nicotinamide (69, 30 mg, 0.068mmol, 27% yield).

[0341] MS Calcd: 437.18; MS Found: 438.1 ([M+H] +< ).

[0342] 1< H NMR (400 MHz, DMSO-d 6 )δ11.91 (s, 1H), 10.75 (s, 1H), 10.45 (s, 1H), 8.55 (s, 1H), 8.43 (s, 1H), 8.07 (s, 1H), 7.55 (dd, J = 8.0, 1.2 Hz, 1H), 7.49 (dd, J= 8.0, 1.2 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 3.95 (s, 3H), 3.73 (s, 3H), 3.71 (s, 3H), 2.01-1.94 (m, 1H), 0.79-0.75 (m, 4H).Example 70 6-(cyclopropylcarboxamido)-4-((4-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide

[0343]

[0344] Step 1: To DMF were added 2,4-difluoro-1-nitrobenzene (70-a, 1g, 6.3mmol), N-methyl methanesulfonamide (690mg, 6.3mmol) and potassium carbonate (1.7g, 12.6mmol). The mixture was heated to 80°C with stirring for 2 hours. When TLC indicated that all starting material was depleted, the reaction mixture was cooled to room temperature, poured into 100ml of water to cause solid precipitation, which was filtered by suction, and purified by column chromatography (ethyl acetate:petroleum ether=1; 2) to provide N-(5-fluoro-2-nitrophenyl)-N-methyl methanesulfonamide (70-b, 823mg, 3.3mmol, 52% yield). MS Calcd: 248; MS Found: 249 ([M-H] -< ).

[0345] Step 2: To methanol(20ml) were added N-(5-fluoro-2-nitrophenyl)-N-methyl methanesulfonamide (70-b, 823mg, 3.3mmol), palladium on carbon (100mg). After atmosphere replacement by hydrogen three times, the mixture was stirred under hydrogen atmosphere at room temperature overnight, and filtered by suction. The filtrate was concentrated under reduced pressure to provide N-(2-amino-5-fluorophenyl)-N-methyl methanesulfonamide (70-c, 642mg, 2.9mmol, 87% yield), which was used directly in the next reaction without further purification. MS Calcd: 218; MS Found: 219 ([M+H] +< ).

[0346] Step 3: To 2.5ml of anhydrous tetrahydrofuran were added N-(2-amino-5-fluorophenyl)-N-methyl methanesulfonamide (70-c, 242mg, 1.1mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 230mg, 1.1mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (2.5ml, 2.5mmol), and stirred at room temperature for 2 hours. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10ml). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-4-((4-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (70-d, 147mg, 0.37mmol, 34% yield). MS Calcd: 402; MS Found: 403 ([M+H] +< ).

[0347] Step 4: 6-chloro-4-((4-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (70-d, 147mg, 0.37mmol), cyclopropylcarboxamide (63mg, 0.74mmol), cesium carbonate (400mg, 1.2mmol), XantPhos(60mg, 0.09mmol) and Pd 2 (dba) 3 (57mg, 0.06mmol) were added to anhydrous dioxane (6ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 120°C with stirring for 2 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-4-((4-fluoro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (70, 32mg, 0.07mmol, 20% yield). MS Calcd: 451; MS Found: 452 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 ) : δ 11.77 (s, 1H), 10.76 (s, 1H), 9.87 (s, 1H), 8.32 (s, 1H), 7.73 (s, 1H), 7.56 (dd, J = 9.6, 2.8 Hz, 1H), 7.50-7.46 (m, 1H), 7.33-7.28 (m, 1H), 3.71 (s, 3H), 3.15 (s, 3H), 3.12 (s, 3H), 1.96-1.93 (m, 1H), 0.77-0.74 (m, 4H).Example 71 6-(cyclopropylcarboxamido)-N-ethyl-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide

[0348]

[0349] Step 1: 1-bromo-2-methoxy-3-nitrobenzene(71-a, 500 mg, 2.16 mmol) and iron powder (900 mg, 16.07 mmol) were sequentially added to a mixed solvent of acetic acid / water (1:1, 15 mL). The reaction mixture was heated to 80°C with stirring for 3 hours. Upon indication of completed reaction by TLC, the reaction mixture was allowed to cool down to room temperature, filtered by suction. The filter cake was washed with ethyl acetate (20 mL) and water (20 mL), followed by isolation of organic phase. The organic phase was sequentially washed with saturated sodium bicarbonate aqueous solution(30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA: PE=10:1) to provide 3-bromo-2-methoxy aniline (71-b, 380 mg, 1.48 mmol, 69% yield). MS Calcd: 200.98; MS Found: 202.07 ([M+H] +< ).

[0350] Step 3: 3-bromo-2-methoxy aniline (71-b, 380 mg, 1.48 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (458mg, 2.20mmol), Pd(dppf)Cl 2 (60 mg, 0.06 mmol) and sodium phosphate (738mg, 4.44 mmol) were dissolved in a mixed solvent of water and dioxane (2ml / 8mL). The mixture was heated to 110°C for 3h. The reaction mixture was concentrated, added with water (10ml), and extracted with ethyl acetate (10 ml x 3). The combined ethyl acetate layers were dried over anhydrous sodium sulfate, filtered by suction, and concentrated to obtain a crude material, which was purified by column chromatography (PE:EA =10:1) to provide 2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)aniline (71-c, 220 mg, 1.08 mmol, 73% yield). MS Calcd: 203.25; MS Found: 204.1 ([M+H] +< ).

[0351] Step 3: To 5ml of anhydrous tetrahydrofuran were added 2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)aniline (71-c, 110 mg, 0.54 mmol) and 4,6-dichloro-N-ethyl nicotinamide (112mg, 0.54 mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (3 ml, 3.0 mmol), and stirred at room temperature for 2 hours. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide white solid 6-chloro-N-ethyl-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (71-d, 70 mg, 0.18mmol, 34% yield).

[0352] Step 4: 6-chloro-N-ethyl-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (71-d, 70 mg, 0.18mmol), cyclopropylcarboxamide (22mg, 0.26mmol), cesium carbonate (127mg, 0.39mmol), XantPhos(30mg, 0.04mmol) and Pd 2 (dba) 3 (24mg, 0.026mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 125°C with stirring for 3 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:10) to provide the title compound: 6-(cyclopropylcarboxamido)-N-ethyl-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (71, 10 mg, 0.023mmol, 12.8% yield). MS Calcd: 434.21; MS Found: 433.26 ([M-H] -< ). 1< H NMR (400 MHz, DMSO-d 6 )δ10.78 (s, 1H), 10.63 (s, 1H), 8.66 (t, J = 5.6 Hz, 1H), 8.52 (s, 1H), 8.16 (s, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.14 (dd, J = 7.8 Hz, 1H), 3.89 (s, 3H), 3.57 (s, 3H), 3.29 (t, J = 7.2, 2H), 2.00 - 1.96 (m, 1H), 1.15 (t, J = 7.2 Hz, 3H), 0.77 (m, 4H).Example 72 N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6-((4-(methanesulfonyl)phenyl)amino)nicotinamide

[0353]

[0354] Step 1: To 5ml of anhydrous tetrahydrofuran were added 2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)aniline (71-c, 110 mg, 0.54 mmol), 4,6-dichloro-N-methoxy nicotinamide (int-1, 112mg, 0.54 mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (3 ml, 3.0 mmol), and stirred at room temperature for 2 hours. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide white solid 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (72-a, 140 mg, 0.36 mmol, 69% yield). MS Calcd: 387.82; MS Found: 386.19 ([M-H] -< ).

