Novel bicyclic compounds as RAD51 inhibitors

Abstract

The present invention relates to novel bicyclic compounds of formula (I), their pharma- ceutically acceptable salts, solvates, polymorphs, tautomers, optical isomers and geometric isomers thereof as inhibitors of RAD51 inhibitors.

Description

[Technical field]

[0001] The present invention relates to a RAD51 inhibitor Agent and The present invention relates to novel bicyclic compounds of formula (I), their pharma- ceutically acceptable salts, solvates, polymorphs, tautomers thereof, stereoisomers, It relates to optical isomers and geometric isomers. [ka]

[0002] The present invention also relates to processes for the preparation of the novel bicyclic compounds of formula (I), pharmaceutical compositions containing them, and their use in the treatment of cancer. [Background technology]

[0003] The RAD51 gene encodes the RAD51 recombinase, a protein essential for DNA double-strand break resolution by homologous recombination. Diseases associated with RAD51 include Fanconi Anemia, Complementation Group R, and Mirror Movements 2. Its associated pathways include meiosis and resolution of D-loop structures. Gene Ontology (GO) annotations associated with this gene include identical protein binding and protein C-terminal binding. An important paralog of this gene is DMC1.

[0004] Members of the RAD51 family are highly similar to bacterial RecA and Saccharomyces cerevisiae RAD51, and are known to be involved in DNA homologous recombination and repair. The protein can interact with the ssDNA binding proteins RPA and RAD52 and is thought to play a role in DNA homologous pairing and strand transfer. The protein has also been found to interact with BRCA1 and BRCA2, which may be important in the cellular response to DNA damage. BRCA2 has been shown to regulate both the subcellular localization and DNA binding ability of this protein. RAD51 function is severely compromised during BRCA2 inactivation, which can lead to genomic instability and tumorigenesis.

[0005] In humans, RAD51 is a 339 amino acid protein that plays a major role in DNA homologous recombination during double-strand break repair. This process involves ATP-dependent DNA strand exchange in which the template strand invades the base-paired strand of a homologous DNA molecule. RAD51 is involved in the search for homology and the strand-pairing step of the process.

[0006] Unlike other proteins involved in DNA metabolism, the RecA / Rad51 family forms helical nucleoprotein filaments on DNA [Structure. 14(6):983-92]. This protein can interact with the ssDNA-binding proteins RPA, BRCA2, PALB2 [Nature Structural & Molecular Biology. 17(10):1247-54] and RAD52.

[0007] The RAD51 protein has a central role in homology-directed repair: it catalyzes strand transfer between a damaged sequence and its undamaged homolog, allowing error-free resynthesis of the damaged region, which is important to prevent spontaneous mutations during DNA replication and repair.

[0008] Numerous studies have reported that RAD51 is overexpressed in different cancers, and in many of these studies, increased expression of RAD51 correlates with decreased patient survival.

[0009] WO 2016 / 140971A1 of the Regents of The University of California discloses compounds having the following formula as RAD51 inhibitors: [ka]

[0010] WO 2021 / 116999A1 from the Italian Institute of Technology discloses a compound of formula (Ia): [ka]

[0011] J. Med. Chem. 2020, 63, 2588-2619 discloses compounds of the formula as RAD5 inhibitors. [ka]

[0012] The treatment of cancer continues to be a challenge, despite the fact that several drugs have been approved with different mechanisms.In view of this, there is an unmet need for new drugs that can treat such diseases more effectively.The present inventors herein describe novel bicyclic compounds as RAD51 inhibitors. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] International Publication No. 2016 / 140971A1 Brochure [Patent Document 2] International Publication No. 2021 / 116999A1 Brochure [Non-patent literature]

[0014] [Non-Patent Document 1] Structure. 14(6):983-92 [Non-Patent Document 2] Nature Structural & Molecular Biology. 17(10):1247-54 [Non-Patent Document 3] J.Med.Chem. 2020, 63, 2588-2619 Summary of the Invention [Problem to be solved by the invention]

[0015] The object of the present invention is to provide novel bicyclic compounds of formula (I), their pharma- ceutically acceptable salts, solvates, polymorphs, tautomers, and the like, as RAD51 inhibitors. stereoisomers, The objective of the present invention is to provide optical and geometric isomers.

[0016] Yet another object of the present invention is to provide processes for the preparation of the novel bicyclic compounds of formula (I) and pharmaceutical compositions containing them.

[0017] Yet another object of the present invention is to provide novel bicyclic compounds of formula (I) for use in the treatment of cancer. [Means for solving the problem]

[0018] The present invention relates to novel bicyclic compounds of formula (I), their pharma- ceutically acceptable salts, solvates, polymorphs, tautomers, stereoisomers, providing optical and geometric isomers, [ka] Ring A is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 6- to 10-membered ring system, and 3- to 10-membered heterocyclyl; Ring B is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl; Ring C is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl; Any of A or B or C may be substituted by one or more identical or different substituents; R 1 and R 2 is present or absent and, if present, is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, -C(O)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, any of the above groups being optionally substituted by one or more identical or different substituents; R 3 is selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; R 4 is hydrogen, alkyl, -C(O)-R 4a any of the above groups may be optionally substituted with one or more identical or different substituents; R 4a is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, any of the above groups being optionally substituted with one or more identical or different substituents; R 5 and R 6 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, cycloalkyl, alkoxy, acylamino, alkylamino, dialkylamino, heterocyclyl, any of the foregoing groups being optionally substituted with one or more of the same or different substituents; R 7 is selected from the group consisting of hydrogen, alkyl, "n" is 0 to 2.

[0019] In another embodiment, the present invention provides a process for the preparation of novel bicyclic compounds of formula (I).

[0020] In yet another embodiment, the present invention provides pharmaceutical compositions comprising the novel bicyclic compounds of formula (I) and processes for their preparation.

[0021] In yet another embodiment, the present invention relates to novel bicyclic compounds of formula (I) and their pharma- ceutically acceptable derivatives, salts and derivatives thereof, as medicaments for the treatment of diseases such as cancer, by inhibiting RAD51. three-dimensional The use of the isomers, as well as mixtures thereof in any ratio, is provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] According to another embodiment, specifically provided is a ring A with a bonded ring, specifically [ka] It is a compound of formula (I) represented by:

[0023] In another embodiment, the present invention provides novel compounds of formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable three-dimensional isomers, wherein "x" is selected from O, S or N; "y" and "z" are independently selected from N, CR', where R' is selected from hydrogen, halogen, and alkyl; Ring C is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl, each of which may be substituted by one or more identical or different substituents; R 3is selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; R 4 is hydrogen, alkyl, -C(O)-R 4a any of the above groups may be optionally substituted with one or more identical or different substituents; R 4a is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, any of the above groups being optionally substituted with one or more identical or different substituents; R 5 and R 6 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, cycloalkyl, alkoxy, acylamino, alkylamino, dialkylamino, heterocyclyl, any of the foregoing groups being optionally substituted with one or more of the same or different substituents; R 7 is selected from the group consisting of hydrogen, alkyl, "n" is 0 to 2.

[0024] In another aspect, the present invention provides novel compounds of formula (Ib) [ka] or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable three-dimensional With respect to the isomers, Ring C is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl, each of which may be substituted by one or more identical or different substituents; R 1 and R 2 is present or absent and, if present, is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, -C(O)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, any of the above groups being optionally substituted by one or more identical or different substituents; R 3 is selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; R 4 is hydrogen, alkyl, -C(O)-R 4a any of the above groups may be optionally substituted with one or more identical or different substituents; R 4a is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, any of the above groups being optionally substituted with one or more identical or different substituents; R 5 and R 6 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, cycloalkyl, alkoxy, acylamino, alkylamino, dialkylamino, heterocyclyl, any of the foregoing groups being optionally substituted with one or more of the same or different substituents; R 7 is selected from the group consisting of hydrogen, alkyl, "n" is 0 to 2.

[0025] In another aspect, the present invention provides novel compounds of formula (Ic) [ka] or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable three-dimensional With respect to the isomers, Ring C is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl, each of which may be substituted by one or more identical or different substituents; "A", "B", "C", and "D" are independently selected from O, S, N, C(R')2, or any two of A and B or C and D represent CR' forming a double bond, where R' is absent or, if present, is selected from hydrogen, halogen, alkyl; R 3 is selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; R 4 is hydrogen, alkyl, -C(O)-R 4a any of the above groups may be optionally substituted with one or more identical or different substituents; R 4a is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, any of the above groups being optionally substituted with one or more identical or different substituents; R 5 and R 6 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, cycloalkyl, alkoxy, acylamino, alkylamino, dialkylamino, heterocyclyl, any of the foregoing groups being optionally substituted with one or more of the same or different substituents; R 7 is selected from the group consisting of hydrogen, alkyl, "n" is 0 to 2.

[0026] In another aspect, the present invention provides novel compounds of formula (Id) [ka] or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable three-dimensional With respect to the isomers, Ring C is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl, each of which may be substituted by one or more identical or different substituents; R 1 and R 2is present or absent and, if present, is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, -C(O)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, any of the above groups being optionally substituted by one or more identical or different substituents; R 3 is selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; R 4 is hydrogen, alkyl, -C(O)-R 4a any of the above groups may be optionally substituted with one or more identical or different substituents; R 4a is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, any of the above groups being optionally substituted with one or more identical or different substituents; R 5 and R 6 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, cycloalkyl, alkoxy, acylamino, alkylamino, dialkylamino, heterocyclyl, any of the foregoing groups being optionally substituted with one or more of the same or different substituents; R 7 is selected from the group consisting of hydrogen, alkyl, "n" is 0 to 2.

[0027] According to another embodiment, specifically provided is a compound in which ring C is specifically [ka] It is a compound of formula (I) represented by:

[0028] Without limiting the scope of the present invention, the following definitions are provided for understanding the detailed description of the invention.

[0029] The term "alkyl" as used herein refers to a hydrocarbon chain that may be a straight or branched chain containing the indicated number of carbon atoms, such as, but not limited to, C1-C 12 An alkyl group may have from 1 to 12 (including the end points) carbon atoms in it. 12 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and isohexyl. Alkyl groups can be unsubstituted or substituted with one or more suitable groups.

[0030] The term "alkenyl" as used herein refers to a linear, branched, unsaturated C1-C6 hydrocarbyl group containing a double bond, including, but not limited to, ethenyl, propenyl, butenyl. An alkenyl group can be unsubstituted or substituted with one or more suitable groups.

[0031] The term "alkynyl" as used herein refers to a linear, branched, unsaturated C1-C6 hydrocarbyl group containing a triple bond, including, but not limited to, acetylenyl, propynyl, butynyl. Alkynyl groups can be unsubstituted or substituted with one or more suitable groups.

[0032] The term "amino" as used herein refers to, but is not limited to, an -N- group in which the nitrogen atom is bonded to a hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, or any suitable group. An amino group can be unsubstituted or substituted with one or more suitable groups.

[0033] The term "aryl" as used herein refers to, but is not limited to, an optionally substituted monocyclic, bicyclic or polycyclic aromatic carbocyclic ring system of about 6 to 14 carbon atoms. 14Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthyl. An aryl group can be unsubstituted or substituted with one or more suitable groups.

[0034] The term "halogen" or "halo" includes fluorine, chlorine, bromine or iodine.

[0035] "Hydroxy" refers to the group --OH.

[0036] The term "cycloalkyl" as used herein refers to, but is not limited to, a non-aromatic, saturated or partially saturated, monocyclic or polycyclic 3-10 membered ring system. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Cycloalkyl groups can be unsubstituted or substituted with one or more suitable groups.

[0037] The term "heterocyclyl" as used herein refers to, but is not limited to, a 3-10 membered non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2, NH, and C(O). Exemplary heterocycloalkyl groups include tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dioxolanyl, 1,4-dioxanyl, azetadine, oxetane, thietane, and the like. Heterocycloalkyl groups can be unsubstituted or substituted with one or more suitable groups.

[0038] The term "heteroaryl" as used herein refers to, but is not limited to, an unsaturated, monocyclic, bicyclic or polycyclic aromatic ring system containing at least one heteroatom selected from oxygen, sulfur and nitrogen. 10Examples of heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, thiadiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic heteroaryl groups include those in which a phenyl, pyridine, pyrimidine, or pyridazine ring is fused to a 5- or 6-membered monocyclic heterocyclyl ring having one nitrogen atom, either with one or two nitrogen atoms in the ring, one oxygen atom or one sulfur atom in the ring, or one O or S ring atom. Heteroaryl groups can be unsubstituted or substituted with one or more suitable groups.

[0039] "Optionally substituted or substituted," as used herein, means that at least one hydrogen atom of an optionally substituted group is replaced with a halogen, nitro, cyano, hydroxy, hydroxylalkyl, amino, oxo (=O), thiooxo (=S), -N(C1-C3 alkyl)(C1-C6 alkyl), -N(C1-C3 alkyl)C(O)(C1-C6 alkyl), -NH ... ), -NHC(O)(cycloalkyl), -NHC(O)(aryl), -NHC(O)(heterocyclyl), -NHC(O)(heteroaryl), -NHC(O)H, -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)NH(cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(heteroaryl), -C(O)N(C1-C6 alkyl)(C1-C6 alkyl), -S This means substituted with suitable substituents including, but not limited to, (O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)NH(cycloalkyl), -S(O)2NH(cycloalkyl), carboxy, -C(O)O(C1-C6 alkyl), -C(O)(C1-C6 alkyl), =N-OH, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl.

[0040] Specific compounds of the present invention that do not depart from the scope of the above definition given under the compounds of formula (I) and specific compounds derived from formula (I) are summarized herein in the following table encompassing the entire range of compounds within the compounds of formula (I).

[0041] 1. 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one 2. 6-chloro-3-(1-(cyclopropanecarbonyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one 3. 6-chloro-3-(5-(4-methoxyphenyl)-1-(tetrahydro-2H-pyran-4-carbonyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one 4. 6-chloro-3-(5-(4-methoxyphenyl)-1-(tetrahydrofuran-3-carbonyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one 5. 6-chloro-3-(5-(4-methoxyphenyl)-1-methyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one 6. 6-Chloro-4-methyl-3-(5-(1-methyl-1H-indol-6-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 7. 6-Chloro-3-(5-( 6 -Methoxy Pyridin-3-yl )-1-Propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one 8. N-(4-(3-(6-chloro-4-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-5-yl)phenyl)propionamide 9. 3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-1,5-naphthyridin-2(1H)-one 10. 4-Methyl-3-(5-(1-methyl-1H-indole- 6 -yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 11. 3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one 12. 4-Methyl-3-(5-(1-methyl-1H-indol-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 13. 3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-1,8-naphthyridin-2(1H)-one 14. 6-(5-(4-Methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-5-methylpyrido-[2,3-d]pyrimidin-7(8H)-one 15. 6-Bromo-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one 16. 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-1,5-naphthyridin-2(1H)-one 17. 6-Chloro-3-(5-(4-methoxyphenyl)-1-propionyl -4,5-dihydro -1H-pyrazol-3-yl)quinolin-2(1H)-one 18. 6-Chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-1,4-dimethylquinolin-2(1H)-one 19. 4-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)isoquinolin-3(2H)-one 20. 5-(5-(4-Methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno-[2,3-b]pyridin-6(7H)-one 21. 5-(5-(6-methoxypyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 22. 5-(5-(4-Methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 23. 6-Chloro-4-cyclopropyl-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 24. 6-Chloro-4-methyl-3-(5-(1-methyl-1H-indol-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 25. 5-(5-(5-methoxypyridin-2-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 26. 4-Methyl-5-(5-(6-oxo-1,6-dihydropyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 27. 5-(5-(4-fluorophenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 28. 5-(5-(4-chlorophenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 29. 5-(5-(5-methoxythiophen-2-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 30. 5-(5-(2-Methoxythiazol-5-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 31. 5-(5-(5-bromothiophen-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 32. 4-Methyl-5-(5-phenyl-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 33. 4-Methyl-5-(1-propionyl-5-(thiophen-3-yl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 34. 5-(5-(4-bromothiophen-2-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 35. 4-Methyl-5-(1-propionyl-5-(pyridin-4-yl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 36. 4-Methyl-5-(1-propionyl-5-(pyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 37. 4-Methyl-5-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 38. 4-Methyl-5-(5-(4-(4-methylpiperazin-1-yl)phenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 39. 5-(5-(4-(dimethylamino)phenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 40. 3-Chloro-5-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 41. 5-(5-(5-methylthiophen-2-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 42. 4-Methyl-5-(1-propionyl-5-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 43. 5-(5-(4-(difluoromethyl)phenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 44. 5-(5-(4-ethylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 45. 4-Methyl-5-(5-(6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 46. ​​4-Methyl-5-(1-propionyl-5-(4-(pyrrolidin-1-yl)phenyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 47. 5-(5-(4-cyclopropylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 48. 4-Methyl-5-(5-(2-methylthiazol-4-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 49. 5-(5-(4-isopropylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 50. 5-(5-(4,6-dimethylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 51. 4-Methyl-5-(5-(2-methylpyrimidin-5-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 52. 5-(5-(5-chloro-6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 53. 5-(5-(4-Methoxy-6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 54. 5-(5-(5,6-dimethylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 55. 5-(5-(5-fluoro-6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 56. 5-(5-(4-chloro-6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 57. 4-Methyl-5-(5-(2-methylthiazol-5-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 58. 5-(5-cyclohexyl-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 59. 6-Chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 60. 4-Methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 61. 6-Chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,5-naphthyridin-2(1H)-one 62. 5-(1-acetyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-7,7a-dihydrothieno[2,3-b]pyridin-6(7H)-one 63. 5-(1-isobutyryl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-7,7a-dihydrothieno[2,3-b]pyridin-6(7H)-one 64. 4-Methyl-5-(5-(p-tolyl)-1-(2,2,2-trifluoroacetyl)-4,5-dihydro-1H-pyrazol-3-yl)-7,7a-dihydrothieno[2,3-b]pyridin-6(7H)-one 65. 5-(5-(2-chloro-4-methylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 66. 5-(5-(2-fluoro-4-methylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 67. 6-Chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one 68. 5-(5-(4-(fluoromethyl)phenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 69. 4-Methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,5-naphthyridin-2(1H)-one 70. 2,4-Dimethyl-5-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 71. 5-(5-benzyl-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 72. 2-Chloro-4-methyl-5-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 73. 4-Methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one 74. 4-Methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one 75. 4,7-Dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 76. 4,5-Dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 77. 4-Methyl-7-morpholino-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 78. 4,8-Dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one 79. 6-Chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one 80. 7-Chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 81. 4,6-Dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one 82. 4-Methyl-7-(4-methylpiperazin-1-yl)-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 83. 7-Fluoro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 84. 4,7-Dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one 85. 4-Methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,6-naphthyridin-2(1H)-one 86. 4-Methyl-7-morpholino-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one 87. 7-(2-Methoxyethoxy)-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one also or a pharma- ceutically acceptable salt thereof. Young is pharma- ceutically acceptable three-dimensional Isomers.

[0042] Some compounds of the present invention have been separated into their pure enantiomers, which are shown in the table below.

[0043] [Table 1(1)] [Table 1(2)] [Table 1(3)] [Table 1(4)]

[0044] A further embodiment of the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable derivative, salt, and three-dimensional The pharmaceutical uses of the isomers, as well as mixtures thereof in any ratio, are included.

[0045] Unless otherwise indicated, the general formula of compound (I) is intended to encompass tautomers and all stereoisomers, optical isomers and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and racemates thereof, as well as mixtures of different proportions of the separate enantiomers, mixtures of diastereomers or mixtures of any of the above-mentioned forms in which such isomers and enantiomers exist, as well as salts, e.g. pharma- ceutically acceptable salts thereof, and solvates thereof, e.g. hydrates, e.g. solvates and hydrates of the free compounds or solvates and hydrates of the salts of the above compounds.

[0046] In general, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example, by separation of the corresponding mixtures, by using stereochemically pure starting materials, and / or by stereoselective synthesis. It is well known in the art how to prepare optically active forms, for example, by resolution of racemates, or by synthesis starting from, for example, optically active starting materials, and / or by using chiral reagents.

[0047] The present invention relates to at least one compound according to formula (I) and / or its pharma- ceutically usable derivatives, salts, tautomers and three-dimensional Further provided are pharmaceutical compositions comprising the isomers (including mixtures thereof in any ratio), optionally an additional second active ingredient, and excipients.

[0048] The term "pharmaceutical acceptable salt" or "pharmaceutical acceptable derivative" is understood to mean an active ingredient comprising a compound of formula (I) in one of the salt forms, in particular when this salt form confers improved pharmacokinetic properties to the active ingredient compared to the free form of the active ingredient or any other salt form of the active ingredient previously used. A pharmaceutical acceptable salt form of an active ingredient can also provide this active ingredient for the first time with desirable pharmacokinetic properties that it did not have initially, and can even positively affect the pharmacodynamics of this active ingredient with regard to its therapeutic effect in the body.

[0049] The term "positional isomer" refers to a positional isomer, which is a category of structural isomers in which a position or a substituent changes position on a parent structure. In this specification, the term positional isomer essentially includes all positional isomers, either as a pure positional isomer or a mixture of two or more positional isomers, without departing from the scope of the compound of formula (I). Since the pharmaceutical activity of the positional isomers of the compounds of the present invention may differ, it may be desirable to use positional isomers. In these cases, positional isomers can be separated at any possible stage by processes well known to those skilled in the art, either as intermediates or final products, or even used as such in synthesis.

[0050] The term "tautomer" refers to a compound of formula (I) of the present invention in which any hydrogen atom is replaced by a hydroxyl group on the carbon bearing the double bond. The present invention includes all possible tautomeric forms.

[0051] The pharmaceutical formulations may be adapted for administration in any desired suitable manner, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) manner. Such formulations may be prepared, for example, by combining the active ingredient with the excipient(s) or adjuvant(s) using any process known in the pharmaceutical art.

[0052] Pharmaceutical formulations suitable for oral administration can be administered as discrete units, such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or effervescent foods; or oil-in-water or water-in-oil liquid emulsions.

[0053] For example, for oral administration as a tablet or capsule, the active ingredient component can be combined with an oral, non-toxic, pharma- ceutically acceptable inert excipient, such as ethanol, glycerol, water, etc. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a pharmaceutical excipient com- minuted in a similar manner, such as, for example, an edible carbohydrate, such as starch or mannitol. Flavorings, preservatives, dispersing agents, and dyes may also be present.

[0054] Capsules are manufactured by preparing a powder mixture as described above and filling formed gelatin shells with the powder mixture. Glidants and lubricants, such as highly dispersed silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation. Disintegrants or solubilizers, such as agar-agar, calcium carbonate or sodium carbonate, can also be added to improve the availability of the medicament after the capsule is ingested.

[0055] In addition, suitable binders, lubricants and disintegrants and dyes can be incorporated into the mixture as well, if desired or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, sweeteners made from corn, natural and synthetic gums such as gum arabic, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. Tablets are formulated, for example, by preparing a powder mixture, granulating or dry-pressing the mixture, adding lubricants and disintegrants, and compressing the entire mixture to obtain tablets. Powder mixtures are prepared by mixing the compound, milled in a suitable manner, with a diluent or base as described above, and optionally with binders, such as carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone, solution retarders, such as paraffin, absorption promoters, such as quaternary salts, and / or absorbents, such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder, such as syrup, starch paste, acadia mucilage, or solutions of cellulose or polymeric materials, and forcing it through a sieve. As an alternative to granulation, the powder mixture can be passed through a tablet press to obtain lumps of non-uniform shape which are broken up to form granules. The granules can be lubricated by the addition of stearic acid, stearates, talc or mineral oil to prevent sticking to the tablet die. The lubricated mixture is then compressed to obtain tablets. The active ingredient can also be mixed with a free flowing inert excipient and then directly compressed to give tablets without granulation or dry pressing steps. A transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymeric material and a gloss layer of wax may be present.Dyes can be added to these coatings so that different dosage units can be distinguished.

[0056] Oral liquids, such as solutions, syrups and elixirs, can be prepared in the form of dosage units, so that a given quantity contains a pre-specified amount of the compound.Syrups can be prepared by dissolving the compound in an aqueous solution with suitable flavor, while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether, preservatives, flavor additives, such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, can also be added.

[0057] Dosage unit formulations for oral administration can, if desired, be microencapsulated. The formulations can also be prepared in such a way that the release is extended or delayed, for example, by coating or embedding particulate material in polymers, wax, etc.

[0058] The formulation may be in the form of a liposome delivery system, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from suitable lipids or phospholipids, or both, such as cholesterol, stearylamine or phosphatidylcholine.

[0059] Pharmaceutical formulations adapted for transdermal administration can be administered as separate plasters for extended, intimate contact with the recipient's epidermis. Thus, for example, the active ingredient can be delivered from the plaster by iontophoresis, as generally described in Pharmaceutical Research, 3(6), 318 (1986).

[0060] Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, liquids, pastes, gels, sprays, aerosols or oils.

[0061] For the treatment of eye or other external tissue, such as mouth and skin, the preparation is preferably applied as a topical ointment or cream.When formulated to give an ointment, the active ingredient can be used with either a paraffinic or water-miscible cream base.Alternatively, the active ingredient can be formulated to give a cream with an oil-in-water cream base or a water-in-oil base.