[0355] Step 2: 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (32061-d, 140 mg, 0.36mmol), cyclopropylcarboxamide (44mg, 0.52mmol), cesium carbonate (256 mg, 0.8mmol), XantPhos(60mg, 0.08mmol) and Pd 2 (dba) 3 (48 mg, 0.052 mmol) were added to anhydrous dioxane (2 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 125°C with stirring for 3 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:10) to provide the title compound: N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6-((4-(methanesulfonyl)phenyl)amino)nicotinamide (72, 30 mg, 0.057mmol, 15.9% yield). MS Calcd: 522.17; MS Found: 523.33 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.83 (s, 1H), 10.06 (s, 1H), 9.69 (s, 1H), 8.37 (s, 1H), 8.18 (s, 1H), 7.93 (s, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.76 (d, J= 8.8 Hz, 2H), 7.40 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 6.64 (s, 1H), 3.90 (s, 3H), 3.74 (s, 3H), 3.62 (s, 3H), 3.12 (s, 3H).Example 73 6-(cyclopropylcarboxamido)-4-((2-(dimethyl phosphoryl)phenyl)amino)-N-methoxy nicotinamide

[0356]

[0357] Step 1: 2-iodo aniline (73-a, 0.3 g, 1.36 mmol), dimethyl phosphorus oxide (128 mg, 1.63 mmol), potassium phosphate (318 mg, 1.50 mmol), palladium acetate (30 mg, 0.14 mmol) and XantPhos (90 mg, 0.16 mmol) were sequentially added to anhydrous dioxane (3 mL). The atmosphere of the mixture was evacuated to vacuum and replaced with nitrogen three times. After stirring at 130°C for 16 hours, TLC indicated a completed reaction. The mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM: MeOH =10:1) to provide 2-(dimethyl phosphoryl) aniline (32117-b, 200 mg, 1.17 mmol, 87% yield). MS Calcd: 169.16; MS Found: 170.12 ([M+H] +< ).

[0358] Step 2: To 5ml of anhydrous tetrahydrofuran were added 2-(dimethyl phosphoryl) aniline (73-b, 200 mg, 1.17 mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 257 mg, 1.17 mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (2.3 ml, 2.3 mmol), and stirred at 50°C for 3 hours. The mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (DCM: MeOH =10:1) to provide 6-chloro-4-((2-(dimethyl phosphoryl)phenyl)amino)-N-methoxy nicotinamide (73-c, 200mg, 0.56 mmol, 48% yield). MS Calcd: 353.74; MS Found: 354.23 ([M+H] +< ).

[0359] Step 3: 6-chloro-4-((2-(dimethyl phosphoryl)phenyl)amino)-N-methoxy nicotinamide (73-c, 100 mg, 0.28 mmol), cyclopropylcarboxamide (48 mg, 0.52 mmol), cesium carbonate (170 mg, 0.0.52 mmol), XantPhos(23 mg, 0.04mmol) and Pd 2 (dba) 3 (27mg, 0.03 mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 125°C with stirring for 3 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-4-((2-(dimethyl phosphoryl)phenyl)amino)-N-methoxy nicotinamide (73, 15 mg, 0.037 mmol, 13% yield). MS Calcd: 402.39; MS Found: 403.33 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.88 (s, 1H), 10.59 (s, 1H), 8.45 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 12.8 Hz, 1H), 7.62 - 7.53 (m, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 3.63 (s, 3H), 1.95 - 1.87 (m, 1H), 1.68 (s, 3H), 1.65 (s, 3H), 0.75 - 0.65 (m, 4H).Example 74 4-((2-(dimethyl phosphoryl)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide

[0360]

[0361] Step 1: 6-chloro-4-((2-(dimethyl phosphoryl)phenyl)amino)-N-methoxy nicotinamide (73-c, 100 mg, 0.28 mmol), 2-amino-6-fluoropyridine (62 mg, 0.56 mmol), cesium carbonate (170 mg, 0.52 mmol), XantPhos(23 mg, 0.04mmol) and Pd 2 (dba) 3 (27mg, 0.03 mmol) were added to anhydrous dioxane (2ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 125°C with stirring for 3 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((2-(dimethyl phosphoryl)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide

[0362] (74, 15 mg, 0.035 mmol, 12.5% yield). MS Calcd: 429.14; MS Found: 430.31 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.82 (s, 1H), 10.55 (s, 1H), 9.73 (s, 1H), 8.43 (s, 1H), 7.90 - 7.81 (m, 1H), 7.77-7.71 (m, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.52-7.49 (m, 2H), 7.37-7.32 (m, 1H), 7.16 (s, 1H), 6.47 (dd, J = 8.0, 6.4 Hz, 1H), 3.63 (s, 3H), 1.70 (s, 3H), 1.67 (s, 3H).Example 75 4-((3-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(cyclopropylcarboxamido)-N-methoxy nicotinamide

[0363]

[0364] Step 1: To N-methyl methanesulfonamide (0.5 g, 4.58 mmol) dissolved in 20 mL of N,N-dimethyl formamide was added sodium hydride (0.24 g, 10 mmol) portionwise. The mixture was heated to 55 °C with continuous stirring for 2 hours, followed by adding 2-fluoro-3-trifluoromethyl nitrobenzene (32182-a, 0.8 g, 4.57 mmol) with continuous stirring at that temperature for 6 hours. Upon indication of completed reaction by TLC, the reaction mixture was added with water (40 mL), extracted with ethyl acetate (30 mL x 2) and washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA:PE=1:1) to provide N-(2-chloro-6-nitrophenyl)-N-methyl methanesulfonamide (75-b, 0.7 g, 2.65 mmol, 58% yield). MS Calcd: 264.68; MS Found: 265.14 ([M+H] +< ).

[0365] Step 2: N-(2-chloro-6-nitrophenyl)-N-methyl methanesulfonamide (75-b, 0.6 g, 2.27 mmol), ammonium chloride (0.75 g, 14 mmol) and iron powder (0.6 g, 10.71 mmol) were sequentially added to 20 mL of mixed solvent of water and ethanol(1:4). The mixture was stirred under reflux for 6 hours. Upon indication of completed reaction by TLC, the reaction mixture was filtered by suction. The filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (EA:PE=1:1) to provide N-(2-amino-6-chloro phenyl)-N-methyl methanesulfonamide (75-c, 0.42 g, 1.8 mmol, 79% yield). MS Calcd: 234.70; MS Found: 235.10 ([M+H] +< ). Step 3: To 10 ml of anhydrous N,N-dimethylacetamide were added N-(2-amino-6-chloro phenyl)-N-methyl methanesulfonamide (75-c, 0.42 g, 1.8 mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 409 mg, 1.86 mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (7.2 ml, 7.2 mmol), and stirred at room temperature for 3 hours. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (20 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-4-((3-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (75-d, 0.7 g, 1.6 mmol, 88% yield). MS Calcd: 418.03; MS Found: 417.03 ([M-H] -< ).

[0366] Step 4: 6-chloro-4-((3-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (75-d, 0.21 g, 0.5 mmol), cyclopropylcarboxamide (85 mg, 1 mmol), cesium carbonate (325 mg, 1 mmol), XantPhos(46mg, 0.05mmol) and Pd 2 (dba) 3 (43mg, 0.075 mmol) were added to anhydrous dioxane (4 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 125°C with stirring for 3 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:10) to provide the title compound: 4-((3-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(cyclopropylcarboxamido)-N-methoxy nicotinamide (75, 40mg, 0.085mmol, 16% yield). MS Calcd: 467.10; MS Found: 468.35 ([M+H] +< ). 1< HNMR (400 MHz, DMSO-d 6 )δ11.88 (s, 1H), 10.85 (s, 1H), 10.13 (s, 1H), 8.39 (s, 1H), 7.92 (s, 1H), 7.51 - 7.34 (m, 3H), 3.72 (s, 3H), 3.17 (s, 3H), 3.12 (s, 3H), 2.00 - 1.93 (m, 1H), 0.78 - 0.76 (m, 4H).Example 76 4-((3-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide

[0367]

[0368] Step 1: 6-chloro-4-((3-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (75-d, 0.15 g, 0.36 mmol), 2-amino-6-fluoropyridine (80 mg, 0.75 mmol), cesium carbonate (230 mg, 0.72 mmol), XantPhos(31mg, 0.054mmol) and Pd 2 (dba) 3 (32mg, 0.036 mmol) were added to anhydrous dioxane (2 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 125°C with stirring for 3 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:10) to provide the title compound: 4-((3-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide (76, 30mg, 0.06mmol, 40% yield). MS Calcd: 494.09; MS Found: 495.34 ([M+H] +< ). 1< HNMR (400 MHz, DMSO-d 6 )δ11.83 (s, 1H), 10.19 (s, 1H), 10.09 (s, 1H), 8.37 (s, 1H), 7.84 - 7.76 (m, 1H), 7.64 - 7.62 (m, 2H), 7.48 - 7.44 (m, 2H), 7.36 (dd, J = 8.0, 1.6 Hz, 1H), 6.58 (dd, J = 8.0, 2.4 Hz, 1H), 3.73 (s, 3H), 3.21 (s, 3H), 3.14 (s, 3H).Example 77 4-((3-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide

[0369]

[0370] Step 1: 6-chloro-4-((3-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (75-d, 0.15 g, 0.36 mmol), 2-amino-5-fluoropyridine (80 mg, 0.75 mmol), cesium carbonate (230 mg, 0.72 mmol), XantPhos(31mg, 0.054mmol) and Pd 2 (dba) 3 (32mg, 0.036 mmol) were added to anhydrous dioxane (2 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 125°C with stirring for 3 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:10) to provide the title compound: 4-((3-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide (77, 30mg, 0.06mmol, 40% yield). MS Calcd: 494.09; MS Found: 495.31 ([M+H]+). 1< H NMR (400 MHz, DMSO-d 6 )δ11.80 (s, 1H), 10.17 (s, 1H), 9.89 (s, 1H), 8.35 (s, 1H), 8.15 (s, 1H), 7.72 - 7.57 (m, 4H), 7.49 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 3.72 (s, 3H), 3.21 (s, 3H), 3.14 (s, 3H).Example 78 4-((3-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy-6-((2-methoxy pyridin-3-yl)amino)nicotinamide

[0371]

[0372] Step 1: 6-chloro-4-((3-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (75-d, 0.2 g, 0.48 mmol), 2-methoxy-3-aminopyridine (120 mg, 0.96 mmol), cesium carbonate (312 mg, 0.96 mmol), XantPhos(42mg, 0.042mmol) and Pd 2 (dba) 3 (48mg, 0.044 mmol) were added to anhydrous dioxane (3 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 125°C with stirring for 3 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:10) to provide the title compound: 4-((3-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy-6-((2-methoxy pyridin-3-yl)amino)nicotinamide (78, 30mg, 0.059mmol, 12% yield). MS Calcd: 506.11; MS Found: 507.40 ([M+H]+). 1< H NMR (400 MHz, DMSO-d 6 )δ11.76 (s, 1H), 10.01 (s, 1H), 8.62 (s, 1H), 8.50 (dd, J = 8.0, 1.6 Hz, 1H), 8.29 (s, 1H), 7.73 (dd, J = 5.6, 2.0 Hz, 1H), 7.52 (dd, J = 8.0, 1.6 Hz, 1H), 7.46 - 7.41 (m, 1H), 7.33 (dd, J = 8.0, 1.6 Hz, 1H), 6.93 (dd, J = 8.0, 1.6 Hz, 1H), 6.83 (s, 1H), 3.91 (s, 3H), 3.72 (s, 3H), 3.20 (s, 3H), 3.13 (s, 3H).Example 79 4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(cyclopropylcarboxamido)-N-methoxy nicotinamide

[0373]

[0374] Step 1: To N-methyl methanesulfonamide (0.5 g, 4.5 mmol) dissolved in 20 mL N,N-dimethyl formamide was added with sodium hydride (0.24 g, 10 mmol) portionwise. After that the reaction mixture was heated to 55 °C with continuous stirring for 2 hours, added with 4-chloro-2-fluoro-1-nitrobenzene (79-a, 800 mg, 4.5 mmol) with continuous stirring at that temperature for 6 hours. Upon indication of completed reaction by TLC, the reaction mixture was added with water (40 mL), and extracted with ethyl acetate (30 mL x 2) and washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA:PE=1:1) to provide N-(5-chloro-2-nitrophenyl)-N-methyl methanesulfonamide (79-b, 0.52 g, 1.96 mmol, 43% yield). MS Calcd: 264.00; MS Found: 263.15 ([M-H] -< ).