[0062] Pharmaceutical formulations adapted for topical application to the eye include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, in particular an aqueous solvent.

[0063] Pharmaceutical formulations adapted for topical application in the mouth include lozenges, pastilles and mouthwashes.

[0064] Pharmaceutical formulations adapted for rectal administration can be administered in the form of suppositories or enemas.

[0065] Pharmaceutical formulations adapted for nasal administration in which the carrier material is a solid include, for example, a coarse powder having a particle size in the range 20 to 500 microns (20-500 μm), which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container containing the powder held close to the nose. Formulations suitable for administration as a nasal spray or nasal drops which comprise a liquid as the carrier material include solutions of the active ingredient in water or oil.

[0066] Pharmaceutical formulations adapted for administration by inhalation encompass fine particle dusts or mists, which can be generated by various types of pressurized dispensers associated with an aerosol, nebulizer or inhaler.

[0067] Pharmaceutical preparations suitable for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray preparations. Pharmaceutical preparations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats, and solutes to render the preparation isotonic with the blood of the recipient to be treated, as well as aqueous and non-aqueous sterile suspensions which may contain suspending media and thickening agents. The preparations may be administered in single-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) state, so that it is only necessary to add a sterile carrier liquid, for example water for injection purposes, immediately prior to use.

[0068] Injection solutions and suspensions prepared according to formulations may be prepared from sterile powders, granules and tablets.

[0069] Of course, in addition to the components particularly mentioned above, the formulations may also include other agents conventional in the art having regard to the particular type of formulation. Thus, for example, formulations suitable for oral administration may include flavoring agents.

[0070] The therapeutically effective amount of the compound of formula (I) and other active ingredients depends on several factors, including, for example, the age and weight of the animal, the exact disease state requiring treatment and its severity, the nature of the formulation and the method of administration, and is ultimately determined by the treating physician or veterinarian. However, the effective amount of the compound is generally in the range of 0.1-100 mg per kg of recipient (mammal) body weight per day, and more typically in the range of 1-10 mg per kg of body weight per day. Thus, the actual amount per day for an adult mammal weighing 70 kg is usually 70-700 mg, which can be administered as individual doses per day, or in a series of partial doses (e.g., 2, 3, 4, 5 or 6 times, etc.) per day, usually so that the total amount per day is the same. The effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as a fraction (fraction) of the effective amount of the compound itself.

[0071] In a further aspect, the present invention relates to processes for the preparation of the novel compounds of formula (I).

[0072] The novel bicyclic compounds of formula (I) may be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred experimental conditions (i.e., reaction temperature, time, moles of reagents, solvent, etc.) are given, it will be understood that other experimental conditions may also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art using routine optimization procedures. Furthermore, by utilizing the procedures described in detail, one skilled in the art can prepare further compounds of the invention claimed in the accompanying documents. Unless otherwise specified, all temperatures are in degrees Celsius (°C).

[0073] Another embodiment of the present invention provides methods useful for preparing compounds of formula (I), which are generally depicted in the schemes below. One of skill in the art will recognize that any of the schemes can be adapted to produce compounds of formula (I) and pharma-ceutically acceptable salts of compounds of formula (I) according to the present invention. All symbols / variables are as defined below unless otherwise indicated.

[0074] [ka] EXAMPLES

[0075] Although the present invention has been described by some preceding examples, it should not be construed as being limited thereby. Rather, the present invention encompasses the general scope disclosed above. Various modifications and embodiments can be made without departing from the spirit and scope of the present invention.

[0076] Example 1: Synthesis of 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one [ka] Step a: Synthesis of 1-(2-amino-5-chlorophenyl)ethan-1-one (1a): To a stirred solution of 2-amino-5-chlorobenzonitrile (5.0 g, 32.00 mmol) in dry THF (50 mL) at 0 °C, methylmagnesium bromide (32.8 mL, 96.0 mmol, 3 M in diethyl ether) was slowly added dropwise over about 15-20 minutes (min). The reaction mixture was heated at 60 °C for 16 hours (h) and the progress of the reaction was monitored by TLC. The reaction mixture was slowly brought to room temperature, cooled to 0 °C, quenched with 2 N HCl (100 mL), and then extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with water (100 mL), brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography eluting with 10-20% ethyl acetate in hexane to give the title compound as a solid. Yield: 3.2 g (60%); 1 H-NMR (300MHz, CDCl3): δ 7.64 (d, J = 2.4 Hz, 1H), 7.22-7.18 (dd, J = 2.4 Hz and 6.6 Hz, 1H), 6.60 (d, J = 8.7 Hz, 1H), 6.26 (bs, 2H), 2.55 (s, 3H).

[0077] Step b: Synthesis of 3-acetyl-6-chloro-4-methylquinolin-2(1H)-one (1b): To a stirred solution of 1-(2-amino-5-chlorophenyl)ethan-1-one (3.2 g, 18.80 mmol) in toluene (32 mL) at room temperature, ethyl acetoacetate (3.68 g, 28.30 mmol) and cerium chloride heptahydrate (3.51 g, 9.40 mmol) were added and the reaction mixture was refluxed for 16 h. The reaction progress was monitored by TLC. The reaction mixture was brought to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 40-50% ethyl acetate in hexane as eluent to give the title compound as a yellow solid. Yield: 1.0 g (23%); 1 H-NMR (300MHz, CDCl3): δ 11.18(bs,1H),7.73(d,J=2.1Hz,1H),7.50(dd,J=2.4Hz and 6.3Hz,1H),7.23(d,J=8.7Hz,1H),2.62(s,3H),2.44(s,3H).

[0078] Step c: Synthesis of (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (1c): To a stirred solution of 3-acetyl-6-chloro-4-methylquinolin-2(1H)-one (1.0 g, 4.20 mmol) in methanol (20 mL), anisaldehyde (0.63 g, 4.60 mmol) was added, the reaction mixture was cooled to 0° C., and then 25% aqueous sodium hydroxide (20 mL) was added dropwise slowly over 10-15 min. The reaction mixture was stirred at room temperature for 16 h and the progress of the reaction was monitored by TLC. The reaction mixture was cooled to 0° C., acidified with 6 N HCl (to pH approx. 4) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (25 mL), dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 30-40% ethyl acetate in hexanes as eluent to give the title compound as an off-white solid. Yield: 0.60 g (61%); 1 H-NMR(300MHz,DMSO-d6):δ 12.07(bs,1H),7.85(d,J=2.1Hz,1H),7.70(d,J=8.7Hz,2H),7.62(dd,J=6.3H z,2.4Hz,1H),7.44-7.37(m,2H),6.98-6.89(m,3H),3.79(s,3H),2.30(s,3H). MS:m / z 354.1[M+H] + .

[0079] Step d: 6-Chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (1d): To a stirred solution of (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (600 mg, 1.69 mmol) in propionic acid (6 mL) was added hydrazine hydrate (0.6 mL) and the reaction mixture was refluxed for 3 h. The reaction progress was monitored by TLC. The pH of the reaction mixture was adjusted to 10 with saturated NaHCO3 solution and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (25 mL), brine solution (25 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to give the crude compound, which was purified by prep. HPLC to give the title compound as an off-white solid. Yield: 80 mg (11%); 1 H-NMR(300MHz,DMSO-d6):δ 12.75(bs,1H),7.94(d,J=2.1Hz,1H),7.58(dd,J=6.6Hz,2.1Hz,1H),7.35(d,J=8.7Hz,1H),7.30(d,J=6.6Hz,2H),6.90(d,J=8.7Hz,2H),5.53(d d,J=4.5Hz and 7.2Hz,1H),3.80-3.76(m,4H),3.21(dd,J=4.5Hz and 14.1Hz,1H),2.69(q,J=7.2Hz,2H),2.61(s,3H),1.14(t,J=7.5Hz,3H);LCMS:m / z 424.2[M+H] + .

[0080] Example 2: Synthesis of 6-chloro-3-(1-(cyclopropanecarbonyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one [ka] Step a: 6-chloro-3-(5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (2a): To a solution of (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (200 mg, 0.56 mmol) in ethanol (10 mL) was added 99% hydrazine hydrate (0.63 g, 0.68 mmol) and refluxed for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature and ethanol was evaporated under reduced pressure. The residue was diluted with water (25 mL) and the resulting solid was filtered, washed with water and dried under vacuum to give the title compound. Yield: 110 mg (53%); 1 H-NMR (300 MHz, DMSO-d6): δ 11.90 (bs, 1H), 7.80 (d, J = 2.1 Hz, 1H), 7.57-7.53 (m, 1H), 7.40-7.28 (m, 3H), 6.91 (d, J = 10.5 Hz, 2H), 4.82-4.75 (m, 1H), 3.74 (s, 3H), 3.27-3.25 (m, 1H), 2.91-2.82 (m, 1H), [3H singlet merged into DMSO peak]. LC-MS: m / z 368.2 [M+H] + .

[0081] Step b: 6-chloro-3-(1-(cyclopropanecarbonyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (2): To a stirred solution of (6-chloro-3-(5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one) (110 mg, 0.29 mmol) in DCM (10 mL) at 0° C. was added pyridine (71 mg, 0.89 mmol), DMAP (5 mg) and cyclopropylcarbonyl chloride (47 mg, 0.44 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was extracted with DCM (50 mL) and water (20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 50-60% ethyl acetate in hexanes as eluent to give the title compound as an off-white solid. Yield: 0.030 g (23%); 1 H-NMR(300MHz,DMSO-d6):δ 12.45(bs,1H),7.76(d,J=2.1Hz,1H),7.46(dd,J=2.1Hz and 6.6Hz,1H),7.37(d,J=8.4Hz,2H),7.18(d,J=8.7Hz,1H),6.90(d,J=8.7Hz,2H),5.60(dd ,J=4.2Hz and 7.8Hz,1H),3.86-3.76(m,4H),3.39(dd,J=4.2Hz and 14.1Hz,1 H),2.66(s,3H),2.63-2.57(m,1H),1.04-1.02(m,2H),0.88-0.79(m,2H). LCMS: m / z 436.2 [M+H].

[0082] Example 3: Synthesis of 6-chloro-3-(5-(4-methoxyphenyl)-1-(tetrahydro-2H-pyran-4-carbonyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one [ka] The title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(1-(cyclopropanecarbonyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 2) using 6-chloro-3-(5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one and tetrahydro-2H-pyran-4-carbonyl chloride as starting materials. Yield: 43%; 1 H-NMR(400MHz,DMSO-d6):δ 12.07(bs,1H),7.89(d,J=2.0Hz,1H),7.62(dd,J=2.4Hz and 8.8Hz,1H),7.36( d,J=8.4Hz,1H),7.21(d,J=8.4Hz,2H),6.91(d,J=8.8Hz,2H),5.47(dd,J=4.4 Hz and 12.0Hz, 1H), 3.86-3.84 (m, 2H), 3.81-3.76 (m, 1H), 3.74 (s, 3H), 3.38-3. 36(m,2H),3.27-3.25(m,1H),3.08-3.02(m,1H),1.63-1.59(m,4H);LCMS:m / z 480.20[M+H] + (The three protons merged into the DMSO peak.)

[0083] Example 4: Synthesis of 6-chloro-3-(5-(4-methoxyphenyl)-1-(tetrahydrofuran-3-carbonyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one [ka] The title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(1-(cyclopropanecarbonyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 2) using 6-chloro-3-(5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one and tetrahydrofuran-3-carbonyl chloride as starting materials. Yield: 47%. 1 H-NMR(400MHz,DMSO-d6):δ 12.07(bs,1H),7.90(d,J=2.0Hz,1H),7.62(dd,J=2.4Hz and 8.8Hz,1H),7.37(d,J=8.8Hz,1H),7.24(d,J=8.4Hz,2H),6.91(d,J=8.4Hz,2H),5.49-5 .46(m,1H),3.92-3.89(m,1H),3.87-3.76(m,1H),3.74(s,3H),3.72-3.6 4(m,4H),3.14-3.13(m,1H),2.53(s,3H),2.02(t,J=8.4Hz,2H);LCMS:m / z 466.10[M+H] + .

[0084] Example 5: Synthesis of 6-chloro-3-(5-(4-methoxyphenyl)-1-methyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one [ka] Step a: 6-chloro-3-(5-(4-methoxyphenyl)-1-methyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one: To a stirred solution of (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (100 mg, 2.8 mmol) in ethanol (10 mL) was added triethylamine (0.114 mL) and methylhydrazine sulfate (122 mg, 0.8 mmol). The reaction mixture was stirred at 90° C. for 16 h. The progress of the reaction was monitored by TLC. The volatiles were removed under reduced pressure and the residue was diluted with dichloromethane (30 mL) and washed with water (10 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give the crude compound, which was purified by column chromatography using 70% ethyl acetate in hexane as eluent to give the title compound as a pale yellow solid. Yield: 10 mg (10%); 1 H-NMR(300MHz, CDCl3):δ 10.47(bs,1H),7.74(d,J=2.1,1H),7.47-7.42(m,3H),7.15(d,J=8.7Hz,1H),6.93(d,J=8.7Hz,2H),4.22(dd,J=9.6Hz and 14.7 Hz,1H),3.83(s,3H),3.58(dd,J=9.9Hz and 16.2Hz,1H),3.03(dd,J=14.7Hz and 16.2Hz,1H),2.83(s,3H),2.64(s,3H);LC-MS:m / z 382.2[M+H] + .

[0085] Example 6: Synthesis of 6-chloro-4-methyl-3-(5-(1-methyl-1H-indol-6-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one [ka] Step a: Synthesis of (E)-6-chloro-4-methyl-3-(3-(1-methyl-1H-indol-3-yl)acryloyl)quinolin-2(1H)-one (6a): Using 3-acetyl-6-chloro-4-methylquinolin-2(1H)-one and 1-methyl-1H-indole-6-carbaldehyde as starting materials, the title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 38%; 1 H-NMR (300 MHz, CDCl3): δ 7.96 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.84 (t, J = 2.1 Hz, 1H), 7.65-7.62 (m, 2H), 7.53 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 9.3 Hz, 1H), 7.33-7.19 (m, 2H), 6.85 (d, J = 16.2 Hz, 1H), 3.80 (s, 3H), 2.33 (s, 3H), 2.32 (s, 3H) (one exchangeable proton not observed by NMR).

[0086] Step b: 6-chloro-4-methyl-3-(5-(1-methyl-1H-indol-6-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one (6): The title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 1). Yield 20%; 1H-NMR (300MHz, CDCl3): δ 12.87(s,1H),7.74(d,J=1.8Hz,1H),7.63(d,J=8.1Hz,1H),7.40(s,1H),7.26- 7.16(m,2H),7.05(t,J=9.9Hz,2H),6.49(d,J=3.0Hz,1H),5.76(dd,J=3.9Hz and 11.7Hz,1H),3.87-3.77(m,1H),3.75(s,3H),3.51(dd,J=4.2Hz and 18Hz,1H),2. 76(q,J=7.5Hz,2H),2.65(s,3H),1.17(t,J=7.5Hz,3H);LCMS(m / z):447.3[M+H] + .

[0087] Example 7: 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl Synthesis of )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one [ka] Step a: Synthesis of (E)-6-chloro-3-(3-(6-methoxypyridin-3-yl)acryloyl)-4-methylquinolin-2(1H)-one (7a) The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-6-chloro-4-methylquinolin-2(1H)-one and 6-methoxynicotinaldehyde as starting materials. Yield: 83%; LCMS: m / z 355.10 [M+H] + .

[0088] Step b: Synthesis of 6-chloro-3-(5-(6-methoxypyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one To a stirred solution of (E)-6-chloro-3-(3-(6-methoxypyridin-3-yl)acryloyl)-4-methylquinolin-2(1H)-one (0.125 g, 0.35 mmol) in propionic acid (3 mL), hydrazine hydrate (0.12 mL) was added and the vial was placed in a microwave and irradiated at 140° C. for 1 h. The reaction mixture was diluted with dichloromethane (30 mL) and washed with saturated sodium bicarbonate solution (20 mL) and water (10 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography using 2-5% methanol in dichloromethane as eluent to give the title compound as an off-white solid. Yield: 47 mg (30%); 1 H-NMR (400 MHz, DMSO-d6): δ 12.01 (bs, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.4, 1H), 5.51 (dd, J = 2.0 Hz and 8.0 Hz, 1H), 3.84 (s, 3H), 3.76 (dd, J = 6.0 Hz and 11.6 Hz, 1H), 3.18 (dd, J = 4.0 Hz and 8.0 Hz, 1H), 2.62 (s, 3H), 2.59 (2H merged with DMSO peak), 1.01 (t, J = 7.2 Hz, 3H); LCMS: m / z 425.20[M+H] + .

[0089] Example 8: Synthesis of N-(4-(3-(6-chloro-4-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-5-yl)phenyl)propionamide [ka] Step a: Synthesis of (E)-N-(4-(3-(6-chloro-4-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-3-oxoprop-1-en-1-yl)phenyl)acetamide (8a) The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-6-chloro-4-methylquinolin-2(1H)-one and N-(4-formylphenyl)acetamide as starting materials. Yield: 39%; LCMS: m / z 381.10 [M+H] + .

[0090] Step b: Synthesis of N-(4-(3-(6-chloro-4-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-5-yl)phenyl)propionamide The title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(5-(6-methoxypyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7) using (E)-N-(4-(3-(6-chloro-4-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-3-oxoprop-1-en-1-yl)phenyl)acetamide as starting material. Yield: 4%; 1 H-NMR(400MHz,DMSO-d6):δ 12.01(bs,1H),9.86(bs,1H),7.89(s,1H),7.61(d,J=8.8Hz,1H),7.54(d,J=8.4Hz,1H),7.36(d,J=8.4Hz,1H),7.21(d,J=8.0Hz,2H),5.47(dd ,J=8.4Hz and 3.6Hz,1H),3.78-3.72(m,1H),3.11-3.05(m,1H),2.62(m,4H),2.29(s,3H),1.07(t,J=7.6Hz,3H),1.03(t,J=7.6Hz,3H);LCMS:m / z 465.10[M+H] + .

[0091] Example 9: Synthesis of 3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-1,5-naphthyridin-2(1H)-one [ka] Step a: Synthesis of 3-acetyl-4-methyl-1,5-naphthyridin-2(1H)-one (9a): Using 1-(3-aminopyridin-2-yl)ethan-1-one and ethyl acetoacetate as starting materials, the title compound was synthesized using the same procedure as that carried out for 3-acetyl-6-chloro-4-methylquinolin-2(1H)-one (compound 1b). Yield: 38%; 1 H-NMR(300MHz, CDCl3):δ 12.11(s,1H),8.54(d,J=3.3Hz,1H),7.71(d,J=7.8Hz,1H),7.57(dd,J=4.2 and 7.8Hz,1H),7.57(d,J=7.8Hz,1H),2.47(s,3H),2.45(s,3H).

[0092] Step b: Synthesis of (E)-3-(3-(4-methoxyphenyl)acryloyl)-4-methyl-1,5-naphthyridin-2(1H)-one (9b): Using 3-acetyl-4-methyl-1,5-naphthyridin-2(1H)-one and 4-methoxybenzaldehyde as starting materials, the title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 56%; 1 H-NMR(300MHz,DMSO):δ 12.03(s,1H),8.56(dd,J=1.5 and 4.2Hz,1H),7.74-7.68(m,3H),7.59(q,J=4.2H z,1H),7.49(d,J=16.2Hz,1H),6.97(t,J=6.6Hz,3H),3.80(s,3H),2.37(s,3H).

[0093] Step c: 3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-1,5-naphthyridin-2(1H)-one (9): The title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 1) using (E)-3-(3-(4-methoxyphenyl)acryloyl)-4-methyl-1,5-naphthyridin-2(1H)-one as starting material. Yield: 21%; 1 H-NMR(300MHz, CDCl3):δ 12.47(bs,1H),8.65(dd,J=1.5Hz and 4.5Hz,1H),7.55(dd,J=1.5Hz and 8.4Hz,1H), 7.43(dd,J=4.2Hz and 8.1Hz,1H),7.38(d,J=8.7Hz,2H),6.91(d,J=8.7Hz,1H),5.6 0(dd,J=3.9Hz and 11.7Hz,1H),3.87-3.77(m,4H),3.41(dd,J=4.2Hz and 18.3Hz,1H) ,2.81(s,3H),2.75(q,J=7.5Hz,2H),1.18(t,J=7.5Hz,3H);LCMS(m / z):391[M+H] + .

[0094] Example 10: 4-Methyl-3-(5-(1-methyl-1H-indole- 6 Synthesis of (1H)-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one [ka] Step a: Synthesis of (E)-4-methyl-3-(3-(1-methyl-1H-indol-5-yl)acryloyl)quinolin-2(1H)-one (10a): Using 3-acetyl-4-methylquinolin-2(1H)-one and 1-methyl-1H-indole-5-carbaldehyde as starting materials, the title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 59%; 1 H-NMR(300MHz, CDCl3):δ 11.30(bs,1H),7.77-7.75(d,J=7.8Hz,1H),7.63-7.58(t,2H),7.47-7.30(m,4H) ,7.26(s,1H),7.13-7.12(m,2H),6.49(d,J=2.4Hz,1H),3.77(s,3H),2.48(s,3H).

[0095] Step b: 4-methyl-3-(5-(1-methyl-1H-indole- 6 Synthesis of 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one: Using (E)-4-methyl-3-(3-(1-methyl-1H-indol-5-yl)acryloyl)quinolin-2(1H)-one as starting material, the title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 1). Yield: 17%; 1H-NMR(300MHz, CDCl3):δ 11.85(s,1H),7.80(d,J=7.8Hz,1H),7.63(d,J=8.4Hz,1H),7.44(bs,1H),7.36(t,J=6.9 Hz,1H),7.28-7.19(m,3H),7.03(d,J=3.3Hz,1H),6.47(d,J=3.0Hz,1H),5.75(dd,J=4.5 and and 11.7Hz, 1H), 3.90 (dd, J = 11.7Hz and 18.3Hz, 1H), 3.77 (s, 3H), 3.49 (dd, J = 4.5Hz and 18.0H z,1H),2.76(q,J=7.5Hz,2H),2.70(s,3H),1.18(t,J=7.5Hz,3H);LCMS(m / z):413.3[M+H] + .

[0096] Example 11: Synthesis of 3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one [ka] Step a: Synthesis of (E)-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (11a): Using 3-acetyl-4-methylquinolin-2(1H)-one and 4-methoxybenzaldehyde as starting materials, the title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 63%; 1 H-NMR(300MHz,DMSO-d6):δ 11.92(s,1H),7.82(d,J=7.2Hz,1H),7.70(d,J=8.7Hz,2H),7.57(t,J=7.8Hz,1H),7. 344-7.36(m,2H),7.26(t,J=7.8Hz,1H),6.98-6.91(m,3H),3.79(s,3H),2.31(s,3H).

[0097] Step b: Synthesis of 3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one: Using (E)-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one as starting material, the title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 1). Yield: 7%; 1 H-NMR(300MHz, CDCl3):δ 13.07(s,1H),7.81(d,J=8.1Hz,1H),7.53-7.43(m,3H),7.32-7.29(m,2H),6.92(d,J=8.7Hz,2H),5.61(dd,J=3.9Hz and 11.7Hz,1H), 3.83-3.73(m,4H),3.48(dd,J=3.9Hz and 18.0Hz,1H),2.74(q,J=6.9Hz,2H),2.66(s,3H),1.18(t,J=7.5Hz,3H);LCMS(m / z):390[M+H] + .

[0098] Example 12: Synthesis of 4-methyl-3-(5-(1-methyl-1H-indol-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one [ka] Step a: Synthesis of (E)-4-methyl-3-(3-(1-methyl-1H-indol-3-yl)acryloyl)quinolin-2(1H)-one (12a): Using 3-acetyl-4-methylquinolin-2(1H)-one and 1-methyl-1H-indole-3-carbaldehyde as starting materials, the title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 50%; 1H-NMR(300MHz,DMSO-d6):δ 11.97(bs,1H),7.82(d,J=8.1Hz,1H),7.56(t,J=8.1Hz,1H),7.33(d,J=8.1Hz,1H),7.25(t,J=8.1Hz,1H),2.45(s,3H),2.33(s,3H).

[0099] Step b: 4-Methyl-3-(5-(1-methyl-1H-indol-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one (12): The title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 1) using (E)-4-methyl-3-(3-(1-methyl-1H-indol-3-yl)acryloyl)quinolin-2(1H)-one as starting material. Yield: 92%; 1 H-NMR (300MHz, CDCl3): δ 12.16 (s, 1H), 7.86 (d, J = 8.4Hz, 1H), 7.63 (d, J = 7.8Hz, 1H), 7.57 (t, J = 7.5Hz, 1H), 7.37 (t, J = 9.0Hz, 2H), 7.29-7.25 (m, 2H), 7.15 (t, J = 7.5Hz, 1H), 7.01 (t, J = 7.5Hz, 1H), 5.76 (dd, J = 4.8Hz and 12.3Hz, 1H), 3.72 (bs, 4H) [signals merged with water in DMSO], 3.27 (dd, J = 4.8Hz and 18.9Hz), 2.57 (bs, 5H), 0.99 (t, J = 7.2Hz, 3H); LCMS (m / z): 413 [M+H] + .

[0100] Example 13: Synthesis of 3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-1,8-naphthyridin-2(1H)-one [ka] Step a: Synthesis of 3-acetyl-4-methyl-1,8-naphthyridin-2(1H)-one (13a): Using 1-(2-aminopyridin-3-yl)ethan-1-one and ethyl acetoacetate as starting materials, the title compound was synthesized using the same procedure as that carried out for 3-acetyl-6-chloro-4-methylquinolin-2(1H)-one (compound 1b). Yield: 23%; 1 H-NMR (300 MHz, DMSO-d6): δ 12.35 (s, 1H), 8.56 (dd, J = 1.5 Hz and 4.8 Hz, 1H), 8.27 (d, J = 7.8 Hz, 1H), 7.31 (dd, J = 4.8 Hz and 8.1 Hz, 1H), 2.45 (s, 3H), 2.33 (s, 3H).

[0101] Step b: Synthesis of (E)-3-(3-(4-methoxyphenyl)acryloyl)-4-methyl-1,8-naphthyridin-2(1H)-one (13b): Using 3-acetyl-4-methyl-1,8-naphthyridin-2(1H)-one and 4-methoxybenzaldehyde as starting materials, the title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 55%; 1 H-NMR(300MHz,DMSO-d6):δ 12.29(s,1H),8.58-8.56(m,1H),8.26(d,J=7.8Hz,1H),7.69(d,J=8.7Hz,2H),7.46 (d,J=16.2Hz,1H),7.35-7.31(m,1H),6.98-6.90(m,3H),3.80(s,3H),2.31(s,3H).

[0102] Step c: Synthesis of 3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-1,8-naphthyridin-2(1H)-one: Using (E)-3-(3-(4-methoxyphenyl)acryloyl)-4-methyl-1,8-naphthyridin-2(1H)-one as starting material, the title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 1). Yield: 9%; 1 H-NMR (300MHz, CDCl3): δ 10.57 (s, 1H), 8.66 (dd, J = 1.5Hz and 4.5Hz, 1H), 8.14 (dd, J = 1.5Hz and 8.1Hz, 1H), 7.32-7.27 (m, 3H), 6.88 (d, J = 8.7Hz, 2H), 5.55 (dd, J = 4.8Hz and 12.0Hz, 1H), 3.92 (dd, J = 12.0Hz and 18.3Hz, 1H), 3.79 (s, 3H), 3.28 (dd, J = 4.5Hz and 18.3Hz, 1H), 2.71 (q, J = 7.5Hz, 2H), 2.66 (s, 3H), 1.16 (t, J = 7.5Hz, 3H); LCMS (m / z): 391.3 [M+H] + .

[0103] Example 14: Synthesis of 6-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-5-methylpyrido-[2,3-d]pyrimidin-7(8H)-one [ka] Step a: Synthesis of 5-bromopyrimidin-4-amine (14a): To a stirred solution of pyrimidin-4-amine (4.0 g, 42.5 mmol) in water (40 mL) was added calcium carbonate (2.10 g, 21 mmol) followed by dropwise addition of bromine (4 mL). The reaction mixture was heated at 60° C. for 2 h and the progress of the reaction was monitored by TLC. The reaction mixture was neutralized with aqueous ammonia (20 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with water (50 mL), brine solution (50 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude compound which was purified by column chromatography using 30% ethyl acetate in hexane as eluent to give the title compound. Yield: 2.0 g (28%). 1 H-NMR (300MHz, CDCl3): δ 8.32 (s, 1H), 7.24 (S, 1H).

[0104] Step b: Synthesis of 1-(4-aminopyrimidin-5-yl)ethan-1-one (14b): To a stirred solution of 5-bromopyrimidin-4-amine (0.5 g, 2.8 mmol) in dioxane (5 mL) was added triethylamine (0.853 mL, 5.78 mmol) and tributyl(1-ethoxyvinyl)stannane (1.35 g, 3.75 mmol). The reaction mixture was stirred at room temperature for 10 min under nitrogen purge. Pd(PPh3)2Cl2 (0.039 g, 0.56 mmol) was added to the reaction mixture and heated at 90 °C overnight. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with dichloromethane (30 mL) and washed with water (10 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography using 5-10% ethyl acetate in hexane as eluent to give the title compound. Yield: 0.150 g (38%). 1 H-NMR (300MHz, CDCl3): δ 8.84 (s, 1H), 8.60 (s, 1H), 5.60 (bs, 2H), 2.59 (s, 3H).

[0105] Step c: 6-Acetyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (14c): To a stirred solution of 1-(4-aminopyrimidin-5-yl)ethan-1-one (0.4 g, 2.9 mmol) in toluene (10 mL) was added cerium chloride (1.6 g, 4.2 mmol) and ethyl acetoacetate (0.549 g, 4.9 mmol). The reaction mixture was heated at 130° C. for 2 days and then at 190° C. for an additional 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with dichloromethane (30 mL) and washed with saturated NaHCO3 solution (20 mL) and water (10 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography using 30% ethyl acetate in hexane as eluent to give the title compound. Yield 0.3 g (51%). 1 H-NMR (300MHz, DMSO-d6): δ 12.76 (bs, 1H), 9.20 (s, 1H), 9.01 (s, 1H), 2.45 (s, 3H), 2.38 (s, 3H).

[0106] Step d: (E)-6-(3-(4-methoxyphenyl)acryloyl)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (14d): The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 6-acetyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one and 4-methoxybenzaldehyde as starting materials. Yield: 42%; 1 H-NMR(300MHz, CDCl3):δ 12.68(s,1H),9.19(s,1H),9.02(s,1H),7.70(d,J=8.7Hz,2H),7.51(d,J=16.5H z,1H),6.98(d,J=8.7Hz,2H),6.91(d,J=16.5Hz,1H),3.80(s,3H),2.34(s,3H).

[0107] Step e: 6-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-5-methylpyrido-[2,3-d]pyrimidin-7(8H)-one: The title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 1) using (E)-6-(3-(4-methoxyphenyl)acryloyl)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one as starting material. Yield: 27%; 1 H-NMR(300MHz, CDCl3):δ 9.93(bs,1H),9.12(s,1H),9,07(s,1H),7.27(d,J=8.4Hz,2H),6.88(d,J=8.7Hz,2H),5.55(dd,J=4.5 and 12.0Hz,1H),3.89(dd,J=1 2.0 and 18.6Hz, 1H), 3.78 (s, 3H), 3.27 (dd, J = 4.5Hz and 18.6Hz, 1H), 2.74-2.71 (m, 5H), 1.16 (t, J = 7.5Hz, 3H), LCMS (m / z): 392.2 [M+H] + .

[0108] Example 15: Synthesis of 6-bromo-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one [ka] Step a: Synthesis of 1-(2-amino-5-bromophenyl)ethan-1-one (15a): The title compound was synthesized using the same procedure as that performed for 1-(2-amino-5-chlorophenyl)ethan-1-one (compound 1a) using 2-amino-5-bromobenzonitrile as the starting material. Yield: 31%; LCMS: m / z 216.0 [M+2H] + .

[0109] Step b: Synthesis of 3-acetyl-6-bromo-4-methylquinolin-2(1H)-one (15b): To a stirred solution of 1-(2-amino-5-bromophenyl)ethan-1-one (0.7 g, 3.097 mmol) in DMF (10 mL) at ambient temperature, ethyl acetoacetate (1.2 g, 9.29 mmol) was added and the reaction vial was placed in a microwave and irradiated at 180 °C for 1.5 h. The reaction mixture was allowed to reach room temperature, diluted with water (30 mL) and extracted with ethyl acetate (2 x 75 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 40-50% ethyl acetate in hexane as eluent to give the title compound as a yellow solid. Yield: 0.65 g (75%); 1 H-NMR (400MHz, DMSO-d6): δ 11.12 (bs, 1H), 7.97 (d, J = 2.0 Hz, 1 H), 7.73 (dd, J = 2.0 Hz and 8.8 Hz, 1 H), 7.28 (d, J = 8.8 Hz, 1 H), 2.45 (s, 3 H), 2.32 (s, 3 H). LCMS:m / z 281.9[M+2H] + .

[0110] Step c: Synthesis of (E)-6-bromo-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (15c) The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 1-(2-amino-5-bromophenyl)ethan-1-one and 4-methoxybenzaldehyde as starting materials. Yield: 98%; 1H-NMR(400MHz,DMSO-d6):δ 12.05(bs,1H),7.97(d,J=2.4Hz,1H),7.74(d,J=2.0Hz,1H),7.72(d,J=2.0Hz,1H),7.70(d,J=8.8Hz,1H),7.42(d,J=1 6.0Hz,1H),7.31(d,J=16.0Hz,1H),6.94(d,J=8.8Hz,2H),6.24(d,J=16.4Hz,1H),3.80(s,3H),2.32(s,3H);LCMS:m / z 400.0[M+2H] + .

[0111] Step d: Synthesis of 6-bromo-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one Using (E)-6-bromo-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that performed for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 35%; 1 H-NMR(400MHz,DMSO-d6):δ 12.06(bs,1H),8.00(d,J=2.0Hz,1H),7.72(dd,J1=2.4Hz and 8.8Hz,1H),7.3 0(d,J=8.8Hz,1H),7.23(d,J=8.8Hz,2H),6.90(d,J=8.8Hz,2H),5.46(dd,J 1=4.0Hz and 11.2Hz,1H),3.79-3.76,(m,1H),3.74(s,3H),3.015(dd,J1=4.4 Hz and 18.4Hz, 1H), 2.60 (m, 2H), 2.52 (s, 3H), 1.01 (t, J=7.2Hz, 3H); LCMS: m / z 470.1[M+H] + .

[0112] Example 16: 6-Chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-1,5-naphthyridin-2(1H)-one [ka] Step a: Synthesis of 3-amino-6-chloropicolinonitrile (16a) To a stirred solution of 6-chloro-3-nitropicolinonitrile (0.5 g, 2.72 mmol) in a mixture of ethanol and concentrated HCl (3:1, 8 mL) was added iron powder (0.52 g, 9.52 mmol) and the reaction mixture was stirred at 90° C. for 30 min. The progress of the reaction was monitored by TLC. The reaction mixture was poured into ice water, basified with aqueous ammonia, and filtered through Celite. The filtrate was extracted with diethyl ether (3×100 mL). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to give the title compound as a yellow solid. Yield: 0.35 g (77%). 1 H-NMR(400MHz,DMSO-d6):δ 7.42(d,J=9.2Hz,1H),7.28(d,J=8.8Hz,1H),6.58(bs,2H);LCMS:m / z 156.9[M+H] + .

[0113] Step b: Synthesis of 1-(3-amino-6-chloropyridin-2-yl)ethan-1-one (16b) The title compound was synthesized using the same procedure as that carried out for 1-(2-amino-5-chlorophenyl)ethan-1-one (compound 1a) using 3-amino-6-chloropicolinonitrile as the starting material. Yield: 77%; 1 H-NMR(400MHz,CDCl3):δ 7.23(d,J=8.8Hz,1H),7.01(d,J=8.8Hz,1H),5.48(bs,2H),2.66(s,3H);LCMS:m / z 171.0[M+H] + .

[0114] Step c: Synthesis of 3-acetyl-6-chloro-4-methyl-1,5-naphthyridin-2(1H)-one (16c) The title compound was synthesized using the same procedure as that carried out for 3-acetyl-6-bromo-4-methylquinolin-2(1H)-one (compound 15b) using 1-(3-amino-6-chloropyridin-2-yl)ethan-1-one as starting material. Yield: 21%; 1 H-NMR (400MHz, DMSO-d6): δ 12.27(bs,1H),7.74(d,J=8.4Hz,1H),7.67(d,J=8.4Hz,1H),2.47(s,3H),2.34(s,3H). LCMS:m / z 237.0[M+H] + .

[0115] Step d: Synthesis of (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methyl-1,5-naphthyridin-2(1H)-one (16d) The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-6-chloro-4-methyl-1,5-naphthyridin-2(1H)-one and 4-methoxybenzaldehyde as starting materials. Yield: 66%; LCMS: m / z 355.1 [M+H] + .

[0116] Step e: Synthesis of 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-1,5-naphthyridin-2(1H)-one Using (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methyl-1,5-naphthyridin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 46%; 1H-NMR(400MHz,DMSO-d6):δ 12.22(bs,1H),7.75(d,J=8.4Hz,1H),7.66(d,J=8.4Hz,1H),7.21(d,J=8.4Hz,2H),6.91(d,J=8.4Hz,2H),5.46(dd,J=8.4Hz and and 4.0Hz,1H),3.80(m,1H),3.74(s,3H),3.17-3.11(m,1H),2.64(q,J=7.6Hz,2H),2.57(s,3H),1.06(t,J=9.2Hz,3H),LCMS:m / z 425.3[M+H] + .

[0117] Example 17: 6-Chloro-3-(5-(4-methoxyphenyl)-1-propionyl -4,5-dihydro Synthesis of (1H-pyrazol-3-yl)quinolin-2(1H)-one [ka] Step a: Synthesis of 3-acetyl-6-chloroquinolin-2(1H)-one (17a): To a stirred solution of 2-amino-5-chlorobenzaldehyde (3.0 g, 1.9 mmol) in xylene (20 mL) was added 2,2,6-trimethyl-4H-1,3-dioxin-4-one (1.91 g, 1.3 mmol) and the reaction mixture was heated at 190° C. for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature and filtered. The resulting solid was washed with xylene and dried under vacuum to give the title compound. Yield 1.2 g (28%); 1 H-NMR (300MHz, CDCl3): δ 12.23(s,1H),8.43(s,1H),8.01(d,J=2.1Hz,1H),7.65(dd,J=2.4Hz and 8.7Hz,1H),7.35(d,J=8.7Hz,1H),2.61(s,3H).

[0118] Step b: Synthesis of (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)quinolin-2(1H)-one (17b): Using 3-acetyl-6-chloroquinolin-2(1H)-one and 4-methoxybenzaldehyde as starting materials, the title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 65%. 1 H-NMR (300 MHz, CDCl3): δ 8.38 (s, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.70 (d, J = 8.7 Hz, 2H), 7.64-7.61 (m, 3H), 7.37 (d, J = 8.7 Hz, 1H), 7.01 (d, J = 8.7 Hz, 2H), 3.81 (s, 3H), [NH protons not visible by NMR].

[0119] Step c: Synthesis of 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one: The title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 1) using (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)quinolin-2(1H)-one as starting material. Yield: 57%; 1 H-NMR (300MHz, CDCl3): δ 12.16(s,1H),8.49(s,1H),7.96(d,J=2.4Hz,1H),7.58(dd,J=2.4Hz and 8.7Hz,1H), 7.32(d,J=8.7Hz,1H),7.11(d,J=8.7Hz,2H),6.88(d,J=8.7Hz,2H),5.45(dd,J=4.5 Hz and 12.0Hz, 1H), 3.88 (dd, J = 12.0Hz and 18.9Hz, 1H), 3.72 (s, 3H), 3.27 (dd, J = 4.5H z and 18.9Hz,1H),2.72(q,J=7.5Hz,2H),1.06(t,J=7.5Hz,3H);LCMS(m / z):410[M+H]+ .

[0120] Example 18: Synthesis of 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-1,4-dimethylquinolin-2(1H)-one [ka] Step a: 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-1,4-dimethylquinolin-2(1H)-one To a stirred solution of 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (40 mg, 0.094 mmol) in DMF (3 mL) at 0 °C was added K2CO3 (39 mg, 0.28 mmol) followed by methyl iodide (14 mg, 0.104 mmol). The reaction mixture was stirred at 60 °C for 3 h. The reaction progress was monitored by TLC. The reaction mixture was diluted with EtOAC (30 mL), water (10 mL) and extracted. The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography using 2-5% methanol in dichloromethane as eluent to give the title compound as an off-white solid. Yield: 19 mg (46%); 1 H-NMR(400MHz,DMSO-d6):δ 7.96(d,J=2.4Hz,1H),7.74(dd,J=2.0Hz and 9.2Hz,1H),7.63(d,J=9.2Hz,1H),7.27(d,J=8.4Hz,2H),6.91(d,J=8.4Hz,2H),5.49-5.45(dd,J=4.0 and 7.6Hz,1H),3.74(s,3H),3.69(t,J=6.4Hz,1H),3.64(s,3H),3.11-3.06(m ,1H),2.58(q,J=7.4Hz,2H),2.53(s,3H),1.01(t,J=7.2Hz,3H);LCMS:m / z 438.1[M+H] + .

[0121] Example 19: 4-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)isoquinolin-3(2H)-one [ka] Step a: Synthesis of 4-bromoisoquinolin-3(2H)-one (19a): To a stirred solution of isoquinolin-3(2H)-one (0.3 g, 2.06 mmol) in DMF (10 mL) at 0° C., NBS (0.404 g, 2.27 mmol) was added portionwise over 5 min. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was poured into ice water. The solid formed was filtered, washed with water and dried under vacuum to give the title compound. Yield: 0.275 g (50%). 1 H-NMR (400 MHz, DMSO-d6): δ 8.91 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.41 (t, J = 7.2 Hz, 1H), [NH protons not visible by NMR]; LCMS: m / z 225.9 [M + 2H] + .

[0122] Step b: Synthesis of 4-acetylisoquinolin-3(2H)-one (19b) The title compound was synthesized using the same procedure as that performed for 1-(4-aminopyrimidin-5-yl)ethan-1-one (compound 14b) using 4-bromoisoquinolin-3(2H)-one as starting material. Yield: 38%; LCMS: m / z 188.0 [M+H] + .

[0123] Step c: Synthesis of (E)-4-(3-(4-methoxyphenyl)acryloyl)isoquinolin-3(2H)-one (19c): The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 4-acetylisoquinolin-3(2H)-one and 4-methoxybenzaldehyde as starting materials. Yield: 51%; LCMS: m / z 306.1 [M+H] + .

[0124] Step d: Synthesis of 4-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)isoquinolin-3(2H)-one Using (E)-4-(3-(4-methoxyphenyl)acryloyl)isoquinolin-3(2H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 29%; 1 H-NMR(400MHz,DMSO-d6):δ 8.92(s,1H),8.38(d,J=9.2Hz,1H),7.96(d,J=8.4Hz,1H),7.66(t,J=7.2H z,1H),7.31(t,J=7.2Hz,1H),7.19(d,J=8.8Hz,2H),6.89(d,J=8.8Hz,2H), 5.46(dd,J=4.0Hz and 12.0Hz,1H),3.95-3.98,(m,1H),3.72(s,3H),3.27-3. 26(m,1H),2.69-2.66(m,2H),2.57(s,3H),1.06(t,J=7.2Hz,3H);LCMS:m / z 376.2[M+H] + .

[0125] Example 20: Synthesis of 5-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno-[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of N-(3-acetylthiophen-2-yl)-3-oxobutanamide (20a): To a stirred solution of 1-(2-aminothiophen-3-yl)ethan-1-one (3.0 g, 21.24 mmol) in xylene (20 mL) was added 2,2,6-trimethyl-4H-1,3-dioxin-4-one (3.62 g, 25.48 mmol) and the reaction mixture was heated at 140 °C for 3 h. The reaction progress was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 20-30% EtOAc in hexanes as eluent to give the title compound as a colorless liquid. Yield: 4.5g (93%); 1 H-NMR(400MHz,DMSO-d6):δ 12.17(bs,1H),7.40(d,J=6.0Hz,1H),7.01(d,J=5.6Hz,1H),3.91(s,3H),2.49(s,3H),2.21(s,3H);LCMS(m / z):223.9[MH] + .

[0126] Step b: Synthesis of 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one (25b): A mixture of (N-(3-acetylthiophen-2-yl)-3-oxobutanamide (4.5 g, 19.97 mmol) and cerium chloride heptahydrate (2.22 g, 5.99 mmol) was heated at 150° C. for 30 min. The reaction progress was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL), water (50 mL) and extracted. The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was diluted with DCM (200 mL) and the resulting solid was filtered and dried under vacuum to give the title compound as an off-white solid. Yield: 1.6 g (38%); 1H-NMR(400MHz,DMSO-d6):δ 12.50(bs,1H),7.32(s,2H),2.46(s,3H),2.35(s,3H);LCMS(m / z):208.1[MH] + .

[0127] Step c: Synthesis of (E)-5-(3-(4-methoxyphenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one (20c): The title compound was synthesized using the same procedure as that performed for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 4-methoxybenzaldehyde as starting materials. Yield: 95%; LCMS (m / z): 326.2 [MH] + .

[0128] Step d: Synthesis of 5-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3 b]pyridin-6(7H)-one (20): To a stirred solution of (E)-5-(3-(4-methoxyphenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one (7.5 g, 23.0 mmol) in propionic acid (75 mL) was added hydrazine hydrate (7.5 mL) and the reaction mixture was refluxed for 5 h. The progress of the mixture was monitored by TLC. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by flash column chromatography using 2-2.5% methanol in DCM as eluent to give the title compound as an off-white solid. Yield: 5.0 g (54%); 1H-NMR(400MHz,DMSO-d6):δ 12.45(bs,1H),7.35-7.31(m,2H),7.20(d,J=8.8Hz,2H),6.89(d,J=8.8,7.5Hz,2H),5.43(dd,J=4.4Hz and 12.0Hz,1H),3. 78-3.75(m,1H),3.73(s,3H),3.14(dd,J=4.4Hz and 18.0Hz,1H),2.62(q,J=7.6Hz,2H),2.54(s,3H),1.03(t,J=7.6Hz,3H). LCMS:m / z 396.2[M+H] + .

[0129] Chiral purification of compound 20 Step e: 20(A): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA / DCM (90 / 10) at 20° C. with a flow rate of 0.7 mL / min. Enantiomer isolated at 14.21 min.

[0130] Step f: 20(B): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA / DCM (90 / 10) at 20° C. with a flow rate of 0.7 mL / min. Enantiomer isolated at 19.36 min.

[0131] Example 21: Synthesis of 5-(5-(6-methoxypyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(6-methoxypyridin-3-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one (21a) The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 6-methoxynicotinaldehyde as starting materials. Yield: 92%; LCMS: m / z 327.1 [M+H] + .

[0132] Step b: Synthesis of 5-(5-(6-methoxypyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one Using (E)-5-(3-(6-methoxypyridin-3-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that performed for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 35%; 1 H-NMR (400MHz, DMSO-d6): δ 8.35(s,1H), 7.85(d,J=7.6,1H), 7.19(d,J=6.0Hz,1H), 7.06(d,J=4.0Hz,1H), 6.85(d,J=8.4Hz,1H), 5.57(d,J=8.8Hz,1H), 4.05(s,3H), 3.88-3.60(m,1H), 3.51-3.46(m,1H), 2.73(q,J=7.6Hz,2H), 2.69(s,3H), 1.15(t,J=7.2Hz,3H), [NH protons not visible by NMR]; LCMS: m / z 397.1[M+H] + .

[0133] Example 22: Synthesis of 5-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of 3-(dichloromethyl)-2-nitrothiophene (22a): To a stirred solution of potassium tert-butoxide (23 mL, 23.2 mmol, 1 M in THF) in DMF (15 mL) at -78 °C, 2-nitrothiophene (1.0 g, 7.74 mmol dissolved in 5 mL of DMF) and chloroform (1.3 mL) were added and the reaction mixture was stirred for 5 min. The reaction mixture was quenched with methanol (2 mL), acetic acid (2 mL), diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 3-5% ethyl acetate in hexane as eluent to give the title compound as a pale yellow solid. Yield: 2.5 g (76%); 1 H NMR (400MHz, DMSO-d6): δ 7.64 (s, 1H), 7.54-7.558 (m, 2H).

[0134] Step b: Synthesis of 2-nitrothiophene-3-carbaldehyde (22b): A solution of 3-(dichloromethyl)-2-nitrothiophene (1.0 g, 4.71 mmol) in formic acid was heated at 100° C. for 48 h. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine solution (15 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 3-5% ethyl acetate in hexane as eluent to give the title compound as a brown solid. Yield: 1.1 g (34%); 1 H NMR (400MHz, DMSO-d6): δ 10.61 (s, 1H), 7.54-7.48 (m, 2H).

[0135] Step c: Synthesis of 2-aminothiophene-3-carbaldehyde (22c): To a stirred solution of 2-nitrothiophene-3-carbaldehyde (1.05 g, 6.68 mmol) in ethanol (13 mL) and water (2 mL) was added iron powder (1.87 g, 33.40 mmol) and ammonium chloride (3.67 g, 66.81 mmol). The reaction mixture was heated at 90° C. for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, filtered through a bed of celite, and the bed of celite was washed with methanol (30 mL). The combined filtrate was evaporated under reduced pressure. The residue was neutralized with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a brown solid. Yield: 500mg (58%); LCMS: m / z 128.0[M+H] + .

[0136] Step d: Synthesis of 5-acetylthieno[2,3-b]pyridin-6(7H)-one (22d): To a stirred solution of 2-aminothiophene-3-carbaldehyde (500 mg, 3.93 mmol) in DMF (8 mL) was added ethyl acetoacetate (0.75 mL, 5.89 mmol) and molecular sieves (200 mg). The reaction vial was placed in a microwave reactor and irradiated at 180 °C for 2 h. The reaction mixture was cooled to room temperature, quenched with brine (10 mL), and then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 20-30% ethyl acetate in hexanes as eluent to give the title compound as a brown solid. Yield: 150 mg (20%); LCMS: m / z 193.9 [M+H] + .