[0375] Step 2: N-(5-chloro-2-nitrophenyl)-N-methyl methanesulfonamide (79-b, 0.19 g, 0.71 mmol), ammonium chloride (0.25 g, 4.7 mmol) and iron powder (0.2 g, 3.57 mmol) were sequentially added to 10 mL of mixed solvent of water and ethanol (1:4), and stirred under reflux for 6 hours. Upon indication of completed reaction by TLC, the reaction mixture was filtered by suction. The filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography to provide N-(2-amino-5-chloro phenyl)-N-methyl methanesulfonamide (79-c, 0.15 g, 0.64 mmol, 90% yield). MS Calcd: 234.02; MS Found: 235.13 ([M+H] +< ).

[0376] Step 3: To 10 ml of anhydrous N,N-dimethylacetamide were added N-(2-amino-5-chloro phenyl)-N-methyl methanesulfonamide (79-c, 0.15 g, 0.64 mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 140 mg, 0.63 mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (2.5 ml, 2.5 mmol) and stirred at room temperature for 3 hours. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5 and extracted with ethyl acetate (20 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (79-d, 240 mg, 0.57 mmol, 89% yield). MS Calcd: 418.03; MS Found: 417.03 ([M-H] -< ).

[0377] Step 4: 6-chloro-4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (79-d, 120 mg, 0.29 mmol), cyclopropylcarboxamide (50 mg, 0.58 mmol), cesium carbonate (190 mg, 0.58 mmol), XantPhos(25mg, 0.04mmol) and Pd 2 (dba) 3 (27mg, 0.029 mmol) were added to anhydrous dioxane (2 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 125°C with stirring for 3 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(cyclopropylcarboxamido)-N-methoxy nicotinamide (79, 20mg, 0.042mmol, 14% yield). MS Calcd: 467.10; MS Found: 468.31 ([M+H] +< ). 1< HNMR (400 MHz, DMSO-d 6 )δ11.78 (s, 1H), 10.82 (s, 1H), 10.04 (s, 1H), 8.35 (s, 1H), 7.90 (s, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.49 - 7.48 (m, 2H), 3.72 (s, 3H), 3.15 (s, 3H), 3.13 (s, 3H), 1.97 (m, 1H), 0.79 - 0.76 (m, 4H).Example 80 4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide

[0378]

[0379] Step 4: 6-chloro-4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (79-d, 120 mg, 0.29 mmol), 2-amino-5-fluoropyridine (65 mg, 0.58 mmol), cesium carbonate (190 mg, 0.58 mmol), XantPhos(25mg, 0.04mmol) and Pd 2 (dba) 3 (27mg, 0.029 mmol) were added to anhydrous dioxane (2 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 125°C with stirring for 3 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((4-chloro-2-(N-methyl methanesulfonamido)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxy nicotinamide (80, 20mg, 0.04mmol, 13% yield). MS Calcd: 494.09; MS Found: 493.23 ([M-H] -< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.51 (s, 1H), 10.15 (s, 1H), 9.86 (s, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 7.67 - 7.56 (m, 6H), 3.71 (s, 3H), 3.17 (s, 3H), 3.16 (s, 3H).Example 81 6-(cyclopropylcarboxamido)-N-methoxy-4-((4-methyl-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide

[0380]

[0381] Step 1: To N-methyl methanesulfonamide (0.5 g, 5.5 mmol) dissolved in 20 mL of N,N-dimethyl formamide was added sodium hydride (0.29g, 12 mmol) portionwise. After that the reaction was heated to 55 °C with continuous stirring for 2 hours, added with 4-bromo-2-fluoro-1-nitrobenzene (81-a, 1.2 g, 5.5 mmol) with continuous stirring at that temperature for 6 hours. Upon indication of completed reaction by TLC, the reaction mixture was added with water (40 mL), and extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA:PE=1:5) to provide N-(5-bromo-2-nitrophenyl)-N-methyl methanesulfonamide (81-b, 0.9 g, 2.9 mmol, 52% yield). MS Calcd: 307.95; MS Found: 307.00 ([M-H] -< ).

[0382] Step 2: N-(5-bromo-2-nitrophenyl)-N-methyl methanesulfonamide (81-b, 0.308 g, 1 mmol), methyl boronic acid (78 mg, 1.3 mmol), potassium phosphate (0.53 g, 2.5 mmol) and Pd(dppf)Cl 2 (0.036 g, 0.05 mmol) were sequentially added to 8 mL of solution of dioxane / water (7 / 1). The atmosphere of the mixture was evacuated to vacuum and replaced with nitrogen three times, and stirred at 110°C for 6 hours. Upon indication of completed reaction by TLC, the mixture was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA:PE=1:1) to provide N-methyl-N-(5-methyl-2-nitrophenyl)methyl methanesulfonamide (81-c, 0.1 g, 0.4 mmol, 40% yield).

[0383] Step 3: N-methyl-N-(5-methyl-2-nitrophenyl)methyl methanesulfonamide (81-c, 0.1 g, 0.4 mmol), ammonium chloride (0.25 g, 4.7 mmol) and iron powder (0.2 g, 3.57 mmol) were sequentially added to 10 mL of mixed solvent of water and ethanol (1:4). The mixture was stirred under reflux for 6 hours. Upon indication of completed reaction by TLC, the reaction mixture was filtered by suction. The filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography to provide colorless oil N-(2-amino-5-methyl phenyl)-N-methyl methanesulfonamide (81-d, 0.06 g, 0.28 mmol, 70% yield). MS Calcd: 214.28; MS Found: 215.16 ([M+H] +< ).

[0384] Step 4: To 10 ml of anhydrous N,N-dimethylacetamide were added N-(2-amino-5-methyl phenyl)-N-methyl methanesulfonamide (81-d, 0.06 g, 0.28 mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 61 mg, 0.28 mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (1.12 ml, 1.12 mmol), and stirred at room temperature for 3 hours. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-N-methoxy-4-((4-methyl-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (81-e, 80 mg, 0.2 mmol, 71% yield), as a tan oil. MS Calcd: 398.08; MS Found: 399.34 ([M+H] +< ).