[0137] Step e: Synthesis of (E)-5-(3-(4-methoxyphenyl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one (22e): The title compound was synthesized using the same procedure as that performed for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetylthieno[2,3-b]pyridin-6(7H)-one and 6-methoxybenzaldehyde as starting materials. Yield: 59%; LCMS: m / z 312.1 [M+H] + .

[0138] Step f: Synthesis of -(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one As the starting material, (E)-5-(3-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7) using 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one. Yield: 18%; 1 H-NMR (400 MHz, DMSO): δ 8.50 (s, 1H), 7.36-7.27 (m, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.44 (dd, J = 6.3 Hz and 11.6 Hz, 1H), 3.89-3.79 (m, 2H), 3.72 (s, 3H), 2.73-2.70 (m, 2H), 1.05 (t, J = 7.6 Hz, 3H), one exchangeable proton was not observed by NMR; LCMS: m / z 382.2 [M+H] + .

[0139] Example 23: Synthesis of 6-chloro-4-cyclopropyl-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one [ka] Step a: (2-amino-5-chlorophenyl)(cyclopropyl)methanone (23a): The title compound was synthesized using the same procedure as that carried out for 1-(2-amino-5-chlorophenyl)ethan-1-one (compound 1a) using 2-amino-5-chlorobenzonitrile and cyclopropylmagnesium bromide as starting materials. Yield: 14%. 1 H-NMR(300MHz, CDCl3):δ 7.91(d,J=2.4Hz,1H),7.20(dd,J=2.4,8.7Hz,1H),6.59(d,J=9Hz,1H),615(bs,2H),2.58-2.51(m,1H),1.21-1.15(m,2H).1.02-0.87(m,2H).

[0140] Step b: 3-Acetyl-6-chloro-4-cyclopropylquinolin-2(1H)-one (23b): The title compound was synthesized using the same procedure as that carried out for 3-acetyl-6-chloro-4-methylquinolin-2(1H)-one (compound 1b) using (2-amino-5-chlorophenyl)(cyclopropyl)methanone as starting material. Yield: 23%; 1 H-NMR(300MHz, CDCl3):δ 8.11(d,J=2.1Hz,1H),7.60(dd,J=2.4,8.7Hz,1H),7.34(d,J=8.7Hz,1H),2.47 (s,3H),2.09-2.03(m,1H),1.22(s,1H),1.10-1.03(m,2H),0.54-0.49(m,2H).

[0141] Step c: (E)-6-chloro-4-cyclopropyl-3-(3-(4-methoxyphenyl)acryloyl)quinolin-2(1H)-one (23c): The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-6-chloro-4-cyclopropylquinolin-2(1H)-one and 4-methoxybenzaldehyde as starting materials. Yield: 24%; 1H-NMR(300MHz, CDCl3):δ 12.42(bs,1H),8.15(d,J=5.1Hz,1H),7.48(t,J=8.7Hz,2H),7.40-7.35(m,2H),7.00-6.87(m, 2H),3.84(s,3H),2.04-1.91(m,1H),1.40-1.21(m,2H),1.21-1.08(m,2H),0.90-0.87(m,2H).

[0142] Step d: 6-chloro-4-cyclopropyl-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one: The title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 1) using (E)-6-chloro-4-cyclopropyl-3-(3-(4-methoxyphenyl)acryloyl)quinolin-2(1H)-one as starting material. Yield: 16%. 1 H-NMR(300MHz, CDCl3):δ 13.03(bs,1H),8.20(d,J=1.5Hz,1H),7.41(d,J=8.7Hz,3H),7.14(d,J=8.7Hz,1H),6.90(d,J=5.7Hz,2H),5.63(dd,J=4.2,11.4Hz,1H),3 .81(s,3H),3.75-3.65(m,1H),3.53(dd,J=4.2,18Hz,1H),2.73(q,J=7.5Hz,2H),2.20-2.10(m,1H),1.28-1.15(m,5H),0.60-0.49(m,2H). LCMS(m / z):450.2[M+H] + .

[0143] Example 24: Synthesis of 6-chloro-4-methyl-3-(5-(1-methyl-1H-indol-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one [ka] Step a: Synthesis of ((E)-6-chloro-4-methyl-3-(3-(1-methyl-1H-indol-3-yl)acryloyl)quinolin-2(1H)-one (24a): The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-6-chloro-4-methylquinolin-2(1H)-one and 1-methyl-1H-indole-3-carbaldehyde as starting materials. Yield: 50%; 1 H-NMR(300MHz,DMSO-d6):δ 12.34(s,1H),8.08(d,J=8.1Hz,2H),7.74-7.63(m,4H),7.51(d,J=1.8Hz,1H),7.37-7. 32(m,2H),6.97(d,J=2.1Hz,1H),6.76-6.71(m,1H),4.36(t,J=6.9Hz,2H),2.42(s,3H).

[0144] Step b: Synthesis of 3-(6-chloro-4-methyl-3-(5-(1-methyl-1H-indol-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-quinolin-2(1H)-one: Using ((E)-6-chloro-4-methyl-3-(3-(1-methyl-1H-indol-3-yl)acryloyl)quinolin-2(1H)-one) as starting material, the title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 1). Yield: 0.2 g. 1H-NMR (300 MHz, DMSO-d6): δ 7.83 (d, J = 2.1 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.57 (dd, J = 2.1 Hz and 8.7 Hz, 1H), 7.42-7.33 (m, 3H), 7.15 (t, J = 6.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 5.05 (t, J = 10.5 Hz, 1H), 3.74 (s, 3H), 3.31-3.26 (m, 1H), 3.14-3.02 (m, 1H), 2.07 (s, 3H), 1.86 (s, 1H), 1.75 (s, 1H), 1.62 (s, 1H), one exchangeable proton not observed by NMR; LCMS: m / z 447.2[M+H] + .

[0145] Example 25: Synthesis of 5-(5-(5-methoxypyridin-2-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(5-methoxypyridin-2-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one (25a): Using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 5-methoxypicolinaldehyde as starting materials, the title compound was synthesized using the same procedure as that performed for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 76%; LCMS (m / z): 327.1 [M+H] + .

[0146] Step b: Synthesis of 5-(5-(5-methoxypyridin-2-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one: Using (E)-5-(3-(5-methoxypyridin-2-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as starting material, 6-chloro-3-(5-(6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that performed for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 34%. 1 H-NMR (400 MHz, DMSO-d6): δ 8.22 (d, J = 2 Hz, 1H), 7.37-7.35 (m, 3H), 7.25 (d, J = 8.8 Hz, 1H), 5.49 (dd, J = 4.4 Hz and 7.2 Hz, 1H), 3.81 (s, 3H), 3.80-3.76 (m, 1H), 3.20 (dd, J = 4.8 Hz and 13.2 Hz, 1H), 2.62 (q, J = 7.6 Hz, 2H), 2.57 (s, 3H), 1.02 (t, J = 7.6 Hz, 3H), one exchangeable proton not observed by NMR; LCMS (m / z): 397.2 [M+H] + .

[0147] Example 26: Synthesis of 4-methyl-5-(5-(6-oxo-1,6-dihydropyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-4-methyl-5-(3-(6-oxo-1,6-dihydropyridin-3-yl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one (26a): Using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 6-oxo-1,6-dihydropyridine-3-carbaldehyde as starting materials, the title compound was synthesized using the same procedure as that performed for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 80%; LCMS (m / z): 313.1 [M+H] + .

[0148] Step b: Synthesis of 4-methyl-5-(5-(6-oxo-1,6-dihydropyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one: Using (E)-4-methyl-5-(3-(6-oxo-1,6-dihydropyridin-3-yl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one as starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 56%. 1 H-NMR (400MHz, DMSO-d6): δ 7.44 (d, J=9.2Hz, 1H), 7.34-7.32 (m, 3H), 6.32 (d, J=9.6Hz, 1H), 5.30 (dd, J=3.81Hz and 7.6Hz, 1H), 3.65-3.61 (m, 1H), 3.21 (dd, J=4.4Hz and 14.0Hz, 1H), 2.56 (q, J=7.6Hz, 2H), 2.52 (s, 3H), 1.02 (t, J=7.6Hz, 3H), (exchangeable protons not visible in NMR); LCMS (m / z): 383.1 [M+H] + .

[0149] Example 27: Synthesis of 5-(5-(4-fluorophenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(4-fluorophenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one (27a): Using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 4-fluorobenzaldehyde as starting materials, the title compound was synthesized using the same procedure as that performed for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 66%, LCMS (m / z): 314.0 [M+H] + .

[0150] Step b: Synthesis of 5-(5-(4-fluorophenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one: Using (E)-5-(3-(4-fluorophenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 12%. 1 H-NMR (400MHz, DMSO-d6): δ 7.37-7.30 (m, 4H), 7.19-7.14 (m, 2H), 5.49 (dd, J=4.4Hz and 7.6Hz, 1H), 3.77 (dd, J=6.4Hz and 12Hz, 1H), 3.14 (dd, J=4.4Hz and 14.0Hz, 1H), 2.66 (q, J=7.2Hz, 2H), 2.54 (s, 3H), 1.03 (t, J=6.4Hz, 3H), one exchangeable proton not observed by NMR; LCMS (m / z): 384.1 [M+H] + .

[0151] Example 28: Synthesis of 5-(5-(4-chlorophenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: (E)-5-(3-(4-chlorophenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one (28a): Using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 4-chlorobenzaldehyde as starting materials, the title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 94%. 1 H-NMR (400 MHz, DMSO-d6): δ 7.77 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 2.0 Hz and 8.4 Hz, 2H), 7.46-7.42 (m, 1H), 7.35-7.32 (m, 2H), 7.14 (d, J = 16.0 Hz, 1H), 2.34 (s, 3H), one exchangeable proton not observed by NMR; LCMS (m / z): 330.0 [M+H] + .

[0152] Step b: Synthesis of 5-(5-(4-chlorophenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one: Using (E)-5-(3-(4-chlorophenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that performed for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 27%. 1H-NMR(400MHz,DMSO-d6):δ 12.51(s,1H),7.42(d,J=8.4Hz,2H),7.33-7.28(m,4H),5.49(dd,J=4.4Hz and 7.6Hz,1H),3.77(dd,J=6.4H z and 12Hz, 1H), 3.14 (dd, J = 4.4Hz and 14.0Hz, 1H), 2.68 (q, J = 7.2Hz, 2H), 2.54 (s, 3H), 1.06 (t, J = 6.4Hz, 3H). LCMS(m / z):400.0[M+H] + .

[0153] Chiral purification of compound 28 Step e: 28(A): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA(100) at 20° C. with a flow rate of 0.7 mL / min. Enantiomer isolated at 19.02 min.

[0154] Step f: 28(B): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA / DCM (90 / 10) at 20° C. with a flow rate of 0.7 mL / min. Enantiomer isolated at 26.79 min.

[0155] Example 29: Synthesis of 5-(5-(5-methoxythiophen-2-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(5-methoxythiophen-2-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one (29a): Using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 5-methoxythiophene-2-carbaldehyde as starting materials, the title compound was synthesized using the same procedure as that performed for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 63%; LCMS (m / z): 332.0 [M+H] + .

[0156] Step b: Synthesis of 5-(5-(5-methoxythiophen-2-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one: Using (E)-5-(3-(5-methoxythiophen-2-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that performed for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 6%; 1 H-NMR (400MHz, DMSO-d6): δ 7.33-7.31 (m, 2H), 6.74 (d, J=4.0Hz, 1H), 6.11 (d, J=3.6Hz, 1H), 5.62 (dd, J1=3.2Hz and 10.8Hz, 1H), 3.80 (s, 3H), 3.72 (dd, J=11.6Hz and 18.4Hz, 1H), 3.34 (dd, J=3.6Hz and 17.6Hz, 1H), 2.56 (q, J=6.8Hz, 2H), 2.51 (s, 3H), 1.04 (t, J=7.6Hz, 3H), one exchangeable proton not observed by NMR; LCMS (m / z): 402.2 [M+H] + .

[0157] Example 30: Synthesis of 5-(5-(2-methoxythiazol-5-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(2-methoxythiazol-5-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one (30a): The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 2-methoxythiazole-5-carbaldehyde as starting materials. Yield: 48%; LCMS (m / z): 332.90 [M+H] + .

[0158] Step b: Synthesis of 5-(5-(2-methoxythiazol-5-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one: Using (E)-5-(3-(2-methoxythiazol-5-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 5%; 1H-NMR (400MHz, DMSO-d6): δ 7.33-7.31 (m, 2H), 7.23 (s, 1H), 5.68 (dd, J=12.0Hz and 18.0Hz, 1H), 3.97 (s, 3H), 3.72 (dd, J=11.6Hz and 18.4Hz, 1H), 3.34 (dd, J=3.2Hz and 3.6Hz, 1H), 2.56 (q, J=6.8Hz, 2H), 2.51 (s, 3H), 1.04 (t, J=7.6Hz, 3H), one exchangeable proton not observed by NMR; LCMS (m / z): 402.90 [M+H] + .

[0159] Example 31: Synthesis of 5-(5-(5-bromothiophen-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(5-bromothiophen-3-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one (31a): Using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 5-bromothiophene-3-carbaldehyde as starting materials, the title compound was synthesized using the same procedure as that performed for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 36%; LCMS (m / z): 382.0 [M+2H] + .

[0160] Step b: Synthesis of 5-(5-(5-bromothiophen-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one: Using (E)-5-(3-(5-bromothiophen-3-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-ylThe title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 5%; 1 H-NMR (400 MHz, DMSO-d6): δ 7.42 (s, 1H), 7.35-7.33 (m, 2H), 7.21 (d, J = 0.8 Hz, 1H), 5.53 (dd, J = 3.2 Hz and 11.2 Hz, 1H), 3.62 (dd, J = 11.6 Hz and 17.6 Hz, 1H), 3.25 (dd, J = 3.6 Hz and 18.0 Hz, 1H), 2.61 (q, J = 7.6 Hz, 2H), 2.50 (s, 3H), 1.03 (t, J = 8.0 Hz, 3H), one exchangeable proton not observed by NMR; LCMS (m / z): 452.1 [M + 2H] + .

[0161] Example 32: Synthesis of 4-methyl-5-(5-phenyl-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of 5-cinnamoyl-4-methylthieno[2,3-b]pyridin-6(7H)-one (32a): Using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and benzaldehyde as starting materials, the title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 98%, 1 H-NMR (400 MHz, DMSO-d6): δ 7.74-7.71 (m, 2H), 7.40-7.45 (m, 4H), 7.39-7.35 (m, 2H), 7.12 (d, J=16.4 Hz, 1H), 2.35 (s, 3H), one exchangeable proton not observed by NMR; LCMS (m / z): 296.1 [M+H] + .

[0162] Step b: Synthesis of 4-methyl-5-(5-phenyl-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one: Using 5-cinnamoyl-4-methylthieno[2,3-b]pyridin-6(7H)-one as starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that performed for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: Yield: 37%; 1 H-NMR (400MHz, DMSO-d6): δ 7.36-7.32 (m, 4H), 7.27-7.25 (m, 3H), 5.48 (dd, J=4.0Hz and 11.6Hz, 1H), 3.80 (dd, J=12.0Hz and 18.4Hz, 1H), 3.14 (dd, J=4.4Hz and 18.4Hz, 1H), 2.66 (q, J=7.2Hz, 2H), 2.55 (s, 3H), 1.04 (t, J=7.2Hz, 3H), [NH protons not visible in NMR]; LCMS (m / z): 366.2 [M+H] + .

[0163] Working Example 33 Synthesis of 4-methyl-5-(1-propionyl-5-(thiophen-3-yl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-4-methyl-5-(3-(thiophen-3-yl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one (33a): Using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and thiophene-3-carbaldehyde as starting materials, the title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 96%. 1H-NMR(400MHz,DMSO-d6):δ 12.24(bs,1H),8.17(d,J=2.0Hz,1H),7.64-7.57(m,2H),7.42-7.38(m,1H),7 .34-7.31(m,2H),6.91(d,J=16.4Hz,1H),2.32(s,3H);LCMS(m / z):302.0[M+H] + .

[0164] Step b: Synthesis of 4-methyl-5-(1-propionyl-5-(thiophen-3-yl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one: Using (E)-4-methyl-5-(3-(thiophen-3-yl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one as starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 35%. 1 H-NMR (400MHz, DMSO-d6): δ 7.50-7.48 (m, 1H), 7.41-7.40 (m, 1H), 7.34-7.33 (m, 2H), 7.10 (d, J=4.0Hz, 1H), 5.60 (dd, J=5.0Hz and 15.2Hz, 1H), 3.69-3.68 (m, 1H), 3.25 (dd, J=3.2Hz and 15.2Hz, 1H), 2.61 (q, J=7.2Hz, 2H), 2.50 (s, 3H), 1.03 (t, J=8.0Hz, 3H), [NH protons not visible in NMR]; LCMS (m / z): 372.0 [M+H] + .

[0165] Chiral purification of compound 33 Step e: 33(A): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA(100) at 20° C. with a flow rate of 0.7 mL / min. Enantiomer isolated at 16.33 min.

[0166] Step f: 33(B): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA / DCM (90 / 10) at 20° C. with a flow rate of 0.7 mL / min. Enantiomer isolated at 21.93 min.

[0167] Example 34: Synthesis of 5-(5-(4-bromothiophen-2-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of ((E)-5-(3-(4-bromothiophen-2-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one (34a)): Using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 4-bromothiophene-2-carbaldehyde as starting materials, the title compound was synthesized using the same procedure as that performed for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 95%. LCMS (m / z): 481.9 [M+2H] + .

[0168] Step b: Synthesis of 5-(5-(4-bromothiophen-2-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one: Synthesis of 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 35%. 1H-NMR (400 MHz, DMSO-d6): δ 7.56 (s, 1H), 7.33 (bs, 2H), 7.14 (s, 1H), 5.77 (d, J = 8.0 Hz, 1H), 3.76 (dd, J = 12 Hz and 18.4 Hz, 1H), 3.37 (bs, 1H), 2.63-2.58 (m, 2H), 2.53 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H), one exchangeable proton not observed by NMR; LCMS (m / z): 452.0 [M+2H] + .

[0169] Example 35: Synthesis of 4-methyl-5-(1-propionyl-5-(pyridin-4-yl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one: [ka] Step a: Synthesis of (E)-4-methyl-5-(3-(pyridin-4-yl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one (35a): The title compound was synthesized using the same procedure as that performed for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and isonicotinaldehyde as starting materials. Yield: 60%; LCMS (m / z): 297.10 [M+H] + .

[0170] Step b: Synthesis of 4-methyl-5-(1-propionyl-5-(pyridin-4-yl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one (35b): Using (E)-4-methyl-5-(3-(pyridin-4-yl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-ylThe title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 5%; 1 H-NMR (400 MHz, DMSO-d6): δ 8.55 (d, J = 5.6 Hz, 2H), 7.35-732 (m, 2H), 7.26 (d, J = 6.0 Hz, 2H), 5.52 (dd, J = 4.4 Hz and 12.0 Hz, 1H), 3.85 (dd, J = 12.0 Hz and 18.0 Hz, 1H), 3.17 (dd, J = 4.4 Hz and 18.0 Hz, 1H), 2.62 (q, J = 6.8 Hz, 2H), 2.55 (s, 3H), 1.04 (t, J = 7.6 Hz, 3H), one exchangeable proton not observed by NMR; LCMS (m / z): 367.2 M+H] + .

[0171] Example 36: Synthesis of 4-methyl-5-(1-propionyl-5-(pyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-4-methyl-5-(3-(pyridin-3-yl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one (36a): Using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and nicotinaldehyde as starting materials, the title compound was synthesized using the same procedure as that performed for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 98%. LCMS (m / z): 297.1 [M+H] + .

[0172] Step b: Synthesis of 4-methyl-5-(1-propionyl-5-(pyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one: Using (E)-4-methyl-5-(3-(pyridin-3-yl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one as starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that performed for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 23%. 1 H-NMR (400MHz, DMSO-d6): δ 12.51 (bs, 1H), 8.53 (d, J = 2.0Hz, 1H), 8.48 (dd, J = 1.6Hz and 4.8Hz, 1H), 7.68 (d, J = 7.6Hz, 1H), 7.40-7.32 (m, 3H), 5.55 (dd, J = 4.4Hz and 11.6Hz, 1H), 3.83 (dd, J = 11.6Hz and 18.4Hz, 1H), 3.24 (dd, J = 4.8Hz and 19.2Hz, 1H), 2.64 (q, J = 7.6Hz, 2H), 2.50 (s, 3H), 1.03 (t, J = 7.6Hz, 3H). LCMS (m / z): 367.1 [M+H] + .

[0173] Example 37: Synthesis of 4-methyl-5-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one [ka] Step a: (E)-4-methyl-5-(3-( p-TolylSynthesis of (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) was used to synthesize the title compound using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 4-methylbenzaldehyde as starting materials. Yield: 96%, 1 H-NMR(400MHz,DMSO-d6):δ 12.24(bs,1H),7.60(d,J=8.0Hz,2H),7.38(d,J=16.4Hz,1H),7.33-7.30(m,2H),7 .22(d,J=8.0Hz,2H),7.06(d,J=16.4Hz,1H),2.33(s,6H);LCMS(m / z):310.2[M+H] + .

[0174] Step b: Synthesis of 4-methyl-5-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one: (E)-4-methyl-5-(3-( p-Tolyl )acryloyl)thieno[2,3-b]pyridin-6(7H)-one to produce 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that performed for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 37%. 1 H-NMR (400MHz, DMSO-d6): δ 7.35-7.34 (m, 2H), 7.19-7.14 (m, 4H), 5.44 (dd, J=4.0Hz and 11.6Hz, 1H), 3.76 (dd, J=11.6Hz and 18.0Hz, 1H), 3.10 (dd, J=4.4Hz and 18.4Hz, 1H), 2.66 (q, J=7.2Hz, 2H), 2.54 (s, 3H), 2.27 (s, 3H), 1.03 (t, J=7.6Hz, 3H), one exchangeable proton not observed by NMR; LCMS (m / z): 380.1 [M+H] + .

[0175] Chiral purification of compound 37 Step e: 37(A): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA(100) at 20° C. with a flow rate of 0.7 mL / min. The isolated enantiomer was at 13.13 min (levo (left-handed, −) isomer).

[0176] Step f: 37(B): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA / DCM (90 / 10) at 20° C. with a flow rate of 0.7 mL / min. The isolated enantiomer was at 18.87 min (dextro (right-handed, +) isomer).

[0177] Example 38: Synthesis of 4-methyl-5-(5-(4-(4-methylpiperazin-1-yl)phenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-4-methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 4-(4-methylpiperazin-1-yl)benzaldehyde as starting materials. Yield: 79%; LCMS: m / z 393.51 [M+H] + .

[0178] Step b: Synthesis of 4-methyl-5-(5-(4-(4-methylpiperazin-1-yl)phenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one Using (E)-4-methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 11%; 1 H-NMR(400MHz,DMSO-d6):δ 12.45(bs,H),7.32-7.31(m,2H),7.12(d,J=8.8Hz,2H),6.883(d,J=8.4Hz,2H),5.381(dd,J=4.4Hz and J=11.6Hz,1H),3.72(m,1H),3.28( LCMS:m / z 464.20[M+H] + .

[0179] Example 39: Synthesis of 5-(5-(4-(dimethylamino)phenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(4-(dimethylamino)phenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 4-(dimethylamino)benzaldehyde as starting materials. Yield: 53%; LCMS: m / z 339.48 [M+H] + .

[0180] Step b: Synthesis of 5-(5-(4-(dimethylamino)phenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 11%; 1 H-NMR (400 MHz, DMSO-d6): δ 7.33 (s, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.8 Hz, 2H), 5.37 (dd, J = 4 Hz and J = 11.2 Hz, 1H), 3.71 (m, 1H), 3.11 (dd, J = 4.4 Hz and J = 18.4 Hz, 1H), 2.86 (s, 6H), 2.59 (m, 2H), 2.54 (s, 3H), 1.02 (t, J = 7.6 Hz, 3H), [NH protons not visible by NMR]; LCMS: m / z 409.30 [M+H] + .

[0181] Example 40: Synthesis of 3-chloro-5-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of 5-acetyl-3-chloro-4-methylthieno[2,3-b]pyridin-6(7H)-one To a stirred solution of 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one (0.12 g, 0.58 mmol) in DMF (5 mL) at 0° C. was added N-chlorosuccinimide (0.85 g, 0.638 mmol). The reaction mixture was stirred at room temperature for 16 h and the progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 10-20% ethyl acetate in hexane as the eluent to give the title compound. Yield: 0.1 g; LCMS: m / z 242.10 [M+H] + .

[0182] Step b: Synthesis of (E)-3-chloro-5-(3-(4-methoxyphenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-3-chloro-4-methylthieno[2,3-b]pyridin-6(7H)-one and 4-methoxybenzaldehyde as starting materials. LCMS: m / z 360.10 [M+H] + .

[0183] Step c: Synthesis of 3-chloro-5-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one Using (E)-3-chloro-5-(3-(4-methoxyphenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-ylThe title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 4%; 1 H-NMR (400MHz, DMSO-d6): δ 7.45(s,1H), 7.20(d,J=8.8Hz,2H), 6.88(d,J=8.8Hz,2H), 5.42(dd,J=4Hz and J=11.6Hz,1H), 3.732(m,4H), 3.10(dd,J=4.4Hz and J=18.4Hz,1H), 2.67-2.55(q,2H), 2.52-2.5(s,3H), 1.025(t,=7.6Hz,3H), [NH protons not visible by NMR]; LCMS: m / z 430.30[M+H] + .

[0184] Example 41: Synthesis of 5-(5-(5-methylthiophen-2-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-4-methyl-5-(3-(5-methylthiophen-2-yl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 5-methylthiophene-2-carbaldehyde as starting materials. Yield: 52%; LCMS: m / z 316.00 [M+H] + .

[0185] Step b: Synthesis of 5-(5-(5-methylthiophen-2-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one Using (E)-4-methyl-5-(3-(5-methylthiophen-2-yl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 10%; 1 H-NMR (400 MHz, DMSO-d6): δ 7.33 (s, 2H), 6.86 (d, J = 3.2 Hz, 1H), 6.62 (d, J = 2 Hz, 1H), 5.69 (dd, J = 3.2 Hz and J = 11.2 Hz, 1H), 3.761 (m, 1H), 3.29 (dd, J = 4.8 Hz and 13.6 Hz, 1H), 2.58-2.50 (m, 5H), 2.38 (s, 3H), 1.043 (t, J = 7.6 Hz, 3H), [NH protons not visible by NMR]; LCMS: m / z 386.0 [M+H] + .

[0186] Example 42: Synthesis of 4-methyl-5-(1-propionyl-5-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-4-methyl-5-(3-(4-(trifluoromethyl)phenyl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one (42a)): Using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 4-(trifluoromethyl)benzaldehyde as starting materials, the title compound was synthesized using the same procedure as that performed for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 82%. LCMS (m / z): 364.1 [M+H] + .

[0187] Step b: Synthesis of 4-methyl-5-(1-propionyl-5-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one: Using ((E)-4-methyl-5-(3-(4-(trifluoromethyl)phenyl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one) as starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 16%; 1 H-NMR (400 MHz, DMSO-d6): δ 7.72 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.35-7.32 (m, 2H), 5.55 (dd, J = 4.4 Hz and 7.6 Hz, 1H), 3.86 (dd, J = 12.0 Hz and 18.4 Hz, 1H), 3.16 (dd, J = 4.8 Hz and 13.6 Hz, 1H), 2.69-2.64 (m, 2H), 2.56 (s, 3H), 1.03 (t, J = 7.6 Hz, 3H), one exchangeable proton not observed by NMR; LCMS (m / z): 434.1 [M+H] + .

[0188] Example 43: Synthesis of 5-(5-(4-(difluoromethyl)phenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(4-(difluoromethyl)phenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 4-(difluoromethyl)benzaldehyde as starting materials. Yield: 79%; LCMS: m / z 346.10 [M+H] + .

[0189] Step b: Synthesis of 5-(5-(4-(difluoromethyl)phenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one Synthesis of 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 19%; 1 H-NMR (400 MHz, DMSO-d6): δ 7.35-7.32 (m, 2H), 7.40 (d, J=3.2 Hz, 1H), 6.26 (d, J=2.0 Hz, 1H), 5.543 (dd, J=4.4 Hz and J=12 Hz, 1H), 3.80 (q, J=7.6 Hz, 1H), 3.14 (dd, J=4.8 Hz and J=18.8 Hz, 1H), 2.64 (m, 2H), 2.55 (s, 3H), 1.04 (t, J=7.2 Hz, 3H), [NH protons not visible by NMR]; LCMS: m / z 416.10 [M+H] + .

[0190] Example 44: Synthesis of 5-(5-(4-ethylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(4-ethylphenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one (44a): Using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 4-ethylbenzaldehyde as starting materials, the title compound was synthesized using the same procedure as that performed for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 83%. LCMS (m / z): 324.1 [M+H] + .

[0191] Step b: Synthesis of 5-(5-(4-ethylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one: Using (E)-5-(3-(4-ethylphenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that performed for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 34%, 1H-NMR (400MHz, DMSO-d6): δ 7.35-7.33 (m, 2H), 7.17-7.14 (m, 4H), 5.55 (dd, J=4.4Hz and 12.0Hz, 1H), 3.78 (dd, J=11.6Hz and 18.4Hz, 1H), 3.12 (dd, J=4.4Hz and 14.0Hz, 1H), 2.64 (q, J=7.6Hz, 2H), 2.63-2.59 (m, 2H), 2.54 (s, 3H), 1.17 (t, J=7.2Hz, 3H), 1.03 (t, J=7.6Hz, 3H), one exchangeable proton not observed by NMR; LCMS (m / z): 394.1 [M+H] + .

[0192] Example 45: Synthesis of 4-methyl-5-(5-(6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-4-methyl-5-(3-(6-methylpyridin-3-yl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one (45a): Using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 6-methylnicotinaldehyde as starting materials, the title compound was synthesized using the same procedure as that performed for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 98%. LCMS (m / z): 311.1 [M+H] + .

[0193] Step b: Synthesis of 4-methyl-5-(5-(6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one: Using (E)-4-methyl-5-(3-(6-methylpyridin-3-yl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one as starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that performed for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 22%, 1H-NMR (400MHz, DMSO-d6): δ 12.50 (bs, 1H), 8.39 (d, J = 2.0Hz, 1H), 7.56 (dd, J = 2.0Hz and 8.0Hz, 1H), 7.35-7.31 (m, 2H), 7.23 (d, J = 8.0Hz, 1H), 5.52 (dd, J = 4.4Hz and 12.0Hz, 1H), 3.78 (dd, J = 12.0Hz and 18.4Hz, 1H), 3.22 (dd, J = 4.0Hz and 18.4Hz, 1H), 2.64 (q, J = 7.6Hz, 2H), 2.58 (s, 3H), 2.44 (s, 3H), 1.02 (t, J = 7.2Hz, 3H); LCMS (m / z): 381.1 [M+H] + .

[0194] Chiral purification of compound 45 Step e: 45(A): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA(100) at 20° C. with a flow rate of 0.7 mL / min. The isolated enantiomer was at 19.45 min (dextro(+) isomer).

[0195] Step f: 45(B): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA / DCM (90 / 10) at 20° C. with a flow rate of 0.7 mL / min. The isolated enantiomer was at 41.22 min (levo(-) isomer).

[0196] Example 46: Synthesis of 4-methyl-5-(1-propionyl-5-(4-(pyrrolidin-1-yl)phenyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one [ka] Step a: 4-methyl-5(-5-(4-(pyrrolidin-1-yl)phenyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one To a solution of (E)-4-methyl-5-(3-(4-(pyrrolidin-1-yl)phenyl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one (155 mg, 0.315 mmol) in ethanol (3 mL) was added 99% hydrazine hydrate (0.1 mL) and refluxed for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature and the ethanol was evaporated under reduced pressure. The residue was diluted with ethanol (15 mL) and the resulting solid was filtered, washed with water and dried under vacuum to give the title compound as an off-white solid. Yield: 50 mg (42%); LC-MS: m / z 378.49 [M+H] + .

[0197] Step b: Synthesis of 4-methyl-5-(1-propionyl-5-(4-(pyrrolidin-1-yl)phenyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one To a stirred solution of 4-methyl-5(-5-(4-(pyrrolidin-1-yl)phenyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one (0.05 g, 0.131 mmol) in DCM (3 mL) at 0° C. was added pyridine (0.031 g, 0.394 mmol), DMAP (0.001 g, 0.157 mmol) and propionyl chloride (0.014 g, 0.0131 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was extracted with DCM (10 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 3-2% methanol in DCM as eluent to give the title compound as an off-white solid. Yield: 0.012 g (19%); 1H-NMR (300 MHz, DMSO-d6): δ 7.336 (s, 2H), 7.091 (d, J=8.8 Hz, 2H), 6.478 (d, J=8.8 Hz, 2H), 5.359 (dd, J=3.6 Hz and J=11.6 Hz, 1H), 3.709 (m, 1H), 3.193 (t, J=6.4 Hz, 4H), 3.14-3.08 (dd, J=4 Hz and J=18.4 Hz), 2.67-2.57 (m, 2H), 2.541 (s, 3H), 1.934 (t, J=6.4 Hz, 4H) [NH protons not visible by NMR]: LCMS: m / z 434.56 [M+H].

[0198] Example 47: Synthesis of 5-(5-(4-cyclopropylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(4-cyclopropylphenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one (47a): Using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 4-cyclopropylbenzaldehyde as starting materials, the title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c). Yield: 86%. 1 H-NMR (400MHz, DMSO-d6): δ 7.56 (d, J = 8.4 Hz, 2H), 7.37-7.33 (m, 1H), 7.26 (d, J = 5.6 Hz, 2H), 7.11-7.08 (m, 3H), 2.30 (s, 3H), 1.96-1.92 (m, 1H), 1.08-0.96 (m, 2H), 0.73-0.66 (m, 2H), one exchangeable proton not observed by NMR; LCMS (m / z): 336.0 [M+H] + .

[0199] Step b: Synthesis of 5-(5-(4-cyclopropylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one: Using (E)-5-(3-(4-cyclopropylphenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that performed for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 14%, 1 H-NMR(400MHz,DMSO-d6):δ 7.34-7.33(m,2H), 7.13(d,J=8.0Hz,2H), 7.05(d,J=8.0Hz,2H), 5.55(dd,J=4.4Hz and 12.0Hz,1H), 3.78(dd,J=11.6Hz and 18.4Hz,1H), 3.12(dd,J=4.4Hz and 18.4Hz,1H), 2.64(q,J=7.6Hz,2H), 2.54(s,3H), 1.90-1.86(m,1H), 1.03(t,J=7.6Hz,3H), 0.94-0.89(m,2H), 0.66-0.62(m,2H), one exchangeable proton not observed by NMR; LCMS(m / z):406.2[M+H] + .

[0200] Example 48: Synthesis of 4-methyl-5-(5-(2-methylthiazol-4-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-4-methyl-5-(3-(2-methylthiazol-4-yl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 2-methylthiazole-4-carbaldehyde as starting materials. Yield: 52%; LCMS: m / z 317.10 [M+H] + .

[0201] Step b: Synthesis of 4-methyl-5-(5-(2-methylthiazol-4-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one Using (E)-4-methyl-5-(3-(2-methylthiazol-4-yl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 51%; 1 H-NMR(400MHz,DMSO-d6):δ 12.45(bs,H),7.33(d,J=5.2Hz,2H),7.23(s,1H),5.57(dd,J=4.4Hz and J=11.6Hz,1H),3.76(q,J= 11.6,1H),3.16(dd,J=4.4Hz and J=18Hz,1H),2.67-2.57(m,8H),1.025(m,J=14.8Hz,3H);LCMS:m / z 387.20[M+H] + .

[0202] Example 49: Synthesis of 5-(5-(4-isopropylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(4-isopropylphenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 4-isopropylbenzaldehyde as starting materials. Yield: 61%; LCMS: m / z 338.10 [M+H] + .

[0203] Step b: Synthesis of 5-(5-(4-isopropylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one Synthesis of 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 20%; 1 H-NMR (400 MHz, DMSO-d6): δ 7.336 (s, 2H), 7.22-7.16 (q, J=8.4 Hz and J=14.8, 4H), 5.443 (dd, J=4.4 Hz and J=12 Hz, 1H), 3.76 (m, J=12 Hz and J=18.4 Hz, 1H), 3.11 (dd, J=4.4 Hz and J=18 Hz, 1H), 2.86 (m, 1H), 2.647 (q, J=7.6 Hz, 2H), 2.55 (s, 3H), 1.19 (d, J=6.8 Hz, 6H), 1.03 (t, J=7.6 Hz, 3H), [NH protons not visible by NMR]; LCMS: m / z 408.10 [M+H] + .

[0204] Example 50: Synthesis of 5-(5-(4,6-dimethylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(4,6-dimethylpyridin-3-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that performed for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 4,6-dimethylnicotinaldehyde as starting materials. Yield: 83%; LCMS: m / z 325.0 [M+H] + .

[0205] Step b: Synthesis of 5-(5-(4,6-dimethylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one Using (E)-5-(3-(4,6-dimethylpyridin-3-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 36%; 1H-NMR (400 MHz, DMSO-d6): δ 8.08 (s, 1H), 7.35-7.34 (m, 2H), 7.06 (s, 1H), 5.60 (dd, J=4.8 Hz and J=12.0 Hz, 1H), 3.88 (dd, J=12.0 Hz and J=18.0 Hz, 1H), 3.06 (dd, J=5.2 Hz and J=18.4 Hz, 1H), 2.69 (q, J=7.6 Hz, 2H), 2.58 (s, 3H), 2.38 (s, 3H), 2.33 (s, 3H), 1.05 (t, J=7.2 Hz, 3H), [NH protons not visible by NMR]; LCMS: m / z 395.10 [M+H] + .

[0206] Example 51: Synthesis of 4-methyl-5-(5-(2-methylpyrimidin-5-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-4-methyl-5-(3-(2-methylpyrimidin-5-yl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 2-methylpyrimidine-5-carbaldehyde as starting materials. Yield: 20%; LCMS: m / z 312.0 [M+H] + .

[0207] Step b: Synthesis of 4-methyl-5-(5-(2-methylpyrimidin-5-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one Using (E)-5-(3-(4,6-dimethylpyridin-3-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-(6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 50%; 1 H-NMR (400 MHz, DMSO-d6): δ 8.66 (s, 2H), 7.33-725 (m, 2H), 5.54 (dd, J=4.4 Hz and J=11.6 Hz, 1H), 3.76 (dd, J=12.4 Hz and J=18.8 Hz, 1H), 3.28 (m, 1H), 2.60 (q, J=7.6 Hz, 2H), 2.58 (s, 3H), 2.54 (s, 3H), 1.01 (t, J=7.6 Hz, 3H), [NH protons not visible by NMR]; LCMS: m / z 382.0 [M+H] + .

[0208] Example 52: Synthesis of 5-(5-(5-chloro-6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(5-chloro-6-methylpyridin-3-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 5-chloro-6-methylnicotinaldehyde as starting materials. Yield: 99%; LCMS: m / z 344.90 [M+H] + .

[0209] Step b: Synthesis of 5-(5-(5-chloro-6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one Using (E)-5-(3-(5-chloro-6-methylpyridin-3-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 10%; 1 H-NMR (400MHz, DMSO-d6): δ 8.38(s,1H), 7.80(s,1H), 7.4-7.32(m,2H), 5.55(dd,J=4.4Hz and J=11.6Hz,1H), 3.76(dd,J=11.6Hz and J=18.4Hz,1H), 3.28(dd,J=4.8Hz and J=18.8Hz,1H), 2.63(q,J=7.6Hz,2H), 2.54(s,3H), 2.52(s,3H), 1.01(t,J=7.6Hz,3H), [NH protons not visible by NMR]; LCMS: m / z 414.90[M+H] + .

[0210] Example 53: Synthesis of 5-(5-(4-methoxy-6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(4-methoxy-6-methylpyridin-3-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 4-methoxy-6-methylnicotinaldehyde as starting materials. Yield: 99%; LCMS: m / z 341.00 [M+H] +.

[0211] Step b: Synthesis of 5-(5-(4-methoxy-6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one Using 5-(5-(4-methoxy-6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 14%; 1 H-NMR (400MHz, DMSO-d6): δ 7.92(s,1H), 7.34-7.32(m,2H), 6.95(s,1H), 5.54(dd,J=4.8Hz and J=12.0Hz,1H), 3.84(s,3H), 3.81(dd,J=11.6Hz and J=18.4Hz,1H), 2.99(dd,J=4.8Hz and J=18.8Hz,1H), 2.62(q,J=7.6Hz,2H), 2.59(s,3H), 2.41(s,3H), 1.05(t,J=7.2Hz,3H), [NH protons not visible by NMR]; LCMS: m / z 411.0[M+H] + .

[0212] Example 54: Synthesis of 5-(5-(5,6-dimethylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(5,6-dimethylpyridin-3-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 5,6-dimethylnicotinaldehyde as starting materials. 1 H-NMR(400MHz,DMSO-d6):δ 12.07(bs,1H),8.52(s,1H),7.95(s,1H),7.41(d,J=16.0Hz,1H),7.34-7.32(m,2H),7.18(d,J=16.4Hz,1H),2.45(s,3H),2.35(m,3H). 2.26(s,3H). Yield: 88%; LCMS: m / z 325.00[M+H] + .

[0213] Step b: Synthesis of 5-(5-(5,6-dimethylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one Using (E)-5-(3-(5,6-dimethylpyridin-3-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 7%; 1H-NMR (400MHz, DMSO-d6): δ 8.20 (d, J=2.0, 1H), 7.42 (s, 1H), 7.34-7.32 (m, 2H), 6.95 (s, 1H), 5.54 (dd, J=4.4Hz and J=12.0Hz, 1H), 3.79 (dd, J=12.0Hz and J=18.4Hz, 1H), 3.20 (dd, J=4.4Hz and J=18.4Hz, 1H), 2.62 (q, J=7.2Hz, 2H), 2.55 (s, 3H), 2.39 (s, 3H), 2.23 (s, 3H), 1.05 (t, J=7.6Hz, 3H), [NH protons not visible by NMR]; LCMS: m / z 395.10 [M+H] + .

[0214] Example 55: Synthesis of 5-(5-(5-fluoro-6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(5-fluoro-6-methylpyridin-3-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 5-fluoro-6-methylnicotinaldehyde as starting materials. 1 H-NMR(400MHz,DMSO-d6):δ 12.09(bs,1H),8.61(s,1H),8.12(d,J=9.6Hz,1H),8.47(d,J=16.8Hz,1H),7.34-7.32(m,2H),7.27(d,J=16.4Hz,1H),2.47(s,3H),2.34(s,3H). Yield: 63%; LCMS: m / z 328.90[M+H] + .

[0215] Step b: Synthesis of 5-(5-(5-fluoro-6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one Using (E)-5-(3-(5-fluoro-6-methylpyridin-3-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 8%; 1 H-NMR (400MHz, DMSO-d6): δ 8.29 (d, J=2.0, 1H), 7.56 (d, J=9.2, 1H), 7.35-7.32 (m, 2H), 5.56 (dd, J=4.4Hz and J=11.6Hz, 1H), 3.77 (dd, J=11.6Hz and J=18.4Hz, 1H), 3.26 (dd, J=4.4Hz and J=18.4Hz, 1H), 2.62 (q, J=7.2Hz, 2H), 2.59 (s, 3H), 2.49 (s, 3H), 1.02 (t, J=7.6Hz, 3H), [NH protons not visible by NMR]; LCMS: m / z 399.00 [M+H] + .

[0216] Example 56: Synthesis of 5-(5-(4-chloro-6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(4-chloro-6-methylpyridin-3-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one To a stirred solution of 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one (0.3 g, 1.44 mmol) in ethanol (10 mL) was added 4-chloro-6-methylnicotinaldehyde (0.34 g, 2.17 mmol), the reaction mixture was cooled to 0° C., and then 25% aqueous sodium hydroxide (1.15 mL) was added dropwise slowly over 3-5 min. The reaction mixture was stirred at room temperature for 1 h and the progress of the reaction was monitored by TLC. The reaction mixture was cooled to 0° C., acidified with 6N HCl (to pH ca. 5) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (25 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 50-60% ethyl acetate in hexane as eluent to give the title compound as an off-white solid. Yield: 0.48g (96%); LCMS: m / z 345.00[M+H] + .

[0217] Step b: Synthesis of 5-(5-(4-chloro-6-methylpyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 2a) using (E)-5-(3-(4-chloro-6-methylpyridin-3-yl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as starting material. Yield: 44%; LCMS: m / z 358.90 [M+H] + .

[0218] Step c: Synthesis of 5-(5-(4-chloro-6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(1-(cyclopropanecarbonyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 2) using 5-(5-(4-chloro-6-methylpyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as starting material. Yield: 47%; 1 H-NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.46 (s, 1H), 7.34-7.32 (m, 2H), 5.69 (dd, J=5.2 Hz and J=11.6 Hz, 1H), 3.91 (dd, J=12.0 Hz and J=18.4 Hz, 1H), 3.13 (dd, J=5.6 Hz and J=18.4 Hz, 1H), 2.66 (q, J=7.2 Hz, 2H), 2.57 (s, 3H), 2.45 (s, 3H), 1.06 (t, J=7.2 Hz, 3H), [NH protons not visible by NMR]; LCMS: m / z 414.90 [M+H] + .

[0219] Example 57: Synthesis of 4-methyl-5-(5-(2-methylthiazol-5-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-4-methyl-5-(3-(2-methylthiazol-5-yl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 2-methylthiazole-5-carbaldehyde as starting materials. Yield: 96%; LCMS: m / z 317.10 [M+H] + .

[0220] Step b: Synthesis of 5-(5-(2-methoxythiazol-5-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one Using (E)-4-methyl-5-(3-(2-methylthiazol-5-yl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 43%; 1 H-NMR (400 MHz, DMSO-d6): δ 7.63 (s, 1H), 7.35-7.32 (m, 2H), 5.81 (dd, J=3.2 Hz and J=11.2 Hz, 1H), 3.79 (dd, J=11.6 Hz and J=18.4 Hz, 1H), 3.39 (dd, J=3.2 Hz and J=18.0 Hz, 1H), 2.59 (q, J=7.2 Hz, 2H), 2.59 (s, 3H), 2.49 (s, 3H), 1.02 (t, J=7.6 Hz, 3H), [NH protons not visible by NMR]; LCMS: m / z 387.0 [M+H] + .

[0221] Example 58: Synthesis of 5-(5-cyclohexyl-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-cyclohexylacryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and cyclohexanecarbaldehyde as starting materials. Yield: 21%; LCMS: m / z 302.00 [M+H] + .

[0222] Step b: Synthesis of 5-(5-cyclohexyl-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one Using (E)-5-(3-cyclohexylacryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 11%; 1 H-NMR(400MHz,DMSO-d6):δ 7.31-7.29(m,2H), 4.40(dd,J=3.2Hz and J=6.8Hz,1H), 3.26(dd,J=11.6Hz and J=18.4Hz,1H), 3.10(dd,J=4.4Hz and J=18.4Hz,1H), 2.62(q,J=7.2Hz,2H), 2.05-2.04(m,1H), 1.69-1.51(m,4H), 1.36-1.32(m,1H), 1.23-1.21(m,2H), 1.18-1.14(m,2H), 1.08(t,J=7.6Hz,3H), 0.98-0.96(m,1H),[NH protons not visible by NMR];LCMS: m / z 372.10[M+H] + .

[0223] Example 59: Synthesis of 6-chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one [ka] Step a: Synthesis of (E)-6-chloro-4-methyl-3-(3-(p-tolyl)acryloyl)quinolin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-6-chloro-4-methylquinolin-2(1H)-one and 4-methylbenzaldehyde as starting materials. 1 H-NMR(400MHz,DMSO-d6):δ 12.09(bs,1H),7.86(d,J=2.0Hz,1H),7.64-7.62(m,3H),7.46(d,J=16.8Hz,1H),7.38(d,J=8. 8Hz,1H), 7.24(d,J=8.0Hz,2H),7.03(d,J=16.0Hz,1H),2.47(s,3H),2.33(s,3H),2.30(s,3H). Yield: 83%; LCMS: m / z 338.00[M+H] + .

[0224] Step b: Synthesis of 6-chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one Using (E)-6-chloro-4-methyl-3-(3-(p-tolyl)acryloyl)quinolin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 11%; 1H-NMR(400MHz,DMSO-d6):δ 12.07(bs,1H),7.89(d,J=2.0,1H),7.62(dd,J=2.4Hz and J=8.8Hz,1H),7.3 7(d,J=8.8,1H),7.18-7.93(m,4H),5.49(dd,J=4.4Hz and J=12.0Hz,1H),3.7 8(dd,J=12.4Hz and J=18.8Hz,1H),3.09(dd,J=4.8Hz and J=18.4Hz,1H),2.62(q,J=7.6Hz,2H),2.59(s,3H),2.28(s,3H),1.03(t,J=7.2Hz,3H),LCMS:m / z 408.20[M+H] + .

[0225] Example 60: Synthesis of 4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one [ka] Step a: Synthesis of (E)-4-methyl-3-(3-(p-tolyl)acryloyl)quinolin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-4-methylquinolin-2(1H)-one and 4-methylbenzaldehyde as starting materials. Yield: 89%; 1 H-NMR(400MHz,DMSO-d6):δ 11.95(bs,1H),7.83(d,J=8.4,1H),7.69(d,J=8.0Hz,1H),7.58(t,J=7.2Hz,2H),7.43(d,J=5.6Hz,1H) ,7.37(d,J=8.4Hz,1H),7.28-7.22(m,3H),7.02(d,J=16.4Hz,1H),2.35(s,3H),2.32(s,3H),LCMS:m / z 304.20[M+H] + .

[0226] Step b: Synthesis of 4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one Using (E)-4-methyl-3-(3-(p-tolyl)acryloyl)quinolin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 37%; 1 H-NMR(400MHz,DMSO-d6):δ 12.07(bs,1H),7.85(d,J=8.0Hz,1H),7.56(t,J=7.2Hz,1H),7.35(d,J=8.0Hz, 1H),7.26(t,J=7.2Hz,1H),7.19-7.14(m,4H),5.48(dd,J=4.4Hz and J=12.0Hz,1 H),3.78(dd,J=12.4Hz and J=18.4Hz,1H),3.09(dd,J=4.8Hz and J=18.4Hz,1H),2. 62(q,J=7.2Hz,2H),2.59(s,3H),2.28(s,3H),1.03(t,J=7.2Hz,3H),LCMS:m / z 374.20[M+H] + .