[0385] Step 5: 6-chloro-N-methoxy-4-((4-methyl-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (81-e, 80 mg, 0.2 mmol), cyclopropylcarboxamide (34 mg, 0.4 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos(18mg, 0.03mmol) and Pd 2 (dba) 3 (20mg, 0.02 mmol) were added to anhydrous dioxane (2 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 125°C with stirring for 3 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-N-methoxy-4-((4-methyl-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (81, 10mg, 0.02mmol, 10% yield). MS Calcd: 447.16; MS Found: 446.25 ([M-H] -< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.77 (s, 1H), 10.75 (s, 1H), 9.90 (s, 1H), 8.31 (s, 1H), 7.84 (s, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.21 (dd, J = 8.0, 2.0 Hz, 1H), 3.71 (s, 3H), 3.11 (s, 3H), 3.09 (s, 3H), 2.33 (s, 3H), 1.99 - 1.93 (m, 1H), 0.78 - 0.71 (m, 4H).Example 82 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-(N-methyl methanesulfonamido)-3-(trifluoromethyl)phenyl)amino)nicotinamide

[0386]

[0387] Step 1: To N-methyl methanesulfonamide (0.4 g, 3.6 mmol) dissolved in 20 mL of N,N-dimethyl formamide was added sodium hydride (0.2 g, 8.3 mmol) portionwise. After that, the reaction mixture was heated to 55°C with continuous stirring for 2 hours, added with 2-fluoro-3-trifluoromethyl nitrobenzene (82-a, 750 mg, 3.6 mmol), and continuously at that temperature stirred for 6 hours. Upon indication of completed reaction by TLC, the reaction mixture was added with water (40 mL), and extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA:PE=1:1) to provide N-methyl-N-(2-nitro-6-(trifluoromethyl)phenyl)methanesulfonamide (82-b, 1.0 g, 3.3 mmol, 92% yield). MS Calcd: 298.24; MS Found: 321.14 ([M+Na +< ] +< ).

[0388] Step 2: N-methyl-N-(2-nitro-6-(trifluoromethyl)phenyl)methanesulfonamide (82-b, 0.65 g, 2.18 mmol), ammonium chloride (0.75 g, 14 mmol) and iron powder (0.6 g, 10.71 mmol) were sequentially added to 20 mL of mixed solvent of water and ethanol (1:4). The mixture was stirred under reflux for 6 hours. Upon indication of completed reaction by TLC, the reaction mixture was filtered by suction. The filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography to provide N-(2-amino-6-(trifluoromethyl)phenyl)-N-methyl methanesulfonamide (82-c, 0.5 g, 1.86 mmol, 85% yield), as a colorless oil. MS Calcd: 268.25; MS Found: 269.18 ([M+H] +< ).

[0389] Step 3: To 10 ml of anhydrous N,N-dimethylacetamide were added N-(2-amino-6-(trifluoromethyl)phenyl)-N-methyl methanesulfonamide (82-c, 0.5 g, 1.86 mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1 , 409 mg, 1.86 mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (7.6 ml, 7.6 mmol), and stirred at room temperature for 3 hours. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (20 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-N-methoxy-4-((2-(N-methyl methanesulfonamido)-3-(trifluoromethyl)phenyl)amino)nicotinamide (82-d, 410 mg, 0.9 mmol, 49% yield), as a yellow powdery solid. MS Calcd: 452.83; MS Found: 453.27 ([M+H] +< ).

[0390] Step 4: 6-chloro-N-methoxy-4-((2-(N-methyl methanesulfonamido)-3-(trifluoromethyl)phenyl)amino)nicotinamide (82-d, 130 mg, 0.29 mmol), cyclopropylcarboxamide (50 mg, 0.58 mmol), cesium carbonate (190 mg, 0.58 mmol), XantPhos(25mg, 0.04mmol) and Pd 2 (dba) 3 (27mg, 0.029 mmol) were added to anhydrous dioxane (2 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 125°C with stirring for 3 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-(N-methyl methanesulfonamido)-3-(trifluoromethyl)phenyl)amino)nicotinamide (82, 20mg, 0.039mmol, 13% yield). MS Calcd: 501.48; MS Found: 502.40 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.92 (s, 1H), 10.87 (s, 1H), 10.09 (s, 1H), 8.41 (s, 1H), 7.82 (s, 1H), 7.80 (d, J= 2.8 Hz, 1H), 7.66 - 7.60 (m, 2H), 3.73 (s, 3H), 3.20 (s, 3H), 3.05 (s, 3H), 1.99 - 1.93 (m, 1H), 0.64-0.60 (m, 4H).Example 83 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)-3-(trifluoromethyl)phenyl)amino)nicotinamide

[0391]

[0392] Step 1: 6-chloro-N-methoxy-4-((2-(N-methyl methanesulfonamido)-3-(trifluoromethyl)phenyl)amino)nicotinamide (82-d, 130 mg, 0.29 mmol), 2-amino-6-fluoropyridine (65 mg, 0.58 mmol), cesium carbonate (190 mg, 0.58 mmol), XantPhos(25mg, 0.04mmol) and Pd 2 (dba) 3 (27mg, 0.029 mmol) were added to anhydrous dioxane (2 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 125°C with stirring for 3 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)-3-(trifluoromethyl)phenyl)amino)nicotinamide (83, 30 mg, 0.056mmol, 19% yield). MS Calcd: 528.48; MS Found: 529.40 ([M+H] +< ). 1< HNMR (400 MHz, DMSO-d 6 )δ11.86 (s, 1H), 10.09 (s, 1H), 10.07 (s, 1H), 8.40 (s, 1H), 7.94 (dd, J = 7.2, 2.4 Hz, 1H), 7.84 - 7.78 (m, 1H), 7.67 - 7.61 (m, 2H), 7.49 - 7.46 (m, 2H), 6.57 (dd, J = 8.0, 2.4 Hz, 1H), 3.73 (s, 3H), 3.23 (s, 3H), 3.07 (s, 3H).Example 84 6-((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)-3-(trifluoromethyl)phenyl)amino)nicotinamide

[0393]

[0394] Step 1: 6-chloro-N-methoxy-4-((2-(N-methyl methanesulfonamido)-3-(trifluoromethyl)phenyl)amino)nicotinamide (82-d, 130 mg, 0.29 mmol), 2-amino-5-fluoropyridine (65 mg, 0.58 mmol), cesium carbonate (190 mg, 0.58 mmol), XantPhos(25mg, 0.04mmol) and Pd 2 (dba) 3 (27mg, 0.029 mmol) were added to anhydrous dioxane (2 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 125°C with stirring for 3 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methyl methanesulfonamido)-3-(trifluoromethyl)phenyl)amino)nicotinamide (84, 30 mg, 0.056mmol, 19% yield). MS Calcd: 528.48; MS Found: 529.40 ([M+H] +< ). 1< HNMR (400 MHz, DMSO-d 6 )δ11.83 (s, 1H), 10.09 (s, 1H), 9.89 (s, 1H), 8.38 (s, 1H), 8.14 (d, J= 3.2 Hz, 1H), 7.92 (dd J = 8.4, 1.6 Hz, 1H), 7.73 - 7.69 (m, 2H), 7.66 - 7.59 (m, 2H), 7.46 (s, 1H), 3.73 (s, 3H), 3.24 (s, 3H), 3.06 (s, 3H).Example 85 6-(cyclopropylcarboxamido)-4-((3-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide

[0395]

[0396] Step 1: To N-methyl methanesulfonamide (0.5 g, 5.5 mmol) dissolved in 20 mL of N,N-dimethyl formamide was added sodium hydride (0.29g, 12 mmol) portionwise. After that, the reaction mixture was heated to 55°C with continuous stirring for 2 hours, added with 4-bromo-2-fluoro-1-nitrobenzene (85-a, 0.8 g, 5.5 mmol), with continuous stirring at that temperature for 6 hours. Upon indication of completed reaction by TLC, the reaction mixture was added with water (40 mL), and extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA:PE=1:5) to provide N-(2-bromo-6-nitrophenyl)-N-methyl methanesulfonamide (85-b, 0.9 g, 2.9 mmol, 52% yield), as a pale yellow solid. MS Calcd: 307.95; MS Found: 306.95 ([M-H] -< ).