[0227] Chiral purification of compound 60 Step e: 60(A): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA(100) at 20° C. with a flow rate of 0.7 mL / min. Enantiomer isolated at 20.97 min.

[0228] Step f: 60(B): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA / DCM (90 / 10) at 20° C. with a flow rate of 0.7 mL / min. Enantiomer isolated at 31.04 min.

[0229] Example 61: Synthesis of 6-chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,5-naphthyridin-2(1H)-one [ka] Step a: Synthesis of (E)-6-chloro-4-methyl-3-(3-(p-tolyl)acryloyl)-1,5-naphthyridin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-6-chloro-4-methyl-1,5-naphthyridin-2(1H)-one and 4-methylbenzaldehyde as starting materials. Yield: 88%; 1 H-NMR(400MHz,DMSO-d6):δ 12.23(bs,1H),7.78(d,J=8.8,1H),7.68(d,J=2.8Hz,1H),7.65(d,J=8.0Hz,2H),7.54(d,J=1 6.4Hz,1H),7.25(d,J=8.0Hz,2H),7.03(d,J=16.4Hz,1H),2.34(s,3H),2.31(s,3H),LCMS:m / z 339.00[M+H] + .

[0230] Step b: Synthesis of 6-chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,5-naphthyridin-2(1H)-one Using (E)-6-chloro-4-methyl-3-(3-(p-tolyl)acryloyl)-1,5-naphthyridin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 34%; 1H-NMR(400MHz,DMSO-d6):δ 12.23(bs,1H),7.75(d,J=8.4Hz,1H),7.56(t,J=8.4Hz,1H),7.16-7.14(m,4H),5.48(dd,J=4.4Hz and J=11.6Hz,1H),3.85(dd,J=12.0Hz and J=18.4Hz,1H),3.14(dd,J=4.4Hz and J=18.4Hz,1H),2.62(q,J=7.2Hz,2H),2.60(s,3H),2.28(s,3H),1.03(t,J=7.2Hz,3H),LCMS:m / z 409.20[M+H] + .

[0231] Example 62: Synthesis of 5-(1-acetyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-7,7a-dihydrothieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of 4-methyl-5-(5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-7,7a-dihydrothieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (compound 2a) using (E)-4-methyl-5-(3-(p-tolyl)acryloyl)-7,7a-dihydrothieno[2,3-b]pyridin-6(3aH)-one and hydrazine hydrate as starting materials. Yield: 72%; LCMS: m / z 324.10 [M+H] + .

[0232] Step b: Synthesis of 5-(1-acetyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-7,7a-dihydrothieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(1-(cyclopropanecarbonyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 2) using 4-methyl-5-(5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-7,7a-dihydrothieno[2,3-b]pyridin-6(3aH)-one and acetyl chloride as starting materials. Yield: 53%; 1 H-NMR (400 MHz, DMSO-d6): δ 7.34-7.32 (m, 2H), 7.18-7.13 (m, 4H), 5.46 (dd, J=4.0 Hz and J=11.6 Hz, 1H), 3.79 (dd, J=11.6 Hz and J=18.4 Hz, 1H), 3.13 (dd, J=4.0 Hz and J=18.0 Hz, 1H), 2.54 (s, 3H), 2.27 (s, 3H), 2.21 (s, 3H), [NH protons not visible by NMR]; LCMS: m / z 366.00 [M+H] + .

[0233] Example 63: Synthesis of 5-(1-isobutyryl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-7,7a-dihydrothieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of 5-(1-isobutyryl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-7,7a-dihydrothieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(1-(cyclopropanecarbonyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 2) using 4-methyl-5-(5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-7,7a-dihydrothieno[2,3-b]pyridin-6(3aH)-one and isobutyryl chloride as starting materials. Yield: 45%;1 H-NMR (400 MHz, DMSO-d6): δ 7.34-7.32 (m, 2H), 7.18-7.13 (m, 4H), 5.46 (dd, J=4.4Hz and J=12.0Hz, 1H), 3.79 (dd, J=12.0Hz and J=18.4Hz, 1H), 3.32-3.27 (m, 1H), 3.13 (dd, J=4.4Hz and J=18.4Hz, 1H), 2.54 (s, 3H), 2.27 (s, 3H), 1.07-1.04 (m, 6H), [NH protons not visible by NMR]; LCMS: m / z 394.20 [M+H] + .

[0234] Example 64: Synthesis of 4-methyl-5-(5-(p-tolyl)-1-(2,2,2-trifluoroacetyl)-4,5-dihydro-1H-pyrazol-3-yl)-7,7a-dihydrothieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of 4-methyl-5-(5-(p-tolyl)-1-(2,2,2-trifluoroacetyl)-4,5-dihydro-1H-pyrazol-3-yl)-7,7a-dihydrothieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for 6-chloro-3-(1-(cyclopropanecarbonyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 2) using 4-methyl-5-(5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-7,7a-dihydrothieno[2,3-b]pyridin-6(3aH)-one and 2,2,2-trifluoroacetic anhydride as starting materials. Yield: 54%; 1H-NMR (400 MHz, DMSO-d6): δ 7.37-7.35 (m, 2H), 7.23-7.18 (m, 4H), 5.63 (dd, J=4.0 Hz and J=11.6 Hz, 1H), 3.77 (dd, J=11.6 Hz and J=18.8 Hz, 1H), 3.39 (dd, J=4.4 Hz and J=18.4 Hz, 1H), 2.55 (s, 3H), 2.29 (s, 3H), [NH protons not visible by NMR]; LCMS: m / z 420.10 [M+H] + .

[0235] Example 65: Synthesis of 5-(5-(2-chloro-4-methylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(2-chloro-4-methylphenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 2-chloro-4-methylbenzaldehyde as starting materials. Yield: 73%; 1 H-NMR(400MHz,DMSO-d6):δ 12.23(bs,1H),7.83(d,J=15.6,1H),7.45(d,J=7.2Hz,1H),7.10(s,1H),701.-6.99(m ,2H),6.90(d,J=7.6Hz,1H),6.86(d,J=5.6Hz,1H),2.37(s,3H),2.26(s,3H),LCMS:m / z 344.00[M+H] + .

[0236] Step b: Synthesis of 5-(5-(2-chloro-4-methylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one Using (E)-5-(3-(2-chloro-4-methylphenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 33%; 1 H-NMR (400MHz, DMSO-d6): δ 7.35-7.32 (m, 2H), 7.31 (s, 1H), 7.13 (d, J=8.0Hz, 1H), 7.00 (d, J=8.0Hz, 1H), 5.67 (dd, J=4.8Hz and J=12.0Hz, 1H), 3.87 (dd, J=12.0Hz and J=18.0Hz, 1H), 3.03 (dd, J=4.8Hz and J=18.4Hz, 1H), 2.72 (q, J=7.2Hz, 2H), 2.59 (s, 3H), 2.49 (s, 3H), 1.02 (t, J=7.6Hz, 3H), [NH protons not visible by NMR]; LCMS: m / z 414.00 [M+H] + .

[0237] Example 66: Synthesis of 5-(5-(2-fluoro-4-methylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(2-fluoro-4-methylphenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 2-fluoro-4-methylbenzaldehyde as starting materials. Yield: 51%; LCMS: m / z 328.00 [M+H] + .

[0238] Step b: Synthesis of 5-(5-(2-fluoro-4-methylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one Using (E)-5-(3-(2-fluoro-4-methylphenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 53%; 1 H-NMR (400MHz, DMSO-d6): δ 7.35-7.32 (m, 2H), 7.09-6.97 (m, 3H), 5.59 (dd, J=4.8Hz and J=12.0Hz, 1H), 3.87 (dd, J=12.4Hz and J=18.4Hz, 1H), 3.26 (dd, J=4.8Hz and J=18.4Hz, 1H), 2.65 (q, J=7.6Hz, 2H), 2.59 (s, 3H), 2.29 (s, 3H), 1.05 (t, J=7.6Hz, 3H), [NH protons not visible by NMR]; LCMS: m / z 398.20 [M+H] + .

[0239] Chiral purification of compound 66 Step e: 66(A): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA(100) at 20° C. with a flow rate of 0.7 mL / min. Enantiomer isolated at 12.43 min.

[0240] Step f: 66(B): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA / DCM (90 / 10) at 20° C. with a flow rate of 0.7 mL / min. Enantiomer isolated at 23.59 min.

[0241] Example 67: Synthesis of 6-chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one [ka] Step a: Synthesis of (E)-6-chloro-4-methyl-3-(3-(p-tolyl)acryloyl)-1,8-naphthyridin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-6-chloro-4-methyl-1,8-naphthyridin-2(1H)-one and 4-methylbenzaldehyde as starting materials. Yield: 90%; LCMS: m / z 339.10 [M+H] + .

[0242] Step b: Synthesis of 6-chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one Using (E)-6-chloro-4-methyl-3-(3-(p-tolyl)acryloyl)-1,8-naphthyridin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 43%; 1H-NMR(400MHz,DMSO-d6):δ 12.53(bs,1H),8.61(d,J=2.4Hz,1H),8.40(d,J=2.0Hz,1H),7.19-7.13(m,4H),5.49(dd,J=4.4Hz and J=11.6Hz,1H),3.82(dd,J=11.6Hz and J=18.4Hz,1H),3.14(dd,J=4.8Hz and J=18.4Hz,1H),2.64(q,J=7.2Hz,2H),2.58(s,3H),2.28(s,3H),1.03(t,J=7.6Hz,3H),LCMS:m / z 409.10[M+H] + .

[0243] Example 68: Synthesis of 5-(5-(4-(fluoromethyl)phenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-5-(3-(4-(fluoromethyl)phenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one and 4-(fluoromethyl)benzaldehyde as starting materials. Yield: 76%; LCMS: m / z 328.00 [M+H] + .

[0244] Step b: Synthesis of 5-(5-(4-(fluoromethyl)phenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one Using (E)-5-(3-(4-(fluoromethyl)phenyl)acryloyl)-4-methylthieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6-Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 34%; 1 H-NMR (400MHz, DMSO-d6): δ 7.40-7.38 (m, 2H), 7.33-7.29 (m, 4H), 5.52 (dd, J=4.0Hz and J=11.6Hz, 1H), 5.45 (s, 1H), 5.33 (s, 1H), 3.83 (dd, J=12.0Hz and J=18.4Hz, 1H), 3.16 (dd, J=4.8Hz and J=18.4Hz, 1H), 2.65 (q, J=7.6Hz, 2H), 2.58 (s, 3H), 2.29 (s, 3H), 1.05 (t, J=7.6Hz, 3H), [NH protons not visible by NMR]; LCMS: m / z 398.20 [M+H] + .

[0245] Example 69: Synthesis of 4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,5-naphthyridin-2(1H)-one [ka] Step a: Synthesis of (E)-4-methyl-3-(3-(p-tolyl)acryloyl)-1,5-naphthyridin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-4-methyl-1,5-naphthyridin-2(1H)-one as the starting material. Yield: 54%; LCMS: m / z 305.00 [M+H] + .

[0246] Step b: Synthesis of 4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,5-naphthyridin-2(1H)-one Using (E)-4-methyl-3-(3-(p-tolyl)acryloyl)-1,5-naphthyridin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 34%; 1 H-NMR(400MHz,DMSO-d6):δ 12.04(bs,1H),8.57(t,J=2.8Hz,1H),7.70(d,J=7.2Hz,1H),7.58(dd,J=4. 8Hz and J=8.0Hz,1H),7.16-7.14(m,4H),5.50(dd,J=4.4Hz and J=12.0Hz,1H),3 .82(dd,J=12.0Hz and J=18.0Hz,1H),3.15(dd,J=4.8Hz and J=18.4Hz,1H),2.62 (q,J=7.2Hz,2H),2.59(s,3H),2.28(s,3H),1.03(t,J=7.6Hz,3H),LCMS:m / z 375.20[M+H] + .

[0247] Example 70: Synthesis of 2,4-dimethyl-5-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of tert-butyl (3-cyano-5-methylthiophen-2-yl)carbamate: To a stirred solution of 2-amino-5-methylthiophene-3-carbonitrile (2.0 g, 14.47 mmol) in DMF (20 mL) at room temperature, diisopropylethylamine (7.8 mL, 43.41 mmol), dimethylaminopyridine (0.17 g, 1.477 mmol), and di-tert-butyl dicarbonate (4.6 mL, 21.70 mmol) were added. The reaction mixture was heated at 90° C. for 2 h and the progress of the reaction was monitored by TLC. The reaction mixture was slowly brought to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 10-20% ethyl acetate in hexane as eluent to give the title compound as a yellow solid. Yield: 2.3 g (66%); 1 H-NMR (400MHz, DMSO-d6): δ 10.92 (bs, 1H), 7.09 (d, J = 1.2Hz, 1H), 2.45 (s, 3H), 1.41 (s, 9H).

[0248] Step b: Synthesis of tert-butyl (3-acetyl-5-methylthiophen-2-yl)carbamate: To a stirred solution of tert-butyl (3-cyano-5-methylthiophen-2-yl)carbamate (2.3 g, 9.62 mmol) in dry THF (25 mL) at 0° C., methylmagnesium bromide (32.8 mL, 96.0 mmol, 3M in diethyl ether) was slowly added dropwise over about 10-15 min. The reaction mixture was heated at 50° C. for 2-3 h and the progress of the reaction was monitored by TLC. The reaction mixture was slowly brought to room temperature, cooled to 0° C., quenched with 2N HCl (100 mL), and then extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water (100 mL), brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography eluting with 20-25% ethyl acetate in hexane to give the title compound as a solid. Yield: 1.03 g (41%); 1H-NMR (400MHz, DMSO-d6): δ 10.92 (bs, 1H), 6.76 (d, J = 1.2Hz, 1H), 2.42 (s, 3H), 2.36 (s, 3H), 1.52 (s, 9H).

[0249] Step c: Synthesis of 1-(2-amino-5-methylthiophen-3-yl)ethan-1-one To a stirred solution of tert-butyl (3-acetyl-5-methylthiophen-2-yl)carbamate (1 g, 3.90 mmol) in dry DCM (10 mL) at 0° C. was added 4 m HCl. The reaction mixture was stirred at room temperature for 5-6 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure, quenched, and then diluted with ethyl acetate (150 mL). The organic layer was washed with saturated NaHCO3 (50 mL), water (50 mL), brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography eluting with 30-35% ethyl acetate in hexane to give the title compound as a solid. Yield: 0.48 g (79%); 1 H-NMR (400MHz, DMSO-d6): δ 7.89 (bs, 2H), 6.63 (d, J=1.2Hz, 1H), 2.21 (s, 3H), 2.19 (s, 3H).

[0250] Step d: Synthesis of N-(3-acetyl-5-methylthiophen-2-yl)-3-oxobutanamide: To a stirred solution of 1-(2-amino-5-methylthiophen-3-yl)ethan-1-one (0.485 g, 3.10 mmol) in xylene (10 mL) was added 2,2,6-trimethyl-4H-1,3-dioxin-4-one (0.6 mL, 4.66 mmol) and the reaction mixture was heated at 140° C. for 3 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 20-30% EtOAc in hexane as eluent to give the title compound as a colorless liquid. Yield: 0.54 g (72%); 1 H-NMR (400MHz, DMSO-d6): δ 11.93(bs,2H),7.08(d,J=1.2Hz,1H),3.88(s,3H),2.43(s,3H),2.35(s,3H),2.21(s,3H).

[0251] Step e: Synthesis of 5-acetyl-2,4-dimethylthieno[2,3-b]pyridin-6(7H)-one: A mixture of N-(3-acetyl-5-methylthiophen-2-yl)-3-oxobutanamide (0.54 g, 2.25 mmol) and cerium chloride heptahydrate (0.25 g, 0.66 mmol) was heated at 160° C. for 30 min. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), water (50 mL) and extracted. The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was diluted with DCM (50 mL) and the resulting solid was filtered and dried under vacuum to give the title compound as an off-white solid. Yield: 0.16 g (33%); 1 H-NMR (400MHz, DMSO-d6): δ 12.23 (bs, 1H), 7.03 (s, 1H), 2.46 (s, 3H), 2.35 (s, 3H), LCMS: m / z 222.00 [M+H] + .

[0252] Step f: Synthesis of (E)-2,4-dimethyl-5-(3-(p-tolyl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one: The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-2,4-dimethylthieno[2,3-b]pyridin-6(7H)-one and 4-methylbenzaldehyde as starting materials. Yield: 89%; 1 H-NMR (400MHz, DMSO-d6): δ 7.61 (d, J = 8.4, 2H), 7.37 (d, J = 16.0Hz, 1H), 7.23 (d, J = 8.0Hz, 2H), 7.07 (s, 1H), 7.04 (d, J = 5.2Hz, 1H), 2.56 (s, 3H), 2.32 (s, 3H), 2.29 (s, 3H), [NH protons not visible by NMR]; LCMS: m / z 324.1 [M+H] + .

[0253] Step g: Synthesis of 2,4-dimethyl-5-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one Using (E)-2,4-dimethyl-5-(3-(p-tolyl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 18%; 1H-NMR (400MHz, DMSO-d6): δ 7.10-7.13 (m, 4H), 7.04-7.10 (s, 1H), 5.45 (dd, J=4.0Hz and J=12.0Hz, 1H), 3.76 (dd, J=12.0Hz and J=18.4Hz, 1H), 3.11 (dd, J=4.0Hz and J=18.0Hz, 1H), 2.60 (q, J=7.6Hz, 2H), 2.58 (s, 3H), 2.49 (s, 3H), 2.28 (s, 3H), 1.01 (t, J=7.2Hz, 3H), [NH protons not visible by NMR]; LCMS: m / z 394.10 [M+H] + .

[0254] Example 71: Synthesis of 5-(5-benzyl-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of (E)-4-methyl-5-(4-phenylbut-2-enoyl)thieno[2,3-b]pyridin-6(7H)-one To a stirred solution of 5-acetyl-4-methylthieno[2,3-b]pyridin-6(7H)-one (100 mg, 0.483 mmol) and 2-phenylacetaldehyde (86 mg, 0.74 mmol) in methanol (3 mL) was added piperidine (123 mg, 1.44 mmol) and the reaction mixture was heated in a microwave at 90° C. for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL) and the resulting solid was filtered and dried under vacuum to give the title compound as a green solid. Yield: 110 mg (73%); LCMS: m / z 310.0 [M+H] + .

[0255] Step b: Synthesis of 5-(5-benzyl-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one Using (E)-4-methyl-5-(4-phenylbut-2-enoyl)thieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 14%; 1 H-NMR (400MHz, DMSO-d6): δ 7.30-7.24(m,5H), 7.22-7.18(m,2H), 4.77(dd,J=4.4Hz and J=9.2Hz,1H), 3.51(dd,J=11.2Hz and J=18.4Hz,1H), 2.97(d,J=6.4Hz,1H), 2.94(dd,J=11.2Hz and J=18.4Hz,1H), 2.65(q,J=7.6Hz,2H), 2.06(s,3H), 2.29(s,3H), 1.12(t,J=7.6Hz,3H), [NH protons not visible by NMR]; LCMS: m / z 379.90[M+H] + .

[0256] Example 72: Synthesis of 2-chloro-4-methyl-5-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one [ka] Step a: Synthesis of 2-amino-5-chlorothiophene-3-carbonitrile (72a): To a stirred solution of 2-aminothiophene-3-carbonitrile (2.0 g, 16.10 mmol) in DMF (20 mL) at 0° C., N-chlorosuccinimide (2.36 g, 17.71 mmol) was added. The reaction mixture was stirred at room temperature for 16 h and the progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 10-20% ethyl acetate in hexane as eluent to give the title compound as a yellow solid. Yield: 1.2 g, 48%; 1 H-NMR (400MHz, DMSO-d6): δ 6.57 (s, 1H), 4.78 (bs, 2H).

[0257] Step b: Synthesis of tert-butyl (5-chloro-3-cyanothiophen-2-yl)carbamate (72b): The title compound was synthesized using the same procedure as that carried out for tert-butyl (3-cyano-5-methylthiophene-2-yl)carbamate (70a) using 2-amino-5-chlorothiophene-3-carbonitrile as starting material. Yield: 34%; 1 H-NMR (400MHz, CDCl3): δ 7.68 (bs, 1H), 6.75 (s, 1H), 1.54 (s, 9H).

[0258] Step c: Synthesis of tert-butyl (3-acetyl-5-chlorothiophen-2-yl)carbamate (72c): The title compound was synthesized using the same procedure as that carried out for tert-butyl (3-acetyl-5-methylthiophen-2-yl)carbamate (70b) using tert-butyl (3-cyano-5-methylthiophen-2-yl)carbamate as starting material. Yield: 66%; 1 H-NMR (400MHz, CDCl3): δ 10.99 (bs, 1H), 6.96 (s, 1H), 2.42 (s, 3H), 1.54 (s, 9H).

[0259] Step d: Synthesis of 1-(2-amino-5-chlorothiophen-3-yl)ethan-1-one (72d) The title compound was synthesized using the same procedure as that followed for 1-(2-amino-5-methylthiophen-3-yl)ethan-1-one (70c) using tert-butyl (3-acetyl-5-chlorothiophen-2-yl)carbamate as starting material. Yield: 65%; 1 H-NMR (400MHz, DMSO-d6): δ 8.15 (bs, 2H), 6.96 (s, 1H), 2.24 (s, 3H).

[0260] Step e: Synthesis of N-(3-acetyl-5-chlorothiophen-2-yl)-3-oxobutanamide (72e): The title compound was synthesized using the same procedure as that carried out for N-(3-acetyl-5-methylthiophen-2-yl)-3-oxobutanamide (70d) using 1-(2-amino-5-methylthiophen-3-yl)ethan-1-one as starting material. Yield: 70%; 1 H-NMR (400MHz, DMSO-d6): δ 12.14 (bs, 1H), 7.52 (s, 1H), 3.94 (s, 2H), 2.47 (s, 3H), 3.20 (s, 3H).

[0261] Step f: Synthesis of 5-acetyl-2-chloro-4-methylthieno[2,3-b]pyridin-6(7H)-one (72f): The title compound was synthesized using the same procedure as that carried out for N-(3-acetyl-5-methylthiophen-2-yl)-3-oxobutanamide (70d) using N-(3-acetyl-5-methylthiophen-2-yl)-3-oxobutanamide as starting material. Yield: 41%; LCMS: m / z 242.0.1 [M+H] + .

[0262] Step g: Synthesis of (E)-2-chloro-4-methyl-5-(3-(p-tolyl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one (72g): The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 5-acetyl-2-chloro-4-methylthieno[2,3-b]pyridin-6(7H)-one and 4-methylbenzaldehyde as starting materials. Yield: 70%; LCMS: m / z 344.0 [M+H] + .

[0263] Step h: Synthesis of 2-chloro-4-methyl-5-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one Using (E)-2-chloro-4-methyl-5-(3-(p-tolyl)acryloyl)thieno[2,3-b]pyridin-6(7H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 15%; 1 H-NMR (400 MHz, DMSO-d6): δ 7.52 (s, 1H), 7.10-7.13 (m, 4H), 5.45 (dd, J=4.0 Hz and J=11.6 Hz, 1H), 3.78 (dd, J=12.0 Hz and J=18.4 Hz, 1H), 3.10 (dd, J=4.4 Hz and J=18.4 Hz, 1H), 2.64 (q, J=7.6 Hz, 2H), 2.49 (s, 3H), 2.27 (s, 3H), 1.03 (t, J=7.2 Hz, 3H), [NH protons not visible by NMR]; LCMS: m / z 414.00 [M+H] + .

[0264] Example 73: Synthesis of 4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one [ka] Step a: Synthesis of (E)-4-methyl-3-(3-(p-tolyl)acryloyl)-1,8-naphthyridin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-4-methyl-1,8-naphthyridin-2(1H)-one and 4-methylbenzaldehyde as starting materials. Yield: 38%; LCMS: m / z 305.40 [M+H] + .

[0265] Step b: Synthesis of 4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one Using (E)-4-methyl-3-(3-(p-tolyl)acryloyl)-1,8-naphthyridin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 40%; 1 H-NMR(400MHz,DMSO-d6):δ 12.34(bs,1H),8.57(dd,J=1.6Hz and J=4.8Hz,1H),8.31(d,J=8.4Hz,1H),7.34( dd,J=4.8Hz and J=8.0Hz,1H),7.22-7.14(m,4H),5.50(dd,J=4.4Hz and J=11.6Hz, 1H),3.82(dd,J=12.0Hz and J=18.4Hz,1H),3.10(dd,J=4.4Hz and J=18.4Hz,1H),2 .62(q,J=7.6Hz,2H),2.59(s,3H),2.28(s,3H),1.03(t,J=7.2Hz,3H),LCMS:m / z 375.20[M+H] + .