[0397] Step 2: N-(2-bromo-6-nitrophenyl)-N-methyl methanesulfonamide (85-b, 0.5 g, 1.6 mmol), cyclopropyl boronic acid (180 mg, 2.2 mmol), potassium phosphate (850 g, 4 mmol) and Pd(dppf)Cl 2 (0.06 g, 0.08 mmol) were sequentially added to 8 mL of solution of dioxane / water (7 / 1). The atmosphere of the mixture was evacuated and replaced with nitrogen three times, and stirred at 110°C for 6 hours. Upon indication of completed reaction by TLC, the mixture was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA:PE=1:1) to provide N-(2-cyclopropyl-6-nitrophenyl)-N-methyl methanesulfonamide (85-c, 0.23 g, 0.85 mmol, 53% yield), as a colorless oil. MS Calcd: 270.07; MS Found: 293.19 ([M+Na] +< ).

[0398] Step 3: N-(2-cyclopropyl-6-nitrophenyl)-N-methyl methanesulfonamide (85-c, 0.23 g, 0.85 mmol), ammonium chloride (0.25 g, 4.7 mmol) and iron powder (0.2 g, 3.57 mmol) were sequentially added to 10 mL of mixed solvent of water and ethanol (1:4) ∘ The mixture was stirred under reflux for 6 hours. Upon indication of completed reaction by TLC, the reaction mixture was filtered by suction. The filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA =1:1) to provide N-(2-amino-6-cyclopropyl phenyl)-N-methyl methanesulfonamide (85-d, 0.17 g, 0.7 mmol, 83% yield), as a colorless oil. MS Calcd: 240.09; MS Found: 241.17 ([M+Na] +< ).

[0399] Step 4: To 10 ml of anhydrous N,N-dimethylacetamide were added N-(2-amino-6-cyclopropyl phenyl)-N-methyl methanesulfonamide (85-d, 0.17 g, 0.7 mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 160 mg, 0.72 mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (2.8 ml, 2.8 mmol), and stirred at room temperature for 3 hours. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (PE:EA =1:1) to provide 6-chloro-4-((3-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (85-e, 240 mg, 0.56 mmol, 80% yield), as a tan oil. MS Calcd: 424.10; MS Found: 425.35 ([M+H] +< ).

[0400] Step 5: 6-chloro-4-((3-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (85-e, 120 mg, 0.3mmol), cyclopropylcarboxamide (50g, 0.6mmol), cesium carbonate (190g, 0.6mmol), XantPhos(26mg, 0.045 mmol) and Pd 2 (dba) 3 (27mg, 0.03 mmol) were added to anhydrous dioxane (2 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 125°C with stirring for 3 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-4-((3-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (85, 20mg, 0.04mmol, 14% yield). MS Calcd: 473.17; MS Found: 474.38 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.82 (s, 1H), 10.78 (s, 1H), 9.98 (s, 1H), 8.36 (s, 1H), 7.87 (s, 1H), 7.32 - 7.20 (m, 2H), 6.70 (dd, J = 8.0, 1.6 Hz, 1H), 3.73 (s, 3H), 3.19 (s, 3H), 3.10 (s, 3H), 2.18 - 2.12 (m, 1H), 1.99 - 1.92 m, 1H), 1.07 - 0.97 (m, 2H), 0.83 - 0.65 (m, 6H).Example 86 4-((3-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(6-fluoropyridin-2-yl)-N-methoxy nicotinamide

[0401]

[0402] Step 1: 6-chloro-4-((3-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-N-methoxy nicotinamide (85-e, 120 mg, 0.3mmol), 2-amino-6-fluoropyridine (67g, 0.6mmol), cesium carbonate (190g, 0.6mmol), XantPhos(26mg, 0.045 mmol) and Pd 2 (dba) 3 (27mg, 0.03 mmol) were added to anhydrous dioxane (2 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 125°C with stirring for 3 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 4-((3-cyclopropyl-2-(N-methyl methanesulfonamido)phenyl)amino)-6-(6-fluoropyridin-2-yl)-N-methoxy nicotinamide (86, 20mg, 0.04mmol, 14% yield). MS Calcd: 500.16; MS Found: 499.28 ([M-H] -< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.82 (s, 1H), 10.02 (d, J = 5.4 Hz, 2H), 8.35 (s, 1H), 7.84 - 7.76 (m, 1H), 7.57 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 6.70 (d, J = 7.4 Hz, 1H), 6.55 (d, J = 10.1 Hz, 1H), 3.73 (s, 3H), 3.23 (s, 3H), 3.12 (s, 3H), 2.16 (dq, J = 8.4, 5.3, 4.2 Hz, 1H), 1.10 - 0.95 (m, 2H), 0.89 - 0.80 (m, 1H), 0.65 (dt, J = 9.0, 4.5 Hz, 1H).Example 87 6-(cyclopropylcarboxamido)-N-methoxy-4-((3-(1-methyl-1H-pyrazol-4-yl)-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide

[0403]

[0404] Step 1: N-(2-bromo-6-nitrophenyl)-N-methyl methanesulfonamide (85-b, 0.25 g, 0.8 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (220 mg, 1.04 mmol), potassium phosphate (424 mg, 2 mmol) and Pd(dppf)Cl 2 (0.03 g, 0.04 mmol) were sequentially added to 8 mL of solution of dioxane / water (7 / 1). The atmosphere of the mixture was evacuated to vacuum and replaced with nitrogen three times, followed by stirring at 110°C for 6 hours. Upon indication of completed reaction by TLC, the mixture was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA:PE=2:1) to provide N-methyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-6-nitrophenyl)methanesulfonamide (87-a, 0.16 g, 0.51 mmol, 64% yield). MS Calcd: 310.07; MS Found: 311.21 ([M+H] +< ).

[0405] Step 2: N-methyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-6-nitrophenyl)methanesulfonamide (87-a, 0.16 g, 0.51 mmol), ammonium chloride (0.25 g, 4.7 mmol) and iron powder (0.2 g, 3.57 mmol) were sequentially added to 10 mL of mixed solvent of water and ethanol (1:4), followed by stirring under reflux for 6 hours. Upon indication of completed reaction by TLC, the reaction mixture was filtered by suction. The filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA =1:2) to provide N-(2-amino-6-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl methanesulfonamide (87-b, 0.12 g, 0.42 mmol, 84% yield). MS Calcd: 280.10; MS Found: 281.24 ([M+H] +< ).

[0406] Step 3: To 10 ml of anhydrous N,N-dimethylacetamide were added N-(2-amino-6-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl methanesulfonamide (87-b, 0.12 g, 0.42 mmol) and 4,6-dichloro-N-methoxy nicotinamide (int-1, 100 mg, 0.45 mmol). The mixture was added at room temperature with a solution of LiHMDS in tetrahydrofuran (1.72 ml, 1.72 mmol), and stirred at room temperature for 3 hours. Upon indication of completed reaction by TLC, the mixture was adjusted with aqueous hydrochloride (1N) to pH 5, and extracted with ethyl acetate (10 ml x 3). The combined organic layers were dried, concentrated and then purified by column chromatography (EA) to provide 6-chloro-N-methoxy-4-((3-(1-methyl-1H-pyrazol-4-yl)-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (87-c, 140 mg, 0.56 mmol, 80% yield). MS Calcd: 464.10; MS Found: 465.38 ([M+H] +< ).

[0407] Step 4: 6-chloro-N-methoxy-4-((3-(1-methyl-1H-pyrazol-4-yl)-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (87-c, 70 mg, 0.15 mmol), cyclopropylcarboxamide (25 mg, 0.3 mmol), cesium carbonate (100 mg, 0.3mmol), XantPhos(26mg, 0.045 mmol) and Pd 2 (dba) 3 (27mg, 0.03 mmol) were added to anhydrous dioxane (2 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 125°C with stirring for 3 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-(cyclopropylcarboxamido)-N-methoxy-4-((3-(1-methyl-1H-pyrazol-4-yl)-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (87, 10mg, 0.019mmol, 12% yield). MS Calcd: 513.18; MS Found: 514.35 ([M+H] +< ). 1< H NMR (400 MHz, DMSO-d 6 )δ11.83 (s, 1H), 10.79 (s, 1H), 10.01 (s, 1H), 8.39 (s, 1H), 8.07 (s, 1H), 7.43 - 7.37 (m, 2H), 7.33 (dd, J = 6.4, 3.2 Hz, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 3.14 (s, 3H), 2.82 (s, 3H), 1.95 - 1.92 (m, 1H), 0.76 - 0.74 (m, 4H).Example 88 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((3-(1-methyl-1H-pyrazol-4-yl)-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide

[0408]

[0409] Step 1 6-chloro-N-methoxy-4-((3-(1-methyl-1H-pyrazol-4-yl)-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (87-c, 70 mg, 0.15 mmol), 2-amino-6-fluoropyridine (35 mg, 0.3 mmol), cesium carbonate (100 mg, 0.3mmol), XantPhos(26mg, 0.045 mmol) and Pd 2 (dba) 3 (27mg, 0.03 mmol) were added to anhydrous dioxane (2 ml). After the atmosphere of the mixture was evacuated to vacuum and refilled with nitrogen, the reaction mixture was heated to 125°C with stirring for 3 hours, and filtered by suction. The filtrate was concentrated and purified by high performance preparative thin layer chromatography (MeOH:DCM=1:20) to provide the title compound: 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((3-(1-methyl-1H-pyrazol-4-yl)-2-(N-methyl methanesulfonamido)phenyl)amino)nicotinamide (88, 10mg, 0.019mmol, 12% yield). MS Calcd: 540.17; MS Found: 541.37 ([M+H] +< ). 1H NMR (400 MHz, DMSO-d 6 )δ11.84 (s, 1H), 10.02(s, 1), 9...

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: wherein: X is CRa; Y is CH; Ra is hydrogen; R0 is hydrogen; R1 is selected from the group consisting of C1-6 alkyl optionally substituted by from one to seven R1a groups; R1a is selected from the group consisting of deuterium, F and Cl; R2 is selected from the group consisting of C3-6 cycloalkyl-C(O)-, C3-6 heterocyclyl-C(O)- wherein the C3-6 heterocyclyl contains from one to two heteroatoms selected from N, O and S, phenyl, and 5-6 membered heteroaryl containing from one to two heteroatoms selected from N, O and S, wherein the C3-6 cycloalkyl, C3-6 heterocyclyl containing from one to two heteroatoms selected from N, O and S, phenyl, and 5-6 membered heteroaryl containing from one to two heteroatoms selected from N, O and S are respectively and optionally substituted by from one to two R2a groups; R2a is selected from the group consisting of C1-6 alkyl, halogen, C1-6 alkoxy, C3-6 cycloalkyl, cyano, halo C1-6 alkyl, C1-6 alkyl substituted by hydroxyl group, and C1-6 alkyl-S(O)2-; R3 is selected from the group consisting of phenyl, pyridinyl, 2-pyridinonyl and indazolyl, wherein the phenyl, pyridinyl, 2-pyridinonyl and indazolyl are optionally substituted by from one to three R3a groups; R3a is selected from the group consisting of F, Cl, Br, I, CN, -NO2, -ORb, -SRb,-C(O)ORb, -C(O)NRbRc, -NRbC(O)Rc, -NRbC(O)ORc, -NRbC(O)NRcRc, -NRbS(O)2Rc, -S(O)2Rc, -S(O)2NRcRc, -P(O)RbRc, C1-6 alkyl optionally substituted by from one to three Rd groups, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 5-9 membered heteroaryl containing from one to three heteroatoms selected from N, O and S and optionally substituted by from one to three Rd groups, and 5-6 membered saturated heterocyclyl containing from one to two heteroatoms selected from N, O and S; Rb is selected from the group consisting of hydrogen, C1-6 alkyl optionally substituted by from one to three Rd groups, and 4-6 membered saturated heterocyclyl containing from one to two oxygen atoms; Rc is selected from the group consisting of hydrogen, C1-6 alkyl and C3-6 cycloalkyl; Rd is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I,-OCF3, -CF3, -(CH2)r-CN, -NO2, -ORe, -(CH2)r-CORc, -NReRe, -NReC(O)ORc, C1-C6 alkyl, C3-6 cycloalkyl, and -(CH2)r-phenyl; Re is hydrogen; p is 0, 1 or 2, and r is 0, 1, 2, 3 or 4.