[0266] Example 74: Synthesis of 4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one [ka] Step a: Synthesis of 3-acetyl-4-methyl-1,7-naphthyridin-2(1H)-one To a stirred solution of 1-(3-aminopyridin-4-yl)ethan-1-one (0.3 g, 2.20 mmol) in xylene (10 mL) was added 2,2,6-trimethyl-4H-1,3-dioxin-4-one (0.6 mL, 4.66 mmol) and cerium chloride heptahydrate (0.24 g, 0.66 mmol). The reaction mixture was heated at 140° C. for 3 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 2-3% methanol in dichloromethane as eluent to give the title compound as a yellow solid. Yield: 0.21 g , 48%; 1 H-NMR (400MHz, DMSO-d6): δ 12.27(bs,1H),8.68(s,1H),8.40(d,J=5.6Hz,1H),7.76(d,J=1.4Hz,1H),2.46(s,3H),2.28(s,3H).

[0267] Step b: Synthesis of (E)-4-methyl-3-(3-(p-tolyl)acryloyl)-1,7-naphthyridin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-4-methyl-1,7-naphthyridin-2(1H)-one and 4-methylbenzaldehyde as starting materials. Yield: 73%; LCMS: m / z 305.40 [M+H] + .

[0268] Step c: Synthesis of 4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one Using (E)-4-methyl-3-(3-(p-tolyl)acryloyl)-1,7-naphthyridin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 36%; 1 H-NMR(400MHz,DMSO-d6):δ 12.21(bs,1H),8.69(s,1H),8.41(d,J=5.6Hz,1H),7.78(d,J=8.8Hz,1H),7.19-7.14(m,4H),5.50(dd,J=4.8Hz and J=12.80Hz,1H),3.82(dd,J= 12.0Hz and J=18.4Hz,1H), 3.10(dd, J=4.4Hz and J=18.4Hz,1H), 2.62(q,J=7.6Hz,2H), 2.59(s,3H),2.28(s,3H),1.03(t,J=7.2Hz,3H), LCMS: m / z 375.50[M+H] + .

[0269] Chiral purification of compound 74 Step e: 74(A): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA(100) at 20° C. with a flow rate of 0.7 mL / min. Enantiomer isolated at 12.51 min.

[0270] Step f: 74(B): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA / DCM (90 / 10) at 20° C. with a flow rate of 0.7 mL / min. Enantiomer isolated at 16.94 min.

[0271] Example 75: Synthesis of 4,7-dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one [ka] Step a: Synthesis of 3-acetyl-4-methyl-1,7-naphthyridin-2(1H)-one The title compound was synthesized using the same procedure as that performed for 3-acetyl-4-methyl-1,7-naphthyridin-2(1H)-one (compound 74a) using 1-(2-amino-4-methylphenyl)ethan-1-one as starting material. Yield: 68%; LCMS: m / z 215.30 [M+H] + .

[0272] Step b: Synthesis of (E)-4,7-dimethyl-3-(3-(p-tolyl)acryloyl)quinolin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-4-methyl-1,7-naphthyridin-2(1H)-one and 4-methylbenzaldehyde as starting materials. Yield: 59%; LCMS: m / z 317.20 [M+H] + .

[0273] Step c: Synthesis of 4,7-dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one Using (E)-4,7-dimethyl-3-(3-(p-tolyl)acryloyl)quinolin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that performed for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 35%; 1H-NMR(400MHz,DMSO-d6):δ 11.84(bs,1H),7.75(d,J=8.4Hz,1H),7.19-7.14(m,5H),7.10(d,J=8.8Hz,1H),5.48(dd,J=4.4Hz and J=11.6Hz,1H),3.82(dd,J=12.0Hz and J=18.4Hz,1H),3.10(dd,J=4.4Hz and J=18.4Hz,1H),2.62(q,J=7.6Hz,2H),2.39(s,3H),2.28(s,3H),1.03(t,J=7.2Hz,3H),LCMS:m / z 387.70[M+H] + .

[0274] Example 76: Synthesis of 4,5-dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one [ka] Step a: Synthesis of 3-acetyl-4-methyl-1,7-naphthyridin-2(1H)-one The title compound was synthesized using the same procedure as that performed for 3-acetyl-4-methyl-1,7-naphthyridin-2(1H)-one (compound 74a) using 1-(2-amino-6-methylphenyl)ethan-1-one as starting material. Yield: 91%; LCMS: m / z 216.00 [M+H] + .

[0275] Step b: Synthesis of (E)-4,5-dimethyl-3-(3-(p-tolyl)acryloyl)quinolin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-4-methyl-1,7-naphthyridin-2(1H)-one and 4-methylbenzaldehyde as starting materials. Yield: 51%; 1H-NMR(400MHz,DMSO-d6):δ 11.88(bs,1H),7.64(d,J=7.6,2H),7.44(d,J=11.6Hz,1H),7.39(d,J=16.8Hz,1H),7.23(d,J=7.6Hz ,2H),7.04(d,J=7.2Hz,1H),6.95(d,J=16.4Hz,1H),2.74(s,3H),2.49(s,3H),2.33(s,3H),LCMS:m / z 324.1[M+H] + LCMS: m / z 318.10 [M+H] + .

[0276] Step c: Synthesis of 4,5-dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one Using (E)-4,5-dimethyl-3-(3-(p-tolyl)acryloyl)quinolin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 22%; 1 H-NMR(400MHz,DMSO-d6):δ 11.87(bs,1H),7.40(t,J=7.6Hz,1H),7.23-7.14(m,5H),7.10(d,J=7.2Hz,1H),5.50(dd,J=4.4Hz and J=11.6Hz,1H),3.76(dd,J=12.0Hz and J=1 8.4Hz,1H),3.04(dd,J=7.7Hz and J=18.4Hz,1H),2.75(s,3H),2.62(q,J=7.6Hz,2H),2.64(s,3H),2.28(s,3H),1.03(t,J=7.2Hz,3H),LCMS:m / z 388.20[M+H] + .

[0277] Example 77: Synthesis of 4-methyl-7-morpholino-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one [ka] Step a: Synthesis of 4-morpholino-2-nitrobenzonitrile (77a): To a stirred solution of 4-chloro-2-nitrobenzonitrile (4.0 g, 21.9 mmol) in THF (40 mL) at room temperature was added morpholine (5.66 mL, 65.70 mmol). The reaction mixture was stirred at 80° C. for 16 h and the progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 10-20% ethyl acetate in hexane as eluent to give the title compound as an orange solid. Yield: 4.0 g, 78%; 1 H-NMR (400MHz, DMSO-d6): δ 7.88 (d, J = 8.8, 1H), 7.73 (d, J = 2.8 Hz, 1 H), 7.37 (dd, J = 2.8 Hz and J = 9.2 Hz, 1 H), 3.72 (t, J = 4.8 Hz, 4 H), 3.43 (t, J = 5.2 Hz, 4 H).

[0278] Step b: Synthesis of 2-amino-4-morpholinobenzonitrile (77b): To a stirred solution of 4-morpholino-2-nitrobenzonitrile (2.0 g, 8.58 mmol) in methanol (20 mL) at room temperature was added 10% Pd / c (200 mg). The reaction mixture was stirred under a hydrogen balloon for 3 h and the progress of the reaction was monitored by TLC. The reaction mixture was filtered through Celite and the filtrate was evaporated under reduced pressure to give the title compound as an orange solid. Yield: 1.65 g, 94%; LCMS: m / z 204.10 [M+H] + .

[0279] Step c: Synthesis of 1-(2-amino-4-morpholinophenyl)ethan-1-one (77c): The title compound was synthesized using the same procedure as for tert-butyl (3-acetyl-5-methylthiophen-2-yl)carbamate (70b) using tert-butyl (3-cyano-5-methylthiophen-2-yl)carbamate as starting material. Yield: 23%; LCMS: m / z 221.20 [M+H] + .

[0280] Step d: Synthesis of 3-acetyl-4-methyl-7-morpholinoquinolin-2(1H)-one (77d) The title compound was synthesized using the same procedure as that performed for 3-acetyl-4-methyl-1,7-naphthyridin-2(1H)-one (compound 74a) using 1-(2-amino-4-morpholinophenyl)ethan-1-one as starting material. Yield: 15%; LCMS: m / z 287.50 [M+H] + .

[0281] Step e: Synthesis of (E)-4-methyl-7-morpholino-3-(3-(p-tolyl)acryloyl)quinolin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-4-methyl-7-morpholinoquinolin-2(1H)-one and 4-methylbenzaldehyde as starting materials. Yield: 58%; 1 H-NMR(400MHz,DMSO-d6):δ 11.59(bs,1H),7.66(d,J=9.2Hz,1H),7.61(d,J=8.4Hz,2H),7.41(d,J=16.4Hz,1H),7.24(d,J=8.4Hz,2H),7.04(d,J=16.4Hz,1H) ),6.99(d,J=2.0Hz,1H),6.72(d,J=2.0Hz,1H),3.77(t,J=4.4Hz,4H),3.23(t,J=4.8Hz,4H),2.32(s,3H),2.27(s,3H),LCMS:m / z 389.20[M+H] + .

[0282] Step f: Synthesis of 4-methyl-7-morpholino-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one Using (E)-4-methyl-7-morpholino-3-(3-(p-tolyl)acryloyl)quinolin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 25%; 1 H-NMR(400MHz,DMSO-d6):δ 11.58(bs,1H),7.66(d,J=9.2Hz,1H),7.23-7.14(m,4H),6.97(dd,J=2.0Hz and and J=9.2Hz,1H),6.69(d,J=2.4Hz,1H),5.45(dd,J=4.4Hz and J=11.6Hz,1H),3. 80-3.72(m,5H),3.34-3.21(m,4H),3.11(dd,J=4.4Hz and J=18.0Hz,1H),2.62 (q,J=7.6Hz,2H),2.48(s,3H),2.26(s,3H),1.03(t,J=7.2Hz,3H),LCMS:m / z 459.20[M+H] + .

[0283] Example 78: Synthesis of 4,8-dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one [ka] Step a: Synthesis of 2-methyl-3-nitropyridin-4-ol (78a): 2-Methylpyridin-4-ol (2.0 g, 18.32 mmol) was added to a mixture of fuming nitric acid and concentrated H2SO4. The reaction mixture was stirred at 130°C for 2 hours and the progress of the reaction was monitored by TLC. The reaction mixture was brought to room temperature, neutralized with sodium bicarbonate, and the resulting solid was filtered and dried under vacuum to give the title compound as a yellow solid. Yield: 1.5 g, 53%; 1 H-NMR (400MHz, DMSO-d6): δ 7.51 (d, J = 6.4, 1H), 6.03 (d, J = 6.4Hz, 1H), 2.13 (s, 3H).

[0284] Step b: Synthesis of 4-chloro-2-methyl-3-nitropyridine (78b): 2-Methyl-3-nitropyridin-4-ol (2.0 g, 12.90 mmol) was added to a solution of POCl3 (10 mL) at room temperature. The reaction mixture was stirred at 110 °C for 2 h and the progress of the reaction was monitored by TLC. The reaction mixture was brought to room temperature, then evaporated under reduced pressure, quenched with ice water, neutralized with sodium bicarbonate, and then extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and evaporated under reduced pressure to obtain the crude compound, which was purified by flash column chromatography using 10-20% ethyl acetate in hexane as eluent to obtain the title compound as a reddish liquid. Yield: 0.8 g, 36%; 1 H-NMR (400MHz, CDCl3): δ 8.52 (d, J = 5.2, 1H), 7.35 (d, J = 5.2Hz, 1H), 2.60 (s, 3H).

[0285] Step c: Synthesis of 1-(2-methyl-3-nitropyridin-4-yl)ethan-1-one (78c): The title compound was synthesized using the same procedure as that carried out for 1-(4-aminopyrimidin-5-yl)ethan-1-one (compound 14b) using 4-chloro-2-methyl-3-nitropyridine as starting material. Yield: 66%; 1H-NMR (400MHz, CDCl3): δ 8.79 (d, J = 4.8, 1H), 7.40 (d, J = 5.2 Hz, 1H), 2.69 (s, 3H), 2.60 (s, 3H).

[0286] Step d: Synthesis of 1-(3-amino-2-methylpyridin-4-yl)ethan-1-one (78d): The title compound was synthesized using the same procedure as that carried out for 2-amino-4-morpholinobenzonitrile (compound 93b) using 1-(2-methyl-3-nitropyridin-4-yl)ethan-1-one as starting material. Yield: 68%; 1 H-NMR (400MHz, CDCl3): δ 7.88 (d, J = 5.6, 1H), 7.37 (d, J = 5.2 Hz, 1H), 6.25 (bs, 2H), 2.59 (s, 3H), 2.48 (s, 3H).

[0287] Step e: Synthesis of 3-acetyl-4,8-dimethyl-1,7-naphthyridin-2(1H)-one (78e): The title compound was synthesized using the same procedure as that carried out for 3-acetyl-4-methyl-1,7-naphthyridin-2(1H)-one (compound 74a) using 1-(3-amino-2-methylpyridin-4-yl)ethan-1-one as starting material. Yield: 61%; 1 H-NMR (400MHz, CDCl3): δ 11.50(bs,1H),8.27(d,J=5.6,1H),7.60(d,J=5.6Hz,1H),2.67(s,3H),2.45(s,3H). 2.32(s,3H). LCMS:m / z 217.00[M+H] + .

[0288] Step f: Synthesis of (E)-4,8-dimethyl-3-(3-(p-tolyl)acryloyl)-1,7-naphthyridin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-4,8-dimethyl-1,7-naphthyridin-2(1H)-one and 4-methylbenzaldehyde as starting materials. Yield: 81%; 1 H-NMR(400MHz,DMSO-d6):δ 11.45(bs,1H),8.29(d,J=5.6Hz,1H),7.65-7.60(m,3H),7.50(d,J=16.8Hz,1H),7.25(d ,J=8.0Hz,2H),7.04(d,J=16.4Hz,1H),2.67(s,3H),2.29(s,3H),2.24(s,3H),LCMS:m / z 319.1[M+H] + .

[0289] Step g: Synthesis of 4,8-dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one Using (E)-4,8-dimethyl-3-(3-(p-tolyl)acryloyl)-1,7-naphthyridin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 32%; 1 H-NMR(400MHz,DMSO-d6):δ 11.44(bs,1H),8.29(d,J=5.6Hz,1H),7.63(d,J=5.2Hz,1H),7.20-7.14(m,4H),5.50(dd,J=4.4Hz and J=12.0Hz,1H),3.86(dd,J=12.0Hz and J=1 8.4Hz,1H),3.04(dd,J=4.4Hz and J=18.0Hz,1H),2.68(s,3H),2.62(q,J=7.6Hz,2H),2.59(s,3H),2.28(s,3H),1.03(t,J=7.2Hz,3H),LCMS:m / z 389.00[M+H]+ .

[0290] Chiral purification of compound 78 Step e: 78(A): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA(100) at 20° C. with a flow rate of 0.7 mL / min. The isolated enantiomer was at 16.67 min (dextro(+) isomer).

[0291] Step f: 78(B): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA / DCM (90 / 10) at 20° C. with a flow rate of 0.7 mL / min. The isolated enantiomer was at 20.64 min (levo(-) isomer).

[0292] Example 79: Synthesis of 6-chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one [ka] Step a: Synthesis of 3-acetyl-6-chloro-4-methyl-1,7-naphthyridin-2(1H)-one The title compound was synthesized using the same procedure as that performed for 3-acetyl-4-methyl-1,7-naphthyridin-2(1H)-one (compound 74a) using 1-(5-amino-2-chloropyridin-4-yl)ethan-1-one as starting material. Yield: 48%; LCMS: m / z 237.00 [M+H] + .

[0293] Step b: Synthesis of (E)-6-chloro-4-methyl-3-(3-(p-tolyl)acryloyl)-1,7-naphthyridin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-6-chloro-4-methyl-1,7-naphthyridin-2(1H)-one and 4-methylbenzaldehyde as starting materials. Yield: 75%; LCMS: m / z 339.00 [M+H] + .

[0294] Step c: Synthesis of 6-chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one Using (E)-6-chloro-4-methyl-3-(3-(p-tolyl)acryloyl)-1,7-naphthyridin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 20%; 1 H-NMR(400MHz,DMSO-d6):δ 12.30(bs,1H),8.48(s,1H),7.89(s,1H),7.18-7.12(m,4H),5.49(dd,J=4.4Hz and J=11.6Hz,1H),3.77(dd,J=12.0Hz and J=18.4 Hz,1H),3.07(dd,J=7.8Hz and J=18.4Hz,1H),2.62(q,J=7.6Hz,2H),2.53(s,3H),2.28(s,3H),1.03(t,J=7.2Hz,3H),LCMS:m / z 409.10[M+H] + .

[0295] Example 80: Synthesis of 7-chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one [ka] Step a: Synthesis of 3-acetyl-7-chloro-4-methylquinolin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for 3-acetyl-4-methyl-1,7-naphthyridin-2(1H)-one (compound 74a) using 1-(2-amino-4-chlorophenyl)ethan-1-one as starting material. Yield: 55%; 1 H-NMR (400MHz, DMSO-d6): δ 12.08(bs,1H),8.68(s,1H),7.86(d,J=8.8Hz,1H),7.35(s,1H),7.30(d,J=8.4Hz,1H),2.45(s,3H),2.32(s,3H). LCMS:m / z 235.90[M+H] + .

[0296] Step b: Synthesis of (E)-7-chloro-4-methyl-3-(3-(p-tolyl)acryloyl)quinolin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-7-chloro-4-methylquinolin-2(1H)-one and 4-methylbenzaldehyde as starting materials. Yield: 93%; LCMS: m / z 337.90 [M+H] + .

[0297] Step c: Synthesis of 7-chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one Using (E)-7-chloro-4-methyl-3-(3-(p-tolyl)acryloyl)quinolin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 62%; 1H-NMR(400MHz,DMSO-d6):δ 12.02(bs,1H),7.88(d,J=8.8Hz,1H),7.73(d,J=2.0Hz,1H),7.30(dd,J=2. 0Hz and J=8.8Hz,1H),7.19-7.11(m,4H),5.47(dd,J=4.4Hz and J=11.6Hz,1H),3 .77(dd,J=12.0Hz and J=18.4Hz,1H),3.07(dd,J=4.4Hz and J=18.0Hz,1H),2.62 (q,J=7.6Hz,2H),2.53(s,3H),2.28(s,3H),1.03(t,J=7.2Hz,3H),LCMS:m / z 408.10[M+H] + .

[0298] Chiral purification of compound 80 Step e: 80(A): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA(100) at 20° C. with a flow rate of 0.7 mL / min. Enantiomer isolated at 17.01 min.

[0299] Step f: 80(B): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA / DCM (90 / 10) at 20° C. with a flow rate of 0.7 mL / min. Enantiomer isolated at 25.77 min.

[0300] Example 81: Synthesis of 4,6-dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one [ka] Step a: Synthesis of 3-acetyl-4,6-dimethyl-1,7-naphthyridin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for 3-acetyl-4-methyl-1,7-naphthyridin-2(1H)-one (compound 74a) using 1-(5-amino-2-methylpyridin-4-yl)ethan-1-one as starting material. Yield: 58%; 1H-NMR (400MHz, DMSO-d6): δ 12.14 (bs, 1H), 8.56 (s, 1H), 7.61 (s, 1H), 2.53 (s, 3H), 2.45 (s, 3H), 2.30 (s, 3H). LCMS:m / z 217.30[M+H] + .

[0301] Step b: Synthesis of (E)-4,6-dimethyl-3-(3-(p-tolyl)acryloyl)-1,7-naphthyridin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-4,6-dimethyl-1,7-naphthyridin-2(1H)-one and 4-methylbenzaldehyde as starting materials. Yield: 89%; LCMS: m / z 318.80 [M+H] + .

[0302] Step c: Synthesis of 4,6-dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one Using (E)-4,6-dimethyl-3-(3-(p-tolyl)acryloyl)-1,7-naphthyridin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 26%; 1H-NMR(400MHz,DMSO-d6):δ 12.07(bs,1H),8.58(s,1H),7.63(s,1H),7.19-7.13(m,4H),5.50(dd,J=4.8Hz and J=12.0Hz,1H),3.81(dd,J=12.0Hz and J=18.4Hz,1H ),3.11(dd,J=4.8Hz and J=18.0Hz,1H),2.62(q,J=7.6Hz,2H),2.59(s,3H),2.53(s,3H),2.28(s,3H),1.03(t,J=7.2Hz,3H),LCMS:m / z 388.90[M+H] + .

[0303] Example 82: Synthesis of 4-methyl-7-(4-methylpiperazin-1-yl)-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one [ka] Step a: Synthesis of 3-acetyl-4-methyl-7-(4-methylpiperazin-1-yl)quinolin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for 3-acetyl-4-methyl-1,7-naphthyridin-2(1H)-one (compound 74a) using 1-(2-amino-4-(4-methylpiperazin-1-yl)phenyl)ethan-1-one as starting material. Yield: 39%; 1 H-NMR(400MHz,DMSO-d6):δ 12.57(bs,1H),7.60(d,J=9.2Hz,1H),6.92(d,J=2.8Hz,1H),6.74(d,J=2 .4Hz,1H),345-3.40(m,4H),2.45(s,3H),2.35-2.30(m,4H),2.27(s,3H). LCMS:m / z 300.30[M+H] + .

[0304] Step b: Synthesis of (E)-4-methyl-7-(4-methylpiperazin-1-yl)-3-(3-(p-tolyl)acryloyl)quinolin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-4-methyl-7-(4-methylpiperazin-1-yl)quinolin-2(1H)-one and 4-methylbenzaldehyde as starting materials. Yield: 89%; LCMS: m / z 402.40 [M+H] + .

[0305] Step c: Synthesis of 4-methyl-7-(4-methylpiperazin-1-yl)-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one Using (E)-4-methyl-7-(4-methylpiperazin-1-yl)-3-(3-(p-tolyl)acryloyl)quinolin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 48%; 1 H-NMR (400 MHz, DMSO-d6): δ 11.51 (bs, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.19-7.12 (m, 4H), 6.96 (dd, J = 2.0 Hz and J = 9.6 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 5.45 (dd, J = 4.4 Hz and J = 11.6 Hz, 1H), 3.79 (dd, J = 12.0 Hz and J = 18. 4Hz,1H),3.45(s,3H),3.28-3.27(m,4H),3.11(dd,J=4.4Hz and J=18.0Hz,1H),2.62(q,J= 7.6Hz,2H),2.58-2.50(m,4H),2.27(s,3H),2.23(s,3H),1.03(t,J=7.2Hz,3H),LCMS:m / z 472.50[M+H] + .

[0306] Chiral purification of compound 82 Step e: 82(A): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA(100) at 20° C. with a flow rate of 0.7 mL / min. Enantiomer isolated at 31.40 min.

[0307] Step f: 82(B): HPLC using chiral pack IA 5 uM, 4.6×250 mm, eluent IPA / DCM (90 / 10) at 20° C. with a flow rate of 0.7 mL / min. Enantiomer isolated at 44.02 min.

[0308] Example 83: Synthesis of 7-fluoro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one [ka] Step a: Synthesis of 3-acetyl-7-fluoro-4-methylquinolin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for 3-acetyl-4-methyl-1,7-naphthyridin-2(1H)-one (compound 74a) using 1-(2-amino-4-fluorophenyl)ethan-1-one as starting material. Yield: 39%; 1 H-NMR (400MHz, DMSO-d6): δ 12.06 (bs, 1H), 7.90 (t, J = 8.0Hz, 1H), 7.15 (dd, J = 8.8Hz and J = 18.8Hz, 2H), 2.45 (s, 3H), 2.33 (s, 3H). LCMS:m / z 220.20[M+H] + .

[0309] Step b: Synthesis of (E)-7-fluoro-4-methyl-3-(3-(p-tolyl)acryloyl)quinolin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-7-fluoro-4-methylquinolin-2(1H)-one and 4-methylbenzaldehyde as starting materials. Yield: 89%; LCMS: m / z 321.90 [M+H] + .

[0310] Step c: Synthesis of 7-fluoro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one Using (E)-7-fluoro-4-methyl-3-(3-(p-tolyl)acryloyl)quinolin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 48%; 1 H-NMR(400MHz,DMSO-d6):δ 12.01(bs,1H),7.93(t,J=6.4Hz,1H),7.19-7.08(m,6H),5.50(dd,J=4.4Hz and J=12.4Hz,1H),3.81(dd,J=12.0Hz and J=18.4H z,1H),3.11(dd,J=4.8Hz and J=18.0Hz,1H),2.62(q,J=7.6Hz,2H),2.59(s,3H),2.28(s,3H),1.03(t,J=7.2Hz,3H),LCMS:m / z 391.90[M+H] + .

[0311] Example 84: Synthesis of 4,7-dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one [ka] Step a: Synthesis of 3-acetyl-4,7-dimethyl-1,8-naphthyridin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for 3-acetyl-4-methyl-1,7-naphthyridin-2(1H)-one (compound 74a) using 1-(2-amino-6-methylpyridin-3-yl)ethan-1-one as starting material. Yield: 56%; 1 H-NMR (400MHz, DMSO-d6): δ 9.01(bs,1H),8.68(s,1H),7.96(d,J=8.4Hz,1H),7.11(d,J=8.0Hz,1H),2.61(s,3H),2.60(s,3H),2.42(s,3H). LCMS:m / z 216.80[M+H] + .

[0312] Step b: Synthesis of (E)-4,7-dimethyl-3-(3-(p-tolyl)acryloyl)-1,8-naphthyridin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-4,7-dimethyl-1,8-naphthyridin-2(1H)-one and 4-methylbenzaldehyde as starting materials. Yield: 78%; LCMS: m / z 318.80 [M+H] + .