2. The compound or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein: X is CRa; Ra is hydrogen; R0 is hydrogen; R1 is selected from the group consisting of methyl, ethyl, isopropyl, t-butyl, trideuterated methyl and 2,2,2-trifluoroethyl; R2 is selected from the group consisting of cyclopropylcarbonyl, phenyl, pyrazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, wherein the cyclopropylcarbonyl, phenyl, pyrazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl are optionally substituted by from one to two R2a groups; R2a is selected from the group consisting of methyl, F, methoxy, cyclopropyl, cyano, -CF3, hydroxymethyl and methanesulfonyl; R3 is selected from the group consisting of phenyl, pyridinyl, 2-pyridinonyl and indazolyl, wherein the phenyl, pyridinyl, 2-pyridinonyl and indazolyl are optionally substituted by from one to three R3a groups; R3a is selected from the group consisting of F, Cl, Br, I, CN, -ORb, -C(O)NRbRc,-NRbS(O)2Rc, -S(O)2Rc, -S(O)2NRcRc, -P(O)RbRc, C1-6 alkyl optionally substituted by from one to three Rd groups, C2-6 alkynyl, C3-6 cycloalkyl, 5-9 membered heteroaryl containing from one to three heteroatoms selected from N, O and S and optionally substituted by from one to three Rd groups, and 5-6 membered saturated heterocyclyl containing from one to two heteroatoms selected from N, O and S; Rb is selected from the group consisting of hydrogen; methyl, ethyl and isopropyl, each optionally substituted by from one to three Rd groups; and Rc is selected from the group consisting of hydrogen, methyl, and cyclopropyl; Rd is selected from the group consisting of deuterium, F, Cl, hydroxyl, methyl, cyclopropyl and isopropyl.

3. The compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2, wherein: X is CH; R1 is selected from the group consisting of methyl, ethyl, isopropyl, t-butyl, trideuterated methyl and 2,2,2-trifluoroethyl; R2a is selected from the group consisting of methyl, F, methoxy, cyclopropyl, cyano, -CF3, hydroxymethyl and methanesulfonyl; R3a is selected from the group consisting of F, Cl, Br, I, CN, -ORb, -C(O)NRbRc,-NRbS(O)2Rc, -S(O)2Rc, -S(O)2NRcRc, -P(O)RbRc, C1-3 alkyl optionally substituted by from one to three Rd groups, C2-4 alkynyl, C3-5 cycloalkyl, 5-9 membered heteroaryl containing from one to three heteroatoms selected from N, O and S and optionally substituted by Rd group, and 5-6 membered saturated heterocyclyl containing from one to two heteroatoms selected from N, O and S, wherein the 5-9 membered heteroaryl containing from one to three heteroatoms selected from N, O and S is selected from the group consisting of thiazolyl, benzimidazolyl, pyrazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl and pyrazinyl, wherein the 5-6 membered saturated heterocyclyl containing from one to two heteroatoms selected from N, O and S is selected from the group consisting of morpholinyl and piperidinyl; Rb is selected from the group consisting of hydrogen; methyl, ethyl and isopropyl, each optionally substituted by from one to three Rd groups; and Rc is selected from the group consisting of hydrogen, methyl and cyclopropyl; Rd is selected from the group consisting of deuterium, F, Cl, hydroxyl, methyl, cyclopropyl and isopropyl.

4. The compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2, wherein: R2 is selected from the group consisting of 5. The compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2, wherein: R3 is selected from the group consisting of:

6. The compound or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein: X is CH; Y is CH; R0 is hydrogen; R1 is ethyl; R2 is selected from the group consisting of pyridinyl, pyrimidinyl, -C(O)-C3-6 cycloalkyl and -C(O)-C3-6 heterocyclyl, wherein the C3-6 heterocyclyl contains from one to two heteroatoms selected from N, O and S; wherein the C3-6 cycloalkyl and C3-6 heterocyclyl are respectively and optionally substituted by from one to three R2a groups; R2a is selected from the group consisting of C1-6 alkyl, halogen, C1-6 alkoxy, C3-6 cycloalkyl, cyano, halo C1-6 alkyl, C1-6 alkyl substituted by hydroxyl group, and C1-6 alkyl-S(O)2-; R3 is phenyl optionally substituted by from one to three R3a groups; R3a is selected from the group consisting of -(CH2)r-ORb, -NRbS(O)pRc, F, Cl, C1-6 alkyl, C3-6 cycloalkyl, triazolyl, pyrazolyl, pyrimidinyl and pyrazinyl; wherein the C1-6 alkyl, C3-6 cycloalkyl, triazolyl, pyrazolyl, pyrimidinyl and pyrazinyl are, respectively and independently, optionally substituted by from one to three Rd groups; Rb is selected from the group consisting of hydrogen, C1-6 alkyl optionally substituted by from one to three Rd groups, and 4-6 membered saturated heterocyclyl containing from one to two oxygen atoms; Rc is selected from the group consisting of hydrogen, C1-6 alkyl and C3-6 cycloalkyl; Rd is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, OCF3, CF3, -(CH2)r-CN, NO2, ORe, -(CH2)r-CORc, -NReRe, -NReC(O)ORc, C1-C6 alkyl, C3-6 cycloalkyl, and -(CH2)r-phenyl; Re is hydrogen; p is 0, 1 or 2, and r is 0, 1, 2, 3 or 4.

7. The compound or a pharmaceutically acceptable salt thereof as claimed in claim 6, wherein, R2a is selected from the group consisting of methyl, F, methoxy, cyclopropyl, cyano, -CF3, hydroxymethyl and methanesulfonyl.

8. The compound or a pharmaceutically acceptable salt thereof as claimed in claim 6, wherein, R2 is selected from the following structures: and 9. The compound or a pharmaceutically acceptable salt thereof as claimed in claim 6, wherein, Rb is selected from the group consisting of hydrogen; methyl, ethyl, and isopropyl, each optionally substituted by from one to three Rd groups; and 10. The compound or a pharmaceutically acceptable salt thereof as claimed in claim 6, wherein, Rc is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl.

11. The compound or a pharmaceutically acceptable salt thereof as claimed in claim 6, wherein, Rd is selected from the group consisting of F, Cl, hydroxyl, methyl, cyclopropyl and -CH2CN.

12. The compound or a pharmaceutically acceptable salt thereof as claimed in claim 6, wherein, R3 is selected from the following structures:

13. The compound or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the compound is selected from the group consisting of: Compound #StructureCompound #Structure2 157 4 159 10 160 12 162 13 166 14 167 16 170 18 171 19 173 20 174 21 175 22 176 29 177 36 178 38 179 41 180 42 181 43 182 44 183 45 185 46 186 47 187 60 188 61 189 62 190 63 197 68 198 69 200 70 202 79 204 80 194 81 192 90 193 95 203 97 230 98 229 101 201 102 191 106 205 108 207 109 208 110 209 111 210 112 211 113 212 114 213 115 214 116 215 118 217 119 218 125 219 126 220 127 222 128 223 129 224 130 225 131 226 132 234 133 235 134 236 136 237 138 238 139 239 141 240 142 242 143 243 144 244 145 245 146 248 151 258 153 268 154 273 155 277 156 279 14. A pharmaceutical composition, comprising the compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-13, and optionally comprising, a pharmaceutical acceptable carrier and / or adjuvant and / or diluent.

15. The compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-13 or the pharmaceutical composition as claimed in claim 14, for use in treating and / or preventing a related disease mediated by TYK2; preferably, the related disease mediated by TYK2 includes inflammatory disease, autoimmune disease and cancer.