[0313] Step c: Synthesis of 4,7-dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one Using (E)-4,7-dimethyl-3-(3-(p-tolyl)acryloyl)-1,8-naphthyridin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 28%; 1H-NMR(400MHz,DMSO-d6):δ 12.20(bs,1H),8.18(d,J=8.4Hz,1H),7.21-7.13(m,5H),5.48(dd,J=4.4Hz and J=12.0Hz,1H),3.81(dd,J=12.0Hz and J=18.4Hz,1H), 3.10(dd,J=4.4Hz and J=18.4Hz,1H),2.62(q,J=7.6Hz,2H),2.54(s,3H),2.49(s,3H),2.27(s,3H),1.03(t,J=7.2Hz,3H),LCMS:m / z 389.00[M+H] + .

[0314] Example 85: Synthesis of 4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,6-naphthyridin-2(1H)-one [ka] Step a: Synthesis of 3-acetyl-4-methyl-1,6-naphthyridin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for 3-acetyl-4-methyl-1,7-naphthyridin-2(1H)-one (compound 74a) using 1-(4-aminopyridin-3-yl)ethan-1-one as starting material. Yield: 42%; 1 H-NMR (400MHz, DMSO-d6): δ 12.25(bs,1H),9.02(s,1H),8.53(d,J=4.0Hz,1H),7.23(d,J=6.0Hz,1H),2.45(s,3H),2.40(s,3H). LCMS:m / z 202.80[M+H] + . Step b: Synthesis of (E)-4-methyl-3-(3-(p-tolyl)acryloyl)-1,6-naphthyridin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-4-methyl-1,6-naphthyridin-2(1H)-one and 4-methylbenzaldehyde as starting materials. Yield: 93%; LCMS: m / z 304.90 [M+H] + .

[0315] Step c: Synthesis of 4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,6-naphthyridin-2(1H)-one Using (E)-4-methyl-3-(3-(p-tolyl)acryloyl)-1,6-naphthyridin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 15%; 1 H-NMR(400MHz,DMSO-d6):δ 12.20(bs,1H),9.05(s,1H),8.53(d,J=4.0Hz,1H),7.24(d,J=5.6Hz,1H),7.18-7.14(m,4H),5.50(dd,J=4.4Hz and J=11.6Hz,1H),3.77(dd,J= 12.0Hz and J = 18.4Hz, 1H), 3.09 (dd, J = 4.4Hz and J = 18.0Hz, 1H), 2.62 (q, J = 7.6Hz, 2H), 2.59 (s, 3H), 2.28 (s, 3H), 1.03 (t, J = 7.2Hz, 3H), LCMS: m / z 375.00[M+H] + .

[0316] Example 86: Synthesis of 4-methyl-7-morpholino-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one [ka] Step a: Synthesis of 6-chloro-2-((4-methoxybenzyl)amino)nicotinic acid: To a stirred solution of 2,6-dichloronicotinic acid (10 g, 52.08 mmol) in dry DMF (40 mL) was added K2CO3 (14.38 g, 104.16 mmol) and then the reaction mixture was cooled to 0° C. Finally, PMB-Cl (9.28 g, 67.70 mmol) was added dropwise over 10 min and the reaction mixture was heated at 100° C. for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was poured into ice water (50 mL), acidified with 10% KHSO4, and the resulting solid was filtered and dried under vacuum to give the title compound as an off-white solid. Yield: 13 g (86%). LCMS: m / z 293.00 [M+H] + .

[0317] Step b: Synthesis of 6-chloro-N-methoxy-2-((4-methoxybenzyl)amino)-N-methylnicotinamide: To a stirred solution of 6-chloro-2-((4-methoxybenzyl)amino)nicotinic acid (3.0 g, 10.27 mmol) in DMF (30 mL) was added N,O-dimethylhydroxylamine hydrochloride (1.49 g, 15.40 mmol), DIPEA (8.0 mL, 46.21 mmol) followed by HATU (5.86 g, 15.40 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 5 h and the progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 10-20% ethyl acetate in hexane as eluent to give the title compound as an orange solid. Yield: 2.5g, 73%; LCMS: m / z 336.0[M+H] + .

[0318] Step c: Synthesis of 1-(6-chloro-2-((4-methoxybenzyl)amino)pyridin-3-yl)ethan-1-one To a stirred solution of 6-chloro-N-methoxy-2-((4-methoxybenzyl)amino)-N-methylnicotinamide (2.5 g, 7.462 mmol) in dry THF (25 mL) at 0° C., methylmagnesium bromide (8.7 mL, 26.11 mmol, 3M in diethyl ether) was slowly added dropwise over about 10-15 min. The reaction mixture was stirred at room temperature for 2-3 h and the progress of the reaction was monitored by TLC. The reaction mixture was cooled to 0° C., quenched with saturated NH4Cl (100 mL) and then extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water (100 mL), brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography eluting with 10-15% ethyl acetate in hexane to give the title compound as a solid. Yield: 1.5g (71%); LCMS: m / z 290.90[M+H] + .

[0319] Step d: Synthesis of 1-(2-((4-methoxybenzyl)amino)-6-morpholinopyridin-3-yl)ethan-1-one To a stirred solution of 1-(6-chloro-2-((4-methoxybenzyl)amino)pyridin-3-yl)ethan-1-one (1.5 g, 6.52 mmol) in DMSO (15 mL) at room temperature was added morpholine (0.9 mL, 9.78 mmol) and K2CO3 (2.7 g, 19.56 mmol). The reaction mixture was stirred at 120 °C for 2 h and the progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 15-20% ethyl acetate in hexane as eluent to give the title compound as a yellow solid. Yield: 1.13 g, 64%; LCMS: m / z 341.90 [M+H] + .

[0320] Step e: Synthesis of 1-(2-amino-6-morpholinopyridin-3-yl)ethan-1-one To a stirred solution of 1-(2-((4-methoxybenzyl)amino)-6-morpholinopyridin-3-yl)ethan-1-one (500 mg, 1.46 mmol) in DCM (10 mL) was added TFA (3.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 h and the progress of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure and diluted with ethyl acetate (100 mL). The organic layer was washed with saturated NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 30-40% ethyl acetate in hexane as eluent to give the title compound as a brown solid. Yield: 220 mg, 68%; 1 H-NMR(400MHz,DMSO-d6):δ 7.85(d,J=8.8Hz,1H),6.11(d,J=9.2Hz,1H),3.64(t,J=4.4Hz,4H),3.57(t,J=5.2Hz,4H),2.34(s,3H),LCMS:m / z 341.90[M+H] + .

[0321] Step f: Synthesis of 3-acetyl-4-methyl-7-morpholino-1,8-naphthyridin-2(1H)-one The title compound was synthesized using the same procedure as that performed for 3-acetyl-4-methyl-1,7-naphthyridin-2(1H)-one (compound 74a) using 1-(2-amino-6-morpholinopyridin-3-yl)ethan-1-one as starting material. Yield: 58%; LCMS: m / z 288.0 [M+H] + .

[0322] Step g: Synthesis of (E)-4-methyl-7-morpholino-3-(3-(p-tolyl)acryloyl)-1,8-naphthyridin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-4-methyl-7-morpholino-1,8-naphthyridin-2(1H)-one and 4-methylbenzaldehyde as starting materials. Yield: 63%; LCMS: m / z 390.10 [M+H] + .

[0323] Step h: Synthesis of 4-methyl-7-morpholino-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one Using (E)-4-methyl-7-morpholino-3-(3-(p-tolyl)acryloyl)-1,8-naphthyridin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-yl The title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 62%; 1 H-NMR(400MHz,DMSO-d6):δ 12.73(bs,1H),7.99(d,J=9.2Hz,1H),7.19-7.11(m,4H),6.80(d,J=9.2Hz,1H) ,5.45(dd,J=4.4Hz and J=12.0Hz,1H),3.80(dd,J=12.0Hz and J=18.4Hz,1H),3.70 (t,J=4.8Hz,4H),3.62(t,J=4.8Hz,4H),3.10(dd,J=4.4Hz and J=18.0Hz,1H),2. 62(q,J=7.6Hz,2H),2.45(s,3H),2.27(s,3H),1.03(t,J=7.2Hz,3H),LCMS:m / z 460.20[M+H] + .

[0324] Example 87: Synthesis of 7-(2-methoxyethoxy)-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one [ka] Step a: Synthesis of 1-(2-amino-6-(2-methoxyethoxy)pyridin-3-yl)ethan-1-one: To a stirred solution of 1-(2-amino-6-chloropyridin-3-yl)ethan-1-one (100 mg, 0.588 mmol) in dry THF (10 mL) was added KOtBu (132 mg, 1.17 mmol) and 2-methoxyethan-1-ol (67 mg, 0.88 mmol) at room temperature, and then the reaction mixture was heated at 70 °C for 3 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 15-20% ethyl acetate in hexane as eluent to give the title compound as an off-white solid. Yield: 30 mg, 25%; 1 H-NMR(400MHz,DMSO-d6):δ 7.87(d,J=8.8Hz,1H),6.11(d,J=8.4Hz,1H),4.47(t,J=4.4Hz,2H),3.71(t,J=4.4Hz,2H),2.47(s,3H).LCMS:m / z 211.0[M+H] + .

[0325] Step b: Synthesis of 3-acetyl-7-(2-methoxyethoxy)-4-methyl-1,8-naphthyridin-2(1H)-one To a stirred solution of 1-(2-amino-6-(2-methoxyethoxy)pyridin-3-yl)ethan-1-one (65 mg, 0.308 mmol) in dioxane (10 mL) was added 2,2,6-trimethyl-4H-1,3-dioxin-4-one (66 mg, 0.46 mmol). The reaction mixture was heated at 120° C. for 5 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography using 2-3% methanol in dichloromethane as eluent to give the title compound as a brown solid. Yield: 40 mg, 48%; LCMS: m / z 277.0 [M+H] + .

[0326] Step c: Synthesis of (E)-7-(2-methoxyethoxy)-4-methyl-3-(3-(p-tolyl)acryloyl)-1,8-naphthyridin-2(1H)-one The title compound was synthesized using the same procedure as that carried out for (E)-6-chloro-3-(3-(4-methoxyphenyl)acryloyl)-4-methylquinolin-2(1H)-one (compound 1c) using 3-acetyl-7-(2-methoxyethoxy)-4-methyl-1,8-naphthyridin-2(1H)-one and 4-methylbenzaldehyde as starting materials. Yield: 57%; LCMS: m / z 379.10 [M+H] + .

[0327] Step d: Synthesis of 7-(2-methoxyethoxy)-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one Using (E)-7-(2-methoxyethoxy)-4-methyl-3-(3-(p-tolyl)acryloyl)-1,8-naphthyridin-2(1H)-one as the starting material, 6-chloro-3-(5-( 6 -Methoxy Pyridin-3-ylThe title compound was synthesized using the same procedure as that carried out for )-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one (Example 7). Yield: 38%; 1 H-NMR(400MHz,DMSO-d6):δ 12.73(bs,1H),8.19(d,J=8.8Hz,1H),7.18-7.13(m,4H),6.76(d,J=4.0Hz,1H),5 .47(dd,J=4.4Hz and J=12.0Hz,1H),4.47(t,J=4.0Hz,2H),3.77(dd,J=12.0Hz and J=1 8.4Hz,1H),3.69(t,J=4.4Hz,2H),3.29(s,3H),3.10(dd,J=4.4Hz and J=18.0Hz,1H) ,2.62(q,J=7.6Hz,2H),2.52(s,3H),2.27(s,3H),1.03(t,J=7.2Hz,3H),LCMS:m / z 449.10[M+H] + .

[0328] Below is a list of abbreviations used in the present invention. ACN Acetonitrile Aq aqueous, aqueous solution bs wide single line °C degree Celsius temperature CHCl3Chloroform d double line DCM Dichloromethane dd Double line double line DIPEA N,N-Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF Dimethylformamide DMSO Dimethyl sulfoxide EtOAc Ethyl acetate EtOH Ethanol g grams h time HCl Hydrochloric acid Hz Hertz HPLC High Performance Liquid Chromatography LC Liquid Chromatography m multiplet MeOH Methanol mg milligram MHz Megahertz min mL Milliliters mM millimolar concentration mmol MS mass spectrometry MW Microwave NaOH Sodium hydroxide NBS N-Bromosuccinimide nM nanomolar NMR nuclear magnetic resonance spectroscopy O / N Overnight Prep. RT room temperature t triple line TEA Triethylamine THF Tetrahydrofuran TLC Thin Layer Chromatography

[0329] Pharmacological activity: Antiproliferation assay in MDA MB231 cells MDA MB231 cells were seeded in 96-well plates at a seeding density of 250 cells / well. Cells were allowed to settle overnight under standard incubator conditions (37°C, 5% CO2). The following day, treatment with increasing doses of test and reference compounds was performed on each well, and cells were further incubated for another 4 days under standard cell culture conditions. On the fifth day, the medium was replenished with fresh treatment, and cells were incubated for a total treatment period of 9 days. On the final day, appropriate amounts of Cell Titer Glo reagent were added to the treatment (and control) wells, and the plate was kept on a plate shaker at 300 RPM for 15 minutes. Luminescence readings (RLU) were taken after the plate was kept in the dark for an additional 10 minutes.

[0330] RLU is directly proportional to ATP content and directly related to the number of metabolically active cells in each well.

[0331] Calculation: a. Blank correction: The RLU of wells containing no cells is considered as blank and is subtracted from all RLU of treated and control wells. % Inhibition = 100 - [(treated RLU - blank RLU) / (control RLU - blank RLU) x 100] Symbols in the table: ≧50% +; and <50% +++

[0332] [Table 2(1)] [Table 2(2)]

[0333] [Table 3]

Claims

1. Novel bicyclic compounds of formula (I) 【Chemistry 1】 Ring A is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 6- to 10-membered ring systems, and 3- to 10-membered heterocyclyl; Ring B is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl; Ring C is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl; Any of A or B or C may be substituted by one or more identical or different substituents; R １ and R ２ is present or absent and, if present, is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, -C(O)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, any of said groups being optionally substituted with one or more identical or different substituents; R ３ is selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; R ４ is hydrogen, alkyl, -C(O)-R ４ａ any of said groups being optionally substituted with one or more identical or different substituents; R ４ａ is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, any of said groups being optionally substituted with one or more identical or different substituents; R ５ and R ６ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, cycloalkyl, alkoxy, acylamino, alkylamino, dialkylamino, heterocyclyl, any of which may be optionally substituted with one or more of the same or different substituents; R ７ is selected from the group consisting of hydrogen, alkyl, "n" is 0 to 2 A compound of formula (I).

2. The ring A together with the attached ring is specifically 【Chemistry 2】 2. The compound of formula (I) according to claim 1, represented by: or a pharma- ceutically acceptable salt or stereoisomer thereof.

3. The compound is of formula (Ia) 【Chemistry 3】 or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable positional isomer thereof, wherein: "x" is selected from O, S, or NR', where R' is selected from hydrogen, alkyl; "y" and "z" are independently selected from N, CR", where R" is selected from hydrogen, halogen, and alkyl; Ring C is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl, optionally substituted by one or more of the same or different substituents; R ３ is selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; R ４ is hydrogen, alkyl, -C(O)-R ４ａ any of said groups being optionally substituted with one or more identical or different substituents; R ４ａ is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, any of said groups being optionally substituted with one or more identical or different substituents; R ５ and R ６ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, cycloalkyl, alkoxy, acylamino, alkylamino, dialkylamino, heterocyclyl, any of which may be optionally substituted with one or more of the same or different substituents; R ７ is selected from the group consisting of hydrogen, alkyl, "n" is 0 to 2 2. Novel bicyclic compounds of formula (I) according to claim 1.

4. The compound is of formula (Ib) 【Chemistry 4】 or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable positional isomer thereof, wherein: Ring C is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl, optionally substituted by one or more of the same or different substituents; R １ and R ２ is present or absent and, if present, is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, -C(O)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, any of said groups being optionally substituted with one or more identical or different substituents; R ３ is selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; R ４ is hydrogen, alkyl, -C(O)-R ４ａ any of said groups being optionally substituted with one or more identical or different substituents; R ４ａ is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, any of said groups being optionally substituted with one or more identical or different substituents; R ５ and R ６ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, cycloalkyl, alkoxy, acylamino, alkylamino, dialkylamino, heterocyclyl, any of which may be optionally substituted with one or more of the same or different substituents; R ７ is selected from the group consisting of hydrogen, alkyl, "n" is 0 to 2 2. Novel bicyclic compounds of formula (I) according to claim 1.

5. The compound is of formula (Ic) 【Chemistry 5】 or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable positional isomer thereof, wherein: Ring C is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl, optionally substituted by one or more of the same or different substituents; "A", "B", "C", and "D" are independently O, S, NR', C(R") ２ or any of the two A and B or C and D represent CR' forming a double bond, R' being absent or, if present, being selected from hydrogen, alkyl and R" being hydrogen, halogen and alkyl; R ３ is selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; R ４ is hydrogen, alkyl, -C(O)-R ４ａ any of said groups being optionally substituted with one or more identical or different substituents; R ４ａ is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, any of said groups being optionally substituted with one or more identical or different substituents; R ５ and R ６ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, cycloalkyl, alkoxy, acylamino, alkylamino, dialkylamino, heterocyclyl, any of which may be optionally substituted with one or more of the same or different substituents; R ７ is selected from the group consisting of hydrogen, alkyl, "n" is 0 to 2 2. Novel bicyclic compounds of formula (I) according to claim 1.

6. The compound is of formula (Id) 【Chemistry 6】 or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable positional isomer thereof, wherein: Ring C is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl, optionally substituted by one or more of the same or different substituents; R １ and R ２ is present or absent and, if present, is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, -C(O)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, any of said groups being optionally substituted with one or more identical or different substituents; R ３ is selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; R ４ is hydrogen, alkyl, -C(O)-R ４ａ any of said groups being optionally substituted with one or more identical or different substituents; R ４ａ is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, any of said groups being optionally substituted with one or more identical or different substituents; R ５ and R ６ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, haloalkyl, cycloalkyl, alkoxy, acylamino, alkylamino, dialkylamino, heterocyclyl, any of which may be optionally substituted with one or more of the same or different substituents; R ７ is selected from the group consisting of hydrogen, alkyl, "n" is 0 to 2 2. Novel bicyclic compounds of formula (I) according to claim 1.

7. Specifically, the ring C is 【Chemistry 7】 7. The novel bicyclic compound of formula (I) according to any one of claims 3 to 6, represented by:

8. 1. 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one 2. 6-chloro-3-(1-(cyclopropanecarbonyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one 3. 6-chloro-3-(5-(4-methoxyphenyl)-1-(tetrahydro-2H-pyran-4-carbonyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one 4. 6-chloro-3-(5-(4-methoxyphenyl)-1-(tetrahydrofuran-3-carbonyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one 5. 6-chloro-3-(5-(4-methoxyphenyl)-1-methyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one 6. 6-Chloro-4-methyl-3-(5-(1-methyl-1H-indol-6-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 7. 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one 8. N-(4-(3-(6-chloro-4-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-5-yl)phenyl)propionamide 9. 3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-1,5-naphthyridin-2(1H)-one 10. 4-Methyl-3-(5-(1-methyl-1H-indol-5-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 11. 3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one 12. 4-Methyl-3-(5-(1-methyl-1H-indol-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 13. 3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-1,8-naphthyridin-2(1H)-one 14. 6-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-5-methylpyrido-[2,3-d]pyrimidin-7(8H)-one 15. 6-Bromo-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-2(1H)-one 16. 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-1,5-naphthyridin-2(1H)-one 17. 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-1H-pyrazol-3-yl)quinolin-2(1H)-one 18. 6-chloro-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-1,4-dimethylquinolin-2(1H)-one 19. 4-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)isoquinolin-3(2H)-one 20. 5-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno-[2,3-b]pyridin-6(7H)-one 21. 5-(5-(6-methoxypyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 22. 5-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 23. 6-chloro-4-cyclopropyl-3-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 24. 6-chloro-4-methyl-3-(5-(1-methyl-1H-indol-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 25. 5-(5-(5-methoxypyridin-2-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 26. 4-Methyl-5-(5-(6-oxo-1,6-dihydropyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 27. 5-(5-(4-fluorophenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 28. 5-(5-(4-chlorophenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 29. 5-(5-(5-methoxythiophen-2-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 30. 5-(5-(2-methoxythiazol-5-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 31. 5-(5-(5-bromothiophen-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 32. 4-Methyl-5-(5-phenyl-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 33. 4-Methyl-5-(1-propionyl-5-(thiophen-3-yl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 34. 5-(5-(4-bromothiophen-2-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 35. 4-Methyl-5-(1-propionyl-5-(pyridin-4-yl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 36. 4-Methyl-5-(1-propionyl-5-(pyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 37. 4-Methyl-5-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 38. 4-Methyl-5-(5-(4-(4-methylpiperazin-1-yl)phenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 39. 5-(5-(4-(dimethylamino)phenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 40. 3-chloro-5-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 41. 5-(5-(5-methylthiophen-2-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 42. 4-Methyl-5-(1-propionyl-5-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 43. 5-(5-(4-(difluoromethyl)phenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 44. 5-(5-(4-ethylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 45. 4-Methyl-5-(5-(6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 46. ​​4-Methyl-5-(1-propionyl-5-(4-(pyrrolidin-1-yl)phenyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 47. 5-(5-(4-cyclopropylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 48. 4-Methyl-5-(5-(2-methylthiazol-4-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 49. 5-(5-(4-isopropylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 50. 5-(5-(4,6-dimethylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 51. 4-Methyl-5-(5-(2-methylpyrimidin-5-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 52. 5-(5-(5-chloro-6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 53. 5-(5-(4-methoxy-6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 54. 5-(5-(5,6-dimethylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 55. 5-(5-(5-fluoro-6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 56. 5-(5-(4-chloro-6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 57. 4-Methyl-5-(5-(2-methylthiazol-5-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 58. 5-(5-cyclohexyl-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 59. 6-Chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 60. 4-Methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 61. 6-Chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,5-naphthyridin-2(1H)-one 62. 5-(1-acetyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-7,7a-dihydrothieno[2,3-b]pyridin-6(7H)-one 63. 5-(1-isobutyryl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl-7,7a-dihydrothieno[2,3-b]pyridin-6(7H)-one 64. 4-Methyl-5-(5-(p-tolyl)-1-(2,2,2-trifluoroacetyl)-4,5-dihydro-1H-pyrazol-3-yl)-7,7a-dihydrothieno[2,3-b]pyridin-6(7H)-one 65. 5-(5-(2-chloro-4-methylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 66. 5-(5-(2-fluoro-4-methylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 67. 6-Chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one 68. 5-(5-(4-(fluoromethyl)phenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 69. 4-Methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,5-naphthyridin-2(1H)-one 70. 2,4-Dimethyl-5-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 71. 5-(5-benzyl-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one 72. 2-Chloro-4-methyl-5-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one 73. 4-Methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one 74. 4-Methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one 75. 4,7-Dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 76. 4,5-dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 77. 4-Methyl-7-morpholino-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 78. 4,8-Dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one 79. 6-Chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one 80. 7-Chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 81. 4,6-Dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one 82. 4-Methyl-7-(4-methylpiperazin-1-yl)-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 83. 7-Fluoro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one 84. 4,7-Dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one 85. 4-Methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,6-naphthyridin-2(1H)-one 86. 4-Methyl-7-morpholino-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one 87. 7-(2-methoxyethoxy)-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,8-naphthyridin-2(1H)-one or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable positional isomer thereof. A novel bicyclic compound selected from the group consisting of:

9. (R)-5-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one (S)-5-(5-(4-methoxyphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one (R)-5-(5-(4-chlorophenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one (S)-5-(5-(4-chlorophenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one (R)-4-Methyl-5-(1-propionyl-5-(thiophen-3-yl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one (S)-4-Methyl-5-(1-propionyl-5-(thiophen-3-yl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one (R)-4-methyl-5-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b] (S)-4-Methyl-5-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one pyridin-6(7H)-one (R)-4-Methyl-5-(5-(6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one (S)-4-Methyl-5-(5-(6-methylpyridin-3-yl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-6(7H)-one (R)-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one (S)-4-Methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one (R)-5-(5-(2-fluoro-4-methylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one (S)-5-(5-(2-fluoro-4-methylphenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylthieno[2,3-b]pyridin-6(7H)-one (R)-4-Methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one (S)-4-Methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one (R)-4,8-Dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one (S)-4,8-Dimethyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,7-naphthyridin-2(1H)-one (R)-7-chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one (S)-7-Chloro-4-methyl-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one (R)-4-methyl-7-(4-methylpiperazin-1-yl)-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one (S)-4-Methyl-7-(4-methylpiperazin-1-yl)-3-(1-propionyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one Novel bicyclic regioisomeric compounds selected from:

10. 10. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt or stereoisomer thereof, and a pharma- ceutically acceptable carrier or excipient.

11. 10. A compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt or stereoisomer thereof, for use as a medicament.

12. 10. A method of inhibiting RAD51 protein, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 9.

13. 13. The method according to claim 12 for the treatment of cancer associated with the RAD51 protein.

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